WO2007022900A1

WO2007022900A1 - Preparation of thioalkylamines with high yields

Info

Publication number: WO2007022900A1
Application number: PCT/EP2006/008060
Authority: WO
Inventors: Sergiy Pazenok
Original assignee: Bayer Cropscience Ag
Priority date: 2005-08-24
Filing date: 2006-08-16
Publication date: 2007-03-01
Also published as: KR20080036645A; BRPI0615131A2; TW200800868A; JP2009505997A; EP1919860A1; IL189297A0; MX2008002330A; CN101248040A

Abstract

The present invention relates to a novel process for the preparation of compounds of the formula (I) by mixing in a first step amino alcohols of the formula (II) with sulfuric acid to yield the salt, by then reacting them in a second step in a drying device to give sulfuric acid esters of the general formula (III) and by reacting these sulfuric acid esters in a third 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 with high yields

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. 19J4, 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 2045 905). This method employs hydrocyanic acid in excess, which must be handled with the utmost caution. In the case that nitriles 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 contains an excess of sulfuric acid which has to be neutralized before the second step can be performed, thus increasing the formation of poorly soluble salts (Na₂SO₄). The yield of the second step is also adversely affected by the additional dilution.

We have now found that compounds of the formula (I)

in which

R¹ and R² in each case independently of one another represent hydrogen, C|-C₄-alkyl, C₃-Cg- cycloalkyl, C₃-C₈-cycloalkyI-C|-C₄-alkyl, 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, C_t-C₄-alkyl, C₃-Cg-cycloalkyl, C_rC₄- alkoxy, C_rC₄-alkylthio, C_rC₄-alkylsulfinyl, C_rC₄-alkylsulfonyl, carboxyl, C₁-C₄- alkoxycarbonyl, CrC₄-alkoxy-Ci-C₄-alkyl, Ci-C₄-alkylcarbonyl, halo-Ci-C₄-alkyl, halo-C_r C₄-alkoxy, halo-C_rC₄-alkylthio, halo-Ci-C₄-alkylsulfϊnyl, halo-C_rC₄-alkylsulfonyl, halo- C_rC₄-alkylcarbonyl, phenylcarbonyl, phenoxycarbonyl, amino, Ci-C₄-alkylamino and di- (C_rC₄-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 C_rC₂-alkylenedioxy; unsubstituted or mono- to pentasubstituted phenyl-Ci-O-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, C,-C₄- alkylsulfonyl, halo-C_rC₄-alkyl, halo-Ci-C₄-alkoxy, halo-Ci-C₄-alkylthio, halo-C_rC₄-alkyl- sulfinyl and halo-C|-C₄-alkylsulfonyl; R³ and R⁴ independently of one another represent hydrogen or C|-C₄-alkyl,

R⁵ and R⁶ independently of one another represent hydrogen, Ci-C₄-allcyl, 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-Cg-cycloalkyl, Ci-C₄- alkoxy, C_rC₄-alkyIthio, C,-C₄-alkylsulfinyl, C_rC₄-alkylsulfonyl, halo-C,-C₄-alkyl, halo-

C_rC₄-alkoxy, halo-C_rC₄-alkylthio, halo-C_rC₄-alkylsulfinyl and halo-C_rC₄-alkylsulfonyl; unsubstituted or mono- to pentasubstituted phenyl-C_rC₄-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_rC₄-alkoxy, C,-C₄-alkylthio, C,-C₄-alkylsulfinyl, CpC₄- alkylsulfonyl, halo-C_rC₄-alkyl, halo-C_rC₄-alkoxy, halo-C|-C₄-alkylthio, halo-C_rC₄-alkyl- sulfinyl and halo-Ci-C₄-alkylsulfonyl,

R represents unsubstituted or mono- or polysubstituted Q-Cn-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, hydroxy, Ci-C₄-alkoxy, halo-Ci-C₄-alkoxy, C_rC₄-alkylthio, C]-C₄-alkylsulfinyl and CpC₄-alkylsuI- fonyl; unsubstituted or mono- or polysubstituted C₃-C₈-CyC loalky I or C₃-C₈-cycloalkyl-Cp

