CN110015944A - A kind of synthetic method of highly selective luliconazole intermediate - Google Patents
A kind of synthetic method of highly selective luliconazole intermediate Download PDFInfo
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- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
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Abstract
The present invention discloses a kind of synthetic method of highly selective luliconazole intermediate, use (-)-diisopinocampheylchloroborane base chloroborane for high-selectivity catalyst, in the reaction system of tetrahydrofuran, (S) -2,2', 4'- trichloro-benzenes ethanol synthesis liquid is obtained using low-temperature reduction, it is quenched again, organic solvent extraction, dry concentration, obtain (S) -2,2', 4'- trichlorine benzyl carbinol crude product of grease；Most high-purity (S) -2,2', 4'- trichlorine benzyl carbinol is obtained through alkane reagent stirring and crystallizing afterwards.Using (-)-diisopinocampheylchloroborane base chloroborane as catalyst, step is few, combined coefficient is high, easy to operate, at low cost for synthesis of the invention, and selectivity of product is high.
Description
Technical field
The present invention relates in the synthetic method of luliconazole intermediate, more particularly to a kind of highly selective luliconazole
The synthetic method of mesosome.
Background technique
Luliconazole is that Nihon Nihyaku Co., Ltd (NihonNohyaku Co, Ltd) is anti-in one kind of research and development in 1997
Fungi preparation is listed in Japan, for treating tinea pedis, jock itch and ringworm of the body etc. for 2005 for the first time.To 2013 successively China,
India and U.S.'s listing.Luliconazole stores rate height in skin, and medication cycle is short, good effect, and potential applicability in clinical practice is good.Lu
Due to acquiring a certain degree of difficulty containing an imidazole group and two chiral centres, synthesis in vertical health azoles structure.
Shown in formula I, there are two kinds of configurations of R, S in luliconazole synthesis process, in addition to this there are also Z, E configuration, synthesize
Cheng Zhong can generate tetra- isomers of RE, RZ, SE and SZ.ZE isomers can efficiently separate detection in lamellae, pass through HPLC
Also it can efficiently separate.RS configuration lamellae can not detect, cannot not effective checking R S structure contents using chiral column.So
During synthesizing luliconazole intermediate, RS configuration preference is a vital control point.
As described in Formula II, compound 2 (R:Cl, Br etc.) is the key intermediate for synthesizing luliconazole, usually by compound
1 selective reduction obtains.Nihon Nihyaku Co., Ltd is in patent (US5900488), with (S) -2- methyl-CBS- oxazaborolidine
For catalyst, compound 2 is prepared in borine tetrahydrofuran reducing agent, and product ee value 80% isolates and purifies relatively difficult.Di
The Patent No. 201510927724.5 of peak et al. application is celebrated, patent name is in " a kind of luliconazole synthetic method "
In state's patent of invention, using similar above-mentioned Japan Patent method, with N, N- diethylaniline borane is instead of borine tetrahydrofuran
It is relatively difficult still to have the shortcomings that product isolates and purifies for reducing agent prepare compound 2.
Patent No. 201280063528.2, patent name are that the Chinese invention of " preparation method of travoprost " is special
In benefit, discloses and replace borine tetrahydrofuran to synthesize travoprost intermediate with catecholborane.With reference to its synthetic method,
Inventor carries out experiment condition and gropes to find, with catecholborane and (S) -2- methyl-CBS- oxazaborolidine network synthesis catalytic
Agent, at the compound 2 in Formula II, reaction product ee value reaches 92%, but by-product catechol complex compound and production for selective reduction
Object polarity is very close to isolating and purifying difficulty.
Summary of the invention
In order to overcome the shortage of prior art, the object of the present invention is to provide a kind of at low cost, purifying simply and with height
The synthetic method of the luliconazole intermediate of selectivity.
