CN1093853C - 制备(s)－4－氨基－庚－5,6－二烯酸的新方法及其中间体 - Google Patents
制备(s)－4－氨基－庚－5,6－二烯酸的新方法及其中间体 Download PDFInfo
- Publication number
- CN1093853C CN1093853C CN99117511A CN99117511A CN1093853C CN 1093853 C CN1093853 C CN 1093853C CN 99117511 A CN99117511 A CN 99117511A CN 99117511 A CN99117511 A CN 99117511A CN 1093853 C CN1093853 C CN 1093853C
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- CN
- China
- Prior art keywords
- acid
- phenyl
- alkyl
- butyrolactam
- succinimide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- XWILORJMRMFKPM-ZCFIWIBFSA-N (4s)-4-aminohepta-5,6-dienoic acid Chemical compound C=C=C[C@@H](N)CCC(O)=O XWILORJMRMFKPM-ZCFIWIBFSA-N 0.000 title abstract 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 57
- 239000003153 chemical reaction reagent Substances 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 229960002317 succinimide Drugs 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 14
- 229940053198 antiepileptics succinimide derivative Drugs 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- -1 lithium triethylborohydride Chemical group 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 238000005194 fractionation Methods 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 abstract description 28
- 239000000543 intermediate Substances 0.000 abstract description 10
- 239000013038 irreversible inhibitor Substances 0.000 abstract description 2
- 102100035923 4-aminobutyrate aminotransferase, mitochondrial Human genes 0.000 abstract 1
- 101710115046 4-aminobutyrate aminotransferase, mitochondrial Proteins 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- REZQBEBOWJAQKS-UHFFFAOYSA-N triacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO REZQBEBOWJAQKS-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000000654 additive Substances 0.000 description 8
