CN1498201A - 二环羧酸衍生物的制备方法 - Google Patents
二环羧酸衍生物的制备方法 Download PDFInfo
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- CN1498201A CN1498201A CNA028063260A CN02806326A CN1498201A CN 1498201 A CN1498201 A CN 1498201A CN A028063260 A CNA028063260 A CN A028063260A CN 02806326 A CN02806326 A CN 02806326A CN 1498201 A CN1498201 A CN 1498201A
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- 239000002253 acid Substances 0.000 title claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 title 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 4
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- 125000006239 protecting group Chemical group 0.000 claims abstract description 3
- -1 C 1-6Alkyl Chemical group 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 12
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- 125000000217 alkyl group Chemical group 0.000 claims description 5
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- 238000000034 method Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 5
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- OEBJBBSPVBRJFD-UHFFFAOYSA-N 4-hydroxy-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid Chemical class OC1CC(=O)C2C(C(O)=O)C12 OEBJBBSPVBRJFD-UHFFFAOYSA-N 0.000 abstract 1
- 125000005358 mercaptoalkyl group Chemical group 0.000 abstract 1
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- 229910052731 fluorine Inorganic materials 0.000 description 9
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- 229910052736 halogen Inorganic materials 0.000 description 4
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- 239000012046 mixed solvent Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
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- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
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- 238000010511 deprotection reaction Methods 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 230000003449 preventive effect Effects 0.000 description 3
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- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