C₄-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, Cj-Q-alkyl and C]-C₄-alkoxy; unsubstituted or mono- to pentasubstituted phenyl, where the substituents are identical or different and are selected from the group consisting of halogen, C|-C₆-alkyl, C₃-C₈-cycloalkyl, Ci-C₄-alkoxy, halo-CpC₄- 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-alkyI; naphthyl; unsubstituted or mono- or polysubstituted heteroaryl, where the substituents are identical or different and are selected from the group consisting of halogen, C|-C₄-alkyl, CpC₄-alkoxy, unsubstituted or mono- to penta- substituted phenyl, where the substituents are identical or different and are selected from the group consisting of halogen and C_rC₄-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-alkylene,

R¹ furthermore represents together with R³ or R⁵ C₃-C₅-alkylene,

R³ and R⁴ furthermore together represent Q-Cβ-alkylene, R³ and R⁵ furthermore together represent C₂-C₄-alkylene,

R⁵ and R⁶ furthermore together represent C₄-C₆-alkylene,

are obtained by mixing 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 sulfuric acid to give the corresponding salts in solution, by then converting them in a second step to 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 third 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.

In contrast to the current state of the art the second reaction step according to the invention is not done in a reaction vessel but in a drying device. The very fast removal of water from the reaction mixture drives the reaction. Using this process the sulfuric acid does not have to be used in excess over the alcohol and thus pure product without remaining acid is obtained. Additionally, no organic solvents are used in the process according to invention, making the process also ecologically advantageous as compared to the process described in WO 01/23350 where toluene is used to remove water from the reaction mixture.

Because the amino alcohol and sulfuric acid are used in equimolar amounts in the first step, only a minor amount of base (about one mole per mole of alcohol) has to be added in the second step to keep the pH value high enough to avoid decomposition of the mercaptan salt. This also allows to perform the third reaction step in a very concentrated reaction mixture which is also beneficial for yield.

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 and yield. This leads to the technical advantage of a high space-time yield.

Detailed description of the process according to the invention

Using 2-amino-2-methyl-l-propanol and methyl mercaptan sodium salt as starting materials, the course of the reaction of the process according to the invention can be outlined by reaction scheme

me 1

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

0 R¹ and R² in each case independently of one another represent hydrogen, Ci-C₄-alkyl, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyl-Ci-C₂-alkyl, 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 fluorine, chlorine, bromine, iodine, cyano, nitro, C_rC₄-alkyl, C₃-C₆-cycloalkyl, C_rC₄-alkoxy, C_rC₄-alkyIthio, C_rC₄-alkylsulfinyl, C_rC₄-alkylsuifonyl, 5 carboxyl, Ci-C₄-alkoxycarbonyl, Ci-C₄-alkoxy-C₁-C₄-alkyl, Ci-C₄-alkylcarbonyl, halo-C_r

C₄-alkyl, halo-CrQ-alkoxy, halo-Q-Q-alkylthio, halo-C_rC₄-alkylsulfinyl, halo-C_rC₄- alkylsulfonyl, halo-C]-C₄-alkylcarbonyl, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms, phenylcarbonyl, phenoxycarbonyl, amino, Ci-C₄-alkyl- amino 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 C_rC₂-alky- lenedioxy; unsubstituted or mono- to pentasubstituted phenyl-C_rC₂-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, C_rC₄-alkyl, C₃-C₆-cycloalkyl, Cj-C₄- alkoxy, C_rC₄-alkylthio, C_rC₄-alkylsulfinyl, C,-C₄-alkylsulfonyl, halo-C,-C₄-alkyl, halo- C,-C₄-alkoxy, halo-C,-C₄-alkylthio, halo-C_rC₄-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 C_rC₄-alkyl,