To achieve the above object, a kind of synthetic method of highly selective luliconazole intermediate is inventor provided,
The following steps are included:
1) under nitrogen protection, the tetrahydrofuran solution of (-)-DIP-Cl is added in organic solvent A, opens cooling system,
It is cooled to -30~0 DEG C；
2) by 2,2', the mixed liquor of 4'- trichloroacetophenone and organic solvent B be added dropwise in the cooling solution of step 1) into
Row Chemoselective reduction, insulation reaction 2-5 hours；The molar ratio of (-)-DIP-Cl and 2,2', 4'- trichloroacetophenone
For 1~3:1；
3) reaction terminates, and protonic solvent is added dropwise into the reaction solution of step 2) and is quenched, is quenched and finishes, will be quenched
Reaction solution is concentrated, and concentrate is obtained；
4) acid solution and organic solvent are added into the concentrate described in step 3), stirs, layering is isolated organic
Solvent layer is simultaneously concentrated, and (S) -2,2', 4'- trichlorine benzyl carbinol crude product is obtained；
5) alkane reagent is added in (S) -2,2', 4'- trichlorine benzyl carbinol crude product obtained toward step 4), stirred crystallization is taken out
Filter dries filter cake to obtain (S) -2,2', 4'- trichlorine benzyl carbinol sterling.
The present invention uses (-)-diisopinocampheylchloroborane base chloroborane referred to as (-)-DIP-Cl for high-selectivity catalyst, in tetrahydro
In the reaction system of furans, (S) -2,2', 4'- trichloro-benzenes ethanol synthesis liquid is obtained using low-temperature reduction.Reaction terminates, through quenching
It goes out, organic solvent extraction, dry concentration, obtains (S) -2,2', 4'- trichlorine benzyl carbinol crude product of grease；Most tried afterwards through alkane
High-purity (S) -2,2', 4'- trichlorine benzyl carbinol can be obtained in agent stirring and crystallizing.Synthesis of the invention is with (-)-diisopinocampheylchloroborane base
Chloroborane is catalyst, and step is few, combined coefficient is high, easy to operate, at low cost, and selectivity of product is high.
Further, the organic solvent A of the step 1) is one of the following: acetone, dimethyl sulfoxide, bis- formyl of N, N-
Amine, tetrahydrofuran or toluene.
Further, in the step 1), system temperature is reduced to -30~-25 DEG C after unlatching cooling system.By low
Temperature reaction, improves reaction selectivity, is conducive to reaction and converts to target compound.
Further, the organic solvent B of the step 2) is one of the following: acetone, dimethyl sulfoxide, bis- formyl of N, N-
Amine, tetrahydrofuran or toluene.
Preferably, the organic solvent B of the step 2) is tetrahydrofuran or toluene.
Further, the molar ratio of (-)-DIP-Cl and 2,2', 4'- trichloroacetophenone is 1.5:1.Reaction mass is adopted
It can guarantee fully reacting with the ingredient proportion, react not exclusively if feeding intake lower than if the ratio, made if feeding intake higher than the ratio
At material waste.
Further, the protonic solvent in the step 3) is one of the following: methanol, ethyl alcohol or water, preferably first
Alcohol.By carrying out quenching reaction, the generation of side reaction is reduced.The present invention uses methanol, and water or ethyl alcohol are quenched, and is quenched anti-
Should be mild, it can then occur acutely to generate heat with acid flux material, generate bulk gas, threat is generated to the personal safety of operator.
Further, the acid solution in the step 4) is one of the following: the dilute hydrochloric acid that concentration is 1~10%, dense
The solution of sodium bisulfite that the dilute sulfuric acid or concentration that degree is 1~10% are 1~10%.Preferably, the acidity in the step 4)
Solution is the dilute hydrochloric acid of concentration 5%.Excess borane compound is decomposed sufficiently by the way that acid flux material is added, and avoids remaining on conjunction
At product in.
Further, the organic solvent in the step 4) is one of the following: methylene chloride, ethyl acetate or toluene,
Preferably ethyl acetate.
