EP1981841A1 - Preparation of thioalkylamines using chlorosulfonic acid - Google Patents

Preparation of thioalkylamines using chlorosulfonic acid

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Publication number
EP1981841A1
EP1981841A1 EP06776867A EP06776867A EP1981841A1 EP 1981841 A1 EP1981841 A1 EP 1981841A1 EP 06776867 A EP06776867 A EP 06776867A EP 06776867 A EP06776867 A EP 06776867A EP 1981841 A1 EP1981841 A1 EP 1981841A1
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EP
European Patent Office
Prior art keywords
alkyl
halo
different
alkoxy
group
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German (de)
French (fr)
Inventor
Harry Blaschke
Sergiy Pazenok
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Bayer CropScience AG
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Bayer CropScience AG
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Priority to EP06776867A priority Critical patent/EP1981841A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/24—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfuric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated

Definitions

  • the present invention relates to a novel process for the preparation of known thioalkylamine derivatives.
  • thioalkylamine derivatives can be divided into two groups, thiols and sulfides. For the preparation of both classes the methods discussed below have been described.
  • a first method for the preparation of thiols is based on the hydrolytic cleavage of thiazoline or thiazolidinone derivatives (cf. e.g. J. Med. Chem. 1965. 8, 762; JP 59-231064, Bull. Soc. Chim. Fr. 1967, 3637).
  • thiazoline or thiazolidinone derivatives have to be prepared first via several reaction steps the overall yield of this method is very low.
  • Thiols can be obtained furthermore by a process comprising reacting sulfates of amino alcohols with ammonium sulfide (cf. e.g. Nihon Kagaku Kaishi 1979, 149). This method requires long reactions times in a sealed reaction vessel, which causes high costs because of the required production plants having low productivity.
  • reaction of oxazoline- or oxazolidinone derivatives with thiols is a method for the preparation of sulfides (cf. e.g. J. Org. Chem. 1992. 57, 6257; J. Med. Chem. 1984. 27. 1354).
  • a hydrolytic process is required to obtain reaction products as amides according to this method.
  • no reaction is observed, if the oxazolidine ring of the starting compounds is e.g. alkyl substituted.
  • aromatic sulfides can be prepared using this method because of the acidity of the mercaptans.
  • the hydrolytic cleavage of amides which can be obtained by reaction of amino alcohols with mercaptans in the presence of carboxylic acids, also furnishes sulfides (cf. e.g. DE-OS 14 93 534).
  • This method has to be carried out at high temperature and under pressure using long reaction times and is therefore restricted to the synthesis of sulfides. Additionally a hydrolytic step is required to obtain the reaction products from amides.
  • a method for the conversion of thioalkylalcohols into thioalkylamines is represented by the Ritter reaction with subsequent hydrolytic cleavage (cf. e.g. DE-OS 20 45 905). This method employs - -
  • a further method for the preparation of thioalkylamine derivatives uses as starting material amino alcohols which are reacted with sulfuric acid to give the corresponding esters in a first step (cf. WO 01/23350). After evaporation to dryness this esters are further converted by reaction with mercaptans. The required evaporation after the first reaction step causes problems when this process is employed to a large scale production.
  • R 1 and R 2 in each case independently of one another represent hydrogen, Ci-C 4 -alkyl, C 3 -Cg- cycloalkyl, C 3 -C 8 -cycloalkyl-C ⁇ -C 4 -alkyI, hydroxy-C
  • R 3 and R 4 independently of one another represent hydrogen or Ci-C 4 -alkyl
  • R 5 and R 6 independently of one another represent hydrogen, Ci-C 4 -alkyl, unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro, C]-C 4 -alkyl, C 3 -Cg-cycloalkyl, Q-C 4 - alkoxy, C,-C 4 -alkylthio, C,-C 4 -alkylsulfinyl, C,-C 4 -alkylsulfonyl, halo-C,-C 4 -alkyl, halo-
  • R represents unsubstituted or mono- or polysubstituted Ci-Ci 2 -alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, hydroxy,
  • n 1, 2, 3, 4, 5, 6, 7 or 8, where the group C(R')R 2 may be identical or different, when n is greater than 1,
  • R 1 and R 2 furthermore together represent C 2 -C 5 -alkyIene, R 1 furthermore represents together with R 3 or R 5 C 3 -C 5 -alkylene,
  • R 3 and R 4 furthermore together represent C 4 -C 6 -alkylene
  • R 3 and R 5 furthermore together represent C 2 -Gralkylene
  • R 5 and R 6 furthermore together represent C 4 -C 6 -alkylene
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n have the above given meanings
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n have the above given meanings
  • M represents hydrogen, ammonium or an alkali metal atom
  • the thioalkylamines of the formula (I) can be obtained in a simple manner in a very good space-time yield.
  • the reaction according to the invention therefore has the advantage of an increased reaction rate. This leads to the technical advantage of a high space-time yield.
  • the process according to the invention has the further advantage that the solution of the intermediates of formula (III) need not to be evaporated to dryness.
  • the reaction mixture can be stirred at any time of the process which decreases the risk of a breaking reaction vessel in industrial plants.
  • the formula (II) provides a general definition of the amino alcohols required as starting materials for carrying out the first step of the process according to the invention.
  • Preferred as starting material are amino alcohols of the formula (II), in which
  • R 1 and R 2 in each case independently of one another represent hydrogen, C
  • R 3 and R 4 independently of one another represent hydrogen or Ci-C 4 -alkyl
  • R 5 and R 6 independently of one another represent hydrogen, C r C 4 -alkyl, unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, Ci-Q-alkyl, C 3 -C 6 -cycloalkyl, C
  • n 1, 2, 3, 4, 5 or 6, where the group C(R ] )R 2 may be identical or different, when n is greater than 1,
  • R 1 and R 2 furthermore together represent C 2 -C 5 -alkylene
  • R 1 furthermore represents together with R 3 or R 5 C 3 -C 5 -alkylene
  • R 3 and R 4 furthermore together represent C 4 -C 6 -alkylene
  • R 3 and R 5 furthermore together represent C 2 -C 4 -alkyIene
  • R 5 and R 6 furthermore together represent C 4 -C 6 -alkylene.
  • Particularlv preferred as starting material are amino alcohols of the formula (II), in which
  • R 1 and R 2 in each case independently of one another represent hydrogen, methyl, ethyl, n-, i-pro- pyl, n-, i-, S-, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutyl- ethyl, cyclopentylethyl, cyclohexylethyl, hydroxymethyl, hydroxyethyl; unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl,
  • R 3 and R 4 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl,
  • R 5 and R 6 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, methylthio, ethylthio, n-, i-propylthio, n-, i-, s-
  • n 1, 2, 3, 4, 5 or 6, where the group C(R*)R 2 may be identical or different, when n is greater than 1 ,
  • R 1 and R 2 furthermore together represent -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ),,-, -(CH 2 ) 5 -,
  • R 1 furthermore represents together with R 3 or R 5 -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -,
  • R 3 and R 4 furthermore together represent -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -,
  • R 3 and R 5 furthermore together represent -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -,
  • R 5 and R 6 furthermore together represent -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -.
  • R 1 and R 2 in each case independently of one another represent hydrogen, methyl, ethyl, n-, i-pro- pyl, n-, i-, s-, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl; unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, cyclopropyl, cyclopenty!, cyclohexyl, methoxy, ethoxy, n-, i-prop
  • R 3 and R 4 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl,
  • R 5 and R 6 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl, unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, methylthio, ethylthio, n-, i-propylthio, n-, i-, s-, t-butylthio
  • n 1, 2, 3 or 4, where the group C(R')R 2 may be identical or different, when n is greater than 1 ,
  • R 1 and R 2 furthermore together represent -(CH 2 ) r , -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -,
  • R 1 furthermore represents together with R 3 or R 5 -(CH 2 V, -(CH 2 J 4 -, -(CH 2 ) 5 -,
  • R 3 and R 4 furthermore together represent -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -,
  • R 3 and R 5 furthermore together represent -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ),,-,
  • R 5 and R 6 furthermore together represent -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -.
