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Title:
A PROCESS FOR PREPARATION OF ENANTIOMERICALLY PURE POLYSUBSTITUTED 1,4-DIHYDROPYRIDINES
Document Type and Number:
WIPO Patent Application WO/1990/009376
Kind Code:
A1
Abstract:
A process for the optical resolution of racemic 1,4-dihydropyridines, containing isothioureido groups. Salification of racemic isothioureas with optically active acids produces diasteroisomeric mixtures of isothiouronium salts, that, using conventional techniques, are separated in the individual components to give optically pure isothioureides of 1,4-dihydropyridines and salts thereof with conventional acids. Said optically pure 1,4-dihydropyridines can then be subjected to desulphuration and to different transformations to give other enantiomerically pure and therapeutically useful 1,4-dihydropyridines.

Inventors:
Gandolfi, Carmelo A. (Via S. Uguzzone 5, Milano, I-20126, IT)
Frigerio, Marco (Via S. Uguzzone 5, Milano, I-20126, IT)
Riva, Carlo (Via S. Uguzzone 5, Milano, I-20126, IT)
Zaliani, Andrea (Via S. Uguzzone 5, Milano, I-20126, IT)
Long, Giorgio (Via S. Uguzzone 5, Milano, I-20126, IT)
Di Domenico, Roberto (Via S. Uguzzone 5, Milano, I-20126, IT)
Application Number:
PCT/EP1990/000243
Publication Date:
August 23, 1990
Filing Date:
February 15, 1990
Export Citation:
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Assignee:
BOEHRINGER MANNHEIM ITALIA S.P.A. (Via S. Uguzzone 5, Milano, I-20126, IT)
Gandolfi, Carmelo A. (Via S. Uguzzone 5, Milano, I-20126, IT)
Frigerio, Marco (Via S. Uguzzone 5, Milano, I-20126, IT)
Riva, Carlo (Via S. Uguzzone 5, Milano, I-20126, IT)
Zaliani, Andrea (Via S. Uguzzone 5, Milano, I-20126, IT)
Long, Giorgio (Via S. Uguzzone 5, Milano, I-20126, IT)
Di Domenico, Roberto (Via S. Uguzzone 5, Milano, I-20126, IT)
International Classes:
C07B55/00; A61K31/4422; A61P9/12; C07B57/00; C07D211/90; C07D401/12; C07D405/00; C07D405/12; C07D409/00; C07D413/00; C07D413/04; A61K31/44; (IPC1-7): A61K31/44; C07B57/00; C07D211/90; C07D405/00; C07D409/00; C07D413/00
Domestic Patent References:
WO1987000836A11987-02-12
WO1988007531A11988-10-06
WO1988007525A11988-10-06
Foreign References:
EP0225175A21987-06-10
EP0186028A21986-07-02
EP0273349A21988-07-06
Other References:
Monatshefte fur Chemie, Volume 87, No. 2, 1956, (Wien, AT), W. KLOTZER: "Optische-Aktive alpha-Phenylathyl-Thiuroniumsalze als Neue Spaltbasen. Darstellung der beiden Antipoden der 3,3-Diphenyl-3-Cyano-1-Methyl-Propancarbonsaure-(1) pages 346-353
Attorney, Agent or Firm:
Minoja, Fabrizio (Studio Consulenza Brevettuale, Via Rossini 8, Milano, I-20122, IT)
Download PDF:
Claims:
CLAIMS
1. An optical resolution process for asymmetrical poly substituted 1,4dihydropyridines, wherein one of the substituents includes one isothioureido moiety com¬ prising: a) salification of the isothioureido moiety with chiral acids; b) separation of the diastereoisomers isothiouronium salts and their transformation in isothioureido functions or other isothiouronium salts with achiral acids; c) optional transformation of the compounds obtained in b) by reactions of desulphuration, hydrolysis, Sacylation, Salkylation, esterification.
2. A process for preparation of enantiomerically pure 1,4dihydropyridines of formula I wherein: A R3 is a free or esterified carboxy group (C02 3ι) R4 is a member selected from the group consisting of: a substituted or unsubstituted phenyl; a substituted or unsubstituted 0 or βnaphtyl; a substituted or unsubstituted 5 or 6 membered heterocyclic ring, containing at least one heteroatom selected from N, S and 0, a benzofused 5 or 6 membered heterocyclic ring as above defined, preferably linked through the phenyl ring; Re is a free or esterified carboXy group (C02R 2), C≡N, N02, C0NHR51, P(0)(OR51)2 or a COR52 group; R6 is (C^Cg)alkyl, (C1C4)haloalkyl, # CHO, C≡N, a carboxyester (C02R33), an acetal CH(ORg^) (0Rg2) pr a linear or cyclic thioacetal CH(SRg1) (SRg2) ; R2 is a member selected from the group consisting o 2 a substituted or unsubstituted phenyl; a (CH2)nHet group wherein Het is an heterocyclic ring as above defined; a (C2Cg)alkenyl or alkinyl chain; a (C^Cgjalkyl chain unsubstituted or substituted, by one or more substituents selected from a free or esterified carboxy group (C02R34), C≡N, 0R24, SR24, N(R24)R25, Cl, Br, I, a substituted or unsubstituted phenyl, a 5 or 6 membered cycloaliphatic ring optionally substituted by one or more heteroatoms selected from N, S and 0; carbonyl, cis or trans oxyrane, and/or aziridine groups; R2 , R 2 and R23, are independently selected from hydrogen, (CιC4)alkyl, phenyl(C*LC4)alkyl or (cl 4)acyl, or R21 nd R22 taken together with the carbon atom to which they are linked to form a group (CH2)n wherein n is an integer 2 to 4; Rj and 2j are independently hydrogen, (C*—C4)alkyl, phenyl(C1C4)alkyl, cyano(CLC4)alkyl, (Cj C4) alkoxycarbonyl(C C )alkyl, benzoyl, (C,C4acyl) ; R2 and R27 , that can be the same or different, are a (Cj^Cg)alkyl or aryl(Cj—Cg)alkyl group; ς31 R 32 R 33 and R 34 that may be the same or different, are selected from (C,C4)alkyl, (C,C3)alkoxy(C,C4) alkyl, (C2Cg)alkenyl or phenyl(C2Cg)alkenyl, mono, di or trihaloalkyl; 51 is a (CjC^alkyl, (CιC3)alkoxy(C*LC4)alkyl, aryl or aryl(C,C4)alkyl; R52 is a (C^C^alkyl or phenyl; Rgl and Rg2 may be (Cι~C4)alkyl or phenyl(C^C^)alkyl, and each of 0Rgl, 0Rg2, SΪQ . or SRg2, taken together with the carbon atom to which they are linked, form respectively a 1,3dioxolane or a 1,3dithiolane ring, which may be optionally substituted by (C,C3)alkyl or halo(C1C3)alkyl; () is a monovalent anion selected from chlorine, bromine, iodine and BF4~(); (C^C24)acyl is the residue of an aliphatic, aromatic, cycloaliphatic, arylaliphatic , heterocyclic, heteroali phatic and heteroarylaliphatic carboxylic acid; n is an integer 1 to 4, comprising: a) salification of racemic isothioureides of formula II wherein R21' R^ 2222' Λ '2233' Λ4' RΛ6 and n are as above defined for formula I while R3' and Rr ' have the same meanings as in formula I except for the free car oxyl, with chiral HB* acids; b) separation of diastereoisomeric ' isothiouronium salts of formula Ia^.HB* and Ia2HB* ^.HB*) (Ia2HB*) wherein R2 R22 , R23' R3' > R5' R4' R6 and n are as above defined, and their transformation into the cor¬ responding isothioureae or into other isothiouronium salts with achiral acids; c) optional transformation of compounds la,, Ia2 or their salts into other compounds I wherein A is SH, S(C C24)acyl, SR2, or S+(R2g)R2 wherein R2, 2g and R 27 are as defined for formula I; d) optional transformation of compounds of formula' la, , into compounds I wherein A is hydrogen, by means of desulphuration under suitable conditions.
3. ,*"_.
4. A process according to claim 2, ierein e ±s a _ Cθ2R3 group and one of groups R3, or R3 is "an allyl residue of formula CH2CH=CHR33, wherein R^., is hydrogen, C,C3alkyl or phenyl, comprising, subsequently to the resolution phase, selective hydrolysis of the allyl ester, optionally followed by riesterifiσatiόn, hydrolysis of the other carboxyester group and its riesterification under suitable conditions and with suitable sequences, so as to convert an isomer into the other by inversion of the R3 and R5 groups.
5. A process according to claim 3, characterized in that the selective hydrolysis of the allyl ester is carried out under transfer hydrogenolysis conditions, in presence of an hydrogen transfer catalyst, of a phosphine and of an ammonium or alkylammonium salt.
6. A process according to claims 3 or 4, characterized in that one of the carboxyesters is tbutyl or tri chloroethyl ester.
7. A process according to claim 2 for the preparation of compounds I wherein A is hydrogen comprising desul phuration of compounds I wherein A is a group S+(R2 )R27 by means of metal hydrides.
8. A process according to claim 2 for the preparation of compounds I wherein A is hydrogen, comprising desul¬ phuration of compounds I wherein A is SH, SR and S(C*j—C24)acyl by means of NiRaney or Na/Hg amalgams.
9. A process according to claim 6, wherein the group R4 does not include N02 or alkylthio groups.
10. A process according to claims 68 for the prepara¬ tion of optical isomers of nitrendipine, nimodipine, ni soldipine, nicardipine, niludipine, felodipine, isradipi ne, ryodipine, amlodipine, nivaldipine and Fr 34235.
11. A process for preparation of optical isomers of 1,4dihydropyridines of formula I wherein A is hydrogen, characterized in that an optical isomer of 1,4dihydropyridines of formula I, wherein A is s(c2ic24~acyl')SR2' ~S+ (R26 R27 ^s desulphurated.
12. Isothioureides of formula II: wherein 2i R22' R23' R3' R4' R5' R6 an^~ n are as defined in claim 2 for formula I.
13. Isothiouronium salts of formula II.HB: wherein Λl2222' RΛ 2233' Λ3' RΛ4' Λ5' RΛ,6 are as defined in claim 2 for formula I, HB is an organic or inorganic acid and n is the integer 2, 3 or 4.
14. Compounds of formula I in enantiomerically pure form: wherein R3, R4, R^, Rg and A are as defined in claim 2, with the proviso that when n is 1, A is different from hydrogen.
Description:
A PROCESS FOR PREPARATION OF ENANTIOMERICALLY PURE POLYSUBSTITUTED 1,4-DIHYDROPYRIDINES

BACKGROUND OF THE INVENTION

A large number of drugs, currently in clinical use, are chiral molecules containing one or more asymmetric centers; in many cases these drugs are used as racemic mixtures even if the therapeutic effect is sometimes due to only one of the isomers forming the racemic mixture.

A great attention is recently directed to the role of stereoselectivity principles in the design of biologically active molecules. Since the stereoselectivity principle is a general rule in biology rather than an exception, often only one of the components of a racemic mixture (the "eutomer") is the active drug while the other one, that is not comple¬ mentary to the receptor (the "distomer 11 ), is poorly active, or inactive if not even an antagonist.

Except for a few cases when a racemate is more active, less toxic or of longer (or shorter) duration of action than the single components of the racemic mixture, the use of pure enantiomers instead of racemates is today preferred, in order to reduce the xenobiotic load in the living organism, and to avoid risks of toxic side'-effects due to the disto er or its metabolites (see for example E.J. Ariens, "Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacol gy", Eur. J. Clin. Pharmacol., 26, 663, 1984).

The increasing use of "eutomers" in therapy instead t . of racemates requires, of course, the development of

effective, economic and industrially applicable methods of stereoselective synthesis and/or separation and resolution of diastereoisomers and racemates. Optical resolution is often an expensive process and the majority of the methods involves the loss of 50% of the starting racemic material, at least.

The above considerations apply also to the 1,4-di- hydropyridine Ca-antagonist family of drugs, that in the last ten years have been introduced in the market for treatment of several cardiovascular diseases, including hypertension, angina of different aetiologies and different types of arrythmias.

The C-4 carbon atom of 1,4-dihydropyridines (see figure 1) is a prochiral atom. When at least one of the substituents, bound to the C- and C-, carbon atoms, is different from those on the symmetric Cg and Cr positions of the ring, the C-4 carbon atom is chiral and the compounds are racemates. Nifedipine, (dimethyl, 2,6-dimethyl-4-(2-nitrophenyl) l.4-dihydropyridine-3,5-dicarboxylate) is a symmetrical molecule while many other drugs ( for ex. nitrendipine, nimodipine, nisoldipine, nicardipine, niludipine, felodipine, isradipine, ryodipine, Fr 24235, amlodipine and nivaldipine) are chiral 1,4-dihydropyridines that have been used in mammalians and humans as racemates; some of them are already marketed.

Only few dihydropyridines are available for investigation as pure enantiomers, even if it is by now well established that the principles of stereoselectivity apply also to this family of drugs.

Qualitative and quantitative differences between enantiomers of 1,4-dihydropyridines may be shown by "in vitro" studies on tissue preparations or on "in toto" organs (see for example H. Glossmann et al. , Arzneim. Forsch./Drug. Res., 35 (12a), 1917 1985).

More recently, a report by T. Kazuharu (J» Med. Chem., 29, 2504, 1986) points out the importance of stereoselectivity: of the four possible diastereoisomers the S,S enantiomer [ (S,S)-YM-09730) ] proved to have the greatest potency and the longest duration of action. r

The use of enantio erically pure 1,4-dihydropy- ridines was recently claimed in EP 0240828 and 0273344. i - At present, few and very complex methods are available for preparing enantiomerically pure dihydropyridines.

In absence of basic groups (that could Jhen be salified with optically active acids), the known methods require the selective cleavage of an ester group to form a racemic monocarboxylic acid that is salified with optically pure bases. The mixture of diasteroisomeric salts is separated to recover enantiomerically pure acids that are then esterified with chiral and achiral alcohols

,- t * *- to give the desired pure enantiomers. The chiral alcoh I.orls used in this esterification process must be pure enantiomers to avoid formation and separation * - of diasteroisomers. Thus, for instance, the preparation of nicardipine enantiomers (J. Shibanuma et al., Chem. Phar . Bull., 28, 2809, 1980) , involves the synthesis of racemic l-ethoxy-5-methoxycarbonyl-2,6-dimethyl-4-(3-ni- trophenyl)-l,4-dihydropyridin-3-carboxylic acid, crystal-

lization of diastereoisomeric salts with cinchonine and cinchonidine followed by esterification of the obtained S- and R- carboxylic acids with the appropriate amino-alkanol and final elimination of the N-ethoxymethylene protective group. More recently the same procedure and intermediates were used in the synthesis of four YM-09730 diastereoisomers (T. Kazuharu, above cited) .

In both cases the synthesis of the racemic acid involves the use of ethoxy-methylene-chloride, whose mutagenicity is well ascertained.

More recently, to overcome this drawback, mono tert-butyl esters have been introduced as precursors of the carboxy group of racemic 1,4-dihydropyridines; tert- butyl esters may be selectively cleaved by reaction with trialkyl silyl iodides (JP Pat. Appln. 1161-263). The procedure is particularly convenient in the absence of other ether and/or thioether groups that could be simultaneously cleaved, when present. Alternative procedures involve the synthesis of diasteroisomeric mixtures of optically active 1,4-dihydropyridines, wherein one of the carboxy groups is esterified by an optically active alcohol. Since the components of the mixture may be separated by fractional crystallization or by chromatographic techniques the subsequent selective removal of the chiral alcohols yields pure enantiomeric acids that are esterified with an achiral alcohol (E. Winger et al. DE 2935451, 1981). Enantiomeric Ca-agonist or Ca-antagonist 4-aryl-5-nitro-l,4-dihydropyridines were prepared using this procedure (EP 186028); the removal of

the optically active 2-πιethoxy-2-phenylethanol was carried out by selective saponification. To achieve total selectivity during the removal of chiral alcohols (made possible by reductive cleavage with zinc in acetic acid) , A.J.G. Baxter et al. (Abst. 310, IX Medicinal Chem. Symp., Berlin, 1986) used (S)-l-phenyl-2-trichloroethanol as an alternative for creating diasteroselectivity; in this way both the enantiomers of FPL 61810XX were prepared; only one of them, the (+) enantiomer, showed Ca-antagonist properties. The most evident drawbacks of these methods are: a) expensive and complex operations during the separation of diastereoisomers; b) availability of unexpensive enantiomerically pure alcohols, that cannot be recycled when removed by reductive cleavage.

Finally, EP 273349 discloses a resolution process comprising the salification with optically active bases of racemic l,4-(lH)-dihydropyridines carrying a free carboxy group that were presumably obtained by direct Hantzsch synthesis, whose compatibility with the used reagents and esterification methods has to be clarified. DISCLOSURE OF THE INVENTION

The present invention discloses a process for the optical resolution of asymmetrical polysubstituted" 1,4- -dihydropyri ines, wherein one of the substituents inclu¬ des one isothioureido moiety, which process comprising: a) salification of the isothioureido moiety with chiral acids; b) separation of the diastereoisomers isothiouronium

salts and their transformation into isothioureido moie¬ ties or other isothiouronium salts with achiral acids; c) optional transformation of the compounds obtained in b) by reactions of desulphuration, hydrolysis, S-acyla- tion, S-alkylation, esterification.

For the first time, the present invention discloses a resolution process using isothioureido groups as suitable resolution and salification centers. Two previous known examples of optically active isothiouronium salts involve a resolution process comprising the exchange reaction between salts of optically active carboxylic acids and those of racemic isothiouronium salts with achiral acids and fractional crystallization of the diastereoisomeric mixture (Monatsh. Chem. ___]_, 346, 1956 and Che ica Scripta 2Q_, 32 1982).

These resolution methods based on an exchange reaction fail to be of general applicability and exhibit many disadvantages, such as: - the use of protic solvent helps the exchange reaction between ionic species but it often makes crystallization of diastereoisomeric salts difficult;

- in protic and aqueous solvents, an excess of basic salts may cause the base-catalyzed cleavage of isothiouronium salts so as to release thiols and thiourea or salts thereof;

- the co-precipitation of salts (originated from the achiral counter-ions) makes the purification of desired diasteroisomeric isothiouronium salts difficult; - increased costs due to the additional process of

salification of the resolving chiral acid with a suitable cation with the risk of decreasing the enantiomeric purity of the resolving acids.

The present invention provides simple ' and economic methods for the optical resolution comprising the direct reaction of new isothioureas, as free bases, with conventional chiral acids. The advantages of the present process are even more surprising in that, till now, said isothioureas were unknown compounds aηd thought to be poorly stable and then unsuitable for their use in a resolution process.

Contrary to the known methods, the process of the present invention avoids the use of salts of resolving acid that should be prepared "ad hoc", when not commercially available. The method of the present invention provides also very high yields of enantiomers of high optical purity.

If desired, the overall process may be performed in an one-step procedure without isolating racemic isothioureas, as crystalline intermediates.

Since, in 1,4-dihydropyridines, the " isothioureido

_ * group may be easily introduced and' isothioureas are easily transformed, the process of the invention is particularly flexible and adaptable to different synthetic procedures.

