CN110128497A - A kind of fulvestrant preparation method - Google Patents
A kind of fulvestrant preparation method Download PDFInfo
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- CN110128497A CN110128497A CN201810135074.4A CN201810135074A CN110128497A CN 110128497 A CN110128497 A CN 110128497A CN 201810135074 A CN201810135074 A CN 201810135074A CN 110128497 A CN110128497 A CN 110128497A
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Abstract
The present invention provides a kind of synthetic methods that fulvestrant is new, and reaction condition is mild, and route is simple, and each reaction intermediate yield and purity are higher, do not need column chromatography, can be obtained by the fulvestrant of high-purity by recrystallization, are suitble to industrialized production.For the present invention the specific technical proposal is: in a solvent, type I compound and reagent carry out II compound of halogenating reaction production, II compound of formula and thiocarbamide III compound of back flow reaction production in a solvent；Pass through nucleophilic substitution, V compound of hydrolysis production in lye and III compound of organic solvent Chinese style and IV compound of formula；In a solvent, V compound of formula is oxidized to fulvestrant through peracetic acid hydrogen peroxide oxidation system.
Description
Technical field
The invention belongs to pharmaceutical chemistry to synthesize field, and in particular to a kind of fulvestrant preparation method.
Background technique
Fulvestrant, molecular formula C32H47F5O3S, the entitled 7 α-[9- (4,4,5,5,5- five fluorine amyl group sulfinyl) of chemistry
Nonyl] female black -1,3,5 (10)-triolefin -3,17- beta-diol, structural formula is as follows:
Patent US4659516 describes the preparation method of fulvestrant, and the smell of raw materials used five fluorine amyl hydrosulfide makes us making
It vomits, and starting material is more expensive is not easy to buy, the purity and yield of products obtained therefrom is not high, is not suitable for industrialized production, the work
The synthetic route of skill is as follows:
Patent WO2003031399 describes the preparation method of fulvestrant, this route methods severe reaction conditions is related to
Hydrogenation, amplifying operation is dangerous, and yield and quality be not high, is not suitable for industrialized production, the synthetic route of the technique is such as
Under:
Patent US20060030552 describes the preparation method of fulvestrant, and the route raw material is simple and easy to get, reaction condition
Mildly, reaction step is simple, but qualified fluorine dimension department can just be obtained by being easy to generate double sulphur impurities and have to pass through column chromatography
Group's product, the synthetic route of the technique are as follows:
To sum up, the prior art there are unstripped gas highly seasoned, price, severe reaction conditions, it is difficult to amplification production, impurity is more,
The disadvantages such as yield and purity are low.
Summary of the invention
The present invention is optimized and is improved in prior art basis, provides a kind of new fulvestrant synthetic method,
Reaction raw materials are commercialized products, and reaction condition is mild, and route is simple, each reaction intermediate yield and purity compared with
Height does not need column chromatography, can be obtained by the fulvestrant of high-purity by repeated recrystallize, is suitble to industrialized production.
The present invention the specific technical proposal is:
In a solvent, formula I and reagent carry out halogenating reaction production II, and back flow reaction generates in a solvent for formula II and thiocarbamide
Formula III:
Pass through nucleophilic substitution in lye and organic solvent Chinese style III and formula IV, hydrolysis production V:
In a solvent, formula V is oxidized to fulvestrant through peracetic acid hydrogen peroxide oxidation system:
Preferably, the step 1) formula II prepares agents useful for same and is selected from thionyl chloride or phosphorus oxychloride, R Cl.
Preferably, step 1) formula II prepares the solvent and is selected from ethyl acetate, acetone, methylene chloride, DMF, acetonitrile, first
One or more of pure and mild ethyl alcohol, more preferably selects one or both of ethyl acetate and methylene chloride.
Preferably, step 1) formula III preparation described in solvent be selected from DMF, acetonitrile, methanol, ethyl alcohol, isopropanol, butanol and
One or more of water more preferably selects one or both of isopropanol and ethyl alcohol.
It preferably, further include re-crystallization step during step 1) preparation formula III, recrystallization method particularly includes: end of reaction
Feed liquid be concentrated under reduced pressure into 60 DEG C without fraction, recrystallization solvent is added into reaction flask and stirs 30 minutes, is cooled to 0~10 DEG C,
Stirring 120 minutes filters, 60 DEG C of decompression dryings.
Preferably, the recrystallization solvent of step 1) preparation formula III is selected from ethyl acetate, acetone, methylene chloride, toluene, hexamethylene
One or more of alkane and normal heptane more preferably select one or more of methylene chloride, toluene and ethyl acetate.
Preferably, organic solvent used in step 2) nucleophilic substitution reaction is DMF, and lye is 50% potassium hydroxide solution.
Preferably, reaction solvent for use is ethyl acetate and 4% acetum after step 2) hydrolysis.
Preferably, during step 3) prepares fulvestrant, solvent for use is ethyl acetate.
