WO2018045629A1 - 一种制备伏立康唑左旋樟脑磺酸盐以及伏立康唑的方法 - Google Patents

一种制备伏立康唑左旋樟脑磺酸盐以及伏立康唑的方法 Download PDF

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WO2018045629A1
WO2018045629A1 PCT/CN2016/105312 CN2016105312W WO2018045629A1 WO 2018045629 A1 WO2018045629 A1 WO 2018045629A1 CN 2016105312 W CN2016105312 W CN 2016105312W WO 2018045629 A1 WO2018045629 A1 WO 2018045629A1
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solvent
butanol
voriconazole
difluorophenyl
triazol
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PCT/CN2016/105312
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English (en)
French (fr)
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黄虎
黄文锋
涂国良
徐中明
吴强晖
孟昭旸
方玉玲
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浙江华海药业股份有限公司
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Priority to EP16915563.7A priority Critical patent/EP3511326B1/en
Priority to EP22154723.5A priority patent/EP4019509A1/en
Priority to ES16915563T priority patent/ES2911289T3/es
Priority to US16/330,692 priority patent/US11919884B2/en
Publication of WO2018045629A1 publication Critical patent/WO2018045629A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/19—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/60—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members
    • C07C2603/66—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members containing five-membered rings

Definitions

  • the present invention relates to a process for the preparation of voriconazole L-camphorsulfonate and voriconazole.
  • Voriconazole (VRC, UK109496) is a new antifungal drug synthesized by Pfizer Inc. on the basis of fluconazole. It is mainly used for patients with progressive and fatal immune damage. Due to the wide antifungal spectrum of voriconazole, strong antibacterial effect, good safety, and the rapid increase in the demand for antifungal drugs in the domestic market, the market prospect is huge.
  • Voriconazole its chemical name is: (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4- Triazol-1-yl)-2-butanol, the structural formula is as shown in formula I:
  • the voriconazole racemate is an important intermediate, the chemical name is: (2R, 3S/2S, 3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidine-4- Base)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, the structural formula is as shown in formula II:
  • the voriconazole racemate needs to be resolved in one step to obtain voriconazole, ie (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H -1,2,4-Triazol-1-yl)-2-butanol.
  • the second is to adopt Chiral resolving agents are used for separation. The recovery of chiral resolving agents is relatively simple and can be used repeatedly. This method is often used in industrial production.
  • Patent EP 2 444 398 A2 discloses a method for the resolution of a voriconazole racemate using a chiral resolving agent.
  • the resolving agent used is levocamphorsulfonic acid, and the resolving solvent is a mixed solvent of methanol and acetone.
  • the reaction route is as follows:
  • the above split method has the following problems:
  • an aspect of the present invention provides a method for preparing voriconazole L-camphorsulfonate, comprising the steps of:
  • Method 2 (a) (2R,3S)/(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H- A mixture of 1,2,4-triazol-1-yl)-2-butanol mixture and L-camphorsulfonic acid is dissolved and crystallized in a first solvent, and the crystalline enriched (2S, 3R)-2- is removed by filtration. Levorotatory brain of (2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol Sulfonate; or
  • (a') will be (2R,3S)/(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1
  • the left-handed camphorsulfonate of a mixture of 2,4-triazol-1-yl)-2-butanol is dissolved and crystallized in a first solvent, and the crystalline enriched (2S,3R)-2-(2, L-camphorsulfonate of 4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol ;
  • step (b) concentrating the filtrate obtained by filtration in step (a) or (a') to dryness to obtain a solid;
  • step (c) dissolving and crystallizing the solid obtained in the step (b) in a second solvent to obtain (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidine-4- L-camphorsulfonate of 1-(1H-1,2,4-triazol-1-yl)-2-butanol.
  • a dissolving solvent different from the prior art is used, which can reduce the amount of solvent used, reduce production cost, increase productivity, and is extremely industrially productive.
  • the inventive method 2 uses a completely different method: first (2S, 3R)-2-(2,4- Dephosphorization of difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol isomer, then The solid obtained by concentrating the filtrate ((2R,3S)/(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H- (1,2,4-triazol-1-yl)-2-butanol mixture) redissolved and crystallized to obtain (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro L-camphorsulfonate of pyrimidin-4-y
