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The preparation method of (s)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid
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A tert-butoxycarbonyl and azaspiro technology, which is applied in the directions of organic chemistry methods, chemical instruments and methods, and bulk chemical production, etc., can solve the problems of high market cost of compounds, complicated chiral separation operations, and unfavorable industrial production. , to achieve the effect of high chiral splitting yield, convenient configuration conversion, and avoiding loss
Active Publication Date: 2022-03-08
苏州楚凯药业有限公司
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[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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Embodiment 1
[0052]
[0053] HOBt (1.5g, 11mmol) and DCC (2g, 10mmol) were added to 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid racemate (2.4 g, 10 mmol) in THF (50 mL), stirred for 1 h, then added chiral benzylamine (2.5 g, 10 mmol). Warm up to room temperature for 3 h, 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 (yield 42%), 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), cooled to 0°C, added 40% NaOH solution (1g), warmed to room temperature for 4h, added 1M hydrochloric acid to adjust the pH1 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] Dissolve compound II (2.6g, 5.4mmol, I:II=5:95) in THF (20mL), cool down to 0°C, add 40% NaOH solution (1.3g), warm up to room temperature for 4h, add 1M hydrochloric acid Adjust to pH1 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 present invention belongs to the technical field of organic synthesis, and specifically relates to an antiviral drugledipasvir chiral intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylate The preparation method of the acid is to condense the 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid racemate with a chiral amine resolution reagent to obtain amides (I) and ( Ⅱ), the compound (I) is hydrolyzed to obtain the target compound (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (Ⅲ), after the compound (Ⅱ) is hydrolyzed The enantiomer (IV) is obtained, the compound (IV) is removed from the Boc to obtain (VII) through configuration conversion, and the compound (VII) is amino-protected to obtain the target compound (III). The invention provides a simple cost-reducing industrial production route for the antiviral drugledipasvir chiral intermediate, has simple reaction operation, high chiral resolution yield and low cost.
Description
technical field [0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of ledipasvir chiral intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid. Background technique [0002] Hepatitis C virus, referred to as hepatitis C, is a viral hepatitis caused by hepatitis C virus (HCV) infection. According to the statistics of the World Health Organization, the global HCV infection rate is about 3%. After HCV infection, it causes liver inflammation. As a result, liver function decline or even failure. The pathological manifestations are mainly hepatocytenecrosis and lymphocyte infiltration. [0003] Ledipasvir (Ledipasvir), formerly known as GS-5885, is an NS5A protease inhibitor developed by Gilead Sciences. It is used in combination with Sovaldi, another anti-hepatitis C heavy product of the company. The trade name is : Harvoni, approved by the U.S. FDA on October 10, 2014, and appro...
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