It preferably, further include re-crystallization step during step 3) prepares fulvestrant, recrystallization solvent for use is selected from second
One or more of acetoacetic ester, acetone, methylene chloride, hexamethylene and normal heptane, more preferably select methylene chloride and ethyl acetate
One or both of.
It is further preferred that II intermediate of formula the preparation method comprises the following steps:
Pentafluorobenzyl pentanol, reaction dissolvent and triethylamine are put into reaction flask, starts stirring, is cooled to 0~10 DEG C, are started slow
Dropwise addition reagent, 0~10 DEG C of temperature control.It is added dropwise and is warming up to 20 DEG C, the reaction was continued 2 hours.End of reaction is added into reaction flask
Purified water stirs 10 minutes, stands liquid separation, discards water phase.Organic phase is concentrated to dryness, and obtains II intermediate of formula.
The reagent is selected from thionyl chloride or phosphorus oxychloride.
The reaction dissolvent is preferably methylene chloride；By quality g: in terms of volume mL, reaction dissolvent additional amount is preferably five fluorine
Amylalcohol: reaction dissolvent 1:6-16.
The structural formula of the Pentafluorobenzyl pentanol may be:
It is further preferred that III intermediate of formula the preparation method comprises the following steps:
II intermediate of throw-in type, thiocarbamide and reaction dissolvent in reaction flask, stirring are warming up to 80~85 DEG C of reflux, heat preservation reflux
Reaction 12~14 hours, end of reaction, feed liquid are concentrated under reduced pressure into 60 DEG C without fraction, recrystallization solvent stirring are added into reaction flask
30 minutes, it is cooled to 0~10 DEG C, is stirred 120 minutes, is filtered, 60 DEG C of decompression dryings obtain III intermediate of formula.
Reaction dissolvent used in preparation formula III is selected from one of DMF, acetonitrile, methanol, ethyl alcohol, isopropanol, fourth alcohol and water
Or it is several, more preferably select one or both of isopropanol and ethyl alcohol.
By quality g: in terms of volume mL, reaction dissolvent additional amount is preferably II intermediate of formula: reaction dissolvent 1:6-16.
Recrystallization solvent is preferably methylene chloride；By quality g: in terms of volume mL, recrystallization solvent additional amount is preferably formula II
Intermediate: recrystallization solvent 1:6-16.
It is further preferred that V intermediate of formula the preparation method comprises the following steps:
III intermediate of formula, organic solvent and formula IV are added into reaction flask, stirs to being completely dissolved, is cooled to 0~10 DEG C,
Lye is slowly added dropwise, controls interior 0~10 DEG C of temperature, drips off 0~10 DEG C of temperature control and be stirred to react 90 minutes, be warming up to 40 DEG C, be added
70mL purified water is stirred to react 2 hours.Ethyl acetate and 4% acetum is added, continues stirring 10 minutes, stands 10 minutes,
Liquid separation.Organic to be added to 35mL saturated salt solution agitator treating, organic phase is dry with anhydrous sodium sulfate, filters, and filtrate decompression is dense
60 DEG C are reduced to without efflux, obtains V intermediate of formula.
The organic solvent is preferably DMF；By quality g: in terms of volume mL, organic solvent additional amount is preferably among formula III
Body: organic solvent 1:10-20.
The lye is preferably 50% potassium hydroxide solution.
By quality g: in terms of volume mL, ethyl acetate additional amount is preferably III intermediate of formula: ethyl acetate 1:10-20.Into
The step of one step is preferred, and intermediate V prepares fulvestrant are as follows:
V intermediate of throw-in type, reaction dissolvent and glacial acetic acid in reaction flask, stirring are cooled to 0~5 DEG C, are slowly added dropwise 30%
Hydrogen peroxide solution controls interior 20~25 DEG C of temperature, is stirred to react 13~14 hours, and end of reaction is cooled to 0~5 DEG C, is added dropwise 10%
Sodium sulfite solution quenching reaction.Liquid separation, organic layer are added 50mL saturated salt solution and stir 10 minutes, stand, layering.Organic phase
It is dry with anhydrous sodium sulfate.It filters, filtrate decompression is concentrated into 60 DEG C without efflux, obtains off-white color fulvestrant crude product, crude product is used
Recrystallization solvent repeatedly crystallizes, and at least 2 times, crystallizes to obtain white fulvestrant.
Reaction dissolvent is preferably ethyl acetate；By quality g: in terms of volume mL, reaction dissolvent additional amount is preferably among formula V
Body: reaction dissolvent 1:6-16.
Recrystallization solvent is preferably ethyl acetate.
Reaction condition of the present invention is mild, and route is simple, and each reaction intermediate and product yield and purity are higher, does not need column
Chromatography, can be obtained by the fulvestrant of high-purity by repeated recrystallize, and 99.8% or more purity is suitble to heavy industrialization
Production.
Specific embodiment
The present invention is further illustrated below by embodiment.Should correct understanding: the embodiment of the present invention be only
Be for illustrating the present invention, rather than limiting the invention, so, to of the invention simple under the premise of method of the invention
It improves and belongs to the scope of protection of present invention.