- 230000000996 additive effect Effects 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VVUHUDLLBPXWMP-UHFFFAOYSA-N O=P1CCCCO1 Chemical class O=P1CCCCO1 VVUHUDLLBPXWMP-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000005906 dihydroxylation reaction Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000003797 solvolysis reaction Methods 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- IRXBNHGNHKNOJI-UHFFFAOYSA-N butanedioyl dichloride Chemical compound ClC(=O)CCC(Cl)=O IRXBNHGNHKNOJI-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 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 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical class CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XUJHKPSBHDQIOD-UHFFFAOYSA-N (2-bromo-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)C(Br)C1C2(C)C XUJHKPSBHDQIOD-UHFFFAOYSA-N 0.000 description 1
- AVXBCNFAWJPVFX-UHFFFAOYSA-N (4,7-dimethyl-3-oxo-7-bicyclo[2.2.1]heptanyl)methanesulfonic acid Chemical compound C1CC2(C)C(=O)CC1C2(CS(O)(=O)=O)C AVXBCNFAWJPVFX-UHFFFAOYSA-N 0.000 description 1
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- PKRSYEPBQPFNRB-UHFFFAOYSA-N 2-phenoxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1OC1=CC=CC=C1 PKRSYEPBQPFNRB-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 229910001038 basic metal oxide Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical group [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000003949 imides Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 230000007935 neutral effect Effects 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
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- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
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- Hydrogenated Pyridines (AREA)
