TW201713610A - Method for preparation of carboxylic acid chlorides from methyl ketones - Google Patents

Abstract

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

Description

Method for preparing carboxylic acid chloride from methyl ketone

The present invention discloses a process for preparing a carboxylic acid chloride starting from a methyl ketone using sulfur chloride.

Carboxylic acid chlorides are important synthetic intermediates useful in the preparation of guanamines, esters, ketones and various heterocycles. Neodymium chloride is usually prepared from carboxylic acids, but in some cases these carboxylic acids are not readily available.

A process for the direct conversion of an aromatic or heteroaromatic hydrocarbon to aryl sulfonium chloride comprises the reaction of the aromatic or heteroaromatic hydrocarbon with oxalic acid chloride. US 2002/0062043 A1 discloses a process for the preparation of benzamidine chloride by reacting biphenyl with grass mash in the presence of Lewis acid. However, grass ash is a relatively expensive reagent.

Newman, M.S., et al., Organic Syntheses 1937, 17, 65, discloses the preparation of beta-naphthoic acid from methyl-beta-naphthone by haloform reaction. In order to obtain mercapto chloride, a second reaction step is required. The haloform reaction needs to be carried out in water as well as in a dilute system, and the residual hypochlorite needs to be destroyed after the reaction, which can be carried out, for example, with sulfite. All of this produces significant amounts of wastewater and salts such as chlorides, sulfites and sulfates.

Treatment of aromatic or heteroaromatic hydrocarbons with phosgene, diphosgene or triphosgene in the presence of Lewis acid typically produces significant amounts of by-products of the corresponding symmetric ketones. Neubert, M.E., et al., Organic Syntheses 1983, 61, 8, discloses the preparation of benzamidine chloride from phosgene and discusses that the formation of ketones can be reduced by, inter alia, the use of an excess of grass mash, which is again expensive.

However, Friedel-Crafts acetylation of aromatic or heteroaromatic hydrocarbons is usually carried out in high yields from a wide variety of different starting materials. If an electron-rich aromatic or heteroaromatic hydrocarbon is used as the starting material, Friedel-Crafts acetylation can usually be carried out using only a catalytic amount of acid and in an environmentally friendly manner (see, for example, G. Sartori, R Maggi, Chem. Rev. 2006, 1077-1104). Therefore, an ethoxylated aromatic or heteroaromatic hydrocarbon is a readily available compound.

Thiophene chloride is an important synthetic intermediate, for example for the synthesis of pharmaceuticals and agrochemicals. They can be prepared in a number of different ways, each with advantages and disadvantages. Of particular interest are those methods that require only inexpensive starting materials and reagents, are easy to perform, and produce only a small amount of waste.

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

The preparation of compounds of the formula (THIOXA-1) is disclosed in WO 2014/008257 A2.

5-Chloro-2-thiophenecarboxamidine chloride is an intermediate for the preparation of rivaroxaban (antithrombotic agent) having a CAS number of 366789-02-8 and a chemical name of (S)-5-chloro- N-{2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolin-5-ylmethyl}thiophene-2-carboxamide And it is a compound of the formula (RIVA-1).

A rivaroxaban and a process for its preparation are disclosed in US 2003/0153610 A1, which discloses another process for its preparation, US Patent No. 6,107,519, which discloses certain precursors used in the preparation.

Adiwidjaja et al., Angew. Chem. Int. Ed. Engl. 1980, 19, 563-564, reported the reaction of sulfinium chloride with acetophenone in pyridine, which provides yields of 36% and 15 respectively. a mixture of % benzamidine chloride and a compound of formula (8b).

Thus Adiwidjaja discloses that the conversion of an aliphatic methyl ketone to an aromatic methyl ketone reduces yield and results in a mixture of the desired product and by-products.

Edwards et al., J. Org. Chem. 1966, 31, 1283 to 1285, in the second paragraph of the right column on page 1284, discloses that thiophenes are acid sensitive and are polymerized to tar once treated with aluminum chloride: "Using thiophene, chlorination Aluminum and the same anhydride, the formation of tar is so great that the result is meaningless."

There is a need for a process for the preparation of a carboxylic acid chloride such as benzamidine chloride or thiophene guanidine chloride which has few steps with high yields, allowing the preparation to be free of by-products or at least only minor amounts of The product, starting from a relatively inexpensive material, does not necessarily require expensive grassy chlorine, does not necessarily require aluminum chloride or hypochlorite, and does not produce large amounts such as, for example, aluminum chloride, hypochlorite or sulfite. Salts such as salts that can be produced can even be carried out without a solvent, and it is not mandatory to use a continuous reactor unit when it is expanded to accommodate production.

Unexpectedly, a method for preparing a carboxylic acid chloride such as benzamidine chloride and thiophene guanidine chloride which satisfies the above requirements is used, which is to use a relatively inexpensive sulfur chloride such as acetophenone and ethyl hydrazine. The corresponding methyl ketone precursor such as thiophene is initiated. Contrary to what is disclosed by Adiwidjaja and Edwards, the yield and purity of the process are quite high, without the formation of significant amounts of by-products as mentioned in the Adiwidjaja publication, without the need for aluminum chloride, hypochlorite Or sulfite, the reaction can be carried out even without a solvent, it is not mandatory to require a continuous reactor unit, and methyl ketone as a substrate is readily available (for example, in the case of aromatic methyl ketones, Friedel-Krafts is obtained and is therefore relatively inexpensive. It is advantageous not to use grass chlorinated chlorine, but instead use sulphur chloride, which is less than one-twentieth of the molecular weight of the grass.

Unexpectedly, the yield of the claimed method, as shown in Example 7 and Example 12, far exceeds 70%, which is higher than the yield of the method disclosed by Adiwidjaja, Adiwidjaja reported The yield of the corresponding conversion of acetophenone to benzamidine chloride was 36%.

In the text below, the ambient pressure is usually 1 bar, depending on the weather; halide refers to F ^- , Cl ^- , Br ^- or I ^- , preferably Cl ^- , Br ^- or I ^- , more preferably Cl ^- or Br ^- Halogen means F, Cl, Br or I, preferably Cl, Br or I, more preferably Cl or Br; MeTHF methyltetrahydrofuran MTBE methyl tert-butyl ether THF tetrahydrofuran; wt-% by weight; if not stated otherwise .

