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CN107353303B - 一种福沙匹坦磷酸酯中间体的制备方法 - Google Patents

一种福沙匹坦磷酸酯中间体的制备方法 Download PDF

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CN107353303B
CN107353303B CN201610300890.7A CN201610300890A CN107353303B CN 107353303 B CN107353303 B CN 107353303B CN 201610300890 A CN201610300890 A CN 201610300890A CN 107353303 B CN107353303 B CN 107353303B
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aprepitant
fosaprepitant
phosphate intermediate
fosaprepitant phosphate
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CN107353303A (zh
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何先亮
张继承
栗增
黄鲁宁
陈茜
陶安平
顾虹
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Shanghai Aobo biomedical Co.,Ltd.
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Priority to US16/099,157 priority patent/US11091508B2/en
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    • 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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Abstract

本发明的目的是提供一种福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV)的制备方法，该制备方法具有原料易得，条件温和，收率高，工艺简洁等优点，降低了生产成本，适合工业化生产。具体合成方法如下所示：
Figure DDA0000985102560000011
具体的，本发明涉及一种福沙匹坦磷酸酯中间体的制备方法，其特征在于，阿瑞匹坦(Aprepitant，I)与亚磷酸酯(II)在卤代烷烃和碱的作用下在溶剂中发生磷酰化反应得到福沙匹坦关键中间体的福沙匹坦磷酸酯中间体(Fosaprepitantphosphate，IV)。其中，R1、R2各自独立地选自C1‑C7烷基或苄基。优选为甲基、乙基，苄基。