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- 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
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
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- C07C2602/14—All rings being cycloaliphatic
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Abstract
本发明提供下式(2)表示的2-氧代二环〔3.1.0〕己-3-烯-6-甲酸衍生物的制备方法,其特征在于,使右式(1)表示的4-羟基-2-氧代二环〔3.1.0〕己烷-6-甲酸衍生物在酸或碱的存在下反应。(式中,R1表示氢原子、C1-6烷基、C3-6环烷基、C3-6环烷基C1-6烷基、取代或未取代的苯基取代的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、C1-6巯基烷基或者取代或未取代的苯基,R2表示氢原子或羟基的保护基。)(式(2)中,R1与上述相同。)提供对于2-氨基-3-氟二环〔3.1.0〕己烷-2,6-二甲酸衍生物的有效合成有用的化合物的制备方法。
Description
技术领域
本发明涉及2-氧代二环〔3.1.0〕己-3-烯-6-甲酸衍生物的制备方法。
背景技术
谷氨酸受体之一的メタボトロピツク谷氨酸受体在药理学上分为3个组。据说其中第2组(mGluR2/mGluR3)与腺苷酸环化酶结合,抑制环腺苷酸(cAMP)的ホルスコリン刺激性蓄积(Trends Pharmacol.Sci.,14 13(1993)),因此作用于第2组メタボトロピツク谷氨酸受体的化合物对于精神分裂症、焦虑及其相关疾病、抑郁、二极性障碍、癫痫等精神医学障碍,药物依症、认知障碍、阿耳茨海默氏病、亨廷顿氏舞蹈病、帕金森氏病、伴有肌肉僵直的运动障碍、脑缺血、脑衰竭、脊髓障碍、头部障碍等神经学疾病具有治疗效果和预防效果。
此外,在国际专利申请WO9938839中,作为作用于第2组メタボトロピツク谷氨酸受体的化合物,记载了2-氨基-3-氟二环〔3.1.0〕己烷-2,6-二甲酸(3),而且在国际专利申请WO0037410中,作为其制备方法,提出了如下述反应式1(式中,R1与本说明书中的定义相同)所示的2-氨基-3-氟二环〔3.1.0〕己烷-2,6-二甲酸(3)的制备方法。
另外,化合物(1)及其制备方法如下述反应式2(式中,R1和R2与本说明书中的定义相同)所示,记载在国际专利申请WO0058258中,但是并没有涉及由化合物(1)制备化合物(2)(包括化合物(2’))的方法的记载。
反应式1
反应式2
本发明的目的在于提供一种2-氧代二环〔3.1.0〕己-3-烯-6-甲酸衍生物(2)的制备方法,该化合物对于2-氨基-3-氟二环〔3.1.0〕己烷-2,6-二甲酸的有效合成是有用的合成中间体,且2-氨基-3-氟二环〔3.1.0〕己烷-2,6-二甲酸作用于第2组メタボトロピツク谷氨酸受体,对精神分裂症、焦虑及其相关疾病、抑郁、二极性障碍、癫痫等精神医学障碍,以及药物依赖症、认知障碍、阿耳茨海默氏病、亨廷顿氏舞蹈病、帕金森氏病、伴有肌肉僵直的运动障碍、脑缺血、脑衰竭、脊髓障碍、头部障碍等神经学疾病具有治疗效果和预防效果。
发明公开
本发明人为了实现上述目的进行了悉心研究,结果发现了合成2-氨基-3-氟二环〔3.1.0〕己烷-2,6-二甲酸的有用合成中间体2-氧代二环〔3.1.0〕己-3-烯-6-甲酸衍生物(2)的有效制备方法,从而完成了本发明。
也就是说,本发明为式(2)表示的2-氧代二环〔3.1.0〕己-3-烯-6-甲酸衍生物的制备方法,其特征在于,使式(1)表示的4-羟基-2-氧代二环〔3.1.0〕己烷-6-甲酸衍生物在酸或碱的存在下反应,
(式中,R1表示氢原子、C1-6烷基、C3-6环烷基、C3-6环烷基C1-6烷基、取代或未取代的苯基取代的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、C1-6巯基烷基或者取代或未取代的苯基,R2表示氢原子或羟基的保护基。)
(式中,R1与上述定义相同。)
本发明中使用的用语定义如下。在本发明中,“Cn-m”表示其后面的基团具有n~m个碳原子。
