I. Description:

TECHNICAL FIELD

This invention relates to new and useful N-cyano-N'- phenylcarboxami dines and to their chemical method of preparation. More particularly, the instant invention is concerned with use of the novel carboxamidine compounds as starting material for a one-step synthesis of antihypertensive agents such as the various 4-amino-2-(4-substituted piperazine-1-yl) quinazolines described in U.S. Patents 3,511,836; 3,669,968; 4,001,237;

4,001,238; co-pending U.S. patent application Serial No. 770,966, filed February 22, 1977; and the 2-(4-substituted homopiper- azino)-4-amino-6,7-dimethoxy-quinazolines of U.S. Patent 3,920,636.

BACKGROUND OF PRIOR ART

F. H. S. Curd, et al., J. Chem. Soc, 1759 (1948) describes a procedure for the preparation of 2,4-dichloroquinazolines. As illustrated below, the Curd, et al. process involves cyclization of an ortho-ureido derivative (1) of various aromatic acids, amides, nitriles and esters with aqueous base or acid to form a 2,4-(lH,3H) quinazolinedione (2) which is chlorinated to the 2,4- _^ dichloroquinazoline (3).

-2-

(3)

The foregoing procedure of Curd, et al. had been employed in the preparation of various quinazolines disclosed in Hess, U.S. Patents 3,511,836 and 3,669,568; Cronin, U.S. Patent 3,517,005; Partyka, et al., U.S. Patents 4,001,237 and 4,001,238 and U.S. Patent Application Serial No. 659,059.

Hess U.S. Patent 3,935,213 describes a process for preparing quinazolines illustrated b formula (6) which involves the use of compounds of formulas (4) and (5) as set forth below.

(A) (5) ⁽ 6)

OM

"

German Patent 2,261,739 (1974) (See Che . Abs. 81_, 84394q (1974)) discloses the following synthesis of quinazolin-2,4-diones:

0

Z. Budesinsky, et al., Coll. Czech. Chem. Commun., 37. _> 2779 (1972) report that treatment of l-aryl-3-acyl ureas (7) with polyphosphoric acid yields 4-aroyl (or alkyl )-2-(lH)-quin- azo

W. Ried, et al., Chem. Ber. , 109, 2706 (1976) (Chem. Abs. (1976)) describes the reaction of chloroformami dines of formula (9) with cyanamide derivatives of formula (10) to yield 4-amidino-quinazolines of formula (11).

The process of the instant invention for preparing quinazolines characterized by formula (I) below and the Ried, et al. procedure set forth above differ significantly in a number of respects. In the Ried, et al. procedure, the cyaπo nitrogen in the cyanamide derivative (10) becomes part of the quinazoline ring (i.e., the number 3 position) whereas in the instant invention, the cyano nitrogen of cyanamide becomes the 4-amino group attached to the quinazoline ring.

10 BRIEF SUMMARY OF INVENTION

Broadly described, this invention is concerned with a new process for the preparation of antihypertensive quinazolines generally typified by formula I

The instant process invol ves a one-step conversion of novel 15 piperazinyl substi tuted N-cyano-N ' -phenylcarboxamidines to formula I quinazol ine products .

DETAILED DESCRIPTION OF INVENTION

20 As indicated hereinabove, one aspect of the instant invention- is concerned with a process for preparing quinazol ine compound of formula I

wherein n is equal to 2 or 3; A is hydrogen or lower alkoxy of 1 to 4 carbon atoms inclusive;

B and C are independently selected from the group consisting of lower alkoxy of 1 to 4 carbon atoms inclusive;

is selected from the group consisting of lower alkyl of ^' from 1 to 6 carbon atoms inclusive; R^CO in which R~ is cycloalkenyl, cycloal yl, methylcycloal yl in which cycloalkyl and cycloalkenyl are from 3 to 8 carbon atoms inclusive; hydroxyalkoxy from 2 to 6 carbon atoms inclusive or phenyl ; and ZC=0 in which Z is a hetero- cyclic radical selected from the group consisting of-

in which X is either oxygen or sulfur, R is lower alkyl of 1 to 6 carbon atoms inclusive, R. is selected from the group consisting of hydrogen,

a ino, lower alkyl of 1 to 4 carbon atoms inclusive and NHCO ^-R in which R_* is lower alkyl of 1 to 4 carbon atoms inclusive, R. and are independently selected from the group consisting of hydrogen, 5 lower alkyl of 1 to 6 carbon atoms inclusive, lower alkoxy of 1 to 6 carbon atoms inclusive, and lower alkyl thiσ of 1 to 6 carbon atoms inclusive

which comprises cyclizing a cyanocarboxamidine of formula II

wherein the symbols "A, B, C, n and R, are as recited above.