  • the two isomers of the 2,4-triazol-1-yl)-2-butanol mixture may be in any ratio, for example, the ratio of voriconazole to its isomer may be 99:1-40:60, in one implementation In the example, the ratio can be 1:1.
  • (2R,3S)/(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1) in Method 2 The two isomers of the 2,4-triazol-1-yl)-2-butanol mixture may be in any ratio, for example, the ratio of voriconazole to its isomer may be from 50:50 to 1:99.
  • Process 2 of the invention is highly suitable for the recovery of the mother liquor after voriconazole racemate resolution, for example, in Process 1, which is very beneficial for increasing the overall yield of the split and reducing the cost.
  • the second solvent used in the step (c) of the method 2 is not particularly limited, and a solvent such as acetone and methanol used in the method for splitting the voriconazole racemate reported in the prior art can be referred to.
  • the second solvent is a mixed solvent of acetone and water.
  • the first solvent is selected from the group consisting of a mixture of a C 4 -C 8 ketone solvent and water, isopropanol or ethanol.
  • the amount of the first solvent to be used is not particularly limited as long as the mixture can be completely dissolved therein to obtain a clear solution.
  • the volume ratio of the C 4 -C 8 ketone solvent to water is from 100:1 to 1:100, preferably from 50:1 to 5:1, more preferably from 25:1 to 10:1.
  • the C 4 -C 8 ketone solvent is preferably methyl ethyl ketone, methyl isobutyl ketone or methyl methyl ketone.
  • the crystallization temperature of the step (a) or (a') may be 0 to 40 ° C, preferably 15 to 25 ° C.
  • the volume ratio of acetone to water may be from 100:1 to 1:100, preferably from 15:1 to 5:1.
  • the amount of acetone and water in the method 1 or the second solvent in the method 2 is relative to (2R, 3S) / (2S, 3R)-2-(2,4-difluorophenyl)-3-(
  • the mixture of 5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol may be 10-30 mL/g, preferably 10-15 mL/g.
  • the crystallization temperature in the step (c) of the method 1 or the method 2 is 0 to 40 ° C, preferably 15 to 30 ° C.
  • Another aspect of the present invention also provides a method of preparing voriconazole comprising dissolving voriconazole L-camphorsulfonate prepared according to the method described above to obtain voriconazole.
  • a further aspect of the invention provides a (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1, Crystallization of L-camphorsulfonate of 2,4-triazol-1-yl)-2-butanol, wherein (2S,3R)-2-(2,4-difluorophenyl)- L-camphorsulfonate of 3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol with (2R,3S)-2 -(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol
  • the proportion of camphor sulfonate is greater than 1, preferably greater than 5, further preferably in the crystallization (2S,
  • the method 1 was used for the separation, and the voriconazole racemate (15 g), L-camphorsulfonic acid (10 g), acetone (150 mL) and water (15 mL) were mixed, and the temperature was raised to 50 ° C to completely dissolve the solid until the solution was clarified. The temperature was naturally lowered to 20 ° C, stirred at 20 ° C for 2 hours, and filtered to obtain a solid crystal, wherein the compound of formula III had an ee% of 99.7% and a yield of 40.4%.
  • This embodiment uses Method 2 for splitting.
  • the concentrated solid was added to the flask, acetone (205.2 mL), water (20.5 mL) was added, the temperature was raised to 50 ° C, the mixture was stirred and dissolved, and the temperature was slowly lowered to 25 ° C. The mixture was stirred at 25 ° C for 2 hours, filtered, and the filter cake was used.
  • the acetone/water mixed solution (V/V 10:1, 33 mL) was rinsed once and filtered to give a solid, wherein the compound of formula III had an ee% of 99.6% and a yield of 12.1%.
  • the yield of the compound of the formula III obtained cumulatively with the method of Example 1 was 47.6%.
  • This embodiment uses Method 2 for splitting.
  • the voriconazole racemate (15.1 g) was dissolved in acetone (288 mL), and a solution of L-camphorsulfonic acid (8.51 g) in methanol (96 mL) was added, the mixture was warmed to 50 ° C, the solution was clarified, and the temperature was slowly lowered to 20 ° C, and at 20 After stirring at ° C for 18 hours, filtration and HPLC detection, the ee% of voriconazole L-camphorsulfonate was 99.8%, and the yield was 35%.
  • the solvent used in the existing acetone and methanol solvent system is relatively large, about 24.5 ml / g, and the minimum of the method of the present invention can reach 10 ml / g; while the alcohol and acetone used in the comparative example
  • the boiling points of the two solvents are relatively close, and the volatility is relatively strong, making it difficult to separate, so the use of the method in the comparative example greatly increases the production cost.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

