CN1726031A - 8-三烷基硅氧基-2-甲基-9-苯基-7-氧代-7,8,9,10-四氢咪唑并[1,2-h][1,7]二氮杂萘 - Google Patents
8-三烷基硅氧基-2-甲基-9-苯基-7-氧代-7,8,9,10-四氢咪唑并[1,2-h][1,7]二氮杂萘 Download PDFInfo
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- 150000005054 naphthyridines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 150000002466 imines Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 abstract 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 abstract 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 4
- -1 heptyl (5-methyl hexyl) Chemical group 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- SWHFSXDXCWCNKQ-UHFFFAOYSA-N ethyl 3-anilino-2-hydroxypropanoate Chemical compound CCOC(=O)C(O)CNC1=CC=CC=C1 SWHFSXDXCWCNKQ-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- MXBVNILGVJVVMH-UHFFFAOYSA-N 1,7-naphthyridine Chemical compound C1=NC=CC2=CC=CN=C21 MXBVNILGVJVVMH-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UWMJRBYGKZOPCC-UHFFFAOYSA-N 1-chloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)NC1=O UWMJRBYGKZOPCC-UHFFFAOYSA-N 0.000 description 1
- AQZMINLSVARCSL-UHFFFAOYSA-N 4-chloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound ClC1=CC(=O)C(C#N)=C(C#N)C1=O AQZMINLSVARCSL-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- RISRGKINPSVAJP-UHFFFAOYSA-N [Li].C(CCC)(=O)O Chemical compound [Li].C(CCC)(=O)O RISRGKINPSVAJP-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 150000005232 imidazopyridines Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000010413 mother solution Substances 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
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical class O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- RWMKSKOZLCXHOK-UHFFFAOYSA-M potassium;butanoate Chemical compound [K+].CCCC([O-])=O RWMKSKOZLCXHOK-UHFFFAOYSA-M 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000005057 refrigeration Methods 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
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000007984 tetrahydrofuranes Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
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- 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
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Abstract
8-三烷基硅氧基-2-甲基-9-苯基-7-氧代-7,8,9,10-四氢咪唑并[1,2-h][1,7]二氮杂萘,式(1)化合物及其盐是制备预防和治疗肠胃病的化合物的有用的中间体。其中R1是氢,甲基或羟甲基,R2a和R2b都是氢或一起表示一个键,R3是1-7C烷基,R4是1-7C烷基,和R5是1-7C烷基。
Description
发明领域
本发明涉及新的化合物,其作为制备药物的中间体应用于制药工业。
现有技术
国际专利申请WO 02/34749、WO 01/72757、WO 01/72756、WO01/72754、WO 00/17200和WO 98/42707公开了具有特殊取代模式的三环咪唑并吡啶衍生物,其适用于治疗胃肠疾病。在该专利申请中,给出了反应示意流程,其中表明从咪唑并吡啶-8-酮开始制得了最终产品。这些咪唑并吡啶-8-酮更详细地描述在国际专利申请WO 01/72748中。
发明内容
本发明涉及一类化合物,其可用作制备现有技术中提及的化合物的重要的中间体;还涉及具有类似基本结构的其他化合物。
因此,第一方面,本发明涉及式1化合物及其盐,
其中,R1是氢、甲基或羟甲基,
R2a和R2b都是氢或一起表示一个键,
R3是1-7C烷基,
R4是1-7C烷基,和
R5是1-7C烷基。
1-7C烷基表示具有1-7个碳原子的直链或支链烷基。可提及的实例有庚基,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化合物的适宜的盐具体是与强碱形成的所有的盐,例如钠、钾或锂盐。
所要强调的式1化合物为这样一些化合物及其盐,其中
R1是甲基,
R2a和R2b都是氢或一起表示一个键,
R3是1-7C烷基,
R4是1-4C烷基,
R5是1-4C烷基。
优选的式1化合物为这样一些化合物及其盐,其中
R1是甲基,
R2a和R2b都是氢或一起表示一个键,
R3是叔丁基,
R4是甲基,和
R5是甲基。
本发明化合物可以例如按照下面的反应示意流程来制备。示意流程
