CN103641881A - Preparation method for Ulipristal intermediate - Google Patents
Preparation method for Ulipristal intermediate Download PDFInfo
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- CN103641881A CN103641881A CN201310594529.6A CN201310594529A CN103641881A CN 103641881 A CN103641881 A CN 103641881A CN 201310594529 A CN201310594529 A CN 201310594529A CN 103641881 A CN103641881 A CN 103641881A
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Abstract
The invention relates to a preparation method for a steroid hormone drug intermediate, specifically to a preparation method for a Ulipristal intermediate. The product is prepared from a compound I by cyanation reaction, ethylene glycol protective reaction and ketal protection reaction. The method provided by the invention has the characteristics of cheap raw materials and high yield, and the prepared product is stable. The reaction route is shown as the specification.
Description
Technical field
The present invention relates to the preparation method of steroid hormone pharmaceutical intermediate, specifically relate to a kind of preparation method of Wu Lisita intermediate.
Background technology
Document A practical large-scale synthesis of17 α-acetoxy-11 β-(4-N, N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (CDB-2914), Steroids 65 (2000) 395-400 disclose the synthetic route of Wu Lisita important intermediate A in a kind of prior art, and concrete route is as follows:
This circuit is long, from A2 to A5, experience 17 hydroxyl protections, methyl on lithium reagent, hydrolysis, ketal protection.Shortcoming is that route is long, and process is loaded down with trivial details, and yield is on the low side, and cost is higher.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of new, and raw material is cheap, the preparation method of the Wu Lisita intermediate that yield is high and stable.
Wu Lisita intermediate of the present invention is suc as formula shown in IV, and by chemical compounds I, through cyanogenation, ethylene glycol protective reaction and ketal protective reaction make product, and reaction scheme is as follows:
The step of cyanogenation is, 1w(weight part) chemical compounds I, 0.5～2.5w organic solvent and 0.1～3.0w acetone cyanohydrin mix, add 1.0～5.0w water, 0.01～0.5w Anhydrous potassium carbonate or anhydrous sodium carbonate, temperature control-10～100 ℃ reaction, after having reacted, separated, purification, obtains compound ii.
The step of ethylene glycol protective reaction is, 1w compound ii, 2～20w ethylene glycol and 0.01～0.5w tosic acid are 0～100 ℃ of reaction, and after having reacted, separating-purifying, obtains compound III.
The step of ketal protective reaction is; 0.1～4.0w magnesium chips, 1.0～5.0w tetrahydrofuran (THF), 1.0～20.0w toluene and 0.1～2.0w Lithium chloride (anhydrous) mix; add a small amount of Grignard reagent to make initiator; logical monobromethane or methyl chloride gas; the reaction of temperature control 0～100 degree, until magnesium chips is consumed completely, obtains Grignard reagent.
1w compound III and 5w toluene are made into suspension liquid, in 0 ℃, be added drop-wise to below 10～15v(parts by volume, w/v unit is mg/ml or g/l) in above-mentioned Grignard reagent, after having reacted, extract separated, separated product adds 2～7v organic solvent, 0.1～3w ethylene glycol, 0.1～3w trimethyl orthoformate or triethyl orthoformate, 0.01～1w tosic acid, described organic solvent is one or more in chloroform, methylene dichloride, tetrahydrofuran (THF), 0～100 ℃ of temperature control, after having reacted, separating-purifying, obtains compounds Ⅳ.
The invention has the beneficial effects as follows, the present invention, with respect to the route method of bibliographical information, has directly saved two steps, i.e. 17 be hydroxyl upper protection and deprotections.Route and operation have been simplified.The present invention utilizes methyl in Ge Shi method, has omitted upper protection, deprotection steps.The diplomatic quality total recovery that background technology is mentioned is 72.3%, the quality total recovery of the present invention from compound ii to compounds Ⅳ is more than 75%, purity and transformation efficiency detect with HPLC, structural confirmation magnetic resonance detection, the nuclear-magnetism detected characteristics peak of compounds Ⅳ and the hydrogen number of characteristic peak be consistent with bibliographical information all.
Embodiment
Embodiment 1
Cyanogenation
In clean reaction flask, throw 1w chemical compounds I, add 1w methyl alcohol and 0.5w acetone cyanohydrin, dispersed with stirring.Add 1.0w water and 0.05w Anhydrous potassium carbonate, it is muddy that system becomes, 0 ℃ of temperature control, and insulated and stirred reaction 30 hours, adds a small amount of water, continues insulation 25 hours.Make TLC and analyze, developping agent: benzene-acetone=6:1, only has vestige to raw material point.React complete, drip 25v water, w/v unit is mg/ml or g/l.Icy salt solution is cooled to below 50 ℃, crystallization 3h, and with concentrated hydrochloric acid, adjusting system pH is 7, filters and obtains solid, filter cake washs with clear water.Drain as far as possible, then dig out filter cake, drop into 6v methyl alcohol, stir and be warmed up to backflow, then be cooled to 10 ℃ of following static crystallization 3h, be filtered dry solid hot air circulation oven drying, yield 98% left and right, HPLC purity: 97%.
