Preparation method for high-purity edoxaban intermediate

A technology for edoxaban and intermediates, which is applied in the field of preparation of edoxaban intermediates, can solve the problems of high price, unfavorable industrialized production, potential safety hazards, etc., and achieves the effects of low production cost and large-scale industrialized production.

Active Publication Date: 2018-09-04
ASTATECH CHENGDU BIOPHARM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above method also uses expensive chiral alkenoic acid as a raw material, and in the reaction method disclosed in the US patent, it also needs to use highly toxic and dangerous azidation Sodium, which has potential safety hazards and is not conducive to industrial production

Method used

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  • Preparation method for high-purity edoxaban intermediate
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  • Preparation method for high-purity edoxaban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1, the preparation of (1S, 3R, 4R)-3-tert-butoxycarbonylamino-4-hydroxyl-cyclohexanecarboxylic acid

[0036]

[0037] (1) Preparation of 4-iodo-3-cyclohexylcarboxylate

[0038] Dissolve 200g of cyclohexene-1-carboxylic acid (1) in 600mL of dichloromethane, add 200g of sodium bicarbonate, 350g of potassium iodide, and 500mL of water under ice-cooling. After 10 minutes, warm up to room temperature and add 500g of iodine. After 2 hours, , adding sodium thiosulfate aqueous solution (2N, 300mL), after half an hour, separate the layers, extract the aqueous phase once with 500mL dichloromethane, combine the organic phases, dry, and spin dry to obtain 460g white solid (2).

[0039] (2) Preparation of 7-oxabicyclo[4.1.0]heptane-3-carboxylic acid methyl ester

[0040] Add 30 g of 4-iodo-3-cyclohexanecarboxylic acid lactone into 120 mL of methanol, stir at room temperature for 10 minutes, add sodium hydroxide (50 mL, 2.5 N), stop the reaction after 3 hours, add 300 ...

Embodiment 2

[0047] Embodiment 2, the preparation of (1S, 3R, 4R)-3-tert-butoxycarbonylamino-4-hydroxyl-cyclohexanecarboxylic acid

[0048] In 187.5 mL of phosphate buffer solution with pH=8.0, add 50 g of 3-tert-butoxycarbonylamino-4-hydroxy-cyclohexanecarboxylic acid methyl ester prepared in step (4) of Example 1, 1 g of papain, 562.5 mL Toluene, after stirring at 50°C for 48 hours, terminate the reaction, separate the liquids, wash the water phase once with ethyl acetate, continue to add an equal volume of ethyl acetate to the water phase, cool to 0-10°C, and add a certain amount of hydrochloric acid ( 6N), adjust the pH to 2. The liquid was separated, and methyl tert-butyl ether (250 mL) was added to the aqueous phase to extract twice, and the organic phases were combined, dried, and spin-dried to obtain 21 g of a colorless solid, de=99%.

Embodiment 3

[0049]Example 3, (1S, 3R, 4R) Screening of enzymes in the process of (1S, 3R, 4R)-3-tert-butoxycarbonylamino-4-hydroxyl-cyclohexanecarboxylic acid

[0050] 10g of ethyl 3-tert-butoxycarbonylamino-4-hydroxy-cyclohexanecarboxylate, 40mL of PBS (PH=7.2), 10mL of methyl tert-butyl ether were added to a 100mL three-necked flask, and 0.2g of different hydrolysates were added, The reaction was carried out at 30° C. for 48 hours, and the reaction results are shown in Table 1.

[0051] The hydrolysis of different hydrolase catalyzed formula 5 compounds of table 1

[0052]

[0053] The results showed that the effects of alkaline protease, pepsin, trypsin and papain were better, and the de values ​​were all greater than 98%. In terms of overall yield, when the hydrolase is selected from alkaline protease, the effect is the best.

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Abstract

The invention discloses a preparation method for the high-purity edoxaban intermediate (1S,3R,4R)-3-tertbutyloxycarbonylamino-4-hydroxy-naphthenic acid. The preparation method comprises the followingsteps: with 3-amino-4-hydroxy-cyclohexane carboxylate as shown in a formula (IV) which is described in the invention as a raw material, subjecting the raw material to protection by an amino protectivegroup so as to obtain 3-tertbutyloxycarbonylamino-4-hydroxy-cyclohexane carboxylate as shown in a formula (V) which is described in the invention; and carrying out enzyme hydrolysis and splitting soas to obtain optically pure (1S,3R,4R)-3-tertbutyloxycarbonylamino-4-hydroxy-naphthenic acid as shown in a formula (VI) which is described in the invention. The preparation method provided by the invention has the advantages of simple operation, environmental protection, high selectivity, low cost and the like, can realize large-scale industrial production, and is convenient for industrial promotion and application.

Description

technical field [0001] The invention relates to a preparation method of a drug intermediate, in particular to a preparation method of an edoxaban intermediate. Background technique [0002] Edoxaban is a new type of small molecule oral anticoagulant developed by Daiichi Sankyo Co., Ltd., which is a direct inhibitor of coagulation factor Xa and can effectively inhibit the formation of thrombus. In January 2015, the U.S. Food and Drug Administration (FDA) approved the listing of Edoxaban, whose trade name is Savaysa. [0003] Among them, the compound of formula 6 is an important intermediate of edoxaban, and the specific structural formula is as follows: [0004] [0005] CN106316889A discloses the synthetic method of formula 6 compound, and route is as follows: [0006] [0007] In this route, the raw material chiral (S)-cyclohexene-1-carboxylic acid is expensive, which greatly increases the production cost of the compound of formula 6 and is not suitable for industri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P21/06
CPCC12P21/06
Inventor 孙大召颜林刘兴新郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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