Further, step 5) the alkane reagent is one of the following: n-hexane, hexamethylene, petroleum ether or positive heptan
Alkane, preferably n-hexane.The present invention feature small using alkane polarity, is bad relative to dichloro hexane or ethyl acetate
Solvent promotes product crystallization by the way that alkane is added.Particularly, n-hexane is one-component, and at low cost, for most preferred analysis
Brilliant solvent.
Filter cake in the step 5) uses forced air drying or vacuum drying, is preferably dried in vacuo, and temperature is 0~100
DEG C, preferably 25~35 DEG C.
The invention has the benefit that
1. the catalyst of reduction reaction needs first to carry out synthesis or complex reaction in the prior art, operation is not easy to reappear, and
It synthesizes harsher to environmental requirement.And the present invention uses (-)-diisopinocampheylchloroborane base chloroborane referred to as (-)-DIP-Cl for Gao Xuan
Selecting property catalyst can directly be bought, and price is medium, compared with the prior art since (-)-DIP-Cl is technical grade commercial product
Synthesis or the complexation approach of catalyst is omitted, simplifies synthesis procedure, combined coefficient is high, and reduces synthesis cost.
2. catalyst (-)-DIP-Cl has high selectivity, alternative reduction generates target product, and ee value is reachable
95%, pure target product can be obtained through recrystallization.
3. the present invention, using (-)-DIP-Cl as catalyst, reaction terminates (-)-DIP-Cl convenient post-treatment, by-product is generated
Relative product polarity very little can be removed through the washing of too small polar solvent, and the purification process of product is easy to operate.
Specific embodiment
Technology contents, construction feature, the objects and the effects for detailed description technical solution, below in conjunction with specific
Embodiment is explained in detail.
The preparation of embodiment 1 (S) -2,2', 4'- trichlorine benzyl carbinol
Under nitrogen protection, the tetrahydrofuran solution (1mol/L of 18.3ml (-)-DIP-Cl is added into 5ml tetrahydrofuran
Tetrahydrofuran solution), it is then turned on cooling system, reaction solution is cooled to -25 DEG C；
It is added dropwise 2,2' into reaction solution at -25 DEG C, the tetrahydrofuran solution of 4'- trichloroacetophenone (2.70g 2,2',
4'- trichloroacetophenone is dissolved in 10ml tetrahydrofuran), keep this thermotonus 3 hours.
Reaction, which terminates 10ml methanol is added dropwise, to be quenched, and is quenched to finish this reaction solution is concentrated under reduced pressure, in concentrate
5% dilute hydrochloric acid 10ml, ethyl acetate 10ml is added, is layered, water layer is extracted twice using ethyl acetate solution, merges acetic acid second
It is primary to wash acetic acid ethyl acetate extract with saturated sodium bicarbonate solution, then depressurizes acetic acid ethyl acetate extract dense for ester extract liquor
Contracting, obtains (S) -2,2', 4'- trichlorine benzyl carbinol crude product of grease；
After the crude product is cooled to room temperature, under stirring, n-hexane 20ml is slowly added dropwise, stirring precipitates crystal,
It is filtered after continuously stirring 30min, filter cake is washed with 10ml n-hexane, and filter cake 35 DEG C of dryings in a vacuum drying oven obtain
2.30g (S) -2,2', 4'- trichlorine benzyl carbinol sterling, ee value are 98.0%, yield 84.2%.
The preparation of embodiment 2 (S) -2,2', 4'- trichlorine benzyl carbinol ethyl alcohol
Under nitrogen protection, tetrahydrofuran solution (the 1mol/L tetrahydro of 18.3ml (-)-DIP-Cl is added into 5ml acetone
Tetrahydrofuran solution), it is then turned on cooling system, reaction solution is cooled to 0 DEG C；
At 0 DEG C into reaction solution be added dropwise (S) -2,2', 4'- trichloroacetophenone acetone soln (2.70g (S) -2,2',
4'- trichloroacetophenone is dissolved in 10ml acetone), keep this thermotonus 3 hours.
