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Title:
METHOD FOR PREPARATION OF CARBOXYLIC ACID CHLORIDES FROM METHYL KETONES
Document Type and Number:
WIPO Patent Application WO/2016/202757
Kind Code:
A1
Abstract:
The invention discloses a method for the preparation of carboxylic acid chlorides starting from methyl ketones with a sulfur chloride.

Inventors:
ZARAGOZA DOERWALD, Florencio (Baeretstrasse 2, 3930 Visp, 3930, CH)
Application Number:
EP2016/063542
Publication Date:
December 22, 2016
Filing Date:
June 14, 2016
Export Citation:
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Assignee:
LONZA LTD (Lonzastrasse, 3930 Visp, 3930, CH)
International Classes:
C07C51/58; C07D333/38
Other References:
ADIWIDJAJA ET AL., ANGEW. CHEM. INT. ED. ENGL., vol. 19, 1980, pages 563 - 564, XP002752005
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Claims:
Claims

1. Method for the preparation of compound of formula (III);

the method comprises a step ST2;

ST2 comprises a reaction REAC2 of a compound of formula (II) with a compound

SULFCHLO;

SULFCHLO is S2C12, SC12, or a mixture thereof;

wherein

R100 is selected from the group consisting of

phenyl,

phenyl substituted with 1, 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_6 alkyl, C3-8 cycloalkyl, Ci_ 4 alkoxy, N02, CF3, CN, N(R13)(R14)R15, benzyl, phenyl, substituted phenyl, the substituted phenyl substituted by 1, 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_6 alkyl, C3_8 cycloalkyl, Ci_4 alkoxy, N02, CF3, CN and N(R16)(R17)R18,

naphthyl,

naphthyl substituted with 1, 2, 3, 4, 5, 6 or 7 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_6 alkyl, C3_s cycloalkyl, Ci_4 alkoxy, N02, CF3, CN, N(R13)(R14)R15, benzyl, phenyl, substituted phenyl, the substituted phenyl substituted by 1, 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_6 alkyl, C3_8 cycloalkyl, Ci_4 alkoxy, N02, CF3, CN and N(R16)(R17)R18, and residue of formula (RES-I); the (*) in formula (RES-I) denotes the bond to the C(0)C1 residue in formula (III) and to the C(0)CH3 residue in formula (II) respectively;

XI is O, S or N-Rl lO;

R13, R14, R15, R16, R17 and R18 are identical or different and independently from each other selected from the group consisting of H and Ci_8 alkyl;

Rl , R2 and R3 are identical or different and independently from each other selected from the group consisting of H, halogen, C02R4, C(0)C1, phenyl, 2-pyridyl, N02, CN, CF3, Ci_8 alkyl, and Ci_8 alkoxy;

or

Rl and R2 together represent -CH=CH-CH=CH- and form together with the thiophene ring a benzothiophene, and

R3 is selected from the group consisting of H, halogen, C02R4, C(0)C1, phenyl, 2-pyridyl,

N02, CN, CF3, Ci-8 alkyl, and Ci_8 alkoxy;

R4 is Ci_6 alkyl

R101 , R102 and R103 are identical or different and independently from each other

Ci_io alkyl, halogen or phenyl;

Rl 10 is Ci_6 alkyl or phenyl. 2. Method according to claim 1 , wherein

in case that R100 is substituted phenyl, then the phenyl is substituted with 1 , 2, 3, 4 or 5

identical or different substituents independently from each other selected from the group consisting of halogen, Ci_6 alkyl, C3_6 cycloalkyl, Ci_4 alkoxy, N02, CF3, CN, benzyl, phenyl, substituted phenyl, the substituted phenyl substituted by 1 , 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_6 alkyl, C3-6 cycloalkyl, Ci_4 alkoxy, N02, CF3, and CN.

3. Method according to claim 1 or 2, wherein

in case that RlOO is substituted naphthyl, then the naphthyl is substituted with 1, 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_6 alkyl, C3_6 cycloalkyl, Ci_4 alkoxy, N02, CF3, CN, benzyl, phenyl, substituted phenyl, the substituted phenyl substituted by 1, 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_6 alkyl, C3_6 cycloalkyl, Ci_4 alkoxy, N02, CF3, and CN.

4. Method according to one or more of claims 1 to 3, wherein

in case that RlOO is residue of formula (RES-I), the C(0)C1 residue in compound of formula (III) and the C(0)CH3 residue of compound of formula (II) are on position 2 of residue of formula (RES-I).

5. Method according to one or more of claims 1 to 4, wherein

Rl, R2 and R3 are identical or different and independently from each other selected from the group consisting of H, F, CI, Br, C02R4, C(0)C1, phenyl, 2-pyridyl, N02, CN, CF3, alkyl, and Ci_2 alkoxy; or

Rl and R2 together represent -CH=CH-CH=CH- and form together with the thiophene ring a benzothiophene, and

R3 is selected from the group consisting of H, F, CI, Br, C02R4, C(0)C1, phenyl, 2-pyridyl,

NO2, CN, CF3, Ci-4 alkyl, and Ci_2 alkoxy;

R4 is Ci_4 alkyl.

6. Method according to one or more of claims 1 to 5, wherein

residue of formula (RES-I) is selected from the group consisting of

7. Method according to one or more of claims 1 to 6, wherein

Rl is H or CI, and R2 and R3 are H.

8. Method according to one or more of claims 1 to 7, wherein

RlOl, R102 and R103 are identical or different and independently from each other Ci F, CI, or phenyl.

9. Method according to one or more of claims 1 to 8, wherein

XI is O or S.

10. Method according to one or more of claims 1 to 9, wherein

R100 is selected from the group consisting of phenyl, substituted phenyl, naphthyl, substituted naphthyl, and residue of formula (RES-I) with XI being O or S.

11. Method according to one or more of claims 1 to 10, wherein REAC2 is done in the presence of a base or of a salt of a base.

12. Method according to claim 11, wherein

the base is BAS2 and the salt of a base is a salt of BAS2;

BAS2 is selected from the group consisting of pyridine, picoline, chloropyridine,

methylethylpyridine, N(R10)(R11)R12, l,4-diazabicyclo[2.2.2]octane, Phe-N(R20)R21, and mixtures thereof;

RIO, Rl 1 and R12 are identical or different and are independently from each other

Ci_8 alkyl;

R20 and R21 are identical or different and are independently from each other Ci_8 alkyl; and the salt of BAS2 is selected from the group consisting of hydrochloride salt,

hydrobromide salt, acetate salt and trifluoroacetate salt.

13. Method according to one or more of claims 1 to 12, wherein

compound of formula (II) is prepared in a step ST1;

ST1 is done before ST2;

ST1 comprises a reaction REACl of a compound of formula (I) with a compound ACET;

RI OO/H © wherein

R100 is defined as in claim 1, and the (*) in residue of formula (RES-I) denotes the bond to the H in formula (I);

ACET is selected from the group consisting of acetyl chloride, acetic anhydride, acetic acid, ketene, and mixtures thereof.

14. Method according to claim 13, wherein

REACl is done in the presence of an acid ACIl, ACIl is selected from the group consisting of thionyl chloride, BF3-OEt2, perchloric acid, A1C13, polymeric sulfonic acid resin, toluene sulfonic acid, HC1, H2S04, H3P04, Si02, citric acid, tartaric acid, oxalic acid, zeolite, and mixtures thereof.

15. Method for the preparation of compound of formula (THIOXA); (THIOXA)

wherein the method comprises the step ST2;

R30, R31 , R32, R33 and R34 are identical or different and independently from each other selected from the group consisting of H, halogen, CF3, CH3, OCF3, OCH3, CN and

C(H)0;

wherein

ST2, Rl, R2 and R3 are as defined in claim 1; and

RlOO is residue of formula (RES-I) as defined in claim 1 with XI being S.

16. Method according to claim 15, wherein

the method comprises the step ST1 in addition to step ST2;

ST1 is done before ST2;

wherein ST1 is as defined in claim 13 or 14.

