WO2017005606A1

WO2017005606A1 - Method for preparation of carboxylic acid chlorides from methyl ketones with two reagents

Info

Publication number: WO2017005606A1
Application number: PCT/EP2016/065355
Authority: WO
Inventors: Florencio Zaragoza Doerwald
Original assignee: Lonza Ltd
Priority date: 2015-07-09
Filing date: 2016-06-30
Publication date: 2017-01-12
Also published as: TW201713611A

Abstract

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

Description

METHOD FOR PREPARATION OF CARBOXYLIC ACID CHLORIDES FROM METHYL KETONES WITH TWO REAGENTS

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 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. In the following text,

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

chloramine-T CAS 127-65-1;

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 R I CH) i_^ CI ^IIT> the method comprises a step ST2;

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

SULFCHLO and with a compound COMPCHLO;

SULFCHLO is S₂C1₂, SC1₂, or a mixture thereof;

COMPCHLO is selected from the group consisting of sulfuryl chloride, N-chlorosuccinimide, trichloroisocyanuric acid, cyanuric chloride, tosyl chloride, thionyl chloride, chloramine- T, Cl₂, PC1₅ and mixtures 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, residue of formula (RES-I), and

residue of formula (RES-II);

R10 _c/(*)

R102^ I (RES-II)

R103 in formula (RES-I) and in formula (RES-II) denote the bond to the C(0)C1 residue 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_s 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_s 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.

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, 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;

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, C₃ cycloalkyl, C₅ cycloalkyl, C₆ cycloalkyl, Ci_₂ alkoxy, N0₂, CF₃, phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, Ci_₄ alkyl, C₃ cycloalkyl, C₅ cycloalkyl, C₆ cycloalkyl, Ci_ 2 alkoxy, N0₂, and CF₃;

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, Ci_₄ alkyl, C₃ cycloalkyl, C₅ cycloalkyl, C₆ cycloalkyl, Ci_₂ alkoxy, N0₂, CF₃, phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, Ci_₄ alkyl, C₃ cycloalkyl, C₅ cycloalkyl, C₆ cycloalkyl, Ci_ 2 alkoxy, N0₂, and CF₃; 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, C₆ cycloalkyl, Ci_₂ alkoxy, N0₂, CF₃, phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, methyl, ethyl, tert-butyl, C₆ cycloalkyl, Ci_₂ alkoxy, N0₂, and CF₃.

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, 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; 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, C₃ cycloalkyl, C₅ cycloalkyl, C₆ cycloalkyl, Ci_₂ alkoxy, N0₂, CF₃, phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, Ci_₄ alkyl, C₃ cycloalkyl, C₅ cycloalkyl, C₆ cycloalkyl, Ci_ 2 alkoxy, N0₂, and CF₃;

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, C₃ cycloalkyl, C₅ cycloalkyl, C₆ cycloalkyl, Ci_₂ alkoxy, N0₂, CF₃, phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, Ci_₄ alkyl, C₃ cycloalkyl, C₅ cycloalkyl, C₆ cycloalkyl, Ci_ 2 alkoxy, N0₂, and CF₃;

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, C₆ cycloalkyl, Ci_₂ alkoxy, N0₂, CF₃, phenyl, substituted phenyl, the substituted phenyl substituted by 1 substituent selected from the group consisting of F, CI, Br, methyl, ethyl, tert-butyl, C₆ cycloalkyl, Ci_₂ alkoxy, N0₂, and CF₃.

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)CH₃ 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, C0₂R4, C(0)C1, phenyl, 2-pyridyl, N0₂, CN, CF₃, alkyl, and Ci_₂ alkoxy; or

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

N0₂, CN, CF₃, 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, C0₂R4, C(0)C1, phenyl, 2-pyridyl, N0₂, CF₃, methyl, and methoxy; or

R3 is selected from the group consisting of H, F CI, Br, C0₂R4, C(0)C1, phenyl, 2-pyridyl, N0₂, CF₃, 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,

C0₂R4, C(0)C1, phenyl, N0₂, CN, CF₃, 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. 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).

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

also with all their embodiments described herein.

