EP1196401A1

EP1196401A1 - Method for producing 2-aminomethyl-4-cyano-thiazol

Info

Publication number: EP1196401A1
Application number: EP00947968A
Authority: EP
Inventors: Thomas Pfeiffer
Original assignee: BASF SE
Current assignee: Abbott GmbH and Co KG
Priority date: 1999-07-23
Filing date: 2000-07-11
Publication date: 2002-04-17
Also published as: PL355110A1; JP2003505454A; BG106333A; AU6157900A; JP2006219498A; TR200200183T2; HK1048470A1; WO2001007425A1; KR20020022781A; DE19933861A1; CA2380084C; NO20020327L; SK1052002A3; BR0012651A; NO20020327D0; HUP0202109A2; CA2380084A1; CN1364163A; JP4027092B2; MXPA02000716A

Abstract

The present invention relates to a method for producing 2-aminomethyl-4-cyano-thiazol and salts thereof of general formulae (Ia) and (Ib) where n is 1 or 2; when n is 1, then X is chloride, bromide, triflate and hydrogen sulphate; and when n is 2, then X is sulphate. The method involves stirring thioamide of formula (IV) with a bromopyruvic acid ester of formula (V), in which R1 is a linear or branched C¿1-4?, in a R?2¿OH alcohol, wherein R2 is a linear or branched C¿1-8? alkyl, HO-CH2-CH2-, HO-CH2-CH2-CH2- or C1-4 alkyl-O-CH2-CH2-. Said stirring process is carried out at a temperature of -5° C to 40° C until the reaction of the thioamide of formula (IV) is practically complete. This invention also relates to the compounds of formulae (Ia) and (Ib).

Description

Process for the preparation of 2-aminomethyl-4-cyano-thiazole

description

The present invention relates to a new process for the preparation of 2-aminomethyl-4-cyano-thiazole.

The synthesis of 2-aminomethyl-thiazoles which have a functional group in the 4-position, e.g. containing a carboxylic acid, a carboxylic acid ester, a carboxylic acid amide or a carboxylic acid thioamide is described in the literature; Literature (1): J.-L. Bernier, R. Houssin, J.-P. Henichart, Tetrahedron 42, 2695, 1986; Literature (2): U. Schmidt et al. Synthesis 233, 1987; Literature (3): G. Jung et al. Angew. Chem. Int. Ed. 35, 1503, 1996; Literature (4): WO 9806741; Literature (5): Kenner et al. J. Chem. Soc. 2143, 1963.

The processes known from the literature are described for small laboratory batches and are not well suited for some reaction steps for production on an industrial scale. For example, in the literature (2) describes the synthesis of the 4-ethoxycarbonyl-thiazole derivative using a Z protective group (Z = benzyloxycarbonyl). However, after the conversion to the Z-protected 2-aminomethyl-4-cyano-thiazole from the corresponding carboxamide after the methods known from the literature (for example hydrogenolytically or with HBr), the Z protective group can no longer be split off on an industrial scale with the cyano group being completely retained ,

The 2-benzamidomethyl-4-ethoxycarbonyl-thiazole described in literature (5) is also unsuitable after further conversion to the corresponding benzoyl-protected 4-cyano-thiazole for cleavage of the protective group while completely retaining the cyano group.

The structure of the 4-hydroxycarbonyl-thiazole derivative with the BOC protective group (BOC = ter. Butyloxycarbonyl) is described in literature (3), which can be eliminated with the cyano group being completely retained. On the other hand, a precursor to the thiazole derivative, namely the N-BOC-glycinthioamide from the BOC-glycinamide, is carried out using the Lawesson reagent, which when used on an industrial scale compared to the method described in literature (2) with hydrogen sulfide has a significantly higher financial disadvantage would mean. The Lawesson reagent is also used in literature (1). The authors of the literature (3) describe the cyclization to the 4-carboxylic acid of thiazole using bromopyruvic acid. This route is also possible on an industrial scale, but has the disadvantage that the bromopyruvic acid is more unstable than the ethyl bromopyruvate used in literature (1), (2) and (5) and the thiazolecarboxamide only by the route of the thiazolecarboxylic acid with a larger one technical effort can be produced. In addition, the yield of the thiazole carboxylic acid using CaC0 ₃ , as described in literature (3), could not be achieved on a larger scale.