Abstract
本发明涉及制备(S)-4-氨基-庚-5，6-二烯酸和其药用盐(其用作GABA-T的不可逆抑制剂)的新对映有择方法，涉及其新的中间体和其制备方法。
Description
本发明涉及制备(S)-4-氨基-庚-5，6-二烯酸及其可药用盐的两种新方法。这些化合物可用作GABA-T的不可逆抑制剂〔美国专利号4,454,156，1984年6月12日〕。本发明还涉及其新的中间体以及制备其中间体的方法。
本发明的方法和中间体提供了一种制备(S)-4-氨基-庚-5，6-二烯酸的新的对映有择方法。
本发明提供了制备(S)-4-氨基-庚-5，6-二烯酸及其可药用盐的两种新方法，包括下列步骤：
(a).使式(1)的拆分的胺：
其中：
Z为C1-C6烷基、苯基或带有1-3个取代基的取代苯基，取代基选自C1-C4烷基、C1-C4烷氧基或卤素；与合适的琥珀酰亚胺形成试剂反应得到琥珀酰亚胺衍生物；
(b).使琥珀酰亚胺衍生物与合适的还原剂反应得到5’-羟基丁内酰胺衍生物；
(c).使5’-羟基丁内酰胺衍生物依次与合适的脱羟基酸和合适的溶剂解试剂反应得到(S)-5-丙二烯基丁内酰胺；
(d).使(S)-5-丙二烯基丁内酰胺与合适的内酰胺开环试剂反应得到(S)-4-氨基-庚-5，6-二烯酸；
(e).使(S)-4-氨基-庚-5，6-二烯酸任选与合适的可药用酸或碱反应生成其可药用盐。
另外，本发明提供了制备式(3)的5’-羟基丁内酰胺衍生物的新方法：
其中：
Z为C1-C6烷基，苯基或带有1-3个取代基的取代苯基，取代基选自C1-C4烷基、C1-C4烷氧基或卤素；该方法包括下列步骤：
(a).使式(1)的拆分的胺：
其中：
Z为C1-C6烷基、苯基或带有1-3个取代基的取代苯基，取代基选自C1-C4烷基、C1-C4烷氧基或卤素；与合适的琥珀酰亚胺形成试剂反应得到琥珀酰亚胺衍生物；
(b).使琥珀酰亚胺衍生物与合适的还原剂反应得到5’-羟基丁内酰胺衍生物。
另外，本发明提供了制备(S)-4-氨基-庚-5，6-二烯酸及其可药用盐的新方法，包括下列步骤：
(a).使式(3)的5’-羟基丁内酸胺衍生物：其中：
Z为C1-C6烷基、苯基或带有1-3个取代基的取代苯基，取代基选自C1-C4烷基、C1-C4烷氧基或卤素；依次与合适的脱羟基酸和合适的溶剂解试剂反应得到(S)-5-丙二烯基丁内酰胺；
(b).使(S)-5-丙二烯基丁内酰胺与合适的内酰胺开环试剂反应得到(S)-4-氨基-庚-5，6-二烯酸；
(c).使(S)-4-氨基-庚-5，6-二烯酸任选与合适的可药用酸或碱反应生成其可药用盐。
另外，本发明提供了新的下式的琥珀酰亚胺衍生物：
其中：
Z为C1-C6烷基、苯基或带有1-3个取代基的取代苯基，取代基选自C1-C4烷基、C1-C4烷氧基或卤素。此外，本发明提供了新的下式的5’-羟基丁内酰胺衍生物：其中：
Z为C1-C6烷基、苯基或带有1-3个取代基的取代苯基，取代基选自C1-C4烷基、C1-C4烷氧基或卤素。
在本申请中使用：
a).术语“C1-C6烷基”是指含有1-6个碳原子的支链或直链或环状的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、环戊基、正己基、环己基等；
b).术语“C1-C4烷基”是指含有1-4个碳原子的支链或直链烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等；
c).术语“C1-C4烷氧基”是指含1-4个碳原子的支链或直链烷氧基，如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等；
d).术语“卤素”是指氟原子、氯原子、溴原子、或碘原子；
e).术语“取代的苯基”是指：
其中：
Q、Y和X独立地选自：氢、C1-C4烷基、C1-C4烷氧基或卤素；
f).符号
是指从纸平面向前伸出的键。
g).符号“……”是指从纸平面向后伸出的键。
h).符号
是指立体化学未被指明的键。
i).术语“低级链烷醇”是指含有1-4个碳原子的醇，该术语具体包括：甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇和2-丁醇。
j).术语“可药用盐”是指酸加成盐或碱加成盐。