The mass spectrum of fulvestrant: [M-H]-605.3095。
The mass spectrum of intermediate III: [M+H]+237.2082。
Impurity sulfone structural formula:
Impurity A structural formula:
Impurity A oxidation structure formula:
Embodiment 1
Put into reaction flask Pentafluorobenzyl pentanol (5.0g, 0.028mol), 30mL methylene chloride and triethylamine (3.7g,
0.037mol), stirring is started, is cooled to 0~10 DEG C, starts to be slowly added dropwise thionyl chloride (4.0g, 0.0336mol), temperature control 0~
10℃.It is added dropwise and is warming up to 20 DEG C, the reaction was continued 2 hours.25mL purified water, stirring are added into reaction flask for end of reaction
10 minutes, liquid separation is stood, water phase is discarded.Organic phase is concentrated to dryness, and obtains II intermediate 5.23g of formula, molar yield 95%,
HPLC purity 99.2%.
Embodiment 2
Put into reaction flask Pentafluorobenzyl pentanol (5.0g, 0.028mol), 80mL ethyl acetate and triethylamine (3.7g,
0.037mol), stirring is started, is cooled to 0~10 DEG C, thionyl chloride (4.0g, 0.0336mol) is slowly added dropwise), temperature control 0~10
℃.It is added dropwise and is warming up to 20 DEG C, the reaction was continued 3 hours.25mL purified water, stirring 10 are added into reaction flask for end of reaction
Minute, liquid separation is stood, water phase is discarded.Organic phase is concentrated to dryness, and obtains II intermediate 5.12g of formula, molar yield 93%, HPLC
Purity 99.0%.
Embodiment 3
Pentafluorobenzyl pentanol (5.0g, 0.028mol), 30mLDMF and triethylamine (3.7g, 0.037mol) are put into reaction flask, are opened
Dynamic stirring, is cooled to 0~10 DEG C, starts to be slowly added dropwise phosphorus oxychloride (5.2g, 0.034mol), 0~10 DEG C of temperature control.It is added dropwise
20 DEG C are warming up to, the reaction was continued 3 hours.25mL purified water is added into reaction flask for end of reaction, stirs 10 minutes, stands and divides
Liquid discards water phase.Organic phase is concentrated to dryness, and obtains II intermediate 4.95g of formula, molar yield 90%, HPLC purity 99.0%.
Embodiment 4
In reaction flask put into 1 the method for embodiment obtained by II intermediate of formula (4.9g, 0.025mol), thiocarbamide (2.82g,
0.037mol) and 36mL isopropanol, stirring are warming up to 80~85 DEG C of reflux, keep the temperature back flow reaction 12~14 hours, end of reaction,
Feed liquid is concentrated under reduced pressure into 60 DEG C without fraction, and 36mL methylene chloride is added into reaction flask and stirs 30 minutes, is cooled to 0~10 DEG C,
Stirring 120 minutes, filters, and 60 DEG C of decompression dryings obtain III intermediate 6.48g of formula, molar yield 95%, HPLC purity 99.3%.
Embodiment 5
In reaction flask put into 1 the method for embodiment obtained by II intermediate of formula (4.9g, 0.025mol), thiocarbamide (2.82g,
0.037mol) and 96mL ethyl alcohol, stirring are warming up to 80~85 DEG C of reflux, keep the temperature back flow reaction 12~14 hours, end of reaction, material
Liquid is concentrated under reduced pressure into 60 DEG C without fraction, and 96mL ethyl acetate is added into reaction flask and stirs 30 minutes, is cooled to 0~10 DEG C, stirs
It mixes 120 minutes, filters, 60 DEG C of decompression dryings obtain III intermediate 6.41g of formula, molar yield 94%, HPLC purity 99.5%.
Embodiment 6
In reaction flask put into 1 the method for embodiment obtained by II intermediate of formula (4.9g, 0.025mol), thiocarbamide (2.82g,
0.037mol) and 36mLDMF, stirring are warming up to 80~85 DEG C of reflux, keep the temperature back flow reaction 12~14 hours, end of reaction, material
Liquid is concentrated under reduced pressure into 60 DEG C without fraction, and 36mL toluene is added into reaction flask and stirs 30 minutes, is cooled to 0~10 DEG C, stirring 120
Minute, it filters, 60 DEG C of decompression dryings obtain III intermediate 6.20g of formula, molar yield 91%, HPLC purity 99.2%.
Embodiment 7
Into reaction flask be added 5 the method for embodiment obtained by III intermediate of formula (6.0g, 0.022mol), DMF70mL and
Formula IV (10.4g, 0.020mol) stirs to being completely dissolved, is cooled to 0~10 DEG C, 50% potassium hydroxide solution is slowly added dropwise
(17.96g, 0.160mol) controls interior 0~10 DEG C of temperature, drips off 0~10 DEG C of temperature control and be stirred to react 90 minutes, be warming up to 40 DEG C, add
Enter 70mL purified water, is stirred to react 2 hours.70mL ethyl acetate and 70mL4% acetum is added, continues stirring 10 minutes,
10 minutes are stood, liquid separation.Organic to be added to 35mL saturated salt solution agitator treating, organic phase is dry with anhydrous sodium sulfate, filters,
Filtrate decompression is concentrated into 60 DEG C without efflux, obtains V intermediate 10.65g of formula, molar yield 90%, and HPLC purity 99.23% is miscellaneous
Matter A0.12%, complete IV compound 0.45% of formula of unreacted.
Embodiment 8
Into reaction flask be added 5 the method for embodiment obtained by III intermediate of formula (6.0g, 0.022mol), DMF140mL and
Formula IV (10.4g, 0.020mol) stirs to being completely dissolved, is cooled to 0~10 DEG C, 50% potassium hydroxide solution is slowly added dropwise
(17.96g, 0.160mol) controls interior 0~10 DEG C of temperature, drips off 0~10 DEG C of temperature control and be stirred to react 90 minutes, be warming up to 40 DEG C, add
Enter 70mL purified water, is stirred to react 2 hours.140mL ethyl acetate and 140mL4% acetum is added, continues 10 points of stirring
Clock stands 10 minutes, liquid separation.Organic to be added to 35mL saturated salt solution agitator treating, organic phase is dry with anhydrous sodium sulfate, takes out
Filter, filtrate decompression are concentrated into 60 DEG C without efflux, obtain V intermediate 10.64g of formula, molar yield 90%, HPLC purity
99.30%, impurity A 0.18%, complete IV compound 0.42% of formula of unreacted.
Embodiment 9
V intermediate of formula (10.0g, 0.017mol), ethyl acetate obtained by 8 the method for embodiment are put into reaction flask
60mL and glacial acetic acid 6.0g, stirring are cooled to 0~5 DEG C, are slowly added dropwise 30% hydrogen peroxide solution (5.76g, 0.051mol), control
20~25 DEG C of interior temperature is stirred to react 13~14 hours, and end of reaction is cooled to 0~5 DEG C of 10% sodium sulfite solution of dropwise addition and is quenched
Reaction.Liquid separation, organic layer are added 50mL saturated salt solution and stir 10 minutes, stand, layering.Organic phase is dry with anhydrous sodium sulfate
It is dry.It filters, filtrate decompression is concentrated into 60 DEG C without efflux, obtains off-white color fulvestrant crude product 9.76g, crude product ethyl acetate 2
It is secondary to crystallize to obtain white fulvestrant 8.30g, molar yield 85%, HPLC purity 99.82%, impurity sulfone 0.037%, impurity A Asia
Sulfone 0.083%.
Embodiment 10
V intermediate of formula (10.0g, 0.017mol), ethyl acetate obtained by 8 the method for embodiment are put into reaction flask
160mL and glacial acetic acid 6.0g, stirring are cooled to 0~5 DEG C, are slowly added dropwise 30% hydrogen peroxide solution (5.76g, 0.051mol), control
20~25 DEG C of temperature, is stirred to react 13~14 hours, end of reaction is cooled to 0~5 DEG C of 10% sodium sulfite solution of dropwise addition and quenches in system
It goes out reaction.Liquid separation, organic layer are added 50mL saturated salt solution and stir 10 minutes, stand, layering.Organic phase is dry with anhydrous sodium sulfate
It is dry.It filters, filtrate decompression is concentrated into 60 DEG C without efflux, obtains off-white color fulvestrant crude product 9.76g, crude product ethyl acetate 4
It is secondary to crystallize to obtain white fulvestrant 7.03g, molar yield 72%, HPLC purity 99.86%, impurity sulfone 0.022%, impurity A Asia
Sulfone 0.038%.
Comparative example 1
Pentafluorobenzyl pentanol (5.0g, 0.028mol), 30mLDMF and triethylamine (3.7g, 0.037mol) are put into reaction flask, are opened
Dynamic stirring, is cooled to 0~10 DEG C, starts to be slowly added dropwise tribromo oxygen phosphorus (5.2g, 0.034mol), and 0~10 DEG C of temperature control.It is added dropwise
20 DEG C are warming up to, the reaction was continued 3 hours.25mL purified water is added into reaction flask for end of reaction, stirs 10 minutes, stands and divides
Liquid discards water phase.Organic phase is concentrated to dryness, and obtains II intermediate 4.68g of formula, molar yield 84%, HPLC purity 97.2%.
Comparative example 2
Put into reaction flask Pentafluorobenzyl pentanol (5.0g, 0.028mol), 30mL isopropanol and triethylamine (3.7g,
0.037mol), stirring is started, is cooled to 0~10 DEG C, starts to be slowly added dropwise phosphorus oxychloride (5.2g, 0.034mol), temperature control 0~
10℃.It is added dropwise and is warming up to 20 DEG C, the reaction was continued 3 hours.25mL purified water, stirring are added into reaction flask for end of reaction
10 minutes, liquid separation is stood, water phase is discarded.Organic phase is concentrated to dryness, and obtains II intermediate 4.84g of formula, molar yield 88%,
HPLC purity 99.0%.