Description

一种福沙匹坦磷酸酯中间体的制备方法
技术领域
本发明涉及一种制备用于治疗和预防化疗引起的急性恶心和呕吐药物福沙匹坦二甲葡胺的关键中间体福沙匹坦磷酸酯中间体的制备方法，属于医药领域。
背景技术
阿瑞匹坦是由默沙东公司开发的作为第一个NK-1受体拮抗，它可以明显有效的预防化疗引起的急性恶心和呕吐，而其突出优点是还可以用于预防化疗中的呕吐和延迟性呕吐,但是阿瑞匹坦难溶于水，只能口服，有时呕吐患者口服给药难以实现。福沙匹坦二甲葡胺是阿瑞吡坦的前体药物，易溶于水，在体内迅速转化成阿瑞匹坦，其临床疗效和安全性与阿瑞匹坦是相当的，且是注射剂型，在治疗过程中，其可以通过直肠或静脉给药的方式代替口服，所以福沙吡坦二甲葡胺对于口服阿瑞匹坦来说是个很好的补充。
福沙匹坦二甲葡胺的化学名为：1-脱氧-1-(甲基氨基)-D-葡萄糖醇[3-[[(2R,3S)-2-[(1R)-1-[3,5-双(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]膦酸盐，其结构式如下：
Figure BDA0000985102550000011
而福沙匹坦磷酸酯作为制备福沙匹坦二甲葡胺的必备中间体的制备，是商业化中非常重要的一环，原研专利CN1075812C和WO2010018595均报道了同一种合成方法，如下式所示，即用阿瑞匹坦与焦亚磷酸四苄酯，在超低温条件下反应，以六甲基氨基钠为碱来制备福沙匹坦磷酸酯中间体。整个反应条件相对苛刻，需要利用强碱在低温下进行，工艺复杂，条件严苛，且工艺收率不高。
Figure BDA0000985102550000012
专利WO201145817报道了另一种合成方法。如下式所示，该方法是将碱和反应溶剂进行了变化，采用DMF(N,N-二甲基甲酰胺)、环丁砜、DMSO(二甲亚砜)或NMP(N-甲基吡咯烷酮)为溶剂，采用氢氧化锂，氢氧化钠，氢氧化钾，DBU或者DBN为碱制备福沙匹坦磷酸酯中间体。该条件利用高沸点溶剂，后处理产生大量废水，整个工艺环境友好度差，不适合大量商业化生产。
Figure BDA0000985102550000021
鉴于目前福沙匹坦磷酸酯中间体的制备路线较少，且成本较高，故开发工艺简洁、条件温和、收率较高的合成路线是非常必要的。
发明内容
本发明的目的是提供一种福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV)的制备方法，该制备方法原料易得，条件温和，收率高，工艺简洁，适合工业化生产。具体合成方法如下所示：
Figure BDA0000985102550000022
其中，R1、R2各自独立地选自C1-C7烷基或苄基。优选为甲基、乙基，苄基；
本发明涉及一种福沙匹坦磷酸酯中间体的制备方法，其特征在于，阿瑞匹坦(Aprepitant，I)与亚磷酸酯(II)在卤代烷烃和碱的作用下在溶剂中发生磷酰化反应得到福沙匹坦关键中间体的福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV)。
所述的卤代烷烃选自卤代甲烷类化合物，如：四氯化碳、四溴甲烷、三氯氟甲烷、三氯溴甲烷、二氯二氟甲烷、三碘甲烷。
所述的碱选自常用有机碱，如吡啶，三乙胺，二异丙基乙胺，4-二甲氨基吡啶，1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)，或常用的无机碱，如氢氧化钠，氢氧化钾，氢氧化锂，碳酸钠，碳酸钾，碳酸铯。优选为三乙胺，二异丙基乙胺，4-二甲氨基吡啶，氢氧化钠，氢氧化钾。
所述的溶剂选自常用极性溶剂，如二氯甲烷，乙腈，氯仿，四氢呋喃，甲基叔丁基醚。
所述的磷酰化反应温度为-10℃～30℃。
所述反应中阿瑞吡坦的用量与亚磷酸酯(II)的摩尔比为1比1.0到1比2.0；阿瑞吡坦用量和卤代烷烃的摩尔比为1比2.0到1比10.0；阿瑞吡坦用量和碱的摩尔比为1比1.0到1比2.0；
本发明另外提供了一种式IV化合物或其可药用盐，如式IV-1或式IV-2所示，该化合物是阿瑞匹坦(Aprepitant，I)与亚磷酸酯(II)在卤代烷烃(III)和碱的作用下在溶剂中发生磷酰化反应得到福沙匹坦关键中间体的福沙匹坦磷酸酯中间体(Fosaprepitantphosphate，IV)。
Figure BDA0000985102550000031
与现有技术相比，本发明所述的福沙匹坦磷酸酯中间体(Fosaprepitantphosphate，IV)的制备方法具有原料易得，条件温和，收率高，工艺简洁等优点，降低了生产成本，有利于工业生产。
具体实施例
为了进一步了解本发明，下面结合实施例对本发明具体实施方案进行描述，但是应当理解，这些描述只是为进一步说明本发明的特征和优点，而不是对本发明权利要求的限制。本发明使用的起始物料阿瑞吡坦可大宗采购。
实施例1：福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV，其中R1、R2为苄基)
在500mL反应瓶中加入二氯甲烷200mL和(Aprepitant，I)20g，25℃时搅拌至溶清。再依次加入亚磷酸二苄酯9.8g，四氯化碳11.5g，将反应降温至0-5℃，滴加3.79g三乙胺，保持0-10℃反应16-24小时直至TLC显示原料消失。向反应液中加入稀盐酸调节pH至中性，加入100mL水后用200mL*2次二氯甲烷萃取。合并二氯甲烷层以100mL*2次的5％NaCl溶液水洗。将二氯甲烷层以无水硫酸镁干燥后，以甲基叔丁基醚打浆，得福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV)27.5g，收率92.4％。1H NMR(400MHz,CDCl3):δ1.15-1.25(m,2H),1.45(d,3H),2.48(td,1H),2.75(d,1H),2.86(d,2H),3.2(m,1H),3.46(m,2H),3.64(m,1H),4.19(td,1H),4.30(d,1H),4.87(q,1H),5.22(m,4H),7.07(d,2H),7.12(s,2H),7.28(m,4H),7.34(m,4H),7.63(s,1H),9.44(s,1H).Mass:795.2[M+H]+。
实施例2：福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV，其中R1、R2为甲基)