  • amino alcohols of the formula (IT) in which R 1 and R 2 in each case independently of one another represent hydrogen, methyl, ethyl, n-, i-pro- pyl, n-, i-, s-, t-butyl,
  • R 3 and R 4 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl,
  • R 5 and R 6 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl,
  • n 1 or 2
  • the group C(R')R 2 may be identical or different, when n is greater than 1.
  • Amino alcohols of the formula (II) are widely known and/or can be prepared according to known methods.
  • the formula (FV) provides a general definition of the mercaptans or salts thereof required as starting materials for carrying out the second step of the process according to the invention.
  • Preferred as starting material are mercaptans or salts thereof of the formula (FV), in which
  • R represents unsubstituted or mono- or polysubstituted Ci-Ci 2 -alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, Ci-G
  • M represents hydrogen, ammonium or an alkali metal atom (preferably sodium, potassium, lithium and caesium).
  • Particularly preferred as starting material are mercaptans or salts thereof of the formula (FV), in which
  • R represents in each case unsubstituted or mono- or polysubstituted methyl, ethyl, n-, i-pro- pyl, n-, i-, s-, t-butyl, in each case the isomeric pentyls, hexyl, octyl, decyls and dodecyls, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, di- fluorochloromethoxy, fluorodichloromethoxy, methylthio, ethylthio, n-, i-propylthio, n-, i
  • M represents hydrogen, ammonium, sodium, potassium, lithium and caesium.
  • R represents in each case unsubstituted or mono- or polysubstituted methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl, in each case the isomeric pentyls, hexyl, octyl, decyls and dodecyls, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, trifluoromethoxy, trichloromethoxy, methylthio, ethylthio, n-, i-propylthio, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propylsul
  • M represents hydrogen, ammonium, sodium and potassium.
  • R represents in each case unsubstituted or mono- or polysubstituted methyl, ethyl, n-, i-propyl or n-, i-, S-, t-butyl where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, trifluoromethoxy, trichloromethoxy, methylthio, ethylthio, n-, i-propylthio, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propylsulfinyl, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl,
  • M represents sodium or potassium.
  • Mercaptans or salts thereof of the formula (FV) are widely known and/or can be prepared according to known methods.
  • Saturated or unsaturated hydrocarbon radicals e.g. alkyl and alkenyl
  • Optionally substituted radicals may be mono- or polysubstituted, where in the case of polysubstitution the substituents may be identical or different.
  • halogen e.g. haloalkyl
  • Radicals subsituted by halogen are mono- or polysubsituted up to perhalogenation.
  • the halogen atoms may be identical or different.
  • Halogen represents fluorine, chlorine, bromine or iodine.
  • the first step of the reaction according to the invention can be carried out by addition of the chlorosulfonic acid into the amino alcohols of the formula (II). This procedure is preferably carried out with mechanical stirring.
  • the addition of the chlorosulfonic acid into the amino alcohol of the formula (II) is preferably done with cooling to keep the temperature below 70 0 C, while a temperature range between 30 and 50 0 C is particularly preferred. In general a carbonization will not be observed even if higher substituted amino alcohols are employed.
  • the amino alcohols are applied in liquid form or as a solution in inert organic solvent.
  • the first step of the reaction is expediently carried out under atmospheric pressure, although it is also possible to work under reduced or elevated pressure. Particular preference is given to carrying out the reaction under atmospheric pressure.
  • the reaction time can be different depending on the scale of the reaction and may vary between 10 min and 4 hours.
  • the first step of the process is carried out by reacting 0.5 to 2, preferably 0.8 to 1.2, particularly preferably 0.9 to 1.1 moles of amino alcohol per mole of chlorosulfonic acid.
  • the first step of the process is carried out in practice by reacting, for example, 1 mol of an amino alcohol of formula (II) with 1 mol of HSO 3 CI in organic solvent.
  • the sulfuric acid esters of the formula (III) may be isolated. Preferably these esters of formula (III) are used without isolation for the conversion in the second step of the process according to the invention.
  • the second step of the reaction according to the invention can be carried out by addition of the sulfuric acid esters of the formula (HI) into the mercaptans or salts thereof of formula (FV).
  • the addition of the sulfuric acid esters of the formula (111) into the mercaptan or salts thereof of formula (IV) is done within between 10 min up to 2 h, depending on the scale of the reaction, preferably within between 20 min and 2 h, particularly preferably within between 30 min and 1 h.
  • the second step of the reaction according to the invention can be carried out by addition of the sulfuric acid esters of formula (III) as a solution or solid into mercaptans or their salts of formula (FV) preferably in water.
  • the pH of the reaction mixture has to be kept in the range of 10-12 while adding the ester.
  • the base as a solid is added directly to the mercaptide or its salt in water, followed by addition of the sulfonate as a solid or concentrated solution.
  • the addition of the sulfonate to the mixture of mercaptide and NaOH allows to increase the yield up to 92-95% (vers. EP 1231698 yield 82 %).
  • the second step of the process is carried out in the presence of a base.
  • a base examples which may be mentioned are: alkali metal and alkaline earth metal hydroxides, such as NaOH, KOH, Ca(OH)2, alkali metal carbonates or hydrogencarbonates, such as Na2CO3, I ⁇ 2 CO 3 , K2CO3, CS2CO3 or NaHC ⁇ 3 and KHCO3.
  • alkali metal and alkaline earth metal hydroxides such as NaOH, KOH, Ca(OH)2
  • alkali metal carbonates or hydrogencarbonates such as Na2CO3, I ⁇ 2 CO 3 , K2CO3, CS2CO3 or NaHC ⁇ 3 and KHCO3.
  • reaction temperatures employed to the second step of the reaction according to the invention may be varied over a broad range.
  • the reaction is carried out between 30 0 C and 150 0 C, preferably between 50 0 C and 120 0 C, particularly preferably between 7O 0 C and 100 0 C.
  • the second step of the reaction is expediently carried out under atmospheric pressure, although it is also possible to work under reduced or elevated pressure. Particular preference is given to carrying out the reaction under atmospheric pressure.
  • the second step of the reaction according to the invention may be carried out in the presence of a further diluent, where all customary inert organic solvents apply.
  • a further diluent such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decaline; chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichlorethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert.-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1 ,2-dimethoxyethane, 1,2-diethoxyethane or anisole;
  • the second step of the process is carried out in practice by reacting, for example, 1 mol of a sulfuric acid ester of formula (III) with between 1 and 10 mol, preferably between 1 and 5 mol, particularly preferably between 1 and 1.5 mol of a mercaptan or salt thereof of formula (FV) in the presence of a base, to keep the pH value in general between pH 1 1 and 12.
  • the reaction time can be reduced by using Phase transfer catalysts (PTC) like Tetralkylammonium, Tetraalkyl-, Tetraarylphosphonium, Guanidinium or pyridinuim salts.
  • PTC Phase transfer catalysts
  • Prefered catalysts are tetramethylammonium bromide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, tetraphenylphosphonium bromide and 18-crown-6.
  • the end-product can be isolated using standard procedures, e.g. cristallization, chromatography, extraction and distillation.
  • the mixture is cooled to 32 0 C and all the following procedures are performed at this temperature.
  • 100 ml methyl tert.-butyl ether is added, the mixture is stirred and the organic layer is separated.
  • the aqueous layer is extracted with two 100 ml portions of tert.-butyl ether.
  • the combined organic layers were dried over anhydrous sodium sulfate. After filtration the solvent was removed at 2O 0 C and under 150 mbar reduced pressure.

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Abstract

The present invention relates to a novel process for the preparation of compounds of the formula (I) by reacting in a first step amino alcohols of the formula (II) with chlorosulfonic acid to give sulfuric acid esters of the general formula (III) and by reacting these sulfuric acid esters in a second step with mercaptans or salts thereof of the general formula (IV): RSM in each formula, where applicable, R1, R2, R3, R4, R5, R6, R, n and M have the meanings given in the description, in the presence of a diluent and in the presence of a base.