Preferably, the molar amount of SULFCHLO is from 1 to 50 times, more preferably from 1 to 35 times, even more preferably from 1 to 25 times, especially from 1 to 15 times, more especially from 1 to 10 times, even more especially from 1 to 7 times, in particular from 1 to 4 times, more in particular from 1 to 3 times, even more in particular from 1 to 2 times, based on the molar amount of compound of formula (II).

Preferably, any excess of SULFCHLO is recycled.

It is known that S2CI2, also known as disulfur dichloride or even referred to as sulfur monochloride, decomposes upon contact with water, e.g. moisture of air, into HC1, S0₂, and sulfur. It is also known that S₂C1₂ decomposes upon heating into SC1₂, also known as sulfur dichloride, and into other sulfur chlorides. Moreover, S₂C1₂ is prepared by chlorination of sulfur, and, depending on the precise reaction conditions and purification methods used, commercially available S₂C1₂ may contain variable amounts of chlorine and SC1₂. 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 sulfur dichloride, chlorine, hydrogen chloride, S0₂, sulfur, 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.

S₂C1₂ and SC1₂ are equivalent reagents for REAC2. S₂C1₂ is commercially available.

Preferably SULFCHLO is S₂C1₂. COMPCHLO is a chlorinating agent and can be any chlorinating agent commonly used for chlorination.

Preferably, COMPCHLO is selected from the group consisting of sulfuryl chloride, N- chlorosuccinimide, trichloroisocyanuric acid, thionyl chloride, Cl₂, and mixtures thereof; more preferably, COMPCHLO is selected from the group consisting of sulfuryl chloride, trichloroisocyanuric acid, thionyl chloride, Cl₂, and mixtures thereof;

even more preferably, COMPCHLO is sulfuryl chloride, Cl₂ or a mixture thereof;

more preferably, COMPCHLO is sulfuryl chloride.

Preferably, the molar amount of COMPCHLO is from 0.5 to 50 times, more preferably 1 to 50 times, even more preferably from 1 to 35 times, especially from 1 to 25 times, more especially from 1 to 15 times, even more especially from 1 to 10 times, in particular from 1 to 7 times, more in particular from 1 to 4 times, even more in particular from 1 to 3 times, very more in particular from 1 to 2 times, based on the molar amount of compound of formula (II).

The molar amounts of SULFCHLO and of COMPCHLO can be identical or different;

if compound of formula (II) is easily oxidized, or contains easily oxidizable residues , or is easily chlorinated, or contains residues that can be easily chlorinated, such as, for instance, thienyl residue, furyl residue, pyrrolyl residue, indenyl residue, aminophenyl residue, alkoxyphenyl residue, or alkoxynaphthyl residue, then the molar amount of SULFCHLO preferably exceeds the molar amount of COMPCHLO;

if compound of formula (II) is easily reduced, or contains easily reducible residue, such as, for instance, nitro residue, carbonyl residue, sulfoxide residue, nitroso residue, formyl residue, or quinonesresidue, then the molar amount of COMPCHLO preferably exceeds the molar amount of SULFCHLO.

Preferably, the molar amounts of SULFCHLO and of COMPCHLO are identical or different and independently from each other from 1 to 4 times, more preferably from 1 to 3 times, even more preferably from 1 to 2 times, based on the molar amount of compound of formula (II).

Preferably, REAC2 is done in the presence of a base or of a salt of a base. Preferably, the base is a base BAS2 and is selected from the group consisting of pyridine, picoline, chloropyridine, methylethylpyridine, 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 the base is a salt of BAS2 and is selected from the group consisting of

hydrochloride salt, hydrobromide salt, acetate salt and trifluoroacetate salt. Preferably, R10, 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. Preferably, SOLV2 is selected from the group consisting of benzene, toluene, xylene, chlorobenzene, nitrobenzene, anisole, dichlorobenzene, dichloroethane, trichloroethane, and mixtures thereof;

more 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;

even 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 0.1 to 100 times, more preferably from 0.1 to 50 times, even more preferably from 0.5 to 50 times, of the weight of compound of formula (II).

Preferably, any SOLV2 is recycled. Preferably, REAC2 is done in SOLV2.

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.

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.

