CN1362948A - 3s-3-氨基-3-芳基丙酸及其衍生物的制备方法 - Google Patents
3s-3-氨基-3-芳基丙酸及其衍生物的制备方法 Download PDFInfo
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- CN1362948A CN1362948A CN00807448A CN00807448A CN1362948A CN 1362948 A CN1362948 A CN 1362948A CN 00807448 A CN00807448 A CN 00807448A CN 00807448 A CN00807448 A CN 00807448A CN 1362948 A CN1362948 A CN 1362948A
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- pyridyl
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- 238000000034 method Methods 0.000 title claims description 44
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 title abstract description 43
- 235000019260 propionic acid Nutrition 0.000 title abstract description 27
- 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 title description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 105
- 150000001875 compounds Chemical class 0.000 claims description 64
- -1 alkyl acetate Chemical compound 0.000 claims description 41
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
- 239000002253 acid Substances 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 21
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 9
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 claims description 4
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 4
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 3
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 claims description 3
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- 239000007787 solid Substances 0.000 description 41
- 239000000203 mixture Substances 0.000 description 37
- 239000000047 product Substances 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 27
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 27
- 238000003756 stirring Methods 0.000 description 26
- 125000004076 pyridyl group Chemical group 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000002002 slurry Substances 0.000 description 19
- 238000010992 reflux Methods 0.000 description 18
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- QOTCEJINJFHMLO-UHFFFAOYSA-N 3-amino-3-pyridin-3-ylpropanoic acid Chemical compound OC(=O)CC(N)C1=CC=CN=C1 QOTCEJINJFHMLO-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 6
- 239000005695 Ammonium acetate Substances 0.000 description 6
- 235000019257 ammonium acetate Nutrition 0.000 description 6
- 229940043376 ammonium acetate Drugs 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000012066 reaction slurry Substances 0.000 description 5
- JXHZRQHZVYDRGX-UHFFFAOYSA-M sodium;hydrogen sulfate;hydrate Chemical compound [OH-].[Na+].OS(O)(=O)=O JXHZRQHZVYDRGX-UHFFFAOYSA-M 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000011031 large-scale manufacturing process Methods 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
