CN114163380A - 阿伐可泮中间体及其制备方法和用途 - Google Patents
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
- B01J31/185—Phosphites ((RO)3P), their isomeric phosphonates (R(RO)2P=O) and RO-substitution derivatives thereof
- B01J31/186—Mono- or diamide derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/822—Rhodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供一种阿伐可泮中间体(式I化合物),该化合物可以作为阿伐可泮原料或中间体以合成阿伐可泮。本发明还提供阿伐可泮中间体式I化合物的制备方法,经过3步反应得到目标产物阿伐可泮中间体式I化合物,整个路线设计新颖,避免了现有技术采用的手性拆分过程,实用性较强,且收率高,反应速度快,副产物少,非常适合工业化应用。
Description
技术领域
本发明涉及阿伐可泮,具体涉及阿伐可泮中间体及其制备方法和用途。
背景技术
阿伐可泮是美国凯莫森特里克斯股份有限公司开发的治疗严重活动性抗中性粒细胞胞浆自身抗体相关性血管炎药物。严重活动性抗中性粒细胞胞浆自身抗体相关性血管炎是一种罕见的累及小血管的全身性自身免疫性疾病。此前数十年,糖皮质激素被用于治疗严重活动性抗中性粒细胞胞浆自身抗体相关性血管炎,虽然随着治疗方法的不断优化,患者的预后得以改善,但长期使用激素产生的器官损害和其他毒性反应威胁着患者健康。阿伐可泮Ⅲ期临床试验数据表明,阿伐可泮治疗严重活动性抗中性粒细胞胞浆自身抗体相关性血管炎的患者26周缓解效果与***相似,而治疗52周持续缓解效果明显优于***。因此,阿伐可泮能减少糖皮质激素的使用甚至代替激素,将开创一个新的治疗严重活动性抗中性粒细胞胞浆自身抗体相关性血管炎的时代。
阿伐可泮结构式如下:
CN106999481A公开了阿伐可泮的制备方法,该方法不仅制备步骤冗长,而且需要使用二甲苯酰基-L-酒石酸拆分,终产物收率低。
发明内容
为了解决现有技术中的问题,本发明提供一种化合物(式I),该化合物可以作为阿伐可泮原料或中间体以合成阿伐可泮。
除特殊说明外,本发明所述份数均为重量份,所述百分比均为质量百分比。
为实现上述目的,本发明的技术方案为:
式I化合物,具有如下结构式:
其中R1为卤素;R2为COR4;R4为卤素或OC1-C6的烷氧基。
在一个实施方案中,所述卤素选自氟、氯、溴或碘;优选氟、氯或溴。
在一个实施方案中,所述OC1-C6的烷氧基选自甲氧基或乙氧基。
在一个实施方案中,R1为氟。
在一个实施方案中,R4为甲氧基。
在一个实施方案中,R1为氟;R2为COR4;R4为甲氧基。
在一个实施方案中,本发明还提供式I化合物在作为阿伐可泮原料或中间体中的用途。
在一个实施方案中,I化合物可能在阿伐可泮终产物中作为杂质出现,因此本发明还提供式I化合物在作为阿伐可泮杂质对照品中的用途。
式II化合物,具有如下结构式:
其中R1为卤素;R2为COR4;R3为硝基或氨基;R4为卤素或OC1-C6的烷氧基。
在一个实施方案中,所述卤素选自氟、氯、溴或碘;优选氟、氯或溴。
在一个实施方案中,所述OC1-C6的烷氧基选自甲氧基或乙氧基。
在一个实施方案中,R1为氟。
在一个实施方案中,R4为甲氧基。
在一个实施方案中,R1为氟;R2为COR4;R3为硝基;R4为甲氧基。
在一个实施方案中,式II化合物可能在式I化合物终产物中作为杂质出现,因此本发明还提供式II化合物在作为式I化合物杂质对照品中的用途。
在一个实施方案中,本发明所述式I化合物由式II化合物还原制得。
上述式II化合物还原制备式I化合物,涉及两个手性位置,同时还要进行硝基还原。研究发现,不同催化剂及配体对反应影响很大,一旦控制不好,就可能出现副产物多,收率低,且ee值偏低的情形。此外,反应条件也会影响产物的收率及ee值。发明人经过大量实验后发现,使用二(1,5-环辛二烯)四氟硼酸铑(I)(Rh(COD)2BF4为催化剂, (R)-Ligand 1为催化剂的配体,二氯甲烷为溶剂,在1个大气压的氢气里于20-30℃反应12-24小时,副产物较少,终产物式II化合物收率较高,且ee值高。
本发明所述(R)-Ligand 1的结构式为:
式IV化合物,具有如下通式:
其中R1为卤素。
在一个实施方案中,本发明式II化合物由式III化合物和式IV化合物偶联制得,反应式如下:
