CN104529864A - Preparation method of bazedoxifene acetate crystal form A - Google Patents

Preparation method of bazedoxifene acetate crystal form A Download PDF

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CN104529864A
CN104529864A CN201410835099.7A CN201410835099A CN104529864A CN 104529864 A CN104529864 A CN 104529864A CN 201410835099 A CN201410835099 A CN 201410835099A CN 104529864 A CN104529864 A CN 104529864A
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drying
organic solvent
hours
crystal form
vacuum
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CN104529864B (en
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宋波
白雪松
贾贵鹏
刘沫毅
刘蕴秀
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China Resources Saike Pharmaceutical Co Ltd
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China Resources Saike Pharmaceutical Co Ltd
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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 belongs to the technical field of chemical pharmacy and relates to a preparation method of a bazedoxifene acetate crystal form A. The preparation method of the bazedoxifene acetate crystal form A comprises the following steps: step 1, in the presence of palladium/carbon serving as a catalyst, dissolving hexamethyleneimine benzyloxy benzpyrole and ammonium formate in a benign organic solvent to have reaction; step 2, after the reaction is finished completely, filtering the palladium on activated carbon, cooling the filtrate, adding acetic acid and a toxic inorganic solvent, stirring, crystallizing, filtering and drying to obtain a crude crystal form A product; step 3, under the protection and presence of inert gas, dissolving the crude crystal form A product in the benign organic solvent, heating and dissolving; step 4, thermally filtering the solution, cooling the filtrate, dropwise adding the toxic inorganic solvent and crystallizing; step 5, after the crystallization is ended, filtering the solution and drying the solid to obtain the bazedoxifene acetate crystal form A.

Description

The preparation method of a kind of bazedoxifene acetate Form A
Technical field
The invention belongs to technical field of pharmaceutical chemistry, relate to the preparation method of a kind of bazedoxifene acetate Form A.
Background technology
Bazedoxifene acetate (Bazedoxifene Acetate), chemistry is by name: 1 ?[4 ?(2 ?azepine suberane ?1 ?base ?oxyethyl group) ?benzyl] ?2 ?(4 ?hydroxyl base ?phenyl) ?3 ?first base ?1H ?Yin diindyl ?5 ?phenol acetate, and structural formula is as follows:
Bazedoxifene acetate (Bazedoxifene Acetate), for the selective estrogen receptor modulators class medicine that Ligand company and Wyeth, Almirall company develop cooperatively, in April, 2009 is ratified first in Europe, commodity are called " Conbriza ", in June, 2010 is in Japanese Initial Public Offering, commodity are called " Viviant ", after this also go on the market in Spain.This medicine obtains listing approval in Korea S at present, but not yet list marketing, in U.S. FDA is evaluated.
Preclinical test data show, bazedoxifene acetate has more target activity than other selective estrogen receptor modulatorss (SERMs) known today, are so far " the best of like product ".Clinical study shows, in increase bone density and reduction risk of bone fracture, be significantly better than placebo, and bazedoxifene acetate does not stimulate uterus and mammary gland cell, therefore can not cause uterine endometrium and cyclomastopathy, security is good.Postmenopausal osteoporotic patients group is huge, and its harm caused should not be underestimated.Bazedoxifene acetate, compared with similar drugs, has good pharmacological effect and security advantages, has wide market outlook.
Bazedoxifene acetate Form A is compared with crystal form B, C, D, there is better bioavailability in pharmaceutical preparation, and former grinding in medicine is crystal form A, therefore need that a kind of cost is low, easy to operate, circulation ratio be strong, easily industrialization, yield and the high crystal form A preparation method of purity.
Hexamethylene imine benzyloxy indoles debenzylation prepares the method bibliographical information of WAY 140424, such as CN100339371C, is all the reactions adopting palladium carbon and pressurized with hydrogen.Yet there are no the reaction for hexamethylene imine benzyloxy indoles debenzylation of useful palladium carbon and ammonium formiate.As everyone knows, palladium carbon and pressurized with hydrogen hydrogenation require strict to conversion unit, need to use autoclave, industrial production cost is higher.The present invention uses palladium carbon and ammonium formiate hydrogenation, and common reactor such as ceramic still or glass kettle can meet the demands, easy suitability for industrialized production.