R⁵ and R⁶ independently of one another represent hydrogen, Q-Q-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-G_t-alkyl, C₃-C₆-cycloaIkyI, C_rC₄-a^]koxy, C,-C₄-alkylthio, C,-C₄-alkylsulfinyl, C|-C₄-aikylsulfonyI, halo-Ci-C₄-alkyl, halo-C_rC₄-alkoxy, halo-C_rC₄-alkylthio, halo-C,-C₄-a]kylsulfiny] 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-CrC₂-alkyl, 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-C₈-cycloalkyl, Ci-C₄- alkoxy, Ci-C₄-alkylthio, Ci-C₄-alkyIsulfinyl, C_rC₄-alkyIsulfonyl, halo-Ci-C₄-alkyl, halo- Ci-C₄-alkoxy, halo-Ci-C₄-alkylthio, halo-C|-C₄-alkylsulfinyl and halo-C_rC₄-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-alkylene,

R⁵ and R⁶ furthermore together represent C₄-C6-alkylene.

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, 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, methylsulfϊnyl, 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, di- fluoromethylsulfinyl, dichloromethylsulflnyl, difluorochloromethylsulfinyl, fluorodi- chloromethylsulflnyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethyl- sulfonyl, dichloromethylsulfonyl, difluorochloromethylsulfonyl, fluorodichloromethyl- sulfonyl, trifluoromethylcarbonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, meth- oxymethyl, ethoxyethyl, methoxyethyl, ethoxymethyl, methylcarbonyl, ethylcarbonyl, phenylcarbonyl, phenoxycarbonyl, amino, methylamino, ethylamino, propylamine, dimethylamino, diethylamino; phenyl, which is substituted at two adjacent carbon atoms by -(CH₂V, -(CH₂V, -OCH₂O-, -O(CH₂)₂O-; in each case unsubstituted or mono- to tri- substituted 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-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, di- fluoromethylsulfinyl, dichloromethylsulflnyl, difluorochloromethylsulfinyl, fluorodi- chloromethylsulfinyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethyl- sulfonyl, dichloromethylsulfonyl, difluorochloromethylsulfonyl, fluorodichloromethyl- sulfonyl;

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- sulflnyl, 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, difluoromethylsulfmyl, dichloromethylsulfϊnyl, difluorochloromethylsulfinyl, fluorodi- chloromethylsulfinyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethyl- sulfonyl, dichloromethylsulfonyl, difluorochloromethylsulfonyl and fluorodichloro- methylsulfonyl; in each case unsubstituted or mono- to trisubstituted benzyl or phenylethyl, where in each case the substitυents 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, difluoromethylsulfϊnyl, dichloromethylsulfϊnyl, difluorochloromethylsulfinyl, fluorodi- chloromethylsulfinyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethyl- sulfonyl, dichloromethylsulfonyl, difluorochloromethylsulfonyl, fluorodichloromethyl- sulfonyl,

n represents 1, 2, 3, 4, 5 or 6, 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 -(CH₂)₂-, -(CH₂)₃-, -(CH₂V, -(CH₂)₅-,

R¹ furthermore represents together with R³ or R⁵ -(CH₂)₃-, -(CH₂)₄-, -(CH₂)₅-,

R³ and R⁴ furthermore together represent -(CH₂),,-, -(CH₂)₅-, -(CH₂)₆-,

R³ and R⁵ furthermore together represent -(CH₂)₂-, -(CH₂)₃-, -(CH₂)₄-, R⁵ and R⁶ furthermore together represent -(CH₂V, -(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, 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, trifluoro- methyl, difluoromethyl, trifluoromethoxy, 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),,-, -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-propylsulfinyl, n-, i-, S-, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propylsulfonyl, n-, i-, S-, t-butylsulfonyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylsulfinyl, trifluoromethylsulfonyl;

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-butylsulfonyl, 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, methylsulfmyl, 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)₂-, -(CH₂)₃-, -(CH₂),,-, -(CH₂)₅-,

R¹ furthermore represents together with R³ or R⁵ -(CH₂)₃-, -(CH₂),,-, -(CH₂)₅-,

R³ and R⁵ furthermore together represent -(CH₂)₂-, -(CH₂)₃-, -(CH₂)₄-,

R⁵ and R⁶ furthermore together represent -(CH₂),,-, -(CH₂)₅-, -(CH₂)₆-.

