CN1183092C - 中间体及使用该中间体的含氟氨基酸化合物的制造方法 - Google Patents
中间体及使用该中间体的含氟氨基酸化合物的制造方法 Download PDFInfo
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- CN1183092C CN1183092C CNB998145483A CN99814548A CN1183092C CN 1183092 C CN1183092 C CN 1183092C CN B998145483 A CNB998145483 A CN B998145483A CN 99814548 A CN99814548 A CN 99814548A CN 1183092 C CN1183092 C CN 1183092C
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- alkyl
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- carboxylic acid
- derivative
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- -1 amino acid compound Chemical class 0.000 title claims abstract description 59
- 238000000034 method Methods 0.000 title claims abstract description 35
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- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 48
- 239000011737 fluorine Substances 0.000 claims abstract description 44
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 18
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical class CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 45
- 238000004519 manufacturing process Methods 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 10
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- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 229940053195 antiepileptics hydantoin derivative Drugs 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- 239000004593 Epoxy Substances 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
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- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
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- 125000004494 ethyl ester group Chemical group 0.000 description 34
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- ANUFAWHRSIJTHW-UHFFFAOYSA-N 2-methylheptanedioic acid Chemical compound OC(=O)C(C)CCCCC(O)=O ANUFAWHRSIJTHW-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
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- AEDIXYWIVPYNBI-UHFFFAOYSA-N heptanamide Chemical class CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000007670 refining Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
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- 150000002148 esters Chemical group 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
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- 229910052760 oxygen Inorganic materials 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
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- 239000003292 glue Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
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- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
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- 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