Report in US2005/0227965 a kind of in the ethanol with ethyl acetate sex change crystallization prepare the method for A crystalline substance; Report a kind of method that mixed crystal from crystal form B or crystal form A and B prepares crystal form A in WO2009/102771 A1, comprise and a kind ofly preparing the method for crystal form A with crystallization in Denatured alcohol or sex change ethyl acetate solution.Report in WO2009/102773 A1 a kind of in the ethanol with cyclohexane/acetone sex change crystallization prepare the method for crystal form A; Report a kind of method strengthening the stability of bazedoxifene acetate Form A simultaneously, comprise and keep bazedoxifene acetate Form A to avoid when dried forms contacting with the steam of certain solvent (as ethanol).Report in CN104030963A and bazedoxifene acetate is dissolved in the solvent of Denatured alcohol, and by this solvent rising temperature for dissolving, after being then cooled to suitable temperature, separate out the method for crystal form A.All Denatured alcohol is employed in above method, and all report crystal form A in US2005/0227965 with WO2009/102773 A1 and contact with ethanol or its steam and easily can change crystal form B into, all report crystal form A in WO2010151541A and WO2012037187A can turn crystalline substance obtain crystal formation D under certain solvent (as ethyl acetate: ethanol=2.5:1), long-time and low temperature (as 0.5 DEG C) condition, when this makes people prepare high purity crystal form A in Denatured alcohol, face arduous challenge.
Report in WO2012/089593 A1 and bazedoxifene acetate is dissolved in cyclic ether solvents that is single or that mix (as tetrahydrofuran (THF), 1,4 ?dioxane, methyltetrahydrofuran) in, filter, filtrate stirring and crystallizing obtains crystal form A, in embodiment 1, disclose amorphous bazedoxifene acetate be dissolved in tetrahydrofuran (THF) the example preparing crystal form A, in this patent, do not have the report of industrial production scale.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, a kind of preparation method of bazedoxifene acetate is provided.
Preparation method of the present invention has that cost is low, easy to operate, circulation ratio is strong, easily industrialization, without the need to crystal seed induction, the crystal form A yield obtained and purity high.
The synthetic route of sour WAY 140424 of the present invention is as follows:
The preparation method of sour WAY 140424 of the present invention, comprises the following steps:
Step 1, under the condition being catalyzer, is dissolved in hexamethylene imine benzyloxy indoles and ammonium formiate in optimum organic solvent and reacts with palladium carbon;
Step 2, filters out palladium carbon after reacting completely, add acetic acid and bad organic solvent after filtrate cooling, stir, crystallization, then filters, dry, obtains crystal form A crude product;
Step 3, under protection of inert gas exists, is dissolved in crystal form A crude product in optimum organic solvent, heating for dissolving;
Step 4, by solution heat filtering, drips bad organic solvent, crystallization after filtrate cooling;
Step 5, after crystallization terminates, solution filters, and solid drying obtains bazedoxifene acetate Form A.
Wherein, in step 1, described catalyzer is palladium carbon, palladium content in palladium carbon: 3% to 30%, moisture content in palladium carbon: 40% to 60%; Palladium carbon: hexamethylene imine benzyloxy indoles=0.05 ?0.2:1 (W/W), preferred 0.1:1.
The amount ratio of hexamethylene imine benzyloxy indoles and ammonium formiate is: 1:0.145 ?0.58 (W/W), be preferably 1:0.29.
Optimum organic solvent is selected from: tetrahydrofuran (THF), methyltetrahydrofuran or 1,4 ?one or more mixed solvents in dioxane.During for tetrahydrofuran (THF) as optimum organic solvent, temperature of reaction is 30 to 65 DEG C, during for methyltetrahydrofuran as optimum organic solvent, temperature of reaction 30 to 78 DEG C, for 1,4 ?dioxane as optimum organic solvent time, temperature of reaction is 30 to 100 DEG C.
