CN102993257A

CN102993257A - New fulvestrant preparation method

Info

Publication number: CN102993257A
Application number: CN 201110273964
Authority: CN
Inventors: 陈玮琳; 王腾; 刘燕兵; 廖贵林
Original assignee: HUZHOU RONGDA MEDICINE CO Ltd
Current assignee: HUZHOU RONGDA MEDICINE CO Ltd
Priority date: 2011-09-13
Filing date: 2011-09-13
Publication date: 2013-03-27

Abstract

The present invention provides a new fulvestrant synthesis method. The technical scheme of the method comprises: adopting 6-ketoestradiol as a starting raw material, and adopting a six-step reaction to prepare fulvestrant, wherein reaction conditions are mild, the total yield is about 40%, product purity is high, all the raw materials are domestic chemical products, operation is convenient, cost is low, and the method is applicable for large-scale production.

Description

A kind of new preparation method of fulvestrant

Technical field

The present invention relates to a kind of estrogen receptor (ER) inhibitor-lower a kind of new preparation process of adjusting

Background technology

Fulvestrant (Fulvestrant), chemistry 7 α-[9-(4,4,5,5,5-, five fluorine amyl group sulfinyls) nonyl] by name-female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3β, its structural formula is:

Fulvestrant is the anti-breast cancer new drug by the exploitation of Astrazeneca company.In 2002 in U.S.'s Initial Public Offering, and in 2004 by European Union's approval listing.Fulvestrant is the novel estrogen receptor blocker of a class, is used for the treatment of the postmenopausal women with advanced mammary cancer that the estrogen antagonist therapy for treating is invalid, estrogen receptor is positive.The listing of fulvestrant is to suffer from the postmenopausal women of mammary cancer to have brought new selection

US Patent No. 4659516 (EP0138504) discloses the synthetic method of a series of similar compounds of fulvestrant.This route obtains the finished product fulvestrant by the reaction of 10 steps from 6-dehydrogenation nandrolone acetic ester, reactions steps is very loaded down with trivial details, 7 α in the grignard reaction: 7 β=1.9: 1, and total molar yield is less than 10%.Its route is as follows:

The disclosed another kind of route of WO03031399 and WO02032922 also is from 6-dehydrogenation nandrolone acetic ester is raw material, used short synthetic route, but do not overcome the higher defective of impurity isomer 7 β content in the grignard reaction, its 7 α: 7 β=2.5: 1, and its intermediate does not all have the process of separation and purification, so the purifying of the finished product is very difficult.Its route is as follows:

US Patent No. 20060030552 and wo2006015081 then disclose the improvement route of upper 2 routes 7 α: the ratio of 7 β brings up to 7: 1-12: more than 1, but its step is longer, and have multistep to require column chromatography, be unfavorable for fairly large production, total recovery is not high.

Wo2009039700 discloses another synthesis mode, and the method makes fulvestrant through the reaction of 6 steps from estradiol is the beginning raw material, and multistep very low temperature (78 ℃) reaction and too much column chromatography are wherein arranged, and is not suitable for large-scale production.Its route is as follows:

For these reasons, be necessary to develop a kind of simple effectively, cheaply, be suitable for the method for suitability for industrialized production fulvestrant.

Summary of the invention

In order to address the above problem, the invention provides a kind of preparation method of fulvestrant.

Preparation method of the present invention can represent with following reaction formula:

Technical scheme of the present invention mainly may further comprise the steps:

(1) 6-ketoestradiol diacetate esters (Compound I I)

In a kind of aprotic polar solvent, such as amides, ketone, nitrile, methyl-sulphoxide, pyridine etc., preferred pyridine.Use a kind of esterification means commonly used protection hydroxyl, comprise acid anhydrides, acyl chlorides etc., first-selected aceticanhydride, aceticanhydride are suitably excessive, and temperature of reaction is at 0-100 ℃, preferred 25 ℃;