The process and the methods of the present invention may be usefully carried out when an isothioureido group is present in the molecule, independently on its position on the 1,4-dihydropyridine ring. However, according to the disclosure of the present invention, an alkylisό-

thioureido group is preferably linked to the 2- (or 6-) carbon atom of the 1,4-dihydropyridine ring; said group may be transformed into other groups characterizing many of the known racemic dihydropyridines. The present invention relates to the preparation of enantiomers of formula I:

wherein:

A is hydrogen, ' -SH, -S-(C-,-C 24 )- -acyl, -S 2 or a sulphonium salt of formula -s' + 'R 2 gR 2 7 γ (->. R3 is a free or esterified carboxy group (-CO2R 3 --) ; R * is a member selected from the group consisting of:

- a substituted or unsubstituted phenyl;

- a substituted or unsubstituted t l -or β-naphtyl;

- a substituted or unsubstituted 5- or 6- membered heterocyclic ring, containing at least one heteroatom selected from N, S and 0,

- a benzo-fused 5- or 6- membered heterocyclic ring as above defined, preferably linked through the phenyl ring; R 5 is a free or esterified carboxy group (-CO-R 32 ) C=-N, - 0 2 , -CO-NH-R 51 , -P(0)(OR 51 ) 2 or a CO-R 52 group;

R 6 is (C-L-Cg)-alkyl, (C 1 ~C 4 )-halo-alkyl, -CHO, -CΞN, a carboxyester (-CO2R3 3 ), an acetal -CH(ORg -, ) (O g2) or a linear or cyclic thioacetal -CH(SRg, ) (SR g2 ) ; R 2 is a member selected from the group consisting of: - a substituted or unsubstituted phenyl; y

- a (CH2) n -Het group wherein Het is an heterocyclic ring as above defined;

- a (C 2 -Cg)alkenyl or alkinyl chain;

- a (C-i-Cg)alkyl chain unsubstituted or substituted by one or more substituents selected from a free or esterified carboxy group (-CO2R34), -C≡N, -0-R 24 , -S-R 24 , -N( 2 )R25 > Cl, Br, I, a substituted or unsubstituted phenyl, a 5 or 6 membered cycloaliphatic ring optionally substituted by one or more heteroatoms selected from N,, S and O; carbonyl, cis or trans oxyrane, and/or aziridine groups;

R 21' R 22 an< ^ R 23' re independently selected from hydrogen, (C- ^)-alkyl, phenyl- (.C^-C^)-alkyl or (C-^-C 4 )-acyl, or R 21 and R22 taken together with the carbon atom to which they are linked to form a group -(CH2) - wherein m is an integer 2 to 4; R2 and R2 are independently hydrogen, (C-, —C. )-alkyl, phenyl(C 1 -C 4 )-alkyl, alkoxycarbonyl-(C 1 -C 4 R 2 g and R 2 7 ' that can be the same or different, are a (C-^-Cg)-alkyl or aryl-(C 1 ~Cg)-alkyl group;

R 31' R 32' R 33 and R 34' tnat ma y be the same or different, are selected from )- alkyl, (C 2 -Cg)-alkenyl or phenyl-(C 2 -Cg)-alkenyl, mono-, di- or tri-halo-alkyl;

51 is a (C 1 -C 4 ) -alkyl , ( c ι*- c 3 ) -alkoxy- (C 1 -C 4 ) -alkyl , aryl or aryl- tC^-C^ -alkyl ;

R 52 is a (C 1 -C 4 )-alkyl or phenyl;

R gl and R g2 may be (C- L -C 4 )-alkyl or phenyl-(C 1 -C 4 )-alkyl, and each of 0R 62' SR 61 or SR 62' ta3 en together with the carbon atom to which they are linked, form respectively a 1,3-dioxolane or a 1,3-dithiolane ring, which may be optionally substituted by (C- j -C,)-alkyl or halo-(C^~C 3 )-alkyl; Y^ " ' is a monovalent anion selected from chlorine, bromine, iodine and BF 4 ~(-);

(C-^-C 2 )acyl is the residue of an aliphatic, aromatic, cycloaliphatic, arylaliphatic, heterocyclic, heteroali- phatic and heteroarylaliphatic carboxylic acid; n is an integer 1 to 4.

When one of R 2 , R3, R 4 , R ς and Rg is a substituted phenyl, the phenyl ring is preferably substituted by one to three substituents, independently selected from halogen (F, Cl, Br, I), nitro, cyano, -CF3, -CC1 3 , mono- or polyfluoroalkyl (1 to 5 C-atoms), formyl, (C*,-C 4 )- -alkyl, ( c ι _C 4)-alkoxy, phenoxy, OCH 2 F, 0CF 3 , mono- or polyfluoroalkylthio (1 to 5 C-atoms), alkylsulphinyl (1 to 5 C-atoms), -CONH 2 , -S0 2 H 2 , -S0 2 NH-(^-^)-alkyl, azido, (C-^-Cq )-alkylthio, ( c ι _ 4)-acylamino, NH-S0 2 — (C 1 -C 4 )-alkyl, -NHS0 2 CgH 5 , mono-(C*-_-C 4 )-alkylamino, di-(C-,-C 4 )- alkylamino, -CO2 3-1, cis- or trans-(C 2 -Cg)- -alkenyl-C0 2 R -, , cis- or (C2-Cg)-alk nyl-Cθ2 31 , -(C 2 -Cg)-alkynyl-C=N.

The substituted 5- or 6-membered heterocyclic ring of 2 and. 4 may be substituted by one to three

substituents independently selected from the group consisting of phenyl-( C-^-C^)-alkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, (C- L -C 4 )-alkylthio, ( C ι -C 4)-alkoxy, -COR^^ , C≡N, -C0NH 2 , amino, mono-(C,-C )-alkylamino, di-(C,-C 4 )-alkylamino, Cl, Br, F, I, mono- or polyfluoro (C-^-Cς)-alkyl, nitro, azido, (C- L -C 4 )-acylamino, (C-^-C^ ) - -alkyl sulfonylamino, phenyl, p-tolylsulfon lamino, -S0 2 NH 2 , S0 2 -(C 1 -C 4 )alkyl, C = O, C ~~ S or N 0.

Examples of the compounds of formula I and of the appropriate meanings of the various substituents in said compounds are disclosed, for instance, in WO/EP/8700836.

The enantiomers of formula I are prepared by a process comprising: a) salification of an enantiomer of a chiral acid of formula HB* with a racemic isothiourea of formula II

-s-c(-~ 21-N 2 2 2 2R 2 23

wherein 23./ R 22' R 23' R 4' R 6 nci n are a *^ above defined, 3' and R ' are the same as the above specified R 3 and R 5 , with the proviso that a free carboxy group is excluded; b) separation of the diastereoisomeric salt of formula (Ia- HB*) from that of formula (Ia 2 .HB*) and optional transformation of each salt into the respective free base, i.e. the isothiourea of formula la-, or Ia ?

(Ia^HB*) (la .HB*) wherein R3' , R 4 , J* 5 ', Λg, ~~2± - Λ 22 R2 and n are as above defined, and, if desired, said free base is then transformed into other isothiouronium salts by treatment with achiral acids; c) optional transformation of an enantiomeric isothiourea of formula la,, Ia 2 (or of a salt thereof) into another enantiomer of formula I, and I2 respectively wherein A* is SH, S-(C 1 -C 2 4)acyl, -SR 2 , or -S (+ ^ (R 2 g)R 2 7 γ(") 5 being and n as above defined; d) optional desulfuration of an enantiomer of formula I,, I , Ia^ or Ia 2 to obtain an enantiomer of formula I wherein A is hydrogen.

A further peculiar embodiment of the present invention is a method for preparing a pure enantiomer of formula I from a racemic compound of formula I' wherein R 3 and R 5 are carboxyester groups different from each other so as to make possible their selective, independent cleavage, and -(CH 2 -, n -A and Rg are the same groups or one of them can be transformed into the other one.

Step by step, selective and differentiated cleavage of one of the two R3 and R 5 ester groups yields a mono carboxylic acid that can then be esterified again (or

optionally transformed into an amide -CO-N$-Rc-ι ) according to different sequences so that an enantiomer may be transformed into the opposite one.

The following reaction scheme illustrates said aspect of the invention, making reference to enantiomers of formula I' wherein both (C^J-A and g are methyl. N and M are ester residues which can be selectively and independently cleaved: allyl esters are particularly preferred groups either for -C0 2 or -C0 2 M. The same reaction scheme is also applicable when (CH 2 ) n A and Rg are different, provided that one of them is transformed into the other one somewhere in the synthetic route.

1. CCOM hydrolysis

2. Esterification by

-or- 1.COON hydrolysis

2. Esterification by E' <H

Diastereoisomeric mixtures of salts and/or amides can be obtained by treatment of a racemic isothiourea of formula II with chiral enantiomeric acids. These mixtures are then subjected to optical resolution processes based, for instance, on separation of diastereoisomers by crystallization, distillation, filtration, extraction, thin layer chromatography and/or by high, low or room pressure chromatography on inert or chiral supports,, using known procedures, including the crystallization of diastereoisomeric mixtures from enantiomerically pure chiral solvents. *

The preferred resolution technique of a racemate of formula II comprises the salification of said racemate with an enantiomerically pure chiral acid HB* to form a diastereoisomeric mixture of isothiouronium salts of formula (II.HB*) that is then separated into the single , diastereoisomerically pure, salts of formulae (Ia,.HB*) and (Ia 2 .HB*), respectively.

This separation is preferably carried out by fractional crystallization, in solvents such as: water, (C-^-C,**)-alcohol, (C-^-Cg)-alkyl acetates and/or formates (ethyl acetate), cycloaliphatic or aromatic hydrocarbons, (cyclohexane, benzene, toluene, o-, m-, p-xylene;) * ethers (tetrahydrofuran, dimethoxyethane, 1,4-dioxane, methyl- ale, diethylether) ; ketones, (acetone and methylethyl- ketone); amides (formamide, N,N-dimethylformamide, N-methylpyrrolidone) , sulphσxides (dimethylsulphojs Lde) and the like or mixtures thereof.

In general, the preferred enantiomerically pure chiral acids HB* are those allowing the best possible

resolution process with the minimum number of recrystallizations.

In the specific case of the present invention, a complete or almost complete separation of the diastereo- isomeric pure salts of formula (Ia,.HB*) from those of formula (Ia 2 .HB*) is often obtained at the first crystallization step; one or at most two recrystallizations are enough to reach optical purities of 99.9 % or more. Cheap and conventional optically pure acids, widely available, are very effective and may be conveniently used.

Suitable examples of said acids are: camphoric, mandelic, abietic, 3-bromo-campho-10-sulphonic acids; tartaric acid and its 0,0•-diesters, such as 0,0'-dibenzoyltartaric or 0,0'-di-p-tolyltartaric; malic acids and the esters thereof, o(-methoxy-phenylacetic acid, β(.-methoxy-oC-trifluoromethyl-phenylacetic acid; o^-aminoacids and amides thereof, such as alanine, proline, phenylglycine, phenylala ine, threonine, cysteine, cystine, homocysteine, homocystine, aspartic and glutamic acids and amides such as: N-benzoyl, N-acetyl, N-phtaloyl, N-BOC or N-tert-butoxycarbonyl amides; or l,3-thiazolidine-4-carboxylic or N-thia-3-aza- -cyclo-hexane-4-carboxylic acids and amides thereof (e.g. N-benzoyl, N-acetyl, N-BOC); chiral phosphonic acids, etc. The present invention includes also the resolution agents that have not been specifically mentioned herein. The salification process of a racemate of formula II with an enantiomerically pure chiral acid HB* is carried out in a solute/solvent ratio ranging from 5 ml to 60 ml of

solvent for 1 g of salt, at temperatures ranging from about room temperature to the reflux temperature of the solvent, to obtain complete dissolution of the reagents. Hot solutions are left to cool to temperatures compatible with the freezing point of the solvent in the range from -30°C to +50°C, to crystallize the less soluble diastereoisomeric salt of formula (Ia,HB*), that is then separated by filtration and/or centrifugation. Preferably the reaction is carried out at room temperature, u≤ing a solvent alone rather than a mixture of solvents. "

Since thioureas, like racemates of formula (II) or the single enantiomers of formula (la,) and/or (Ia 2 ), are monobasic species, polybasic resolving acids HB* may be used in the range from equimolecular to equivalent amounts; equimolecular amounts are preferred.

During the resolution process, the mother liqϊors from the crystallization of the less soluble diastereoisomeric salt are enriched in the pther enantiomer that, if desired, may be recovered as isothiourea free base, by treatment of said mother liquors with stoichio etrical or slightly higher amounts of bases. Said bases can be selected from an hydrate, bicarbonate or carbonate of an alkali or alkali-earth metal in solid form or as diluted aqueous solutions. As an alternative, neutralization is carried out " by treatment with ammonia or its aqueous solutions. She crude enriched isothioureido enantiomer, as free base, may be subjected to resolution by salification with the opposite optical antipode of the previous HB* resolving acid. In this connection, during the neutralization

process, particularly preferred solvents are those (for example ethyl acetate, benzene and toluene), that are immiscible with water and are suitable to maintain the isothioureas dissolved as free bases in the organic phase. At the same time, the chiral resolving acids are removed in the aqueous phase with aqueous alkaline washings that are collected and acidified to recover the chiral acids that may then be recycled. Enantiomerically pure isothiouronium salts of formulae (Ia,.HB*) and (Ia 2 .HB*) are obtained in yields ranging from 70-75 % to a value even higher than 85-90 %. After recovery of an isothiourea of formula la from its isothiouronium salt (Ia.HB*), as above described, the enantiomeric acid HB* is also recovered in high yields, 85-90 % at least. Transformation of an isothiouronium salt of formula (II.HB) or (Ia- j ^HB*) and/or (Ia 2 .HB*) into its isothiourea, as free base, of formula Ila, la, or Ia 2 is preferably carried out under inert gas atmosphere, at temperatures ranging from 0 β C to 40°C, and preferably from 5°C to 20°C. If desired, enantiomeric isothioureas of formula la, or Ia 2 may be salified with achiral acids to give isothiouronium salts of formula (Ia,.HB) and/or (Ia 2 -HB).

A suspension of an appropriate isothiouronium salt of formulae (II.HB, Ia-^HB, Ia^HB*, Ia 2 -HB or Ia 2 " .HB*) in a suitable solvent such as (C,-C ς )-alcohols, an aromatic hydrocarbon (benzene, toluene), a halogenated hydrocarbon (dichloromethane or 1,2-dichloroethane) , an ester as a (C-^-Cg)-alkyl formate and/or acetate), water or mixtures thereof can be transformed into an

isothiourea of formulae (II, la, or Ia 2 ) by treatment with concentrated aqueous solutions of an inorganic base, for example alkali or alkali-earth hydroxides, bicarbona- tes and/or carbonates, ammonia and its aqueous solutions, or with solutions of )-trial- kylamine in said solvents. The reaction is preferably carried out by treating vigorously stirred suspensions of said isothiouronium salts in lower alcohols, for example methanol or ethanol, with aqueous solutions containing at least equimolar amounts of a base such as sodium or potassium hydroxide, bicarbonate or carbonate at 5-20°C, for a time ranging from few minutes to 12 hours.

It is particularly preferred the gradual addition of equimolar amounts of a base to a Vigorously stirred suspension of isothiouronium salt in a mixture of water and a water-immiscible solvent to secure dissolution in the organic phase of the isothiourea that is 'formed by ion exchange reaction. If desired, at the end of the ion exchange reaction the organic phase may be separated and washed to neutrality, dried and then the isothiourea as free base may be isolated in crystalline form w by concentrating the solution under vacuum.

In the specific case of the compounds of the present invention, the above reaction conditions are particularly mild and suitable for preparing isothioureas of ' high purity, in almost quantitative yields, from isothiouro¬ nium salts, even though the latter are known to be easily cleaved and converted into mercaptanes by treatment with diluted aqueous weak bases. In fact, a known method for f the preparation of thiols involves the reaction of alkyl

halides (or sulphonic esters) with thiourea or N-alkyl isothiourea to give isothiouronium salts, that are hydrolyzed to thiols by treatment with aqueous bases. In opposition to thiols that are easily oxydized to disulphides, the isothiouronium salts are quite stable to air oxydation and since they can be easily converted, they are preferred in organic synthesis and used as masked thiol groups.

Accordingly, when desired, mercaptanes of formula (I) wherein A is SH may be prepared from pure enantiomeric isothiouronium salts of formula (Ia,.HB, Ia^.HB*, la 2 .HB and/or Ia 2 .HB*) by treatment with diluted aqueous bases: said thiols may then be transformed into another compound of formula (I) wherein A is -S-(C ~C 4 )-acyl by reaction with a suitable activated form (such as anhydride, mixed anhydride, imidazolide, chloride) of a C,-C 24 -aliphatic, cycloaliphatic, aromatic, arylaliphatic or heteroaromatic acid, etc.

Racemic isothiouronium salts of formula II wherein n is the integer 1 and B is preferably chlorine or the residue of a monovalent achiral organic acid have been described in WO 8700836 and in Italian Application No. 21876 A/85 in the Applicant's name.

The isothiouronium salts of formula (II.HB), wherein n is different from 1, are new and can be prepared by treatment of compounds of formula (IV)

wherein A is chlorine, bromine, iodine or a sulfonate ester and R3, R 4 , Re and Rg are as above defined, with thiourea and N-alkyl derivatives thereof, using well known methods. Isothiouronium salts are preferably prepared from halides or εulfonates, melting a mixture of the solid reagents or heating their solutions in a solvent selected from dimethylformamide, N-methyl- -pyrrolidone, dimeth Isulphoxide, ethanol, methanol, acetonitrile, water or mixtures thereof. 1,4-Dihydropyridines of formula (IV) are well-known from EP 83315, DE 2629892, Synth. Comm 16_, 529, 1086 and Tethr. Lett. 29, 6335, 1988.

Other isothiouronium salts have been disclosed in EP 225175. Isothioureas of formulae II, Ia- j^ and Ia 2 are new and are an object of the present invention together * with processes for the preparation thereof.

Both isothioureas of formula la,, Ia 2 and/or isothiouronium salts thereof, and thiols and/or (C 1 -C 24 )-acylthioesters thereof of formula I (A = SH, C 1 -C 24 -acyl-S) , when reacted with electrophilic species of formula R 2 / produce compounds of formula I, wherein A is a S 2 group.

The preferred electrophilic species of formula R 2 -Φ are selected from: ______ a diazonium salt wherein φ is a diazonium group and R 2 is an aryl and/or heterqaryl radical; b_)_ a substituted or unsubstituted alkyl hali^de and/or sulphonate of a suitable substituted or unsubstituted alcohol wherein R 2 is an alkyl residue as above defined containing also 3-membered heterocyclic

*"• _ rings such as oxyrane, thiirane, azyridine,

N-(C,-Cg)-alkylazyridine and φ is an halogen (Cl, Br, I ) or a suitable sulfonate residue such as CH3SO3-, CgH c S0 3 -, p-methyl-CgH 4 S0 3 -, or camphosulfonate or trifluoromethanesulphonate (F 3 C-S0 3 ); c_)_ a Michael acceptor wherein R 2 is a (C 2 -Cg)-alk-l-ene or a (C 2 -Cg)alk-l-yne and φ is the activating residue selected from -N0 2 , -C≡N, -C0NH 2 , -Cθ2 31 , -CO(C--_-C 4 )-alkyl, -COCgH 5 , -CgH 5 -(C 1 -C 4 )-alkyl-CO- groups.

