KR20050059526A - Novel process for preparation of peptide thrombin inhibitor - Google Patents

Abstract

The present invention relates to a novel method for preparing a compound of formula (1), which is a thrombin inhibitor having an excellent antithrombotic effect and high absorption upon oral administration. According to the preparation method of the present invention, the compound of formula (1), which is an anticoagulant, may be prepared by a shorter and more effective synthetic step.

Description

Novel process for preparation of peptide thrombin inhibitor

The present invention relates to a novel preparation method and intermediate for preparing a peptidic thrombin inhibitor represented by the following formula (1), which is very effective in inhibiting thrombogenesis and has high oral absorption. More specifically, a compound of formula (2) is prepared by using a compound of formula (3) (Domestic Application No. 10-2002-0013770) as a starting material, and a compound of formula (1) is prepared using the compound. It is about how to.

[Formula 1]

Conventional methods for preparing compounds of formula (1) are described in WO0039124. However, the method has a disadvantage in that the synthesis process is complicated and the manufacturing process and manufacturing time is long. The present inventors thus prepared a compound of formula (1) in a shorter synthesis step using a novel compound of formula (2). According to the present invention, unlike the prior art, it is possible to prepare a compound of formula (1) while simultaneously removing two protection groups. The compound of formula (2) as an intermediate may be prepared using the compound of formula (3) as a starting material.

Also, the oxadiazolone group of formula (2) may be selected from ClCOOR (R is ethyl, phenyl, 2-ethyl hexyl, etc .; J. Med. Chem., 1992, 35 (20), 3691), COCl ₂ (J. Heterocycl. Chem , 1996, 33 (2), 275), ClCOOCCl ₃ (Sci. Pharm., 2001, 69 (4), 265) or EtOCOOEt (Chim. Ther., 1977, 12, 87) and the like are known. have.

The present invention has been made to solve the above problems of the prior art to prepare a compound of formula (2) using the compound of formula (3) as a starting material, and to use the compound of formula (1) It is an object to provide a process for preparation in short synthetic steps and novel intermediates used therein.

It is an object of the present invention to provide a novel process for preparing a compound of formula (1) comprising the step of hydrogenating a compound of formula (6) to produce a compound of formula (1).

[Formula 1]

Another object of the present invention

a) coupling a compound of formula (2) with a compound of formula (10) to prepare a compound of formula (4);

b) deprotecting the compound of formula (4) to prepare a compound of formula (5);

and c) alkylating the compound of formula (5) with benzyl halo acetate to produce the compound of formula (6).

[Formula 2]

Another object of the present invention

a) reacting a compound of formula (3) with hydroxylamine to produce a compound of formula (7);

b) condensing the compound of formula (7) with a compound of formula (8) to produce a compound of formula (9);

c) preparing a compound of formula (2) by hydrolyzing the compound of formula (9) in the presence of triphenylphosphine, followed by hydrolysis. It is to provide a method for preparing a compound.

[Formula 3]

ClCOOR

In which R is C _1-10 alkyl or phenyl.

Another object of the present invention is to provide novel compounds of formulas (2), (4), (5), (6), (7) and (9), which are used as intermediates in the process. It is.

Hereinafter, the present invention will be described in more detail.

The process for preparing the compound of formula (1) of the present invention is to react the compound of formula (3) with hydroxylamine to prepare the compound of formula (7), which is reacted with formula (8) to 5-oxo-1 To prepare a compound of formula (9) having a 2,4-oxadiazole ring, iminophosphorane (Staudinger Reaction), and then hydrolyzed to prepare a compound of formula (1) A compound of formula (2), which is an important intermediate required, is prepared, which is then subjected to a coupling reaction with a compound of formula (10) (see WO0039124) to prepare a compound of formula (4), Deprotection of the protecting group to prepare a compound of formula (5), and to prepare a compound of formula (6) through an alkylation reaction (hydrogenation) to give a compound of formula (1) It is to provide a method of manufacturing. The above preparation method is shown in Scheme (1).

First, the preparation method of the compound of the formula (2) which is an important intermediate will be described in detail.

First, the compound of formula (3) may be reacted with hydroxyl amine in the same manner as a conventional method (Domestic Application No. 10-2002-0003649) to prepare a compound of formula (7).

The preparation method of formula (2) of the present invention comprises the step of introducing a 5-oxo-1,2,4-oxadiazole ring to the compound of formula (3) and the azide compound of formula (9) It is produced by the reaction to hydrolysis.

Compounds of formula (9) with 5-oxo-1,2,4-oxadiazole ring are prepared by condensation of the amidoxime compound of formula (7) with formula (8) in the presence of a base. In this case, the base used is preferably an organic base such as pyridine or triethylamine.

