CN107176964B - 一种福沙匹坦的精制除钯工艺 - Google Patents
一种福沙匹坦的精制除钯工艺 Download PDFInfo
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- CN107176964B CN107176964B CN201610133979.9A CN201610133979A CN107176964B CN 107176964 B CN107176964 B CN 107176964B CN 201610133979 A CN201610133979 A CN 201610133979A CN 107176964 B CN107176964 B CN 107176964B
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- 238000000746 purification Methods 0.000 title description 2
- VRQHBYGYXDWZDL-OOZCZQCLSA-N fosaprepitant dimeglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NN(P(O)(O)=O)C(=O)N1 VRQHBYGYXDWZDL-OOZCZQCLSA-N 0.000 claims abstract description 57
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Classifications
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
本发明提供了一种降低福沙匹坦二甲葡胺中钯含量的方法,包括以下步骤:制备福沙匹坦二甲葡胺溶液;加入巯基硅胶除钯剂,搅拌过滤后,减压蒸馏浓缩;将含福沙匹坦的浓缩液加入适量溶剂溶解后,滴加至反溶剂中,静置析晶,干燥后得到福沙匹坦二甲葡胺成品。本发明提供的除钯方法效率较高,能把福沙匹坦成品中钯残留量从起始高ppm值降至5ppm以下,符合注射用药对于钯含量的限度要求。相对于有机磷试剂,本发明提供的除钯剂安全低毒,且通过简单的过滤即可从溶液中去除。本工艺具有显著的成本优势,适合工业化生产。
Description
技术领域
本发明属于药物化学范畴,具体涉及一种降低福沙匹坦二甲葡胺中钯含量的方法
背景技术
福沙匹坦,又名福沙吡坦,英文名Fosaprepitant。FDA批准的是Fosaprepitantdimeglumine,中文名为福沙匹坦二甲葡胺,2008年1月25日获得上市许可,用于治疗化疗诱导的恶心和呕吐及术后恶心和呕吐,规格为115mg和150mg,西林瓶包装,剂型为注射用粉针,商品名为EMEND,与阿瑞匹坦的商品名相同。同时,福沙匹坦二甲葡胺也在瑞典、捷克、葡萄牙和英国上市,商品名为IVEMEND。
福沙匹坦二甲葡胺的化学名为脱氧-1-(甲氨基)-D-山梨醇[3-[[(2R,3S)-2-[(1R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)-4-吗啉基]甲基]-2,5-二氢-5-氧代-1H-1,2,4-三唑-1-基]磷酸盐(2:1),分子式为C23H22F7N4O6P.2C7H17NO5,分子量为1004.83,其为白色至类白色粉末,有引湿性,在甲醇和水中易溶,在无水乙醇中极微溶解。它属于称作人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。福沙匹坦二甲葡胺是阿瑞匹坦口服制剂的前体药物,静脉注射后迅速转化为阿瑞匹坦。115mg福沙匹坦(相当于188mg福沙匹坦二甲葡胺)在15分钟内静脉输注至人体内,输液结束后30分钟内,福沙匹坦的血药浓度即降至或低于定量限浓度10ng/ml,福沙匹坦几乎完全转化为阿瑞匹坦。
