A method for preparing an argatroban intermediate, ethyl 4-methyl-2-piperidinecarboxylate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of an intermediate 4-methyl-2-piperidinecarboxylic acid ethyl ester of argatroban. The application takes SM-1 as a starting material, realizes single bromination of an alpha position of a carbonyl group of the SM-1, and prepares a target compound through a rearrangement reaction. Compared with the prior art, the application can effectively avoid the use of a toxic cyanide in the prior art, can avoid a catalytic hydrogenation reaction, is safe in operation, can effectively reduce production cost, and is suitable for industrialized scale production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an intermediate 4-methyl-2-piperidinecarboxylic acid ethyl ester of argatroban. BACKGROUND

[0002] Argatroban monohydrate is an antithrombotic drug developed by Mitsubishi Chemical Institute in Japan, which was first marketed in Japan in 1990, approved by the FDA in the United States in 2000, and marketed in China in 2002. The product is a white crystal or crystalline powder, and the trade name is Norpramin. Argatroban is an artificially synthesized monovalent small molecule direct thrombin inhibitor, which can selectively and reversibly bind to the catalytic site of thrombin, not only inactivating liquid-phase thrombin, but also inactivating thrombin combined with fibrin thrombus. It has good curative effect on chronic arterial occlusion, acute ischemic stroke, and heparin-induced thrombocytopenia and thrombosis.

[0003] The chemical name of argatroban is (2R, 4R)-4-methyl-1-[N-[(3-methyl-1, 2, 3, 4-tetrahydro-8-quinolinyl) sulfonyl]-L-arginyl]-2-piperidinecarboxylic acid; the most commonly used form is monohydrate, and the pharmaceutical chemical ingredient is a mixture of 21(R) and 21(S) with a ratio of 64-65:36-35 (US6440417B1), and the structural formula is as follows:

[0004]

[0005] There are four chiral centers in the argatroban molecule, wherein the chiral centers at positions 5 of the arginine fragment and positions 7 and 9 of the piperidinecarboxylic acid fragment have a determined configuration, and the chiral center at position 21 of the tetrahydroquinoline ring does not have a determined configuration. Such chiral centers are very easy to racemize when the pH and temperature conditions change, thereby increasing the difficulty of synthesis of argatroban. The synthesis methods of argatroban reported in reference patents EP0008746A1, US4258192A, US4201863A and EP0823430A1 mainly mention two synthesis routes, which are the amino protection method and the non-protection method. The two routes are formed by different reaction sequences of nitro-L-arginine as a starting material and (2R, 4R)-4-methyl-2-piperidinecarboxylic acid ethyl ester or 3-methyl-8-quinoline sulfonyl chloride. The specific synthesis routes are as follows:

[0006] Amino protection method: the amino group of nitro-L-arginine is protected by Boc, then the peptide bond is formed with (2R,4R)-4-methyl-2-piperidinecarboxylic acid ethyl ester, the Boc protecting group is removed, and then the reaction with 3-methyl-8-quinoline sulfonyl chloride is carried out, followed by ester hydrolysis, hydrogenation to remove the nitro group and reduction of the quinoline ring to obtain argatroban (EP0008746A1, CN1951916A, US4258192A, US4201863A, etc.). The synthetic route is shown as follows:

[0007]

[0008] Non-protection method: nitro-L-arginine is first reacted with 3-methyl-8-quinoline sulfonyl chloride, then reacted with (2R,4R)-4-methyl-2-piperidinecarboxylic acid ethyl ester, followed by ester hydrolysis, and finally hydrogenation to remove the nitro group and reduction of the quinoline ring to obtain argatroban (US4117127A, EP0823430A1, EP0008746A1, CN101348481A, etc.). The synthetic route is shown as follows:

[0009]

[0010] As can be seen from the above, (2R,4R)-4-methyl-2-piperidinecarboxylic acid ethyl ester can be used as a related intermediate for the synthesis of argatroban, and the structural formula is as follows:

[0011]

[0012] The preparation method of (2R,4R)-4-methyl-2-piperidinecarboxylic acid ethyl ester includes the following methods:

