CN113461615A - 一种4-氟-1h-吡唑的制备方法 - Google Patents
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- RYXJXPHWRBWEEB-UHFFFAOYSA-N 4-fluoro-1h-pyrazole Chemical compound FC=1C=NNC=1 RYXJXPHWRBWEEB-UHFFFAOYSA-N 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 9
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
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- LIAWOTKNAVAKCX-UHFFFAOYSA-N hydrazine;dihydrochloride Chemical compound Cl.Cl.NN LIAWOTKNAVAKCX-UHFFFAOYSA-N 0.000 claims description 13
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 8
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- 238000009776 industrial production Methods 0.000 abstract description 4
- XHTYQFMRBQUCPX-UHFFFAOYSA-N 1,1,3,3-tetramethoxypropane Chemical compound COC(OC)CC(OC)OC XHTYQFMRBQUCPX-UHFFFAOYSA-N 0.000 abstract description 3
- 125000003226 pyrazolyl group Chemical group 0.000 abstract description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract 1
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- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 7
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- 239000002994 raw material Substances 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- CSUFEOXMCRPQBB-UHFFFAOYSA-N 1,1,2,2-tetrafluoropropan-1-ol Chemical compound CC(F)(F)C(O)(F)F CSUFEOXMCRPQBB-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
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- WNDHCIJGEKNYNF-UHFFFAOYSA-N 5-fluoro-1h-pyrazole Chemical class FC=1C=CNN=1 WNDHCIJGEKNYNF-UHFFFAOYSA-N 0.000 description 1
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- GBLBJPZSROAGMF-BATDWUPUSA-N pralsetinib Chemical compound CO[C@]1(CC[C@@H](CC1)C1=NC(NC2=NNC(C)=C2)=CC(C)=N1)C(=O)N[C@@H](C)C1=CC=C(N=C1)N1C=C(F)C=N1 GBLBJPZSROAGMF-BATDWUPUSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
- C07D231/16—Halogen atoms or nitro radicals