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- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- VUVORVXMOLQFMO-UHFFFAOYSA-N 3-pyridin-3-ylprop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=CN=C1 VUVORVXMOLQFMO-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
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- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 3
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- 238000001291 vacuum drying Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
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- 239000005557 antagonist Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
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- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- IJXJGQCXFSSHNL-QMMMGPOBSA-N (R)-(-)-2-Phenylglycinol Chemical compound OC[C@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-QMMMGPOBSA-N 0.000 description 1
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- IMWMEIWYPWVABQ-UHFFFAOYSA-N 6-methylpyridine-3-carbaldehyde Chemical compound CC1=CC=C(C=O)C=N1 IMWMEIWYPWVABQ-UHFFFAOYSA-N 0.000 description 1
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- MXFOQDIIUIHMIC-UHFFFAOYSA-N ethyl 2-pyridin-3-ylprop-2-enoate Chemical compound CCOC(=O)C(=C)C1=CC=CN=C1 MXFOQDIIUIHMIC-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
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- 150000002466 imines Chemical class 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation 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
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- QVALADMDSAWGJO-UHFFFAOYSA-N tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate oxolane Chemical compound C(C)(C)(C)OC(=O)OC(=O)OC(C)(C)C.O1CCCC1 QVALADMDSAWGJO-UHFFFAOYSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000002885 thrombogenetic effect Effects 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及3S-3-氨基-3-芳基丙酸及其衍生物的一种制备方法。
Description
相关申请的相互参照
本申请要求1999年3月22日提交的US临时申请60/126,227为优先权基础。
技术领域
本发明涉及3S-3-氨基-3-芳基丙酸及其衍生物的一种制备方法。
发明背景
R1是芳基、杂芳基、取代芳基或取代杂芳基,R2是氢、烷基或芳烷基,或以上化合物的酸加成盐,用作合成专利申请WO 97/41102中所述的化合物的中间体,该申请在此引为参考。
WO 97/41102所述的化合物是血小板纤维蛋白原受体的拮抗剂(GP IIb/IIIa拮抗剂)。因此,用于治疗血小板原因造成的血栓形成疾病,如动脉和静脉血栓、急性心肌梗塞、溶栓治疗及血管成形术后重栓塞、炎症、不稳定型心绞痛和血管栓塞性疾病。
制备式I化合物的已知方法,包括锂-N-(三甲硅烷基)-(R)-苯乙酰胺与3-吡啶基丙烯酸乙酯进行不对称Michael加成反应,得到β-氨基乙酯[Rico,J.G.;Lindmark,R.J.;Rogers,T.E.;Bovy,P.R.J.Org.Chem.1993,58,7948]。此方法会形成无用的酰胺锂,且难以除去N-甲基苄基基团。
J.Org.Chem.vol.61,p.2222(1996)公开了一种方法,其中将乙酸乙酯的烯醇酸锂加入对映体纯的硫亚胺(sulfinimine)中,所得产物经层析纯化并在酸性条件下脱保护基,得到β-氨基酯,对映体过量值高于90%,但因需要用色谱方法纯化,不适于大规模生产。类似地,J.Org.Chem.,vol64,p.12(1999)公开了一种方法,将乙酸甲酯的烯醇酸钛加入对映体纯的叔丁基硫亚胺中,得到β-氨基酯,对映体过量值约90%。
WO 98/02410公开了一种立体选择性加成方法,将从溴乙酸叔丁酯中制备的Reformatsky试剂与从3-吡啶醛和(R)-2-苯基甘氨醇(glycinol)制备的对映体纯的亚胺加成。N-(1-苯基-2-羟乙基)基团在乙醇中与NaIO4进行氧化裂解反应,然后再进行酸性水解,得到对映体纯的β-氨基酸叔丁酯。但本方法需使用氧化剂,不适于大规模生产。
WO 97/41102公开了一种用青霉酰胺酶进行的(±)β-苯乙酰胺基酸的酶解方法,得到S-酸。该方法因需利用酶,对于大规模生产也是无效和不实际的。
因此,需要有一种既适于大规模生产,又可达到所要求纯度和产量的方法。
发明概述