Description

Preparation of thioalkylamines using chlorosulfonic acid
The present invention relates to a novel process for the preparation of known thioalkylamine derivatives.
Because of their chemical structure thioalkylamine derivatives can be divided into two groups, thiols and sulfides. For the preparation of both classes the methods discussed below have been described.
A first method for the preparation of thiols is based on the hydrolytic cleavage of thiazoline or thiazolidinone derivatives (cf. e.g. J. Med. Chem. 1965. 8, 762; JP 59-231064, Bull. Soc. Chim. Fr. 1967, 3637). As thiazoline or thiazolidinone derivatives have to be prepared first via several reaction steps the overall yield of this method is very low.
Thiols can be obtained furthermore by a process comprising reacting sulfates of amino alcohols with ammonium sulfide (cf. e.g. Nihon Kagaku Kaishi 1979, 149). This method requires long reactions times in a sealed reaction vessel, which causes high costs because of the required production plants having low productivity.
The reaction of oxazoline- or oxazolidinone derivatives with thiols is a method for the preparation of sulfides (cf. e.g. J. Org. Chem. 1992. 57, 6257; J. Med. Chem. 1984. 27. 1354). A hydrolytic process is required to obtain reaction products as amides according to this method. However, no reaction is observed, if the oxazolidine ring of the starting compounds is e.g. alkyl substituted. Furthermore, only aromatic sulfides can be prepared using this method because of the acidity of the mercaptans.
The hydrolytic cleavage of amides, which can be obtained by reaction of amino alcohols with mercaptans in the presence of carboxylic acids, also furnishes sulfides (cf. e.g. DE-OS 14 93 534). This method has to be carried out at high temperature and under pressure using long reaction times and is therefore restricted to the synthesis of sulfides. Additionally a hydrolytic step is required to obtain the reaction products from amides.
The reaction of aziridines with sulfur compounds like mercaptans represents a method for preparing of sulfides and thiols (cf. e.g. Tetrahedron 1992. 48, 2359; Tetrahedron Lett. 1983. 24, 2131). High demands on safety requirements have to be made for industrial scale production using this method, because highly toxic and possibly instable aziridines have to be prepared and isolated.
A method for the conversion of thioalkylalcohols into thioalkylamines is represented by the Ritter reaction with subsequent hydrolytic cleavage (cf. e.g. DE-OS 20 45 905). This method employs - -
hydrocyanic acid in excess, which must be handled with the utmost caution. In the case that nitrites which can be easily handled are employed the hydrolytic process causes problems.
A further method for the preparation of thioalkylamine derivatives uses as starting material amino alcohols which are reacted with sulfuric acid to give the corresponding esters in a first step (cf. WO 01/23350). After evaporation to dryness this esters are further converted by reaction with mercaptans. The required evaporation after the first reaction step causes problems when this process is employed to a large scale production.
A further method for the preparation of thioalkylamine derivatives from amino alcohols was described in WO 03/099777 using oleum as reactant. However, using the described process, the reaction mixture has to be diluted during neutralization steps thus limiting yield. Furthermore, poorly soluble salts are formed during the second reaction step causing problems for large scale production.
We have now found that compounds of the formula (I)
in which
R1 and R2 in each case independently of one another represent hydrogen, Ci-C4-alkyl, C3-Cg- cycloalkyl, C3-C8-cycloalkyl-Cι-C4-alkyI, hydroxy-C|-C4-alkyl; unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro, Ci-C4-alkyl, Q-Cg-cycloalkyl, Cj-C4- alkoxy, CrC4-alkylthio, CrC4-alkylsulfinyl, CrC4-alkylsulfonyl, carboxyl, Q-C4- alkoxycarbonyl, CrC4-alkoxy-Ci-C4-alkyl, C]-C4-alkylcarbonyl, halo-Ci-C4-alkyl, halo-Ct- C4-alkoxy, halo-CrC4-alkylthio, halo-Ci-C4-alkylsulfinyl, halo-C|-C4-alkylsulfonyl, halo- C|-C4-alkylcarbonyl, phenylcarbonyl, phenoxycarbonyl, amino, Ci-C4-alkylamino and di- (Ci-C4-alkyl)-amino (where the alkyl groups can be identical or different); phenyl, which is substituted at two adjacent carbon atoms by C3-C4-alkylene or Ci-C2-alkylenedioxy; unsubstituted or mono- to pentasubstituted phenyl-Ci-C4-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro, C|-C4-alkyl, C3-C8-cycloalkyl, CrC4-alkoxy, C,-C4-alkylthio, C,-C4-alkylsulfinyl, C1-C4- alkylsulfonyl, halo-Ci-G|-alkyl, halo-Ci-C4-alkoxy, halo-Ci-C4-alkylthio, halo-Ci-C4-alkyl- sulfinyl and halo-Ci-C4-alkylsulfonyl;
R3 and R4 independently of one another represent hydrogen or Ci-C4-alkyl,
R5 and R6 independently of one another represent hydrogen, Ci-C4-alkyl, unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro, C]-C4-alkyl, C3-Cg-cycloalkyl, Q-C4- alkoxy, C,-C4-alkylthio, C,-C4-alkylsulfinyl, C,-C4-alkylsulfonyl, halo-C,-C4-alkyl, halo-
CpQ-alkoxy, halo-C|-C4-alkylthio, halo-CrC4-alkylsulfinyl and halo-C|-C4-alkylsu!fonyl; unsubstituted or mono- to pentasubstituted phenyl-Ci-C4-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro,
C,-C4-alkyl, C3-C8-cycloalkyl, C,-C4-alkoxy, C,-C4-alkylthio, C,-C4-alkylsulfinyl, CrC4- alkylsulfonyl, halo-C,-C4-alkyl, halo-CrC4-alkoxy, halo-CrC4-alkylthio, halo-C|-C4-alkyl- sulfinyl and halo-C|-C4-alkylsulfonyl,
R represents unsubstituted or mono- or polysubstituted Ci-Ci2-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, hydroxy,
C]-C4-alkoxy, halo-Ci-C4-alkoxy, Ci-C4-alkylthio, Ci-C4-alkylsulfinyl and Ci-C4-alkylsul- fonyl; unsubstituted or mono- or polysubstituted C3-Cg-cycloaIkyl or C3-Cg-cycIoalkyl-Cr C4-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, Ci-C4-alkyl and Ci-C4-alkoxy; unsubstituted or mono- to penta- substituted phenyl, where the substituents are identical or different and are selected from the group consisting of halogen, CpCβ-alkyl, C3-Cg-cycloalkyl, CrQ-alkoxy, halo-Cj-C4- alkyl, halo-Ci-C4-alkoxy; unsubstituted or mono- to pentasubstituted phenyl-Ci-C4-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen and Ci-C4-alkyl; naphthyl; unsubstituted or mono- or polysubstituted hetero- aryl, where the substituents are identical or different and are selected from the group consisting of halogen, CrC4-alkyl, Ci-C4-alkoxy, unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of halogen and CrC4-alkyl,
n represents 1, 2, 3, 4, 5, 6, 7 or 8, where the group C(R')R2 may be identical or different, when n is greater than 1,
and when n represents 1,
R1 and R2 furthermore together represent C2-C5-alkyIene, R1 furthermore represents together with R3 or R5 C3-C5-alkylene,
R3 and R4 furthermore together represent C4-C6-alkylene,
R3 and R5 furthermore together represent C2-Gralkylene,
R5 and R6 furthermore together represent C4-C6-alkylene,
are obtained by reacting in a first step amino alcohols of the formula (II)
in which
R1, R2, R3, R4, R5, R6 and n have the above given meanings,
with chlorosulfonic acid to give sulfuric acid esters of the general formula (III)
in which
R1, R2, R3, R4, R5, R6 and n have the above given meanings,
and by reacting these sulfuric acid esters in a second step with mercaptans or salts thereof of the general formula (FV)
RSM (IV)
in which
R has the above given meanings, and
M represents hydrogen, ammonium or an alkali metal atom,
in the presence of a base and preferably in the presence of a diluent. Surprisingly, using the process according to the invention, the thioalkylamines of the formula (I) can be obtained in a simple manner in a very good space-time yield.
The reaction according to the invention therefore has the advantage of an increased reaction rate. This leads to the technical advantage of a high space-time yield. The process according to the invention has the further advantage that the solution of the intermediates of formula (III) need not to be evaporated to dryness. The reaction mixture can be stirred at any time of the process which decreases the risk of a breaking reaction vessel in industrial plants.
In contrast to the method described in WO 01/23350 there is no water being formed during the reaction but HCl which evaporates from the reaction mixture thus driving the reaction equilibrium towards the products. There are also no poorly soluble salts being formed as product as in the method described in WO 03/099777.
Detailed description of the process according to the invention
Using 2-amino-2-methyl-l-propanoI and methyl mercaptan sodium salt as starting materials, the course of the reaction of the process according to the invention can be outlined by scheme 1.
Scheme 1
The formula (II) provides a general definition of the amino alcohols required as starting materials for carrying out the first step of the process according to the invention.
Preferred as starting material are amino alcohols of the formula (II), in which