Most 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,

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.

Emphasized as starting material are amino alcohols of the formula (II), in which R¹ and R² in each case independently of one another represent hydrogen or methyl,

R³ and R⁴ represent hydrogen,

R⁵ and R⁶ independently represent hydrogen and

n represents 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 third step of the process according to the invention.

Preferred as starting material are mercaptans or salts thereof of the formula (IV), in which

R represents unsubstituted or mono- or polysubstituted Ci-C₁₂-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, C]-C₄-alkoxy, halo-CpGi-alkoxy having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms, Ci-C₄-alkylthio, Ci-Gi-alkylsulfinyl and C_rC₄-alkylsulfonyl; unsubstituted or mono- or polysubstituted C₃-C₆-cycIoalkyl or C₃-Ce-

where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine,

and Ci-G,-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, Q-Q-alkyl, CrC₆-cycloalkyl, Ci-C₄-alkoxy, halo-Ci-Q-alkyl, halo-C_r G_t-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 Ci-C₄-alkyl; naphthyl; unsubstituted or mono- or polysubstituted heteroaryl (preferably furyl, thienyl, pyrrolyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1 ,2,4-oxadiazolyl, 1,3,4-oxadiazolyI, 1,2,4- thiadiazolyl, 1,3,4-thiadiazoIyl, 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-G_t-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 Ci-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 polysubstiruted 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 poly substituted 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 unsub- stituted 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-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, 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 (FV), 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, methylsulfϊnyl, 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 (IV), in which

R represents in each case unsubstituted or mono- or polysubstituted methyl, ethyl, n-, i-pro- pyl 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.

Emphasized as starting material are mercaptans or salts thereof of the formula (FV), in which

R represents methyl and

M represents sodium.

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 polysub- stitution 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 — salt formation - according to the invention can be carried out by addition of the amino alcohols of the formula (II) into the diluted (50-70 % (w/w) ) sulfuric acid, for example. Sulphuric acid

Scheme 2

The addition of the amino alcohol of the formula (II) into the sulfuric acid is preferably done in water with cooling to keep the temperature below 6O⁰C, while a temperature range between 4O⁰C 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. Solutions with up to 40-80 % in water may also be used.

The reaction temperatures employed to the first step of the reaction according to the invention may be varied over a broad range. In general the reaction is carried out between 20⁰C and 7O⁰C, preferably between 30-60⁰C, particularly preferably between 40⁰C and 50⁰C.

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 first step of the reaction is expediently carried out using roughly equimolar amounts of amino alcohol and sulfuric acid, i.e. between 0.8 and 1.2, preferably between 0.9 and 1.1 moles of amino alcohol per mole sulfuric acid.

The reaction time can be different depending on the scale of the reaction and may vary between 10 min and 4 hours, althought the reaction is usually complete immediately after mixing of the reagents.

Scheme 3

The second reaction step of the process (sulfonate formation, cf. scheme 3) is carried out in a drying device. Generally, any drying device capable of handling the used chemicals is suitable, e.g. drying ovens, freeze dryers, spray dryers, combination dryers, rotary dryers, contact dryers, convection dryers, radiation dryers, infrared radiation dryers, microwave radiation dryers, vacuum dryers, ultraviolet radiation dryers, fluid bed dryers, belt dryers or conveyer dryers. Preferred drying devices are drying ovens, spray dryers and conveyer dryers. Particularly preferred are drying ovens.

The second step of the reaction is expediently carried out under atmospheric pressure at elevated temperature (50 - 200 ⁰C, preferably 100 - 150 ⁰C), although it is also possible to work under reduced pressure in order to accelerate the removal of water. Particular preference is given to carrying out the reaction under reduced pressure (10 - 50 mbar) at elevated temperature (80 - 120⁰C) to reduce reaction time and increase space-time yield.

