WO2012028162A1 - Process for preparing oxindoles and ortho-substituted anilines and the use thereof as intermediates for syntheses - Google Patents

Abstract

A process for preparing compounds of the formula (4), wherein a mixture of an aniline (compound of the formula Q) is reacted with a thioether (compound of the formula W) in the presence of sulfuryl chloride as a chlorinating agent and of an organic solvent at a reaction temperature in the range of between -60°C and -10°C. In a subsequent process, this compound is converted further in the presence of an acid catalyst to the indole of the formula (7) or the oxindole of the formula (8).

Description

 Process for the preparation of oxindoles and ortho-substituted anilines and their use as intermediates for syntheses

description

The invention relates to the technical field of chemical synthesis of biologically active compounds, preferably for intermediates for the

Synthesis of fine chemicals and active ingredients from the pharmaceutical and / or agricultural sectors.

In principle, the selective exchange of hydrogen on an aromatic system with a substituted carbon atom is one of the fundamental transformations in organic chemistry and is thus known.

A class of compounds which can be prepared in this way are e.g. optionally substituted 3-alkylthioindole-2-ones (3- (alkylsulfanyl) -1,3-dihydro-2H-indol-2-ones), which in turn are substituted into optionally substituted 2-oxindoles (1,3-dihydro-2H-indole-1-ol) 2-one) can be implemented. Optionally substituted oxindoles and their precursors, such as optionally substituted 3-alkylthioindole-2-ones, are versatile

Intermediates for Drug Synthesis (Bioorg.Med.Chem.Lett. 2006, 16, 2109, JP 2008-101014, WO 96/41799 A1). Further use as precursors for pharmaceutical compounds are described in: US 2005/0090541 A1, EP 636608 A, US 4690943 A.

Most of the various syntheses of oxindoles described use a variation of a Friedel-Crafts reaction (Stolle Synthesis, W.C. Sumpter, Chem. Rev. 1945, 37, 443-449). However, Stolle syntheses are of limited use because they require strong acidic conditions and an electron-rich aniline. In addition, however, also radical, nitrenium ion and organolithium reactions and photochemically dependent methods are known. These are also limited by the type of oxindoles to be produced, the compatibility of

CONFIRMATION COPY Substrates, the reaction conditions and the fact that the aromatic already has to have a halogen substituent, which is then replaced.

(Radical method: Zard et al., Tetrahedron Lett., 1994, 35, 9553-9556; Zard et al., Tetrahedron Lett., 1994, 35, 1719-1722; Jones et al., Tetrahedron Lett., 1994, 35, 7673) Kikugawa et al., Chem. Letters 1987, 1771-1774; Clark et al.,

Synthesis 1991, 871-878; Yonemitsu et. al., Chem. Pharm. Bull. 1981, 29, 128-136; s. Scheme 1).

Scheme 1 - Known Oxindole Syntheses:

The method of Gassman et al. (Organic Synthesis Coli., Vol. 6, 601 and Vol. 56, 72), which of aniline and methyl thioacetate ester via chlorination and

Treatment with triethylamine at -70 ° C appears suitable in terms of feasibility, availability of starting materials, short reaction rate and reproducibility. However, it is also described that good yields can only be achieved if the unstable N-chloro (1) or N-sulfonium (2) intermediates are formed below -65 ° C, normally at -78 ° C (Gassman et al., J. Am. Chem Soc, 1974, 96 (17), 5508; Gassman et al., J. Am. Chem. Soc., 1974, 96 (17), 5512; WO 96/41799 A1; see Scheme 2). Scheme 2 - Reaction via aniline chlorination:

Q = aniline

 A = chlorinating agent (e.g., tert-butyl hypochlorite, t-BuOCl)

 W = thioether (R1-S-CHR2R3)

 C = tertiary amine base (e.g., triethylamine)

The chlorinating agent of choice according to the literature is the unstable and explosive tert-butyl hypochlorite, since the by-product of the chlorination then gives the neutral tert-butyl alcohol. In the few cases where sulfuryl chloride (SO ₂ Cl ₂ ) was employed, a second non-nucleophilic base such as "proton sponge" was used (Johnson, J. Org. Chem. 1990, 55, 1374, Warpehoski, Tetrahedron Lett., 1986, 27, 4103). Since both variants are carried out at low temperatures, however, this is not a viable solution on a technical (industrial) scale.

Wright et al. (Tetrahedron Lett., 1996, 37, 4631) describe an alternative wherein the chlorosulfonium intermediate (3) was prepared from a sulfoxide and oxalyl chloride (see Scheme 3). Here, the chlorosulfonium intermediate (3) is also unstable. For this reaction, the sulfoxide must first be prepared and isolated. For stability, the reaction must proceed at -78 ° C and to avoid reaction between aniline and oxalyl chloride, the reaction is carried out in stages. Scheme 3 - Reaction via chlorosulfonium intermediate:

W = thioether (R1 -S-CHR2R3)

 A = chlorinating agent (e.g., tert-butyl hypochlorite, t-BuOCl)

Q = aniline

 C = tertiary amine base (e.g., triethylamine)

E = oxalyl chloride (COCI) ₂

Those described by these methods (Scheme 2 or Scheme 3)

Compounds (4) can be mechanistically produced only via the compounds (2). Inevitably, the use of a base (C) for rearrangement to the compounds (4) is necessary. In the literature, an additional base to aniline (compounds of formula Q) is called as "proton sponge" or triethylamine. The additional base used in these processes must inevitably be recovered in industrial (industrial) scale syntheses and separated from the unreacted compounds of the formula Q in order to be able to use the re-isolated compounds of the formula Q as starting materials.