在500mL反应瓶中加入甲基叔丁基醚100mL和(Aprepitant，I)10g，25℃时搅拌至溶清。再依次加入亚磷酸二甲酯3.1g和三氯溴甲烷18.6g，将反应降温至0-5℃，滴加3.6g二异丙基乙胺，反应升至20-30℃反应16-24小时直至TLC显示原料消失。向反应液中加入稀盐酸调节pH至中性，加入50mL水后用100mL*2次二氯甲烷萃取。合并二氯甲烷层以50mL*2次的5％NaCl溶液水洗。将二氯甲烷层以无水硫酸镁干燥后，以甲基叔丁基醚打浆，得福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV，其中R1、R2为甲基)10.9g，收率90.6％。1HNMR(400MHz,CDCl3)δ8.08(s,1H),7.77(q,J＝1.8Hz,1H),7.64(t,J＝2.1Hz,1H),7.37(dt,J＝3.0,1.5Hz,1H),7.31(ddd,J＝7.1,5.8,1.1Hz,2H),7.18–7.10(m,2H),5.58(d,J＝7.0Hz,1H),4.68(qt,J＝6.8,1.0Hz,1H),4.17–4.00(m,3H),3.98(dt,J＝7.0,1.0Hz,1H),3.81(d,J＝12.5Hz,1H),3.39(d,J＝10.8Hz,6H),2.93(ddd,J＝12.5,11.2,3.5Hz,1H),2.44(dt,J＝12.6,1.8Hz,1H),1.49(d,J＝6.9Hz,3H).Mass:643.1[M+H]+。
实施例3：福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV，其中R1、R2为乙基)
在500mL反应瓶中加入氯仿133mL和(Aprepitant，I)13.3g，25℃时搅拌至溶清。再依次加入亚磷酸二乙酯6.87g和三碘甲烷98.0g，将反应降温至0-5℃，滴加6.1g的4-二甲氨基吡啶，反应升至10-20℃反应16-24小时直至TLC显示原料消失。向反应液中加入稀盐酸调节pH至中性，加入130mL水后用270mL*2次二氯甲烷萃取。合并二氯甲烷层以130mL*2次的5％NaCl溶液水洗。将二氯甲烷层以无水硫酸镁干燥后，以甲基叔丁基醚打浆，得福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV，其中R1、R2为乙基)15.1g，收率90.4％。1HNMR(400MHz,CDCl3)δ8.13(s,1H),7.77(q,J＝1.7Hz,1H),7.64(q,J＝2.5,2.0Hz,1H),7.37(t,J＝1.8Hz,1H),7.31(ddd,J＝7.0,5.8,1.1Hz,2H),7.14(dd,J＝8.9,7.5Hz,2H),5.59(d,J＝6.9Hz,1H),4.73–4.64(m,1H),4.18–4.02(m,5H),4.04–3.95(m,2H),3.92–3.78(m,2H),3.64(dp,J＝12.5,8.1Hz,1H),2.94(ddd,J＝12.5,11.1,3.5Hz,1H),2.43(dt,J＝12.7,1.9Hz,1H),1.49(d,J＝6.9Hz,3H),1.20(t,J＝8.0Hz,3H),1.12(t,J＝7.9Hz,3H).Mass:671.2[M+H]+。
实施例4：福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV，其中R1、R2为苄基)
在500mL反应瓶中加入乙腈200mL和(Aprepitant，I)20g，25℃时搅拌至溶清。再依次加入亚磷酸二苄酯14.7g，四氯化碳28.9g，将反应降温至-10-0℃，滴加含有3.1g KOH的水溶液25mL，保持反应0-10℃反应16-24小时直至TLC显示原料消失。向反应液中加入稀盐酸调节pH至中性，加入100mL水后用200mL*2次二氯甲烷萃取。合并二氯甲烷层以100mL*2次的5％NaCl溶液水洗。将二氯甲烷层以无水硫酸镁干燥后，以甲基叔丁基醚打浆，得福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV)25.8g，收率88.4％。1H NMR(400MHz,CDCl3):δ1.15-1.25(m,2H),1.45(d,3H),2.48(td,1H),2.75(d,1H),2.86(d,2H),3.2(m,1H),3.46(m,2H),3.64(m,1H),4.19(td,1H),4.30(d,1H),4.87(q,1H),5.22(m,4H),7.07(d,2H),7.12(s,2H),7.28(m,4H),7.34(m,4H),7.63(s,1H),9.44(s,1H).Mass:795.2[M+H]+。
实施例5：福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV，其中R1、R2为苄基)
在500mL反应瓶中加入四氢呋喃200mL和(Aprepitant，I)20g，25℃时搅拌至溶清。再依次加入亚磷酸二苄酯12.8g，四氯化碳28.9g，将反应降温至-10-0℃，滴加含有2.5gNaOH的水溶液20mL，保持反应0-10℃反应16-24小时直至TLC显示原料消失。向反应液中加入稀盐酸调节pH至中性，加入100mL水后用200mL*2次二氯甲烷萃取。合并二氯甲烷层以100mL*2次的5％NaCl溶液水洗。将二氯甲烷层以无水硫酸镁干燥后，以甲基叔丁基醚打浆，得福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV)26.2g，收率89.8％。1H NMR(400MHz,CDCl3):δ1.15-1.25(m,2H),1.45(d,3H),2.48(td,1H),2.75(d,1H),2.86(d,2H),3.2(m,1H),3.46(m,2H),3.64(m,1H),4.19(td,1H),4.30(d,1H),4.87(q,1H),5.22(m,4H),7.07(d,2H),7.12(s,2H),7.28(m,4H),7.34(m,4H),7.63(s,1H),9.44(s,1H).Mass:795.2[M+H]+。
本发明提出的一种福沙匹坦磷酸酯中间体的制备方法已通过实施例进行了描述，相关技术人员明显能在不脱离本发明内容、精神和范围内对本文所述的福沙匹坦磷酸酯中间体的制备方法进行改动或适当变更与组合，来实现本发明技术。特别需要指出的是，所有相类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明的精神、范围和内容中。