10 Preferred embodiments of the foregoing process for the preparation of compounds characterized by formula I are those wherein;

(a) The compound of formula II employed in 4-methyl- piperazine--l-[N-cyano-N'-(3,4-dimethoxyphenyl)]-

15 carboxam dine;

(b) The compound of formula II employed is 4-(2-furoyl)- piperazine-l-[N-cyano-N'-(3,4-dimethoxyphenyl)l- carboxam dine;

(c) The compound of formula II employed is 4-(5-meth lthio- 20 l,3,4-oxadiazole-2-carbonyl)piperazine-l-[N-cyano-N'-

(3, -dimethox pheny1)]carboxamidine;

(d) The cyclization process is carried out by treating the compound of formula II with phosphorus trichloride or phosphorus pentachloride in a solvent amount of phosphorus oxychlόride; (e) The cyclization process is carried out by treating the compound of formula II with phosphorus tribromide or phosphorus pentabro ide in a solvent amount of phosphorus oxybro ide;

(f) The cyclization process is carried out by treating the compound of formula II with aqueous hydrochloric acid;

(g) The cyclization process is carried out by treating the compound of formula. II with hydrogen chloride in phosphorus oxychloride; (h) The cyclization process is carried out by treating the compound of formula II with a ewis acid catalyst; (i) The cyclization process is carried out at a temperature of 25-125°; (j) The cyclization process is carried out at a temperature of 70-100°;

(k) The cyclization process is carried out for a period of 1 to 3 hours ^' at a temperature in the range of 70-100°.

A preferred embodiment of the present invention is a process he preparation of a quinazoline of formula la

which comprises cyclizing a cyanocarboxamidine having formula I la

Another preferred embodiment of the present invention is the process for the preparation of a quinazoline of formula lb

which comprises cyclizing a cyanocarboxamidine having formula lib

Another preferred embodiment of the present invention is a process for the preparation of a quinazoline of formula Ic

OMP

which comprises cyclizing a cyanocarboxamidine having formula He

Another preferred embodiment of the present invention is the process for the preparation of a quinazoline of formula Id

0CH ₃

which comprises cyclizing a cyanocarboxamidine having formula Ild

Preferred groups of compounds contemplated within the class of cyanocarboxamidines of formul II are those wherein:

(a) the A, B and C substituted phenyl radical is 3,4- di ethoxyphenyl, n is 2, or 3 and R, is selected from the group consisting of methyl, cyclopentyl, 2-furoyl , 5-methylthio-l ,3,4-oxadiazole-2-carbonyl , 2-methyl -2-hydroxypropoxycarbonyl ;

(b) The A, B and C substituted phenyl radical is 2,3,4- tri ethoxyphenyl , n is 2 or 3 and R, is selected from the group consisting of methyl, cyclopentyl

2-f uroy 1 , 5-methyl thi o-l , 3 , -oxadi azol e-2-carbonyl , 2-meth l -2-hydroxypropoxycarbonyl .

Particularly prepared cyanocarboxami dines of formula II are :

4-methyl pi perazi ne-1 - [N-cyano-N ' - (3 ,4-dimethoxyphenyl ) ] - carboxamidine;

4- (2-f uroyl ) pi perazi ne-1 - [N-cyano-N ' - ( 3 , -di methoxy- phenyl ) ] car box ami di ne ;

4- ( 5-methyl thi o-l , 3 , 4-oxadi azol e- -carbony 1 ) pi perazi ne-1 -

[N-cyano-N' -(3,4-dimethoxyphenyl )] carboxamidine; 4- ( 2-methyl -2-hydroxypropoxycarbonyl ) pi perazi ne-1 - [N-cyan

N' -( ,3,4- tri e thoxyphenyl )] carboxamid ne;

