CN1671658A - 氨基吡咯烷衍生物的制备方法 - Google Patents
氨基吡咯烷衍生物的制备方法 Download PDFInfo
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- CN1671658A CN1671658A CNA038185032A CN03818503A CN1671658A CN 1671658 A CN1671658 A CN 1671658A CN A038185032 A CNA038185032 A CN A038185032A CN 03818503 A CN03818503 A CN 03818503A CN 1671658 A CN1671658 A CN 1671658A
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- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical class NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 title description 2
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical class NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- 125000006239 protecting group Chemical group 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- DZAHXNNEQCZPGJ-UHFFFAOYSA-N CCCCOC(OC)=O.COC(O)=O Chemical class CCCCOC(OC)=O.COC(O)=O DZAHXNNEQCZPGJ-UHFFFAOYSA-N 0.000 claims description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 claims description 2
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical class ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 claims description 2
- QGRRJTQMMXJUNP-UHFFFAOYSA-N 1-pyrrolidin-1-ylpyrrolidine Chemical compound C1CCCN1N1CCCC1 QGRRJTQMMXJUNP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- 125000005905 mesyloxy group Chemical group 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract description 2
- 239000003905 agrochemical Substances 0.000 abstract description 2
- 229940124587 cephalosporin Drugs 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- -1 sulfonyloxy methyl oxygen Chemical class 0.000 description 7
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- LFLBHTZRLVHUQC-UHFFFAOYSA-N butyl methanesulfonate Chemical compound CCCCOS(C)(=O)=O LFLBHTZRLVHUQC-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- GVPDRYJFYUWXQK-UHFFFAOYSA-N 3-bromopyrrolidin-2-one Chemical compound BrC1CCNC1=O GVPDRYJFYUWXQK-UHFFFAOYSA-N 0.000 description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 2
- 238000009834 vaporization Methods 0.000 description 2