术语“可药用酸加成盐”是指(S)-4-氨基-庚-5，6-二烯酸或其任何中间体的任何无毒有机酸或无机酸的加成盐。形成合适的盐的无机酸实例包括盐酸、氢溴酸、硫酸和磷酸以及酸的金属盐如正磷酸-氢钠和硫酸氢钾。形成合适的盐的有机酸实例包括一、二和三羧酸，这些酸的实例为乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯基乙酸、肉桂酸、水场酸、2-苯氧基苯甲酸和磺酸如对甲苯碘酸、甲磺酸和2-羟基乙磺酸。这些盐可以水合形式或基本上无水形式存在。
术语“可药用碱加成盐”是指(S)-4-氨基-庚-5，6-二烯酸或其任何中间体的任何无毒有机碱或无机碱的加成盐。形成合适的盐的碱实例包括碱金属或碱土金属氢氧化物如氢氧化钠、钾、钙、镁或钡；氨以及脂族、环状或芳族有机胺如甲胺、二甲胺、三甲胺、三乙胺、二乙胺、异丙基二乙胺、吡啶和甲基吡啶。
正如本领域普通技术人员所公知的那样，对于式(1)、(2)和(3)化合物的立体化学的(R)-和(S)-的Cahn-Ingold-Prelog符号取决于Z的性质。
就本申请而言，N-取代的丁内酰胺衍生物中表示位置的数字具有双重性，涉及N-取代的丁内酰胺环上位置的数字带有“′”，而涉及不在N-取代的丁内酰胺环上的位置的数字不带有“′”。
本发明包括的化合物的实例包括：
(R)-N-(1-苯基-丁-3-炔)琥珀酰亚胺；
(R)-N-〔1-(4-氯苯基)-丁-3-炔〕琥珀酰亚胺；
(R)-N-〔1-(4-溴苯基)-丁-3-炔〕琥珀酰亚胺；
(R)-N-〔1-(4-甲基苯基)-丁-3-炔〕琥珀酰亚胺；
(R)-N-〔1-(4-甲氧基苯基)-丁-3-炔〕琥珀酰亚胺；
(R)-N-〔1-(2，4-二甲基苯基)-丁-3-炔〕琥珀酰亚胺；
(R)-N-〔1-(2，4，6-三甲基苯基)-丁-3-炔〕琥珀酰亚胺；
(S)-N-(1-乙基-丁-3-炔)琥珀酰亚胺；
(S)-N-(1-丙基-丁-3-炔)琥珀酰亚胺；
(R)-N-(1-叔丁基-丁-3-炔)琥珀酰亚胺；
(R)-N-(1-环己基-丁-3-炔)琥珀酰亚胺；
(1R，5’R和1R，5’S)-N-(1-苯基-丁-3-炔)-5’-羟基丁内酰胺；
(1R，5’R和1R，5’S)-N-〔1-(4-氯苯基)-丁-3-炔〕-5’-羟基丁内酰胺；
(1R，5’R和1R，5’S)-N-〔1-(4-溴苯基)-丁-3-炔〕-5’-羟基丁内酰胺；
(1R，5’R和1R，5’S)-N-〔1-(4-甲基苯基)-丁-3-炔〕-5’-羟基丁内酰胺；
(1R，5’R和1R，5’S)-N-〔1-(4-甲氧基苯基)-丁-3-炔〕-5’-羟基丁内酰胺；
(1R，5’R和1R，5’S)-N-〔1-(2，4-二甲基苯基)-丁-3-炔〕-5’-羟基丁内酰胺；
(1R，5’R和1R，5’S)-N-〔1-(2，4，6-三甲基苯基)-丁-3-炔〕-5’-羟基丁内酰胺；
(1S，5’R和1S，5’S)-N-(1-乙基-丁-3-炔)-5’-羟基丁内酰胺；
(1S，5’R和1S，5’S)-N-(1-丙基-丁-3-炔)-5’-羟基丁内酰胺；
(1R，5’R和1R，5’S)-N-(1-叔丁基-丁-3-炔)-5’-羟基丁内酰胺；
(1R，5’R和1R，5’S)-N-(1-环己基-丁-3-炔)-5’-羟基丁内酰胺。
正如本领域普通技术人员所理解的那样，本申请公开的方法可用于制备本文所公开的4-氨基-庚-5，6-二烯酸的任何一种对映体和琥珀酰亚胺衍生物的任何一种对映体以及本文所公开的5’-羟基丁内酰胺衍生物的所有非对映体。制备4-氨基-庚-5，6-二烯酸的对映体取决于原料的立体化学。
制备(S)-4-氨基-庚-5，6-二烯酸的一般合成方法如路线A所示。在路线A中，除非另有说明，所有取代基如上所定义。在路线A中所用的原料、试剂、工艺和方法是本领域普通技术人员公知的和理解的。路线A
用本领域公知的方法如用为此目的的试剂形成的加成盐的分级重结晶法制得拆分的结构式(1)的胺，正如在“Enantiomers，Racemates，and Resolutions”，J.Jacques，A.Collet，& S.H.Wilen，Wiley(1981)和J.Org、Chem.，50，4508-4514(1985)，W.ten Hoere & H.Wynberg中所描述的。
