CN106957235A - A kind of preparation method of TAM - Google Patents
A kind of preparation method of TAM Download PDFInfo
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- CN106957235A CN106957235A CN201710248170.5A CN201710248170A CN106957235A CN 106957235 A CN106957235 A CN 106957235A CN 201710248170 A CN201710248170 A CN 201710248170A CN 106957235 A CN106957235 A CN 106957235A
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- tam
- catalyst
- ethyl acetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
Abstract
The present invention relates to a kind of preparation method of TAM, it is characterised in that comprises the steps：Take Toremifene, catalyst and alkali cpd, be added in alcohols solvent, under an atmosphere of hydrogen, 0.1~1.0MPa, stirring reaction 10~24 hours at 20~150 DEG C；Then reaction system is down to room temperature, suction filtration or removes solvent under reduced pressure at normal pressure；Add ethyl acetate and water washing, stratification, take upper organic phase anhydrous sodium sulfate drying, sodium sulphate is filtered to remove, ethyl acetate is removed under reduced pressure, slurry is obtained, acetone is added into slurry, the weight ratio of the volumetric usage of acetone and the slurry is 2~5ml/g, is then heated to 50~56 DEG C of dissolvings, is cooled to 0 DEG C and separates out crystallization；Is dried in crystallization white needles TAM obtain.
Description
Technical field
The present invention relates to field of medicine and chemical technology, a kind of preparation method of TAM is referred specifically to.
Background technology
TAM (tamoxifen) is triphenylethylene class compound, is sent out by primer of diethylstilbestrol oestrogen-like hormone
Put on display the antiestrogen of coming.
The synthetic method of TAM is more.2012, Haroutounian et al. made to the synthetic method of TAM
Detailed summary, summarizes 8 class synthesis strategy (K.M.Kasiotis and of TAM
S.A.Haroutounian.Tamoxifen：a synthetic overview.Curr.Org.Chem.2012,16,335-
352).In these methods, majority has been related to the reactions that orgnometallic catalyst or organometallic reagent are participated in, synthetic route compared with
Long, stereoselectivity is not high, operates relatively complicated.Especially during using the organometallic reagent with greater activity,
It there are many potential safety hazards.Wherein, the method for being adapted to preparation of industrialization TAM mainly has following two：
Method one：
The above method is reacted using intermolecular Mcmurry, and occurring coupling reaction under zinc powder and titanium tetrachloride effect obtains
To TAM and its mixture of isomers, then E- isomers acquisition TAM is removed through refined split
(EP0126470).This method production hour is long, and lock out operation is extremely difficult, and solid waste and the useless amount of liquid are big, and the fractionation of isomers causes
Product yield is low.
Method two：
The above method is the mixture that three-level dehydration of alcohols is obtained to TAM and its E- isomers, it is also desirable to by refined
The method of fractionation obtains TAM, equally exists the low problem of man-hour length, yield.
The content of the invention
The technical problems to be solved by the invention be for prior art present situation provide a kind of simple technique, high income and
The preparation method of environment-friendly TAM.
The present invention solve the technical scheme that is used of above-mentioned technical problem for：The preparation method of the TAM, its feature
It is to comprise the steps：
Toremifene, catalyst and alkali cpd are taken, is added in alcohols solvent, under an atmosphere of hydrogen, 0.1~
1.0MPa, stirring reaction 10~24 hours at 20~150 DEG C；
The catalyst is palladium-carbon catalyst or platinum carbon catalyst, the consumption of the catalyst for Toremifene 1%~
15wt%；
The consumption of the alkali cpd is 1~5 times of mole of Toremifene；
The consumption of the solvent is 2~20 times of Toremifene quality；
Then reaction system is down to room temperature, suction filtration or removes solvent under reduced pressure at normal pressure；
Ethyl acetate and water washing, stratification are added, upper organic phase anhydrous sodium sulfate drying is taken, is filtered to remove sulphur
Sour sodium, removes ethyl acetate under reduced pressure, obtains slurry, and acetone, the volumetric usage of acetone and the pulpous state are added into slurry
The weight ratio of thing is 2~5ml/g, is then heated to 50~56 DEG C of dissolvings, is cooled to 0 DEG C and separates out crystallization；Crystallization is carried out
Drying to obtain white needles TAM.
It is preferred that the content of palladium or platinum is 1%~20wt% in the catalyst.
The solvent preferably is selected from methanol, ethanol, isopropanol or n-butanol.
