CN111518019B - 一种棕榈酸帕里哌酮中间体的制备方法 - Google Patents
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Abstract
本发明涉及一种棕榈酸帕里哌酮中间体的制备方法。本发明涉及一种如式二所示结构的棕榈酸帕利哌酮中间体合成方法，该方法能够极大提高此类中间体纯度及收率，从而减少棕榈酸帕利哌酮的纯化操作，在棕榈酸帕利哌酮的合成过程中，首次利用有机路易斯酸做催化剂完成傅克反应，将制备棕榈酸帕利哌酮中间体的收率提高2.5倍以上。
Description
技术领域
本发明涉及一种棕榈酸帕利哌酮中间体的制备方法。
背景技术
棕榈酸帕利哌酮是由强生公司开发上市，其注射剂为长效的新型抗精神分裂症药物。帕利哌酮是利培酮的主要代谢产物。其作用机制尚不清楚，但目前认为是通过对中枢多巴胺2(D2)受体和5-羟色胺2(5HT2A)受体拮抗的联合作用介导的。帕利哌酮也是α1和α2肾上腺素能受体以及H1组胺受体的拮抗剂，这可能是该药物某些其他作用的原因。帕利哌酮与胆碱能毒蕈碱受体或β1-和β2-肾上腺素受体无亲和力。在体外，(+)-和(-)-帕利哌酮对映体的药理学作用是相似的。
棕榈酸帕利哌酮具有如式一所示的结构：
式一：棕榈酸帕利哌酮
文献US8481729B2、US7629469B2、US8940749B2、CN101014601B提供了棕榈酸帕利哌酮的几种合成方法，但这些方法的总收率均小于9％，且原料药成本很高。
发明内容
发明人发现，棕榈酸帕利哌酮是由肟化物及羟基四氢吡啶化合物缩合产生，肟化物以及羟基四氢吡啶化合物的质量和收率，直接影响到成品棕榈酸帕利哌酮的质量和收率，而肟化物的制备关键步骤为傅克工序，傅克工序反应的优劣关键又在于如何提高式二中间体的质量与收率：
式二：棕榈酸帕利哌酮中间体
其中R1代表乙酰基、甲酰基、Bn、Cbz、Fmoc、Tfa、Trt、Pht、Alloc、Teoc、Tos、PMB、Dmb等。
在制备棕榈酸帕利哌酮的各种反应路线中，都经过如式二所示结构的特殊中间体，该中间体的制备均采用路易斯酸催化的傅克反应，式二所示结构的中间体的纯度和收率会决定合成路线的总收率。
一般来说，制备棕榈酸帕利哌酮关键步骤的化合物对反应条件控制严格，本研究惊奇的发现，通过简单、温和的方式即可制备出高质量高收率的式二中间体化合物，相对于现有技术，式二中间体收率能提高2.5倍以上。
以R1＝乙酰基为例，反应式如下：
当反应采用二氯甲烷作为溶剂、三氟甲磺酸三甲基硅酯作为路易斯酸催化剂，在5±8℃条件下反应，随着反应时间延长，杂质的变化如图1所示，实验结果表明：随着反应时间增加，体系中杂质逐渐减少，纯度和收率逐渐增加。反应8h，体系仍有部分原料未反应完全，反应11h，体系已反应完全，延长反应时间至15h，收率和纯度均无明显变化。选择合适的体系温度和时间，可有效的减少棕榈酸帕利哌酮中间体的杂质含量，使得棕榈酸帕利哌酮中间体总收率提高2.5倍以上。
本发明首次成功利用有机路易斯酸(三氟甲磺酸三甲基硅酯、三氟化硼乙醚)做催化剂完成傅克反应，利用该中间体做为起始物料后续反应转化为目标产物，能够制备得到高质量的原料药，提升总体收率，减少纯化操作，节约成本。
本发明所涉及的棕榈酸帕利哌酮中间体结构中R1代表乙酰基、甲酰基、Bn、Cbz、Fmoc、Tfa、Trt、Pht、Alloc、Teoc、Tos、PMB、Dmb等；最优选乙酰基。
