TW200800868A - Preparation of thioalkylamines with high yields - Google Patents

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) 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

200800868 IX. Description of the Invention: [Technical Field to Which the Invention Is Ascribed] The present invention relates to a novel process for producing a known sulfanylamine derivative. 5 [Prior Art] Because of the chemical structure of the thiol amine derivative, it can be divided into two groups of thiols and sulfides. When preparing the second class, the method 10 discussed below has been described. The first method for preparing thiols is based on the hydrolytical cleavage of thiazoline or thiazolidinone derivatives (see, for example, Journal of Medicinal Chemistry 12M, 8 >762; JP 59-231064, French Journal of Scientific Chemistry 1967, 3637). . Since the thiazolium or thiazolidinone derivatives must first be prepared via a number of reaction steps, the overall yield of the process is extremely low. The thiol can be obtained by a method comprising reacting a sulfate of an amino alcohol with ammonium sulfide (see, for example, Japanese Chemical Journal 1979, 149). This method • requires a long reaction time in a closed reaction vessel, resulting in high costs due to the low productivity of the required production plant. The reaction of the azole or the oxazolone derivative with the thiol is a method for preparing a sulphurized sulphur (see, for example, the Journal of Organic Chemistry 19921, 6257; the medicinal thousand ^ IHi, Li, 135 sentences. The hydrolysis process is required. To obtain the reaction product of the decylamine according to the present method. However, if the oxazolidine ring of the starting compound is substituted, for example, by an alkyl group, no reaction is observed. Further, due to the nature of the thiol, the method is used. Only aromatic sulfides can be prepared. The reaction of the amine alcohol with the mercaptan in the presence of a carboxylic acid can be used to obtain the water-cracking (four) feed of the indoleamine of 200800868 ((4). The method must be at high temperature and pressure. Under the make, from the guanamine cap ship.

10 15

A method in which a nitrogen-acrylic bite (a-) and a sulfur compound are like a sulfide of a mercaptan and a mercaptan (see, for example, a tetrahedral crystal, 48, = tetrahedral crystal dish 'heart (3)). In the industry "safety regulations must be highly required when using this method, as it is necessary to prepare and separate the aziridine which may be unstable. The method of converting the sulphur-burning alcohol to the sulphur-alkylamine is carried out by the Reiter (10) reaction. Hydrolyzed crackers are representative (see, for example, DE_〇s 2〇45(10)5.) This method requires extreme care to use excess hydrocyanic acid. In the case of nitrile, it can be easily manipulated but the hydrolysis process causes problems. In other processes for the preparation of a base amine derivative, the amino alcohol is reacted with sulfuric acid as a starting material in the first step to obtain a related vinegar (see 01/23350). After evaporation to dryness, the ester is further reacted with a mercaptan. The method is used in large-scale production, and the evaporation required after the first reaction step causes problems. Another method for preparing a sulfanylamine from an amino alcohol using oleum as a reactant is described. WO 03/099777. However, using the method described, the reaction mixture contains excess sulfuric acid which must be neutralized prior to the second step, thereby increasing the formation of sparingly soluble salts (Na2SO4). The yield in the second reaction is also adversely affected by additional dilution. 20 200800868 [Summary of the Invention] The present inventors have discovered a compound of the formula (1) R6R5N-

R1\ R

• SR R7n R4 where 10 15 is independently represented by hydrogen in each month, crc4-alkyl, c3_-8 calcined base c3-C8-cycloalkyl-Ci-Cr alkyl, via-Ci a -cv alkyl group; an unsubstituted or mono- to penta-substituted phenyl group wherein the substituents are the same or different and are selected from the group consisting of halogen, cyano, nitro, Crcv alkyl, c3_C8_cycloalkyl, k alkoxy, Ci_cr alkylthio, CrC4-alkylsulfinyl, cvcv alkylsulfonyl, carboxyl, Ci_C4_alkoxy, CV alkoxy-cvcv Base, Ci_C4_alkylcarbonyl, halogen·cv alkyl, dentate-CrC4·alkoxy, halogen-CVC4_alkylthio, halogen-cvcv-sulfenylsulfonyl, halogen-cvcv alkylsulfonyl , dentate-CVCc alkylcarbonyl, phenylcarbonyl, phenoxycarbonyl, amine, CKV alkylamino and: (CrC4 alkyl)-amine (wherein the alkyl groups may be the same or different); benzene a group which is substituted on two adjacent carbon atoms by a cvc4-extension group or a CrC2-alkylene dioxy group, an unsubstituted or mono- to penta-substituted phenylalkyl group wherein the substituents are the same Or different and selected from the following Base =, including · halogen, cyano, nitrate, ketone, crc4-alkyl, cvcv cycloalkyl, CVC4_ alkoxy, Cr (V alkylthio, Ci 々 20 200800868 keite ,Ci-CV basestone xanthene, halogen-CrC4-alkyl, halogen-CVCV alkoxy, dentate-CrC4-alkylthio, dentate_Ci_cv alkyl- sulphate and halogen-C〗-C4 - burned stone yellow wine base; R3 and R4 stand independently of each other to represent hydrazine or CVCr alkyl group, R and R independently of each other represent 虱, C 〖-C4~ alkyl, unsubstituted or mono- to penta-substituted phenyl, wherein The substituents are the same or different and are selected from the group consisting of: halogen, cyano, nitro, alkyl, C3-CV cycloalkyl, alkoxy, Crk alkylthio, CVCr alkyl Sulfonyl, Ci-C4_alkylsulfonyl, quaternary _Q-cv alkyl, oxy, _ prime <1<:4-alkylthio, halogen-CrCr alkyl sulfinyl and Haloalkylsulfonyl; unsubstituted or mono- to penta-substituted phenyl-Ci_C4-alkyl, wherein the substituents are the same or different and are selected from the group consisting of: arginyl, cyano , nitro, cvc4-alkyl, cvcv cycloalkyl, cvcv Oxy, CrCV alkylthio, Ci_C4_alkylsulfinyl, Ci-cv alkylsulfonyl, halogen·Ci_C4_alkyl, halogen-CrCr alkoxy, haloalkylthio, alizarin a broad Cc alkyl-sulfinyl group and a halogen-CrC4_alkylsulfonyl group, R represents an unsubstituted or mono- or polysubstituted CrCT alkyl group, wherein the substituents are the same or different and are selected from the following The group includes: * t, a mercapto group, a ci_c4-alkoxy group, a halogen-Cl-C4-alkoxy group, a CVCV alkylthio group, a CrC4 group, and a C1_C4·alkylsulfonyl group; a substituted or mono- or polysubstituted C3_C8-cycloalkyl or c3 C8 cycloalkyl group, wherein the substituents are the same or not 200800868 5

10 15 20 ] is selected from the group consisting of a puncturing group, including a cyano group, a C"C4 phenyl group, a aryl group, an unsubstituted or mono- to penta-substituted benzene compound, wherein the substituents are the same or different and Is selected from the group consisting of: _, CVQ-alkyl, c3_c8_cycloalkyl, Ci_ = gas group, S-fluorene, halogen, halogen; Phenyl-C]nonylalkyl, wherein the substituents are the same or different and are selected from the group consisting of: a di-f-alkyl group; a tea group; unsubstituted or mono- or multi-fed An aryl group which has the same or different substituents and is selected from the group consisting of: halogen, Cl-C4. alkyl, Ci-c4-burning oxygen i is the same: two or early to five. a substituted phenyl group, wherein the substituent q_e4 ^ is selected from the group consisting of: halo and η ί , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Different, ', and when η represents 1, R and R2 together represent a C2-C5-extension group, and % represents a group together with R3 or R5 c3_C5_alkylene, and R4 represents a stretching group, R and R5 are again - representing C2 々 stretching base, R 2 and R6 are - Representative alkylene CVCV, in the # in the amine of formula (11) of alcohol rVn