如上所述,本发明涉及制备式I化合物的方法,该方法包括将式II化合物进行反应其中,R1是芳基、杂芳基、取代芳基或取代杂芳基,pH范围约在7-11,形成式III化合物。其中,R5是N-叔丁氧基羰基,式III化合物与至少0.5当量(1R,2S)-(-)麻黄碱在一种乙酸烷基酯溶剂中反应,形成式IV的盐,其中,Ph是苯基,式IV的盐与一种无机碱在水中反应,形成式V化合物的羧酸盐,用pKa小于或等于3的酸将式V化合物的该羧酸盐酸化至pH约为3.5-6.5,生成式V化合物。式V化合物在温度低于约25℃时反应,生成式I化合物。
本发明还涉及式Va中间体,即(3S)-3-[(叔丁氧基)羰基]氨基-3-[3’-吡啶基]丙酸的一种新的结晶形式,其中,Boc是(叔丁氧基)羰基确定的晶型2结构,其由X粉末衍射花样鉴定。发明详述
除非另有说明,此处所述的″烷基″无论单独使用或作为取代基部分,均包括含1-10个碳原子的直链及支链。如烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
除非另有说明,此处所述的″烷氧基″指上述直链及支链烷基的氧醚基。如甲氧基、乙氧基、正丙氧基、仲丁氧基、叔丁氧基、正己氧基等。
除非另外说明,在此所指的″芳基″,指未取代的芳基,如苯基、萘基等。芳基可被一个或两个取代基所取代。芳基上合适的取代基分别选自卤素、烷基、烷氧基、芳烷基、-NR3 2(其中R3是烷基)及R4CONH(其中R4是苯基或烷基)。
除非另外说明,在此所指的″杂芳基″指任何五元或六元单环结构,环上含有至少一个选自O,N和S的杂原子,或指双环体系,其中杂芳基与一个芳基稠合。适宜的杂芳基的实例包括但不限于吡咯基、吡啶基、吡嗪基、嘧啶基、吡唑基、哒嗪基、呋喃基、吡喃基、咪唑基、噻吩基、噁唑基、异噻唑基、异噁唑基、呋咱基、苯并噻吩基、苯并呋喃基、吲哚基、异吲哚基、中氮茚基、吲唑基、嘌呤基、异喹啉基、喹啉基、异噻唑基等。杂芳基上可有一个或两个取代基。杂芳基上适宜的取代基分别选自卤素、烷基、烷氧基、芳烷基、-NR3 2(其中R3是低级烷基)和R4CONH(其中R4是苯基或烷基)。杂芳基可通过环上任何的杂原子或碳原子连接,以形成稳定的结构,除非该杂芳环只含有一个杂原子,此时该杂芳基只能在一个碳原子位置相连接。
优选的杂芳基是吡啶基,优选的杂芳基可被一个或两个上述取代基所取代。最优选的,吡啶基是未取代的。
除非另有说明,此处所述的″芳烷基″指任何被芳基,如苯基、萘基等取代的烷基。
除非另有说明,此处所述的″卤素″指氯、溴、氟和碘。
除非另有说明,此处所述的″pKa小于或等于3的酸″包括一氯乙酸、二氯乙酸、三氯乙酸、盐酸、氢溴酸、氢碘酸、高氯酸、苦味酸、硝酸、硫酸、磷酸、甲磺酸、甲苯磺酸(tosic)、三氟甲磺酸、三氟乙酸、硫酸氢钾、硫酸氢钠、柠檬酸等。
除非另有说明,此处所述的″无机碱″指有一价阳离子的碱,如碳酸锂、碳酸钠、碳酸钾、氢氧化锂、氢氧化钠、氢氧化钾、氢氧化四丁铵、氢氧化三甲基苄基铵等。
除非另有说明,此处所述的″烷基醇″指上述直链或支链烷基的羟基衍生物,如甲醇、乙醇、正丙醇、异丙醇、异丁醇、叔丁醇等。
除非另有说明,此处所述的″S″和″R″指具有S或R构型的手性中心。
在优选的本发明实例中,化合物式I中R1是未取代的苯基、取代苯基、未取代嘧啶基、取代嘧啶基、未取代吡啶基、取代吡啶基、未取代萘基或取代萘基。适宜的取代基分别选自卤素、烷基、烷氧基、芳烷基、-NR3 2(其中R3是烷基)和R4CONH(其中R4是苯基或烷基)。更优选的,R1是2-吡啶基、3-吡啶基、4吡啶基、6-甲基吡啶基、5-溴吡啶基、6-氯吡啶基或5,6-二氯吡啶基。最优选的,R1是3-吡啶基。优选的R2是烷基,更优选的是甲基或乙基,最优选的是甲基。
在本发明一个实例中,其中,式I化合物以酸加成盐形式存在,酸是前述pKa小于或等于3的酸,但不包括硫酸氢钾、硫酸氢钠和柠檬酸。优选的式I化合物是盐酸加成盐。
本发明涉及制备式I化合物或其酸加成盐的方法,其中,R1和R2如上所述,该方法包括使式II化合物反应,形成式III化合物 其中,R5是N-叔丁氧基羰基,使式III化合物反应,形成式IV的盐其中,Ph是苯基,使式IV的盐反应,生成式V化合物
使式V化合物反应,生成式I化合物。
根据本发明,式II化合物(为已知物,或用下述已知方法制备:[Profft,V.E.;Becker,F.J.,J.Prakt.Chem.1965,30(1-2),18])与二碳酸二叔丁基酯(di-tert-butyl dicarbonate)在一种有机溶剂中反应,如,1,4-二氧六环,叔丁醇或四氢呋喃,优选的是四氢呋喃,加入前述的一种无机碱水溶液,优选氢氧化钠,反应温度约在0~100℃,优选温度约在0~35℃,反应的pH范围约在7~11,优选范围约在9.9~10.2,生成式III化合物。
优选的,所需的式III化合物经减压蒸除有机溶剂进行分离,然后加入前述pKa小于或等于3的酸将残余的水溶液酸化,优选用硫酸氢钠或柠檬酸,至pH约在3.5~6.5,优选的至pH约3.8,过滤或用有机溶剂萃取,如用二氯甲烷、1,2-二氯乙烷、氯仿、二氧六环、甲苯、乙酸烷基酯(如乙酸乙酯)或它们的混合物,优选的是乙酸乙酯,任选地减压蒸馏除去有机溶剂。
式III化合物与至少0.5当量(1R,2S)-(-)麻黄碱反应,优选用0.5~1.0当量(1R,2S)-(-)麻黄碱,在乙酸烷基酯溶剂中,优选用乙酸乙酯,反应温度约在25~78℃,生成式IV的盐。
式IV的盐与前述无机碱在水中进行反应,优选的是用氢氧化钠,形成式V化合物羧酸盐(溶于水溶液)。
用一种有机溶剂萃取,除去(1R,2S)-(-)麻黄碱,分离出所需式V化合物,所用的有机溶剂是基本不与水相溶的,如二氯甲烷、1,2-二氯乙烷、乙酸烷基酯或芳香烃,如甲苯,或酮,如甲基异丁基丙酮,然后加入前述pKa小于或等于3的酸,以酸化该残余的水溶液,优选用硫酸氢钠或硫酸,至pH约在3.5~6.5,优选至pH约3.8,过滤,得到式V化合物。当所用基本不与水相溶的有机溶剂是甲苯时,优选的是在用甲苯萃取之前,将含式V化合物水溶液加热至70-80℃,用甲苯萃取后冷却至室温,然后再进行酸化。
式V化合物与前述pKa小于或等于3的酸反应,不包括硫酸氢钾、硫酸氢钠及柠檬酸,优选的是盐酸,溶剂是C1-C10烷基醇,优选的是甲醇,反应温度低于约25℃,生成相应的式I化合物,用常规方法,如用过滤方法分离。
滤方法分离。
晶型2的式Va化合物经X粉末衍射花样进行鉴定,用SiemensD5000衍射计,系统操作条件如下:
a)CuKa射线,35mA,40KV
b)光学参数
1mm隙,Goebel镜,0.6mm隙,及试管及样品间垂直
soller隙,
样品与检测计之间LiF单色仪
c)在0.02步扫描 5-35°2θ,扫描速度1°2θ/分钟
d)零背景样品槽
粉末X-射线衍射结果
角度2θ | d值 埃 | 强度Cps | 强度% |
5.186 | 17.028 | 1.67 | 0.1 |
