KR100403950B1 - Process for preparing 5-aminomethyl-2-thiophenecarbonitrile·HCl - Google Patents

Abstract

The present invention provides a novel method for effectively synthesizing a compound of formula 6, which is an important intermediate of oral anticoagulants (Thrombin Inhibitor):

[Formula 6]

According to the method of the present invention, the intermediate of the anticoagulant can be obtained in high yield.

Description

Process for preparing 5-aminomethyl-2-thiophenecarbonitrile hydrochloride {Process for preparing 5-aminomethyl-2-thiophenecarbonitrileHCl}

The present invention relates to a novel process for preparing 5- (aminomethyl) -2-thiophencarbonitrile hydrochloride of formula (6).

[Formula 6]

The compound of formula 6 is an important oral constituting the N-terminal group of the raw pharmaceutical material (domestic application number: KR1998-0060266, KR1999-0033490, WO 00/39124) that is being developed as a new oral anticoagulant (thrombin inhibitor) It is part of the compound (PCT / US95 / 02558, WO 95/23609), which is not only part but also usefully used for the development of blood clotting prevention and thrombosis treatment in other mammals. Accordingly, there is a growing interest in preparing the above formula (6).

In Korean Patent Application Nos. 1998-0060266 and 1999-0033490, a method for preparing compound (6) is shown as in Scheme 1.

Scheme 1

In Scheme 1, compound (3) is brominated with NBS (N-bromosuccinimide) and benzoyl peroxide, followed by iminodicarboxylic acid di-t-butyl ester [(Me ₃ COCO) ₂ NH] is added 1.1 equivalents to Compound (4), 1.2 equivalents of 60% NaH at low temperature is added thereto, the mixture is stirred at room temperature while distilled under reduced pressure, and volatiles are removed. The obtained compound (7) is passed through hydrochloric acid gas to form hydrochloride of the primary amine. At this time, the desired solvent (6) can be obtained as a solid by distilling the reaction solvent to about 1/4 in volume ratio, and then adding crystals to diethyl ether. However, this reaction has the disadvantage that the price of iminodicarboxylic acid di-t-butyl ester [(Me ₃ COCO) ₂ NH] is too expensive. This may be a problem for mass production in future product development.

In order to solve the above problems, the present inventors have diligently studied to find out that the compound of Formula 6 can be produced in high yield without using the iminodicarboxylic acid di-t-butyl ester. The invention has been completed.

Therefore, an object of the present invention is to prepare a compound of formula 5 by azide-comprising the compound of formula 4 obtained by bromination of the compound of formula 3, and then after iminophosphorane (Staudinger Reaction) It is to provide a method for preparing a compound of formula 6 by hydrolysis:

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

The preparation method of the present invention comprises azide-forming a compound of Formula 4 and hydrolyzing the azide compound by iminophosphoran production reaction.

In the azide reaction, the azide compound used as the azide agent may be a compound having N ₃ ^- ions, an example of which is a metal salt of azide. For example, NaN ₃ , KN _3, etc. can be mentioned.

The reaction solvent is selected from the group consisting of dimethylformamide, benzene and carbon tetrachloride, and in order to facilitate the progress of the reaction, an optional phase transfer catalyst may be used.

As the phase transfer catalyst, quaternary ammonium compounds such as benzyltriethylammonium chloride, tetrabutylammonium bromide, methyltrioctylammonium chloride or hexadecyltrimethylammonium chloride are used. These quaternary ammonium compounds have large organic groups and are soluble in both water and organic solvents. For NaN ₃ reaction Na ⁺ N ₃ ^- is dissolved in the aqueous layer, since there insoluble organic layers, reacted with quaternary ammonium compounds (tetrabutylammonium bromide when Na ⁺ N ₃ of the water ^layer-is Bu ₄ N ⁺ N ₃ ^- the organic layer was formed to move to the N ₃ ^- go to that the reaction), the organic layer may be formed of the reaction.

When the iminophosphoran production reaction is carried out from the azide compound represented by the formula (5), the reaction can be promoted by reacting in the presence of triphenylphosphine (PPh ₃ ). In this case, Pd / C in the presence of H ₂ may be used instead of triphenylphosphine, but may be unsuitable in a large-scale process due to a problem of treating N ₂ generated during the reaction.

In the present invention, the abbreviations used throughout the specification are as follows:

Ac: Acetyl group

NBS: N-bromosuccinimide

AIBN: 2,2'-azobis (2-methylpropionitrile)

Ph: Phenyl

Et: ethyl

Me: methyl

EA: ethyl acetate

MDC: methylene chloride

Boc: Butoxycarbonyl

THF: tetrahydrofuran

Hereinafter, the present invention can be represented by the following scheme 2 as an example.

