CN106631971B - A kind of preparation method of bazedoxifene acetate - Google Patents
A kind of preparation method of bazedoxifene acetate Download PDFInfo
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- CN106631971B CN106631971B CN201611178128.2A CN201611178128A CN106631971B CN 106631971 B CN106631971 B CN 106631971B CN 201611178128 A CN201611178128 A CN 201611178128A CN 106631971 B CN106631971 B CN 106631971B
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- microreactor
- chemical compounds
- bazedoxifene acetate
- bazedoxifene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
Abstract
The invention discloses a kind of preparation methods of bazedoxifene acetate.This method is using Raney's nickel as catalyst, in microreactor at 20~40 DEG C, controls under 0.1~0.5Mpa of Hydrogen Vapor Pressure, chemical compounds I is reacted to obtain Bazedoxifene with hydrogen.This method substitutes expensive palladium carbon using the lower Raney's nickel of price, and production cost is effectively reduced；Using microreactor, production is in pipelined operation, and reaction efficiency is high, and reaction condition is mild, and safe operation is controllable, and the reaction time is short, at low cost, obtains product yield height, high-quality, it is easier to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of bazedoxifene acetate, belongs to pharmaceutical technology field.
Background technique
Bazedoxifene (bazedoxifene) is selective estrogen receptor modulators of new generation (SERM), contestable suppression
System 1713 --- the combination of estradiol and estrogen receptor ERoc and ER13 has estrogen agonist activity to bone, can improve
The bone density of vertebra and hip, therefore can significantly reduce the vertebral fracture risk of osteoporosis menopausal women.Its structural formula is as follows
It is shown:
There are many synthetic method of Bazedoxifene, but most synthetic methods all first prepare 1- [4- (2- azacyclo- at present
Heptane -1- base-ethyoxyl)-benzyl] -5- benzyloxy -2- (4- benzyloxy-phenyl) -3- Methyl-1H-indole, it is then hydrogenated
Reduction debenzylation is protected to obtain Bazedoxifene.It is all urged using palladium carbon in the method major part patent of debenzylation and document in the route
Change hydrogenation reduction, as US2012253038A1, WO2009012734A2 and document 1-2 (document 1: Wei Jinqiang, Liu Wenjie,
Jiang Jieying waits bazedoxifene acetate synthesising process research [J] chemical research and application, 2015,27 (8), 1217-1210；Text
2: Chen Shan, Liu Xiangkui, Yu Xiong are offered, synthesis [J] Chinese Journal of New Drugs of bazedoxifene acetate, 2013 (13), 1571- are waited
1573).Its reaction equation is as follows:
The method of above-mentioned hydrogenating reduction deprotection is although simple and feasible, but using palladium carbon costly and needs to exist in reaction
It is reacted under high temperature and pressure (high pressure of 3-10Mpa), complicated for operation and the high requirements on the equipment, depositing may occur in operation
The security risk of leakage, explosion etc., industrialization amplification have difficulties.
Summary of the invention
Shortcoming and defect present in for the above preparation method, the present invention provide a kind of system of new bazedoxifene acetate
Preparation Method.This method uses microreactor, using the lower Raney's nickel of price as catalyst, at low-temp low-pressure (0.1-0.5Mpa)
Under can carry out fast reaction, and achieve higher reaction yield.Compared to existing preparation method, reaction condition of the invention
Mildly, cost of material is low, and the reaction time is extremely short, can pile line operation, high income and post-processing step is simple is easier to this technique
In industrialized production.
The technical scheme is that a kind of preparation method of bazedoxifene acetate, comprising: under the action of catalyst, 1-
[4- (2- azepan -1- base-ethyoxyl)-benzyl] -5- benzyloxy -2- (4- benzyloxy-phenyl) -3- Methyl-1H-indole
(chemical compounds I) reacts to obtain Bazedoxifene (compound ii) with hydrogen；Bazedoxifene obtains bazedoxifene acetate through acidifying with acetic acid；
It is characterized in that in microreactor at 20~40 DEG C, controlling 0.1~0.5Mpa of Hydrogen Vapor Pressure using Raney's nickel as catalyst
Under, chemical compounds I and hydrogen, which carry out reacting 1s-10s, obtains Bazedoxifene.Chemical equation is as follows.