Said reactions of thiols or masked thiols of formula I with electrophiles are preferably carried out in the presence of bases and under inert gas atmosphere to avoid disulfide by-product formation. The amounts of the bases range from catalytic to stoichiometric amounts or higher when H-φ acids are released during the reaction; preferably a base excess is used. Preferred bases are organic bases such as a tertiary amine, e.g. triethylamine, diazabicyclononene, diazabicycloundecene or an aromatic amine, e.g. pyridine, an alkyl-substituted pyridine, tetra ethyl-pyridine, or an anionic ion-exchange resin or, more preferably, an inorganic base e.g. an alkali or an alkali-earth oxide, hydroxyde, carbonate or bicarbonate or (C,-C ς )-alcoholate. The base can be used as a solid material or in a diluted solution in media such as water, (C-, -C<- )-alcohols, όiioxane, tetrahydrofuran, (C-^-C--)-ylycols and mixtures the ' reof. Ammonia and its solution in the same media can also be used. Most preferably, such reactions with electrophiles are carried out using "phase transfer " conditions, so that the base may be used as a solid and not necessarely in solution. The preferred solvents are those immiscible

with water that were previously used during salification and resolution steps. The reaction temperatures,, range from room temperature to the solvent reflux temperature. The reaction times can range from few minutes to several days, but usually do not exceed a period from six to eight hours at room temperature. When, in a comppund of formula I, one or both of R 3 and R ς ar<e allyl esters, they may be selectively cleaved by "transfer hydrogenolysis" under very mild conditions by treatment with an ammonium and/or alkylammoniu ^ salt * iπ the presence of a phoεphine and a hydrogen transfer catalyst. Ammonium formate is the preferred salt; triphenyl and tributyl phosphine are particularly useful.

Preferred transfer catalyst is palladium (Pd) on carbon, finely dispersed in a concentration from 2 to 15%. Preferred solvents are (C j -Cg)-alcohols, acetonitrile and other aliphatic nitriles; ethers sufch as tetrahydrofuran, dioxane, dimethoxyethane, amides such as dimethylformamide, formamide, water and mixtures thereof. The reaction may be carried out at a temperature ranging from 0 C C to the solvent reflux temperature in a time ranging from some minutes to several hours. ■>

The hydrolysis of these allyl esters όcciirs in almost theoretical yields. When desired, each of these dihydropyridine acids can be transformed into another compound of formula I by esterification with a suitable alcohol, using " known methods. When R 3 and 4 are carboxyester groups which may be selectively hydrolized (e.g. one is an allyl ester and the other one is a t-butyl or trichloroethylester)

enantiomerically pure 1,4-dihydropyridines may be converted into the specular enantiomer, as shown in the above scheme, by suitable sequence of selective cleavage and reaction with appropriate alcohols, either racemic or optically pure.

A further advantage of the present invention is the preparation of single enantiomers of diastereoisomeric dihydropyridines when, according to this procedure, enantiomeric dihydropyridines having free carboxy groups at positions •' and/or 5 are reacted with optically active alcohols or amines.

Sulfonium salts of formula I wherein A is -S^'- ^yY may be prepared by treatment of a compound

R 26 of formula I, wherein A is more preferably -SR 2 , with an excess of a (C-^-Cg)-alkyl halide or a phenyl-(C-^-C J-aralkyl halide or with a trialkyloxonium tetrafluoroborate of formula [(Ro β -^ R 27^ BF 4 ^~' being R 2 g and R 2 y as above defined. Preferred reaction conditions include the use of an excess of the selected halide in the presence or not of an inert solvent. Suitable solvents are dioxane, tetrahydrofuran, dimethoxyethane, an aromatic hydrocarbon such as benzene, toluene, amides such as dimethyl- formamide, N-methylpyrrolidone or esters such as ethyl acetate and mixtures thereof; preferred temperatures range from the room temperature to the reflux temperature of the mixture.

The use of a slight molar excess of trialkyloxonium tetrafluoroborates in dimethoxyethane, at room

temperature for several hours is particularly preferred; often the sulfonium salt separates as a crystalline product from the reaction mixture.

Enantiomerically pure 1,4-dihydropyridines of formula I wherein A is hydrogen are obtained by reacting one of said sulphonium salts with an hydride selected from sodium, lithium, zinc or tetraalkyϊammonium (e.g.tetrabutylammonium) borohydride, tri-(te t-butyl) aluminium hydride, diisobutyl-aluminium hydride or lithium aluminium hydride.

Desulfuration of sulphonium salts is a very selective process that occurs under e_έtremely mild conditions; the choice of solvent and the preferred experimental conditions depend on the selected hydrid . Anhydrous solvents such as 1,2-dimethoxyethane, tetrahydrofuran, diethylether, dioxane, toluene and benzene or mixtures thereof are preferably used with aluminium hydrides, while in the case of borohydrides additional solvents can be conveniently used, for instance: aprotic dipolar solvents such. , as

£

N,N-dimethylformamide, dimethylsulphoxide, N-methyl-pyr- rolidone, sulpholane, (C,-Cc)-alcohols, ethyleneglycol, polyethyleneglycols, halogenated solvents such as 1,2-dichloroethane and dichloromethane or thereof. Preferably a molar excess of the hydride is used, at a temperature from 0°C to reflux temperature. The use of borohydrides at room temperature, for a reaction time ranging from few min. to 4 hrs. is preferred. Hydride-promoted removal of the sulphonium residue

occurs under particularly mild and selective conditions without affecting the 1,4-dihydropyridine, whose reactivity towards hydrides is known (see for example A. Sauvins et al. , Heterocycles 2J_, 291, 1988) or other possible reducible groups.

For example, (+) and (-) enantiomers of dimethyl- [6-methyl-5-carbomethoxy-3-carboethoxy-4-(3-nitrophenyl)- l,4-dihydropyridin-2-yl]-methyl-ethyl-sulphonium tetra¬ fluoroborate are quantitatively desulphurated to give the corresponding crystalline (+) and (-) enantiomers of 2,6-dimethyl-3-carboethoxy-5-carbomethoxy-4-(3-nitrophe¬ nyl)-1,4-dihydropyridine by reaction with sodium- borohydride in dimethylformamide at 5-10°C.

Alternative use of classic reagents, as Ni-Raney or Na/Hg amalgam, in the desulphuration process is expected to be less useful, due to the concomitant reduction of nitro groups to amino groups.

However, when the phenyl group R 4 of the sulphurated compounds of formula I is not substituted by nitro or azido groups, classic desulfurating agents such as Ni-Raney or Na/Hg amalgams can also be used for the preparation of enantiomerically pure 1,4-dihydropyridine of formula I wherein A is hydrogen. Sometimes the reduction of the nitro group of the R 4 substituent might be synthetically useful since the formed amino group could be transformed into other groups via diazonium salts. Preferred concentrations of Na in Hg amalgams range from 2 to 10%; preferred ratios between sulphurated substrate and desulfurating reagents (Ni-Raney) or Na/Hg range from equimolar to 520 times molar excess.

Anhydrous solvents used with Na/Hg amalgams include (C-.-C--)-alcohols, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, dimethylformamide, N-methylpyrrolidone; in the case of Ni-Raney also water and acetone or mixtures thereof can be used; the reaction temperature ranges from 40°C to the reflux temperature of the mixture. Even though a series of side-reactions (including saturation of olefins and of aromatic rings, alcohol from ketones, rearrangement and condensation reactions) have been reported during the desulfuration with Ni-Raney (see for instance G.R. Pettit, "Desulfuration with Raney Nickel" in Organic Reactions, vol.XII, pag.360362, R.E. Krieger Publ. Co., Halabar, Florida, 1975) , no side reactions such as oxydation or dimerization of the 1,4-dihydropyridine ring or reduction to tetrahydro- or hexahydropyridines, could be observed.

Surprisingly, nitrovinyi groups of compounds of formula I (when R 5 is N0 2 ) are substantially inert to ttøe reductive action of desulfurating agents such as Ni-Raney or Na/Hg. The substantial stability of said nitrovinyi group is remarkable when compared with that of ortho-, meta- or para- nitro groups possibly present in the R. phenyl substituent that, on the contrary, are partially or completely reduced to amino groups. It is also remarkable that, in enantiomers., of formula I, different reduction rates to amino are observed along the o-, m- and p- nitrophenyl R 4 substituents, ranging from a maximum to a minimum rate changing the nitro group position from para- " to ortho-. After short reaction times, the desulfuration of C-4 m-

or o-nitrophenyl substituted compounds may proceed in a 40-50% extent without noticeable reduction of the nitro groups.

The examples reported herebelow further illustrate the present invention. In said examples the following abbreviations are used: MeOH = methanol, EtOH = ethanol, AcOEt = ethyl acetate, AcOH = acetic acid, THF = tetrahydrofuran, DMF = dimethylformamide, DMSO = dimethylsulphoxide, at reflux = at the reflux tempe- rature.

PREPARATION 1

A solution of (+)-2-chloromethyl-3-carboethoxy-5-ni- tro-4-(m-nitrophenyl)-6-methyl-l,4-dihydropyridine (g 1.1), thiourea (g 0.23) in EtOH (ml 10) is heated to reflux for two hours.

After cooling, the crystalline precipitate of (±)-S-[(6-methyl-3-carboethoxy-5-nitro-4-(m-nitrophenyl)- -1,4-dihydropyridin-2-yl)-methyl]-isothiouronium chloride (g 1.26, m.p. 198-200°C) is collected by filtration. PREPARATION 2

A solution of (±)-2-chloromethyl-3,5-dicarboethoxy- 4-(3-nitrophenyl)-6-methyl-l,4-dihydropyridine (g 6) and 3,4,5,6-tetrahydro-2-mercaptopyrimidine (g 1.8) in MeOH (ml 50) is heated at reflux for two hours. After cooling to room temperature, g 7 of (±)-2-[ (1,4,5,6-te- trahydropyrimidin-2-yl)thio-]-methyl-3,5-dicarboethoxy- 6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine hydrochlo- ride (m.p. 217-219°C) are obtained. PREPARATION 3 A solution of (±)-2-chloromethyl-3-carbomethoxy-5-

-carboethoxy-4-(3-trifluoromethylphenyl)-6-methyl-l,4-di¬ hydropyridine (g 1.5) and 2-imidazolidinthione (g 0.5) in benzene (ml 20) is heated to reflux for 6 hours. fter cooling, the precipitate of (±)-2-[ (4,5-dihydroimidazol- -2-yl)thio-]-methyl-3-carbomethoxy-5-carboethoxy-4-(3-tri- fluoromethylphenyl)-6-methyl-l,4-dihydropyridine hydro- chloride (m.p. 190-192°C) is collected by filtration. PREPARATION 4

A mixture of (±)-2-chloromethyl-3,5-dicarbo£thσxy- 4-(3-nitrophenyl)-6-methyl-l,4-dihydropyridine (g 6), thiourea (g 1.2) and EtOH (ml 60) is heated to reflux for three hours. After cooling to room temperature, 4.8 g of (±)-S-[(6-methyl-3,5-dicarboethoxy-4-(3-nitrophenyl)-1 , - dihydropyridin-2-yl)-methyl]-isothiouronium chloride (m.p. 219-220°C) are obtained. PREPARATION 5

A mixture of ethyl 4-chloro-3-oxobutanoate (12.1 g) , benzo-[c]-furazan-4-aldehyde (10 g) , acetic acid (mi 0.2) and benzylamine (ml 0.37) is stirred for 24 hours at room temperature and is then diluted with acetonitrile (ml 95). After addition of 8.5 g of methyl 3-aminocrotonate, the solution is heated for three hours to 60°C, cooled to 35°C and then treated with g 4.8 of p-toluenesulphonic acid. After further 30 minutes, the stirred solution' is treated with 2 ml of a 28% solution of ammonium hydrate, concentrated under vacuum to 1/3 of its volume and finally diluted with water (150 ml). After extraction with ethyl acetate (3 x 40 ml) and usual workup, by evaporation of the solvent and crystallization, 18 g of 2-chlorometh l-6-methyl-3-carboethoxy-5-carbomethoxy-4-

(benzo-[c]-furazan-4-yl)-1,4-dihydropyridine are obtained m.p. 121-122°C (from MeOH) ; m.p. 92-94°C (from Et j O).

In the same way, by reaction of benzo-[c]-furazan-4- aldehyde with a suitable alkyl 4-chloro-3-oxobutanoate and a suitable enamine selected from alkyl 3-aminocroto- nate, 3-aminocrotonitrile and 2-amino-lnitroprop-l-ene, the following compounds are obtained:

2-chloromethyl-6-methyl-3-carboethoxy-5-cyano-4-(benzo- -[c]-furazan-4-yl)-1,4-dihydropyridine, m.p. 125-126°C; 2-chloromethyl-6-methyl-3-σarbomethoxy-5-isopropoxycarbo- nyl-4-(benzo-[c]-furazan-4-yl)-1,4-dihydropyridine m.p. 146-148°C;

2-chloromethyl-6-methyl-3-carboethoxy-5-nitro-4-(benzo- -tc]-f razan-4-yl)-1,4-dihydropyridine; 2-chlorometh l-6-methyl-3-carbomethoxy-5-allyloxycarbo- nyl-4-(benzo-[c]- urazan-4-yl)-1,4-dihydropyridine.

A solution of 2-chloromethyl-6-methyl-3-carbome- thoxy-5-all loxycarbonyl-4-(benzo-[c]-furazan-4-yl)-1,4- dihydropyridine (g 2.4) and thiourea (g 0.6) in methanol (ml 40) is heated at reflux for 4 hours. After cooling a solid of (+)-S-[(6-methyl-3-carbomethoxy-5-allyloxycarbo- nyl-4-(benzo-[c]-f razan-4-yl)-1,4-dihydropyridin-2-yl)- methyl]-isothiouronium chloride (2.23 g) is separated, filtered and dried under vacuum. PREPARATION 6

Using the aldehydes 5-formylbenzo-[b]-l,4-dioxane and 6-formylbenzo-[c]-l,4-dioxane in the procedure of preparation 5, the following compounds are prepared: 2-chloromethyl-6-methyl-3-carboethoxy-5-tert-butoxycarbo- nyl-4-(benzo-[b]-1, -dioxan-5-yl)-1,4-dihydropyridine,

m.p . 128-130 °C ;

2-chloromethyl-6-methyl-3-carboethoxy-5-tert-butόxycarbo - nyl-4- (benzo- [c ] -1 , 4-dioxan-6-yl ) -1 , 4-dihydropyridine , m.p . 115-117 °C ; 2-chlorometh l-6-methyl-3-carboethoxy-5-carbomethoxy-4- (benzo- [b ] -l , 4-dioxan-5-yl ) -1 , 4-dihydropyridine , m.p . ,

121-122°C ;

2-chlorometh l-6-methyl-3-carboethoxy-5-tert-butoxycairbo- nyl-4- (benzo- [ c ] -1 , 4-dioxan-6-yl ) -1 , 4-dihydropyridine , m.p. 137-139 °C;

2-chloromethyl-6-methyl-3-carboethoxy-5-cyaHo-4-(benzό- -fb]-l,4-dioxan-5-yl)-1,4-dihydropyridine, m.p. 130-132 β C.

Under inert gas atmosphere, a stirred suspension of 2-chloromethyl-6-methyl-3-carboethoxy-5-cyano-4*-(ben^o- -[b]-l,4-dioxan-5-yl)-1,4-dihydropyridine (3.7 g) "and thiourea (0.82 g) in 5 ml of N-methylpyrrolidone is heated to 95-105°C for 20 minutes. The clear solution is cooled, diluted with EtOH (20 ml) to ' ---separate 3.8 g of (±)-S-[(6-methyl-5-cyano-4-(benzo-[b]-l,4-diσxan-5-yl)-§ <■- carboethoxy-1,4-dihydropyridin-2-yl)-methyl]isothiouro- • nium chloride, m.p. 235-237°C. PREPARATION 7 k >

A solution of ethyl o-(2-chloroacetyl)-3-chlorocin- namate in EtOH (50 ml) and a 3-cyano-3-aminop_έ * openoic ester (for ex. ethyl 3-cyano-3-aminopropeno ' ate g 1.45) is heated to reflux for 3 hours, cooled to 40°C and treated with a solution of p-toluenesulphonic acid (g 1 * 9) in EtOH (10 ml). After 2 hours the mixture is 'concentrated to small volume, diluted with water and extracted with

AcOEt (3 x 25 ml). The organic phases are combined, washed with water, 5% aqueous K 2 C0 3 , water, dried and evaporated to dryneεs. By chromatography on silica gel column (Si0 2 , 80 g, eluent AcOEt hexane 3/7) 3.1 g of 2-chloromethyl-6-cyano-4-(3-chlorophenyl)-3,5-dicarboetho- xy-1,4-dihydropyridine are obtained.

A stirred mixture of the compound with thiourea (0.8 g) in 5 ml DMF is heated to 95-105°C for 30 minutes, cooled, diluted with EtOH (15 ml) to obtain a crystalline precipitate of (±)-S-t (6-cyano-4-(3-chlorophenyl)-3,5-di- carboethoxy-1,4-dihydropyridin-2-yl)-methyl]-isothiouro¬ nium chloride. PREPARATION 8

Using ethyl 3,3-diethoxymethyl-3-amino-propenoate and ethyl 3-ethoxyσarbonyl-3-amino-propenoate instead of ethyl 3-cyano-3-amino-propenoate in the procedure of preparation 7, the following compounds are prepared: 2-chloromethyl-6-diethoxymethyl-4-(3-chlorophenyl)-3,5-di- carboethoxy-1,4-dihydropyridine; 2-chloromethyl-6-ethoxycarbonyl-4-(3-chlorophenyl)-3,5-di- carboethoxy-1,4-dihydropyridine;

(±)-S-[(6-diethoxymethyl-4-(3-chlσrophenyl)-3,5-dicarbo e- thoxy-1,4-dihydropyridin-2-yl)-methyl]-isothiouronium chloride; (±)-S-[(6-ethoxycarbonyl-4-(3-chlorophenyl)-3,5-dicarboe- thoxy-1,4-dihydropyridin-2-yl)-methyl]-isothiouronium chloride. PREPARATION 9

Using in the procedure of preparation 5 the aldehy- des of the group consisting of benzaldehyde, ^-pyridinyl

carboxyaldehyde and 2-thiophene carboxaldehyde and an enamine of the group consisting of l-acetyl-2-aminσprope- ne, l-benzoyl-2-aminopropene and l-(2-phenylacetyl)- -2-aminopropene instead of methyl-3-aminocrotonate, the following compounds are prepared: ' •.