The reasons why the reaction is so sensitive to reaction temperatures above -70 ° C and why it has always been carried out stepwise are manifold. First of all, the functional groups participating in the reaction, ie the nitrogen atom of the aniline and the sulfur atom of the thioether, are present unchanged in both the product (4) and the starting material. Thus, selective chlorination would not be expected during the reaction in which the product (4) is formed the same. For this reason, all methods known from the literature use a stepwise reaction.

In addition, at temperatures higher than -65 ° C, the N-chloroaniline can be converted into a chlorinated ring in the aromatics, as well as other oxidation products (dimers) form. Thus, it is not surprising that the much less electron-rich and thus much less reactive for core chlorination acetanilide forms only core chlorination with tert-butyl hypochlorite at 0 ° C. (Lengyel et al., Synth., Comm., 1998, 28 (10) , 1891-1896).

Furthermore, the sulfonium intermediates (2) or (3) can be eliminated in the presence of bases to form the reactive by-product (5), which would condense, for example, with an aniline, irreversibly producing the minor component (6) (see Scheme 4). , This corresponds to the so-called Pummerer oxidation of the R2-CH-R3 radical.

It is an object of the present invention to provide a modified process which has improved production compared to the above-mentioned processes

Compounds (4) via intermediates (2) (sulfonium salts) on an industrial scale with advantages such as improved overall yield and / or product purity, reduced use of starting materials, dispensing with other excipients (such as a second base) or simplified procedure (such as reactions in higher temperature) or use technically (industrially) more suitable solvents (less toxic, better recoverable).

The compounds (4) thus prepared should preferably also have a

Further processing to oxindoles (1, 3-dihydro-2H-indole-2-ones), which may also be intermediates for the synthesis of fine chemicals and drugs from the pharmaceutical and / or agriculture. Surprisingly, it has now been found that despite the above-mentioned problems, the reaction could be modified so that it can be carried out on an industrially feasible scale.

The invention relates to a process for the preparation of compounds of the formula (4):

wherein

 R1 = C1-C6 alkyl, substituted alkyl, aryl or substituted aryl,

 preferably C1-C4 alkyl;

 R2 = H, C1-C6 alkyl or substituted alkyl;

R3 = electron withdrawing or activating group, such as -CO-R1; -CO-X, where X = OR1, SR1, NR2R2 ', where R2' is defined as R2 and may be the same or different than R2; R2 and R2 'can form a ring; SO (n ') - R1, where n' = 0, 1, or 2; -CN; -NO ₂₎ aryl or heteroaryl;

R4 = F, Cl, Br, I, CF _3, CN, N0 _2, COX;

 wherein X = OR1, SR1, NR2R2 ', wherein R2' is as R2 defined above and may be the same or different than R2, preferably F or Cl, in particular 2-F;

 n = 1 - 4, preferably 1 - 2, in particular 1;

 R5 = H, C1-C6 alkyl or substituted alkyl,

means characterized in that one is a mixture an aniline (compound of formula Q):

worin die Reste R4, n und R5 wie in Formel (4) definiert sind, mit einem Thioether (Verbindung der Formel W):

wherein the radicals R4, n and R5 are as defined in formula (4) with a thioether (compound of the formula W):

(W) wherein the radicals R 1, R ₂ and R _{3 are} as defined in formula (4) in the presence of sulfuryl chloride (SO ₂ Cl ₂ ) as a chlorinating agent and an organic solvent at a reaction temperature in the range between -60 and -10 ° C, especially between -50 and -20 ° C, to the compound of formula (4) on the mechanistic intermediate of the formula (2).

The resulting selective and clean reaction with good yields is particularly surprising and contrary to the belief that it is reported that good yields can only be achieved when the unstable N-chloro- (1) or N-sulfonium- (2) Scheme 2) below -65 ° C, normally at -78 ° C (Gassman et al., J. Am. Chem Soc, 1974, 96 (17), 5508; Gassman et al. , J. Am. Chem. Soc., 1974, 96 (17), 5512, WO 96/41799 A1). The thioether (compound of the formula W) used in the process according to the invention has the following structure:

 (W) where

 R1 = C1-C6 alkyl, substituted alkyl, aryl or substituted aryl, preferably

C1-C4 alkyl;

R2 = H, C1-C6 alkyl or substituted alkyl;

 R3 = electron withdrawing or activating group, such as -CO-R1; -CO-X,

 where X = OR1, SR1, NR2R2 ', where R2 "is defined as R2 and may be the same or different than R2; R2 and R2' may form a ring;

SO (n ') - R1, where n' = 0, 1, or 2; -CN; -N0 _2, aryl or heteroaryl; means.

 Insofar as reference is made below to thioethers, the above-mentioned

Meant connection.

The aniline (compound of the formula Q) used in the process according to the invention has the following structure:

wobei

in which

R4 = F, Cl, Br, I, CF3 _> CN, NO2 _> COX;

wherein X = OR1, SR1, NR2R2 ', wherein R2' is as R2 defined above and may be the same or different than R2, preferably F or Cl, in particular 2-F; n = 1 - 4, preferably 1 - 2, in particular 1;

R5 = H, C1-C6 alkyl or substituted alkyl,

means.