Scheme 2

The reaction conditions of Scheme 2 are summarized as follows.

After dissolving the compound (3) in cyclohexane, benzene or carbon tetrachloride, the mixture is heated and mixed with 0.9 equivalent of NBS and 0.01 equivalent of AIBN [2,2-azobis (2-methylpropionitrile)]. In this case, 0.9 equivalents of NBS and 0.01 equivalents of AIBN are used, and the reaction temperature can be up to 60 to 85 ° C. depending on the solvent. The bromo compound (4) thus obtained is obtained by fractional distillation. The azido compound (5) can be obtained by dissolving bromo compound (4) in DMF (N, N-dimethylformamide) solvent and then adding sodium azide (NaN ₃ ) dissolved in water dropwise at room temperature. After the reaction solvent was distilled under reduced pressure, tetrahydrofuran (THF) solvent was added to Compound (5), and 1.0 equivalent of triphenylphosphine (PPh ₃ ) was added in small portions at a temperature not exceeding 30 ° C, followed by stirring at room temperature. After stirring, water was added and heated to 50 ° C. At this time, the amount of triphenylphosphine can be up to 1.0 to 1.5 equivalents, and the heating temperature can be varied from 50 to 150 ° C. depending on the soluble solvent. The compound thus obtained may be treated with an acid group followed by hydrochloric acid aqueous solution to obtain compound (6) of Scheme 1 as a solid.

On the other hand, the compound of formula 3 used as a starting material can be used as it is commercially available, to prepare a compound of formula 2 by bromination of the compound of formula (1), and can be used to prepare a cyanation again:

[Formula 1]

[Formula 2]

The manufacturing method of the present invention can be carried out by integrating the above steps.

An example of a process for preparing a compound of Formula 3 is shown in Scheme 3:

Scheme 3

Specifically, Reaction Scheme 3 will be described. First, in the first reaction, chloroform and acetic acid, which are reaction solvents, are first added, and then the amount of NBS (N-bromosuccinimide) is 0.94 equivalents to Compound (1), and the temperature increases. It is a reaction, so it needs attention. In this step, by using NBS instead of bromine, there is an advantage of suppressing the occurrence of position-selective isomers in which bromine is substituted at the 3 position. At this time, when NBS input is completed, the temperature is raised to 50 ° C from room temperature. The second reaction to make compound (3) using 1.18 equivalents of CuCN and stirred for 6 hours at 160 ℃ reaction temperature. After the reaction was completed, ammonia water was added and air was stirred for 14 hours. At this time, attention is required because it is difficult to process the remaining CuCN after the reaction, the desired compound (3) can be obtained through the vacuum distillation.

In preparing the compound (3) in the compound (2) during the reaction process, Zn (CN) ₂ + PdCl ₂ (PPh ₃ ) ₂ , or Zn (CN) ₂ + Pd (PPh ₃ ) ₄ is used instead of CuCN. Can be reacted. However, in this case, the reaction is not better than that of CuCN.

Hereinafter, the present invention will be described in detail with reference to Examples, but these Examples do not limit the technical scope of the present invention.

Example 1: Preparation of 2-bromo-5-methylthiophene (2)

49.0 g (0.50 mol) of 2-methylthiophene (1) was added to a mixture of 300 mL of chloroform and 300 mL of acetic acid. While stirring at room temperature, 86.2 g (0.47 mol) of NBS was slowly added thereto (exothermic reaction: 2340 ° C.). After heating to 50 ° C. and stirring for 3 hours, 600 mL of water was added and the organic layer was separated. The separated organic layer was washed with 300 mL of 2 N KOH and 300 mL of water, and then the organic layer was separated. The separated organic layer was dried over MgSO ₄ , filtered and concentrated to give 83.0 g (yield: 93.8%) of 2-bromo-5-methylthiophene (2).

¹ H NMR (CDCl ₃ ) δ 6.81 (d, 1H), 6.51 (m, 1H), 2.43 (s, 3H)

FAB MS: 178 [M + 1] ⁺

Example 2: Preparation of 5-methyl-2-thiophencarbonitrile (3)

58.0 g (0.33 mol) of 2-bromo-5-methylthiophene (2) was dissolved in 170 mL of DMF, and then 35.2 g (0.39 mol) of CuCN was added thereto, and the mixture was stirred at 160 ° C. for 6 hours. After the reaction was completed, 300 mL of ammonia water was added to the hot reaction solution, and the mixture was stirred for 14 hours while passing through air. The mixture was filtered to remove solids, extracted with 500 mL of Et ₂ O, and then extracted with 200 mL. The combined organic layers were washed with 300 mL of 0.5 N HCl and then 300 mL of water. Drying with MgSO ₄ , filtration, concentration and distillation under reduced pressure yielded 23.5 g (yield: 57.9%) of 5-methyl-2-thiophencarbonitrile (3).

