CN1265664A - [2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基]乙基膦酸的制备方法 - Google Patents
[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基]乙基膦酸的制备方法 Download PDFInfo
- Publication number
- CN1265664A CN1265664A CN98807848A CN98807848A CN1265664A CN 1265664 A CN1265664 A CN 1265664A CN 98807848 A CN98807848 A CN 98807848A CN 98807848 A CN98807848 A CN 98807848A CN 1265664 A CN1265664 A CN 1265664A
- Authority
- CN
- China
- Prior art keywords
- amino
- ethyl
- dioxo
- alkyl ester
- ester
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title abstract 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 34
- 150000002148 esters Chemical class 0.000 claims abstract description 31
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- ZTWTYVWXUKTLCP-UHFFFAOYSA-L ethenyl-dioxido-oxo-$l^{5}-phosphane Chemical compound [O-]P([O-])(=O)C=C ZTWTYVWXUKTLCP-UHFFFAOYSA-L 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 150000003009 phosphonic acids Chemical class 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 11
- 229920002554 vinyl polymer Polymers 0.000 claims description 11
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 claims description 10
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims description 10
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 6
- VBUWHAJDOUIJMV-UHFFFAOYSA-N tert-butyl n-propylcarbamate Chemical compound CCCNC(=O)OC(C)(C)C VBUWHAJDOUIJMV-UHFFFAOYSA-N 0.000 claims description 6
- JLZOGLJEROCEQF-UHFFFAOYSA-N 3-aminopropylcarbamic acid Chemical compound NCCCNC(O)=O JLZOGLJEROCEQF-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 claims description 5
- 229960001826 dimethylphthalate Drugs 0.000 claims description 5
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 2
- 239000005977 Ethylene Substances 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 abstract description 8
- 238000010511 deprotection reaction Methods 0.000 abstract description 5
- POHWAQLZBIMPRN-UHFFFAOYSA-N tert-butyl n-(3-aminopropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCN POHWAQLZBIMPRN-UHFFFAOYSA-N 0.000 abstract description 4
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 2
- 230000002461 excitatory amino acid Effects 0.000 abstract description 2
- 239000003257 excitatory amino acid Substances 0.000 abstract description 2
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- VWKKMPUBSCMAEC-UHFFFAOYSA-N 2-[3-[(2-methylpropan-2-yl)oxycarbonylamino]propylamino]ethylphosphonic acid Chemical compound CC(C)(C)OC(=O)NCCCNCCP(O)(O)=O VWKKMPUBSCMAEC-UHFFFAOYSA-N 0.000 abstract 1
- 230000001773 anti-convulsant effect Effects 0.000 abstract 1
- 229960003965 antiepileptics Drugs 0.000 abstract 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 abstract 1
- MJUJXFBTEFXVKU-UHFFFAOYSA-N diethyl phosphonate Chemical compound CCOP(=O)OCC MJUJXFBTEFXVKU-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- -1 carbobenzoxy-(Cbz) protecting group Chemical group 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 5
