CN1071161A - 1,5-二芳基吡唑抗炎剂的配向合成 - Google Patents
1,5-二芳基吡唑抗炎剂的配向合成 Download PDFInfo
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- 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
- C07D231/12—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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
- C07D307/58—One oxygen atom, e.g. butenolide
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Abstract
本发明提供了一种制备1,5-二芳基吡唑抗炎剂
的方法。将6-芳基-4,6-二氧代己酸用乙酐或乙酰
氯处理,得到烯醇内酯,将其加入甲基羟基胺中得到
二酮异羟肟酸。然后,该二酮异羟肟酸用4-甲氧基
苯肼盐酸盐处理,得到1,5-二芳基吡唑。还公开了
该合成路线中的新的中间化合物。
Description
吡唑的标准合成方法包括β-二羰基化合物与肼在适度的条件下的反应。参见A.R.Katritzky在“杂环化学原理”,Academic Press,New York(1968)第139页中所介绍的方法。当肼是单取代的并且与所述β-二羰基化合物的两个羰基相连的取代基不相同时,可能有两种异构产物。虽然,1,5-二苯基吡唑在减轻炎症和抑制花生四烯酸级联反应的环氧酶合和/或脂氧酶合代谢方面具有优异的活性,但1,3-二苯基吡唑未显示这样优异的活性。
已开发了一种合成方案,通过该方案在制备1,5-二芳基吡唑时可达到高度的配向性。为了使不需要的异构体的产率减至最低,将单取代的肼与带有含羧酸部分的脂族或芳族侧链的β-二羰基化合物化合。Murray,W.等人在Synthesis,18-20(1991年1月)和美国专利NO.4,898,952中介绍了该方案。
Tepoxalin,3-[5-(4-氯苯基)-1-(4-甲氧基苯基)-3-吡唑基]-N-羟基-N-甲基丙酰胺是一种有效的花生四烯酸级联反应的环氧酶合和脂氧酶合代谢的抑制剂。参见Wachter,M.等人的美国专利NO.4,826,868(1989)和Robinson,C.的“未来的药物”15,9,202(1990)。在美国专利NO.4,898,952中公开了一种合成Tepoxalin的方法。该方法在合成中使用二氯甲烷和草酰氯。由于考虑成本和毒性,希望能够合成Tepoxalin,但在该方法的最后一步中不使用二氯甲烷或草酰氯。从最后一步中排除这些反应剂比在早先的步骤中更重要,因为早期的纯化和操作将稀释反应物流中痕量的这些化合物并且在它们达到最终产物以前而将其除去。如果在最后一步中使用它们,则最终的纯化必须除去所有痕量的这些物质。在本发明中所述的合成结构Ⅱ的方法不需要使用草酰氯。制备结构Ⅱ的方法在最后一步中也不需要使用二氯甲烷,而代之以毒性较小的醇溶剂。
因此,本发明提供了一种制备某种1,5-二芳基吡唑的方法,该方法根本不使用草酰氯而且在合成的最后一步中不使用二氯甲烷。结果,基本上消除了毒性的问题。本发明还提供了可用于合成1,5-二芳基吡唑的新的中间化合物。本发明还提供了一种制备这些新的中间体的方法。
更具体地讲,本发明涉及一种按照下列总的合成方案制备下式Ⅳ的化合物的方法,
其中R是Cl或CH3。
起始的式Ⅰ的6-芳基-4,6-二氧代己酸、6-(4-氯苯基)-4,6-二氧代己酸或6-(4-甲基苯基)-4,6-二氧代己酸可以用Murray,W.在J.Org,Chem.,55,3424(1990)中所述的方法,通过用琥珀酐使合适的苯乙酮阴离子酰化而进行合成。在本发明合成反应的第一步中,将起始的6-芳基-4,6-二氧代己酸用乙酐或乙酰氯处理,并在约50℃的温度下加热至回流,最好是保持回流约5-60分钟。此后,真空除去乙酐或乙酰氯,所得的式Ⅱ产物用合适的溶剂或溶剂偶例如乙醚或己烷/二氯甲烷进行结晶。然后将该式Ⅱ的化合物缓慢加入N-甲基羟基胺盐酸盐、胺碱例如三乙胺、Hunig′s碱,吡啶或二甲基吡啶或其它合适的胺碱和合适的溶剂例如二氯甲烷或氯仿的混合物中。需要胺碱以生成N-甲基羟基胺,后者是活性组分。该反应在约-10~20℃,最好是约0℃的温度下进行。