[0013] US4072757A uses 4-methylpiperidine as the starting material, which is chlorinated by NaOCl, and then subjected to elimination reaction under basic conditions, followed by nucleophilic addition with KCN under acidic conditions to obtain 2-cyano-4-methylpiperidine, which is hydrolyzed to obtain 4-methyl-2-piperidinecarboxylic acid. CN101348481A continues to esterify it to obtain the key intermediate 4-methyl-2-piperidinecarboxylic acid ethyl ester (I). Then (I) is first separated by column chromatography to obtain trans-4-methyl-2-piperidinecarboxylic acid ethyl ester, and finally resolved by L-(+)-tartaric acid to obtain the target product (2R,4R)-4-methyl-2-piperidinecarboxylic acid ethyl ester. However, this process needs to use toxic potassium cyanide, and the operation safety is low. The synthetic route is shown as follows:

[0014]

[0015] Tetrahedron Letters, 42 (2001) 2119-2120 also uses 4-methylpiperidine as a starting material, first reacts with Boc anhydride, then in the presence of s-BuLi, electrophilic addition with ethyl chloroformate or carbon dioxide, esterification, and then separation according to the above method. However, this process needs to use s-BuLi when preparing the trans intermediate, the reaction process is harsh (-90℃, 4-5h), and it is difficult to industrialize production. The synthetic route is shown below:

[0016]

[0017] Chinese patent CN101712645A uses diethyl oxalate, 1-bromo propylene and metal Mg in THF to perform Grignard reaction, then performs nucleophilic substitution reaction with methyl cyanoacetate to obtain ethyl 2-carbonyl-4-methyl-5-cyanopentanoate, then performs cyclization reaction to obtain key intermediate (I), then performs benzyl ester protection reaction on the amino group, and then performs deprotection reaction to obtain trans ethyl 4-methyl-2-piperidinecarboxylate, and finally performs separation to obtain the target product. This method has too many steps, needs to use Grignard reagent reaction which is harsh to reaction conditions, and has poor selectivity due to the use of diethyl oxalate as a starting material, and there are double-substituted impurities. In addition, the benzyl ester protection and deprotection are only for removing the cis isomer, which is complicated to operate, and the deprotection by palladium-carbon hydrogenation has safety problems and is not conducive to large-scale production. The synthetic route is shown below:

[0018]

[0019] Chinese patent CN102887854B uses 4-methylpyridine-2-carboxylate as a starting material, uses phosphomolybdic acid as a catalyst to oxidize to obtain 4-methylpyridine-2-carboxylate nitroxide, and then uses methanol or ethanol as a solvent, reduces to form a salt to obtain 4-methylpiperidine-2-carboxylate hydrochloride. However, the oxidation step needs to use multiple oxidizing agents, which has low safety in operation; in addition, a large amount of metal oxide solid waste is generated during post-treatment, which has great environmental pressure; and it needs to use noble metal catalysts, which has high production cost. The synthetic route is shown below:

[0020]

[0021] As can be seen from the above, ethyl 4-methyl-2-piperidinecarboxylate (I) is used in the synthesis of (2R,4R)-ethyl 4-methyl-2-piperidinecarboxylate in multiple routes, and therefore ethyl 4-methyl-2-piperidinecarboxylate (I) can be used as a related intermediate for synthesizing (2R,4R)-ethyl 4-methyl-2-piperidinecarboxylate or argatroban, which directly affects the production, market supply and quality of the drug, and the structural formula is as follows:

[0022]

[0023] In view of the problems existing in the prior art in preparing 4-methyl-2-piperidinecarboxylic acid ethyl ester (I), it is of great significance to find a process for preparing 4-methyl-2-piperidinecarboxylic acid ethyl ester (I) which is suitable for industrial production, has mild reaction conditions, simple operation process, high product yield and purity, and low production cost, and is suitable for industrial production of (2R, 4R)-4-methyl-2-piperidinecarboxylic acid ethyl ester or argatroban. SUMMARY

[0024] In view of the problems existing in the prior art in preparing 4-methyl-2-piperidinecarboxylic acid ethyl ester (I), the present application provides a new synthesis method of 4-methyl-2-piperidinecarboxylic acid ethyl ester (I). The method can effectively avoid the use of toxic cyanide and noble metal catalyst, and has mild reaction conditions, simple operation process, low production cost, and can obtain 4-methyl-2-piperidinecarboxylic acid ethyl ester (I) with high yield and purity.