R1 and R2 in each case independently of one another represent hydrogen, C|-C4-alkyl, C3-Ce- cycloalkyl, C3-C6-cycIoalkyI-C|-C2-alkyI, hydroxy-C|-C4-alkyl; unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, Ci-Gf-alkyl, C3-C6-cycloalkyl, CrC4-alkoxy, C)-C4-alkylthio, Ci-Gralkylsulfinyl, Ci-C4-alkyIsulfonyl, carboxyl, CrC4-alkoxy- carbonyl, CrC4-alkoxy-Ci-C4-alkyl, d-Q-alkylcarbonyl, halo-C|-C4-alkyl, halo-CrC4-alkoxy, halo-CrC4-alkylthio, halo-Ci-C4-alkylsulfinyl, halo-CrC4-alkylsulfonyl, halo-CrC4-alkylcarbonyl, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms, phenylcarbonyl, phenoxycarbonyl, amino, Ci-C4-alkylamino and di-(C|-C4-alkyI)-amino (where the alkyl groups can be identical or different); phenyl, which is substituted at two adjacent carbon atoms by C3-C4- alkylene or Ci-C2-alkylenedioxy; unsubstituted or mono- to pentasubstituted phenyl-C|-C2-alkyI, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, Ci-C4-alkyl, Qj-Cβ-cycloalkyl, Ci-C4-alkoxy, Cr C4-alkylthio, CrC4-aIkylsulfinyl, C,-C4-alkylsuIfonyl, halo-CrC4-alkyl, halo-C,-C4-alkoxy, halo- Ci-C4-alkylthio, halo-Ci-C4-alkylsulfinyl and halo-C)-C4-alkylsulfonyl, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms;
R3 and R4 independently of one another represent hydrogen or Ci-C4-alkyl,
R5 and R6 independently of one another represent hydrogen, CrC4-alkyl, unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, Ci-Q-alkyl, C3-C6-cycloalkyl, C|-C4-alkoxy, CrC4-alkylthio, CrC4-alkylsulfinyl, CrC4-alkylsulfonyI, halo-Ci-C4-a!kyl, halo-C,-C4-alkoxy, halo-C,-C4-alkylthio, halo-CrC4-alkylsulfinyl and halo-Ci-C4-aIkylsulfonyl, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms; unsubstituted or mono- to pentasubstituted phenyl-Q-Q-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, CrC4-alkyl, C3-C8-cycloalkyl, CpC4- alkoxy, C,-C4-alkylthio, CrC4-alkylsulfinyl, CrC4-alkylsulfonyl, halo-CrC4-alkyl, halo-
Ci-C4-alkoxy, halo-CrC4-alkylthio, halo-Ci-C4-alkylsulfinyl and halo-C|-C4-alkylsulfonyl, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms;
n represents 1, 2, 3, 4, 5 or 6, where the group C(R])R2 may be identical or different, when n is greater than 1,
and when n represents 1,
R1 and R2 furthermore together represent C2-C5-alkylene,
R1 furthermore represents together with R3 or R5 C3-C5-alkylene,
R3 and R4 furthermore together represent C4-C6-alkylene,
R3 and R5 furthermore together represent C2-C4-alkyIene,
R5 and R6 furthermore together represent C4-C6-alkylene. Particularlv preferred as starting material are amino alcohols of the formula (II), in which
R1 and R2 in each case independently of one another represent hydrogen, methyl, ethyl, n-, i-pro- pyl, n-, i-, S-, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutyl- ethyl, cyclopentylethyl, cyclohexylethyl, hydroxymethyl, hydroxyethyl; unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, methylthio, ethylthio, n-, i-propylthio, n-, i-, S-, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propylsulfinyl, n-, i-,
S-, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, n-, i-, s-, t-butyl- sulfonyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, difluoro- chloromethyl, fluorodichloromethyl, trifluoromethoxy, trichloromethoxy, difluorometh- oxy, dichloromethoxy, difluorochloromethoxy, fluorodichloromethoxy, trifluoromethyl- thio, trichloromethylthio, difluoromethylthio, dichloromethylthio, difluorochloromethyl- thio, fluorodichloromethylthio, trifluoromethylsulfinyl, trichloromethylsulfinyl, difluoro- methylsulfinyl, dichloromethylsulfinyl, difluorochloromethylsulfinyl, fluorodichloro- methylsulfinyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethylsulfonyl, dichloromethylsulfonyl, difluorochloromethylsulfonyl, fluorodichloromethylsulfonyl, trifluoromethylcarbonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, methoxymethyl, ethoxyethyl, methoxyethyl, ethoxymethyl, methylcarbonyl, ethylcarbonyl, phenylcarbonyl, phenoxycarbonyl, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino; phenyl, which is substituted at two adjacent carbon atoms by -(CH2)3-, -(CH2V, -OCH2O-, -O(CH2)2O-; in each case unsubstituted or mono- to trisubstituted benzyl or phenylethyl, where in each case the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, methylthio, ethylthio, n-, i-propylthio, n-, i-, S-, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propylsulfinyl, n-, i-, S-, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, n-, i-, S-, t-butyl- sulfonyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, difluorochloro- methyl, fluorodichloromethyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, difluorochloromethoxy, fluorodichloromethoxy, trifluoromethylthio, trichloromethylthio, difluoromethylthio, dichloromethylthio, difluorochloromethylthio, fluorodichloromethylthio, trifluoromethylsulfinyl, trichloromethylsulfinyl, difluoromethyl- sulfinyl, dichloromethylsulfϊnyl, difluorochloromethylsulfinyl, fluorodichloromethyl- sulfinyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethylsulfonyl, dichloromethylsulfonyl, difluorochloromethylsulfonyl, fluorodichloromethylsulfonyl;
R3 and R4 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl,
R5 and R6 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, methylthio, ethylthio, n-, i-propylthio, n-, i-, s-, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propyl- sulfinyl, n-, i-, S-, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, n-, i-, S-, t-butylsulfonyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, difluorochloromethyl, fluorodichloromethyl, trifluoromethoxy, trichloromethoxy, difluoro- methoxy, dichloromethoxy, difluorochloromethoxy, fluorodichloromethoxy, trifluoro- methylthio, trichloromethylthio, difluoromethylthio, dichloromethylthio, difluorochloro- methylthio, fluorodichloromethylthio, trifluoromethylsulfinyl, trichloromethylsulfinyl, difluoromethylsulfinyl, dichloromethylsulfϊnyl, difluorochloromethylsulfinyl, fluoro- dichloromethylsulfinyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoro- methylsulfonyl, dichloromethylsulfonyl, difluorochloromethylsulfonyl and fluorodichloromethylsulfonyl; in each case unsubstituted or mono- to trisubstituted benzyl or phenylethyl, where in each case the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, methylthio, ethylthio, n-, i-propylthio, n-, i-, S-, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propylsulfinyl, n-, i-, S-, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, n-, i-, S-, t-butylsulfonyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, difluorochloromethyl, fluorodichloromethyl, trifluoromethoxy, trichloromethoxy, difluoro- methoxy, dichloromethoxy, difluorochloromethoxy, fluorodichloromethoxy, trifluoro- methylthio, trichloromethylthio, difluoromethylthio, dichloromethylthio, difluorochloro- methylthio, fluorodichloromethylthio, trifluoromethylsulfinyl, trichloromethylsulfinyl, difluoromethylsulfinyl, dichloromethylsulfinyl, difluorochloromethylsulfinyl, fluorodi- chloromethylsulfϊnyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoro- methylsulfonyl, dichloromethylsulfonyl, difluorochloromethylsulfonyl, fluorodichloro- methyisulfonyl,
n represents 1, 2, 3, 4, 5 or 6, where the group C(R*)R2 may be identical or different, when n is greater than 1 ,
and when n represents 1 ,
R1 and R2 furthermore together represent -(CH2)2-, -(CH2)3-, -(CH2),,-, -(CH2)5-,
R1 furthermore represents together with R3 or R5 -(CH2)3-, -(CH2)4-, -(CH2)5-,
R3 and R4 furthermore together represent -(CH2)4-, -(CH2)5-, -(CH2)6-,
R3 and R5 furthermore together represent -(CH2)2-, -(CH2)3-, -(CH2)4-,
R5 and R6 furthermore together represent -(CH2)4-, -(CH2)5-, -(CH2)6-.
Very particularly preferred as starting material are amino alcohols of the formula (II), in which
R1 and R2 in each case independently of one another represent hydrogen, methyl, ethyl, n-, i-pro- pyl, n-, i-, s-, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl; unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, cyclopropyl, cyclopenty!, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, S-, t-butoxy, methylthio, ethylthio, n-, i-propylthio, n-, i-, S-, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propylsulfinyl, n-, i-, s-, t-butylsulflnyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, n-, i-, s-, t-butylsulfonyl, trifluoro- methyl, difluoromethyl, trifiuoromethoxy, difluoromethoxy, trifluoromethylsulfinyl, trifluoromethylsulfonyl, trifluoromethylcarbonyl, carboxyl, methoxycarbonyl, methoxy- methyl, ethoxyethyl, methoxyethyl, ethoxymethyl, methylcarbonyl, ethylcarbonyl, phenyl- carbonyl, phenoxycarbonyl, amino, methylamino, ethylamino, propylamino, dimethyl- amino, diethylamino; phenyl, which is substituted at two adjacent carbon atoms by
-(CH2)3-, -(CH2)4-, -OCH2O-, -O(CH2)2O-; unsubstituted or mono- to trisubstituted benzyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, S-, t-butoxy, methylthio, ethylthio, n-, i-propylthio, n-, i-, s-, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-pro- pylsulfϊnyl, n-, i-, s-, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, n-, i-, S-, t-butylsulfonyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylsulfinyl, trifluoromethylsulfonyl;
R3 and R4 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl,
