New preparation method of oseltamivir intermediate

A technology of oseltamivir and intermediates, applied in the field of compound synthesis, can solve the problems of inability to significantly improve the total yield, unsafe, limited sources, etc., achieve great feasibility and prospects, cheap and easily available reagents, and simple operation. Effect

Active Publication Date: 2015-03-25
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that less safe sodium azide and intermediates containing sodium azide are used. At the same time, the raw material shikimic acid is extracted from traditional Chinese medicine, and the production area is limited to China and Southeast Asia. The source is limited and cannot meet the larg...

Method used

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  • New preparation method of oseltamivir intermediate
  • New preparation method of oseltamivir intermediate
  • New preparation method of oseltamivir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The preparation of compound shown in formula III

[0054]

[0055] Add the compound shown in formula II (510.0mg, 1.0mmol) and 10mL of methanol to a 50mL reaction bottle to dissolve, add 2mL of 2mol / L hydrochloric acid, stir at room temperature, and react for about 6 hours. TLC traces the reaction to the compound shown in structural formula II. After the disappearance of the starting compound, the reaction was stopped, and the solvent was removed by rotary evaporation to obtain a substantially pure compound represented by structural formula III with a yield of 98%.

Embodiment 2

[0057] The preparation of compound shown in formula IV

[0058]

[0059]The compound shown in formula III (453mg, 1.0mmol) was dissolved in 20mL of dichloromethane, cooled to 0°C, and ethyl chloroformate (109mg, 1.0mmol) and triethylamine (202mg, 2.5mmol) were added to react for half an hour and gradually React at room temperature for 1 hour, remove the solvent by rotary evaporation, add hydroxylamine hydrochloride (104 mg, 1.5 mmol) and 20 mL of methanol, stir at room temperature, stop the reaction after about 4 hours of reaction, remove the solvent by rotary evaporation, add about 30 mL of water to the system, Separate the organic phase, add 5 mL of 1N dilute hydrochloric acid, extract with dichloromethane (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain the substantially pure compound shown in formula IV. The yield 92%.

[0060] 1HNMR (400MHz, CDCl3) 8.02(s, 1H), 7.38(d, J=8.0Hz, 2H), 7.07...

Embodiment 3

[0063] The preparation of compound shown in formula V

[0064]

[0065] Dissolve the compound shown in Formula IV (454mg, 1.0mmol) in 10mL of dichloromethane, then add triethylamine (166μL, 1.2mmol), 4mL of acetic anhydride, react at room temperature for about half an hour, stop the reaction, and rotavap to obtain essentially The pure compound represented by formula V has a yield of 99%.

[0066] 1HNMR (400MHz, CDCl3) 7.38 (d, J = 8.0Hz, 2H), 7.07 (d, J = 8.0Hz, 2H), 4.70-4.80 (m, 1H), 4.05-4.17 (m, 1H), 4.02 ( t,J=3.2Hz,1H),3.86-3.98(m,1H),3.75(m,1H),3.54(m,1H),3.17(quintet,J=4.8Hz,1H),2.76(dt,J =13.2,3.6Hz,1H),2.68(dt,J=13.2,3.6Hz,1H),2.31(s,3H),2.28(q,J=13.2Hz,1H),2.17(s,3H),1.28 -1.48(m,2H),1.23(t,J=7.2Hz,3H),1.03-1.18(m,2H),0.76(t,J=7.2Hz,3H),0.63(t,J=7.2Hz, 3H);

[0067] HRMS (ESI) 533.1937 [(M+Na)+].

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Abstract

The invention provides a new method for preparing an intermediate (VI) of oseltamivir shown in a formula (I). Starting from a known intermediate (II) reported in a document, chiral acetyl ammonia is built based on a key lossen rearrangement reaction step to obtain a known oseltamivir intermediate structure in the document, so that the use operation of the dangerous sodium azide is avoided, and the high reaction yield is maintained. The method has the advantages that operation is safe and convenient, cheap raw materials are cheap and available. The formula is shown in the specification.

Description

technical field [0001] The invention relates to the field of compound synthesis, in particular to a new preparation method of an oseltamivir intermediate. Background technique [0002] The molecular formula of oseltamivir is C 16 h 28 N 2 o 4 , the chemical name is: (3R,4R,5S)-4-acetamide-5-amino-3-(1-propoxyethyl ester)-1-cyclohexene-1-carboxylic acid ethyl ester, the structural formula is as follows: [0003] [0004] Jointly developed by Gilead Company of the United States and Roche Company of Switzerland, it is made into a medicine in the form of its phosphate salt. The trade name is Tamiflu. It was launched in Switzerland in 1999 and approved to be listed in China in 2002. It is currently recognized as the most effective anti-avian flu It is also a national strategic reserve drug. Therefore its synthesis is very important. [0005] The synthetic route jointly developed by Gilead Company of the United States and Roche Company of Switzerland uses shikimic acid as...

Claims

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Application Information

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IPC IPC(8): C07C323/61C07C319/20
Inventor 拉吉夫·库马尔·沙玛李英姿
Owner SUNSHINE LAKE PHARM CO LTD
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