[0025] The specific technical scheme of the present application is as follows:

[0026] A preparation method of argatroban intermediate 4-methyl-2-piperidinecarboxylic acid ethyl ester (I) is characterized by using compound SM-1 as raw material, first reacting with copper bromide to obtain compound I-1, and then reacting compound I-1 under the action of a base to obtain target compound I; the base is one or a combination of sodium ethoxide and potassium ethoxide; the reaction formula is as follows:

[0027]

[0028] Preferably, a preparation method of argatroban intermediate 4-methyl-2-piperidinecarboxylic acid ethyl ester (I) has the following specific steps:

[0029] Step 1: under the protection of inert gas, at room temperature, compound SM-1 and copper bromide are added to organic solvent A, and the temperature is controlled at T A After the reaction is completed, compound I-1 is obtained;

[0030] Step 2: at room temperature, compound I-1 and a base are added to organic solvent B, and the temperature is controlled at T B After the reaction is completed, target compound I is obtained.

[0031] Preferably, the organic solvent A in step 1 is one or a combination of chloroform, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran and acetonitrile, and more preferably is one or a combination of isopropyl acetate, chloroform and ethyl acetate.

[0032] Preferably, the molar ratio of SM-1 to copper bromide in step 1 is 1:1.8-3.2, preferably 1:2.2.

[0033] Preferably, the temperature T in step 1 is controlled at 40-100℃, preferably 60-75℃. A Preferably, the temperature T in step 1 is controlled at 40-100℃, preferably 60-75℃.

[0034] Preferably, the inert gas in step 1 is an inert gas commonly used in the art, such as nitrogen, argon.

[0035] In a preferred embodiment, step 1 further requires a post-treatment operation, specifically: the reaction solution is cooled to room temperature, filtered, and the filtrate is washed with saturated sodium bicarbonate solution and saturated brine respectively, and the organic phase is concentrated to dryness under reduced pressure to obtain compound I-1.

[0036] Preferably, the base in step 2 is one or a combination of sodium ethoxide, potassium ethoxide, preferably sodium ethoxide.

[0037] Preferably, the organic solvent B in step 2 is one or a combination of ethanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, preferably ethylene glycol dimethyl ether.

[0038] Preferably, the molar ratio of I-1 to base in step 2 is 1:3-12, preferably 1:4.

[0039] Preferably, the temperature T in step 2 is controlled at 10-50℃, preferably 20-25℃. B Preferably, the temperature T in step 2 is controlled at 10-50℃, preferably 20-25℃.

[0040] In a preferred embodiment, step 2 further requires a post-treatment operation, specifically: the reaction solution is diluted with purified water, extracted with an organic solvent, the organic phases are combined, washed with purified water and saturated brine, and the organic phase is concentrated to dryness under reduced pressure to obtain the target compound I. Preferably, the extraction solvent is one of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether.

[0041] Compared with the prior art, the present application has the following advantages:

[0042] (1) The present application realizes the single bromination of the α-position of the carbonyl group of SM-1 and obtains the target compound through rearrangement. The whole process is simple, can effectively avoid the use of the toxic cyanide in the prior art, and can also avoid catalytic hydrogenation reaction, which is not only safe to operate but also effectively reduces the production cost.

[0043] (2) The use of copper bromide as the bromination reagent can effectively avoid the generation of dibromide, and the obtained intermediate has high purity and does not need to be refined.

[0044] (3) The target product obtained by the process has high purity and yield, and is suitable for industrial scale-up production. DETAILED DESCRIPTION

[0045] The present application will be further described by the following examples. It should be understood that these examples are only used to illustrate the present application, and are not intended to limit the present application. Therefore, any simple improvement on the present application under the premise of the present application falls within the scope of the present application.

[0046] The purity of 4-methyl-2-piperidinecarboxylic acid ethyl ester is determined by GC, and the chromatographic conditions are as follows:

[0047] Chromatographic conditions and system suitability test: 5% phenyl-methyl polysiloxane as stationary liquid, capillary column (30 m x 0.53 mm x 5 μm);

[0048] Column temperature: 150°C;

[0049] Detector (FID) temperature: 250°C;

[0050] Injection port temperature: 200°C;

[0051] Determination method: 0.3 μL of the product is precisely measured and injected into a gas chromatograph, and the chromatogram and main peak retention time are recorded for 2 times. The content of diastereoisomer (relative retention time is about 1.1) in the test sample is not more than 3.0%, the content of other single impurity is not more than 0.5%, and the total content of other impurities is not more than 2.0% according to the area normalization method.

[0052] Retention time: about 17.5 min [(R,R) / (S / S)]; about 19.0 min [(R,S) / (S / R)].

[0053] In the following examples, various processes and methods not described in detail are conventional methods known in the art.

