CN114957106B - 药物吡非尼酮的流动相自动合成方法 - Google Patents
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Abstract
本发明涉及药物合成技术领域,具体公开了一种药物吡非尼酮的流动相自动合成方法。本发明的方法为:(1)3‑氧代戊酸乙酯与苯胺混合,室温下生成固体产物3‑氧代‑N‑苯基戊酰胺;(2)3‑氧代‑N‑苯基戊酰胺与35%‑40%的甲醛水溶液,在Cu‑壳聚糖为催化剂下,0‑30℃下发生成环反应,得到5‑甲基‑1‑苯基吡啶‑2,4(1H,3H)‑二酮;(3)5‑甲基‑1‑苯基吡啶‑2,4(1H,3H)‑二酮经还原得到产物吡非尼酮。本发明方法与传统方案相比大大降低了生产成本,与此同时实现室温条件下生产,提高了生产过程中的安全性。
Description
技术领域
本发明涉及药物合成技术领域,具体涉及一种药物吡非尼酮的流动相自动合成方法。
背景技术
吡非尼酮由日本盐野义于2008年上市,已获得美国食品药品监督管理局批准,是第一个通过重复、随机、安慰剂对照的Ⅲ期临床试验证明对特发性肺纤维化(IPF)有一定疗效的药物;且该药在肾间质纤维化、肝纤维化等纤维化疾病也有较好疗效;同时还在肾脏疾病(局灶性节段性肾小球硬化症)、肥厚性心肌病、成年人I型多发性神经纤维瘤、青少年I型多发性神经纤维瘤和丛状神经纤维瘤、糖尿病伴有肾脏疾病、子宫平滑肌瘤的Ⅱ期临床研究等方面有广泛应用。
现有的合成吡非尼酮的方法主要有两类:
(1)5-甲基吡啶-2-醇与卤代苯在金属催化剂,反应条件在120-180℃的条件下生成产物吡非尼酮。此系列反应在有机溶剂存在的条件下,反应温度较高,生产过程十分危险。
(2)三组分反应体系,虽然反应条件比较温和,但是反应副反应多,产率低,并不适合工业生产。
以上两类合成方案都存在着成本高,反应条件苛刻,产率低的缺点,由于以上因素都极大地限制了此类合成方法的实际应用,也制约了吡非尼酮作为各类疾病有效药物的推广。
发明内容
本发明的目的在于克服上述技术不足,提供一种药物吡非尼酮的流动相自动合成方法。
本申请旨在从不同的原料出发,通过新的合成路线,将原工艺中涉及的高温部分能够在流动相反应器中室温完成。在大大降低生产成本的同时,将生产过程中最关键的步骤在流动相反应器中完成,实现了连续、安全、高效地合成药物吡非尼酮。与此同时大大降低了环境污染与废弃物排放,契合我国对化工药物生产企业的环保要求。
为达到上述技术目的,本发明提供的技术方案如下:
一种药物吡非尼酮的合成方法,包括以下步骤:
(1)3-氧代戊酸乙酯(丙酰乙酸乙酯)与苯胺混合,室温下生成固体产物3-氧代-N-苯基戊酰胺;反应式如下:
进一步,所述3-氧代戊酸乙酯与苯胺的物质的量之比为1:(1.2-1.5),优选物质的量之比为1:1.2;
(2)3-氧代-N-苯基戊酰胺与35wt%-40wt%的甲醛水溶液(福尔马林),在Cu-壳聚糖为催化剂下,0-30℃(优选温度25-30℃)下发生成环反应,得到5-甲基-1-苯基吡啶-2,4(1H,3H)-二酮;反应式如下:
进一步,所述3-氧代-N-苯基戊酰胺与甲醛的物质的量之比为1:(1.2-1.3),优选物质的量之比为1:1.2;
进一步,所述Cu-壳聚糖催化剂:由壳聚糖加入醋酸铜水溶液搅拌反应,之后洗涤干燥制得。
(3)5-甲基-1-苯基吡啶-2,4(1H,3H)-二酮经还原得到产物吡非尼酮;反应式如下:
优选的,一种药物吡非尼酮的流动相自动合成方法,包括以下步骤:
S1、3-氧代戊酸乙酯(丙酰乙酸乙酯)与苯胺按照物质的量之比为1:1.2混合,室温下生成固体产物3-氧代-N-苯基戊酰胺,直接过滤分离;