R3 ——OH R4 (II) -10- 200800868 where R1 ' R2, R3, R4, R5 ' Rln has the meaning given above, mixed with sulfuric acid to obtain the relevant salt in solution, and then equal to the emperor Conversion of three to citric acid vinegar of general formula (m) ' R1\ r6r5hn- R7n R4

-〇S(X (III) wherein 10 15 20 R1, R2, R3, R4, R5, 116 and n have the meanings given above, and by using these sulfates in the difference with the formula (1) a thiol or a salt thereof RSM (IV) wherein R has the meaning given above, and Μ represents hydrazine, ammonium or a metal atom, which is reacted in the presence of a base and in the presence of a diluent. Compared with the state of the art, the second reaction step according to the invention is not carried out in the reaction of the genus but in the drying apparatus. The water is rapidly removed from the reaction mixture to mobilize the reaction. Using the method, sulfuric acid It is not necessary to exceed the excess of the alcohol and thus obtain a pure product free of residual acid. In addition, in contrast to the process described in WO 01/23350, in which the terpene is used to remove moisture from the reaction mixture, according to the process of the invention The use of an organic solvent also gives the method an ecological advantage. Since the first step uses an equimolar amino alcohol and sulfuric acid, only a small amount of base is required in the second step of -11-200800868 (every pH value) High enough to avoid thiol m VIII #一吴斗)乂% Polar compounds also goes to maintain the reaction mixture was concentrated Ϊ:.. Which is also conducive to yield 5

Lo obtained; it can be used in a simple manner in accordance with the method of the present invention. The thioguanamine of the formula (I) is excellent in yield. The & μ reaction according to the present invention has the technical advantage of increasing the reaction rate and yield to produce a high I time yield. The process of the process according to the invention using 2-amino-2-methylpropanol and sodium decyl mercaptan as the starter can be summarized by the illustration.

The formula (Π) is a general definition of the amino alcohol required to carry out the first step of the process according to the invention as a starting material. 2〇^ The progress of the starting material is the amino alcohol of the formula (II), wherein V and R2 in each case independently represent hydrogen, C^CU-alkyl, C3-C6-cycloalkyl-C3< 6-cycloalkyl-CrC2-alkyl, hydroxy-CrC4-alkyl; unsubstituted or mono- to penta-substituted phenyl, wherein the substituents are the same or different and are selected from the group consisting of : fluorine, gas, bromine, iodine, cyano, fluorenyl, CrC4-alkyl, C3-C6·cycloalkan-12· 200800868 200800868 10 15 ginsyl, C1-C4-alkoxy, alkylthio, C1- C4-alkylsulfinyl, crcv sulfonyl, fluorenyl, crc4-alkoxycarbonyl, cvc4-alkoxy-CrCV alkyl, CrCV alkyl, halogen-CrC4-alkyl, self -Crc4-alkoxy, a cyclin-CrC4-alkylthio group, a halogen-Q-CV alkyl sulfinyl group, a dentate-Crc4_alkylsulfonyl group, a halogen carbonyl group, each having i to 9 The same or different fluorine, chlorine and / or bromine atoms, phenylcarbonyl, phenoxycarbonyl, amine, CrC4_alkylamino and dioxyl crc4-alkyl)-amino group (wherein the alkyl group can be Is the same or different); phenyl, which is attached to the adjacent carbon atom (: 3<4_alkylene or 01<2-alkylenedioxy substituted, unsubstituted or mono- to penta-substituted styryl <1_Cr alkyl, wherein the substituents are the same or different and are The group selected from the group consisting of fluorine, chlorine, molybdenum, hydrazine, cyano, nitro, Cr c4. alkyl, cvcv ring, CrCV alkoxy, Ci oxime, Q.CV Ya button base, CrC4 {base secret base, tooth beauty care Fu accounted for Λ burned milk base, element -Ci_c4-face f sulfur base, «.CVCV material bismuth sulfonyl group, each has! 4 '-I ^4 ^ / or a desert atom; 9 identical or different fluorine, chlorine and 20 R3 and R4 independently of each other represent hydrogen or Ci 々, R5 and R6 independently of each other represent hydrogen, c to five substituted benzene a group wherein 14 = 'substituted or mono- to the following groups, including the oxime substituents are the same or different and are selected from the group, _ group ==, play, dish, base, nitrate 3C (r% Calcination, CrC4-alkoxy, Ci_-13- 200800868 c4·alkylthio, crcv-based sulphate, Ci_C4•alkyl sulphate, halogen-Cl々, halogen-CKV, Halogen_Cl_C4-alkylthio, i (: & Si Yaxian and halogen -c-wide = 4-alkyl-based - each having i to 9 identical or different 5 fluoro, chloro and/or bromine atoms; unsubstituted or mono- to penta-substituted phenyl-CVC2. Wherein the substituents are the same or different and are selected from the group consisting of: fluorine, chlorine, desert, broken, cyano, wall, base, CrC4. alkyl, C3-C8_cycloalkyl, CVC4-burning Oxygen, Cl_C4-alkylthio, Cl々michylene, CrQ•丝醯10, halogen-CrC4·alkyl, halogen-C “C4-alkoxy, halogen_Ci_CV alkyl Sulfur, specthalin-Cl_C4_alkylsulfinyl and halogen_C1_C4-alkylsulfonyl, each having from i to 9 identical or different fluorine, chlorine and/or bromine atoms; η represents 1' 2 , 3 '4, 5 or 6, when η is greater than 丨, wherein 15 Cd^R2 groups may be the same or different, 0 and when η represents 1, R1 and R2 together represent C2_C5-alkylene, R1 Representing R3 or R5 C3-C5-alkylene, R3 and R4 together represent (: 4-0:6-alkylene, 2〇R3 and R5 together represent C2-CV alkyl, R5 and R6 Together, they represent a C4-C6-alkylene group. The promoter of the epidemic is an amino alcohol of the formula (II), wherein R1 and R2 independently of each other represent hydrogen, methyl, ethyl, n-, i-propyl, n-, iso-, second- , tert-butyl, cyclopropyl, 200800868 cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl decyl, cyclobutylmethyl, cyclopentyl decyl, cyclohexylmethyl, cyclopropylethyl, Cyclobutyl-ethyl, cyclopentylethyl, cyclohexylethyl, hydroxyindenyl, hydroxyethyl; unsubstituted or mono- to trisubstituted phenyl, wherein the 5 substituents are the same or different and Is selected from the group consisting of: appearance, chlorine, bromine, moth, cyano, nitro, fluorenyl, ethyl, n-, i-propyl 