5.405 | 16.338 | 4.17 | 0.2 |
6.069 | 14.550 | 163 | 6.2 |
6.526 | 13.532 | 1350 | 51.1 |
7.659 | 11.534 | 28.3 | 1.1 |
9.111 | 9.698 | 22.5 | 0.9 |
10.786 | 8.196 | 1417 | 53.6 |
13.073 | 6.767 | 83.3 | 3.2 |
15.660 | 5.654 | 659 | 25.0 |
17.063 | 5.192 | 1105 | 41.8 |
18.405 | 4.817 | 102 | 3.8 |
18.843 | 4.706 | 212 | 8.0 |
19.108 | 4.641 | 343 | 13.0 |
19.679 | 4.507 | 417 | 15.8 |
20.755 | 4.276 | 36.7 | 1.4 |
21.514 | 4.127 | 2641 | 100.0 |
22.796 | 3.898 | 652 | 24.7 |
23.944 | 3.713 | 101 | 3.8 |
24.363 | 3.650 | 340 | 12.9 |
25.502 | 3.490 | 89.2 | 3.4 |
25.640 | 3.471 | 89.2 | 3.4 |
26.265 | 3.390 | 172 | 6.5 |
26.786 | 3.326 | 98.3 | 3.7 |
27.770 | 3.210 | 1152 | 43.6 |
28.722 | 3.106 | 164 | 6.2 |
29.151 | 3.061 | 764 | 28.9 |
29.656 | 3.010 | 70.8 | 2.7 |
30.468 | 2.9315 | 58.3 | 2.2 |
31.214 | 2.8631 | 61.7 | 2.3 |
31.868 | 2.8058 | 61.7 | 2.3 |
32.301 | 2.7692 | 95.8 | 3.6 |
32.874 | 2.7222 | 147 | 5.6 |
33.480 | 2.6743 | 53.3 | 2.0 |
34.081 | 2.6285 | 122 | 4.6 |
34.626 | 2.5884 | 68.3 | 2.6 |
下列实施例对本发明进行的详尽描述是为了说明本发明,而非对本发明进行限制。
实施例1
3-氨基-3-(3’-吡啶基)丙酸步骤A
在反应瓶中加入300g(264.3mL)(2.8mol)冷3-吡啶甲醛和60mL无水乙醇,反应温度达13℃。剧烈搅拌下,在约2分钟的时间内加入291.36g(2.8mol)丙二酸固体,然后再加入90mL乙醇,紧接着用10分钟时间加入323.73g(4.2mol)乙酸铵固体,然后再加入250mL乙醇。加料期间,将反应液冷却至约38℃。加热亮橙色的混合液,并保持缓慢回流5小时。除去加热罩,将混合液冷至室温过夜。吸滤收集固体50分钟,用400mL甲醇(30分钟)洗。用第二部分200mL甲醇(10分钟)洗滤饼。将滤饼抽滤60分钟使其部分干燥。然后在35-40℃真空干燥38小时至恒重。得到303.38g(65.2%)3-氨基3-(3’-吡啶基)丙酸,为白色粉末。步骤B
在反应瓶中加入594.52g 3-氨基-3-(3’-吡啶基)丙酸及反式3-(3’-吡啶基)丙烯酸的混合物和1,600mL甲醇。剧烈搅拌下,加热该浆状物,并保持缓慢回流1.25小时。趁热过滤该反应浆,先用2×80mL,然后用160mL热(>50℃)甲醇洗(30分钟)。将滤饼抽滤1.25小时使其部分干燥。然后在35-40℃真空干燥21.5小时,得到540.22g(按重量算收率90.9%)产物,为白色粉末。
在反应瓶中加入540.12g 3-氨基-3-(3’-吡啶基)丙酸及反式3-(3’-吡啶基)丙烯酸的混合物和1,600mL甲醇。剧烈搅拌下,加热该浆状物,并保持缓慢回流5-6小时。趁热过滤该反应浆,用3×160mL热(>50℃)甲醇洗(35分钟)。将滤饼抽滤1.75小时,使其部分干燥,得到814.45g(按重量算收率>100%)产物,为白色固体(湿滤饼)。
在反应瓶中加入814.35g 3-氨基-3-(3’-吡啶基)丙酸及反式3-(3’-吡啶基)丙烯酸的混合物(湿滤饼)和1,600mL甲醇。剧烈搅拌下,加热该浆状物,并保持缓慢回流3.75小时。趁热过滤该反应浆,用3×160mL热(>50℃)甲醇洗(20分钟)。将滤饼抽滤17.25小时,使其部分干燥,在40-45℃进一步真空干燥20小时,得到390.69g(65.7%按投入的原料重量算收率),产物为白色粉末。
实施例2
3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸
剧烈搅拌下,在反应瓶中加入200mL四氢呋喃和170.88g(1.03mol)3-氨基-3-(3’-吡啶基)丙酸、614mL四氢呋喃。在室温(22℃),用约2分钟时间缓慢倾入514mL(1.03mol)2M氢氧化钠溶液。在加料期间,反应温度升至26℃,大部分固体溶解。在室温再搅拌45分钟后,出现稍混浊的无色溶液;在24℃,pH 10.57。在1L恒压加料漏斗中装入407mL四氢呋喃和365.3mL(1.54mol)二碳酸二叔丁基酯。在另一个一升恒压加料漏斗中装入771mL(1.54mol)2M氢氧化钠溶液。用约25分钟时间将二碳酸二叔丁基酯四氢呋喃溶液以细流缓慢加入,同时观测pH值。一旦pH达到约9.90,开始伴随加入2M氢氧化钠溶液。外部冷却反应液,使反应温度维持低于35℃。在加入四氢呋喃/二碳酸二叔丁基酯溶液期间,保持pH在9.9-10.2。之后,用81mL新取的四氢呋喃正向冲洗盛过二碳酸酯/四氢呋喃溶液的加料漏斗,再继续加入余量2M氢氧化钠溶液,以保持pH在9.9-10.2。加毕余量的2M氢氧化钠溶液,移去pH检测仪,在室温下搅拌反应液17小时。剧烈搅拌下,在约3小时时间内经分步加入393.0g(2.85mol)硫酸氢钠一水合物,使pH从在21℃ 7.68降至在27℃ 3.87。剧烈搅拌下,将该多相的混合物在冰水浴中冷却75分钟。将1,285mL水加入安放在旋转蒸发器上的5L圆底广口烧瓶中,并在瓶的外壁做上标记。然后将烧瓶倒空,加入反应浆。用2×250mL 98/2(v/v)四氢呋喃-水溶液冲洗烧瓶。在25℃浓缩该反应浆液约3小时,至体积约为1,285mL。用4×650mL二氯甲烷提取浓缩的混合物。剧烈搅拌下,用23.5g(0.20mol)无水硫酸镁干燥合并的提取液45分钟。过滤后,在25℃浓缩所得无色澄明滤液90分钟,至成为可流动的浆状。在35℃,在<5mm Hg压力下,进一步小心浓缩45分钟至浓缩液成为粘稠浆状。