Scheme 4

The third step of the reaction according to the invention (cf. scheme 4) 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 5).

Scheme 5

Additionally it allows to maximize reactant concentration, improving the time space yield of the reaction and decreasing waste. The addition of the sulfuric acid ester of formula (III) is done within between 10 min up to 2 h depending on the scale of the reaction, preferably between 20 min and 1 h, particularly preferably between 30 min and 1 h.

The third 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, Li₂CO₃, K2CO3, CS2CO3 or NaHCOβ and KHCO3. Preference is given to Na2CO3, KOH, NaOH and NaHCO3, in particular NaOH.

The reaction temperatures employed to the third 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 6O⁰C and 100⁰C.

The third 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 third 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, dichlorethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert.-butyl ether, methyl tert-amyl ether, 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-methylpyrrolidone; esters, such as methyl acetate or ethyl acetate, sulfoxides, such as dimethyl sulfoxide, or sulfones, such as sulfolane. Prefered are the inert solvents which can be easily separated from the product via simple distillation.

The third step of the process is carried out in practice by reacting, for example, 1 mol of an sulfuric acid ester of formula (III) with between 1 and 5 mol, preferably between 1 and 3 mol, particularly preferably between 1 and 1.5 mol of a mercaptan or salt thereof of formula (PV) in the presence of a base, to keep the pH value in general between pH 11 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. The examples are not to be understood as in any way limiting.

Preparation examples

Example 1

(2S)-l-(Methylthio)propan-2-amine

75 g (1 mol) of (2S)-2-aminopropanol (L-Alaninol) and 1 mol Of H₂SO₄ as 80 % (w/w) aqueous solution were mixed together under cooling to keep the temperature below 50°C. The formed solution was dried in the vacuum oven at 1 1O⁰C for 2.5 h to give 155 g of a white solid, of (2S) - 2- ammoniopropylsulfate, corresponding to a yield of 100 %. 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 ground (2S)-2-ammoniopropylsulfate 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 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.

Comparative preparation examples

Example 1 : Preparation of 2-Methy 1-1 -(methIythio)propane-2 -amine

Preparation according to the invention

89 g (1 mol) of 2-amino-2-methyl-l-propanol and 1 mol Of H₂SO₄ as 50% (w/w) aqueous solution were mixed together under cooling to keep the temperature below 50⁰C. The formed solution was kept in the vacuum oven at 120⁰C for 3 h to give a white solid. 169 g of 2-ammonio-2- methlypropylsulfate could be isolated, corresponding to a yield of 100 %.

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 ground 2-ammonio-2-methlypropylsulfate was added within 30 min. The mixture was then stirred for 5-10 h at 9O⁰C and cooled to 30⁰C. The upper organic layer was separated to give 169 g of the product 2-Methy l-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. 55-58 ⁰C / 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 an 1 1 flat- bottomed flask with flat-flange joint and the 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 9O⁰C. 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 3O⁰C. 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 65°C for 6 h.

The mixture is cooled to 32°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 20⁰C 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-methyl- 1 -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 EP 1216988.

Yield 81 %.