-2-chloromethyl-6-methyl-3-carboethoxy-5-acetyl-4-phenyl- 1,4-dihydropyridine;

-2-chloromethyl-6-methyl-3-carboethoxy-5-acetyl-4-(2-thie - nyl)-1,4-dihydropyridine; -2-chloromethyl-6-methyl-3-carboethoxy-5-benzoyl-4- 2-thi- enyl)-1,4-dihydropyridine;

-2-chloromethyl-6-methyl-3-carboethoxy-5-(2-ρhenylacetyl ) -4-(pyridin-2-yl)-1,4-dihydropyridine. PREPARATION 10 According to the procedures of the preparations from 1 to 7, by treatment of a (±)-2-chloromethyl-1,4-dihydro¬ pyridine with thiourea and/or a N-alkylthiourea selected from N-methylthiourea, N,N'-dimeth Ithiourea, 2-imidazo- lidinthione, l-methyl-2-imidazolidinthione, 3,4,5,6-te- trahydro-2-mercaptopyrimidine, the following racemates are obtained:

-S-[(6-methyl-5-cyano-4-(3-nitrophenyl)-3-carboethoχy-l, 4 -dihydropyridin-2-yl)methyl]-isothiouronium - chloride, m.p. 198-200°C, (isothiourea, free base, m.p. 123-125 β C); -S-[(6-methyl-5-acetyl-4-phenyl-3-carboethoxy-l,4-dihydro- -pyridin-2-yl)methyl]-isothiouronium chloride; -S-[ (6-methyl-5-carbomethoxy-4-(3-nitrophenyl)-3-carboe- thoxy-1,4-dihydropyridin-2-yl)methyl]-isothiouronium chloride, m.p. 173-176°C; (isothiourea free base m.p. 131-133 β C);

-S-[ (6-methyl-5-carboisopropoxy-4-(3-nitrophenyl)-3-carbo- ethoxy-1,4-dihydropyridin-2-yl)methyl]-isothiouronium chloride;

-S-[(6-methyl-3,5-dicarboethoxy-(2-chlorophenyl)-1,4-dihy - dropyridin-2- 1)methy1]-isothiourea;

-S-[ (6-methyl-5-carbomethoxy-3-carboethoxy-(3-chlorophe¬ nyl)-1,4-dihydropyridin-2-yl)methyl]-isothiouronium chlo¬ ride; -S-[ (6-methyl-3,5-dicarboethoxy-4-(2-trifluoromethylphe- nyl)-l,4-dihydropyridin-2-yl)methyl]-isothiouronium chlo¬ ride;

-S-[(6-methyl-5-carbomethoxy-3-carboethoxy-4-(2-trifluoro ¬ methylphenyl)-1,4-dihydropyridin-2-yl)methyl]-N-methyliso- thiouronium chloride; -s-[ (6-methyl-3-carboethoxy-5-cyano-4-(2-trifluoromethyl¬ phenyl)-1,4-dihydropyridin-2-yl)methyl]isothiouronium fu- marate;

-S-[ (6-methyl-5-carbomethoxy-3-carboethoxy-4-(4-fluorophe- nyl)-1,4-dihydropyridin-2-yl)methyl]-N,N•-dimethyl iso- thiouronium chloride;

-S-[(6-methyl-5-carbomethoxy-3-carboethoxy-4-(3-trifluoro ¬ methylphenyl)-1,4-dihydropyridin-2-yl)methyl]isothiouro¬ nium chloride;

-S-[ (6-methyl-5-carbomethoxy-3-carboethoxy-4-(4-nitroρhe- nyl)-l,4-dihydropyridin-2-yl)methyl]-isothiouronium chlo¬ ride;

-S-[ (6-meth 1-5-carbornethoxy-3-carboethoxy-4-(2-nitrophe- nyl)-1,4-dih dropyridin-2-yl)methyl]-isothiouronium chlo¬ ride; -2-[ (l,4,5,6-tetrahydropyrimidin-2-yl)thio]-methyl-5-car-

bomethoxy-3-carboethoxy-6-methyl-4-(3-nitrophenyl)1,4-di¬ hydropyridine hydrochloride, m.p. 240-242°C; -2-[ (4,5-dihydroimidazol-2-yl)thio]methyl-3-carbomethoxy- -5-carbomethoxy-4-(3-trifluoromethylphenyl)-6-methyl-l,4- dihydropyridine, m.p. 190-192°C;

-2-[(4,5-dihydroimidazol-2-yl)thio]methy1-3,5-dicarbo- ethoxy-4-(3-nitrophenyl)-6-methyl-l,4-dihydropyridine hydrochloride, m.p. 211-213°C; -2-[(1,4,5,6-tetrahydropyrimidin-2-yl)thio]methyi-5-tert- -butoxycarbonyl-3-ethoxycarbonyl-4-(3-nitrophenyl)-6-me¬ thyl-l,4-dihydropyridine.HCl, m.p. 203-204°C; -2-[ (l-methyl-4,5-dihydroimidazol-2-yl)thio]methyl-3,5- -dicarboethoxy-4-(3-chlorophenyl)-6-methyl-l,4-dihydropy¬ ridine hydrochloride; -2-[(1-methy1-4,5-dihydroimidazol-2-yl)thio]methyl-3-car- boethoxy-5-carbomethoxy-4-(3-cyanophenyl)-6-methyl-l,4-di¬ hydropyridine hydrochloride;

-2-[ (l-methyl-4,5-dihydroimidazol-2-yl)thio]methyl-3-car- boethoxy-5-carbomethoxy-4-(4-chlorophenyl)-6-methyl- ^ l,4- -dihydropyridine hydrochloride;

-2-[(l-methyl-4 ,5-dihydroimidazol-2-yl hio]methyl-3-£:ar- boethoxy-5-carbomethoxy-4-(2,3-dichlorophenyl)-6-methyl- -1,4-dihydropyridine hydrochloride; -2-1(4,5-dihydroimidazol-2-yl)thio]methyl-3, ' 5-dicarboe- thoxy-4-(3-chlorophenyl)-6-methyl-l,4-dihydropyridine hydrochloride; " ~ -

-2-[(4,5-dihydroimidazol-2-yl)thio]methyl-3-carboe.thoxy- 5 -nitro-4-(3-trifluoromethylphenyl)-6-methyl-l,4-dihydro¬ pyridine hydrochloride; -S-[(6-fluoromethyl-3,5-dicarbomethoxy-4-(3-nitrophenyl)-

1,4-dihydropyridin-2-yl)methyl]-isothiouronium chloride;

-S-[ (6-formyl-3,5-dicarboethoxy-4-(3-chlorophenyl)-1,4-di- hydropyridin-2-yl)-methyl]-isothiouronium chloride; -S-[ (6-diethoxymethyl-3-carboethoxy-4-(3-chlorophenyl)- -l,4-dihydropyridin-2-yl)methyl]-isothiouronium chloride; -S-[(6-cyano-3-carboethoxy-5-(2-methoxyethoxy)-carbonyl-4 -(3-thienyl)-1,4-dihydropyridin-2-yl)methyl]-isothiouro¬ nium chloride; -S-[(6-cyano-5-carboethoxy-3-isopropoxycarbonyl-4-(benzo- [b]-1,4-dioxan-5-yl)-1,4-dihydropyridin-2-yl)methyl]-iso¬ thiouronium chloride;

-S-[(6-cyano-3 ,5-dicarboethoxy-4-(benzo-[c]-furazan-4-yl) -1,4-dihydropyridin-2-yl)-methyl]-isothiouronium chlori¬ de; -S-[(6-σyano-3,5-dicarbomethoxy-4-(3-trifluoromethylphe- nyl)-1,4-dihydropyridin-2-yl)methyl]-isothiouronium chlo¬ ride;

-S-[(6-methyl-3-carboethoxy-5-allyloxycarbonyl-4-(3-nitro ¬ phenyl)-1,4-dihydropyridin-2-yl)methyl]-isothiouronium chloride;

-S-[(6-methyl-3-carboraethoxy-5-(2-butenoxycarbonyl)-4-(2 - σhlorophenyl)-1,4-dihydropyridin-2-yl)methyl]-isothiouro¬ nium chloride; -S-[(6-methyl-3-carboethoxy-5-tert-butoxycarbonyl-4-(3-ni- trophenyl)-1,4-dihydropyridin-2-yl)methyl]-isothiouronium chloride;

-S-[(6-methyl-3-carbomethoxy-5-allyloxycarbonyl-4-(3-ni¬ trophenyl)-1,4-dihydropyridin-2-yl)methyl]-isothiouronium chloride; -S-[ (6-methyl-3-allyloxycarbonyl-5-carbomethoxy-4-(3-ni-

-trophenyl)-1,4-dihydropyridin-2-yl)methyl]-isothiouro¬ nium chloride;

-S-[(6-methyl-3,5-diallyloxycarbonyl-4-(3-nitrophenyl)- l,4-dihydrσpyridin-2-yl)methyl]-isothiouronium chloride; -S-[ (6-methyl-3-carbomethoxy-5-allyloxycarbonyL-4-(2,3-di- chlorophenyl)-1,4-dihydropyridin-2-yl)methyl]isothiouro¬ nium chloride;

-S-[ (6-methyl-3-carboethoxy-5-acetyl-4-(2-thienyl)-1,4-di- hydropyridin-2-yl)methyl]-isothiouronium chloride; -S-[(6-methyl-3-carboethoxy-5-benzoyl-4-(2-thienyl)-l,4— dihydropyridin-2-yl)methyl]-isothiouronium chloride; -S-[(6-methyl-3-carboethoxy-5-(2-phenylacetyl)-4-(pyridy- n-2-yl)-1,4-dihydropyridin-2-yl)methyl]-isothiouronium chloride; -S-[ (6-methyl-3-carboethoxy-5-carbomethoxy-4-(benzo-[c]- -furazan-4-yl)-1,4-dihydropyridin-2-yl)methyl]-isothluro- nium chloride;

-S-[ (6-methyl-3-allyloxycarbonyl-5-carbometboxy-4-benzo- -[c]-furazan-4-yl)-1,4-dihydropyridin-2-yl)methyl]-iso-~ thiouronium chloride.

EXAMPLE 1

A suspension of (+)-S-[(6-methyl-3,5-dicarboefehoxy- -4-(3-nitrophenyl)-l,4-dihydropyridin-2-yl)methyl]-iso- thiouronium chloride (g 1) in AcOEt (ml 20) and water (ml 10) is added in 30• with sodium bicarbonate (g 0.1)' at room temperature and under vigorous stirring. The phases are separated and the aqueous phase is extracted with AcOEt (2 x 5 ml). The organic phases are combined, washed with a NaCl saturated solution and dried on Na,SO Λ . After evaporation of the solvent and crystallization from Et 2 0,

0.9 g of (±)-S-[ (6-methyl-3,5-dicarboethoxy-4-(3-nitro¬ phenyl)-l,4-dihydropyridin-2-yl)methyl]-isothiourea are obtained (m.p. 119-121°C). EXAMPLE 2 A mixture of (±)-S-[(6-methyl-3,5-dicarboethoxy-4-

-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)methyl]-isothio urea (g 21), 0,0'-dibenzoyl-D-tartaric acid (g 18) and acetonitrile (ml 600) is heated to the reflux temperature for one hour. After spontaneous cooling at room tempe- rature, the solution is cooled to 0°C and stirred for one hour to separate a solid that is filtered and washed with acetonitrile (ml 40). Said crystalline material [g 15.8, m.p. 158-160°C; [o< D = +80.8° [« 578 = +85.51° W 546 = +103.7° (c = 1.1, MeOH)] is crystallized by heating in acetonitrile (ml 240) for one hour at the reflux tempera¬ ture. The solution is cooled to room temperature and stirred for one hour at 0°C, to separate 14.5 g of (+)-S-[(6-methyl-3,5-dicarboethoxy-4-(3-nitrophenyl)-1,4- dihydropyridin-2-yl)methyl]-isothiouronium 0,0'-diben- zoyl-D-tartrate [m.p. 161-162°C; [eC] D -= +81.5°; [OC ] 57Q = +85.4°; [0O 5 6 = +102.1°, c = 1.4, MeOH].

The mother liquors from the first crystallization are evaporated to dryness under vacuum. The residue is partitioned between AcOEt (ml 250) and 1.1 % aqueous solution of sodium bicarbonate (2-50 ml), by stirring for 1.5 hours. After separation and elimination of the aqueous phase, the organic phase is washed with brine, dried (Na 2 S0 4 ) and evaporated to dryness. A stirred solution of the crude residue (g 14.15) and of 0,0'-dibenzoyl-L-tartaric acid in acetonitrile (590 ml)

is maintained for 6 hours at room temperature and then for a night at 4°C to separate a precipitate, that is filtered and washed with cold acetonitrile (ml 50). The crystalline material [g 15.06, m.p. 156-158°C; [o<] D - -76.8°; [øU 546 = -91.4°, c = 1.4, MeOH] is dissolved in hot acetonitrile (ml 230). The stirred solution is cooled at room temperature, maintained for 6.5 hours at A °C to separate g 12.1 of: (-)-S-[(6-methyl-3,5-dicarboethoxy-4- -(3-nitrophenyl-l,4-dihydropyridin-2-yl)methyl]-isothio- urσnium 0,0'-dibenzoyl-L-tartrate, (m.p. 160-161°C; e<] D = -72.4°, ] 578 = -77.4-; ] 5 = -92.9', C = 1,6, MeOH].

The chiral isothioureas are obtained as free bases by treatment of chiral isothiouronium salts with bases. Thus sodium bicarbonate (g 0.105) is added to a stirred suspension of the 0,0•-dibenzoyltartrate isothiouronium salt (g 1) in a biphasic water/AcOEt (1:1, 4& ml) mixture. After 10 minutes the aqueous phase is separated, washed with AcOEt (2 x 5 ml) and discarded. The organic phases are combined, washed with 5% aqueous NaHCθ3 solution (2 x 5 ml) and dried. The residue is triturated with Et 2 0 (ml 7) to give (+)-S-[ (6-methyl-3,5- -dicarboethoxy-4-(3-nitrophenyl)-1,4-dihydropyridin-2-yl) methyl]-isothiourea [g 0.85; m.p. 124-126°C; [o(] D = -69.4°, [0U 578 = -73.0°; W 5A6 = -83.5°; c l ' = 1.3, CH CI ) •

The optical purity of the single enantiomers, that is ascertained by 1H NMR analysis in the presence of the chiral tris-[3-(trifluoromethylhydroxymethylene)-d-cam- phorate]-praseodimium (III) lantanide reagent, is > 98%.

EXAMPLE 3

A KHC0 3 (g 106.3) aqueous solution (1100 ml) and 28% aqueous ammonia (35 ml) are added to a stirred suspension of (±)-S-[(6-methyl-5-carbomethoxy-3-carboethoxy-4-(3-ni- trophenyl)-1,4-dihydropyridin-2-yl) ethyl]-isothiouronium chloride (g 500) in AcOEt (5000 ml) cooled at +35°C. 30 Minutes after, the organic phase is separated, washed with brine (2 x 800 ml), dried on Na 2 S0 4 (g 400) and filtered. L-(+)-mandelic acid (98%; g 164.8) is then added to the stirred solution in AcOEt of the rac-isothiourea, thus obtained as free base, to give, 4 hours later, a crystalline solid that is filtered (g 260; m.p. 164-166 β C; [o(] D = +20.9°, c = 2.1, DMF) and crystallized from EtOH (1300 ml, 50°C, 1 h) to give 247 g of (+)-S-[(6-methyl-5-carbomethoxy-3-carboethoxy-4-(-3-nitro¬ phenyl)-1 , -dihydropyridin-2—yl)methyl]-isothiouronium L-mandelate (m.p. 166-168°C) , io( O = +20.9°, = +19.9°, c = 2.3, DMF). The mother liquors from the first crystallization from ethyl acetate (5000 ml), are concentrated to half volume under vacuum, and under stirring at +35°C are treated with a KHC0 3 (g 67) aqueous solution (ml 700) and then with 28% aqueous ammonia (ml 30). 30 minutes later the organic phase is separated, washed with brine (2 x 350 ml), dried on Na 2 S0 4 (g 250) and filtered.

Following addition of D-(-)-mandelic acid (98%; g

96) thereto and stirring for 6 hours at room temperature give a solid (g 282; m.p. 163-166°C; [-<] Ό =-19.0 * , c = 2.7, DMF) that is crystallized from EtOH (1300 ml; 50°C;

1 h) to give 260 g of (-)-S-[ (6-methyl-5-carbomethoxy-3- -carboe thoxy-4- ( 3-nitrophenyl ) -1 , 4 -dihydr opyr idin-2 -y 1 ) me¬ thyl] -isothiouronium D-mandelate, (m.p. 165-167°C; [o^] D = -21.3 β ,[e0 578 = -21.3 * [*0 546 = -20.8°, c = 2.2, Did?). The free bases:

( + ) -S- [ ( 6-methyl-5-carbomethoxy-3-carboe thoxy-4- ( 3-nitro¬ phenyl ) -1 , 4-dihydropyridin-2-yl )methyl ] isothiourea (m.p . 122-124°C; [o] D = +64.2°; foU 578 = 75.8°; c = 2.0 CH 2 C1 2 ) and its (-)enantiomer (m.p. 123-124 °C; fe D = -64.4° [0U 578 = -66.9°; i 5A6 =-75.6°, c 2.0

CH 2 C1 2 ) are obtained by L- and D-mandelate isothiouronium salts using the procedure of example 2 (AcOEt/H 2 0/ NaHC0 3 ) . EXAMPLE 4 Using BOC-L-phenylalanine and BOC-L-leucine, as re¬ solving agents of (±)-S-[ (6-methyl-5-carbomethoxy-3-car- boe thoxy-4- ( 3 -ni trophenyl ) -1 , 4 -dihydr opyridin-2-yl ^me¬ thyl] -isothiourea, in the procedure of example 2, the following isothiouronium salts are obtained:

[θ0 578 = +27.6° to(] 546 = +34.8°; c = 2.1, MeOH); ( + ) -S- [ ( 6-methyl-5-carbomethoxy-3-carboe thoxy-4- ( 3-ni * trq- phenyl )-l,4-dihydropyridin-2-yl] -isothiouronium L-feoc-

-leucinate (m.p. 136-137°C, [o(] D = +2.3° [o< 578 = +3.2° [oy 546 = + 6.7°; c = 2.5, MeOH). EXAMPLE 5

Powdered KHCO3 (g 17) and water (ml 280) are added to a stirred suspension of: (±)-S-[ (6-methyl-5-nitro-4-

-(3-nitrophenyl)-3-carboethoxy-1,4-dihydropyridin-2-yl)- -methyl]isothiouronium chloride (g 70) in EtOH (ml 280), cooled at +10/+20°C. One hour after, at room temperature (23-25°C) , the solid material is filtered and washed with water (300 ml), obtaining (±)-S-[(6-methyl-5-nitro-4-(m- -nitrophenyl)-3-carboethoxy-1,4-dihydropyridin-2-yl)-me¬ thyl] isothiourea (64 g, m.p- 143-144°C), that is added to a solution of L-(+)-mandelic acid (g 24) in acetoni¬ trile (ml 800). The mixture is warmed to 40-50°C until a clear solution is obtained, that is then filtered, cooled and left for one night at room temperature.

The collected precipitate (g 33.4, m.p. 145-147°C; [θ] D = -27.5° DMF, c = 2.1) is recrystallized from acetonitrile (ml 270) to give g 32.7 of enantiomerically pure (-)-S-[ (6-methyl-5-nitro-4-(3-nitrophenyl)-3-carbo- ethoxy-1,4-dihydropyridin-2-yl)methyl]-isothiouronium L - andelate (m.p. 147-148°C; [oQ D = -29,5°; [c] 578 = -35.0° c = 2.0 in DMF).

The first mother liquors are evaporated to dryness, the crude residue (g 53) is treated in EtOH (ml 200) with KHC0 3 (g 10.5) and water (ml 300) to separate g 35.2 of a solid material that is dissolved in a solution of D-(-)-mandelic acid (g 13.3) in acetonitrile (ml 390). After a night at 4°C, the solid obtained (g 36.7; m.p. 146-147°C; [o D = +29°, c = 2.0, DMF), is recrystallized from acetonitrile, to give g 35.3 of (+)-S-[ (6-methyl-5- -nitro-4-(3-nitrophenyl)-3-carboethoxy-l,4-dihydropyridi- n-2-yl)-methyl]-isothiouronium D-mandelate (m.p. 146- -147°C; tø D = +29.0°; [eC- 578 = +34.0°; c = 1.9 DMF). EXAMPLE 6

A solution of (±)-S-[ (6-meth l-5-dyano-4 * --(3-nitro¬ phenyl)-3-carboethoxy-1,4-dihydropyridin-2-yl)methyl]-iso¬ thiourea (g 37) and L-(+)-mandelic acid (g 1 f .9) in acetonitrile (ml 400) is stirred for 4 hours at- room temperature. One night after, at +4°C, g 10.2 of a solid ([ ] D = +128.5°, c = 1.2, MeOH) are filtered and the mother liquors are evaporated to dryness under vacuum. A

_ solution of the crude residue in 1,2-dichloroethane (ml

100) is stirred overnight at room temperature to separate a second crystalline crop (g 9.9, [<?Q D = +119.5°, c = 1.3, MeOH). The combined crystals are recrystallized from acetonitrile (ml 100) to give 18.2 g of (+)-S-[(6-me- thyl-5-cyano-4-(3-nitrophenyl)-3-carboethoxy-1,4-dihydro- pyridin-2-yl)methyl]-isothiouronium L-mandelate (m.p. 161-163-C; [θ(] D = +129.5°, [ø(] 578 = +133.5°, &*U 54 g = +161.3°, ? 3 g = +460.1°; c = 0.97, MeOH: isothiourea free base [ø(] D = +217.7°, [« 578 = +235.5°, [ J 546 » = +816.9°; CH 2 C1 2 , c = 0.7).