- YLFBFPXKTIQSSY-UHFFFAOYSA-N dimethoxy(oxo)phosphanium Chemical compound CO[P+](=O)OC YLFBFPXKTIQSSY-UHFFFAOYSA-N 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- YOTZYFSGUCFUKA-UHFFFAOYSA-N dimethylphosphine Chemical compound CPC YOTZYFSGUCFUKA-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- BVXLLZBMCZWPGZ-UHFFFAOYSA-N [SiH4].[Br-].C[NH+](C)C Chemical compound [SiH4].[Br-].C[NH+](C)C BVXLLZBMCZWPGZ-UHFFFAOYSA-N 0.000 description 3
- 125000005600 alkyl phosphonate group Chemical group 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical class NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 2
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- NPILPEKWDDMYJS-UHFFFAOYSA-N C[SiH](C)C.[Br] Chemical compound C[SiH](C)C.[Br] NPILPEKWDDMYJS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- SVXPPSFKJQWISH-UHFFFAOYSA-N benzyl carbamoperoxoate Chemical group NC(=O)OOCC1=CC=CC=C1 SVXPPSFKJQWISH-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ZIXPVRHDBQPBDT-UHFFFAOYSA-N methylaminophosphonic acid Chemical compound CNP(O)(O)=O ZIXPVRHDBQPBDT-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- KBJXDTIYSSQJAI-UHFFFAOYSA-N propylcarbamic acid Chemical compound CCCNC(O)=O KBJXDTIYSSQJAI-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- ZTWTYVWXUKTLCP-UHFFFAOYSA-N vinylphosphonic acid Chemical compound OP(O)(=O)C=C ZTWTYVWXUKTLCP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及式Ⅰ化合物[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸的制备方法,该化合物是在与兴奋性氨基酸过多释放有关的情况下用作抗惊厥剂和神经保护剂的NMDA拮抗剂。在本发明方法中,将3-氨基丙基氨基甲酸1,1-二甲基乙酯与乙烯基膦酸二烷基酯反应,得到N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二烷基酯(d),产率80%。将(d)与3,4-二烷氧基环丁-3-烯-1,2-二酮反应,得到[3-[[2-(二烷氧基磷酰基)乙基]-(2-烷氧基-3,4-二氧代-1,2-环丁烯-1-基)氨基]丙基—氨基甲酸1,1-二甲基乙酯(e),产率96%。在三氟乙酸中将(e)脱保护并环化,得到[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸二烷基酯(c),产率58%。用溴三甲基硅烷处理该膦酸二乙酯(c),得到化合物(Ⅰ)。
Description
本发明涉及式I化合物[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸的制备方法,该化合物是在与兴奋性氨基酸过多释放有关的情况下用作抗惊厥剂和神经保护剂的NMDA拮抗剂。
在US 5,168,103中公开了式I化合物及其制备方法。在所公开的方法中,将3-氨基丙基氨基甲酸苯基甲酯与2-氧代乙基膦酸二烷基酯和氰基硼氢化钠反应,得到中间体[3-[[2-(二烷氧基氧膦基)乙基]氨基]丙基]氨基甲酸苯基甲酯(a),产率36%。将(a)与3,4-烷氧基(或3,4-二芳基烷氧基)环丁-3-烯-1,2-二酮如3,4-二乙氧基环丁-3-烯-1,2-二酮反应,得到[3-[[2-(二烷氧基磷酰基)乙基]-(2-烷氧基-3,4-二氧代-1-环丁烯-1-基)氨基]丙基-氨基甲酸苯基甲酯(b),产率89%。除去苄氧羰基保护基,并通过用10%披钯碳和1,4-环己二烯处理使(b)环化,得到[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸二烷基酯(c),产率62%。用溴三甲基硅烷处理双环二酯(c),得到[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸(I),产率78%。该一系列反应的总产率为15.5%。
在本发明方法中,如同下面反应方案1步骤II中所说明的,用3-氨基丙基氨基甲酸二烷基酯(IV)与乙烯基膦酸二烷基酯(V)进行反应,得到N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二烷基酯(VI)。如下文所述,本发明方法所提供的优于US 5,168,103方法的进一步改进是制备I的总产率增加至38.8%。
本发明一方面提供了制备[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸的方法,该方法包括下列步骤:
a) 将3,4-二-C1-C4烷氧基环丁-3-烯-1,2-二酮与N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸的二-C1-C6烷基酯反应,得到[3-[[2-(二-C1-C6烷氧基磷酰基)乙基]-(2-C1-C6烷氧基-3,4-二氧代-1-环丁烯-1-基)氨基]丙基-氨基甲酸叔丁酯;
b) 除去步骤(a)产物的3-氨基保护基;
c) 将步骤(b)的产物环化,形成双环中间体[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸二-C1-C6烷基酯;以及
d) 将步骤(c)的二-C1-C6-烷基酯转化为膦酸产物。
步骤(a)优选在无水甲醇或乙醇中、在室温(25-30℃)下进行。步骤(a)、(b)和(c)优选就地进行。步骤(b)优选在二氯甲烷中、于-5℃-25℃进行。步骤(d)优选在二氯甲烷或乙腈中、于约20℃温度下进行。在步骤(a)中优选的3,4-二-C1-C4-烷氧基环丁-3-烯-1,2-二酮是3,4-二乙氧基环丁-3-烯-1,2-二酮。
本发明的另一方面是,通过包括乙烯基膦酸二-C1-C6烷基酯与3-氨基丙基氨基甲酸1,1-二甲基乙酯反应的方法制备步骤(a)的N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸的二-C1-C6烷基酯。优选的乙烯基膦酸二-C1-C6烷基酯是乙烯基膦酸二甲酯或乙烯基膦酸二乙酯,最优选的是乙烯基膦酸二甲酯。
另一方面,本发明提供了下列化合物:
N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸的二-C1-C6烷基酯;
N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸的二甲酯或N-[3-(叔丁氧羰基氨基)丙基]-2-氨基甲基膦酸的二乙酯;
[3-[[2-(二-C1-C6烷氧基磷酰基)乙基]-(2-C1-C4烷氧基-3,4-二氧代环丁-1-烯基)氨基]丙基氨基甲酸叔丁酯;和
[3-[[2-(二乙氧基磷酰基)乙基]-(2-乙氧基-3,4-二氧代环丁-1-烯基)氨基]丙基-氨基甲酸叔丁酯或[3-[[2-(二乙氧基磷酰基)乙基]-(2-甲氧基-3,4-二氧代环丁-1-烯基)氨基]丙基氨基甲酸叔丁酯。
在下面反应方案1中举例说明本发明方法,其中“烷基”用乙基代表,“烷氧基”用乙氧基代表,并且如下做进一步描述:
在步骤1中,1,3-二氨基丙烷(II)与二叔丁基碳酸酯(III)反应,得到3-氨基丙基氨基甲酸1,1-二甲基乙酯(IV)。
在步骤2中,氨基甲酸酯(IV)与乙烯基膦酸二-C1-C6烷基酯(V)反应,得到N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸的二-C1-C6烷基酯(VI)。在说明性实例中,V是乙烯基膦酸二乙酯,该步骤产率为80%。然而,乙烯基膦酸二甲酯提供了可比的产率,并且是商业上优选的,因为它更易于大量获得。
在步骤3中,氨基膦酸二-C1-C6烷基酯(VI)与3,4-二-C1-C4烷氧基环丁-3-烯-1,2-二酮(VII)反应,得到[3-[[2-(二-C1-C6烷氧基磷酰基)乙基]-(2-C1-C4烷氧基-3,4-二氧代-1-环丁烯-1-基)氨基]丙基氨基甲酸1,1-二甲基乙酯(VIII)。在说明性实例中,在两种情况下,烷基均是乙基,该步骤的产率是96%。该步骤优选在无水甲醇或乙醇中、于室温下进行。
在步骤4中,在三氟乙酸中使(VIII)脱保护,然后用三乙胺作为环化剂环化,得到[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸二-C1-C6烷基酯(IX)。在说明性实例中,产物IX的产率是58%。脱保护优选在二氯甲烷中、在-5℃~25℃下进行。环化反应优选在二氯甲烷或乙腈中、特别优选在二氯甲烷中,于约20℃进行。
在步骤5中,用溴三甲基硅烷处理膦酸二乙酯(IX),得到化合物I,产率87%。按照本发明方法制备[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸(I)的总产率为38.8%,这比US 5,168,103公开的15.5%的产率有显著的改进。
步骤2、3和4优选就地进行。
在上述一系列反应中,术语“烷基”是指直链或支链C1-C6烷基,术语“烷氧基”是指C1-C6烷氧基,不包括其中烷基是甲基、乙基或丁基的方形酸酯化合物VII。产率是指其中“烷基”是乙基并且“烷氧基”是乙氧基的具体情况。
本发明方法的优点有几个方面。首先,1,3-丙二胺以极好的产率被二碳酸二叔丁酯一保护。比起用苄基氯甲酸酯制备苄氧基氨基甲酸酯保护基来说,该反应的危险性低。第二,该一保护的1,3-丙二胺可以以极好的产率与乙烯基膦酸二乙酯反应,而无需使用附加的试剂例如氰基硼氢化钠和酸,这些试剂并非都是没有危险的,当如前述公开使用2-氧代乙基膦酸二乙酯时这些试剂是需要的。第三,叔丁氧羰基易于用酸除去,而除去苄氧羰基则需要使用钯催化剂和氢源。
下面的反应方案I总结了本发明的方法。在该反应方案中,“烷基”以乙基代表,“烷氧基”用乙氧基代表。
下面的具体实施例用于说明本发明的方法,而不构成对本发明方法任何方面的限制。本领域专业人员知晓可等同用于实施本发明方法的其它方法或改变的方法。
实施例1
3-(叔丁氧羰基氨基)丙胺
在-3℃至+2℃和搅拌下,用约8小时,于1,3-二氨基丙烷(500克,6.75摩尔,Aldrich D2,360-2)在四氢呋喃(1.6升)中的溶液中滴加二碳酸二叔丁酯(300克,1.375摩尔,Aldrich 19,913-3)在四氢呋喃(800毫升)中的溶液。在0℃搅拌所得白色悬浮液,并使其缓缓温热至室温过夜。真空浓缩反应混合物,将残余物溶解在乙酸乙酯和饱和氯化钠溶液的混合物中。水层用乙酸乙酯萃取。合并的提取液用饱和氯化钠洗涤,用硫酸镁干燥并过滤,得到油状物(约245克,定量产生)。将所得油悬浮在水(200毫升)中,并冷却至0℃--5℃。加入溴甲酚绿(3毫升,0.04%水溶液;Aldrich 31,870-1)得到蓝色溶液。在剧烈搅拌下,滴加1N盐酸(1.4升),得到淡蓝色至绿/黄色溶液(pH约5-6,pH试纸)。该悬浮液用二氯甲烷(2×300毫升)萃取,水层用2.5N氢氧化钠碱化至pH约12。碱性水层用二氯甲烷(5×300毫升)萃取,有机层用饱和氯化钠溶液(2×100毫升)洗涤,用无水碳酸钾粉末干燥,经硅藻土过滤并浓缩,得到淡蓝色油状物,放置使其结晶(165克,69%)(非常吸湿的固体)。NMR(CDCl3,400 MHz):1.43(s,9H),1.61(p,2H),1.59(s,2H),2.76(t,2H),3. 20(q,2H),4.95(br,1H).