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- 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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Abstract
通式(1)所示(1S,5R,6S)-或(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物;该衍生物的制造方法;和对精神病学疾病或神经病学疾病有治疗效果和预防效果、对第2群代谢移变型谷氨酸受体有作用的含氟氨基酸的高效率制造方法,其特征在于使上述化合物(1)加氢,然后进一步使之转化成乙内酰脲或氨基氰化物,随后水解。在式(1)中,R代表OR1或NR1R2(其中,R1和R2相同或不同,各自代表氢、C1-6烷基、C3-6环烷基、(C3-6环烷基)(C1-6烷基)、芳基、芳基(C1-6烷基)、(C1-6烷氧基)(C1-6烷基)、C1-6羟烷基、(C1-6烷硫基)(C1-6烷基)或C1-6巯基烷基)。
Description
技术领域
本发明涉及3-氟-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物及其制造方法,和含氟氨基酸衍生物(2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸)的制造方法。
背景技术
近年来,继谷氨酸受体基因的克隆,又查明谷氨酸受体有数目惊人的亚型存在。现在,谷氨酸受体大体上分类为受体具有离子通道型结构的“离子移变型”和受体与G-蛋白质共轭的“代谢移变型”两种。进而,离子移变型受体在药理学上又分类为N-甲基-D-天冬氨酸(NMDA)、α-氨基-3-羟基-5-甲基异噁唑-4-丙酸盐(AMPA)和红藻氨酸盐这3种(Science,
258,597-603,1992),代谢移变型受体又分类为类型1~8这8种(J.Neurosci.,
13,1372-1378,1993;Neuropharmacol.,34,1-26,1995)。
代谢移变型谷氨酸受体在药理学上又分类为3群。其中,第2群(mGluR2/mGluR3)能结合腺苷酸环化酶和抑制环腺苷一磷酸(cAMP)的马胆碱刺激性的积累(Trends Pharmacol.Sci.,
14,13(1993)),因而对第2群代谢移变型谷氨酸受体有作用的化合物,预期对精神分裂症、不安及其相关疾病、郁抑症、二极性障碍、癫痫等精神医学性障碍、例如药物依赖症、认知障碍、阿尔茨海默病、亨廷顿舞蹈病、帕金森病、伴随肌强直的运动障碍、脑局部缺血、脑机能不全、脊髓障碍、头部障碍等神经学疾病有治疗效果和预防效果。
因此,本申请人的国际专利申请PCT/JP99/00324描述了作为对第2群代谢移变型谷氨酸受体有作用的化合物的2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸,进而,在同一说明书中,作为其制造方法,提出了如下所述的合成法,即:使(1S,5R,6S)或(1SR,5RS,6SR)-2-氧代双环[3.1.0]己烷-6-羧酸衍生物(8)氟化,和乙内酰脲化,再进行水解。
要说明的是,迄今为止,除上述合成机理外,2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸的合成方法尚无报告。
发明公开
本发明的目的是提供对精神分裂症、不安及其相关疾病、郁抑症、二极性障碍、癫痫等精神医学性障碍、例如药物依赖症、认知障碍、阿尔茨海默病、亨廷顿舞蹈病、帕金森病、伴随肌强直的运动障碍、脑局部缺血、脑机能不全、脊髓障碍、头部障碍等神经学疾病有治疗效果和预防效果、对第2群代谢移变型谷氨酸受体有作用的含氟氨基酸衍生物(2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸)的更高效率制造方法,和可用于这种制造方法的新型合成中间体及其制造方法。
本发明者等人对含氟氨基酸衍生物〔(1S,2S,3S,5R,6S)或(1SR,2SR,3SR,5RS,6SR)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸〕的制造方法进行锐意探讨的结果,发现以(1S,5R,6S)或(1SR,5RS,6SR)-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物作为起始原料、经由新型合成中间体(1S,5R,6S)或(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物的高效率制造方法,终于完成本发明。
即,本发明是式(1)所示3-氟-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物
〔R表示OR1或NR1R2,R1和R2相同或不同,表示氢原子、C1~C6烷基、C3~C6环烷基、C3~C6环烷基C1~C6烷基、芳基、芳基C1~C6烷基、C1~C6烷氧基C1~C6烷基、C1~C6羟烷基、C1~C6烷硫基C1~C6烷基,或C1~C6巯基烷基〕,和式(1)的衍生物的制造方法,其特征在于包含用过氧化物氧化式(2)所示(1S,5R,6S)或(1SR,5RS,6SR)-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物
〔式中,R与上述相同〕,制成式(3)所示(1S,3R,4R,5R,6S)或(1SR,3RS,4RS,5RS,6SR)-环氧衍生物
〔式中,R与上述相同〕,并使其与氟化剂反应的步骤
以及式(7)所示(1S,2S,3S,5R,6S)或(1SR,2SR,3SR,5RS,6SR)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸、其医药上可接受的盐、或其水合物的制造方法,
其特征在于包含通过使式(1)的衍生物加氢,制成式(4)所示(1S,3S,5R,6S)或(1SR,3SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸衍生物
〔式中,R与上述相同〕,然后进行乙内酰脲化或氨基氰化物化,制成式(5)所示(1S,2S,3S,5R,6S)或(1SR,2SR,3SR,5RS,6SR)-乙内酰脲衍生物