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- OGNROIRTCSDKHY-UHFFFAOYSA-N 2-bromo-4-chlorobutanoyl chloride Chemical compound ClCCC(Br)C(Cl)=O OGNROIRTCSDKHY-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- GTTSNKDQDACYLV-UHFFFAOYSA-N Trihydroxybutane Chemical compound CCCC(O)(O)O GTTSNKDQDACYLV-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical class CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 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
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-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
- 238000012546 transfer Methods 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Classifications
-
- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/10—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 no 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
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明涉及制备式(I)的3-氨基-吡咯烷衍生物的方法其中R1表示氢或氨基保护基;Z表示氢或氨基保护基;且*表示手性中心。3-氨基-吡咯烷衍生物、特别是旋光3-氨基-吡咯烷衍生物是制备农用化学品和药学活性物质如乙烯基吡咯烷酮-头孢菌素衍生物的重要中间体。
Description
本发明涉及用于制备外消旋和旋光3-氨基-吡咯烷衍生物的新方法和该方法用于制备头孢菌素衍生物的应用。
3-氨基-吡咯烷衍生物、特别是旋光3-氨基-吡咯烷衍生物是制备农用化学品和药学活性物质如乙烯基吡咯烷酮-头孢菌素衍生物的重要中间体。
可以用本身已知的方法如EP-A-0218249中所述的方法、从1,2,4-三取代的丁烷衍生物如三溴丁烷或三羟基丁烷开始制备3-氨基-吡咯烷衍生物。然后如果需要,可将外消旋衍生物通过外消旋物拆分而转化为旋光3-氨基-吡咯烷衍生物,JP 09124595-A。如J.Med.Chem.1764(92),35中所述、基于4-羟基脯氨酸的转化而制备旋光3-氨基-吡咯烷衍生物的方法经过三个步骤得到旋光3-氨基-吡咯烷。
如例如英国专利No.1392194、EP-A-0391169和美国专利No.4916141中所述的制备3-氨基-吡咯烷衍生物的已知方法费时且产生昂贵的中间体。因此,对制备3-氨基-吡咯烷衍生物、特别是旋光3-氨基-吡咯烷衍生物的其他方法极为关注。由此,Tomori等(Heterocycles,1997,1,213-225)已经由(S)-3-苄氧基羰基氨基-1,4-二甲磺酰氧基丁烷、通过用过量的烯丙基胺环化并用钯/炭将形成的(S)-1-烯丙基-3-(苄氧基羰基氨基)吡咯烷脱烯丙基而合成了(S)-3-(叔-丁氧基羰基氨基)-吡咯烷。然而,烯丙基胺作为一种有毒、易燃且昂贵的液体,在工业规模上并不实用;而且,钯是昂贵的催化剂。现已发现:通过用羟胺或其酸加成盐、特别是盐酸羟胺替代烯丙基胺,可在工业规模上以高产量安全地制备3-氨基-吡咯烷衍生物、特别是旋光3-氨基吡咯烷衍生物,羟胺或其酸加成盐、特别是盐酸羟胺便宜且更易于处理、无所述任何缺点,且为固体、易溶于极性有机溶剂如四氢呋喃、乙醇、三乙胺或它们的混合物。然后通过用便宜的催化剂阮内镍催化还原以除去所得N-羟基-3-被保护的氨基-吡咯烷中的羟基。
依照这些发现,本发明涉及式I的3-氨基吡咯烷衍生物的制备方法,
其中:R1表示氢或氨基保护基;
Z表示氢或氨基保护基;且
*表示手性中心,
该方法包括在羟胺或其酸加成盐存在下将式II化合物
其中:X表示被保护的羟基;
Z1表示氨基保护基;且
*具有上述含义,
转化成通式III的N-羟基-吡咯烷衍生物,
其中Z1和*具有上述含义,
随后将通式III化合物的N-羟基通过用阮内镍氢化而还原为通式IV的仲胺,
其中Z1和*具有上述含义;
并且如果需要,通过与其中R10是氨基保护基且X1是卤素或离去基团的式R10X1化合物反应对N1仲氨基进行保护,以生成通式V化合物,
