Process for preparation of lactone derivatives and intermediates thereof

一种化合物、独立地的技术，应用在制备内酯衍生物领域，能够解决产品de值不能达到所需水平等问题

Inactive Publication Date: 2019-06-04
PHARMA SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

By using the method described in Scheme 3, the γ-lactone can be scaled up to kilogram quantities, but the de value of the final product cannot reach the desired level

Method used

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  • Process for preparation of lactone derivatives and intermediates thereof
  • Process for preparation of lactone derivatives and intermediates thereof
  • Process for preparation of lactone derivatives and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0199] Embodiment 1: Preparation of 2-fluoropropionyl chloride (3)

[0200]

[0201] Chlorosulfonic acid (660 mL, 10 mol, 20 eq) was added to a solution of phthaloyl dichloride (1.4 L, 10 mol, 20 eq) and ethyl 2-fluoropropionate (600 g, 5 mol) at room temperature . The solution was heated at 120°C for 4 hours. 2-(R)-Fluoropropionyl chloride was distilled from the reaction mixture under reduced pressure and recovered as a colorless oil (320 g, 58.2%). 1 H-NMR (CDCl 3 , 400MHz): δ5.08 (dq, J = 48.8, 6.8Hz, 1H), 1.63 (dd, J = 22.8, 6.8Hz, 3H).

Embodiment 2

[0202] Example 2: Preparation of (4R)-3-(2-fluoropropionyl)-4-isopropyloxazolidin-2-one (4)

[0203]

[0204] Under a nitrogen atmosphere at -50°C, n-butyllithium (2.5M in hexane, 30mL, 75mmol, 1.1eq) was added to 4-(R)-4-isopropyl-2-oxazolidinone ( 8.8g, 68.2mmol, 1 equivalent) in dry THF (80mL) solution. After 30 minutes, 2-fluoropropionyl chloride (6.8 mL, 0.9 equiv) was added, and the solution was stirred at -50°C for 4 hours. Then with saturated NH 4 Cl solution (50mL) quenched the reaction, extracted with MTBE (80mL*2), washed with brine and washed with MgSO 4 dry. The solvent was removed under reduced pressure. The product was purified by silica (hexane / EtOAc=10 / 1) and recovered as a brown oil (9 g, 74.8%). 1 H-NMR (CDCl 3 ,400MHz):δ6.00(dm,J=49.2Hz,1H),4.27-4.53(m,3H),2.43(dm,J=52.6Hz,1H),1.63(td,J=23.2Hz,3H) , 0.92 (dq, J=17.8Hz, 6H).

Embodiment 3

[0205] Example 3: Preparation of (4S)-3-(2-fluoropropionyl)-4-isopropyloxazolidin-2-one (5)

[0206]

[0207] Under a nitrogen atmosphere at -50°C, n-butyllithium (2.5M in hexane, 75mL, 187mmol, 1.1 equiv) was added to 4-(S)-4-isopropyl-2-oxazolidinone ( 22g, 170mmol, 1 equivalent) in dry THF (200mL) solution. After 30 minutes, 2-fluoropropionyl chloride (17 mL, 153 mmol, 0.9 equiv) was added, and the solution was stirred at -50°C for 1 hour. After the starting material is completely consumed, it is then washed with saturated NH 4 Cl solution (125mL) quenched the reaction, extracted with MTBE (200mL*2), washed with brine and washed with MgSO 4 dry. The solvent was removed under reduced pressure. The product was purified by silica (Hexane / EtOAc = 10 / 1) and recovered as a brown oil (34 g, 83.3%). 1 H-NMR (CDCl 3 ,400MHz):δ5.93(dm,J=48.8Hz,1H),4.19-4.17(m,3H),2.35(dm,J=52.8Hz,1H),1.55(td,J=23.6Hz,3H) , 0.85 (dq, J=18Hz, 6H).

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Abstract

A novel process for the preparation of lactone derivatives, and intermediates thereof is described. The lactone derivatives are important precursors for the synthesis of anti-hepatitis C virus agents,including sofosbuvir.

Description

technical field [0001] The present invention relates to novel processes for the preparation of lactone derivatives and novel intermediates thereof. In particular, the present invention relates to more efficient methods for the preparation of lactone derivatives, which are important precursors for the synthesis of anti-hepatitis C viral agents, including sofosbuvir. Background technique [0002] Hepatitis C virus (HCV) infection represents a global health threat requiring more effective treatment options. According to the World Health Organization (WHO), there are 130 million to 170 million people worldwide with detectable HCV antibodies, and about 60-85% of them develop chronic disease, leading to liver cirrhosis (5-25%) and hepatocellular carcinoma ( 1-3%) and liver failure. Although existing treatments including pegylated interferon- (Peg-IFN) and ribavirin (RBV) exist, due to various adverse reactions, intolerance, low efficacy and in These existing treatments are subo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33C07D263/26
CPCC07D307/33C07D263/26Y02P20/55
Inventor 陈平彭少平李因强李大峰董学军
Owner PHARMA SHANGHAI
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