CN108948080A - 一种福沙匹坦药用盐的制备方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明属于医药化学技术领域,具体涉及福沙匹坦双葡甲胺的一种新制备方法。该制备方法以三乙基硅烷代替氢气,能够避免使用高压设备,提高安全性,所得产品外观好,纯度高,适合工业化大生产。
Description
技术领域
本发明属于医药化学技术领域,具体涉及福沙匹坦双葡甲胺的一种新制备方法。该制备方法以三乙基硅烷代替氢气,能够避免使用高压设备,提高安全性,所得产品外观好,纯度高,适合工业化大生产。
背景技术
福沙匹坦双葡甲胺是阿瑞匹坦(Aprepitant)的的水溶性磷酰基前体药物,经静脉注射后可迅速在体内通过磷酸化途径转化为阿瑞匹坦,适用于不能口服、吞咽困难或消化功能低下的患者。福沙匹坦双葡甲胺与阿瑞匹坦属于称作人P物质/神经激肽1(NK-1)选择性高亲和性受体阻断剂,主要通过阻断大脑恶心和呕吐信号新颖的作用机制发挥作用;福沙匹坦双葡甲胺具有式I所示结构:
目前,文献报道的福沙匹坦双葡甲胺的合成方法,大多最后一步都是钯催化氢化,需要耐高压反应釜,安全性差,且生产规模严重受限,不适合工业化大生产。如专利WO9523798(中国同族CN1075812A)报道以阿瑞匹坦为原料经过膦酰化反应得到阿瑞匹坦的磷酰二苄酯,在N-甲基-D-葡糖胺存在下经过钯碳加氢还原成盐制备福沙匹坦双葡甲胺。专利WO2006010110(中国同族CN101056672A)对专利WO9523798路线进行了改进,用甲醇处理得到的阿瑞匹坦磷酰二苄酯得到阿瑞匹坦的磷酰单苄酯,但仍需要经过钯碳催化加氢制备福沙匹坦双葡甲胺。
发明内容
本申请提出了一种新颖、简单、高效的制备福沙匹坦双葡甲胺的方法。该方法包括以下步骤:中间体II或中间体III在钯催化剂和三乙基硅烷作用下脱除苄氧基,并与N-甲基-D葡糖胺成盐,从而制备得到福沙匹坦双葡甲胺。
其中,R独立地选自氢原子、C1~4烷基、卤原子、氰基、三氟甲基,优选氢原子;所述C1-4烷基优选甲基、乙基、丙基、丁基;所述卤原子选自氟原子、氯原子、溴原子、碘原子。
具体地,本申请所述福沙匹坦双葡甲胺的制备方法包括以下步骤:
(1)将中间体II或III、钯催化剂、N-甲基-D葡萄胺、三乙基硅烷加入反应溶剂中,搅拌反应,过滤去除钯催化剂,加入反溶剂I中,搅拌析晶,过滤,干燥,得到福沙匹坦双葡甲胺粗品;
(2)将步骤(1)所得粗品溶于甲醇中,所得溶液加入到反溶剂II中,搅拌析晶,过滤,干燥,得到福沙匹坦双葡甲胺;
其中,所述反应溶剂选自甲醇、乙醇、乙二醇,或者甲醇、乙醇、乙二醇中的一种或多种与水组成的混合溶剂;所述钯催化剂选自钯碳、氢氧化钯;反溶剂I、反溶剂II独立地选自异丙醇、丙酮、2-丁酮、甲基异丁基酮、乙酸正丁酯、乙酸乙酯、乙酸丙酯、甲基叔丁基醚、乙醚、异丙醚。
步骤(1)中,钯催化剂与中间体II或III的质量投料比为0.1~1:1,优选0.1~0.3:1;N-甲基-D葡萄胺与中间体II或III的摩尔投料比为2~3:1;三乙基硅烷与中间体II或III的摩尔投料比为1~6:1,优选2~4:1;反应溶剂与与中间体II或III的体积质量比为5~20:1,单位:ml/g;反溶剂I与与中间体II或III的体积质量比为25~60:1,单位:ml/g。
步骤(1)中搅拌反应的时间为1~6h,反应温度为0~60℃,优选20~40℃;析晶搅拌时间为10~60min;搅拌析晶的温度为10~50℃,优选20~40℃。
步骤(2)中甲醇与福沙匹坦双葡甲胺粗品的投料比为5~20:1,单位:ml/g;反溶剂II与福沙匹坦双葡甲胺粗品的投料比为25~60:1,单位:ml/g。
步骤(2)的析晶搅拌时间为10~60min;析晶温度为10~50℃,优选20~40℃。
在本发明的一个优选实施方案中,福沙匹坦双葡甲胺的制备方法包括以下步骤:
1)向反应瓶中加入中间体IIa或IIIa、N-甲基-D葡糖胺、10%钯碳、三乙基硅烷和甲醇,室温搅拌反应2小时;反应结束后,过滤去除钯碳,向所得滤液中加入异丙醇,搅拌析晶,过滤,滤饼真空干燥,得福沙匹坦双葡甲胺粗品;