4- (cycl opentyl carbonyl ) pi perazi ne-1 - [N-cyano-N '-(3,4- di me thoxyphen l ) ] carboxami di ne ;

4- (2-f uroyl ) omopi perazi ne-1 - [N-cyano-N ' - (3 ,4-dimethoxy- phenyl] carboxamidine

It is to be understood that the term "cycloalkyl " as used here includes cycloalkyl radical s containing 3 to 8 ring carbon atoms inclusive and encompasses such groups as cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , cycloheptyl and cyclooctyl . The term "methyl cycloalkyl " refers to the aforementioned cycl oal kyl radical s containing from 3 to 8 ring carbons inclusive having a methyl substi tuent and encompasses such groups as 1-methyl- cyclopropyl , 1 -methyl cycl opentyl , 2-methyl cycl opentyl , 3- e thy! cyc opentyl , 1 -methyl cycl ohexyl , 2-methyl cycl oheptyl , 4-methyl cycl ohexyl , and the like. By the term "cycloalkenyl " , it is intended to refer to those having from 4 to 8 ring carbon atoms inclusive containing a single ring carbon-carbon double bond encompassing such groups as 1-cyclobutenyl , 1-cyclopentenyl , 2-cyclopentenyl , 3-cyclopentenyl , 1-cyclohexenyl , 2-cyclohexenyl , and the like.

It is also to be understood that by the terms "lower alkyl" and "lower alkoxy", as used herein, it is meant that the carbon chain which comprises these groups include both straight and branched carbon radicals of the designated number

of carbon atoms inclusive. Exemplary of carbon chain radicals have 1 to 4 carbon atoms inclusive are methyl, ethyl, propyl, isopropyl, 1-methy!propyl, 2-methylpropyl, and tert.-butyl.

By the term "independently selected", as used herein, it is meant that the recited substituents such as A, B, C, R, and R may or may not be identical.

Conversion of formula II carboxamidines to quinazolines of formula I is carried out by treating the formula II carboxamidines with cyclizing reagents such as phosphorus trichloride or phosphorus pentachloride in a solvent amount of phosphorus oxychloride. Other phosphorus ha!ides and phosphorus oxyhalides such as phosphorus tribromide and phosphorus pentabro ide in a solvent amount phosphorus oxybro ide may be employed. Ring closure of the carboxa idines of formula II to the quinazoline compounds of formula I is acid catalyzed with reagents such as aqueous hydrochloric acid, hydrogen chloride in phosphorus oxychloride, trichloroacetic acid or Lewis acid catalyst such as ZnCl ₂ J FeClg, A Clg, AlBr.,, and the like.

With respect to carrying out the reaction with phosphorus halides, approximately equi olar portions of the formula II carboxamidines and phosphorus halides are employed with a convenient solvent amount of phosphorus oxyhalide relative to the amount of carboxamidine starting material. The term "solvent amount" used herein, refers to a quantity of phosphorus oxychloride or phosphorus oxybromide sufficient to provide good mixing and handling characteristics with respect to the ■ ' reaction mixtures. For this purpose, a ratio of from about 2 to 15 ml. of the phosphorus halide for each gram of the carboxamidine reactant of formula II is generally preferred.

Cot ionly used temperatures for carrying out the cyclization reaction range from about 25-125° with a particularly preferred temperature range of from about 70-100°. As will be appreciated

by those ski l led i n the art, reaction time and conditions required for cycl i zation of the compounds of formul a II and. formation of the compounds of formul a I vary according to several factors such as temperatures and reaction times . For instance , at lower temperatures , long reaction periods are needed, while at higher temperatures , the cycl ization reacti on i s completed in a shorter time. Reaction periods from about 0.5 to 24 hrs . can be used with a period of 1.0 to 3.0 hrs. preferred at a temperature in the range of about 70-100 .

During the cyclization reaction of the. formul a II carbox¬ amidines , the cyano carbon acts as a carbonium ion forming a carbon-carbon bond with the benzene nucleus thereby establ ishing the quinazol ine ring while the cyano ni trogen becomes the quinazoline 4-amino group.