福沙匹坦二甲葡胺的制备方法一般有两种,一种方法是按文献J.Med.Chem.2000,43:1243-1241报道,以阿瑞吡坦作为起始原料,在(三甲基硅基)氨基钠碱性环境催化作用下与焦磷酸四苄酯反应,磷酸化生成福沙匹坦二苄酯,后者再与葡甲胺反应,在钯碳催化剂作用下氢化脱磷酸而成。
还有一种方法是先把福沙匹坦二苄酯在甲醇热溶液中转化为更为稳定的福沙匹坦单苄酯,然后也是通过钯碳催化加氢反应得到目标产物,不同的是所需加氢时间较长。具体合成路线如下:
以上两种合成方法中均不可避免的使用了金属钯(钯炭)作为催化剂,而钯炭催化剂具有催化活性高、选择性好,在石油化工、精细化工和有机合成中占有举足轻重的地位。自从1872年发现钯炭对苯环上的硝基加氢还原反应具有催化作用以来,钯炭催化加氢以其流程简、转化率高、产率高和三废少等优点,引起了国内外极大的关注,氢化反应中的选择加氢以及氧化反应中选择氧化生产乙醛、醋酸乙烯、甲基丙烯酸甲酯均广泛采用和开发钯催化剂。对石油重整反应钯也是常选取的催化剂组分之一。
在制药工业中,钯属于毒性较大的重金属(2B亚组)需要严格控制药品中的残留量,参照ICH Q3D,EMEA关于金属催化剂或金属试剂残留量限度规定的指导原则((EMEA2008年2月21日颁布GUIDELINE ON THE SPECIFICATION LIMITS FOR RESIDUES OF METALCATALYSTS OR METAL REAGENTS)以及USP PF 37(3)Elemental Impurities--Limits andprocedure等限度要求口服制剂不超过10ug/g,注射剂不超过1ug/g,吸入剂不超过0.1ug/g。本品每日最大给药量为150mg(以福沙匹坦二甲葡胺计245.3mg静脉滴注),一般除了严格控制重金属含量外,还需要将钯残留最高限度控制为5ppm甚至更低。
常见的钯清除的方法有蒸馏、过滤、吸附,鳌合和重结晶等,然而由于福沙匹坦二甲葡胺的热不稳定性,应用这些方法来除钯具有一些严重的弊端,如活性药物成分的流失,产品降解,除钯效率低下,葡甲胺流失等。因此需要寻求更为合理的除钯方法,建立适合本品的可行除钯工艺。
默克公司在申请号为200580038036.8,公开号为CN101056672A的中国发明专利中采用了三烷基磷法除钯,将含有福沙匹坦二甲葡胺的甲醇溶液在室温20℃下与三烷基膦作用过夜,以除去催化剂钯。在其具体实施例中,使用了三正丁基膦(每克钯碳20~100uL)。由于使用量的三丁基膦较多,后续重结晶时所用反溶剂为乙腈,而三丁基膦在其中的溶解度很低,容易有残留,而且三丁基膦具有中等毒性,大鼠口服半数致死量(LD50)为750mg/kg,因此该法对药品的安全性有一定影响。
为了克服上述技术的缺点,江苏奥赛康药业股份有限公司采用三丁基膦和三苯基膦联用法,在公开号为CN102838634A的中国发明专利中以每克钯碳用0.5~1.5ug三苯基膦和0.5~2uL三丁基膦联合使用处理福沙匹坦二甲葡胺的甲醇水溶液(16:1),同样也需要室温下氩气保护搅拌过夜。除钯完毕先浓缩4倍再用乙腈做反溶剂重结晶,该法除钯效果较好(低于1ppm),相比单独用三丁基膦和三苯基膦除钯的钯残留下降了10倍多,但残留的三苯基膦和三丁基膦均还有0.02~0.11%,考虑到福沙匹坦二甲葡胺的静脉滴注给药方式,该法仍存在一定的安全隐患。
上述除钯方法的改进提示了开发出更安全、高效,低毒的方法越来越迫切,因此本发明着重开发用量更低的新型树脂吸附除钯工艺。
发明内容