The subject of the invention is a process for the preparation of a compound of formula (III); The method comprises the step ST2; ST2 comprises the reaction REAC2 of the compound of the formula (II) and the compound SULFCHLO; SULFCHLO is S ₂ Cl ₂ , SCl ₂ , or a mixture thereof; wherein R100 is selected from the group consisting of phenyl groups, which are independently selected from halogen, C via 1, 2, 3, 4 or 5 identical or different _1-6 alkyl, C _3-8 cycloalkyl, C _1-4 alkoxy, NO ₂ , CF ₃ , CN, N(R13)(R14)R15, benzyl, phenyl and substituted phenyl a substituted group of substituted phenyl groups, wherein the substituted phenyl group is selected from 1, 2, 3, 4 or 5 identical or different independently of each other selected from the group consisting of halogen, C _1-6 alkyl, C ₃ Substituted by a group consisting of _-8 cycloalkyl, C _1-4 alkoxy, NO ₂ , CF ₃ , CN and N(R16)(R17)R18, naphthyl, via 1, 2, 3, 4, 5, 6 or 7 identical or different independently of each other selected from the group consisting of halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-4 alkoxy, NO ₂ , CF ₃ , CN, N (R13) (R14) a substituted naphthyl group of a group consisting of R15, a benzyl group, a phenyl group and a substituted phenyl group, wherein the substituted phenyl group is the same as 1, 2, 3, 4 or 5 Or different from each other independently selected from halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-4 alkoxy, NO ₂ , CF ₃ , C Substituent substitution of the group consisting of N and N(R16)(R17)R18, and a residue of the formula (RES-I); The (*) in the formula (RES-I) represents a bond respectively bonded to the C(O)Cl residue in the formula (III) and the C(O)CH ₃ residue in the formula (II); X1 is O , S or N-R110; R13, R14, R15, R16, R17 and R18 are the same or different and are independently selected from the group consisting of H and C _1-8 alkyl; R1, R2 and R3 are the same Or different and independently selected from H, halogen, CO _{2 R} 4 , C(O)Cl, phenyl, 2-pyridyl, NO ₂ , CN, CF ₃ , C _1-8 alkyl and C _1-8 a group consisting of alkoxy groups; or R1 and R2 together represent -CH=CH-CH=CH- and together with the thiophene ring form benzothiophene, and R3 is selected from H, halogen, CO _{2 R} 4 , C(O)Cl, a group consisting of phenyl, 2-pyridyl, NO ₂ , CN, CF ₃ , C _1-8 alkyl and C _1-8 alkoxy; R 4 is C _1-6 alkyl R101, R102 and R103 are the same Or different and independently of each other, C _1-10 alkyl, halogen or phenyl; R110 is C _1-6 alkyl or phenyl.

Preferably, in the case where R100 is a substituted phenyl group, the phenyl group is selected from 1, 2, 3, 4 or 5 identical or different independently of each other from a halogen, a C _1-6 alkyl group, Substituted by a substituent of the group consisting of C _3-6 cycloalkyl, C _1-4 alkoxy, NO ₂ , CF ₃ , CN, benzyl, phenyl, and substituted phenyl, substituted phenyl 1, 2, 3, 4 or 5 identical or different independently of each other selected from the group consisting of halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, NO ₂ , CF ₃ Substituted with a substituent of the group consisting of CN; more preferably, the phenyl group is independently selected from F, Cl, Br, C _1-4 alkyl, C ₃ ring via 1, 2 or 3 identical or different a substituent substituted with a group consisting of an alkyl group, a C ₅ cycloalkyl group, a C ₆ cycloalkyl group, a C _1-2 alkoxy group, a NO ₂ , a CF ₃ group, a phenyl group, and a substituted phenyl group, wherein the substituted group The phenyl group is selected from the group consisting of F, Cl, Br, C _1-4 alkyl, C ₃ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C _1-2 alkoxy, NO ₂ and CF. Substituting a substituent of the group consisting of ₃ ; even more preferably, the phenyl group is independently selected from each other via 1 or 2 identical or different Of F, Cl, Br, C _1-4 alkyl, C ₃ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C _1-2 alkoxy, NO _2, CF _3, phenyl, and by Substituted by a substituent consisting of a substituted phenyl group, wherein the substituted phenyl group is selected from the group consisting of F, Cl, Br, C _1-4 alkyl, C ₃ cycloalkyl, C ₅ cycloalkyl, C Substituent substitution of a group consisting of ₆ cycloalkyl, C _1-2 alkoxy, NO ₂ and CF ₃ ; in particular, the phenyl group is independently selected from F, Cl via 1 or 2 identical or different Substituted by a group consisting of Br, methyl, ethyl, tert-butyl, C ₆ cycloalkyl, C _1-2 alkoxy, NO ₂ , CF ₃ , phenyl, and substituted phenyl, The substituted phenyl group is composed of one selected from the group consisting of F, Cl, Br, methyl, ethyl, t-butyl, C ₆ cycloalkyl, C _1-2 alkoxy, NO ₂ and CF ₃ . Substituent substitution.

Preferably, in the case where R100 is a substituted naphthyl group, the naphthyl group is selected from 1, 2, 3, 4 or 5 identical or different independently of each other from a halogen, a C _1-6 alkyl group, Substituted by a substituent of the group consisting of C _3-6 cycloalkyl, C _1-4 alkoxy, NO ₂ , CF ₃ , CN, benzyl, phenyl, and substituted phenyl, wherein the substituted phenyl group of 3, 4 or 5 identical or different are independently selected from the group consisting of halo, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, NO _2, CF Substituting a substituent of the group consisting of ₃ and CN; more preferably, the naphthyl group is independently selected from F, Cl, Br, C _1-4 alkyl, C ₃ naphthenic groups via 1 or 2 identical or different independently of each other. Substituted by a substituent of the group consisting of C ₅ cycloalkyl, C ₆ cycloalkyl, C _1-2 alkoxy, NO ₂ , CF ₃ , phenyl and substituted phenyl, substituted phenyl Consists of one selected from the group consisting of F, Cl, Br, C _1-4 alkyl, C ₃ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C _1-2 alkoxy, NO ₂ and CF ₃ Substituted substituents; even more preferably, the naphthyl group is independently selected from F or Cl via 1 or 2 identical or different Br, C _1-4 alkyl, C ₃ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C _1-2 alkoxy, NO _2, CF _3, phenyl and substituted phenyl groups Substituted substituents of the group wherein the substituted phenyl group is selected from the group consisting of F, Cl, Br, C _1-4 alkyl, C ₃ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, Substituent substitution of a group consisting of C _1-2 alkoxy, NO ₂ and CF ₃ ; in particular, the naphthyl group is independently selected from F, Cl, Br, methyl via 1 or 2 identical or different Substituted by a substituent of the group consisting of ethyl, tert-butyl, C ₆ cycloalkyl, C _1-2 alkoxy, NO ₂ , CF ₃ , phenyl, substituted phenyl, substituted phenyl Substituted by a substituent selected from the group consisting of F, Cl, Br, methyl, ethyl, t-butyl, C ₆ cycloalkyl, C _1-2 alkoxy, NO ₂ and CF ₃ .

Preferably, and in the case where R100 is a residue of the formula (RES-I), the C(O)Cl residue in the compound of formula (III) and the C(O)CH ₃ residue of the compound of formula (II) are both At the 2 position of the residue of the formula (RES-I).

Preferably, R1, R2 and R3 are the same or different and are independently selected from H, F, Cl, Br, CO _{2 R} 4 , C(O)Cl, phenyl, 2-pyridyl, NO ₂ , a group consisting of CN, CF ₃ , C _1-4 alkyl and C _1-2 alkoxy; or R 1 and R 2 together represent -CH=CH-CH=CH- and together with the thiophene ring form benzothiophene, and R3 Free choice of H, F, Cl, Br, CO _{2 R} 4 , C (O) Cl, phenyl, 2-pyridyl, NO ₂ , CN, CF ₃ , C _1-4 alkyl and C _1-2 alkoxy a group consisting of; R 4 is a C _1-4 alkyl group; in another preferred embodiment, R 1 , R 2 and R 3 are the same or different and are independently selected from H, Cl, Br, CO _{2 R} 4 , a group consisting of NO ₂ , CN, CF ₃ , C _1-4 alkyl and C _1-2 alkoxy; and R 4 is a C _1-4 alkyl group; more preferably, R 1 , R 2 and R 3 are the same or different And independently of each other selected from the group consisting of H, F, Cl, Br, CO _{2 R} 4 , C(O)Cl, phenyl, 2-pyridyl, NO ₂ , CF ₃ , methyl and methoxy; R1 and R2 together represent -CH=CH-CH=CH- and form a benzothiophene together with the thiophene ring, and R3 is selected from the group consisting of H, F, Cl, Br, CO _{2 R} 4 , C(O)Cl, phenyl, 2 -pyridine Group NO _2, CF _3, methyl and methoxy group consisting of; R4 is C _1-2 alkyl; In another preferred embodiment, R1, R2 and R3 are the same or different and independently of one another Selected from the group consisting of H, Cl, Br, CO ₂ R4, C(O)Cl, phenyl, NO ₂ , CN, CF ₃ , C _1-2 alkyl and C _1-2 alkoxy; and R 4 It is a C _1-2 alkyl group.

