CN101914091B

CN101914091B - Method for preparing voriconazole intermediate

Info

Publication number: CN101914091B
Application number: CN201010244337.9A
Authority: CN
Inventors: 刘节根; 潘领庆; 蹇锋
Original assignee: Zhejiang Huahai Pharmaceutical Co Ltd
Current assignee: Shanghai Aobo biomedical Co.,Ltd.; Zhejiang Huahai Pharmaceutical Co Ltd
Priority date: 2010-07-25
Filing date: 2010-07-25
Publication date: 2015-05-27
Anticipated expiration: 2030-07-25
Also published as: CN101914091A

Abstract

The invention relates to a method for preparing (2R,3S/2S,3R)-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (I) acid salt, which comprises the following steps: (a) reacting 2',4'-difluoro-2-[-1-(1H-1,2,4,-triazol)]phenyl ketone (II) or a salt thereof with 4-chloro-6-ethyl-5- fluoropyrimidine (III) in the presence of an organic metal lithium compound and an aprotic solvent to obtain a compound of a formula (I); and (b) processing the compound of the formula (I) with acid, crystallizing and separating to obtain the target compound. The acid slat forming and crystallizing method adopted by the invention can effectively separate (2R, 3S/2S,3S) enantiomer pairs of the intermediate (I) obtained by an organic metal lithium compound route.

Description

A kind of method preparing voriconazole intermediate

Technical field

The present invention relates to and prepare voriconazole intermediate (2R, 3S/2S, 3R)-3-(the chloro-5-FU of 6--4-base)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl) method of-2-butanols acid salt.

Background technology

Voriconazole is New-type wide-spectrum antifungal drug in triazole class, up to now, the synthetic method about voriconazole reported, all relate to key intermediate (2R, 3S/2S, 3R)-3-(the chloro-5-FU of 6--4-base)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazole-1-base)-2-butanols (I) synthesis.

Report application lithium salts in Chinese patent CN1026788C and carry out the method that linked reaction prepares intermediate (I), its synthetic route is as follows:

The method be make under the effect of organo-metallic lithium compound (II) formed lithium salts, then add be incorporated into compound (III) carbonyl on obtain target compound (I).The cold condition (-78 DEG C) that this reaction needed one is harsh, there is no space multistory selectivity, and (2R, 3S/2S, the 3R) of target compound (I) and (2R, 3R/2S, the ratio that 3S) the two pairs of enantiomorphs are right is 1: 1.1, required (2R, 3S/2S, 3R) enantiomorph is to use chromatographic separation, is therefore difficult to be applied to industrialized production.

Summary of the invention

(the 2R that object of the present invention provides a kind of synthetic route applying organo-metallic lithium easily to prepare purity to be greater than 90%, 3S/2S, 3R)-3-(the chloro-5-FU of 6--4-base)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) method of-2-butanols acid salt.

Concrete scheme provided by the invention is as follows:

The method of (2R, 3S/2S, 3R) is prepared by one-3-(the chloro-5-FU of 6--4-base)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-2-butanols acid salt, comprises following steps:

A () is under organometallic lithium compounds and non-proton organic solvent exist, 2 ', 4 '-two fluoro-2-[1-(1H-1,2,4-triazolyl)] methyl phenyl ketone (II) or its salt and the chloro-6-ethyl-5-FU (III) of 4-be obtained by reacting formula (I) compound;

B the acid of () formula (I) compound processes, crystallization, separation obtain (2R, 3S/2S, 3R)-3-(the chloro-5-FU of 6--4-base)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols acid salt.

In the solution of the present invention, wherein in step (a), organometallic lithium compounds is preferably lithium diisopropyl amido, butyllithium, hexamethyldisilazane lithium, phenyl lithium, is more preferably diisopropylamine lithium; Non-proton organic solvent is normal heptane, normal hexane, hexanaphthene, sherwood oil, ether, methyl tertiary butyl ether, and tetrahydrofuran (THF) or their mixture, be more preferably normal heptane, tetrahydrofuran (THF), MTBE mixtures; Temperature of reaction general control carries out at-70 DEG C ~-50 DEG C, preferably the scope of-70 DEG C ~-60 DEG C.

Wherein the described acid of step (b) is selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, methylsulfonic acid, camphorsulfonic acid, phosphoric acid, the gentle Phenylsulfonic acid of tosic acid, more preferably hydrochloric acid.

The present invention is compared with CN1026788C, (2R is obtained as reaction system using aprotic organic solvent, 3S/2S, 3R): (2R, 3R/2S, 3S) mol ratio is approximately 3-(the chloro-5-FU of 6--4-the base)-2-(2 of 1.7: 1, 4-difluorophenyl)-1-(1H-1, 2, 4-triazol-1-yl)-2-butanols (I), then upper acid salt is become by chemistry, the method of crystallization obtains the (2R that purity is greater than 90%, 3S/2S, 3R)-3-(the chloro-5-FU of 6--4-base)-2-(2, 4-difluorophenyl)-1-(1H-1, 2, 4-triazol-1-yl) acid salt of-2-butanols, compared with adopting chromatography separating method with CN1026788C, operation simplifies greatly.