Reaction, which terminates 10ml methanol is added dropwise, to be quenched, and is quenched to finish this reaction solution is concentrated under reduced pressure, concentrate adds
Enter 10% dilute hydrochloric acid 5ml, ethyl acetate 10ml, be layered, water layer is extracted twice using ethyl acetate solution, combined ethyl acetate
It is primary to wash acetic acid ethyl acetate extract with saturated sodium bicarbonate solution, then depressurizes acetic acid ethyl acetate extract dense for extract liquor
Contracting, obtains (S) -2,2', 4'- trichlorine benzyl carbinol crude product of grease；
After the crude product is cooled to room temperature, under stirring, n-hexane 20ml is slowly added dropwise, stirring precipitates crystal,
It is filtered after continuously stirring 30min, filter cake is washed with 10ml n-hexane, and filter cake 35 DEG C of dryings in a vacuum drying oven obtain
2.09g (S) -2,2', 4'- trichlorine benzyl carbinol sterling, ee value are 98%, yield 76.5%.
The preparation of embodiment 3 (S) -2,2', 4'- trichlorine benzyl carbinol ethyl alcohol
Under nitrogen protection, tetrahydrofuran solution (the 1mol/L tetrahydro of 18.3ml (-)-DIP-Cl is added into 5ml toluene
Tetrahydrofuran solution), it is then turned on cooling system, reaction solution is cooled to 0 DEG C；
At 0 DEG C into reaction solution be added dropwise (S) -2,2', 4'- trichloroacetophenone toluene solution (2.70g (S) -2,2',
4'- trichloroacetophenone is dissolved in 10ml toluene), keep this thermotonus 2 hours.
Reaction, which terminates 10ml methanol is added dropwise, to be quenched, and is quenched to finish this reaction solution is concentrated under reduced pressure, concentrate adds
Enter 10% dilute hydrochloric acid 5ml, ethyl acetate 10ml, be layered, water layer is extracted twice using ethyl acetate solution, combined ethyl acetate
It is primary to wash acetic acid ethyl acetate extract with saturated sodium bicarbonate solution, then depressurizes acetic acid ethyl acetate extract dense for extract liquor
Contracting, obtains (S) -2,2', 4'- trichlorine benzyl carbinol crude product of grease；
After the crude product is cooled to room temperature, under stirring, n-hexane 20ml is slowly added dropwise, stirring precipitates crystal,
It is filtered after continuously stirring 30min, filter cake is washed with 10ml n-hexane, and filter cake 35 DEG C of dryings in a vacuum drying oven obtain
2.24g (S) -2,2', 4'- trichlorine benzyl carbinol sterling, ee value are 97.5%, yield 81.9%.
The preparation of embodiment 4 (S) -2,2', 4'- trichlorine benzyl carbinol ethyl alcohol
Under nitrogen protection, toward 5ml N, the tetrahydrofuran solution of 18.3ml (-)-DIP-Cl is added in N- diformamide
(1mol/L tetrahydrofuran solution), is then turned on cooling system, and reaction solution is cooled to 0 DEG C；
The N, N- diformamide solution (2.70g of (S) -2,2', 4'- trichloroacetophenone is added dropwise into reaction solution at 0 DEG C
(S) -2,2', 4'- trichloroacetophenone is dissolved in 10ml N, N- diformamide), keep this thermotonus 3 hours.
Reaction terminates dropwise addition 10ml methanol and is quenched, and is quenched and finishes, and 10% dilute hydrochloric acid, 5 ml, acetic acid is added toward reaction solution
Ethyl ester 10ml, layering, water layer are extracted twice using ethyl acetate solution, and combined ethyl acetate extract liquor uses saturated sodium bicarbonate
Solution washing acetic acid ethyl acetate extract is primary, and then acetic acid ethyl acetate extract is concentrated under reduced pressure, obtains (S) -2 of grease,
2', 4'- trichlorine benzyl carbinol crude product；
After the crude product is cooled to room temperature, under stirring, n-hexane 20ml is slowly added dropwise, stirring precipitates crystal,
It is filtered after continuously stirring 30min, filter cake is washed with 10ml n-hexane, and filter cake 35 DEG C of dryings in a vacuum drying oven obtain
2.15g (S) -2,2', 4'- trichlorine benzyl carbinol sterling, ee value are 97.0%, yield 78.7%.