Comparative example 3
Put into reaction flask Pentafluorobenzyl pentanol (5.0g, 0.028mol), 65mL methylene chloride and triethylamine (3.7g,
0.037mol), stirring is started, is cooled to 0~10 DEG C, starts that thionyl chloride (4.0g, 0.0336mol) is slowly added dropwise), temperature control 0
~10 DEG C.It is added dropwise and is warming up to 20 DEG C, the reaction was continued 2 hours.25mL purified water is added into reaction flask, stirs for end of reaction
It mixes 10 minutes, stands liquid separation, discard water phase.Organic phase is concentrated to dryness, and obtains II intermediate 4.62g of formula, molar yield 84%,
HPLC purity 99.0%.
Comparative example 4
Put into reaction flask Pentafluorobenzyl pentanol (5.0g, 0.028mol), 65mL methylene chloride and triethylamine (3.7g,
0.037mol), stirring is started, is cooled to 0~10 DEG C, starts that thionyl bromide (6.98g, 0.0336mol) is slowly added dropwise), temperature control 0
~10 DEG C.It is added dropwise and is warming up to 20 DEG C, the reaction was continued 2 hours.25mL purified water is added into reaction flask, stirs for end of reaction
It mixes 10 minutes, stands liquid separation, discard water phase.Organic phase is concentrated to dryness, and obtains II intermediate 5.67g of formula, molar yield 84%,
HPLC purity 97.0%.
Comparative example 5
In reaction flask put into 1 the method for embodiment obtained by II intermediate of formula (4.9g, 0.025mol), thiocarbamide (2.82g,
0.037mol) and 36mL acetone, stirring are warming up to 55~60 DEG C of reflux, keep the temperature back flow reaction 12~14 hours, end of reaction, material
Liquid is concentrated under reduced pressure into 60 DEG C without fraction, and 36mL methylene chloride is added into reaction flask and stirs 30 minutes, is cooled to 0~10 DEG C, stirs
It mixes 120 minutes, filters, 60 DEG C of decompression dryings obtain III intermediate 5.59g of formula, molar yield 82%, HPLC purity 98.7%.
Comparative example 6
In reaction flask put into 1 the method for embodiment obtained by II intermediate of formula (4.9g, 0.025mol), thiocarbamide (2.82g,
0.037mol) and 36mL acetone, stirring are warming up to reflux, keep the temperature back flow reaction 12~14 hours, end of reaction, 60 DEG C of decompressions are steamed
It is dry, obtain III intermediate 6.48g of formula, molar yield 95% (the complete raw material of unreacted and other impurities do not effectively remove), HPLC
Purity 95.7%.
Comparative example 7
In reaction flask put into 1 the method for embodiment obtained by II intermediate of formula (4.9g, 0.025mol), thiocarbamide (2.82g,
0.037mol) and 120mL acetone, stirring are warming up to 55~60 DEG C of reflux, keep the temperature back flow reaction 12~14 hours, end of reaction,
Feed liquid is concentrated under reduced pressure into 60 DEG C without fraction, and 120mL methylene chloride is added into reaction flask and stirs 30 minutes, is cooled to 0~10 DEG C,
Stirring 120 minutes, filters, and 60 DEG C of decompression dryings obtain III intermediate 5.45g of formula, molar yield 80%, HPLC purity 98.9%.
Comparative example 8
In reaction flask put into 1 the method for embodiment obtained by II intermediate of formula (4.9g, 0.025mol), thiocarbamide (2.82g,
0.037mol) and 36mL acetone, stirring are warming up to 55~60 DEG C of reflux, keep the temperature back flow reaction 12~14 hours, end of reaction, material
Liquid is concentrated under reduced pressure into 60 DEG C without fraction, and 36mLDMF is added into reaction flask and stirs 30 minutes, is cooled to 0~10 DEG C, stirring 120
Minute, it filters, 60 DEG C of decompression dryings obtain III intermediate 5.59g of formula, molar yield 82%, HPLC purity 98.1%.
Comparative example 9
II intermediate of formula (6.0g, 0.025mol), thiocarbamide obtained by 4 the method for comparative example are put into reaction flask
(2.82g, 0.037mol) and 36mL acetone, stirring are warming up to 55~60 DEG C of reflux, keep the temperature back flow reaction 12~14 hours, reaction
It finishing, feed liquid is concentrated under reduced pressure into 60 DEG C without fraction, and 36mLDMF is added into reaction flask and stirs 30 minutes, is cooled to 0~10 DEG C,
Stirring 120 minutes, filters, and 60 DEG C of decompression dryings obtain III intermediate 6.39g of formula, molar yield 81%, HPLC purity 96.0%.