Ethylene glycol protective reaction
Reaction flask in dried and clean adds 1w compound ii, 15w ethylene glycol to stir 5min, drops into 0.05w tosic acid, is warmed up to 10 ℃, insulation reaction 1 hour.TLC analyzes, and raw material reaction is more than 95%, and 10 ℃ of temperature controls drip the triethylamine of 0.05V, adjust system pH to neutral, add tap water elutriation, cool to 0 ℃ of crystallization 2 hours, suction filtration.Solid is dry in Hotaircirculatingoven.Yield: 106%, HPLC purity, 95% left and right.
Ketal protective reaction
Reaction flask in dried and clean adds 0.5w magnesium chips, 1.5w tetrahydrofuran (THF), 5w toluene, 0.5w Lithium chloride (anhydrous), add a small amount of Grignard reagent to make initiator, logical methyl bromide gas, 20 ℃ of reactions of temperature control are until magnesium chips is consumed complete substantially, system is cooled to below 0 ℃, 1w compound III is made into suspension liquid with 5w toluene, be added drop-wise in above-mentioned Grignard reagent, system venting heat release is obvious, drip off, drip 2 hours some plates of Bi Baowen and detect raw material residue situation, react complete, by system cancellation in the aqueous ammonium chloride solution of precooling, cancellation is complete, with concentrated hydrochloric acid, adjusting system pH is 7, layering is obvious, water toluene extracting twice, merge organic phase, with concentrated dry after saturated brine washing, become oily.Add chloroform, 0.5w ethylene glycol, 0.5w triethyl orthoformate, 15 ℃ of temperature controls, add 0.05w tosic acid, insulation reaction 3 hours, some plate detects raw material residue, reacts complete, add triethylamine to adjust system pH to neutral, concentrated, system is separated out solid, adds methyl alcohol, cool to below 0 ℃, crystallization is suction filtration after 3 hours, obtains compounds Ⅳ crude product, yield 84%, HPLC purity 94%, compounds Ⅳ is methylene dichloride (DCM) dissolving decolouring for crude product, with methanol solvate, methylene dichloride is replaced, and obtains compounds Ⅳ fine work.
Embodiment 2
Cyanogenation
In clean reaction flask, throw 1w chemical compounds I, add 2w methyl alcohol and 2.5w acetone cyanohydrin, dispersed with stirring.Add 5.0w water and 0.5w anhydrous sodium carbonate, it is muddy that system becomes, 80 ℃ of temperature controls, and insulated and stirred reaction 3 hours, adds a small amount of water, continues insulation 15 hours.Make TLC and analyze, developping agent: benzene-acetone=6:1, only has vestige to raw material point.React complete, drip 5v water, w/v unit is mg/ml or g/l.Icy salt solution is cooled to below 50 ℃, crystallization 3h, and with concentrated hydrochloric acid, adjusting system pH is 7, filters and obtains solid, filter cake washs with clear water.Drain as far as possible, then dig out filter cake, drop into 2v ethanol, stir and be warmed up to backflow, then be cooled to 10 ℃ of following static crystallization 3h, be filtered dry solid hot air circulation oven drying, yield 96% left and right, HPLC purity: 96%.
Ethylene glycol protective reaction
Reaction flask in dried and clean adds 1w compound ii, 15w ethylene glycol to stir 5min, drops into 0.5w tosic acid, is warmed up to 90 ℃, insulation reaction 1 hour.TLC analyzes, and raw material reaction is more than 95%, and 90 ℃ of temperature controls drip the triethylamine of 0.5V, adjust system pH to neutral, add tap water elutriation, cool to 0 ℃ of crystallization 2 hours, suction filtration.Solid is dry in Hotaircirculatingoven.Yield: 108%, HPLC purity, 95% left and right.
Ketal protective reaction
Reaction flask in dried and clean adds 4w magnesium chips, 5w tetrahydrofuran (THF), and 20w toluene, 2w Lithium chloride (anhydrous), adds a small amount of Grignard reagent to make initiator, logical methyl chloride gas, 100 ℃ of reactions of temperature control are until magnesium chips is consumed complete substantially.System is cooled to below 0 ℃, 1w compound III is made into suspension liquid with 5w toluene, be added drop-wise in above-mentioned Grignard reagent, system venting heat release is obvious, drips off, and drips 2 hours some plates of Bi Baowen and detects raw material residue situation, react complete, by system cancellation, in the aqueous ammonium chloride solution of precooling, cancellation is complete, and with concentrated hydrochloric acid, adjusting system pH is 6, layering is obvious, water toluene extracting twice, merges organic phase, with concentrated dry after saturated brine washing, becomes oily.Add methylene dichloride, 3w ethylene glycol, 3w trimethyl orthoformate, 75 ℃ of temperature controls, add 0.8w tosic acid, insulation reaction 3 hours, some plate detects raw material residue, reacts complete, add triethylamine to adjust system pH to neutral, concentrated, system is separated out solid, adds methyl alcohol, cool to below 0 ℃, crystallization is suction filtration after 3 hours, obtains compounds Ⅳ crude product, yield 84%, HPLC purity 94%, compounds Ⅳ is ethyl acetate (EA) dissolving decolouring for crude product, with methanol solvate, methylene dichloride is replaced, and obtains compounds Ⅳ fine work.