It is imperative that a hydrogen atom is in the ortho position to the nitrogen atom of the aniline. The ring may be substituted with one or more substituents R4. As far as reference is made below to aniline, the above-mentioned compound is meant.

Suitable chlorinating agents are all those known to the person skilled in the art

Chlorinating agents in question, such as trichloroisocyanuric acid, tert-butyl hypochlorite and sulfuryl chloride. Preference is given to chlorinating agents such as sulfuryl chloride (SO ₂ Cl ₂ ), which surprisingly generate HCl against the literature, without the need for a second, non-nucleophilic base.

The reaction in the process according to the invention can be carried out with various

Solvents are carried out.

Thus, non-polar organic solvents can be used, such as chloroalkanes (for example dichloromethane and dichloroethane), aromatics (for example benzene, toluene, xylene), haloaromatics (for example chlorobenzene, dichlorobenzene),

substituted aromatics (for example, benzotrifluoride, chlorobenzotrifluoride,

Chlorotoluene, chloroylol) alone or as mixtures with one another or as

Mixtures with alkanes and cycloalkanes.

In addition, however, polar organic solvents are also suitable. This is contrary to the teachings of Gassman (J. Am. Chem. Soc, 972, 94, 3891), according to which N-chloro derivatives are less stable in polar solvents. Thus, in the process of the invention, the reaction may preferably be carried out in an ester solvent such as, for example, C1-C6 alkyl acetate (for example, methyl acetate, ethyl acetate, n-propyl acetate, iso-propyl acetate, 2-methyl-prop-1-ylacetate, n-butyl acetate, But -2-ylacetat, Pentylacetate, Hexylacetate and Cyclalkylacetate, C1-C6 alkyl and Cycloalkylpropionates, C1-C6 alkyl and cycloalkyl-n-butyrates, -iso-butyrates, - pentanoates and -hexanoates and -cyclopentanoates and -cyclohexanoates) or in mixtures thereof or in admixture with other solvents. Ester solvents have the advantage over other solvents, such as the dichloromethane used in the literature, that they are more technically (industrially) suitable (less toxic, better recoverable).

The process according to the invention for the preparation of compounds of the formula (4) is based on the fact that the two compounds aniline (compound of the formula Q) and thioether (compound of the formula W) can be advantageously premixed.

The resulting selective and clean reaction is special

surprising and contrary to the doctrine that Gassman demonstrated that, depending on the substituent, N-chlorination or S-chlorination is optimal for the reaction (Gassman, J. Am. Chem. Soc, 1974, 96 (17), 5512). , Furthermore, one would expect from a mixture consisting of aniline and thioether, no selectivity in a chlorination, why after previous

Doctrine was only gradually worked.

For good product yields it has been shown that it is advantageous to use up to 1

Equivalent, preferably 0.5 to 1, 0 equivalents, more preferably 0.7 to 1, 0 equivalents, particularly preferably 0.8 to 0.95 equivalents of

To use chlorinating agent. The chlorinating agent is added to a mixture of one equivalent of the thioether (compound of formula W) and a technically economical excess of the aniline (compound of formula Q) of 2.0 to 5.0 equivalents, preferably 2.0 to 3.0 equivalents preferably 2.0 to 2.5 equivalents added.

The chlorinating agent may preferably be prediluted with a solvent or a solvent mixture and may preferably be pre-cooled. A particular embodiment of the invention is that, for good product yields, a portion of the aniline (between 1 and 99% by weight, preferably between 20 and 80% by weight, particularly preferably 30 to 70% by weight of the total amount of aniline) is separated from but simultaneously or partially simultaneously with the chlorinating agent.

A particular embodiment of the invention with regard to a simplified (industrial) process sequence is that in the process according to the invention for the preparation of compounds of formula (4) can be dispensed with the addition of an additional tertiary amine, whereby the reuse of unreacted, re-isolated aniline (Compound of formula Q) is simplified.

So it was found that a surplus of the surprisingly

electron-poor anilines acts as a mild base in the formation of product of formula (4). This is surprising over the standard Gassman reaction which uses the addition of an additional tertiary amine (see Schemes 2 and 3: C = tertiary amine base, e.g., triethylamine). The aniline is evidently able to catalyze the rearrangement to the product of formula (4) and therefore also to eliminate HCl from a chlorosulfonium intermediate of formula (3), which would only lead to side reactions. Nevertheless, and especially because of this, it is very surprising that the reaction can be carried out in this way. At the same time, the omission of an additional tertiary amine in the process according to the invention is advantageous because it is possible to dispense with a subsequent complicated separation of recovered aniline and tertiary amine.

