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Preparation method of upatinib chiral intermediate

A technology of upatinib and intermediates, which is applied in the field of preparation of upatinib chiral intermediates, can solve problems such as cumbersome operations, unfavorable industrial production, etc., and achieves high process efficiency, high economic and industrial application value, Less side effects

Pending Publication Date: 2022-04-12
HANGZHOU XINBOSI BIOMEDICAL CO LTD
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

The process has been split many times, the operation is cumbersome, and the actual yield is below 20%, which is not conducive to industrial production

Method used

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  • Preparation method of upatinib chiral intermediate
  • Preparation method of upatinib chiral intermediate
  • Preparation method of upatinib chiral intermediate

Examples

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Embodiment 1

[0038] Preparation of compound 2: Add benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (compound 1, 100 g, 456 mmol) into a 2L four-neck flask, add chloroform (800 mL), 2,6-bis[(4R)-4-tert-butyl-2-oxazolinyl]pyridine (3.0 g, 9.1 mmol) and ytterbium trichloride hexahydrate (3.5 g, 9.1 mmol), Stir at room temperature for 30 min. Start to cool down to -15~-10°C, slowly add 100ml of trimethylsilyl cyanide (54.3g, 547mmol) in chloroform solution dropwise, and stir at -15~-10°C for 12h after the addition is complete. After the reaction, the temperature was slowly raised to about 0°C, 500 mL of water and 57 g of solid sodium bicarbonate were added, and stirred for 30 min. Filter, stand to separate the layers, collect the lower organic phase, extract the upper aqueous phase with 200 mL of chloroform, combine the organic phases, and wash with 500 mL of saturated brine. The organic phase was placed in a water bath at 35°C and concentrated under reduced pressure to dryness to obtai...

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Abstract

The invention relates to a preparation method of an upatinib chiral intermediate as shown in a formula 6. The method comprises the following steps: by taking 6-oxa-3-azabicyclo [3.1. 0] hexane-3-carboxylic acid benzyl ester as a raw material, carrying out asymmetric ring-opening reaction under the catalytic action of a pyridine bisoxazoline ytterbium chloride complex to obtain the upatinib chiral intermediate. Removing trimethylsilyl at the C-4 position, forming methanesulfonate with hydroxyl at the C-4 position, carrying out a series of reactions of configuration inversion at the 4 position, and finally hydrolyzing under an alkaline condition to obtain the Upatinib chiral intermediate compound 6. The method has the advantages of cheap and easily available raw materials, simple process operation, high product chiral purity, high atom utilization rate, easy industrialization, and high economic and industrial application values.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of a chiral intermediate of upatinib. Background technique [0002] Upadacitinib is a selective and reversible JAK1 inhibitor, developed by AbbVie Pharmaceuticals of the United States, and has shown good efficacy in clinical trials for the treatment of various autoimmune and inflammatory diseases . In 2019, Upatinib was launched in the United States and was approved to treat patients with moderate and severe rheumatoid arthritis. In 2021, based on the results of key clinical trials, the drug will submit an application for a new indication for ankylosing spondylitis. The structural formula of Upadatinib is as follows: [0003] [0004] Upadatinib contains two chiral centers, so the introduction of chiral groups is the key to the preparation process. (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid (compound 6) is the key chiral in...

Claims

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Application Information

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IPC IPC(8): C07D207/16C07F7/18
Inventor 陈德宝丁建圣刘艳华
Owner HANGZHOU XINBOSI BIOMEDICAL CO LTD
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