S2、调节微通道反应器的温度为0-30℃;所述微通道反应器中装载有非均相催化剂,所述非均相催化剂为Cu-壳聚糖,其由壳聚糖加入醋酸铜水溶液搅拌反应,之后洗涤干燥制得;
S3、将S1中获得的产物3-氧代-N-苯基戊酰胺溶解于四氢呋喃(THF),与35wt%-40wt%的甲醛水溶液(福尔马林),按照反应物3-氧代-N-苯基戊酰的物质的量与甲醛的物质的量之比为1:1.2加入流动相反应器中,得到5-甲基-1-苯基吡啶-2,4(1H,3H)-二酮;
S4、将S3中获得产物5-甲基-1-苯基吡啶-2,4(1H,3H)-二酮经硼氢化钠还原得到吡非尼酮粗品,过滤,使用乙酸乙酯萃取,留取有机相,柱层析获得最终产物吡非尼酮。
与现有技术相比,本发明具有的优点及有益效果包括:
1、与现有各项技术相比,本申请原料成本低,生产所需反应仪器简单,生产过程也不会对生产设备造成损失,大大降低了生产成本;
2、与现有各项技术相比,生产全部使用THF和水作为溶剂,极大的减少了生产过程中有机溶剂的使用,降低了成本,减少了污染,增加了生产过程中的安全保障;
3、与现有各项技术相比,生产过程全部在室温下完成,且热效应不明显,不需要额外控温,大大提高了生产过程的安全性。
4、与现有各项技术相比,生产过程中最关键的步骤在流动相反应器中完成,便于控制生产进度,提高生产的安全性;
5、生产过程中没有副反应发生,产物便于分离,未反应的原料都可以循环应用,降低了成本,有利环境保护。
附图说明
图1为本发明药物吡非尼酮的流动相自动合成方法的流程图。
图2为本发明实施例1制备的吡非尼酮的核磁1HNMR谱图。
图3为本发明实施例1制备的吡非尼酮的核磁13C NMR谱图。
具体实施方式
以下是申请人结合具体实施例及附图,对本发明的技术方案作进一步的描述。
图1为本发明药物吡非尼酮的流动相自动合成方法的流程图。
实施例1:一种药物吡非尼酮的流动相自动合成方法
A.取1L 3-氧代戊酸乙酯(1.012kg,7.02mol)与0.77L苯胺(0.78kg,8.424mol),加入5L容器搅拌半小时,过滤,烘干后,获得1.32kg固体产物,即3-氧代-N-苯基戊酰胺。
B.调节微通道反应器的温度为25-30℃;所述微通道反应器中装载有非均相催化剂,所述非均相催化剂由壳聚糖加入醋酸铜水溶液搅拌反应,之后洗涤干燥制得。
C.将A中制得产物全部溶解于5L THF中,得溶液1。同时向B所述微通道反应器中通入两种溶液,分别为前述溶液1,流量为5mL/min,以及溶液2:37wt%的福尔马林,流量为0.63mL/min(3-氧代-N-苯基戊酰胺与甲醛的物质的量之比为1:1.2。得到5-甲基-1-苯基吡啶-2,4(1H,3H)-二酮的THF和水的混合溶液。
D.将C中溶液加入过量的硼氢化钠(400g,约10.6mol),室温搅拌4h,过滤,使用乙酸乙酯萃取,留取有机相。
E.将D中有机相使用乙酸乙酯与正己烷体积比例为1:18柱分离,获得产物吡非尼酮湿品。
F.旋干溶剂,称重,得到产物1.212kg,6.54mol,总产率93.16%。
产物吡非尼酮核磁谱图见图2、图3,数据如下:
1H NMR(400MHz,Chloroform-d)δ7.55-7.46(m,2H),7.47-7.36(m,2H),7.14(dt,J=2.7,1.0Hz,1H),6.64(d,J=9.4Hz,1H),2.13(d,J=1.0Hz,3H).
13C NMR(100MHz,Chloroform-d)δ161.85,142.70,141.24,135.45,129.43,128.46,126.70,121.60,114.93,17.17.
