Synthetic method of fulvestrant side chain intermediate

A technology of fulvestrant and its synthesis method, which is applied in the field of drug synthesis, can solve problems such as unfavorable industrial production, pungent smell, and relatively large environmental impact, and achieve improved reagent use efficiency, avoiding environmental pollution, and production process operation simple effect

Active Publication Date: 2017-11-07
连云港恒运药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In the prior art, methanesulfonyl chloride or p-toluenesulfonyl chloride are used as esterification reagents, because the acid chloride is very easy to hydrolyze, has a pungent smell, and reacts violently, which is not conducive to industrial production and has a greater impact on the environment

Method used

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  • Synthetic method of fulvestrant side chain intermediate
  • Synthetic method of fulvestrant side chain intermediate
  • Synthetic method of fulvestrant side chain intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of p-toluenesulfonic acid supported on molecular sieve

[0028] Weigh 100 g of 4A molecular sieve, soak in 1 L of 25% p-toluenesulfonic acid aqueous solution for 30 hours, and filter with suction. Dry it in an oven at 105°C for 8 hours, and put it in a desiccator after cooling for later use. The loading of p-toluenesulfonic acid was determined to be 35.6% by gravimetric method.

Embodiment 2

[0030] Add 20ml of pentafluoropentanol to the reaction flask, add 10g of p-toluenesulfonic acid supported on molecular sieve prepared according to Example 1, react at 65°C for 4 hours, filter and recover the molecular sieve, naturally cool and crystallize the filtrate, and recover pentafluoropentanol by filtration, the filter cake Dry to obtain 5.6 g of pentafluoropentanol p-toluenesulfonate, with a yield of 85% based on p-toluenesulfonic acid.

Embodiment 3

[0032] Add 30ml of pentafluoropentanol to the reaction flask, add 10g of p-toluenesulfonic acid loaded on molecular sieve prepared according to Example 1, react at 50°C for 6 hours, filter and recover the molecular sieve, naturally cool and crystallize the filtrate, and recover pentafluoropentanol by filtration, the filter cake After drying, 4.9 g of pentafluoropentanol p-toluenesulfonate was obtained, with a yield of 74% based on p-toluenesulfonic acid.

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Abstract

The invention relates to a preparation method of a side chain intermediate of fulvestrant, specifically, pentafluoropentanol reacts with p-toluenesulfonic acid loaded on a molecular sieve to prepare pentafluoropentanol p-toluenesulfonate, pentafluoropentanol 4,4,5,5,5‑pentafluoropentylisothiourea methanesulfonate is obtained by reacting p-toluenesulfonate with thiourea in ethanol. The invention avoids the use of acid chlorides, optimizes the production process, improves the reaction yield and reduces environmental pollution.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing a fulvestrant side chain intermediate. Background technique [0002] Fulvestrant, molecular formula C 32 h 47 f 5 o 3 S, the chemical name is 7-α-[9-(4,4,5,5,5-pentafluoropentasulfinyl)nonyl]estra-1,3,5-(10)-triene- 3,17-β-diol, the structural formula is as follows: [0003] [0004] The structure of fulvestrant can be divided into two parts, estradiol and 7α-alkyl group, and its preparation method can be summarized into two general directions at present: one is to use the more expensive dehydronandrolone acetate as the mother nucleus to carry out A series of reactions are performed to obtain fulvestrant; the second is to prepare fulvestrant by taking the derivative of estradiol as the starting material as the nucleus. The difficulty and focus of the synthesis is how to connect the 7α-alkyl group in the core structure, namely: the synthesis of 9-br...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C309/73C07C303/28C07C335/32C07C309/30C07C303/32
CPCY02P20/582C07C303/28C07C303/32C07C335/32C07C309/73C07C309/30
Inventor 张丰盈丁丹丹杨芳芳王义飞
Owner 连云港恒运药业有限公司
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