例如，使下式的外消旋的胺：其中Z如上述拆分的胺(1)中所定义，与加成盐形成试剂反应，如酒石酸、10-樟脑横酸、8-樟脑磺酸、3-溴樟脑-10-磺酸、联萘基磷酸、5，5-二甲基-2-羟基-4-(2-甲氧基苯基)-1，3，2-二氧杂磷杂环己烷2-氧化物，5，5-二甲基-2-羟基-4-(2-乙氧基苯基)-1，3，2-二氧杂磷杂环己烷2-氧化物；优选5，5-二甲基-2-羟基-4-(2-甲氧基苯基)-1，3，2-二氧杂磷杂环己烷2-氧化物。通过加热加成盐形成试剂和外消旋的胺在极少量体积的合适溶剂如乙醇、丙醇、异丙醇或醇和水的混合物中的混合物制得加成盐，冷却后过滤收集沉淀出的盐，如果需要提高对映体纯度，可用合适的溶剂如乙醇、丙醇、异丙醇或醇和水的混合物重复进行重结晶、拆分的胺可按本领域公知的通过萃取回收游离胺那样进行回收，通过蒸发和蒸馏或通过重结晶形成的盐来分离出游离胺。
在步骤a中，结构式(1)的拆分的胺与合适的琥珀酰亚胺形成试剂反应生成结构式(2)的琥珀酰亚胺衍生物。
例如，结构式(1)的拆分的胺或结构式(1)的拆分的胺的盐与合适的琥珀酰亚胺形成试剂反应。合适的琥珀酰亚胺形成试剂在本领域中是公知的，包括但不限于琥珀酰氯、琥珀酸和琥珀酐，优选琥珀酐。反应可任选在合适的碱存在下进行。合适的碱可用于中和拆分的胺的盐，或在反应过程中当合适的琥珀酰亚胺形成试剂如琥珀酰氯产生酸时可用于中和释出的酸。合适的碱包括但不限于三乙胺、异丙基二乙胺、吡啶、碳酸氢钠和碳酸钠。反应可在合适的溶剂中进行，例如甲苯、苯或二甲苯可用于其中合适的琥珀酰亚胺形成试剂为琥珀酐或琥珀酸的反应，而二氯甲烷、DMF、THF或THF/水可用于其中合适的琥珀酰亚胺形成试剂为琥珀酰氯的反应。正如本领域所公知的，可通过萃取和蒸发从反应区域中分离出结构式(2)的琥珀酰亚胺衍生物。结构式(2)的琥珀酰亚胺衍生物可用本领域公知的方法如色谱法和重结晶纯化。
在步骤b中，结构式(2)的琥珀酰亚胺衍生物与合适的还原剂反应得到结构式(3)的5’-羟基丁内酰胺衍生物。
正如本领域所公知和理解的那样，该还原反应得到的结构式(3)的5’-羟基丁内酰胺衍生物为在5’位上的立体异构体的混合物。
合适的还原剂在本领域中是公知的且包括但不限于三叔丁氧基铝氢化锂、硼氢化钾、三仲丁基硼氢化锂、硼氢化锂、硼氢化钠和三乙基硼氢化锂，优选硼氢化钠和三乙基硼氢化锂，最优选三乙基硼氢化锂。
例如，结构式(2)的琥珀酰亚胺衍生物与摩尔过量的合适的还原剂反应。反应可在合适的溶剂中进行，用于氢化物还原反应的合适溶剂在本领域中是公知的，例如甲苯、乙醚、甲基叔丁基醚和四氢呋喃(THF)。反应可在不超过酰亚胺官能团的还原温度并使反应以常规速度进行的温度如-78℃下进行。可通过萃取从反应区域中分离出结构式(3)的5’-羟基丁内酰胺衍生物，然后用本领域公知的方法如色谱法和重结晶纯化得到结构式(3)的5’-羟基丁内酰胺衍生物。
在步骤C中，使结构式(3)的5’-羟基丁内酰胺衍生物依次与合适的脱羟基酸和合适的溶剂解试剂反应得到(S)-5-二烯基丁内酰胺(4)。
正如本领域所公知的，合适的脱羟基酸为质子酸，如盐酸、氢溴酸、硫酸、磷酸、三氟乙酸、甲酸、三氟甲磺酸、甲磺酸和对甲苯磺酸，优选三氟乙酸和甲酸，最优选三氟乙酸。
现有技术提示该反应通过路线A1所示的理论上的中间体(a)和(b)进行；〔H.Ent等人，Tet.Lets.，24，2109-2112，(1983)；A.L.Castelhano & A.Krantz，J.Am.Chem.Soc.，106，1877-1879，(1984)；Synthesis，71-82，(1989)〕。
本发明并不受在现有技术中这些理论上的中间体的描述和提出所限制。
例如，结构式(3)的5’-羟基丁内酰胺衍生物与合适的脱羟基酸如三氟乙酸反应。反应在合适的溶剂中进行，溶剂如二氯甲烷，氯仿、四氯化碳、乙醚、甲基叔丁基醚和四氢呋喃。反应在0℃至回流温度下进行，并搅拌1-48小时。然后使反应混合物与本领域公知的合适的溶剂解试剂反应，溶剂解试剂如甲醇、乙醇或水，优选水。用本领域公知的方法如萃取和蒸发从反应区域中分离出(S)-5-丙二烯基丁内酰胺(4)，然后用本领域公知的方法如色谱法和重结晶纯化得到(S)-5-丙二烯基丁内酰胺(4)。