本发明在于克服现有技术的不足,提供一种安全、高效,低毒的福沙匹坦二甲葡胺中的钯去除方法。
本发明所述的福沙匹坦二甲葡胺,具有如式(Ι)所示结构:
本发明提供了一种降低福沙匹坦二甲葡胺中钯含量的方法,所述方法包括以下步骤:
(1)制备福沙匹坦二甲葡胺溶液;
(2)加入巯基硅胶除钯剂,搅拌过滤后,减压蒸馏浓缩;
(3)将含福沙匹坦的浓缩液加入适量溶剂1溶解后,滴加至反溶剂2中,静置析晶,干燥后得到福沙匹坦二甲葡胺成品;其中所述的溶剂1选自甲醇、水或甲醇水的混合物;反溶剂2选自丙酮、异丙醇、无水乙腈、无水乙醇或其混合物。
上述方法步骤(1)中,可以是将已合成好的福沙匹坦二甲葡胺粗品溶于合适的溶剂制备得到福沙匹坦二甲葡胺溶液;或是福沙匹坦二苄酯和葡甲胺(化学名:N-甲基-D-葡萄糖胺)在钯碳催化氢化后的反应液;或是福沙匹坦单苄酯和葡甲胺(化学名:N-甲基-D-葡萄糖胺)在钯碳催化氢化后的反应液。其中合适的溶剂选自水、甲醇或其混合溶剂,优选为水和甲醇的混合溶剂。所述反应液可以未经过脱溶剂和去钯处理直接用于后续步骤的处理,也可先经纯化处理后再用于后续步骤的处理,优选未经脱溶剂和去钯处理直接用于后续步骤的处理。
本发明的一个具体实施方式中,其中所述的福沙匹坦二甲葡胺溶液通过以下方式制备:将福沙匹坦二苄酯和葡甲胺在水/甲醇混合溶剂中以10%Pd/C催化剂作用下氢化成盐,反应后得到福沙匹坦二甲葡胺溶液,所述溶液未经过脱水、脱甲醇和其他去钯处理直接用于后续步骤的处理。
上述方法步骤(2)中,本发明所述的巯基硅胶除钯剂为金属吸附剂。金属吸附剂具有较高的吸附性,对所有常用的贵重金属的不同氧化态都适用。在多种金属离子存在的情况下,可以选择性的回收所需金属。其使用的溶剂和pH范围很广,在水溶液和有机溶液中均可使用。具有吸附速度较快,热稳定性、物理稳定性、化学稳定性和机械稳定性等优点。同时,也可用来贵重金属回收。目前,可被金属吸附剂吸附的金属范围包括:Na、Mg、Al、K、Ca、Sc、Ti、V、Cr、Mn、Fe、Co、Ni、Cu、Zn、Ga、Ge、As、Sr、Zr、Nb、Mo、Ru、Rh、Pd、Ag、Cd、In、Sn、Sb、Cs、Ba、La、Hf、Ta、W、Re、Os、Ir、Pt、Au、Hg、Ti、Pb、Bi、Ce和U等。
本发明所述的带有巯基的硅胶吸附剂选自以下的材料:SiliaBond胺、SiliaBond二元胺、SiliaBond三胺四乙酸、SiliaBond硫醇、SiliaBond硫脲、SiliaBond溴丙烷、SiliaBond二硫三嗪;优选SiliaBond硫醇,其别名为JYG-01-Ⅱ,结构式如下所示(黑圈表示硅胶基质):
众所周知,福沙匹坦二甲葡胺的残留钯的去除有一定的难度。首选是福沙匹坦二甲葡胺在制备工程中所使用的钯碳催化剂用量比较高(5~40%),导致反应液的钯含量一般在1000ppm以上;其次福沙匹坦与葡甲胺按照摩尔数形成1:2的复合盐结构,除钯过程和后续重结晶时也要维持稳定的1:2比例才能保证药品在质控的pH范围内,再次通过三正丁基膦单独使用或与三苯基膦联合使用的方式来除钯,容易在成品中会有残留,不能保证产品的安全。发明人曾采用活性炭、硅藻土、活性白土或氧化铝鞥作为除钯剂(10~20%),将福沙吡坦二甲葡胺粗品溶于醇溶剂中搅拌除钯,然后以无水乙醇和无水乙腈的混合溶剂作为反溶剂进行重结晶,但多次试验证明这些方法无法将钯残留限度降低到5ppm以下。最后,意外发现采用巯基硅胶特别是JYG-01-Ⅱ,可以通过本发明所述的方法可以简单,高效,安全地将钯残留量降至5ppm以下。
上述方法步骤(2)中,所述除钯剂的用量为福沙匹坦二甲葡胺重量的10~500%,优选为福沙匹坦二甲葡胺重量的20~100%。
上述方法步骤(2)中,所述加入除钯剂后的搅拌温度为20~35℃,搅拌时间为0.5~30h。优选加入除钯剂后的搅拌温度为25~30℃,搅拌时间为1~6h。
