CN106957235B - A kind of preparation method of tamoxifen - Google Patents
A kind of preparation method of tamoxifen Download PDFInfo
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- CN106957235B CN106957235B CN201710248170.5A CN201710248170A CN106957235B CN 106957235 B CN106957235 B CN 106957235B CN 201710248170 A CN201710248170 A CN 201710248170A CN 106957235 B CN106957235 B CN 106957235B
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- tamoxifen
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- 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 methods of tamoxifen, it is characterised in that includes the following steps: to take Toremifene, catalyst and alkali cpd, be added in alcohols solvent, under an atmosphere of hydrogen, 0.1~1.0MPa, is stirred to react 10~24 hours at 20~150 DEG C；Then reaction system is down to room temperature, filtered, normal pressure or evaporating solvent under reduced pressure；Ethyl acetate and water washing is added, stratification, take upper organic phase anhydrous sodium sulfate dry, it is filtered to remove sodium sulphate, removes ethyl acetate under reduced pressure, obtains slurry, 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 dissolutions, is cooled to 0 DEG C of precipitation crystallization；Crystallization is dried and obtains white needles tamoxifen.
Description
Technical field
The present invention relates to field of medicine and chemical technology, refer specifically to a kind of preparation method of tamoxifen.
Background technique
Tamoxifen (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 tamoxifen is more.2012, Haroutounian et al. made the synthetic method of tamoxifen
Detailed summary, summarizes 8 class synthetic strategy (K.M.Kasiotis and of tamoxifen
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 participate in, synthetic route compared with
Long, stereoselectivity is not high, operates relatively complicated.Especially during using the organometallic reagent with greater activity,
There is many security risks.Wherein, there are mainly two types of for the method for suitable preparation of industrialization tamoxifen:
Method one:
The above method is reacted using intermolecular Mcmurry, and coupling reaction occurs under zinc powder and titanium tetrachloride effect and obtains
To tamoxifen and its mixture of isomers, is then split through purification and remove E- isomers acquisition tamoxifen
(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 that three-level dehydration of alcohols is obtained the mixture of tamoxifen and its E- isomers, it is also desirable to pass through purification
The method of fractionation obtains tamoxifen, equally exists the problems such as working hour is long, yield is low.
Summary of the invention
The technical problem to be solved by the present invention is to the status for the prior art provide a kind of simple process, high income and
The preparation method of environmental-friendly tamoxifen.
The technical scheme of the invention to solve the technical problem is: the preparation method of the tamoxifen, feature
It is to include the following steps:
Toremifene, catalyst and alkali cpd are taken, is added in alcohols solvent, under an atmosphere of hydrogen, 0.1~
1.0MPa, it is stirred to react 10~24 hours at 20~150 DEG C；
The catalyst is palladium-carbon catalyst or platinum carbon catalyst, the dosage of the catalyst be Toremifene 1%~
15wt%；
The dosage of the alkali cpd is 1~5 times of mole of Toremifene；
The dosage of the solvent is 2~20 times of Toremifene quality；
Then reaction system is down to room temperature, filtered, normal pressure or evaporating solvent under reduced pressure；
Ethyl acetate and water washing, stratification is added, takes upper organic phase to be dried, filtered with anhydrous sodium sulfate and removes desulfuration
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 object is 2~5ml/g, is then heated to 50~56 DEG C of dissolutions, is cooled to 0 DEG C of precipitation crystallization；Crystallization is carried out
Drying to obtain white needles tamoxifen.
It is preferred that the content of palladium or platinum is 1%~20wt% in the catalyst.
The solvent preferably is selected from methanol, ethyl alcohol, isopropanol or n-butanol.
The alkali cpd preferably is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or magnesium hydroxide.
For the present invention using Toremifene as raw material, palladium charcoal or platinum charcoal are catalyst, and high temperature occurs in the alcohols solvent of alkalinity
The hydrogenation of high pressure, chemical equation are as follows:
Process flow is simple, and solvent can be occurred with recovery, no side reaction, tamoxifen high income, good product purity；
And reaction process stabilization, safety, selectivity are good, used catalyst can be environmentally protective with recycling and reusing, environmental-friendly.
Detailed description of the invention
Fig. 1 be the embodiment of the present invention 1 in products therefrom nuclear magnetic resonance spectroscopy (1H NMR) figure.
Fig. 2 is high performance liquid chromatography (HPLC) figure of products therefrom in the embodiment of the present invention 1.
Specific embodiment
The utility model is described in further detail below in conjunction with figure embodiment.
Embodiment 1
Into 1L hydrogenation reaction cauldron, 40g Toremifene, 400g methanol, 8.3g potassium hydroxide, 10% palladium charcoal of 4g, use is added
The nitrogen of 0.2MPa is replaced 3 times, then is replaced 3 times with the hydrogen of 0.2MPa, and 0.3~0.5MPa of Hydrogen Vapor Pressure, reaction temperature are kept
It 70 DEG C, is stirred to react 14 hours.It is down to room temperature, is filtered, is removed methanol under reduced pressure, add 250mL ethyl acetate and 100mL water washing,
Stratification, ethyl acetate layer use 100mL water washing primary again, stratification, after organic phase is dried, filtered with anhydrous sodium sulfate
It removes ethyl acetate under reduced pressure, adds 120mL acetone heating for dissolving to be placed on 0 DEG C of crystallization and stay overnight, filter, 60 DEG C of air blast are dried white
Needle-like solid tamoxifen 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 content 99.85%.
