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Preparation method of ledipasvir intermediate

A technology of intermediates and compounds, which is applied in the field of preparation of ledipasvir intermediates, can solve the problems of price reaction raw materials, condensation reagent reaction purification difficulties, etc., and achieve the goal of not being easy to oxidize and discolor, reducing the residue of impurities, and improving the reaction yield Effect

Active Publication Date: 2016-09-28
ASTATECH CHENGDU BIOPHARM CORP
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to provide a preparation method of ledipasvir intermediate to solve the problem of unavoidable use of expensive reaction raw materials, condensation reagents and reaction purification difficulties in the existing synthesis process

Method used

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  • Preparation method of ledipasvir intermediate
  • Preparation method of ledipasvir intermediate
  • Preparation method of ledipasvir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] a) Add compound 1 (30.0g, 122.5mmol), MTBE (300ml) and NMM (14.8g, 146.9mmol, 1.2eq) into a 500ml three-necked flask, lower the internal temperature to T1 HNMR (400MHz, CDCl 3 ): δ8.52(s,1H),7.35(s,1H),7.01(s,1H),6.78-6.75(m,2H),4.15(s,1H),3.92-3.87(d,J=20.0 Hz,2H),3.03(s,1H),1.87-1.77(m,2H),1.70-1.68(m,2H),1.65-1.60(m,2H),1.50(s,9H),1.40-1.37( d, J=12Hz, 1H).

[0037] b) Add compound 3 (29.0g, 87.6mmol) into a 250ml three-necked flask, add DMF150ml, lower the internal temperature to T=-5-0°C, add NBS (15.6g, 87.6mmol, 1eq), and react for 0.5h after adding , the reaction was quenched with water, extracted with ethyl acetate (200ml*2), the organic layers were combined, washed with water, and concentrated under reduced pressure to obtain compound 4. Compound 4 was dissolved in MTBE (300ml), added acetic acid (26.3g, 438mmol, 5eq), heated to 55°C for 10h, washed with 5% NaOH aqueous solution, separated, washed the organic layer with water, concentrated to dryness, and ad...

Embodiment 2

[0039] a) Add compound 1 (30.0g, 122.5mmol) into a 500ml three-necked flask, add ethyl acetate (300ml), add NMM (14.8g, 146.9mmol, 1.2eq), and lower the internal temperature to T=-10°C-- 5°C, add isobutyl chloroformate (16.7g, 122.5mmol, 1eq) dropwise, react at temperature for 5h, then add compound 2, keep warm for one hour, return to room temperature and react for 8h, add water to quench, and use ethyl acetate ( 200ml*2) extraction, combined organic layers, washed the organic layer with water, and concentrated under reduced pressure to obtain the crude product of compound 3.

[0040] b) Add the crude product of compound 3 (40g, 120.8mmol) into a 500ml three-necked flask, add DMF200ml, cool the ice-salt bath to T=-5°C-5°C, add NBS (19.4g, 108.7mmol, 0.9eq), add After the reaction was completed for 0.5h, water was added to quench the reaction, extracted with ethyl acetate (200ml*2), the organic layers were combined, washed with water, and concentrated under reduced pressure to ...

Embodiment 3

[0042] a) Add compound 1 (50.0g, 204.1mmol) in a 1000ml three-necked flask, add isopropyl acetate (400ml), add triethylamine (24.7g, 245.0mmol, 1.2eq), drop to internal temperature T=-10 ℃--5℃, dropwise add pivaloyl chloride (25.0g, 122.5mmol, 1eq), after the dropwise addition is complete, T=-5℃-10℃ for 4h, then add 100ml of isopropyl acetate solution of compound 2 (23.2 g, 214mmol, 1.05eq), after adding, keep warm for one hour, slowly return to room temperature and react for 8h, add water to quench, extract with isopropyl acetate (300ml*2), combine the organic layers, and use 1N HCl aqueous solution ( 100ml), washed with water (100ml), the organic phase was concentrated under reduced pressure to obtain the crude product of compound 3, the crude product of compound 3 was dissolved by adding 5 times the mass of isopropyl acetate, heated and dissolved, concentrated to 1 times the volume, added 4 times the volume of petroleum ether to crystallize, Compound 3 was obtained, 54 g (p...

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Abstract

The invention discloses a preparation method of a ledipasvir intermediate shown as formula (III). The method is characterized by taking (1R, 3S,4S)-N-t-butyloxycarbonyl-2-azabicyalo[2.2.1] heptane-3-carboxylic acid and o-phenylenediamine as raw materials and synthesizing (1R, 3S,4S)-3-(6-bromine-1H-benzimidazole-2-yl)-2-azabicyalo[2.2.1] heptane-2-carboxylic acid tert-butyl ester by using an anhydride mixing method. The whole route is low in production cost and high in yield; the formed monoamide is easy to purify; the generation and the residual of impurities are reduced; the o-phenylenediamine used as the raw material is cheap and easily-available, is hard to oxidize and discolor and can be stored in bulks; the industrial production is facilitated. The formula (III) is described in the description.

Description

technical field [0001] The invention relates to a preparation method of a ledipasvir intermediate, which belongs to the field of medicine. Background technique [0002] Ledipasvir is an NS5A protease inhibitor developed by Gilead Sciences. After the compound completed Phase III clinical trials, the tablet of the fixed-dose combination of ledipasvir / sofosbuvir for the treatment of genotype I hepatitis C was included in the United States Pharmacopoeia on February 10, 2014. [0003] At present, patents such as US20130273005 and US2013324496 have reported the synthesis process of ledipasvir in detail, all of which involve the key intermediate (Ⅲ) shown in the following structure: [0004] [0005] For the preparation of the compound of formula (Ⅲ), the method reported in existing literature is through 4-bromo-1,2-phenylenediamine and (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-aza Bicyclo[2.2.1]heptane-3-carboxylic acid is condensed with 4-bromo-o-phenylenediamine under EDC.HCl / HO...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
CPCC07B2200/07C07D209/52
Inventor 陈兴胡刚何帅杰庄明晨杨佑喆
Owner ASTATECH CHENGDU BIOPHARM CORP
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