上述方法步骤(2)中,过滤过程可以是先经过0.45~5μm初过滤再经过0.22μm滤膜过滤,也可以直接经过0.22μm滤膜过滤,优选经0.22μm聚四氟乙烯材质的有机滤膜过滤。
上述方法步骤(3)中,用于溶解福沙匹坦二甲葡胺浓缩液的溶剂1选自甲醇、水或甲醇与水的混合溶液,优选的溶剂为甲醇或甲醇水溶液,水含量不得高于50%;用于重结晶的反溶剂2选自丙酮、异丙醇、无水乙醇、无水乙腈中的一种或几种,优选的溶剂为丙酮和异丙醇,更优选为丙酮。
上述方法步骤(3)中,重结晶的溶剂1和反溶剂2的体积比为1:1~1:10,优选的体积比为1:3~1:6,最优选的比例为1:5。
本发明的一个具体实施方式中,其中用于溶解福沙匹坦二甲葡胺浓缩液的溶剂1为甲醇,用于重结晶的溶剂2为丙酮,两者的体积比为1:5,在氮气保护下将福沙匹坦二甲葡胺甲醇溶液滴加至丙酮中析晶。将结晶产物固液分离,真空干燥,即得到福沙匹坦二甲葡胺原料药成品,检测钯残留量远远低于5ppm,符合注射用药对于钯含量的限度要求。
与现有技术相比,本发明提供的除钯方法效率较高,除钯吸附剂不仅价格低廉,去除简单,对福沙匹坦二甲葡胺的吸附也很低;福沙匹坦二甲葡胺原料药的pH控制在7.0~8.5之间;葡甲胺含量也稳定在37.0~41.0%。钯残留量从起始高ppm值降至5ppm以下,符合注射用药对于钯含量的限度要求。相对于有机磷试剂,本发明提供的除钯剂安全低毒,且通过简单的过滤即可从溶液中去除。因此本工艺具有显著的成本优势,适合工业化生产。
具体实施方式
为便于理解,以下通过具体的实施例对本发明进行详细的描述。需要特别指出的是,具体事例仅仅是为了说明,显然本领域的普通技术人员可以根据本发明说明,在本发明的范围内对本发明做出各样的修正。
实施例1 福沙匹坦二甲葡胺的制备
将15.0g福沙匹坦二苄酯、9.2g葡甲胺、4.7g 10%Pd/C、24mL Mili-Q水,300mL甲醇投入加氢釜中,0.38~0.42Mpa,18~22℃下氢化2小时。反应结束后,加氢液经0.22μm聚四氟乙烯滤膜过滤,加入15g JYG-01-Ⅱ(购自苏博科能公司),25℃搅拌18小时。除钯结束后,除钯液经0.22μm聚四氟乙烯滤膜过滤,适量甲醇洗涤。减压蒸馏除去甲醇和水得到浓缩液,再用80mL甲醇溶解,氮气保护下滴加至400mL丙酮中,固液分离,真空干燥,得到16.0g福沙匹坦二甲葡胺成品。
钯含量的检测方法:原子吸收光谱法:
(1)检测条件
测定吸收线:247.6nm
狭缝宽度:0.7nm
背景校正方式:塞曼效应
空心阴极灯电流:10.0mA
积分方式:峰面积
积分时间:5.0s
表石墨炉升温程序
<u>No</u> | <u>Type</u> | <u>温度(℃)</u> | <u>坡升时间(s</u>) | <u>保留时间(s)</u> |
<u>1</u> | <u>Drying</u> | <u>110</u> | <u>1</u> | <u>30</u> |
<u>2</u> | <u>Drying</u> | <u>130</u> | <u>15</u> | <u>30</u> |
<u>3</u> | <u>Pyrolysis</u> | <u>900</u> | <u>10</u> | <u>30</u> |
<u>4</u> | <u>Atomize</u> | <u>2300</u> | <u>0</u> | <u>5</u> |
<u>5</u> | <u>Cleanout</u> | <u>2450</u> | <u>1</u> | <u>5</u> |
(2)标准曲线