Embodiment

Below in conjunction with specific embodiment, the invention will be further described, but protection scope of the present invention is not limited thereto.

Embodiment one

Under nitrogen protection, 100ml normal heptane is added in there-necked flask, 20ml methyl tertiary butyl ether and the chloro-6-ethyl-5-FU (50mmol) of 8.03g 4-join in reaction flask, after cooling to-70 DEG C, 28mlLDA (50mmol) within 15 minutes, is dripped at-70 DEG C ~-60 DEG C, 11.16g 2-(2 is dripped after 15 minutes, 4-difluorophenyl)-1-(1H-1, 2, 4-triazole) solution (first filtering insoluble impurities) of-2-ethyl ketone (50mmol) and 100ml tetrahydrofuran (THF), react 1 ~ 3 hour under the condition of-60 ~-70 DEG C, then below-50 DEG C, drip 10ml Glacial acetic acid essence to go out reaction, be warmed up to about 0 DEG C and add 80ml water, stir 30min separatory, after separatory, organic layer 100ml × 3 are washed three times, by solvent evaporated after dried over mgso, obtain yellow oil, add 50ml normal hexane, stir 4 hours, filtration obtains brown solid, solid 20ml tetrahydrofuran (THF) dissolves, then 60ml normal hexane 25 DEG C of crystallizatioies are slowly dripped after 3 hours, filtering solid, 40ml acetic acid ethyl dissolution is used after filtrate evaporate to dryness, drip the saturated hydrochloric acid aqueous isopropanol of 1.5ml, stirring and crystallizing is filtered after 3 hours and is obtained white solid, and with a small amount of ethyl acetate and n-hexane solid, then vacuum-drying 8 hours at 45 DEG C, obtain 2.5g target product (2R, 3S/2S, 3R)-3-(the chloro-5-FU of 6--4-base)-2-(2, 4-difluorophenyl)-1-(1H-1, 2, 4-triazol-1-yl) hydrochloride of-2-butanols, yield is 11.8%, HPLC purity assay is 97.51%.

Embodiment two

Under nitrogen protection, 100ml normal heptane is added in there-necked flask, 20ml methyl tertiary butyl ether and 8ml Diisopropylamine, cool to about-20 DEG C, drip 20ml n-Butyl Lithium (50mmol), keep-20 DEG C to stir after 2 hours and cool to about-70 DEG C,-70 DEG C ~-60 DEG C dripped the chloro-6-ethyl-5-FU of 8.03g4-in 15 minutes, continue after 30min to drip 11.16g2-(2, 4-difluorophenyl)-1-(1H-1, 2, 4-triazole) solution (first filtering insoluble impurities) of-2-ethyl ketone and 100ml tetrahydrofuran (THF), react 1 ~ 3 hour under the condition of-60 ~-70 DEG C, then below-50 DEG C, drip 10ml Glacial acetic acid essence to go out reaction, be warmed up to about 0 DEG C and add 80ml water, stir 30min separatory, after separatory, organic layer 100ml × 3 are washed three times, by solvent evaporated after dried over mgso, obtain yellow oil, add 40ml normal hexane, stir 4 hours, filtration obtains brown solid, solid 25ml tetrahydrofuran (THF) dissolves, then 90ml normal hexane 25 DEG C of crystallizatioies are slowly dripped after 3 hours, filtering solid, 50ml acetic acid ethyl dissolution is used after filtrate evaporate to dryness, drip 1.3ml concentrated hydrochloric acid, stirring and crystallizing is filtered after 3 hours and is obtained white solid, and with a small amount of ethyl acetate and n-hexane solid, then vacuum-drying 8 hours at 45 DEG C, obtain 2.6g target product (2R, 3S/2S, 3R)-3-(the chloro-5-FU of 6--4-base)-2-(2, 4-difluorophenyl)-1-(1H-1, 2, 4-triazol-1-yl) hydrochloride of-2-butanols, yield is 12.52%, HPLC purity assay is 95.71%.

Claims

1. prepare the method for (2R, 3S/2S, 3R)-3-(the chloro-5-FU of 6--4-base)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-2-butanols acid salt, comprise following steps:

A () is by 2 ', 4 '-two fluoro-2-[1-(1H-1,2,4-triazolyl)] methyl phenyl ketone (II) or its salt and the chloro-6-ethyl-5-FU (III) of 4-carry out the formula that is obtained by reacting (I) compound under the existence of organometallic lithium compounds and non-proton organic solvent, and wherein non-proton organic solvent is the mixture of normal heptane, tetrahydrofuran (THF) and methyl tertiary butyl ether;

B the acid of () formula (I) compound processes, crystallization, separation obtain (2R, 3S/2S, 3R)-3-(the chloro-5-FU of 6--4-base)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols acid salt

2. the method for claim 1, organometallic lithium compounds is lithium diisopropyl amido, butyllithium, hexamethyldisilazane lithium, phenyl lithium.

3. the method for claim 1, acid is selected from: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, methylsulfonic acid, camphorsulfonic acid, phosphoric acid, tosic acid, Phenylsulfonic acid.

4. method as claimed in claim 3, acid is hydrochloric acid.