(2) 1-iodo-9-(4,4,5,5,5-, five fluorine, penta sulfenyl) nonane (compound IV) compound III is at methylene dichloride, in the inert solvents such as THF, use excessive acyl chlorides, such as methylsulfonyl chloride, Tosyl chloride etc., preferred active higher methylsulfonyl chloride and 9-(4,4,5,5,5-five fluorine penta sulfenyl)-and 1 nonyl alcohol is reacted into carboxylate, and temperature of reaction is at 0-40 ℃, preferred 25 ℃.Then in acetone with potassiumiodide generation substitution reaction, temperature of reaction is for refluxing, the reaction times is 12 hours, generates iodo compound IV

(3) 3,17 β-diacetate esters-7 α-[9-(4,4,5,5,5-, five fluorine, penta sulfenyl) nonyl]-female-1,3,5 (10)-triolefins-6-ketone

Compound I I and compound IV are at a kind of anhydrous non-protonic solvent, in ether, THF such as THF, use highly basic such as oxyhydroxide, potassium alcoholate, sodium alkoxide etc., preferred potassium tert.-butoxide, under lower temperature-78 ℃-0 ℃, alkylated reaction occurs, preferred-40 ℃ of temperature of reaction, reaction times 6-24 hour, preferred 12 hours.Product content is lower herein, needs to use column chromatography purification.The column chromatography eluent can be toluene, the sherwood oil mixed solution of ethyl acetate,

(4) 7 α-[9-(4,4,5,5,5-, five fluorine, penta sulfenyl) nonyl]-female-1,3,5 (10)-triolefins-3,17 β-diacetate esters

Compound V uses suitable reductive agent, and 6 carbonyl reductions are become methylene radical, such as Pd, and Pt, Ni sodium borohydride, the general reductive agent such as POTASSIUM BOROHYDRIDE, preferred palladium carbon.10% palladium carbon particularly preferably.Temperature of reaction 30-80 ℃, preferred 70 ℃, react and be normal pressure

(5) 7 α-[9-(4,4,5,5,5-, five fluorine, penta sulfenyl) nonyl]-female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3β

Compound vi is hydrolyzed through highly basic, generates compound vi I, and wherein alkali is sodium hydroxide or potassium hydroxide

(6) fulvestrant

Compound vi I uses general gentle oxygenant, and sulphur is oxidized to sulfoxide, and wherein oxygenant is sodium periodate, metachloroperbenzoic acid, hydrogen peroxide etc., preferred sodium periodate.Obtain the crude product column chromatography and re-use the ethyl acetate crystallization, obtain high-purity fulvestrant after making with extra care

The technical program prepares fulvestrant take the 6-ketoestradiol as starting raw material by six-step process, and reaction conditions is gentle, and total recovery is about 40%, and product purity is high, and all raw materials are all the production domesticization chemical product, and are easy and simple to handle, and cost is low, is suitable for large-scale production.

Specific embodiments:

Embodiment 1

With 9g 9-(4,4,5,5,5. five fluorine, penta sulfenyl)-1 nonyl alcohol (0.028mol) is dissolved in the 100ml methylene dichloride, adds 4ml N, the N-diisopropylamine joins in the reaction flask, cool to 10 ℃, slowly drip the 2.3ml methylsulfonyl chloride, add, 25 ℃ were reacted 2 hours, add the water washing organic layer 3 times, anhydrous sodium sulfate drying, concentrating under reduced pressure is done.Add 150ml acetone, logical nitrogen protection adds the 6g potassiumiodide, and rapid stirring refluxed 12 hours, reacted complete, and the evaporated under reduced pressure dissolving adds 100ml water and 100ml toluene, and organic layer washes with water 2 times again.Be evaporated to driedly, get the 11g brown oil, column chromatography obtains the faint yellow oily thing of 9g, yield 75%.

Embodiment 2

Under the nitrogen protection, 15g estradiol-6-ketone (52mmol) is dissolved in the pyridine of 150ml drying, drips the 50ml aceticanhydride about 10 ℃, dropwise, 25 ℃ of reactions are spent the night, and TLC follows the tracks of, and raw material disappears, and is evaporated to dried.Obtain faint yellow oily thing 17.5g, yield 92%.