标准品的配制:取Pd标准溶液(Merck,1000μg/ml)1.0ml,用0.2%HNO3溶液稀释至100ml容量瓶(10μg/ml),再取1.0ml上述溶液,用0.2%HNO3溶液稀释至10ml容量瓶,做为储备液(1μg/ml)。取上述储备液适量,用0.2%HNO3溶液稀释至每ml含钯10、20、30、40、50ng的溶液作为系列标准溶液,精密量取20μl注入石墨炉原子化器中,测量吸收度,同时做试剂空白。
标准曲线绘制:以浓度为x轴,峰面积为y轴,按非线性过零点方式绘制标准曲线。
(3)供试品残留量测定:
取供试品约0.15g,精密称定,置聚四氟乙烯罐中,加入6.0ml硝酸,1.0ml过氧化氢,于微波消解仪中消化,消解完全后置电热板上加热去酸,近干后,用0.2%HNO3洗入20ml容量瓶中。精密量取20μl注入石墨炉原子化器中,测量吸收度,同时做试剂空白。按上述标准曲线计算含量原子吸收法检测,不得过5ppm。
实施例2 福沙匹坦二甲葡胺的制备
将15.0g福沙匹坦二苄酯、9.2g葡甲胺、4.7g 10%Pd/C、24mL Mili-Q水,300mL甲醇加入到加氢釜中,0.38~0.42Mpa,18~22℃下氢化2小时。反应结束后,加氢液经0.22μm聚四氟乙烯滤膜过滤,加入15g JYG-01-Ⅱ,25℃搅拌24小时。除钯结束后,除钯液经0.22μm聚四氟乙烯滤膜过滤,适量甲醇洗涤。减压蒸馏除去甲醇和水,再用80mL甲醇溶解,氮气保护下滴加至400mL丙酮中,固液分离,真空干燥,得到16.0g福沙匹坦二甲葡胺成品。取适量福沙匹坦二甲葡胺样品,测定钯残留。按照实施例1中的ICP-MS方法测定,钯含量为4.1ppm。
实施例3 福沙匹坦二甲葡胺的制备
将15.0g福沙匹坦二苄酯、9.2g葡甲胺、4.7g 10%Pd/C、24mL Mili-Q水,300mL甲醇加入到加氢釜中,0.38~0.42Mpa,18~22℃下氢化2小时。反应结束后,加氢液经0.22μm聚四氟乙烯滤膜过滤,加入15g JYG-01-Ⅱ,30℃搅拌18小时。除钯结束后,除钯液经0.22μm聚四氟乙烯滤膜过滤,适量甲醇洗涤。减压蒸馏除去甲醇和水,再用80mL甲醇溶解,氮气保护下滴加至400mL丙酮中,固液分离,真空干燥,得到16.0g福沙匹坦二甲葡胺成品。取适量福沙匹坦二甲葡胺样品,测定钯残留。按照实施例1中的方法测定,钯含量为4.0ppm。
实施例4 福沙匹坦二甲葡胺的制备
将15.0g福沙匹坦二苄酯、9.2g葡甲胺、4.7g 10%Pd/C、24mL Mili-Q水,300mL甲醇加入到加氢釜中,0.38~0.42Mpa,18~22℃下氢化2小时。反应结束后,加氢液经0.22μm聚四氟乙烯滤膜过滤,加入15g JYG-01-Ⅱ,30℃搅拌24小时。除钯结束后,除钯液经0.22μm聚四氟乙烯滤膜过滤,适量甲醇洗涤。减压蒸馏除去甲醇和水,再用80mL甲醇溶解,氮气保护下滴加至400mL丙酮中,固液分离,真空干燥,得到16.0g福沙匹坦二甲葡胺成品。取适量福沙匹坦二甲葡胺样品,测定钯残留。按照实施例1中的方法测定,钯含量为3.5ppm。
实施例5 福沙匹坦二甲葡胺的制备
将15.0g福沙匹坦二苄酯、9.2g葡甲胺、4.7g 10%Pd/C、24mL Mili-Q水,300mL甲醇加入到加氢釜中,0.38~0.42Mpa,18~22℃下氢化2小时。反应结束后,加氢液经0.22μm聚四氟乙烯滤膜过滤,加入30g JYG-01-Ⅱ,25℃搅拌18小时。除钯结束后,除钯液经0.22μm聚四氟乙烯滤膜过滤,适量甲醇洗涤。减压蒸馏除去甲醇和水,再用80mL甲醇溶解,氮气保护下滴加至400mL丙酮中,固液分离,真空干燥,得到15.6g福沙匹坦二甲葡胺成品。取适量福沙匹坦二甲葡胺样品,测定钯残留。按照实施例1中的方法测定,钯含量为2.5ppm。
实施例6 福沙匹坦二甲葡胺的制备
