CN103664869A - Synthetic method of raloxifene intermediate - Google Patents
Synthetic method of raloxifene intermediate Download PDFInfo
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- CN103664869A CN103664869A CN201310705961.8A CN201310705961A CN103664869A CN 103664869 A CN103664869 A CN 103664869A CN 201310705961 A CN201310705961 A CN 201310705961A CN 103664869 A CN103664869 A CN 103664869A
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- compound
- raloxifene
- synthetic method
- reaction
- methoxy
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- JCDUEYBFRFGFQS-QFNQXPJWSA-N C/C(/C(c1c(-c(cc2)ccc2OC)[s]c2cc(OC)ccc12)=O)=C\C=C(/C)\OCCN1CCCCC1 Chemical compound C/C(/C(c1c(-c(cc2)ccc2OC)[s]c2cc(OC)ccc12)=O)=C\C=C(/C)\OCCN1CCCCC1 JCDUEYBFRFGFQS-QFNQXPJWSA-N 0.000 description 1
- HRWAGCVMOGWQJF-UHFFFAOYSA-N COc(cc1)ccc1-c([s]c1c2)cc1ccc2OC Chemical compound COc(cc1)ccc1-c([s]c1c2)cc1ccc2OC HRWAGCVMOGWQJF-UHFFFAOYSA-N 0.000 description 1
- IQCKPSHHESGYOJ-UHFFFAOYSA-N ClC(c(cc1)ccc1OCCN1CCCCC1)=[ClH] Chemical compound ClC(c(cc1)ccc1OCCN1CCCCC1)=[ClH] IQCKPSHHESGYOJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a raloxifene intermediate 6-methoxy-2-(4-methoxy phenyl)-3-[4-(2-piperidyl ethyoxyl)benzoyl]-benzothieno[b]hydrochloride, namely a compound 2. The method uses Mo(CO)6 as a catalyst for catalyzing a compound 3 and a compound 4 to perform a Friedel-Crafts acylation reaction to synthesize the compound 2. According to the method, Mo(CO)6 is adopted as the catalyst for performing the Friedel-Crafts acylation reaction, the selectivity is good, few side reactions are generated, the reaction yield reaches up to 95%, the HPLC (high performance liquid chromatography) purity of the raloxifene intermediate is 98%, and the needs of subsequent reactions are met.
Description
Technical field:
The synthetic method that the present invention relates to a kind of raloxifene intermediate, belongs to field of medicine and chemical technology.
Background of invention:
RALOXIFENE HCL is the s-generation selective estrogen receptor modulators of Lilly Co., Eli.'s research and development, for prevention and treatment osteoporosis and mammary cancer, has following formula chemical structure:
6-methoxyl group-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidyl oxyethyl group) benzoyl]-thionaphthene [b] hydrochloride; it is compound 2; be the synthetic key intermediate of RALOXIFENE HCL, obtain this compound high-purity high-yield and be significant for the synthetic of RALOXIFENE HCL.
J.Med.Chem., 1984,27,1057-1066. has reported that Aluminum chloride anhydrous is catalyzer, and compound 3 and compound 4 are prepared compound 2 by friedel-crafts acylation:
Reaction yield is only 65.5%, has the aromatic nucleus of three electron riches due to substrate compounds 4 simultaneously, causes the selectivity of reaction poor, and by product is many, is difficult for purifying.
EP0062503A1 adopts Aluminum chloride anhydrous to carry out friedel-crafts acylation equally, by " one kettle way ", directly obtains hydrochloric acid thunder Lip river former times phenol, and except having the same shortcoming, the metallic aluminium of end product is residual more, and aluminum pollution is serious.
CN1132205, from compound 3 and compound 4s, replaces Aluminum chloride anhydrous with boron trichloride or boron tribromide, by " one pot ", directly obtains hydrochloric acid thunder Lip river former times phenol.Although avoided aluminum pollution, product yield has reached 88%, yet boron trichloride or boron tribromide are expensive, has strong impulse simultaneously, and the moisture absorption is very easily not suitable for suitability for industrialized production:
Summary of the invention:
Main purpose of the present invention is to provide raloxifene intermediate 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidyl oxyethyl group) benzoyl of a kind of highly selective, high yield] synthetic method of-thionaphthene [b] hydrochloride.
Technical scheme of the present invention is a kind of 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidyl oxyethyl group) benzoyl]-thionaphthene [b] hydrochloride, the synthetic method of compound 2, is characterized in that,
Compound 3 and compound 4 are joined in organic solvent, add hexacarbonylmolybdenum in batches, magnetic agitation reaction, filtration, filtrate are respectively washed once through water, saturated aqueous common salt successively after completion of the reaction, and organic phase is concentrated, the dry target product 2 that obtains.