The preparation of the thiazolecarboxylic acid ethyl ester was very incomplete according to the procedure described in literature (1) with ethyl bromofruvate in diethyl ether. Instead of the specified reaction time of 3 h, even after 20 h, the starting material (thioamide) was only partially reacted based on our own investigations. The desired thiazolecarboxylic acid ethyl ester was formed in addition to a number of secondary components, but the stated yield could not be achieved in any experiment.

The procedure for cyclization to the thiazolecarboxylic acid ester described in literature (2) could also not be used successfully. The use of ethanol at 65 ° C in the presence of molecular sieves led to a rapid cleavage of the BOC protective group due to the formation of HBr. Even at 40 ° C in ethanol as well as with other alcohols (e.g. methanol or isopropanol) the regulation from literature (2) could not be realized with yields> 70%. The addition of basic solution also did not lead to higher yields.

2-Aminomethyl-4-cyano-thiazole would be interesting as an intermediate for the production of serine protease-inhibiting, low-molecular substances (e.g. thrombin inhibitors), if it were technically easily accessible. Such thrombin inhibitors are e.g. mentioned in WO 9806741. In addition, the 2-aminomethyl-4-cyanothiazole can be used for the production of further thrombin inhibitors and their prodrugs, such as e.g. N- (Ethoxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl- [2- (4-hydroxyamidino) thiazole] methylamide hydrochloride.

An object of the invention is to provide a process for the preparation of 2-aminomethyl-4-cyanothiazole, as a result of which this synthesis building block is available in a cost-effective manner for further syntheses. It has surprisingly been found that the cyclization of the thioamide with the bromopyruvic acid ester is possible without addition of bases and without addition of molecular sieve in alcohol at room temperature with a yield of almost 90%. The yield is strongly dependent on the dilution of the starting materials in alcohol and reaches its maximum after a reaction time of about 5 h. The reaction in alcoholic solution is preferably carried out in a concentration range of less than 0.75 mol / 1 based on thioamide (IV). A concentration of over 0.25 mol / 1 to 0.55 mol / 1 based on IV is particularly preferred. At concentrations of 1 mol / 1, the reaction no longer proceeds with satisfactory yields. According to the invention, the reaction temperature is in the range from -5 ° C. to 40 ° C., preferably in the range between 5 ° C. and 30 ° C., in particular at 10 ° C. to 25 ° C. At 65 ° C, as in literature (2), no or hardly BOC-protected thiazolecarboxylic acid ester can be isolated after less than 5 h, even at higher dilution. In the series of alcohols, higher yields could be achieved with iso-propanol than with methanol. Small amounts of water do not interfere with the cyclization, so that dehydrating agents such as molecular sieves can advantageously be dispensed with.

The aminolysis of the thiazolecarboxylic acid ester with aqueous ammonia to give the thiazolecarboxamide was equally surprising. A reaction could only be observed when more than two molar equivalents of NH _{3 were added} . An excess of at least 5 molar equivalents of NH ₃ , in particular values of at least 10 molar equivalents of NH, is preferred. Alcohol can also be used as a solubilizer. In the alcohol series, however, the yields with methanol were higher than with isopropanol.

The thiazolecarboxylic acid ester can be obtained in crystalline form. To remove the solvent, it is necessary to trap the HBr with bases. Dilute sodium hydroxide solution or ammonia can be used for this purpose under pH control. By hydrolysis of the ester with e.g. Sodium hydroxide solution and subsequent pH-controlled addition of acid can also be used in this way to produce the corresponding BOC-protected thiazolecarboxylic acid easily and with good yields.

For synthesis on an industrial scale, it is advantageous to prepare the thiazolecarboxamide in a one-pot process without isolating the ester. Starting from the thioamide, a yield of> 60% of crystalline amide can be produced with little technical effort. The conversion to 2-aminomethyl-4-cyano-thiazole can then easily be carried out by dehydration with, for example, trifluoroacetic anhydride and subsequent mild cleavage of the BOC protective group. The present invention relates to a process for the preparation of 2-aminomethyl-4-cyano-thiazole and its salts of the formulas Ia and Ib,

(Ia) (Ib) in which n = 1 or 2 and for n = 1 X means chloride, bromide, triflate and hydrogen sulfate and for n = 2 X means sulfate,

which by introducing the tert. Butyioxycarbonyl protective group (BOC) on the nitrogen of the aminoacetonitrile, a subsequent addition of hydrogen sulfide on the nitrile group, the cyclization of this N-BOC-glycine-thioamide with bromopyruvic acid ester according to Scheme A to the corresponding thiazole-4-carbonate ester, from there can be converted to the thiazole-4-carboxamide and ultimately to the 4-cyano-thiazole derivative.