将15.0g福沙匹坦二苄酯、9.2g葡甲胺、4.7g 10%Pd/C、24mL Mili-Q水,300mL甲醇加入到加氢釜中,0.38~0.42Mpa,18~22℃下氢化2小时。反应结束后,加氢液经0.22μm聚四氟乙烯滤膜过滤,加入30g JYG-01-Ⅱ,30℃搅拌24小时。除钯结束后,除钯液经0.22μm聚四氟乙烯滤膜过滤,适量甲醇洗涤。减压蒸馏除去甲醇和水,再用80mL甲醇溶解,氮气保护下滴加至400mL丙酮中,固液分离,真空干燥,得到15.6g福沙匹坦二甲葡胺成品。取适量福沙匹坦二甲葡胺样品,测定钯残留。按照实施例1中的方法测定,钯含量为1.5ppm。
实施例7 福沙匹坦二甲葡胺的制备
将15.0g福沙匹坦二苄酯、9.2g葡甲胺、4.7g 10%Pd/C、26mL Mili-Q水,300mL甲醇加入到加氢釜中,0.33~0.42Mpa,18~22℃下氢化2小时。反应结束后,加氢液经0.22μm聚四氟乙烯滤膜过滤后等分成两份:一份加入4.5g硅藻土,20~25℃搅拌16小时除钯,另一份不除钯。除钯液经0.22μm聚四氟乙烯滤膜过滤,适量甲醇洗涤。减压蒸馏除去甲醇和水,再用50mL甲醇溶解,氮气保护下滴加至250mL丙酮中,固液分离,真空干燥,得到7.95g福沙匹坦二甲葡胺成品,不除钯的样品减压蒸馏除去甲醇和水,再用50mL甲醇溶解,氮气保护下滴加至250mL丙酮中,固液分离,真空干燥,得到7.7g福沙匹坦二甲葡胺成品。取适量福沙匹坦二甲葡胺样品,测定钯残留。按照实施例1中的方法测定,除钯样品的钯含量为99.8ppm,不除钯的粗品的钯含量为97.7ppm。
实施例8 福沙匹坦二甲葡胺的制备
将15.0g福沙匹坦二苄酯、9.2g葡甲胺、4.7g 10%Pd/C、26mL Mili-Q水,300mL甲醇加入到加氢釜中,0.33~0.42Mpa,18~22℃下氢化2小时。反应结束后,加氢液经0.22μm聚四氟乙烯滤膜过滤后等分成三份:一份加入1.0g硅藻土,20~25℃搅拌16小时除钯(A);一份采用三丁基膦除钯,加入0.2mL三丁基膦,20度搅拌过夜(B);另一份不除钯(C)。A除钯液经0.22μm聚四氟乙烯滤膜过滤,适量甲醇洗涤。减压蒸馏除去甲醇和水,再用33mL甲醇溶解,氮气保护下滴加至165mL丙酮中,固液分离,真空干燥,得到3.3g福沙匹坦二甲葡胺成品;B除钯液经0.22μm聚四氟乙烯滤膜过滤,适量甲醇洗涤。减压蒸馏除去甲醇和水,再用33mL甲醇溶解,氮气保护下滴加至165mL丙酮中,固液分离,真空干燥,得到1.1g福沙匹坦二甲葡胺成品;C不除钯的样品减压蒸馏;除去甲醇和水,再用33mL甲醇溶解,氮气保护下滴加至165mL丙酮中,固液分离,真空干燥,得到5.7g福沙匹坦二甲葡胺成品。取适量福沙匹坦二甲葡胺样品,测定钯残留。按照实施例1中的方法测定,A除钯样品的钯含量为90.9ppm,B除钯样品的钯含量为12.5ppm;C不除钯的粗品的钯含量为95.6ppm。
Claims (1)
1.一种降低福沙匹坦二甲葡胺中钯含量的方法,所述方法包括以下步骤:
将15.0g福沙匹坦二苄酯、9.2g葡甲胺、4.7g10%Pd/C、24mL Mili-Q水,300mL甲醇加入到加氢釜中,0.38~0.42 MPa ,18~22℃下氢化2小时;反应结束后,加氢液经0.22μm聚四氟乙烯滤膜过滤,加入30g SiliaBond硫醇JYG-01-Ⅱ,30℃搅拌24小时;除钯结束后,除钯液经0.22μm聚四氟乙烯滤膜过滤,适量甲醇洗涤;减压蒸馏除去甲醇和水,再用80mL甲醇溶解,氮气保护下滴加至400mL丙酮中,固液分离,真空干燥,得到15.6g福沙匹坦二甲葡胺成品。
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