R5 and R6 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl, unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, methylthio, ethylthio, n-, i-propylthio, n-, i-, s-, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propylsulfinyl, n-, i-, S-, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, n-, i-, s-, t-butyl- sulfonyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylsulfinyl, trifluoromethylsulfonyl; unsubstituted or mono- to trisubstituted benzyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, methylthio, ethylthio, n-, i-propylthio, n-, i-, S-, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propylsulfinyl, n-, i-, s-, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, n-, i-, s-, t-butylsulfonyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylsulfinyl, trifluoromethylsulfonyl,
n represents 1, 2, 3 or 4, where the group C(R')R2 may be identical or different, when n is greater than 1 ,
and when n represents 1 ,
R1 and R2 furthermore together represent -(CH2)r, -(CH2)3-, -(CH2)4-, -(CH2)5-,
R1 furthermore represents together with R3 or R5 -(CH2V, -(CH2J4-, -(CH2)5-,
R3 and R4 furthermore together represent -(CH2)4-, -(CH2)5-, -(CH2)6-,
R3 and R5 furthermore together represent -(CH2)2-, -(CH2)3-, -(CH2),,-,
R5 and R6 furthermore together represent -(CH2)4-, -(CH2)5-, -(CH2)6-.
Most particularly preferred as starting material are amino alcohols of the formula (IT), in which R1 and R2 in each case independently of one another represent hydrogen, methyl, ethyl, n-, i-pro- pyl, n-, i-, s-, t-butyl,
R3 and R4 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl,
R5 and R6 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl,
n represents 1 or 2, where the group C(R')R2 may be identical or different, when n is greater than 1.
Amino alcohols of the formula (II) are widely known and/or can be prepared according to known methods.
The formula (FV) provides a general definition of the mercaptans or salts thereof required as starting materials for carrying out the second step of the process according to the invention.
Preferred as starting material are mercaptans or salts thereof of the formula (FV), in which
R represents unsubstituted or mono- or polysubstituted Ci-Ci2-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, Ci-G|-alkoxy, halo-C|-C4-alkoxy having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms, CrC4-alkylthio, Ci-Gj-alkylsulfinyl and Ci-Gj-alkylsulfonyl; unsubstituted or mono- or polysubstituted C3-C6-cycloalkyl or C3-C6- cycloalkyl-C|-C2-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, Ci-C4-alkyl and CrC4-alk- oxy; unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-alkoxy, halo-CrC4-alkyl, halo-Ci- C4-aIkoxy, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms; unsubstituted or mono- to pentasubstituted phenyl-Ci-C2-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine and CrC4-alkyl; naphthyl; unsubstituted or mono- or polysubstituted heteroaryl (preferably furyl, thienyl, pyrrolyl, oxazolyl, oxazolinyl, isoxa- zolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1 ,2,3-triazolyl,
1 ,2,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl), where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, C)-C4-alkyl, Ci-C4-alkoxy, unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine and C|-C4-alkyl,
M represents hydrogen, ammonium or an alkali metal atom (preferably sodium, potassium, lithium and caesium).
Particularly preferred as starting material are mercaptans or salts thereof of the formula (FV), in which
R represents in each case unsubstituted or mono- or polysubstituted methyl, ethyl, n-, i-pro- pyl, n-, i-, s-, t-butyl, in each case the isomeric pentyls, hexyl, octyl, decyls and dodecyls, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, di- fluorochloromethoxy, fluorodichloromethoxy, methylthio, ethylthio, n-, i-propylthio, n-, i-, S-, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propylsulfinyl, n-, i-, s-, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, n-, i-, s-, t-butylsulfonyl; in each case unsubstituted or mono- or polysubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy; unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, difluorochloro- methyl, fluorodichloromethyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, difluorochloromethoxy, fluorodichloromethoxy; in each case unsubstituted or mono- to trisubstituted benzyl or phenylethyl, where in each case the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine and methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl; naphthyl; in each case unsubstituted or mono- or polysubstituted furyl, thienyl, pyrrolyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1 ,2,4- oxadiazolyl, 1 ,3,4-oxadiazoIyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, where in each case the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine and methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl,
M represents hydrogen, ammonium, sodium, potassium, lithium and caesium.
Very particularly preferred as starting material are mercaptans or salts thereof of the formula (IV), in which
R represents in each case unsubstituted or mono- or polysubstituted methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl, in each case the isomeric pentyls, hexyl, octyl, decyls and dodecyls, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, trifluoromethoxy, trichloromethoxy, methylthio, ethylthio, n-, i-propylthio, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propylsulfinyl, t-butylsulfinyl, methylsulfo- nyl, ethylsulfonyl, n-, i-propylsulfonyl, t-butylsulfonyl; in each case unsubstituted or mono- or polysubstituted cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, methyl, ethyl, n-, i-propyl, t-butyl, methoxy, ethoxy, n-, i-propoxy, t-butoxy; unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, S-, t-butoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy; unsubstituted or mono- to trisubstituted benzyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine and methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl; naphthyl; in each case unsubstituted or mono- or polysubstituted furyl, thienyl, pyrrolyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1 ,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1 ,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, where in each case the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, methoxy, ethoxy, n-, i-propoxy, n-, i-, S-, t-butoxy, unsubstituted or mono- to trisubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine and methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl,
M represents hydrogen, ammonium, sodium and potassium.
Most particularly preferred as starting material are mercaptans or salts thereof of the formula (FV), in which
R represents in each case unsubstituted or mono- or polysubstituted methyl, ethyl, n-, i-propyl or n-, i-, S-, t-butyl where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, trifluoromethoxy, trichloromethoxy, methylthio, ethylthio, n-, i-propylthio, t-butylthio, methylsulfinyl, ethylsulfinyl, n-, i-propylsulfinyl, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, t-butylsulfonyl.
M represents sodium or potassium.
Mercaptans or salts thereof of the formula (FV) are widely known and/or can be prepared according to known methods.
Saturated or unsaturated hydrocarbon radicals, e.g. alkyl and alkenyl, can in each case be straight- chain or branched as far as this is possible, including in combination with heteroatoms, e.g. in alkoxy.
Optionally substituted radicals may be mono- or polysubstituted, where in the case of polysubstitution the substituents may be identical or different.
Radicals subsituted by halogen, e.g. haloalkyl, are mono- or polysubsituted up to perhalogenation. In the case of multiple halogenation the halogen atoms may be identical or different. Halogen represents fluorine, chlorine, bromine or iodine.
However, it is also possible to combine the above-mentioned general or preferred radical definitions or illustrations with one another as desired, i.e. between the respective ranges and preferred ranges. The definitions apply both to the end products and, correspondingly, to the precursors and intermediates.
The first step of the reaction according to the invention can be carried out by addition of the chlorosulfonic acid into the amino alcohols of the formula (II). This procedure is preferably carried out with mechanical stirring. The addition of the chlorosulfonic acid into the amino alcohol of the formula (II) is preferably done with cooling to keep the temperature below 700C, while a temperature range between 30 and 500C is particularly preferred. In general a carbonization will not be observed even if higher substituted amino alcohols are employed.
The amino alcohols are applied in liquid form or as a solution in inert organic solvent. Preference is given to using optionally halogenated aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decaline; chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichlorethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert.-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,2-diethoxyethane or anisole; nitriles, such as acetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrroli- done or hexamethylphosphoric triamide; esters, such as methyl acetate or ethyl acetate, sulfoxides, such as dimethyl sulfoxide, or sulfones, such as sulfolane. Preference is given to the solvents which can be easily separated from the product via distillation.
