CN102050709B - Method for preparing 2-[2-(2,2,2-trifluoro-ethyoxyl) phenoxyl] alcohol - Google Patents
Method for preparing 2-[2-(2,2,2-trifluoro-ethyoxyl) phenoxyl] alcohol Download PDFInfo
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- CN102050709B CN102050709B CN201010599662.7A CN201010599662A CN102050709B CN 102050709 B CN102050709 B CN 102050709B CN 201010599662 A CN201010599662 A CN 201010599662A CN 102050709 B CN102050709 B CN 102050709B
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- ethyoxyl
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Abstract
The invention discloses a method for preparing 2-[2-(2,2,2-trifluoro-ethyoxyl) phenoxyl] alcohol. The method comprises the following steps of: dissolving 2-(2,2,2-trifluoro-ethyoxyl) phenol into an organic solvent; adding alkali, stirring and heating to 60-140 DEG C; then adding ethylene oxide for reacting for 2-48 hours; concentrating or adding water for washing; extracting with an extractant and drying; and filtering and concentrating to obtain a 2-[2-(2,2,2-trifluoro-ethyoxyl) phenoxyl] alcohol product. The preparation method of the 2-[2-(2,2,2-trifluoro-ethyoxyl) phenoxyl] alcohol, which is provided by the invention, can be used for obtaining the target compound only by one step, thereby avoiding using a highly toxic product, such as bromoacetate and a highly dangerous product such as lithium aluminum hydride which is extremely easy to catch fire and not suitable for industrial production. The preparation method has the advantages of simple and convenient process and high product yield and effectively reduces the production cost.
Description
Technical field
The present invention relates to the synthetic intermediate 2-[2-of bulk drug silodosin (Silodosin) (2,2,2-trifluoro ethoxy) phenoxy group] preparation method of ethanol.
Background technology
Silodosin (Silodosin, KMD-3213) is the selectivity α 1A-suprarenal gland energy retarding agent of Japanese Kissei drugmaker exploitation, can be used for the symptom that treatment is relevant with benign prostatic hyperplasia (BPH) or hypertrophy.Preclinical study shows, silodosin to the selective effect of urethra respectively compared with Prazosin (prazosin) and Tan Luoxingao 12 and 7.5 times.KDM-3213 can obviously suppress the human prostate contraction that norepinephrine causes; The bladder hyperactivity of rat benign prostatauxe model is had to the restraining effect of dose-dependently, and can improve the pressure threshold of bladder contracts.These Notes of Key Datas, KDM-3213 is except improving bladder function, also effective to alleviating benign prostatauxe related symptoms.
Ⅰ
Structural formula I compound called after 2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethanol, it is the main intermediate of synthetic silodosin (Silodosin), structural formula I compound is by known method synthetic (as US5387603A and EP 0600675) at present, and its synthetic route is as follows:
The high-risk product Lithium Aluminium Hydride that above-mentioned synthetic method is mainly used highly toxic product ethyl bromoacetate and very easily caught fire and be not suitable for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of medicine intermediate 2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] preparation method of ethanol, the method only needs single step reaction can obtain target compound, avoid using highly toxic product as ethyl bromoacetate and the high-risk product Lithium Aluminium Hydride that very easily catches fire and be not suitable for suitability for industrialized production, reduced cost simultaneously.
2-[2-of the present invention (2,2,2-trifluoro ethoxy) phenoxy group] preparation method of ethanol is by 2-(2,2,2-trifluoro ethoxy) phenol is dissolved in organic solvent, adds alkali and stirs and be heated to 60～140 ℃, then adds reacting ethylene oxide 2～48h, concentrated or add water washing, extraction agent extraction, dry, filtering and concentrating obtains product 2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethanol.
Described organic solvent can be for low mass molecule alcohol be as methyl alcohol, ethanol or ethylene glycol etc., also can for the boiling points such as DMF, DMSO higher to 2-(2,2, the 2-trifluoro ethoxy) solvent that phenol solvability is strong, wherein, the preferred low mass molecule alcohol of the present invention is as methyl alcohol, ethanol or ethylene glycol etc.
Alkali of the present invention can be for mineral alkali be as sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood etc., also can be the organic basess such as triethylamine, its consumption and 2-(2,2,2-trifluoro ethoxy) mol ratio of phenol is 0.8～3:1, wherein, and the consumption of preferred bases and 2-(2,2,2-trifluoro ethoxy) mol ratio of phenol is 1.
The mol ratio of described 2-(2,2,2-trifluoro ethoxy) phenol and oxyethane is 1:1～4, and preferably the mol ratio of 2-(2,2,2-trifluoro ethoxy) phenol and oxyethane is 1:2.
Described temperature of reaction is preferably 70～120 ℃.
The described reaction times is preferably 12～36h.
Described extraction agent can be for methylene dichloride or chloroform etc. are to product 2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] the good solvent of dissolve with ethanol.
2-[2-(2 of the present invention, 2,2-trifluoro ethoxy) phenoxy group] preparation method of ethanol only needs single step reaction can obtain target compound, highly toxic product have been avoided using as ethyl bromoacetate and the high-risk product Lithium Aluminium Hydride that very easily catches fire and be not suitable for suitability for industrialized production, operational process of craft is easy, product yield is high, effectively reduces production cost.
Accompanying drawing explanation
Fig. 1 is 2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethanol hydrogen nuclear magnetic resonance spectrogram;
Fig. 2 is Fig. 1 partial enlarged drawing;
Fig. 3 is Fig. 1 partial enlarged drawing.