Optimum organic solvent: hexamethylene imine benzyloxy indoles=3 ?12:1 (V/W), preferred 6:1.
Wherein, in step 2, filtrate cooling 5 to 20 DEG C, is preferably 10 to 15 DEG C.
Bad organic solvent is selected from: one or more mixed solvents in normal hexane, normal heptane, hexanaphthene, ether, dimethyl ether, Di Iso Propyl Ether or methyl tertiary butyl ether.
Bad organic solvent: hexamethylene imine benzyloxy indoles=2.5 ?10:1 (V/W), be preferably 5:1.
Acetic acid: hexamethylene imine benzyloxy indoles=0.0925 ?0.37:1 (W/W), be preferably 0.185:1.
Crystallization: 2 to 48 hours, preferably 10 ?crystallization 12 hours at 15 DEG C.
Drying mode is selected from: conventional drying, high-pressure drying or vacuum-drying, preferred vacuum-drying, and vacuum-drying is carried out in constant temperature drying under reduced pressure case, and drying temperature is 40 to 60 degrees Celsius, and time of drying is 4 to 48 hours.Preferably, 50 DEG C of vacuum-drying 10 hours.
Wherein, in step 3, optimum organic solvent is selected from: tetrahydrofuran (THF), methyltetrahydrofuran or 1,4 ?one or more mixed solvents in dioxane.During for tetrahydrofuran (THF) as optimum organic solvent, temperature of reaction is 30 to 65 DEG C, during for methyltetrahydrofuran as optimum organic solvent, temperature of reaction 30 to 78 DEG C, for 1,4 ?dioxane as optimum organic solvent time, temperature of reaction is 30 to 100 DEG C.
Optimum organic solvent: crystal form A crude product=4 ?16:1 (V/W), preferred 8:1.
Wherein, in step 4, bad organic solvent is selected from: one or more mixed solvents in normal hexane, normal heptane, hexanaphthene, ether, dimethyl ether, Di Iso Propyl Ether or methyl tertiary butyl ether.
Bad organic solvent: crystal form A crude product=2.5 ?10:1 (V/W), preferred 5:1
Filtrate cooling 5 to 20 DEG C, is preferably 10 to 15 DEG C.
Crystallization: 2 to 48 hours, preferably 10 ?crystallization 12 hours at 15 DEG C.
Wherein, in step 5, drying mode is selected from: conventional drying, high-pressure drying or vacuum-drying, preferred vacuum-drying, and vacuum-drying is carried out in constant temperature drying under reduced pressure case, and drying temperature is 40 to 60 degrees Celsius, and time of drying is 4 to 48 hours.Preferably, 50 DEG C of vacuum-drying 10 hours.
Preferably, preparation method of the present invention, comprises the following steps:
Take 2kg hexamethylene imine benzyloxy indoles, 0.58kg ammonium formiate, 0.2kg palladium carbon joins in the reactor that 12L tetrahydrofuran (THF) is housed, be heated to 45 ?50 DEG C reaction 2 ?3 hours, after reacting completely, suction filtration falls palladium carbon, solution be cooled to 10 ?15 DEG C, then add 0.37kg acetic acid and 10L methyl tertiary butyl ether successively, solution continue 10 ?stir 12 hours at 15 DEG C, suction filtration, solid 50 DEG C of vacuum-dryings 10 hours, obtain crystal form A crude product
Taking 1kg crystal form A crude product joins in the reactor that 8L tetrahydrofuran (THF) is housed; be warming up under protection of inert gas 45 ?50 DEG C; the complete molten rear solution of solid filters; filtrate continuation be cooled to 10 ?15 DEG C; then add 5L methyl tertiary butyl ether, solution 10 ?15 DEG C of insulation crystallizatioies 12 hours, crystallization terminates rear suction filtration; solid 50 DEG C of vacuum-dryings 10 hours, obtain crystal form A sterling.
For further illustrating beneficial effect of the present invention, applicant screens reaction conditions of the present invention.