一种制备伏立康唑左旋樟脑磺酸盐以及伏立康唑的方法。制备伏立康唑左旋樟脑磺酸盐的方法包括：方法1：将(2R,3S)/(2S,3R)异构体混合物和左旋樟脑磺酸溶解在水和丙酮中，析晶过滤得伏立康唑左旋樟脑磺酸盐；方法2：(a)将异构体混合物和左旋樟脑磺酸的混合物在第一溶剂中溶解并析晶后过滤；或者(a')将异构体混合物的左旋樟脑磺酸盐在第一溶剂中溶解并析晶后过滤；(b)将步骤(a)或(a')中过滤所得滤液浓缩至固体；(c)将步骤(b)得到的固体在第二溶剂中溶解并析晶得到伏立康唑左旋樟脑磺酸盐。通过调整拆分溶剂，有效降低了生产成本，并有利于拆分溶剂的回收。

Description

一种制备伏立康唑左旋樟脑磺酸盐以及伏立康唑的方法
本申请要求于2016年9月8日提交中国专利局、申请号为201610811521.4发明名称为“一种制备伏立康唑拆分中间体的方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种制备伏立康唑左旋樟脑磺酸盐以及伏立康唑的方法。
背景技术
伏立康唑(voriconazole，VRC，UK109496)是美国辉瑞公司在氟康唑基础上合成的一种新型抗真菌药，主要用于进行性、有致命危险的免疫损害患者。由于伏立康唑抗真菌谱广、抗菌效力强，安全性好，且国内市场对抗真菌药物的需求增长迅速，因此市场前景巨大。
伏立康唑，其化学名为：(2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇，结构式如式Ⅰ所示：
Figure PCTCN2016105312-appb-000001
伏立康唑外消旋体作为一种重要的中间体，化学名为：(2R,3S/2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇，结构式如式Ⅱ所示：
Figure PCTCN2016105312-appb-000002
该伏立康唑外消旋体需要一步拆分得到伏立康唑，即(2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇。异构体的分离一般有两种方法，第一种是在反应过程中手性诱导，这种方法一般需要采用手性催化剂，成本比较高，不利于大规模的工业生产，第二种是采用手性拆分剂进行拆分，手性拆分剂的回收比较简便，一般可以反复使用，这种方法在工业生产中经常采用。
专利EP2444398A2中公开了一种伏立康唑外消旋体使用手性拆分剂的拆分方法，使用的拆分剂是左旋樟脑磺酸，拆分溶剂是甲醇和丙酮的混合溶剂，反应路线如下：
Figure PCTCN2016105312-appb-000003
上述拆分方法存在以下问题：
1、甲醇和丙酮这两种溶剂沸点比较接近，且挥发性都比较强，很难进行分离，因此，拆分溶剂的回收是一个很大的问题，使用目前的拆分溶剂既增加了生产成本，同时也不符合环保生产的要求；
2、在拆分过程中，拆分溶剂的使用量非常大，产能较低，严重影响了拆分物伏立康唑的大规模生产；
3、拆分母液中仍然残留有较多的式Ⅲ所示化合物以及如下式IV所示的异构体(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐：
Figure PCTCN2016105312-appb-000004
发明内容
为解决上述问题，本发明的一方面提供一种制备伏立康唑左旋樟脑磺酸盐的方法，包括如下步骤：
方法1：将(2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物和左旋樟脑磺酸溶解在水和丙酮组成的混合溶剂中，降温析晶，过滤去除结晶，烘干滤液得到伏立康唑左旋樟脑磺酸盐；
方法2：(a)将(2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物和左旋樟脑磺酸的混合物在第一溶剂中溶解并析晶，过滤除去结晶的富含(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐；或者