Embodiment
The following examples, for to the further describing of content of the present invention, do not form the restriction to connotation of the present invention.
embodiment 1
By 2-(2,2,2-trifluoro ethoxy) phenol (5g, 0.03mol) join in ethanol (40ml), stir and make to dissolve completely at ambient temperature, hydro-oxidation potassium (1.8g, 0.032mol), heating makes to reflux, and slowly passes into oxyethane (2.4g, 0.05mol), under reflux conditions stirring reaction, after 24 hours, is concentrated into dry, dissolving adds methylene chloride, washing, saturated sodium-chloride washing, dry.Elimination siccative, filtrate decompression is concentrated into dry, obtains product 3.75g, yield 61%.
1hNMR (CDCl
3for solvent) 6.90～7.10ppm(m, 4H), 4.39ppm (q, 2H), 4.12ppm (m, 2H), 3.94ppm (t, 2H).Proterties: faint yellow oily matter, thin layer detects: gel GF 254 plate, developping agent: ethyl acetate: sherwood oil=1:3, colour developing: fluorescence Rf=0.55～0.65.
embodiment 2
By 2-(2,2,2-trifluoro ethoxy) phenol (25g, 0.13mol) join in ethylene glycol (200ml), stir and make to dissolve completely at ambient temperature, hydro-oxidation potassium (9.5g, 0.17mol), under 110～120 ℃ of conditions, slowly pass into oxyethane (13g, 0.30mol), and maintain stirring reaction after 24 hours, and cooling, add water, with dichloromethane extraction three times, washing, saturated sodium-chloride washing, dry.Elimination siccative, filtrate decompression is concentrated into dry, obtains product 20g, yield 65%.
1hNMR: consistent with embodiment 1.Proterties: faint yellow oily matter, thin layer detects: gel GF 254 plate, developping agent: ethyl acetate: sherwood oil=1:3, colour developing: fluorescence Rf=0.55～0.65.
embodiment 3
By 2-(2,2,2-trifluoro ethoxy) phenol (5g, 0.03mol) join in methyl alcohol (50ml), stir and make to dissolve completely at ambient temperature, add triethylamine (3.04g, 0.03mol), heating makes to reflux, and slowly passes into oxyethane (2.64g, 0.06mol), under reflux conditions stirring reaction, after 36 hours, is concentrated into dry, dissolving adds methylene chloride, washing, saturated sodium-chloride washing, dry.Elimination siccative, filtrate decompression is concentrated into dry, obtains product 3.87g, yield 63%.
1hNMR: consistent with embodiment 1.Proterties: faint yellow oily matter, thin layer detects: gel GF 254 plate, developping agent: ethyl acetate: sherwood oil=1:3, colour developing: fluorescence Rf=0.55～0.65.
embodiment 4
By 2-(2,2,2-trifluoro ethoxy) phenol (25g, 0.13mol) join DMSO(200ml) in, stir and make to dissolve completely at ambient temperature, hydro-oxidation potassium (16.8g, 0.30mol), under 80～100 ℃ of conditions, slowly pass into oxyethane (22g, 0.50mol), and holding temperature stirring reaction is after 10 hours, cooling, add water, with chloroform extraction three times, washing, saturated sodium-chloride washing, dry.Elimination siccative, filtrate decompression is concentrated into dry, obtains product 19g, yield 62%.
1hNMR: consistent with embodiment 1.Proterties: faint yellow oily matter, thin layer detects: gel GF 254 plate, developping agent: ethyl acetate: sherwood oil=1:3, colour developing: fluorescence Rf=0.55～0.65.
Claims (1)
1.2-[2-(2, 2, 2-trifluoro ethoxy) phenoxy group] preparation method of ethanol, it is characterized in that: by the 2-of 25g (2, 2, 2-trifluoro ethoxy) phenol joins 200ml ethylene glycol, stir and make to dissolve completely at ambient temperature, the potassium hydroxide that adds 9.5g, under 110～120 ℃ of conditions, slowly pass into the oxyethane of 13g, and maintain stirring reaction after 24 hours, cooling, add water, with dichloromethane extraction three times, saturated sodium-chloride washing, dry, elimination siccative, filtrate decompression is concentrated into dry, obtain product 2-[2-(2, 2, 2-trifluoro ethoxy) phenoxy group] ethanol 20g, yield 65%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010599662.7A CN102050709B (en) | 2010-12-22 | 2010-12-22 | Method for preparing 2-[2-(2,2,2-trifluoro-ethyoxyl) phenoxyl] alcohol |
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| CN201010599662.7A CN102050709B (en) | 2010-12-22 | 2010-12-22 | Method for preparing 2-[2-(2,2,2-trifluoro-ethyoxyl) phenoxyl] alcohol |
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| CN102050709B true CN102050709B (en) | 2014-09-10 |
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| CN201010599662.7A Expired - Fee Related CN102050709B (en) | 2010-12-22 | 2010-12-22 | Method for preparing 2-[2-(2,2,2-trifluoro-ethyoxyl) phenoxyl] alcohol |
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| CN109516933B (en) * | 2018-10-29 | 2021-03-02 | 安徽省庆云医药股份有限公司 | Preparation method of silodosin intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5387603A (en) * | 1992-12-02 | 1995-02-07 | Kissei Pharmaceutical Co., Ltd. | 1,5,7-trisubstituted indoline compounds and salts thereof |
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- 2010-12-22 CN CN201010599662.7A patent/CN102050709B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5387603A (en) * | 1992-12-02 | 1995-02-07 | Kissei Pharmaceutical Co., Ltd. | 1,5,7-trisubstituted indoline compounds and salts thereof |
Non-Patent Citations (2)
| Title |
|---|
| 2,4-二硝基苯氧乙醇的合成研究;杨凤玲等;《杭州化工》;20041231;第34卷(第3期);17-19 * |
| 杨凤玲等.2 4-二硝基苯氧乙醇的合成研究.《杭州化工》.2004 |
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