CN1764665A - 咪唑并吡啶－8－酮的生产方法 - Google Patents
咪唑并吡啶－8－酮的生产方法 Download PDFInfo
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- 230000036571 hydration Effects 0.000 description 1
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- ISRXMEYARGEVIU-UHFFFAOYSA-N n-methyl-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C)C(C)C ISRXMEYARGEVIU-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及通过使用NBS作为氧化剂生产7－(三烷基－甲硅烷氧基)－2，3－二甲基－8－苯基－8，9－二氢－7H－1，3a，9－三氮杂环戊二烯并[a]萘－6－酮及其相关化合物的方法。
Description
发明领域
本发明涉及一种新方法，用于医药工业中生产药物的中间体的合成。
现有技术
国际专利申请WO98/42707、WO01/72756、WO01/72757和WO02/34749公开了具有非常特异的替代模式的三环咪唑并吡啶衍生物，适合于治疗胃肠道紊乱。在上述专利申请中，已给出反应流程，其中阐明了从咪唑并吡啶-8-酮出发的终产物的合成。国际专利申请WO01/72748对这些咪唑并吡啶-8-酮有更详细的描述。在几篇文献中描述了N-溴代琥珀酰亚胺在脱氢过程中的应用，如Karmakar等，Journal of the American Chemical Society 77，55-69(1955)；Zechmeister等，Journal of the American Chemical Society 75，4493-4495(1953)和Snyder等，Journal of the American Chemical Society 71，1395-1396(1949)。
发明详述
本发明涉及一种方法，用于制备现有技术中提及化合物的关键中间体和具有相似基本结构的其它化合物。
本发明第一个方面涉及式1化合物及其盐的生产方法，
其中，
R1为氢、甲基或羟甲基，
R2为1-7C-烷基，
R3为1-7C-烷基，
R4为1-7C-烷基。
1-7C-烷基代表具有1-7个碳原子的直链或支链烷基基团。可以提及的实例是庚基、异庚基(5-甲基己基)、己基、异己基(4-甲基戊基)、新己基(3，3-二甲基丁基)、戊基、异戊基(3-甲基丁基)、新戊基(2，2-二甲基丙基)、丁基、异丁基、仲丁基、叔丁基、丙基、异丙基、乙基和甲基。
式1化合物的适合盐尤其都是酸加成盐。可特别提及的是常用无机酸和有机酸的盐。适当的是水溶性和水不溶性酸加成盐，使用的酸比如为盐酸、氢溴酸、磷酸、硝酸、硫酸、乙酸、柠檬酸、D-葡糖酸、苯甲酸、2-(4-羟基苯甲酰)苯甲酸、丁酸、磺基水杨酸、马来酸、月桂酸、苹果酸、延胡索酸、琥珀酸、草酸、酒石酸、双羟萘酸、硬脂酸、甲苯磺酸、甲磺酸或3-羟基-2-荼酸，在盐制备中具体采用等摩尔还是非等摩尔的酸取决于它是一元酸抑或是多元酸，希望形成哪种盐。
本发明化合物和它们的盐，如果被分离，例如在晶体形式中，可能含有不同量的溶剂，这为本领域的那些技术人员所已知。因此本发明还包括式1化合物的所有溶剂化物特别是所有的水化物，以及式1化合物盐的所有溶剂化物特别是所有的水化物。
本发明方法的特征在于式2化合物
经过NBS(N-溴代琥珀酰亚胺)脱氢(氧化)而成，其中R1、R2、R3和R4具有上述给出的意义。
使用NBS的脱氢(氧化)反应在惰性溶剂中进行，例如，在氯代烃如四氯化碳或二氯甲烷中，或在酮如丙酮或丁酮中，或在醚如四氢呋喃或二噁烷中，或在二甲亚砜或乙腈中。