(a’)将(2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物的左旋樟脑磺酸盐在第一溶剂中溶解并析晶，过滤除去结晶的富含(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐；
(b)将步骤(a)或(a’)中过滤所得的滤液浓缩至干，得到固体；
(c)将步骤(b)得到的固体在第二溶剂中溶解并析晶得到(2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐。
本发明的方法1中使用了与现有技术不同的拆分溶剂，能够降低溶剂的使用量，使生产成本降低，提高产能，极具工业生产价值。
与直接使混合物中的伏立康唑与拆分剂结合，然后析晶分离的现有技术相比，本发明方法2使用了完全不同的方法：首先将(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇异构体析晶去除，然后将滤液浓缩得到的固体((2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物)再次溶解析晶得到(2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐。
其中，方法1中的(2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物中两种异构体可为任意比例，例如伏立康唑与其异构体的比例可为99:1-40:60，在一个实施例中该比例可为1:1。
其中，方法2中的(2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物中两种异构体可为任意比例，例如伏立康唑与其异构体的比例可为50:50-1:99。
上述方法1和方法2中，优选的(2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物与左旋樟脑磺酸比例例如为1:1-1:1.5。
发明的方法2非常适用于使用例如方法1中伏立康唑外消旋体拆分后母液的回收，这对于提高拆分总收率并降低成本非常有益。
本发明的上述方法中，对方法2的步骤(c)中使用的第二溶剂不做特别限制，可以参考现有技术报道的拆分伏立康唑外消旋体的方法所使用的溶剂例如丙酮和甲醇的混合溶剂，或者本发明提供的丙酮和水的混合溶剂。在一个实施例中，所述第二溶剂为丙酮和水的混合溶剂。
上述方法中，所述第一溶剂选自C4-C8酮类溶剂和水的混合物，异丙醇或者乙醇。所述第一溶剂的用量没有特别限制，只要能够实现混合物在其中完全溶解获得澄清溶液即可。
上述方法中，所述C4-C8酮类溶剂和水的体积比为100:1-1:100，优选为50:1-5:1，更优选为25:1-10:1。
所述C4-C8酮类溶剂优选为丁酮，甲基异丁基酮或甲基丁酮。
所述步骤(a)或(a’)的析晶温度可以为0-40℃，优选为15-25℃。
所述丙酮和水的体积比可以为100:1-1:100，优选为15:1-5:1。
所述方法1中的丙酮和水或方法2中的第二溶剂的使用量相对于(2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物可以为10-30mL/g，优选为10-15mL/g。
方法1或方法2的步骤(c)中的析晶温度为0-40℃，优选15-30℃。
本发明的另一方面还提供一种制备伏立康唑的方法，包括将根据以上所述的方法制备得到的伏立康唑左旋樟脑磺酸盐加碱游离得到伏立康唑。
本发明的又一方面提供一种富含(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐的结晶，其中，所述结晶中(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐与(2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐的比例大于1，优选大于5，进一步优选为所述结晶中 (2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐的纯度大于90％，优选大于98％。