[0054] Synthesis of intermediate I-1:

[0055] Example 1

[0056] Under nitrogen protection, SM-1 (12.72 g, 0.10 mol) and copper bromide (48.57 g, 0.22 mol) are added into isopropyl acetate (200 ml), and the reaction is carried out at a temperature of 65-70°C. After detection, the reaction is completed, the reaction liquid is cooled to room temperature, filtered, washed with saturated sodium bicarbonate solution (30 ml x 3) and saturated brine (30 ml x 2), and the organic phase is concentrated to dryness under reduced pressure to obtain compound I-1, with a yield of 94.7% and a purity of 99.16%.

[0057] Example 2

[0058] Under nitrogen protection, SM-1 (12.72 g, 0.10 mol) and copper bromide (41.95 g, 0.19 mol) were added to a mixed solution of ethyl acetate (100 ml) and chloroform (100 ml). The reaction was refluxed under controlled temperature. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was washed with saturated sodium bicarbonate solution (30 ml × 3) and saturated brine (30 ml × 2). The organic phase was concentrated to dryness under reduced pressure to obtain compound I-1 with a yield of 91.2% and a purity of 98.90%.

[0059] Example 3

[0060] Under nitrogen protection, SM-1 (12.72 g, 0.10 mol) and copper bromide (39.73 g, 0.18 mol) were added to butyl acetate (200 ml), and the reaction was controlled at 95-100 ° C. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was washed with saturated sodium bicarbonate solution (30 ml × 3) and saturated brine (30 ml × 2). The organic phase was concentrated to dryness under reduced pressure to obtain compound I-1 with a yield of 88.5% and a purity of 98.94%.

[0061] Example 4

[0062] Under nitrogen protection, SM-1 (12.72 g, 0.10 mol) and copper bromide (70.64 g, 0.32 mol) were added to tetrahydrofuran (200 ml), and the reaction was refluxed under temperature control. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was washed with saturated sodium bicarbonate solution (30 ml × 3) and saturated brine (30 ml × 2). The organic phase was concentrated to dryness under reduced pressure to obtain compound I-1 with a yield of 93.1% and a purity of 99.07%.

[0063] Example 5

[0064] Under argon protection, SM-1 (12.72 g, 0.10 mol) and copper bromide (72.85 g, 0.33 mol) were added to a mixed solvent of isopropyl acetate (100 ml) and acetonitrile (100 ml). The reaction was refluxed under controlled temperature. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was washed with saturated sodium bicarbonate solution (30 ml × 3) and saturated brine (30 ml × 2). The organic phase was concentrated to dryness under reduced pressure to obtain compound I-1 with a yield of 89.7% and a purity of 98.86%.

[0065] Synthesis of Compound I

[0066] Example 6

[0067] Compound I-1 (10.30 g, 0.05 mol), sodium ethoxide (13.61 g, 0.20 mol) were added into dimethoxyethane (100 ml) at room temperature, and the reaction was controlled at 20-25 °C. After the reaction was completed, the reaction solution was diluted with purified water (1000 ml), extracted with dichloromethane (150 ml x 3), the organic phases were combined, washed with purified water (80 ml x 3), saturated brine (100 ml x 3), and the organic phase was concentrated to dryness under reduced pressure to obtain the target compound I with a yield of 92.9% and a purity of 99.26%.

[0068] Example 7

[0069] Compound I-1 (10.30 g, 0.05 mol), sodium ethoxide (10.21 g, 0.15 mol) were added into ethanol (100 ml) at room temperature, and the reaction was controlled at 35-40 °C. After the reaction was completed, the reaction solution was diluted with purified water (1000 ml), extracted with dichloromethane (150 ml x 3), the organic phases were combined, washed with purified water (80 ml x 3), saturated brine (100 ml x 3), and the organic phase was concentrated to dryness under reduced pressure to obtain the target compound I with a yield of 90.4% and a purity of 98.72%.

[0070] Example 8

[0071] Compound I-1 (10.30 g, 0.05 mol), sodium ethoxide (6.81 g, 0.10 mol) were added into dimethoxyethane (100 ml) at room temperature, and the reaction was controlled at 45-50 °C. After the reaction was completed, the reaction solution was diluted with purified water (1000 ml), extracted with methyl tert-butyl ether (150 ml x 3), the organic phases were combined, washed with purified water (80 ml x 3), saturated brine (100 ml x 3), and the organic phase was concentrated to dryness under reduced pressure to obtain the target compound I with a yield of 87.3% and a purity of 98.45%.

