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Continuous synthesis method of oseltamivir phosphate intermediate

A technology for oseltamivir phosphate and intermediates, which is applied in the field of continuous synthesis of oseltamivir phosphate intermediates, can solve problems such as safety accidents, equipment corrosion, strong corrosion, etc., to prevent safety accidents, avoid corrosion, The effect of ensuring production safety

Active Publication Date: 2019-09-03
湖南华腾制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Among them, the step of silane reduction, namely Two technical difficulties are involved: one is that the reaction needs to be carried out at an ultra-low temperature below -32°C, and it is even necessary to control the temperature below -40°C in industrial production, so liquid nitrogen is needed to cool down, which is costly; It needs to be carried out at ultra-low temperature and has high requirements for reaction equipment. Usually, only stainless steel reaction kettles can be used. However, titanium tetrachloride is extremely corrosive to stainless steel equipment, and it is very prone to leakage problems caused by equipment corrosion, which is easy to cause security incident

Method used

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  • Continuous synthesis method of oseltamivir phosphate intermediate
  • Continuous synthesis method of oseltamivir phosphate intermediate
  • Continuous synthesis method of oseltamivir phosphate intermediate

Examples

Experimental program
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Embodiment 1

[0030]

[0031] Add mesylate (compound II, 5.5g, 15.8mmol) and triethylsilane (2.38g, 20.5mmol) into dichloromethane (32g) and stir to dissolve to obtain solution 1. Titanium tetrachloride (3.3 g, 17.3mmol) was added into dichloromethane (20g) to obtain solution 2, solution 1 was pumped into the microchannel reaction with pump A at a speed of 1g / min and solution 2 was simultaneously pumped into the microchannel reaction with pump B at a speed of 0.58g / min The reaction is carried out in the microchannel of the device (coiled tube, length 26m, equivalent diameter 4mm), the temperature is set to -15°C, the retention time of the reaction solution is 20min, and the continuous reaction solution is obtained. After the reaction is completed by HPLC detection, the continuous reaction solution The solution was poured into ice water to extract the liquid separation, and then saturated NaHCO 3 Washing, separating, collecting the organic phase, drying and concentrating to obtain 5.5 g o...

Embodiment 2

[0034]

[0035] Add mesylate (compound II, 5.5g, 15.8mmol) and triethylsilane (2.75g, 23.7mmol) into dichloromethane (35.8g) and stir to dissolve to obtain solution 1. Titanium tetrachloride ( 3.3g, 17.3mmol) was added in dichloromethane (18g) to obtain solution 2, solution 1 was pumped into the microchannel reaction with pump A at a speed of 2g / min and solution 2 was simultaneously pumped into the microchannel reaction with pump B at a speed of 1g / min React in the microchannel (coil pipe, length 10m, equivalent diameter 5mm), temperature is set to -20 ℃, and the retention time of reaction liquid is 30min, obtains continuous reaction liquid, HPLC detects that reaction is finished, and this continuous reaction The solution was poured into ice water to extract the liquid separation, and then saturated NaHCO 3 Washing, separating, collecting the organic phase, drying, and concentrating to obtain 5.2 g of compound I.

[0036] After calculation, the yield of compound I in Examp...

Embodiment 3

[0038]

[0039] Add mesylate (compound II, 5.5g, 15.8mmol) and triethylsilane (1.83g, 15.8mmol) into dichloromethane (16.8g) and stir to dissolve to obtain solution 1. Titanium tetrachloride ( 3.3g, 17.3mmol) was added to dichloromethane (16.8g) to obtain solution 2, and solution 1 was pumped simultaneously with pump A at a rate of 0.5g / min and solution 2 was simultaneously pumped with pump B at a rate of 0.5g / min Enter in the microchannel of microchannel reactor (coil pipe, long 50m, equivalent diameter 1mm) to react, temperature is set to-20 ℃, and the retention time of reaction solution is 10min, obtains continuous reaction solution, HPLC detects that reaction is finished, and this The continuous reaction solution was poured into ice water for extraction and separation, and then saturated NaHCO 3 Wash, separate, collect the organic phase, dry and concentrate to obtain 5.0 g of compound I.

[0040] After calculation, the yield of compound I in Example 3 was 90.7%.

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Abstract

The present invention relates to a continuous synthesis method of an oseltamivir phosphate intermediate, wherein methanesulfonate, triethylsilane, dichloromethane and titanium tetrachloride are subjected to a reaction in a micro channel reactor at a temperature of -10 to -20 DEG C according to a molar ratio of 1:(1-1.5):(25-40):(1-1.5), wherein the residence time of the reaction materials is 10-30min. According to the present invention, the method does not need to carry out the reaction at an ultra-low temperature, and does not require the use of a stainless steel reaction kettle as a reaction device, such that the occurrence of safety accidents is avoided.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a continuous synthesis method of an oseltamivir phosphate intermediate. Background technique [0002] Oseltamivir phosphate (Tamiflu) is considered to be the most effective and specific influenza treatment drug at present. It is a prodrug of influenza neuraminidase type A and type B inhibitors, and its chemical name is (3R ,4R,5S)-4-acetamide-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester, the structural formula is as follows: [0003] [0004] Oseltamivir phosphate currently on the market is exclusively produced by Roche Pharmaceuticals, its generic name is Tamiflu, and its chemical substance registration number CASRN is 204255-11-8. Tamiflu was approved by the FDA in 1999 to be marketed in the United States, and in July 2004 was approved to be marketed in China. Tamiflu is a very effective drug for influenza treatment, with good safety, drug ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/30C07C309/66
CPCC07B2200/07C07C303/30C07C2601/16C07C309/66
Inventor 陈芳军张安林陈毅征蒋江平赵春晖
Owner 湖南华腾制药有限公司
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