〔式中,R与上述相同〕,或式(6)所示(1S,2S,3S,5R,6S)或(1SR,2SR,3SR,5RS,6SR)-氨基氰化物衍生物
〔式中,R与上述相同〕,和使这些水解的步骤。
本发明中使用的用语定义如下。在本发明中,“Cn~Cm”表示其后续基团有n~m个碳原子。
C1~C6烷基表示有1~6个碳原子的直链状或支链状烷基,是诸如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、己基、异己基等。
C3~C6环烷基表示有3~6个碳原子的环烷基,是诸如环丙基、环戊基、环己基等。
C3~C6环烷基C1~C6烷基具有C3~C6环烷基与C1~C6烷基的复合形态,是诸如环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基等。
芳基是苯基、萘基等,较好是苯基。芳基C1~C6烷基表示有至少一个以上芳基、较好苯基取代的、有1~6个碳原子的直链状或支链状烷基,是诸如苄基、二苯甲基、1-苯基乙基、2-苯基乙基等。
C1~C6烷氧基C1~C6烷基具有C1~C6烷氧基与C1~C6烷基的复合形态。其中,C1~C6烷氧基系指有1~6个碳原子的直链状或支链状烷氧基,是诸如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基、异戊氧基等。因此,C1~C6烷氧基C1~C6烷基的实例包括甲氧乙基、乙氧乙基、丙氧乙基、异丙氧乙基、丁氧乙基、异丁氧乙基、戊氧乙基、异戊氧乙基等。
C1~C6羟烷基表示有至少一个羟基取代的C1~C6烷基。因此,C1~C6羟烷基的实例包括2-羟基乙基、3-羟基丙基、2,3-二羟基丙基等。
C1~C6烷硫基C1~C6烷基具有C1~C6烷硫基与C1~C6烷基的复合形态。其中,C1~C6烷硫基系指有1~6个碳原子的直链状或支链状烷硫基,是诸如甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、异丁硫基、叔丁硫基、戊硫基、异戊硫基等。因此,C1~C6烷硫基C1~C6烷基的实例包括甲硫甲基、2-甲硫基乙基等。
C1~C6巯基烷基表示有至少一个巯基取代的C1~C6烷基。因此,C1~C6巯基烷基的实例包括2-巯基乙基、3-巯基丙基、2,3-二巯基丙基等。
本发明衍生物的特征在于在R1和/或R2是氢原子以外的基团的情况下,各该基团上的至少一个氢原子被从下列组成的一组中选择的基团取代:卤素原子、烷基、烷氧基、烷硫基、硝基、氨基、羟基、硫醇基、甲酰基、羧基、酰基、烷氧羰基、氰基、氨基甲酰基、芳基和杂环基。
具体说,上述各种基团,其基团上的至少一个氢原子也可以被下列非氢原子或基团取代:例如,氟原子、氯原子、溴原子、碘原子等卤素原子;硝基;氨基;羟基;硫醇基;甲酰基;羧基;氰基;氨基甲酰基;甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、叔戊基等烷基;苯基、萘基、联苯基、蒽基、吡咯基、吡啶基、噻吩基等芳基和杂环基;甲氧羰基、乙氧羰基等烷氧羰基;乙酰基、苯甲酰基等酰基;甲氧基、乙氧基、丙氧基等烷氧基;甲硫基、乙硫基、丙硫基等烷硫基等。因此,例如,2,2,2-三氯乙基、五取代苯氧基、2,6-二甲基环己基和4-甲氧基苄基等也包含在R1和R2的范围内。要说明的是,这些取代基中的碳原子数不包含在上述的n或m中。
此外,本发明中医药上可接受的盐,是诸如与硫酸、盐酸、磷酸等无机酸的盐,与乙酸、草酸、乳酸、酒石酸、富马酸、马来酸、甲磺酸、苯磺酸等有机酸的盐,与三甲胺、甲胺等胺的盐,或与钠离子、钾离子、钙离子等金属离子的盐。
式(1)和(7)的化合物可以用以下所示的合成法制造(以下反应式中,R表示与上述相同的取代基)。
步骤A:(1S,5R,6S)或(1SR,5RS,6SR)-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物(2)(以下称之为“烯酮衍生物(2)”)与惰性溶剂中的过氧化物一起,在-30℃~150℃、较好0℃~50℃的反应温度反应,得到环氧衍生物(3)。
其中,惰性溶剂是诸如甲醇、乙醇、异丙醇、乙二醇等醇类,诸如二乙基醚、四氢呋喃、二噁烷、1,2-二甲氧基乙烷等醚类,诸如苯、甲苯等烃类,诸如N,N-二甲基甲酰胺等酰胺类,诸如丙酮、甲·乙酮等酮类,乙腈、水、乙酸、三氟乙酸等,或从这些溶剂中选择的混合溶剂等。过氧化物是诸如间氯过苯甲酸、过乙酸等有机羧酸过氧化物,叔丁基氢过氧化物等醇的过氧化物,或过氧化氢等。
步骤B:环氧衍生物(3)与氟化剂在惰性溶剂中,在-30℃~200℃或0℃~150℃的反应温度反应,合成了本发明化合物3-氟-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物(1)。
其中,惰性溶剂是诸如甲醇、乙醇、异丙醇、乙二醇等醇类、二乙基醚、四氢呋喃、二噁烷、1,2-二甲氧基乙烷等醚类、苯、甲苯等烃类、N,N-二甲基甲酰胺等酰胺类等或这些的混合溶剂,作为氟化剂,有诸如氟、氟化氢、酸性氟化钾(HKF2)等无机氟化合物,氟化四丁铵等季铵氟化化合物,三氟甲磺酸N-氟吡啶鎓、N-氟-N-叔丁基苯磺酰胺、N-氟糖精磺内酰胺、N-氟二(苯磺)酰亚胺、N-氟邻苯磺酰亚胺等的N-氟型氟化化合物,ClO3F、CF3COOF等。
步骤C:3-氟-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物(1)在惰性溶剂中,在-30℃~100℃、较好0℃~50℃的反应温度加氢,导致(1S,3S,5R,6S)或(1SR,3SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸衍生物(4)(以下称之为“氟酮衍生物(4)”) 。
其中,惰性溶剂是诸如甲醇、乙醇、异丙醇、乙二醇等醇类、二乙基醚、四氢呋喃、二噁烷、1,2-二甲氧基乙烷等醚类、苯、甲苯等烃类、N,N-二甲基甲酰胺等酰胺类等,水,或这些的混合溶剂等。
作为加氢时的催化剂,可以用诸如钯/活性炭、钯黑、二氧化铂、阮内镍等作为加氢催化剂常用的金属。此步骤中进行的加氢,由于氢原子是对5元环上3-4位双键的立体选择性加成的。因而,借此可使氟酮衍生物(4)中的氟原子有所希望的立体配置。
步骤D和E:氟酮衍生物(4)采用Strecker氨基酸合成(Ann.,75,27(1850);