Comparative example 10
III intermediate of formula (6.0g, 0.022mol), methylene chloride obtained by 5 the method for embodiment are added into reaction flask
70mL and formula IV (10.4g, 0.020mol) stir to being completely dissolved, are cooled to 0~10 DEG C, it is molten that 30% sodium carbonate is slowly added dropwise
Liquid (33.95g, 0.160mol) controls interior 0~10 DEG C of temperature, drips off 0~10 DEG C of temperature control and be stirred to react 90 minutes, be warming up to 40 DEG C,
70mL purified water is added, is stirred to react 2 hours.70mL ethyl acetate and 140mL4% acetum is added, continues 10 points of stirring
Clock stands 10 minutes, liquid separation.Organic to be added to 35mL saturated salt solution agitator treating, organic phase is dry with anhydrous sodium sulfate, takes out
Filter, filtrate decompression are concentrated into 60 DEG C without efflux, obtain V intermediate 9.82g of formula, molar yield 83%, HPLC purity 96.0%,
Impurity A 2.50%, complete IV compound 1.40% of formula of unreacted.
Comparative example 11
Into reaction flask be added 5 the method for embodiment obtained by III intermediate of formula (6.0g, 0.022mol), DMF70mL and
Formula IV (10.4g, 0.020mol) stirs to being completely dissolved, is cooled to 0~10 DEG C, 50% potassium hydroxide solution is slowly added dropwise
(17.96g, 0.160mol) controls interior 0~10 DEG C of temperature, drips off 0~10 DEG C of temperature control and be stirred to react 90 minutes, be warming up to 40 DEG C, add
Enter 70mL purified water, is stirred to react 2 hours.70mL methylene chloride and 70mL4% acetum is added, continues stirring 10 minutes,
10 minutes are stood, liquid separation.Organic to be added to 35mL saturated salt solution agitator treating, organic phase is dry with anhydrous sodium sulfate, filters,
Filtrate decompression is concentrated into 60 DEG C without efflux, obtains the intermediate 9.70g of formula V, molar yield 82%, HPLC purity 98.2%, impurity
A0.62%, complete IV compound 1.08% of formula of unreacted.
Comparative example 12
Into reaction flask be added 5 the method for embodiment obtained by III intermediate of formula (6.0g, 0.022mol), DMF200mL and
Formula IV (10.4g, 0.020mol) stirs to being completely dissolved, is cooled to 0~10 DEG C, 50% potassium hydroxide solution is slowly added dropwise
(17.96g, 0.160mol) controls interior 0~10 DEG C of temperature, drips off 0~10 DEG C of temperature control and be stirred to react 90 minutes, be warming up to 40 DEG C, add
Enter 70mL purified water, is stirred to react 2 hours.200mL ethyl acetate and 200mL4% acetum is added, continues 10 points of stirring
Clock stands 10 minutes, liquid separation.Organic to be added to 35mL saturated salt solution agitator treating, organic phase is dry with anhydrous sodium sulfate, takes out
Filter, filtrate decompression are concentrated into 60 DEG C without efflux, obtain V intermediate 10.05g of formula, molar yield 85%, HPLC purity 98.0%,
Impurity A 0.62%, complete IV compound 1.08% of formula of unreacted.
Comparative example 13
Into reaction flask be added 9 the method for comparative example obtained by III intermediate of formula (7.0g, 0.022mol),
DMF200mL and formula IV (10.4g, 0.020mol) stir to being completely dissolved, are cooled to 0~10 DEG C, 50% hydrogen-oxygen is slowly added dropwise
Change potassium solution (17.96g, 0.160mol), controls interior 0~10 DEG C of temperature, drip off 0~10 DEG C of temperature control and be stirred to react 90 minutes, heat up
To 40 DEG C, 70mL purified water is added, is stirred to react 2 hours.200mL ethyl acetate and 200mL4% acetum is added, continues
Stirring 10 minutes stands 10 minutes, liquid separation.It is organic to be added to 35mL saturated salt solution agitator treating, organic phase anhydrous slufuric acid
Sodium is dry, filters, and filtrate decompression is concentrated into 60 DEG C without efflux, obtains V intermediate 9.58g of formula, molar yield 81%, HPLC is pure
Degree 95.8%, impurity A 1.32%, complete IV compound 1.78% of formula of unreacted.
Comparative example 14
In reaction flask put into 8 the method for embodiment obtained by V intermediate of formula (10.0g, 0.017mol), toluene 80mL and
Glacial acetic acid 6.0g, stirring are cooled to 0~5 DEG C, are slowly added dropwise 30% hydrogen peroxide solution (5.76g, 0.051mol), control interior temperature 20
It~25 DEG C, is stirred to react 13~14 hours, end of reaction is cooled to 0~5 DEG C of 10% sodium sulfite solution quenching reaction of dropwise addition.Point
Liquid, organic layer are added 50mL saturated salt solution and stir 10 minutes, stand, layering.Organic phase is dry with anhydrous sodium sulfate.It filters,
Filtrate decompression is concentrated into 60 DEG C without efflux, obtains off-white color fulvestrant crude product 9.76g, crystallizes for crude product ethyl acetate 2 times
White fulvestrant 7.81g, molar yield 76%, HPLC purity 99.55%, impurity sulfone 0.165%, impurity A sulfoxide
0.069%.
