- Preparation method of bazedoxifene acetate crystal form A
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The invention discloses a preparation method of a bazedoxifene acetate crystal form A. The method comprises the following steps: taking 1-(4-(2-(azepine-1-yl) ethoxy) benzyl)-5-(benzyloxy)-2-(4-(benzyloxy) phenyl)-3-methyl-1H-indole as a raw material; preparing bazedoxifene acetate free alkali, preparing a bazedoxifene acetate crude product, preparing a bazedoxifene acetate crystal form B, preparing a bazedoxifene acetate crystal form C and preparing the bazedoxifene acetate crystal form A. A mixed solvent is adopted in the hydrogenation process of the method; the rate and the activity of thepalladium-carbon reduction reaction are improved; an antioxidant is added, so that the stability of the bazedoxifene free alkali is improved, the conversion from the crystal form B to the crystal formC is increased in the middle, key parameters for converting the crystal form C into the crystal form A are found, the purity of the crystal form A in the next step is greatly improved, and the production cost for producing the bazedoxifene acetate crystal form A is effectively reduced.
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Paragraph 0032-0034; 0044; 0047
(2020/04/22)
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- Preparation method and application of bazedoxifene acetate crystal form D
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The invention belongs to the field of medicines, and in particular relates to a preparation method and application of a bazedoxifene acetate crystal form D. The method comprises the following steps: dissolving a compound A into a first good organic solvent; adding a catalyst and ammonium formate into the first good organic solvent, and performing a reaction; performing filtration to remove the catalyst, washing the filtrate by using an inorganic alkali aqueous solution, and separating an organic phase; performing concentration on the organic phase to obtain a bazedoxifene free alkali; dissolving the bazedoxifene free base into a second good organic solvent; adding glacial acetic acid into the second good organic solvent, and performing crystallization; and performing filtration to obtain the bazedoxifene acetate crystal form D, wherein the compound A has a structure represented by a formula I shown in the description. The technical solution provided by the invention does not require high-pressure hydrogenation, the solvent system is simple, the reaction equipment requirements are low, the industrialization is easy to realize, and the obtained bazedoxifene acetate crystal form D hashigh purity.
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Paragraph 0055; 0061-0067; 0075; 0081-0085; 0093; 0099-0102
(2019/07/04)
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- PROCESS FOR THE PREPARATION OF BAZEDOXIFENE
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The invention relates to a process for preparation of the compound 3-methyl-5-benzyloxy-2-(4-benzyloxyphenyl)-1H-indole 5, an intermediate for the synthesis of bazedoxifene and bazedoxifene acetate.
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- Acetic acid [...] and intermediate preparation method
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The invention discloses a bazedoxifene acetate intermediate and a preparation method thereof. The invention also discloses a method for preparing bazedoxifene acetate from the bazedoxifene acetate intermediate. The invention provides a method for preparing a novel intermediate of bazedoxifene acetate key as shown in the formula (II), the intermediate employs C1-6 alkyl acyl as protective group, and the method for preparing bazedoxifene acetate using the intermediate has the following advantages: (1) high pressure hydrogenation reaction with high risk for deprotection according to the traditional method (using benzyl as a protective group for protecting phenolic group) is avoided, and thereby greatly reducing danger of the experiment; 2. the reaction time is reduced and the industrial energy consumption is reduced; 3. the reaction of the present invention does not need palladium 10% on carbon; the preparation method is environmental friendly, and is suitable for industrial production, and has the advantages of mild condition and operation convenience.
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Paragraph 0081; 0082; 0083; 0086; 0088; 0090
(2018/07/07)
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- Industrial production method for bazedoxifene acetate
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The invention discloses an industrial production method for bazedoxifene acetate. The production method comprises the following steps: taking p-hydroxy benzaldehyde as a starting material, substituting with chloracetyl-hexamethyleneimine, reducing with borohydride and chlorinating with a chlorinating agent to obtain a compound 4; reacting the compound 4 with 5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole to obtain a compound 5; and carrying out debenzylation to obtain a compound 6, and salifying with acetic acid to obtain a target compound which is the bazedoxifene acetate. The defective workmanship of preparation in the prior art is solved, the used reagent is low in cost and easy to obtain, environmental pollution is small, safety is high, an operation process is simple, and thus, the bazedoxifene acetate is suitable for being produced industrially.