在下面的示意流程中,式1化合物的制备用实例方式描述,式中R2a和R2b都是氢(相当于式1a化合物)。
初始的式(2)化合物叙述于WO 01/72748。式(3)的硅醚也是本发明的主题,它可按照专家已知的方法来制备,例如,在碱性条件下,使苯基异丝氨酸乙酯与叔丁基二甲基氯化硅反应。(2)与(3)的反应优选在合适的催化剂存在下进行,例如,对甲苯磺酸,并且同时进行除水。最初形成中间体亚胺,然后进行环闭合,该反应通过使用强碱来进行,例如叔丁酸钾,叔丁酸锂,双(三甲基硅基)氨基钠,或优选的二异丙基氨基锂。
为了制备如下的式1化合物,其中R2a和R2b一起表示一个键(相当于式1b化合物),
将式1a化合物用适当的试剂脱氢(氧化),例如使用二氧化锰,1,3-二氯-5,5-二甲基乙内酰脲或2,3-二氯-5,6-二氰基-p-苯并醌(DDQ)。
例如在国际专利申请WO 98/42707中的示意流程8中作为中间体列出的8-羟基-7-氧代-7,8,9,10-四氢咪唑并[1,2-h][1,7]二氮杂萘可从化合物1b通过例如用盐酸水解制得。因此,本发明还涉及式1b化合物通过其水解在制备式4化合物中的应用。
下面的实施例用来更加详细地说明本发明,并不限制本发明。类似地,其他的式1化合物(此处没有明确地叙述其制备方法)可以通过类似方法或者用本领域技术人员本身熟悉的方法、用常规技术来制得。缩写min表示分钟,h表示小时。
实施例
1.苯基异丝氨酸乙酯的叔丁基-二甲基-硅醚
将1323克(4.06摩尔)(R,R)-苯基异丝氨酸乙酯溶解于6.6升二氯甲烷中。向此溶液中加入397.4克咪唑和724克叔丁基二甲基氯化硅。将混合物在室温搅拌16小时。然后依次用6升和4升水洗涤该反应混合物。得到的清亮二氯甲烷层用硫酸钠干燥,过滤并减压浓缩。得到的1509克标题化合物不需纯化可直接用于实施例2。
2.7-(叔丁基-二甲基硅烷基氧)-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
往溶解在10.5升甲苯中的实施例1得到的1509克苯基异丝氨酸乙酯的叔丁基-二甲基硅醚中加入14克对甲苯磺酸一水合物和736克2,3-二甲基-6,7-二氢-5-H-咪唑并[1,2-a]吡啶-8-酮。将混合物搅拌并在回流状态下煮沸,直到在所用的Dean-Stark集水器中收集到80毫升水为止。将混合物冷冻至-15℃,加入6升四氢呋喃。用1小时往此溶液中滴加6升2M的二异丙基氨基锂(在四氢呋喃/正庚烷中的溶液)。将该混合物在没有外部冷却的条件下搅拌30分钟(温度升至-5℃),然后用7升氯化铵水溶液使反应终止。分出两层。有机层用硫酸钠干燥并过滤。真空除去溶剂后,分离出1811克粗的7-(叔丁基-二甲基-硅烷基氧)-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。将该物质溶解于3.9升沸腾的甲醇中,并搅拌冷冻至-5℃。收集形成的沉淀,并用1.75升冷甲醇洗涤。干燥后得到558克标题化合物。将母液浓缩至1.5升,并在-5℃搅拌几小时。收集沉淀,用0.25升甲醇洗涤。分离出另一部分96.5克标题化合物。总收率是654.5克(38.5%)。
3.7-(叔丁基-二甲基-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
将558克(1.32摩尔)7-(叔丁基-二甲基-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-酮溶于2.6升THF和5.36升甲苯中。将混合物搅拌并在5℃的冰/水浴中冷冻。用1小时时间分批加入376克(1.66摩尔)DDQ。在15℃继续搅拌另外2小时。氧化完全以后(用HPLC检查),反应混合物用2.066升2M氢氧化钠水溶液骤冷。将得到的悬浮液过滤,滤饼用1升甲苯洗涤。将呈两层体系的滤液分开,有机层用2升10%氯化钠水溶液洗。用硫酸钠干燥后,有机层经过滤并减压浓缩。粗产品用0.5升甲醇处理,并再次真空浓缩。将536克标题化合物粗品溶于700毫升甲醇并冷冻至-15℃。收集形成的沉淀,用100毫升冷(-15℃)甲醇洗涤并干燥。得到342克标题化合物黄色固体。
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
将386.5克(0.916摩尔)7-(叔丁基-二甲基-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升甲醇中并在冰/水浴上冷却至10℃。然后加入0.734升30%HCl水溶液。悬浮液变成清澈的,几秒钟之后形成新的沉淀。将得到的悬浮液搅拌2小时。加入1.1升25%氨水后,将此碱性悬浮液(pH=9.6)搅拌1小时。收集形成的固体并用1.1升水洗涤,然后干燥。为了除去剩余的硅基原料,该固体用1升乙醚洗涤并再次干燥。得到273.5克标题化合物。
Claims (8)
1.式1化合物及其盐,
其中R1是氢、甲基或羟甲基,
R2a和R2b都是氢或一起表示一个键,
R3是1-7C烷基,
R4是1-7C烷基,和
R5是1-7C烷基。
2.权利要求1的式1化合物及其盐,其中
R1是甲基,
R2a和R2b都是氢或一起表示一个键,
R3是1-7C烷基,
R4是1-4C烷基,和
R5是1-4C烷基。
3.权利要求1的式1化合物及其盐,其中
R1是甲基,
R2a和R2b都是氢或一起表示一个键,
R3是叔丁基,
R4是甲基,和
R5是甲基。
4.权利要求1的式1化合物及其盐,其中
R2a和R2b都是氢,其可用式1a表征,
式中R1是氢,甲基或羟甲基,
R3是1-7C烷基,
R4是1-7C烷基,和
R5是1-7C烷基。
5.权利要求1的式1化合物及其盐,其中
R2a和R2b一起表示一个键,其可用式1b表征,
式中R1是氢,甲基或羟甲基,
R3是1-7C烷基,
R4是1-7C烷基,和
R5是1-7C烷基。
8.权利要求5的式1b化合物通过将其水解用于制备式4化合物,
其中R1是氢,甲基或羟甲基。
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BR0316752A (pt) | 2005-10-25 |
PL375933A1 (en) | 2005-12-12 |
HRP20050632A2 (hr) | 2006-04-30 |
EP1585516A2 (en) | 2005-10-19 |
ZA200504045B (en) | 2006-07-26 |
NO20053271L (no) | 2005-07-04 |
US20060041134A1 (en) | 2006-02-23 |
JP2006515848A (ja) | 2006-06-08 |
WO2004056362A2 (en) | 2004-07-08 |
EA010107B1 (ru) | 2008-06-30 |
CA2509882A1 (en) | 2004-07-08 |
EA200500903A1 (ru) | 2005-12-29 |
KR20050088176A (ko) | 2005-09-02 |
RS20050449A (en) | 2007-11-15 |
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