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

Preferably, TEMP2 is more or less constant over TIME2 or REAC2 is done at at least two different temperatures, firstly at a temperature TEMP2-1 and then at a temperature TEMP2-2;

preferably, TEMP2-1 is from -20 °C to 100 °C, more preferably from -10 °C to 95 °C, even more preferably from 0 °C to 90 °C; preferably, TEMP2-2 is from 85 °C to 250 °C, more preferably from 90 °C to 200 °C, even more preferably from 100 °C to 175 °C.

Preferably, REAC2 is done at TEMP2-1 for a time TIME2-1;

preferably, TIME2-1 is from 0.1 h to 48 h, more preferably from 0.5 h to 30 h, even more preferably from 1 h to 24 h.

Preferably, REAC2 is done at TEMP2-2 for a time TIME2-2;

preferably, TIME2-2 is from 0.9 h to 48 h, more preferably from 1.5 h to 30 h, even more preferably from 2 h to 24 h.

SULFCHLO and COMPCHLO can be mixed with compound of formula (II) simultaneously or consecutively.

It is possible to split up the amount of SULFCHLO and/or the amount of COMPCHLO and/or the amount of compound of formula (II) into two or more portions and then to mix any of these portions in an alternating way with each other in any order,

Preferably, SULFCHLO and COMPCHLO are mixed with compound of formula (II)

simultaneously, or at first SULCHLO is mixed with compound of formula (II) resulting in a first mixture and then COMPCHLO is mixed with said resulting first mixture.

In one especial embodiment, REAC2 is done in two consecutive steps, a first step

STEPMIX2-1 and a second step STEPMIX2-2, in STEPMIX2-1 SULFCHLO is mixed and reacted with compound of formula (II) resulting in a mixture MIX2-1, in

STEPMIX2-2 COMPCHLO is mixed and reacted with MIX2-1 resulting in a mixture MIX2-2.

Preferably, STEPMIX2-1 is done at TEMP2-1 and STEPMIX2-2 is done at TEMP2-2;

with any of the embodiments of TEMP2-1 and TEMP2-2;

more preferably STEPMIX2-1 is done at TEMP2-1 for TIME2-1 and STEPMIX2-2 is done at TEMP2-2 for TIME2-2;

with any of the embodiments of TEMP2-1, TIME2-1, TEMP2-2 and TIME2-2;

especially,

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.

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 C5-8 alkane, C5-8 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'"^H © wherein

R100 is defined as herein, also with all its embodiments, except for residue of formula

(RES-II), 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, 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.

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, BF₃-OEt₂,

perchloric acid, A1C1₃, polymeric sulfonic acid resin, toluene sulfonic acid, HC1, H₂S0₄, H₃P0₄, Si0₂, zeolite, and mixtures thereof;

more preferably, ACIl is selected from the group consisting of thionyl chloride, perchloric acid, A1C1₃, polymeric sulfonic acid resin, montmorillonite, H₃P0₄, and mixtures thereof; especially, ACIl is thionyl chloride, perchloric acid, A1C1₃ or H₃P0₄.

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, CF₃, CH₃, OCF₃, OCH₃, 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);

(IV-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 the use of the method for the preparation of compound of formula (III), said method being the method as defined herein that comprises ST2, in or for the preparation of compound of formula (THIOXA); also with all embodiments as defined herein.

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, 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 herein, also with all their embodiments; and

(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 comprsies 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. Further subject of the invention is the use of the method for the preparation of compound of formula (III), said method being the method as defined herein that comprises ST2, in or for the preparation of compound of formula (RIVA-I); also with all embodiments as defined herein. Examples

Example 1: 2-thiophene carbonyl chloride

To a mixture of 2-acetylthiophene (0.108 ml, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.50 ml) was added S₂CI₂ (0.20 ml, 2.5 mmol) while stirring at room temperature. After stirring for 2.5 h S0₂C1₂ (0.162 ml, 2.0 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 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 had been formed in 83% yield.

1H NMR (CDCI₃, 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).