Scheme A describes an advantageous, technically easy to carry out process:

Scheme A

BOC O H _S

HY H-N ", CN __. BOC-NH _CN »BOC-NH

NH "

(II) (III) (IV)

COOR ¹

Br R2θH

O (V)

The aminoacetonitrile II is commercially available as a salt (sulfate, hydrogen sulfate, chloride) or as a free base. The intermediate compounds III to VII are mentioned in references (1) and (3) (V and VI each as ethyl ester). The 4-cyano-thiazoles VIII and IX are new.

The intermediate compounds III, VI and VIII can advantageously be converted into the respective secondary product by this process, without further workup.

The 4-cyano-thiazole salt IX, which is contained in the general formula Ia, can be reacted with bases to the salt-free form of the formula Ib under pH-controlled conditions.

The invention further relates to processes for the preparation of 2-aminomethyl-4-cyano-thiazole and its salts of the formulas Ia and Ib

in which n = 1 or 2 and for n = 1 X chloride, bromide, triflate and hydrogen sulfate and for n = 2 X sulfate. In the process according to the invention, the thioamide of the formula IV

BOC-NH

NH "(IV) with a bromopyruvic acid ester of the formula V,

COOR ¹

Br (V) in which R ^{1 is} branched or linear Cι_ ₄ alkyl, in an alcohol R ² 0H, in which R ^{2 is} branched or linear Cι_ ₈ alkyl, H0-CH ₂ -CH ₂ -, H0-CH ₂ -CH ₂ -CH ₂ - or Cι_ ₄ alkyl-0-CH ₂ -CH ₂ - means, stirred at 5 ° C to 40 ° C until the reaction of thioamide IV is substantially complete.

In addition, according to the invention, the thiazole carboxylic acid ester of the formula VI,

wherein R ^{1 is} branched or linear Cι_ ₄ alkyl, are stirred until essentially complete reaction in an alcohol R ² 0H at 0 ° C to 40 ° C with 5 to 50 molar equivalents of NH ₃ an aqueous ammonia solution.

The process according to the above steps can be carried out without isolating intermediate VI.

The thiazolecarboxamide of the formula VII

can be filtered off as a solid.

Furthermore, the amide VII to the BOC-protected 4-cyano-thiazole of the formula VIII

dehydrated and the BOC protective group split off.

The invention further relates to a process for the preparation of the compound of the formula VI

wherein the thioamide of formula IV s

BOC-NH

NH ₂ < ^IV > with a bromopyruvic acid ester of the formula V,

in which R ^{1 is} branched or linear C ₄ alkyl, in an alcohol R ² OH, in which R ^{2 is} branched or linear C 1 -alkyl,

HO-CH ₂ -CH ₂ -, HO-CH ₂ -CH ₂ -CH ₂ - or Cι_ ₄ -alkyl-0-CH ₂ -CH ₂ - means at 5 ° C to 40 ° C until the reaction is essentially complete of the thioamide IV is stirred. If necessary, in the preparation of the compound of formula VII

the thiazolecarboxylic acid ester of the formula VI formed in accordance with the previous process,

wherein R ^{1 is} branched or linear Cι_ ₄ alkyl, stirred until essentially complete reaction in an alcohol R ² 0H at 0 ° C to 40 ° C with 5 to 50 molar equivalents of NH ₃ an aqueous ammonia solution.

Alternatively, one proceeds in the preparation of a compound of formula VI

so that after reaction of the thioamide of formula IV

BOC-NH

NH "(IV) 0.9 to 3 molar equivalents of a base, for example an A in, an alkali metal carbonate, alkali metal bicarbonate or alkali metal hydroxide is dissolved in water or undissolved, and after adding water, if necessary, as much of the solvent R ² 0H is distilled off until the ester VI begins to precipitate; if necessary, the mixture is cooled by cooling the mixture and further addition of water, and the thiazolecarboxylic acid ester is filtered off.