17. Method according to claim 15 or 16, wherein

Rl, R2, R3, R30, R31, R32, R33 and R34 are H.

18. Method for the preparation of compound of formula (RIVA-I);

(RIVA-I) R50, R51 , R52 and R53 are identical or different and independently of one another each is selected from the group consisting of H, halogen, CF3, CN, N02, C(0)-NH2,

C(0)-Ci_6 alkyl, O-R60; N(R60)R61 and Ci_6 alkyl;

R60 and R61 are identical or different and independently of one another each is selected from the group consisting of H, Ci_4 alkyl and C(0)R63;

R63 is selected from the group consisting of Ci_4 alkyl-NH2, NH2, NH-Ci_4 alkyl,

N(Ci_4 alkyl)Ci_4 alkyl and Ci_8 alkyl;

R43, R44, R45, R46, R47 and R48 are identical or different and independently of one another each represents H or Ci_6 alkyl; wherein the method comprises the step ST2;

wherein

ST2, Rl, R2 and R3 are as defined in claim 1; and

R100 is residue of formula (RES-I) as defined in claim 1 with XI being S.

19. Method according to claim 18, wherein

wherein the method comprises the step ST1 in addition to step ST2;

ST1 is done before ST2;

wherein ST1 is as defined in claim 13 or 14.

20. Method according to claim 18 or 19, wherein

the compound of formula (RIVA-I) is the compound of formula (RIVA-II);

wherein R50, R51, R52, R53, R43, R44, R45, R46, R47 and R48 are as defined in claim 18.

21. Method according to one or more of claims 18 to 20, wherein

the compound of formula (RIVA-I) is the compound of formula (RIVA-1).

Description:
METHOD FOR PREPARATION OF CARBOXYLIC ACID CHLORIDES FROM

METHYL KETONES

The invention discloses a method for the preparation of carboxylic acid chlorides starting from methyl ketones with a sulfur chloride.

BACKGROUND OF THE INVENTION

Carboxylic acid chlorides are important synthetic intermediates, which can be used for the preparation of amides, esters, ketones, and various heterocycles. Acyl chlorides are usually prepared from carboxylic acids, but there are instances where these carboxylic acids are not readily available.

Methods for the direct conversion of arenes or heteroarenes into aroyl chlorides include the reaction of said arenes or heteroarenes with oxalyl chloride. US 2002/0062043 Al discloses a method for the preparation of biphenylcarbonylchlorides by reacting biphenyls with oxalyl chloride in the presence of a Lewis acid. Oxalyl chloride is, however, a relative expensive reagent.

Newman, M.S., et al, Organic Syntheses 1937, 17, 65, discloses the preparation of beta- naphthoic acid by haloform reaction from methyl beta-naphthyl ketone. For obtaining the acid chloride a second reaction step is required. The haloform reaction needs to be done in water and in a diluted system, and residual hypochlorite needs to be destroyed after the reaction, which can be done e.g. with sulfite. All this leads to significant amounts of waste water and salts, such as chloride, sulfite and sulfate.

Treatment of arenes or heteroarenes with phosgene, diphosgene, or triphosgene in the presence of a Lewis acid usually yields significant amounts of the respective symmetric ketones as byproducts. Neubert, M.E., et al, Organic Syntheses 1983, 61, 8, discloses the preparation of a benzoyl chloride with phosgene and discusses that the formation of the ketone can be reduced by i.a. using excess of oxalyl chloride, which again is expensive.

The Friedel-Crafts acetylation of arenes or heteroarenes, however, usually proceeds in high yield with a large variety of different starting materials. If electron-rich arenes or heteroarenes are used as starting materials, the Friedel-Crafts acetylation can often be performed with only catalytic amounts of acids, and in an environmentally friendly way (see, e.g., G. Sartori, R. Maggi, Chem. Rev. 2006, 1077-1104). Thus, acetylated arenes or heteroarenes are readily available compounds. Thiophene carbonyl chlorides are important synthetic intermediates, for instance for the synthesis of drugs and agrochemicals. They can be prepared by a number of different routes, each having advantages and disadvantages. Of particular interest are methods that only require inexpensive starting materials and reagents, are easy to perform, and generate only small amounts of waste.

2-Thiophenecarbonyl chloride is an intermediate for the preparation of Tioxazafen, a nematicide, with CAS 330459-31-9 and with the chemical name 3-phenyl-5-(thiophen-2-yl)- 1,2,4-oxadiazole and which is the compound of formula (THIOXA-1).

(THIOXA-1)

WO 2014/008257 A2 discloses the preparation of compound of formula (THIOXA-1).

5-Chloro-2-thiophenecarbonyl chloride is an intermediate for the preparation of Rivaroxaban, an anti-thrombotic agent, with CAS 366789-02-8 and with the chemical name (S)-5-Chlor-N- {2-0X0-3- [4-(3-oxomorpholin-4-yl)phenyl]- 1 ,3-oxazolidin-5- ylmethyl}thiophen-2-carbamid and which is compound of formula (RIVA-1).

US 2003/0153610 Al discloses Rivaroxaban and a method for its preparation, US

2015/0133657 Al discloses another method for its preparation, US Patent 6,107,519 discloses certain precursors used in said preparation.

Adiwidjaja et al. in Angew. Chem. Int. Ed. Engl. 1980, 19, 563 to 564, report the reaction of thionyl chloride with acetophenone in pyridine, which provides a mixture of benzoyl chloride and compound of formula (8b) with 36% and 15% yield respectively.

Adiwidjaja therefore discloses that the switch from aliphatic methyl ketones to aromatic methyl ketones lowers the yield and leads to mixtures of the desired product with by products.

Edwards et al. in J. Org. Chem. 1966, 31, 1283 to 1285, disclose on page 1284 right coloumn second paragraph, that thiophene is sensitive to acids and polymerizes to tar upon treatment with aluminum chloride: "With thiophene, aluminum chloride, and the same anhydride, tar formation was so great that the results were meaningless".

There was a need for a method for preparation of carboxylic acid chlorides such as benzoyl chlorides or thiophene carbonyl chlorides that has few steps, with high yields, that allows the preparation without or at least with only minor amounts of by products, that starts with relatively inexpensive substrates, that does not require mandatorily the expensive oxalyl chloride, that does not need mandatorily aluminum chloride or hypochlorite, that does not create large amounts of salt as for example aluminum chloride, hypochlorite or sulfite would do, that can be done even without a solvent, and that does not require mandatorily the use of a continuous reactor set up when it is scaled up for production. Unexpectedly a method for preparation of carboxylic acid chlorides such as benzoyl chlorides and thiophenecarbonyl chlorides starting from the respective methyl ketone precursors, such as acetophenones and acetyl thiophenes with comparatively inexpensive a sulfur chloride was found which meets the needs mentioned above. Contrary to the disclosure of Adiwidjaja and of Edwards the yields and the purities are comparatively high, no significant amounts of by products such as mentioned in Adiwidjaja are formed, no aluminum chloride, hypochlorite or sulfite is required, the reaction can be done even without a solvent, no continuous reactor set up is mandatorily required, and the methyl ketones as substrates are readily available for example in case of aromatic methyl ketones by Friedel-Crafts acetylation and are therefore also comparatively inexpensive. Advantageously no oxalyl chloride is required, instead a sulfur chloride, which is by far less expensive with less than one twentieth of the price based on molecular weight, is used. Unexpectedly the yield of the claimed method is higher, as shown in examples 7 and 12 with a yield well over 70%, than the yield of the method disclosed by Adiwidjaja, who reports a yield of 36% for the respective conversion of acetophenone to benzoyl chloride. In the following text,

ambient pressure means usually 1 bar, depending on the weather;

halide means F , CI , Br or I , preferably CI , Br or I , more preferably CI or Br ; halogen means F, CI, Br or I, preferably CI, Br or I, more preferably CI or Br;

MeTHF methyl tetrahydrofuran

MTBE methyl tert-butyl ether

THF tetrahydrofuran;

wt-%) percent by weight;

if not otherwise stated. SUMMARY OF THE INVENTION

Subject of the invention is a method for the preparation of compound of formula (III);