在一个实施方案中,本发明式II化合物的制备方法为:化合物III用无水丙酮溶解,加入K2CO3和溶解有化合物IV的DMF溶液,在室温搅拌反应30-40小时后,加入无水Na2SO4,然后于40-60℃继续搅拌反应2-5小时,然后分离得到化合物II。
式IV化合物可能在式II化合物终产物中作为杂质出现,因此本发明还提供式IV化合物在作为式II化合物杂质对照品中的用途。
在一个实施方案中,IV化合物由式VI化合物和式V化合物反应制得,反应式如下:
在一个实施方案中,本发明式IV化合物制备方法为:用无水THF溶解化合物V(2-氟-6-甲基苯甲酸),于低温反应槽中降温到-5~0℃后滴加草酰氯的THF溶液,加完后移到室温下搅拌反应1-3小时,反应体系降温到-5~0℃后滴加含有吡啶和化合物VI的 THF溶液,加完后移到室温继续搅拌反应3-5小时,分离得到化合物IV。
化合物III的制备方法为:氮气保护情况下,在溶解有NaH和对硝基苯乙酮的THF溶液中滴加含氯甲酸甲酯的THF溶液,然后回流2-4小时,待反应体系降温到室温,用醋酸终止反应,分离得到化合物III。
有益效果:
本发明提供一种化合物(式I),该化合物可以作为阿伐可泮原料或中间体以合成阿伐可泮。本发明整个路线设计新颖,避免了现有技术采用的手性拆分过程,实用性较强,且收率高,反应速度快,副产物少,非常适合工业化应用。本发明使用二(1,5-环辛二烯)四氟硼酸铑(I)(Rh(COD)2BF4为催化剂,(R)-Ligand 1为催化剂的配体,二氯甲烷为溶剂,在1个大气压的氢气里于20-30℃反应12-24小时手性还原制备式II化合物,终产物收率高,且ee值高。本发明经过3步反应得到阿伐可泮中间体式I化合物,总收率可达63.59%(以2-氟-6-甲基苯甲酸计)。总而言之,本发明制备方法简单,原料价廉易得,反应条件温和,不需要大型设备,终产物收率高,纯度高,适合工业化生产。
具体实施方式
下面通过具体实施例对本发明进行具体描述,在此指出以下实施例只用于对本发明进行进一步说明,不能理解为对本发明保护范围的限制,本领域的技术熟练人员可以根据上述发明内容对本发明作出一些非本质的改进和调整。本发明所用原料及试剂均为市售产品。
实施例1化合物I的合成
式II化合物(R1为氟;R2为COR4;R3为硝基;R4为甲氧基)还原制备式I化合物(R1为氟;R2为COR4;R4为甲氧基)反应路线为:
在含有二(1,5-环辛二烯)四氟硼酸铑(I)(Rh(COD)2BF4,81mg,0.2mmol)和配体(R)-Ligand 1(174mg,0.4mmol)的二氯甲烷(20mL)的反应瓶中,加入化合物II(4g,10mmol)的异丙醇溶液(40mL)。然后在1个大气压的氢气里于室温搅拌 18小时,TLC显示反应完全。反应液用200mL乙酸乙酯稀释,然后分别用饱和NaHCO3水溶液(100mL X2)、饱和NaCl水溶液(100mL X2)洗涤,有机层经无水Na2SO4干燥后减压浓缩,剩余物经硅胶柱分离(乙酸乙酯/石油醚=1/5)得到3.6g化合物I,白色固体,收率96%,ee值98.8%。H1 NMR(400MHz,CDCl3):δ(ppm):7.52(m,1H), 7.32-6.99(m,4H),6.61(m,2H),4.18(m,1H),3.76(s,3H),3.61-3.32(m,4H),2.88(m, 1H),2.46(s,3H),2.12(m,1H),1.78-1.61(m,3H).MS(m/z)371(M+1).
实施例2化合物II的合成
式II化合物(R1为氟;R2为COR4;R3为硝基;R4为甲氧基)由式III化合物(R2为COR4;R3为硝基;R4为甲氧基)和式IV化合物(R1为氟)偶联制得,反应式如下:
把4.9g(22mmol)化合物III溶解于100mL无水丙酮中,然后加入4.2g(30mmol)K2CO3,及5.5g(20mmol)化合物IV的10mL的DMF溶液,在室温搅拌36小时后,加入5g无水Na2SO4,然后于50℃继续搅拌3小时,TLC显示反应完全。反应液经减压浓缩后的残余物加入到200mL乙酸乙酯中,经饱和NaCl(100mL X2)水溶液洗涤,有机层用无水Na2SO4干燥后过滤浓缩的粗品经硅胶柱分离(乙酸乙酯/石油醚=1/10)得到6.3g化合物II,黄色固体,收率72%。黄色固体。H1 NMR(400MHz,CDCl3):δ(ppm): 8.38(d,J=8.7Hz,2H),8.01(d,J=8.7Hz,2H),7.51(m,1H),7.31-7.03(m,2H),3.87-3.60(m, 5H),2.79-2.52(m,5H),1.78-1.55(m,2H).MS(m/z)399(M+1).