(2)向反应瓶中加入福沙匹坦双葡甲胺粗品、甲醇,室温搅拌溶解;将所得溶液加入丙酮中,搅拌析晶,过滤,滤饼真空干燥得白色固体。
在本发明中,所述中间体IIIa是指R为氢原子的中间体II,即[3-[2(R)-[(1R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3(S)-(4-氟苯基)-4-吗啉-4-基]甲基]-5-氧代-4,5-二氢-[1,2,4]-三唑-1-基]磷酸单苄酯;所述中间体IIa是指R均为氢原子的中间体II,即[3-[2(R)-[(1R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3(S)-(4-氟苯基)-4-吗啉-4-基]甲基]-5-氧代-4,5-二氢-[1,2,4]-三唑-1-基]磷酸二苄酯。
需要指出的是,在本发明中,如未作特殊说明,所述反应溶剂及相关试剂的用量为反应的常规用量,本领域的技术人员根据现有技术即可确定;本发明使用的试剂为常规试剂,可以通过市场购买得到,所用起始原料和反应物均可以通过现有技术或公开的现有文献制备得到。虽然本发明对反应物投料比及反应溶剂/析晶溶剂的用量进行了适当限定,但这些限定范围仍然属于本领域的常规用量,限定用量范围并非说明范围之外的用量不能实现本发明或者进行化学制备反应,而是发明人在综合反应条件、后处理操作,反应成本等因素后在常规用量的范围内明确了更为适合本发明或本反应的用量范围。本领技术人员仍然可以根据本领域公知常识基本化学原理在本发明记载的反应物和溶剂用量范围之外适量确定用量。
本发明通过对钯催化剂、三乙基硅烷投料比及反应温度的研究,克服了目前安全性差,生产规模严重受限的缺点,达到了以下技术效果:
(1)用三乙基硅烷代替氢气,避免使用高压力设备,安全性得以提高,生产规模得以扩大,适合工业化大生产;
(2)采用本发明得到的产品外观好,纯度高,纯度达99.5%以上,单一杂质均小于0.1%。
具体实施方式
以下通过具体的实施方式,对本发明的上述内容做进一步的详细说明,但不应将此理解为对本发明保护主题的任何限制。凡基于本发明上述内容所实现的技术方案均属于本发明的范围。本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。本领域技术人员清楚,在下文中,如果未特别说明,本发明所进行的操作是本领域常规的室温条件下进行,所述室温具有本领域公知的技术含义,一般是指10~30℃,优选15~25℃,更优选20~25℃。
实施例1:[3-[2(R)-[(1R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3(S)-(4-氟苯基)-4-吗啉-4-基]甲基]-5-氧代-4,5-二氢-[1,2,4]-三唑-1-基]磷酸二苄酯(IIa)的制备
向反应瓶中依次加入300ml四氢呋喃、14.0g阿瑞匹坦、22.3g焦磷酸四苄酯,氮气保护,降温至0~10℃。控温0~10℃加入33.6kg六甲基二硅氮烷钠溶液。加毕,保温反应1小时。饱和碳酸氢钠溶液淬灭反应,甲基叔丁基醚萃取。有机层分别用0.5M硫酸氢钾溶液、饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,无水硫酸钠干燥。过滤,浓缩得黄色油状物。加入300ml环己烷,5~15℃下搅拌2~3小时。过滤,滤饼真空干燥2~3小时,得白色固体16.9g,收率81.1%。
实施例2[3-[2(R)-[(1R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3(S)-(4-氟苯基)-4-吗啉-4-基]甲基]-5-氧代-4,5-二氢-[1,2,4]-三唑-1-基]磷酸单苄酯(IIIa)的制备
向反应瓶中加入50ml甲醇和10.0g中间体IIa,控温40~50℃搅拌8小时,降温至0~5℃,保温搅拌2~3小时,过滤,滤饼真空干燥2~3小时,得白色固体8.0g,收率89.8%。