Contriver has screened the impact of recrystallization temperature on product HPLC purity, crystal formation, granularity, total recovery and proterties, and result is as shown in table 1.Find from experimental result: temperature is 25 ~ 35 DEG C time, and easily generate the product containing crystal form B, granularity is also less; Temperature, 5 ~ 20 DEG C time, can obtain highly purified crystal form A; Wen Du ?5 ~ 0 DEG C time, easily generate the product containing crystal formation D, granularity is also larger.Go out to be suitable for generate the temperature range of crystal form A from the experimental results at 5 ~ 20 DEG C, preferably 10 ~ 15 DEG C.
Table 1
ait is different as the case may be that experiment condition removes recrystallization temperature, and other conditions all use as method in embodiment 1;
bcrystal formation quantitatively uses dsc measurement, with reference to method disclosed in CN101977897A specification sheets;
cgranulometry adopts Malvern 2000 type laser particle analyzer to carry out drying measure.
The present invention also screens following reaction conditions:
1, the screening of 10% palladium carbon consumption:
Table 2
10% palladium carbon (water content about 50%) a Bazedoxifene acetate debenzylation with become salt refining after, crystal form A total recovery
0.05kg 35.24％
0.1kg 45.23％
0.2kg 49.46％
0.4kg 49.21％
0.6kg 50.34％
aexperiment condition palladium removing carbon consumption is different as the case may be, and other conditions all use as method in embodiment 1.
Result shows: find lower lower than yield during 0.1kg after 10% palladium carbon consumption screening, and less higher than yield change after 0.2kg, in conjunction with the consideration on cost, selects palladium carbon: hexamethylene imine benzyloxy indoles=0.05 ?0.2:
1 (W/W), preferred 0.1:1.
2, the selection of optimum organic solvent:
Table 3
ait is different as the case may be that experiment condition removes optimum organic solvent, and other conditions all use as method in embodiment 1.
Result shows: optimum organic solvent screening discovery cyclic ether solvents, yield difference is less.
3, the selection of bad organic solvent:
Table 4
ait is different as the case may be that experiment condition removes bad organic solvent, and other conditions all use as method in embodiment 1.
Result shows: screen bad organic solvent and find to be unfavorable for suitability for industrialized production when just starting easily to form bulk thick solid when being added dropwise to alkane (as normal hexane, normal heptane, hexanaphthene), and adopt time ether solvent (as ether, dimethyl miaow, Di Iso Propyl Ether, methyl tertiary butyl ether) and do not have bulk thick solid to separate out, be beneficial to suitability for industrialized production.Through comparing, preferable methyl tertbutyl ether is as bad organic solvent.
Preferred step by step by above-mentioned preparation condition, just obtains preparation method of the present invention.
The present invention is compared with immediate prior art (as WO2012/089593 A1), maximum difference is: (1) uses ammonium formiate and palladium carbon to carry out debenzylation to intermediate hexamethylene imine benzyloxy indoles to prepare WAY 140424 first, and during aftertreatment, salify, crystallization obtain crystal form A crude product; (2) more good solvent (as cyclic ethers class) is used to dissolve crystal form A crude product, use more good solvent can ensure do not have solid to separate out in solution filtration, temperature-fall period, avoid occurring in Crystallization Process turn brilliant or generate other crystal formations except crystal form A; (3) after bazedoxifene acetate solution being cooled to the temperature of suitable crystallization, drip bad organic solvent, crystallization solvent is made to become optimum and bad organic mixed solvent, and the single or hybrid ring ether solvents used in WO2012/089593 A1, the present invention uses mixed solvent to have clear improvement compared to tool in prior art (as WO2012/089593 A1) effect on recrystallization temperature, crystallization speed, crystallization yield, operation repeatability and operation controllability; (4) strong, the easily industrialization of low, easy to operate, the circulation ratio of above preparation method's cost, without the need to crystal seed induction, the crystal form A yield obtained and purity high.This method solve the problem that crystal form A is all the time difficult on a large scale, stablizes industrialization production, achieve unforeseeable effect, there is outstanding substantial feature and significant progress compared with prior art (as WO2012/089593 A1).