When the iminophosphoran production reaction is carried out from the azide compound of formula (9), the compound of formula (2) can be prepared by reacting in the presence of triphenylphosphine (PPh ₃ ).

Solvents that can be used in the reactions of the above step may be a solvent selected from the group consisting of aliphatic hydrocarbons, organic chlorine solvents, nitriles and ethers alone, or a mixed solvent in which the selected solvent is mixed with xylene or dioxane. desirable. As the aliphatic hydrocarbon, hexane or heptane is preferably used, and as the organic chlorine solvent, methylene chloride, chloroform, 1,1-dichloroethane, 1,2-dichloroethane 1,1,2-trichloroethane, or Preference is given to using 1,1,2,2-tetrachloroethane, preferably acetonitrile as the nitrile, and dialkyl ether as the ether.

Referring to the production method of the formula (2) according to the present invention in detail, for example as in Scheme (2).

The reaction scheme will be described in detail with the reaction conditions including the amount of each sample, reaction temperature, separation method, and the like.

First, in the first reaction, amidoxime compound (3) using hydroxylamine hydrochloride and triethylamine was used as a starting material compound (3) prepared by the method described in the inventor's previous patent (Domestic Application No. 10-2002-0013770). 7) can be prepared and compound (9) can be obtained by condensation reaction of compound (7) with ethyl chloroformate in the presence of pyridine.

1.0 equivalent of triphenylphosphine (PPh ₃ ) is subdivided into compound (9) at a temperature not exceeding 30 占 폚 and stirred at room temperature. After stirring, an aqueous solution of caustic soda was added and stirred at room temperature. At this time, the amount of triphenylphosphine can be up to 1.0-1.5 equivalents. The compound thus obtained can be treated with a hydrochloric acid solution to obtain the compound of formula (2) as a solid. Methylene chloride was used as solvent in the above reactions.

The process for preparing formula (1) using formula (2) of the present invention provides a compound of formula (4) by coupling a compound of formula (10) with a compound of formula (2), and deprotecting it. To prepare a compound of formula (5), and to alkylate it with benzyl halo acetate to prepare a compound of formula (6), and to hydrogenate it to prepare a compound of formula (1).

Benzylhalo acetate in the reaction is preferably benzylbromo acetate.

In the above reaction, the method of preparing the compound of formula (1) by hydrogenation of the compound of formula (6) is preferably reacted in the presence of hydrogen and Pd / C catalyst.

A method for preparing the compound of formula (1) from the compound of formula (2) according to the present invention will be described in detail with reference to Reaction Scheme (3).

The base used in the coupling reaction of the compound of formula (2) with the compound of formula (10) is 4-methylmorpholine, which is carboxylic by adding ClCOOR (where R is isobutyl or isopropyl). Carboxylic-carbonic anhydride may be prepared by activating the compound of Formula 10 so that the amine of compound 2 is easily added.

Subsequently, the compound of formula (5) is prepared by removing the boc group with hydrochloric acid, followed by alkylation with benzylbromo acetate to prepare the compound of formula (6), which is prepared using Pd / C. The compound of formula (1) can be produced by hydrogenation under a catalyst. As such, the method of preparing formula (1) from the compound of formula (6) according to the present invention has the advantage of removing two protecting groups at the same time.

Descriptions of abbreviations and terms used in the present specification are as follows.

Ph: phenyl

Bn: benzyl

Boc: t-butyloxycarbonyl

TEA: triethylamine

PPh ₃ : triphenylphosphine

EA: ethyl acetate

i-Bu: isobutyl

Br: bromo

Dpa: Diphenylalanine

Pro: Proline

thioph: thiophene

Oxa: 1,2,4-oxadiazole-5 (4H) -one

amid: amidine

The invention is explained in more detail by the following examples. However, these examples are only to aid the understanding of the present invention, and the scope of the present invention in any sense is not limited thereto.

Example 1: Preparation of ClH ₃ N-CH ₂ -thioph-Oxa (2)

a) Preparation of 5- (azidomethyl) -N'-hydroxy-2-thiophencarboxymidamide (7)

Dissolve 20.35 g (0.12 mol) of 5- (azidomethyl) -2-thiophencarbonitrile in 100 mL of ethanol, add 25.49 g (1.20 mol) of NH ₂ OH.HCl to the reaction solution, and cool to 10 ° C. 46.91 mL (1.10 mol) of triethylamine were added dropwise for 1 hour. After stirring for 2 hours at room temperature, ethanol was distilled under reduced pressure, two-phase (300) of water and 300 mL of methylene chloride was extracted and extracted. The extracted methylene chloride solution was distilled under reduced pressure to give 77.63 g (yield: 96.8%) of 5- (azidomethyl) -N'-hydroxy-2-thiophencarboxymidamide (7).