'different second second-butyl' ring Propyl 'cyclo-butyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, iso-propoxy'-n-'iso-'second-'tris-butoxy'曱Sulfone 10 group, ethylthio group, n-, i-propylthio group, n-, iso-, second-'second-butylthio group, fluorenyl hydrazine Base, positive-'iso-propyl sulphite yellow brewing base 'distinct second third-d A sulfinyl group, a methylsulfonyl group, an ethylsulfonyl group, a n-, an iso-propyl stellite base, a positive second, a second, a butyl, a sulphate, a sulphide Trichloromethyl 'difluoroindolyl' dichloromethyl, difluorochloroindole φ, fluorodichloroindenyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloroanion Base, difluorochloromethoxy, fluorodioxyloxy, trifluoro-decylthio, trichlorodecylthio, difluoromethylthio, dichlorodecylthio, difluorochloroindenyl Sulfhydryl, fluorodichloroindenylthio, tris 20 fluoromethylsulfinyl, trimethylsulfenylsulfonyl, difluoromethylsulfinyl, dichloroindenylsulfinyl, difluoro Chloromethylsulfinyl, fluorodichloromethylsulfinyl, trifluoromethylsulfonyl, trichlorosulfonylsulfonyl, difluorodecylsulfonyl, dihalosulfonyl, Difluorochloroindolylsulfonyl, fluorodichloromethylsulfonyl, trifluoromethylcarbonyl, carboxyl, -15- 200800868 decyloxycarbonyl, ethoxycarbonyl, decyloxymethyl, ethoxylated , methoxyethyl, ethoxylated fluorenyl, fluorenylcarbonyl, ethylcarbonyl, Alkyl, phenoxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino; phenyl, 5 Substituted by -(ch2)3-, _(CH2)4-, -OCH2O-'-0(CH2)20-; in each case unsubstituted or mono- to tri-substituted benzyl Or a phenylethyl group, wherein in each case Φ the substituents are the same or different and are selected from the group consisting of fluorine, chlorine, molybdenum, iodine, cyano, nitro, methyl, ethyl , 10 n-'iso-propyl'-different second second-butyl'cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, iso-propoxy Base, n-, iso-, second-, third-butoxy, thiolthio, ethylthio, n-, iso-propylthio, n-, iso-, second-, Tri-butylthio, decylsulfinyl, ethylsulfinyl 15 aryl 'n-'iso-propyl-arsenite-positive-'iso-'second-' third · butyl Kea stone yellow wine base, base stone base, ethyl stone yellow base, positive-'iso-propyl stone yellow base 'positive-' different-' second-' -Butyl yellow wine, trifluoromethyl, trichloroindenyl, difluoromethyl, dichloroindenyl, difluorochloromethyl, fluorodichloroindenyl, trifluoromethoxy, trichloromethoxy , 20 difluoromethoxy, dichloromethoxy, difluorochloromethoxy, fluorodichloromethoxy, trifluoromethylthio, trichloromethylthio, difluorodecylthio Chloromethylthio 'difluorochloroindolylthio' fluorodichloromethylthio, trifluoromethylsulfinyl, trichloromethylsulfinyl, difluorodecylsulfinyl, two Chlorosulfonylsulfinyl, difluoro gas sulfoximine-16- 200800868 5-fluorodichloromethyl sulphate yellow trifluoromethyl sulphate, trichloro fluorenyl fluorenyl, difluoromethyl Further, S-blue, dichloromethyl fluorenyl, difluorochloroindolylsulfonyl, fluorodichlorosulfonylsulfonyl; R3 and R4 independently of each other represent hydrogen, fluorenyl, ethyl, ortho-, Isopropyl, 5 positively different -, second-butyl 'R5 and R6 independently of each other represent hydrogen, methyl, ethyl, n-, i-propyl, n-, iso-, second-, a third-butyl group, an unsubstituted or mono- to tri-substituted phenyl group, wherein The groups are the same or different and are selected from the group consisting of fluorine, chlorine, bromine, moth, nitrogen, nitro, methyl 10, ethyl, n-, isopropyl, n-, iso- , second-, third-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n--iso-propoxy-positive-'iso-' Di-, tert-butoxy, methylthio, ethylthio, n-, i-propylthio, n-, iso-, second-, tert-butylthio, fluorenyl Sulfosyl, 15 ethylsulfinyl, n-, iso-propyl-sulfinyl, n-, iso-, φ second-, tert-butylsulfinyl, sulfhydryl Sulfhydryl, ethylsulfonyl, n-, iso-propylsulfonyl, n-, iso-, second-, tert-butylsulfonyl, trifluoromethyl, trichloroindolyl, Fluorinyl, dihalofluorenyl, difluorochloroindenyl, fluorodichloroindenyl, trifluoromethoxy, trichloro 20 methoxy, difluoromethoxy, dichloromethoxy, difluorochloro Oxyl, fluorodichloromethoxy, trifluoromethylthio, trichlorosulfonylthio, difluorodecylthio, dichlorodecylthio, difluorochlorosulfonyl sulfur , fluorodichloroindenylthio, trifluoromethylsulfinyl, trichlorosulfenylsulfinyl, difluorodecylsulfinyl, dichloroindenylsulfinyl, difluorochloroguanidine基•17- 200800868 sulfinyl, fluorodichloromethanesulfinyl, trifluorosulfonylsulfonyl, trichlorosulfanyl yellow-branched 'difluorofluorenyl yellow wine, dichloromethyl feldspar Stuffed base, difluorochloromethylsulfonyl and fluorodichlorosulfonylsulfonyl; unsubstituted or mono- to trisubstituted n- or phenylethyl in each case, 5 in each case The substituents are the same or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-, i-propyl, n-, and -, second-, third--butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, iso-propoxy, positive, iso- , second-, third-10-butoxy, methylthio, ethylthio, n-, iso-propylthio, n-, iso-, second-, tert-butylthio , methylsulfinyl, ethylsulfinyl, n-, iso-propylsulfinyl, positive - , iso-, second-, tert-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, iso-propylsulfonyl, n-, iso-, second- , 3-15 butyl-sulfonyl, trifluoromethyl, trichloromethyl, difluoromethyl, di-n-chloroindolyl, difluorochloromethyl, fluorodichloroindenyl, trifluoromethoxy , tri-methoxy, difluoromethoxy, dichloromethoxy, difluorochlorooxyl ^ I dichloromethoxy, trifluoromethylthiotrichlorosulfanylthio, difluoroanthracene Thiothio, dichloroindenylthio, difluorochloroindenylthio, fluoro 20 dichloromethylthio, trifluoromethylsulfinyl, trichloromethylsulfinyl, difluorodecyl Sulfosyl, dichloromethylsulfinyl, difluorochloroindenylsulfinyl, fluorodichlorodecylsulfenyl, trifluoromethylsulfonyl, trichlorosulfonylsulfonyl, Difluoromethylsulfonyl, dichlorosulfonylsulfonic acid, dichlorochlorinyl based, gas dichloroindenyl, -18- 200800868 η represents 1,2,3,4,5 or 6. When η is greater than 1, wherein the C(Ri)R2 groups may be the same or different, and when η represents 1,

