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Argatroban intermediate as well as preparation method and application thereof

A technology for argatroban and intermediates, which is applied in the field of argatroban intermediates and their preparation, and can solve the problems of difficult solids, many impurities, affecting intermediate storage and quality control, and the like

Inactive Publication Date: 2020-11-20
YANGZHOU ZHONGBAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The inventor synthesized argatroban monohydrate according to the method of US Patent No. 4,258,192, and found that compound VII, as the key intermediate of the two synthetic routes, has poor crystallinity and is not easy to become a solid, and exists in the form of oil, which affects the storage and quality of the intermediate Control, obtain final product purity and only have 99.38%, (referring to reference example 4), impurity is more, is difficult to meet drug declaration requirement

Method used

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  • Argatroban intermediate as well as preparation method and application thereof
  • Argatroban intermediate as well as preparation method and application thereof
  • Argatroban intermediate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Embodiment 1: the synthesis of compound 3

[0065]

[0066] At -20°C, 9.0 g (88.9 mmol) of triethylamine and 12.2 g (89.3 mmol) of isobutyl chloroformate were added to a solution containing 36.2 g (88.6 mmol) of compound 1 in anhydrous tetrahydrofuran (450 ml) to keep - After stirring at 20°C for 10 minutes at 300 rpm, 10.6 g (62.0 mmol) of compound 2 was added thereto. After stirring at -20°C for 10 minutes, it was raised to room temperature within 1 hour and reacted for 16 hours. TLC (petroleum ether / ethyl acetate=10 / 1) Monitor the completion of the reaction, spin off the solvent tetrahydrofuran, then add ethyl acetate to it, successively use 5% (w / w) sodium bicarbonate solution, 10% (w / w) citric acid and saturated saline After washing, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 44.1 g of compound 3 with a yield of 88.7% and a purity of 98.3%.

[0067] The mass spectrum NMR data of compound 3 is:...

Embodiment 2

[0068] Embodiment 2: the synthesis of compound 4

[0069]

[0070] Under an ice-water bath, add 200mL of 4mol / L methanolic hydrogen chloride solution to the methanol solution (100ml) containing 40g (71.3mmol) of compound 3, control the internal temperature below 20°C, stir at 300rpm for 3 hours, then add 10% hydrogen Sodium oxide aqueous solution was 35mL, and then 200mL of methyl tert-butyl ether was added, a solid was formed, the stirring was continued for half an hour, filtered, the filter cake was washed and dried with methyl tert-butyl ether to obtain 27.9g of compound 4, yield: 85.2%, Purity: 97.4%.

[0071] The mass spectrum NMR data of compound 4 is: ESI-MS (m / z): 462.3[M+H] + ;1H NMR (400MHz, DMSO-d6)δ:8.05(s,2H),7.40(s,1H),7.34(m,4H),7.32(dd,1H),5.04(s,2H),4.46(m ,1H),4.14(m,3H),3.42(m,4H),2.44(s,1H),2.08(s,1H),2.03(m,2H),1.74(m,4H),1.64(m, 3H), 1.22(t,3H), 0.86(d,3H).

Embodiment 3

[0072] Embodiment 3: the synthesis of compound 6

[0073]

[0074] At 0°C, add 18.5g (183mmol) triethylamine to a solution containing 27.4g (59.5mmol) of compound 4 in dichloromethane (200ml), then add 14.7g (60.8mmol) of compound 5 to it, and heat up to 75 °C for more than 5 hours, followed by TLC until the reaction was complete.

[0075] The reaction solution was washed twice with water, the organic phase was dried with anhydrous sodium sulfate, the solvent was evaporated to dryness and then crystallized with 30% (v / v) acetonitrile aqueous solution to obtain 34.4g of compound 6 with a yield of 86.7% and a purity of 98.8%. from figure 1 and figure 2 It can be seen that compound 6 is a better solid.

[0076] The mass spectrum NMR data of compound 6 is: ESI-MS (m / z): 667.3[M+H] + ;1H NMR (400MHz, DMSO-d6)δ:8.92(d,1H),8.48(s,1H),8.20(m,3H),7.70(m,1H),7.33(m,4H),7.32(m ,2H),5.02(s,2H),4.78(s,1H),4.58(s,1H),4.35(s,1H),4.05(m,1H),3.92(m,1H),3.69(m, 1H), 3.03(d, 3H), 2.54(...

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Abstract

The invention discloses an argatroban intermediate as well as a preparation method and application thereof. The preparation method of the intermediate comprises the following steps: S1, carrying out amidation reaction on N[alpha]-BOC-N[omega]-Cbz-L-arginine shown in a formula 1 and (2R,4R)-4-methyl-2-piperidine carboxylic acid ethyl ester shown in a formula 2 under the action of isobutyl chloroformate to obtain a compound shown in a formula 3; S2, removing tert-butyloxycarbonyl from the compound shown in the formula 3 to obtain a compound shown in a formula 4; and S3, carrying out condensationreaction on the compound shown in the formula 4 and 3-methyl-8-quinoline sulfonyl chloride shown in a formula 5 under an alkaline condition to obtain a compound shown in a formula 6. The benzyloxycarbonyl is adopted to protect guanidyl, structures of all intermediate compounds are not reported in literature, and the key intermediate compound 6 after the protecting group is changed is easy to crystallize to form solid, so that the purity is improved, the quality is easy to control, and the industrial production is facilitated.

Description

technical field [0001] The invention belongs to the field of organic synthesis of medicines, and specifically relates to an intermediate of argatroban and its preparation method and application. Background technique [0002] The incidence of stroke has been on the rise in recent years, and ischemic stroke is the main type of stroke. At present, most of the drugs for the treatment of acute ischemic stroke in the domestic market are biochemical preparations extracted from organisms, but they can easily cause allergic reactions in the human body, and their clinical application is very risky. Argatroban is a synthetic small-molecule thrombin inhibitor that can selectively and reversibly bind to the catalytic site of thrombin to directly inactivate thrombin, independent of the level of antithrombin in the body. [0003] Argatroban was first synthesized by Mitsubishi Chemical Research Institute in Japan. It was first approved in Japan for the treatment of peripheral thrombosis an...

Claims

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Application Information

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IPC IPC(8): C07K5/072C07K1/06C07K1/02C07K1/30
CPCC07K5/06095Y02P20/55
Inventor 张冠亚金昌明韩晓秋
Owner YANGZHOU ZHONGBAO PHARMA
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