Claims (8)
1. the preparation method of Yi Zhong Wu Lisita intermediate, is characterized in that, by chemical compounds I, through cyanogenation, ethylene glycol protective reaction and ketal protective reaction make product, and reaction scheme is as follows:
2. the preparation method of Wu Lisita intermediate as claimed in claim 1, is characterized in that, the step of cyanogenation is, chemical compounds I, organic solvent and acetone cyanohydrin mix, and add water, Anhydrous potassium carbonate or anhydrous sodium carbonate, temperature control-10～100 ℃ reaction, separated, purification, obtains compound ii.
3. the preparation method of Wu Lisita intermediate as claimed in claim 2, it is characterized in that, the weight proportion of described chemical compounds I, organic solvent and acetone cyanohydrin is 1:0.5～2.5:0.1～3.0, and the weight proportion of chemical compounds I, water, Anhydrous potassium carbonate or anhydrous sodium carbonate is 1:1.0～5.0:0.01～0.5.
4. the preparation method of Wu Lisita intermediate as claimed in claim 1, is characterized in that, the step of ethylene glycol protective reaction is, compound ii, ethylene glycol and tosic acid be 0～100 ℃ of reaction, separated, purify, and obtains compound III.
5. the preparation method of Wu Lisita intermediate as claimed in claim 4, is characterized in that, the weight proportion of compound ii, ethylene glycol and tosic acid is 1:2～20:0.01～0.5.
6. the preparation method of Wu Lisita intermediate as claimed in claim 1; it is characterized in that, the step of ketal protective reaction is that compound III and toluene are made into suspension liquid; in 0 ℃, be added drop-wise to below in Grignard reagent; after having reacted, extract separation, separated product adds organic solvent, ethylene glycol, trimethyl orthoformate or triethyl orthoformate, tosic acid; 0～100 ℃ of temperature control; after having reacted, separating-purifying, obtains compounds Ⅳ.
7. the preparation method of Wu Lisita intermediate as claimed in claim 6, is characterized in that, the weight proportion of compound III, ethylene glycol, trimethyl orthoformate or triethyl orthoformate is 1:0.1～3:0.1～3.
8. the preparation method of the Wu Lisita intermediate as described in claim 6 or 7, is characterized in that, the weight proportion of compound III and tosic acid is 1:0.01～1.
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Citations (7)
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| CN102516345A (en) * | 2011-11-01 | 2012-06-27 | 上海优拓医药科技有限公司 | Preparation method of ulipristal acetate and key intermediate thereof |
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| CN102942612A (en) * | 2012-10-30 | 2013-02-27 | 四川大学 | Novel method for synthesizing ulipristal acetate |
| CN103130862A (en) * | 2011-11-30 | 2013-06-05 | 成都伊诺达博医药科技有限公司 | Novel synthetic method of ulipristal acetate key intermediate 3, 20-bis (ethylenedioxy)-19-norpregna-5, 9-dien-17-ol |
| CN103145787A (en) * | 2012-12-25 | 2013-06-12 | 常州市亚邦医药研究所有限公司 | Novel preparation method of ulipristal acetate key intermediate |
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Patent Citations (7)
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| CN86102502A (en) * | 1986-08-29 | 1988-04-20 | 上海市计划生育科学研究所 | 11,17 two △ that replace 4,9The synthetic method of-estradiene compound |
| CN102268058A (en) * | 2011-05-24 | 2011-12-07 | 湖南诺凯生物医药有限公司 | Method for preparing 17 alpha-hydropxygenenolone or analogue thereof |
| CN102516345A (en) * | 2011-11-01 | 2012-06-27 | 上海优拓医药科技有限公司 | Preparation method of ulipristal acetate and key intermediate thereof |
| CN103130862A (en) * | 2011-11-30 | 2013-06-05 | 成都伊诺达博医药科技有限公司 | Novel synthetic method of ulipristal acetate key intermediate 3, 20-bis (ethylenedioxy)-19-norpregna-5, 9-dien-17-ol |
| CN102603842A (en) * | 2012-02-20 | 2012-07-25 | 湖南诺凯生物医药有限公司 | Preparation method of hydrocortisone acetate or analogue thereof |
| CN102942612A (en) * | 2012-10-30 | 2013-02-27 | 四川大学 | Novel method for synthesizing ulipristal acetate |
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