¹³C NMR (CDCI₃, 100 MHz) delta = 159.5, 137.9, 137.7, 137.1, 128.6. Example 2: 2-thiophene carbonyl chloride

To a mixture of 2-acetylthiophene (4.32 ml, 40.0 mmol), pyridine (0.645 ml, 8.0 mmol), and chlorobenzene (14 ml) was added dropwise S₂CI₂ (6.39 ml, 80.0 mmol) while stirring and cooling to 15 °C with a water bath. After stirring at room temperature for 2.5 h SO₂CI₂ (6.5 ml, 80 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then placed in an oil-bath having a temperature of 142 °C and stirred under slight reflux for 17 h. The mixture was allowed to cool to room temperature, diluted with hexane (40 ml), heated to reflux, decanted hot from a black oil, and then distilled under reduced pressure. The fraction containing 2-thiophene carbonyl chloride (bp 80 °C, 15 mbar) weighted 4.98 g, and had a content of 65% as determined by 1H NMR. The yield of 2-thiophene carbonyl chloride was 56%.

Example 3: 2-thiophene carbonyl chloride

To a mixture of 2-acetylthiophene (0.108 ml, 1.0 mmol) and pyridine (0.008 ml, 0.10 mmol) were added S₂CI₂ (0.24 ml, 3.0 mmol) and then SO₂CI₂ (0.242 ml, 3.0 mmol), and the mixture was stirred at 70 °C for 7.5 h. Then the mixture was stirred at 137 °C for 16.5 h. 1H NMR of the mixture indicated that mainly 2-thiophene carbonyl chloride had been formed.

Example 4: 2-thiophene carbonyl chloride To a mixture of 2-acetylthiophene (0.108 ml, 1.0 mmol), pyridine (0.016 ml, 0.20 mmol), and chlorobenzene (0.35 ml) was added S₂CI₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After stirring for 1 h 45 min, SO₂CI₂ (0.162 ml, 2.0 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 14 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 had been formed in 90% yield.

Example 5: 2-thiophene carbonyl chloride

To a mixture of 2-acetylthiophene (0.108 ml, 1.0 mmol), pyridine (0.016 ml, 0.20 mmol), and chlorobenzene (0.35 ml) was added S₂CI₂ (0.12 ml, 1.5 mmol) while stirring at room temperature. After stirring for 1 h 45 min, SO₂CI₂ (0.162 ml, 2.0 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 14 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 had been formed in 86% yield.

Example 6: 4-nitrobenzoyl chloride

To a mixture of 4-nitroacetophenone (0.165 g, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂CI₂ (0.12 ml, 1.5 mmol) while stirring at room temperature. After stirring for 2.5, S0₂C1₂ (0.162 ml, 2.0 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 1 h. The mixture was then stirred at 132 °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 4-nitrobenzoyl chloride had been formed in 90% yield.

Example 7: benzoyl chloride

To a mixture of acetophenone (0.117 ml, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂CI₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After stirring for 3 h, S0₂C1₂ (0.162 ml, 2.0 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 17 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 had been formed in 87% yield. Example 8: 5-Chloro-2-thiophenecarbonyl chloride

To a mixture of 2-acetyl-5-chlorothiophene (0.161 mg, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂CI₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After 2 h SO₂CI₂ (0.121 ml, 1.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 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 5-chloro-2-thiophene carbonyl chloride had been formed in 80% yield.

1H NMR (PhCl, CDCI₃, 400 MHz) delta = 7.99 (d, J = 4 Hz, 1H), 6.86 (d, J = 4 Hz, 1H).

Example 9: Furan-2-carbonyl chloride

To a mixture of 2-acetylfuran (0.100 ml, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂CI₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After 2 h SO₂CI₂ (0.121 ml, 1.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 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 furan- 2-carbonyl chloride had been formed in 65% yield.

1H NMR (PhCl, CDC1₃, 400 MHz) delta = 7.63 (s, 1H), 7.39 (m, 1H), 6.51 (m, 1H)

Example 10: 4-Methoxybenzoyl chloride

To a mixture of 4'-methoxyacetophenone (150 mg, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂CI₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After 2 h S0₂C1₂ (0.121 ml, 1.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 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 4-methoxybenzoyl chloride had been formed in 86% yield.

1H NMR (PhCl, CDC1₃, 400 MHz) delta = 7.99 (d, J = 8 Hz, 2H), 6.86 (d, J = 8 Hz, 2H), 3.78 (s, 3H).