The 1,2-dichloroethane mother liquors are treated with a 5% aqueous solution of NaHC0 3 (2 x 100 ml), "water (2 x 50 ml), dried on Na 2 S0 4 , combined with 0,0'-dibenzoyl-L-tartaric acid (g 21.3) and then evaporated to dryness under vacuum. A stirred solution of the residue in acetonitrile (ml 600) separates after 4 hours at room temperature a crystalline precipitate (g 34, [ø(J D = -99.6°, MeOH, c = 1.2° that is recrystallized from acetonitrile (ml 600) to give g 32 of (-)-S-[(6-methyl-5-cyano-4-(3-nitrophenyl)-3-carboethoxy- l,4-dihydroρyridin-2-yl)methyl]-isothiouronium 0,0'-di- -benzoyl-L-tartrate (m.p. 156-158°C, [PC--, = -103°,

[o0 578 = -108°, [oU 546 = -131°, [c ] 436 = -355°, c = 1.0,

MeOH; isothiourea free base : [oϋ D = -208°, [< > ] 5 ^g=

-230°, [« ] 54 g = -283°, [o*0 43 g = -816°, c = 0.5, CH 2 Cl 2 ) .

EXAMPLE 7 g 3.4 of finely powdered NaHC0 are added to a solution of g 20 of (+)S-[ (6-methyl-3~carboethoxy-5-car- bomethoxy-4-(2 ,3-dichlorophenyl)-1,4-dihydropyridin-2-yl)- methyl]-isothiouronium chloride in AcOEt (ml 600) at room temperature under stirring. After 30', the organic phase is washed with water (3 x 100 ml), aqueous sodium bicarbonate (5%, 3 x 100 ml) and brine (2 x 50 ml) and finally is dried on Na 2 S0 4 . The organic phase is divided in two parts of ml 300 each, that are treated respectively with: 0,0'-dibenzoyl-L-tartaric acid (g 7.6) and 0,0'-dibenzoyl-D-tartaric acid (g 7.6). Both the solutions are left at room temperature for a night and then are filtered to give respectively g 11.3 of a levorotatory salt (tø(] D = -90°, c = 0.5, MeOH) and g 11.1 of a dextrorotatory salt ( [o] D - +89°, c = 0.5 MeOH). After crystallization from hot methanol (ml 220) , these salts give respectively: (-)-S[(6-methyl-3-carboethoxy- -5-carbonethoxy-4-(2,3-dichlorophenyl)1,4-dihydropyridin- 2-yl)methyl]isothiouronium 0,0'-dibenzoyl-L-tartrate

( &0 D = -90% W 5 78 = "92 °' -<-546 β - 110 °' ^436 = -310°, c = 0.5, MeOH), and (+)-S-[(6-methyl-3-carbo- ethoxy-5-carbome thoxy-4- ( 2 , 3-dichlorophenyl ) -1 , 4-dihy dro- pyridin-2-yl )methyl ] -isothiouronium 0,0' -dibenzoyl-D-tar- trate ( [ c ] D = +89°, [cU 578 = + 94°, [cC] 546 = +114°,

[^] 436 = +313°, MeOH, c = 0.5). An inversion of the sign of deviation of the

polarized light plane is observed when isothioureae are isolated as free bases from their isothiouronium salt's. (+)-S-[(6-methyl-3-carboethoxy-5-carbomethoxy-4(2,3-di- chlorophenyl)-1,4-dihydropyridin-2-yl)methyl]-isothiourea UoU D = +45°, [ cU 578 = +41°, tø 5 6 = +46 °' G ^ ' 0-2, MeOH) is obtained starting from (-)-isothiouronium 0,0'-dibenzoyl-L-tartrate salt while the levorotatory (-)-S-[ (6-methyl-3-carboethoxy-5-carbomethoxy-4-(2^3- -dichlorophenyl)-1,4-dihydropyridin-2-yl)methyl]-is ' όthiou- rea ([o(] D = -39°, l-M 578 = -40°, __ct] 546 = -46°, c = 0..3, MeOH) is obtained from (+)-isothiouronium 0,0•-dibenzoyl- D-tartrate salt. EXAMPLE 8 Using the procedures described in one of the * examples from 1 to 7, the pure (Σ3) and (R) enantiomers of the following isothioureae are obtained:

-S-[(6-methyl-5-cyano-4-(3-nitrophenyl)—3-carboethoxy-1 ,4 -dihydropyridin-2-yl)methyl]-isothiourea; -S-[ (6-methyl-5-acetyl-4-phenyl-3-carboethoxy-1,4-dih dro- pyridin-2-yl)methyl]-isothiourea;

-S-[(6-methyl-5-carboisopropoxy-4-(3-nitrophenyl)-3-carbo - ethoxy-1,4-dihydropyridin-2-yl)methyl]-isothiourea; -S-[ (6-methyl-3,5-dicarboethoxy-4-(2-chlorophenyl)-1, -di- hydropyridin-2-yl)methyl]-isothiourea; -s-[ (6-methyl-5-carbomethoxy-3-carboethoxy-4-(2-chlorophe- nyl)-1,4-dihydropyridin-2-ylJmethyl]-isothiourea; -S-[ (6-methy1-5-carbomethoxy-3-carboethoxy)-4-(3-chloro¬ phenyl)-l,4-dihydropyridin-2-yl)methyl]-isothiourea; -S-[ (6-methyl-3,5-dicarboethoxy-4-(2-trifluoromethylphe- nyl)-l,4-dih drσpyridin-2-yl)methyl]-isothiourea;

-S-[ (6-methyl-5-carbomethoxy-3-carboethoxy-4-(2-trifluoro- methylphenyl-1,4-dihydropyridin-2-yl)methyl]-N-methyl]-

-isothiourea;

-S-[(6-methyl-3-carboethoxy-5-cyano-4-(2-trifluoro-methyl - -phenyl)-1,4-dihydropyridin-2-yl)methyl]-isothiourea;

-S-[ (6-methyl-5-σarbomethoxy-3-carboethoxy-4-(4-fluorophe- nyl)-1,4-dihydropyridin-2-yl)meth l]-N,N'-dimethyliso- thiourea;. -S-[(6-methyl-5-carbomethoxy-3-carboethoxy-4-(3-trifluoro- methylphenyl)-1, -dihydropyridin-2-yl)methyl]isothiourea; -S-[(6-methyl-5-carbomethoxy-3-carboethoxy-4-phenyl-l,4- -dihydropyridin-2-yl) ethyl]-N,N'-dimethylisothiourea; -S-[(6-methyl-5-carbomethoxy-3-carboethoxy-4-(4-nitrophe¬ nyl)-1,4-dihydropyridin-2-yl)methyl]-isothiourea; -S-[(6-methyl-5-carbomethoxy-3-carboethoxy-4-(2-nitrophe¬ nyl)-1,4-dihydropyridin-2-yl)methyl]isothiourea; -2-[(1,4,5,6-tetrahydropyrimidin-2-yl)thio]methyl-5-carbo- methoxy-3-carboethoxy-6-methyl-4-(3-nitrophenyl)-1,4-dihy¬ dropyridine; -2-[(4,5-dihydroimidazol-2-yl)thio]methyl-3,5-dicarbome- thoxy-4-(3-trifluoromethylphenyl)-6-methyl-l,4-dihydro-py- ridine;

-2-[(4,5-dihydroimidazol-2-yl) hio]methyl-3,5-dicarboe- thoxy-4-(3-nitrophenyl)-6-methyl-l,4-dihydropyridine; -2-[ (1,4,5,6-tetrahydropyrimidin-2-yl)thio]methyl-5-tert- butoxycarbonyl-3-ethoxycarbonyl-4-(3-nitrophenyl)-6-me- thyl]-1,4-dihydropyridine;

-2-[(l-methyl-4,5-dihydroimidazol-2-yl)thio]methyl-3,5-di ¬ carboethox -4-(3-chlorophenyl)-6-methyl-l,4-dihydropyridi- ne:

-2-[(l-methyl-4,5-dihydroimidazol-2-yl)thio]methyl-3-car- boethoxy-5-carbomethoxy-4-(3-cyanophenyl)-(j-methyl-l,4-di¬ hydropyridine; -2-[(l-methyl- ,5-dihydroimidazol-2-yl)thio]methyl-3-car- boethoxy-5-carbomethoxy-4-(4-chlorophenyl)-6-methyl-l,4- -dihydropyridine;

-2-[(l-methyl-4,5-dihydroimidazol-2-yl)thio]methyl-3-car- boethoxy-5-carbomethoxy-4-(2,3-dichlorophenyl)-6-methyl- -1, -dihydropyridine; -2-[(4,5-dihydroimidazol-2-yl)thio]methyl-3,5-dicarbQ- ethoxy-4-(3-chlorophenyl)-6-methyl-l,4-dihydropyridine; -2-[(1,4,5,6)-te rahydropyrimidin-2-yl)thio]methyl-5-[2- -(N-benzyl-N-methyl)-amino]-ethoxycarbonyl-3-ethoxycarbo- nyl-4-(3-nitrophenyl)-6-methyl-l,4-dihydropyridine; -2-[(4,5-dihydroimidazol-2-yl)thio]methyl-3-carboethoxy-5- -nitro-4-(3-trifluoromethylphenyl)-6-methyl-l,4-dihydropy- ridine;

-S-[(6-fluoromethyl-3,5-dicarbomethoxy-4-(3-nitrophenyl)- 1,4-dihydropyridin-2-yl)methyl]-isothiourea; -S-[(6-ethoxycarbonyl-3,5-dicarboethoxy-4-(3-chlorophe- - nyl)-1,4-dihyropyridin-2-yl)methyl]-isothiourea; -S-[(6-diethoxymethyl-3-carboethoxy-5-nitro-4-(β-pyridi- nyl)-1,4-dihydropyridin-2-yl)methyl]-isothiourea; -S-[ (6-cyano-3-carboethoxy-5-(2-methoxyethoxy)-carbonyl-4 -(3-thienyl)-1,4-dihydroρyridin-2-yl)methyl]-isothiourea; -S-[ (6-cyano-5-carboethoxy-3-carboisopropoxy-4-(benzo—[b] -1,4-dioxan-5-yl)-1, -dihydropyridin-2-yl)methyl]isothio¬ urea; -S-[ (6-σyano-3,5-dicarboethoxy-4-(benzo-[c]-furazan-4-yl) -1,4-dihydropyridin-2-yl)methyl]-isothiourea;

-S-[(6-cyano-3,5-dicarbomethoxy-4-(3-trifluoromethyl-phe- nyl)-1,4-dihydropyridin-2-yl)methyl]-isothiourea; -S-[ (6-methyl-3-carboethoxy-5-allyloxycarbonyl-4-(3-nitro¬ phenyl)-1,4-dihydropyridin-2-yl)methyl]isothiourea; -S-[(6-methyl-3-σarbomethoxy-5-(2-butenoxycarbonyl)-4-(2- chlorophenyl)-1,4-dihydropyridin-2-yl)methyl]-isothio¬ urea;

-S-[(6-methyl-3-carboethoxy-5-tertbutoxycarbonyl-4-(3-ni trophenyl)-l,4-dihydropyridin-2-yl)methyl]-isothiourea; -S-[ (6-methyl-3-carbomethoxy-5-allyloxycarbonyl-4-(3-ni¬ trophenyl)-1,4-dihydropyridin-2-yl)methyl]-isothiourea; -S-[(6-methyl-3-allyloxycarbonyl-5-carbomethoxy-4-(3-ni¬ trophenyl)-1,4-dihydropyridin-2-yl)methyl]-isothiourea; -S-( -methyl-3,5-diallyloxycarbonyl-4-(3-nitrophenyl)-1,4 -dihydropyridin-2-yl)methyl]-isothiourea;

-S-[ (-6-methyl-3-carbomethoxy-5-allyloxycarbonyl-4-(2,3- -dichlorophenyl)-1,4-dihydropyridin-2-yl)methyl]-isothio¬ urea; -S-[(6-methyl-3-carboethoxy-5-acetyl-4-(2-thienyl)-1,4-di- hydropyridin-2-yl)methyl]-isothiourea;

-S-[(6-methyl-3-carboethoxy-5-benzoyl-4-(2-thienyl)-1,4- -dihydropyridin-2-yl)methyl]-isothiourea;

-S-[ (6-methyl-3-carboethoxy-5-(2-phenylacetyl)-4-(pyridin- -2-yl)-1,4-dihydropyridin-2-yl)methyl]-isothiourea; -(-)-S-[ (6-methyl-3-carboethoxy-5-carbomethoxy-4-(benzo- -[c]-furazan-4-yl)-1,4-dihydroρyridin-2-ylJmethyl]-iso¬ thiourea;

-(-)-S-[ (6-methyl-3-allyloxycarbonyl-5-carbomethoxy-4- -(benzo-[c]-furazan-4-yl)-1,4-dihydropyridin-2-yl)methyl] -isothiourea;

-S-[ (6-methyl-3-allyloxycarbonyl-5-tertbutoxycarbonyl-r4- (3-nitrophenyl)-1,4-dihydropyridin-2-yl)methyl]-isothio¬ urea; -S-[(6-methyl-3-allyloxycarbonyl-4-tertbutoxycarbonyl- -(2,3-dichlorophenyl)-1,4-dihydroρyridin-2-yl)methyl]-iso¬ thiourea. EXAMPLE 9

An aqueous solution of NaOH (20%, ml 11.5) is added to a stirred solution of (-)-S-[ (6-methyl-5-cyano-4-(3- -nitrophenyl)-3-carboethoxy-l,4-dihydropyridin-2-yl) e¬ thyl]-isothiouronium O^'-dibenzoyl-L-tartrate (g 10) and 2-bromoethylamine hydrobromide (g 6.56) in ethanol/water

~

(50/50, ml 50), under a nitrogen atmosphere. After one hour at room temperature, the mixture is diluted with water (ml 100) and extracted with AcOEt (5 x 50 ml).

The combined organic phases are extracted several times with 7.5% aqueous acetic acid (4 x 50 ml) and then are eliminated. The combined aqueous extracts are reextracted with Et-0 (3 x 30 ml) to remove neutral impurities, alkalinized by aqueous sodium bicarbonate

(until pH = 8.5) and finally extracted with AcOEt (4 x 40 ml). Said organic extracts are combined, dried and evaporated to dryness; chromatographic purification of the residue by column chromatography on Si0 2 , (g 30, eluent CHCl 3 /MeOH 95/5) gives g 3.4 of (-)-2-(aminoethyl- thio)-methyl-3-carboethoxy-5-cyano-4-(3-nitrophenyl)-6-me- thyl-1,4-dihydropyridine (m.p. 142-144°C, AcOEt); [00 D = -184°, [oU 578 = -196°, [«(] 546 = -240- [oU 43 g = -698°, c = 1.0, MeOH). Using in the same procedure, the (+)-S-[ (6— ethyl-

-3-carboethoxy-5-cyano-4-(3-nitrophenyl)-1,4-dihydropyri- din-2-yl)methyl]-isothiouronium L-mandelate (g 4), the (+)-S-2-(aminoethyl)-thiomethyl-3-carboethoxy-5-cyano-4- -(3-nitrophenyl)-6-methyl-l,4-dihydropyridine (g 2.4, m.p. = 140-144°C; [oU = +186°, [θ 578 = +197°, [o] 546 = +240°, [C 436 = +698°, c = 0.9, MeOH) are obtained. EXAMPLE 10

A solution of (+)-S-[(6-methyl-5-carbomethoxy-3-car- boethoxy-4-(3-nitrophenyl)-1,4-dihydropyridin-2-yl)me- thyl]-isothiouronium L-mandelate (g 8.5), N-(2-chloro- ethyl)-N-(2-cyanoethyl)-formamide (g 2.8) and LiOH (g 1.3) in DMF (ml 70) is stirred for 50' at room temperature, poured into ice and saturated NaH 2 P0 4 aqueous solution (ml 300) and extracted with AcOEt (3 x 100 ml). The combined organic phases are washed with brine (3 X 20 ml), dried (Na 2 S0 4 ) and evaporated to dryness under vacuum. After purification of the residue (g 7.9) by chromatography (Si0 2 , g 250, eluent Et 2 0) , g 5.8 of (-)-2-[2-N-formyl-N-(2-cyanoethyl)-aminoethyl- thio]methyl-3-carboethoxy-5-carbornethoxy-4-(3-nitrophe¬ nyl)-6-methy1-1,4-dihydropyridine are obtained as an amorphous solid ( [θ(J O = -17.9°, - 578 = -20°, &-C] 546 = -25.2; c = 1.6, CH 2 C1 2 ). EXAMPLE 11 Using N-(2-chloroethyl)-formamide instead of N-(2-

-chloroethyl)-N-(2-cyanoethyl)-formamide in the procedure of example 10, the following compounds are obtained: -(-) -2-[2-(N-formyl)aminoethylthio]-3-carboethoxy-5-carbo- methoxy-4-(3-nitrophenyl)-6-methyl-l,4-dihydropyridine ([θG D = -14°, c = 1.3, MeOH), m.p. 80-82°C (from Et 2 0,

white); 102-103°C (from AcOEt, yellow); * "

-(+)-2-[2-(N-for yl)aminoethylthio]-3-carboethoxy-5-carbo- methoxy-4-(3-nitrophenyl)-6-methyl-l ,4-dihydropyridine (toOo = +13.70°, c = 1.3, MeOH), m.p. 81-83°C (from Et 2 0, white) . '

EXAMPLE 12

A mixture of (+)-S-[(6-methyl-5-nitro-4-(3-nitro¬ phenyl)-3-carboethoxy-1,4-dihydropyridin-2-yl)methyl]- -isothiouronium D-mandelate (4.0 g) , 2-bromoethylamine hydrobromide (g 10.7), hexadecyl-tributyl-phosphonium bromide (g 1.0), benzene (ml 40) and NaOH (20%, ml 11.4) is vigorously stirred for 10• , and then diluted with a mixture of water (ml 200) and AcOEt (ml 100). After separation of the phases, the aqueous' phase is reextracted with AcOEt (2 x 30 ml) and eliminated. The organic phases are combined, washed with NaHC0 3 (saturated solution 2 x 50 ml), dried (Na 2 S0 4 ) and then evaporated to dryness in the presence of Si0 2 (g ' 15).,'

The residue is eluted through a chroma ographic column (Si0 2 g 60), using MeOH/CHCl 3 10/90 ' as eluent.

The eluted fractions, containing 'the desired amine, are combined and after addition of fumaric acid (g 0.6) are evaporated to dryness under vacuum.

By trituration of the residue with Et 2 0, g 2.2 " of (+)-2-(2-aminoethylthio)-methyl-5-nitro-4-(3-nitrophe yl) -6-methyl-3-carboe hoxy-1 ,4-dihydropyridine hemifumar te (tø ] D - +56°, c = 2.0, DMF) are obtained.

Using in the same procedure the levόrotatory isothiouronium salt the : (-)-2-(2-aminoethylthio)methyl-5-nitro-4-(3-nitrophenyl)-

3-carboethoxy-6-methyl-l,4-dihydropyridine hemifumarate (to^] D = 54°, c = 2.0, DMF) is also prepared. EXAMPLE 13

A solution of 1-formylimidazole (prepared reacting carbonyldiimidazole, g 3.3, with formic acid, ml 0.80 at 0°C, in THF (ml 30)) is added dropwise to a solution in dry THF (ml 15) cooled at 0°C of (-)-2-[(1,4,5,6-tetrahy- dropyrimidin-2-yl)thio]methyl]-3,5-dicarboe hoxy-4-(3-ni¬ trophenyl)-6-methyl-l,4-dihydropyridine (g 5.1; free base, isolated from the mandelate salt by treatment with AcOEt/aqueous Na 2 C0 ).