¹ H NMR (CDCl ₃ ) δ 7.43 (d, 1H), 6.77 (d, 1H), 2.55 (s, 2H)

FAB MS: 124 [M + 1] ⁺

Example 3. Preparation of 5-bromomethyl-2-thiophencarbonitrile (4)

35.0 g (0.284 mol) of 5-methyl-2-thiophencarbonitrile (3) is dissolved in 210 mL of benzene. The solution was heated to reflux and a mixture of 45.5 g (0.256 mol) NBS and 4.66 g (0.028 mol) AIBN was added in portions. After 1 hour it was cooled to room temperature and washed with 210 mL of 5% sodium bicarbonate solution and 100 mL of 10% brine. MgSO₄, 5-bromomethyl-2-thiophencarbonitrile (4) 33.1 g (yield: 63.9%) were obtained.

¹ H NMR (CDCl ₃ ) δ 7.47 (d, 1H), 7.10 (d, 1H), 4.64 (s, 2H)

FAB MS: 203 [M + 1] ⁺

Example 4. 5-Aminomethyl-2-thiophencarbonitrile. Preparation of HCl (6).

5-bromomethyl-2-thiophencarbonitrile (4) 214.1 g (1.74 mol) was dissolved in 1.2 L of DMF, followed by NaN₃169.7 g (2.61 mol) to H₂A solution dissolved in 0.4 L of O was added dropwise at room temperature over 0.5 hour. After stirring for 4 hours at room temperature, EtOAc 1.2 L and H₂1.2 L of O was added to the reaction solution. The separated aqueous layer was extracted twice with 1 L of EtOAc and the combined organic layers were washed with 1 L of water. MgSO by separating organic layer₄Dried over, filtered and concentrated under reduced pressure. 1 L of THF was added when the total volume became 1 L and distilled under reduced pressure again, and distillation was stopped when the total volume became 1 L. 1 L of THF is added to the residue, and PPh within the range not exceeding 30 ° C.₃456.4 g (1.74 mol) was added for 1 hour (note that it generates a lot of fever and bubbles every time). After stirring for 1 hour at room temperature₂O313 mL (17.4 mol) was added and heated to 50 ° C. After 3 hours, the mixture was distilled under reduced pressure to remove volatiles, and MDC 2 L was added to the concentrate. After extracting twice with 1 L of 2N HCl, the aqueous layers were collected and washed with 1 L of MDC. The aqueous layer was cooled to 10 ° C. and the pH was adjusted to about 10 by adding NaOH little by little while not exceeding 20 ° C. The aqueous layer was extracted three times with 1 L of MDC. MgSO separated organic layer₄Dry with filtration, remove volatiles, and concentrate Et into concentrate₂O 2 L is added. The reaction solution was cooled and 0.44 L of about 3.8 N HCl EtOAc solution was added little by little to no more than 25 ° C. After stirring for 2 hours at room temperature, the mixture was filtered and the filter cake was washed with Et.₂O was washed with 0.5 L and dried with nitrogen. Dry Mass: 197.3 g (Yield: 64.9%)

¹ H NMR (CD ₃ OD) δ 7.77 (d, 1H), 7.34 (d, 1H), 4.41 (s, 2H)

FAB MS: 139 [M + 1] ⁺

According to the preparation method of the present invention, the intermediate for preparing an anticoagulant may be synthesized from the compound of Chemical Formula 1 in high yield as well as in mass production.

Claims (7)

To azide the compound of formula (4) obtained by bromination of the compound of formula (3) to prepare a compound of formula (5), then iminophosphorane (Stinophosphorane) production reaction (Staudinger Reaction) characterized in that the hydrolysis To prepare a compound of formula [Formula 3] [Formula 4] [Formula 5] [Formula 6] The method of claim 1 wherein the azide agent in the azide reaction is selected from the group consisting of NaN ₃ and KN ₃ . The process according to claim 1, wherein the reaction solvent in the azide reaction is selected from the group consisting of dimethylformamide, benzene and carbon tetrachloride. The process of claim 1 wherein the azide reaction is reacted in the presence of a phase transfer catalyst. The process of claim 4 wherein the phase transfer catalyst is selected from the group consisting of benzyltriethylammonium chloride, tetrabutylammonium bromide, methyltrioctylammonium chloride and hexadecyltrimethylammonium chloride. The method of claim 1 wherein the iminophosphoran production reaction is carried out in the presence of triphenylphosphine. The method according to claim 1, wherein the compound of formula 1 is brominated with a compound of formula 3 to prepare a compound of formula 2, and then cyanated to be used. [Formula 1] [Formula 2]