The carboxamidines of formul a II used as starti ng material s in the instant process for preparation of quinazol ine compounds of formul a I are themselves new compounds which are prepared by

(a) treating the corresponding urea or thiourea of ■ formula III

wherein the symbols "A, B, C, n, and R," are as recited above and Y is sulfur or oxygen with an R-X alkylating reagent in which R is lower alkyl

of 1 to 4 carbon atoms incl usive or an aryl derivati ve containi ng electron wi thdrawing groups (e.g. , 2,4-d nitrophenyl ) , X is halogen (e. g. , Cl , Br, and I) , l ower al kyl SO, of 1 to 4 carbon atoms inclusive, phenyl SO.,, F ₃ CS0 ₃ , and the l ike to provide a hydrohalide intermediate of formula IV

wherein the symbols "A, B, C, n, R, R, , X and Y" are as recited above, and then (b) ^" reacting the halide intermediate IV with cyanamide to provide carboxamidines of formula II.

Alkylation of urea and thiourea starting materials of formula III and subsequent reaction with cyanamide is normally carried out in a reaction inert organic solvent. Suitable solvents include dioxane, tetrahydrofuran, dimethyl sulfoxide, d ethyl sulfoxide, and alkanol solvents such as ethanol, ethanol , or isoa yl alcohol. The reaction can be conducted at temperatures varying within the range of from about 25 to 100°C. for a period of about 0.5 to 24 hrs.

In addition to the above process, al ernate methods for preparing carboxamidines of formula II can be employed as depicted in the reaction schemes below.

Method A

(V)

Formula II

(VI)

Method B

(VII)

Formula II

(VIII)

Thus, reaction of (CH ₃ S) ₂ C=NCN or chemical equivalents thereof with formula V anilides or formula VII piperazines wherein the symbols "A, B, C, n and R," are as previously defined provide cyano intermediates VI and VIII, respectively. Treating the cyano intermediate VI with a piperazine of Formula VII or the cyano intermediate VIII with an aniline of Formula V affords the formula II carboxamidines.

The formula III urea and thioureas are obtained by reacting appropriately substituted phenylisocyanates and phenyl- isothiocyanates with N-substituted piperazines and homopiperazines in an inert reaction solvent such as ethanol. Required piperazine and homopiperazine starting material is obtained by conventional procedures; e.g. acylation of piperazine or homopiperazine with

Q

ZCCl wherein Z is as previously defined.

In addi tion to being useful intermediates i n the preparation of the compounds of formul a I , the carboxamidines of formula II are also valuable for their anti -ulcer properties , for instance, 4- (2-furoyl )pi perazi ne-1- [N-cyano-N ¹ - (3, 4-dime thoxyphenyl )] - carboxamidine and 4- (5-methyl thi o-l ,3,4-oxadiazole-2-carbonyl )- pi perazi ne-1 - [N-cyano-N ¹ -3, 4-dimethoxyphenyl ] carboxami dine at a subcutaneous dose of 10 g/kg and 3 g/kg body weight, respectively, inhi bit acid secretion i n the pylorus l i gated rat model of Shray, Gastroenterol ogy, 5_, 43 (1946) .

The fol lowing examples further illustrate the present invention and wil l enable others ski lled in the art to understand i t more completely. It is to be understood that the invention is not l imi ted solely to the particular examples given below. Al l temperatures expressed herein are in degrees centri grade.

Example 1

4-Methylpiperazine-1-[N-cyano-N'-(3,4-dimethoxypheny1)1 carboxamidine

(a) A solution of 3,4-dimethoxyphenyl isothiocyanate 5 (6.8 g., 34.8 rrmoles) obtained according to the procedure of G. M. Dyson, et al., J. Chem. Soc, 436 (1927) in 34 ml. of absolute ethanol is added to a stirred solution of N-methyl- piperazine (3.49 g., 30.8 πrnoles) in 100 ml. of absolute ethanol. After heating the solution of reflux for a 2 hr.

10 period, the solvent is removed under reduced pressure. The semi-solid residue thus obtained is first crystallized from toluene to provide 8.95 g. (87% yield), m.p. 156-159.5° of the carbothioamide intermediate. Crystallization of this material from nitro ethane affords analytically pure 4-

15 methyl pi perazi ne-l-(N-3,4-dime thoxyphenyl ) carbothioamide, m.p. 158-161°.