¹ H NMR (CDCl ₃ ) 7.20 (d, 1H), 6.97 (d, 1H), 4.98 (s, 2H), 4.46 (s, 2H)

b) Preparation of 3- [5- (azidomethyl) -2-thienyl] -Oxa (9)

4.96 ml of ethyl chloroformate, while stirring 10.08 g (51.11 mmol) of 5- (azidomethyl) -N'-hydroxy-2-thiophencarboxymidamide (7) in the presence of 12.32 g (0.16 mol) of pyridine (51.92 mmol) was added dropwise for 30 minutes. The reaction solution was heated to reflux, stirred for 3 hours, and cooled to room temperature. 100 mL of methylene chloride and 50 mL of H ₂ O were added to form a two-phase extraction. The organic layer was extracted with 50 mL of 1 N hydrochloric acid (No. 2), 50 mL of H ₂ O, and finally [5% sodium chloride]. 20 mL + 20% sodium bicarbonate 20 mL], dried over anhydrous sodium sulfate, filtered, washed with 50 mL of methylene chloride, and then the organic layer was put back into the reactor.

¹ H NMR (CDCl ₃ ) 13.18 (s, 1H), 7.63 (d, 1H), 7.28 (d, 1H), 4.77 (s, 2H)

c) Preparation of ClH ₃ N-CH ₂ -thioph-Oxa (2).

13.61 g (51.90 mol) of PPh ₃ was added to the methylene chloride solution of azido compound (9) in b) five times for one hour so as not to exceed 30 ° C. (Be careful not to get a lot of heat and nitrogen bubbles every time.) After stirring at room temperature for 4 hours, 5 mL of 6N caustic soda was added thereto, and the mixture was stirred at room temperature for 1 hour. After methylene chloride was removed by distillation under reduced pressure, 200 mL of an ethyl acetate solution of about 3 N hydrochloric acid was added dropwise so as not to exceed 25 ° C. After stirring for 1 hour at room temperature, the mixture was filtered, washed with 100 mL of ethyl acetate, and dried over nitrogen to obtain 8.0 g (yield: 67.0%).

¹ H NMR (CDCl ₃ ) 13.27 (d, 1H), 8.64 (s, 3H), 7.74 (d, 1H), 7.40 (d, 1H), 4.31 (s, 2H)

Example 2: Preparation of ClH-D-Dpa-Pro-NH-CH ₂ -5- (2-Oxa) -thioph (5)

a) Preparation of BOC-D-Dpa-Pro-NH-CH ₂ -5- (2-Oxa) -thioph (4)

4.4 g (10 mmol) of Compound (10) was dissolved in 20 ml of methylene chloride and cooled to 20 ° C. 1.2 mL (11 mmol) of 4-methylmorpholine was added to the solution, and then 1.3 mL (10 mmole) of isobutyl chloroformate was added dropwise while paying attention to exotherm. After the addition was completed, the mixture was stirred at 20 ° C. for 30 minutes, and then 2.8 g (12 mmoles) of Compound (2) and 1.2 ml (11 mmoles) of 4-methylmorpholine were added sequentially. The reaction was completed by stirring at the same temperature for 2 hours. After raising the reaction solution to room temperature, methylene chloride was distilled under reduced pressure. Compound (4) thus obtained was directly used for the next reaction.

¹ H NMR (CDCl ₃ ) 13.01 (s, 1H), 8.29 (s, 1H), 7.56 (s, 1H), 7.37 (m, 2H), 7.29-7.21 (m, 10H), 7.09 (d, 1H) , 5.11 (t, 1H), 4.41 (d, 1H), 4.31 (dd, 1H), 3.89 (d, 1H), 3.65 (d, 1H), 3.11 (s, 1H), 1.75-1.65 (m, 2H ), 1.47 (s, 2H), 1.35 (s, 1H), 1.23 (s, 9H)

FAB MS: 618 [M + 1] ⁺

b) Preparation of ClH-D-Dpa-Pro-NH-CH ₂ -5- (2-Oxa) -thioph (5)

Compound (4) was added to about 3M dichloromethane saturated with 200 ml of hydrochloric acid gas and stirred at room temperature for 16 hours. Compound 5 was obtained after the reaction was completed. The resulting solid was filtered and washed with 50 ml of methylene chloride to obtain 4.93 g (yield: 89%) of compound (5).