实施例2
N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二乙酯
在氮气氛下,向3-(叔丁氧羰基氨基)丙胺(77克,0.44摩尔)在甲醇(500毫升)中的溶液中加入乙烯基膦酸二乙酯97%(75克,0.44摩尔;Aldrich11,613-0),并在约20℃水浴中保持48小时。将反应混合物真空浓缩,将残余物(约160克)置于“Florisil”垫(3”×6”)上,用二氯甲烷/己烷1∶1、二氯甲烷以及最后用10%甲醇/二氯甲烷洗脱,得到无色油状标题化合物(121克,80%)。NMR(CDCl3,400 MHz):1.32(t,6H),1.43(s,9H),1.65(t,2H),1.80 (br,1H),1.97(dt,2H),2.67(t,2H),2.85 (dt,2H),3.20(q,2H),4.09(m,4H),5.08(br,1H).
实施例3
3-[[2-(二乙氧基磷酰基)乙基]-(2-乙氧基-3,4-二氧代环丁-1-
烯基)氨基]丙基氨基甲酸叔丁酯
在氮气氛下,向3,4-二乙氧基-3-环丁烯-1,2-二酮(45克,0.265摩尔;Aldrich 31,077-8)在无水乙醇(1.2升)中的溶液中滴加N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二乙酯(80克,0.24摩尔)在无水乙醇(600毫升)中的溶液,并在室温搅拌反应混合物15小时。将反应混合物真空浓缩,将残余物置于硅胶垫(6”×4”)上,并首先用二氯甲烷/己烷1∶1混合物洗脱以除去过量的3,4-二乙氧基-3-环丁烯-1,2-二酮,最后用10%甲醇/二氯甲烷洗脱,经蒸发后,得到粘稠油状的标题化合物(107克,96%)。
NMR:(CDCl3,400 MHz):1.34(t,6H),1.43(s,9H),1.46(t,3H),1.80(m,2H),2.12(m,2H),3.14(m,2H),3.49(t,1H),3.66(m,1H),3.73(t,1H),3.90(m,1H),4.10(m,4H),4.74(m,4H),5.05(br,H).
实施例4
[2-(8,9-二氧代-2,6-二氮杂双环[5.2.0]壬-1(7)-烯-2-基)乙
基]膦酸二乙酯
将N-[3-(叔丁氧羰基氨基)丙基]-N-[4-乙氧基-2,3-二氧代环丁-1-烯-1-基]-2-氨基乙基膦酸二乙酯(100克,0.22摩尔)在二氯甲烷(600毫升)中的溶液在冰中冷却,并用三氟乙酸(300毫升)处理。使反应混合物温热至室温过夜。在最高40℃的温度下,将该溶液真空浓缩,并与甲苯(2×500毫升)共蒸发,得到粘稠的油(159.5克),将所得油溶解在无水乙醇(1.5升)中,并用8小时滴加到三乙胺(350ml)在乙醇(1.5升)中的溶液中,在室温搅拌8小时。将反应混合物真空浓缩得油状物,并将所得油状物溶解在乙酸乙酯(1升)中。使化合物结晶并在冰中冷却,过滤并用乙酸乙酯洗涤,最后用己烷洗涤,得到白色固体状标题化合物(40克,58%)。NMR(CDCl3,400 MHz):1.34(t,6H),2.06(m,2H),2.20(dt,2H),3.50(m,4H),4.05(m,2H),4.15(m,4H),7.87(br,1H).MS(DEI)M+m/z 316.