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Paragraph 0016; 0027; 0066-0068
(2018/03/25)
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- Bazedoxifene Acetate polymorphism A preparation method
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The present invention discloses a Bazedoxifene Acetate polymorphism A preparation method, wherein a raw material Bazedoxifene free alkali is dissolved in a single solvent methanol, and salt forming and crystallization are performed to directly obtain the
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Paragraph 0028; 0034; 0039; 0040
(2018/04/02)
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- Preparation method of bazedoxifene acetate
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The invention discloses a preparation method of bazedoxifene acetate. The method is characterized in that raney nickel is used as a catalyst, and a compound I and hydrogen react in a microreactor to obtain bazedoxifene under the conditions that the temperature is 20 to 40DEG C and the hydrogen pressure is controlled to be 0.1 to 0.5Mpa. According to the method, the raney nickel with lower price is used to replace expensive palladium carbon, so that the production cost is effectively reduced, the microreactor is used and the production is in streamline operation; an obtained product is high in yield and good in quality; the preparation method has the advantages of high reaction efficiency, mild reaction conditions, safe and controllable operation, short reaction time and low cost; the method is easier for industrial production (The formula is shown in the description).
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Paragraph 0029-0032
(2017/07/01)
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- Method for the preparation of high purity Bazedoxifene Acetate
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The present invention relates to a method for producing bazedoxifene acetate using a reducing agent or a reducing agent and an antioxidant and, more specifically, to a method for producing bazedoxifene acetate with high purity by removing bazedoxifene N-oxide within less than 0.01%.COPYRIGHT KIPO 2017
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Paragraph 0055; 0056
(2017/08/15)
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- A preparation method of A palestinian multi-past profuse crystal acetate
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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.
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Paragraph 0083; 0084; 0085; 0086; 0087-0095
(2017/04/28)
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- Preparation method of bazedoxifene acetate and crystal form A
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A preparation method of bazedoxifene acetate is characterized by including the following steps: (1) performing a reaction by mixing and suspending a compound represented in the formula (A), ammonium formate or cyclohexadiene, and a palladium-carbon catalyst in an organic solvent, reaction terminal being detected with TLC or HPLC; (2), filtering and washing a reaction product, adding acetic acid with stirring, and filtering and drying the mixture to prepare the bazedoxifene acetate. The invention also provides a preparation method of a bazedoxifene acetate crystal form A. The preparation method is free of hydrogen and avoids usage of special devices, such as a hydrogenation kettle, while a safe hydrogen donor is employed, so that the method can be carried out even with a common reaction kettle and a reaction workshop, thereby reducing dangerousness of the synthesis and building and operation cost of a special device workshop. The preparation method of the crystal form A, compared with the prior art, is simple in operation, is free of a crystal seed for inducing crystallization, is high in crystal form purity and is simple in solvent system which can be recycled and reused.
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Paragraph 0026; 0027; 0028; 0029; 0030
(2016/11/07)
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- B palestinian multi-past fragrance acetate method for preparing polymorph
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The invention discloses a preparation method of bazedoxifene acetate polycrystalline type B. Bazedoxifene free alkali and glacial acetic acid are taken as raw materials and salified to obtain the bazedoxifene acetate polycrystalline type B. The operation
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Paragraph 0039-0040
(2018/01/19)
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- palestinian multi-past fragrance method for the preparation of acetic acid
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The invention discloses a preparation method of bazedoxifene acetate. The method comprises the following steps: carrying out a condensation cyclization reaction on 1-(4-Pg1 oxygroup phenyl) propyl alcohol (II) and N-{4-(2-azacycloheptane-1-yl-ethyoxyl-ben
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- PROCESSES AND INTERMEDIATES FOR PREPARING INDOLE PHARMACEUTICALS
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The invention described herein pertains to processes and intermediates for preparing indole containing pharmaceuticals, particularly to processes and intermediates for preparing selective estrogen receptor modulators, such as bazedoxifene.