Furthermore, the reaction of the thioamide of the formula IV

with the Brombrentraubensäureester of formula V

_{/ \} OOR ¹ ^Br ^ Y (V)

O in the solvent R ² 0H, in which R ^{2 is} preferably C ₅ alkyl, in the presence of 1 to 3 mol equivalents of solid alkali metal bicarbonate and are worked up as described above.

The process can also be carried out so that in the preparation of a compound of formula VII,

after the implementation of the thioamide of formula IV s

BOC-NH

NH "(IV) 1 to 5 molar equivalents of NH ₃ is added to the solvent in the form of an aqueous ammonia solution, 30% to 60% of the alcohol R ² 0H, where R ^{2 is} preferably C ₅ alkyl, distilled off, another 5 to 50 Mol equivalent NH ₃ in the form of the aqueous ammonia and the resulting thiazolecarboxamide is filtered off, if necessary after cooling the mixture.

The invention further relates to compounds of the formulas Ia and Ib,

in which n = 1 or 2 and for n = 1 X means chloride, bromide, triflate and hydrogen sulfate and for n = 2 X means sulfate,

and compound of formula X

wherein R ^{3 is} a benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl,

Trifluormethylacetyl-, acetyl or benzoyl radical means.

Preparation of the interconnections and the final product: example 1

Preparation of 2-aminomethyl-4-cyano-thiazole hydrochloride and 2- (N-tert. Butyloxycarbonyl-aminomethyl) -4-cyano-thiazole:

a) Boc-2-aminomethyl-thiazole 4-carboxamide

At a temperature of 10 ° C., pyruvic acid ethyl ester (386 g, 1.98 mol) was added dropwise to a solution of Boc-Glycinthioa id (370 g, 1.94 mol) in 3.9 liters of ethanol and then for 5 h at 20 to Stirred at 25 ° C. Then 299 ml of a 25% aqueous ammonia solution were added.

380 ml of ethanol were distilled off from 940 ml of this mixture (corresponds to 19.9% of the total volume), a further 908 ml of a 25% strength aqueous ammonia solution were added and the mixture was stirred at 20 to 25 ° C. for 110 h. The mixture was cooled to 0 ° C., the solid was filtered off, washed twice with water and dried. 60.1 g of the BOC-protected thiazolecarboxamide with an HPLC purity of 97.9 area% were obtained, which corresponded to a yield of 60.5% over these two stages.

ⁱ H-NMR (DMSO-d ⁶ , in ppm): 8.16 (s, 1H, Ar-H), 7.86 (t, broad, 1H, NH), 7.71 and 7.59 (2x s , broad, each 1H, NH ₂ ), 4.42 (d, 2H, CH ₂ ), 1.41 (s, 9H, tert.butyl)

b) 2-aminomethyl-4-cyano-thiazole hydrochloride

Boc-2-aminomethyl-thiazole 4-carboxamide (75.0 g, 0.29 mol) were suspended in 524 ml of methylene chloride and at -5 to 0 ° C. with triethylamine (78.9 g, 0.78 mol) and 79 , 5 g (0.38 mol) of trifluoroacetic anhydride. The mixture was stirred for 1 h, the mixture was allowed to warm to 20-25 ° C., 1190 ml of water were added and the phases were separated. 160 ml of 5 to 6 N isopropanolic hydrochloric acid were added to the organic phase, the mixture was heated to boiling for 3 h, allowed to stir at 20 to 25 ° C. overnight, cooled to -5 to 0 ° C. for 2.5 h and the solid was filtered off , This was washed with methylene chloride and dried. 48.1 g of 2-aminomethyl-4-cyano-thiazole were obtained with an HPLC purity of 99.4 area%, which corresponds to a yield of 94.3% over these two stages.

^ - R (DMSO-d ⁶ , in ppm): 8.98 (s, broad, 2H, NH ₂ ), 8.95 (s, 1H, Ar-H), 4.50 (s, 2H, CH ₂ ) Example 2

Preparation of 2- (N-tert.butyloxycarbonylaminomethyl) -4-cyano-thiazole:

The BOC-protected 2-aminomethyl-4-cyano-thiazole was isolated from another synthesis approach with an almost quantitative yield in accordance with the previously described synthesis instructions.