具体实施方式
实施例1：
本实施例使用方法1进行拆分，伏立康唑外消旋体(15g)、左旋樟脑磺酸(10g)、丙酮(150mL)和水(15mL)混合，升温至50℃使固体完全溶解至溶液澄清，自然降温至20℃，在20℃搅拌2小时，过滤得到固体结晶，其中式III化合物的e.e.％为99.7％，产率40.4％。
实施例2：
本实施例使用方法1进行拆分，伏立康唑外消旋体(9g)，左旋樟脑磺酸(6g)、丙酮(150mL)和水(30mL)混合，升温至50℃使固体完全溶解至溶液澄清，自然降温至0℃，在0℃搅拌2小时，过滤得到固体结晶，其中式III化合物的e.e.％为99.3％，产率30.1％。
实施例3：
本实施例使用方法1进行拆分，将伏立康唑外消旋体(9g)、左旋樟脑磺酸(6g)、丙酮(150mL)和水(15mL)混合，升温至50℃使固体完全溶解至溶液澄清，自然降温至25℃，在25℃搅拌2小时，过滤得到固体结晶，其中式III化合物的e.e.％为99.7％，产率36.6％。
实施例4：
本实施例使用方法1进行拆分，将伏立康唑外消旋体(15g)、左旋樟脑磺酸(10g)、丙酮(150mL)和水(10mL)混合，升温至50℃使固体完全溶解至溶液澄清，自然降温至25℃，在25℃搅拌2小时，过滤得到固体结晶，其中式III化合物的e.e.％为99.8％，产率37.5％。
实施例5：
本实施例使用方法2进行拆分。
对根据实施例1方法多次获得的拆分母液进行浓缩得到固体(100g，其中式III化合物：式IV化合物＝18：82)，将固体加入到烧瓶中，同时加入丁酮(300mL)，水(15mL)，升温至50℃搅拌30分钟，降温至25℃搅拌2小时，过滤除去固体结晶(该固体结晶中含式IV纯度99.27％)。将滤液浓缩干，得到固体(34.2g，其中式III化合物：式IV化合物＝55：45)。
将浓缩后的固体加入到烧瓶中，加入丙酮(205.2mL)，水(20.5mL)，升温至50℃搅拌溶清，缓慢降温至25℃，在25℃保温搅拌2小时，过滤，滤饼用丙酮/水混合溶液(V/V10:1，33mL)淋洗一次，过滤得到固体，其中式III化合物的e.e.％为99.6％，产率12.1％。与实施例1中方法累计获得的式III化合物的产率为47.6％。
实施例6：
本实施例使用方法2进行拆分。
将伏立康唑外消旋体(30g)、左旋樟脑磺酸(200g)、丁酮(150mL)和水(7.5mL)混合，升温至50℃，溶液澄清，自然降温至25℃，在25℃搅拌2小时，过滤除去固体(该固体中含式IV纯度98.9％)。将滤液进行浓缩，得到固体(34.2g，其中式III化合物：式IV化合物＝70：30)。
将浓缩后的固体加入到烧瓶中，加入丙酮(205.2mL)，水(20.5mL)，升温至50℃保温搅拌1h，缓慢降温至25℃，在25℃保温搅拌2小时，过滤，滤饼用丙酮/水混合溶液(V/V＝10:1，33mL)淋洗一次，烘干得到18.5g固体，其中式III化合物的e.e.％为99.4％，产率37％。
实施例7-11：
考察不同溶剂体系对收集富含式IV所示的异构体的效果，所得到的结果如下表所示：
Figure PCTCN2016105312-appb-000005
Figure PCTCN2016105312-appb-000006
对比例：
伏立康唑外消旋体(15.1g)溶于丙酮(288mL)中，加入左旋樟脑磺酸(8.51g)的甲醇(96mL)溶液，升温至50℃，溶液澄清，缓慢降温至20℃，并在20℃搅拌18小时，过滤，HPLC检测，伏立康唑左旋樟脑磺酸盐的e.e.％＝99.8％，产率35％。
由以上对比例可以看出，使用现有的丙酮和甲醇溶剂体系溶剂用量较大，为约24.5ml/g，而本发明方法中最小可以达到10ml/g；同时对比例中使用的醇和丙酮这两种溶剂沸点比较接近，且挥发性都比较强，很难进行分离，因此使用对比例中的方法大大增加了生产成本。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明保护的范围之内。