LC分析(柱:Microsorb-MV C18,150×4.6mm;洗脱剂:30/70MeOH/0.01 M NH4H2PO4pH 4.7;流速:1mL/分钟;UV检测器210nm)
分析:C13H21N2O5P的计算值:C,49.36;H,6.69;N,8.85%。
实测值:C,49.47;H,6.74;N,8.77%。
实施例5
[2-(8,9-二氧代-2,6-二氮杂双环[5.2.0]壬-1(7)-烯-2-基)乙
基]膦酸
在氮气氛下,向[2-(8,9-二氧代-2,6-二氮杂双环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸二乙酯(37.6克,0.12摩尔)在二氯甲烷(350毫升)中的溶液中快速滴加溴三甲基硅烷(83毫升,96.3克,0.63摩尔;Aldrich 19,440-9)。将反应混合物在约20℃的水浴中保持15小时。将澄清的溶液真空浓缩,并在剧烈振摇下,将泡沫状的残余物溶解在丙酮(600毫升)中,得到稀悬浮液。加入水(50毫升,2.78摩尔),得到立即固化的胶状沉淀。将该悬浮液剧烈振摇10分钟,过滤并用丙酮洗涤,得到黄色固体化合物。将该固体溶解在沸水(450毫升)中,将该热溶液经带有槽纹的滤纸过滤以除去少量不溶性物质。将澄清的水溶液在冰中冷却,立即开始结晶。通过缓缓加入丙酮(800毫升)使该稠的结晶物质稀释,保持冷却1小时,过滤并用丙酮洗涤,然后用己烷洗涤,得到淡黄色固体状标题化合物(20.2克)。由母液中得到第二批产物(由LC测得纯度为100%)(6.5克),总产率为87%。NMR(DMSO-d6,400 Mhz):1.90(m,4H),3.25(m,2H),3.36(m,2H),3.84(q,2H),8.45(s,1H).LC分析(柱:NOVA Pak C18,300×3.9mm;洗脱剂:20/80 MeOH/0.005MPic A;流速:1mL/分钟;UV检测器210nm)
分析:C9H13N2O5P·0.1H2O的计算值:C,41.26;H,5.08;N,10.69%。
实测值:C,41.17;H,5.04;N,10.42%。Karl-Fischer分析:0.55%H2O;MS:-FAB[M-H]-m/z 259。
实施例6
制备3-(叔丁氧羰基氨基)丙胺
(“t-BOC-丙胺”)
在25-30℃,用4小时,将二碳酸二叔丁酯(0.5千克,2.29摩尔)在甲醇中的溶液加至过量(5当量)1,3-二氨基丙烷(0.83千克,11.2摩尔)中。滤出产物1,3-二氨基丙烷叔丁氧基碳酸酯,并真空蒸馏除去甲醇。将残余的油溶解在乙酸乙酯中,用盐水洗涤,加入水,并将pH调节至5.5。分离各层,使水相强碱化,碱性水溶液用甲苯萃取6次。合并的甲苯提取液用硫酸钠干燥并浓缩,得到t-BOC-丙胺(0.365千克),产率77.4%,总不纯率11.5%。
实施例7
制备[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-
2-基)乙基]膦酸二甲酯(“二甲基膦酸酯”)A.制备t-BOC-膦酸二甲酯
将t-BOC-丙胺,98%(0.67千克,3.77摩尔)和乙烯基膦酸二甲酯(0.59千克,4.12摩尔)在无水甲醇(2.7升)中的溶液在室温搅拌2天,得到二甲基膦酸酯产物。B.制备t-BOC-膦酸二甲基乙基方形酸酯
用6小时,将A中的二甲基膦酸酯产物溶液加至3,4-二乙氧基-3-环丁烯-1,2-二酮(“方形酸乙酯”)(0.55千克,3.23摩尔)在无水甲醇(3.24升)中的溶液中。在0-5℃搅拌过夜后,将反应混合物蒸馏浓缩。加入甲苯(1升),并反复蒸馏至最终1.6升体积的3-[[2-(二乙氧基磷酰基)乙基]-(2-乙氧基-3,4-二氧代环丁-1-烯基)氨基]丙基氨基甲酸叔丁酯(“t-BOC-膦酸二甲基乙基方形酸酯”)。C.制备脱保护的膦酸二甲基乙基方形酸酯
在0-5℃,向B的t-BOC-膦酸二甲基乙基方形酸酯溶液中加入甲苯(5.0升),然后用0.25-5小时加入三氟乙酸(4.71千克,41.31摩尔),同时保持温度低于15℃。在室温搅拌4小时后,将反应混合物浓缩,得到粗产物脱保护的膦酸二甲基乙基方形酸酯。D.制备二甲基膦酸酯
向由C得到的反应产物浓缩物中加入无水甲醇(4.5升),并在室温下、用6小时,将所得溶液加至过量的三乙胺(2.9千克,28.66摩尔)在无水甲醇中的溶液中。将反应混合物浓缩,然后加入乙酸乙酯,由此沉淀出标题的二甲基膦酸酯产物。过滤并用冷乙酸乙酯洗涤滤饼后,得到产率为50.4%的[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸二甲酯(“二甲基膦酸酯”)(0.56千克),浓度97.6%,单不纯率为1.05%,总不纯率为1.76%。
实施例8
制备与纯化[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-
1(7)-烯-2-基)乙基]膦酸
在室温和搅拌下,将97.6%的溴三甲基硅烷〔0.55千克,3.59摩尔〕加入二甲基膦酸酯(0.46千克,1.56摩尔)在乙腈(4.1升)中的悬浮液中。然后将所得溶液加入搅拌着的乙腈-水中。从溶液中沉淀出乳白色固体状的标题膦酸。使该浆液冷却至0℃,过滤收集产物。将湿的滤饼在水中搅拌,加入30%氢氧化钠至pH 13。形成溶液。加入盐酸至pH 1.0。从溶液中沉淀出白色固体状的标题膦酸。在布氏漏斗中收集产物并用冰冷的水洗涤。然后从水中重结晶来纯化标题膦酸。将湿的滤饼溶解在12份水中,在布氏漏斗中经纸过滤,并浓缩滤液。一旦冷却,标题的膦酸即从溶液中结晶出来。使该浆料冷却至0℃,经布氏漏斗收集。滤饼用水洗涤,在65℃经真空炉干燥,得到标题的膦酸,纯化后的产率为86%,浓度99.9%,单一不纯率为0.05%,总不纯率为0.13%。
Claims (15)
1.[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸的制备方法,该方法包括下列步骤:
a)将3,4-二-C1-C4烷氧基环丁-3-烯-1,2-二酮与N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸的二-C1-C6烷基酯反应,得到[3-[[2-(二-C1-C6烷氧基磷酰基)乙基]-(2-C1-C6烷氧基-3,4-二氧代-1-环丁烯-1-基)氨基]丙基-氨基甲酸叔丁酯;
b)除去步骤(a)产物的3-氨基保护基;
c)将步骤(b)的产物环化,形成双环中间体[2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基)乙基]膦酸二-C1-C6烷基酯;以及