在室温进一步真空干燥60小时,得到227.24g(83.0%)产物,为透明的不流动玻璃态。经1H NMR检测,纯度为89.8%(w/w)。
实施例3
(3S)-3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸,
(1R,2S)-(-)-麻黄碱盐步骤A
在反应瓶中加入2,750mL乙酸乙酯和227.23g(0.77mol)3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸。剧烈搅拌下,加热该溶液至反应温度62℃。在64℃,用约9分钟时间缓慢滴加新配制的126.9g(0.77mol)(1R,2S)-(-)-麻黄碱在350mL乙酸乙酯中的溶液。用50mL乙酸乙酯冲洗含麻黄碱溶液的加液漏斗。在澄明,无色溶液(63℃)中种入晶种,待1-2分钟,产生大量的沉淀产物(结晶过程中,增加搅拌速度,以保持反应浆液保持良好搅拌)。将该浆液缓慢冷至室温,18小时后,抽滤收集固体,并用2×125mL新取乙酸乙酯洗(15分钟)。经抽滤35分钟,部分干燥滤饼。在40-45℃进一步真空干燥21小时,得到153.04g(46.3%)产物,为蓬松的白色固体。步骤B
在反应瓶中加入415.33g(0.96mol)(3S)-3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸,(1R,2S)-(-)-麻黄碱盐和9L乙酸乙酯。剧烈搅拌下,加热所产生的浆状液,并保持缓慢回流30分钟。继续剧烈搅拌下将该浆液缓慢冷至室温。15小时后,加入250mL新取乙酸乙酯,恢复剧烈搅拌。再过2小时后,抽滤收集固体,并用2×450mL新取乙酸乙酯洗(10分钟)。经抽滤75分钟,部分干燥滤饼。在50-55℃进一步真空干燥44小时,得到311.25g(74.9%)产物,为蓬松的白色固体。
实施例4
(3S)-3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸
在烧杯中加入303.47g(0.67mol)(3S)-3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸,(1R,2S)-(-)-麻黄碱盐和792mLmilliquat水。搅拌5分钟后,浆液的pH在21℃是7.32。剧烈搅拌下,在约2分钟时间内将总量595mL(0.60mol)1M氢氧化钠溶液慢慢倾入,至在23℃pH为11.00。再过5分钟(pH10.86),继续剧烈搅拌下加入20mL(0.02mol)1M氢氧化钠溶液,至在23℃pH为11.00。再搅拌65分钟后,(pH在22℃是10.73),加入50mL(0.05mol)1M氢氧化钠溶液至在22℃pH是11.07。稍混浊的无色溶液用12×880mL二氯甲烷洗,最后一次洗过之后,pH在20℃为7.76。剧烈搅拌下,用10分钟,分步加入47.89g(0.35mol)硫酸氢钠一水合物至在21℃的pH为5.18。在混浊溶液中种入晶种,并搅拌所得浆状物5分钟。结晶过程中,在21℃pH增至5.76。用25分钟另加入47.82g(0.34mol)硫酸氢钠一水合物,至在22℃ pH 3.79。在冰水浴中冷却该浆状物40分钟,过滤(5分钟),经抽滤20分钟,使部分干燥。滤饼在50-55℃真空干燥17小时,得到151.72g(85.1%)产物,为无色晶状固体。
实施例5
(3S)-3-氨基-3-(3’-吡啶基)丙酸甲酯二盐酸盐
在圆底烧瓶中加入142.01g(0.53mol)(3S)-3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸和1,350mL甲醇。在25℃将混合液在非真空条件下用旋转蒸发器旋转2小时,然后小心浓缩为无色可流动的浆状物。将该浆状物溶于1,350mL甲醇,以转至一反应瓶中。在冰水浴中冷却该不透明溶液至0-5℃。然后用约3小时通入氯化氢约194.4g(5.33mol)于该溶液中。在加料期间,将反应温度保持低于15℃。然后种入晶种,该浆状物温热至室温,并搅拌2小时。在冰水浴中冷却该浆状物30分钟。抽滤收集固体,用2×65mL冷(0-5℃)甲醇洗(5分钟)。将滤饼抽滤约20分钟,使部分干燥。进一步在室温真空干燥14小时,得到105.21g(77.9%)产物,为白色晶状粉末。
实施例6
3-氨基-3-[3’-(6-甲基)吡啶基]丙酸
在6-甲基吡啶-3-甲醛(23.5g,0.149mol)、乙酸铵(22.9g,1.5当量)和乙醇(350mL)的混合物中加入丙二酸(20.5g,1当量)。将混合物加热回流6小时,冷却至室温,过滤。用乙醇(2×30mL)和乙醚(2×100mL)洗过滤的固体,干燥,得产物为白色固体(23.2g,66%)。
实施例7
3-氨基-3-[3’-(5-溴)吡啶基]丙酸
在5-溴吡啶-3-甲醛(40.4g,0.21mol)、乙酸铵(24.3g,1.5当量)和无水乙醇(650mL)的混合物中加入丙二酸(21.8g,1当量)。将混合物加热回流6.5小时,冷却至室温,过滤。用乙醇和乙醚洗过滤的固体,干燥,得粗产物(28.0g,55%)。将此固体在500mL甲醇中加热回流30分钟,趁热过滤,用热甲醇洗,干燥,得产物为白色固体(17.4g,34%)。
实施例8
3-氨基-3-[3’-(6-氯)吡啶基]丙酸
在6-氯吡啶-3-甲醛(32.6g,0.229mol)、乙酸铵(26.5g,1.5当量)和无水乙醇(300mL)的混合物中加入丙二酸(23.8g,1当量)。将混合物加热回流2.5小时,冷却至室温,过滤。用乙醇和乙醚洗过滤的固体,干燥,得粗产物(30.6g,66%)。将此固体在500mL甲醇中加热回流,趁热过滤,用热甲醇(3×150mL)和乙醚洗,干燥,得标题化合物(24.5g,53%)。将此固体在500mL甲醇中加热回流,趁热过滤,用热甲醇和乙醚洗,干燥,得产物为白色固体(21.0g,46%)。
实施例9
3-氨基-3-[3’-(5,6-二氯)吡啶基]丙酸
在5,6-二氯吡啶-3甲醛(9.4g,0.053mol)、乙酸铵(6.2g,1.5当量)和无水乙醇(100mL)的混合物中加入丙二酸((5.6g,1当量)。将混合物加热回流8小时,冷却至室温,搅拌过夜,过滤。用乙醇和乙醚洗过滤的固体,干燥,得粗产物(7.0g,56%)。将此固体在125mL甲醇中加热回流15分钟,趁热过滤,用热甲醇(50mL)洗,干燥,得产物为白色固体(4.4g;35%)。
实施例10
3-[(叔丁氧基)羰基]氨基-3-[3’-(6-甲基)吡啶基]丙酸