The invention also provides the process for the preparation of compounds of the formulas (7) and (8):

wherein

 R1 = C1-C6 alkyl, substituted alkyl, aryl or substituted aryl,

 preferably C1-C4 alkyl;

 R2 = H, C1-C6 alkyl or substituted alkyl;

R4 = F, Cl, Br, I, CF ₃₎ CN, N0 _2, COX;

 wherein X = OR1, SR1, NR2R2 ', wherein R2' is as R2 defined above and may be the same or different than R2, preferably F or Cl, in particular 2-F;

 n = 1 - 4, preferably 1 - 2, in particular 1;

 R5 = H, C1-C6 alkyl or substituted alkyl;

 R6 = C1-C6 alkyl or substituted alkyl, preferably C1-C4 alkyl or OH;

 where compounds of the formula (4):

with the abovementioned definitions of the radicals R, R2, R4 and R5 and wherein R3 is an electron-withdrawing or activating group, such as -CO-R1; - CO-X, where X = OR1, SR1, NR2R2 ', where R2' is defined as R2 and may be the same or different than R2; R2 and R2 'can form a ring; SO (n ') - R1, where n' = 0, 1, or 2; -CN; -NO ₂ , aryl or heteroaryl; is prepared according to the above-described inventive method for the preparation of compounds of formula (4), without isolation of the compounds of formula (4), optionally in the presence of an acid catalyst, to the indole of formula (7) or the oxindole of the formula (8).

In the case of R3 = CO-R1, the indole of the formula (7) is obtained, while in the case of R3 = COX the oxindole of the formula (8) or the indole of the formula (7) with R6 = OH is obtained. Therefore, for the purposes of the present invention, these specific indoles are also encompassed by the term "oxindole".

For the acid catalyst in the process according to the invention mineral or organic acids such as H ⁺ X ^" , where X ^" = F, CI ^" , Br ^" , Γ, HSO4 ^" , BF ₄ ^" , H2PO4 ^" , SO ₄ ^2" , ΗΡθ PO ₄ ^{3 "} , R'SO ₃ ^" , R "HPO ₃ ^" , R "'PO ₃ ² -, R""CO ₂ ^- means, or

Mixtures thereof are used. Preference is given to mineral acids, in particular HCl, in gaseous form or in a solvent, preferably water or alcohol. The acid catalyst used in the process according to the invention is used in amounts which are customary for the person skilled in the art.

Based on the standard method of Gassman et. al. (J. Am. Chem. Soc., 1974, 96 (17), 5508) are several oxindoles or ortho-substituted anilines

been synthesized. Thus, for example, the intermediate 7-fluoro-3-methylthio-oxindole was synthesized by way of the synthesis of a 7-fluoroisatin (Wierenga et al., Tetrahedron Lett. 1983, 24, 2437). An example of a 7-fluoro-3-methylthio-4-nitro-oxindole prepared by the Gassman process using proton sponge and triethylamine can be found in Tetrahedron Lett. 2005, 46, 4613. The invention therefore also provides the compounds of the formula (4 ') which are obtainable by the process according to the invention described above and which are new, as intermediates for the preparation of fine chemicals and active ingredients from the pharmaceutical or agricultural sector:

 (4 ') where

 R1 = C2-C6 alkyl, benzyl;

R2 = H;

R3 = C0 ₂ R ", where R" = C1-C6 can be alkyl, benzyl ester;

 R4 = 2-F, 2-CI;

 R5 = H, C1-C4 alkyl;

means.

Preference is given to compounds of the formula (4 ') where

R1 = ethyl;

R2 = H;

R3 = C0 ₂ methyl, C0 ₂ ethyl;

 R4 = 2-F, 2-CI;

 R5 = H, methyl, ethyl;

means.

wobei The invention also provides end products of the formula (7 ') which are obtainable by the process according to the invention described above and which are new:

in which

 R1 = C2-C6 alkyl, benzyl;

 R4 = 7-F, 7-CI;

 R5 = H, C1-C4 alkyl;

 R6 = C1-C6 alkyl;

means

Preference is given to compounds of the formula (7 '), where

 R1 = ethyl;

 R4 = 7-F, 7-CI;

 R5 = H, methyl;

 R6 = C1-C6 alkyl;

means.

The invention also provides the compounds of the formula (8 ') which are obtainable by the process according to the invention described above and which are novel, as intermediates for the preparation of fine chemicals and active ingredients from the pharmaceutical or agricultural sector:

(8 ') where R1 = C2-C6 alkyl, benzyl;

 R2 = H;

 R4 = 7-F, 7-CI;

 R5 = H, C1-C4 alkyl;

means.

Preference is given to compounds of the formula (8 '), where

 R1 = ethyl;

 R2 = H;

 R4 = 7-F, 7-CI;

 R5 = H, methyl;

means.

The invention also relates to the use of the new compounds of the formulas (4 '), (7') and (8 ') obtained according to the invention prepared by the process according to the invention for the preparation of

Further processing products, wherein the group SR1 is replaced by a known to those skilled Desulfonierungsverfahren by hydrogen.

In the context of the chemical terms used in this description, the definitions customary for the person skilled in the art apply, unless otherwise specifically defined. The radicals alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino and alkylthio and the corresponding unsaturated and / or substituted radicals in the carbon skeleton are each straight-chain or branched. Unless specifically stated, these radicals are the lower carbon skeletons, e.g. with 1 to 6 C atoms or with unsaturated groups having 2 to 6 C atoms, preferred.

Alkyl radicals, also in the composite meanings such as alkoxy, haloalkyl, etc., mean e.g. Methyl, ethyl, n- or i-propyl, n-, i-, t- or 2-butyl, pentyls, hexyls, such as n-hexyl, i-hexyl and 1,3-dimethylbutyl, heptyls, such as n-heptyl, 1-methylhexyl and 1, 4-dimethylpentyl.