The preparation of embodiment 5 (S) -2,2', 4'- trichlorine benzyl carbinol ethyl alcohol
Under nitrogen protection, the tetrahydrofuran solution (1mol/L tetra- of 36ml (-)-DIP-Cl is added into 5ml dimethyl sulfoxide
Hydrogen tetrahydrofuran solution), it is then turned on cooling system, reaction solution is cooled to 0 DEG C；
Dimethyl sulfoxide solution (2.70 g (S)-of (S) -2,2', 4'- trichloroacetophenone are added dropwise into reaction solution at 0 DEG C
2,2', 4'- trichloroacetophenone are dissolved in 10ml dimethyl sulfoxide), keep this thermotonus 3 hours.
Reaction terminates dropwise addition 10ml methanol and is quenched, and is quenched and finishes, and 10% dilute hydrochloric acid, 5 ml, acetic acid is added toward reaction solution
Ethyl ester 10ml, layering, water layer are extracted twice using ethyl acetate solution, and combined ethyl acetate extract liquor uses saturated sodium bicarbonate
Solution washing acetic acid ethyl acetate extract is primary, and then acetic acid ethyl acetate extract is concentrated under reduced pressure, obtains (S) -2 of grease,
2', 4'- trichlorine benzyl carbinol crude product；
After the crude product is cooled to room temperature, under stirring, n-hexane 20ml is slowly added dropwise, stirring precipitates crystal,
It is filtered after continuously stirring 30min, filter cake is washed with 10ml n-hexane, and filter cake 35 DEG C of dryings in a vacuum drying oven obtain
2.42g (S) -2,2', 4'- trichlorine benzyl carbinol sterling, ee value are 98.2%, yield 89.4%.
((-)-DIP-Cl feeds intake as 0.8N) for the preparation of embodiment 6 (S) -2,2', 4'- trichlorine benzyl carbinol
Under nitrogen protection, the tetrahydrofuran solution (1mol/L tetra- of 12ml (-)-DIP-Cl is added into 5ml tetrahydrofuran
Hydrogen tetrahydrofuran solution)；It is then turned on cooling system, reaction solution is cooled to -30 DEG C；
It is added dropwise 2,2' into reaction solution at -30 DEG C, the tetrahydrofuran solution of 4'- trichloroacetophenone (2.70 g2,2',
4'- trichloroacetophenone is dissolved in 10ml tetrahydrofuran), keep this thermotonus 5 hours.
Reaction, which terminates 10ml methanol is added dropwise, to be quenched, and is quenched to finish this reaction solution is concentrated under reduced pressure, in concentrate
5% sodium sulfite 10ml, ethyl acetate 10ml is added, is layered, water layer is extracted twice using ethyl acetate solution, merges acetic acid
It is primary to wash acetic acid ethyl acetate extract with saturated sodium bicarbonate solution, then depressurizes acetic acid ethyl acetate extract for ethyl ester extract liquor
Concentration, obtains (S) -2,2', 4'- trichlorine benzyl carbinol crude product of grease；
After the crude product is cooled to room temperature, under stirring, n-hexane 20ml is slowly added dropwise, stirring precipitates crystal,
It is filtered after continuously stirring 30min, filter cake is washed with 10ml n-hexane, and filter cake 25 DEG C of dryings in a vacuum drying oven obtain
1.65g2,2', 4'- trichlorine benzyl carbinol sterling, ee value are 98%, yield 61.1%.