在步骤d中，用合适的内酰胺开环试剂处理(S)-5-丙二烯基丁内酰胺(4)得到(S)-4-氨基-庚-5，6-二烯酸(5)。
合适的内酰胺开环试剂包括但不限于盐酸或氢溴酸的水溶液或氢氧化钾的水溶液，优选盐酸水溶液。
例如，(S)-5-丙二烯基丁内酰胺(4)与1M盐酸水溶液在20℃至回流温度下反应18小时至10天。可用本领域公知的方法，纯化(S)-4-氨基-庚-5，6-二烯酸(5)，例如将反应混合物的pH调至5，接着进行离子交换色谱和重结晶得到(S)-4-氨基-庚-5，6-二烯酸。
另外，使(S)-5-丙二烯基丁内酰胺(4)与摩尔过量的氢氧化钾水溶液反应，一般使用大约1.05-1.5当量。反应在溶剂中进行，如水或含有低级链烷醇的水，低级链烷醇如甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇或2-丁醇，优选2-丙醇。水和低级链烷醇的相对比例可在较宽的范围内变化且其比例对水解来说并不重要。反应在60℃至回流温度下进行1小时至24小时。如果需要的话，通过调节反应介质中的低级链烷醇的比例从反应区域中回收(S)-4-氨基-庚-5，6-二烯酸。反应介质含有60％V/V至大约90％V/V低级链烷醇，优选85％，然后用合适的酸如乙酸或丙酸酸化混合物，通过过滤回收沉淀出的(S)-4-氨基-庚-5，6-二烯酸(5)。
在任选的步骤e中，正如本领域所公知的那样，(S)-4-氨基-庚-5，6-二烯酸与可药用酸生成可药用酸加成盐，或与可药用碱生成可药用碱加成盐。
下列实施例表示路线A所述的典型的合成。应当理解这些实施例仅用于说明而不是对本发明范围的任何限制。在下列实施例中所用的下列术语具有指定的含义：“g”是指克、“mg”是指毫克、“mmol”是指毫摩尔、“mL”是指毫升、“℃”是指摄氏温度、“Rf”是指保留指数、“mp”是指熔点、“dec”是指分解、“〔α〕D 20”是指用1分米管在20℃下用钠焰D线测得的旋光率，“C”是指浓度g/mL，“M”是指摩尔，“MeOH”是指甲醇，“2-PrOH”是指异丙醇，以及“TLC”是指薄层色谱法。
实施例1(R)-1-氨基-1-苯基-丁-3-炔盐酸盐
将(RS)-1-氨基-1-苯基-丁-3-炔〔Zh.Org.Khim.18(4)，980-983(1982)A.Mostamandi，L.A.RemiZova，A.L.PavienKova，I.A.Favorskaya〕(20.0g，138mmol)和(-)-5，5-二甲基-2-羟基-4-(2-甲氧基苯基)-1，3，2-二氧杂磷杂环己烷2-氧化物(35.0g，129mmol)熔于回流的乙醇(300ml)中。将溶液冷却至室温并过滤收集沉淀，用少量异丙醇/乙醇(L/L)冲洗沉淀。用乙醇两次重结晶得到(R)-1-氨基-1-苯基-丁-3-炔5，5-二甲基-2-羟基-4-(2-甲氧基苯基)-1，3，2-二氧杂磷杂环己烷2-氧化物盐(21g)。将(R)-1-氨基-1-苯基-丁-3-炔5，5-二甲基-2-羟基-4-(2-甲氧基苯基)-1，3，2-二氧杂磷杂环己烷2-氧化物盐(21g，50.4mmol)与1M氢氧化钾水溶液(100ml)和甲苯(50ml)的混合物混合并搅拌0.75小时。分离各层，用甲苯(50ml)萃取水层，合并有机层，干燥(Na2SO4)并过滤得到溶液。向溶液中通过入氯化氢气体，直至溶液饱和，然后过滤除去沉淀，并用甲苯冲洗。并用甲苯冲洗。用丁酮(120ml)重结晶得到7.0g标题化合物。旋光率〔α〕D 20＝11.0°(C＝0.500，MeOH)。
实施例2(R)-N-(1-苯基-丁-3-炔)琥珀酰亚胺
将(R)-1-氨基-1-苯基-丁-3-炔盐酸盐(4.0g，22.1mmol)、琥珀酐(4.4g，44.2mmol)和三乙胺(3.1ml，22.1mmol)的甲苯(200ml)溶液混合并搅拌1小时，冷却至室温，加入三乙胺(3.1ml，2.2g，22.1mmol)，然后再搅拦18小时。冷却至室温，倾入水(200ml)中，分离各层，用乙酸乙酯萃取水层。将合并的有机层混合并干燥(MgSO4)。其空浓缩合并的有机层得到粗的(R)-N-(1-苯基-丁-3-炔)琥珀酰亚胺。用闪式色谱法纯化(35％乙酸乙酯/庚烷)，合并含有产物的馏分并浓缩，重结晶(2-PrOH/庚烷)得到4.02g标题化合物：mp；109℃，Rf＝0.23，硅胶TLC，35％乙酸乙酯/庚烷。旋光率〔α〕D 20＝20.0°(C＝1.000，MeOH)。元素分析：C14H13NO2计算值：C，76.99；H，5.70；N，6.16；实测值：C，76.84；H，5.83；N，5.99。
