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Preparation method of (S)-5-(tert-butyloxycarbonyl)-5-azaspiro [2, 4] heptane-6-carboxylic acid

A technology of tert-butoxycarbonyl and azaspiro, applied in the direction of organic chemistry methods, chemical instruments and methods, organic racemization, etc., can solve the problems of high market cost of compounds, complicated chiral resolution operation, unfavorable industrial production, etc. Achieve the effect of high chiral resolution yield, convenient configuration conversion, and avoid loss

Active Publication Date: 2020-06-19
苏州楚凯药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The disadvantage of this route is: the chiral resolution operation is complicated, the price of the resolution reagent (1S, 2R)-1-amino-2-indanol is higher, and the yield is only 33%, the cost is higher, and it is not conducive to industrial production
[0016] As can be seen from the several methods of ledipasvir chiral intermediates reported in the above literature, chiral resolution is the synthesis of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane -The key step of 6-carboxylic acid, the current method is to use acid and resolution reagent to form salt and precipitate, because it is easy to absorb moisture after forming salt and the rate of salt formation is not high, resulting in low resolution yield
On the other hand, the product of another configuration after splitting is treated as a by-product and not recycled, which also causes the current market cost of this compound to be relatively high

Method used

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  • Preparation method of (S)-5-(tert-butyloxycarbonyl)-5-azaspiro [2, 4] heptane-6-carboxylic acid
  • Preparation method of (S)-5-(tert-butyloxycarbonyl)-5-azaspiro [2, 4] heptane-6-carboxylic acid
  • Preparation method of (S)-5-(tert-butyloxycarbonyl)-5-azaspiro [2, 4] heptane-6-carboxylic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052]

[0053] Add HOBt (1.5g, 11mmol) and DCC (2g, 10mmol) to 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid racemate (2.4 g, 10mmol) in THF (50mL), stirred for 1h, and then added chiral benzylamine (2.5g, 10mmol). Warm up to room temperature and react for 3 hours, filter, rinse with ethyl acetate, and concentrate the filtrate to obtain 4.7 g (9.9 mmol) of a mixture of compounds I and II (I:II=45:55). The mixture was recrystallized with isopropanol to obtain 2.0 g of compound I (42% yield), and the mother liquor was concentrated to obtain 2.6 g of compound II (yield 55%, I:II=5:95). 1 H NMR(CDCl 3 )δ: 7.27-7.48 (m, 10H), 5.02-5.06 (m, 3H), 4.25 (m, 1H), 3.22-3.32 (m, 2H), 1.94 (m, 2H), 1.51 (d, 3H) , 1.41 (m, 9H), 0.40-0.46 (m, 4H).

Embodiment 2

[0055]

[0056] Compound I (2g, 4.2mmol) was dissolved in THF (20mL), the temperature was lowered to 0°C, 40% NaOH solution (1g) was added, and the temperature was raised to room temperature to react for 4h, and 1M hydrochloric acid was added to adjust the pH to 1 H NMR(CDCl 3 )δ: 11.5 (s, 1H), 4.25 (m, 1H), 3.22-3.32 (m, 2H), 1.94 (m, 2H), 1.41 (m, 9H), 0.45-0.51 (m, 4H).

Embodiment 3

[0058]

[0059] Compound II (2.6g, 5.4mmol, I:II=5:95) was dissolved in THF (20mL), the temperature was lowered to 0℃, 40% NaOH solution (1.3g) was added, and the temperature was raised to room temperature to react for 4h, and 1M hydrochloric acid was added Adjust to pH 1 H NMR(CDCl 3 )δ: 11.0 (s, 1H), 4.22 (m, 1H), 3.17-3.22 (m, 2H), 1.89 (m, 2H), 1.38 (m, 9H), 0.42-0.50 (m, 4H).

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Abstract

The invention relates to the technical field of organic synthesis. The invention specifically relates to a preparation method of an antiviral drug ledipasvir chiral intermediate (S)-5-(tert-butyloxycarbonyl)-5-azaspiro [2, 4] heptane-6-carboxylic acid. The preparation method comprises the following steps: condensing 5-(tert-butyloxycarbonyl)-5-azaspiro [2.4] heptane-6-carboxylic acid racemate anda chiral amine resolution reagent to obtain amides (I) and (II); hydrolyzing the compound (I) to obtain a target compound (S)-5-(tert-butyloxycarbonyl)-5-azaspiro [2.4] heptane-6-carboxylic acid (III), hydrolyzing the compound (II) to obtain an enantiomer (IV), removing Boc from the compound (IV), performing configuration conversion to obtain a compound (VII), and performing amino protection on the compound (VII) to obtain the target compound (III). The invention provides a simple and convenient cost-reducing industrial production route for the chiral intermediate of the antiviral drug ledipasvir, and has the advantages of simple reaction operation, high chiral resolution yield and lower cost.

Description

Technical field [0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of the chiral intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid of Ledipavir chiral intermediate. Background technique [0002] Hepatitis C virus, referred to as hepatitis C for short, is a type of viral hepatitis caused by hepatitis C virus (HCV) infection. According to the World Health Organization, the global HCV infection rate is about 3%. HCV infection causes liver inflammation. As a result, liver function decreases or even fails. The pathological manifestations are mainly hepatocyte necrosis and lymphocyte infiltration. [0003] Ledipasvir (Ledipasvir), formerly GS-5885, is an NS5A protease inhibitor developed by Gilead Sciences. It is used in combination with the company’s other heavyweight anti-hepatitis C product, Sovaldi, under the trade name : Harvoni, the US FDA approved its listing on October 10, 20...

Claims

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Application Information

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IPC IPC(8): C07D209/54C07B57/00
CPCC07D209/54C07B57/00C07B2200/07Y02P20/55
Inventor 张中剑刘现军郑行行余飞飞黄文飞
Owner 苏州楚凯药业有限公司
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