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, C|-Gi-alkyl, C₃-

Cg-cycloalkyl, C₃-C8-cycloalkyl-C)-C₄-alkyl, hydroxy-C_rC₄-alkyl; unsubstituted or mono- to pentasubstiruted 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, C_rC₄-alkoxy, Ci-C₄-alkylthio, C,-C₄-alkylsulfinyl, Ci-C₄- alkylsulfonyl, carboxyl, Ci-C₄-alkoxycarbonyl, Ci-C₄-alkoxy-C_rC₄-alkyl, Ci-C₄- alkylcarbonyl, halo-C_rC₄-alkyl, halo-Ci-C₄-alkoxy, halo-C]-C₄-alkylthio, halo-C_r C₄-alkylsulfinyl, halo-Ci-C₄-alkylsulfonyl, halo-Ci-Q-alkylcarbonyl, phenyl- carbonyl, phenoxycarbonyl, amino, CrQ-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 pentasubstiruted phenyl-Ci-C₄-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro, Ci-C₄-alkyl, C₃-Cg-cycloalkyl, C|-C₄-alkoxy, CpQ-alkyl- thio, C_rC₄-alkylsulfinyl, C_rC₄-alkylsulfonyl, halo-C_rC₄-alkyl, halo-C,-C₄-alkoxy, halo-C_rC₄-alkylthio, halo-C_rC₄-alkylsulfinyl and halo-C_rC₄-alkylsulfonyl;

R³ and R⁴ independently of one another represent hydrogen or Ci-C₄-alkyl,

R⁵ and R⁶ independently of one another represent hydrogen, C]-C₄-alkyl, unsubstituted or mono- to pentasubstiruted phenyl, 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_rC₄-alkoxy, C_rC₄-alkylthio, Ci-C₄-alkylsulfinyl, C_rC₄-alkyl- sulfonyl, halo-Ci-C₄-alkyl, halo-C_rC₄-alkoxy, halo-C|-C₄-alkylthio, halo-Ci-G,- alkylsulfinyl and halo-Ci-C₄-alkylsulfonyl; unsubstituted or mono- to pentasub- stituted phenyl-Ci-C₄-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, cyano, nitro, Ci-C₄-alkyl, C₃-Cg- cycloalkyl, C,-C₄-alkoxy, C_rC₄-alkylthio, C,-C₄-a]kylsulfinyl, C,-C₄-a]kyisulfonyl, halo-C,-C₄-alkyl, halo-C_rC₄-alkoxy, halo-C,-C₄-alkylthio, haIo-C,-C₄-alkylsulfinyl and halo-C]-C₄-alkylsulfonyl,

R represents unsubstituted or mono- or polysubstituted CpCπ-alkyl, where the substituents are identical or different and are selected from the group consisting of halogen, hydroxy, CpQ-alkoxy, halo-Ci-C₄-alkoxy, CpQ-alkylthio, Ci-C₄-alkyl- sulfinyl and C_rC₄-alkylsulfonyI; unsubstituted or mono- or polysubstituted C₃-Cg- cycloalkyl or C₃-C₈-cycloalkyl-C₁-C₄-a!kyl, where the substituents are identical or different and are selected from the group consisting of halogen, C_rC₄-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-C₆-alkyl, C₃-C₈-cycloalkyl, C|-C₄-alkoxy, halo-C]-C₄-alkyl, halo-Q- C₄-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 C_rC₄-alkyl; naphthyl; unsubstituted or mono- or polysubstituted heteroaryl, where the substituents are identical or different and are selected from the group consisting of halogen, Ci-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 halogen and C_r C-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-alkylene,

R¹ furthermore represents together with R³ or R⁵ C₃-C₅-alkylene,

R³ and R⁴ furthermore together represent Gj-Cβ-alkylene,

R³ and R⁵ furthermore together represent C₂-C₄-alkylene,

R⁵ and R⁶ furthermore together represent C₄-C_δ-alkylene,

characterized in that 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,

are mixed with sulfuric acid, that they are then reacted in a drying device 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 that the sulfuric acid esters in a third 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 .

2. Process according to Claim 1, characterized in that a compound of the formula (II), in which

R¹ and R² in each case independently of one another represent hydrogen, Ci-Gj-alkyl, C₃-

