CN103709090A - Preparation method of bazedoxifene acetate and key intermediate thereof - Google Patents
Preparation method of bazedoxifene acetate and key intermediate thereof Download PDFInfo
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- CN103709090A CN103709090A CN201410018918.9A CN201410018918A CN103709090A CN 103709090 A CN103709090 A CN 103709090A CN 201410018918 A CN201410018918 A CN 201410018918A CN 103709090 A CN103709090 A CN 103709090A
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- preparation
- compound
- bazedoxifene acetate
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- alkali
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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
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- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention belongs to the field of medicinal chemistry, and discloses a preparation method of bazedoxifene acetate. The method comprises the following steps: carrying out condensation reaction on a compound I and a compound II in an organic solvent under an alkaline condition, so as to obtain an intermediate III; hydrolyzing and salifying the intermediate III, so as to obtain the target compound, namely bazedoxifene acetate (TM). By adopting the method, the productivity and the quality of bazedoxifene acetate can be obviously improved.
Description
Technical field
The present invention relates to preparation method and the key intermediate of bazedoxifene acetate.
Background technology
Bazedoxifene acetate chemical name:: 1-[4-(2-azepine ring-1-in heptan base-oxyethyl group)-benzyl]-2-(4-hydroxyl-phenyl)-3-methyl isophthalic acid
h-indoles-5 phenol acetate, a kind of new selective estrogenic agents, can cover vertebra and femoral neck bone mineral density, and significantly reduces the vertebral fracture risk of the menopausal women of suffering from osteoporosis.
Its main preparation methods is as follows at present:
Main drawback is the high-pressure hydrogenation that needs of reaction, has operational safety hidden danger, and industrialization amplification has difficulties.
Summary of the invention
The object of the present invention is to provide the preparation method that a kind of bazedoxifene acetate is new, the method can obviously be improved productive rate and the quality of bazedoxifene acetate.
(1), in organic solvent, there is condensation reaction and obtain intermediate III in Compound I and Compound I I under alkaline condition;
(2) the intermediate III hydrolysis, the salify that step (1) are made, obtain target compound bazedoxifene acetate (TM).
I II III
III TM
Wherein, Compound I is 3-methyl-5-acetoxyl group-2-(4-acetoxyl group phenyl)-1H-indoles.
Compound I I is.Methyl (4-(2-(hexamethylene imino--1-yl) ethylphenyl) methanesulfonates.
Compound III is 1-[4-(2-azepine ring-1-in heptan base-oxyethyl group)-benzyl]-2-(4-acetoxyl group-phenyl)-3-methyl-5-acetyl oxygen-1
h-indoles.
Compound TM is bazedoxifene acetate.
The temperature of reaction of step (1), step (2) is 0～150 ℃, preferably 50-80 ℃;
Organic solvent in step (1) be tetrahydrofuran (THF), toluene,
n,
n-dimethyl formamide, dioxane, one or more in pyridine, acetonitrile, methylene dichloride, chloroform, preferably toluene;
In step (1), the equivalence ratio of Compound I, Compound I I, alkali is 1.0:1.0:1.0～1:1.5:2.0, preferably 1.0:1.1:1.2;
In step (1) alkali be in triethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, saleratus, salt of wormwood one or more, preferred triethylamine;
In step (2) alkali be in sodium hydroxide, potassium hydroxide, lithium hydroxide one or more, preferred sodium hydroxide.
Each optimum condition in preparation method of the present invention can arbitrary combination obtain each preferred embodiment of the present invention.
The reagent that the present invention is used and raw material be commercially available obtaining all.
Beneficial effect of the present invention has been to provide the preparation method that a kind of bazedoxifene acetate is new, and this preparation method can obviously improve productive rate and the purity of product.
embodiment
With embodiment, further illustrate the present invention below, but the present invention is not limited.
embodiment 1: 1-[4-(2-azepine ring-1-in heptan base-oxyethyl group)-benzyl]-2-(4-acetoxyl group-phenyl)-3-methyl-5-acetyl oxygen-1
hthe preparation of-indoles (compound III).
In 1000ml there-necked flask, add 32.3g(0.1mol) Compound I, 36.1 grams of (0.11mol) Compound I I, 500ml toluene, stir, be heated to 75 ℃ of reaction 4h, TLC point sample detects, show that reaction is complete, distillation, removes solvent, obtain residue, add 100ml water, ethyl acetate is extracted (200ml * 3), anhydrous sodium sulfate drying, elimination siccative, underpressure distillation, obtain shallow white solid 51.2, yield: 92.5%.
MS(+1):555.2。
1HNMR：δ(ppm，CDCl
3)，7.45-7.46(d，2H，Ar-H),7.12-7.13(d，2H，Ar-H)，7.06-7.10(m，3H，Ar-H)，6.95-6.96(d，2H，Ar-H)，6.73-6.75(d，2H，Ar-H)，5.11(s，2H,CH
2),4.10-4.12(t，2H，CH
2)， 2.78-2.79(t，2H, CH
2)，2.36-2.38(t，4H, CH
2×2)，2.09(s，3H, CH
3)，2.07(s，3H, CH
3)，1.39-1.41(m，4H, CH
2×2)，1.29-1.31(m，4H, CH
2×2)。
embodiment 2: the preparation of bazedoxifene acetate (compound TM)
III TM
In 500ml there-necked flask, add 27.2g(0.05mmol) compound III, 200ml1N(0.20mol) sodium hydroxide solution, stir, be warming up to 55 ℃ of reaction 2h, TLC point sample detects, show that reaction is complete, be cooled to room temperature, regulate pH to neutral, separate out solid, vacuum-drying, obtain white solid 20.6g, yield: 87.6%, the solid of acquisition is placed in to the there-necked flask of 500ml, add 250ml acetone, add 20ml acetic acid, be heated to 60 ℃, reaction 3h, TLC detects, react complete, cooling, boil off solvent and unnecessary acetic acid, pure water washing (100ml * 3), dry, obtain white solid 20.1g, yield 87.0%.