The first step of the reaction is expediently carried out under atmospheric pressure, although it is also possible to work under reduced or elevated pressure. Particular preference is given to carrying out the reaction under atmospheric pressure.
The reaction time can be different depending on the scale of the reaction and may vary between 10 min and 4 hours.
The first step of the process is carried out by reacting 0.5 to 2, preferably 0.8 to 1.2, particularly preferably 0.9 to 1.1 moles of amino alcohol per mole of chlorosulfonic acid.
The first step of the process is carried out in practice by reacting, for example, 1 mol of an amino alcohol of formula (II) with 1 mol of HSO3CI in organic solvent. The sulfuric acid esters of the formula (III) may be isolated. Preferably these esters of formula (III) are used without isolation for the conversion in the second step of the process according to the invention.
The second step of the reaction according to the invention can be carried out by addition of the sulfuric acid esters of the formula (HI) into the mercaptans or salts thereof of formula (FV). The addition of the sulfuric acid esters of the formula (111) into the mercaptan or salts thereof of formula (IV) is done within between 10 min up to 2 h, depending on the scale of the reaction, preferably within between 20 min and 2 h, particularly preferably within between 30 min and 1 h. The second step of the reaction according to the invention can be carried out by addition of the sulfuric acid esters of formula (III) as a solution or solid into mercaptans or their salts of formula (FV) preferably in water. The pH of the reaction mixture has to be kept in the range of 10-12 while adding the ester. Preferably the base as a solid is added directly to the mercaptide or its salt in water, followed by addition of the sulfonate as a solid or concentrated solution. The addition of the sulfonate to the mixture of mercaptide and NaOH allows to increase the yield up to 92-95% (vers. EP 1231698 yield 82 %).
Such a procedure allows to avoid the formation of unstable, toxic and explosive ethylene imine which is formed immediately after the sulfonate is added to the base at pH 10-12 (cf. scheme 2).
Scheme 2
Additionally it allows to maximize reactant concentration, improving the time space yield of the reaction and decreasing waste.
The second step of the process is carried out in the presence of a base. Examples which may be mentioned are: alkali metal and alkaline earth metal hydroxides, such as NaOH, KOH, Ca(OH)2, alkali metal carbonates or hydrogencarbonates, such as Na2CO3, IΛ2CO3, K2CO3, CS2CO3 or NaHCθ3 and KHCO3. Preference is given to Na2CO3, KOH, NaOH and NaHCθ3, in particular NaOH.
The reaction temperatures employed to the second step of the reaction according to the invention may be varied over a broad range. In general the reaction is carried out between 300C and 1500C, preferably between 500C and 1200C, particularly preferably between 7O0C and 1000C.
The second step of the reaction is expediently carried out under atmospheric pressure, although it is also possible to work under reduced or elevated pressure. Particular preference is given to carrying out the reaction under atmospheric pressure.
The second step of the reaction according to the invention may be carried out in the presence of a further diluent, where all customary inert organic solvents apply. Preference is given to using optionally halogenated aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decaline; chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichlorethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert.-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1 ,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles, such as acetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile; amides, such as N,N-dimethylfbrmamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrroIidone or hexamethylphosphoric triamide; esters, such as methyl acetate or ethyl acetate, sulfoxides, such as dimethyl sulfoxide, or sulfones, such as sulfolane.
The second step of the process is carried out in practice by reacting, for example, 1 mol of a sulfuric acid ester of formula (III) with between 1 and 10 mol, preferably between 1 and 5 mol, particularly preferably between 1 and 1.5 mol of a mercaptan or salt thereof of formula (FV) in the presence of a base, to keep the pH value in general between pH 1 1 and 12.
The reaction time can be reduced by using Phase transfer catalysts (PTC) like Tetralkylammonium, Tetraalkyl-, Tetraarylphosphonium, Guanidinium or pyridinuim salts. At the same time the use of PTC allows to increase the yield. Prefered catalysts are tetramethylammonium bromide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, tetraphenylphosphonium bromide and 18-crown-6.
The end-product can be isolated using standard procedures, e.g. cristallization, chromatography, extraction and distillation.
The process according to the invention is illustrated by the preparation examples given below.
Examples
Example 1: 2-Methyl-l-(methylthio)propane-2-amine
Preparation according to the invention
89 g (1 mol) of 2-amino-2-methyl-l-propanol and 1 mol HSO3CI were mixed together in 200 ml dimethoxyethane under cooling to keep the temperature below 50°C. The formed precipitate was filtered off and dried in vacuum to give a white solid. 2-Ammonio-2-methylpropylsulfate (159 g) was isolated, corresponding to a yield of 94 %.
Sodium mercaptide (1.2 mol) as 20 % solution in water was placed into a flask and 40 g (1 mol) of NaOH (solid) was added under stirring. The mixture was intensively stirred and 169 g (1 mol) of
2-ammonio-2-methlypropylsulfate was added within 30 min. The mixture was then stirred for 5-10 h at 900C and cooled to 300C. The upper organic layer was separated to give 169 g of the product
2-methyl-l-(methlythio)propane-2-amine with a purity of 53 % (47 % water content). The product can be dried over MgSO4 or azeotropically with hexane to give 1 10 g (90 % of theory) of the amine with purity of 97 %. B.p. 55 - 580C / 25 mbar.
Preparation according to WO 03/099777
The oleum (120.1 g of 20 % SO3 in H2SO4, i.e. 0.3 mol = 0.6 eq. SO3) is placed in a 1 1 flat- bottomed flask with flat-flange joint and 2-amino-2-methyl-l-propanol (46.9 g, 0.5 mol = 1 eq., 95 %) is added slowly with mechanical stirring directly into the oleum so that 2-amino-2-methyl-l- propanol touches the glass surface of the flask. The temperature is maintained by cooling between 85°C and 900C. Stirring of the reaction mixture at 900C is continued for additional 30 min. After cooling to room temperature the mixture is first diluted with 200 ml of water and then 45 % sodium hydroxide solution in water is added. The temperature in both procedures should not exceed 300C. Under cooling the methyl mercaptane sodium salt solution (183.6 g, 0.5 mol = 1 eq., 19.1 % in water) is added and then stirring is continued at 60 to 650C for 6 h.
The mixture is cooled to 320C and all the following procedures are performed at this temperature. 100 ml methyl tert.-butyl ether is added, the mixture is stirred and the organic layer is separated. The aqueous layer is extracted with two 100 ml portions of tert.-butyl ether. The combined organic layers were dried over anhydrous sodium sulfate. After filtration the solvent was removed at 2O0C and under 150 mbar reduced pressure.
Yield: 62.7 g (crude product, purity according to internal standard: 68.8 %, i.e. 72 % of the theory) of 2-methy]-l-methylthio-2-propanamine.
1H NMR (d6-DMSO): δ 1.04 (s, 6H), 1.44 (broad, 2H), 2.10 (s, 3H), 2.48 (s, 2H) ppm.
GC/MS-coupling: m/z (%) = 104 (3) [M-15]+, 58 (100), 42 (11), 41 (8), 31 (5).
Preparation according to WO 01/23350
Yield 81 %.
Example 2: (2S)-l-(Methylthio)propan-2-amine
75 g (1 mol) of (2S)-2-aminopropanol (L-Alaninol) and 1 mol of HSO3CI were mixed together in 300 ml acetonitrile under cooling to keep the temperature below 25°C. The formed precipitate was filtered off and dried in the vacuum oven at 40°C to give 147 g of (2S)-2-ammoniopropylsulfate as a white solid, corresponding to a yield of 95 %. M.p. 260-2630C.
1H NMR (d6-DMSO): δ 1.2 (d, 3H), 3.4 (m, IH), 3.6-3.8 (d.m. ABX
system, 2 H), 7.8 (broad .s., NH3) ppm.
Sodium mercaptide (1.2 mol) as 20 % solution in water was placed into a flask and 40 g (1 mol) of NaOH (solid) was added under stirring. The mixture was intensively stirred and 155 g (1 mol) of (2S)-2-ammoniopropylsulfate was added within 30 min. The mixture was then stirred for 5-10 h at 900C and cooled to 3O0C. The upper organic layer was separated to give 159 g of the product (2S)-l-(methylthio)propane-2-amine with a purity of 62 % (38 % water content). The product can be dried over MgSO4 or azeotropically with hexane to give 102 g (94 % of theory) of the amine with purity of 97 %. B.p. 154 0C.

