CN103408399B - A kind of synthetic method with optically active alcohol - Google Patents
A kind of synthetic method with optically active alcohol Download PDFInfo
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- CN103408399B CN103408399B CN201310364510.2A CN201310364510A CN103408399B CN 103408399 B CN103408399 B CN 103408399B CN 201310364510 A CN201310364510 A CN 201310364510A CN 103408399 B CN103408399 B CN 103408399B
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Abstract
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.The object of the invention is to find a kind of simple to operate, raw materials cost is low, purifying process is simple, has the synthetic method of optically active alcohol shown in the formula I that productive rate is high.The reduction of formula II compound is prepared type I compound by (S)-CBS-Me or (+)-DIP-Cl by the present invention, only use reductive agent, and corresponding solvent system, without the need to increasing other catalyzer, decrease raw material input cost, and reaction conditions is required loose, without the need to the severe condition such as high temperature, high pressure, be suitable for suitability for industrialized 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
Type I compound
be a kind of important intermediate of receptor antagonist pharmaceuticals, the complex process degree of its synthesis, and the price of synthesis material, directly affect final cost of drugs.
In order to reduce medicine synthesising process difficulty, medicament-saving synthesis cost, we conduct extensive research the synthesis of type I compound, and find that conventional to go back the reduction effect of original reagent to type I compound poor, the yield of reduction after product is lower.And utilize general reduction reaction operating process, not only manipulation flow process is complicated, and expensive starting materials, is not suitable for industrialized mass.
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, has the synthetic method of optically active alcohol shown in the formula I that productive rate is high.
Concrete technical scheme is:
There is a synthetic method for optically active alcohol, described in there is optically active alcohol for compound shown in formula I,
(formula I),
Described type I compound is formed through reduction by formula II,
(formula II),
Its concrete reactions steps is as follows:
Add in enough solvents by compound shown in formula II, 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 DEG C, adds the S-CBS-Me toluene solution of 1mol/L;
Drip the borane dimethylsulf iotade of 10mol/L, dropwise with the speed of 2.5 ~ 3ml/ min, in dropping process, keep system temperature lower than-8 DEG C;
Keep reaction system at-5 ~ 0 DEG C, utilize TLC to follow the tracks of, to raw material completely dissolve, drip successively methyl alcohol, 6% hydrogen peroxide and sulfuric acid, hierarchy of control temperature is lower than 0 DEG C; Stirring at room temperature 30min is risen to after dripping off;
Leave standstill, after solution layering, collect water layer and organic layer respectively;
Water layer dichloro hexane extracts, and by dichloro hexane extraction liquid and original machine also laminated;
Organic layer is used saturated aqueous common salt, water washing successively, then selects anhydrous sodium sulfate drying, concentrating under reduced pressure obtains oily matter;
Oily matter vacuum-drying at 20 DEG C, obtains type I compound;
The mol ratio of described formula II compound and borane dimethylsulf iotade is 1:1.1 ~ 1.5; The amount ratio of described formula II compound and S-CBS-Me is the S-CBS-Me solution that 1mol formula II compound adds 5% ~ 15%.
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 disclosed the possibility of another reaction, reactions steps is as follows:
Add in enough solvents by compound shown in formula II, 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 DEG C, 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 raw material completely dissolve;
Evaporated under reduced pressure solution, adds methylene dichloride and dissolves;
With the repeated multiple times washing of the hydrochloric acid of 1mol/L, remove washings, by organic phase solution concentrating under reduced pressure;
Add dissolve with methanol solution in enriched material, and with the repeated multiple times washing of normal hexane, merge n-hexane liquid;
In n-hexane liquid, add methanol solution, leave standstill, after complete layering, get methanol layer;
Methanol layer solution is concentrated obtains oily matter, and vacuum-drying at 38 DEG C, obtains type 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 only uses reductive agent, and corresponding solvent system, without the need to increasing other catalyzer, decreases raw material input cost, and requires loose to reaction conditions, without the need to the severe condition such as high temperature, high pressure, is suitable for suitability for industrialized production.
Embodiment
Embodiment 1
Adopt (S)-CBS-Me, dimethyl thioether reduction system reducing.
Chloro-1-(3, the 4-difluorophenyl of 42.64g 2-is added in 500ml there-necked flask) ethyl ketone (formula II compound, molecular weight 190.6; 0.224 mol; 1eq), 240ml anhydrous methylene chloride is added, stirring and dissolving, nitrogen protection.Be cooled to-11 DEG C, add 22 mL S-CBS toluene solutions (1M).Drip 29 ml borane dimethylsulf iotade (10M), about 10 min drip off, and dropping process keeps below-8 DEG C.Keep-5 ~ 0 DEG C.TLC follows the tracks of raw material completely dissolve.Drip 25ml methyl alcohol successively, drip the hydrogen peroxide of 102.5ml 6%, drip 72ml 2N sulfuric acid, hierarchy of control temperature is lower than 0 DEG C.Stirring at room temperature 30min is risen to after dripping off.Separatory, water layer dichloro hexane 300ml extracts, and merge organic layer, with saturated aqueous common salt, water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains oily matter 44.8g.Vacuum-drying at product 20 DEG C, obtains product 41.5g, yield 96.5%.