其中R10、Z1和*具有上述含义,
并且如果需要,通过催化氢化将3-仲氨基脱保护,以生成通式VI化合物,
其中R10和*具有上述含义。
在上述定义中,在本发明范围内的术语“被保护的羟基”包括酯基,例如磺酸酯如甲磺酸酯、甲苯磺酸酯、对-溴苯磺酸酯或对-硝基苯磺酸酯。这些基团特别是在闭环反应条件下被选择性裂解使得在2位的氨基保护基Z不被释放的基团。甲磺酸酯和甲苯磺酸酯(甲基磺酰氧基和甲苯磺酰氧基)是特别优选的被保护的羟基X。
在本发明范围内的术语“氨基保护基”包括低级烷基、苄基、低级链烯基、低级烷氧羰基、低级链烯氧羰基、苄氧羰基等。特别优选叔-丁氧羰基、烯丙氧羰基和苄氧羰基,尤其是后者。
术语“离去基团”包括卤素原子如氯与溴,和低级烷基磺酰氧基或低级烷基苯磺酰氧基如甲基磺酰氧基或甲苯磺酰氧基,还有碳酸酐残基如叔-丁氧羰基氧基。
在本发明范围内的术语“低级烷基”包括直链和支链的、任选地具有1至8个碳原子的手性烃基,如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、异丙基、异丁基、叔丁基、2-甲基丁基等。“低级烷氧基”具有类似的含义。
术语“低级链烯基”包括具有2至8个碳原子的烯属直链和支链基团如乙烯基、烯丙基、3-丁烯基、1,3-丁二烯基。
术语“低级烯丙基”、“低级烷氧基”和“低级链烯基”在与如“羰基”的组合如“丁氧羰基”、“烯丙氧基羰基”中保持原义。
在本发明方法的一个特别优选的方面,在约0℃至反应混合物的沸点下、在极性溶剂如四氢呋喃、乙醇、三乙胺或二甲亚砜或其混合物、尤其优选在三乙胺中,用盐酸羟胺将旋光R-形式的2-(苄氧羰基氨基)-1,4-二甲磺酰氧基丁烷环化。随后,将所得式III的N-羟基-3-被保护的吡咯烷的羟基以还原方式、于室温、氢气氛下用阮内镍氢化而除去。随后,可将所得式IV的仲胺优选用叔丁氧基羰基、通过与二碳酸二叔丁基酯、优选在室温下反应进行N-保护。所得式V的双保护产物的苄氧羰基保护基方便地用氢和钯/炭、优选在室温下通过催化除去。
所得式VI的伯胺特别适于制备通式A的乙烯基吡咯烷酮-头孢菌素衍生物,
其中:Y表示CH或氮;
R1表示氢或氨基保护基;且
*表示手性中心。
式A化合物是具有高抗菌活性、尤其是抗金黄色葡萄球菌(Staphylococcus aureus)(MRSA)和铜绿假单孢菌(Pseudomonas aeruginosa)的耐甲氧苯青霉素菌株的头孢菌素衍生物。
通式A化合物可按照EP-A-849269、依照方案I制备:
方案1
在方案1中,Y、R1和*具有上述含义;Ph是苯基,BOC是叔-丁氧基羰基,CHPh2是二苯甲基。
为获得通式A化合物,按照上述本发明的方法制备式I的3-氨基吡咯烷衍生物,然后依照方案1使其与2-溴-4-氯丁酰氯反应,将由此得到的N-取代的3-溴-2-吡咯烷酮(1)转化成维悌希盐(2),使该维悌希盐与双保护的3-烯头孢菌素(3)反应。将所得缩合产物(4)氧化为5-亚砜(5),将其用PBr3还原异构化为2-烯头孢菌素(6),将后者N-脱保护并用活化的酰基衍生物(8)酰化,以生成(9),将(9)以两步脱保护以生成(10),最后得到式A的终产物。
下列实施例用于阐述本发明。
实施例1
(R)-3-(苄氧基羰基氨基)-N-羟基-吡咯烷
将(R)-2-(苄氧基羰基氨基)-1,4-二甲磺酰氧基丁烷(2.0g;5.0mmol)溶解于Et3N/DMSO混合物(1∶1,20ml)中。加入盐酸羟胺(1.4g;20.2mmol),将混合物在60℃加热过夜。将该混合物倾入HCl水溶液中(用NaHCO3将pH调至pH=6)并用AcOEt萃取两次。将有机相用水洗涤并经Na2SO4干燥。将固体滤出并除去溶剂。得到浅黄色油(1.4g,纯度73%)(产率:85%)。将粗标题化合物就此使用。
实施例2
(R)-3-(苄氧基羰基氨基)-N-(叔-丁氧基羰基)-吡咯烷
将以上所得粗(R)-3-(苄氧基羰基氨基)-N-羟基-吡咯烷(1.4g)溶解于乙醇(10ml)中。向该混合物中加入阮内镍(约2g)。将反应在减压和提供氢气条件下脱气(三次),随后置于氢气气氛中(1巴)。反应在6小时后结束,生成粗(R)-3-(苄氧基羰基氨基)-吡咯烷,通过加入二碳酸二叔丁基酯(1.0g,4.58mmol)将其原位处理;将混合物搅拌1小时。除去溶剂并将残余物置于正己烷/AcOEt混合物(1∶1,20ml)中,并经硅胶垫过滤。将该硅胶用正己烷/AcOEt混合物(1∶1;250ml)洗涤。蒸发有机相。得到的化合物是纯度优良即至少90-95%纯度的无色油,该纯度使其足以用于进一步反应,例如用于实施例3中。
NMR:(CDCl3;300MHz):7.34(m;5H);5.1(s(宽峰);2H;4.83(m(宽峰);1H);4.22(m(宽峰);1H);3.60(dd;1H);3.41(m(宽峰);2H);3.18(m(宽峰);1H);2.12(M;1H);1.82(m(宽峰);1H);1.45(s;9H)。