Example 11: 4-Phenylbenzoyl chloride To a mixture of 4-acetylbiphenyl (196 mg, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂CI₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After 2 h SO₂CI₂ (0.121 ml, 1.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 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

4-phenylbenzoyl chloride had been formed in 90% yield.

1H NMR (PhCl, CDCI₃, 400 MHz) delta = 8.06 (d, J = 8 Hz, 2H), 7.58 (d, J = 8 Hz, 2H), 7.53 (d, J = 8 Hz, 2H), 7.43-7.32 (m, 3H).

Example 12: 2-Naphthalenecarbonyl chloride

To a mixture of 2-acetylnaphthalene (170 mg, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂CI₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After 2 h SO₂CI₂ (0.121 ml, 1.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 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-naphthalenecarbonyl chloride had been formed in 91% yield.

1H NMR (PhCl, CDCI3, 400 MHz) delta = 8.58 (s, 1H), 7.91 (d, J = 8 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.74 (t, J = 8 Hz, 1H), 7.55 (t, J = 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1H).

Example 13: 4-Fluorobenzoyl chloride

To a mixture of 4'-fluoroacetophenone (0.121 ml, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂CI₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After 2 h S0₂C1₂ (0.121 ml, 1.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 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

4-fluorobenzoyl chloride had been formed in 83% yield.

1H NMR (PhCl, CDC1₃, 400 MHz) delta = 8.04 (m, 2H), 7.07 (m, 2H)

Example 14: 3-(Trifluoromethyl)benzoyl chloride

To a mixture of 3'-(trifluoromethyl)acetophenone (0.152 ml, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂C1₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After 2 h S0₂C1₂ (0.121 ml, 1.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 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 had been formed in 87% yield.

1H NMR (PhCl, CDCI3, 400 MHz) delta = 8.29 (s, 1H), 8.19 (d, J = 8 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.55 (t, J = 8 Hz, 1H).

Example 15: 2-Thiophenecarbonyl chloride - Thionylchloride

To a mixture of 2-acetylthiophene (0.108 ml, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂C1₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After 2 h SOCl₂ (0.109 ml, 1.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 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-thiophenecarbonyl chloride had been formed in 83% yield.

Example 16: 2-Thiophenecarbonyl chloride - Cyanuric chloride

To a mixture of 2-acetylthiophene (0.108 ml, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂C1₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After 2 h cyanuric chloride (189 mg, 1.03 mmol) was added in portions, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 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-thiophenecarbonyl chloride had been formed in 30% yield.

Example 17: Thiophene-2-carbonyl chloride

To sulfur monochloride (16.0 ml, 200 mmol) at room temperature was added 5 ml of a solution of 2-acetylthiophene (12.6 g, 100 mmol) and pyridine (1.61 ml, 20 mmol) in chlorobenzene (40 ml). The mixture was heated to about 80 °C, until a HC1 formation set in. The mixture was then cooled down to room temperature with a water-bath, and the remainder of the 2-acetylthiophene solution was added to the stirred reaction mixture at such a rate, that HC1 formation did not become too violent, what took about 1.5 h. The mixture was then stirred at room temperature for 5 h. Sulfuryl chloride (12.1 ml, 150 mmol) was then added dropwise within 35 min. The resulting mixture was stirred at room temperature for 0.5 h, and then at slight reflux (oil-bath: 140 °C) for 15 h.

The resulting mixture was allowed to cool to room temperature and hexane (200 ml) was added. The mixture was stirred at room temperature for approximately 2 h, whereupon a clear solution and a dark, oily precipitate resulted. The clear solution was decanted off the dark oil, the flask was rinsed with hexane (10 ml), and the combined hexane phases concentrated under reduced pressure. The residue was distilled under vacuum. The main product was collected at 6 mbar, 63 °C. The yield of 2-thiophenecarbonyl chloride was 66%. Example 18: 4-Nitrobenzoyl chloride