In particular, the residue of the formula (RES-I) is selected from the group consisting of , , , , , , , , , , , , , , , , , , , , .

More particularly, R1 is H or Cl, and R2 and R3 are H.

More particularly, the residue of the formula (RES-I) is a residue of the formula (RES-I-1-X1) or a residue of the formula (RES-I-2-X); Even more particularly, the residue of formula (RES-I) is a residue of formula (RES-I-1) or a residue of formula (RES-I-2).

A specific embodiment of the compound of formula (III) is selected from the group consisting of a compound of formula (III-1), a compound of formula (III-2) and a compound of formula (III-3).

Preferably, R101, R102 and R103 are the same or different and independently of each other are _C1-10 alkyl, F, Cl or phenyl; more preferably, R101, R102 and R103 are methyl, F, Cl Or phenyl.

Preferably, R 110 is methyl or phenyl.

Preferably, X1 is O or S, and more preferably, X1 is S.

Preferably, R100 is selected from the group consisting of a phenyl group, a substituted phenyl group, a naphthyl group, a substituted naphthyl group, and a residue of the formula (RES-I) wherein X1 is O or S, more preferably, R100 is selected. Free phenyl, substituted phenyl, naphthyl, substituted naphthyl, and the group of formula (RES-I) wherein X1 is S; and all of their embodiments described herein.

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

Preferably, any excess of SULFCHLO is reused.

It is known that S ₂ Cl ₂ , also known as disulfide dichloride or even known as sulfur monochloride, decomposes into HCl, SO ₂ and sulfur upon contact with water (for example, moisture in air). It is also known that upon heating, S ₂ Cl ₂ decomposes into SCl ₂ , also known as sulfur dichloride, and decomposes into other sulphur chlorides. Furthermore, S ₂ Cl _{2 is} prepared by chlorination of sulfur, and depending on the precise reaction conditions and purification methods used, commercially available S ₂ Cl ₂ may contain varying amounts of chlorine and SCl ₂ . Thus SULFCHLO, ie used in REAC2, is preferably used in the form of the compound COMPSULFCHLO, which can have various properties, various impurity levels and various impurity distributions. Thus COMPSULFCHLO may contain, for example, up to 5%, 10%, 20%, 30% or even up to 50% chlorine, hydrogen chloride, SO ₂ , sulfur, or SCl ₂ in the case of SULFCHLO as S ₂ Cl ₂ , or A mixture of impurities, this % is % by weight based on the total weight of COMPSULFCHLO.

Preferably, however, COMPSULFCHLO comprises from 50 to 100%, more preferably from 70 to 100%, even more preferably from 80 to 100%, especially from 90 to 100%, more particularly from 95 to 100%, of SULFCHLO, which is based on COMPSULFCHLO % by weight of the total weight.

S ₂ Cl ₂ and SCl ₂ are equivalent reagents for REAC2. S ₂ Cl ₂ is commercially available.

Preferably, SULFCHLO is S ₂ Cl ₂ .

Preferably, REAC2 is carried out 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 changed during the reaction so that the reaction proceeds under a temperature distribution.

Preferably, REAC2 is carried out at a pressure of from ambient to 100 bar, more preferably from ambient pressure to 75 bar, even more preferably from ambient pressure to 50 bar, especially from ambient pressure to 30 bar, more particularly from ambient pressure to 25 bar. Even more particularly the environmental pressure is 20 bar.

The pressure of REAC2 can be adjusted according to the selected REAC2 temperature 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 carried out in the presence of a salt of a base or a base.

Preferably, the base is BAS2 and the base salt is a salt of BAS2; BAS2 is selected from the group consisting of pyridine, picoline, chloropyridine, methylethylpyridine, 4-(dimethylamino)pyridine, N(R10) ( R11) a group consisting of R12, 1,4-diazabicyclo[2.2.2]octane, Phe-N(R20)R21, and mixtures thereof; R10, R11 and R12 are the same or different and independent of each other Is a C _1-8 alkyl group; R 20 and R 21 are the same or different and are independently C _1-8 alkyl; and the salt of BAS 2 is selected from the group consisting of hydrochloride, hydrobromide, acetate and a group consisting of fluoroacetates.

Preferably, R10, R11 and R12 are the same or different and independently from each other C _1-4 alkyl; R20 and R21 are the same or different and independently of one another C _l-2 alkyl.

More preferably, BAS2 is selected from the group consisting of pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2-chloropyridine, 2-methyl-5-ethylpyridine, triethylamine, tributylamine a group consisting of 1,4-diazabicyclo[2.2.2]octane, N,N-dimethylaniline, and mixtures thereof; even more preferably, BAS2 is selected from the group consisting of pyridine, 3-methylpyridine, a group consisting of 2-chloropyridine, 2-methyl-5-ethylpyridine, triethylamine, tributylamine, and mixtures thereof; in particular, BAS2 is selected from the group consisting of pyridine, 3-methylpyridine, 2-chloropyridine a group consisting of 2-methyl-5-ethylpyridine, and mixtures thereof.

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

Preferably, the molar amount of BAS2 is 0.001 to 1 times, more preferably 0.005 to 0.5 times, and even more preferably 0.01 to 0.3 times the molar amount of the compound of the formula (II).

REAC2 can be carried out without water, that is, in the absence of a solvent, or REAC2 can be carried out in a solvent SOLV2 selected from the group consisting of benzene, toluene, xylene, chlorobenzene, nitrobenzene, anisole, dichlorobenzene, a group consisting of ethyl chloride, trichloroethane, and mixtures thereof; preferably, SOLV2 is selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, nitrobenzene, anisole, 1 a group consisting of 2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,2-dichloroethane, and mixtures thereof; more preferably, SOLV2 is selected from toluene, ortho A group consisting of 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 the weight of the compound of formula (II).

Preferably, any SOLV2 is reused.

Preferably, no solvent is used in REAC2.

ST2 may include step ST-HEAT2 after REAC2, and in ST-HEAT2, the reaction mixture from REAC2 is subjected to elevated temperature TEMP-HEAT2, preferably TEMP-HEAT2 is from 80 °C to 250 °C, more preferably 100 °C 200 ° C, even more preferably 120 ° C to 175 ° C.

The time TIME-HEAT2 of the reaction mixture 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 first performs time TIME1 at temperature TEMP1 and then TIME2 at temperature TEMP2; TEMP1 is 40 to 85 °C, TIME1 is 2 to 60 h, TEMP2 is 135 to 145 °C, and TIME2 More preferably, TEMP2 is 50 to 80 ° C, TIME 2 is 3 to 10 h, TEMP-HEAT 2 is 135 to 145 ° C, and TIME-HEAT 2 is 10 to 25 h.

In another preferred embodiment, REAC2 first performs time TIME1 at temperature TEMP1 and then TIME2 at temperature TEMP2; TEMP2-1 is -20 °C to 100 °C, and TIME2-1 is 0.1 h to 48 h, TEMP2-2 is 85 ° C to 250 ° C, and TIME 2-2 is 0.9 h to 48 h; more specifically, TEMP2-1 is ‐10 ° C to 95 ° C, TIME 2-1 is 0.5 h to 30 h, TEMP 2-2 is 90 ° C to 200 ° C, and TIME 2-2 is 1.5 h to 30 h; even more specifically, TEMP2-1 is 0 ° C to 90 ° C, TIME2-1 is 1 h to 24 h, and TEMP 2-2 is 100 ° C to 175 °C, and TIME2-2 is 2 h to 24 h.