Cycloalkyl means a carbocyclic saturated ring system preferably having 3 to 8 C atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Halogen is, for example, fluorine, chlorine, bromine or iodine. Haloalkyl means by halogen, preferably by fluorine, chlorine and / or bromine, in particular by fluorine and / or chlorine, partially or completely substituted alkyl, e.g.

onohaloalkyl (= monohaloalkyl), perhaloalkyl, CF _3, CHF _2, CH ₂ F, CF ₃ CF _2, CH ₂ FCHCI, CCl _3, CHCl 2, CH ₂ CH ₂ CI; Haloalkoxy is, for example, OCF ₃ , OCHF ₂ , OCH ₂ F, CF ₃ CF ₂ O, OCH ₂ CF ₃ and OCH ₂ CH ₂ Cl; the same applies to other halogen-substituted radicals.

Aryl is a mono-, bi- or polycyclic aromatic system,

for example, phenyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl, pentalenyl, fluorenyl and the like, preferably phenyl.

A heterocyclic radical or ring (heterocyclyl) may be saturated, unsaturated or heteroaromatic; it preferably contains one or more, in particular 1, 2 or 3 heteroatoms in the heterocyclic ring, preferably from the group N, O, and S; it is preferably an aliphatic heterocyclyl radical having 3 to 7 ring atoms or a heteroaromatic radical having 5 or 6 ring atoms. The heterocyclic radical may be e.g. a heteroaromatic radical or ring (heteroaryl), e.g. a mono, bi or polycyclic aromatic system in which at least 1 ring contains one or more heteroatoms, for example pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, furyl, pyrrolyl, pyrazolyl and imidazolyl, or is a partially or fully hydrogenated radical such as oxiranyl, pyrrolidyl, piperidyl, piperazinyl, dioxolanyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydrofuryl. Substituents for a substituted heterocyclic radical are those mentioned below

Substituents in question, in addition also oxo. The oxo group may also be attached to the hetero ring atoms, which may exist in different oxidation states, e.g. at N and S, occur.

Substituted radicals, such as a substituted alkyl, aryl, phenyl, benzyl, Heterocyclyl and heteroaryl, mean, for example, one of

unsubstituted parent derived substituent radical, where the

Substituents, for example, one or more, preferably, 2 or 3 radicals from the group halogen, alkoxy, haloalkoxy, alkylthio, hydroxy, amino, nitro, carboxy, cyano, azido, alkoxycarbonyl, alkylcarbonyl, formyl, carbamoyl, mono- and dialkylaminocarbonyl, sulfamoyl, Mono and dialkylaminosulfonyl, substituted amino such as acylamino, mono and dialkylamino, and alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl and, in the case of cyclic radicals, also alkyl and

Haloalkyl mean; in the term "substituted radicals" such as substituted alkyl etc. are as substituents in addition to those mentioned saturated

hydrocarbon-containing radicals corresponding unsaturated aliphatic and aromatic radicals, such as optionally substituted phenyl, phenoxy, etc.

locked in. For radicals having C atoms, those having 1 to 4 C atoms, in particular 1 or 2 C atoms, are preferred. Preferred are usually

Substituents from the group halogen, e.g. Fluorine and chlorine, (C 1 -C 4) alkyl, preferably methyl or ethyl, (C 1 -C 4) haloalkyl, preferably trifluoromethyl, (C 1 -C 4) alkoxy, preferably methoxy or ethoxy, (C 1 -C 4) haloalkoxy, nitro and cyano. Particularly preferred are the substituents methyl and fluorine.

Of the formulas (4 '), (7') and (8 '), all stereoisomers are also included, as appropriate. Such compounds contain one or more asymmetric carbon atoms, which are not specified separately in the general formulas. The possible defined by their specific spatial form possible stereoisomers, such as enantiomers, diastereomers, can be prepared by conventional methods from mixtures of

Stereoisomers or by stereoselective reactions in

Combination with the use of stereochemically pure starting materials

getting produced.

The compounds of the formulas Q and W to be used according to the invention are known or can be prepared analogously to generally known processes.

The inventive method for obtaining compounds of formula (4) is for example, carried out so as to submit aniline (compound of formula Q) and thioether (compound of formula W) in the solvent and, preferably under inert gas, cooled down. To this stirred solution, a mixture of chlorinating agent and solvent is added dropwise. The reaction is then heated and diluted with an aqueous acid. The phases are separated and the organic phase is washed with an aqueous acid. The organic phase is then dried and, if the compound of formula (4) is a solid, concentrated in vacuo and possibly an anti-solvent added and stirred for several hours. The solid (compound of formula (4)) is filtered off and mixed with the anti-solvent or solvent mixture

washed. In case the compound of formula (4) is an oil, the organic phase is concentrated in vacuo.

The process according to the invention for obtaining compounds of the formulas (7) and (8) is carried out, for example, by introducing aniline (compound of the formula Q) and thioether (compound of the formula W) in the solvent and cooling it down, preferably under protective gas. To this stirred solution, a mixture of chlorinating agent and solvent is added dropwise. The reaction is then heated and diluted with an aqueous acid. The phases are separated and the organic phase is washed with an aqueous acid. The organic phase is then, possibly for compounds of the formula (7) and preferably for compounds of the formula (8), admixed with an acid catalyst and stirred for several hours. 90% of the solvent is then removed in vacuo and an anti-solvent added and stirred for several hours. The solid (compound of formula (7) or (8)) is filtered off and washed with the anti-solvent or solvent mixture.