The mixture is stirred for 1 hour at room temperature,diluted with water (150 ml) and extracted with diethyl ether (3 x 30 ml). The combined organic phases are dried (Na 2 S0 4 ), evaporated under vacuum and the residue is triturated with cold ethanol to give g 4.5 of (-)-2-[(1-formyl-1,4,5,6-tetrahydropyrimidin-2-yl)- thio]methyl-3,5-dicarboethoxy-4-(3-nitrophenyl)-6-methyl- 1,4-dihydropyridine. 1 HNMR (CDC1 3 ) < £ : 1.0-1.2 (6H) 1.8-2.3 (5H) 4.4-4.8 (6H) 5.1 (1H) 6.9 (1H) 7.18.2 (4H) 9.2 (1H). EXAMPLE 14

A mixture of (+)-S-[(5-carbomethoxy-3-carboethoxy-4- -(3-nitrophenyl)-6-methyl-l,4-dihydropyridin-2-yl)-me- thyl]-isothiouronium chloride (mg 500), t-butyl chlpro- acetate (mg 230), NaOH (35%, ml 2), benzyltriethylammo¬ nium bromide (BTEAB, mg 73) and 1,2-dichloroethane (ml 5) is stirred at room temperature for two hours, and diluted with water (ml 5). The organic phase is separated, washed with water (4 x 3 ml), dried (Na 2 S0 4 ) and evaporated

under vacuum to crystallize from diethylether g 0.48 of ( + )-2-(tert-butoxycarbonylmethylthio)methyl-3-carboethox y- -5-carbomethoxy-4-(3-nitrophenyl)-6-methyl-l,4-dihydropy¬ ridine. 1 HNMR (CDC1 3 ) $ : 0.91.2 (12H) 2.1 (3H) 3.43.8 (4H) 4.34.8 (6H) 5.1 (1H) 7.08.2 (5H). EXAMPLE 15

A mixture of (-)-S-[(5-cyano-3-carboethoxy-4-(3-ni¬ trophenyl)-6-methyl-l ,4-dihydropyridin-2-yl)methyljisothi ourea (mg 500), 3-chloromethylpyridinium hydrochloride (mg 190), benzyltriethylammonium chloride (BTEAC mg 80), KOH (4 M, ml 2) and benzene (ml 5) is stirred at room temperature for 15 minutes to separate a precipitate that is filtered and triturated with diethyl ether to give mg 450 of (-)-2-(3-pyridinylmethylthio)methyl-5-cyano-3-car- boethoxy-4-(3-nitrophenyl)-6-methyl-l,4-dihydropyridine. E NMR (CDC1 3 ) £ : 1.9-1.1 (3H) 2.3 (3H) 4.3-4.9 (6H) 5.1 (1H) 6.8 (1H) 7.2-8.2 (4H). EXAMPLE 16 A mixture of (+)-S-[(5-carbomethoxy-3-carboethoxy-4- -(3-nitrophenyl)-6-methyl-l,4-dihydropyridin-2-yl)mβthyl] -isothiourea (mg 500), 2,4-difluorobenzenediazonium tetrafluoroborate (mg 242), K 2 C0 3 (mg 440) and BTEAC (mg 73) in benzene (ml 5) is stirred at room temperature for 6 hours, mg 30 of (+)-2-(2,4-difluorophenylthio)-methyl- -3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl- 1,4-dihydropyridine (as an amorphous solid) are obtained

__ r t ' after the usual work-up and chromatographic purification on Si0 2 (g 15, eluted in order with hexane/diisopropyl ether 50/50 and with hexane/ethyl acetate 80/20).

-• NMR ( & CDCI3) = 8.05-6.65 (8H,m) 5.05 (lH,s) 4.41 (2H,sb), 4.10 (2H,q) 3.60 (3H,s) 2.18 (3H,s) 1.14 (3H,t). EXAMPLE 17

A mixture of (-)-2-[ (1,4,5,6-tetrahydropyrimidin-2-

5 -yl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitro¬ phenyl)-6-methyl-l,4-dihydropyridine (g 2), hexadecyltri- butyl phosphonium bromide (mg 180), 2-bromoethylaminehy- drobromide (mg 900), NaOH (35%, ml 8) and benzene is stirred for 40 minutes at room temperature. After the 10 usual work-up, an oily residue is obtained that is dissolved in ethyl acetate and treated with fumaric acid to give 1.9 g of (-)-2-(aminoethylthio)methyl-3-carbo- ethoxy-5-carbomethoxy-4-(3-nitrophenyl)-6-methyl-l,4-dihy¬ dropyridine fumarate, m.p. 104-110°C [o] D =-11 (C = 4 in

15. MeOH) .

EXAMPLE 18

Using in the procedures described in examples 13-17, a solvent selected from the group of benzene, toluene, 1,2-dichloroethane, methylene chloride, ethyl acetate, a

20 base selected from the group of , Na 2 C0 3 , KOH and NaOH and a "phase transfer" catalyst selected from the group of tetrabutylammonium bromide, benzyltriethyl- ammonium chloride, benzyltriethylammonium bromide, dode- cyltrimethylammonium bromide, hexadecyltrimethylammonium

25 chloride and hexadecyltrimethylammonium bromide, by reaction of a suitable electrophilic reagent (selected in the group of alkyl halide and sulphate or sulphonate, diazonium salts and of a Michael acceptor, such as o - and β- unsaturated esters, ketones and/or nitriles) with a

30 racemic salt of: S-(l,4-dihydropyridin-2-yl-methyl)-iso-

thiouronium as those described in preparations 1-5, and/or with a diastereoisomerically pure isothiouronium salt and/or with an enantiomerically pure S-(1, -dihydro- pyridin-2-ylmethyl)-isothiourea of examples 2-8, the following 6-methyl-l,4-dihydropyridines are obtained as pure enantiomers and/or racemates (±) :

-2-(2-cyanoethylthiomethyl)-5-cyano-3-carboethoxy-4-(3-ni ¬ trophenyl), (+) m.p. 136-137°C; ,-

-2-(2-cyanoethylthiomethyl)-5-carboisopropoxy-3-carbo- ethoxy-4-(3-nitrophenyl) , (+) m.p. 95-98°C;

-2-(2-cyanoethylthiomethyl)-3,5-dicarboethoxy-4-(2-chloro - phenyl) ;

-2-(2-cyanoethylthiomethyl)-5-carbomethoxy-3-carboethoxy-

4-(2-chlorophenyl) ; -2-(2-cyanoethylthiomethyl)-5-carbomethoxy-3-carboethoxy-

4-(3-chlorophenyl) ;

-2-(2-cyanoethylthiomethyl)-3,5-dicarboethoxy-4-(2-tri- fluoromethylphenyl);

-2-(2-cyanoethylthiomethyl)-5-carbomethoxy-3-carboethoxy- 4-(2-tri luoromethyIphenyl); -2-(2-cyanoethylthiomethyl)-5-carbomethoxy-3-carboethoxy-

4-(3-trifluoromethylphenyl) ;

-2-(2-cyanoethylthiomethyl)-5-carbome hoxy-3-carboethoxy-

4-(phenyl) ; -2-(2-cyanoethylthiomethyl)-5-carbomethoxy-3-carboethoxy-

4-(4-nitrophenyl) ;

-2-(2-cyanoethylthiomethyl)-5-carbomethoxy-4-(2-nitrophe- nyl) ;

-2-(2-aminoethylthio)methyl-5-carbomethoxy-3-carboethoxy- 4-(3-methoxyphenyl) , (+) m.p. 124-130°C (fumarate);

-2-(2-aminoethylthio)-methyl-5-carbomethoxy-3-carboethoxy-

-4-(3-cyanophenyl) , (+) m.p. 172-174°C (fumarate),

99-100°C (base);

-2-(2-aminoethylthio)-methyl-5-carbomethoxy-3-carboethoxy - -4-(2,3-dichlorophenyl) , (+) m.p. 128-130°C (fumarate);

-2-(2-aminoethylthio)-methy1-5-carbomethoxy-3-carboethoxy -

-4-(4-chlorophenyl) , (+) m.p. 89-91°C (base);

-2-(2-aminoethylthio)methyl-5-nitro-3-carboethoxy-4-(3-ni ¬ trophenyl), (+) m.p. 182-185°C (fumarate); -2-(2-N,N-dimethylaminoethylthio)-methy1-5-carbomethoxy-

3-carboethoxy-4-(3-nitrophenyl) , (+) m.p. 191-194°C

(hydrochloride);

-2-(2-N-methylaminoethylthio)-methyl-5-carbomethoxy-3-car - boethoxy-4-(3-nitrophenyl) , (+) m.p. 205-207°C (fumarate) ;

-2-(2-N-butylaminoethylthio)-methy1-3,5-dicarboethoxy-4-

(3-nitrophenyl), (+) m.p. 129-131°C (hydrochloride);

-2-(2-N-acetylaminoethylthio)-methyl-5-carboethoxy-3-car- bomethoxy-4-(3-nitrophenyl) , (+) m-p. 115-116°C; -2-(2-N-formylaminoethylthio)-methyl-5-carboethσxy-3-car-

-bomethoxy-4-(3-nitrophenyl) , (+) m.p. 111-112°C;

-2-[2-N-(2-cyanoethyl)aminoethylthio]methy1-3,5-dicarbo- ethoxy-4-(3-nitrophenyl) , (+) m.p. 105-107°C (fumarate);

-2-[2-N-formyl-N-(2-cyanoethyl)aminoethylthio]methy1-5- -carbomethσxy-3-carboethoxy-4-(3-nitrophenyl) , (+) m.p.

114-115-C;

-2-(2,3-dihydroxyethylthio)methyl-3,5-dicarboethoxy-4-(3- nitrophenyl) (+) m.p. 98-102°C;

-2-(2,3-dihydroxyethylthio)methyl-5-carbomethoxy-3-carbo- Gthoxy-4-(2-chlorophenyl) ;

-2-(2-hydroxyethylthio)methyl-3,5-dicarboethoxy-4-(3-=*ni- trophenyl), (±) m.p. 119-120°C; (-) m.p. 127-128°C [ø(] D = -8.1; (+) m.p. 128-129°C [c] D = +9°C (c = 1 MeOH); -2-allylthiomethyl-5-carbomethoxy-3-carboethoxy-4-(3-ni- trophenyl), (+) m.p. 74-77°C;

-2-(2-propargylthiomethyl-5-carbomethoxy-3-carboethoxy-4- (3-nitrophenyl), (+) m.p. 110-112°C;

-2-ethylthiomethyl-3,5-dicarboethoxy-4-(3-nitrophenyl) , (+) m.p.l20-121°C; -2-benzylthiomethyl-3,5-dicarboethoxy-4-(3-nitrophenyl) , (+) m.p. 91-93°C;

-2-phenylethylthiomethyl-3,5-dicarboethoxy-4-(3-nitrophe nyl), (+) m.p.73-75°C; -2-(2-nitrophenylthio)-methyl-3,5-dicarboethoxy-4-(3-ni- trophenyl), (+) m.p. 135-136°C;

-2-furfurylthiomethyl-3,5-dicarboethoxy-4-(3-nitrophe¬ nyl), (+) m.p. 73-75°C;

-2-(3-pyridinylmethyl)-thiomethyl-3 ,5-diearboethoxy-4-(3- chlorophenyl) ; -2-furfurylthiomethyl-3,5-dicarboethoxy-4-(3-chlorophe¬ nyl);

-2-[ 2-(2-phenyl-2-oxoethyl)-thio]-methyl-3-carboethoxy-5- carbomethoxy-4-(3-nitrophenyl) , (+) m.p.l52-154 β C; -2-[ (oxyran-2-yl)methylthio]-methyl-3,5-dicarboetlioxy-4- -(3-nitrophenyl), (+) m.p. 107-109°C;

-2-[(oxyran-2-yl)-methylthio]-methyl-3-carboethoxy-5-car- bomethoxy-4-(3-chlorophenyl) (+) m.p. 80-84°C; -2-[4-(N-phtalimido -butylthio]-methyl-3-carboethoxy-5- -carbomethoxy-4-(3-nitrophenyl) , (+) m.p. 125-127°C; -2-(2-aminoethylthio)-methy1-5-[2-(N-benzyl-N-methyl)-ami-

no]-ethoxycarbonyl-3-ethoxycarbonyl-4-(3-nitrophenyl) ,

(+) m.p. 135-136°C (. 2 HCl . H 2 0) ;

-2-[2-(N-N-butylaminoethylthio)-methyl-3-carboethoxy-5-ni - tro-4-(3-nitrophenyl) , (+) m.p. 198-200°C (fumarate); -2-(2-aminoethylthio)-methyl-3-carboethoxy-5-nitro-4-(3-

-trifluoromethylphenyl) , (+) m.p.l52-155°C (fumarate);

-2-(2-aminoethylthio)-methyl-3-carboethoxy-5-cyano-4-(3-

-nitrophenyl) , (+) m.p.lδl-183°C (fumarate);

-2-(2-aminoethylthio)-methyl-5-tert-butoxycarbonyl-3-etho - xyσarbon l-4-(3-nitrophenyl) ;

-(+)-2-(2-N-formylaminoethylthio)-methyl-3-carboethoxy-5- cyano-4-(3-nitrophenyl) , m.p. 143-146°C; ldQ O - +164.5°,

(c = 1.4 MeOH) ;

- (- ) -2- ( 2-N-f ormyl aminoe thy lthio) -methyl-3-carboethoxy-5- cyano-4- (m-nitrophenyl ) , m.p. 143-145°C; toO n -165°, c -

1.5, MeOH);

- ( + ) -2- ( 2-N-f ormyl-N-2-cyanoethylaminoethylthio ) -methyl-3 -carboethoxy-5-cyano-4- ( 3-nitrophenyl ) , [eO D = +113°, c = 1.7, MeOH); - ( - ) -2- ( 2-N-f ormyl-N-2-cyanoe thyl aminoe thy lthio ) -methyl-3 -c arboe thoxy-5-cyano-4- ( 3-nitrophenyl ) , [o(] D = -111°, c = 1.7, MeOH) ;

- ( + ) -2- ( aminoe thy lthio ) -methy l-3-carboethoxy-5-carbometho- xy-4-( 3-nitrophenyl) fumarate ([c \ 3 D = +13°, c = 4, MeOH); - ( - ) -2- ( aminoethyl-thio ) -methyl-3-carboe thoxy-5-carbometho- xy-4-( 3-nitrophenyl) fumarate ( ic\ D = -11°, c = 4, MeOH);

- ( + ) -2- ( 2-N-f ormyl aminoethyl-thio ) -3-carboethoxy-5-nitro-4 -(3-nitrophenyl), ( [CU D = +6.2°, c = 2.0 DMF);

- ( - ) -2- ( 2-N-f ormyl aminoethyl-thio ) -3-c arboe thoxy-5-nitr o-4 -(3-nitrophenyl), ( [d_] O = -5.7°, c = 2.0 DMF);

-(+) -2-(cyanoethylthio)-methyl-5-carbomethoxy-3-carboetho- xy-4-(2-chlorophenyl) ;

- (- ) -2- (cyanoethylthio ) -methy 1- 5-carbome thoxy-3 -carboe tho¬ xy-4- (2-chlorophenyl) ; - (+ ) -2- (methylthio ) -methyl-5-nitr o-3-carboe thoxy-4- (3-ni¬ trophenyl ) ;

- ( - ) -2- (methylthio ) -methyl-5-nitr o-3-c arboe thoxy-4- (3-ni¬ trophenyl ) ; -( + ) -2- (methylthio) -methy l-5-nitro-3-carbome thoxy-4- (2- -trif luorome thylphenyl) ; "- *

- ( - ) -2- (methylthio ) -methy 1-5-nitr o-3-carbome thoxy-4- ( 2- -tr if luorome thylphenyl) ;

- (+ ) -2- (methylthio ) -methyl-5-cyano-3-carbome thoxy-4- ( 2- -tr if luorome thylphenyl) ; - (-) -2- (methylthio ) -methyl-5-cyano-3-carbomethoxy-4- (2- -tr if luorome thylphenyl) ; '

-(+) -2- (methylthio )-methyl-5-carbome thoxy-3 -carboethoxy-4 (3-nitrophenyl) m.p. 87-88°C [<>U D = +24.8°, t< ]5 78 = +27.1° lo0 5 4 Q = +36 * 4 ' c = 2 -l EtOH; - ( - ) -2- (methylthio ) -methyl-5-carbometho , xy-3~carboethoxy-4 -(3-nitrophenyl) m.p. 88-89°C [<β O = -24.5°, C<?0 578 = -26.7° tø 54 g = -36.2, c = 2.1 EtOH;

- (+ ) -2- (benzylthio ) -methy 1-5-nitr o-3-carboethoxy-4- <fl f 4- -benzodioxan-5-yl) ; - (- ) -2- (benzylthio ) -methyl-5-nitro-3-carboethoxy-4- (1,4- -benzodioxan-5-yl) ;

- (+ ) -2- (benzylthio ) -methy 1-5-cy ano-3-car boethoxy-4- ( 1 , 4- -benzodioxan-5-yl) ;

- (- ) -2- (benzylthio ) -methy l-5-cyano-3-carboethoxy-4'- (1,4- -benzodioxan-5-yl) ;

-(+)-2-(benzylthio)-methyl-3,5-dicarboethoxy-4-(benzodi- oxan-5-yl) ;

-(-)-2-(benzylthio)-methyl-3,5-dicarboethoxy-4-(benz-di- oxan-5-yl) ; -(+)-2-(3-pyridinylmethyl)-thiomethyl-3,5-dicarbomethoxy-

4-(benzodioxan-6-yl) ;

-(-)-2-(3-pyridinylmethyl)thiomethyl-3,5-diearbomethoxy-4

-(benzodioxan-6-yl) ;

-(+)-2-(3-pyridinylmethyl)-thiomethyl-3,5-dicarbomethoxy- 4-(benzofurazan-4-yl);

-(+)-2-(3-pyridinylmethyl)-thiomethyl-5-cyano-3-carbome- thoxy-4-(benzofurazan-4-yl) ;

-(-)-2-(3-pyridinylmethyl)-thiomethyl-5-cyano-3-carbome- thoxy-4-(benzofurazan-4-yl) ; -(+)-2-(3-pyridinylmethyl)-thiomethyl-5-nitro-3-carboter- butoxy-4-(benzofurazan-4-yl) ;

-(-)-2-(3-pyridinylmethyl)-thiomethyl-5-nitro-3-carboter- butoxy-4-(benzofurazan-4-yl) ;

-(+)-2-(tertbutoxycarbonylthio)-methyl-5-nitro-3-carboe- thoxy-4-(2,3-dichlorophenyl);

-(-)-2-(tertbutoxycarbonylthio)-methyl-5-nitro-3-carboe- thoxy-4-(2,3-dichlorophenyl) ;

-(+)-2-(tertbutoxycarbonylthio)-methyl-5-cyano-3-carboe- thoxy-4-(2,3-dichlorophenyl) ; -(-)-2-(tertbutoxycarbonylthio)-methyl-5-cyano-3-carbqe- thoxy-4-(2,3-dichlorophenyl) ;

-(-) -2-(tertbutoxycarbonylthio)-methyl-5-carbomethoxy-3-

-carboethoxy-4-(2,3-dichlorophenyl);

- ( + ) -2- ( aminoe thylthio ) -methyl- 3 -carboe thoxy-5-car borne tho- xy-4- ( 3-nitrophenyl ) fumarate (m.p . 105-112 °C [o ] D =

+3 . 6 ° , MeOH, c = 9 .4 ) ;