Ri and R2 together represent -(CH2)2-, -(CH2)3-, -(032)4-,-5(CH2)5-, and R1 represents R3 or R5-(CH2)3-,- (CH2)4-, -(CH2)5--, R3 and R4 together represent -(CH2)4-, -(CH2)5-,-(CH2)6-, and R3 and R5 together represent - (CH2)2·, -(CH2)3-, -(CH2)4-, R5 and R6 together represent -(CH2)4-, -(012)5-, -(CH2)6. 10 very particularly preferred starter substance is the formula (ID of the amino alcohol, wherein R1 and R2 in each case independently represent hydrogen, methyl, ethyl, positive-'iso-propyl' positive second third - Butyl, cyclopropyl 5 cyclopentyl, cyclohexyl, cyclopropyl decyl, cyclopentyl fluorenyl, cyclohexyl fluorenyl, hydroxymethyl, hydroxyethyl; unsubstituted or mono- to tri- 15 substituted A phenyl group wherein the substituents are the same or different and are selected from the group consisting of: fluorine, chlorine, bromine, moth, cyano, nitro, methyl, ethyl, ortho-, hetero- Propyl, n-, iso-, second-, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, iso-propoxy, positive-, Iso-, second-, third-butoxy, 20-mercaptothio-ethylthio-n--iso-propylthio-positive-'iso-, second-, third-butyl Thio, fluorenylsulfinyl, ethylsulfinyl, n-, iso-propyl fluorenyl, n-, iso-, second-, tri-butylsulfinyl, hydrazine Sulfosyl, ethyl sulfonyl, n-, iso-propyl sulfonyl, positive-, iso-, second-, Tris-butylsulfonate 200800868, trifluoromethyl, difluorodecyl, trifluoromethoxy, difluoromethoxy, trifluoromethylsulfinyl, trifluoromethylsulfonyl, trifluoro Mercaptocarbonyl, carboxyl, methoxycarbonyl, methoxyindolyl, ethoxyethyl, decyloxyethyl, ethoxylated fluorenyl, fluorenylcarbonyl, ethylcarbonyl-5, phenylcarbonyl, benzene Oxycarbonyl, amine, mercaptoamine, ethylamino, propylamino, dimethylamino, diethylamino; phenyl, which is attached to two adjacent carbon atoms - ( CH2) 3-, -(CH2)4-, -o-och2o-, -o(ch2)2o-substituted; unsubstituted or mono- to trisubstituted benzyl, wherein the substituents are the same or different and are a group selected from the lower 10 columns, including: halogen, cyano, decyl, fluorenyl, ethyl, n-'iso-propyl'---iso-'second-'-^-butyl' Cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, iso-propoxy, n-, iso-, second-, tri-butoxy, decylthio, Ethylthio, n-, i-propylthio, n-, iso-, second, 15th tri-butyl sulfide Base, fluorenyl sulfoximine, ethyl sulfinyl, n-, isopropyl sulfite, yellow aryl, di-iso-di-di-di-butyl sulphate, fluorenyl sulfonyl, ethyl sulfonate Sulfhydryl, n-, i-propylsulfonyl 'distinct-' second bis-butyl ketone yellow trimethyl, difluorodecyl, trifluoromethoxy, difluorodecyloxy , trifluoromethyl 20 sulfinyl, trifluoromethylsulfonyl; R3 and R4 independently of each other represent hydrazine, fluorenyl, ethyl, n-, iso-propyl, dimorphic di-di-butyl 'R5 and R6 independently of each other represent argon, fluorenyl, ethyl, n-, i-propyl, n-, i-, second-, tert-butyl, unsubstituted or mono- to tri-20 - 200800868 Substituted phenyl, wherein the substituents are the same or different and are selected from the group consisting of: fluorine, chlorine, molybdenum, moth, cyano, nitro, methyl, ethyl 'positive _ ' -propyl, n--iso-'second-' third to butyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, 5 n-, iso-propoxy, positive -,iso-,second-,third-butoxy, thiolthio, ethylthio, positive-, different -propylthio, n-, iso-, second-, tert-butylthio, methylsulfinyl, ethylsulfinyl fluorenyl, n-, iso-propylsulfinyl ,正-,异·,Second-,Second·Butyl stellite Yellow-branched 'Methyl-based base' Ethyl continuation base 5--10 iso-propyl sulfonyl, positive-, Iso-, second-, tert-butylsulfonyl, trifluoromethyl, difluorodecyl, trifluoromethoxy, difluoromethoxy, trifluoromethylsulfinyl, trifluoromethyl A sulfonyl group; an unsubstituted or mono- to trisubstituted benzyl group wherein the substituents are the same or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyanide 15 group, Nitro, methyl, ethyl, n-, i-propyl, n-, i-, Φ second-, third-butyl, cyclopropyl, cyclopentyl, cyclohexyl, decyloxy, B Oxygen, n-, iso-propoxy, n-, iso-, second, third-butoxy, decylthio, ethylthio, n-, iso-propylthio Different second second · butyl thio ' fluorene sulphate yellow 20 base, ethyl sulphate, n-, iso-propyl sulphate, positive - Iso-, second-, tert-butylsulfinyl, fluorenylsulfonyl, ethylsulfonyl, n-, iso-propylsulfonyl, n-, iso-, second-, Tertiary-butylsulfonyl, trifluoromethyl, difluorodecyl, trifluoromethoxy, difluoromethoxy, trifluoromethyl sulfoxide, trifluoromethyl sulfonium - 21 - 200800868 , η represents 1, 2, 3 or 4, and when η is greater than 1, wherein the C^R^R2 groups may be the same or different, and when η represents 1, 5 R1 and R2 together represent -(CH2)2 -, -(CH2)3-, -(CH2)4-, -(CH2)5-, R1 represents and R3 or R5-(CH2)3., -(CH2)4_,-(CH2)5-- As a result, _ R3 and R4 together represent -(CH2)4-, -(CH2)5-, -(CH2)6-, and R3 and R5 together represent -(CH2)2-,-(0^)3- , -(CH2)4-, 10 R5 and R6 together represent -(CH2)4-,-(CH2)5-,-(CH2)6-, the most particularly preferred starting material is the formula (ID of the amino alcohol, Wherein R1 and R2 independently represent hydrogen in each case, methyl, ethyl, n--iso-propyl'---iso-'di-di-di-di-butyl' R3 and R4 are independently represented氲, sulfhydryl, ethyl, n-, iso-propyl, 15 ortho Second-butyl' • R5 and R6 independently of each other represent hydrogen, fluorenyl, ethyl, n-, iso-propyl, divalent second, second-butyl' η represents 1 or 2, when η is greater than 1 Wherein the C^RbR2 groups may be the same or different. The starting material emphasized by 20 is an amino alcohol of the formula (II), wherein R1 and R2 independently represent hydrogen or a fluorenyl group in each case, R3 and R4 represent hydrazine, R5 and R6 independently represent hydrogen and η represents 1. -22- 200800868 Ready. The amino alcohols of the formula σι) are widely known and/or can be provided according to known methods. The formula (IV) provides a general definition of the thiol or its salt required for the animal. As a start