91,349(1850))、Bucheerer-Bergs反应(J.Prakt,Chem.,
140,69(1934))或这些的改进方法,转化成乙内酰脲衍生物(5)或氨基氰化物衍生物(6)等,并通过使这些衍生物水解,得到(1S,2S,3S,5R,6S)或(1SR,2SR,3SR,5RS,6SR)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸(7)(以下称之为“含氟氨基酸衍生物(7)”)。
较好的是,氟酮衍生物(4)与氰化钠或氰化钾和碳酸铵,在诸如乙醇等醇类或醇类与水的混合溶剂中,较好在20℃~50℃反应12小时~48小时,导致合成中间体乙内酰脲衍生物(5)。随后,用诸如氢氧化钠等碱、或盐酸、氢溴酸、硫酸等酸,在诸如乙醇等醇类、二噁烷等醚类、丙酮等酮类、水、或这些的混合溶剂等惰性溶剂中,进行水解,合成含氟氨基酸衍生物(7)。
在用(1SR,5RS,6SR)-烯酮衍生物(2)作为起始原料的情况下,通过步骤A、B、C和D合成的乙内酰脲衍生物(5)或氨基氰化物衍生物(6),借助于使用了诸如纤维素氨基甲酸酯衍生物、直链淀粉氨基甲酸酯等手性载体的HPLC法,就可以进行光学分离。进而,通过步骤A、B、C和D合成的乙内酰脲衍生物(5)或氨基氰化物衍生物(6)在一般的碱性条件下或酸性条件下进行酯水解而衍生的羧酸衍生物和通过步骤E得到的含氟氨基酸衍生物(7),借助于使用了诸如纤维素氨基甲酸酯衍生物、直链淀粉氨基甲酸酯等手性载体的HPLC法进行光学分离,或通过使用诸如(+)或(-)-1-苯基乙胺、(+)或(-)-苯基甘氨酸醇、(+)或(-)-2-氨基-1-丁醇、(+)或(-)-丙氨酸醇、番木鳖碱、辛可尼定、辛可宁、奎宁、奎尼定、脱氢枞胺等旋光性胺类进行光学分离均可。
含氟氨基酸衍生物(7)中,氨基用适当保护基保护后,用烷基卤或醇按一般方法酯化,再脱除氨基的保护基,就可以转化成酯形态。这里,氨基的保护、酯化和氨基的脱保护,可以按照《有机合成中的保护基》(Theodora W.Greene和Peter G.M.Wuts著)(其内容纳入本文中)等中记载的一般方法实施。上述酯形态对第2群代谢移变型谷氨酸受体不产生影响。然而,这种酯形态在生物体内会水解成羧酸,并变成会对第2群代谢移变型谷氨酸受体产生影响的羧酸。这样,酯形态起到了药物前体的作用,因而是极其有用的化合物。要说明的是,氨基氰化物衍生物(6)和含氟氨基酸衍生物(7)以及用上述方法得到的含氟氨基酸衍生物(7)的酯形态,可以用诸如(+)或(-)-二对甲苯酰基酒石酸、(+)或(-)-二苯甲酰基酒石酸、(+)或(-)-酒石酸、(+)或(-)-扁桃酸、(+)或(-)-樟脑酸、或者(+)或(-)-樟脑磺酸等旋光性有机酸类进行光学分离。
实施本发明的最佳形态
本发明有代表性的实施例列举如下,但本发明并不限定于这些实施例。
实施例1:
(1S,3R,4R,5R,6S)-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酸乙酯及(1SR,3RS,4RS,5RS,6SR)-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酸乙酯和异丙酯的制造
将0.60g(1SR,5RS,6SR)-2-氧代双环[3.1.0]-己-3-烯-6-羧酸乙酯溶解于4ml甲苯中,加入0.8ml 70%氢过氧化叔丁基水溶液和0.3ml 10%氢氧化苄基三甲基铵/甲醇溶液,然后在室温下搅拌20分钟。将反应混合物倒入水中,用乙醚萃取。有机层用饱和氯化钠水溶液洗涤后用无水硫酸镁干燥,滤除干燥剂后进行减压浓缩。残留物用色谱法精制(硅胶:ワコウ胶C 200(和光纯药),洗脱液:己烷/乙酸乙酯=6∶1),得到0.58g(1SR,3RS,4RS,5RS,6SR)-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酸乙酯。
(1SR,3RS,4RS,5RS,6SR)-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酸乙酯的质子NMR和质谱数据如下:
1H-NMR(CDCl3)δ(ppm);1.28(3H,t,J=7.0Hz),2.09(1H,t,J=3.1Hz),2.21(1H,ddt,J=5.3Hz,2.4Hz,1.1Hz),2.96(1H,m),3.25(1H,dt,J=2.4Hz,1.1Hz),4.00(1H,t,J=2.4Hz),4.17(2H,q,J=7.0Hz).
MS(EI)m/e;182(M+)。
按上述同样的方法,用2.80g(1SR,5RS,6SR)-2-氧代双环[3.1.0]-己-3-烯-6-羧酸异丙酯制得了2.42g(1SR,3RS,4RS,5RS,6SR)-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酸异丙酯。
(1SR,3RS,4RS,5RS,6SR)-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酸异丙酯的质子NMR和质谱数据如下:
1H-NMR(CDCl3)δ(ppm);1.24(3H,d,J=6.2Hz),1.25(3H,d,J=6.2Hz),2.06(1H,t,J=3.1Hz),2.19(1H,m),2.94(1H,m),3.23(1H,m),4.00(1H,t,J=2.3Hz),5.01(1H,sept,J=6.2Hz).
MS(EI)m/e;196(M+).
此外,按上述同样的方法,用7.00g(1S,5R,6S)-2-氧代双环[3.1.0]-己-3-烯-6-羧酸乙酯制得了5.52g(1S,3R,4R,5R,6S)-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酸乙酯。
(1S,3R,4R,5R,6S)-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酸乙酯的质子NMR、质谱和比旋光度数据如下:
H-NMR(CDCl3)δ(ppm);1.28(3H,t,J=7.0Hz),2.09(1H,t,J=3.1Hz),2.21(1H,ddt,J=5.3Hz,2.4Hz,1.1Hz),2.96(1H,m),3.25(1H,dt,J=2.4Hz,1.1Hz),4.00(1H,t,J=2.4Hz),4.17(2H,q,J=7.0Hz).
MS(EI)m/e;182(M+).