NBS和式2化合物的反应在-70℃至+50℃之间可以容易的发生，优选为在0℃至30℃之间，随后借助于碱，优选为有机碱如胺类，例如二异丙胺，甲基-二异丙胺或特别是三乙胺。有利的是，在第一步反应中将1.0当量的NBS加入到式2化合物的溶液中，紧接着开始加入碱。
按本发明的方法制备的优选式1化合物为其中
R1为甲基，
R2为1-7C-烷基，
R3为1-4C-烷基，
R4为1-4C-烷基的化合物以及它们的盐。
按本发明的方法制备的特别优选式1化合物为其中
R1为甲基，
R2为叔丁基，
R3为甲基，
R4为甲基的化合物以及它们的盐。
式2的起始化合物可依照以下反应流程制备。
流程
式(3)的起始化合物已知于WO01/72748。按照专家已知的方法，如在碱性条件下将苯基异丝氨酸乙酯和叔丁基二甲基甲硅烷基氯反应，可以制备式(4)的甲硅烷基醚。(3)和(4)的反应优选在恰当催化剂如对甲苯磺酸存在下，同时除去水的情况下进行。最初生成的中间体亚胺接着通过使用强碱而闭环，强碱例如为叔丁醇钾、叔丁醇锂、双(三甲基甲硅烷基)氨基钠或优选为二异丙氨基锂。
式1化合物对于合成国际专利申请WO98/42707和WO01/72756中所描述的化合物而言是非常有价值的中间体。例如在国际专利申请WO98/42707流程8中作为中间体给出的8-羟基-7-氧代-7，8，9，10-四氢咪唑[1，2-h][1，7]萘啶，就是通过水解式1化合物获得，例如用盐酸水解。
以下的实施例用于更详细的阐明本发明但不是限制它。同样的，制备未详细描述的式1的其它化合物可以通过类似的方式或由本领域技术人员所熟悉的常用方法技术制备。简写min代表分钟，h代表小时，而RT指室温。
实施例
1.苯基异丝氨酸乙酯的叔丁基-二甲基-甲硅烷醚
1323克(4.06摩尔)的(R，R)-苯基异丝氨酸乙酯溶解于6.6升二氯甲烷中。向溶液中加入397.4克咪唑和724克叔丁基-二甲基-甲硅烷基氯。以上混合物在室温搅拌16小时。接着分别用6升和4升水洗涤。所得的澄清二氯甲烷层用硫酸钠干燥，过滤，减压浓缩。得到的1509克标题化合物，无需进一步纯化直接在实施例2中使用。
2.7-(叔丁基-二甲基-甲硅烷氧基)-2，3-二甲基-8-苯基-5，7，8，9-四氢-4H-1，3a，9-三氮杂-环戊二烯并[a]萘-6-酮
1509克苯基异丝氨酸乙酯的叔丁基-二甲基-甲硅烷基醚(实施例1中所得)溶解在10.5升甲苯中，再加入14克一水合对甲苯磺酸和736克2，3-二甲基-6，7-二氢-5H-咪唑并[1，2-a]吡啶-8-酮。回流下搅拌和沸腾该混合物直到所用的Dean-Stark收集器中收集了80毫升水。将混合物冷却到-15℃并加入6升的THF。向该溶液逐滴加入6升浓度为2M的二异丙氨基锂(THF/正庚烷溶液)，1小时内完成。搅拌此混合物30分钟，无需外部冷却(温度上升至-5℃)，然后用7升氯化氨的水溶液终止反应。分离两层，有机层用硫酸钠干燥后过滤。经真空除去溶剂后，分离得到1811克粗制的7-(叔丁基-二甲基-甲硅烷氧基)-2，3-二甲基-8-苯基-5，7，8，9-四氢-4H-1，3a，9-三氮杂-环戊二烯并[a]萘-6-酮。将其溶解在3.9升沸腾的甲醇中，边搅拌边冷却到-5℃。收集形成的沉淀并用1.75升冷甲醇润洗。干燥后得到558克标题化合物。母液则浓缩至1.5升并在-5℃搅拌数小时。收集所得沉淀，用0.25升甲醇润洗。得到另一部分96.5克标题化合物，总产量为654.5克(38.5％)。
3.7-(叔丁基-二甲基-甲硅烷氧基)-2，3-二甲基-8-苯基-8，9-二氢-7H-1，3a，9-三杂氮-环戊二烯并[a]萘-6酮
25克(59.1毫摩尔)的7-(叔丁基-二甲基-甲硅烷氧基)-2，3-二甲基-8-苯基-5，7，8，9-四氢-4H-1，3a，9-三氮杂-环戊二烯并[a]萘-6-酮悬浮在150毫升乙腈中。混合物置于15℃恒温器中搅拌并冷却。将10.52克(1当量)的N-溴代琥珀酰亚胺的100毫升乙腈溶液在1小时内逐滴加入上述溶液，同时保证溶液温度为15℃。当N-溴代琥珀酰亚胺滴加完成后，15℃下边搅拌边加入22.5毫升三乙胺，45分钟内完成。在15℃下继续搅拌2小时。将所得混悬物冷却至10℃后，缓缓加入138毫升水，在30分钟内完成。该悬浮物冷却至5℃后，继续搅拌30分钟然后过滤。所得黄色滤饼用125毫升甲醇/水(85∶15(体积))洗涤两次后干燥。得到标题化合物的黄色固体。