Claims (5)
1.一种药物吡非尼酮的合成方法,其特征在于,包括以下步骤:
(1)3-氧代戊酸乙酯与苯胺混合,生成固体产物3-氧代-N-苯基戊酰胺;反应式如下:
(2)3-氧代-N-苯基戊酰胺与35wt%-40wt%的甲醛水溶液,在Cu-壳聚糖为催化剂下,发生成环反应,得到5-甲基-1-苯基吡啶-2,4(1H,3H)-二酮;反应式如下:
(3)5-甲基-1-苯基吡啶-2,4(1H,3H)-二酮经还原得到产物吡非尼酮;反应式如下:
所述步骤(2)在微通道反应器中反应,调节微通道反应器的温度为0-30℃,所述微通道反应器中装载有非均相催化剂Cu-壳聚糖。
2.根据权利要求1所述的药物吡非尼酮的合成方法,其特征在于,所述步骤(2)中非均相催化剂Cu-壳聚糖,其由壳聚糖加入醋酸铜水溶液搅拌反应,之后洗涤干燥制得;
所述步骤(2)为:将步骤(1)获得的产物3-氧代-N-苯基戊酰胺溶解于四氢呋喃所得溶液与35wt%-40wt%的甲醛水溶液加入微通道反应器中,得到5-甲基-1-苯基吡啶-2,4(1H,3H)-二酮。
3.根据权利要求1或2所述的药物吡非尼酮的合成方法,其特征在于,所述步骤(2)中3-氧代-N-苯基戊酰胺与甲醛的物质的量之比为1:(1.2-1.3)。
4.根据权利要求3所述的药物吡非尼酮的合成方法,其特征在于,所述步骤(1)中3-氧代戊酸乙酯与苯胺的物质的量之比为1:(1.2-1.5)。
5.根据权利要求1或2所述的药物吡非尼酮的合成方法,其特征在于,包括以下步骤:
S1、3-氧代戊酸乙酯与苯胺按照物质的量之比为1:1.2混合,生成固体产物3-氧代-N-苯基戊酰胺,直接过滤分离;
S2、调节微通道反应器的温度为0-30℃;所述微通道反应器中装载有非均相催化剂Cu-壳聚糖,所述非均相催化剂由壳聚糖加入醋酸铜水溶液搅拌反应,之后洗涤干燥制得;
S3、将S1中获得的产物3-氧代-N-苯基戊酰胺溶解于四氢呋喃,与35wt%-40wt%的甲醛水溶液,按照反应物3-氧代-N-苯基戊酰的物质的量与甲醛的物质的量之比为1:1.2加入微通道反应器中,得到5-甲基-1-苯基吡啶-2,4(1H,3H)-二酮;
S4、将S3中获得产物5-甲基-1-苯基吡啶-2,4(1H,3H)-二酮经硼氢化钠还原得到吡非尼酮粗品,过滤,使用乙酸乙酯萃取,留取有机相,柱层析获得最终产物吡非尼酮。
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WO2008157786A1 (en) * | 2007-06-20 | 2008-12-24 | Auspex Pharmaceutical, Inc. | Substituted n-aryl pyridinones as fibrotic inhibitors |
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CN111848503A (zh) * | 2020-09-10 | 2020-10-30 | 苏州富德兆丰生化科技有限公司 | 吡非尼酮的合成方法 |
CN112250620A (zh) * | 2020-11-18 | 2021-01-22 | 沈阳三九药业有限公司 | 一种吡非尼酮的合成方法 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008157786A1 (en) * | 2007-06-20 | 2008-12-24 | Auspex Pharmaceutical, Inc. | Substituted n-aryl pyridinones as fibrotic inhibitors |
CN111423366A (zh) * | 2020-04-28 | 2020-07-17 | 山东汇海医药化工有限公司 | 一种吡非尼酮的制备方法 |
CN111848503A (zh) * | 2020-09-10 | 2020-10-30 | 苏州富德兆丰生化科技有限公司 | 吡非尼酮的合成方法 |
CN112250620A (zh) * | 2020-11-18 | 2021-01-22 | 沈阳三九药业有限公司 | 一种吡非尼酮的合成方法 |
Non-Patent Citations (1)
Title |
---|
壳聚糖负载铜催化剂在有机反应中的应用研究进展;张瑶瑶等;《有机化学》;第42卷(第1期);33-53 * |
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