((-)-DIP-Cl feeds intake as 1.2N) for the preparation of embodiment 7 (S) -2,2', 4'- trichlorine benzyl carbinol
Under nitrogen protection, 22ml (-)-DIP-Cl tetrahydrofuran solution (1mol/L tetrahydro is added into 5ml tetrahydrofuran
Tetrahydrofuran solution), it is then turned on cooling system, reaction solution is cooled to -25 DEG C；
It is added dropwise 2,2' into reaction solution at -25 DEG C, the tetrahydrofuran solution of 4'- trichloroacetophenone (2.70 g2,2',
4'- trichloroacetophenone is dissolved in 10ml tetrahydrofuran), keep this thermotonus 3 hours.
Reaction, which terminates 10ml methanol is added dropwise, to be quenched, and is quenched to finish this reaction solution is concentrated under reduced pressure, concentrate adds
Enter 1% dilute sulfuric acid 50ml, ethyl acetate 10ml, be layered, water layer is extracted twice using ethyl acetate solution, combined ethyl acetate
It is primary to wash acetic acid ethyl acetate extract with saturated sodium bicarbonate solution, then depressurizes acetic acid ethyl acetate extract dense for extract liquor
Contracting, obtains (S) -2,2', 4'- trichlorine benzyl carbinol crude product of grease；
After the crude product is cooled to room temperature, under stirring, n-hexane 20ml is slowly added dropwise, stirring precipitates crystal,
It is filtered after continuously stirring 30min, filter cake is washed with 10ml n-hexane, and filter cake 100 DEG C of dryings in a vacuum drying oven obtain
2.35g2,2', 4'- trichlorine benzyl carbinol sterling, ee value are 98%, yield 86.8%.
The preparation of embodiment 8 (S) -2,2', 4'- trichlorine benzyl carbinol
Under nitrogen protection, 18.3ml (-)-DIP-Cl tetrahydrofuran solution (1mol/L tetra- is added into 5ml tetrahydrofuran
Hydrogen tetrahydrofuran solution), it is then turned on cooling system, reaction solution is cooled to -10 DEG C；
It is added dropwise 2,2' into reaction solution at -10 DEG C, the tetrahydrofuran solution of 4'- trichloroacetophenone (2.70 g2,2',
4'- trichloroacetophenone is dissolved in 10ml tetrahydrofuran), keep this thermotonus 3 hours.
Reaction, which terminates 10ml ethyl alcohol is added dropwise, to be quenched, and is quenched to finish this reaction solution is concentrated under reduced pressure, concentrate adds
Enter 10% dilute hydrochloric acid 5ml, ethyl acetate 10ml, be layered, water layer is extracted twice using ethyl acetate solution, combined ethyl acetate
It is primary to wash acetic acid ethyl acetate extract with saturated sodium bicarbonate solution, then depressurizes acetic acid ethyl acetate extract dense for extract liquor
Contracting, obtains (S) -2,2', 4'- trichlorine benzyl carbinol crude product of grease；
After the crude product is cooled to room temperature, under stirring, n-hexane 20ml is slowly added dropwise, stirring precipitates crystal,
It is filtered after continuously stirring 30min, filter cake is washed with 10ml n-hexane, and filter cake 35 DEG C of dryings in a vacuum drying oven obtain
2.26g2,2', 4'- trichlorine benzyl carbinol sterling, ee value are 98%, yield 83.7%.
The preparation of embodiment 9 (S) -2,2', 4'- trichlorine benzyl carbinol)
Under nitrogen protection, 18.3ml (-)-DIP-Cl tetrahydrofuran solution (1mol/L tetra- is added into 5ml tetrahydrofuran
Hydrogen tetrahydrofuran solution), it is then turned on cooling system, reaction solution is cooled to -25 DEG C；
2,2', 4'- trichloroacetophenone tetrahydrofuran solution (2.70 g2,2', 4'- is added dropwise into reaction solution at -25 DEG C
Trichloroacetophenone is dissolved in 10ml tetrahydrofuran), keep this thermotonus 3 hours.