[0072] Example 9

[0073] Compound I-1 (10.30 g, 0.05 mol), sodium ethoxide (40.83 g, 0.60 mol) were added into tetrahydrofuran (100 ml) at room temperature, and the reaction was controlled at 15-20 °C. After the reaction was completed, the reaction solution was diluted with purified water (1000 ml), extracted with dichloromethane (150 ml x 3), the organic phases were combined, washed with purified water (80 ml x 3), saturated brine (100 ml x 3), and the organic phase was concentrated to dryness under reduced pressure to obtain the target compound I with a yield of 91.5% and a purity of 99.10%.

[0074] Example 10

[0075] Compound I-1 (10.30 g, 0.05 mol), sodium ethoxide (44.23 g, 0.65 mol) were added into 1,4-dioxane (100 ml) at room temperature, and the reaction was controlled at 10-15 °C. After the reaction was detected to be completed, the reaction liquid was diluted with purified water (1000 ml), and then extracted with ethyl acetate (150 ml x 3). The organic phase was combined, washed with purified water (80 ml x 3), saturated brine (100 ml x 3), and then concentrated to dryness under reduced pressure to obtain the target compound I with a yield of 88.6% and a purity of 98.81%.

[0076] Example 11

[0077] Compound I-1 (10.30 g, 0.05 mol), potassium ethoxide (16.83 g, 0.20 mol) were added into diethyl ether (100 ml) at room temperature, and the reaction was controlled at 20-25 °C. After the reaction was detected to be completed, the reaction liquid was diluted with purified water (1000 ml), and then extracted with chloroform (150 ml x 3). The organic phase was combined, washed with purified water (80 ml x 3), saturated brine (100 ml x 3), and then concentrated to dryness under reduced pressure to obtain the target compound I with a yield of 92.5% and a purity of 99.17%.

[0078] Example 12

[0079] The ethyl 4-methyl-2-piperidinecarboxylate (5 g) prepared in Example 6 was resolved with L-tartaric acid according to the prior art (Zhou Ding. Synthesis of Anticoagulant Argatroban [D]. Hebei: Hebei Medical University, 2013: 16-18.), and (2R,4R)-ethyl 4-methyl-2-piperidinecarboxylate was obtained, and the structure confirmation data thereof were as follows: 1 H-NMR (600 MHz, CDCl3) δ: 4.17 (q, J = 7.10 Hz, 2H), 3.63 (t, J = 4.52 Hz, 1H), 2.80-2.87 (m, 2H), 2.17 (s, 1H), 2.04-2.07 (m, 1H), 1.51-1.60 (m, 2H), 1.42-1.47 (m, 1H), 1.27 (t, J = 7.16 Hz, 3H), 1.15-1.21 (m, 1H), 0.94 (d, J = 6.54 Hz, 3H); 13 C-NMR (151 MHz, CDCl3) δ: 173.44, 61.80, 56.47, 43.93, 35.58, 33.16, 28.20, 21.58, 14.46; ESI-HRMS (m / z): 172.1326 [M+H] + .

Claims

1. A method for preparing 4-methyl-2-piperidinic acid ethyl ester, an intermediate of argatroban, characterized in that: Compound SM-1 is used as a raw material and first reacted with copper bromide to obtain compound I-1. Compound I-1 is then reacted in the presence of a base to obtain the target compound I; the base is sodium ethoxide, potassium ethoxide, or a combination thereof; the reaction formula is as follows: 。 2. The preparation method according to claim 1, characterized in that The specific steps are as follows: Step 1: Under inert gas protection, add compound SM-1 and copper bromide to organic solvent A at room temperature, and control the temperature T A After the reaction is completed, compound I-1 is obtained; Step 2: Add compound I-1 and base to organic solvent B at room temperature, and control the temperature T B After the reaction is completed, the target compound I is obtained.

3. The preparation method according to claim 2, characterized in that The organic solvent A in step 1 is one or a combination of chloroform, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, and acetonitrile.

4. The preparation method according to claim 2, characterized in that The molar ratio of SM-1 to copper bromide in step 1 is 1:1.8-3.

2.

5. The preparation method according to claim 2, characterized in that The temperature control T described in step 1 A It is 40~100℃.

6. The preparation method according to claim 2, characterized in that The base described in step 2 is sodium ethoxide.

7. The preparation method according to claim 2, characterized in that The organic solvent B described in step 2 is one of ethanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether, or a combination thereof.

8. The method according to claim 2, characterized in that The molar ratio of I-1 to the base in step 2 is 1:3-12.

9. The method according to claim 2, characterized in that The temperature control T described in step 2 B 10~50℃.

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