C1-6基表示直链状或支链状的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、1-乙基丙基、己基、异己基、2-乙基丁基、庚基、异戊基、己基、异己基等。C3-6环烷基是指环丙基、环丁基、环戊基、环己基等。C3-6环烷基C1-6烷基是指环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基等。取代或未取代的苯基是指在苯环上具有1~3个选自氢原子、氟原子、氯原子、溴原子等卤素原子、C1-6基、C1-6烷酰基、氰基、硝基、羟基、甲氧基等C1-6烷氧基的任意基团的苯基。取代或未取代的苯基取代的C1-6烷基是指被1个或2个苯基取代的直链状或支链状烷基,例如苯甲基、二苯基甲基、1-苯基乙基、2-苯基乙基、4-甲氧基苯甲基等。C1-6烷氧基C1-6烷基是指直链状或支链状的烷氧基烷基,例如甲氧基甲基、乙氧基甲基、甲氧基乙基、乙氧基乙基、丙氧基乙基、异丙氧基乙基、丁氧基乙基、异丁氧基乙基、戊氧基乙基、异戊氧基乙基等。C1-6羟烷基是指2-羟基乙基、3-羟基丙基、2,3-二羟基丙基等。C1-6烷酰基是指直链状或支链状烷酰基,例如甲酰基、乙酰基、新戊酰基等。C1-6烷硫基C1-6烷基是指直链状或支链状的烷硫基烷基,例如甲硫基甲基、2-甲硫基乙基等。C1-6巯基烷基是指2-巯基乙基、3-巯基丙基、2,3-二巯基丙基等。
对于上述各种基团,其基团上的至少1个氢原子可以被氟原子、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、噻吩基等芳基或杂环基团;甲氧基羰基、乙氧基羰基等烷氧基羰基;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、丙硫基等烷硫基等非氢原子或基团取代。因此,例如2,2,2-三氯乙基、2,6-二甲基环己烷-1-基和2,4-二甲基戊烷-3-基等也包括在R1的范畴内。另外,这些取代基中的碳原子数不包括在上述n或m中。羟基的保护体是指被一般的羟基保护基保护的形态,例如三甲基甲硅烷氧基、叔丁基二甲基甲硅烷氧基等甲硅烷氧基保护体,或乙酰氧基、三氟乙酰氧基等酰基化体等。
式(1)表示的化合物中存在4个手性碳,另外,式(2)表示的化合物中存在3个手性碳。因此,本发明化合物可以作为光学活性体、其对映异构体、消旋体等对映异构体混合物以及非对映异构体混合物存在。也就是说,式(1)和(2)表示的化合物的光学活性体、其对映异构体、消旋体等对映异构体混合物以及非对映异构体混合物均包括在本发明的化合物内。
本发明的式(2)的化合物可以通过以下的反应制备。
以下的反应式中,R1和R2与上述相同,X1表示氯原子、溴原子、碘原子、三氟甲磺酰氧基、甲磺酰氧基、对甲苯磺酰氧基等磺酰氧基,X2表示式R3S(O)n-或R3Se(O)n-(式中,R3表示甲基、乙基和苯基,n表示0~2的整数)表示的基团。另外,关于反应中使用的一般性羟基的保护和脱保护,详细记载于“PROTCTTVE GROUPS IN ORGANIC SYNTHESIS,THEODORA W.GREENE and PETER G.M.WUTS著”中,该文献的公开也援引到本说明书中。
通过使R2为氢原子以外的化合物(1)的羟基保护基在通常的脱保护条件下脱保护后或在保护的状态下,在酸或碱存在下,在苯、甲苯、己烷等烃类溶剂,二氯甲烷、氯仿等卤素类溶剂,甲醇、乙醇、异丙醇等醇类,四氢呋喃、乙醚、1,2-二甲氧基乙烷等醚类,N,N-二甲基甲酰胺、N-甲基吡咯烷酮等酰胺类,乙腈、二甲基亚砜、六甲基磷酰胺或它们的混合溶剂中进行反应,可以衍生得到化合物(2)。其中,碱表示三乙胺、二异丙基乙胺、吡啶、1,8-二氮杂二环〔5.4.0〕-7-十一碳烯等胺类,碳酸钾、碳酸钠、碳酸氢钠等无机碱类,甲醇钠、乙醇钠、叔丁醇钾等金属醇化物类等,酸表示氯化氢、溴化氢、硫酸等无机酸类,对甲苯磺酸、甲磺酸、三氟乙酸、乙酸等有机酸类。另外,R2为氢原子的化合物(1)在磷酰氯-吡啶、亚硫酰氯-吡啶等条件下脱水,可以得到化合物(2)。
另外,R2为氢原子的化合物(1)也可以在苯、甲苯、己烷等烃类溶剂,二氯甲烷、氯仿等卤素类溶剂,四氢呋喃、乙醚、1,2-二甲氧基乙烷等醚类,N,N-二甲基甲酰胺、N-甲基吡咯烷酮等酰胺类,乙腈或它们的混合溶剂等惰性溶剂中,在三乙胺、二异丙基乙胺、吡啶、4-二甲氨基吡啶等胺类,碳酸钾、碳酸氢钠等无机碱类等碱存在或不存在的条件下,与三氟甲磺酸酐、N-苯基二(三氟甲磺酰亚胺)、甲磺酰氯、对甲苯磺酰氯等磺酰基化试剂反应,或者与亚硫酰氯、草酰氯、三苯基膦-四溴化碳、N-溴代琥珀酰亚胺-三苯基膦、碘-三苯基膦等卤化试剂反应制得化合物(10)以后,在苯、甲苯、己烷等烃类溶剂,二氯甲烷、氯仿等卤素类溶剂,四氢呋喃、乙醚、1,2-二甲氧基乙烷等醚类,N,N-二甲基甲酰胺、N-甲基吡咯烷酮等酰胺类,乙腈或它们的混合溶剂等惰性溶剂中,用三乙胺、二异丙基乙胺、吡啶、1,8-二氮杂二环〔5.4.0〕-7-十一碳烯等胺类,碳酸钾、碳酸氢钠、氢化钠等无机碱类,甲醇钠、叔丁醇钾等金属醇化物类等反应,衍生得到化合物(2)。
而且,化合物(10)在氢化钠、碳酸钾、三乙胺等碱的存在下,与苯硫醇、甲硫醇等硫醇类,苯硒醇等硒醇类反应,转变成化合物(11)后,在惰性溶剂中,在碱存在的条件下反应,或者用间氯过苯甲酸、过氧化氢等氧化剂氧化后,在惰性溶剂中,在碱存在或不存在的条件下反应,可以得到化合物(2)。其中,惰性溶剂是指苯、甲苯、己烷等烃类溶剂,二氯甲烷、氯仿等卤素类溶剂,甲醇、乙醇、异丙醇等醇类,四氢呋喃、乙醚、1,2-二甲氧基乙烷等醚类,N,N-二甲基甲酰胺、N-甲基吡咯烷酮等酰胺类,乙腈、二甲基亚砜、六甲基磷酰胺,或它们的混合溶剂,另外碱是指三乙胺、二异丙基乙胺、吡啶、1,8-二氮杂二环〔5.4.0〕-7-十一碳烯等胺类,碳酸钾、碳酸钠、碳酸氢钠等无机碱类,甲醇钠、乙醇钠、叔丁醇钾等金属醇化物类等。