Reaction, which terminates 10ml methanol is added dropwise, to be quenched, and is quenched to finish this reaction solution is concentrated under reduced pressure, concentrate adds
Enter 5% dilute hydrochloric acid 10ml, methylene chloride 10ml, be layered, water layer is extracted twice using dichloromethane solution, merges methylene chloride
It is primary to wash dichloromethane extract with saturated sodium bicarbonate solution, then depressurizes dichloromethane extract dense for extract liquor
Contracting, obtains (S) -2,2', 4'- trichlorine benzyl carbinol crude product of grease；
After the crude product is cooled to room temperature, under stirring, hexamethylene 20ml is slowly added dropwise, stirring precipitates crystal,
It is filtered after continuously stirring 30min, filter cake is washed with 10ml hexamethylene, and filter cake 0 DEG C of drying in a vacuum drying oven obtains
2.31g2,2', 4'- trichlorine benzyl carbinol sterling, ee value are 98%, yield 85.3%.
The preparation of embodiment 10 (S) -2,2', 4'- trichlorine benzyl carbinol
Under nitrogen protection, 18.3ml (-)-DIP-Cl tetrahydrofuran solution (1mol/L tetra- is added into 5ml tetrahydrofuran
Hydrogen tetrahydrofuran solution), it is then turned on cooling system, reaction solution is cooled to -30 DEG C；
2,2', 4'- trichloroacetophenone tetrahydrofuran solution (2.7 g2,2', 4'- tri- is added dropwise into reaction solution at -30 DEG C
Chloro-acetophenone is dissolved in 10ml tetrahydrofuran), keep this thermotonus 3 hours.
Reaction, which terminates 10ml water is added dropwise, to be quenched, and is quenched to finish this reaction solution is concentrated under reduced pressure, concentrate is added
5% dilute hydrochloric acid 10ml, ethyl acetate 10ml, layering, water layer are extracted twice using ethyl acetate solution, combined ethyl acetate extraction
Liquid is taken, it is primary to wash toluene extract liquor with saturated sodium bicarbonate solution, then takes liquid to be concentrated under reduced pressure toluene, obtains grease
(S) -2,2', 4'- trichlorine benzyl carbinol crude product；
After the crude product is cooled to room temperature, under stirring, petroleum ether 20ml is slowly added dropwise, stirring precipitates crystal,
It is filtered after continuously stirring 30min, filter cake 10ml petroleum ether, filter cake 35 DEG C of dryings in a vacuum drying oven obtain
2.18g2,2', 4'- trichlorine benzyl carbinol sterling, ee value are 98%, yield 80.5%.
The preparation of embodiment 11 (S) -2,2', 4'- trichlorine benzyl carbinol
Under nitrogen protection, 18.3ml (-)-DIP-Cl tetrahydrofuran solution (1mol/L tetra- is added into 5ml tetrahydrofuran
Hydrogen tetrahydrofuran solution), it is then turned on cooling system, reaction solution is cooled to -30 DEG C；
2,2', 4'- trichloroacetophenone tetrahydrofuran solution (2.7 g2,2', 4'- tri- is added dropwise into reaction solution at -30 DEG C
Chloro-acetophenone is dissolved in 10ml tetrahydrofuran), keep this thermotonus 3 hours.
Reaction, which terminates 10ml water is added dropwise, to be quenched, and is quenched to finish this reaction solution is concentrated under reduced pressure, concentrate is added
5% dilute hydrochloric acid 10ml, toluene 10ml, layering, water layer are extracted twice using toluene solution, and combining methylbenzene extract liquor uses saturated carbon
Sour hydrogen sodium solution washing toluene extract liquor is primary, then takes liquid to be concentrated under reduced pressure toluene, obtains (S) -2,2', 4'- of grease
Trichlorine benzyl carbinol crude product；
After the crude product is cooled to room temperature, under stirring, normal heptane 20ml is slowly added dropwise, stirring precipitates crystal,
It is filtered after continuously stirring 30min, filter cake is washed with 10ml normal heptane, and filter cake 35 DEG C of dryings in a vacuum drying oven obtain
2.25g2,2', 4'- trichlorine benzyl carbinol sterling, ee value are 98.2%, yield 83.1%.