O

(III)

R100' the method comprises a step ST2;

ST2 comprises a reaction REAC2 of a compound of formula (II) with a compound

SULFCHLO;

SULFCHLO is S 2 C1 2 , SC1 2 , or a mixture thereof;

wherein

R100 is selected from the group consisting of

phenyl, phenyl substituted with 1, 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_ 6 alkyl, C3-8 cycloalkyl, Ci_ 4 alkoxy, N0 2 , CF 3 , CN, N(R13)(R14)R15, benzyl, phenyl, substituted phenyl, the substituted phenyl substituted by 1, 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_ 6 alkyl, C 3 _8 cycloalkyl, Ci_ 4 alkoxy, N0 2 , CF 3 , CN and N(R16)(R17)R18,

naphthyl,

naphthyl substituted with 1, 2, 3, 4, 5, 6 or 7 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_ 6 alkyl, C 3 _s cycloalkyl, Ci_ 4 alkoxy, N0 2 , CF 3 , CN, N(R13)(R14)R15, benzyl, phenyl, substituted phenyl, the substituted phenyl substituted by 1, 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_ 6 alkyl, C 3 _ 8 cycloalkyl, Ci_ 4 alkoxy, N0 2 , CF 3 , CN and N(R16)(R17)R18, and residue of formula (RES-I);

the (*) in formula (RES-I) denotes the bond to the C(0)C1 residue in formula (III) and to the C(0)CH 3 residue in formula (II) respectively;

XI is O, S or N-Rl lO;

R13, R14, R15, R16, R17 and R18 are identical or different and independently from each other selected from the group consisting of H and Ci_ 8 alkyl;

Rl, R2 and R3 are identical or different and independently from each other selected from the group consisting of H, halogen, C0 2 R4, C(0)C1, phenyl, 2-pyridyl, N0 2 , CN, CF 3 , Ci_8 alkyl, and Ci_ 8 alkoxy;

or Rl and R2 together represent -CH=CH-CH=CH- and form together with the thiophene ring a benzothiophene, and

R3 is selected from the group consisting of H, halogen, C0 2 R4, C(0)C1, phenyl, 2-pyridyl,

N0 2 , CN, CF 3 , Ci-8 alkyl, and Ci_ 8 alkoxy;

R4 is Ci_6 alkyl

R101 , R102 and R103 are identical or different and independently from each other

Ci_io alkyl, halogen or phenyl;

Rl 10 is Ci_6 alkyl or phenyl.

DETAILED DESCRIPTION OF THE INVENTION

Preferably, in case that R100 is substituted phenyl, then the phenyl is substituted with 1 , 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, Ci_ 4 alkoxy, N0 2 , CF 3 , CN, benzyl, phenyl, substituted phenyl, the substituted phenyl substituted by 1 , 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, Ci_ 4 alkoxy, N0 2 , CF 3 , and CN;

more preferably, the phenyl is substituted with 1 , 2 or 3 identical or different substituents independently from each other selected from the group consisting of F, CI, Br, Ci_ 4 alkyl, C 3 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , CF 3 , phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, Ci_ 4 alkyl, C 3 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , and CF 3 ;

even more preferably, the phenyl is substituted with 1 or 2 identical or different substituents independently from each other selected from the group consisting of F, CI, Br, C 1-4 alkyl, C 3 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , CF 3 , phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, Ci_ 4 alkyl, C 3 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , and CF 3 ;

especially, the phenyl is substituted with 1 or 2 identical or different substituents

independently from each other selected from the group consisting of F, CI, Br, methyl, ethyl, tert-butyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , CF 3 , phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, methyl, ethyl, tert-butyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , and CF 3 . Preferably, in case that R100 is substituted naphthyl, then the naphthyl is substituted with 1 , 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_ 6 alkyl, C3-6 cycloalkyl, Ci_ 4 alkoxy, N0 2 , CF 3 , CN, benzyl, phenyl, substituted phenyl, the substituted phenyl substituted by 1 , 2, 3, 4 or 5 identical or different substituents independently from each other selected from the group consisting of halogen, Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, Ci_ 4 alkoxy, N0 2 , CF 3 , and CN; more preferably, the naphthyl is substituted with 1 or 2 identical or different substituents independently from each other selected from the group consisting of F, CI, Br, Ci_ 4 alkyl, C 3 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , CF 3 , phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, Ci_ 4 alkyl, C 3 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , and CF 3 ;

even more preferably, the naphthyl is substituted with 1 or 2 identical or different substituents independently from each other selected from the group consisting of F, CI, Br, Ci_ 4 alkyl, C 3 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , CF 3 , phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, Ci_ 4 alkyl, C 3 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , and CF 3 ;

especially, the naphthyl is substituted with 1 or 2 identical or different substituents

independently from each other selected from the group consisting of F, CI, Br, methyl, ethyl, tert-butyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , CF 3 , phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, methyl, ethyl, tert-butyl, C 6 cycloalkyl, Ci_ 2 alkoxy, N0 2 , and CF 3 .

Preferably and in case that R100 is residue of formula (RES-I), the C(0)C1 residue in

compound of formula (III) and the C(0)CH 3 residue of compound of formula (II) are on position 2 of residue of formula (RES-I). Preferably, Rl , R2 and R3 are identical or different and independently from each other selected from the group consisting of H, F, CI, Br, C0 2 R4, C(0)C1, phenyl, 2- pyridyl, N0 2 , CN, CF 3 , alkyl, and Ci_ 2 alkoxy; or

Rl and R2 together represent -CH=CH-CH=CH- and form together with the thiophene ring a benzothiophene, and R3 is selected from the group consisting of H, F, CI, Br, C0 2 R4, C(0)C1, phenyl, 2-pyridyl,

N0 2 , CN, CF 3 , Ci-4 alkyl, and Ci_ 2 alkoxy;

R4 is Ci_4 alkyl; in another preferred embodiment, Rl, R2 and R3 are identical or different and independently from each other selected from the group consisting of H, CI, Br, C02R4, N02, CN, CF3, alkyl, and Ci_ 2 alkoxy; and

R4 is CI -4 alkyl; more preferably, Rl, R2 and R3 are identical or different and independently from each other selected from the group consisting of H, F CI, Br, C0 2 R4, C(0)C1, phenyl, 2-pyridyl, N0 2 , CF 3 , methyl, and methoxy; or

Rl and R2 together represent -CH=CH-CH=CH- and form together with the thiophene ring a benzothiophene, and

R3 is selected from the group consisting of H, F CI, Br, C0 2 R4, C(0)C1, phenyl, 2-pyridyl, N0 2 , CF 3 , methyl, and methoxy;

R4 is Ci_ 2 alkyl; in another more preferred embodiment, Rl, R2 and R3 are identical or different and

independently from each other selected from the group consisting of H, CI, Br,

C0 2 R4, C(0)C1, phenyl, N0 2 , CN, CF 3 , Ci_ 2 alkyl, and Ci_ 2 alkoxy; and R4 is Ci_ 2 alkyl.

Especially, residue of formula (RES-I) is selected from the group consisting of

More especially, Rl is H or CI, and R2 and R3 are H.

More in particular, residue of formula (RES-I) is residue of formula (RES-I-l-Xl) or residue of formula (RES-I-2-X);

even more in particular, residue of formula (RES-I) is residue of formula (RES-I- 1) or residue of formula (RES-I-2).

(RES-I-2)

Specific embodiments of compound of formula (III) are selected from the group consisting of compound of formula (III-l), compound of formula (ΙΠ-2) and compound of formula (III-3).

Preferably, RlOl , R102 and R103 are identical or different and independently from each other

Ci_io alkyl, F, CI, or phenyl;

more preferably, RlOl , Rl 02 and R103 are methyl, F, CI or phenyl.

Preferably, Rl 10 is methyl or phenyl.

Preferably, XI is O or S, more preferably, XI is S.