Embodiment 2
Adopt (+)-DIP-Cl reduction system reducing.
Chloro-1-(3, the 4-difluorophenyl of 10g 2-is added in reaction flask) ethyl ketone (formula II compound molecular weight 190.6,0.0524 mol, 1eq), and THF, stirring and dissolving.Nitrogen protection, 10 DEG C of instillation (+) DIP-Cl 41g (53%) 0.0682mol, drip off for about 10 minutes.Stirring at room temperature, it is complete that TLC monitors raw material reaction.The heavy 40g of system after evaporated under reduced pressure system solvent, add 50ml methylene dichloride to dissolve, with time washing of 1mol/L hydrochloric acid 50ml × 4, organic phase is spin-dried for heavy 30g and adds 50ml dissolve with methanol, time washing of normal hexane 50ml × 3, normal hexane is laminated and with the back extraction of 50ml methyl alcohol, methanol layer merges, and concentrating under reduced pressure obtains oily matter 12g.38 DEG C of vacuum are dry.Obtain 9.5g, yield 94%.
Comparative example 1
Adopt trimethoxy borine, S-diphenylprolinol, borine dme reduction system reducing (i.e. oxazole borane reduction system).
Under room temperature, trimethoxy borine 0.27g is added the toluene 13mL solution of the S-phenylbenzene Prolinol 0.47g through stirring.By this mixture in 40
otemperature is remained on 35 ~ 45 after stirring 90 minutes by C
oc, added borane dimethylsulf iotade 2.23g through 15 minutes.In 40
oc stirs 60 minutes, in 2 hours, then add chloro-1-(3, the 4-difluorophenyl of 7g 2-) the 18ml toluene solution of ethyl ketone (formula II compound).Dropwise, in 40
oc stirs 60 minutes, is then cooled to 10
oc.Methyl alcohol 10g is added in 20 minutes.Mixture is cooled to 20
oc, then stirs 30 minutes.Then, 45 are being no more than
obelow C concentrates, and washs 4 times, strip with toluene 20mL to obtained water layer with the aqueous acetic acid 28mL of 10% to toluene solution.Merge organic layer and use 15mL water washing.Concentration of organic layers obtains.38 DEG C 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, without the need to the participation of a large amount of auxiliary reagent, is suitable for industrialization promotion.
Claims (2)
1. there is a synthetic method for optically active alcohol, described in there is optically active alcohol for compound shown in formula I,
(formula I),
It is characterized in that: described type I compound is formed through reduction by formula II,
(formula II),
Its concrete reactions steps is as follows:
(1) add in enough solvents by compound shown in formula II, described solvent is methylene dichloride;
(2) under nitrogen protection, abundant stirring and dissolving; Mixing solutions is cooled to-11 DEG C, adds the S-CBS-Me toluene solution of 1mol/L;
(3) drip the borane dimethylsulf iotade of 10mol/L, dropwise with the speed of 2.5 ~ 3ml/ min, in dropping process, keep system temperature lower than-8 DEG C;
(4) keep reaction system at-5 ~ 0 DEG C, utilize TLC to follow the tracks of, to raw material completely dissolve, drip successively methyl alcohol, 6% hydrogen peroxide and sulfuric acid, hierarchy of control temperature is lower than 0 DEG C; Stirring at room temperature 30min is risen to after dripping off;
(5) leave standstill, after solution layering, collect water layer and organic layer respectively;
(6) water layer dichloro hexane extracts, and by dichloro hexane extraction liquid and original machine also laminated;
(7) organic layer is used saturated aqueous common salt, water washing successively, then select anhydrous sodium sulfate drying, concentrating under reduced pressure obtains oily matter;
(8) oily matter vacuum-drying at 20 DEG C, obtains type I compound;
The mol ratio of described formula II compound and borane dimethylsulf iotade is 1:1.1 ~ 1.5; The amount ratio of described formula II compound and S-CBS-Me is the S-CBS-Me solution that 1mol formula II compound adds 5% ~ 15%.
2. there is a synthetic method for optically active alcohol, described in there is optically active alcohol for compound shown in formula I,
(formula I),
It is characterized in that: described type I compound is formed through reduction by formula II,
(formula II),
Its concrete reactions steps is as follows:
(1) add in enough solvents by compound shown in formula II, described solvent is tetrahydrofuran (THF);
(2) under nitrogen protection, abundant stirring and dissolving;
(3) under the temperature condition of 10 DEG C, 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 raw material completely dissolve;
(5) evaporated under reduced pressure solution, adds methylene dichloride and dissolves;
(6) with the repeated multiple times washing of hydrochloric acid of 1mol/L, washings is removed, by organic phase solution concentrating under reduced pressure;
(7) add dissolve with methanol solution in enriched material, and with the repeated multiple times washing of normal hexane, merge n-hexane liquid;
(8) in n-hexane liquid, add methanol solution, leave standstill, after complete layering, get methanol layer;
(9) methanol layer solution is concentrated obtains oily matter, and vacuum-drying at 38 DEG C, obtains type I compound;
Described formula II compound is 1:1.0 ~ 5.0 with the mol ratio of (+) DIP-Cl.
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