The following examples illustrate the process according to the invention in more detail without restricting the process according to the invention to it. In the following examples, amounts are by weight unless otherwise specified (in the description, by weight,% by weight was used as an analogy). For units of measure, physical quantities and the like become common Abbreviations used, for example h = hour (s), mpt. = Melting point (m.p.), I = liter, ml = milliliter, g = gram, min = minute (s), in vacuo = "in vacuum" = under reduced pressure, d. Th. = Percent yield according to theory.

Examples

Synthetic Example 1:

 2-Chloroaniline (20.4 g) and methyl methylmercaptoacetate (8.36 g) were initially charged in chlorobenzene (77 ml) and cooled to -30 ° C. under protective gas. To this stirred solution was added dropwise a solution of sulfuryl chloride (8.45 g) in chlorobenzene (67 ml) in 30 minutes. The reaction mixture was warmed to -5 ° C and diluted with 0.4N hydrochloric acid (110 ml). The phases were separated and the organic phase was washed with 0.4N hydrochloric acid (4 x 110 ml). The organic phase was then treated with 10% HCl in MeOH (2 mL) and stirred for 16 hours. 90% of the solvent was removed in vacuo, heptane (120 ml) added and stirred for 4 hours. The solid was filtered off and washed with heptane (2 x 50 ml). 7-Chloro-3-methylthio-oxindole (9.36 g 70% of theory) is obtained. mpt .: 167-170 ° C.

Synthetic Example 2:

2-Chloroaniline (20.4 g) and methyl methylmercaptoacetate (8.36 g) were initially charged in chlorobenzene (77 ml) and cooled to -30 ° C. under protective gas. To this stirred solution was added dropwise a solution of sulfuryl chloride (8.45 g) in chlorobenzene (67 ml) in 30 minutes. The reaction mixture was warmed to -5 ° C and diluted with 0.4N hydrochloric acid (110 ml). The phases were separated, the organic phase washed with 0.4N hydrochloric acid (4 x 110 ml) and water (50 ml) and dried over sodium sulfate. The organic phase was filtered and distilled off in vacuo. This gives (2-amino-3-chlophenyl) - (methylthio) acetic acid methyl ester as a brown-red oil (10.9 g of 71% of theory). Synthesis Example 3:

 4-Chloroaniline (20.4 g) and methyl methylmercaptoacetate (8.36 g) were initially charged in n-butyl acetate (77 ml) and cooled to -30 ° C. under protective gas. To this stirred solution was added a solution of sulfuryl chloride (8.45g) in

N-butyl acetate (67 ml) was added dropwise in 30 minutes. The reaction was warmed to 10 ° C and diluted with 0.4N hydrochloric acid (110ml). The phases were separated and the organic phase was washed with 0.4N hydrochloric acid (2 x 110 ml). The organic phase was then treated with 10% HCl in MeOH (2 mL) and stirred for 16 hours. 90% of the solvent was removed in vacuo, heptane (120 ml) added and stirred for 4 hours. The solid was filtered off and washed with heptane (2 x 50 ml). 5-Chloro-3-methylthio-oxindole (7.89 g 59% of theory) is obtained. mpt .: 154-157 ° C.

Synthetic Example 4:

 2-Fluoroaniline (17.8 g) and methyl methylmercaptoacetate (8.36 g) were initially charged in n-butyl acetate (77 ml) and cooled to -30 ° C. under protective gas. To this stirred solution was added a solution of sulfuryl chloride (8.45g) in

N-butyl acetate (67 ml) was added dropwise in 30 minutes. The reaction was warmed to 10 ° C and diluted with 0.4N hydrochloric acid (110ml). The phases were separated and the organic phase washed with 0.4N hydrochloric acid (1 x 110 ml). The organic phase was then treated with 10% HCl in MeOH (2 mL) and stirred for 16 hours. 90% of the solvent was removed in vacuo and heptane (120 ml) added and stirred for 4 hours. The solid was filtered off and washed with heptane (2 x 50 ml). 7-Fluoro-3-methylthio-oxindole (9.17 g, 72% of theory) is obtained. mpt .: 156-159 ° C.

Synthesis Example 5:

 2-Fluoroaniline (17.8 g) and methyl methylmercaptoacetate (8.36 g) were initially charged in n-butyl acetate (77 ml) and cooled to -30 ° C. under protective gas. To this stirred solution was added a solution of sulfuryl chloride (8.45g) in

N-butyl acetate (67 ml) was added dropwise in 30 minutes. The reaction was warmed to 10 ° C and diluted with 0.4N hydrochloric acid (110ml). The phases became separated, the organic phase washed with 0.4 N hydrochloric acid (1 x 110 ml) and water (50 ml) and dried over sodium sulfate. The organic phase was filtered and distilled off in vacuo. This gives (2-amino-3-fluorophenyl) - (methylthio) acetic acid methyl ester as a brown oil (12.5 g 73% of theory).