To sulfur monochloride (1.20 ml, 15.0 mmol) at room temperature was added 1.5 ml of a solution of 4-nitroacetophenone (1.65 g, 10.0 mmol) and pyridine (0.121 ml, 1.50 mmol) in chlorobenzene (5.0 ml; warming to 50°C was required in order to get a solution). The mixture was heated to about 80 °C, until a HCl formation set in. The mixture was then cooled down to room temperature with a water-bath, and the remainder of the 4-nitroacetophenone solution was added to the stirred reaction mixture at such a rate, that HCl formation did not become too violent, what took about 15 min. The mixture was then stirred at room temperature for 2.5 h. Sulfuryl chloride (1.61 ml, 20.0 mmol) was then added dropwise within 10 min. The resulting mixture was stirred at room temperature for 0.5 h, and then at slight reflux (oil-bath: 137 °C) for 15 h.

The resulting mixture was allowed to cool to room temperature and hexane (40 ml) was added. The mixture was stirred at room temperature for approximately 2 h, whereupon a clear solution and a dark, oily precipitate resulted. The clear solution was decanted off the dark oil, the flask was rinsed with hexane (3 ml), and the combined hexane phases were allowed to crystallize at 4 °C for 6 h. Filtration, washing with hexane (3 ml) and drying under reduced pressure yielded 882 mg of 4-nitrobenzoyl chloride, with a content of 93%, as determined by 1H NMR with an internal standard. The mother liquor was kept at -20 °C overnight, whereby additional 545 mg of product with a content of 91% was obtained.

The total yield of 4-nitrobenzoyl chloride was 71%.

1H NMR (CDC1₃, 400 MHz) delta 8.40-8.36 (m, 2H), 8.34 to 8.30 (m, 2H)

1³C NMR (CDCI3, 100 MHz) delta 167.0, 151.6, 138.0, 132.2, 124.0

Example 19: 4-Phenylbenzoyl chloride To sulfur monochloride (1.6 ml, 20 mmol) at room temperature was added 2 ml of a solution of 4-phenylacetophenone (1.96 g, 10.0 mmol) and pyridine (0.121 ml, 1.50 mmol) in chlorobenzene (10.0 ml; warming to 50°C was required in order get a solution). The mixture was heated to about 80 °C, until a HCl formation set in. The mixture was then cooled down to room temperature with a water-bath, and the remainder of the 4-phenylacetophenone solution was added to the stirred reaction mixture at such a rate, that HCl formation did not become too violent, what took about 45 min. The mixture was then stirred at room temperature for 4 h. Sulfuryl chloride (1.21 ml, 15.0 mmol) was then added dropwise within 20 min. The resulting mixture was stirred at room temperature for 0.5 h, and then at slight reflux (oil-bath: 137 °C) for 15.5 h.

The mixture was allowed to cool to room temperature and hexane (40 ml) was added. The mixture was stirred at room temperature for approximately 2 h, whereupon a clear solution and a dark, oily precipitate resulted. The clear solution was decanted off the dark oil, the flask was rinsed with hexane (3 ml), and the combined hexane phases were allowed to crystallize at 20 °C for 0.5 h and at 4 °C for 3.5 h. Filtration, washing with hexane (6 ml) and drying under reduced pressure yielded 1.59 g of 4-phenylbenzoyl chloride, with a content of 96%, as determined by 1H NMR with an internal standard. The mother liquor was kept at -20 °C overnight, whereby additional 316 mg of product with a content of 92% was obtained.

The total yield of 4-phenylbenzoyl chloride was 83%.

1H NMR (CDCls, 400 MHz) delta 8.17 (m, 2H), 7.71 (m, 2H), 7.62 (m, 2H), 7.50 to 7.40 (m, 3H)

¹³C NMR (CDCI3, 100 MHz) delta 168.1, 148.1, 139.1, 132.1, 131.9, 129.1, 128.9, 127.5, 127.4 Example 20: 2-Naphthalenecarbonyl chloride

To a solution of 2-acetylnaphthalene (3.42 g, 20.1 mmol) and pyridine (0.242 ml, 3.0 mmol) in chlorobenzene (7.0 ml) was added sulfur monochloride (3.20 ml, 40 mmol) at room temperature, and the solution was stirred at room temperature for 3.5 h, while cooling with a water-bath so that the temperature was kept at approximately 20 °C. Then sulfuryl chloride (2.43 ml, 30.1 mmol) was added dropwise at room temperature within 0.5 h, and the mixture was stirred at room temperature for further 40 min. The mixture was then stirred at reflux (oil bath: 137 °C) for 18 h.