在加完式Ⅱ的化合物后,最好将该混合物搅拌约1-6小时并使其温热至约室温。然后,最好通过加入酸例如HCl水溶液或稀硫酸水溶液使该混合物分层,并分离开各层。溶剂层最好用酸例如HCl洗涤(一次或多次),再用盐水洗涤(一次或多次),然后将该溶剂层最好是用Na SO干燥,过滤并真空浓缩。然后将所得的式Ⅲ化合物最好是用合适的溶剂或溶剂偶例如二氯甲烷/己烷、乙醚或乙酸乙酯进行结晶。
然后将该式Ⅲ的化合物与4-甲氧基苯肼盐酸盐、胺碱例如前面所述的那些胺碱和合适的醇溶剂例如甲醇、乙醇或丙醇混合。然后最好将所得混合物进行搅拌,并在约50℃的温度下加热回流约1-24小时,更好是3-8小时。然后最好将该混合物冷至约室温并真空浓缩成残留物。将该残留物分配在合适的溶剂如乙醚或乙酸乙酯和水之间。然后分离出有机层,最好是用合适的酸洗涤(一次或多次),干燥,过滤,此后浓缩得到残留物。最后,将所得的式Ⅳ产物用合适的溶剂或溶剂偶例如乙酸乙酯/己烷、乙醚或乙醚/己烷进行结晶。
当起始化合物是6-(4-甲基苯基)-4,6-二氧代己酸时,本发明合成反应的第一步得到其中R是CH3的新的式Ⅱ化合物,5-[1-(4-甲基苯基)-1-氧代-1-乙烷-2-亚基]-2-氧代-2,3,4,5-四氢呋喃。第二步得到其中R是CH3的新的式Ⅲ化合物,6-(4-甲基苯基)-4,6-二氧代-N-羟基-N-甲基丙酰胺。最后一步得到3-[5-(4-甲基苯基)-1-(4-甲氧基苯基)-3-吡唑基]-N-羟基-N-甲基丙酰胺。
当起始化合物是6-(4-氯苯基)-4,6-二氧代己酸时,本发明合成反应的第一步得到其中R为Cl的新的式Ⅱ化合物,5-[1-(4-氯苯基)-1-氧代-1-乙烷-2-亚基]-2-氧代-2,3,4,5-四氢呋喃。第二步得到其中R为Cl的新的式Ⅲ化合物,6-(4-氯苯基)-4,6-二氧代-N-羟基-N-甲基丙酰胺。最后一步得到Tepoxalin,3-[5-(4-氯苯基)-1-(4-甲氧基苯基)-3-吡唑基]-N-羟基-N-甲基丙酰胺。
本发明还涉及可用于制备所要求的式Ⅳ化合物的新的式Ⅱ和Ⅲ的中间化合物。
在下列每个实验实施例中,熔点是在Thomas-Hoover设备上测定的并且未进行修正。在Beckman IR-B分光光度仪上记录红外光谱(IR)并用厘米的倒数表示。氢原子的核磁共振(NMR)谱在GE QE 300或IBM WP-100光谱仪上于所指明的溶剂中用四甲基硅烷作为内标进行测定。其数值以TMS的低磁场的ppm表示。在Finnigan MAT8230 Double Focusing高分辨率质谱仪上得到直接的化学电离(DCI)质谱。
实施例1:合成5-[1-(4-氯苯基)-1-氧代-1-乙烷-2-亚基]-2-氧代-2,3,4,5-四氢呋喃(步骤1)。
按照Murray,W.等人在J.Org.,Chem.,55,3424(1990)中所述的方法合成其中R为Cl的式Ⅰ化合物。通过将2.54g(0.01mol)式Ⅰ的化合物悬浮于40ml乙酐中而合成其中R为Cl的式Ⅱ化合物。将该混合物加热回流并保持回流20分钟。此时该溶液开始变暗。真空除去乙酐,所得的棕色残留物用二氯甲烷/己烷进行结晶,得到1.92g(81%)棕黄色针状物,mp150-151℃。用己烷/40% EtOAc的TLC表示为具有下列特征的单个化合物:
C12H9ClO3的分析计算值 C,60.90;H,3.84
实验值 C,60.66;H,3.79
MS(DCl):m/z=237(M+H),
IR(KBr):1827cm-1,1686cm-1,1596cm-1,
1H NMR(DMSO d6)2.8(t,2H,J=8Hz),3.5(t,2H,J=8Hz),6.9(s,1H),7.4(d,2H,J=8Hz),8.0(d,2H,J=8Hz).