Anal-. Calcd. for C H ₂₁ N ₃ 0 ₂ S: C, 56.92; H, 7.16; N, 14.23; S, 10.85. Found: C, 56.74; H, 7.38; N, 14.40; S, 10.90.

(b) Methyl iodide (1.2 g., 0.0303 mole) is added to a 20., suspension of 4-methyl piperazine-l-(N-3, 4-di e thoxyphenyl )- carbothioamide (8.95 g., 0.0303 mole) in 125 ml. of methanol. The reaction mixture is then stirred at reflux temperature for a period of 2 hr. and cooled to 25 . Cyanamide (8.7 g., 0.27 mole) is added to the cooled solution and reflux continued

Bυ E

OMPI W1PO

for an additional 16 hr. period. After the solvent is removed under reduced pressure, residual oil is made strongly basic with acqueous 4.0 N sodium hydroxide and then extracted with chloroform. The chloroform extracts are washed with water, saturated brine solution and dried. Concentration of the dried solution affords a residual gum which when rubbed under cold toluene provides 4.46 g., (49% yield) of crystalline material, m.p. 155-158°. Recrystallization from toluene affords analytically pure 4-methyl pi perazi ne-1- [N-cyano-N ¹ - (3,4-dimethoxyphenyl)] -carboxamidine, m.p. 160-163°.

Anal. Calcd. for C ₁₅ H ₂₁ N ₃ 0 ₂ : C, 59.39; H, 6.98; N, 23.09. Found: C, 58.95; H, 6.83; N, 22.35.

(c) Following the procedure of Example 1(a), but employing an equimolar amount of 3,4-dimethoxyphenylisocyanate in place of 3, 4-dime thoxyphenyl isothiocyanate, there is produced N-(3,4- di me thoxyphenyl ) -4-methyl -1 -pi perazi necarboxa ide. The carboxami de treated with methyl iodide and then with cyanamide according to the procedure of Example 1(b) provides 4-methyl - p i peraz ne-1 - [N-cyano-N '-( 3 , -d me thoxyphenyl )] carboxami di ne .

Example 2

4- (2.-Furoyl)pi perazi ne-1- [N-cyano-N '-(3,4-dimethoxyphenyl)l carboxamidine

(a) A solution of 3,4-dimethoxyphenyl isothiocyanate (3,21 g., 16.4 mmoles) in 10 ml. of absolute ethanol is added to _, a stirred solution of l-(2-furoyl)piperazine (2: 96 g., 16.4 imioles) prepared according to the procedure of M. Desai, et al., Org. Prep. Proced. Int., 8_, 85 (1976) in 35 ml. of absolute ethanol and the reaction solution refluxed for a period of 2.5 hr. Concentration of the reaction mixture under reduced pressure provides a dark yellow gum which rubbed under cold ethanol affords 5.39 g., (87% yield) of yellow solid material, m.p. 183-187°. Crystallization of this material from acetonitrile affords analytically pure 4-(2-furoyl)- piperazine-l-(N-3,4-dimethoxypheπyl)-carbothioamidε, m.p. 185-188°.

Anal. Calcd. for C ₁₈ H _{21 3} 0 ₄ S: C, 57.59; H, 5.64; N, 11.19; S, 8.54. Found: C, 57.23; H, 5.48; N, 11.53; S ^' , 8.54.

(b) To a suspension of 4-(2-furoyl)piperazine-l-(N-3,4-dimethox _j - phenyl )carbothioamide (22.0 g., 0.0586 mole) in 400 ml. of methanol is added methyl iodide (8.32 g., 0.0586 mole). The mixture is stirred and refluxed for a period of 2.5 hr. and then cooled to 20°. Cyanamide (18.7 g., 0.445 mole) is added to the cooled solution, and the mixture refluxed for an additional period of 16 hr. and the solvent evaporated under reduced pressure to provide an oily residue which is made strongly basic with aqueous 4.0 N sodium hydroxide. The basic mixture is extracted with chloroform and the chloroform extracts washed first with water and then with saturated brine solution. After drying, the chloroform extract is concentrated under reduced pressure providing a residual gum which is crystallized by rubbing under cold ethanol to afford 11.1 g. (49% yield) of white solid, m.p. 181-183.5°. Crystallization of this material from ethanol provides analytically pure 4- (2-f uroyl) pi perazi ne-1- [N-cyano- N'-(3,4-dimethoxyphenyl)] carboxamidine, m.p. 186.5-188.5 .