Hexane (50 ml) was added, and the solution was decanted off precipitated sulfur and pyridine hydrochloride. The solid was rinsed with hexane (10 ml). The combined liquid phases were concentrated under reduced pressure (30 mbar, 40 °C), and the residue was distilled (bulb-to- bulb). 2-Naphthalenecarbonyl chloride boiled at 210-220 °C (10 mbar). The yield was 78%.

Example 21: 3,4-Dimethoxybenzoyl chloride

To a mixture of 3',4'-dimethoxyacetophenone (0.180 mg, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S₂CI₂ (0.16 ml, 2.0 mmol) while stirring at room temperature. After 2 h S0₂C1₂ (0.121 ml, 1.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 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 3,4-dimethoxybenzoyl chloride had been formed in 77% yield.

1H NMR (PhCl, CDCI₃, 400 MHz) delta = 7.75 (d, J = 8 Hz, 1H), 7.45 (s, 1H), 6.82 (d, J = 8 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H). Example 22: Naphthalene-2-carbonyl chloride

To sulfur monochloride (2.4 ml, 30 mmol) at room temperature was added 1 ml of a solution of 2-acetylnaphthalene (2.556 g, 15.02 mmol) and pyridine (0.182 ml, 2.25 mmol) in chlorobenzene (5 ml). The mixture was stirred at about 80 °C, until a steady HC1 evolution set in, which happened after about 10 min. The mixture was then cooled to room temperature with a water bath, and the remainder of the ketone solution was added to the stirred reaction mixture in ca. 20 min. The mixture was then stirred at room temperature for 5.5 h. Sulfuryl chloride (1.818 ml, 22.5 mmol) was then added dropwise within 10 min. The resulting mixture was stirred at room temperature for 0.5 h, and then at slight reflux (oil bath: 137 °C) for 15 h.

Chlorobenzene and sulfur chlorides were evaporated (40 mbar, 120 °C), and the residue was diluted with hexane (50 ml). The mixture was stirred at room temperature for 15 min, filtered, and after rinsing with hexane (20 ml) the combined hexane phases were allowed to crystallize at -30 °C. Inverse filtration, washing with cold hexane, and drying under reduced pressure yielded 2.17 g of naphthalene-2-carbonyl chloride, with a purity of 90%>. The yield was 69%>. 1H NMR (CDCI₃, 400 MHz) delta 8.68 (s, 1H), 8.00 (dd, J = 8 Hz, 1 Hz, 1H), 7.95 (d, J = 8 Hz, 1H), 7.86 (m, 2H), 7.65 (m, 1H), 7.57 (m, 1H)

1³C NMR (CDCI₃, 100 MHz) delta 168.4, 136.4, 134.8, 132.3, 130.4, 130.0, 129.9, 128.8, 127.9, 127.4, 125.3 Example 23: 4-Methoxybenzoyl chloride

To sulfur monochloride (3.2 ml, 40 mmol) at room temperature was added 2 ml of a solution of 4-methoxyacetophenone (3.03 g, 20.1 mmol) and pyridine (0.242 ml, 3.0 mmol) in chlorobenzene (7 ml). The mixture was stirred at about 80 °C, until a steady HC1 evolution set in, which happened after about 10 min. The mixture was then cooled to room temperature with a water bath, and the remainder of the ketone solution was added to the stirred reaction mixture in 30 min. The mixture was then stirred at room temperature for 6 h. Sulfuryl chloride (2.43 ml, 30.0 mmol) was then added dropwise within 10 min. The resulting mixture was stirred at room temperature for 0.5 h, and then at slight reflux (oil bath: 137 °C) for 15 h. Chlorobenzene and sulfur chlorides were evaporated (40 mbar, 120 °C), and the residue was dissolved in THF (5 ml), the solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was diluted with hexane (30 ml). The mixture was stirred at room temperature for 15 min, decanted, and allowed to crystallize at -30 °C for 3 h. Inverse filtration and drying under reduced pressure yielded 63% (purity 89%) of 4-methoxybenzoyl chloride.