在冷的(5℃)3-氨基-3-[3’-(6-甲基)吡啶基]丙酸(23.2g,0.128mol)、1N氢氧化钠(256mL,2当量)和二氧六环(150mL)的溶液中加入二碳酸二叔丁基酯(27.9g,1当量)。搅拌该混合物1.5小时,移去冰浴,继续搅拌16小时。真空除去二氧六环,用10%柠檬酸(250mL)将所得的混合物水溶液pH调至4。在冰浴中冷却该溶液,搅拌30分钟,过滤,得到7.7g白色粉末。减压过滤,至体积为一半,用氯化钠(30g)处理,冷却70小时,过滤,得到二次产物(22.4g)。合并两次产物,得白色固体(30.1g,84%)。
实施例11
3-[(叔丁氧基)羰基]氨基-3-[3’-(5-溴)吡啶基]丙酸
在冷的(5℃)3-氨基-3-[3’-(5-溴)吡啶基]丙酸(17.4g,0.071mol)、1N氢氧化钠(142mL,2当量)和二氧六环(100mL)的溶液中加入二碳酸二叔丁基酯(15.5g,1当量)。将该混合物温热至室温并搅拌过夜。真空除去二氧六环,用10%柠檬酸将所得的混合物水溶液pH调至3-4。用9/1(v/v)氯仿/二氧六环(3×150mL)提取该溶液,用无水硫酸钠干燥合并的提取液,过滤,浓缩,得到产物为白色固体(21.1g,86%)。
实施例12
3-[(叔丁氧基)羰基]氨基-3-[3’-(6-氯)吡啶基]丙酸
在冷的(5℃)3-氨基-3-[3’-(6-氯)吡啶基]丙酸(21.0g,0.105mol)、1N氢氧化钠(210mL,2当量)和二氧六环(150mL)的溶液中加入二碳酸二叔丁基酯(22.89g,1当量)。将该混合物温热至室温并搅拌过夜。真空除去二氧六环,用10%柠檬酸将所得的混合物水溶液pH调至3-4。过滤该混合物,用水洗该固体,在空气中干燥过夜,得到产物为白色固体(21.5g,68%)。
实施例13
3-[(叔丁氧基)羰基]氨基-3-[3’-(5,6-二氯)吡啶基]丙酸
在冷的(5℃)3-氨基-3-[3’-(5,6二氯)吡啶基]丙酸(4.4g,0.019mol)、1N氢氧化钠(37.6mL,2当量)和二氧六环(30mL)的溶液中加入二碳酸二叔丁基酯(4.1g,1当量)。将该混合物温热至室温并搅拌过夜。真空除去二氧六环,用10%柠檬酸将所得的混合物水溶液pH调至3-4。在室温下再次搅拌后,过滤该混合物,用水洗该固体,在空气中干燥,得到产物为白色固体(5.0g,79%)。
实施例14(3S)-3-[(叔丁氧基)羰基]氨基-3-[3’-(6-甲基)吡啶基]丙酸,
(1R,2S)-(-)-麻黄碱盐
在3-[(叔丁氧基)羰基]氨基-3-[3’-(6-甲基)吡啶基]丙酸(3.85g,0.0137mol)和温的乙酸乙酯(170mL)的浆状液中加入(1R,2S)-(-)-麻黄碱(2.31g,1当量)在乙酸乙酯(60mL)中的溶液。将该混合物加热回流,得澄明溶液。在室温下放置5分钟后,在该温热溶液中种入晶种,并冷至室温。当该溶液温度达30℃,该盐开始结晶。结晶15分钟后,将该混合物过滤,用乙酸乙酯(50mL)和乙醚(50mL)洗该固体产物,干燥,得白色粉末(1.9g,31%)。
16小时后,在室温下从母液中分离出二次产物(0.33g,5.4%)。合并两次产物,加入乙酸乙酯(60mL),调成浆状,过滤,得到2.2g(36%)产物,为白色固体。
实施例15(3S)-3-[(叔丁氧基)羰基]氨基-3-[3’-(5-溴)吡啶基]丙酸,
(1R,2S)-(-)-麻黄碱盐
在3-[(叔丁氧基)羰基]氨基-3-[3’-(5-溴)吡啶基]丙酸(21.0g,0.061mol)和乙酸乙酯(125mL)的溶液中加入(1R,2S)-(-)-麻黄碱(10.1g,1当量),得澄明溶液。种入晶种后,在室温静置过夜,过滤该混合物,用冷乙酸乙酯和乙醚洗该固体产物,干燥,得到产物为白色粉末(8.3g,27%)。
实施例16(3S)-3-[(叔丁氧基)羰基]氨基-3-[3’-(6-氯)吡啶基]丙酸,
(1R,2S)-(-)-麻黄碱盐
在3-[(叔丁氧基)羰基]氨基-3-[3’-(6-氯)吡啶基]丙酸(21.4g,0.071mol)和乙酸乙酯(250mL)的浆状液中加入(1R,2S)-(-)-麻黄碱(11.79g,1当量)。将该混合物加热回流,得澄明溶液。将溶液冷却至室温,种入晶种。结晶后,再加入乙酸乙酯(700mL),加热该浆状物至沸,然后慢慢冷至室温。搅拌过夜后,过滤该混合物,用乙酸乙酯和乙醚洗该固体产物,干燥,所得产物为蓬松的白色固体(15.36g,46%)。
实施例17(3S)-3-[(叔丁氧基)羰基]氨基-3-[3’-(5,6-二氯)吡啶基]丙酸,
(1R,2S)-(-)-麻黄碱盐
在3-[(叔丁氧基)羰基]氨基-3-[3’-(5,6-二氯)吡啶基]丙酸(4.9g,0.015mol)和乙酸乙酯(150mL)的浆状液中加入(1R,2S)-(-)-麻黄碱(2.42g,1当量)。将该混合物加热回流,过滤以除去少量不溶性物质。将该澄明滤液慢慢冷至室温。过滤该混合物,固体产物用乙酸乙酯和乙醚洗,干燥,得粗产物(3.1g)。用沸腾乙酸乙酯(75mL)重结晶,得纯化产物为白色固体(2.8g,38%)。
实施例18
3-氨基-3-(3’-吡啶基)丙酸
将乙酸铵(194.28g,2.52mol)悬浮于乙醇(285g)。用10分钟于15℃-20℃在悬浮液中加入吡啶-3-carbaldehyde(62.9g,1.68mol)的乙醇(80g)溶液。搅拌反应混合物1小时至澄明黄色溶液形成,然后加入丙二酸(174.86g,1.68mol)在乙醇(235g)中的悬浮液(在30分钟内)。在室温30分钟后,加热回流该混合物5小时(78℃)。可观测到有气体逸出。3-4小时后,白色固体开始沉淀出。冷却该橙色悬浮液至15℃-20℃,得到稠的浆状液,往其中加入甲醇(80g),再次将该混合物加热回流(65℃)。将悬浮液趁热过滤,滤饼用三部分热甲醇(120g)洗(在55-65℃)。将湿产物在70-80℃真空干燥,得到的产物为无色固体(137.73g,49.3%)。LC纯度95.8%。
实施例19
3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸
在15-25℃将3-氨基-3-(3’-吡啶基)丙酸(73.00g,0.439mol)悬浮于四氢呋喃(239.5g)。在10-20分钟内加入氢氧化钠(43.93g,1.10mol)的纯水(395.4g)溶液,得一淡黄色溶液。2-3小时内加入BOC-酐(143.82g,0.659mol)的四氢呋喃(124.2g)溶液,同时保持溶液温度不超过30℃。在15-25℃搅拌该溶液过夜(约17小时)。在1-2小时内加入硫酸氢钠一水合物(167.9g,1.22mol)的水(160g)溶液。调pH约为3.8-3.9。可观测到有固体沉淀,并有大量气体逸出。将悬浮物冷却至5-10℃,过滤,用四氢呋喃(50g)洗。蒸馏该合并一起的滤液,使之减少至原体积的1/3,然后加入乙酸乙酯(102.9g),蒸除等体积的溶剂,再次加入乙酸乙酯(99.4g),再蒸除同样体积的溶剂。在所产生的乳状水液中加入氯化钠(64.6g)和乙酸乙酯(100.5g)。分出相,用乙酸乙酯(3×20g)洗水相。用无水硫酸钠(20g)干燥合并一起的有机相,滤除干燥剂,用乙酸乙酯(5g)洗滤饼,所得溶液(约250g)直接用于下步反应。