Accompanying drawing explanation
Accompanying drawing 1: the X-diffracting spectrum of embodiment 1 bazedoxifene acetate Form A.
Accompanying drawing 2: the DSC collection of illustrative plates of embodiment 1 bazedoxifene acetate Form A.
Accompanying drawing 3: the TGA collection of illustrative plates of embodiment 1 bazedoxifene acetate Form A.
Accompanying drawing 4: the X-diffracting spectrum of embodiment 2 bazedoxifene acetate Form A.
Accompanying drawing 5: the X-diffracting spectrum of embodiment 3 bazedoxifene acetate Form A.
Accompanying drawing 6: the X-diffracting spectrum of embodiment 4 bazedoxifene acetate Form A.
Embodiment
Below describe technical scheme of the present invention in detail.The embodiment of the present invention is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to technical scheme of the present invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in right of the present invention.
Compound crystal form of the present invention characterizes and characterizes by its X-ray powder diffraction.The X-ray powder diffraction of this crystal-form compound uses CuK with x-ray diffractometer (XD2/3 Series diffractive instrument, Beijing Puxi General Instrument Co., Ltd) αradiation is measured.The method of X-ray powder diffraction is as follows:
Sweep velocity: 2 degrees/min.
Target: CuK α.
Voltage: 36 kilovolts (kV).
Electric current: 20 milliampere(mA)s (mA).
Sweep limit: from 3 to 50.0 degree.
Sampling step is wide: 0.0100 degree.
Multiplicity: 1 time.
Compound crystal form of the present invention characterizes and also characterizes by its DSC-TGA collection of illustrative plates.The dsc measurement of this crystal-form compound measures with DSC-TGA thermal analyzer (TA Q600 type thermal analyzer, TA instrument company of the U.S.).Wherein dsc measurement uses aluminium crucible with cover, 10 DEG C/min temperature rise rate.TGA measures and uses ceramic crucible, 10 DEG C/min temperature rise rate.
The preparation of embodiment 1 bazedoxifene acetate Form A
Take hexamethylene imine benzyloxy indoles (2kg), ammonium formiate (0.58kg), 10% palladium carbon (0.2kg, water content 50%) join containing tetrahydrofuran (THF) (12L) reactor, be heated to 45 ?50 DEG C reaction about 2 ?3 hours, after reacting completely, suction filtration falls palladium carbon, solution be cooled to 10 ?15 DEG C, then add acetic acid (0.37kg) and methyl tertiary butyl ether (10L) respectively in batches, solution continue 10 ?15 DEG C stir 12 hours.Suction filtration, solid 50 DEG C of vacuum-dryings 10 hours, obtain white powdery solids 1.12kg, yield 68.7%.
Taking the above crystal form A crude product (1kg) obtained joins in the reactor containing tetrahydrofuran (THF) (8L); be warming up under protection of inert gas 45 ?50 DEG C; the complete molten rear solution of solid filters; filtrate continuation be cooled to 10 ?15 DEG C; then add methyl tertiary butyl ether (5L) in batches, solution 10 ?15 DEG C of insulation crystallizatioies 12 hours.Crystallization terminates rear suction filtration, and solid 50 DEG C of vacuum-dryings 10 hours, obtain white powdery solids 0.72kg, and yield is 72.0%, HPLC purity is 99.88%, and crystal form A purity is greater than 99%.
The preparation of embodiment 2 bazedoxifene acetate Form A
Take hexamethylene imine benzyloxy indoles (2kg), ammonium formiate (0.58kg), 10% palladium carbon (0.1kg, water content 50%) join containing tetrahydrofuran (THF) (12L) reactor, be heated to 45 ?50 DEG C reaction about 2 ?3 hours, after reacting completely, suction filtration falls palladium carbon, solution be cooled to 10 ?15 DEG C, then add acetic acid (0.185kg) and methyl tertiary butyl ether (5L) respectively in batches, solution continue 10 ?15 DEG C stir 12 hours.Suction filtration, solid 50 DEG C of vacuum-dryings 10 hours, obtain crystal form A crude product.