The alkali cpd preferably is selected from NaOH, potassium hydroxide, sodium carbonate, potassium carbonate or magnesium hydroxide.
The present invention is using Toremifene as raw material, and palladium charcoal or platinum charcoal are catalyst, occur high temperature in the alcohols solvent of alkalescence
The hydrogenation of high pressure, chemical equation is as follows：
Technological process is simple, and solvent can be with recovery, and no side reaction occurs, TAM high income, good product purity；
And course of reaction stabilization, safety, selectivity are good, used catalyst can be environment-friendly with recycling, environmental protection.
Brief description of the drawings
Fig. 1 be the embodiment of the present invention 1 in products therefrom proton nmr spectra (1H NMR) figure.
Fig. 2 is high performance liquid chromatography (HPLC) figure of products therefrom in the embodiment of the present invention 1.
Embodiment
The present invention is described in further detail below in conjunction with accompanying drawing embodiment.
Embodiment 1
Into 1L hydrogenation reaction cauldrons, 40g Toremifenes are added, 400g methanol, 8.3g potassium hydroxide, the palladium charcoals of 4g 10% are used
0.2MPa nitrogen displacement 3 times, then replaced 3 times with 0.2MPa hydrogen, keep 0.3~0.5MPa of Hydrogen Vapor Pressure, reaction temperature
70 DEG C, stirring reaction 14 hours.Room temperature is down to, suction filtration removes methanol, plus 250mL ethyl acetate and 100mL water washings under reduced pressure,
Stratification, ethyl acetate layer uses 100mL water washings once again, stratification, organic phase anhydrous sodium sulfate drying, after filtering
Remove under reduced pressure and 0 DEG C of crystallization is placed in after ethyl acetate, plus 120mL acetone heating for dissolving stays overnight, suction filtration, 60 DEG C of air blast are dried white
Needle-like solid TAM 31.5g, yield 86%.Mp:96.5~98 DEG C,1H NMR(400MHz,CDCl3):δ 0.93 (t, J=
7.6Hz,3H,CH2CH 3),2.29(s,6H,NMe 2), 2.46 (q, J=7.6Hz, 2H, CH 2CH3), 2.65 (t, J=5.6Hz, 2H,
OCH2CH 2NMe2), 3.93 (t, J=7.6Hz, 2H, OCH 2CH2NMe2), 6.56 (d, J=8.8Hz, 2H, Ar-H), 6.77 (d, J
=8.8Hz, 2H, Ar-H), 7.11-7.37 (m, 10H, Ar-H) .HPLC contents 99.85%.
Embodiment 2
Into 1L hydrogenation reaction cauldrons, 40g Toremifenes are added, 400g ethanol, 7.1g NaOH, the platinum charcoals of 4g 10% are used
0.2MPa nitrogen displacement 3 times, then replaced 3 times with 0.2MPa hydrogen, keep 0.3~0.5MPa of Hydrogen Vapor Pressure, reaction temperature
90 DEG C, stirring reaction 12 hours.Room temperature is down to, suction filtration removes ethanol, plus 250mL ethyl acetate and 100mL water washings under reduced pressure,
Stratification, ethyl acetate layer uses 100mL water washings once again, stratification, organic phase anhydrous sodium sulfate drying, after filtering
Remove under reduced pressure and 0 DEG C of crystallization is placed in after ethyl acetate, plus 120mL acetone heating for dissolving stays overnight, suction filtration, 60 DEG C of air blast are dried white
Needle-like solid TAM 31.1g, yield 84.9%.Mp：96.3~97.8 DEG C.
Embodiment 3
Into 1L hydrogenation reaction cauldrons, 40g Toremifenes are added, 400g ethanol, 8.3g potassium carbonate, the palladium charcoals of 3g 10% are used
0.2MPa nitrogen displacement 3 times, then replaced 3 times with 0.2MPa hydrogen, keep 0.5~0.7MPa of Hydrogen Vapor Pressure, reaction temperature
90 DEG C, stirring reaction 12 hours.Room temperature is down to, suction filtration removes ethanol, plus 250mL ethyl acetate and 100mL water washings under reduced pressure,
Stratification, ethyl acetate layer uses 100mL water washings once again, stratification, organic phase anhydrous sodium sulfate drying, after filtering
Remove under reduced pressure and 0 DEG C of crystallization is placed in after ethyl acetate, plus 120mL acetone heating for dissolving stays overnight, suction filtration, 60 DEG C of air blast are dried white
Needle-like solid TAM 32g, yield 87.5%.Mp：96~97.5 DEG C.
Embodiment 4
Into 1L hydrogenation reaction cauldrons, 40g Toremifenes are added, 600g isopropanols, 9g NaOH, the palladium charcoals of 4g 10% are used
0.2MPa nitrogen displacement 3 times, then replaced 3 times with 0.2MPa hydrogen, keep 0.3~0.5MPa of Hydrogen Vapor Pressure, reaction temperature
80 DEG C, stirring reaction 15 hours.Room temperature is down to, suction filtration removes isopropanol, plus 250mL ethyl acetate and 100mL washings under reduced pressure
Wash, stratification, ethyl acetate layer uses 100mL water washings once again, stratification, organic phase anhydrous sodium sulfate drying, mistake
Removed under reduced pressure after filter and 0 DEG C of crystallization is placed in after ethyl acetate, plus 120mL acetone heating for dissolving stays overnight, suction filtration, 60 DEG C of air blast are dried
White needles TAM 31.7g, yield 86.5%.Mp：96.2~98 DEG C.
Embodiment 5
Into 1L hydrogenation reaction cauldrons, 40g Toremifenes are added, 300g methanol, 9g sodium carbonate, the palladium charcoals of 4g 10% are used
0.2MPa nitrogen displacement 3 times, then replaced 3 times with 0.2MPa hydrogen, keep 0.3~0.5MPa of Hydrogen Vapor Pressure, reaction temperature
80 DEG C, stirring reaction 15 hours.Room temperature is down to, suction filtration removes methanol, plus 250mL ethyl acetate and 100mL water washings under reduced pressure,
Stratification, ethyl acetate layer uses 100mL water washings once again, stratification, organic phase anhydrous sodium sulfate drying, after filtering
Remove under reduced pressure and 0 DEG C of crystallization is placed in after ethyl acetate, plus 120mL acetone heating for dissolving stays overnight, suction filtration, 60 DEG C of air blast are dried white
Needle-like solid TAM 32g, yield 87.5%.Mp：96.5~98 DEG C.
Embodiment 6
Into 1L hydrogenation reaction cauldrons, addition 40g Toremifenes, 400g n-butanols, 8.3g potassium hydroxide, the palladium charcoals of 5g 5%,
Replaced 3 times with 0.2MPa nitrogen displacement 3 times, then with 0.2MPa hydrogen, keep 0.8~1.0MPa of Hydrogen Vapor Pressure, reaction temperature
70 DEG C of degree, stirring reaction 14 hours.Room temperature is down to, suction filtration removes n-butanol, plus 250mL ethyl acetate and 100mL washings under reduced pressure
Wash, stratification, ethyl acetate layer uses 100mL water washings once again, stratification, organic phase anhydrous sodium sulfate drying, mistake
Removed under reduced pressure after filter and 0 DEG C of crystallization is placed in after ethyl acetate, plus 120mL acetone heating for dissolving stays overnight, suction filtration, 60 DEG C of air blast are dried
White needles TAM 31.7g, yield 86.5%.Mp：96.3~97.8 DEG C.
Embodiment 7
Into 1L hydrogenation reaction cauldrons, 40g Toremifenes are added, 400g ethanol, 8.3g magnesium hydroxides, the palladium charcoals of 5g 5% are used
0.2MPa nitrogen displacement 3 times, then replaced 3 times with 0.2MPa hydrogen, keep 0.5~0.7MPa of Hydrogen Vapor Pressure, reaction temperature
90 DEG C, stirring reaction 12 hours.Room temperature is down to, suction filtration removes ethanol, plus 250mL ethyl acetate and 100mL water washings under reduced pressure,
Stratification, ethyl acetate layer uses 100mL water washings once again, stratification, organic phase anhydrous sodium sulfate drying, after filtering
Remove under reduced pressure and 0 DEG C of crystallization is placed in after ethyl acetate, plus 120mL acetone heating for dissolving stays overnight, suction filtration, 60 DEG C of air blast are dried white
Needle-like solid TAM 32.3g, yield 88.1%.Mp：96.2~97.5 DEG C.
Claims (4)
1. a kind of preparation method of TAM, it is characterised in that comprise the steps：
Take Toremifene, catalyst and alkali cpd, be added in alcohols solvent, under an atmosphere of hydrogen, 0.1~1.0MPa, 20
Stirring reaction 10~24 hours at~150 DEG C；
The catalyst is palladium-carbon catalyst or platinum carbon catalyst, the consumption of the catalyst for Toremifene 1%~
15wt%；
The consumption of the alkali cpd is 1~5 times of mole of Toremifene；
The consumption of the solvent is 2~20 times of Toremifene quality；
Then reaction system is down to room temperature, suction filtration or removes solvent under reduced pressure at normal pressure；
Ethyl acetate and water washing, stratification are added, upper organic phase anhydrous sodium sulfate drying is taken, is filtered to remove sulfuric acid
Sodium, removes ethyl acetate under reduced pressure, obtains slurry, and acetone, the volumetric usage of acetone and the slurry are added into slurry
Weight ratio be 2~5ml/g, be then heated to 50~56 DEG C of dissolvings, be cooled to 0 DEG C separate out crystallize；Crystallization is done
It is dry to obtain white needles TAM.
2. the preparation method of TAM according to claim 1, it is characterised in that palladium or platinum contains in the catalyst
Measure as 1%~20wt%.
3. the preparation method of TAM according to claim 1 or 2, the solvent be selected from methanol, ethanol, isopropanol or
N-butanol.
4. the preparation method of TAM according to claim 3, it is characterised in that the alkali cpd is selected from hydroxide
Sodium, potassium hydroxide, sodium carbonate, potassium carbonate or magnesium hydroxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2016102603939 | 2016-04-19 | ||
| CN201610260393.9A CN106397226A (en) | 2016-04-19 | 2016-04-19 | Novel preparation method for tamoxifen |
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| CN106957235A true CN106957235A (en) | 2017-07-18 |
| CN106957235B CN106957235B (en) | 2019-04-26 |
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| CN201610260393.9A Pending CN106397226A (en) | 2016-04-19 | 2016-04-19 | Novel preparation method for tamoxifen |
| CN201710248170.5A Active CN106957235B (en) | 2016-04-19 | 2017-04-17 | A kind of preparation method of tamoxifen |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106397226A (en) * | 2016-04-19 | 2017-02-15 | 福安药业集团宁波天衡制药有限公司 | Novel preparation method for tamoxifen |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT383344B (en) * | 1982-05-27 | 1987-06-25 | Farmos Oy | METHOD FOR PRODUCING (Z) -1,2-DIPHENYL-1- (4- (2- (N, N-DIMETHYLAMINO) ETH XY) PHENYL) -1-BUTEN |
| CN103450036A (en) * | 2013-08-15 | 2013-12-18 | 凯莱英医药集团（天津）股份有限公司 | Preparation method of high-purity tamoxifen citrate |
| WO2015155753A2 (en) * | 2015-08-10 | 2015-10-15 | Suzhou M-Conj Biotech Co., Ltd | Novel linkers and their uses in specific conjugation of drugs to a biological molecule |
| CN106397226A (en) * | 2016-04-19 | 2017-02-15 | 福安药业集团宁波天衡制药有限公司 | Novel preparation method for tamoxifen |
-
2016
- 2016-04-19 CN CN201610260393.9A patent/CN106397226A/en active Pending
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2017
- 2017-04-17 CN CN201710248170.5A patent/CN106957235B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT383344B (en) * | 1982-05-27 | 1987-06-25 | Farmos Oy | METHOD FOR PRODUCING (Z) -1,2-DIPHENYL-1- (4- (2- (N, N-DIMETHYLAMINO) ETH XY) PHENYL) -1-BUTEN |
| CN103450036A (en) * | 2013-08-15 | 2013-12-18 | 凯莱英医药集团（天津）股份有限公司 | Preparation method of high-purity tamoxifen citrate |
| WO2015155753A2 (en) * | 2015-08-10 | 2015-10-15 | Suzhou M-Conj Biotech Co., Ltd | Novel linkers and their uses in specific conjugation of drugs to a biological molecule |
| CN106397226A (en) * | 2016-04-19 | 2017-02-15 | 福安药业集团宁波天衡制药有限公司 | Novel preparation method for tamoxifen |
Non-Patent Citations (3)
| Title |
|---|
| 国家环境保护总局科技标准司: "《危险废物污染防治技术指南》", 30 September 2004 * |
| 徐峰，胡惟孝: "抗雌激素药三苯氧胺制备方法的进展", 《浙江化工》 * |
| 梅和珊 等: "他莫昔芬合成路线图解", 《中国医药工业杂志》 * |
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| CN106397226A (en) | 2017-02-15 |
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