MS:(M+H+):321.3(M+NH4 +):338.2。
实施例2也可在压力反应器中在压力范围1-50kg、更优选1-20kg、最优选在3.8kg压力下加压进行。此外,该反应可在20℃-100℃、更优选40℃-60℃、最优选在55℃的温度下进行。
实施例3
(R)-3-氨基-N-(叔-丁氧基羰基)-吡咯烷
将(R)-3-(苄氧基羰基氨基)-N-(叔-丁氧基羰基)-吡咯烷(300mg)溶于乙醇(5ml)中。加入10%钯/炭(20mg)。将反应脱气三次并置于氢气气氛(1巴)中。该反应在两小时后结束。除去溶剂,将残余物置于乙酸乙酯(5ml)中并通过硅胶垫过滤。用乙酸乙酯(50ml)洗涤硅胶。蒸发有机相。获得所需定量产量(175mg)的(R)-3-氨基-N-(叔-丁氧基羰基)-吡咯烷,为无色油。
NMR:(CDCl3;300MHz):3.6-3.3(m(宽峰);3H);3.05(m(宽峰);1H);2.29(s(宽峰);2H);2.05(m;1H);1.66(m(宽峰);1H);1.46(s;9H)。
MS:(M+H+):187.3。
实施例3也可在压力反应器中在压力范围为1-50kg、更优选5-40kg、最优选在20kg压力下加压进行。此外,该反应可在酸(在加入Pd/C之后)如乙酸、HCl或高氯酸存在下进行。最优选使用高氯酸。
(R)-3-氨基-N-(叔-丁氧羰基)-吡咯烷可用于代替EP-A-0849269实施例2中的N-烯丙氧基羰基衍生物,并随后在实施例3-11中生成式A-1的(6R,7R)-7-[(Z)-2-(5-氨基-[1,2,4]噻二唑-3-基)-2-羟基亚氨基-乙酰氨基]-8-氧代-3-[(E)-(R)-2-氧代-[1,3′]联吡咯烷基-3-亚基甲基]-5-硫杂-1-氮杂-双环[4.2.0]辛-2-烯-2-甲酸。
实施例4
将27L二甲亚砜、9.5kg(R)-2-(苄氧基羰基氨基)-1,4-二甲磺酰氧基丁烷和6.68kg盐酸羟胺装入200L反应器中,将反应混合物室温搅拌至悬浮状。缓慢加入27L三乙胺,由此温度升至45-50℃。将反应物在55℃下维持4小时。通过NMR或HPLC(高效液相色谱)监控反应。随后将反应混合物冷却至室温。
另外,用含14.2L浓盐酸水溶液的100L 0℃的水制备溶液。将上述反应物加入该溶液并将pH值调至1.0-1.5。将水层洗涤两次,每次用10L 1∶1的乙酸乙酯和正己烷,并用15kg碳酸氢钠中和。将反应混合物搅拌30分钟并将pH调至约7.0-7.5。将水层萃取三次,每次用15L乙酸乙酯。将合并的有机相洗涤两次,每次用15L水,再用10L盐水(饱和氯化钠水溶液)。
减压蒸发溶剂,蒸发结束时用10L正己烷反萃取油状残余物。将正己烷蒸出,再加入正己烷并搅拌混合物以析出产物。滤出粗(R)-3-(苄氧基羰基氨基)-N-羟基-吡咯烷并直接用于实施例5。所得白色固体经贮藏变成黄色。
产量:4.6-5.0kg(80-85%),纯度超过95%。
实施例5
将22.5L乙醇、4.5kg(R)-3-(苄氧基羰基氨基)-N-羟基-吡咯烷和1.35kg阮内镍装入50L高压釜中。将高压釜置于氢气气氛(50psi=3.5巴)下并搅拌4小时。通过HPLC和TLC监测反应。
反应后,滤出催化剂并减压蒸发除去溶剂。将残余物即粗(R)-3-(苄氧基羰基氨基)-吡咯烷溶于20L乙醇,然后溶解4.15kg二碳酸二叔丁基酯。将反应混合物在室温下搅拌2小时,通过HPLC和TLC监测反应。减压下蒸出溶剂,将反应混合物反萃取两次,每次加2L甲苯。
获得5.7kg粗(R)-3-(苄氧基羰基氨基)-N-(叔-丁氧基羰基)-吡咯烷,为黄色油状残余物,于20L反应器中将其溶解在11.4L二氯甲烷中、然后加入2.85kg硅胶和57g活性炭提纯。将反应混合物在室温下搅拌2小时,滤出固体并用10L二氯甲烷充分洗涤。将合并的有机层在减压下蒸发,生成5.1kg(R)-3-(苄氧基羰基氨基)-N-(叔-丁氧基羰基)-吡咯烷,为无色油。
实施例6
将51L乙醇、5.1kg(R)-3-(苄氧基羰基氨基)-N-(叔-丁氧基羰基)-吡咯烷、0.51g 5%钯/炭和0.5L高氯酸装入高压釜。将高压釜置于氢气气氛(100psi=7巴)下1小时;通过NMR监控反应。反应完成后,滤出催化剂并在减压下除去溶剂。
将油状残余物溶解于10L乙酸乙酯中,并将有机层用10L水、然后用10L 10%的碳酸钠水溶液洗涤。将有机相经硫酸钠干燥并在减压下蒸发除去溶剂。获得2.5kg(R)-3-氨基-N-(叔-丁氧基羰基)-吡咯烷,为无色油。NMR谱与实施例3所报道的相同。
Claims (10)
1.制备式I的3-氨基吡咯烷衍生物的方法,
其中:R1表示氢或氨基保护基;
Z表示氢或氨基保护基;且
*表示手性中心,
该方法包括在羟胺或其酸加成盐存在下将式II化合物
其中:X表示被保护的羟基;