Taking the above crystal form A crude product (1kg) obtained joins in the reactor containing tetrahydrofuran (THF) (8L); be warming up under protection of inert gas 45 ?50 DEG C; the complete molten rear solution of solid filters; filtrate continuation be cooled to 10 ?15 DEG C; then add methyl tertiary butyl ether (5L) in batches, solution 10 ?15 DEG C of insulation crystallizatioies 12 hours.Crystallization terminates rear suction filtration, and solid 50 DEG C of vacuum-dryings 10 hours, obtain crystal form A sterling, and total recovery is 45.23%.
The preparation of embodiment 3 bazedoxifene acetate Form A
Take hexamethylene imine benzyloxy indoles (2kg), ammonium formiate (0.58kg), 10% palladium carbon (0.4kg, water content 50%) join containing tetrahydrofuran (THF) (12L) reactor, be heated to 45 ?50 DEG C reaction about 2 ?3 hours, after reacting completely, suction filtration falls palladium carbon, solution be cooled to 10 ?15 DEG C, then add acetic acid (0.185kg) and methyl tertiary butyl ether (5L) respectively in batches, solution continue 10 ?15 DEG C stir 12 hours.Suction filtration, solid 50 DEG C of vacuum-dryings 10 hours, obtain crystal form A crude product.
Taking the above crystal form A crude product (1kg) obtained joins in the reactor containing tetrahydrofuran (THF) (8L); be warming up under protection of inert gas 45 ?50 DEG C; the complete molten rear solution of solid filters; filtrate continuation be cooled to 10 ?15 DEG C; then add methyl tertiary butyl ether (5L) in batches, solution 10 ?15 DEG C of insulation crystallizatioies 12 hours.Crystallization terminates rear suction filtration, and solid 50 DEG C of vacuum-dryings 10 hours, obtain crystal form A sterling, and total recovery is 49.21%.
The preparation of embodiment 4 bazedoxifene acetate Form A
Take hexamethylene imine benzyloxy indoles (2kg), ammonium formiate (0.58kg), 10% palladium carbon (0.6kg, water content 50%) join containing tetrahydrofuran (THF) (12L) reactor, be heated to 45 ?50 DEG C reaction about 2 ?3 hours, after reacting completely, suction filtration falls palladium carbon, solution be cooled to 10 ?15 DEG C, then add acetic acid (0.185kg) and methyl tertiary butyl ether (5L) respectively in batches, solution continue 10 ?15 DEG C stir 12 hours.Suction filtration, solid 50 DEG C of vacuum-dryings 10 hours, obtain crystal form A crude product.
Taking the above crystal form A crude product (1kg) obtained joins in the reactor containing tetrahydrofuran (THF) (8L); be warming up under protection of inert gas 45 ?50 DEG C; the complete molten rear solution of solid filters; filtrate continuation be cooled to 10 ?15 DEG C; then add methyl tertiary butyl ether (5L) in batches, solution 10 ?15 DEG C of insulation crystallizatioies 12 hours.Crystallization terminates rear suction filtration, and solid 50 DEG C of vacuum-dryings 10 hours, obtain crystal form A sterling, and total recovery is 50.34%.
The present invention is not limited to above-mentioned embodiment.The present invention expands to any new feature of disclosing in this manual or any combination newly, and the step of the arbitrary new method disclosed or process or any combination newly.

Claims (10)

1. prepare a preparation method of bazedoxifene acetate Form A, comprise the following steps:
Step 1, under the condition being catalyzer, is dissolved in hexamethylene imine benzyloxy indoles and ammonium formiate in optimum organic solvent and reacts with palladium carbon;
Step 2, filters out palladium carbon after reacting completely, add acetic acid and bad organic solvent after filtrate cooling, stir, crystallization, then filters, dry, obtains crystal form A crude product;
Step 3, under protection of inert gas exists, is dissolved in crystal form A crude product in optimum organic solvent, heating for dissolving;
Step 4, by solution heat filtering, drips bad organic solvent, crystallization after filtrate cooling;
Step 5, after crystallization terminates, solution filters, and solid drying obtains bazedoxifene acetate Form A.