Technical scheme of the present invention is, reacting selected organic solvent is methylene dichloride, chloroform, 1, one or more mixed solvents in 2-ethylene dichloride, dithiocarbonic anhydride, preferably methylene dichloride or 1,2-ethylene dichloride, solvent load is 8-10 times (mL/g) of compound 3;
Technical scheme of the present invention is that the mol ratio of each reactant consumption is compound 3: compound 4: Mo (CO)
6≈ 1: 1: 0.01-0.04; Temperature of reaction is 5-20 ℃; Reaction times is 0.5-3h.
The invention has the beneficial effects as follows Mo (CO)
6for carrying out friedel-crafts acylation, catalyst compound 3 and compound 4 prepare compound 2, good reaction selectivity, and by product is few, and reaction yield is up to 95%, and product HPLC purity is 98%, meets the needs of subsequent reactions.
Embodiment:
Embodiment 1:
In the reaction flask of 2L, add compound 3 (121.68g, 0.4mol), compound 4 (108.14g, 0.4mol) and methylene dichloride (1200ml), be cooled to 5 ℃, adds Mo (CO) in batches
6(10.56g, 0.04mol), stirring reaction 3h at this temperature.Filter, filtering solid, filtrate is water and saturated aqueous common salt washed twice (300ml * 2) successively, and organic phase obtains light yellow solid through concentrated by rotary evaporation, dries to obtain target product 204.9g for 70 ℃, yield 95.2%, HPLC purity is 99.1%.
Embodiment 2:
In the reaction flask of 500ml, add compound 3 (30.42g, 0.1mol), compound 4 (27.03g, 0.1mol), 1,2-ethylene dichloride (250ml), is cooled to 10 ℃ by system, adds Mo (CO) in batches
6(2.64g, 0.01mol), stirring reaction 2h at this temperature.Filter, filtering solid, filtrate is water and saturated aqueous common salt washed twice (70ml * 2) successively, and organic phase obtains light yellow solid through concentrated by rotary evaporation, dries to obtain target product 52.25g for 70 ℃, yield 97.1%, HPLC purity is 98.3%.
Embodiment 3:
In the reaction flask of 1L, add compound 3 (60.84g, 0.2mol), compound 4 (54.07g, 0.2mol), methylene dichloride (500ml) adds Mo (CO) at 20 ℃ in batches
6(5.28g, 0.02mol), stirring reaction 0.5h at this temperature.Filter, filtering solid, filtrate is water and saturated aqueous common salt washed twice (100ml * 2) successively, and organic phase obtains light yellow solid through concentrated by rotary evaporation, dries to obtain target product 103.96g for 70 ℃, yield 96.6%, HPLC purity is 98.1%.
Claims (5)
1. a raloxifene intermediate 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidyl oxyethyl group) benzoyl]-thionaphthene [b] hydrochloride; it is the synthetic method of compound 2; it is characterized in that; compound 3 and compound 4 react under the effect of catalyzer hexacarbonylmolybdenum; synthetic compound 2
2. synthetic method according to claim 1, is characterized in that, the solvent that reacts used is methylene dichloride or 1,2-ethylene dichloride.
3. synthetic method according to claim 1, is characterized in that, compound 3: compound 4: Mo (CO)
6mol ratio be 1: 1: 0.01-0.04.
4. synthetic method according to claim 1, is characterized in that, temperature of reaction is 5-20 ℃.
5. synthetic method according to claim 1, is characterized in that, the reaction times is 0.5-3h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310705961.8A CN103664869A (en) | 2013-12-13 | 2013-12-13 | Synthetic method of raloxifene intermediate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310705961.8A CN103664869A (en) | 2013-12-13 | 2013-12-13 | Synthetic method of raloxifene intermediate |
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| Publication Number | Publication Date |
|---|---|
| CN103664869A true CN103664869A (en) | 2014-03-26 |
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| CN201310705961.8A Pending CN103664869A (en) | 2013-12-13 | 2013-12-13 | Synthetic method of raloxifene intermediate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851634A (en) * | 2020-01-03 | 2021-05-28 | 江苏美迪克化学品有限公司 | Preparation method of raloxifene hydrochloride |
-
2013
- 2013-12-13 CN CN201310705961.8A patent/CN103664869A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851634A (en) * | 2020-01-03 | 2021-05-28 | 江苏美迪克化学品有限公司 | Preparation method of raloxifene hydrochloride |
| CN112851634B (en) * | 2020-01-03 | 2021-11-16 | 江苏美迪克化学品有限公司 | Preparation method of raloxifene hydrochloride |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20151030 Address after: 264400 No. 46, Guangzhou Road, Wendeng Economic Development Zone, Shandong, Weihai Applicant after: WEIHAI DIJIA PHARMACEUTICAL CO., LTD. Address before: 264209 No. 196, science and technology road, torch hi tech Industrial Development Zone, Shandong, Weihai Applicant before: Disha Pharmaceutical Group Shandong Disha Pharmaceutical Co., Ltd. |
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| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140326 |