Embodiment 3

10g6-ketoestradiol diacetate esters (26.5mmol) is dissolved among the 30mlTHF, and 0 ℃ of THF solution that adds potassium tert.-butoxide adds, 0 ℃ of reaction 2 hours, cool to-40 ℃, slowly be added dropwise to 18g 1-iodo-9-(4,4,5,5,5-, five fluorine, penta sulfenyl) the 50mlTHF solution of nonane (70mmol) dropwises, slowly be warmed up to 0 ℃, insulation reaction is spent the night.React complete, add entry and ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying is evaporated to driedly, obtains 15.5g, and use the ethyl acetate of 5%-20%: the sherwood oil column chromatography obtains weak yellow liquid to 10.8g, yield 59.2%.

Embodiment 4

With 3,17 β-diacetate esters-7 α-[9-(4,4; 5,5,5-, five fluorine, penta sulfenyl) nonyl]-female-1; 3,5 (10)-triolefins-6-ketone 11.8g (17.1mmol) are dissolved in the 150ml acetic acid; under the nitrogen protection; add 1g 10%Pd-C, be warmed up to 70 ℃, change nitrogen into hydrogen; insulation reaction 3 hours, TLC tracks to the raw material completely dissolve.Cooling is filtered, and filtrate adds 200ml ethyl acetate and 50ml water, separates organic layer, washing.Be concentrated into driedly, obtain oily matter 10.1g, yield 89%.

Embodiment 5

With reactant of upper step 7 α-[9-(4,4,5,5,5-, five fluorine, penta sulfenyl) nonyl]-female-1,3,5 (10)-triolefins-3,17 β-diacetate esters 10g (14.8mmol) is dissolved in the 100ml methyl alcohol, slowly adds the aqueous sodium hydroxide solution of 10g 50%.Room temperature reaction 5 hours, TLC follows the tracks of, and reacts complete, adds the 100ml ethyl acetate, tells the upper strata, water washing.Be concentrated into driedly, obtain the faint yellow oily thing of 7.9g, yield 91%.

Embodiment 6

18g is joined among 35ml methyl alcohol and the 100mlTHF, cool to 0 ℃, slowly drip 10% sodium periodate aqueous solution 150ml, add, 0 ℃ of insulation reaction 12 hours reacts complete, adds 150ml methylene dichloride and 50ml water, tell methylene dichloride, wash evaporated under reduced pressure 2 times.Add the oily matter that the 50ml acetic acid ethyl dissolution obtains, crystallization is 1 hour under 0 ℃ of stirring, filters the solid that obtains.After using the ethyl acetate decolorizing and refining behind the column chromatography, 30 ℃ of vacuum-dryings obtain the 12g white solid, yield 81%.

Claims

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

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

(1) Compound I and suitably excessive aceticanhydride, reaction generates compound II under 20-60 ℃ of environment, and wherein aceticanhydride also can be other protectiveness acid anhydrides;

(2) compound III in suitable solvent with methylsulfonyl chloride or Tosyl chloride etc. under 0-30 ℃ of environment, be reacted into carboxylate, be that suitable salt compounded of iodine replaces to generate compound IV

(3) substitution reaction under-78 ℃ to 0 ℃ environment, occurs and generates compound formula V in the non-proton organic solvents such as THF in formula II and formula IV

(4) compound V is through the reduction of 5%-10% palladium carbon, reacting generating compound formula VI, and wherein reductive agent also can be the reductive agent that other can reducing carbonyl, such as Pt-C, metallic reducing agent or the sodium borohydrides such as Ni, the general reductive agent such as POTASSIUM BOROHYDRIDE

(5) formula VI generates compound formula 7 through macromolecule alkali for hydrolysis, and wherein alkali is sodium hydroxide, the highly basic such as potassium hydroxide, and reaction solvent can be methyl alcohol, in the alcohols such as ethanol

(6) compound of formula VII uses suitable oxidant reaction to generate fulvestrant under 0-60 ℃ environment, and wherein oxygenant is sodium periodate, metachloroperbenzoic acid, hydrogen peroxide etc.