CN102993259A

CN102993259A - Preparation method of fulvestrant intermediate

Info

Publication number: CN102993259A
Application number: CN 201110278101
Authority: CN
Inventors: 陈玮琳
Original assignee: Individual
Current assignee: Individual
Priority date: 2011-09-15
Filing date: 2011-09-15
Publication date: 2013-03-27

Abstract

The invention provides a novel synthetic method of a fulvestrant intermediate. The technical scheme is as follows: the novel synthetic method comprises the following steps of: carrying out 7-site alkylation addition on 6-carbonyl estradiol diacetate and 1,9-halogenated bi-nonane under the action of potassium tert-butoxide; then carrying out hydrogenation reduction by using palladium carbon, so as to remove 6-site carbonyl; subsequently, condensing the product obtained from the former step with penta-fluorin amyl alcohol methyl sulfonyl ester under an alkaline condition; and finally, hydrolyzing 3-site and 17-site ester groups. The fulvestrant intermediate can be obtained by only four steps of reaction in all, the reaction condition is moderate, the raw materials are all domestic chemical products, and the preparation method is easy to operate and low in cost, and is suitable for industrial production.

Description

A kind of preparation method of fulvestrant intermediate

Technical field

The present invention is a kind of preparation method of fulvestrant intermediate, and (formula V) is as follows for its structure:

Background technology

Fulvestrant is a kind of estrogen antagonist, and it reduces its effect take the female acceptor of breast cancer cell as target spot, but is the antiestrogen of unique widespread use after tamoxifen effect failure, is the choice drug for the treatment of at present hormone-sensitive type mammary cancer.Wherein relate to a crucial intermediate (7a, 17b)-7-[9-[(4,4,5,5,5-, five fluorine amyl groups) sulphur] nonyl] female steroid-1,3,5 (10)-triolefins-3, the 17-glycol, its purity is very large to the quality influence of fulvestrant.Now existing more bibliographical information its synthetic as,

European patent EP 0138504 and US Patent No. 4659516 have been reported the general synthetic method with the fulvestrant similar compound, and its crucial synthetic method is that 7 form replaces in its structural formula.This method step is longer, and yield is very undesirable.World patent WO0232922 and WO03031399 had reported again its special route that improves afterwards, and its step is greatly reduced, and yield also increases.

The described synthetic route of US Patent No. 20060030552 and WO2006015081 then effectively reduces the ratio of the isomer of 7 bit formats reaction, but used raw material is still expensive, and cost is very high.

US Patent No. 2010174101 has been used different composition principles 7 alkylations, has also obtained certain achievement, but this route conditions is harsh, and yield is lower, is not suitable for large-scale production.

Nowadays fulvestrant usage quantity and range of application rapid growth for this reason, need to find a kind ofly can overcome above problem, can mass-producing synthesize the method for highly purified fulvestrant intermediate.

Summary of the invention

The invention provides one very simply effectively, the method for the fulvestrant key intermediate that is produced on a large scale.Use 6-carbonyl estradiol diacetate esters and 1,7 alkylation additions occur in 9-dihalo nonane under the potassium tert.-butoxide effect, and then use palladium carbon hydrogenating reduction to remove 6 carbonyls, subsequently under alkaline condition with the ester condensation of Pentafluorobenzyl pentanol methylsulfonyl, be hydrolyzed at last 3 and 17 ester groups.Altogether only need the reaction of 4 steps, it is as follows just can to obtain fulvestrant intermediate synthetic line:

Detailed description:

1) in the solvent such as THF of drying, under the suitable temperature as-40-0 ℃ between, under the effect of highly basic, make 7 deprotonations of 6-carbonyl estradiol diacetate esters (formula I), with 1,9-dihalo nonane such as 1,9-, two bromononane generation addition reactions.Its substitution product is purer single optical isomer under lower temperature, and after obtaining Compound I I and using column chromatography purification, the HPLC purity is more than 95%, and also purifying not directly carries out the next step.

2) in acidic medium such as acetic acid, use 6 carbonyls of palladium carbon hydrogenating reduction.Temperature of reaction can be finished between 20-100 ℃ more rapidly, obtains the formula III compound.

3) the formula III compound after 6-20 hour, behind the generation mercaptan, obtains product IV with the ester condensation of Pentafluorobenzyl pentanol methylsulfonyl with the thiocarbamide back flow reaction again under alkaline condition in toluene

4) compound IV is hydrolyzed under strong alkaline condition and obtains fulvestrant intermediate V, and purity can reach more than 95% behind the use rapid column chromatography

Specific embodiments:

Embodiment 1

In reaction flask, add 6-carbonyl estradiol diacetate esters and THF, cool to 0 ℃, slowly add potassium tert.-butoxide, add and continue reaction 1 hour.Then continue to cool to-20 ℃, drip the THF solution of 1,9-, two bromononanes, add and slowly be warmed up to 0 ℃ afterwards.React after raw material finishes less than 1%. reactions and add entry and methylene dichloride, separate the upper strata after, wash 3 times.40 ℃ of vacuum concentration obtain yellow liquid, and purifying does not directly carry out next step.

Embodiment 2

Products obtained therefrom among the embodiment 1 is joined in the reactor, pass into the nitrogen replacement air 3 times after adding acetic acid, add again palladium carbon, begin to warm to 50 ℃, change nitrogen into hydrogen, be reacted to raw material less than after 1%.Cooling, filter out catalyzer after, add entry and toluene, after organic layer uses salt water washing 3 times, 45 ℃ of vacuum concentration, the oily matter that obtains obtains weak yellow liquid after using rapid column chromatography.

Embodiment 3

Embodiment 2 products obtained therefroms are joined in the toluene, add thiocarbamide, refluxed 12 hours, then cooling is concentrated into dried.Add the sticky solid that the DMF dissolving obtains under the room temperature, then add 20% aqueous sodium hydroxide solution, under rapid stirring, add subsequently Pentafluorobenzyl pentanol methylsulfonyl ester, reacted 30 minutes, use TLC (ethyl acetate and the agent of sherwood oil Mixed Expansion) to follow the tracks of raw material to disappearing.React complete rear adding toluene and water, organic layer saturated common salt water washing 3 times.Be concentrated into do after, directly carry out next step

Embodiment 4

Embodiment 3 resulting products are added in the reactor, add methyl alcohol and potassium hydroxide aqueous solution, 30 ℃ were reacted 2 hours, use TLC (ethyl acetate and the agent of sherwood oil Mixed Expansion) to follow the tracks of raw material to disappearing, react and add entry and ethyl acetate after complete, organic layer washes 3 times with water after nearly neutrality, is concentrated into dried, obtain a faint yellow oily thing after using rapid column chromatography, content is greater than 95%.

Claims

1. a structural formula is suc as formula the compound of V:

2. the preparation method of a fulvestrant intermediate is characterized in that, may further comprise the steps:

4) compound IV is hydrolyzed under strong alkaline condition and obtains fulvestrant intermediate V, and purity can reach more than 95% behind the use rapid column chromatography.