实施例3(1R，5’R和1R，5’S)-N-(1-苯基-丁-3-炔)-5’-羟基丁内酰胺
将(R)-N-(1-苯基-丁-3-炔)琥珀酰亚胺(0.1g，0.44mmol)的THF(2ml)溶液冷却至-78℃，加入三乙基硼氢化锂溶液(0.66ml，1M的THF溶液，0.66mmol)，加入的速度应使温度升高不超过-65℃，加完后搅拌1小时。加入饱和的碳酸氢钠溶液(1ml)，使反应混合物温热至室温。真空浓缩得到油状物，将油状物溶于乙酸乙酯(10ml)中，用水(10ml)洗涤，分离各层，用乙酸乙酯(10ml)萃取水层。合并有机层并用饱和的氯化钠溶液选涤，干燥(MgSO4)并真空浓缩得到油状物。用闪式色谱法纯化(35％乙酸乙酯/庚烷)，合并含有产物的馏份并浓缩得到标题化合物，它为在5’位非对映体的7∶3混合物，它为经冷却固化的油状物。Rf＝0.04，硅胶TLC，35％乙酸乙酯/庚烷。MS(CI/CH4)∶M+H＝230，旋光率〔α〕D 20＝23.2°(C＝2.000，MeOH)。
实施例4(S)-5-丙二烯基内酰胺
将三氟乙酸(12ml，15.6mmol)滴加到(1R，5’R和1R，5’S)-N-(1-苯基-丁-3-炔)-5’-羟基丁内酰胺(1.67g，7.29mmol)的二氯甲烷(50ml)溶液中并搅抖小时，用水(10ml)处理反应混合物，并分离各层，用饱和氯化钠溶液(10ml)洗涤，干燥(MgSO4)有机层并浓缩得到油状物。用闪式色谱法纯化(2％甲醇/二氯甲烷)，合并含有产物的馏份并浓缩得到固体标题化合物，Rf＝0.29，硅胶TLC，2％甲醇/二氯甲烷，元素分析，C7H9NO计算值：C，67.77；H，7.29；N，11.29；实测值：C，67.71；H，7.35；N，11.03。旋光率〔α〕D 20＝71.0°(C＝1.060，MeOH)。
实施例5(S)-4-氨基-庚-5，6-二烯酸
将(S)-5-丙二烯基丁内酰胺(0.11g，0.89mmol)和1M盐酸(4ml)加热至90℃，并维持18小时。冷却至室温。加入1M氢氧化钠，直至溶液的pH为5。用离子交换色谱法纯化(Dowex1×2，100目，氢氧化物形式)，将混合物加到柱中，用水洗涤树脂，直至柱中的流出物为中性。用0.25M乙酸水溶液洗脱产物，合并含有产物的馏份并真空浓缩至大约20ml，冷冻干燥得到0.1g标题化合物：mp；135℃(dec)。旋光率〔α〕D 20＝40.6℃(C＝1.020，MeOH)。
实施例6(S)-4-氨基-庚-5，6-二烯酸
将(S)-5-丙二烯基丁内酰胺(10mmol)与在水(1.1ml)和2-丙醇(13.2ml)中的钾(11mmol)混合并加热回流，12小时后，冷却反应混合物，缓慢加入乙酸(11mmol)，在冰浴中冷却反应混合物并过滤得到标题化合物。
Claims (10)
1.制备下式化合物的方法：
其中：
Z为C1-C6烷基、苯基或带有1-3个取代基的取代苯基，取代基选自C1-C4烷基、C1-C4烷氧基或卤素；该方法包括下列步骤：
(a).使下式的拆分的胺：
其中：
Z为C1-C6烷基、苯基或带有1-3个取代基的取代苯基，取代基选自C1-C4烷基、C1-C4烷氧基或卤素；
与合适的琥珀酰亚胺形成试剂反应得到琥珀酰亚胺衍生物；
(b).使琥珀酰亚胺衍生物与合适的还原剂反应得到5′-羟基丁内酰胺衍生物。
2.根据权利要求1的方法，其中合适的琥珀酰亚胺形成试剂为琥珀酐。
3.根据权利要求1的方法，其中合适的还原剂为硼氢化钠。
4.根据权利要求的方法，其中合适的还原剂为三乙基硼氢化锂。
5.下式化合物：其中：
Z为C1-C6烷基、苯基或带有1-3个取代基的取代苯基，取代基选自C1-C4烷基、C1-C4烷氧基或卤素。
6.根据权利要求5的化合物，其中Z为苯基。
7.根据权利要求5的化合物，其中Z为叔丁基。
8.下式化合物：
其中：
Z为C1-C6烷基、苯基或带有1-3个取代基的取代苯基，取代基选自C1-C4烷基、C1-C4烷氧基或卤素。