实施例2:合成6-(4-氯苯基)-4,6-二氧代-N-羟基-N-甲基丙酰胺(步骤2)
如下制备其中R为Cl的式Ⅲ化合物,将步骤1制得的式Ⅱ化合物(2.36g,0.01mol)溶于CH2Cl2(40ml)中并将该溶液滴加到N-甲基羟基胺盐酸盐(1.28g,0.015mol)和Et3N(1.5g,0.015mol)于0℃的CH2Cl2(60ml)中的混合物中。加完以后,将该混合物温热至室温。然后将该混合物在室温下搅拌2小时。将20ml 10%CHl加入该混合物并分离开各层。CH2Cl2层用20ml 10%CHl洗涤一次并用20ml盐水洗涤一次。将该溶剂层用Na2SO4干燥,过滤并真空浓缩,得到黄色固体,用CH2Cl2/己烷进行结晶,得到1.96g(69%)黄色固体mp 135-137℃,它具有下列特征:
C13H14Cl NO4的分析计算值 C,55.03;H,4.98;N,4.94
实验值 C,55.06;H,5.21;N,4.82
MS(DCl):m/z=284(M+H),
IR(KBr):3163cm-1,1607cm-1,1591cm-1,
1H NMR(DMSO d6)2.7(s,4H),3.1(s,3H),6.2(s,1H),7.4(d,2H,J=8Hz),7.8(d,2H,J=8Hz),9.5(br s,1H).
实施例3:合成3-[5-(4-氯苯基)-1-(4-甲氧基苯基)-3-吡唑基]-N-羟基-N-甲基丙酰胺(步骤3)
按照下列方案制备其中R为Cl的式Ⅳ的Tepoxalin:将步骤2制得的化合物Ⅲ(1.42g,5mmol)、4-甲氧苯肼盐酸盐(0.96g,5.5mmol)和Et3N(0.8ml,5.5mmol)混合,在回流的甲醇(100ml)中搅拌6小时。将该混合物冷却并真空浓缩,然后分配在水(50ml)和乙醚(100ml)之间。乙醚层用5%HCl,2%NaHCO3和盐水洗涤,用Na2SO4干燥,过滤并浓缩至棕黄色油状物,在硅胶上进行层析并用EtOAc/己烷进行结晶,得到1.22g(62%)白色固体,mp 124-126℃。
C20H20ClN3O3的分析计算值 C,62.26;H,5.22;N,10.89
实验值 C,62.44;H,5.20;N,10.99
MS(DCl):m/z=386(M+H),
IR(KBr)3150cm-1,1660cm-1,
1H NMR(CDCl3)2.7-3.5(m,4H),3.2(s,3H),3.8(s,3H),6.3(s,1H),6.7-7.4(m,8H),10.7(br s,1H).
Claims (10)
2、根据权利要求1的方法,其中所述胺碱是三乙胺。
3、根据权利要求2的方法,其中步骤ⅱ)在溶剂存在下进行。
4、根据权利要求2的方法,其中步骤ⅲ)在溶剂存在下进行。
7、根据权利要求6的方法,其中所述式Ⅱ化合物是通过使式Ⅰ化合物与乙酐或乙酰氯反应而制备的。
8、根据权利要求6的方法,其中所述胺碱是三乙胺。
10、根据权利要求9的方法,其中所述胺碱是三乙胺。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US766,611 | 1991-09-26 | ||
US07/766,611 US5117054A (en) | 1991-09-26 | 1991-09-26 | N-hydroxy, N-methyl propanamides |
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CN1071161A true CN1071161A (zh) | 1993-04-21 |
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CN92111454A Pending CN1071161A (zh) | 1991-09-26 | 1992-09-26 | 1,5-二芳基吡唑抗炎剂的配向合成 |
Country Status (16)
Country | Link |
---|---|
US (1) | US5117054A (zh) |
EP (1) | EP0534800A3 (zh) |
JP (1) | JPH05320137A (zh) |
KR (1) | KR930005982A (zh) |
CN (1) | CN1071161A (zh) |
AR (1) | AR248396A1 (zh) |
AU (1) | AU2358592A (zh) |
CA (1) | CA2079045A1 (zh) |
FI (1) | FI924307A (zh) |
HU (1) | HUT62862A (zh) |
IL (1) | IL103173A0 (zh) |
MX (1) | MX9205491A (zh) |
NO (1) | NO923728L (zh) |
TW (1) | TW215085B (zh) |
ZA (1) | ZA927393B (zh) |
ZW (1) | ZW15092A1 (zh) |
Cited By (1)
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CN100387594C (zh) * | 2003-04-03 | 2008-05-14 | 麦克公司 | 二芳基取代的吡唑类代谢型谷氨酸受体-5调节剂 |
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US5117054A (en) * | 1991-09-26 | 1992-05-26 | Ortho Pharmaceutical Corporation | N-hydroxy, N-methyl propanamides |
FR2692575B1 (fr) * | 1992-06-23 | 1995-06-30 | Sanofi Elf | Nouveaux derives du pyrazole, procede pour leur preparation et compositions pharmaceutiques les contenant. |
DE19723631A1 (de) * | 1997-06-05 | 1998-12-10 | Consortium Elektrochem Ind | Mehrkomponentensystem zum Verändern, Abbau oder Bleichen von Lignin, ligninhaltigen Materialien oder ähnlichen Stoffen sowie Verfahren zu seiner Anwendung |
ES2232482T3 (es) * | 1999-08-03 | 2005-06-01 | Ortho-Mcneil Pharmaceutical, Inc. | Procedimiento de reparacion de 1,5-diarilpirazoles sustituidos en la posicion 3. |