d)将步骤(c)的二-C1-C6-烷基酯转化为膦酸产物。
2.根据权利要求1的方法,其中步骤(a)、(b)和(c)的反应就地进行。
3.根据权利要求1或2的方法,其中步骤(a)的反应在无水甲醇或乙醇中、于室温下进行。
4.根据权利要求1-3任何一项的方法,其中步骤(b)的反应在二氯甲烷中、于-5℃至25℃温度下进行。
5.根据权利要求1-4任何一项的方法,其中步骤(d)的反应在二氯甲烷或乙腈中、于约20℃温度下进行。
6.根据权利要求1-5任何一项的方法,其中3,4-二-C1-C4-烷氧基环丁-3-烯-1,2-二酮是3,4-二乙氧基环丁-3-烯-1,2-二酮
7.根据权利要求1-6任何一项的方法,其中通过包括乙烯基膦酸-C1-C6烷基酯与3-氨基丙基氨基甲酸1,1-二甲基乙酯反应的方法,制备N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸的二-C1-C6烷基酯。
8.N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二-C1-C6烷基酯的制备方法,包括将乙烯基膦酸二-C1-C6烷基酯与3-氨基丙基氨基甲酸1,1-二甲基乙酯反应。
9.根据权利要求7或8的方法,其中乙烯基膦酸二-C1-C6烷基酯是乙烯基膦酸二甲酯或乙烯基膦酸二乙酯。
10.根据权利要求7-9任何一项的方法,其中乙烯基膦酸二-C1-C6烷基酯与3-氨基丙基氨基甲酸1,1-二甲基乙酯的反应在无水甲醇中、于约20℃进行。
11.根据权利要求1-10任何一项的方法,其中N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二-C1-C6烷基酯是N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二甲酯或N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二乙酯。
12.化合物N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二-C1-C6烷基酯。
13.化合物N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二甲酯或化合物N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二乙酯。
14.化合物3-[[2-(二-C1-C6烷氧基磷酰基)乙基]-(2-C1-C6烷氧基-3,4-二氧代环丁-1-烯基)氨基]丙基氨基甲酸叔丁酯,其中烷氧基是相同或不同的。
15.化合物3-[[2-(二乙氧基磷酰基)乙基]-(2-乙氧基-3,4-二氧代环丁-1-烯基)氨基]丙基氨基甲酸叔丁酯。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US90509197A | 1997-08-01 | 1997-08-01 | |
US08/905091 | 1997-08-01 | ||
US08/905,091 | 1997-08-01 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2003101201207A Division CN1257174C (zh) | 1997-08-01 | 1998-07-31 | N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二烷基酯的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1265664A true CN1265664A (zh) | 2000-09-06 |
CN1149218C CN1149218C (zh) | 2004-05-12 |
Family
ID=25420284
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB988078481A Expired - Fee Related CN1149218C (zh) | 1997-08-01 | 1998-07-31 | [2-((8,9)-二氧代-2,6-二氮杂双环[5.2.0]-壬-1(7)-烯-2-基]乙基膦酸的制备方法 |
CNB2003101201207A Expired - Fee Related CN1257174C (zh) | 1997-08-01 | 1998-07-31 | N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二烷基酯的制备方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2003101201207A Expired - Fee Related CN1257174C (zh) | 1997-08-01 | 1998-07-31 | N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二烷基酯的制备方法 |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP1000072B1 (zh) |
JP (1) | JP4383651B2 (zh) |
KR (1) | KR100606580B1 (zh) |
CN (2) | CN1149218C (zh) |
AT (1) | ATE232875T1 (zh) |
AU (1) | AU746119B2 (zh) |
BR (1) | BR9811807A (zh) |
CA (1) | CA2297411C (zh) |
DE (1) | DE69811507T2 (zh) |
DK (1) | DK1000072T3 (zh) |
ES (1) | ES2190091T3 (zh) |
HK (1) | HK1027814A1 (zh) |
HU (1) | HUP0002505A3 (zh) |
IL (2) | IL163574A (zh) |
NO (1) | NO325420B1 (zh) |
NZ (1) | NZ502509A (zh) |
RU (1) | RU2205834C2 (zh) |
SI (1) | SI1000072T1 (zh) |