Anal. Calcd. for C ₁₉ H ₂₁ N ₅ 0 ₄ : C, 59.52; H, 5.52; N, 18.27. Found: C, 59.13; H, 5.40; N, 18.07.

(c) Following the procedure of Example 2(a), but employing equimolar amount of 3,4-dimethoxypheny.lisocyanate in place of 3,4-

^ URE f OMP WIP

dimethoxyphenylisothiocyanate, there is obtained N-(3,4-dimethoxy- pheπyl ) -4- (2-f uroyl)-! -pi perazi necarboxa ide. Reaction of the carboxami de with methyl iodide and then with cyanamide according to the procedure of Example 2(b) provides 4-(2-furoyl)piperazine-l-[N- cyano-N'-( 3, -dime thoxyphenyl)] carboxami dine.

Example 3

4-(5-Methylthio-1,3,4-oxadiazole-2-carbonyl)piperazine-1- [N-cyano-N'-(3,4-dimethoxyphenyl)]carboxamidine

(a) l-(5-Methylthio-l ,3,4-oxadiazole-2-carbonyl)piperazine hydrochloride (5.29 g., 0.02 mole) is first added to a stirred solution of triethylamine (2.02 g., 0.02 mole) in 50 ml. of absolute ethanol followed in 5 n. by a solution of 3,4-dimethoxyphenyl isothiocyanate (3.90 g., 0.02 mole) in 15 ml. of absolute ethanol to provide a pale yellow gummy precipitate. The reaction mixture is heated to reflux (during which time the gum crystallizes), diluted with 28 ml. of absolute ethanol, refluxed for an additional 3 hr. period and filtered. The collected material is washed with absolute ethanol and crystallized from methanol to provide 4.41 g. (52% yield) of 4-(5-methylthio-l,3,4-oxadiazole-2-carbonyl)piperazine-l-(N- 3,4- dimethoxyphenyl)carbothioamide, m.p. 143.5-147°.

Anal. Calcd. for ₁₇ H ₂₁ N ₅ 0 ₄ S ₂ : C, 48.21; H, 5.00, N, 16.54; S, 15.14. Found: C, 48.28; H, 4.90; N, 16.46; S, 15.19.

(b) Methyl iodide (1.06 g. , 7.44 mmoles) is added to a suspension of 4-(5-methylthio-l,3,4-oxadiazole-2-carbonyl)- piperazine-l-(N-3,4-dimethoxyphenyl )carbothioamide (3.15 g.,

7.44 mmoles) in 100 ml. of methanol. The mixture is stirred at reflux temperature for a period of 2.5 hr. and the resulting

solution concentrated under reduced pressure to a volume of about 60 ml. where a precipitate begins. The mixture is chilled at 0° and filtered to yield 2.93 -g. (70%) yield) of 1 -[methyl thio-[N-(3, 4- dimethoxyphenyl)[iminocarbonyl]-4-(5-mεthylthio-l,3,4-oxadi azole-2- carbonyl) -pi perazi ne hydroiodide, m.p. 180.5-185 (dec). Crystal¬ lization from ethanol provided analytically pure hydroiodide inter¬ mediate, m.p. 184-187° (dec).

Anal.- Calcd. for C _lg H ₂₃ N ₅ 0 ₄ S ₂ HI: C, 38.24; H, 4.28; N, 12.39. Found: 38.49; H, 4.44; N, 12.01.

(c) Cyanamide (0.66 g., 15.7 moles) is added to 1 -[me thy! thi o-

[N- (3, 4-dimethoxyphenyl)]iminocarbonyl] -4- (5-methyl thi o-l ,3,4-oxa- diazole-2-carbonyl)piperazine (2.44 g., 5.58 mmoles) free base in 35 ml. of absolute ethanol. The mixture is stirred at reflux tem¬ perature for a period of 20 hr. , cooled in an ice bath and filtered to provide 1.12 g. (49% yield) of off-white solid, m.p. 175-181°. Crystallization of this material from methanol affords analytically pure 4- (5-methyl thi o-l ,3,4-oxadiazole-2-carbonyl)piperazine-l-[N- cyano-N'-( 3, 4-dime thox phenyl)] carboxami dine, m.p. 174-178 .