ST-HEAT2 can be carried out in a solvent SOLV-HEAT2 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-dichloro a group consisting of benzene, 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, a group consisting of 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 the weight of the compound of formula (II).

Preferably, any SOLV-HEAT2 is reused.

Depending on the boiling point of SOLV-HEAT2 and the desired TEMP-HEAT2, ST-HEAT2 can be carried out at the corresponding necessary or higher pressure.

If both SOLV2 and SOLV-HEAT2 are used at the same time, preferably SOLV2 and SOLV-HEAT2 are the same.

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

Preferably, any SOLV 2 is evaporated after REAC 2 or after ST 2 to obtain a first residue mixed with ether. The ether is preferably ether ETH, and ETH is preferably selected from the group consisting of diethyl ether, THF, methyltetrahydrofuran, methyl tert-butyl ether and dioxane. The resulting mixture is filtered and concentrated, preferably under reduced pressure, to give a second residue. The second residue is mixed with an alkane ALK, which is preferably selected from the group consisting of C _5-8 alkanes, C _5-8 cycloalkanes, and mixtures thereof; more preferably, ALK is selected from the group consisting of hexane, heptane, octane, a group consisting of cyclohexane, methylcyclohexane, and mixtures thereof; more preferably, ALK is selected from the group consisting of n-hexane, n-heptane, cyclohexane, methylcyclohexane, and mixtures thereof; A mixture comprising a product solution dissolved in an alkane and a residue insoluble in an alkane is formed under heating. The product solution dissolved in the alkane is separated from the insoluble residue, which can be carried out by a conventional method such as decantation, filtration or phase separation. Typically, once cooled, the product has crystallized from the solution, or the alkane is evaporated, preferably under reduced pressure.

In the case where R100 is the phenyl group, the substituted phenyl group, the naphthyl group, the substituted naphthyl group or the residue of the formula (RES-I), the compound of the formula (II) may be Prepared in step ST1, in this case, the method comprises ST1 and ST2; ST1 is carried out before ST2; ST1 comprises the reaction REAC1 of the compound of formula (I) and the compound ACET; Wherein R100, as defined herein, also includes all embodiments thereof, and wherein (*) in the residue of formula (RES-I) represents a bond to H in formula (I); ACET is selected from ethyl chloroform, A group consisting of acetic anhydride, acetic acid, ketene, and mixtures thereof.

When the (*) in the residue of the formula (RES-I) represents a bond to H in the formula (I), the compound of the formula (I) is a compound of the formula (RES-IH); Wherein R1, R2, R3 and X1 are as defined herein, and all embodiments thereof are also included.

Preferably, the ACET is selected from the group consisting of ethyl chloroform, 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 the molar amount of the compound of formula (I).

In the case where ACET is acetic anhydride, the specified minimum amount of ACET based on 1 mole of the molar amount of the compound of formula (I) can be reduced to 0.5 times the molar amount of the compound of formula (I).

Preferably, any excess of ACET is reused.

Preferably, REAC1 is carried out 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, REAC1 is carried out at a pressure of from ambient to 25 bar and more preferably from ambient pressure to 20 bar.

The pressure of REAC1 can be adjusted according to the temperature selected by REAC1 and the boiling point of ACET.

Preferably, the reaction time of REAC1 is from 30 min to 24 h, more preferably from 1 h to 12 h.

Preferably, REAC1 is carried out in the presence of acid ACI1 selected from the group consisting of sulfoxide, BF3-OEt2, perchloric acid, AlCl3, polymeric sulfonic acid resins, toluenesulfonic acid, HCl, H2SO4, H3PO4, SiO2, citric acid a group consisting of tartaric acid, oxalic acid, zeolite, and mixtures thereof.

The zeolite may be any zeolite, preferably montmorillonite or bentonite, more preferably montmorillonite, or even better selected smectite K10®, BASF, Germany (also available from Sigma Aldrich, CAS No. 1318-93-0) .

Preferably, ACI1 alkylene selected from the group consisting of sulfuryl chloride, BF ₃ -OEt _2, perchloric acid, AlCl _3, polymeric sulfonic acid resin, toluenesulfonic acid, HCl, H2SO4, H3PO4, SiO2 , zeolites, and mixtures thereof More preferably, ACI1 is selected from the group consisting of sulfinium chloride, perchloric acid, AlCl ₃ , polymeric sulfonic acid resins, montmorillonite, H ₃ PO ₄ , and mixtures thereof; in particular, ACI1 is a sulfurous group; Chlorine, perchloric acid, AlCl ₃ or H ₃ PO ₄ .

Preferably, the molar amount of ACI1 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 the molar amount of the compound of the formula (I).

REAC1 can be carried out in a solvent SOLV1 selected from the group consisting of benzene, toluene, xylene, chlorobenzene, nitrobenzene, dichlorobenzene, dichloromethane, dichloroethane, carbon disulfide, and mixtures thereof; SOLV1 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, a group consisting of dichloromethane, 1,2-dichloroethane, carbon disulfide, and mixtures thereof; more preferably, SOLV1 is selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, dichloromethane a group consisting of 1,2-dichloroethane, and mixtures thereof.

Preferably, the weight of SOLV1 is from 0.5 to 100 times, more preferably from 1 to 50 times the weight of the compound of formula (I).

Preferably, any SOLV1 is reused.

After ST1, the compound of formula (II) can be isolated and purified by methods well known to those skilled in the art. These methods include, for example, hydrolysis, distillation (preferably fractionation under reduced pressure), crystallization, extraction, or a combination of these methods.

Preferably, the solvents SOLV1 and SOLV2 are identical.

ST1 and ST2 can be carried out in one kettle.

Another subject of the invention is a process for the preparation of a compound of the formula (THIOXA); Wherein said method comprises the step ST2; R30, R31, R32, R33 and R34 are the same or different and are independently selected from the group consisting of H, halo, CF _3, CH ₃ from each other, OCF _3, OCH _3, CN and C (H a group consisting of O; wherein, ST2, R1, R2 and R3 are as defined herein, including all embodiments thereof; and R100 is a residue of formula (RES-I) wherein X1 is S; another subject of the invention Is a method for preparing a compound of the formula (THIOXA), wherein the method comprises, in addition to step ST2, step ST1; ST1 is performed before ST2; wherein ST1 is as defined herein, including all embodiments thereof; Any individual embodiment or any combination of two or more embodiments, embodiments of any of these steps are as described herein; in particular, R30, R31, R32, R33 and R34 are H; In an embodiment, R1, R2 and R3 are H; more particularly, R1, R2, R3, R30, R31, R32, R33 and R34 are H.

Preferably, the method for preparing a compound of the formula (THIOXA) starting from a compound of the formula (III) wherein R100 is a residue of the formula (RES-I) and X1 is S has the step ST3; ST3 is carried out after ST2; ST3 includes a reaction REAC3 in which a compound of formula (III) wherein R100 is a residue of formula (RES-I) and X1 is S is reacted with a compound of formula (IV).

A detailed description of ST3 is disclosed in WO 2014/008257 A2.

A specific embodiment of ST3 is disclosed in Examples 2, 3, 7, 9, 10, 11 and 12 of WO 2014/008257 A2.

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

More preferably, the compound of formula (III) is a compound of formula (III-1).

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

When a compound of formula (III) is contacted with a compound of formula (IV), a reaction mixture is formed.

Preferably, REAC3 is carried out in the presence of solvent SOLV3.

Preferably, SOLV3 is an organic solvent that is immiscible with water.