实施例3福沙匹坦双葡甲胺粗品的制备
向反应瓶中加入5.0g中间体IIa、2.8gN-甲基-D葡糖胺、0.5g10%钯碳、1.9g三乙基硅烷和50ml甲醇,室温搅拌反应2小时。反应结束后,过滤去除钯碳,向滤液中加入150ml异丙醇,搅拌析晶,过滤,滤饼真空干燥5~6小时得白色固体5.1g,收率80.7%。HPLC纯度99.5%;
实施例4福沙匹坦双葡甲胺粗品的制备
向反应瓶中加入5.0g中间体IIIa、3.2gN-甲基-D葡糖胺、0.5g10%钯碳、2.1g三乙基硅烷和50ml甲醇,室温搅拌反应2小时。反应结束后,过滤去除钯碳,向滤液中加入150ml异丙醇,搅拌析晶,过滤,滤饼真空干燥5~6小时得白色固体6.3g,收率88.4%。HPLC纯度99.4%;
实施例5福沙匹坦双葡甲胺的制备
向反应瓶中加入5.0g福沙匹坦双葡甲胺粗品、40ml甲醇,室温搅拌溶解。所得溶液加入到250ml丙酮中,搅拌析晶,过滤,滤饼真空干燥8~10小时,得白色固体4.5g,收率90.0%;HPLC纯度99.8%。
Claims (8)
1.一种制备福沙匹坦双葡甲胺的方法,其包括以下步骤:中间体II或中间体III在钯催化剂和三乙基硅烷作用下脱除苄氧基,并与N-甲基-D葡糖胺成盐,制备得到福沙匹坦双葡甲胺;
其中,R独立地选自氢原子、C1~4烷基、卤原子、氰基、三氟甲基,优选氢原子;所述C1-4烷基优选甲基、乙基、丙基、丁基;所述卤原子选自氟原子、氯原子、溴原子、碘原子。
2.根据权利要求1所述的方法,其特征在于,该方法包括以下步骤:
(1)将中间体II或III、钯催化剂、N-甲基-D葡萄胺、三乙基硅烷加入反应溶剂中,搅拌反应,过滤去除钯催化剂,加入反溶剂I中,搅拌析晶,过滤,干燥,得到福沙匹坦双葡甲胺粗品;
(2)将步骤(1)所得粗品溶于甲醇中,所得溶液加入到反溶剂II中,搅拌析晶,过滤,干燥,得到福沙匹坦双葡甲胺。
3.根据权利要求2所述的方法,其特征在于,所述反应溶剂选自甲醇、乙醇、乙二醇,或者甲醇、乙醇、乙二醇中的一种或多种与水组成的混合溶剂;所述钯催化剂选自钯碳、氢氧化钯;反溶剂I、反溶剂II独立地选自异丙醇、丙酮、2-丁酮、甲基异丁基酮、乙酸正丁酯、乙酸乙酯、乙酸丙酯、甲基叔丁基醚、乙醚、异丙醚。
4.根据权利要求2所述的方法,其特征在于,步骤(1)中,钯催化剂与中间体II或III的质量投料比为0.1~1:1,优选0.1~0.3:1;N-甲基-D葡萄胺与中间体II或III的摩尔投料比为2~3:1;三乙基硅烷与中间体II或III的摩尔投料比为1~6:1,优选2~4:1;反应溶剂与与中间体II或III的体积质量比为5~20:1,单位:ml/g;反溶剂I与与中间体II或III的体积质量比为25~60:1,单位:ml/g。
5.根据权利要求2所述的方法,其特征在于,步骤(1)中搅拌反应的时间为1~6h,反应温度为0~60℃,优选20~40℃;析晶搅拌时间为10~60min;搅拌析晶的温度为10~50℃,优选20~40℃。
6.根据权利要求2所述的方法,其特征在于,步骤(2)中甲醇与福沙匹坦双葡甲胺粗品的投料比为5~20:1,单位:ml/g;反溶剂II与福沙匹坦双葡甲胺粗品的投料比为25~60:1,单位:ml/g。
7.根据权利要求2所述的方法,其特征在于,步骤(2)的析晶搅拌时间为10~60min;析晶温度为10~50℃,优选20~40℃。
8.根据权利要求1或2所述的方法,其特征在于,该方法包括以下步骤:
(1)向反应瓶中加入中间体IIa或IIIa、N-甲基-D葡糖胺、10%钯碳、三乙基硅烷和甲醇,室温搅拌反应2小时;反应结束后,过滤去除钯碳,向所得滤液中加入异丙醇,搅拌析晶,过滤,滤饼真空干燥,得福沙匹坦双葡甲胺粗品;
(2)向反应瓶中加入福沙匹坦双葡甲胺粗品、甲醇,室温搅拌溶解;将所得溶液加入丙酮中,搅拌析晶,过滤,滤饼真空干燥得白色固体;
其中,所述中间体IIIa是指R为氢原子的中间体II,所述中间体IIa是指R均为氢原子的中间体II。
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