Claims (11)

  1. 一种制备伏立康唑左旋樟脑磺酸盐的方法，包括如下步骤：
    方法1：将(2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物和左旋樟脑磺酸溶解在水和丙酮组成的混合溶剂中，降温析晶，过滤去除结晶，烘干滤液得到伏立康唑左旋樟脑磺酸盐；
    方法2：(a)将(2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物和左旋樟脑磺酸的混合物在第一溶剂中溶解并析晶，过滤除去结晶的富含(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐；或者
    (a’)将(2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物的左旋樟脑磺酸盐在第一溶剂中溶解并析晶，过滤除去结晶的富含(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐；
    (b)将步骤(a)或(a’)中过滤所得的滤液浓缩至干，得到固体；
    (c)将步骤(b)得到的固体在第二溶剂中溶解并析晶得到(2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐。
  2. 根据权利要求1所述的方法，其中所述第一溶剂体系选自C4-C8酮类溶剂和水的混合物，异丙醇或者乙醇。
  3. 根据权利要求1所述的方法，其中所述第二溶剂为丙酮和水或者甲醇和丙酮的混合溶剂。
  4. 根据权利要求1-3任一项所述的方法，其中所述C4-C8酮类溶剂和水的体积比为100:1-1:100，优选为50:1-5:1，更优选为25:1-10:1。
  5. 根据权利要求1-3任一项所述的方法，其中所述C4-C8酮类溶剂为丁酮，甲基异丁基酮或甲基丁酮。
  6. 根据权利要求5所述的方法，其中所述步骤(a)或(a’)的析晶温度为0-40℃，优选为15-25℃。
  7. 根据权利要求1-3任一项所述的方法，其中所述丙酮和水的体积比为100:1-1:100，优选为15:1-5:1。
  8. 根据权利要求1-3任一项所述的方法，其中所述方法1中的丙酮和水或方法2中的第二溶剂的使用量相对于(2R,3S)/(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇混合物为10-30mL/g，优选为10-15mL/g。
  9. 根据权利要求1所述的方法，其中方法1或方法2的步骤(c)中的析晶温度为0-40℃，优选15-30℃。
  10. 一种制备伏立康唑的方法，包括将根据权利要求1-10任一项所述的方法制备得到的伏立康唑左旋樟脑磺酸盐加碱游离得到伏立康唑。
  11. 一种富含(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐的结晶，其中，所述结晶中(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐与(2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐的比例大于1，优选大于5，进一步优选为所述结晶中(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇的左旋樟脑磺酸盐的纯度大于90％，优选大于98％。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1473825A (zh) * 2002-08-07 2004-02-11 张文祥 制备伏立康唑的方法
WO2008075205A2 (en) * 2006-07-13 2008-06-26 Medichem, S.A. Improved process for the preparation of voriconazole
WO2010095145A1 (en) * 2009-02-17 2010-08-26 Glenmark Generics Limited Process for the preparation of voriconazole
CN105503834A (zh) * 2015-12-23 2016-04-20 浙江华海药业股份有限公司 一种伏立康唑中间体的合成方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9516121D0 (en) 1995-08-05 1995-10-04 Pfizer Ltd Organometallic addition to ketones
EP1899327A1 (en) * 2005-06-30 2008-03-19 MSN Laboratories Limited Improved process for the preparation of 2r, 3s-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol (voriconazole)
WO2007132354A2 (en) 2006-02-01 2007-11-22 Medichem, S.A. Process for preparing voriconazole, new polymorphic form of intermediate thereof, and uses thereof
KR100889937B1 (ko) * 2007-08-06 2009-03-20 한미약품 주식회사 보리코나졸의 제조방법
WO2009084029A2 (en) 2007-12-03 2009-07-09 Neuland Laboratories Ltd Improved process for the preparation of (2r,3s)-2-(2,4- difluqrophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol
KR101109215B1 (ko) 2009-06-17 2012-01-30 보령제약 주식회사 보리코나졸의 신규 중간체 및 이를 이용한 보리코나졸의 제조방법
CN102516233B (zh) * 2011-12-09 2014-04-09 北京联本医药化学技术有限公司 生产伏立康唑的方法
CN102807563B (zh) * 2012-08-27 2015-05-20 南京华威医药科技开发有限公司 伏立康唑及其中间体的制备方法
BR112015007821B1 (pt) 2012-10-15 2022-02-15 Pfizer Ireland Pharmaceuticals Processo para a preparação de voriconazol e análogos do mesmo

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1473825A (zh) * 2002-08-07 2004-02-11 张文祥 制备伏立康唑的方法
WO2008075205A2 (en) * 2006-07-13 2008-06-26 Medichem, S.A. Improved process for the preparation of voriconazole
WO2010095145A1 (en) * 2009-02-17 2010-08-26 Glenmark Generics Limited Process for the preparation of voriconazole
CN105503834A (zh) * 2015-12-23 2016-04-20 浙江华海药业股份有限公司 一种伏立康唑中间体的合成方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3511326A4 *

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