Preferably, SOLV3 dissolves the compound of formula (IV) and the 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 carried out in the presence of a base BAS3.

Preferably, BAS3 is an aqueous solution of a 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 the addition of additional BAS3 to the reaction mixture or REAC3.

Preferably, the temperature of the REAC 3 does not exceed 85 ° C; more preferably, the temperature of the REAC 3 is maintained between 55 ° C and 75 ° C.

Preferably, REAC3 is carried out in the presence of 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, and tetra A group consisting of butyl ammonium iodide, tetrabutylphosphonium bromide, tetrabutylphosphonium chloride, and benzyltrimethylammonium hydroxide; even more preferably, PTC3 is tetrabutylammonium hydroxide.

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

Preferably, REAC3 is carried out in the presence of water.

Another subject of the invention is a process for the preparation of a compound of the formula (RIVA-I); R50, R51, R52 and R53 are the same or different and are independently selected from the consisting of H, _{halo, CF 3, CN, NO 2} , C (O) -NH 2, C (O) -C 1 - 6 alkyl a group consisting of O‐R60, N(R60)R61 and C _1-6 alkyl; R60 and R61 are the same or different and are independently selected from H, C _1-4 alkyl and C(O)R63 the group consisting of; R63 selected from the group consisting of C _1-4 alkyl _{-NH 2, NH 2, NH-} C 1-4 alkyl, N (C _{1 - 4} alkyl) C _1-4 alkyl, and C _{1 - 8} alkoxy group consisting of the group; R43, R44, R45, R46 , R47 and R48 are the same or different and independently of one another, denote H or C _{1 - 6} alkyl; wherein said method comprises the step ST2; wherein ST2, R1, R2 And R3 as defined herein, including all embodiments thereof; and R100 is a residue of formula (RES-I) wherein X1 is S; another subject of the invention is a compound for the preparation of a compound of formula (RIVA-I) a method, wherein the method comprises, in addition to step ST2, step ST1; ST1 is performed before ST2; wherein ST1 is as defined herein, including all of its embodiments; further comprising any separate embodiment or comprising two or more Implementation Any combination of these steps in any one of embodiments as described herein; in particular, the compound of formula (RIVA-I) is a compound of formula (RIVA-II); More particularly, the compound of formula (RIVA-I) is a compound of formula (RIVA-1).

Preferably, the method for preparing a compound of formula (RIVA-I) starting from a compound of formula (III) wherein R100 is a residue of formula (RES-I) and X1 is S has step ST4; ST4 is after ST2 Carrying out; ST4 includes the reaction REAC4, in REAC4, reacting a compound of formula (III) wherein R100 is a residue of formula (RES-I) and X1 is S with a compound of formula (RIVA-Ia); Preferably, the residue of formula (RES-I) is a residue of formula (RES-I-2); more preferably, the residue of formula (RES-I) is a residue of formula (RES-I-2) and formula ( The RIVA-Ia) compound is a compound of the formula (RIVA-1a).

A detailed description of ST4 is disclosed in US 2003/0153610 A1.

Preferably, the compound of the formula (III) in ST2 and ST4 in the process for producing the compound of the formula (RIVA-I) is a compound of the formula (III-1) or a compound of the formula (III-2); more preferably, The compound of formula (III) is a compound of formula (III-2).

Preferably, REAC4 is carried out in a solvent SOLV4 selected from the group consisting of halogenated hydrocarbons, ethers, alcohols, hydrocarbons, dimethylformamide, dimethyl hydrazine, acetonitrile, pyridine, hexamethylphosphonium triamine, water and a group consisting of its mixture.

The halogenated hydrocarbon is preferably selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene and trichloroethylene. The group consisting of.

The ether is preferably selected from the group consisting of diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diglyme.

The alcohol is preferably selected from the group consisting of methanol, ethanol, propanol, and butanol.

The hydrocarbon is preferably selected from the group consisting of benzene, xylene, toluene, hexane and cyclohexane.

REAC4 can be carried out in the presence of a base BAS4 which can be any conventional inorganic or organic base.

BAS4 is preferably selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide, decylamine, amines, and mixtures thereof; alkali metal hydroxide Preferably, the object is sodium hydroxide or potassium hydroxide; the alkali metal carbonate is preferably sodium carbonate or potassium carbonate; the guanamine is preferably selected from the group consisting of sodium amide, lithium bis(trimethylmethyl)amide and diisopropylamino. The group consisting of lithium; the amine is preferably selected from the group consisting of triethylamine, diisopropylethylamine, diisopropylamine, 4-N,N-dimethylaminopyridine and pyridine.

BAS4 can be used in the following amounts: 1 to 5 mol, preferably 1 to 2 mol, based on 1 mol of the compound of the formula (RIVA-Ia).

Preferably, REAC4 is carried out at a temperature of from -78 ° C to reflux temperature, more preferably from 0 ° C to reflux temperature, wherein the reflux temperature is the reflux temperature at the corresponding pressure.

Preferably, the REAC 4 is carried out at a pressure of from 0.5 to 5 bar, more preferably at atmospheric pressure.

In the case where the compound of the formula (RIVA-I) is a compound of the formula (RIVA-1) and the residue of the formula (RES-I) is a residue of the formula (RES-I-2), in another preferred embodiment, The preparation of the compound of the formula (RIVA-1) starting from the compound of the formula (III) wherein the residue of the formula (RES-I) is a residue of the formula (RES-I-2) has the step ST5; the detailed description of ST5 is disclosed in US 2015 /0133657 A1; ST5 is carried out after ST2; ST5 includes reaction REAC5, and in REAC5, a compound of formula (III) with formula (RES-I) residue is a residue of formula (RES-I-2) and formula (RIVA) -10) compound reaction; The reaction product of REAC5 is a compound of formula (RIVA-11); Preferably, step ST6 is performed after ST5; ST6 comprises a reaction REAC6 in which a compound of formula (RIVA-11) is reacted with a compound of formula (RIVA-12) in the presence of phosgene or phosgene equivalent; The reaction product of REAC6 is a compound of formula (RIVA-13); Preferably, step ST7 is carried out after ST6; ST7 comprises the reaction REAC7, and in the REAC7, the compound of the formula (RIVA-13) is cyclized to give the compound of the formula (RIVA-1).

The phosgene equivalent is preferably diphosgene or triphosgene or carbon monoxide equivalent.

The carbon monoxide equivalent is preferably carbonyldiimidazole or disuccinimide carbonate.

The compound of the formula (RIVA-10) can also be used in the form of their salts, preferably the hydrochloride. The compound of the formula (RIVA-10) is a known compound and can be prepared according to known methods, for example, as disclosed in U.S. Patent No. 6,107,519 or US 2015/0133657 A1.

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

Preferably, REAC5 is carried out in a solvent which may 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.

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

Preferably, REAC6 is carried out in a solvent. The solvent in REAC6 may be dichloromethane, dichloroethane, or a mixture thereof.

REAC6 can be carried out in the presence of a base, and the base in REAC6 can be pyridine, dimethylaminopyridine, triethylamine, sodium carbonate, potassium carbonate, or a mixture thereof; more preferably pyridine, triethylamine, sodium carbonate, carbonic acid Potassium, 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 the first step of REAC 6, the phosgene or phosgene equivalent is mixed with a compound of formula (RIVA-11), optionally also with a base of REAC6, optionally in a solvent of REAC6, and then A compound of the formula (RIVA-12) is added to the second step of REAC6.

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

Preferably, the first step of REAC6 has a reaction temperature of 5 to 25 °C.

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

Preferably, the second step of REAC6 has a reaction temperature of 10 to 35 °C.

