CN103408399A - Synthesis method of alcohol with optical activity - Google Patents
Synthesis method of alcohol with optical activity Download PDFInfo
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- CN103408399A CN103408399A CN2013103645102A CN201310364510A CN103408399A CN 103408399 A CN103408399 A CN 103408399A CN 2013103645102 A CN2013103645102 A CN 2013103645102A CN 201310364510 A CN201310364510 A CN 201310364510A CN 103408399 A CN103408399 A CN 103408399A
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Abstract
The invention relates to the field of chemistry, particularly relates to the field of compound preparation, most particularly relates to a synthesis method of alcohol with optical activity, and aims to find a synthesis method of alcohol with optical activity, which is simple in operation, low in raw material cost, simple in purification process and high in yield, wherein the alcohol is shown as the formula I. According to the invention, a compound II is reduced through (S)-CBS-Me or (+)-DIP-Cl to prepare a compound I, only a reducing agent and corresponding solvent systems are needed, but other catalysts do not need to be added, so that the raw material input cost is reduced; and the requirement for the reaction condition is lower, and harsh conditions such as high temperature, high pressure and the like do not need, so that the synthesis method is suitable for industrial production.
Description
Technical field
The present invention relates to chemical field, particularly the preparation field of compound, more specifically relate to a kind of synthetic method with optically active alcohol.
Background technology
Formula I compound
Be a kind of important intermediate of receptor antagonist pharmaceuticals, the complex process degree that it is synthetic, and the price of synthesis material, directly affect final cost of drugs.
In order to reduce the medicine synthesising process difficulty, medicament-saving synthesizes cost, and our synthetic conducting extensive research to formula I compound finds that conventional to go back original reagent poor to the reduction effect of formula I compound, and the yield of reduction after product is lower.And utilize general reduction reaction operating process, not only manipulation flow process complexity, and raw material costliness, be not suitable for industrialized mass.
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Summary of the invention
The object of the invention is to find a kind of simple to operate, raw materials cost is low, purifying process is simple, shown in the high formula I of productive rate, has the synthetic method of optically active alcohol.
Concrete technical scheme is:
A kind of synthetic method with optically active alcohol, it is described that to have optically active alcohol be compound shown in the formula I,
Described formula I compound is to be formed through reduction by the formula II,
(formula II),
Its concrete reactions steps is as follows:
Compound shown in the formula II is added in enough solvents, and described solvent is any one in methylene dichloride, tetrahydrofuran (THF), ether, isopropyl ether, toluene;
Under nitrogen protection, abundant stirring and dissolving; Mixing solutions is cooled to-11 ℃, adds the S-CBS-Me toluene solution of 1mol/L;
Drip the borine dimethyl sulphide of 10mol/L, dropwise with the speed of 2.5 ~ 3ml/ min, in the dropping process, keep system temperature lower than-8 ℃;
Keep reaction system at-5 ~ 0 ℃, utilize TLC to follow the tracks of, to the raw material completely dissolve, drip successively methyl alcohol, 6% hydrogen peroxide and sulfuric acid, hierarchy of control temperature is lower than 0 ℃; After dripping off, rise to stirring at room 30min;
Standing, after the solution layering, collect respectively water layer and organic layer;
Water layer extracts with dichloro hexane, and by dichloro hexane extraction liquid and former organic also laminated;
Organic layer is used to saturated aqueous common salt, water washing successively, then select anhydrous sodium sulfate drying, concentrating under reduced pressure obtains oily matter;
Oily matter, 20 ℃ of lower vacuum-dryings, obtains formula I compound;
The mol ratio of described formula II compound and borine dimethyl sulphide is 1:1.1 ~ 1.5; The amount ratio of described formula II compound and S-CBS-Me is that 1mol formula II compound adds 5% ~ 15% S-CBS-Me solution.
Wherein S-CBS-Me refers to the compound with following structure:
Described S-CBS-Me directly needs buying according to purity, or according to the preparation method's preparation in existing open source literature.
Further, we also disclose the possibility of another reaction, and reactions steps is as follows:
Compound shown in the formula II is added in enough solvents, and described solvent is any one in methylene dichloride, tetrahydrofuran (THF), ether, isopropyl ether, toluene;
Under nitrogen protection, abundant stirring and dissolving;
Under the temperature condition of 0 ~ 50 ℃, drip (+) DIP-Cl, drop rate is 3.5 ~ 4.5g/min;
Keep reaction system at ambient temperature, utilize TLC to follow the tracks of, to the raw material completely dissolve;
Evaporated under reduced pressure solution, add methylene dichloride to dissolve;
With the repeated multiple times washing of the hydrochloric acid of 1mol/L, remove washings, by the organic phase solution concentrating under reduced pressure;
In enriched material, add dissolve with methanol solution, and, with the repeated multiple times washing of normal hexane, merge the normal hexane washings;
In the normal hexane washings, add methanol solution, standing, after complete layering, get methanol layer;
Methanol layer solution is concentrated obtains oily matter, and 38 ℃ of lower vacuum-dryings, obtain formula I compound;
Described formula II compound is 1:1.0 ~ 5.0 with the mol ratio of (+) DIP-Cl.