-(-)-2-(aminoethylthio)-methy1-3-c rboethoxy-5-carbometho¬ xy-4-(3-nitrophenyl) fumarate (m.p. 104-115°C [e^] D -

-3.4°, MeOH, c β 9.7); -(+)-2-(2-aminoethylthio)-methyl-3-carboethoxy-5-carbome- thoxy-4-(3-chlorophenyl) ;

-(-)-2-(2-aminoethylthio)-methyl-3-carboe hoxy-5-carbbme- thoxy-4-(3-chlorophenyl) ;

-(+)-2-(2-aminoethylthio)-methyl-3-carboethoxy-5-allyloxy - carbonyl-4-(3-chlorophenyl);

-(+)-2-(2-aminoethylthio)-methyl-3-carboethoxy-5-allyloxy - carbonyl-4-(3-chlorophenyl) ;

-(+)-2-(2-aminoethylthio)-methy1-3-carboethoxy-5-terbuto- xycarbonyl-4-(3-nitrophenyl); -(-)-2-(2-aminoethylthio)-methyl-3-carboethoxy-5-teipbuto- xycarbonyl-4-(3-nitrophenyl);

-(+)-2-(2-N-for ylaminoethylthio)-methyl-3-tertbutoxyqar- bonyl-5-cyano-4-(3-nitrophenyl) ;

-(-)-2-(2-N-formylaminoethylthio)-methy1-3-tertbutoxycar- bonyl-5-cyano-4-(3-nitrophenyl) ;

-(+)-2-(2-N-formylaminoethylthio)-methyl-3-tertbutoxycar- bonyl-5-nitro-4-(2-trifluoromethylphemyl) ; t- -(-)-2-(2-N-formylaminoethylthio)-methyl-3-tertbutoxycar- bonyl-5-nitro-4-(2-trifluoromethylphenyl); -(+)-2-(2-N-acetylaminoethylthio)-methyl-3-carboethoxy-5- carbomethoxy-4-(3-nitrophenyl) (m.p. 127-131°C, L OΌ =

+15.3°, MeOH, c = 3.3);

-(-)-2-(2-N-acetylaminoethylthio)-methyl-3-carboethoxy-5- carbomethoxy-4-(3-nitrophenyl) (m.p. 125-128°C, fc» D - -15.0°, MeOH, c = 3.7);

-(+)-2-(2-aminoethylthiomethyl-3-carboethoxy-5-carbometho- xy-4-(3-pyridinyl) ;

-(-)-2-(2-aminoethylthiomethyl-3-carboethoxy-5-carbometho ¬ xy-4-(3-pyridinyl) ; -(+) -2-(2-N-formylaminoethylthio)-methyl-3-carboethoxy-5- nitro-4-(3-pyridinyl) ;

-(-)-2-(2-N-formylaminoethylthio)-methyl-3-carboethoxy-5- nitro-4-(3-pyridinyl) ; -(+)-2-(2-N- formylaminoethylthio)-methy1-3-carboethoxy-5 -cyano-4-(2-furanyl) ;

- ( -) -2- ( 2-N-f ormyl aminoe thy lthio ) -methyl-3-carboethoxy-5- cyano-4-(2-furanyl) ;

- (+ ) -2- (benzylthio ) -methy 1- 3 -carboe thoxy- 5 -cyano-4- ( 2 -phe¬ nyl) ; - ( - ) -2- (benzylthio ) -methy 1-3-carboe hoxy-5-cyano-4- ( 2-phe- nyl ) ;

- ( + ) -2- (benzylthio ) -methyl-3 , 5-dicarboethoxy-4- ( 3-nitro¬ phenyl ) ( [o ] D = +25.5 ° , [o(] 578 = +26.4 ° , [o ] 546 = +29.8° , c = 2.1 CH 2 C1 2 ) ; - ( - ) -2- (benzylthio ) -methyl-3 , 5-dicarboethoxy-4- ( 3-nitro¬ phenyl ) { [OQ Ό = -26.3 ° , [e<] ] 578 = -27.2° , [o0 546 = -30 .4 ° , c = 2.8 CH 2 C1 2 ) ; and the following disubstituted 1, 4-dihydropyridines :

- (+ ) -2- (benzylthio ) -methyl-3-carboethoxy-5-carbomethoxy-4 ( 3-nitrophenyl ) -6-f luorome thy 1-1 , 4-dihydropyridine ;

- ( - ) -2- ( benzylthio ) -methyl-3 , 5-dicarboethoxy-4- ( 3-nitro¬ phenyl ) -6-f luorome thyl-1 , 4-dihydropyridine ;

- ( + ) -2- (2-aminoethylthio ) -methy 1-3-c arboethoxy-5-carbome- thoxy-4- ( 3-nitrophenyl ) -6-f luorome thyl-1 , 4-dihydropyridi- ne ;

-(-)-2-(2-am noethylth o)-methyl-3-carboethoxy-5—carbome¬ thoxy-4-(3-nitrophenyl)-6-fluoromethyl-1,4-dihydropyridi¬ ne; -(+)-2-(2-N-formylaminoethylthio)-methyl-3-carboethoxy-5- carbomethoxy-4-(3-nitrophenyl)-6-fluoromethy1-1,4-dihydro¬ pyridine;

-(-)-2-(2-N-formylaminoethylthio)-methyl-3-carboethoxy-5- carbomethoxy-4-(3-nitrophenyl)-6-fluoromethyl-1,4-dihydro- pyridine; -(+)-2-(2-aminoethylthio)-methyl-3,5-dicarboethoxy-4-(3- -chlorophenyl)-6-formyl-1,4-dihydropyridine; -(-)-2-(2-aminoethylthio)-methyl-3,5-dicarboethoxy-4-(3- -chlorophenyl)-6-formyl-1,4-dihydropyridine; -(+)-2-(2-N-formylaminoethylthio)-methyl-3-carboethoxy-5- nitro-4-(3-pyridinyl)-6-diethoxymethyl-1,4-dihydropyridi- ne; *

-(-)-2-(2-N-formylaminoethylthio)-methy1-3-carboethoxy-5- nitro-4-(3-pyridinyl)-6-diethoxymethyl-l,4-dihydropyridi¬ ne; -(+)-2-(benzylthio)-methy1-3-carboethoxy-5-(2-methoxyetho- xy)-4-(3-thienyl)-6-cyano-l,4-dihydropyridine; -(-)-2-(benzylthio)-methyl-3-carboethoxy-5-(2-methoxyetho- xy)-4-(3-thienyl)-6-cyano-l,4-dihydropyridine; * -(+)-2-(2-aminoethylthio)-methyl-3,5-dicarboethoxy-4-(3- -chlorophenyl)-6-cyano-l,4-dihydropyridine;

-(-)-2-(2-aminoethylthio)-methyl-3,5-dicarboethoxy-4-(3- chlorophenyl)-6-cyano-l,4-dihydropyridine; -2-(2-aminoethylthio)-methy1-3-carboethoxy-5-carbomethoxy -4-phenyl-6-methyl-l,4-dihydropyridine. EXAMPLE 19

Under inert gas atmosphere, a stirred suspension of (+)-2-(2-chloroethyl)-3-carboethoxy-5-carbomethoxy-4-

(2,3-dichlorophenyl)-6-methyl-l,4-dihydropyridine (g 6.4), thiourea (g 1.5) in N-methylpyrrolidone (ml 25) is heated at 95-105°C to give a complete solution. 20 minutes after, the mixture is cooled to 40-50°C, diluted with AcOEt (40 ml) and filtered to obtain g 6.2 of (+)-S-[ (6-methyl-3-carboethoxy-5-carbomethoxy-4-(2,3-di¬ chlorophenyl)-1,4-dihydropyridin-2-yl)ethyl]-isothiouro- nium chloride.

In a period of 15 minutes, finely powdered NaHC0 3 is added to a vigorously stirred suspension of the isothiouronium salt, in AcOEt/water (60ml/20 ml); the mixture is stirred to obtain a complete dissolution of the reagents. The aqueous phase is eliminated; after the usual work-up from the organic phase g 5.6 of (+)-S-[(6-methy1-3-carboe hoxy-5-carbomethoxy-4-(2,3-di¬ chlorophenyl)-1,4-dihydropyridin-2-yl)ethyl]-isothiourea are obtained by crystallization from Et 2 0/MeOH. A solution of the thiourea in acetonitrile (50 ml) -- is treated with (L)-mandelic acid (g 2.05) to obtain 2.3 g of (+)-S-[ (6-methy1-3-carboethoxy-5-carbomethoxy-4- -(2,3-dichlorophenyl)ethyl]-isothiouronium L-mandelate.

Under inert gas atmosphere, a stirred solution of this salt in DMF (10 ml) is treated with KHC0 3 (g 0.8) and after 10 minutes, with a Ni Raney suspension (g 10 of an aqueous suspension) in DMF (10 ml). After an hour at room temperature, the mixture is filtered on "celite", the filtrate is concentrated under vacuum to a small volume (5 ml), diluted with water (50 ml) and extracted

with AcOEt (4 x 10 ml). After the usual work-up, by evaporation of the solvent and crystallization from Et 2 0, g 1.1 of (+)-2-ethyl-6-methyl-3-carboethoxy-5-carbome- thoxy-4-(2,3-dichlorophenyl)-1,4-dihydropyridine are ob- tained. Using in the same procedure the enantiomer (D)-mandelic acid, (-)-2-ethyl-6-methyl-3-carboethoxy-5- -carbomethoxy-4-(2,3-dichlorophenyl)-1,4-dihydropyridine is obtained. EXAMPLE 20 Under inert gas atmosphere, a solution of (-)-2- -[(1,4,5,6-tetrahydropyrimidin-2-yl)thioJmethyl-3-carboe- thoxy-5-carbomethoxy-4-(3-trifluoromethylphenyl)-6-methyl

-1,4-dihydropyridine (g 6.5) in EtOH (ml 20) and Kffbθ 3 (g v 0.4) is added dropwise to a stirred Ni-Raney suspension (g 13) in EtOH. After 30 minutes, the solution" is filtered, evaporated to dryness under vacuum and the residue is partitioned between AcOEt (ml 30) and water.

1.9 g of (-)-2,6-dimethyl-3-carboethoxy-5-carbome- thoxy-4-(3-trifluoromethylphenyl)-1,4-dihydropyridine, m.p. 134-135°C are obtained from the organic phase after the usual work-up and crystallization from Et 2 0. EXAMPLE 21

Desulfuration, with Ni-Raney (g 10) suspended in DMF (ml 10), of a solution of KHC0 3 (g 0.67) and of 3 g of (-)-S-[6-methyl-3-carboethoxy-5-carbomethoxy-4-(2,3-di¬ chlorophenyl)-1,4-dihydropyridin-2-yl)methy1]-isothiouro¬ nium L-0,0•-dibenzoyltartrate in DMF (ml 10) at room temperature for an hour produces g 1.09 of (-)-2,6-dime- thyl-3-carboethoxy-5-carbomethoxy-4-(2,3-dichlorophenyl)- -1,4-dihydropyridine (m.p. 140-141°C [oU D - -4.4°, c =

4 .1 , CH 2 C1 2 ) .

EXAMPLE 22

Under nitrogen atmosphere and stirring, a MeOH solution (15 ml) of g 0.85 of (+)2-ethylthiomethyl-3- carboethoxy-5-carbomethoxy-4-(3-chlorophenyl)-6-methyl-

1,4-dihydropyridine, cooled at 30°C is treated with NaH 2 P0 4 (g 1.45) and with Na/Hg amalgam (2.64 g) (10% in Na). After 15 minutes the solution is filtered and evaporated to a small volume under vacuum. The residue is partitioned between water (ml 20) and AcOEt (3 x 30 ml), the organic phases are collected to give after the usual work-up 0.56 g of (+)-2,6~dimethyl-4-(3-chlorophenyl)-3- -carboethoxy-5-carbomethoxy-l,4-dihydropyridine Wi n - +5.5°; c = 4.1 CH 2 C1 2 . EXAMPLE 23

Under nitrogen atmosphere, a stirred solution of (+)-2-ethylthiomethyl-3-carboethoxy-5-allyloxycarbonyl-4- (2,3-dichlorophenyl)-methy1-1,4-dihydropyridine (g 1.1), ammonium formate (g 0.4), triphenylphosphine (g 0.02) in dioxane (15 ml) is treated with 10% Pd on C (0.03 g) and heated at the reflux temperature for an hour. The mixture is filtered, concentrated to a small volume, diluted with ice (10 g) and NaOH IN (30 ml) and finally extracted with AcOEt (2 x 8 ml). The organic extracts are eliminated while the aqueous phase is acidified with H 2 S0 4 2N to pH 12. A precipitate (g 0.78) of (+)-2-ethylthiomethyl-3- -carboethoxy-5-carboxy-4-(2,3- dichlorophenyl)-6-methyl- -1,4-dihydropyridine is collected by filtration and dried under vacuum. EXAMPLE 24

Under an inert gas atmosphere, a stirred aqueous suspension of Ni-Raney (3g) is added to a solution of g 1.5 of (-)-S-[6-methyl-3-carbomethoxy-5-nitro-4'-(2-tri- fluoromethylphenyl)-1, -dihydropyridin-2-yl)methyl]iso- thiourea in DMF (12 ml). After 20 minutes ≥t room temperature, the mixture is filtered, diluted with water, acidified with H 2 S0 4 2N to pH 2.3 and extracted with AcOEt (3 x 20 ml). After usual working of the organic phase, g 1.04 of (-)-2,6-dimethyl-3-carbomethoxy-5-nitro- -4-(2-trifluoromethylphenyl)-l,4-dihydropyrid±ne m.p. 131-133°C, [o] D = -22.1, [«0 546 • = -32.7 (c -~ 1.88 dioxane) are obtained. EXAMPLE 25

Using in the procedure of example 24, the (-)-S-[6- -methyl-3-carbomethoxy-5-nitro-4-(2-trifluoromethylphe- nyl)-1,4-dihydropyridin-2-yl)methyl]-isothiouronium * 0,0- -dibenzoyl-L-tartrate (m.p. 163-164°C; [dL] O = -72, c = 2.03 MeOH) and the following isothioureas: (-)-S-[6-methyl-3-carbomethoxy-5-nitro-4-(3-nitrophenyl)- l,4-dihydropyridin-2-yl)methyl]-isothiourea and (-)-S-[6- -methyl-3-carboethoxy-5-carbomethoxy-4-(3-nitrophenyl)-1, 4-dihydropyridin-2-yl)methyl]-isothiourea the followings: (+)2,6-dimethyl-3-carbomethoxy-5-nitro-4-(2-trifluorome- thylphenyl)-1,4-dihydropyridine m.p.65-70 β C, [(k3 D = +20.1 (c = 1.91 dioxane); 2,6-dimethyl-3-carbomethoxy-5-nitro- -4-(3-nitrophenyl)-1,4-dihydropyridine and 2,6-dimethyl- -3-carboethoxy-5-carbomethoxy-4-(3-nitrophenyl)-1,4-dihy¬ dropyridine, m.p. 158-159°C; [ø D = +16.3 * , c = 2,1 EtOH, are obtained with a 40-45% yield. EXAMPLE 26

Under nitrogen atmosphere, a stirred solution of ( + )-2-methylthiomethyl-6-methyl-5-carbomethoxy-3-carboe- thoxy-4-(3-nitrophenyl)-1,4-dihydropyridine (g 1.5) in anhydrous 1,2-dimethoxyethane is treated with g 1.6 of trimethyloxonium tetrafluoborate at room temperature for 30 minutes to separate a crystalline precipitate of (+)-S-dimethyl-[6-methy1-5-carbomethoxy-3-carboethoxy-4- -(3-nitrophenyl)-1, -dihydropyridin-2-yl]-methylsulphoxo- niu tetrafluoborate (g 1-8, m.p. 165-166°C). EXAMPLE 27

Using in the procedure of example 26 2-alkyl- thiomethyl and/or 2-benzylthiomethyl-l,4-dihyropyridines, the following sulphonium salts are also obtained: -(-)-S-methyl,ethyl-[6-methyl-5-cyano-3-carboethoxy-4(3- -nitrophenyl)-1,4-dihydropyridin-2-yl]-methylsulphonium tetrafluoborate,

-(+)-S-methyl,benzyl-[6-methy1-5-nitro-3-carboethoxy-4- (1,4-benzodioxan-5-yl)-1,4-dihydropyridin-2-yl]-methylsul¬ phonium tetrafluoborate, -(-)-S-[N-2-formylamino]ethyl,methyl-[6-methyl-5-carbome- thoxy-3-carboethoxy-4-(3-nitrophenyl)-1,4-dihydropyridin- 2-yl]-methylsulphonium tetrafluoborate. EXAMPLE 28

A solution of sulphonium salts of examples 26 and 27 (for instance a stirred solution of (+)-S-methylbenzyl- -[6-methyl-5-nitro-3-carboethoxy-4-(1,4-benzodioxan-5-yl)- -1,4-dihydropyridin-2-yl]-methylsulphonium tetrafluobora¬ te (g 1.8) in DMSO (ml 16), cooled at 5-10°C, is treated with 0.15 g of sodium borohydride added at small portions. The solution at room temperature is stirred for

further 15 minutes , diluted with water (ml 100) and extracted with AcOEt (3 x 30 ml). From the organic phases, after the usual work-up and crystallization from ethyl ether, g 1-1 of (+)-2,6-dimethyl-5-nitro-3-carboe- thoxy-4-(l,4-benzodioxan-5-yl)-1,4-dihydropyridine are obtained. In the same way, the following compounds are prepared: (+)-2,6-dimethyl-5-carbomethoxy-3-carboethoxy-4-(3-nitro- r" phenyl)-1,4-dihydropyridine; (+)-2,6-dimethyl-5-cyano-3-carboethoxy-4-(3-nitTQphenyl)- 1,4-dihydropyridine; * f

(-)-2,6-dimethyl-5-carbomethoxy-3-carboethoxy-4-(3-nitro phenyl)-1,4-dihydropyridine. EXAMPLE 29 A mixture of (+)-2-methylthiomethyl-6-methyi-5-car- bomethoxy-3-carboe hoxy-4-(3-nitrophenyl)-1,4-dihydropy¬ ridine (g 1.9) and methyl iodide (ml 19) is heated at reflux temperature for 48 hours. After filtration, the solution is evaporated to dryness and the residue is dissolved in DMF (ml 20). The stirred solution, cooled at 0-5°C, is treated with 0.18 g of sodium borohydride, added at small portions. The mixture is then left at room temperature for 30 minutes and diluted frith water (100 ml) and extracted with AcOEt. g 1.6 of (+)-2,6-dimethyl- -5-carbomethoxy-3-carboethoxy-4-(3-nitrophenyl)-1,4-dihy¬ dropyridine, m.p. 158-159°C, fe( D = +16.3 * , 3 546 = +20.5° (c = 2,1 EtOH) are obtained after the usual work-up and crystallization from Et 2 0. EXAMPLE 30 By desulphuration of an enantiomerically pure isc?-

thiourea and/or enantiomerically pure isothiouronium salt prepared in accordance with one of procedures of examples 28 and 19, and/or by desulphuration of an enantiomerical¬ ly pure 2-thioalky1-1,4-dihydroρyridine prepared in ac- cordance with one of the procedures of examples 919, starting from one of the isothioureae and/or isothiouro¬ nium salts prepared in accordance with procedures of example 19-29, the following enantiomerically pure 1,4- -dihydropyridines are prepared: (+)-2,6-dimethy1-3-carboethoxy-5-carbornethoxy-4-(2,3-di¬ chlorophenyl)-1,4-dihydropyridine, m.p. 139-141°C; [ ff Q O = +3.9°, [θ0 546 = -4.9°, c = 4 CH 2 C1 2 ;

2-methyl-3-isopropoxycarbonyl-5-carbomethoxy-4-(2,3-dichl o¬ rophenyl)-6-fluoromethyl-1,4-dihydropyridine, enantiomer (+): ] D =+43°; enantiomer (-): [<?Q Ό =-42.8°, c = 5 DMF; (+)-2,6-dimethyl-3-isoproρoxycarbonyl-5-carbomethoxy-4- -(benzofurazan-4-yl)-1,4-dihydropyridine, (-)2,6-dimethyl-3-carboethoxy-5-carbomethoxy-4-(3-nitro¬ phenyl)-1,4-dihydropyridine, m.p. 158-159° [*U D = -15.8°, c = 2.1 EtOH;

2,6-dimethyl-3-carbomethoxy-5-isopropoxycarbonyl-4-(3-ni trophenyl)-1,4-dihydropyridine, m.p. 133-136°C; enantio¬ mer (+): [øQ D = +22°; enantiomer (-): [Ø( Ώ = -23.5°; EtOH, c = 2.7; (±)-2,6-dimethyl-3-carboethoxy-5-isopropoxycarbonyl-4-(3- nitrophenyl)-1,4-dihydropyridine, m.p. 139-141°C. EXAMPLE 31

At room temperature and under a nitrogen atmosphere, a stirred solution of 13 g of (-)-S-[6-methyl-3-allyl- oxycarbonyl-5-carbomethoxy-4-(3-nitrophenyl)-1,4-dihydro-

pyridin-2-yl]-methylisothiourea in MeOH (ml 120) is treated with methyl iodide (g 4.3) and 15 ml of ' a 10% aqueous solution of NaOH for 4 hours.