Claims

Patent Claims
1. Process for preparing compounds of the formula (I)
in which
R1 and R2 in each case independently of one another represent hydrogen, Ci-C4-alkyl, C3-
Cg-cycloalkyl, C3-C8-cycloalkyl-Ci-C4-aIkyl, hydroxy-Ci-C4-alkyl; unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro, Ci-C4-alkyl, C3-C8-cycloalkyl, Ci-C4-alkoxy, CrC4-alkyIthio, CrC4-alkyIsulfinyl, C,-C4- alkylsulfonyl, carboxyl, C)-C4-alkoxycarbonyl, C]-C4-alkoxy-Ci-C4-alkyl, CrC4- alkylcarbonyl, halo-Ci-C4-alkyl, halo-Ci-C4-alkoxy, halo-CpQ-alkylthio, haIo-Cr C4-alkylsulfinyl, halo-C]-C4-alkylsulfonyl, halo-Cj-Q-alkylcarbonyl, phenylcarb- onyl, phenoxycarbonyl, amino, CrC4-alkylamino and di-(CrC4-alkyl)-amino (where the alkyl groups can be identical or different); phenyl, which is substituted at two adjacent carbon atoms by C3-C4-alkylene or Ci-C2-alkylenedioxy; unsubstituted or mono- to pentasubstituted phenyl-Q-Q-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro, Ci-C4-alkyl, C3-C8-cycloalkyl, Q-Q-alkoxy, C]-C4-alkyl- thio, C)-C4-alkylsulfinyl, Ci-C4-alkylsulfonyl, halo-C]-C4-alkyl, halo-Ci-C4-alkoxy, halo-Ci-C4-alkylthio, halo-C|-C4-alkylsulfinyl and halo-Ci-C4-alkylsulfonyl;
R3 and R4 independently of one another represent hydrogen or Ci-C4-alkyI,
R5 and R6 independently of one another represent hydrogen, C]-C4-alkyl, unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro, Ci-C4-alkyl, C3-C8-cycloalkyl, CrC4-alkoxy, CrC4-alkylthio, C,-C4-alkylsulfinyl, Ci-C4- alkylsulfonyl, halo-Ci-C4-alkyl, halo-C|-C4-alkoxy, halo-Ci-C4-alkyIthio, halo-Cr C4-aIkylsulfinyl and halo-Ci-C4-alkylsulfonyl; unsubstituted or mono- to pentasubstituted phenyl-Ci-Gj-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro, Q-Q-alkyl, C3-Cg- cycloalkyl, CrC4-alkoxy, C1-C4-alkylthio, C,-C4-alkylsulfinyl, CrC4-alkylsulfonyl, halo-Ci-Gt-alkyl, halo-Ci-C4-alkoxy, haIo-Ci-C4-alkylthio, halo-Ci-C4-alkylsulfinyl and halo-Ci-Gi-alkylsulfonyl,
R represents unsubstituted or mono- or polysubstituted CrC|2-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, hydroxy, Ci-C4-alkoxy, halo-C|-C4-alkoxy, C)-C4-alkylthio, CrC4-alkyI- sulfinyl and Ci-C4-alkylsulfonyl; unsubstituted or mono- or polysubstituted Cβ-Cg- cycloalkyl or C3-C8-cycloalkyI-C|-C4-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, CpQ-alkyl and Ci-C4-alkoxy; unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of halogen, Ci-Cβ-alkyl, C3-Cg-cycIoalkyl, CpQ-alkoxy, halo-CrC4-alkyI, halo-Cr Q-alkoxy; unsubstituted or mono- to pentasubstituted phenyl-C|-C4-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen and Cj-Q-alkyl; naphthyl; unsubstituted or mono- or poly- substituted heteroaryl, where the substituents are identical or different and are selected from the group consisting of halogen, C)-C4-alkyl, Cj-Q-alkoxy, unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of halogen and Cj- Q-alkyl,
n represents 1, 2, 3, 4, 5, 6, 7 or 8, where the group C(R1 )R2 may be identical or different, when n is greater than 1 ,
and when n represents 1 ,
R1 and R2 furthermore together represent C2-C5-alkylene,
R1 furthermore represents together with R3 or R5 C3-C3-alkylene,
R3 and R4 furthermore together represent C4-C6-alkylene,
R3 and R5 furthermore together represent C2-C4-alkylene,
R5 and R6 furthermore together represent C4-C6-alkylene,
characterized in that in a first step amino alcohols of the formula (H)
in which
R » ' , D R^ , n R3 , n R4 , n R5 , τ R>6 and n have the above given meanings,
are reacted with chlorosulfonic acid to give sulfuric acid esters of the general formula (III)
in which
R , R , R , R , R , R and n have the above given meanings,
and that these sulfuric acid esters in a second step are reacted with mercaptans or salts thereof of the general formula (FV)
RSM (IV)
in which
R has the above given meanings, and
M represents hydrogen, ammonium or an alkali metal atom,
in the presence of a base and preferably in the presence of a diluent.
Process according to Claim 1, characterized in that a compound of the formula (II), in which
R1 and R in each case independently of one another represent hydrogen, Q -Chalky 1, C3- C6-cycloalkyl, C3-C6-cycloalkyl-Ci-C2-alkyl, hydroxy-CrC4-alkyl; unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, CrC4-alkyl, C3-C6-cycloalkyl, CrC4-alkoxy, CrC4-alkylthio, C,-C4- alkylsulfϊnyl, Ci-Q-alkylsulfonyl, carboxyl, Ci-C4-alkoxycarbonyI, Ci-C4-alkoxy- C|-C4-aIkyI, CrC4-alkyIcarbonyl, halo-C,-C4-alkyl, halo-C,-C4-aIkoxy, haIo-C,-C4- alkylthio, halo-CrC4-alkylsulfinyl, halo-Ci-C4-alkylsulfonyl, halo-C)-C4-alkyl- carbonyl, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms, phenylcarbonyl, phenoxycarbonyl, amino, C|-C4-alkylamino and di-(Ci-C4-aIkyl)-amino (where the alkyl groups can be identical or different); phenyl, which is substituted at two adjacent carbon atoms by C3-C4-alkylene or Cr C2-alkylenedioxy; unsubstituted or mono- to pentasubstituted phenyl-Ci-C2 jalkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, CpGj-alkyl, C3-Cn- cycloalkyl, Ci-C4-alkoxy, Ci-C4-alkylthio, C]-C4-alkylsulfinyl, C|-C4-alkylsulfonyl, halo-Ci-C4-alkyl, halo-CrC4-alkoxy, halo-C|-C4-alkylthio, halo-d-Q-alkylsulfinyl and halo-Ci-C4-alkylsulfonyl, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms;
R3 and R4 independently of one another represent hydrogen or Q-Q-alkyl,
R5 and R6 independently of one another represent hydrogen, Ci-C4-alkyl, unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, Ci-C4-alkyl, C3-C6-cycloalkyl, CrQ-alkoxy, CpQ-alkylthio, Ci-C4- alkylsulfinyl, C,-C4-alkylsulfonyl, halo-CrC4-alkyl, halo-C,-C4-alkoxy, halo-C,-