Preferably, the organic solvent used in above-mentioned reaction is any one or the solvent 1 and solvent 2 in solvent 1
Mixed solvent.Solvent 1: methanol, ethyl alcohol, isopropanol；Solvent 2: ethyl acetate or isopropyl acetate.
Preferably, the dosage of Raney's nickel be 1~10%g/g (in terms of chemical compounds I), preferably 2~4%.
Concrete scheme of the invention is as follows:
1) prepare slurry: chemical compounds I is dissolved in organic solvent, Raney's nickel is added and is mixed evenly that be suspended in it molten
In liquid, it is spare to obtain slurry；
2) microreactor reacts: with air in the heating zone of nitrogen displacement microreactor, microreactor heating zone is heated to
20~40 DEG C, using hydrogen displacement nitrogen and control 0.1~0.5Mpa of Hydrogen Vapor Pressure；Slurry is inputted by micro- reaction using mashing pump
The heating zone reaction 1s-10s (reaction time is controlled by heating zone duct length and charging rate) of device, it is post-treated to obtain vinegar
Sour Bazedoxifene.
The microreactor includes that heating zone and cooling zone are sequentially connected by pipeline；The front end of the heating zone is equipped with liquid
Body import and gas feed.After slurry and hydrogen enter heating zone reaction from liquid-inlet and gas feed respectively, enter back into cold
But area is cooling, and is collected by external collector.Microreactor of the invention is provided by healthy and free from worry (Shanghai) Management Co., Ltd.
Preferably, step 1) consumption of organic solvent is 5-20ml/g, preferably 5-10ml/g (in terms of chemical compounds I).
Preferably, the post-processing of the step 2) are as follows: cool down after the reaction was completed, be filtered to remove insoluble matter, delay into filtrate
It is slow that acetic acid is added dropwise, slowly there is white solid precipitation, be added dropwise, be cooled to 10 DEG C -20 DEG C, keeps the temperature crystallization, suction filtration, forced air drying
Obtain bazedoxifene acetate.
The present invention is experimentally confirmed: since the activity of Raney's nickel is lower than palladium carbon, directly substituting palladium carbon, high temperature with Raney's nickel
It is reacted under high pressure, hydrogenation reaction is not exclusively (see comparative example 1).It is low in low temperature using microreactor using palladium carbon as catalyst simultaneously
Pressure is reacted, and the yield of product is general (see comparative example 2), and microreactor and Raney's nickel catalyst are combined, low
Higher yield can be obtained under warm low pressure.Its reason speculates are as follows: the micro-structure of the inside of microreactor has it very
Big surface area/volume ratio rate.It is tiny grey powder on Raney's nickel surface, but from microcosmic angle, each of powder
Molecule is all a three-dimensional porous structure, and this porous structure greatly increases its surface area.The two combines, chemical combination
Object I, Raney's nickel and hydrogen moment are sufficiently mixed, while contacting abundant thus fully reacting each other, to obtain higher receipts
Rate.
Beneficial effects of the present invention: expensive palladium carbon is substituted using the lower Raney's nickel of price, production cost is effectively reduced；
Using microreactor, production is in pipelined operation, and reaction efficiency is high, and reaction condition is mild (low-temp low-pressure), and safe operation can
Control, the reaction time is short, at low cost, obtains product yield height (>=95%), high-quality, it is easier to industrialized production.
Detailed description of the invention
Fig. 1 is micro-reaction device schematic diagram of the invention.
Specific embodiment
The present invention is further illustrated combined with specific embodiments below, but protection scope of the present invention is not limited to
This:
Micro-reaction device as shown in Figure 1 includes microreactor, mashing pump, collector, heat exchanger, nitrogen and hydrogen storage
Equipment and pipeline are several.
The microreactor includes that heating zone and cooling zone are sequentially connected by pipeline；The front end of the heating zone is equipped with liquid
Body import and gas feed.After slurry and hydrogen enter heating zone reaction from liquid-inlet and gas feed respectively, enter back into cold
But area is cooling, and is collected by external collector.