Synthetic Example 6:

 2-Fluoroaniline (17.8 g) and methyl methylmercaptoacetate (8.36 g) were initially charged in n-butyl acetate (77 ml) and cooled to -50 ° C. under protective gas. To this stirred solution was added a solution of sulfuryl chloride (8.45g) in

N-butyl acetate (67 ml) was added dropwise over 30 minutes at an internal temperature of -53 to -48 ° C. The reaction was warmed to 10 ° C, diluted with 0.4N hydrochloric acid (110 ml) and stirred for 5 min. The phases were separated and the organic phase was washed with 0.4N hydrochloric acid (1 x 110 ml). The organic phase was treated with conc. HCl (0.2 ml). The reaction mixture was stirred for 24 hours, once more with conc. HCl (0.05 ml) and allowed to stand for 16 hours at 4 ° C. About 90% of the solvent was removed in vacuo, heptane (120 ml) added and stirred for 5 hours. The solid was filtered off, washed with heptane (2 x 50 ml) and dried. 7-fluoro-3-methylthio-oxindole (8.71 g, 63% of theory) is obtained. LCMS: M + H = 198 (100%). The 1 H NMR agrees with the in

Synthesis Example 7 described match.

Synthesis Example 7:

 2-Fluoroaniline (18.1 g) and methyl methylmercaptoacetate (8.58 g) were initially charged in n-butyl acetate (80 ml) and cooled to -20 ° C. under protective gas. To this stirred solution was added a solution of sulfuryl chloride (8.77g) in

N-Butyl acetate (70 ml) in 30 minutes at an internal temperature of -25 to -18 ° C added dropwise. The reaction was warmed to 10 ° C over 60 minutes and diluted with 0.4N hydrochloric acid (110 ml). The phases were separated and the organic phase was washed with 0.4N hydrochloric acid (1 x 110 ml). The organic phase was then treated with conc. Hydrochloric acid (0.5 ml) and MeOH (2 ml) and stirred for 16 hours. About 90% of the solvent was removed in vacuo, n-heptane (120 ml) added and stirred for 3 hours. The solid was filtered off and washed with heptane washed. 7-Fluoro-3-methylthio-oxindole (7.85 g, 55% of theory) is obtained. 1 H-NMR (CDCl ₃ ): d = 2.06 (s, 3H), 4.32 (s, 1H), 7.02-7.05 (m, 2H), 7.17-7.19 (m, 1H), 8.3 (s, broad, 1 H).

Synthetic Example 8:

 2-Fluoroaniline (17.8 g) and methyl methylmercaptoacetate (8.36 g) were initially charged in dichloromethane (77 ml) and cooled to -30 ° C. under protective gas. To this stirred solution was added dropwise a solution of sulfuryl chloride (8.45 g) in n-butyl acetate (67 ml) in 30 minutes at an internal temperature of -33 to -28 ° C. The reaction was warmed to 10 ° C, diluted with 0.4N hydrochloric acid (110 ml) and stirred for 5 min. The phases were separated and the organic phase was washed with 0.4N hydrochloric acid (1 x 110 ml). The organic phase was then treated with conc. HCl (0.2 ml). The reaction mixture was stirred for 16 hours, treated with conc. HCl (0.05 ml), stirred for 7 hours, again with conc. HCl (0.05 ml) and stirred for 16 hours. About 90% of the

Solvent was removed in vacuo, heptane (110 ml) added and 5

Hours stirred. The solid was filtered off, washed with heptane (2 x 50 ml) and dried. 7-Fluoro-3-methylthio-oxindole (5.84 g 42% of theory) is obtained. LCMS and 1 H-NMR are consistent with those described in Synthesis Examples 6 and 7.

Synthetic Example 9:

 2-Fluoroaniline (7.73 g) and methyl methylmercaptoacetate (8.36 g) were initially charged in n-butyl acetate (67 ml) and cooled to -35 ° C. under protective gas. To this stirred solution was added a solution of sulfuryl chloride (8.45g) in

Acetic acid n-butyl ester (67 ml) and parallel thereto 2-fluoroaniline (10.04 g) in

Acetic acid n-butyl ester (10ml) added directly in the reaction solution in 25 minutes, the temperature rising to -29 ° C. After 15 minutes at -30 ° C, the reaction was warmed to 10 ° C and 0.4N hydrochloric acid (110ml) was added dropwise. The phases were separated and the organic phase was washed with 0.4N hydrochloric acid (1 x 110 ml). The organic phase was treated with 10% HCl in MeOH (1, 9ml) and stirred for 16 hours. 95% of the solvent was removed in vacuo, Heptane (120ml) was added and the reaction mixture stirred for 3 hours. The solid was filtered off and washed with heptane (2 x 50 ml). 7-fluoro-3-methylthio-oxindole (8.87 g, 70.0% of theory) is obtained.

Synthetic Example 10:

2-Fluoroaniline (18.1 g) and 1- (methylsulfanyl) acetone (7.44 g) were initially charged in n-butyl acetate (80 ml) and cooled to -30 ° C. under protective gas. While stirring, a solution of sulfuryl chloride (8.77 g) in n-butyl acetate (70 ml) was added dropwise over 30 minutes and stirred for 1.5 hours at an internal temperature of -35 to -28 ° C. The reaction mixture was warmed to 0 ° C and the phases separated. The organic phase was extracted with 0.5N hydrochloric acid (2 times 80 ml) and water (40 ml), dried with a little sodium sulfate and concentrated in vacuo. The residue is combined three times with ethyl acetate and concentrated. 7-Fluoro-2-methyl-3- (methylsulfanyl) -1H-indole is obtained as a brown oil (9.67 g, 59% of theory). 1 H-NMR (CDCl ₃ ): d = 2.26 (s, 3H), 2.55 (s, 3H), 6.87 (dd, 1H), 7.03-7.08 (m, 1H), 7.43 (d, H), 8.24 (s, wide, 1H). LCMS: M + H = 196.