The mixture is concentrated to a small volume under vacuum, diluted with water and extracted with AcOEt (3 x 40 ml), to give after the usual work-up g 11.9 of (-)2-methylthiomethyl-6-meth l-3-allyl6xycarbonyl-5-car- bomethoxy-4-(3-nitrophenyl)-l,4-dihydrόpyridine. A stir¬ red solution of this compound in anhydrous 1,2-dimethoxy- ethane (ml 80) is cooled to 0-5°C, and treated with g 12.3 of trimethyloxonium tetrafluoroborate to separate at room temperature after about 45 minutes a precipitate of (_)-s-dimethyl-[6-methyl-3-allyloxycarbonyl-5-carbometho- xy-4-(3-nitrophenyl)-1,4-dihydropyridin-2-yl]-methylsul- phonium tetrafluoborate (g 12.2) that is filtered and dissolved in DMF (ml 60). To the stirred ' solution, cooled to 5-10°C, g 1.3 of sodium borohydride .are added in small portions during a 5 minute period. 45 minutes after, the mixture is diluted with water (ml 340) and extracted with AcOEt. The usual work-up gives g 9.7 of : (-)-2,6-dime- thyl-3-allyloxycarbonyl-5-carbomethoxy-4-(3-nitrophenyl)-

4

-1,4-dihydropyridine.

A solution of 8 g of said compound in dioxane (100 ml) is treated with triphenylphosphine (g 0.15), ammonium formate (g 3.2) and 10% Pd on C (0.25 g) and-the mixture is refluxed for 1 hour. After cooling and filtration, Jhe filtrate is concentrated to a small volume, diluted with water, adjusted to pH 8.2/8.5 with N NaOH and extracted with Et 2 0 (3 x 25 ml) to remove neutral impurities. The basic aqueous phase is acidified with 2N H 2 S0 4 ' o

separate , at a pH 1.2 a crystalline precipitate (g 6.4 ) of (- ) -2 , 6-dime thy l-3-carbomethoxy-5-carboxy-4- ( 3-nitro¬ phenyl) -1, 4-dihydropyridine , m.p. 215-217°C; [ø(] D = -20 ° (c = 0.7 , acetone) . EXAMPLE 32

Using in the procedure of example 30 the enantiomeric isothiourea, the (+)-2,6-dimethyl-3-carbome- thoxy-5-carboxy-4-(3-nitrophenyl)-1,4-dihydropyridine, m.p.214-218°C; [0(] D = +21° (c = 0.7) acetone, is obtained, after drying under vacuum. A solution of 0.8 g of this compound in dichloromethane (ml 10) is reacted with PC1 5 (g 0.42) at 0°C for 15 minutes and then at room temperature for one hour. The mixture is then cooled at 30°C and treated with a solution of 2(N-benzyl,N- -methylamino)ethanol (g 2.89) in methylene chloride to give after usual work-up and column purification (Si0 2 /Et 2 0/AcOEt 90/10), g 0.3 of (-)-2,6-dimethyl-3-car- bomethoxy-5-[2-(N-benzyl-N-methyl)-ethoxy]-carbonyl-4-(3- nitrophenyl)-1,4-dihydropyridine, m.p. 105-107°C; to^l n = -26°, c = 5, MeOH. EXAMPLE 33

A solution of S-[6-methyl-3-terbutoxycarbonyl-5- -allyloxycarbonyl-4-(2,3-dichlorophenyl)-1 ,4-dihydropyri- din-2-yl)-methyl]-isothiouronium L-mandelate (g 6.7), LiOH (g 1.35) and benzyl chloride (g 1.4) in DMF (ml 40) is stirred, under nitrogen atmosphere and at room tem¬ perature, for one hour and is then diluted with a 10% NaH 2 P0 4 aqueous solution (ml 400). After several extractions with Et 2 0 (6 x 25 ml), the combined organic phases are washed with water, dried and evaporated to

dryness. The residue (g 4.97) of 2-benzylthiomethyl-6-me- thyl-3-tertbutoxycarbonyl-5-allyloxycarbonyl-4-(2,3-di¬ chlorophenyl)-1,4-dihydropyridine is dissolved in 1,2-di- methoxyethane (ml 35) and the solution is cooled to 0-3°C and treated with triethyloxonium tetrafluoborate (g 1.7). The precipitate of S-benzyl,ethyl-[6-methyl-3-tertbutoxy- carbonyl-5-allyloxycarbonyl-4-(2,3-dichlorophenyl)-1,4-di- hydropyridin-2yl]-sulphonium (g 5.04) is dissolved in DMF and treated with g 0.4 of sodium borohydride to give g 3.9 of enantiomerically pure 2,6-dimethyl-3-tertbutoxy- carbonyl-5-allyloxycarbonyl-4-(2,3-dichlorophenyl)-1,4-di¬ hydropyridine. EXAMPLE 34

A solution of g 0.7 of (+)-2-ethylthiomethyl-5-car- boxy-4-(2,3-dichlorophenyl)-6-methyl-l,4-dihydropyridine in EtOH (ml 20) and KHC0 3 (g 0.21) is added to a stirred Ni-Raney suspension in EtOH (ml 10). After 30 minutes the catalyst is filtered, the filtrate is concentrated to a small volume, diluted with water and acidified to IpH 12 with H 2 S0 4 2N * τhe crystalline precipitate of (+)-2,6-dimethyl-3-carboethoxy-5-carboxy-4-(2,3-dichloro¬ phenyl)-6-methyl-l,4-dihydropyridine (g 0.47) is collec¬ ted by filtration and dried under vacuum. EXAMPLE 35 Using in procedures of examples 23, 31-34 a suitable allylester of 3 and/or 5-carboxy-l,4-dihydropyridiιie, the following enantiomerically pure carboxylic acids are obtained: 2,6-dimeth 1-3-carbomethoxy-5-carboxy-4-(3-nitrophenyl)- -1,4-dihydropyridine,

2 , 6-dimethyl-3-carboethoxy-5-carboxy-4- ( 2-ni trophenyl ) - -1 , 4-dihydropyridine ,

2-methyl-6-f luorome thy 1-3-carboe thoxy-5 -carboxy-4- ( 3-ni¬ trophenyl ) -1 , 4-dihydropyridine , 2-methyl-6-f luorome thyl-3-carboethoxy-5-carboxy-4- ( 2-ni- trophenyl ) -1 , 4-dihydropyridine ,

2-methyl-6-f ormyl-3-c arboe thoxy-5-carboxy-4- (3-nitrophe¬ nyl ) -1 , 4-dihydropyridine , 2 , 6-dime thy 1-3-carbome thoxy-5-carboxy-4- ( 3-methoxyphenyl ) -1,4-dihydropyridine, m.p. 235-236°C; enantiomer ( + ) [ C ( Ό

= +1.5°; enantiomer (-) [o(] D = -1.7° (c = 5 DMF), 2 , 6-dime thyl-3-carbomethoxy-5-carboxy-4- (3-chlorophenyl ) - 1,4-dihydropyridine, m.p. 213°C; enantiomer ( + ) [e3 D •= +9.5°, enantiomer (-) [o(3 D = -7.5°; c = 4.7 DMF, (+)-2, 6-dimethyl-3-carboxy-5-nitro-4-( 3-pyridinyl) -1,4-di¬ hydropyridine ,

2 , 6-dime thyl-3-carbomethoxy-5-carboxy -4- (benzofurazan-4- yl ) -1 , 4-dihydropyridine , , 6-dime thy 1-3-carbome thoxy-5-carboxy-4- (benzodioxan-5yl ) -1,4-dihydropyridine,

2 , 6-dime hyl-3-carbomethoxy-5-carboxy -4- (benzodioxan-6- -yl ) -1 , 4-dihydropyridine ,

(-)-2 , 6-dime thy l-3-isopropoxycarbonyl-5-carboxy-4- ( 3-ni¬ trophenyl) -1,4-dihydropyridine, m.p. 194-195 °C; [<j(] D = -30°, c = 5 DMF,

2 , 6-dim thyl-3-carboxy-5-cyano-4- ( 2 , 3-dichlorophenyl ) -1 , 4 -dihydropyridine ,

2 , 6-dime thyl-3-carboxy-5-nitro-4- ( 2 , 3-dichlorophenyl ) -1 , 4 -dihydropyridine , 2 , 6-dimethyl-3-terbutoxycarbonyl-5-carboxy-4- ( 2 , 3-dichlo-

rσphenyl)-1,4-dihydropyridine.

The above compounds, if desired, are then transfor¬ med into an activated form of said carboxylic acids (mixed anhydrides, chlorides, imidazolides, hydroxysucci- nimide esters) and then reacted with a suitable primary and/or secondary amine and/or with a suitable alcohol to obtain amides and esters of said acids." EXAMPLE 36

Under inert gas atmosphere, a stirred solution of (+)-[(6-methyl-3-carboethoxy-5-carbomethoxy-4-(3-nitro¬ phenyl)-1,4-dihydropyridin-2-yl)methyl]isothiouronium L-mandelate (g 1) in DMF (ml 7) is added dropwdj.se to a Ni-Raney suspension (g 10) and KHC0 3 (g 0.19) in DMF (ml 3). After 1 hour the solution is filtered, added with water (ml 200) and extracted with AcOEt (3 x 40 ml). The organic phase obtained is washed with water (3 x 100 ml),

~ r anidried on N 2 S0 4 and the solvent is evaporated under reduced pressure. The crude mixture, recrystallized from Et 2 0 gives mg 430 of (-)-2,6-dimethyl-3-carboeth>xy-5- -carbomethoxy-4-(3-aminophenyl)-l,'4-dihydropyridine, m.p. 176-179°C, [o ] D = -6.08°, kϋ 578 = -7.00°, t*3 54 g = -7.3° (c = 2.4 CH 2 C1 2 ) . EXAMPLE 37

Under inert gas atmosphere and under stirring, a suspension of Ni-Raney (g 4) in acetone (15 ml) is heated to reflux for 2 hours. After cooling* at room temperature a solution of (-)-[(6-methy1-3-carboethoxy-5-carbometho¬ xy-4-(3-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]-iso- thiourea (g 1.5) in acetone (ml 10) is added to* it; the mixture is stirred for 2 hours, filtered and evaporated

to dryness. The residue is partitioned between AcOEt (ml

30) and aqueous H 2 S0 4 4N; the organic phase is extracted several times with aqueous H 2 S0 4 4N (8 x 5 ml), with water to neutrality and then dried on Na 2 S0 4 . By evaporation of the solvent and subsequent crystallization from Et 2 0, g 0.65 of (+)-2,6-dimethyl-3-carboethoxy-5- -carbomethoxy-4-(3-nitrophenyl)-1,4-dihydropyridine [ P D = +16.3°, c = 0.7 EtOH are obtained.

The acid extracts are combined and alkalinized to pH 7-8 with aqueous NaOH 2N solution and extracted with AcOEt (3 x 20 ml). After the usual work-up, g 0.42 of (+)-2,6-dimethyl-3-carboethoxy-5-carbomethoxy-4-(4-amino- phenyl)-1,4-dihydropyridine ([o ] D = +7°, c = 2.3 CH 2 C1 2 ) are obtained from the organic phase. Subsequent acetylation gives:

(-)-2,6-dimethy1-3-carboethoxy-5-carbomethoxy-4-(3-acetyl - aminophenyl)-1,4-dihydropyridine [#3 D = -1«1° / c = 2.3 DMF. EXAMPLE 38 Under inert gas atmosphere Ac 2 0 (43 mcl) is added to a stirred solution of (-)-2,6-dimethyl-3-carboethoxy-5- -carbome hoxy-4-(3-aminophenyl)-1,4-dihydropyridine (100 mg) in pyridine (ml 1). 90 minutes after dilution with water (ml 50), extraction with AcOEt (3 x 10 ml) and crystallization from Et 2 0 70/EtOH 10, give mg 85 of (+)-2,6-dimethyl-3-carboethoxy-5-carbomethoxy-4—(3-acetyl- aminophenyl)-1,4-dihydropyridine m.p. 197-199°C te r) = +0.87°, [e(] 578 = +2.00°, [<<] 54 g = +1.64° c = 2.2 DMF. EXAMPLE 39 Under inert gas atmosphere 4N aqueous NaOH (ml 1.93)

are added to a stirred solution of (+)-[(6-methyl-3-car- boethoxy-5-carbomethoxy-4-(2,3-dichlorophenyl)-l,4-dihy- dropyridin-2-yl)-methyl]isothiouronium-0,0'-dibenzoyl-D- -tartrate (g 0.7) and triethylbenzylammonium chloride (mg 60) in benzene (ml 7). After 5 minutes, the mixture is heated with acetic acid to pH 5, the organic phase is separated, washed with water (3 x 5 ml), dried on Na 2 S0 4 and the solvent is evaporated under reduced pressure. The crude residue is purified by Si0 2 gel chromatography (30/1; eluent CHCl 3 90/hexane 20), to give 240 mg of (+)-2-mercaptomethyl-3-carboethoxy-5-carbomethoxy-4-(2,3- -dichlorophenyl)-1,4-dihydropyridine, oil [<- D = +17.86°, [ 0 U578 = 19.47°, [θ0 546 = +25.12°, c = 2.8 CH 2 Cl 2 . EXAMPLE 40 Under inert gas atmosphere, a stirred solution of (-)-[(6-methyl-3-carboethoxy-5-carbomethoxy-4-(2,3-dichlo¬ rophenyl)-1,4-dihydropyridin-2-yl)-methyl]-isothiouronium -0,0 f -dibenzoyl-L-tartrate (g 0.55) and triethylbenzylam¬ monium chloride (mg 46) in benzene (ml 6) is treated with ml 1.5 of aqueous NaOH 4N, after 5 1 ith glaciali AcOH up to pH 5. The organic phase is separated,washed with water

(3 5 ml), dried on Na 2 S0 4 . The crude residue is treated

-, in pyridine (6 ml) with mcl 95 of Ac-,0. 40' afteϊj, the reaction mixture is diluted with water (m •l -l10 * 0), extracted with Et 2 0 (3 x 10 ml); the combined organic i<t. phases are washed with water (5 x 20 ml), dried on

Na 2 S0 4 . After removal of solvent in vacuum the crude residue is crystallized from hexane/Et 2 0 50/10, tyo give mg 240 of (-) -2-acetylthiomethyl-3-carboethoxy-5-carb |rιe- thoxy-4- ( 2 , 3-dichlorophenyl ) -1 , 4-dihy dropyridine , m.p .

155-157°, [oU D = -16.8°, [<JU 578 = -18.44°, fot] 546 = -24.45°, c = 2.5 CH 2 C1 2 . EXAMPLE 41

A suspension of 2-methylthiomethyl-6-methyl-4-(3-ni- trophenyl)-3-carboethoxy-5-carboallyloxy-l,4-dihydropyri¬ dine (g 0.27), palladium on charcoal (10% 6 mg) , ammonium formate (mg 71) and triphenylphosphine (mg 3) in anhy¬ drous 1,4-dioxane, is heated at the reflux temperature for 8 hours. The reaction mixture is cooled at room temperature, poured into an aqueous solution of hydrochloric acid (pH = 2) and extracted with ethyl acetate (2 x 20 ml). The combined organic extracts are washed with agueous sodium carbonate (IN; 3 x 10 1), the basic washings are collected, acidified to pH 5-6 with diluted aqueous hydrochloric acid. The resulting suspension is extracted with ethyl acetate (2 x 25 ml) the combined organic extracts are dried on Na 2 S0 4 and evaporated under reduced pressure to give mg 160 of 5-carboxy-2-methylthiomethyl-6-methyl-4-(3-nitrophenyl)-3 -carboethoxy-1,4-dihydropyridine as an amorphous solid.

NMR {$, CDC1 3 ) 10,5 (sb, 1H) 8,3-8,0 (m, 2H) 7,7-7,4 (m, 2H) 7,2 (sb, 1H) 5,2 (s,lH) 4,3-4,0 (2 q, 4H) 2,4 (s, 3H) 2,0 (s, 3H) 1,25 (t, 3H). M + 393. EXAMPLE 42 A sample of (+) tertbutyl,allyl 2,6-dimethyl-4-phe- nyl-l,4-dihydropyridine-3 ,5-dicarboxylate is treated in dioxane with 10% Pd on C, ammonium formate and triphenyl- phospine to give (+)-tertbutyl 2,6-dimethy1-4-phenyl- -5-carboxy-l,4-dihydropyridine-3-carboxylate. 4-morpholino-ethyl-isonitrile ( 0.63 ml) is added to

a stirred solution of 1,5 g of said acid and 0.86 "-g of N-hydroxysuccinimide in dry THF ( 15 ml), cooled at 0°C. The mixture is stirred at room temperature for 30 min. , diluted with aqueous N HCl, concentrated in vacuum and extracted with AcOEt to give after the usual work-up a sample of 2,6-dimethyl-4-phenyl-3-tert-butoxycarl * nyl-5- -carboxy-1,4-dihydropyridine N-hydroxysuccinimido ester. By reaction in DMF of said ester with N-methylpiperazine for an hour at room temperature, dilution with" water and usual work-up of the reaction mixture gives B-methy1,N'- -(2,6-dimethyl-4-phenyl-3-tertbutoxycarbonyl-l,4-dihydro- pyridin-5yl)-carbonyl-piperazine. EXAMPLE 43

A sample of (+) tertbutyl-2,6-dimethyl-4-phenyl-5- -carboxy-1,4-dihydropyridine-3-carboxylate ii * reacted with an ethereal solution of diazomethane to give a sample of (+) tertbutyl,methyl 2,6-dimethyl-4-phenyl-l,4- -dihydroρyridine-3,5-carboxyla e. To a stirred solution of said diester ( 1.5 g) in chloroform (15 ml), cooled at -12°C, dropwise is added a chloroform (4 ml) solution of trimeth lsilyl iodide ( 0.53 ml) in an hour. The mixture is maintained for a further hour at 0°C, diluted with aqueous Na 2 S0 3 , acidified with 2N HCl and diluted with water. A white crystalline precipitate of methyl 2,6-dimethyl-4-phenyl-3-carboxy-l,4-dihydropyridine-5-car- boxylate ( 1.14 g) is filtered.

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