A kind of preparation method of edoxaban intermediate

A technology for edoxaban and intermediates, which is applied in the field of preparation of edoxaban intermediates, can solve the problems of unsuitability for industrial production, high price, and increased production costs of compounds of formula 6, and achieve large-scale industrial production, The effect of low production cost

Active Publication Date: 2020-09-04
ASTATECH CHENGDU BIOPHARM CORP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The above method also uses expensive chiral (S)-cyclohexene 1-carboxylic acid as raw material to first obtain the lactone and then synthesize the compound of formula 6, which greatly increases the production cost of the compound of formula 6 and is not suitable for industrial production

Method used

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  • A kind of preparation method of edoxaban intermediate
  • A kind of preparation method of edoxaban intermediate
  • A kind of preparation method of 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] The preparation route is as follows:

[0037]

[0038] (1) Preparation of 4-iodo-3-cyclohexylcarboxylate

[0039] 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).

[0040] (2) Preparation of 7-oxabicyclo[4.1.0]heptane-3-carboxylic acid methyl ester

[0041] 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....

Embodiment 2

[0049] Embodiment 2, the screening of enzyme in the compound process of preparation formula 7

[0050] Dissolve methyl 3-tert-butoxycarbonylamino-4-hydroxy-cyclohexanecarboxylate (5 g) in methyl tert-butyl ether (50 mL), add enzyme (0.1 g), vinyl acetate (2 g), 40 °C and stirred for 48 hours, the reaction results are shown in Table 2.

[0051] The resolution of the compound of formula 5 catalyzed by different hydrolases in table 2

[0052]

[0053] The results showed that porcine pancreas lipase, bovine pancreas lipase, lipase AK and lipase PS had better effects, and the de values ​​were all greater than 96%. In terms of overall yield, when the hydrolase is selected from lipase PS, the effect is the best.

Embodiment 3

[0054] Example 3, Preparation of (1S, 3R, 4R)-3-tert-butoxycarbonylamino-4-hydroxyl-cyclohexanecarboxylic acid

[0055] 50 g of 3-tert-butoxycarbonylamino-4-hydroxyl-cyclohexanecarboxylic acid methyl ester prepared in step (4) of Example 1 was dissolved in 250 mL of ethyl acetate, and 0.83 g of bovine pancreatic lipase and 20 g of vinyl acetate were added. After stirring at 55°C for 24 hours, the reaction was terminated, the reaction solution was spin-dried, and purified by column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain 19.5 g of a white solid, de = 90%.

[0056] Dissolve 10 g of white solid in 50 mL of tetrahydrofuran, add 50 mL of water and 1 g of LiOH, and react at 50° C. for 24 hours. Wash the reaction solution with ethyl acetate, continue to add an equal volume of ethyl acetate to the water phase, cool down to 0-10°C, add a certain amount of hydrochloric acid (6N), and adjust the pH to about 2. The liquid was separated, the aqueous phase was ext...

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Abstract

The invention discloses a preparation method of edoxaban intermediate (1S, 3R, 4R)-3-tert-butoxycarbonylamino-4-hydroxy-cyclohexanecarboxylic acid. According to the preparation method, 3-amino-4-hydroxy-cyclohexane carboxylate represented by formula IV is taken as a raw material, protective reaction with amino protection groups is carried out so as to obtain 3-tert-butoxycarbonylamino-4-hydroxy-cyclohexane carboxylate represented by formula V, enzyme catalyzed esterification resolution reaction is carried out so as to obtain optically pure (1S, 3R, 4R)-3-tert-butoxycarbonylamino-4-hydroxy-cyclohexane carboxylate represented by formula VII, and at last lithium hydroxide hydrolysis is adopted so as to obtain the (1S, 3R, 4R)-3-tert-butoxycarbonylamino-4-hydroxy-cyclohexanecarboxylic acid represented by formula VI. The preparation method possesses following advantages: operation is simple, the preparation method is green, is friendly to the environment, and is high in selectivity and lowin cost, large scale industrialized production can be realized, and it is convenient for industrial popularization.

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 compounds of formula 7 and formula 6 are important intermediates of edoxaban, and the specific structural formula is as follows: [0004] [0005] Among them, the compound of formula 7 has been commercially available, but it is expensive. And the cost of the synthesis method of the formula 7 compound reported in the current patent is also very high, such as CN201510719370.5 and US 7342014B2, its synthesis route is as follows: [0006...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/08C07C229/48C12P41/00C07C269/04C07C269/06C07C271/24C07D307/00C07D303/40C07D301/02
CPCC07C227/08C07C269/04C07C269/06C07D301/02C07D303/40C07D307/00C12P41/008C07C229/48C07C271/24Y02P20/55
Inventor 谢开龙王鸿江孙大召郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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