C₆-cycloalkyl, Cj-C₆-cycloalkyl-C|-C₂-alkyl, 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 fluorine, chlorine, bromine, iodine, cyano, nitro, Ci-C₄-alkyl, C₃-C₆-cycloalkyl, Cι-C₄-alkoxy, C_rC₄-alkyIthio, Cj-C₄- alkylsulfinyl, Ci-C₄-alkylsulfonyl, carboxyl, Ci-C₄-alkoxycarbonyl, Ci-C₄-alkoxy- C_rC₄-alkyl, C,-C₄-aIkylcarbonyl, halo-C_rC₄-alkyl, halo-Ci-C₄-alkoxy, halo-C_rC₄- alkylthio, halo-Ci-C₄-alkylsulfϊnyl, halo-Ci-C₄-alkylsulfonyl, halo-C_rC₄-alkylcarb- onyl, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms, phenylcarbonyl, phenoxycarbonyl, amino, C_rC₄-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-aIkyIene or C_rC₂-alkylene- dioxy; unsubstituted or mono- to pentasubstituted phenyl-C_rC₂-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, C|-C₄-alkyl, C₃-C₆-cycloalkyl, Q- Q-alkoxy, Q-Q-alkylthio, Ci-C₄-alkylsulfϊnyl, C₁-C₄-alkylsulfonyI, halo-C_rC₄- alkyl, halo-Ci-C₄-alkoxy, halo-Ci-C₄-alkylthio, halo-C_rC₄-alkylsulfinyl and halo- C_rC₄-alkylsulfonyI, 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, 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, C_rC₄-alkyl, C₃-C₆-cycloalkyl, C_rC₄-alkoxy, C,-C₄-alkylthio, C_rC₄- alkylsulfinyl, C_rC₄-alkylsulfonyl, halo-C_rC₄-alkyl, halo-C_rC₄-alkoxy, halo-Ci- C₄-alkylthio, halo-Ci-Q-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-C|-C₂-alkyl, where the substituents are identical or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, C_rC₄-alkyl, C₃-C₈-cycloalkyl, C_rC₄-alkoxy, Ci-C₄- alkylthio, Ci-C₄-alkylsulfinyl, C,-C₄-alkylsulfonyl, halo-C,-C₄-alkyl, halo-C,-C₄- alkoxy, halo-Ci-C₄-alkylthio, halo-Ci-C₄-alkylsulfinyl and halo-Ci-C₄-alkylsulf- onyl, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms;

and when n represents 1 , R¹ and R² furthermore together represent C₂-C₅-alkylene,

R¹ furthermore represents together with R³ or R⁵ C₃-C₅-alkyIene,

R³ and R⁴ furthermore together represent C₄-C₆-alkylene,

R³ and R⁵ furthermore together represent C₂-C₄-alkylene,

R⁵ and R⁶ furthermore together represent G_t-C₆-alkylene,

is used.

3. Process according to Claim 1 or Claim 2, characterized in that a compound 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, CrQ-alkoxy, halo-Ci-Gj-alkoxy having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms, Ci-C₄- alkylthio, C_rC₄-alkylsulfinyl 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, Ci-C₄-alkyl and C|-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, C|-C₄-alkyl, C₃-C₆-cycloalkyl, C,-C₄-alkoxy, halo-Ci-C₄-alkyl, halo-Ci-Q-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 C_rC₄-aIkyl; 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-thiadiazoIyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1 ,2,5-thiadiazoIyl, 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_rC₄-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 Ci-C₄-alkyl, M represents hydrogen, ammonium or an alkali metal atom

is used.

4. Process according to Claim 1 , characterized in that a compound 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,

n represents 1 or 2, where the group C(R')R² may be identical or different, when n is greater than 1 ,

and a compound 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 reaction step is carried out in a drying oven, conveyer dryer or spray dryer.

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 sulfuric 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 third 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 third reaction step.

9. Process according to any one of Claims 1 to 8, characterized in that the third 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.

10. Process according to any one of Claims 1 to 9, characterized in that the second step of the process is carried out at a temperature of between 50⁰C and 200⁰C.

1 1. Process according to any one of Claims 1 to 10, characterized in that the third step is carried out using a phase transfer catalyst.

12. Process according to any one of Claims 1 to 1 1, characterized in that between 1 and 5 moles of mercaptane or salt thereof are used per mole of sulfonate ester in the third reaction step.