Preferably, R100 is selected from the group consisting of phenyl, substituted phenyl,

naphthyl, substituted naphthyl, and residue of formula (RES-I) with XI being O or S, more preferably, R100 is selected from the group consisting of phenyl, substituted phenyl, naphthyl, substituted naphthyl, and residue of formula (RES-I) with XI being S;

also with all their embodiments described herein.

Preferably, the molar amount of SULFCHLO is from 2 to 50 times, more preferably from 2 to 35 times, even more preferably from 2 to 25 times, especially from 2 to 15 times, more especially from 2 to 10 times, even more especially from 2 to 7 times, based on the molar amount of compound of formula (II). Preferably, any excess of SULFCHLO is recycled.

It is known that S 2 CI 2 , also known as disulfur dichloride or even referred to as sulfur monochloride, decomposes upon contact with water, e.g. moisture of air, into HC1, SO 2 , and sulfur. It is also known that S 2 CI 2 decomposes upon heating into SC1 2 , also known as sulfur dichloride, and into other sulfur chlorides. Moreover, S 2 C1 2 is prepared by chlorination of sulfur, and, depending on the precise reaction conditions and purification methods used, commercially available S 2 CI 2 may contain variable amounts of chlorine and SCI 2 . Therefore SULFCHLO, that is used in REAC2, is preferably used in form of a compound

COMPSULFCHLO, COMPSULFCHLO may have various qualities, various impurity contents and various impurity profiles. Therefore COMPSULFCHLO may contain e.g. up to 5%, 10%, 20%, 30% or even up to 50%, the % being % by weight based on the total weight of COMPSULFCHLO, of chlorine, hydrogen chloride, SO 2 , sulfur, or of SCI 2 for the case of SULFCHLO being S 2 CI 2 , or of mixtures of said impurities.

Therefore preferably, COMPSULFCHLO contains 50 to 100%, more preferably 70 to 100%, even more preferably 80 to 100%, especially 90 to 100%, more especially 95 top 100%), of SULFCHLO, the % being % by weight based on the total weight of

COMPSULFCHLO. S 2 CI 2 and SCI 2 are equivalent reagents for REAC2. S 2 CI 2 is commercially available.

Preferably SULFCHLO is S 2 C1 2 .

Preferably, REAC2 is done at a temperature TEMP2 of from -20 °C to 250 °C, more

preferably from -10 °C to 200 °C, even more preferably from 0 °C to 175 °C, especially from 40 °C to 175 °C.

TEMP2 can be varied during the course of the reaction, so that the reaction is done with a temperature profile.

Preferably, REAC2 is done at a pressure of from ambient pressure to 100 bar, more preferably of from ambient pressure to 75 bar, even more preferably of from ambient pressure to 50 bar, especially of from ambient pressure to 30 bar, more especially of from ambient pressure to 25 bar, even more especially of from ambient pressure to 20 bar.

The pressure of REAC2 can be adjusted according to the chosen temperature of REAC2 and the boiling point of SULFCHLO. Preferably, the reaction time TIME2 of REAC2 is from 1 h to 96 h, more preferably from 2 h to 60 h, even more preferably from 3 h to 48 h.

Preferably, REAC2 is done in the presence of a base or of a salt of a base.

Preferably, the base is BAS2 and the salt of a base is a salt of BAS2;

BAS2 is selected from the group consisting of pyridine, picoline, chloropyridine,

methylethylpyridine, 4-(dimethylamino)pyridine, N(R10)(R1 1)R12, 1 ,4- diazabicyclo[2.2.2]octane, Phe-N(R20)R21 , and mixtures thereof;

RIO, Rl 1 and R12 are identical or different and are independently from each other

Ci_8 alkyl;

R20 and R21 are identical or different and are independently from each other Ci_s alkyl; and the salt of BAS2 is selected from the group consisting of hydrochloride salt,

hydrobromide salt, acetate salt and trifluoroacetate salt.

Preferably, RIO, Rl 1 and R12 are identical or different and are independently from each other alkyl;

R20 and R21 are identical or different and are independently from each other Ci_ 2 alkyl.

More preferably, BAS2 is selected from the group consisting of pyridine, 2-picoline, 3- picoline, 4-picoline, 2-chloropyridine, 2-methyl-5-ethylpyridine, triethylamine, tributylamine, l ,4-diazabicyclo[2.2.2]octane, Ν,Ν-dimethylaniline, and mixtures thereof; even more preferably, BAS2 is selected from the group consisting of pyridine, 3 -picoline, 2- chloropyridine, 2-methyl-5-ethylpyridine, triethylamine, tributylamine, and mixtures thereof;

especially, BAS2 is selected from the group consisting of pyridine, 3 -picoline, 2- chloropyridine, 2-methyl-5-ethylpyridine, and mixtures thereof.

Preferably, the salt of BAS2 is selected from the group consisting of hydrochloride salt, acetate salt and trifluoroacetate salt;

more preferably, the salt of BAS2 is selected from the group consisting of hydrochloride salt, and acetate salt. Preferably, the molar amount of BAS2 is from 0.001 to 1 times, more preferably from 0.005 to 0.5 times, and even more preferably from 0.01 to 0.3 times, based on the molar amount of compound of formula (II). REAC2 can be done neat , that is without a solvent, or REAC2 can be done in a solvent

SOLV2, SOLV2 is selected from the group consisting of benzene toluene, xylene, chlorobenzene, nitrobenzene, anisole, dichlorobenzene, dichloroethane, trichloroethane, and mixtures thereof;

preferably, SOLV2 is selected from the group consisting of toluene, o-xylene, m-xylene, p- xylene, chlorobenzene, nitrobenzene, anisole, 1,2-dichlorobenzene, 1,3-dichlorobenzene,

1 ,4-dichlorobenzene, 1 ,2-dichloroethane, and mixtures thereof;

more preferably, SOLV2 is selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, 1 ,2-dichloroethane, and mixtures thereof. Preferably, the weight of SOLV2 is from 0.5 to 100 times, more preferably from 1 to 50 times, of the weight of compound of formula (II).

Preferably, any SOLV2 is recycled. Preferably, no solvent is used in REAC2.

ST2 can comprise after REAC2 a step ST-HEAT2, in ST-HEAT2 the reaction mixture

resulting from REAC2 is subjected to an elevated temperature TEMP-HEAT2, TEMP- HEAT2 is preferably from 80 °C to 250 °C, more preferably from 100 °C to 200 °C, even more preferably from 120 °C to 175 °C.

The time TIME-HEAT2, during which the reaction mixture is subjected to TEMP-HEAT2, is preferably from 30 min to 96 h, more preferably from 1 h to 60 h, even more preferably from 2 h to 48 h. In a preferred embodiment, REAC2 is done at first at a temperature TEMPI for a time TIME1, and then at a temperature TEMP2 for a time TIME2;

TEMPI is from 40 to 85°C,

TIME1 is from 2 to 60 h,

TEMP2 is from 135 to 145°C, and TIME2 is from 10 to 25 h;

more preferably,

TEMP2 is from 50 to 80°C,

TIME2 is from 3 to 10 h,

TEMP-HEAT2 is from 135 to 145°C, and

TIME-HEAT2 is from 10 to 25 h.

In another preferred embodiment, REAC2 is done at first at a temperature TEMPI for a time TIME1, and then at a temperature TEMP2 for a time TIME2;

TEMP2- 1 is from -20 °C to 100 °C,

TIME2-1 is from 0.1 h to 48 h,

TEMP2-2 is from 85 °C to 250 °C, and

TIME2-2 is from 0.9 h to 48 h;

more especially,

TEMP2- 1 is from - 10 °C to 95 °C,

TIME2-1 is from 0.5 h to 30 h,

TEMP2-2 is from 90 °C to 200 °C, and

TIME2-2 is from 1.5 h to 30 h;

even more especially,

TEMP2-1 is from 0 °C to 90 °C,

TIME2-1 is from 1 h to 24 h,

TEMP2-2 is from 100 °C to 175 °C, and

TIME2-2 is from 2 h to 24 h. ST-HEAT2 can be done in a solvent SOLV-HEAT2, SOLV-HEAT2 is selected from the group consisting of benzene, toluene, xylene, chlorobenzene, nitrobenzene, anisole, dichlorobenzene, dichloroethane, and mixtures thereof;

preferably, SOLV-HEAT2 is selected from the group consisting of toluene, o-xylene, m- xylene, p-xylene, chlorobenzene, nitrobenzene, anisole, 1 ,2-dichlorobenzene, 1,3- dichlorobenzene, 1 ,4-dichlorobenzene, 1 ,2-dichloroethane, and mixtures thereof;

more preferably, SOLV-HEAT2 is selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, 1 ,2-dichloroethane, and mixtures thereof. Preferably, the weight of SOLV-HEAT2 is from 0.5 to 100 times, more preferably from 1 to 50 times, of the weight of compound of formula (II).