After REAC6, the compound of formula (RIVA-13) can be separated from the reaction mixture by the following methods: layer separation, concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and can be further dried ( RIVA-13) compound.

Preferably, the cyclization of REAC7 is carried out in a solvent. The solvent in REAC7 may be acetone, acetonitrile, methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, water or a mixture thereof.

REAC7 can be carried out in the presence of a base. The base in REAC7 may be potassium carbonate, potassium hydrogencarbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium hydride, or a mixture thereof.

The base in REAC7 may be added to a mixture containing a solvent of the compound of the formula (RIVA-13) and REAC7 or to a mixture containing a compound of the formula (RIVA-13) formed in REAC6.

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

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

The compound of the formula (RIVA-I), the compound of the formula (RIVA-II) and the compound of the formula (RIVA-1) can be separated from any reaction mixture by the following methods: layer separation, concentration, distillation, decantation, filtration, evaporation, Centrifugation, or a combination thereof, and these compounds can be further dried. EXAMPLES Example 1: 2-Thiophenium Carbonium Chloride

A mixture of 2-ethenylthiophene (0.108 ml, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol) and dithiodichloride (0.240 ml, 3.0 mmol) was stirred at 137 ° C for 18 h. The mixture was diluted with CDCl ₃ (2 ml), and an internal standard (iBu ₃ PO ₄ , 0.0552 ml, 0.20 mmol) was added and the mixture was analyzed. ¹ H NMR indicated that 2-thiophenecarbenium chloride had been formed (yield 78%). ¹ H NMR (CDCl ₃ , 400 MHz) δ = 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 (CDCl ₃ , 100 MHz) δ = 159.5, 137.9, 137.7, 137.1, 128.6. Example 2: 5-Chloro-2-thiophene carbonium chloride

A mixture of 2-ethinyl-5-chlorothiophene (0.163 g, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol) and dithiodichloride (0.240 ml, 3.0 mmol) was stirred at 137 ° C for 20 h. The mixture was diluted with CDCl ₃ (2 ml), and an internal standard (iBu ₃ PO ₄ , 0.0552 ml, 0.20 mmol) was added and the mixture was analyzed. ¹ H NMR indicated that 5-chloro-2-thiophenecarbenium chloride had been formed (yield 68%). ¹ H NMR (CDCl ₃ , 400 MHz) δ = 7.80 (d, J = 4 Hz, 1H), 7.06 (d, J = 4 Hz, 1H). ¹³ C NMR (CDCl ₃ , 100 MHz) δ = 158.5, 143.1, 137.5, 134.9, 128.3. Example 3: 4-fluorobenzhydrazide chloride

A mixture of 4-fluoroacetophenone (0.138 g, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol) and dithiodichloride (0.240 ml, 3.0 mmol) was stirred at 137 ° C for 20 h. The mixture was diluted with CDCl ₃ (2 ml), and an internal standard (iBu ₃ PO ₄ , 0.0552 ml, 0.20 mmol) was added and the mixture was analyzed. ¹ H NMR indicated that 4-fluorobenzimid chloride had formed (yield 81%). ¹ H NMR (CDCl ₃ , 400 MHz) δ = 8.15 (m, 2H), 7.20 (m, 2H). ¹³ C NMR (CDCl ₃ , 100 MHz) δ = 168.3, 166.8, 165.7, 134.1, 134.0, 129.3, 116.3, 116.1. Example 4: 4-methoxybenzhydryl chloride

A mixture of 4-methoxyacetophenone (0.150 g, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol) and dithiodichloride (0.240 ml, 3.0 mmol) was stirred at 137 ° C for 20 h. The mixture was diluted with CDCl ₃ (2 ml), and an internal standard (iBu ₃ PO ₄ , 0.0552 ml, 0.20 mmol) was added and the mixture was analyzed. ¹ H NMR indicated that 4-methoxybenzimid chloride had formed (yield: 91%). ¹ H NMR (CDCl ₃ , 400 MHz) δ = 7.96 (d, J = 8 Hz, 2H), 6.86 (d, J = 8 Hz, 2H), 3.80 (s, 3H). ¹³ C NMR (CDCl ₃ , 100 MHz) δ = 166.0, 164.4, 132.9, 124.3, 113.2, 54.8. Example 5: 3-(Trifluoromethyl)benzhydryl chloride

A mixture of 3-(trifluoromethyl)acetophenone (0.188 g, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol) and disulfide dichloride (0.240 ml, 3.0 mmol) was stirred at 137 ° C for 20 h . The mixture was diluted with CDCl ₃ (2 ml), and an internal standard (iBu ₃ PO ₄ , 0.0552 ml, 0.20 mmol) was added and the mixture was analyzed. ¹ H NMR indicated that 3-(trifluoromethyl)benzimidium chloride had formed (yield 76%). ¹ H NMR (CDCl ₃ , 400 MHz) δ = 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). ¹³ C NMR (CDCl ₃ , 100 MHz) δ = 167.2, 134.2, 134.0, 131.74 (quartett, J = 32 Hz), 131.6 (quadruple, J = 3 Hz), 129.8, 127.9 (four Heavy peak, J = 3 Hz), 123.1 (quadruple peak, J = 270 Hz, CF ₃ ). Example 6: 2-Thiophenium Carbonium Chloride

A mixture of 2-ethenylthiophene (0.108 ml, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol) and dithiodichloride (0.320 ml, 4.0 mmol) was stirred at 70 ° C for 3.5 h. It was then stirred at 137 ° C for 18 h. The mixture was diluted with CDCl ₃ (2 ml), and an internal standard (iBu ₃ PO ₄ , 0.0552 ml, 0.20 mmol) was added and the mixture was analyzed. ¹ H NMR indicated that 2-thiophenecarbenium chloride had been formed (yield 86%). Example 7: Benzamidine chloride

A mixture of acetophenone (0.117 ml, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol) and dithiodichloride (0.320 ml, 4.0 mmol) was stirred at 70 ° C for 3.5 h. It was then stirred at 137 ° C for 18 h. The mixture was diluted with CDCl ₃ (2 ml), and an internal standard (iBu ₃ PO ₄ , 0.0552 ml, 0.20 mmol) was added and the mixture was analyzed. ¹ H NMR indicated that benzamidine chloride had formed (yield 82%). ¹ H NMR (CDCl ₃ , 400 MHz) δ = 8.10 (d, J = 8 Hz, 2H), 7.68 (t, J = 8 Hz, 1H), 7.51 (t, J = 8 Hz, 2H). ¹³ C NMR (CDCl ₃ , 100 MHz) δ = 168.2, 135.2, 134.2, 131.2, 128.8. Example 8: Furan-2-carbon ruthenium chloride

A mixture of 2-ethylmercaptofuran (0.100 ml, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol) and disulfide dichloride (0.280 ml, 3.5 mmol) was stirred at 70 ° C for 2.5 h then at 138 ° C Stir under 19h. The mixture was diluted with CDCl ₃ (2 ml), and an internal standard (iBu ₃ PO ₄ , 0.0552 ml, 0.20 mmol) was added and the mixture was analyzed. ¹ H NMR indicated that furan-2-carbonium chloride had formed (yield: 44%). ¹ H NMR (CDCl ₃ , 400 MHz) δ = 7.77 (s, 1H), 7.51 (m, 1H), 6.65 (m, 1H). Example 9: 4-Nitrobenzidine chloride