Claims

claims 1. Process for the preparation of compounds of formula (4):

wherein  R1 = C1-C6 alkyl, substituted alkyl, aryl or substituted aryl,  preferably C1-C4 alkyl;  R2 = H, C1-C6 alkyl or substituted alkyl; R3 = electron withdrawing or activating group, such as -CO-R1; -CO-X, where X = OR1, SR1, NR2R2 ', where R2' is defined as R2 and may be the same or different than R2; R2 and R2 'can form a ring; SO (n ') - R1, where n' = 0, 1, or 2; -CN; -NO ₂ , aryl or heteroaryl; R4 = F, Cl, Br, I, CF _3, CN, N0 _2, COX;  wherein X = OR1, SR1, NR2R2 ', wherein R2' is as R2 defined above and may be the same or different than R2, preferably F or Cl, in particular 2-F;  n = 1 - 4, preferably 1 - 2, in particular 1;  R5 = H, C1-C6 alkyl or substituted alkyl, characterized in that a mixture of an aniline (compound of formula Q):

wherein the radicals R4, n and R5 are as defined in formula (4) with a thioether (compound of the formula W):

(W) in which the radicals R1, R2 and R3 are as defined in formula (4), in the presence of sulfuryl chloride (SO ₂ Cl ₂₎ as a chlorinating agent and an organic solvent at a reaction temperature in the range between -60 and -10 ° C, especially between -50 and -20 ° C, to  Implementation of the compound of the formula (4). 2. The method according to claim 1, characterized in that the reaction in ester solvents selected from the group consisting of C1-C6 Alkyl acetates and cyclalkyl acetates, C 1 -C 6 alkyl and cycloalkyl propionates, C 1 -C 6 alkyl and cycloalkyl n-butyrates, isobutyrates, pentanoates and hexanoates and cyclopentanoates and cyclohexanoates or in mixtures thereof or in admixture with other solvents becomes. 3. The method according to claim 1 or 2, characterized in that for good product yields up to 1 equivalent of the chlorinating agent to a mixture of one equivalent of the thioether (W) and 2.0 to 5.0 equivalents, of the aniline (Q) is added. 4. The method according to any one of claims 1 to 3, characterized in that a subset of the aniline between 1 and 99 wt.% Of the total amount of aniline separated from, but simultaneously or partially simultaneously with the  Chlorinating agent is added. 5. The method according to any one of claims 1 to 4, characterized in that is omitted after the addition of the aniline (Q) on the addition of an additional tertiary amine. 6. Process for the preparation of compounds of formulas (7) and (8):

 (7) (8)  wherein  R1 = C1-C6 alkyl, substituted alkyl, aryl or substituted aryl,  preferably C1-C4 alkyl;  R2 = H, C1-C6 alkyl or substituted alkyl; R4 = F, Cl, Br, I, CF _3, CN, N0 _2, COX; where X = OR1, SR1, NR2R2 ', where R2' is defined as R2 above and may be identical or different from R2, preferably F or Cl, in particular 2-F; n = 1 - 4, preferably 1 - 2, in particular 1; R5 = H, C1-C6 alkyl or substituted alkyl;  R6 = C1-C6 alkyl or substituted alkyl, preferably C1-C4 alkyl or OH; where compounds of the formula (4):

(4) having the abovementioned definitions of the radicals R1, R2, R4, n and R5 and wherein R3 is an electron-withdrawing or activating group, such as -CO-R1; - CO-X, where X = OR1, SR1, NR2R2 ', where R2' is defined as R2 and may be the same or different than R2; R2 and R2 'can form a ring; SO (n ') - R1, where n' = 0, 1, or 2; -CN; -NO ₂ , aryl or heteroaryl; means prepared by a method according to any one of claims 1 to 5; without isolation of the compounds of formula (4), optionally in Presence of an acid catalyst to which indole of formula (7) or the oxindole of formula (8) are reacted. 7. Use of the compounds of the formula (4 ')

 (4 ')  in which  R1 = C2-C6 alkyl, benzyl;  R2 = H; R3 = C0 ₂ R ", where R" = C1-C6 can be alkyl, benzyl ester; R4 = 2-F, 2-CI;  R5 = H, C1-C4 alkyl;  means; for the production of active ingredients from agriculture. 8. Use of the compounds of the formula (7 ¹ )

in which  R1 = C2-C6 alkyl, benzyl;  R4 = 7-F, 7-CI;  R5 = H, C1-C4 alkyl;  R6 = C1-C6 alkyl; means; for the production of active ingredients from agriculture. 9. Use of the compounds of the formula (8 ')

in which  R1 = C2-C6 alkyl, benzyl;  R2 = H;  R4 = 7-F, 7-CI;  R5 = H, C1-C4 alkyl;  means; for the production of active ingredients from agriculture.