Preferably, any SOLV-HEAT2 is recycled.

Depending on the boiling point of SOLV-HEAT2 and of the desired TEMP-HEAT2, ST- HEAT2 can be done under the respective necessary or higher pressure.

If both SOLV2 and SOLV-HEAT2 are used, then preferably SOLV2 and SOLV-HEAT2 are identical.

After ST2, compound of formula (III) can be isolated and purified by methods well-known to those skilled in the art. These include, for instance, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, extraction, or a combination of these methods.

Preferably, after the REAC2 or after ST2 any SOLV2 is evaporated off, the resulting in a first residue which is mixed with an ether. The ether is preferable an ether ETH, ETH is preferably selected from the group consisting of diethyl ether, THF, MeTHF, MTBE and dioxane. The resulting mixture is filtered and concentrated, preferably under reduced pressure, resulting in a second residue. This second residue is mixed with an alkane ALK,

ALK is preferably selected from the group consisting of C 5 _s alkane, C 5 _s cycloalkane and mixtures thereof;

more preferably ALK is selected from the group consisting of hexane, heptane, octane,

cyclohexane, methyl cyclohexane and mixtures thereof;

more preferably more preferably ALK is selected from the group consisting of n-hexane, n- heptane, cyclohexane, methyl cyclohexane and mixtures thereof;

optionally under heating, forming a mixture comprising a solution of the product in the alkane and a residue that is insoluble in the alkane. The solution of the product in the alkane is separated from the insoluble residue, this can be done by conventional means such a decanting, filtration or phase separation. Often the product crystallizes already from the solution upon cooling, or the alkane is evaporated off, preferably under reduced pressure. In case that R100 is said phenyl, said substituted phenyl, said naphthyl, said substituted naphthyl or said residue of formula (RES-I), then compound of formula (II) can be prepared in a step ST1, in this case the method then comprises ST1 and ST2;

ST1 is done before ST2;

ST1 comprises a reaction REAC1 of a compound of formula (I) with a compound ACET;

R100' (I) wherein

R100 is defined as herein, also with all its embodiments, and the (*) in residue of formula (RES-I) denotes the bond to the H in formula (I);

ACET is selected from the group consisting of acetyl chloride, acetic anhydride, acetic acid, ketene, and mixtures thereof. When the (*) in residue of formula (RES-I) denotes the bond to the H in formula (I) then compound of formula (I) is a compound of formula (RES-I-H);

with Rl, R2, R3 and XI as defined herein, also with all their embodiments.

Preferably, ACET is selected from the group consisting of acetyl chloride, acetic anhydride, and mixtures thereof.

Preferably, the molar amount of ACET is from 1 to 50 times, more preferably from 1 to 35 times, and even more preferably from 1 to 20 times, based on the molar amount of compound of formula (I). In case of ACET being acetic anhydride, the stated minimum amount of ACET of 1 time, based on the molar amount of compound of formula (I), could possibly be lowered to 0.5 times, based on the molar amount of compound of formula (I). Preferably, any excess of ACET is recycled.

Preferably, REACl is done at a temperature of from -10 °C to 200 °C, more preferably from 0

°C to 150 °C, even more preferably from 20 °C to 125 °C.

Preferably, REACl is done at a pressure of from ambient pressure to 25 bar, more preferably from ambient pressure to 20.

The pressure of REACl can be adjusted according to the chosen temperature of REACl and the boiling point of ACET.

Preferably, the reaction time of REACl is from 30 min to 24 h, more preferably from 1 h to 12 h.

Preferably, REACl is done in the presence of an acid ACIl, ACIl is selected from the group consisting of thionyl chloride, BF 3 -OEt 2 , perchloric acid, A1C1 3 , polymeric sulfonic acid resin, toluene sulfonic acid, HC1, H 2 S0 4 , H 3 P0 4 , Si0 2 , citric acid, tartaric acid, oxalic acid, zeolite, and mixtures thereof.

Zeolite can be any zeolite, preferably montmorrilonte or bentonite, more preferably

montmorillonite, even more preferably Montmorillonite K10®, BASF, Germany (also available at Sigma Aldrich, CAS Number 1318-93-0). Preferably, ACIl is selected from the group consisting of thionyl chloride, BF 3 -OEt 2 ,

perchloric acid, A1C1 3 , polymeric sulfonic acid resin, toluene sulfonic acid, HC1, H 2 S0 4 , H 3 P0 4 , Si0 2 , zeolite, and mixtures thereof;

more preferably, ACIl is selected from the group consisting of thionyl chloride, perchloric acid, A1C1 3 , polymeric sulfonic acid resin, montmorillonite, H 3 P0 4 , and mixtures thereof; especially, ACIl is thionyl chloride, perchloric acid, A1C1 3 or H 3 P0 4 .

Preferably, the molar amount of ACIl is from 0.001 to 1 times, more preferably from 0.005 to 0.5 times, and even more preferably from 0.01 to 0.20 times, based on the molar amount of compound of formula (I). REACl can be done in a solvent SOLVl, SOLVl is selected from the group consisting of benzene toluene, xylene, chlorobenzene, nitrobenzene, dichlorobenzene,

dichloromethane, dichloroethane, carbon disulfide, and mixtures thereof;

preferably, SOLVl is selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, nitrobenzene, 1 ,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, dichloromethane, 1 ,2-dichloroethane, carbon disulfide, and mixtures thereof;

more preferably, SOLVl is selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, dichloromethane, 1 ,2-dichloroethane, and mixtures thereof.

Preferably, the weight of SOLVl is from 0.5 to 100 times, more preferably from 1 to 50 times, of the weight of compound of formula (I). Preferably, any SOLVl is recycled.

After STl, compound of formula (II) can be isolated and purified by methods well-known to those skilled in the art. These include, for instance, hydrolysis, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, extraction, or a combination of these methods.

Preferably, the solvents SOLVl and SOLV2 are identical.

STl and ST2 can be done in one pot. Further subject of the invention is a method for the preparation of compound of formula

(THIOXA);

(THIOXA)

wherein the method comprises the step ST2;

R30, R31 , R32, R33 and R34 are identical or different and independently from each other selected from the group consisting of H, halogen, CF 3 , CH 3 , OCF 3 , OCH 3 , CN and

C(H)0;

wherein

ST2, Rl, R2 and R3 are as defined herein, also with all their embodiments; and

RlOO is residue of formula (RES-I) with XI being S; further subject of the invention is a method for the preparation of compound of formula

(THIOXA),

wherein the method comprises the step ST1 in addition to step ST2;

ST1 is done before ST2;

wherein ST1 is as defined herein, also with all its embodiments;

also with any individual embodiment or with any combination of two or more embodiments, the embodiments as described herein for any of these steps; especially, R30, R31, R32, R33 and R34 are H;

in another especial embodiment, Rl, R2 and R3 are H;

more especially, Rl, R2, R3, R30, R31, R32, R33 and R34 are H.

Preferably, the method for preparation of compound of formula (THIOXA) starting from compound of formula (III) with RlOO being residue of formula (RES-I) with XI being S has a step ST3;

ST3 is done after ST2; ST3 comprises a reaction REAC3, in REAC3 the compound of formula (III) with RlOO being residue of formula (RES-I) with XI being S is reacted with a compound of formula (IV).

Details for ST3 are disclosed in WO 2014/008257 A2.