Wherein, (+) DIP-Cl refers to the compound with following structure:
Described (+) DIP-Cl directly needs buying according to purity, or according to the preparation method's preparation in existing open source literature.
Technical scheme disclosed in this invention, method one is simple to operate, and reaction conditions requires loose, and productive rate is higher; Method two is only used reductive agent, and corresponding solvent system, without increasing other catalyzer, has reduced the raw material input cost, and reaction conditions is required loosely, without severe condition such as high temperature, high pressure, to be suitable for suitability for industrialized production.
Embodiment
Embodiment 1
Adopt (S)-CBS-Me, dimethyl thioether reduction system reducing.
In the 500ml there-necked flask, add the chloro-1-(3 of 42.64g 2-, the 4-difluorophenyl) ethyl ketone (formula II compound, molecular weight 190.6; 0.224 mol; 1eq), add the 240ml anhydrous methylene chloride, stirring and dissolving, nitrogen protection.Be cooled to-11 ℃, add 22 mL S-CBS toluene solutions (1M).Drip 29 ml borine dimethyl sulphides (10M), approximately 10 min drip off, and the dropping process keeps below-8 ℃.Keep-5 ~ 0 ℃.TLC follows the tracks of the raw material completely dissolve.Drip successively 25ml methyl alcohol, drip the hydrogen peroxide of 102.5ml 6%, drip 72ml 2N sulfuric acid, hierarchy of control temperature is lower than 0 ℃.After dripping off, rise to stirring at room 30min.Separatory, water layer, with dichloro hexane 300ml extraction, merges organic layer, uses saturated aqueous common salt, water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtain oily matter 44.8g.20 ℃ of lower vacuum-dryings of product, obtain product 41.5g, yield 96.5%.
Embodiment 2
Adopt (+)-DIP-Cl reduction system reducing.
In reaction flask, add the chloro-1-(3 of 10g 2-, the 4-difluorophenyl) ethyl ketone (formula II compound molecular weight 190.6,0.0524 mol, 1eq), and THF, stirring and dissolving.Nitrogen protection, 10 ℃ splash into (+) DIP-Cl 41g (53%) 0.0682mol, approximately dripped off in 10 minutes.Stirring at room, TLC monitoring raw material reaction is complete.The heavy 40g of system after evaporated under reduced pressure system solvent, add the 50ml methylene dichloride to dissolve, with 1mol/L hydrochloric acid 50ml * 4 washings, organic phase is spin-dried for heavy 30g and adds the 50ml dissolve with methanol, normal hexane 50ml * 3 time washing, normal hexane is laminated and with the back extraction of 50ml methyl alcohol, and methanol layer merges, and concentrating under reduced pressure obtains oily matter 12g.38 ℃ of vacuum are dry.Obtain 9.5g, yield 94%.
Comparative Examples 1
Adopt trimethoxy borine, S-diphenylprolinol, borine dme reduction system reducing (being oxazole borane reduction system).
The toluene 13mL solution that under room temperature, trimethoxy borine 0.27g is added to the S-phenylbenzene Prolinol 0.47g through stirring.By this mixture in 40
oC stirred after 90 minutes, and temperature is remained on to 35 ~ 45
oC, added borine dimethyl sulphide 2.23g through 15 minutes.In 40
oC stirred 60 minutes, then in 2 hours, added the chloro-1-(3 of 7g 2-, 4-difluorophenyl) the 18ml toluene solution of ethyl ketone (formula II compound).Dropwise, in 40
oC stirred 60 minutes, then was cooled to 10
oC.In 20 minutes, add methyl alcohol 10g.Mixture is cooled to 20
oC, then stirred 30 minutes.Then, be no more than 45
oC is following concentrated, and the aqueous acetic acid 28mL with 10%, to toluene solution washing 4 times, strips to resulting water layer with toluene 20mL.Merge organic layer and use the 15mL water washing.Concentrated organic layer obtains.38 ℃ of vacuum are dry.Obtain 5.0g, yield 71%.
By above experimental data, we can see, utilize two kinds of synthetic method yields disclosed in this invention far away higher than traditional reduction system.
And processing step disclosed in this invention is simple, the participation without a large amount of auxiliary reagents, be suitable for industrialization promotion.