The starting material for R is a thiol of the formula (IV) or a salt thereof, wherein 10 15 20 is a second or a mono- or poly-substituted CrCi 2 -alkyl group, wherein the koji is the same or different and is selected from the following Groups, including: m hard, silk, Ci_c4• silk base, tooth with i to 9.2, different fluorine, gas and/or bromine atoms _C1 々

ρ 1 C 4 alkylthio, C 1 -C 4 ·alkyl fluorenyl and C 4 4 fluorenyl fluorenyl, unsubstituted or via a single or multiple = group or % Å group, wherein the substituent is Mesh: or different and selected from the group 'including: fluorine, chlorine, = broken (VQ-alkyl and (oxy); unsubstituted or phenyl substituted by early-to-five, Wherein the substituent is a group selected from the group consisting of: gas, chlorine, evolved, broken, Ci-pyringyl, C3-C6-alkali, Ci_c4_alkoxy, halogen-Ci-Cg, halogen- Cl_C4-alkoxy, each having 1 to 9 identical or different fluorine, chlorine and/or bromine atoms; unsubstituted or mono- to penta-substituted phenyl-CVCV alkyl, wherein the substituents are the same or different And a group selected from the group consisting of: fluorine, chlorine, bromine, moth and C1_C4_alkyl, n-butyl, unsubstituted or mono- or polysubstituted heteroaryl (preferably furanyl, Thienyl, pyrrolyl, oxazolyl, oxazoline, isoxazolyl, thiazolyl 'isothiazolyl, imidazolyl, pyrazole-23- 200800868, 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-tridecyl, 1,2,4-trisalyl , Sijunji, Tonbityl, pyrimidinyl, hydrazine, pyridinyl, tri-farming), wherein the substituents are 5 which are the same or different and are selected from the group consisting of fluorine, chlorine, and desert , moth, C1-C4-homo, C1-C4-alkoxy' unsubstituted or mono- to penta-substituted phenyl, wherein the substituents are the same or different and the φ is selected from the group consisting of Including ····················································································· a salt thereof, wherein R represents an unsubstituted or mono- or polysubstituted thiol group in each case, ethyl 'n-'iso-propyl'---iso-'second-'third-but a group, in each case isomeric pentyl, hexyl, octyl, decyl and decyldialkyl, wherein the substituents are the same or different and are selected from the following ingyl groups' including: fluorine, chlorine, Bromine, moth, mercapto, decyloxy, ethoxy, n-isopropyl, -iso-, second-, tri-butyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, difluorochloromethoxy, fluorodichloroguanidine Oxyl, decylthio, ethyl 20 thio, n-, i-propylthio, n-, iso-, second-, tert-butylthio, methylsulfinyl, B Isosulfonyl, n-, i-propyl sulfite, n-, iso-, second-, third-butyl sulphate, fluorenyl sulfonyl, ethyl sulfonyl, positive , iso-propylsulfonyl, n-iso-, second-, second-butyl phosgene; unsubstituted or mono- or polysubstituted cyclopropyl, ring in each case -24-200800868 Butyl, cyclodecyl, cyclohexyl, cyclopropyl decyl, cyclobutyl decyl, cyclopentyl decyl, cyclohexyl decyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl , cyclohexylethyl, wherein the substituents are the same or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, methyl, ethyl, n-, iso-propyl, n- , iso-, second-, tri-butyl, decyloxy, ethoxy, n-, iso-propoxy , n-, iso-, second--, tri-butoxy; unsubstituted or mono- to trisubstituted phenyl, wherein the substituents are the same or different and are selected from the group consisting of Package 10 includes: fluorine, chlorine, molybdenum, moth, sulfhydryl, ethyl, n-, i-propyl, n-, iso-, second-, tri-butyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, methoxy, ethoxy, n-, i-propoxy, n-, iso-, second-, tri-butoxy, trifluoromethyl, trichloromethane , difluorodecyl, dichloromethyl, difluoromethyl, fluorodichloropyrene 15 , trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethyl oxy, two Fluorochloromethoxy, fluorodichloromethoxy; unsubstituted or mono- to trisubstituted benzyl or phenylethyl in each case, wherein in each case the substituents are the same or different and are selected From the following groups, including: fluorine, chlorine, bromine, iodine and methyl, ethyl, n-, iso--2-mercaptopropyl, n-, iso-, second-, third-butyl; naphthalene Unsubstituted or mono- or polysubstituted furyl, thienyl, 1 in each case 1 than aryl, fluorenyl, 嗤 林 林 ,, iso-salt, thiol, isothiazolyl, imidazolyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3·thia-25- 200800868 oxazolyl, 1,2,5_ Thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetradecyl, 吼η定, TI 密基基, 塔ϋ井基, 0 ti well base, a trimorphinyl group, wherein in each case the substituents are the same or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, methyl, ethyl 5, n-, i-propyl, N-, iso-, second-, tri-butyl, methoxy, ethoxy, n-, iso-propoxy, n-, iso-, second-, tri-butoxy, Unsubstituted or mono- to trisubstituted phenyl, _ wherein the substituents are the same or different and are selected from the group consisting of: fluorine, chlorine, bromine, iodine and decyl, ethyl, plus - , iso-propyl, 10--, iso-, second-, and tri-butyl, Μ represents hydrogen, ammonium, sodium, potassium, and hydrazine. A particularly preferred starting material is a thiol of the formula (IV) or a salt thereof, wherein R represents an unsubstituted or mono- or polysubstituted thiol group in each case, ethyl 'n-'iso-propyl' a positive-'iso-'second-'------- 15-amino group, in each case isomeric pentyl, hexyl, octyl, decyl and decyldialkyl, wherein the substituents are the same or different and are a group selected from the group consisting of fluorine, chlorine, bromine, moth, mercapto, methoxy, ethoxy, n-, iso-propoxy, n-, iso-, second-, third -butoxy, trifluoromethoxy, trichloromethoxy, decylthio, ethylthio 20, n-, iso-propylthio, tert-butylthio, decylsulfin Sulfhydryl, ethylsulfinyl, n-, iso-propylsulfinylene, tert-butylsulfinyl, fluorenylsulfonyl, ethylsulfonyl, n-, i-propyl Sulfosyl, tert-butylsulfonyl; in each case unsubstituted or mono- or polysubstituted cyclopropyl, cyclodecyl, cyclohexyl, -26- 200800868 cyclopropylmethyl, Cyclopentyl fluorenyl, cyclohexylmethyl, wherein the substituents are the same or different Is selected from the group consisting of: fluorine, chlorine, desert, hydrazine, decyl, ethyl, n-, i-propyl, tri-butyl, decyloxy, ethoxy, positive - , iso-propoxy, tert-butoxy 5 -yl; unsubstituted or mono- to trisubstituted phenyl, wherein the substituents are the same or different and are selected from the group consisting of: fluorine, Chlorine, bromine, iodine, sulfhydryl, ethyl, n-, i-propyl, n-, i--, second-, tri-butyl, cyclopropyl, cyclopentyl, cyclohexyl, anthracene , ethoxy, n-, i-propoxy, n-, iso-, second-, 10-t-butoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy; a substituted or mono- to trisubstituted benzyl group wherein the substituents are the same or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine and decyl, ethyl, ortho-, Iso-propyl, n-, i-, second-, tri-butyl; naphthyl; unsubstituted or 15 mono- or poly-substituted fluorenyl, decyl, hydrazine in each case咯基,崎崎基, φ 今嗤 林林基, 异四嗤基,嗔峻基, 异嗔嗤基Imidyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazole Base, 1,2,3-thiadiazolyl, 1,2,5-thiadiinyl, 1,2,3-trimethyl, 1,2,4-trisyl, tetrasal, σ定20 base, pyrimidinyl, hydrazine, pyridinyl, tri-negative, wherein in each case the substituents are the same or different and are selected from the group consisting of: fluorine, chlorine, bromine, hydrazine Base, ethyl, n-, i-propyl, n-, i-, second-, tri-butyl, decyloxy, ethoxy, n-, iso-propoxy, positive-, iso- -, a second-, a third-butoxy group is a phenyl group which is substituted or mono- to tri-substituted, wherein the substituents are the same or different and are selected from the group consisting of the following, including : fluorine, chlorine, bromine and methyl, ethyl, n-, i-propyl, n-, i-, second-, and third-butyl, 5 Μ represents hydrogen, ammonium, sodium and potassium. The most particularly preferred starting material is a thiol of the formula αν) or a compound thereof, wherein R represents an unsubstituted or mono- or polysubstituted sulfhydryl group in each case, _ethyl, n-, i-propyl or a positive-, an iso-, a second-, a third-butyl group, wherein the substituents are the same or different and are selected from the group consisting of fluorine, chlorine, molybdenum, moth, rhodium, and oxime Base, ethoxy, n-, iso-methoxyl, n-, i-, second-, tri-butoxy, trifluoromethoxy, trichlorodecyloxy, decylthio, B Thiothio, n-, iso-propylthio, tert-butylthio, methylsulfinyl, ethylsulfinyl, n-, iso-propylsulfinyl, 15th Tri-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-, i-propyl, and second-butyl phosgene. Μ stands for sodium or potassium. The promoter substance to be emphasized is a thiol of the formula (IV) or a salt thereof, wherein R represents a thiol group and 20 代表 represents sodium. The thiol of formula (IV) or a salt thereof is widely known and/or can be prepared according to known methods. The saturated or unsaturated hydrocarbon group, for example, an alkyl group and a thiol group, may be linear or branched as much as possible in each case, including, for example, a combination of a hetero atom and a hetero atom in the alkoxy group. The optionally substituted group may be mono- or polysubstituted, and in the case where the substituent may be (four) or not (f). In the middle of the sputum, a group substituted with auxin, such as a halogen group, is subjected to monodentate to over-toothing. In the case of multiple toothing, the fangs = generations are the same or different. Halogen represents fluorine Hn ', atom. However, it is also possible that the above-mentioned or preferred groups are defined or combined as desired, that is, the gates in the respective ranges and preferred ranges are defined for the final product. And, the relevant application is on the day. ..., T interbody 2 According to the invention. Salt formation - reaction of the example b (II) of the amino alcohol is added to the diluted (50 - 70% (w/w) sulfuric acid and the line 0 15

NK

Sulphuric acid HO

Whso,

HO Fig. 2 Although the temperature is particularly preferably in the range of between 40 ° C and 50 ° C, the addition of the amino alcohol of formula 20 (Π) to sulfuric acid should be carried out under cooling to keep the temperature below (9). Generally, no carbonization is observed even when a highly substituted amino alcohol is used. The amino alcohol is applied in a liquid form. A solution containing up to 40-80% in water can also be used. The reaction temperature used in the first step of the reaction according to the present invention can be varied within a wide range from -29 to 200800868 5, usually in the range of 2〇t and 7 (between rc and preferably 30-', / long/6 〇°C, especially between 4°C and 50°C. Although it may also act under reduced or rising pressure, the second phase of the reaction is favorable at atmospheric pressure. Reduced in Dabu. The amount of amino alcohol and sulfur should be between 0. 9 and

The first step of the reaction is carried out using substantially equimolar acid, i.e., each mole of sulfuric acid is between 88 and 12, and 1·1 mole of amino alcohol. The anti-correction can be based on the scale of the reaction (4) and can vary between 1G and 4 hours, although the reaction is often completed immediately after the reagents are mixed.

Nh3+hso4'

15 The third reaction step of the method of _ > ( (formation of sulfonate, see Figure 3) is carried out in a drying apparatus. Generally, any dry device capable of operating the chemicals used is suitable, for example, a drying oven, a freeze dryer, a spray drying such as a dry combination, a rotary dryer, a contact dryer, and a radiation drying 2 genus. Infrared dryer, microwave radiation dryer, vacuum dryer, UV radiation dryer, fluid bed dryer, belt dryer or transport drying benefit. Preferred drying devices are drying ovens, spray dryers and conveyor dryers. Particularly preferred is a drying oven. Although it may also act under reduced pressure to accelerate the removal of water' -30· 200800868 The second step of the reaction is carried out at atmospheric pressure at an elevated temperature (50-200 ° C, preferably 10 (M50 ° C)). It is advantageous. Particularly preferred reaction is carried out at a reduced temperature (10-50 mbar) at an elevated temperature (80-120 °C) to reduce the reaction time and increase the interval-time yield.

MeS H〆

CH3SNa + NaOH Figure 4 The third step of the reaction according to the invention (see Figure 4) can be carried out by adding a sulfate of the formula (ΠΙ) such as a solution or a solid to the thiol of the formula (IV) or the like The salt should be completed in water. When the ester is added, the pH of the reaction mixture must be maintained in the range of 10-12. Preferably, the solid base is added directly to the thiolate or a salt thereof in water, followed by the addition of a sulfonate such as a solid or concentrated solution. The addition of a sulfonate to a mixture of a thiolate and NaOH increases the yield by 15 92-95% (82% relative to EP1231698). φ These steps allow for the formation of unstable, toxic and explosive ethyleneimine which is formed immediately after the addition of the sulfonate to a base of pH 10-12 (see Figure 5).

KpH 10-12 \_7 —^ \7 h3n 〇S〇3- nh Figure 5 In addition, it allows the maximum concentration of reactants to improve the time interval of reaction and reduce waste. -31- 200800868 The addition of sulfuric acid S of formula (III) depends on the scale of the reaction between 10 minutes and 2 hours, preferably between 20 minutes and 1 hour, especially between 30 minutes. And completed between 1 hour. The third step of the process is carried out in the presence of a base. Examples 5 which may be mentioned are: alkali metal and alkaline earth metal hydroxides, for example, NaOH, KOH,

Ca(OH)2, metal carbonate or bicarbonate, for example, Na2C03, Li2C03, K2C03, Cs2C03 or NaHC03 and KHC03 较好 Preferably _ Na2C03, KOH, NaOH and NaHC03, in particular NaOH. The reaction temperature used in the third step of the reaction according to the present invention can be varied over a wide range. Usually, the reaction is between 3 CTC and 150 ° C, preferably between 50 ° C and 120 ° C, particularly preferably between 6 ° t: and 100 t:. Although it is also possible to act under reduced or elevated pressure, the third step of the reaction is advantageously carried out at atmospheric pressure. It is particularly preferred that the reaction be carried out at atmospheric pressure 15. φ The third step of the reaction according to the invention can be carried out in the presence of other diluents, all of which are customary. It is preferred to use an optionally oxidized aliphatic, alicyclic or aromatic hydrocarbon such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene or diphenylene or 20 decalin; chlorobenzene, dichlorobenzene, dichlorodecane, dichloroethane or trichloroethane; ethers such as diethyl ether, diisopropyl ether, methyl third-butyl ether, sulfhydryl third -pentyl ether, 1,2-dimethoxyethane, 1,2,diethoxyethane or phenyl ether; nitriles such as acetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile; Amines, for example, N,N-didecyl decylamine, N,N-dimercaptoacetamide, N-mercaptomethyl hydrazine-32- 200800868 Ξ: A: Γ 酮 ketone;, class, for example cool Acid vinegar or acetaminophen sulphate type 'for example, scorpion slate' or stone type, for example, burnt stone = ' = easily separated from the product by early distillation. j is; 丨 between 1 and 3 mo, 牿 10 15 rvi = the thiol or its salt of formula (IV) between the materials, in the presence of "holding value ^ between the pH 1 丨 and 12 The reaction is completed and the reaction can be carried out by using a phase transfer catalyst (PTC) image. Reduced by burning of ammonium, tetraalkyl-, tetraaryl scale, gUanidinium or vanadium ingots. The use of PTC can increase the yield. The preferred catalyst is tetradecylammonium bromide, tetrabutylammonium. a hydroxide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, phenyl sulfonate bromide and 18_crown-6 (18-crown_6). The product can be subjected to standard procedures, for example, crystallization. The chromatographic separation method, the extraction method and the distillation method are separated. The method according to the present invention is illustrated by the following preparation examples. [Embodiment] Preparation of Shame 20 Example 1

(2s) _l-(methylthio)propenolamine-33- 200800868 75 g (1 mol) (2S), 2-aminopropanol (L-Alaninol) and 1 mol 80% (w/w/ The aqueous solution of HJO4 was mixed together while cooling to keep the temperature below 50 C. The resulting solution was dried in a vacuum oven for 2 hours to give 155 g of (2S)-2-ammoniopropylsulfate 5 salt as a white solid, corresponding to 1% yield. The melting point is 260-263 °C.屯NMR (d6-DMSO): δ 1.2 (d,3H), 3.4 (m,1H),3·6·3·8 (dm· ΑΒΧ system, 2Η), 7·8 (width.s·,ΝΗ3) Ppm. • A 20% aqueous solution of sodium thiolate (1.2 mol) was placed in the flask and 40 g (1 mol) of NaOH (solid) was added with stirring. The mixture was stirred vigorously and 155 g (1 mol) of (2S)-2-ammoniopropyl sulfate was added over 1 ° 3 min. The mixture was then stirred at 9 (TC for 5-10 hours and cooled to 3 ° C. The above organic layer was separated to give 159 g of product (2S)-l- (曱) with purity 62% (38% water). The product can be dried on MgS 4 or azeotroped with hexane to give 102 g (94% of theory) of amine with a purity of 97%, 15 154 ° C. _ 1Prepare your h Example 1 · Preparation of 2-methylmethylthio)propanamine

20 H3C h3c According to the present invention, 89 g (1 mol) of 2-amino-2-mercapto-1-propanol is cooled with an aqueous solution of 1 mol 50% (recover/re) ηα〇4 to maintain The temperature is below 5〇. Your Majesty • 34- 200800868 Mix together. The resulting solution was maintained in a vacuum oven at 12 (rc dried for 3 hours to give a white solid. 169 g of 2-ammonyl-2-methylpropyl sulfate was isolated, corresponding to 100% yield An aqueous solution of 20% sodium thiolate (1.2 mol) was placed in the flask and 4 g (1 mol) NaOH (solid) was added with stirring 5. The mixture was stirred vigorously and 169 g was added over 30 minutes ( 1 mole) ground ammonium 2-methylpropyl sulfate. The mixture was then stirred at 90 ° C for 5-10 hours and cooled to C. The above organic layer was separated to give 169 g purity 53 % (曱%-1-methylthio)propanamine of % (47% water content). The product is dried on 10 MgS〇4 or combined with hexane to obtain 1 gram (9 of theory) 〇%) Amine with 97% purity, boiling point 55-58 ° C / 25 mbar. The method of 摅 摅 WO 03/099777 will be oleum (120.1 g containing 20% S03 in H2S04, 15 , 〇·3 mol = 〇 · 6 equivalents 〇 3) placed in a 1 liter flat-bottomed flask with a flat-flange joint φ (1) at-flange j〇int) and 2-amino-2-indenyl propylene Alcohol (46.9 g, 〇·5 mol = 1 equivalent; 95%) with mechanical agitation To slowly added directly to 2-amino-2-methyl-contact surface of the oil in a glass flask. The temperature is maintained between 85 and 90 ° C by cooling. The reaction was mixed and the mixture was stirred at 90 C for an additional 30 minutes. After cooling to room temperature, the mixture was first diluted with 200 ml of water and then a 45% aqueous solution of sodium hydroxide was added. The temperature in the second process should not exceed 3〇〇c. A sodium methyl mercaptan sodium salt solution (183.6 g, 0.55 mol = 1 equivalent; 19·ΐ〇/〇 in water) was added under cooling and stirring was continued at 60X: to 65 ° C for 6 hours. -35- 200800868 The mixture was cooled to 32 ° C and all subsequent steps were carried out at this temperature. 100 ml of methyl third-butyl ether was added, the mixture was stirred and the organic layer was separated. The aqueous phase was extracted with two portions of 100 mL of tri-butyl ether. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was removed at 20 ° C under reduced pressure of 150 mbar. Yield: 62.7 g (crude product, purity according to the internal standard of the invention, 68.8%, i.e., 72% of theory) 2-methyl-1-mercaptothio-2-propanamine. W NMR (d6-DMSO): δ 1.04 (s, 6H), 1·44 (width, 2H), 2·10 10 (s, 3Η), 2·48 (s, 2Η) ppm. GC/MS-coupling: m/z (%) = 104 (3) [M-15]+,58 (100),42 (11),41 (8),31 (5) 制According to the method of EP 1216988 15 The yield was 81%. -36-

Claims (1)

200800868 X. Patent application scope: 1. A method for preparing a compound of the formula (1), /R1\ R3 (I) R6R5n-4---I-SR \ R2/n R4 wherein 10 15 20 R1 and R2 in each case independently represent hydrogen, Ci_C4_alkyl, c3-c8-cycloalkyl, c3-c8-cycloalkyl, hydroxy-CrCr alkyl; unsubstituted or via _ to a penta-substituted phenyl group wherein the substituents are the same or different and are selected from the group consisting of halogen, cyano, nitro, Ci_c4_alkyl, c3_Cs-cycloalkyl, CrCr alkoxy , CVCV alkylthio, Cl_〇4_alkylsulfinyl, Cl_Czr alkylsulfonyl, carboxyl, Ci-C4-alkoxycarbonyl, crC4-alkoxy-CrC4-alkyl, CrC4-fired Carbonyl group, halogen-CrCr alkyl group, halogen alkoxy group, halogen_CrC4-unitylthio group, _suxin-(: 4-alkylsulfinyl alcohol, ketone-crcv alkylsulfonyl, halogen _ CrC4_alkylcarbonyl, phenyl-carbonyl, phenoxycarbonyl, amine, cle Q-alkylamino and 〉(crcvalkyl)-amine (the _alkyl group may be the same or different); benzene a group substituted by a Q-Cr alkyl group or a crc2_alkylenedioxy group on two adjacent carbon atoms; unsubstituted or mono- to penta-substituted phenyl-Ci-C4-burned a group wherein the substituents are the same or different and are selected from the group below Including: halogen, cyano, nitro, Ci_C4-alkane; 37- 200800868, C3-C8-cycloalkyl, Ci-Q-alkoxy, crc4-alkyl-thio, CrCV alkyl , CVCV alkyl sulfhydryl, halogen-CrCV alkyl, halogen-Crar alkoxy, halogen-CVC4-alkylthio, halogen-CrC4_alkylsulfinyl and halogen-CrCzr alkylsulfonyl; R and R independently of each other represents hydrogen or (^<4-alkyl, 10 R and R 6 independently of each other represent argon, C^Cr alkyl, unsubstituted or mono- to penta-substituted phenyl, wherein the substituents are the same or different and are selected from the group consisting of halogen. , cyano group, 20 nitro, CVCV alkyl, C3-C8-cycloalkyl, cvc4-alkoxy, C1-C4-alkylthio, C1-C4-alkyl sulphate, c" c4-alkyl sulfonate Sulfhydryl, cyclin-Crc4_alkyl, halogen alkoxy, il-CrCr thiol, dentate-CVCV alkylsulfinyl and halogen-Crar alkylsulfonyl; unsubstituted or a two-ear-to-five substituted phenyl-C-C4-alkyl group, wherein the substituents are the same or different and are selected from the group consisting of dentin, cyano, nitro, Ci-CV Alkyl, c3-c8-cycloalkyl, Ci cv alkoxy, CrQ·alkylthio, crcv alkyl sulfite, CVCr alkylsulfonyl, halogen-CrCr alkyl, halogen-CrCV alkoxy , halogen-CrCf alkylthio, halogen_ci<V-alkylsulfinyl and halogen-Ci_C4_alkylsulfonyl, R represents unsubstituted or mono- or polysubstituted crc12-alkyl, wherein The substituents are the same or different and are selected from the group consisting of halogen, hydroxy, CVC 4 alkoxy, halogen · -38- 200800868 Ci-CV alkoxy, Ci-C4-alkylthio, Anthracenyl- sulphate and Ci_C4_alkyl group; unsubstituted or unsubstituted or A mono- or poly-substituted CrQ-cycloalkyl group or a CrC8·cycloalkylalkyl group wherein the substituents are the same or different and are selected from the group consisting of the following 5, including halogen, CrQ-alkyl and crC4 An alkoxy group; an unsubstituted or mono- to penta-substituted phenyl group wherein the substituents are the same or different and are selected from the group consisting of halogen, Ci-€6-alkyl, C3-C8-cycloalkyl, alkoxy, i-Cr-cc alkyl, halogen-CrC4. alkoxy; phenyl-crc4-alkyl which is not substituted or mono- to penta-substituted, wherein the substituent Groups which are the same or different and are selected from the group consisting of: halogen and CrCp alkyl; naphthyl; unsubstituted or mono- or poly-substituted heteroaryl, wherein the substituents are the same or different and are a group selected from the group consisting of halogen, c^c^alkyl, C1-C4-alkoxy, unsubstituted or mono- to penta-substituted®, wherein the substituents are the same or different And is selected from the group consisting of: halogen and CrC4_alkyl, η represents or 8, when η is greater than i, wherein the qR^R2 groups may be the same or different, 20 When η represents 1, R1 and r2 together represent CVC5-alkylene, and ^ represents R3 or R5cvcv extended alkyl, R31R54 together represent C4-C6-extension base, and R3 and R5 together represent Calcination, -39- 200800868 R5 and R6 together represent C4-C6-alkylene, which is characterized by the amino alcohol of formula (II) / R1\ R3 r6r5n r I 0H (id 5 in the first step) 10 15 \ R7n R4 wherein R1, R2, R3, R4, R5, R6 and n have the meanings given above, mixed with sulfuric acid, and then equal to the reaction in the drying apparatus to obtain the sulfate of the formula (III) r6r5hn+- R3 —〇S〇; R4 (ΠΙ) wherein R1, R2, R3, R4, R5, R6 and η have the meanings given above, and the sulfate is in the third step with the sulfur of the formula (IV) An alcohol or a salt thereof RSM (IV) 20 wherein R has the meaning given above, and Μ represents hydrogen, money or a metal atom, and is reacted in the presence of a base and suitably in the presence of a diluent. 2. The method of claim 1, characterized in that a compound of the formula (II) -40 - 200800868 is used, wherein R1 and R2 independently represent hydrogen in each case, CrC4-alkyl, Q-CV ring An alkyl group, a c3_C6_cycloalkyl group _ci_c2_alkyl group, a hydroxy-CrCr alkyl group; an unsubstituted or mono- to penta-substituted phenyl group, wherein the substituents are the same or different and are selected from the group consisting of Group, including: fluorine, chlorine, bromine, moth, cyano, ruthenium, Cr c4-alkyl, C3_C6-ring, KirC4i oxy, _1 thiol, Cr (V alkyl sulfinyl, Ci_c4-alkylsulfonyl, carboxy, CVCV alkoxycarbonyl, Ci-C4_alkoxy-10C<valkyl, .-anthracene-alkylcarbonyl, halogen-CVCV alkyl, dentate-CVCp-alkane Oxygen, dentate thiol, halogen-CrCV alkyl sulfinylene, dentate-Crc4_alkylsulfonyl, halogen-CVC4.alkyl-based, each having from 1 to 9 identical or different a fluorine, chlorine and/or bromine atom, a phenylcarbonyl group, a 15 phenoxycarbonyl group, an amine group, a CrC4-alkylamino group, and a di((c^Cr Φ alkyl)-amino group (wherein the alkyl group may be Same or different); phenyl 'its Substituted by a C3_C4_alkylene group or a Ci-C2_alkylenedioxy group on two adjacent carbon atoms, an unsubstituted or mono- to penta-substituted phenyl-CrC2-alkyl group, wherein The groups are the same or different and are selected from the group consisting of fluorine, chlorine, earth, hindrance, oxy, nitro-, C1-C4-alkyl, C3-C6-cycloalkyl, CrCr alkoxy Base, CVCr alkylthio group, CrCzr sulfonyl sulfinyl group, CrCr decyl fluorenyl group, halogen _crc4-alkyl group, halogen-CrC4·alkoxy group, halogen-CrC4-alkylthio group, -41- 200800868 halogen -CVCr alkyl sulfinyl group and dentate lentil - alkyl sulfonyl group, each having 1 to 9 identical or different fluorine, or bromine atoms, · and 及 and R4 independently of each other represent hydrazine or CrC4_alkyl , R 5 and Λ 6 independently of each other represent hydrogen, Cl anthracenyl, unsubstituted or mono- to penta-substituted phenyl, wherein the substituents are the same or different and are selected from the group consisting of fluorine, Chlorine, desert, hard, cyano, nitro, crc4-alkyl, c3-cv cyclodecyl, CVCV alkoxy, Cl_C4_alkylthio, Ci_C4_alkylsulfinyl, CrCV alkylsulfonate base Halogen-Crar alkyl, halogen-Cl-C4_alkoxy 'halogen-q-cv alkylthio, _--CrCV alkyl sulfinyl and halogen-CrC4-alkylsulfonyl, each having 1 to 9 identical or different fluorine, chlorine and/or desert atoms; unsubstituted or mono- to penta-substituted phenyl-Ci_Cr alkyl, wherein the substituents are the same or different and are selected from the group consisting of Group, including: fluorine, gas, bromine, iodine, cyano, nitro, crc4-alkyl, (V (V ring alkyl, CrCV alkoxy, Ci-cv alkylthio, Crar alkyl sulfinium) a group, a Ci_c4_alkylsulfonyl group, a halogen-CrCV alkyl group, a halogen-Crc4-alkoxy group, a halogen-CrCr alkylthio group, an alkylsulfinyl group, and a halogen-CrCr alkylsulfonyl group, each having至至9 identical or different gas, gas and / or bromine atoms; η represents 1 ' 2,3 ' 4,5 or 6, when η is greater than i, wherein the CXRbR2 group can be the same or different, -42· 200800868 and when η represents 1, R1 and R2 are again - representing Μ" stretching base, R3 is also represented by mvcvcv stretching base - R and R4 again - representing C4_C6_alkyl, Ή5 together represent C2- C4-Alkyl' R and R are together Table C4_C6 - extension base. Characterized by the use of a compound of the formula (IV) of claim 1 or 2, wherein 10 15 20 R 2 is unsubstituted or mono- or polysubstituted C1_C12-alkyl, wherein the substituent is Groups which are the same or different and are selected from the group consisting of: fluorine, chlorine, desert, argon, light base, Cl_C4-alkoxy, having 1 to 9 identical or different fluorine, gas and/or bromine atoms Halogen-CVC4-alkoxy, Ci_c4•alkylthio, c-C, 4-alkylsulfinyl and Ci_C4_alkylsulfonyl; c3々 not taken or substituted by single or township环环或々环烧土-cvcvalkyl, wherein the substituents are the same or different and are derived from the following groups: including: fluorine, chlorine, bromine, iodine, Cr C4, and Cl_C4_morphoxy; a substituted or mono- to penta-substituted phenyl group wherein the substituents are the same or not, including ♦ fluoro, chloro, chloro, chloro, chloro, Ci-C 4 · alkoxy, 6 _Ci_ CV 炫 base, dentate _C!_C4_ methoxy, each with the same or different fluorine, chlorine and / or atomic filling, · not or mono- to five-substituted phenyl-CI_C2 · appearance Base, hair 2 -43- 200800868 Groups which are the same or different and are selected from the group consisting of: fluorine, chlorine, desert, broken and C1-C4-alkyl; steam base; unsubstituted or single - or a polysubstituted heteroaryl group (preferably furanyl, thienyl, σpiro, mercapto, 4 syllidyl, iso- 4 sigma, 喧5 w waki, isoindolyl, miso base , 1 to Junki, 1,2,4-uf dimercapto, 1,3,4-indenyl, 1,2,4-indenyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-trisole 10, 1,2,4-trisal, tetradecyl, ratio a base group, a succinyl group, a sulphate group, a sulphate group, a sulphate group, a sulphonate group, wherein the substituents are the same or different phases and are selected from the group consisting of fluorine, chlorine, > Stinky, moth, C1-C4.alkyl, C1-C4-alkoxy' unsubstituted or mono- to penta-substituted phenyl, wherein the substituents are the same or different and are selected from the group consisting of Including · · fluorine, chlorine, > stinky, Egyptian C1-C4-alkyl ' 15 代表 represents hydrogen, ammonium or metal atom. φ 4. The method of claim 1, wherein the compound of formula (II) is used, wherein R1 and R2 independently of each other represent hydrazine, methyl, ethyl, ortho-propyl' Orthogonal second 'second-butyl' 20 R3 and R4 independently of each other represent argon, methyl, ethyl, n-, i-propyl 'different second 'second-butyl' R5 and R6 are independent of each other Represents hydrogen, fluorenyl, ethyl, n-, i-propyl, n-, i-, second, third-butyl, η represents 1 or 2, when η is greater than 1, wherein C^R^R2 The group -44- 200800868 may be the same or different, and a compound of the formula (IV), wherein R represents an unsubstituted or mono- or polysubstituted sulfhydryl group in each case, ethyl, ortho-, hetero- a propyl or n-, i-, second, 5th tri-butyl group, wherein the substituents are the same or different and are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, hydrazine Oxyl, ethoxy, n-, i-propyl, n-, i-, second-φ, tri-butoxy, trifluoromethoxy, trichloromethoxy, decylthio, Ethylthio, n-, iso-propyl , tert-butyl 10-ylthio, decylsulfinyl, ethylsulfinyl, n-, iso-propylsulfinylene, tri-butylsulfinyl, sulfhydryl Base, ethyl rhein acid group, n-, iso-propyl schistosyl, tert-butylsulfonyl group, Μ represents nano or oblique. The method of any one of claims 1 to 4, characterized in that the second step is carried out in a drying oven, a transport dryer and a spray dryer. 6. The method of any one of claims 1 to 5, wherein the first reaction step uses 0.8 to 1.2 moles of 20 amino alcohol per mole of sulfuric acid. 7. The method of any one of claims 1 to 6, wherein the base used in the third step of the method is selected from the group consisting of: metallurgical and soil-measured metal hydroxides. Check the metal carbonate or bicarbonate. The method of any one of claims 1 to 7 wherein the aqueous solution of a thiol or a salt thereof is used in the third reaction step. The method of any one of claims 1 to 8, wherein the third reaction step is carried out first by preparing a solution of a thiol or a salt thereof and a base, and then adding the sulfonate. The method of any one of claims 1 to 9, wherein the second step of the method is carried out at a temperature φ between 50 ° C and 200 ° C. The method of any one of claims 1 to 10, characterized in that the third step is carried out using a phase transfer catalyst. The method of any one of claims 1 to 11, wherein the third reaction step is a thiol or a salt thereof having between 1 and 5 moles per mole of the sulfonate. -46- 200800868 VII. Designated representative map: (1) The representative representative of the case is: ($). (2) A brief description of the component symbols of this representative figure: None 10 VIII. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: None 15