实施例20
(3S)-3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸,
(1R,2S)-(-)-麻黄碱盐
将3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸(250g)在含3[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸(71.5g,0.269mmol)及乙酸乙酯(178.5g)的乙酸乙酯中的溶液加热至60-70℃。10分钟内加入(-)-麻黄碱(48.80g,0.295mol)的乙酸乙酯(90.0g)溶液。将此澄明溶液冷却至20-30℃此时产物结晶为体积较大的白色固体。开始结晶后,加入乙酸乙酯(270g)保持混合物可以搅动。将悬浮物冷却至15-25℃,搅拌3-5小时,滤集固体,用乙酸乙酯(90g)分两部分洗滤饼。在70-80℃真空干燥,得到的产物为无色固体(52.72g,28%)。LC纯度大于99%。
实施例21
(3S)-3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸
在15-25℃,将(3S)-3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸(1R,2S)-(-)-麻黄碱盐(25.11g,0.058mol)溶于水(50.0g)。10-20分钟内加入氢氧化钠(2.63g,0.066mol)的水(23.3g)溶液,得一澄明溶液。剧烈搅拌下加入甲苯(17.4g),将产生的乳状液加热至70-80℃。停止搅拌后,将澄明的有机相从略混浊的水相中分出。用甲苯(4×17.4g)在70-80℃提取水相。然后将水相冷却至15-25℃,过滤,用水(2.5g)洗滤液。在合并的滤液中加入硫酸氢钠一水合物(9.50g,0.069mol)的水(12.1g)溶液,使pH为3.6-3.9,并有产物结晶。将该反应混合物冷却至0-5℃,再搅拌1小时,滤集产物,用两部分水(5g)洗,在40-50℃真空干燥,得到的产物为无色固体(11.08g,72%)。LC纯度高于95%。
实施例22
(3S)-3-氨基-3-(3’-吡啶基)丙酸甲酯二盐酸盐
在0-5℃将(3S)-3-[(叔丁氧基)羰基]氨基-3-(3’-吡啶基)丙酸(9.93g,0.037mol)溶于甲醇(45.8g),2-3小时内在溶液中通入氯化氢(34.2g,0.938mol),同时保持溶液温度低于约15℃。氯化氢加毕,在20-25℃搅拌该反应混合物至少2小时,然后冷却至0-5℃。在0-5℃搅拌30分钟后,滤集固体,用冷甲醇(14.2g)(约0-5℃)分两部分洗,在20-30℃真空干燥,得到的产物为无色固体(7.86g,83%)。LC纯度高于95%。
Claims (26)
粉末X-射线衍射结果
角度2θ
d值 埃
强度Cps
强度%
5.186
17.028
1.67
0.1
5.405
16.338
4.17
0.2
6.069
14.550
163
6.2
6.526
13.532
1350
51.1
7.659
11.534
28.3
1.1
9.111
9.698
22.5
0.9
10.786
8.196
1417
53.6
13.073
6.767
83.3
3.2
15.660
5.654
659
25.0
17.063
5.192
1105
41.8
18.405
4.817
102
3.8
18.843
4.706
212
8.0
19.108
4.641
343
13.0
19.679
4.507
417
15.8
20.755
4.276
36.7
1.4
21.514
4.127
2641
100.0
22.796
3.898
652
24.7
23.944
3.713
101
3.8
24.363
3.650
340
12.9
25.502
3.490
89.2
3.4
25.640
3.471
89.2
3.4
26.265
3.390
172
6.5
26.786
3.326
98.3
3.7
27.770
3.210
1152
43.6
28.722
3.106
164
6.2
29.151
3.061
764
28.9
29.656
3.010
70.8
2.7
30.468
2.9315
58.3
2.2
31.214
2.8631
61.7
2.3
31.868
2.8058
61.7
2.3
32.301
2.7692
95.8
3.6
32.874
2.7222
147
5.6
33.480
2.6743
53.3
2.0
34.081
2.6285
122
4.6
34.626
2.5884
68.3
2.6
4.权利要求2所述的方法,还包括用pKa小于或等于3的酸将式III化合物酸化至pH约在3.5~6.5,以分离式III化合物。
5.权利要求2所述的方法,其中,所述乙酸烷基酯溶剂是乙酸乙酯。
6.权利要求2所述的方法,其中,式III化合物与(1R,2S)-(-)麻黄碱的反应温度范围约在25~78℃。
7.权利要求2所述的方法,还包括用pKa小于或等于3的酸将式V化合物的羧酸盐酸化,至pH约3.8,生成式V化合物。
8.权利要求2所述的方法,其中,所述pKa小于或等于3的酸选自一氯乙酸、二氯乙酸、三氯乙酸、盐酸、氢溴酸、氢碘酸、高氯酸、苦味酸、硝酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟甲磺酸、三氟乙酸、硫酸氢钾、硫酸氢钠和柠檬酸。
9.权利要求2所述的方法,还包括式V化合物与pKa小于或等于3的酸反应,所述酸不包括硫酸氢钾、硫酸氢钠和柠檬酸。
10.权利要求3所述的方法,还包括用pKa小于或等于3的酸将式III化合物酸化至pH约在3.5~6.5。
11.权利要求3所述的方法,其中,所述乙酸烷基酯溶剂是乙酸乙酯。
12.权利要求3所述的方法,其中,式III化合物与(1R,2S)-(-)麻黄碱的反应温度约在25~78℃。
13.权利要求3所述的方法,还包括用pKa小于或等于3的酸将式V化合物的羧酸盐酸化至pH约3.8,生成式V化合物。
14.权利要求3所述的方法,其中,所述pKa小于或等于3的酸选自一氯乙酸、二氯乙酸、三氯乙酸、盐酸、氢溴酸、氢碘酸、高氯酸、苦味酸、硝酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟甲磺酸、三氟乙酸、硫酸氢钾、硫酸氢钠和柠檬酸。
15.权利要求3所述的方法,还包括式V化合物与pKa小于或等于3的酸反应,所述酸不包括硫酸氢钾、硫酸氢钠和柠檬酸。