ⁱ H NMR (DMSO-d ⁶ , in ppm): 8.75 (s, Ar-H), 7.90 (t, broad, NH), 4.42 (d, CH ₂ ), 1.40 ( s, tert.butyl)

Example 3

Preparation of 2- (N-tert.butyloxycarbonylaminomethyl) -4-ethoxycarbonylthiazole:

Method A:

To 5.0 g (24.2 mmol) of thioamide in 47 ml of isopropanol were added 24.6 mmol of ethyl bromopyruvate at 20 to 25 ° C. and the mixture was stirred for 5 hours. Then 24.0 mmol of NaOH as 20% sodium hydroxide solution were added, the product was extracted with methyl tert-butyl ether, the organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate and the solvent was stripped off completely. 6.2 g of the thiazolecarboxylic acid ethyl ester were obtained, which corresponds to a yield of 89.6%.

ⁱ H-NMR (DMSO-d ⁶ , in ppm): 8.41 (s, 1H, Ar-H), 7.86 (t, broad, NH), 4.41 (d, 2H, CH ₂ ), 4.30 (q, 2H, CH ₂ ), 1.40 (s, 9H, tert.butyl), 1.30 (t, 3H, CH ₃ )

Method B:

To 200 g (1.05 mol) of thioamide in 2.0 l of ethanol and 105 g of KHC0 ₃ powder, 1.07 mol of ethyl bromopyruvate were added at 20 ° to 25 ° C. and the mixture was stirred overnight. Then 225 ml of water and 50 g of 20% sodium hydroxide solution were added, about 600 ml of ethanol were distilled off, 500 ml of water were added and the mixture was cooled to 0.degree. The precipitated solid was filtered off and dried. 246 g of ethyl thiazole carboxylate were obtained, which according to NMR was clean. This corresponds to a yield of 81.7%. Example 4

Preparation of 2- (N-benzyloxycarbonylaminomethyl) -4-cyano-thiazole: 5

To 110 g (0.38 mol) of Z-protected (Z = benzyloxycarbonyl) 2-aminomethyl-4-aminocarbonyl-thiazole in 1.1 liters of dichloromethane were added 101 g of triethylamine and 103 g of trifluoroacetic anhydride at -5 to 0 ° C. , After stirring for 1 h, the mixture was warmed to 20 to 10 25 ° C. and stirred overnight. The organic phase was extracted twice with 1760 ml of water, dried over sodium sulfate and the solvent was stripped off completely. This gave 102.9 g of the approximately 95% product, which corresponds to a yield of approximately 94%.

15 ⁱ H-MR (DMSO-d6, in ppm): 8.77 (s, IH, Ar-H), 8.32 (t, broad, NH), 7.43 - 7.20 (m, 5H, Ar-H), 5.10 (s, 2H, OCH ₂ ), 4.52 (d, 2H, CH ₂ )

Example 5

Preparation of N- (ethoxycarbonylmethylene) - (D) -cyclohexylalanyl- ⁰ 3, 4-dehydroprolyl- [2- (4-hydroxyamidino) thiazole.methylamide hydrochloride

The 2-aminomethyl-4-cyano-thiazole hydrochloride obtained under b) in Example 1 is further processed as follows: 5 c) 3, 4-dehydroprolyl- [2- (4-cyano) -thiazolmethyl] amide hydrochloride

2-Aminomethyl-4-cyano-thiazole hydrochloride (64 g, 364 mol) was added to a solution of Boc-3,4-dehydroproline (77.5 g, 349 mmol) in methylene chloride (150 ml). While stirring, diisopropylethylamine (157 g, 1.2 mol) was added dropwise to the suspension at temperatures from 0 to 10 ° C. Propane-5-phosphonic anhydride (50% in ethyl acetate, 290 g, 456 mmol) was then added dropwise at a temperature of -2 to -5 ° C. in 2 h. After 13 h, the mixture was heated to 20 ° C. and 240 ml of methylene chloride and then 310 ml of water were added. The organic phase was separated off, the aqueous phase was washed with 200 ml of methylene chloride and the organic phases were combined. The collected organic phases were mixed with 200 ml of water and the pH with conc. Hydrochloric acid adjusted to pH 3. The organic phase was separated again and then washed with 200 ml of water. The solvent of the organic phase was distilled off and the residue was taken up in 860 ml of isopropanol. 140 ml (about 2 molar equivalents) of isopropanolic hydrochloric acid were added and the mixture was heated to 40 to 45 ° C. After approx The deprotection was complete for 12 hours (DC control). A further 140 ml of isopropanol were added and the solution was heated to 80 ° C. for one hour. The mixture was then slowly cooled to 0 ° C. and stirred at 0 ° C. for 18 hours, the title compound precipitating out as a salt. The product was filtered off and the crystals were washed with pre-cooled isopropanol and then with diisopropyl ether. 680 g (yield 72%) of the title compound were isolated as a white crystalline product.