Embodiment 2
Into 1L hydrogenation reaction cauldron, 40g Toremifene, 400g ethyl alcohol, 7.1g sodium hydroxide, 10% platinum charcoal of 4g, use is added
The nitrogen of 0.2MPa is replaced 3 times, then is replaced 3 times with the hydrogen of 0.2MPa, and 0.3~0.5MPa of Hydrogen Vapor Pressure, reaction temperature are kept
It 90 DEG C, is stirred to react 12 hours.It is down to room temperature, is filtered, is removed ethyl alcohol under reduced pressure, add 250mL ethyl acetate and 100mL water washing,
Stratification, ethyl acetate layer use 100mL water washing primary again, stratification, after organic phase is dried, filtered with anhydrous sodium sulfate
It removes ethyl acetate under reduced pressure, adds 120mL acetone heating for dissolving to be placed on 0 DEG C of crystallization and stay overnight, filter, 60 DEG C of air blast are dried white
Needle-like solid tamoxifen 31.1g, yield 84.9%.Mp:96.3~97.8 DEG C.
Embodiment 3
Into 1L hydrogenation reaction cauldron, 40g Toremifene, 400g ethyl alcohol, 8.3g potassium carbonate, 10% palladium charcoal of 3g, use is added
The nitrogen of 0.2MPa is replaced 3 times, then is replaced 3 times with the hydrogen of 0.2MPa, and 0.5~0.7MPa of Hydrogen Vapor Pressure, reaction temperature are kept
It 90 DEG C, is stirred to react 12 hours.It is down to room temperature, is filtered, is removed ethyl alcohol under reduced pressure, add 250mL ethyl acetate and 100mL water washing,
Stratification, ethyl acetate layer use 100mL water washing primary again, stratification, after organic phase is dried, filtered with anhydrous sodium sulfate
It removes ethyl acetate under reduced pressure, adds 120mL acetone heating for dissolving to be placed on 0 DEG C of crystallization and stay overnight, filter, 60 DEG C of air blast are dried white
Needle-like solid tamoxifen 32g, yield 87.5%.Mp:96~97.5 DEG C.
Embodiment 4
Into 1L hydrogenation reaction cauldron, 40g Toremifene, 600g isopropanol, 9g sodium hydroxide, 10% palladium charcoal of 4g, use is added
The nitrogen of 0.2MPa is replaced 3 times, then is replaced 3 times with the hydrogen of 0.2MPa, and 0.3~0.5MPa of Hydrogen Vapor Pressure, reaction temperature are kept
It 80 DEG C, is stirred to react 15 hours.It is down to room temperature, filters, removes isopropanol under reduced pressure, 250mL ethyl acetate and 100mL is added to wash
It washs, stratification, ethyl acetate layer uses 100mL water washing primary again, stratification, and organic phase is dry with anhydrous sodium sulfate, mistake
It removes ethyl acetate after filter under reduced pressure, adds 120mL acetone heating for dissolving to be placed on 0 DEG C of crystallization and stay overnight, filter, 60 DEG C of air blast are dried
White needles tamoxifen 31.7g, yield 86.5%.Mp:96.2~98 DEG C.
Embodiment 5
Into 1L hydrogenation reaction cauldron, 40g Toremifene, 300g methanol, 9g sodium carbonate, 10% palladium charcoal of 4g, use is added
The nitrogen of 0.2MPa is replaced 3 times, then is replaced 3 times with the hydrogen of 0.2MPa, and 0.3~0.5MPa of Hydrogen Vapor Pressure, reaction temperature are kept
It 80 DEG C, is stirred to react 15 hours.It is down to room temperature, is filtered, is removed methanol under reduced pressure, add 250mL ethyl acetate and 100mL water washing,
Stratification, ethyl acetate layer use 100mL water washing primary again, stratification, after organic phase is dried, filtered with anhydrous sodium sulfate
It removes ethyl acetate under reduced pressure, adds 120mL acetone heating for dissolving to be placed on 0 DEG C of crystallization and stay overnight, filter, 60 DEG C of air blast are dried white
Needle-like solid tamoxifen 32g, yield 87.5%.Mp:96.5~98 DEG C.