The present invention uses (-)-diisopinocampheylchloroborane base chloroborane referred to as (-)-DIP-Cl for high-selectivity catalyst, due to
(-)-DIP-Cl is technical grade commercial product, can directly buy, and price is medium, catalyst is omitted compared with the prior art
Synthesis or complexation approach simplify synthesis procedure, and combined coefficient is high, and reduces synthesis cost.
It should be noted that being not intended to limit although the various embodiments described above have been described herein
Scope of patent protection of the invention.Therefore, based on innovative idea of the invention, the change that carried out to embodiment described herein and
Modification or the equivalent structure or equivalent process transformation made by using the contents of the present specification, directly or indirectly by the above skill
Art scheme is used in other related technical areas, is included within scope of patent protection of the invention.
Claims (10)
1. a kind of synthetic method of highly selective luliconazole intermediate, it is characterised in that: itself the following steps are included:
1) under nitrogen protection, the tetrahydrofuran solution of (-)-DIP-Cl is added in organic solvent A, opens cooling system, cooling
To -30~0 DEG C；
2) by 2,2', the mixed liquor of 4'- trichloroacetophenone and organic solvent B, which is added dropwise in the cooling solution of step 1), to be selected
Property reduction reaction, insulation reaction 2-5 hours；The molar ratio of (-)-DIP-Cl and 2,2', 4'- trichloroacetophenone is 1~3:
1；
3) reaction terminates, and protonic solvent is added dropwise into the reaction solution of step 2) and is quenched, is quenched and finishes, by quenching reaction liquid
It is concentrated, obtains concentrate；
4) acid solution and organic solvent are added into the concentrate described in step 3), stirs, organic solvent layer is isolated in layering
And be concentrated, obtain (S) -2,2', 4'- trichlorine benzyl carbinol crude product；
5) alkane reagent is added in (S) -2,2', 4'- trichlorine benzyl carbinol crude product obtained toward step 4), stirred crystallization, filtering will
Filter cake dries to obtain (S) -2,2', 4'- trichlorine benzyl carbinol sterling.
2. the synthetic method of highly selective luliconazole intermediate according to claim 1, it is characterised in that: the step
Rapid organic solvent A 1) is one of the following: acetone, dimethyl sulfoxide, N, N- diformamide, tetrahydrofuran or toluene.
3. the synthetic method of highly selective luliconazole intermediate according to claim 1, it is characterised in that: the step
It is rapid 1) in, system temperature is reduced to -30~-25 DEG C after opening cooling system.
4. the synthetic method of highly selective luliconazole intermediate according to claim 1, it is characterised in that: the step
Rapid organic solvent B 2) is one of the following: acetone, dimethyl sulfoxide, N, N- diformamide, tetrahydrofuran or toluene.
5. the synthetic method of highly selective luliconazole intermediate according to claim 4, it is characterised in that: the step
Rapid organic solvent B 2) is tetrahydrofuran or toluene.
6. the synthetic method of highly selective luliconazole intermediate according to claim 1, it is characterised in that: described
The molar ratio of (-)-DIP-Cl and 2,2', 4'- trichloroacetophenone is 1.5:1.
7. the synthetic method of highly selective luliconazole intermediate according to claim 1, it is characterised in that: the step
It is rapid 3) in protonic solvent be one of the following: methanol, ethyl alcohol or water.
8. the synthetic method of highly selective luliconazole intermediate according to claim 1, it is characterised in that: the step
It is rapid 4) in acid solution be one of the following: concentration be 1~10% dilute hydrochloric acid, concentration be 1~10% dilute sulfuric acid or
The solution of sodium bisulfite that concentration is 1~10%.
9. the synthetic method of highly selective luliconazole intermediate according to claim 1, it is characterised in that: the step
It is rapid 4) in organic solvent be one of the following: methylene chloride, ethyl acetate or toluene.
10. the synthetic method of highly selective luliconazole intermediate according to claim 1, it is characterised in that: described
Step 5) alkane reagent is one of the following: n-hexane, hexamethylene, petroleum ether or normal heptane.
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