WO (1) | WO1999006417A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA78529C2 (en) | 2001-10-10 | 2007-04-10 | Wyeth Corp | Derivatives of [[2-(amino-3,4-dioxo-1-cyclobutene-1-yl)amino]alkyl] acid for treating pain |
EP1611144B1 (en) | 2003-04-09 | 2010-09-15 | Wyeth LLC | Derivatives of 2-(8,9-dioxo-2,6-diazabicyclo(5.2.0)non-1(7)-en-2-yl)alkyl phosphonic acid and their use as n-methyl-d-aspartate (nmda) recetor antagonists |
GT200400213A (es) | 2003-10-22 | 2007-09-05 | Metodos para la preparacion del acido {2-[(8,9)-dioxo-2,6-diaza-biciclo[5.2.0]-non-1(7)-en-2-il]etil} fosfonico y esteres del mismo | |
AU2010226479A1 (en) * | 2009-03-19 | 2011-09-22 | Wyeth Llc | Methods for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7) -en-2-yl)ethyl]phosphonic acid and precursors thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5168103A (en) * | 1991-01-22 | 1992-12-01 | American Home Products Corporation | [[2-(amino-3,4-dioxo-1-cyclobuten-1-yl) amino]alkyl]-acid derivatives |
-
1998
- 1998-07-31 KR KR1020007001078A patent/KR100606580B1/ko not_active IP Right Cessation
- 1998-07-31 AU AU86037/98A patent/AU746119B2/en not_active Ceased
- 1998-07-31 IL IL163574A patent/IL163574A/en not_active IP Right Cessation
- 1998-07-31 JP JP2000505174A patent/JP4383651B2/ja not_active Expired - Lifetime
- 1998-07-31 AT AT98937292T patent/ATE232875T1/de not_active IP Right Cessation
- 1998-07-31 CA CA002297411A patent/CA2297411C/en not_active Expired - Fee Related
- 1998-07-31 IL IL13408298A patent/IL134082A0/xx not_active IP Right Cessation
- 1998-07-31 DE DE69811507T patent/DE69811507T2/de not_active Expired - Lifetime
- 1998-07-31 CN CNB988078481A patent/CN1149218C/zh not_active Expired - Fee Related
- 1998-07-31 DK DK98937292T patent/DK1000072T3/da active
- 1998-07-31 NZ NZ502509A patent/NZ502509A/xx unknown
- 1998-07-31 SI SI9830362T patent/SI1000072T1/xx unknown
- 1998-07-31 EP EP98937292A patent/EP1000072B1/en not_active Expired - Lifetime
- 1998-07-31 ES ES98937292T patent/ES2190091T3/es not_active Expired - Lifetime
- 1998-07-31 WO PCT/US1998/015841 patent/WO1999006417A1/en active IP Right Grant
- 1998-07-31 HU HU0002505A patent/HUP0002505A3/hu unknown
- 1998-07-31 BR BR9811807-2A patent/BR9811807A/pt not_active Application Discontinuation
- 1998-07-31 CN CNB2003101201207A patent/CN1257174C/zh not_active Expired - Fee Related
- 1998-07-31 RU RU2000105273/04A patent/RU2205834C2/ru not_active IP Right Cessation
-
2000
- 2000-01-31 NO NO20000488A patent/NO325420B1/no not_active IP Right Cessation
- 2000-11-08 HK HK00107097A patent/HK1027814A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
IL163574A0 (en) | 2005-12-18 |
DE69811507T2 (de) | 2003-07-24 |
CN1149218C (zh) | 2004-05-12 |
NO325420B1 (no) | 2008-04-21 |
ATE232875T1 (de) | 2003-03-15 |
EP1000072A1 (en) | 2000-05-17 |
RU2205834C2 (ru) | 2003-06-10 |
CN1257174C (zh) | 2006-05-24 |
NO20000488D0 (no) | 2000-01-31 |
NZ502509A (en) | 2002-08-28 |
HUP0002505A3 (en) | 2002-02-28 |