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Abstract
本发明公开了一种4‑氟‑1H‑吡唑的制备方法,具体的,本发明涉及利用一锅法制备4‑氟‑1H‑吡唑(化合物I)的有效方法:选用浓盐酸作为酸,Selectfluor作为氟化试剂,1,1,3,3‑四甲氧基丙烷(化合物II)经过水解、氟代关吡唑环一锅法制得4‑氟‑1H‑吡唑(化合物I)。该方法操作方便,收率稳定,适合工业化生产。
Description
技术领域
本发明涉及药物中间体合成领域,具体地说涉及一种4-氟-1H-吡唑的制备方法。
背景技术
近年来,研究和实验发现具有吡唑环为分子的关键片段的化合物,在药物研发各阶段都有广泛用途,此类化合物具有广泛的生物活性,而且吡唑环上取代位点和取代基的多样性变化使市场化的吡唑类化合物日益丰富,具有很高的实用价值。
氟原子因其强电负性,较小的原子半径,引入氟原子或含氟分子可以提高其亲脂性和代谢稳定性,经常被应用于化合物的结构优化,借以改善化合物的理化性质及药物分子的药效,毒性及代谢过程等。因此,氟代的吡唑环类化合物具有较大的作为药物研发结构优化中间体的潜力。
4-氟-1H-吡唑是一类氟代吡唑类化合物,近年来用于多种药物的研究与开发中,具有广泛的市场前景。其中4-氟-1H-吡唑作为关键分子片段的具有代表性的药物Pralsetinib(化合物IV),是Blueprint Medicines公司开发的口服RET抑制剂;该药物可用于治疗RET融合阳性非小细胞肺癌(NSCLC),2020年1月在美国已经处于III期临床试验阶段;同时该药物用于甲状腺髓样癌和其他RET改变的实体瘤患者的治疗也正在进行早期临床开发。文献Tetrahedron Letters(2010),51(21),2849-2851公开了化合物V,该化合物是一种新型2-咪唑类药物,可以作为有效的,选择性的和中枢神经***渗透性的α1A肾上腺素受体部分激动剂。
目前,文献报道的可用于大规模生产4-氟-1H-吡唑主要有以下两种方法。
方法一
专利WO2013043624A1公开了以下合成方法:
以氟乙酸乙酯为起始原料,经过水解成钠盐生成中间体氟乙酸钠;氟乙酸钠与草酰氯及DMF反应生成3-(二甲基氨基)-2-氟丙-2-烯醛;最后与二盐酸肼反应生成目标产物。此路线中,起始原料氟乙酸乙酯及第一步产物氟乙酸钠都属于高毒化学品,对身体伤害较大,操作中具有安全风险。另外此路线总收率较低,仅有20%,不适合工业化生产。
方法二
以四氟丙醇为起始原料,先与对甲苯磺酰氯反应,羟基保护后生成化合物2;-85℃超低温条件下,化合物2再与丁基锂作用发生氟消除反应后生成化合物3;化合物3再与TBFA,二乙胺反应后生成化合物4;化合物4最后与二盐酸肼反应生成目标产物。此路线共4步反应,总收率为23.7%;其中第二步与丁基锂反应需要严格控制超低温(低于-80℃),否则会有大量副产物产生,此工艺对设备要求高,因此不适合工业化生产。
发明内容
发明目的:本发明的目的是克服上述现有技术存在的不足,提供一种制备4-氟-1H-吡唑(化合物I)的改进方法,该方法原料易得、操作简便、产品纯度高(可达99%)、总收率较高(可达45%),适合大规模制备。
本发明提供了一种化合物I的制备方法,包括:
其中,酸选自浓盐酸;氟化试剂选自Selectfluor试剂;
化合物II在酸作用下与氟化试剂反应后,再加入二盐酸肼。
优选的,选用水作溶剂。
优选的,反应使用一锅法进行。
优选的,化合物II、酸、氟代试剂和二盐酸肼的摩尔比范围为1∶1~1.2∶1.0~1.5∶1.0~1.2。
优选的,化合物II在酸作用下与氟化试剂反应,反应温度范围为20℃~50℃;反应时间为1~3h。
优选的,加入二盐酸肼过程,一次性加入二盐酸肼;
优选的,加入二盐酸肼后,反应温度范围为10~30℃;反应时间为1~2h;
优选的,反应结束后,加入N-溴代丁二酰亚胺或者N-碘代丁二酰亚胺与反应产生的副产物吡唑反应,生成4-溴吡唑或者4-碘吡唑;
优选的,副产物吡唑与N-溴代丁二酰亚胺或者N-碘代丁二酰亚胺反应生成4-溴吡唑或者4-碘吡唑后,采用减压蒸馏提纯,压力范围为50~400Pa。
发明人经过对反应杂质的分析,发现反应结束后,吡唑是该路线中唯一难以除去的副产物,由于氢与氟的差异较小,通过重结晶,调节pH,以及蒸馏,都很难有效得除去杂质;反应结束经过预处理后,通过往体系中加入NBS或者NIS,吡唑与NBS或者NIS反应生成4-溴吡唑或者4-碘吡唑;由于吡唑(沸点186~188℃),4-氟吡唑(沸点193℃),4-溴吡唑(沸点250~260℃),4-碘吡唑(沸点290~300℃),利用化合物沸点差异,通过减压蒸馏的方法可以顺利得到高纯度的目标化合物,大大降低了纯化的难度,使得最终产品的纯度可以高达99%。
有益效果
本发明4-氟-1H-吡唑(化合物I)的制备方法,选用1,1,3,3-四甲氧基丙烷(化合物II)作为起始原料,原料简单易得,价格便宜;使用一锅法反应制备4-氟-1H-吡唑,与现有合成4-氟-1H-吡唑的工艺相比,具有明显的优势。现有技术方法,使用对身体伤害较大的原料,需要经过3~5步合成才能得到目标产品,生产周期长,而本方法对应10公斤级生产仅需要3天,纯化3天(现有技术工艺同等量级需要至少5周);并且本发明无需使用丁基锂等试剂,避免了苛刻的反应条件,只需使用普通的反应釜即可进行生产,降低了成本。三废量大大减少,由现有技术工艺PMI=384降低至PMI=80;本发明的方法收率高,可以达到45%以上,适合工业化生产。
说明书中涉及到的反应试剂的缩写如下所示:
NBS:N-溴代丁二酰亚胺;
NIS:N-碘代丁二酰亚胺;
Selectfluor:1-氯甲基-4-氟-1,4-二氮桥二环[2.2.2]辛烷二四氟硼酸盐;
MTBE:甲基叔丁基醚。
具体实施方式
下面结合具体实施例,进一步阐明本发明,本实施例在以本发明技术方案为前提下进行实施,应理解这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1
化合物I的制备:
28℃下,氮气保护下,将1,1,3,3-四甲氧基丙烷(1.8kg,10.96mol,1.0eq.)、139mL浓盐酸及2.75L水加至5L反应瓶中。20~30℃下搅拌反应2h。20~30℃下往反应体系中加入Selectfluor试剂(4.66kg,13.15mol,1.2eq.),20℃~30℃继续反应2h。向反应瓶中快速加入二盐酸肼(1.27kg,12.06mol,1.1eq.),加毕,反应液有无色液体变成酒红色液体,且有粘稠气泡产生,20℃~30℃下搅拌反应1h。反应体系降温至10~20℃,滴加50%NaOH水溶液(380mL),滴加完,想体系中加入3L MTBE,10~20℃下搅拌1h,垫硅藻土抽滤,滤液分液,水相用MTBE萃取后,合并有机相,干燥后,浓缩除去溶剂得粗品945g。将粗品溶于2.6L DCM中,氮气氛围下,冰水浴降温至0~10℃,往体系中加入NBS(156.3g,0.878mol),加完0~10℃下搅拌反应2~3h。LC-MS显示反应结束。减压浓缩除去溶剂,使用油泵减压蒸馏(100~200Pa),油温40~50℃,收集38~40℃馏分,得化合物I为无色液体380.1g,收率40.28%。纯度99%。1HNMR(400MHz,DMSO,d6)(ppm):7.41~7.39(m,2H)。(ESI-TOF)m/z:[M+H]+calcdfor C3H3N2F:86;found:87。
实施例2
化合物I的制备:
本实施例操作参照实施例1化合物I的制备方法,原料采用不同的投料量,反应结束后加入NBS或者NIS与反应产生的副产物吡唑反应,纯化后得到的结果列于下表1。
表1
Claims (9)
2.根据权利要求1所示的制备方法,其特征在于:选用水作溶剂。
3.根据权利要求1或者权利要求2所述的制备方法,其特征在于:反应使用一锅法进行。
4.根据权利要求3所述的制备方法,其特征在于:化合物II、酸、氟化试剂和二盐酸肼的摩尔比范围为1∶1~1.2∶1.0~1.5∶1.0~1.2。
5.根据权利要求1所述的制备方法,其特征在于:化合物II在酸作用下与氟化试剂反应,反应温度范围为20℃~50℃;反应时间为1~3h。
6.根据权利要求1或者权利要求5所述的制备方法,其特征在于:加入二盐酸肼过程,一次性加入二盐酸肼。
7.根据权利要求6所述的制备方法,其特征在于,加入二盐酸肼后,反应温度范围为10~30℃;反应时间为1~2h。
8.根据权利要求1所述的制备方法,其特征在于,反应结束后,加入N-溴代丁二酰亚胺或者N-碘代丁二酰亚胺与反应产生的副产物吡唑反应,生成4-溴吡唑或者4-碘吡唑。
9.根据权利要求8所述的制备方法,其特征在于,副产物吡唑与N-溴代丁二酰亚胺或者N-碘代丁二酰亚胺反应生成4-溴吡唑或者4-碘吡唑后,采用减压蒸馏提纯。
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