[α]D 25=+12.23(c=0.41,CH2Cl2)
实施例2
(1SR,3RS,4RS,5RS,6SR)-N-甲基-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酰胺和(1SR,3RS,4RS,5RS,6SR)-N,N-二甲基-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酰胺的制造
按与实施例1相同的方法,用1.50g(1SR,5RS,6SR)-N-甲基-2-氧代双环[3.1.0]-己-3-烯-6-羧酰胺制得了1.04g(1SR,3RS,4RS,5RS,6SR)-N-甲基-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酰胺。
H-NMR(CDCl3)δ(ppm);1.82(1H,t,J=2.9Hz),2.18(1H,ddt,J=5.2,2.6,1.1Hz),2.84(3H,d,J=4.8Hz),2.97-3.02(1H,m),3.22(1H,dt,J=2.4,1.1Hz),3.97(1H,t,J=2.4Hz),5.79(1H,s)。
MS(ES)(负)m/e;166(M+-1)。
按上述同样的方法,用2.71g(1SR,5RS,6SR)-N,N-二甲基--2-氧代双环[3.1.0]-己-3-烯-6-羧酰胺制得了1.88g(1SR,3RS,4RS,5RS,6SR)-N,N-二甲基-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酰胺。
1H-NMR(CDCl3)δ(ppm);2.12-2.16(1H,m),2.23(1H,t,J=3.1Hz),2.96(3H,s),3.03-3.07(1H,m),3.14(3H,s),3.24-3.25(1H,m),3.99(1H,t,J=2.3Hz)。
MS(EI)(正)m/e;181(M+)。
实施例3:
(1S,5R,6S)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸乙酯和2-羟基乙酯及(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸乙酯、异丙酯和2-羟基乙酯的制造
在氮气氛围下,2.00g(1SR,3RS,4RS,5RS,6SR)-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酸乙酯和8.60g氟化钾悬浮于30ml乙二醇中,然后在130℃搅拌2小时。将反应混合物倒入水中,用氯仿萃取后用无水硫酸镁干燥,滤除干燥剂后进行减压浓缩。残留物用色谱法精制(硅胶:ワコウ胶C 200(和光纯药),洗脱液:己烷/乙酸乙酯=4∶1-1∶2),得到0.49g(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸乙酯和0.84g(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸2-羟基乙酯。
(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸乙酯的质子NMR和质谱数据如下:
1H-NMR(CDCl3)δ(ppm);1.28(3H,t,J=7.0Hz),2.48(1H,dt,J=3.1Hz,J=0.7Hz),2.58(1H,m),2.81(1H,m),4.17(2H,q,J=7.0Hz),6.91(1H,m)。
MS(CI)m/e;185(M++1)。
(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸2-羟基乙酯的质子NMR和质谱数据如下:
1H-NMR(CDCl3)δ(ppm);1.72-1.92(1H,brs),2.54(1H,t,J=3.0Hz),2.61(1H,m),2.84(1H,m),3.80-3.92(2H,m),4.23-4.30(2H,m),6.92(1H,m).
MS(CI)m/e;201(M++1).
按上述同样的方法,用2.85g(1SR,3RS,4RS,5RS,6SR)-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酸异丙酯制得了1.01g(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸异丙酯和0.49g(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸2-羟基乙酯。
(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸异丙酯的质子NMR和质谱数据如下:
1H-NMR(CDCl3)δ(ppm);1.24(3H,d,J=6.2Hz),1.25(3H,d,J=6.2Hz),2.45(1H,t,J=2.8Hzm),2.57(1H,m),2.79(1H,m),5.00(1H,sept,J=6.2Hz),6.90(1H,m).
MS(CI)m/e;199(M++1).
此外,按上述同样的方法,用5.45g(1S,3R,4R,5R,6S)-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酸乙酯制得了1.01g(1S,5R,6S)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸乙酯和1.67g(1S,5R,6S)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸2-羟基乙酯。
(1S,5R,6S)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸乙酯的质子NMR、质谱和比旋光度数据如下:
1H-NMR(CDCl3)δ(ppm);1.28(3H,t,J=7.0Hz),2.48(1H,dt,J=3.1Hz,J=0.7Hz),2.58(1H,m),2.81(1H,m),4.17(2H,q,J=7.0Hz),6.91(1H,m).
MS(CI)m/e;185(M++1).
[α]D 25=-96.75(c=0.43,CH2Cl2)(1S,5R,6S)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸2-羟基乙酯的质子NMR、质谱和比旋光度数据如下:
1H-NMR(CDCl3)δ(ppm);1.72-1.92(1H,brs),2.54(1H,t,J=3.0Hz),2.61(1H,m),2.84(1H,m),3.80-3.92(2H,m),4.23-4.30(2H,m),6.92(1H,m).
MS(CI)m/e;201(M++1).