本发明提供的中间体制备方法中所使用的反应溶剂一般选择二氯甲烷、1.2-二氯乙烷、氯仿、四氢呋喃、1.4-二氧六环、2-甲基四氢呋喃、苯甲醚等，优选二氯甲烷、氯仿、四氢呋喃，最优选二氯甲烷。
本发明所述的的棕榈酸帕利哌酮中间体的制备方法中将间二氟苯加入有机溶剂中所采用的反应温度一般选择-20℃～20℃；优选0℃～15℃，最优选10℃～15℃；向体系中加入路易斯酸所采用的反应温度一般选择-20℃～20℃；优选0℃～15℃，最优选5℃～11℃；向体系中加入N-乙酰哌啶-4-甲酰氯所采用的反应温度一般选择25-50℃；优选30℃～45℃，最优选30℃～40℃。
本发明所述的的棕榈酸帕利哌酮中间体的制备方法中所采用的路易斯酸催化剂可以选择三氟化硼、三氟甲磺酸三甲基硅酯、四氯化锡、三氯化铝、SbF5、三氯化铁、五氯化铌等，优选三氟化硼、三氟甲磺酸三甲基硅酯、三氯化铝等，最优选三氟化硼和三氟甲磺酸三甲基硅酯。
本发明所述的的棕榈酸帕利哌酮中间体的制备方法中所采用的反应时间一般5～20小时，优选10℃～20小时，最优选11～12小时。
本发明通过简单、温和的方式，制备出高质量高收率的式二中间体化合物，在合适的体系、温度和时间条件下，有效的减少了棕榈酸帕利哌酮中间体的杂质含量，使得棕榈酸帕利哌酮中间体总收率提高2.5倍以上，利用该中间体做为起始物料，能够制备得到高质量的原料药，提升总体收率，减少纯化操作，节约生产成本。
附图说明
图1本发明方法制备中间体杂质随时间变化情况。
具体实施方式
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容，发明人已验证，下述方案在原料用量等比放大或缩小时均具有类似的结果。
实施例1：在氩气保护下，间二氟苯14.4g加入到二氯甲烷20ml中，温度降至10±5℃，分批滴加三氟甲磺酸三甲基硅酯14.17g，控制体系内温度8±3℃，向体系内加入N-乙酰哌啶-4-甲酰氯6.5g，升高体系温度至35±5℃保温反应11h，加入6mol/L盐酸溶液30ml洗涤，加入碳酸氢钠溶液30ml洗涤，加入纯化水30ml洗涤，减压浓缩获得产品7.1g，纯度98.95％。
实施例2：在氩气保护下，间二氟苯14.4g加入到二氯甲烷20ml中，温度降至10±5℃，分批滴加三氟化硼乙醚9.05g，控制体系内温8±3℃，向体系内加入N-乙酰哌啶-4-甲酰氯6.5g，升高体系温度至35±5℃保温反应11h，加入6mol/L盐酸溶液30ml洗涤，加入碳酸氢钠溶液30ml洗涤，加入纯化水30ml洗涤，减压浓缩获得产品6.7g，纯度98.42％。
实施例3：在氩气保护下，间二氟苯14.4g加入到二氯甲烷20ml中，温度降至10±5℃，分批加入三氯化铝8.5g，控制体系内温8±3℃，向体系内加入N-乙酰哌啶-4-甲酰氯6.5g，升高体系温度至35±5℃保温反应11h，加入6mol/L盐酸溶液30ml洗涤，加入碳酸氢钠溶液30ml洗涤，加入纯化水30ml洗涤，减压浓缩获得产品4.7g，纯度94.95％。
对比例1：在氩气保护下，间二氟苯14.4g加入到二氯甲烷20ml中，温度降至10±5℃，分批加入四氯化锡16.61g，控制体系内温8±3℃，向体系内加入N-乙酰哌啶-4-甲酰氯6.5g，升高体系温度至35±5℃保温反应11h，加入6mol/L盐酸溶液30ml洗涤，加入碳酸氢钠溶液30ml洗涤，加入纯化水30ml洗涤，减压浓缩获得产品2.8g，纯度88.71％。