C4-alkylthio, halo-Ci-C4-alkylsulfinyl and halo-Ci-C4-alkylsulfonyl, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms; unsubstituted or mono- to pentasubstituted phenyl-Ci-C∑-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, d-Q-alkyl, C3-C8-cycloalkyl, C|-C4-alkoxy, CrC4- alkylthio, C,-C4-alkylsulfinyl, C,-C4-alkylsulfonyl, halo-C-Gj-alkyl, haIo-C,-C4- alkoxy, halo-Ci-C4-alkylthio, halo-Ci-C4-alkylsulfinyl and halo-C]-C4-alkyl- sulfonyl, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms;
n represents 1,
2, 3, 4, 5 or 6, where the group C(R')R2 may be identical or different, when n is greater than 1,
and when n represents 1,
R1 and R2 furthermore together represent Ca-Cs-alkylene, R1 furthermore represents together with R3 or R5 C3-C5-a]ky]ene,
R3 and R4 furthermore together represent C4-C6-alkylene,
R3 and R5 furthermore together represent C2-C4-alkylene,
R5 and R6 furthermore together represent Q-Cδ-alkylene,
is used.
3. Process according to either Claim 1 or Claim 2, characterized in that a compound of the formula (IV), in which
R represents unsubstituted or mono- or polysubstituted Ci-C)2-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, Ci-C4-alkoxy, halo-Ci-C4-alkoxy having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms, CpC4- alkylthio, CrC4-alkylsulfϊnyl and Ci-C4-alkylsulfonyl; unsubstituted or mono- or polysubstituted C3-C6-cycloalkyl or C3-C6-cycloalkyl-Ci-C2-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, C]-C4-alkyl and Ci-C4-alkoxy; unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, CrC4-alkyl, C3-C6-cyc!oalkyl, C,-C4-alkoxy, halo-CrC4-alkyl, halo-CrC4-alkoxy, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms; unsubstituted or mono- to pentasubstituted phenyl-Ci-C2-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine and CpCj-alkyl; naphthyl; unsubstituted or mono- or polysubstituted heteroaryl (preferably furyl, thienyl, pyrrolyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,4-oxadi- azolyl, 1,3,4-oxadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-thiadiazolyl, 1,2,3-thiadiazolyl,
1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl), where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, Q-Cj-alkyl, CpC4-alkoxy, unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine and C|-C4-alkyl, M represents hydrogen, ammonium or an alkali metal atom (preferably sodium, potassium, lithium and caesium),
is used.
4. Process according to claim 1, characterized in that compounds of the formula (II), in which
R1 and R2 in each case independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl,
R3 and R4 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl,
R5 and R6 independently of one another represent hydrogen, methyl, ethyl, n-, i-propyl, n-, i-, S-, t-butyl,
n represents 1 or 2, where the group C(R')R2 may be identical or different, when n is greater than 1,
and compounds of the formula (FV), in which
R represents in each case unsubstituted or mono- or polysubstituted methyl, ethyl, n-, i-propyl or n-, i-, S-, t-butyl where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, n-, i-propoxy, n-, i-, s-, t-butoxy, trifluoromethoxy, trichloro- methoxy, methylthio, ethylthio, n-, i-propylthio, t-butylthio, methylsulfinyl, ethyl- sulfinyl, n-, i-propylsulfinyl, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, t-butylsulfonyl.
M represents sodium or potassium,
are used.
5. Process according to any one of Claims 1 to 4, characterized in that the second step is carried out by first preparing a solution of mercaptane or a salt thereof and the base, to which then the sulfonate ester is added.
6. Process according to any one of Claims 1 to 5, characterized in that 0.8 to 1.2 moles of amino alcohol per mole of chlorosulfonic acid are used in the first reaction step.
7. Process according to any one of Claims 1 to 6, characterized in that the base employed in the second step of the process is selected from the group consisting of alkali metal and alkaline earth metal hydroxides, alkali metal carbonates or hydrogencarbonates.
8. Process according to any one of Claims 1 to 7, characterized in that an aqueous solution of a mercaptane or salt thereof is used in the second reaction step.
9. Process according to any one of Claims 1 to 8, characterized in that the first step of the process is carried out at a temperature below 7O0C.
10. Process according to any one of Claims 1 to 9, characterized in that the second step is carried out using a phase transfer catalyst.
1 1. Process according to any one of Claims 1 to 10, characterized in that between 1 and 5 moles of mercaptane or salt thereof are used per mole of sulfonate ester in the second reaction step.
EP06776867A 2005-08-24 2006-08-16 Preparation of thioalkylamines using chlorosulfonic acid Withdrawn EP1981841A1 (en)

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EP05018348 2005-08-24
PCT/EP2006/008061 WO2007022901A1 (en) 2005-08-24 2006-08-16 Preparation of thioalkylamines using chlorosulfonic acid
EP06776867A EP1981841A1 (en) 2005-08-24 2006-08-16 Preparation of thioalkylamines using chlorosulfonic acid

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MX (1) MX2008002437A (en)
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WO (1) WO2007022901A1 (en)

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TW201329025A (en) 2011-11-01 2013-07-16 Astex Therapeutics Ltd Pharmaceutical compounds

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US6639109B1 (en) * 1999-09-28 2003-10-28 Nihon Nohyaku Co., Ltd. Process for production of thioalkylamine derivatives
WO2003099777A1 (en) * 2002-05-24 2003-12-04 Bayer Cropscience Ag Process for the preparation of thioalkylamine derivatives

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KR20080036634A (en) 2008-04-28
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IL189465A0 (en) 2008-08-07
TW200722409A (en) 2007-06-16
MX2008002437A (en) 2008-04-03

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