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US4218478A (en) * | 1979-01-05 | 1980-08-19 | Ruiko Oiwa | Trichostatin as an antiprotozoal agent |
US4826868A (en) * | 1986-05-29 | 1989-05-02 | Ortho Pharmaceutical Corporation | 1,5-Diaryl-3-substituted pyrazoles pharmaceutical compositions and use |
US4681894A (en) * | 1986-09-26 | 1987-07-21 | Ortho Pharmaceutical Corporation | Hydroxamic acids and esters |
US4861798A (en) * | 1986-12-29 | 1989-08-29 | Bristol-Myers Company | Lipoxygenase inhibitory compounds |
US4898952A (en) * | 1987-05-29 | 1990-02-06 | Ortho Pharmaceutical Corporation | Regioselective synthesis of a 1,5-disubstituted pyrazole |
AU611437B2 (en) * | 1987-05-29 | 1991-06-13 | Ortho Pharmaceutical Corporation | Pharmacologically active 2- and 3-substituted (1',5'-diaryl-3-pyrazolyl)-n-hydroxypropanamides and method for synthesizing the same |
GB9005028D0 (en) * | 1990-03-06 | 1990-05-02 | Sandoz Ltd | Improvements in or relating to organic compounds |
US5117054A (en) * | 1991-09-26 | 1992-05-26 | Ortho Pharmaceutical Corporation | N-hydroxy, N-methyl propanamides |
-
1991
- 1991-09-26 US US07/766,611 patent/US5117054A/en not_active Expired - Lifetime
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1992
- 1992-09-14 AU AU23585/92A patent/AU2358592A/en not_active Abandoned
- 1992-09-15 IL IL103173A patent/IL103173A0/xx unknown
- 1992-09-22 JP JP4276803A patent/JPH05320137A/ja active Pending
- 1992-09-24 KR KR1019920017427A patent/KR930005982A/ko not_active Application Discontinuation
- 1992-09-24 CA CA002079045A patent/CA2079045A1/en not_active Abandoned
- 1992-09-25 HU HU9203078A patent/HUT62862A/hu unknown
- 1992-09-25 NO NO92923728A patent/NO923728L/no unknown
- 1992-09-25 ZA ZA927393A patent/ZA927393B/xx unknown
- 1992-09-25 FI FI924307A patent/FI924307A/fi not_active Application Discontinuation
- 1992-09-25 ZW ZW15092A patent/ZW15092A1/xx unknown
- 1992-09-25 MX MX9205491A patent/MX9205491A/es unknown
- 1992-09-25 AR AR92323281A patent/AR248396A1/es active
- 1992-09-26 CN CN92111454A patent/CN1071161A/zh active Pending
- 1992-09-28 EP EP19920308811 patent/EP0534800A3/en not_active Withdrawn
- 1992-10-06 TW TW081107906A patent/TW215085B/zh active
Cited By (1)
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CN100387594C (zh) * | 2003-04-03 | 2008-05-14 | 麦克公司 | 二芳基取代的吡唑类代谢型谷氨酸受体-5调节剂 |
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Publication number | Publication date |
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ZW15092A1 (en) | 1994-06-15 |
AU2358592A (en) | 1993-04-01 |
IL103173A0 (en) | 1993-02-21 |
US5117054A (en) | 1992-05-26 |
EP0534800A2 (en) | 1993-03-31 |
ZA927393B (en) | 1994-03-25 |
TW215085B (zh) | 1993-10-21 |
CA2079045A1 (en) | 1993-03-27 |
NO923728D0 (no) | 1992-09-25 |
AR248396A1 (es) | 1995-08-18 |
MX9205491A (es) | 1993-05-01 |
NO923728L (no) | 1993-03-29 |
FI924307A (fi) | 1993-03-27 |
FI924307A0 (fi) | 1992-09-25 |
HUT62862A (en) | 1993-06-28 |
JPH05320137A (ja) | 1993-12-03 |
EP0534800A3 (en) | 1993-06-16 |
HU9203078D0 (en) | 1992-12-28 |
KR930005982A (ko) | 1993-04-20 |
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