The liquid-inlet is connected by pipeline with mashing pump, and slurry is sent by mashing pump through liquid-inlet and is heated
Area.The gas feed is connected with nitrogen, hydrogen storage equipment respectively by pipeline, and pipeline is equipped with check valve, nitrogen or hydrogen
Gas is unidirectionally passed through heating zone from gas feed；The heating zone is connected with heat exchanger (or heater), with realize to heating zone into
Row heating；The rear end of the cooling zone is connected with receiver, and cooler is equipped with the inlet and outlet of recirculated water, to access recirculated water
It is cooled down.
Embodiment 1
1) prepare slurry: 100g chemical compounds I is completely dissolved in 500ml ethyl alcohol, the Raney's nickel of 3g, stirring are added under room temperature
Uniformly, it is spare to obtain slurry.
2) microreactor reacts: air in the heating zone of microreactor is sufficiently displaced from using nitrogen, then by microreactor
Heating zone be preheated to 30 DEG C of interior temperature, then pass to hydrogen, control and the slurries of step 1) are passed through into slurry under pressure 0.2-0.3MPa
Material pump squeezes into 30 DEG C of reaction 3-8s of heating zone temperature control of microreactor；By cooled region, (cooled region is passed through after the reaction was completed
Circulating water) it is cooling after, collect reaction solution；
3) it generates bazedoxifene acetate: being filtered to remove insoluble matter, 10g acetic acid is slowly added dropwise into filtrate, slowly there is white
Solid is precipitated, and is added dropwise, and is cooled to 15 DEG C, keeps the temperature crystallization 1h, filters, forced air drying obtains white solid 77.9g, yield
95.5%, purity 99.3%.
Embodiment 2
1) prepare slurry: 500g chemical compounds I being completely dissolved in 4000ml ethyl alcohol and ethyl acetate (3:1) mixed liquor, often
The lower Raney's nickel that 20g is added of temperature, stirs evenly, spare；
2) microreactor reacts: being sufficiently displaced from air in microreactor using nitrogen, is preheated to interior temperature 40 to microreactor
DEG C, it is passed through hydrogen, reaction controlling pressure 0.3-0.4MPa is squeezed into slurries in microreactor by mashing pump, in heating region control
40 DEG C of reaction 1-5s of temperature；After cooling down (cooled region is passed through circulating water) by cooled region after the reaction was completed, reaction is collected
Liquid；
3) it is filtered to remove insoluble matter, 50g acetic acid is slowly added dropwise into filtrate, slowly has white solid precipitation, is added dropwise,
10 DEG C -20 DEG C of cooling keeps the temperature crystallization 1h, filters, forced air drying obtains white solid 347.3g, yield 96.7%, purity 98.9%.
Comparison example 1: unused microreactor only uses Raney's nickel reaction
100g chemical compounds I is completely dissolved in 500ml methanol, the Raney's nickel of 3g is added under room temperature, stirs evenly, uses 1L
Hydrogen is added after nitrogen displacement in high-pressure hydrogenation reaction kettle, and Hydrogen Vapor Pressure is maintained at 5-6Mpa, is heated to 80 DEG C of temperature, heat preservation is anti-
After answering 8-10h, reaction solution is collected, insoluble matter is filtered to remove, 10g acetic acid is slowly added dropwise into filtrate, slowly there is white solid analysis
Out, it is added dropwise, cools down 10 DEG C -20 DEG C, keep the temperature crystallization 1h, filter, forced air drying obtains white solid 44.2g, molar yield
54.2%, purity 35.9%.
Comparative example 2: Raney's nickel is not used to react using only microreactor
The Raney's nickel of 20g is replaced using the 10%Pd/C of 100g, remaining is the same as embodiment 2.It is reacted to obtain white solid
394.2g, yield 85.2%, purity 98.5%.
Claims (9)
1. a kind of preparation method of bazedoxifene acetate, comprising: under the action of catalyst, chemical compounds I reacts to obtain with hydrogen bar
More former times are fragrant；Bazedoxifene obtains bazedoxifene acetate through acidifying with acetic acid；
It is characterized in that using Raney's nickel as catalyst, in microreactor at 20~40 DEG C, control Hydrogen Vapor Pressure 0.1~
Under 0.5Mpa, chemical compounds I is reacted to obtain Bazedoxifene with hydrogen；
Wherein chemical compounds I is 1- [4- (2- azepan -1- base-ethyoxyl)-benzyl] -5- benzyloxy -2- (4- benzyloxy -
Phenyl) -3- Methyl-1H-indole.