Specific embodiments for ST3 are disclosed in the examples 2, 3, 7, 9, 10, 11 and 12 of WO 2014/008257 A2

Preferably, compound of formula (III) in ST2 and in ST3 in the method for preparation of compound of formula (THIOXA) is compound of formula (III- 1) or compound of formula (III-2);

more preferably, compound of formula (III) is compound of formula (III- 1).

Preferably, compound of formula (IV) is selected from the group consisting of compound of formula (IV- 1), compound of formula (IV-2), compound of formula (IV-3), compound of formula (IV-4), compound of formula (IV-5), compound of formula (IV-6) and compound of formula (IV-7);

(TV-1)

more preferably, compound of formula (IV) is compound of formula (IV- 1) or compound of formula (IV-2).

When compound of formula (III) is brought into contact with compound of formula (IV) a reaction mixture is formed.

Preferably, REAC3 is done in the presence of a solvent SOLV3.

Preferably, SOLV3 is a water-immiscible organic solvent.

Preferably, SOLV3 solubilizes compound of formula (IV) and compound of formula

(THIOXA).

Preferably, SOLV3 forms an azeotrope with water.

Preferably, SOLV3 is selected from the group consisting of 2-methyltetrahydrofuran and butyl acetate;

more preferably, SOLV3 is 2-methyltetrahydrofuran.

Preferably, REAC3 is done in the presence of a base BAS3.

Preferably, BAS3 is an aqueous base.

Preferably, BAS3 is selected from the group consisting of sodium hydroxide, potassium

hydroxide, lithium hydroxide, and calcium hydroxide.

Preferably, the reaction mixture of REAC3 comprises an organic phase and an aqueous phase. Preferably, the pH of the aqueous phase is greater than 8, more preferably greater than 10. Preferably, the pH of the aqueous phase is increased or maintained by adding additional

BAS3 to the reaction mixture or REAC3.

Preferably, the temperature of REAC3 is no greater than 85°C;

more preferably, the temperature of REAC3 is maintained at from 55 °C to 75 °C.

Preferably, REAC3 is done in the presence of a phase transfer catalyst PTC3.

Preferably, PTC3 is selected from the group consisting of quaternary ammonium salts,

phosphonium salts, and crown ethers;

more preferably, PTC3 is selected from the group consisting of tetrabutylammonium

hydroxide, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylphosphonium bromide, tetrabutylphosphonium chloride, and benzyltrimethylammonium hydroxide;

even more preferably, PTC3 is tetrabutylammonium hydroxide.

Preferably, compound of formula (IV) is dissolved in SOLV3 prior to adding the compound of formula (III) to form the reaction mixture of REAC3.

Preferably, REAC3 is done in the presence of water.

Further subject of the invention is a method for the preparation of compound of formula (RIVA-I);

R50, R51 , R52 and R53 are identical or different and independently of one another each is selected from the group consisting of H, halogen, CF 3 , CN, N0 2 , C(0)-NH 2 ,

C(0)-Ci_6 alkyl, O-R60; N(R60)R61 and Ci_ 6 alkyl;

R60 and R61 are identical or different and independently of one another each is selected from the group consisting of H, Ci_ 4 alkyl and C(0)R63;

R63 is selected from the group consisting of Ci_ 4 alkyl-NH 2 , NH 2 , NH-Ci_ 4 alkyl,

N(Ci_ 4 alkyl)Ci_ 4 alkyl and Ci_ 8 alkyl;

R43, R44, R45, R46, R47 and R48 are identical or different and independently of one another each represents H or Ci_ 6 alkyl; wherein the method comprises the step ST2;

wherein

ST2, Rl, R2 and R3 are as defined herein, also with all their embodiments; and

R100 is residue of formula (RES-I) with XI being S; further subject of the invention is a method for the preparation of compound of formula (RIVA-I),

wherein the method comprises the step ST1 in addition to step ST2;

ST1 is done before ST2;

wherein ST1 is as defined herein, also with all its embodiments;

also with any individual embodiment or with any combination of two or more embodiments, the embodiments as described herein for any of these steps; especially wherein the compound of formula (RIVA-I) is the compound of formula

(RIVA-II);

more especially wherein the compound of formula (RIVA-I) is the compound of formula (RIVA-1).

Preferably, the method for preparation of compound of formula (RIVA-I) starting from

compound of formula (III) with RlOO being residue of formula (RES-I) with XI being S has a step ST4;

ST4 is done after ST2;

ST4 comprises a reaction REAC4, in REAC4 the compound of formula (III) with RlOO being residue of formula (RES-I) with XI being S is reacted with a compound of formula (RIVA-Ia); preferably, residue of formula (RES-I) is residue of formula (RES-I-2);

more preferably, residue of formula (RES-I) is residue of formula (RES-I-2) and compound of formula (RIVA-Ia) is compound of formula (RIVA-la).

Details for ST4 are disclosed in US 2003/0153610 Al .

Preferably, compound of formula (III) in ST2 and in ST4 in the method for preparation of compound of formula (RIVA-I) is compound of formula (III-l) or compound of formula (III-2);

more preferably, compound of formula (III) is compound of formula (ΙΠ-2).

Preferably, REAC4 is done in a solvent SOLV4, SOLV4 is selected from the group consisting of halogenated hydrocarbons, ethers, alcohols, hydrocarbons, dimethylformamide, dimethyl sulphoxide, acetonitrile, pyridine, hexamethylphosphoric triamide, water and mixtures thereof.

Halogenated hydrocarbons are preferably selected from the group consisting of

dichloromethane, trichloromethane, carbon tetrachloride, 1 ,2-dichloroethane, trichloroethane, tetrachloroethane, 1 ,2-dichloroethylene and trichloroethylene.

Ethers are preferably selected from the group consisting of diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether and diethylene glycol dimethyl ether.

Alcohols are preferably selected from the group consisting of methanol, ethanol, propanol, butanol. Hydrocarbons are preferably selected from the group consisting of benzene, xylene, toluene, hexane and cyclohexane.

REAC4 can be done in the presence of a base BAS4, BAS4 can be any customary inorganic or organic base.

BAS4 is preferably selected from the group consisting of alkali metal hydroxide, alkali metal carbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium-tert-butoxide, amide, amine, and mixtures thereof;

alkali metal hydroxide is preferably sodium hydroxide or potassium hydroxide;

alkali metal carbonate is preferably sodium carbonate or potassium carbonate;

amide is preferably selected from the group consisting of sodium amide, lithium

bis-(trimethylsilyl)amide and lithium diisopropylamide;

amine is preferably selected from the group consisting of triethylamine,

diisopropylethylamine, diisopropylamine, 4-N,N-dimethylaminopyridine and pyridine.

BAS4 can be employed in an amount of from 1 to 5 mol, preferably from 1 to 2 mol, based on 1 mol of compound of formula (RIVA-Ia).

Preferably, REAC4 is done at a reaction temperature of from -78 °C to reflux temperature, more preferably from 0 °C to reflux temperature, with the reflux temperature being the reflux temperature under the respective pressure.

Preferably, REAC4 is done at a pressure of from 0.5 to 5 bar, more preferably at atmospheric pressure.

In case that compound of formula (RIVA-I) is compound of formula (RIVA-1) and residue of formula (RES-I) is residue of formula (RES-I-2),

then in another preferred embodiment the preparation of compound of formula (RIVA-1) starting from compound of formula (III) with residue of formula (RES-I) being residue of formula (RES-I-2) has a step ST5;

details for ST5 are disclosed in US 2015/0133657 Al;

ST5 is done after ST2; ST5 comprises a reaction REAC5, in REAC5 compound of formula (III) with residue of formula (RES-I) being residue of formula (RES-I-2) is reacted with a compound of formula (RIVA-10); the reaction product of REAC5 is compound of formula (RIVA-11);

preferably, after ST5 a step ST6 is done;

ST6 comprises a reaction REAC6, in REAC6 compound of formula (RIVA-11) is reacted with a compound of formula (RIVA-12) in the presence of phosgene or a phosgene equivalent;

the reaction product of REAC6 is compound of formula (RIVA-13);

preferably, after ST6 a step ST7 is done;

ST7 comprises a reaction REAC7, in REAC7 compound of formula (RIVA-13) is cyclized to obtain compound of formula (RIVA-1). The phosgene equivalent is preferably diphosgene or triphosgene or a carbon monoxide equivalent.