对比例2：在氩气保护下，间二氟苯14.4g加入到二氯甲烷20ml中，温度降至10±5℃，分批加入三氯化铁10.35g，控制体系内温8±3℃，向体系内加入N-乙酰哌啶-4-甲酰氯6.5g，升高体系温度至35±5℃保温反应11h，加入6mol/L盐酸溶液30ml洗涤，加入碳酸氢钠溶液30ml洗涤，加入纯化水30ml洗涤，减压浓缩获得产品3.1g，纯度92.50％。
对比例3：在氩气保护下，间二氟苯14.4g加入到三氯甲烷20ml中，温度降至10±5℃，分批滴加三氟甲磺酸三甲基硅酯14.17g，控制体系内温8±3℃，向体系内加入N-乙酰哌啶-4-甲酰氯6.5g，升高体系温度至35±5℃保温反应11h，加入6mol/L盐酸溶液30ml洗涤，加入碳酸氢钠溶液30ml洗涤，加入纯化水30ml洗涤，减压浓缩获得产品5.6g，纯度96.54％。
对比例4：在氩气保护下，间二氟苯14.4g加入到1，2-二氯乙烷20ml中，温度降至10±5℃，分批滴加三氟甲磺酸三甲基硅酯14.17g，控制体系内温8±3℃，向体系内加入N-乙酰哌啶-4-甲酰氯6.5g，升高体系温度至35±5℃保温反应11h，加入6mol/L盐酸溶液30ml洗涤，加入碳酸氢钠溶液30ml洗涤，加入纯化水30ml洗涤，减压浓缩获得产品5.5g，纯度95.63％。
对比例5：在氩气保护下，间二氟苯14.4g加入到四氢呋喃20ml中，温度降至10±5℃，分批加入三氯化铁10.35g，控制体系内温8±3℃，向体系内加入N-乙酰哌啶-4-甲酰氯6.5g，升高体系温度至35±5℃保温反应11h，加入6mol/L盐酸溶液30ml洗涤，加入碳酸氢钠溶液30ml洗涤，加入纯化水30ml洗涤，减压浓缩获得产品2.5g稠状物，未得到产物，均为极性较小杂质。
对比例6：在氩气保护下，间二氟苯14.4g加入到1.4-二氧六环20ml中，温度降至10±5℃，分批加入四氯化锡16.61g，控制体系内温8±3℃，向体系内加入N-乙酰哌啶-4-甲酰氯6.5g，升高体系温度至35±5℃保温反应11h，加入6mol/L盐酸溶液30ml洗涤，加入碳酸氢钠溶液30ml洗涤，加入纯化水30ml洗涤，减压浓缩获得产品2.6g稠状物，未得到产物，均为极性较小杂质。
对比例7：在氩气保护下，间二氟苯14.4g加入到二氯甲烷20ml中，温度降至10±5℃，分批滴加四氯化锡16.61g，控制体系内温8±3℃，向体系内加入N-乙酰哌啶-4-甲酰氯6.5g，升高体系温度至15±5℃保温反应11h，检验浓缩的固体1.1g，纯度50.35％，主要杂质为未反应完全的原料。
Claims (1)
1.一种如式二所示的棕榈酸帕利哌酮中间体的合成方法
式二：棕榈酸帕利哌酮中间体
所述结构中的R1选自乙酰基；
所述方法包含向体系中加入路易斯酸，混合温度为5℃～11℃；
所述的路易斯酸选自三氟甲磺酸三甲基硅酯或三氟化硼乙醚；
所述方法包含向体系中加入N-乙酰哌啶-4-甲酰氯，反应温度为30℃～40℃；
所述方法包含将间二氟苯加入反应溶剂中，温度为10℃～15℃；所述反应溶剂为二氯甲烷；
所述方法的反应时间为11～12小时。
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