[α]D 25=-181.30(c=0.41,CH2Cl2)
实施例4:
(1SR,5RS,6SR)-N-甲基-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酰胺和(1SR,5RS,6SR)-N,N-二甲基-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酰胺的制造
按与实施例3相同的方法,用0.98g(1SR,3RS,4RS,5RS,6SR)-N-甲基-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酰胺制得了0.57g(1SR,5RS,6SR)-N-甲基-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酰胺。
1H-NMR(CDCl3)δ(ppm);2.24(1H,t,J=2.8Hz),2.56-2.62(1H,m),2.83(3H,d,J=5.0Hz),2.80-2.89(1H,m),5.84(1H,s), 6.89(1H,dt,J=2.8,1.3Hz)。
MS(ES)(Nega)m/e;168(M+-1)。
按上述同样的方法,用1.68g(1SR,3RS,4RS,5RS,6SR)-N,N-二甲基-3,4-环氧-2-氧代双环[3.1.0]己烷-6-羧酰胺制得了,0.84g(1SR,5RS,6SR)-N,N-二甲基-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酰胺。
1H-NMR(CDCl3)δ(ppm);2.56-2.63(2H,m),2.87-2.94(1H,m),2.95(3H,s),3.14(3H,s),6.91(1H,dt,J=2.8,1.3Hz)。
MS(ES)(Nega)m/e;182(M+-1)。
实施例5:
(1S,3S,5R,6S)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸乙酯和2-羟基乙酯及(1SR,3SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸乙酯、异丙酯和2-羟基乙酯的制造
将0.47g(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸乙酯溶解于4.8ml乙醇中,加入48mg 5%钯/活性炭,然后在氢气氛围中在室温下搅拌一夜。反应混合物用硅藻土过滤,将滤液减压浓缩。残留物用色谱法精制(硅胶:ワコウ胶C 200(和光纯药),洗脱液:己烷/乙酸乙酯=4∶1),得到0.36g(1SR,3SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸乙酯。
(1SR,3SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸乙酯的质子NMR和质谱数据如下:
1H-NMR(CDCl3)δ(ppm);1.29(3H,t,J=7.2Hz),2.00-2.70(5H,m),4.18(2H,q,J=7.2Hz),4.51(1H,dd,J=51.0Hz,J=8.1Hz).
MS(Ion Spray)(Nega)m/e;185(M+-1).
按上述同样的方法,用0.83g(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸2-羟基乙酯制得了0.67g(1SR,3SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸2-羟基乙酯,用0.66g(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸异丙酯制得了0.39g(1SR,3SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸异丙酯。
(1SR,3SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸2-羟基乙酯的质子NMR和质谱数据如下:
1H-NMR(CDCl3)δ(ppm);1.92-2.90(6H,m),3.66-4.04(2H,m),4.20-4.50(2H,m),4.55(1H,dd,J=51.2Hz,J=7.5Hz).
MS(Ion Spray)(Nega)m/e;201(M+-1).
(1SR,3SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸异丙酯的质子NMR和质谱数据如下:
1H-NMR(CDCl3)δ(ppm);1.25(3H,d,J=6.2Hz),1.26(3H,d,J=6.2Hz),1.96-2.64(5H,m),4.52(1H,dd,J=50.4Hz,J=7.6Hz)5.02(1H,sept,J=6.2Hz).
MS(EI)m/e;200(M+).
此外,按上述同样的方法,用0.80g(1S,5R,6S)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸乙酯制得了0.61g(1S,3S,5R,6S)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸乙酯,用1.31g(1S,5R,6S)-3-氟-2-氧代双环[3.1.0]-己-3-烯-6-羧酸2-羟基乙酯制得了0.83g(1S,3S,5R,6S)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸2-羟基乙酯。
(1S,3S,5R,6S)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸乙酯,的质子NMR、质谱和比旋光度数据如下:
1H-NMR(CDCl3)δ(ppm);1.29(3H,t,J=7.2Hz),2.00-2.70(5H,m),4.18(2H,q,J=7.2Hz),4.51(1H,dd,J=51.0Hz,J=8.1Hz).
MS(Ion Spray)(Nega)m/e;185(M+-1).
[α]D 22=-11.70(c=0.45,CH2Cl2)
(1S,3S,5R,6S)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸2-羟基乙酯的质子NMR、质谱和比旋光度数据如下:
1H-NMR(CDCl3)δ(ppm);1.92-2.90(6H,m),3.66-4.04(2H,m),4.20-4.50(2H,m),4.55(1H,dd,J=51.2Hz,J=7.5Hz).
MS(Ion Spray)(Nega)m/e;201(M+-1).
[α]D 25=-9.98(c=0.50,CH2Cl2)
实施例6:
(1S,2S,3S,5R,6S)和(1SR,2SR,3SR,5RS,6SR)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸乙酯的制造
将0.33g(1SR,3SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸乙酯溶解在1.7ml水和2.6ml乙醇的混合溶液中,加入0.42g碳酸铵和0.13g氰化钾,然后在35℃搅拌3天。将反应混合物减压浓缩,往残留物中加入饱和氯化钠水溶液,然后用乙酸乙酯和氯仿萃取。有机层用无水硫酸镁干燥,滤除干燥剂后在减压下浓缩,残留物用水/乙醇=1∶1重结晶,然后用色谱法精制(硅胶:ワコウ胶C 200(和光纯药),洗脱液:氯仿/甲醇=30∶1),得到0.23g(1SR,2SR,3SR,5RS,6SR)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸乙酯。
(1SR,2SR,3SR,5RS,6SR)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸乙酯的质子NMR和质谱数据如下:
1H-NMR(DMSO-d6)δ(ppm);1.19(3H,t,J=7.0Hz),1.95-2.46(5H,m),4.06(2H,q,J=7.0Hz),4.81(1H,dd,J=52.4Hz,5.1Hz),8.44(1H,s),10.91(1H,s).
MS(EI)m/e;256(M+).