A carbon monoxide equivalent is preferably carbonyldiimidazole or disuccinimidyl carbonate.

Compound of formula (RIVA-10) can also be used in form of a salt thereof, preferably as a hydrochloride salt. Compound of formula (RIVA-10) is a known compound and can be prepared according to known method, e.g. as disclosed in US Patent 6,107,519 or in US 2015/0133657 Al .

Preferably, REAC5 is done in the presence of a base, such as sodium bicarbonate.

Preferably, REAC5 is done in a solvent, the solvent can be ethyl acetate, hexane, water,

toluene or a mixture thereof.

Preferably, the reaction temperature of REAC5 is from 0 to 40 °C.

Preferably, the reaction time of REAC5 is from 0.5 to 10 h.

The compound of formula (RIVA-11) may be isolated from the reaction mixture after REAC5 by methods including layer separation, concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.

Preferably, REAC6 is done in a solvent. The solvent in REAC6 can be dichloromethane, dichloroethane, or a mixture thereof.

REAC6 can be done in the presence of a base, The base in REAC6 can be pyridine,

dimethylaminopyridine, triethylamine, sodium carbonate, potassium carbonate, or a mixture thereof; more preferably pyridine, triethylamine, sodium carbonate, potassium carbonate, or a mixture thereof.

Preferably, the reaction time of REAC6 is from 0.5 to 10 h.

Preferably, the reaction temperature of REAC6 is from 0 to 35 °C.

Preferably, in a first step of REAC6 the phosgen or phosgene equivalent is mixed with

compound of formula (RIVA-11), optionally also with the base of REAC6, optionally in the solvent of REAC6, thereafter in a second step of REAC6 compound of formula

(RIVA-12) is added.

Preferably, the reaction time of the first step of REAC6 is from 0.5 to 4 h.

Preferably, the reaction temperature of the first step of REAC6 is from 5 to 25 °C.

Preferably, the reaction time of the second step of REAC6 is from 0.5 to 6 h.

Preferably, the reaction temperature of the second step of REAC6 is from 10 to 35 °C. The compound of formula (RIVA-13) may be isolated from the reaction mixture after REAC6 by methods including layer separation, concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.

Preferably, the cyclization of REAC7 is done in a solvent. The solvent in REAC7 can be

acetone, acetonitrile, methanol, ethanol, isopropanol, dioxane, tetrahydofuran, water, or a mixture thereof.

REAC7 can be done in the presence of a base. The base in REAC7 can be potassium

carbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride, or a mixture thereof.

The base in REAC7 may be added to the mixture containing the compound of formula

(RIVA-13) and the solvent of REAC7 or a mixture containing the compound of formula (RIVA-13) in which it is formed in RE AC 6.

Preferably, the reaction temperature of REAC7 is of from 10 to 40 °C.

Preferably, the reaction time of REAC7 is from 2 to 15 h.

Compound of formula (RIVA-I), compound of formula (RIVA-II) and compound of formula (RIVA-1) may be isolated from any reaction mixture by methods including layer separation, concentration, distillation, decantation, filtration, evaporation,

centrifugation, or a combination thereof, and may further be dried.

Examples

Example 1: 2-thiophene carbonyl chloride

A mixture of 2-acetylthiophene (0.108 ml, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), and disulfur dichloride (0.240 ml, 3.0 mmol) was stirred at 137 °C for 18 h. The mixture was diluted with CDC1 3 (2 ml), an internal standard was added (iBu 3 P0 4 , 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that 2-thiophene carbonyl chloride (78% yield) had been formed.

1H NMR (CDC1 3 , 400 MHz) delta = 7.99 (d, br, J = 4 Hz, 1H), 7.83 (d, br, J = 4 Hz, 1H), 7.20 (t, J = 4 Hz, 1H).

13 C NMR (CDC1 3 , 100 MHz) delta = 159.5, 137.9, 137.7, 137.1, 128.6.

Example 2: 5-chloro-2-thiophene carbonyl chloride

A mixture of 2-acetyl-5-chloro-thiophene (0.163 g, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), and disulfur dichloride (0.240 ml, 3.0 mmol) was stirred at 137 °C for 20 h. The mixture was diluted with CDC1 3 (2 ml), an internal standard was added (iBu 3 P0 4 , 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that 5-chloro-2-thiophene carbonyl chloride (68%o yield) had been formed.

1H NMR (CDC1 3 , 400 MHz) delta = 7.80 (d, J = 4 Hz, 1H), 7.06 (d, J = 4 Hz, 1H).

1 3 C NMR (CDC1 3 , 100 MHz) delta = 158.5, 143.1, 137.5, 134.9, 128.3.

Example 3: 4-fluorobenzoyl chloride

A mixture of 4-fluoroacetophenone (0.138 g, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), and disulfur dichloride (0.240 ml, 3.0 mmol) was stirred at 137 °C for 20 h. The mixture was diluted with CDC1 3 (2 ml), an internal standard was added (iBu 3 P0 4 , 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that 4-fluorobenzoyl chloride (81% yield) had been formed.

1H NMR (CDC1 3 , 400 MHz) delta = 8.15 (m, 2H), 7.20 (m, 2H).

13 C NMR (CDC1 3 , 100 MHz) delta = 168.3, 166.8, 165.7, 134.1, 134.0, 129.3, 116.3, 116.1.

Example 4: 4-methoxybenzoyl chloride

A mixture of 4-methoxyacetophenone (0.150 g, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), and disulfur dichloride (0.240 ml, 3.0 mmol) was stirred at 137 °C for 20 h. The mixture was diluted with CDC1 3 (2 ml), an internal standard was added (iBu 3 P0 4 , 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that 4-methoxybenzoyl chloride (91% yield) had been formed.

1H NMR (CDCls, 400 MHz) delta = 7.96 (d, J = 8 Hz, 2H), 6.86 (d, J = 8 Hz, 2H), 3.80 (s, 3H).

1 3 C NMR (CDCI3, 100 MHz) delta = 166.0, 164.4, 132.9, 124.3, 113.2, 54.8. Example 5: 3-(trifluoromethyl)benzoyl chloride

A mixture of 3-(trifluoromethyl)acetophenone (0.188 g, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), and disulfur dichloride (0.240 ml, 3.0 mmol) was stirred at 137 °C for 20 h. The mixture was diluted with CDCI3 (2 ml), an internal standard was added (1BU3PO4, 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that

3-(trifluoromethyl)benzoyl chloride (76% yield) had been formed.

1H NMR (CDCI3, 400 MHz) delta = 8.37 (s, 1H), 8.32 (d, J = 8 Hz, 1H), 7.96 (d, J = 8 Hz, 1H), 7.71 (t, J = 8 Hz, 1H).

1 3 C NMR (CDCI3, 100 MHz) delta = 167.2, 134.2, 134.0, 131.74 (quartett, J = 32 Hz), 131.6 (quartett, J = 3 Hz), 129.8, 127.9 (quartett, J = 3 Hz), 123.1 (quartett, J = 270 Hz, CF 3 ).

Example 6: 2-thiophene carbonyl chloride

A mixture of 2-acetylthiophene (0.108 ml, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), and disulfur dichloride (0.320 ml, 4.0 mmol) was stirred at 70 °C for 3.5 h. Then it was stirred at 137 °C for 18 h. The mixture was diluted with CDCI3 (2 ml), an internal standard was added (1BU3PO4, 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that 2-thiophene carbonyl chloride (86% yield) had been formed. Example 7: benzoyl chloride

A mixture of acetophenone (0.117 ml, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), and disulfur dichloride (0.320 ml, 4.0 mmol) was stirred at 70 °C for 3.5 h. Then it was stirred at 137 °C for 18 h. The mixture was diluted with CDCI3 (2 ml), an internal standard was added

(1BU3PO4, 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that benzoyl chloride (82%> yield) had been formed.