2. preparation method according to claim 1, is characterized in that, in step 1, described catalyzer is palladium carbon, palladium content in palladium carbon: 3% to 30%, moisture content in palladium carbon: 40% to 60%; Palladium carbon: hexamethylene imine benzyloxy indoles=0.05 ?0.2:1 (W/W); The amount ratio of hexamethylene imine benzyloxy indoles and ammonium formiate be 1:0.145 ?0.58 (W/W); Optimum organic solvent is selected from: tetrahydrofuran (THF), methyltetrahydrofuran or 1,4 ?one or more mixed solvents in dioxane; Optimum organic solvent: hexamethylene imine benzyloxy indoles=3 ?12:1 (V/W).
3. preparation method according to claim 1, is characterized in that, in step 1, described catalyzer is palladium carbon, palladium content in palladium carbon: 10%, moisture content in palladium carbon: 50%; Palladium carbon: hexamethylene imine benzyloxy indoles=0.1:1 (W/W); The amount ratio of hexamethylene imine benzyloxy indoles and ammonium formiate is: 1:0.29 (W/W); Optimum organic solvent is selected from: tetrahydrofuran (THF), methyltetrahydrofuran or 1,4 ?one or more mixed solvents in dioxane, during for tetrahydrofuran (THF) as optimum organic solvent, temperature of reaction is 30 to 65 DEG C, during for methyltetrahydrofuran as optimum organic solvent, and temperature of reaction 30 to 78 DEG C, for 1,4 ?dioxane as optimum organic solvent time, temperature of reaction is 30 to 100 DEG C, optimum organic solvent: hexamethylene imine benzyloxy indoles=36:1 (V/W).
4. preparation method according to claim 1, is characterized in that, in step 2, filtrate cooling 5 to 20 DEG C, is preferably 10 to 15 DEG C; Bad organic solvent is selected from: one or more mixed solvents in normal hexane, normal heptane, hexanaphthene, ether, dimethyl ether, Di Iso Propyl Ether or methyl tertiary butyl ether, bad organic solvent: hexamethylene imine benzyloxy indoles=2.5 ?10:1 (V/W), be preferably 5:1; Acetic acid: hexamethylene imine benzyloxy indoles=0.0925 ?0.37:1 (W/W), be preferably 0.185:1; Crystallization: 2 to 48 hours, preferably 10 ?crystallization 12 hours at 15 DEG C; Drying mode is selected from: conventional drying, high-pressure drying or vacuum-drying, preferred vacuum-drying, and vacuum-drying is carried out in constant temperature drying under reduced pressure case, and drying temperature is 40 to 60 degrees Celsius, and time of drying is 4 to 48 hours, preferably, and 50 DEG C of vacuum-drying 10 hours.
5. preparation method according to claim 1, is characterized in that, in step 2, and filtrate cooling 10 to 15 DEG C; Bad organic solvent is selected from: one or more mixed solvents in normal hexane, normal heptane, hexanaphthene, ether, dimethyl ether, Di Iso Propyl Ether or methyl tertiary butyl ether, bad organic solvent: hexamethylene imine benzyloxy indoles=5:1 (V/W); Acetic acid: hexamethylene imine benzyloxy indoles=0.185:1 (W/W); Crystallization: 10 ?crystallization 12 hours at 15 DEG C; Drying mode: vacuum-drying, vacuum-drying is carried out in constant temperature drying under reduced pressure case, and drying temperature is 40 to 60 degrees Celsius, and time of drying is 4 to 48 hours.
6. preparation method according to claim 1, it is characterized in that, in step 3, optimum organic solvent is selected from: tetrahydrofuran (THF), methyltetrahydrofuran or 1,4 ?one or more mixed solvents in dioxane, optimum organic solvent: crystal form A crude product=4 ?16:1 (V/W).