2. a kind of preparation method of bazedoxifene acetate as described in claim 1, characterized in that using in the preparation method has
Solvent, organic solvent are the mixed solvent of any one or solvent 1 and solvent 2 in solvent 1；Wherein, solvent 1: first
Alcohol, ethyl alcohol or isopropanol；Solvent 2: ethyl acetate or isopropyl acetate.
3. a kind of preparation method of bazedoxifene acetate as described in claim 1, characterized in that the matter with chemical compounds I
Meter, the dosage of Raney's nickel are 1~10%.
4. a kind of preparation method of bazedoxifene acetate as claimed in claim 3, characterized in that the matter with chemical compounds I
Meter, the dosage of Raney's nickel are 2~4%.
5. a kind of preparation method of bazedoxifene acetate as described in claim 1, characterized in that the chemical compounds I and hydrogen
The reaction time reacted is 1s-10s.
6. a kind of preparation method of bazedoxifene acetate as described in any one of claim 1-5, characterized in that
1) prepare slurry: chemical compounds I is dissolved in organic solvent, Raney's nickel, which is added, and is mixed evenly makes it be suspended in solution
In, it is spare to obtain slurry；
2) microreactor reacts: with air in the heating zone of nitrogen displacement microreactor, microreactor heating zone is heated to 20~
40 DEG C, using hydrogen displacement nitrogen and control 0.1~0.5Mpa of Hydrogen Vapor Pressure；By the heating zone reaction of slurry input microreactor
1s-10s, it is post-treated to obtain bazedoxifene acetate；
The microreactor includes that heating zone and cooling zone are sequentially connected by pipeline；The front end of the heating zone be equipped with liquid into
Mouth and gas feed.
7. a kind of preparation method of bazedoxifene acetate as claimed in claim 6, characterized in that in terms of chemical compounds I, the step
Rapid 1) consumption of organic solvent is 5-20ml/g.
8. a kind of preparation method of bazedoxifene acetate as claimed in claim 7, characterized in that in terms of chemical compounds I, the step
Rapid 1) consumption of organic solvent is 5-10ml/g.
9. a kind of preparation method of bazedoxifene acetate as claimed in claim 6, characterized in that the post-processing of the step 2)
Are as follows: it cools down after the reaction was completed, is filtered to remove insoluble matter, acetic acid is slowly added dropwise into filtrate, be added dropwise, be cooled to 10 DEG C -20
DEG C, heat preservation crystallization, suction filtration, forced air drying obtain bazedoxifene acetate.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101977897A (en) * | 2008-02-11 | 2011-02-16 | 惠氏有限责任公司 | Methods of preparing polymorphic form a of bazedoxifene acetate |
| US20120330008A1 (en) * | 2011-06-21 | 2012-12-27 | Divi's Laboratories Limited | Novel process for the preparation of bazedoxifene acetate and intermediates thereof |
| CN104030963A (en) * | 2014-06-30 | 2014-09-10 | 四川大学 | Preparation method of bazedoxifene acetate crystal form A |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9751835B2 (en) * | 2013-05-15 | 2017-09-05 | Indiana University Research And Technology Corporation | Processes and intermediates for preparing indole pharmaceuticals |
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2016
- 2016-12-19 CN CN201611178128.2A patent/CN106631971B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101977897A (en) * | 2008-02-11 | 2011-02-16 | 惠氏有限责任公司 | Methods of preparing polymorphic form a of bazedoxifene acetate |
| US20120330008A1 (en) * | 2011-06-21 | 2012-12-27 | Divi's Laboratories Limited | Novel process for the preparation of bazedoxifene acetate and intermediates thereof |
| CN104030963A (en) * | 2014-06-30 | 2014-09-10 | 四川大学 | Preparation method of bazedoxifene acetate crystal form A |
Non-Patent Citations (2)
| Title |
|---|
| 应用微反应器技术合成爵床脂素G关键中间体;王胜鹏，等;《中国医药工业杂志》;20131231;第44卷(第4期);第341-343页 |
| 醋酸巴多昔芬的合成工艺改进;张春来，等;《中国药物评价》;20141231;第31卷(第5期);第264-266页 |
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Effective date of registration: 20200225 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Patentee after: Shandong Anxin Pharmaceutical Co., Ltd Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |