CN104672153B - 6-氟-3-羟基-2-氰基吡嗪的有机胺盐及其制备方法 - Google Patents
6-氟-3-羟基-2-氰基吡嗪的有机胺盐及其制备方法 Download PDFInfo
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- MXHTZQSKTCCMFG-UHFFFAOYSA-N n,n-dibenzyl-1-phenylmethanamine Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)CC1=CC=CC=C1 MXHTZQSKTCCMFG-UHFFFAOYSA-N 0.000 description 1
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- 229910052760 oxygen Inorganic materials 0.000 description 1
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical class ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- UDWXLZLRRVQONG-UHFFFAOYSA-M sodium hexanoate Chemical compound [Na+].CCCCCC([O-])=O UDWXLZLRRVQONG-UHFFFAOYSA-M 0.000 description 1
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- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
6‑氟‑3‑羟基‑2‑氰基吡嗪的有机胺盐的结晶性优异,可用作制备6‑氟‑3‑羟基‑2‑吡嗪酰胺的中间体。
Description
本申请是同名发明名称的中国专利申请第200880109041.7号的分案申请,原案国际申请号为PCT/JP2008/067251,国际申请日为2008年9月25日。
技术领域
本发明涉及用作制备药物的中间体的6-氟-3-羟基-2-氰基吡嗪的有机胺盐及其制备方法。
背景技术
6-氟-3-羟基-2-吡嗪酰胺(以下称为T-705)是用于预防和治疗病毒感染性疾病、特别是流感病毒感染等的化合物。已知T-705例如由6-氟-3-羟基-2-氰基吡嗪制备(专利文献1)。
作为6-氟-3-羟基-2-氰基吡嗪的制备方法,例如已知有以下方法:(1)将3,6-二氟-2-氰基吡嗪与苄醇反应后,再将反应产物脱苄基的方法;(2)对3,6-二氟-2-氰基吡嗪实施与水的反应的方法等(专利文献1)。
但是,这些已知的制备方法存在以下缺点,例如:(A)中间体3-苄基氧基-6-氟-2-氰基吡嗪是不稳定的化合物;(B)需要萃取、柱色谱法和除去溶剂等烦杂的操作;(C)反应混合物为酸性时,会产生有害的氟化氢;(D)收率低等。
近而,6-氟-3-羟基-2-氰基吡嗪可溶于水和多种有机溶剂,因此不易通过简便操作,以高收率从反应混合物中分离。
专利文献1:国际公开第01/60834号小册子
发明内容
发明要解决的课题
强烈期望更优异的制备T-705的中间体及制备该中间体的方法。
解决课题的手段
在这种情况下,本发明人经过深入研究,结果发现,6-氟-3-羟基-2-氰基吡嗪的有机胺盐具有优异的结晶性,可作为制备T-705的有用的中间体。还发现,通过将3,6-二氟-2-氰基吡嗪在碱的存在下与水反应后,加入有机胺,可以简便且高收率地制备6-氟-3-羟基-2-氰基吡嗪的有机胺盐,从而完成了本发明。
发明效果
本发明的6-氟-3-羟基-2-氰基吡嗪的有机胺盐具有优异的结晶性,可以通过简便操作,以高收率从反应混合物中分离,用作制备T-705的中间体。另外,6-氟-3-羟基-2-氰基吡嗪的有机胺盐的制备方法具有以下优点:(1)不经由不稳定的中间体,(2)不需要萃取、柱色谱法和除去溶剂等烦杂的操作,(3)不产生有害的氟化氢,(4)收率高,和(5)所得有机胺盐的纯度高等,因此本发明的方法可用作工业制备6-氟-3-羟基-2-氰基吡嗪的有机胺盐的方法。
具体实施方式
以下详细说明本发明。
在本说明书中,除非有特殊说明,否则有机胺是指三甲胺、三乙胺、三丙胺、三丁胺、三苄胺和N,N-二甲基环己胺等叔胺;二甲胺、二乙胺、二丙胺、二丁胺、二苄胺、N-苄基甲胺和二环己胺等仲胺;甲胺、乙胺、丙胺、丁胺、苄胺和苯胺等伯胺;以及吡啶等。
作为本发明化合物提供的6-氟-3-羟基-2-氰基吡嗪的有机胺盐中,优选以下的化合物。
优选有机胺是仲胺的化合物,更优选二丙胺、二丁胺、二环己胺、二苄胺或N-苄基甲胺,进一步优选二环己胺。
在本发明中,优选的制备方法可举出以下的方法。
在通过将3,6-二氟-2-氰基吡嗪在碱的存在下与水反应后,加入有机胺而制备6-氟-3-羟基-2-氰基吡嗪的有机胺盐的方法中,优选有机胺是仲胺的制备方法,更优选有机胺是二丙胺、二丁胺、二环己胺、二苄胺或N-苄基甲胺的制备方法,进一步优选有机胺是二环己胺的制备方法。
以下说明本发明的制备方法。
式[3]化合物的有机胺盐可以通过将式[1]的化合物在碱的存在下与水反应,形成式[2]的化合物,然后再与有机胺反应来制备。
以下详细说明本发明的制备方法。
[第一工序]
式[2]的化合物可以通过将式[1]的化合物在碱的存在下与水反应来制备。
该反应通常在溶剂的存在下进行,作为所用的溶剂,只要不影响反应进行,就没有特殊限定,例如可举出乙腈等腈类;苯、甲苯和二甲苯等芳烃类;二烷、四氢呋喃、乙二醇二甲醚和二甘醇二甲醚等醚类;丙酮和2-丁酮等酮类;乙醇、丙醇、2-丙醇和丁醇等醇类;N,N-二甲基甲酰胺和N,N-二甲基乙酰胺等酰胺类;以及二甲亚砜等亚砜类等。也可以使用这些溶剂的混合物。本发明的优选的溶剂可举出芳烃类、醚类、酰胺类和亚砜类,更优选酰胺类和亚砜类,进一步优选N,N-二甲基甲酰胺。溶剂的使用量没有特殊限定,但相对于式[1]的化合物,优选为1~50倍量(v/w),更优选为1~15倍量(v/w)。
该反应中所用的碱,只要是通常用于芳香族卤素化合物的亲核取代反应中的羟基化的试剂,就没有特殊限定,例如可举出二异丙基乙胺和三乙胺等有机碱;苄基三甲基氢氧化铵等氢氧化季铵;甲酸钾、甲酸钠、甲酸-三乙胺、乙酸钾、乙酸钠、乙酸-三乙胺、丙酸钠、己酸钠、苯甲酸钠和苯甲酸-三乙胺等羧酸盐;以及氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、磷酸氢二钾和磷酸三钾等无机碱。优选的碱可举出羧酸盐,更优选甲酸钾、甲酸-三乙胺、乙酸钾和乙酸-三乙胺。在本发明中,碱的使用量相对于式[1]的化合物1摩尔,为1摩尔以上,优选为1~10摩尔。
羧酸盐可以在反应体系内制备。
该反应所使用的水的使用量没有特殊限定,相对于式[1]的化合物1摩尔,为1摩尔以上,优选为1~50摩尔。
使用羧酸盐时,式[2]的化合物可以通过将式[1]的化合物在水不存在下与羧酸盐反应后,再与水反应来制备。
反应温度没有特殊限定,200℃以下即可,优选为0~150℃。
反应时间在本发明中也没有特殊限定,5分钟~50小时即可,优选为5分钟~24小时。
式[2]的化合物可以分离和精制,但优选不经过分离而直接用于后续反应。
[第二工序]
式[3]化合物的有机胺盐可以通过将式[2]的化合物与有机胺反应来制备。
该反应通常在溶剂的存在下进行,作为所用的溶剂,只要不影响反应进行,就没有特殊限定,例如可举出乙腈等腈类;苯、甲苯和二甲苯等芳烃类,二烷、四氢呋喃、乙二醇二甲醚和二甘醇二甲醚等醚类;丙酮和2-丁酮等酮类;甲醇、乙醇、丙醇、2-丙醇和丁醇等醇类;N,N-二甲基甲酰胺和N,N-二甲基乙酰胺等酰胺类;二甲亚砜等亚砜类;以及水等。也可以使用这些溶剂的混合物。优选的溶剂可举出选自芳烃类、酮类、醇类、酰胺类和亚砜类中的至少1种溶剂与水的混合溶剂,更优选芳烃类、酮类、或酰胺类与水的混合溶剂。进一步优选甲苯、丙酮、或N,N-二甲基甲酰胺与水的混合溶剂。本发明中溶剂的使用量没有特殊限定,但相对于式[2]的化合物,优选为1~100倍量(v/w),更优选为1~50倍量(v/w)。
该反应中有机胺的使用量没有特殊限定,相对于式[2]的化合物1摩尔,为1摩尔以上,优选为1~2摩尔。
反应温度没有特殊限定,150℃以下即可,优选为0~100℃。
本发明的反应时间也没有特殊限定,1分钟~50小时即可,优选为1分钟~24小时。
该反应优选在碱性条件下进行。例如优选向反应体系中添加选自氨水、氢氧化钾、氢氧化钠、乙酸钾和乙酸钠等的碱。
通过上述制备方法得到的式[3]化合物的有机胺盐可以通过过滤和收集固体成分来分离。
作为本发明的原料使用的式[1]的化合物例如可以根据专利文献1记载的方法,由3,6-二氯-2-氰基吡嗪等来制备。3,6-二氯-2-氰基吡嗪可以通过组合本身已知的方法来制备(专利文献1)。例如式[1]的化合物可以通过3-羟基-6-硝基-2-吡嗪酰胺或6-溴-3-羟基-2-吡嗪酰胺与三氯氧化磷等卤化剂反应来制备。在这些制备中,式[1]的化合物和3,6-二氯-2-氰基吡嗪可以分离和精制,但优选不经过分离而直接用于后续反应。
在由式[1]的化合物制备式[3]的化合物的方法中,专利文献1所述的制备方法的收率为46%(专利文献1;实施例II-5(a))。
与此相比,在由式[1]的化合物制备式[3]化合物的有机胺盐的制备方法中,本发明制备方法的收率为83%(实施例1-1)。
本发明制备方法的收率高,可以用作工业制备方法。
予以说明,式[2]的化合物及其盐以及式[3]的化合物包括6-氟-3-氧代-3,4-二氢-2-氰基吡嗪的互变异构体。本发明包括这样的互变异构体,另外,在本发明中可以使用水合物、溶剂合物和所有的晶形。
实施例
以下举出实施例和制备例说明本发明,但本发明并不限定于此。
DMSO-d6:二甲亚砜-D6
实施例1-1
在25~35℃下,在3,6-二氟-2-氰基吡嗪5.0g的N,N-二甲基甲酰胺溶液17.5mL中滴入乙酸钾7.83g的水溶液3.8mL,在相同温度下搅拌2小时。向反应混合物中加入氨水0.38mL,然后加入水15mL和活性碳0.38g。过滤除去不溶物,用11mL水洗涤滤饼。合并滤液和洗液,用氨水调整至pH9.4,加入丙酮15mL和甲苯7.5mL,然后滴入二环己胺7.71g,在20~30℃下搅拌45分钟。滴加水15mL,将该溶液冷却到10℃,过滤和收集沉淀,得到作为微黄白色固体产物的6-氟-3-羟基-2-氰基吡嗪的二环己胺盐9.44g。
1H-NMR(DMSO-d6)δ值:1.00-1.36(10H,m),1.56-1.67(2H,m),1.67-1.81(4H,m),1.91-2.07(4H,m),3.01-3.18(2H,m),8.03-8.06(1H,m),8.18-8.89(1H,宽峰)
实施例1-2
在5~15℃下,向3,6-二氟-2-氰基吡嗪5.0g的N,N-二甲基甲酰胺溶液17.5mL中添加乙酸4.11mL,然后滴入三乙胺7.27g,搅拌2小时。向反应混合物中加入水3.8mL和氨水0.38mL,然后加入水15mL和活性碳0.38g,过滤除去不溶物,用11mL水洗涤滤饼。合并滤液和洗液,用氨水调整至pH9.2,加入丙酮15mL和甲苯7.5mL,然后滴入二环己胺7.71g。滴加水15mL,将该溶液冷却到5℃,过滤和收集沉淀,得到作为微黄白色固体的6-氟-3-羟基-2-氰基吡嗪的二环己胺盐9.68g。
实施例2~5
与实施例1-1同样操作,得到表1所示的化合物。
[表1]
实施例编号 | 有机胺 | 实施例编号 | 有机胺 |
2 | 二丙胺 | 4 | 二苄胺 |
3 | 二丁胺 | 5 | N-苄基甲胺 |
6-氟-3-羟基-2-氰基吡嗪的二丙胺盐
1H-NMR(DMSO-d6)δ值:0.39(6H,t,J=7.5Hz),1.10(4H,六重峰,J=7.5Hz),2.30-2.38(4H,m),7.54(1H,d,J=8.3Hz)
6-氟-3-羟基-2-氰基吡嗪的二丁胺盐
1H-NMR(DMSO-d6)δ值:0.36(6H,t,J=7.3Hz),0.81(4H,六重峰,J=7.3Hz),0.99-1.10(4H,m),2.32-2.41(4H,m),7.53(1H,d,J=8.3Hz)
6-氟-3-羟基-2-氰基吡嗪的二苄胺盐
1H-NMR(DMSO-d6)δ值:4.17(4H,s),7.34-7.56(10H,m),8.07(1H,d,J=8.3Hz)
6-氟-3-羟基-2-氰基吡嗪的N-苄基甲胺盐
1H-NMR(DMSO-d6)δ值:2.57(3H,s),4.14(2H,s),7.37-7.53(5H,m),8.02-8.08(1H,m)
制备例1
向氢氧化钠37.5g的水溶液600mL中加入甲苯300mL,然后在15~25℃下加入6-氟-3-羟基-2-氰基吡嗪的二环己胺盐150g,在相同温度下搅拌30分钟。分离水层,用甲苯洗涤,加入水150mL,然后在15~30℃下滴入30%过氧化氢溶液106g,在20~30℃下搅拌1小时。加入盐酸39mL,在40~50℃下加入晶种,在相同温度下再滴加盐酸39mL。将该溶液冷却到10℃,过滤和收集沉淀,得到作为淡黄白固体的6-氟-3-羟基-2-吡嗪酰胺65.6g。
1H-NMR(DMSO-d6)δ值:8.50(1H,s),8.51(1H,d,J=7.8Hz),8.75(1H,s),13.41(1H,s)
产业实用性
本发明的6-氟-3-羟基-2-氰基吡嗪的有机胺盐的结晶性优异,可用作6-氟-3-羟基-2-吡嗪酰胺的制备中间体。
Claims (1)
1.6-氟-3-羟基-2-氰基吡嗪的二环己胺盐的制备方法,其包括在碱的存在下使3,6-二氟-2-氰基吡嗪与水反应,然后与二环己胺形成盐,其中该步骤不使用柱色谱法精制。
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CN1418220A (zh) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | 新的吡嗪衍生物或其盐、含有该衍生物或盐的药物组合物和制备二者的中间体 |
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