16.权利要求2所述的方法,其中,R1是2-吡啶基、3吡啶基、4-吡啶基、6-甲基吡啶基、5-溴吡啶基、6-氯吡啶基或5,6-二氯吡啶基。
17.权利要求3所述的方法,其中,R1是2-吡啶基、3-吡啶基、4-吡啶基、6-甲基吡啶基、5-溴吡啶基、6-氯吡啶基或5,6-二氯吡啶基。
18.权利要求2所述的方法,其中,R2是烷基。
19.权利要求3所述的方法,其中,R2是烷基。
20.权利要求2所述的方法,其中,R1是3-吡啶基。
21.权利要求3所述的方法,其中,R1是3-吡啶基。
22.权利要求2所述的方法,其中,R1是3-吡啶基,R2是甲基。
23.权利要求3所述的方法,其中,R1是3-吡啶基,R2是甲基。
24.权利要求2所述的方法,其中,式I的酸加成盐是盐酸盐。
25.权利要求3所述的方法,其中,式I的酸加成盐是盐酸盐。
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JP (1) | JP2002540100A (zh) |
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CA (1) | CA2367969A1 (zh) |
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HU (1) | HUP0201347A3 (zh) |
MX (1) | MXPA01009621A (zh) |
NZ (1) | NZ514383A (zh) |
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US6306909B1 (en) | 1997-03-12 | 2001-10-23 | Queen's University At Kingston | Anti-epileptogenic agents |
JP2002540101A (ja) | 1999-03-22 | 2002-11-26 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | プロピオン酸3−アミノ−3−アリールの合成 |
AU3906300A (en) * | 1999-03-22 | 2000-10-09 | Ortho-Mcneil Pharmaceutical, Inc. | Process of preparing 3s-3-amino-3-aryl propionic acid and derivatives thereof |
CA2448160A1 (en) * | 2001-05-25 | 2002-12-05 | Queen's University At Kingston | Heterocyclic beta-amino acids and their use as anti-epileptogenic agents |
CN101982458B (zh) * | 2010-09-14 | 2013-11-06 | 北京欧凯纳斯科技有限公司 | 3-氨基-3-芳基丙酸及其制备方法 |
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IE58243B1 (en) | 1983-12-07 | 1993-08-11 | Lonza Ag | A process for the preparation of optically-active 3-amino carboxylic acids |
US5254573A (en) | 1991-10-15 | 1993-10-19 | Monsanto Company | Substituted heterocyclic derivatives useful as platelet aggregation inhibitors |
PT923555E (pt) * | 1996-05-01 | 2005-09-30 | Ortho Mcneil Pharm Inc | Derivados carboxamida de pirrolidina, piperidina e hexa-hidroazepina para o tratamento de disturbios tromboticos |
JP2000514809A (ja) | 1996-07-12 | 2000-11-07 | ジー.ディー.サール アンド カンパニー | キラルβ―アミノ酸の不斉合成 |
AU3906300A (en) * | 1999-03-22 | 2000-10-09 | Ortho-Mcneil Pharmaceutical, Inc. | Process of preparing 3s-3-amino-3-aryl propionic acid and derivatives thereof |
DE10111877A1 (de) * | 2001-03-10 | 2002-09-12 | Aventis Pharma Gmbh | Neue Imidazolidinderivate, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
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EP1163222A1 (en) | 2001-12-19 |
AU3906300A (en) | 2000-10-09 |
US20040063960A1 (en) | 2004-04-01 |
HRP20010766A2 (en) | 2002-12-31 |
WO2000056715A1 (en) | 2000-09-28 |
HUP0201347A2 (en) | 2002-09-28 |
JP2002540100A (ja) | 2002-11-26 |
SK13582001A3 (sk) | 2003-02-04 |
MXPA01009621A (es) | 2003-07-21 |
BR0009277A (pt) | 2002-02-05 |
RU2228929C2 (ru) | 2004-05-20 |
CZ20013403A3 (cs) | 2002-07-17 |
KR20020016617A (ko) | 2002-03-04 |
US6673926B2 (en) | 2004-01-06 |
US20030176471A1 (en) | 2003-09-18 |
CA2367969A1 (en) | 2000-09-28 |
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