此外,按上述同样的方法,用0.28g(1S,3S,5R,6S)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸乙酯制得了0.23g(1S,2S,3S,5R,6S)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸乙酯。
(1S,2S,3S,5R,6S)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸乙酯的质子NMR、质谱和比旋光度数据如下:
1H-NMR(DMSO-d6)δ(ppm);1.19(3H,t,J=7.0Hz),1.95-2.46(5H,m),4.06(2H,q,J=7.0Hz),4.81(1H,dd,J=52.4Hz,5.1Hz),8.44(1H,s),10.91(1H,s).
MS(EI)m/e;256(M+).
[α]D 25=+30.11(c=0.12,MeOH)
实施例7:
(1S,2S,3S,5R,6S)和(1SR,2SR,3SR,5RS,6SR)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸的制造
将100mg(1SR,2SR,3SR,5RS,6SR)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸乙酯溶解在1.5ml 60%硫酸中,然后在140℃加热12小时。使反应混合物冷却至室温后用5M氢氧化钠水溶液调至pH8,然后用离子交换色谱法精制(AG1-X8阴离子交换树脂(Bio-Rad),洗脱液:0.1M乙酸-2M乙酸),得到20mg(1SR,2SR,3SR,5RS,6SR)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸。
(1SR,2SR,3SR,5RS,6SR)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸的质子NMR和质谱数据如下:
1H-NMR(TFA-d)δ(ppm);2.49(1H,brs),2.59-3.06(4H,m),5.40(1H,dd,J=52.1Hz,5.3Hz).
MS(CI)m/e;204(M++1).
按上述同样的方法,用0.12g(1S,2S,3S,5R,6S)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸乙酯制得了75mg(1S,2S,3S,5R,6S)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸。
(1S,2S,3S,5R,6S)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸的质子NMR、质谱和比旋光度数据如下:
1H-NMR(TFA-d)δ(ppm);2.49(1H,brs),2.59-3.06(4H,m),5.40(1H,dd,J=52.1Hz,5.3Hz).
MS(CI)m/e;204(M++1).
[α]D 25=+58.61(c=0.20,1N HCl)
实施例8:
(1S,2S,3S,5R,6S)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸的制造
(1)2.2g(1SR,2SR,3SR,5RS,6SR)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸乙酯与17ml 2N氢氧化钠的混合物在室温下搅拌。2小时后加入浓盐酸将pH值调至1.0。过滤分离生成的结晶,经干燥后得到1.81g(1SR,2SR,3SR,5RS,6SR)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸。
(1SR,2SR,3SR,5RS,6SR)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸的质子NMR和质谱数据如下:
1H-NMR(DMSO-d6)δ(ppm);1.85-2.44(5H,m),4.80(1H,dd,J=52.3Hz,5.3Hz),8.44(1H,s),10.88(1H,s),12.30(1H,brs).
MS(FAB)(Nega)m/e;227(M+-1).
(2)1.80g(1SR,2SR,3SR,5RS,6SR)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸在26ml丙酮/水=8∶5的混合溶液中于55℃下搅拌,加入0.96g(R)-(+)-1-苯基乙胺,然后在室温下搅拌15小时。滤出生成的结晶,得到1.30g(R)-(+)-1-苯基乙胺盐。将1.20g该盐悬浮于15ml水中,用1M盐酸将pH值调至1.0,然后在室温下搅拌14小时。过滤分离生成的结晶,得到0.65g(1S,2S,3S,5R,6S)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸。此外,滤液用离子交换色谱法精制(AG 50W-X8阳离子交换树脂(Bio-Rad),洗脱液:1M乙酸),得到0.06g(1S,2S,3S,5R,6S)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸。
(1S,2S,3S,5R,6S)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸的质子NMR、质谱和比旋光度数据如下:
1H-NMR(DMSO-d6)δ(ppm);1.85-2.44(5H,m),4.80(1H,dd,J=52.3Hz,5.3Hz),8.44(1H,s),10.88(1H,s),12.30(1H,brs).
MS(FAB)(Nega)m/e;227(M+-1).