Claims (11)

1.一种福沙匹坦磷酸酯中间体(IV)的制备方法，其特征在于，阿瑞吡坦(I)与亚磷酸酯(II)在卤代烷烃和碱的作用下在溶剂中发生磷酰化反应得到福沙匹坦磷酸酯中间体(IV)，其中R1、R2独立地选自C1-C7的烷基或苄基；
Figure FDA0002528500160000011
所述的卤代烷烃选自卤代甲烷。
2.权利要求1所述的制备方法，所述R1、R2独立地选自甲基、乙基或苄基。
3.权利要求1所述的制备方法，所述卤代甲烷为四氯化碳、四溴甲烷、三氯氟甲烷、三氯溴甲烷、二氯二氟甲烷、三碘甲烷。
4.权利要求3所述的制备方法，所述的卤代甲烷为四氯化碳、三氯溴甲烷和三碘甲烷。
5.权利要求1所述的制备方法，其特征在于，所用的碱为有机碱或无机碱，其中，
有机碱选自吡啶，三乙胺，二异丙基乙胺，4-二甲氨基吡啶，1,8-二氮杂双环[5.4.0]十一碳-7-烯中的一种；
无机碱选自氢氧化钠，氢氧化钾，氢氧化锂，碳酸钠，碳酸钾，碳酸铯中的一种。
6.权利要求5所述的制备方法，所用的碱选自三乙胺，二异丙基乙胺，4-二甲氨基吡啶，氢氧化钠，氢氧化钾。
7.权利要求1所述的制备方法，其特征在于，所述的溶剂选自二氯甲烷，乙腈，氯仿，四氢呋喃，甲基叔丁基醚。
8.权利要求1所述的制备方法，其特征在于，所述的磷酰化反应温度为-10℃～30℃。
9.权利要求1所述的制备方法，其特征在于，所述的阿瑞吡坦用量与亚磷酸酯的摩尔比为1比1.0到1比2.0。
10.权利要求1所述的制备方法，其特征在于，所述的阿瑞吡坦用量和卤代烷烃的摩尔比为1比2.0到1比10.0。
11.权利要求1所述的制备方法，其特征在于，所述的阿瑞吡坦用量和碱的摩尔比为1比1.0到1比2.0。
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