DK1000072T3 (da) | 2003-04-22 |
ES2190091T3 (es) | 2003-07-16 |
NO20000488L (no) | 2000-01-31 |
HUP0002505A2 (hu) | 2000-11-28 |
KR20010022492A (ko) | 2001-03-15 |
IL134082A0 (en) | 2001-04-30 |
KR100606580B1 (ko) | 2006-08-01 |
AU746119B2 (en) | 2002-04-18 |
IL163574A (en) | 2008-06-05 |
CA2297411C (en) | 2008-12-02 |
JP4383651B2 (ja) | 2009-12-16 |
CA2297411A1 (en) | 1999-02-11 |
DE69811507D1 (de) | 2003-03-27 |
JP2001512129A (ja) | 2001-08-21 |
WO1999006417A1 (en) | 1999-02-11 |
AU8603798A (en) | 1999-02-22 |
CN1526714A (zh) | 2004-09-08 |
BR9811807A (pt) | 2000-08-15 |
SI1000072T1 (en) | 2003-06-30 |
HK1027814A1 (en) | 2001-01-23 |
EP1000072B1 (en) | 2003-02-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0895996B1 (de) | Verfahren zur Herstellung von Organosiliciumdisulfanen hoher Reinheit | |
CN1132203A (zh) | 由N-保护的氨基酸酯制备N-保护的氨基酸α-卤代甲基酮和醇的方法 | |
CA2081320A1 (en) | Phosphoramidite derivatives, their preparation and the use thereof in the incorporation of reporter groups on synthetic oligonucleotides | |
Goerlich et al. | Organophosphorus Compounds with Tertiary Alkyl Substituents. VI1: A Convenient Method for the Preparation of Di-1-Adamantylphosphine and Di-1-Adamantylchlorophosphine | |
CN108101942B (zh) | 半富马酸替诺福韦艾拉酚胺生产中潜在杂质的合成方法 | |
CN1257174C (zh) | N-[3-(叔丁氧羰基氨基)丙基]-2-氨基乙基膦酸二烷基酯的制备方法 | |
CA2083307A1 (en) | Aminoalkanephosphinic acids and salts thereof | |
CN113234102A (zh) | 一种三配位磷衍生物及中间体及制备方法 | |
JPH09309891A (ja) | モノアルキルホスホニットを製造する方法 | |
JP2000203814A (ja) | ホスフィン酸の製造方法 | |
US6011168A (en) | Process for the preparation[2-((8,9)-dioxo-2,6-diazabicyclo[5.2.0]-non-1(7)-en-2-yl)ethy l]phosphonic acid | |
JP3569680B2 (ja) | アルキル(アミノ)ジアルコキシシラン類の調製 | |
DD294945A5 (de) | Verfahren zur herstellung von p-substituierten propanphosphinsaeureverbindungen | |
EP0691975B1 (de) | Neue bis(aminomethyl)phosphinsäure-derivate und verfahren zur herstellung von bis(aminomethyl)phosphinsäure-derivaten | |
US20040236144A1 (en) | Method for producing $g(a)-aminophosphonic acids | |
US7186705B2 (en) | Process for the preparation of 3-amino-2-hydroxypropylphosphinic acid derivatives | |
DD243500A1 (de) | Verfahren zur herstellung von phosphonoformiaten | |
JP4084140B2 (ja) | ペンタエリスリトールジホスファイトの製造方法 | |
US5591881A (en) | Stereoselective preparation of (E)-enolthioether derivatives | |
WO2024015263A1 (en) | Process for preparing phosphonate esters | |
Zhu et al. | A convenient synthesis of N-perfluoroalkanesulfonylphosphoramidates | |
SU415267A1 (ru) | Способ получениякремнийорганических соединений,содержащих азот и фосфор | |
CN1072932A (zh) | 氨基链烷膦酸及其盐和/或酯的生产 | |
MXPA00001126A (en) | Process for the preparation of [2-((8,9)- dioxo-2,6-diazabicyclo [5.2. 0]-non-1(7)-en-2-yl)-ethyl]phosphonic acid | |
JP2004035465A (ja) | ペンタエリスリトールジホスファイトの製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040512 Termination date: 20110731 |