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Page/Page column 25; 28; 29
(2014/12/12)
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- NOVEL SALT INTERMEDIATES FOR THE SYNTHESIS OF BAZEDOXIFENE ACETATE AND PROCESS THEREOF
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The present invention relates to novel salts of 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-H-indole which are useful intermediates in the production of (1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1-H- indol-5-ol acetic acid commonly known as bazedoxifene acetate and related compounds.
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Page/Page column 12
(2013/03/26)
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- NOVEL PROCESS FOR THE PREPARATION OF BAZEDOXIFENE ACETATE AND INTERMEDIATES THEREOF
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A novel process is described for the preparation of pharmaceutically useful compounds such as 1-{4-[2-(azepan-1-yl)ethoxy]benzyl}-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol acetic acid commonly known as bazedoxifene acetate of the formula-1 using 2-(4-{[5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl}phenoxy)ethyl-4-methylbenzenzene-1-sulfonate (formula 2a)
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Page/Page column 10
(2013/02/28)
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- PROCESSES FOR THE SYNTHESIS OF BAZEDOXIFENE ACETATE AND INTERMEDIATES THEREOF
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Efficient processes for the synthesis of pharmaceutically useful compounds such as (1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol acetic acid commonly known as bazedoxifene acetate (Formula IX) using cyanomethoxybenzyl halides of Formula III, where X=Halogens e.g., Cl, F, Br, I; G=Any electron donating or electron withdrawing substituent.
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- PREPARATION OF CRYSTALLINE BAZEDOXIFENE AND ITS SALTS
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Aspects of the present disclosure include crystalline bazedoxifene free base, crystalline bazedoxifene acetate Form D, and processes for their preparation. The drug compound having the adopted name "bazedoxifene acetate" has a chemical name 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol acetic acid, and has the chemical structure shown below as Formula I.
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Page/Page column 20
(2012/04/04)
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- PREPARATION OF BAZEDOXIFENE AND ITS SALTS
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Processes for preparing bazedoxifene and its pharmaceutically acceptable salts, substantially free from process related impurities and process intermediates.
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Page/Page column 32; 33
(2011/04/13)
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- SALTS OF BAZEDOXIFENE
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The invention deals with new crystalline salts of bazedoxifene, by means of which a high API quality can be achieved in a high yield.
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Page/Page column 6
(2010/10/03)
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- POLYMORPHIC FORM D OF BAZEDOXIFENE ACETATE AND METHODS OF PREPARING SAME
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The present disclosure relates to polymorphic Form D of bazedoxifene acetate, pharmaceutical compositions and methods of treatment using the same, and methods of preparing the same.
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Page/Page column 17
(2011/01/12)
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- METHODS OF PREPARING POLYMORPHIC FORM A OF BAZEDOXIFENE ACETATE
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The present invention relates to methods of preparing polymorphic Form A of bazedoxifene acetate, and increasing its stability, and polymorphic Form A prepared by such methods.
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Page/Page column 14
(2009/10/09)
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- Bazedoxifene acetate formulations
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The present invention is directed to formulations of bazedoxifene acetate that have reduced polymorph conversion, compositions containing the same, preparations thereof, and uses thereof.
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Page/Page column 6
(2010/11/26)
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- Crystalline polymorph of bazedoxifene acetate
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The present invention is directed to a crystalline polymorph of bazedoxifene acetate, compositions containing the same, preparations thereof, and uses thereof.
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Page/Page column 7-8
(2010/02/14)
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- CRYSTALLINE POLYMORPH OF BAZEDOXIFENE ACETATE
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The present invention is directed to a crystalline polymorph of bazedoxifene acetate, compositions containing the same, preparations thereof, and uses thereof.
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Page/Page column 15-17
(2008/06/13)
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