Free alkali MS(+1): 471.
HNMR：δ(ppm，CDCl
3)， 7.46-7.48(d，2H，Ar-H),7.15-7.17(d，2H，Ar-H)， 6.95-6.96(d，2H，Ar-H)，6..85-6.89(m，3H，Ar-H)，6.73-6.75(d，2H，Ar-H)，5.12(s，2H,CH
2),5.0（s，2H, OH×2），4.12-4.13(t，2H，CH
2)， 2.79-2.81(t，2H, CH
2)，2.36-2.37(t，4H, CH
2×2))，2.20（s，3H, CH
3），2.10（br s，1H， N-H
+），1.40-1.42(m，4H, CH
2×2)，1.30-1.32(m，4H, CH
2×2)。
Claims (7)
1. a preparation method for bazedoxifene acetate, is characterized in that:
(1), in organic solvent, there is condensation reaction and obtain intermediate III in Compound I and Compound I I under alkaline condition;
(2) the intermediate III hydrolysis, the salify that step (1) are made, obtain target compound bazedoxifene acetate (TM);
I II III
III TM
Key intermediate III.
2. preparation method according to claim 1, is characterized in that, the temperature of reaction of step (1), step (2) is 0～150 ℃.
3. preparation method according to claim 1, is characterized in that, the organic solvent in step (1) be tetrahydrofuran (THF), toluene,
n,
n-dimethyl formamide, dioxane, one or more in pyridine, acetonitrile, methylene dichloride, chloroform.
4. preparation method according to claim 1, is characterized in that, in step (1), the equivalence ratio of Compound I, Compound I I, alkali is 1.0:1.0:1.0～1:1.5:2.0.
5. preparation method according to claim 1, is characterized in that, in step (1) alkali be in triethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, saleratus, salt of wormwood one or more.
6. preparation method according to claim 1, is characterized in that, in step (2) alkali be in sodium hydroxide, potassium hydroxide, lithium hydroxide one or more.
7. preparation method according to claim 1, crucial in the middle of III body for the preparation of bazedoxifene acetate and other similar medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410018918.9A CN103709090A (en) | 2014-01-16 | 2014-01-16 | Preparation method of bazedoxifene acetate and key intermediate thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410018918.9A CN103709090A (en) | 2014-01-16 | 2014-01-16 | Preparation method of bazedoxifene acetate and key intermediate thereof |
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|---|---|
| CN103709090A true CN103709090A (en) | 2014-04-09 |
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ID=50402482
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085365A (en) * | 2014-05-12 | 2015-11-25 | 四川科伦药业股份有限公司 | Bazedoxifene acetate and preparation method of intermediate of bazedoxifene acetate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1326347A (en) * | 1998-05-15 | 2001-12-12 | 美国家用产品公司 | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole in combination with estrogens |
| WO2009012734A2 (en) * | 2007-07-25 | 2009-01-29 | Zentiva A.S. | New salts of bazedoxifene |
| CN102395561A (en) * | 2009-04-13 | 2012-03-28 | 桑多斯股份公司 | Processes for the synthesis of bazedoxifene acetate and intermediates thereof |
-
2014
- 2014-01-16 CN CN201410018918.9A patent/CN103709090A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1326347A (en) * | 1998-05-15 | 2001-12-12 | 美国家用产品公司 | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole in combination with estrogens |
| WO2009012734A2 (en) * | 2007-07-25 | 2009-01-29 | Zentiva A.S. | New salts of bazedoxifene |
| CN102395561A (en) * | 2009-04-13 | 2012-03-28 | 桑多斯股份公司 | Processes for the synthesis of bazedoxifene acetate and intermediates thereof |
Non-Patent Citations (2)
| Title |
|---|
| ANDREW TSOTINIS，等: "Synthesis of N1-Phenethyl Substituted Indole Derivatives as New Melatoninergic Agonists and Antagonists", 《CHEM. PHARM. BULL.》 * |
| 陈姗，等: "醋酸巴多昔芬的合成", 《中国新药杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085365A (en) * | 2014-05-12 | 2015-11-25 | 四川科伦药业股份有限公司 | Bazedoxifene acetate and preparation method of intermediate of bazedoxifene acetate |
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| C06 | Publication | ||
| PB01 | Publication | ||
| CB02 | Change of applicant information |
Address after: 225300 Taizhou City, Jiangsu Province medicine City Avenue, No. 1 G06 Applicant after: WANQUAN WANTE PHARMACEUTICAL JIANGSU CO., LTD. Address before: 225300 Taizhou City, Jiangsu Province medicine City Avenue, No. 1 G06 Applicant before: Aventis Pharmaceutical (Jiangsu) Co., Ltd. |
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| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140409 |
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| RJ01 | Rejection of invention patent application after publication |