Anal. Calcd. for C _lg H ₂₁ N ₇ 0 ₄ S: C, 50.12; H, 4.90; N, 22.73. Found: C, 50.08; H, 4.73; N, 22.57.

(d) Following the procedure of Example 3(a), but employing an equimolar amount of 3,4-dimethoxyphenylisocyanate in place of 3,4-dimethoxyphenylisothiocyanate, there is obtained N-(3,4- dimethoxyphenyl)-4-(5-methylthio-l,3,4-oxadiazole-2-carbonyl )-l- piperazine carboxa ide. Reaction of the carboxamide with methyl - ^' iodide and then with cyanamide according to the procedures of Examples 3(b) and 3(c), respectively, provides 4- (5-methyl thi o-l ,3,4- oxadi azol e-2-carbonyl ) pi perazi ne-1 - [N-cyano-N ' -3 , 4-dime thoxyphenyl ) ] - carboxamidine.

4- (2-Me thy! -2-hydroxypropoxycarbonyl)pi perazi ne-l-[N-cyano- N' -2,3,4- tri methoxypheny 1 ] carboxami di ne

OCH,

Reaction of 2,3,4-trimethoxypheπylisothiocyanate with l-(2- methyl-2-hydroxypropoxycarbony!)piperaziπe according to the procedure of Example 1(b) provides 4- (2-methyl -2-hydroxypropoxycarbonyl ) - piperazi ne-l-(N-2, 3, 4- trimethoxypheny!) carbothioamide. Subsequent reaction of the carbothioamide with methyl iodide and then with cyanamide according to the procedure of Example 1(b) accords 4-(2- ethyl -2-hy oxypropoxycarbony! ) pi perazi ne-1 - [N-cyano-N ' -2,3,4- tri ethoxypheny! ] carboxami di ne.

Example 5

4- (Cycl opentyl carbonyl )pi perazi ne-1 - [N-cyano-N ' -(3,4- di e thoxyphenyl ) ] carboxami di ne

Following the procedure of Example 1(a) but employing an equimolar amount of N-(cyclopentylcarbonyl)piperazine in place of N-methyl piperazi ne, there is produced 4- (cycl opentyl carbonyl ) - pi perazi πe-l-(*N- 3", 4-dime thoxyphenyl) carbothioamide. Reaction of the carbothioamide with methyl iodide and then with cyanamide according to the procedure of Example.! (b) affords 4- (cycl opentyl-

carbonyl ) pi perazi ne-1 - [N-cyano-N ' - ( 3, 4-dime thoxyphenyl ] carboxami di ne .

Example 6

4- ( 2-Furoyl ) homopi perazi ne-1 - [N-cyano-N ' - ( 3 , 4-dimethoxypheny 1 ] carboxamidine

Following the procedure of Example l(a-b) but substituting l-(2-furoyl)homopiperazine for l-(2-furoyl)piperazine, the title compound is obtained.

Example 7

4-Ami no-6,7-di me thoxy-2-( 4-methyl pi perazi ne-l-yl ) quinazoline dihydrochloride

Phosphorus pentachloride (0.31 g., 1.48 mmoles) is added with stirring to 10 ml. of phosphorus oxychloride followed in 5 min. by 4-methylpiperazine-l-[N-cyano-N'-(3,4-dimethoxyphenyl)]- carboxamidine of Example 1 (0.45 g., 1.48 mmoles). The reaction mixture is heated at 95-98° for a period of .2.5 hr. during which time a yellow gum forms and changes to a suspended solid by the end of the heating period. The reaction mixture is then cooled to 30° and excess phosphorus oxychloride removed under reduced pressure to provide a residual material which is treated cautiously with ice/ water. The aqueous phase is filtered and the filtrate concentrated under reduced pressure to provide a brown oil which is crystallized by rubbing under cold acetone. Insoluble material is collected and crystallized from methanol. to afford 0.175 g., 31% yield of 4-amino-6,7-dimethoxy-2- (4-methyl piperazi ne-l-yl) -quinazoline dihydrochloride, m.p. 280-282° (dec) identical with the sample

prepared according to the procedure described in U.S. Patent 3,511,836.