A mixture of 4'-nitroacetophenone (165 mg, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol) and disulfide dichloride (0.280 ml, 3.5 mmol) was stirred at 70 ° C for 2.5 h then Stir at 138 ° C for 19 h. The mixture was diluted with CDCl ₃ (2 ml), and an internal standard (iBu ₃ PO ₄ , 0.0552 ml, 0.20 mmol) was added and the mixture was analyzed. ¹ H NMR indicated that 4-nitrobenzhydryl chloride had formed (yield: 83%). ¹ H NMR (CDCl ₃ , 400 MHz) δ = 8.38 (d, J = 8 Hz, 2H), 8.33 (d, J = 8 Hz, 2H). ¹³ C NMR (CDCl ₃ , 100 MHz) δ = 167.0, 151.6, 138.0, 132.3, 124.1. Example 10: 2-naphthylcarbonium chloride

A mixture of 2-acetamidine (170 mg, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol) and disulfide dichloride (0.280 ml, 3.5 mmol) was stirred at 70 ° C for 2.5 h then at 138 ° C Stir for 19 h. The mixture was diluted with CDCl ₃ (2 ml), and an internal standard (iBu ₃ PO ₄ , 0.0552 ml, 0.20 mmol) was added and the mixture was analyzed. ¹ H NMR indicated that 2-naphthylcarbonium chloride had been formed (yield: 82%). ¹ H NMR (CDCl ₃ , 400 MHz) δ = 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 (CDCl ₃ , 100 MHz) δ = 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-Phenylbenzylidene chloride

A mixture of 4'-phenylacetophenone (196 mg, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol) and disulfide dichloride (0.280 ml, 3.5 mmol) was stirred at 70 ° C for 2.5 h then Stir at 138 ° C for 19 h. The mixture was diluted with CDCl ₃ (2 ml), and an internal standard (iBu ₃ PO ₄ , 0.0552 ml, 0.20 mmol) was added and the mixture was analyzed. ¹ H NMR indicated that 4-phenyl benzamidine chloride had formed (yield: 83%). ¹ H NMR (CDCl ₃ , 400 MHz) δ = 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). ¹³ C NMR (CDCl ₃ , 100 MHz) δ = 168.0, 148.1, 139.1, 132.1, 131.8, 129.2, 128.9, 127.5, 127.4. Example 12: Benzamidine chloride

A mixture of acetophenone (1.618 ml, 15.0 mmol), 3-methylpyridine (0.08 ml, 0.82 mmol) and disulfide dichloride (4.80 ml, 60 mmol) was stirred at 70 ° C for 3 h 40 min then Stir at 137 ° C for 17 h. Bulb-to-bulb distillation (10 mbar, 90 to 130 °C) gives a mixture of benzamidine chloride and disulfide dichloride. Using iBu ₃ PO ₄ as an internal standard, the yield of benzamidine chloride was 78% as determined by ¹ H NMR. Example 13: 4-Phenylbenzimidyl Chloride

A mixture of 4'-phenylacetophenone (1.96 g, 9.94 mmol), 3-methylpyridine (0.146 ml, 1.5 mmol) and disulfide dichloride (2.40 ml, 30.0 mmol) was stirred at 60 ° C. h, then stirred at 138 ° C for 15 h. The mixture was cooled to room temperature, diluted with THF (3.sub.3 mL), filtered, and then evaporated. The residue was mixed with hexane (15 ml), heated to reflux and evaporated from a dark darkness. The hexane solution was crystallized overnight at 4 °C. The crystals were filtered off and dried under reduced pressure at room temperature. The solid weighed 1.65 g. The content was determined by ¹ H NMR using an internal standard, indicating a solid purity of 82%. The yield of 4-phenylbenzimid chloride was 62%. Example 14: 4-methoxybenzhydryl chloride

4-methoxyacetophenone (2.25 g, 15.0 mmol) was added in portions to sulphur monochloride (3.60 ml, 45.0 mmol) at a rate that was not too violent at 0.5 °C within 0.5 h. And a solution of pyridine (0.121 ml, 1.5 mmol) in chlorobenzene (2.0 ml). When the addition was completed, the mixture was stirred at 75 ° C for 0.5 h and then stirred under 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 precipitated sulfur and pyridine hydrochloride were decanted from the solution, and the solid was washed with hexane (5 ml). The combined liquid phases were concentrated under reduced pressure (30 mbar, 40 ° C) and the residue was distilled (ball-to-ball). The 4-methoxybenzimid chloride was boiled at 160-165 ° C (8 mbar). The yield was 72%. Example 15: 4-Phenylbenzimidyl Chloride

To the sulfur monochloride (4.80 ml, 60.0 mmol) was added 4-phenylacetophenone (716 mg, 3.31 mmol) and pyridine (0.081 ml, 1.00 mmol) at room temperature, and the mixture was at 80- Stirring was continued at 90 ° C for approximately 10 min at which time HCl began to form. The mixture was then cooled to room temperature with a water bath, then the remaining 4-phenylacetophenone (total: 3.85 g, 19.6 mmol) and pyridine (total: 0.32 ml, 4.0 mmol) were added in three portions over 20 min. . The mixture becomes more and more 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 cooled down and the product was extracted twice with hexane (50 mL each), warmed to reflux and decanted. The combined hexanes were maintained at -30 °C for 3 h, decanted and the solid was recrystallised from hexane (150 ml). 4-Phenylbenzoguanidine chloride (3.06 g, purity: 95%, yield: 68%) was obtained as a yellow needle. Example 16: 3,4-dimethoxybenzhydrazide 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, 0.1 mmol) was stirred at 70 ° C for 4 h then Stir at 136 ° C for 18 h. iBu ₃ PO ₄ (0.0552 ml, 0.20 mmol) and CDCl ₃ were added to the mixture, and analysis by ¹ H NMR indicated that 3,4-dimethoxybenzhydrin chloride was formed in a yield of 79%. ¹ H NMR (CDCl ₃ , 400 MHz) δ 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) ¹³ C NMR (CDCl ₃ , 100 MHz) δ 167.2, 155.2, 149.0, 127.2, 125.5, 112.8, 110.4, 56.3, 56.1

no

no

no

Claims (21)