1H NMR (CDCI3, 400 MHz) delta = 8.10 (d, J = 8 Hz, 2H), 7.68 (t, J = 8 Hz, 1H), 7.51 (t, J = 8 Hz, 2H).

13 C NMR (CDCI3, 100 MHz) delta = 168.2, 135.2, 134.2, 131.2, 128.8. Example 8: furan-2-carbonyl chloride

A mixture of 2-acetylfuran (0.100 ml, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), and disulfur dichloride (0.280 ml, 3.5 mmol) was stirred at 70 °C for 2.5 h and then at 138 °C for 19 h. The mixture was diluted with CDCI 3 (2 ml), an internal standard was added (1BU 3 PO 4 , 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that furan-2-carbonyl chloride (44% yield) had been formed.

1H NMR (CDCI 3 , 400 MHz) delta = 7.77 (s, 1H), 7.51 (m, 1H), 6.65 (m, 1H).

Example 9: 4-nitrobenzoyl chloride

A mixture of 4'-nitroacetophenone (165 mg, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), and disulfur dichloride (0.280 ml, 3.5 mmol) was stirred at 70 °C for 2.5 h and then at 138 °C for 19 h. The mixture was diluted with CDCI 3 (2 ml), an internal standard was added (1BU 3 PO 4 , 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that 4-nitrobenzoyl chloride (83% yield) had been formed.

1H NMR (CDCI 3 , 400 MHz) delta = 8.38 (d, J = 8 Hz, 2H), 8.33 (d, J = 8 Hz, 2H).

1 3 C NMR (CDCI 3 , 100 MHz) delta = 167.0, 151.6, 138.0, 132.3, 124.1.

Example 10: 2-naphthalenecarbonyl chloride

A mixture of 2-acetylnaphthalene (170 mg, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), and disulfur dichloride (0.280 ml, 3.5 mmol) was stirred at 70 °C for 2.5 h and then at 138 °C for 19 h. The mixture was diluted with CDCI 3 (2 ml), an internal standard was added (1BU 3 PO 4 , 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that

2-naphthalenecarbonyl chloride (82% yield) had been formed.

1H NMR (CDCI 3 , 400 MHz) delta = 8.69 (s, 1H), 8.04 to 7.94 (m, 2H), 7.87 (d, J = 8 Hz, 2H), 7.66 (t, J = 8 Hz, 1H), 7.58 (t, J = 8 Hz, 1H).

13 C NMR (CDCI 3 , 100 MHz) delta = 168.4, 136.4, 134.8, 132.3, 130.3, 130.0, 129.9, 128.8, 127.9, 127.5, 125.3.

Example 11: 4-phenylbenzoyl chloride

A mixture of 4'-phenylacetophenone (196 mg, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), and disulfur dichloride (0.280 ml, 3.5 mmol) was stirred at 70 °C for 2.5 h and then at 138 °C for 19 h. The mixture was diluted with CDCI 3 (2 ml), an internal standard was added (1BU 3 PO 4 , 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that

4-phenylbenzoyl chloride (83% yield) had been formed. 1H NMR (CDCI 3 , 400 MHz) delta = 8.16 (d, J = 8 Hz, 2H), 7.70 (d, J = 8 Hz, 2H), 7.62 (d, J =

8 Hz, 2H), 7.50-7.39 (m, 3H).

1 3 C NMR (CDCI3, 100 MHz) delta = 168.0, 148.1, 139.1, 132.1, 131.8, 129.2, 128.9, 127.5,

127.4.

Example 12: benzoyl chloride

A mixture of acetophenone (1.618 ml, 15.0 mmol), 3-picoline (0.08 ml, 0.82 mmol), and disulfur dichloride (4.80 ml, 60 mmol) was stirred at 70 °C for 3 h 40 min and then at 137 °C for 17 h. Bulb-to-bulb distillation (10 mbar, 90 to 130 °C) yielded a mixture of benzoyl chloride and disulfur dichloride. The yield of benzoyl chloride, as determined by 1H NMR with iBu 3 P0 4 as internal standard, was 78%.

Example 13: 4-phenylbenzoyl chloride

A mixture of 4'-phenylacetophenone (1.96 g, 9.94 mmol), 3-picoline (0.146 ml, 1.5 mmol), and disulfur dichloride (2.40 ml, 30.0 mmol) was stirred at 60 °C for 2.5 h and then at 138 °C for 15 h. The mixture was allowed to cool to room temperature, diluted with THF (3.0 ml), filtered over cotton, and the THF was evaporated from the filtrate under reduced pressure at room temperature. The residue was mixed with hexane (15 ml), heated to reflux, and decanted while still hot from the dark precipitate. The hexane solution was allowed to crystallize over night at 4 °C. The crystals were filtered off and dried under reduced pressure at room temperature. The solid weighted 1.65 g. Content determination by 1H NMR with an internal standard indicated, that the solid was 82% pure. The yield of 4-phenylbenzoyl chloride was 62%. Example 14: 4-Methoxybenzoyl chloride

To sulfur monochloride (3.60 ml, 45.0 mmol) at 75 °C was added portionwise within 0.5 h a solution of 4-methoxyacetophenone (2.25 g, 15.0 mmol) and pyridine (0.121 ml, 1.5 mmol) in chlorobenzene (2.0 ml) at such a rate that the HC1 formation did not become too violent. When the addition was finished, the mixture was stirred at 75 °C for 0.5 h, and then stirred at reflux (oil bath: 137 °C) for 15 h. Hexane (40 ml) was added, and the mixture was stirred at room temperature for 1 h. The solution was decanted off precipitated sulfur and pyridine hydrochloride, and the solid was rinsed with hexane (5 ml). The combined liquid phases were concentrated under reduced pressure (30 mbar, 40 °C), and the residue was distilled (bulb-to- bulb). 4-Methoxybenzoyl chloride boiled at 160-165 °C (8 mbar). The yield was 72%. Example 15: 4-Phenylbenzoyl chloride

To sulfur monochloride (4.80 ml, 60.0 mmol) at room temperature were added

4-phenylacetophenone (716 mg, 3.31 mmol) and pyridine (0.081 ml, 1.00 mmol), and the mixture was stirred at 80-90 °C for approximately 10 min, when HC1 formation set in. The mixture was then cooled to room temperature with a water bath, and the remainder of 4-phenylacetophenone (total: 3.85 g, 19.6 mmol) and pyridine (total: 0.32 ml, 4.0 mmol) was added in three portions within 20 min. The mixture became increasingly viscous. After 1 h at room temperature the mixture was heated to 140 °C (oil bath temperature), and stirred at 140°C for 16 h. The mixture was then allowed to cool down, and the product was extracted two times by adding hexane (50 ml each time), heating to reflux, and decanting. The combined hexane phases were kept at -30 °C for 3 h, decanted, and the solid was

recrystallized from hexane (150 ml). 4-Phenylbenzoyl chloride (3.06 g, 95% pure, yield: 68%) was obtained as yellow needles.

Example 16: 3,4-Dimethoxybenzoyl chloride

A mixture of 3,4-dimethoxyacetophenone (0.182 g, 1.00 mmol), sulfur monochloride (0.320 ml, 4.0 mmol), and pyridine (0.008 ml, 0.10 mmol) was stirred at 70 °C for 4 h, and then at 136 °C for 18 h. To the mixture was added iBu 3 P0 4 (0.0552 ml, 0.20 mmol) and CDC1 3 , and analysis by 1H NMR indicated that 3,4-dimethoxybenzoyl chloride had been formed in 79% yield.

1H NMR (CDC1 3 , 400 MHz) delta 7.83 (dd, J = 8 Hz, 1 Hz, 1H), 7.53 (d, J = 1 Hz, 1H), 6.94

(d, J = 8 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H)

1 3 C NMR (CDC1 3 , 100 MHz) delta 167.2, 155.2, 149.0, 127.2, 125.5, 112.8, 110.4, 56.3, 56.1