1H NMR (CDC1₃, 400 MHz) delta 8.07 (d, J = 8 Hz, 2H), 6.96 (d, J = 8 Hz, 2H), 3.90 (s, 3H) ¹³C NMR (CDCI3, 100 MHz) delta 167.1, 165.4, 134.0, 125.5, 114.3, 55.8

Example 24: 3,4-Dimethoxybenzoyl chloride

To sulfur monochloride (2.4 ml, 30 mmol) at room temperature was added 1 ml of a solution of 3,4-dimethoxyacetophenone (2.71 g, 15.02 mmol) and pyridine (0.182 ml, 2.25 mmol) in chlorobenzene (5 ml). The mixture was stirred at about 80 °C, until a steady HC1 evolution set in, which happened after about 10 min. The mixture was then cooled to room temperature with a water bath, and the remainder of the ketone solution was added to the stirred reaction mixture in 20 min. The mixture was then stirred at room temperature for 5 h. Sulfuryl chloride (1.818 ml, 22.5 mmol) was then added dropwise within 10 min. The resulting mixture was stirred at room temperature for 0.5 h, and then at slight reflux (oil bath: 137 °C) for 15 h. Chlorobenzene and sulfur chlorides were evaporated (40 mbar, 120 °C), and the residue was dissolved in THF (5 ml), the solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was diluted with hexane (60 ml). The mixture was heated to reflux, decanted, and allowed to crystallize at 4 °C overnight. The solid was recrystallized once more from toluene (6 ml), to yield 47%> (purity 92%>) of 3,4-dimethoxybenzoyl chloride.

1H NMR (CDCI3, 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) C NMR (CDCI₃, 100 MHz) delta 167.2, 155.2, 149.0, 127.2, 125.5, 112.8, 110.4,56.3,56.1

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 and with a compound COMPCHLO;

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,

residue of formula (RES-II);

Ri0 _c/(*)

R102^ I (RES-II)

R103 in formula (RES-I) and in formula (RES-II) denote the bond to the C(0)C1 residue 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

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 RlOO 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

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

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

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

R101 , R102 and R103 are identical or different and independently from each other C_1-10 alkyl, F, CI, or phenyl.

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

XI is O or S.

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

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

substituted naphthyl, residue of formula (RES -I) with XI being O or S, and residue of formula (RES-II).

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

SULFCHLO is S₂C1₂.

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

COMPCHLO is selected from the group consisting of sulfuryl chloride, N-chlorosuccinimide, trichloroisocyanuric acid, thionyl chloride, Cl₂, and mixtures thereof.

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

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

13. Method according to claim 12, wherein

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

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

R10, 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 the base is selected from the group consisting of hydrochloride salt, hydrobromide salt, acetate salt and trifluoroacetate salt.

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

REAC2 is done in a solvent.

15. Method according to claim 14, wherein

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

16. Method according to one or more of claims 1 to 15, wherein

SULFCHLO and COMPCHLO are mixed with compound of formula (II) simultaneously, or at first SULCHLO is mixed with compound of formula (II) and then COMPCHLO is added to the mixture.

17. Method according to one or more of claims 1 to 16, 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;

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

18. Method according to claim 17, 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.

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

(THTOXA)

wherein the method comprises the step ST2;

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) as defined in claim 1 with XI being S.

20. Method according to claim 19, wherein

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

ST1 is done before ST2;

wherein ST1 is as defined in claim 17 or 18.

21. Method according to claim 19 or 20, wherein

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

22. 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, CF₃, CN, N0₂, C(0)-NH₂,

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

23. Method according to claim 22, wherein

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

ST 1 is done before ST2;

wherein ST1 is as defined in claim 17 or 18.

24. Method according to claim 22 or 23, 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.

25. Method according to one or more of claims 22 to 24, wherein

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

26. Use of the method as defined in one or more of claims 1 to 18, in the preparation of compound of formula (THIOXA), the compound of formula (THIOXA) as defined in claim

19.

27. Use of the method as defined in one or more of claims 1 to 18, in the preparation of compound of formula (RIVA-I) , the compound of formula (RIVA-I) as defined in claim 22.