实施例3化合物IV的合成
IV化合物(R1为氟)由式VI化合物和式V化合物(R1为氟)反应制得,反应式如下:
在带有磁力搅拌的250mL干燥三口烧瓶中加入50mL无水THF和0.2mL无水DMF,及3.1g(20mmol)化合物V(2-氟-6-甲基苯甲酸),于低温反应槽中降温到0℃后,滴加含1.7mL(20mmol)草酰氯的THF(15mL)溶液,加完后移到室温下搅拌2小时。反应体系降温到0℃后,滴加含有1.7mL(40mmol)吡啶和2.8g(20mmol)化合物VI 的THF(20mL)溶液,加完后移到室温继续搅拌4小时,TLC显示反应完全。加入200mL 乙酸乙酯稀释,分别用水(100mL X2)、2M的NaOH水溶液(100mL X2)洗涤、饱和NaHCO3水溶液(100mL X2)洗涤、饱和NaCl水溶液(100mL X2)洗涤,有机层经无水Na2SO4干燥后浓缩得到5g化合物IV,白色固体,收率为92%。H1 NMR(400 MHz,CDCl3):δ(ppm):9.12(s,1H),7.43(m,1H),7.21-6.96(m,2H),3.55-3.39(m,4H), 2.38(s,3H),2.20-2.14(m,2H).MS(m/z)274(M+1),276(M+1).
实施例4化合物III(2-氟-6-甲基苯甲酸)的合成
于带有磁力搅拌和氮气保护的150mL三口反应瓶中,分别加入1.2g(20mmol,60%)NaH、和3.3g(20mmol)对硝基苯乙酮的40mLTHF溶液,然后在磁力搅拌下,滴加含2.1g(22mmol)氯甲酸甲酯的20mLTHF溶液,大约10分钟加完。继续在磁力搅拌下回流3小时,TLC显示反应完全。反应体系降温到室温,用醋酸终止反应,加入200mL 乙酸乙酯稀释,然后经饱和NaCl水溶液(100mL X4)洗涤后,用Na2SO4干燥后浓缩后得到的粗品经硅胶柱分离(乙酸乙酯/石油醚=1/20)得到3.2g化合物III,黄色固体,收率为72%。H1 NMR(400MHz,CDCl3):烯醇式δ(ppm):12.22(s,1H),8.32(d,J=8.9Hz, 2H),7.96(d,J=8.9Hz,2H),5.78(s,1H),3.84(s,3H).MS(m/z)224(M+1)。
Claims (10)
3.如权利要求1或2所述化合物,其特征在于:所述卤素选自氟、氯、溴或碘;优选氟、氯或溴;所述OC1-C6的烷氧基选自甲氧基或乙氧基。
4.如权利要求1或2所述化合物,其特征在于:R1为氟;R2为COR4;R4为甲氧基。
6.权利要求1所述式I化合物在作为阿伐可泮原料或中间体中的用途;或者式I化合物在作为阿伐可泮杂质对照品中的用途。
7.权利要求2所述式II化合物在作为式I化合物杂质对照品中的用途。
8.权利要求5所述式IV化合物在作为式II化合物杂质对照品中的用途。
10.权利要求9所述式I化合物的制备方法,其特征在于:式II化合物由式III化合物和式IV化合物偶联制得,反应式如下:
化合物III用无水丙酮溶解,加入K2CO3和溶解有化合物IV的DMF溶液,在室温反应30-40小时后,加入无水Na2SO4,然后于40-60℃继续反应2-5小时,然后分离得到化合物II;IV化合物由式VI化合物和式V化合物反应制得,反应式如下:
用无水THF溶解化合物V,于低温反应槽中降温到-5~0℃后滴加草酰氯的THF溶液,加完后移到室温下反应1-3小时,反应体系降温到-5~0℃后滴加含有吡啶和化合物VI的THF溶液,加完后移到室温继续反应3-5小时,分离得到化合物IV;
所述化合物III的制备方法为:氮气保护情况下,在溶解有NaH和对硝基苯乙酮的THF溶液中滴加含氯甲酸甲酯的THF溶液,然后回流2-4小时,待反应体系降温到室温,用醋酸终止反应,分离得到化合物III。
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