4.7-羟基-2，3-二甲基-8-苯基-8，9-二氢-7H-1，3a，9-三氮杂-环戊二烯并[a]萘-6-酮
386.5克(0.916摩尔)的7-(叔丁基-二甲基-甲硅烷氧基)-2，3-二甲基-8-苯基-8，9-二氢-7H-1，3a，9-三氮杂-环戊二烯并[a]萘-6酮悬浮于1.4升甲醇中，并用冰浴冷却至10℃。然后加入0.734升30％的盐酸水溶液。混悬物变得澄清，几秒钟后生成新的沉淀。搅拌得到的混悬物2小时。加入1.1升25％氨水后，搅拌该碱性悬液(pH＝9.6)1小时。收集形成的固体，用1.1升水润洗并干燥。为了除去残留的甲硅烷基起始反应物，用1升***润洗固体并再次干燥。得到273.5克标题化合物。
Claims (10)
1.一种式1化合物及其盐的生产方法，
其中
R1为氢、甲基或羟甲基，
R2为1-7C-烷基，
R3为1-7C-烷基，
R4为1-7C-烷基，
所述方法包括用NBS(N-溴代琥珀酰亚胺)脱氢(氧化)式2化合物，
其中R1、R2、R3和R4具有上述含义。
2.权利要求1的生产式1化合物的方法，其中
R1为甲基，
R2为溴，
R2为1-7C-烷基，
R3为1-4C-烷基，
R4为1-4C-烷基。
3.权利要求1的生产式1化合物的方法，其中
R1为甲基，
R2为溴，
R2为叔丁基，
R3为甲基，
R4为甲基。
4.权利要求1的方法，其特征在于，基于所使用的式2化合物的量计算，所使用的NBS的量为约1当量。
5.权利要求1的方法，其特征在于与NBS反应之后，使用有机碱除去HBr。
6.权利要求1的方法，其特征在于与NBS反应之后，使用有机胺除去HBr。
7.权利要求1的方法，其特征在于与NBS反应之后，使用三乙胺除去HBr。
8.权利要求1的方法，其特征在于反应在-70℃到+50℃之间的温度下进行。
9.权利要求1的方法，其特征在于反应在0℃到+30℃之间的温度下进行。
10.权利要求1的方法，其特征在于反应在惰性有机溶剂中进行。
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| CN (1) | CN1764665A (zh) |
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| NO20054977D0 (no) | 2005-10-26 |
| RS20050727A (en) | 2007-11-15 |
| KR20050119145A (ko) | 2005-12-20 |
| JP2006522068A (ja) | 2006-09-28 |
| BRPI0408771A (pt) | 2006-03-28 |
| ZA200506904B (en) | 2007-01-31 |
| NO20054977L (no) | 2005-10-26 |
| AU2004226178A1 (en) | 2004-10-14 |
| EP1613637A1 (en) | 2006-01-11 |
| IS8088A (is) | 2005-10-24 |
| IL170747A0 (en) | 2009-02-11 |
| MXPA05010311A (es) | 2005-11-17 |
| EA200501535A1 (ru) | 2006-06-30 |
| CA2520288A1 (en) | 2004-10-14 |
| WO2004087718A1 (en) | 2004-10-14 |
| US20060194972A1 (en) | 2006-08-31 |
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