7. preparation method according to claim 1, it is characterized in that, in step 3, optimum organic solvent is selected from: tetrahydrofuran (THF), methyltetrahydrofuran or 1,4 ?one or more mixed solvents in dioxane, during for tetrahydrofuran (THF) as optimum organic solvent, temperature of reaction is 30 to 65 DEG C, during for methyltetrahydrofuran as optimum organic solvent, temperature of reaction 30 to 78 DEG C, for 1,4 ?dioxane as optimum organic solvent time, temperature of reaction is 30 to 100 DEG C, optimum organic solvent: crystal form A crude product=8:1 (V/W).
8. preparation method according to claim 1, it is characterized in that, wherein, in step 4, bad organic solvent is selected from: one or more mixed solvents in normal hexane, normal heptane, hexanaphthene, ether, dimethyl ether, Di Iso Propyl Ether or methyl tertiary butyl ether; Bad organic solvent: crystal form A crude product=2.5 ?10:1 (V/W), preferred 5:1; Filtrate cooling 5 to 20 DEG C, is preferably 10 to 15 DEG C; Crystallization: 2 to 48 hours, preferably 10 ?crystallization 12 hours at 15 DEG C.
9. preparation method according to claim 1, it is characterized in that, in step 5, drying mode is selected from: conventional drying, high-pressure drying or vacuum-drying, preferred vacuum-drying, and vacuum-drying is carried out in constant temperature drying under reduced pressure case, drying temperature is 40 to 60 degrees Celsius, time of drying is 4 to 48 hours, preferably, and 50 DEG C of vacuum-drying 10 hours.
10. preparation method according to claim 1, is characterized in that, comprises the following steps:
Taking 2kg hexamethylene imine benzyloxy indoles, 0.58kg ammonium formiate and 0.2kg palladium carbon joins in the reactor that 12L tetrahydrofuran (THF) is housed, be heated to 45 ?50 DEG C reaction 2 ?3 hours, after reacting completely, suction filtration falls palladium carbon, solution be cooled to 10 ?15 DEG C, then add 0.37kg acetic acid and 10L methyl tertiary butyl ether successively, solution continue 10 ?stir 12 hours at 15 DEG C, suction filtration, solid 50 DEG C of vacuum-dryings 10 hours, obtain crystal form A crude product
Taking 1kg crystal form A crude product joins in the reactor that 8L tetrahydrofuran (THF) is housed; be warming up under protection of inert gas 45 ?50 DEG C; the complete molten rear solution of solid filters; filtrate continuation be cooled to 10 ?15 DEG C; then add 5L methyl tertiary butyl ether, solution 10 ?15 DEG C of insulation crystallizatioies 12 hours, crystallization terminates rear suction filtration; solid 50 DEG C of vacuum-dryings 10 hours, to obtain final product.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106748959A (en) * 2017-01-17 2017-05-31 成都归合科技有限公司 A kind of preparation method of pure bazedoxifene acetate Form A
CN111004165A (en) * 2019-12-03 2020-04-14 南京正济医药研究有限公司 Preparation method of bazedoxifene acetate crystal form A

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CN1938272A (en) * 2004-04-07 2007-03-28 惠氏公司 Crystalline polymorph of bazedoxifene acetate
WO2012089593A1 (en) * 2010-12-28 2012-07-05 Sandoz Ag Method of preparing polymorphic pure form a of bazedoxifene acetate
CN104030963A (en) * 2014-06-30 2014-09-10 四川大学 Preparation method of bazedoxifene acetate crystal form A

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Publication number Priority date Publication date Assignee Title
CN1938272A (en) * 2004-04-07 2007-03-28 惠氏公司 Crystalline polymorph of bazedoxifene acetate
WO2012089593A1 (en) * 2010-12-28 2012-07-05 Sandoz Ag Method of preparing polymorphic pure form a of bazedoxifene acetate
CN104030963A (en) * 2014-06-30 2014-09-10 四川大学 Preparation method of bazedoxifene acetate crystal form A

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106748959A (en) * 2017-01-17 2017-05-31 成都归合科技有限公司 A kind of preparation method of pure bazedoxifene acetate Form A
CN111004165A (en) * 2019-12-03 2020-04-14 南京正济医药研究有限公司 Preparation method of bazedoxifene acetate crystal form A

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