N- (tert. Butoxycarbonylmethylene) - (Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl- [2- (4-cyano) thiazole] methylamide

To a solution of N- (tert. Butoxycarbonylmethylene) - (Boc) - (D) -cyclohexylalanine (description described in WO 9806741; 79 g, 206 mmol) in methylene chloride (640 ml) was 3, 4-de-hydroprolyl - [2- (4-cyano) thiazole ethyl _. mid hydrochloride (59 g, 218 mmol) was added. Diisopropylethylamine (112 g, 867 mmol) and propanephosphonic anhydride solution (50% strength in ethyl acetate, 193 g, 303 mmol) were added dropwise at 0 to 10 ° C. The reaction was monitored by TLC. After the reaction was complete, the solution was warmed to room temperature and 180 ml of water were added. The pH of the mixture was conc. Hydrochloric acid adjusted to pH 3. The organic phase was separated and the aqueous phase extracted again with 120 ml of methylene chloride. The combined organic phases were washed with a further 170 ml of water at pH 3 and then washed with 170 ml of water, dried over magnesium sulfate and the solvent was distilled off in vacuo. 117 g (90% yield) of the title compound were obtained as a colorless solid.

N- (tert-Butoxycarbonylmethylene) - (Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl- [2- (4-hydroxyamidino) thiazole.methylamide

N- (tert-Butoxycarbonylmethylene) - (Boc) - (D) -cyclohexylalanyl-3, 4-dehydroprolyl- [2- (4-cyano) thiazole] methylamide (22.2 g, 36.7 mmol) dissolved in ethanol (250 ml), mixed with hydroxylamine hydrochloride (6.41 g, 92.2 mmol) and slowly added to this suspension with cooling (water bath) diisopropylethylamine (23.8 g, 31.6 ml, 184, 5 mmol) added dropwise. After 3 hours of stirring at room temperature, the reaction solution was evaporated in vacuo, taken up in methylene chloride / water, the aqueous phase was adjusted to pH 3 with 2N hydrochloric acid and extracted. The organic phase was washed several times with water, dried over magnesium sulfate and evaporated in vacuo. The residue was extracted with n-hexane, whereby 22.5 g of the title compound were obtained as an almost pure white solid.

N- (Ethoxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydro-prolyl- [2- (4-hydroxyamidino) thiazole] methylamide hydrochloride

N- (tert-Butoxycarbonylmethylene) - (Boc) - (D) -cyclohexylalanyl-3,4-dehydroprolyl- [2- (4-hydroxyamidino) thiazole methylamide (2.0 g, 3.15 mmol) were in ethanol (25 ml) dissolved, mixed with 10 ml of 5N hydrochloric acid in ether and stirred at 60 ° C for 3 h.

Since, according to TLC (methylene chloride / methanol / acetic acid: 100/20/5), the conversion was not yet complete, 10 ml of 5N hydrochloric acid in ether were added and the mixture was stirred again at 60 ° C. for 3 h. After the reaction mixture had been spun in in vacuo, the mixture was co-distilled several times with ethanol and ether in order to remove adhering hydrochloric acid. The product was then dissolved in a little methylene chloride, precipitated with ether, the residue was filtered off with suction and dried in vacuo. 1.65 g of the title compound were obtained as a white, hygroscopic solid. FAB-MS (M + H ⁺ ): 507

Claims

claims

1. Process for the preparation of 2-aminomethyl-4-cyano-thiazole and its salts of the formulas Ia and Ib

(Ia) (Ib) in which n = 1 or 2 and for n = 1 X is chloride, bromide, triflate and hydrogen sulfate and for nn == 22 XX is sulfate, comprising the process step in which the thioamide of the formula IV

BOC-NH

NH "(IV) with a bromopyruvic acid ester of the formula V,

__ ~. .COOR ¹ ^Br ^ T 00 o in which R ^{1 is} branched or linear C ₄ alkyl, in an alcohol R ² 0H, in which R ^{2 is} branched or linear Ci-s-alkyl, HO-CH ₂ -CH ₂ -, HO-CH ₂ - CH ₂ -CH ₂ - or Cι- ₄ alkyl- 0-CH ₂ -CH ₂ - means, is implemented at -5 ° C to 40 ° C.

2. The method according to claim 1, wherein the resulting thiazole carboxylic acid ester of the formula VI,

wherein R ^{1 is} branched or linear Cι_ ₄ alkyl, is reacted in an alcohol R ² 0H at 0 ° C to 40 ° C with 5 to 50 molar equivalents of NH ₃ an aqueous ammonia solution.

3. The method according to claims 1 and 2, wherein the two process steps are carried out without isolation of the intermediate VI.

4. The method according to any one of claims 1 to 3, wherein the thiazolecarboxamide of the formula VII

is filtered off as a solid.

5. The method according to any one of claims 1 to 4, wherein the amide VII subsequently to the BOC-protected 4-cyano-thiazole

Formula VIII

dehydrated and the BOC protecting group is split off.

6. Process for the preparation of the compound of formula VI

wherein the thioamide of formula IV

BOC-NH (IV)

NH "with a bromopyruvic acid ester of the formula V,

_ ^ \ .COOR ¹ ^Br Tf ^ (V)

O in which R ^{1 is} branched or linear C ₄ alkyl, in an alcohol R ² OH, in which R ^{2 is} branched or linear Ci-s-alkyl, HO-CH ₂ -CH ₂ -, HO-CH ₂ -CH ₂ -CH ₂ - or Cι- ₄ alkyl 0-CH ₂ -CH ₂ - means, is implemented at -5 ° C to 40 ° C.

7. Process for the preparation of the compound of formula VII

according to claim 6, wherein the thiazole carboxylic acid ester of the formula VI,

wherein R ^{1 is} branched or linear Cι_ ₄ alkyl, in an alcohol R ² OH at 0 ° C to 40 ° C with 5 to 50 molar equivalents of NH ₃ is reacted with an aqueous ammonia solution.

8. The method according to any one of claims 1 to 7, wherein in the preparation of a compound of formula VI,

after implementation of the thioamide of formula IV

S

BOC- H ^ x ^ _(IV) the solvent 0.9 to 3 molar equivalents of a base in

Water is added or dissolved undissolved, and after addition of water, if appropriate, enough of the solvent R ² OH is distilled off until the ester VI begins to precipitate, if necessary, the precipitation can be completed by cooling the mixture and further addition of water and the thiazolecarboxylic acid ester can be filtered off.

9. The method according to any one of claims 1 to 7, wherein the reaction of the thioamide of the formula IV

with the Brombrentraubensäureester of formula V

_ / _{\ /} COOR ¹ ^Br ^ (V) o in the solvent R ² OH, where R ^{2 is} preferably C ₂ _ ₅ alkyl, in the presence of 1 to 3 mol equivalents of solid alkali metal bicarbonate and worked up as described above becomes.

10. The method according to any one of claims 1 to 9, wherein in the preparation of a compound of formula VII,

after the implementation of the thioamide of the formula IV s BOWMH .. ^ _(IV) 1 to 5 molar equivalents of NH ₃ is added to the solvent in the form of an aqueous ammonia solution, 30% to 60% of the alcohol R ² OH, where R ^{2 is} preferably C ₅ alkyl, distilled off, another 5 to 50 molar equivalents of NH _{3 is added} in the form of the aqueous ammonia and the thiazolecarboxamide which precipitates is filtered off, if appropriate after the mixture has cooled.

11. Connection of the formulas Ia and Ib,

(Ia) (Ib) in which n = 1 or 2 and means for n = 1 X chloride, bromide, triflate and hydrogen sulfate and for n = 2 X means sulfate.

12. Compound of formula X

wherein R ^{3 is} a benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, trifluoromethylacetyl, acetyl or benzoyl radical.