Embodiment 6
Into 1L hydrogenation reaction cauldron, addition 40g Toremifene, 400g n-butanol, 8.3g potassium hydroxide, 5% palladium charcoal of 5g,
It is replaced 3 times with the nitrogen of 0.2MPa, then is replaced 3 times with the hydrogen of 0.2MPa, keep 0.8~1.0MPa of Hydrogen Vapor Pressure, reaction temperature
70 DEG C of degree, is stirred to react 14 hours.It is down to room temperature, filters, removes n-butanol under reduced pressure, 250mL ethyl acetate and 100mL is added to wash
It washs, stratification, ethyl acetate layer uses 100mL water washing primary again, stratification, and organic phase is dry with anhydrous sodium sulfate, mistake
It removes ethyl acetate after filter under reduced pressure, adds 120mL acetone heating for dissolving to be placed on 0 DEG C of crystallization and stay overnight, filter, 60 DEG C of air blast are dried
White needles tamoxifen 31.7g, yield 86.5%.Mp:96.3~97.8 DEG C.
Embodiment 7
Into 1L hydrogenation reaction cauldron, 40g Toremifene, 400g ethyl alcohol, 8.3g magnesium hydroxide, 5% palladium charcoal of 5g, use is added
The nitrogen of 0.2MPa is replaced 3 times, then is replaced 3 times with the hydrogen of 0.2MPa, and 0.5~0.7MPa of Hydrogen Vapor Pressure, reaction temperature are kept
It 90 DEG C, is stirred to react 12 hours.It is down to room temperature, is filtered, is removed ethyl alcohol under reduced pressure, add 250mL ethyl acetate and 100mL water washing,
Stratification, ethyl acetate layer use 100mL water washing primary again, stratification, after organic phase is dried, filtered with anhydrous sodium sulfate
It removes ethyl acetate under reduced pressure, adds 120mL acetone heating for dissolving to be placed on 0 DEG C of crystallization and stay overnight, filter, 60 DEG C of air blast are dried white
Needle-like solid tamoxifen 32.3g, yield 88.1%.Mp:96.2~97.5 DEG C.
Claims (2)
1. a kind of preparation method of tamoxifen, it is characterised in that include the following steps:
Into 1L hydrogenation reaction cauldron, 40g Toremifene, 400g methanol, 8.3g potassium hydroxide, 10% palladium charcoal of 4g, use is added
The nitrogen of 0.2MPa is replaced 3 times, then is replaced 3 times with the hydrogen of 0.2MPa, and 0.3~0.5MPa of Hydrogen Vapor Pressure, reaction temperature are kept
It 70 DEG C, is stirred to react 14 hours；It is down to room temperature, is filtered, it is 8 that filtrate, which is adjusted to pH with 2N dilute hydrochloric acid, removes methanol under reduced pressure, adds
250mL ethyl acetate and 100mL water washing, stratification, organic phase remove acetic acid under reduced pressure after being dried, filtered with anhydrous sodium sulfate
Ethyl ester, add 120mL acetone heating for dissolving be placed on 0 DEG C of crystallization stay overnight, filter, 60 DEG C of air blast dry white needles he not
Former times is fragrant.
2. a kind of preparation method of tamoxifen, it is characterised in that include the following steps:
Into 1L hydrogenation reaction cauldron, 40g Toremifene, 600g isopropanol, 9g sodium hydroxide, 10% palladium charcoal of 4g, use is added
The nitrogen of 0.2MPa is replaced 3 times, then is replaced 3 times with the hydrogen of 0.2MPa, and 0.3~0.5MPa of Hydrogen Vapor Pressure, reaction temperature are kept
It 80 DEG C, is stirred to react 15 hours；It is down to room temperature, is filtered, it is 8 that filtrate, which is adjusted to pH with 2N dilute hydrochloric acid, removes isopropanol under reduced pressure, adds
250mL ethyl acetate and 100mL water washing, stratification, organic phase remove acetic acid under reduced pressure after being dried, filtered with anhydrous sodium sulfate
Ethyl ester, add 120mL acetone heating for dissolving be placed on 0 DEG C of crystallization stay overnight, filter, 60 DEG C of air blast dry white needles he not
Former times is fragrant.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| CN2016102603939 | 2016-04-19 | ||
| CN201610260393.9A CN106397226A (en) | 2016-04-19 | 2016-04-19 | Novel preparation method for tamoxifen |
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| CN106957235A CN106957235A (en) | 2017-07-18 |
| CN106957235B true CN106957235B (en) | 2019-04-26 |
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| CN201710248170.5A Active CN106957235B (en) | 2016-04-19 | 2017-04-17 | A kind of preparation method of tamoxifen |
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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 (3)
| 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 |
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108289964B (en) * | 2015-08-10 | 2022-08-12 | 杭州多禧生物科技有限公司 | Novel linkers and their use for specific coupling of drugs and biomolecules |
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- 2016-04-19 CN CN201610260393.9A patent/CN106397226A/en active Pending
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- 2017-04-17 CN CN201710248170.5A patent/CN106957235B/en active Active
Patent Citations (3)
| 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 |
| 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 (2)
| Title |
|---|
| 他莫昔芬合成路线图解;梅和珊 等;《中国医药工业杂志》;20011231;第32卷(第1期);第45-47页 |
| 抗***药三苯氧胺制备方法的进展;徐峰，胡惟孝;《浙江化工》;20051231;第36卷(第11期);第19-21页 |
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