Example 8

4-Ami no-6 , 7-dimethoxy-2- [4- ( 2-f uroyl ) pi perazi ne-1 -yl ] qui nazol i ne hydrochloride

Hydrogen chloride gas is bubbled for a period of 8 min. into a cold, stirred mixture of 4-(2-furoyl)piperazine-l-[N-cyano-N'- (3, 4-dime thoxyphenyl)] carboxamidine of Example 2 (3.0 g., 7.82 mmoles) in 45 ml. of phosphorus oxychloride. After addition of the hydrogen chloride gas, the reaction mixture is stirred at 25-30° for 10 min. and then heated at 70-75° for a period of 75 mih. during which time a gummy solid separates. The reaction mixture is cooled to 30 , the excess phosphorus oxychloride removed under reduced pressure and residual material rubbed under ice/water to provide a solid. The ^' solid is collected to afford 2.76 g. (84% yield) of 4-amino-6,7- dimethoxy-2- [4-(2-furoyl )piperazine-l-yl]quinazoline hydrochloride identical with a sample prepared according to the procedure of U.S. 3,511,836.

Example 9

4-Amino-6 , 7-dimethoxy-2- [4- ( 5-methyl thi o-l , 3 ,4-oxadi azol e- carbonyl] pi perazi ne-l-yl] quinazoline hydrochloride

Hydrogen chloride gas is bubbled for a period of 4 min. into a cold, stirred mixture of 4-(5-methylthio-l,3,4-oxadiazole-2- - ^' . carbonyl )piperazine-l-[N-cyano-N'-(3,4-dimethoxyphenyl )] carboxamidine of Example 3 (0.16 g., 0.37 mmoles) in 6 ml . of phosphorus oxychloride and the mixture then stirred at 25-30° for an additional 8 min. period and finally heated to 72-75 for a period of 75 min. during which time a pale yellow solid precipitates. After the heating period, the mixture is cooled to 30°, excess phosphorus oxychloride removed

under reduced pressure and residual solid rubbed under ice/water and collected to provide 4-amino-6,7-dimethoxy-2-[4-(5-methylthio- 1 , 3 ,4-oxadi azole-2-carbonyl ] pi perazi ne-1 -y! ] qui nazol i ne hydrochl ori de in 95% yield identical to a sample prepared according to the pro- cedure of U.S. Patent 4,001,238.

Example 10

The cyclization procedure illustrated in Examples 1-3 is repeated with the following cyanocarboxamides:

4-(2-methyl-2-hydroxypropoxycarbony!)piperazine-l- [N-cyano-N'-(2,3,4-trimethoxyphenyl )] carboxamidine,

4- ( cycl opentyl carbonyl ) pi perazi ne-1 - [N-cyano-N '-(3,4- dimethoxyphenyl)] carboxami dine,

4- ( 2-f uroyl ) homopi perazi ne-1 - [N-cyano-N ' - ( 3 , 4-dimethoxy- phenyl ) ] carboxa idi ne ,

to produce respectively,

(a) 4-amino-6,7,8-trimethoxy-2- [4- (2-methyl -2- hydroxy- propoxycarbonyl ) pi perazi ne-l-yl ] qui nazol i ne ,

(b) 4-amino-6,7-dimethoxy-2- [4-cycl opentyl carbonyl )- pi perazi ne-1 -y! ] qui nazol i ne ,

(c) 4-amino-6,7-dimethoxy-2- [4- (2-furoyl homopi perazi ne-l- yl)] quinazoline.

STATEMENT OF INDUSTRIAL APPLICATION

The novel N-cyano-N' -phenyl carboxamidine compounds of this invention are particularly valuable as intermediates in the pre- paration of antihypertensive 4-amino-2-(4-substituted-piperazine-

, l-yl)-quinazolines. The invention includes the method of preparation

OM . W1P

of the novel N-cyano-N'-phenylcarboxamidines as well as the one step synthesis of the aforesaid antihypertensive compounds utilizing the novel N-cyano-N"-phenylcarboxamidines of the invention.

The novel N-cyano-N'-phenylcarboxamidine compounds are also valuable in the treatment of ulcers.