a method for preparing a compound of formula (III); The method comprises the step ST2; ST2 comprises the reaction REAC2 of the compound of the formula (II) with the compound SULFCHLO; the SULFCHLO is S ₂ Cl ₂ , SCl ₂ , or a mixture thereof; Wherein R100 is selected from the group consisting of phenyl groups, which are selected from 1, 2, 3, 4 or 5 identical or different independently of each other from halogen, C _1-6 alkyl, C _3-8 cycloalkyl, a phenyl group substituted with a substituent of a group consisting of C _1-4 alkoxy, NO ₂ , CF ₃ , CN, N(R13)(R14)R15, benzyl, phenyl and substituted phenyl, wherein The substituted phenyl group is selected from 1, 2, 3, 4 or 5 identical or different independently of each other from halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-4 alkoxy. , substituted NO _2, CF ₃ groups, CN, and N (R16) (R17) R18 group consisting of substituents, a naphthyl group, 1,2,3,4,5,6, or 7 via the same or different each independently Selected from halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-4 alkoxy, NO ₂ , CF ₃ , CN, N(R13)(R14)R15, benzyl, phenyl And a substituted naphthyl group of the group consisting of substituted phenyl groups, wherein the substituted phenyl group is selected from 1, 2, 3, 4 or 5 identical or different from each other independently from halogen, C ₁ substituents taken from the group consisting of _1-6 alkyl, C _3-8 cycloalkyl, C _1-4 alkoxy, NO _2, CF _3, CN, and N (R16) (R17) R18 And the formula (RES-I) residue; The (*) in the formula (RES-I) represents a bond respectively bonded to the C(O)Cl residue in the formula (III) and the C(O)CH ₃ residue in the formula (II); X1 is O, S or N-R110; R13, R14, R15, R16, R17 and R18 are the same or different and are independently selected from the group consisting of H and _C1-8 alkyl; R1, R2 and R3 are The same or different and independently selected from H, halogen, CO _{2 R} 4 , C(O)Cl, phenyl, 2-pyridyl, NO ₂ , CN, CF ₃ , C _1-8 alkyl and C _a group consisting of _1-8 alkoxy groups; or R1 and R2 together represent -CH=CH-CH=CH- and together with the thiophene ring form benzothiophene, and R3 is selected from H, halogen, CO ₂ R4, C(O a group consisting of Cl, phenyl, 2-pyridyl, NO ₂ , CN, CF ₃ , C _1-8 alkyl and C _1-8 alkoxy; R 4 is C _1-6 alkyl R101, R102 and R103 They are the same or different and are independently of each other a C _1-10 alkyl group, a halogen or a phenyl group; R110 is a C _1-6 alkyl group or a phenyl group. The method according to claim 1, wherein, in the case where R100 is a substituted phenyl group, the phenyl group is selected from the group consisting of halogen, via 1, 2, 3, 4 or 5 identical or different independently of each other. Substituted by a group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, NO ₂ , CF ₃ , CN, benzyl, phenyl, and substituted phenyl, Wherein the substituted phenyl group is selected from 1, 2, 3, 4 or 5 identical or different from each other independently from halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-4 Substituents of the group consisting of alkoxy, NO ₂ , CF ₃ and CN are substituted. The method according to claim 1 or 2, wherein, in the case where R100 is a substituted naphthyl group, the naphthyl group is independently selected from each other by 1, 2, 3, 4 or 5 identical or different Substituents of the group consisting of halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, NO ₂ , CF ₃ , CN, benzyl, phenyl and substituted phenyl Substituted wherein the substituted phenyl group is selected from 1, 2, 3, 4 or 5 identical or different independently of each other from halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C ₁ Substituents of the group consisting of _-4 alkoxy, NO ₂ , CF ₃ and CN are substituted. The method according to one or more of claims 1 to 3, wherein, in the case where R100 is a residue of the formula (RES-I), the C(O)Cl residue in the compound of the formula (III) and the formula (II) The C(O)CH ₃ residue of the compound is at the 2-position of the residue of the formula (RES-I). The method of one or more of claims 1 to 4, wherein R1, R2 and R3 are the same or different and are independently selected from H, F, Cl, Br, CO ₂ R4, C(O) a group consisting of Cl, phenyl, 2-pyridyl, NO ₂ , CN, CF ₃ , C _1-4 alkyl and C _1-2 alkoxy; or R 1 and R 2 together represent -CH=CH-CH=CH And forming a benzothiophene together with a thiophene ring, and R3 is selected from the group consisting of H, F, Cl, Br, CO _{2 R} 4 , C(O)Cl, phenyl, 2-pyridyl, NO ₂ , CN, CF ₃ , C _a group consisting of _1-4 alkyl and C _1-2 alkoxy; R 4 is C _1-4 alkyl. The method of one or more of claims 1 to 5, wherein the residue of formula (RES-I) is selected from the group consisting of , , , , , , , , , , , , , , , , , , , , . The method of one or more of claims 1 to 6, wherein R1 is H or Cl, and R2 and R3 are H. The method of one or more of claims 1 to 7, wherein R101, R102 and R103 are the same or different and independently of each other are _C1-10 alkyl, F, Cl or phenyl. The method of one or more of claims 1 to 8, wherein X1 is O or S. The method of one or more of claims 1 to 9, wherein R100 is selected from the group consisting of a phenyl group, a substituted phenyl group, a naphthyl group, a substituted naphthyl group, and a formula wherein X1 is O or S (RES-I a group consisting of residues. The method of one or more of claims 1 to 10, wherein REAC2 is carried out in the presence of a salt of a base or a base. The method according to claim 11, wherein the base is BAS2 and the salt of the base is a salt of BAS2; BAS2 is selected from the group consisting of pyridine, picoline, chloropyridine, methylethylpyridine, N(R10) (R11) a group consisting of R12, 1,4-diazabicyclo[2.2.2]octane, phenylalanine-N(R20)R21, and mixtures thereof; R10, R11 and R12 are the same or different and are each other Independently C _1-8 alkyl; R 20 and R 21 are the same or different and independently of each other are C _1-8 alkyl; and the salt of BAS 2 is selected from the group consisting of hydrochloride, hydrobromide, acetate And a group consisting of trifluoroacetate. The method of one or more of claims 1 to 12, wherein the compound of formula (II) is prepared in step ST1; ST1 is carried out before ST2; ST1 comprises the reaction REAC1 of the compound of formula (I) with compound ACET; Wherein R100 is as defined in claim 1, and said (*) in the residue of formula (RES-I) represents a bond to H in formula (I); ACET is selected from the group consisting of acetonitrile, acetic anhydride, acetic acid a group consisting of ketene and mixtures thereof. The method according to claim 13, wherein the REAC1 is carried out in the presence of acid ACI1 selected from the group consisting of sulfoxide, BF ₃ -OEt ₂ , perchloric acid, AlCl ₃ , polysulfonic acid resin, toluenesulfonic acid, HCl a group consisting of H ₂ SO ₄ , H ₃ PO ₄ , SiO ₂ , citric acid, tartaric acid, oxalic acid, zeolite, and mixtures thereof. A method for preparing a compound of the formula (THIOXA); Wherein said method comprises the step ST2; R30, R31, R32, R33 and R34 are the same or different, and are independently selected from the group consisting of H, halo, CF _3, CH ₃ from each other, OCF _3, OCH _3, CN and C ( H) a group consisting of O; wherein, ST2, R1, R2 and R3 are as defined in claim 1; and R100 is a residue of the formula (RES-I) as defined in claim 1, wherein X1 is S. The method of claim 15, wherein the method comprises, in addition to step ST2, step ST1; ST1 is performed before ST2; wherein ST1 is as defined by request item 13 or 14. The method of claim 15 or 16, wherein R1, R2, R3, R30, R31, R32, R33 and R34 are H. a method for preparing a compound of the formula (RIVA-I); R50, R51, R52 and R53 are the same or different and are independently selected from the consisting of H, _{halo, CF 3, CN, NO 2} , C (O) -NH 2, C (O) -C 1 - 6 alkyl a group consisting of O, R60, N(R60)R61 and _C1-6 alkyl; R60 and R61 are the same or different and are independently selected from H, C _1-4 alkyl and C(O) the group consisting of R63; R63 selected from the group consisting of C _1-4 alkyl _{-NH 2, NH 2, NH-} C 1-4 alkyl, N (C _{1 - 4} alkyl) C _1-4 alkyl, and C _{1 - 8} the group consisting of alkyl; R43, R44, R45, R46 , R47 and R48 are the same or different and independently from each other represent H or a C _{1 - 6} alkyl; wherein said method comprises the step ST2; wherein ST2, R1 R2 and R3 are as defined in claim 1; and R100 is a residue of the formula (RES-I) as defined in claim 1, wherein X1 is S. The method of claim 18, wherein the method comprises, in addition to step ST2, step ST1; ST1 is performed before ST2; wherein ST1 is as defined by request item 13 or 14. The method of claim 18 or 19, wherein the compound of the formula (RIVA-I) is a compound of the formula (RIVA-II); Wherein R50, R51, R52, R53, R43, R44, R45, R46, R47 and R48 are as defined in claim 18. The method of one or more of claims 18 to 20, wherein the compound of the formula (RIVA-I) is a compound of the formula (RIVA-1) .