[α]D 22=+36.84(c=0.20,MeOH)
(3)将14.78g(1S,2S,3S,5R,6S)-2-螺-5′-乙内酰脲-3-氟双环[3.1.0]己烷-6-羧酸溶解于246ml 60%硫酸中,然后在140℃搅拌2天。使反应混合物冷却至室温后用5M氢氧化钠水溶液调至pH8,然后用离子交换色谱法精制(AG1-X8阴离子交换树脂(Bio-Rad),洗脱液:0.1M乙酸-2M乙酸),得到7.65g(1S,2S,3S,5R,6S)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸。其比旋光度如下:
[α]D 22=+58.61(c=0.20,1N HCl)。
产业上利用的可能性
本发明化合物(1S,5R,6S)或(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物可用来作为对精神分裂症、不安及其相关疾病、郁抑症、二极性障碍、癫痫等精神医学性障碍、例如药物依赖症、认知障碍、阿尔茨海默病、亨廷顿舞蹈病、帕金森病、伴随肌强直的运动障碍、脑局部缺血、脑机能不全、脊髓障碍、头部障碍等神经学疾病有治疗效果和预防效果、对第2群代谢移变型谷氨酸受体有作用的含氟氨基酸衍生物((1S,2S,3S,5R,6S)或(1SR,2SR,3SR,5RS,6SR)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸)的合成中间原料。
因此,使用(1S,5R,6S)或(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物作为起始原料的本发明含氟氨基酸衍生物的制造方法,由于在其制造的初期阶段立体选择性地导入氟原子成为可能,因而能高效率制造作为目的的上述含氟氨基酸衍生物。
Claims (6)
1.式(1)所示(1S,5R,6S)或(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物
R表示OR1或NR1R2,R1和R2相同或不同,表示氢原子、C1~C6烷基、C3~C6环烷基、C3~C6环烷基C1~C6烷基、芳基、芳基C1~C6烷基、C1~C6烷氧基C1~C6烷基、C1~C6羟烷基、C1~C6烷硫基C1~C6烷基,或C1~C6巯基烷基。
2.权利要求1记载的衍生物,其特征在于在R1和/或R2是氢原子以外的基团的情况下,各该基团上的至少一个氢原子被从下列组成的一组中选择的基团取代:卤素原子、烷基、烷氧基、烷硫基、硝基、氨基、羟基、硫醇基、甲酰基、羧基、酰基、烷氧羰基、氰基、氨基甲酰基、芳基和杂环基。
3.权利要求1记载的羧酸衍生物的制造方法,其特征在于包含
用过氧化物氧化式(2)所示(1S,5R,6S)或(1SR,5RS,6SR)-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物
式中R表示OR1或NR1R2,R1和R2相同或不同,表示氢原子、C1~C6烷基、C3~C6环烷基、C3~C6环烷基C1~C6烷基、芳基、芳基C1~C6烷基、C1~C6烷氧基C1~C6烷基、C1~C6羟烷基、C1~C6烷硫基C1~C6烷基,或C1~C6巯基烷基,制成式(3)所示(1S,3R,4R,5R,6S)或(1SR,3RS,4RS,5RS,6SR)-环氧衍生物的步骤
式中,R与上述相同,和
使上述环氧衍生物与氟化剂反应的步骤。
4.权利要求3记载的方法,其特征在于在式(2)衍生物的R1和/或R2是氢原子以外的基团的情况下,各该基团上的至少一个氢原子被从下列组成的一组中选择的基团取代:卤素原子、烷基、烷氧基、烷硫基、硝基、氨基、羟基、硫醇基、甲酰基、羧基、酰基、烷氧羰基、氰基、氨基甲酰基、芳基和杂环基。
5.式(7)所示的(1S,2S,3S,5R,6S)或(1SR,2SR,3SR,5RS,6SR)-2-氨基-3-氟双环[3.1.0]己烷-2,6-二羧酸、其医药上可接受的盐或其水合物的制造方法,
其特征在于包含将式(1)所示(1S,5R,6S)或(1SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物加氢
式中R表示OR1或NR1R2,R1和R2相同或不同,表示氢原子、C1~C6烷基、C3~C6环烷基、C3~C6环烷基C1~C6烷基、芳基、芳基C1~C6烷基、C1~C6烷氧基C1~C6烷基、C1~C6羟烷基、C1~C6烷硫基C1~C6烷基,或C1~C6巯基烷基,制成式(4)所示(1S,3S,5R,6S)或(1SR,3SR,5RS,6SR)-3-氟-2-氧代双环[3.1.0]己烷-6-羧酸衍生物的步骤
式中,R与上述相同,和
使上述羧酸衍生物发生乙内酰脲化或氨基氰化物化,制成式(5)所示(1S,2S,3S,5R,6S)或(1SR,2SR,3SR,5RS,6SR)-乙内酰脲衍生物
式中,R与上述相同,或式(6)所示(1S,2S,3S,5R,6S)或(1SR,2SR,3SR,5RS,6SR)-氨基氰化物衍生物的步骤
式中,R与上述相同,和
使上述乙内酰脲衍生物或氨基氰化物衍生物水解的步骤。
6.权利要求5记载的方法,其特征在于在式(1)衍生物的R1和/或R2是氢原子以外的基团的情况下,各该基团上的至少一个氢原子被从下列组成的一组中选择的基团取代:卤素原子、烷基、烷氧基、烷硫基、硝基、氨基、羟基、硫醇基、甲酰基、羧基、酰基、烷氧羰基、氰基、氨基甲酰基、芳基和杂环基。
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EP1142860A4 (en) | 2003-06-04 |
KR100567288B1 (ko) | 2006-04-04 |
KR20010101261A (ko) | 2001-11-14 |
DK1142860T3 (da) | 2004-11-22 |
EP1142860B1 (en) | 2004-08-11 |
CA2354619A1 (en) | 2000-06-29 |
US6392086B1 (en) | 2002-05-21 |
AU767592B2 (en) | 2003-11-20 |
HK1047430B (zh) | 2005-06-10 |
PT1142860E (pt) | 2004-11-30 |
JP2000239222A (ja) | 2000-09-05 |
DE69919402T2 (de) | 2005-08-04 |
WO2000037410A1 (en) | 2000-06-29 |
JP4399932B2 (ja) | 2010-01-20 |
ATE273267T1 (de) | 2004-08-15 |
CA2354619C (en) | 2008-04-22 |
ES2226472T3 (es) | 2005-03-16 |
DE69919402D1 (de) | 2004-09-16 |
EP1142860A1 (en) | 2001-10-10 |
AU1688300A (en) | 2000-07-12 |
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