其中,化合物(2)为非对映异构体混合物的场合,可以通过使用常规硅胶的柱色谱法或重结晶法,分离各种非对映异构体。另外,化合物(2)为消旋体等对映异构体混合物的场合,可以通过使用氨基甲酸纤维素衍生物、氨基甲酸淀粉衍生物等手性载体的HPLC法,光学拆分成(+)和(-)的各种光学活性体。另外,通过一般酯部位的水解(PROTECTTVE GROUPS IN ORGANICSYNTHESIS,THEODORA.W.GREENE and PETER G.M.WUTS著记载的方法)将R1转变成氢原子后,与(+)或(-)-1-苯基乙胺、(+)或(-)-苯基甘氨醇(グリシノ-ル)、(+)或(-)-2-氨基-1-丁醇、(+)或(-)-丙氨醇(アラニノ-ル)、马钱子碱、辛可尼丁、辛可宁、激肽、奎尼丁、脱氢松香胺等光学活性的胺类成盐,或者与光学活性的伯胺或仲胺衍生为酰胺衍生物,也可以光学拆分为(+)和(-)的各种光学活性体。
发明的最佳实施方式
以下给出本发明的代表性实施例,但是本发明并不受这些实施例的限定。
实施例1
(1SR,5RS,6SR)-2-氧代二环〔3.1.0〕己-3-烯-6-甲酸乙酯的制备
在室温下,向(1SR,4RS,5RS,6SR)-4-叔丁基二甲基甲硅烷氧基-2-氧代二环〔3.1.0〕己烷-6-甲酸乙酯和(1SR,4SR,5RS,6SR)-4-叔丁基二甲基甲硅烷氧基-2-氧代二环〔3.1.0〕己烷-6-甲酸乙酯的混合物1.03g的氯仿10mL溶液中,加入三氟化硼·乙醚络合物0.13mL,在室温下反应15小时。将反应混合物注入到饱和碳酸氢钠水溶液-冰中,用氯仿萃取3次,用乙酸乙酯萃取2次。合并有机相,用无水硫酸钠干燥后,过滤除去干燥剂,在减压条件下浓缩滤液。将得到的残渣0.72g和对甲苯磺酸·1水合物66mg用苯6mL稀释,加热回流1.5小时。加入对甲苯磺酸·1水合物66mg,再加热回流1小时。将反应混合物冷却至室温后,用饱和碳酸氢钠水溶液和乙酸乙酯分液。用乙酸乙酯萃取水相2次后,合并有机相,用无水硫酸钠干燥。过滤除去干燥剂后,在减压条件下浓缩滤液,用硅胶柱色谱法(Wakogel C-200;己烷/乙酸乙酯=7∶1)精制得到的残渣,得到(1SR,5RS,6SR)-2-氧代二环〔3.1.0〕己-3-烯-6-甲酸乙酯0.44g。
m.p.77~78℃
工业实用性
按照本发明,提供一种2-氧代二环〔3.1.0〕己-3-烯-6-甲酸衍生物(2)(本化合物作为WO9938839记载的对于精神分裂症、焦虑及其相关疾病、抑郁、二极性障碍、癫痫等精神医学障碍,药物依赖症、认知障碍、阿耳茨海默氏病、亨廷顿氏舞蹈病、帕金森氏病、伴有肌肉僵直的运动障碍、脑缺血、脑衰竭、脊髓障碍、头部障碍等神经学疾病具有治疗效果和预防效果的作用于第2组メタボトロピツク谷氨酸受体的2-氨基-3-氟二环〔3.1.0〕己烷-2,6-二甲酸衍生物(3)的合成中间原料有用。)的有效制备方法,从而能够有效地制备WO9938839记载的2-氨基-3-氟二环〔3.1.0〕己烷-2,6-二甲酸衍生物(3)。
Claims (2)
2、如权利要求1所述的2-氧代二环(3.1.0〕己-3-烯-6-甲酸衍生物的制备方法,其中,R1为氢原子或C1-6烷基。
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CN108383719A (zh) * | 2018-05-05 | 2018-08-10 | 湖北荆洪生物科技股份有限公司 | 一种环己甲酸的生产工艺 |
CN108675925A (zh) * | 2018-05-05 | 2018-10-19 | 湖北荆洪生物科技股份有限公司 | 一种环戊甲酸的生产工艺 |
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JP2008100951A (ja) * | 2006-10-19 | 2008-05-01 | Kawaguchi Yakuhin Kk | 2−シクロペンタデセノンの製造方法 |
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CN108675925A (zh) * | 2018-05-05 | 2018-10-19 | 湖北荆洪生物科技股份有限公司 | 一种环戊甲酸的生产工艺 |
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CA2441127A1 (en) | 2002-09-19 |
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