Comparative example 15
V intermediate of formula (10.0g, 0.017mol), ethyl acetate obtained by 8 the method for embodiment are put into reaction flask
80mL and glacial acetic acid 6.0g, stirring are cooled to 0~5 DEG C, are slowly added dropwise 30% hydrogen peroxide solution (5.76g, 0.051mol), control
20~25 DEG C of interior temperature is stirred to react 13~14 hours, and end of reaction is cooled to 0~5 DEG C of 10% sodium sulfite solution of dropwise addition and is quenched
Reaction.Liquid separation, organic layer are added 50mL saturated salt solution and stir 10 minutes, stand, layering.Organic phase is dry with anhydrous sodium sulfate
It is dry.It filters, filtrate decompression is concentrated into 60 DEG C without efflux, obtains off-white color fulvestrant crude product 9.76g, crude product is crystallized with DMF2 times
Obtain white fulvestrant 6.47g, molar yield 63%, HPLC purity 99.58%, impurity sulfone 0.124%, impurity A sulfoxide
0.072%.
Comparative example 16
V intermediate of formula (10.0g, 0.017mol), ethyl acetate obtained by 8 the method for embodiment are put into reaction flask
250mL and glacial acetic acid 6.0g, stirring are cooled to 0~5 DEG C, are slowly added dropwise 30% hydrogen peroxide solution (5.76g, 0.051mol), control
20~25 DEG C of temperature, is stirred to react 13~14 hours, end of reaction is cooled to 0~5 DEG C of 10% sodium sulfite solution of dropwise addition and quenches in system
It goes out reaction.Liquid separation, organic layer are added 50mL saturated salt solution and stir 10 minutes, stand, layering.Organic phase is dry with anhydrous sodium sulfate
It is dry.It filters, filtrate decompression is concentrated into 60 DEG C without efflux, obtains off-white color fulvestrant crude product 9.76g, crude product ethyl acetate 2
It is secondary to crystallize to obtain white fulvestrant 8.01g, molar yield 78%, HPLC purity 99.81%, impurity sulfone 0.044%, impurity A Asia
Sulfone 0.080%.
Comparative example 17
V intermediate of formula (10.0g, 0.017mol), methanol 100mL obtained by 8 the method for embodiment are put into reaction flask,
The aqueous solution (15mL) that sodium metaperiodate (7.95g) is slowly added dropwise is added dropwise under ice bath, restores room temperature reaction 24 hours later, is added five
Excessive sodium metaperiodate is quenched in the aqueous solution (40mL) of water sodium thiosulfate (9.2g), and methanol is removed in reduced pressure, and acetic acid is added
Ethyl ester (100mL) and water (50mL) dissolution, liquid separation, organic phase saturated common salt water washing is dry, is concentrated to dryness, obtains
9.5g white fulvestrant crude product, fulvestrant crude product are recrystallized to give fulvestrant 6.67g by ethyl acetate 2 times, mole
Yield 65%.HPLC purity 92.11%, impurity sulfone 3.64%, impurity A sulfoxide 0.084%.
Comparative example 18
V intermediate of formula (10.0g, 0.017mol), dichloroethanes obtained by 8 the method for embodiment are put into reaction flask
100mL is added metachloroperbenzoic acid (85%, 8.6g) and is heated to 40 DEG C, react 3 hours, five water sodium thiosulfate are added
Excessive metachloroperbenzoic acid is quenched in the aqueous solution (40mL) of (10.0g), and sodium bicarbonate is added, and adjusting PH is about 8, liquid separation,
Organic phase saturated common salt water washing, it is dry, it is concentrated to dryness, obtains 9.0g white fulvestrant crude product, fulvestrant is thick
Product are recrystallized to give fulvestrant 5.55g, molar yield 54% by ethyl acetate 2 times.HPLC purity 92.26%, impurity sulfone
3.74%, impurity A sulfoxide 0.086%, unreacted V intermediate 1.34% of formula.
Comparative example 19
V intermediate of formula (10.0g, 0.017mol), two chloroethenes obtained by 12 the method for comparative example are put into reaction flask
Alkane 100mL is added metachloroperbenzoic acid (85%, 8.6g) and is heated to 40 DEG C, react 3 hours, five water sodium thiosulfate are added
Excessive metachloroperbenzoic acid is quenched in the aqueous solution (40mL) of (10.0g), and sodium bicarbonate is added, and adjusting PH is about 8, liquid separation,
Organic phase saturated common salt water washing, it is dry, it is concentrated to dryness, obtains 8.2g white fulvestrant crude product, fulvestrant is thick
Product are recrystallized to give fulvestrant 4.93g, molar yield 48% by ethyl acetate 2 times.HPLC purity 88.34%, impurity sulfone
4.14%, impurity A sulfoxide 0.166%, unreacted V intermediate 2.21% of formula.