¹ H NMR (CDCl ₃ ) 13.14 (s, 1H), 8.96 (t, 1H), 8.60 (s, 3H), 7.63 (d, 2H), 7.57 (d, 1H), 7.40 (t, 2H), 7.30 ~ 7.20 (m, 6H), 7.05 (d, 1H), 4.90 (d, 1H), 4.45-4.30 (m, 3H), 3.80-3.73 (m, 2H), 2.92 (m, 1H), 1.68 (m , 1H), 1.59 (m, 1H), 1.33 (m, 2H)

FAB MS: 518 [M + 1] ⁺

Example 3: Preparation of HOCO-CH ₂ -D-Dpa-Pro-NH-CH ₂ -5- (2-amid) -thioph (1)

a) Preparation of BnOCO-CH ₂ -D-Dpa-Pro-NH-CH ₂ -5- (2-Oxa) -thioph (6)

4.93 g (8.9 mmol) of compound (5) was dissolved in 10 ml of dimethylformamide, cooled to 20 ° C., and then 8.95 g (39.1 mmol) of benzylbromo acetate was added thereto, followed by diisopropylethylamine. 3.15 g (24.4 mmol) was added dropwise. The reaction solution was stirred at the same temperature for 8 hours to complete the reaction. 20 ml of ethyl ether and 20 ml of water were added to separate the layers. The water layer was washed with 20 ml of ethyl ether to remove impurities formed during the reaction. The separated water layer was extracted twice with 20 ml of ethyl acetate and distilled under reduced pressure to obtain 4.14 g (yield: 70%) of compound (6).

¹ H NMR (CDCl ₃ ) 8.6 (s, 1H), 7.46-7.08 (m, 18H), 5.19-5.09 (m, 5H), 4.80 (s, 1H), 4.53-4.40 (m, 4H), 3.94 ( t, 1H), 2.94 (m, 1H), 1.68 (m, 1H), 1.59 (m, 1H), 1.27 (m, 2H)

FAB MS: 666 [M + 1] ⁺

b) Preparation of HOCO-CH ₂ -D-Dpa-Pro-NH-CH ₂ -5- (2-amid) -thioph (1)

The compound (6) obtained in a) was dissolved in 20 ml of methanol, and 0.2 g of 10% Pd / C was added to carry out the reaction for 4 hours under hydrogen pressure (50 psi). After completion of the reaction, the mixture was filtered through celite, washed with 5 ml of methanol, and the solvent was evaporated under reduced pressure to obtain 3.16 g (yield: 95%) of Compound (1).

FAB MS: 554 [M + 1] ⁺

According to the preparation method of the present invention, the compound of formula (2) may be prepared from the compound of formula (3), and the compound of formula (2) is very effective in inhibiting blood clot production and at the same time has high oral absorption. The compound represented by the formula (1) can be prepared by a new method.

According to the preparation method of the present invention, the compound of formula (1) can be prepared in a shorter synthetic step, because there is an advantage that can remove two protection groups (protection groups) at the same time.

Claims (12)

A process for producing a compound of formula (1), comprising the step of hydrogenating a compound of formula (6) to produce a compound of formula (1). [Formula 6] [Formula 1] Wherein Ph is phenyl and Bn is benzyl. The process of claim 1, wherein the reaction is in the presence of an atmosphere of hydrogen and in the presence of a Pd / C catalyst. The compound of claim 1, wherein the compound of formula a) coupling a compound of formula (2) with a compound of formula (10) to produce a compound of formula (4); b) deprotecting the compound of formula (4) to prepare a compound of formula (5); c) a process comprising the step of alkylating the compound of formula (5) with benzyl halo acetate to produce the compound of formula (6). [Formula 2] [Formula 10] [Formula 4] [Formula 5] Wherein Ph is as defined in claim 1, and boc represents t-butyloxycarbonyl. A compound of formula (6) [Formula 6] Ph and Bn in the formula are as defined in claim 1. A compound of formula (5) [Formula 5] Ph in the above formula is as defined in claim 1. A compound of formula (4) [Formula 4] Ph and boc in the formula are as defined in claim 1 and 3, respectively. The compound of formula (2) [Formula 2] a) reacting a compound of formula (3) with hydroxylamine to prepare a compound of formula (7); b) condensing the compound of formula (7) with a compound of formula (8) to produce a compound of formula (9); c) a compound of formula (2) comprising the step of producing a compound of formula (2) by hydrolyzing the compound of formula (9) in the presence of triphenylphosphine and reacting with iminophosphoran; How to prepare. [Formula 3] [Formula 7] [Formula 8] ClCOOR [Formula 9] [Formula 2] In which R is C _1-10 alkyl or phenyl. The process of claim 8, wherein step b) is reacted in the presence of pyridine or triethylamine. The method according to claim 8, wherein a solvent selected from the group consisting of aliphatic hydrocarbons, organic chlorine solvents, nitriles and ethers is used alone, or a mixed solvent in which the selected solvent is mixed with xylene or dioxane. A compound of formula (7) [Formula 7] A compound of formula (9) [Formula 9]