9.根据权利要求8的化合物，其中Z为叔丁基。
10.根据权利要求8的化合物，其中Z为苯基。
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| EP0094886A1 (en) * | 1982-05-17 | 1983-11-23 | Merrell Toraude Et Compagnie | Aminoalkadiene derivative |
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| US4661510A (en) * | 1983-08-17 | 1987-04-28 | Syntex (U.S.A.) Inc. | α-allenic-α-amino acids as enzyme inhibitors |
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| EP0094886A1 (en) * | 1982-05-17 | 1983-11-23 | Merrell Toraude Et Compagnie | Aminoalkadiene derivative |
| EP0492350A1 (en) * | 1990-12-17 | 1992-07-01 | Merrell Pharmaceuticals Inc. | Process for the production of (S)-vinyl and (S) allenyl gaba |
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| US5654477A (en) | 1997-08-05 |
| DK0705240T3 (da) | 1998-02-09 |
| AU672315B2 (en) | 1996-09-26 |
| HU223066B1 (hu) | 2004-03-01 |
| CN1256266A (zh) | 2000-06-14 |
| GR3026123T3 (en) | 1998-05-29 |
| EP0705240B1 (en) | 1998-01-07 |
| FI956247A (fi) | 1995-12-22 |
| DE69407789T2 (de) | 1998-07-09 |
| CA2166061A1 (en) | 1995-01-05 |
| HUT73629A (en) | 1996-08-28 |
| ATE161822T1 (de) | 1998-01-15 |
| NO955253D0 (no) | 1995-12-22 |
| KR100338207B1 (ko) | 2003-02-11 |
| IL110073A (en) | 2000-09-28 |
| NO306155B1 (no) | 1999-09-27 |
| TW401398B (en) | 2000-08-11 |
| AU6917294A (en) | 1995-01-17 |
| EP0705240A1 (en) | 1996-04-10 |
| JP3671252B2 (ja) | 2005-07-13 |
| ES2114199T3 (es) | 1998-05-16 |
| NO955253L (no) | 1996-02-21 |
| NZ267007A (en) | 1996-12-20 |
| IL110073A0 (en) | 1994-10-07 |
| ZA944381B (en) | 1995-02-09 |
| FI113859B (fi) | 2004-06-30 |
| CN1125937A (zh) | 1996-07-03 |
| DE69407789D1 (de) | 1998-02-12 |
| US5756762A (en) | 1998-05-26 |
| CN1054369C (zh) | 2000-07-12 |
| HU9503708D0 (en) | 1996-02-28 |
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