Comparative example 20
Into reaction flask be added 5 the method for embodiment obtained by III intermediate of formula (6.0g, 0.022mol), DMF200mL and
Formula IV (10.4g, 0.020mol) stirs to being completely dissolved, is cooled to 0~10 DEG C, 50% potassium hydroxide solution is slowly added dropwise
(17.96g, 0.160mol) controls interior 0~10 DEG C of temperature, drips off 0~10 DEG C of temperature control and be stirred to react 90 minutes, 200mL acetic acid is added
Ethyl ester and 100mL4% acetum continue stirring 10 minutes, stand 10 minutes, liquid separation.It is organic to be added to 35mL saturated common salt
Water agitator treating, organic phase is dry with anhydrous sodium sulfate, filters, and filtrate decompression is concentrated into 60 DEG C without efflux, obtains in formula V-I
Mesosome (i.e. impurity A) 10.76g, molar yield 85%, HPLC purity 98.5%.
V-I intermediate (10.0g, 0.016mol) of formula, methanol 40mL, 50% potassium hydroxide solution are added into reaction flask
(7.18g, 0.064mol) is warming up to 40 DEG C, is stirred to react 2 hours.200mL ethyl acetate and 100mL4% acetum is added,
Continue stirring 10 minutes, stands 10 minutes, liquid separation.Organic to be added to 35mL saturated salt solution agitator treating, organic phase is with anhydrous
Sodium sulphate is dry, filters, and filtrate decompression is concentrated into 60 DEG C without efflux, obtains V intermediate 8.59g of formula, molar yield 92%,
HPLC purity 98.0%, impurity A 0.62%, complete IV compound 1.08% of formula of unreacted.
Two step total recoverys 78.2%.
Claims (10)
1. a kind of fulvestrant preparation method, which comprises the steps of:
1) in a solvent, formula I and reagent carry out halogenating reaction production II, formula II and thiocarbamide back flow reaction production in a solvent
III:
2) pass through nucleophilic substitution in lye and organic solvent Chinese style III and formula IV, hydrolysis production V:
3) in a solvent, formula V is oxidized to fulvestrant through peracetic acid hydrogen peroxide oxidation system:
2. preparation method according to claim 1, which is characterized in that II agents useful for same of step 1) preparation formula is selected from thionyl chloride
Or phosphorus oxychloride, R in formula II are as follows: Cl.
3. preparation method according to claim 1, which is characterized in that solvent described in step 1) preparation formula II is selected from acetic acid second
One or more of ester, acetone, methylene chloride, DMF, acetonitrile, methanol and ethyl alcohol, more preferably select ethyl acetate and methylene chloride
One or both of.
4. preparation method according to claim 1, which is characterized in that solvent used in step 1) preparation formula III is selected from DMF, second
One or more of nitrile, methanol, ethyl alcohol, isopropanol, fourth alcohol and water, more preferably select one of isopropanol and ethyl alcohol or two
Kind.
5. preparation method according to claim 1, which is characterized in that further include recrystallization step during step 1) preparation formula III
Suddenly, specific steps are recrystallized are as follows: the feed liquid of end of reaction is concentrated under reduced pressure into 60 DEG C without fraction, and it is molten that recrystallization is added into reaction flask
Agent is stirred 30 minutes, is cooled to 0~10 DEG C, is stirred 120 minutes, is filtered, 60 DEG C of decompression dryings.
6. preparation method according to claim 1, which is characterized in that further include recrystallization step during step 1) preparation formula III
Suddenly, recrystallization solvent is selected from one or more of ethyl acetate, acetone, methylene chloride, toluene, hexamethylene and normal heptane, compared with
It is preferred that selecting one or more of methylene chloride, toluene and ethyl acetate.
7. preparation method according to claim 1, which is characterized in that organic solvent used in step 2) nucleophilic substitution reaction is
DMF, lye are 50% potassium hydroxide solution.
8. preparation method according to claim 1, which is characterized in that step 2) hydrolysis solvent for use be ethyl acetate and
4% acetum.
9. preparation method according to claim 1, which is characterized in that during step 3) prepares fulvestrant, solvent for use
For ethyl acetate.
10. preparation method according to claim 1, which is characterized in that further include weight during step 3) prepares fulvestrant
Crystallisation step, recrystallization solvent for use are selected from one of ethyl acetate, acetone, methylene chloride, hexamethylene and normal heptane or several
Kind.
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| CN114671922A (en) * | 2020-12-24 | 2022-06-28 | 鲁南制药集团股份有限公司 | Fulvestrant related substance |
| CN114685593A (en) * | 2020-12-31 | 2022-07-01 | 鲁南制药集团股份有限公司 | Fulvestrant preparation method and intermediate thereof |
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