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A kind of method for preparing odancate intermediate

A technology of time interval and reaction system, which is applied in the direction of carboxylic acid nitrile preparation, sulfonate ester preparation, chemical instruments and methods, etc., can solve the problems of large-scale production, increased difficulty of product purification, and chiral isomer content Low-level problems, achieving significant social and economic benefits, easy separation and purification, and less solvent consumption

Active Publication Date: 2018-12-21
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] CN1993314A claims that the reduction of imine carboxylate by this method can obtain a higher content of chiral isomers of the desired configuration for the preparation of Odangcate, but in fact the chiral isomers of the desired configuration can be obtained by this method. low isomer content
In addition, the metal borohydride obtained by the method needs to be prepared in an ether solvent, which is not only very cumbersome to operate, but also needs a large amount of solvent to increase the dissolving capacity, and needs to add a cosolvent (such as acetonitrile), so the solvent demand of the reaction is relatively high. Big
At the same time, the intermediate of the imine carboxylate is not separated, and is directly put into the next step reaction, so that some impurities are brought into the follow-up reaction together, which increases the difficulty of product purification
In addition, zinc chloride is very easy to absorb water, and when preparing borohydride, it needs to be carried out under anhydrous conditions, and it is difficult to control when it is enlarged, making its preparation method difficult to apply to large-scale production

Method used

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  • A kind of method for preparing odancate intermediate
  • A kind of method for preparing odancate intermediate
  • A kind of method for preparing odancate intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0059] Embodiment 1: Odangcate intermediate (IA or IB')

[0060]

[0061] Step 1), preparation of imine carboxylate intermediate (II)

[0062] 2,2,2-trifluoro-1-(4'-(methylsulfonyl)biphenyl-4-yl)ethanone (III) 9.1g (26.2mmol, 1eq), 4-fluoro-L-leu Add 4.9g (27.5mmol, 1.05eq) of ethyl acetate (IV) into methanol, stir to dissolve, and add 9.0g (65.2mmol, 2.5eq) of anhydrous potassium carbonate. Heat the reaction system to 50±5°C for 4-5 hours. Cool to 25 ~ 30 ° C, filter off insoluble matter. The filtrate was concentrated, and 100 mL of ethyl acetate was added to the residue to make slurry for 1 hour. After filtering, the filter cake was washed with 50 mL of ethyl acetate, and dried to obtain 13.7 g of an imine carboxylate intermediate (yellow solid).

[0063] Step 2), preparation of ordancate intermediate carboxylic acid (IA)

[0064] Experimental condition A

[0065] Add 2.0g (4mmol, 1eq) of imine carboxylate intermediate (II) into 20mL of methanol, add 1.1g (8mmol, 2e...

Embodiment 2

[0077] Embodiment 2: Preparation of Odangcate (V)

[0078]

[0079] Step 1), preparation of imine carboxylate intermediate (II)

[0080] 2,2,2-Trifluoro-1-(4'-(methylsulfonyl)biphenyl-4-yl)ethanone (III) 41.8g (128mmol, 1eq), 4-fluoro-L-leucine Add 23.7g (134mmol, 1.05eq) of ethyl acetate (IV) into 200mL of methanol, stir to dissolve, and add 44.0g (319mmol, 2.5eq) of anhydrous potassium carbonate. Heat the reaction system to 50±5°C for 4-5 hours. Cool to 25 ~ 30 ° C, filter off insoluble matter. The filtrate was concentrated, and 1000 mL of ethyl acetate was added to the residue to make slurry for 1 hour. After filtering, the filter cake was washed with 200 mL of ethyl acetate, and dried to obtain 65.0 g of an imine carboxylate intermediate (yellow solid).

[0081] Step 2), preparation of ordancate intermediate carboxylic acid (IA)

[0082] Add 65.0g (128mmol, 1eq) of imine carboxylate intermediate (II) to 300mL methanol, add 35.0g (256mmol, 2eq) of anhydrous zinc chl...

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PUM

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Abstract

Provided is a method for preparing an intermediate of formula II for odanacatib, comprising a step of reducing the compound of formula II to a compound of formula IA, wherein the reduction is performed by adding a metal chloride and a metal borohydride to a solvent in which the compound of formula II is dissolved. The preparation method is cost-effective, simple to operate, and easy for separation and purification of the product.

Description

technical field [0001] The invention relates to a preparation method of an intermediate used for preparing odancati. Background technique [0002] Odancati ((2S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-[[(1S)-2,2,2-trifluoro-1-[ 4'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]ethyl]amino]pentanamide, shown in formula V below) is a cathepsin K inhibitor whose indication is Osteoporosis in postmenopausal women. Its mechanism of action is to inhibit the activity of cathepsin K, thereby reducing bone resorption, improving bone density, and exerting an anti-osteoporosis effect. [0003] [0004] In US2013331597, a kind of synthetic method of odancati is recorded, comprising the following steps: [0005] 1), using 2,2,2-trifluoro-1-(4'-(methylsulfonyl)biphenyl-4-yl)ethanone and 4-fluoro-L-leucine ester as raw materials, by synthesizing Obtain the intermediate of imine carboxylate; [0006] 2), prepare zinc borohydride with zinc chloride and sodium borohydride in an ether solven...

Claims

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Application Information

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IPC IPC(8): C07C303/30C07C309/76C07C253/30C07C255/46
CPCC07C253/30C07C255/46C07C303/30C07C309/76
Inventor 毛晖陈国财孙绍光黄金昆
Owner JIANGSU HENGRUI MEDICINE CO LTD
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