Claims (2)
1. synthetic method with optically active alcohol, it is described that to have optically active alcohol be compound shown in the formula I,
(formula I),
It is characterized in that: described formula I compound is to be formed through reduction by the formula II,
Its concrete reactions steps is as follows:
(1) compound shown in the formula II is added in enough solvents, described solvent is any one in methylene dichloride, tetrahydrofuran (THF), ether, isopropyl ether, toluene;
(2) under nitrogen protection, abundant stirring and dissolving; Mixing solutions is cooled to-11 ℃, adds the S-CBS-Me toluene solution of 1mol/L;
(3) drip the borine dimethyl sulphide of 10mol/L, dropwise with the speed of 2.5 ~ 3ml/ min, in the dropping process, keep system temperature lower than-8 ℃;
(4) keep reaction system at-5 ~ 0 ℃, utilize TLC to follow the tracks of, to the raw material completely dissolve, drip successively methyl alcohol, 6% hydrogen peroxide and sulfuric acid, hierarchy of control temperature is lower than 0 ℃; After dripping off, rise to stirring at room 30min;
(5) standing, after the solution layering, collect respectively water layer and organic layer;
(6) water layer extracts with dichloro hexane, and by dichloro hexane extraction liquid and former organic also laminated;
(7) organic layer is used to saturated aqueous common salt, water washing successively, then select anhydrous sodium sulfate drying, concentrating under reduced pressure obtains oily matter;
Oily matter, 20 ℃ of lower vacuum-dryings, obtains formula I compound;
(8) mol ratio of described formula II compound and borine dimethyl sulphide is 1:1.1 ~ 1.5; The amount ratio of described formula II compound and S-CBS-Me is that 1mol formula II compound adds 5% ~ 15% S-CBS-Me solution.
2. a kind of synthetic method with optically active alcohol according to claim 1 is characterized in that reactions steps is as follows:
(1) compound shown in the formula II is added in enough solvents, described solvent is any one in methylene dichloride, tetrahydrofuran (THF), ether, isopropyl ether, toluene;
(2) under nitrogen protection, abundant stirring and dissolving;
(3) under the temperature condition of 0 ~ 50 ℃, drip (+) DIP-Cl, drop rate is 3.5 ~ 4.5g/min;
(4) keep reaction system at ambient temperature, utilize TLC to follow the tracks of, to the raw material completely dissolve;
(5) evaporated under reduced pressure solution, add methylene dichloride to dissolve;
(6) with the repeated multiple times washing of hydrochloric acid of 1mol/L, remove washings, by the organic phase solution concentrating under reduced pressure;
(7) in enriched material, add dissolve with methanol solution, and, with the repeated multiple times washing of normal hexane, merge the normal hexane washings;
(8) in the normal hexane washings, add methanol solution, standing, after complete layering, get methanol layer;
(9) methanol layer solution is concentrated obtains oily matter, and 38 ℃ of lower vacuum-dryings, obtain formula I compound;
Described formula II compound is 1:1.0 ~ 5.0 with the mol ratio of (+) DIP-Cl.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974017A (en) * | 2014-04-09 | 2015-10-14 | 上海医药工业研究院 | Preparation method of (1R,2S)-2-(3,4-difluorophenyl) rolicyprine.D-mandelate |
| CN107793330A (en) * | 2016-08-29 | 2018-03-13 | 鲁南制药集团股份有限公司 | A kind of synthetic method of Ansai Qu chiral intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4868344A (en) * | 1988-03-30 | 1989-09-19 | Aldrich-Boranes, Inc. | Novel process of producing phenyl or substituted phenylalkylamine pharmaceutical agents and novel chiral intermediates of high enantiomeric purity useful therein |
| CN102924457A (en) * | 2011-08-12 | 2013-02-13 | 上海恒瑞医药有限公司 | Triazolopyrimidine derivatives, preparation method and uses thereof |
| EP2589587A1 (en) * | 2011-11-04 | 2013-05-08 | Chemo Ibérica, S.A. | Synthesis of nitrogen substituted cyclopropanes |
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2013
- 2013-08-21 CN CN201310364510.2A patent/CN103408399B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4868344A (en) * | 1988-03-30 | 1989-09-19 | Aldrich-Boranes, Inc. | Novel process of producing phenyl or substituted phenylalkylamine pharmaceutical agents and novel chiral intermediates of high enantiomeric purity useful therein |
| CN102924457A (en) * | 2011-08-12 | 2013-02-13 | 上海恒瑞医药有限公司 | Triazolopyrimidine derivatives, preparation method and uses thereof |
| EP2589587A1 (en) * | 2011-11-04 | 2013-05-08 | Chemo Ibérica, S.A. | Synthesis of nitrogen substituted cyclopropanes |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974017A (en) * | 2014-04-09 | 2015-10-14 | 上海医药工业研究院 | Preparation method of (1R,2S)-2-(3,4-difluorophenyl) rolicyprine.D-mandelate |
| CN104974017B (en) * | 2014-04-09 | 2017-11-17 | 上海医药工业研究院 | The preparation method of (1R, 2S) 2 (3,4 difluorophenyl) cyclopropylamine D mandelates |
| CN107793330A (en) * | 2016-08-29 | 2018-03-13 | 鲁南制药集团股份有限公司 | A kind of synthetic method of Ansai Qu chiral intermediate |
| CN107793330B (en) * | 2016-08-29 | 2020-03-17 | 鲁南制药集团股份有限公司 | Synthetic method of anacetrapib chiral intermediate |
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