Z1表示氨基保护基;且
*具有上述含义,
转化成通式III的N-羟基-吡咯烷衍生物,
其中Z1和*具有上述含义;
随后将通式III化合物的N-羟基通过用阮内镍氢化而还原成通式IV的仲胺,
其中Z1和*具有上述含义;
并且如果需要,通过与其中R10是氨基保护基且X1是卤素或离去基团的式R10X1化合物反应对N1仲氨基进行保护,以生成通式V化合物,
其中R10、Z1和*具有上述含义,
并且如果需要,通过催化氢化将3-仲氨基脱保护,以生成通式VI化合物,
其中R10和*具有上述含义。
2.根据权利要求1的方法,其中使用R-形式的式II起始化合物。
3.根据权利要求1或2的方法,其中使用X为甲磺酰氧基的式II起始化合物。
4.根据权利要求1-3任一项的方法,其中使用Z1为苄氧基羰基的式II起始化合物。
5.根据权利要求1-4任一项的方法,其中使式II的起始化合物与盐酸羟胺反应。
6.根据权利要求1-5任一项的方法,其中使式IV中间体与二碳酸二叔丁基酯反应。
7.根据权利要求1-6任一项的方法,其中式V中间体的3-仲氨基的脱保护通过Pd/C催化氢化而进行。
8.根据权利要求1-7任一项的方法,其中所述反应在压力下进行。
10.根据权利要求10的方法,其用于制备式A-1的(6R,7R)-7-[(Z)-2-(5-氨基-[1,2,4]噻二唑-3-基)-2-羟基亚氨基-乙酰氨基]-8-氧代-3-[(E)-(R)-2-氧代-[1,3′]联吡咯烷基-3-亚基甲基]-5-硫杂-1-氮杂-双环[4.2.0]辛-2-烯-2-甲酸,
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CN101512005B (zh) * | 2006-09-06 | 2013-01-02 | 龙沙股份有限公司 | 通过使用细菌ω-转氨酶光学拆分外消旋胺混合物制备光学活性N-保护的3-氨基吡咯烷或光学活性N-保护的3-氨基哌啶以及相应的酮 |
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EP1818411A1 (en) * | 2006-02-13 | 2007-08-15 | Lonza AG | Process for the preparation of optically active chiral amines |
CN103373953A (zh) * | 2012-04-26 | 2013-10-30 | 上海阳帆医药科技有限公司 | 3-氨基哌啶及其光学异构体的制备方法 |
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CN101512005B (zh) * | 2006-09-06 | 2013-01-02 | 龙沙股份有限公司 | 通过使用细菌ω-转氨酶光学拆分外消旋胺混合物制备光学活性N-保护的3-氨基吡咯烷或光学活性N-保护的3-氨基哌啶以及相应的酮 |
CN101955457A (zh) * | 2010-09-21 | 2011-01-26 | 海门慧聚药业有限公司 | 光学活性3-氨基吡咯烷、3-氨基哌啶烷及其衍生物的一种通用制备方法 |
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TWI258466B (en) | 2006-07-21 |
US20040034236A1 (en) | 2004-02-19 |
CY1105781T1 (el) | 2011-02-02 |
DK1546096T3 (da) | 2006-11-20 |
ES2271652T3 (es) | 2007-04-16 |
BR0313355B1 (pt) | 2014-04-22 |
US20040127703A1 (en) | 2004-07-01 |
AU2003258536B2 (en) | 2009-06-25 |
DE60308204T2 (de) | 2007-08-23 |
US7064199B2 (en) | 2006-06-20 |
TW200403222A (en) | 2004-03-01 |
BR0313355A (pt) | 2005-07-12 |
WO2004013097A1 (en) | 2004-02-12 |
CN1297539C (zh) | 2007-01-31 |
ATE338747T1 (de) | 2006-09-15 |
JP2006506337A (ja) | 2006-02-23 |
CA2491133C (en) | 2009-09-01 |
JP4368304B2 (ja) | 2009-11-18 |
ZA200500290B (en) | 2005-11-14 |
EP1546096B1 (en) | 2006-09-06 |
MXPA05001150A (es) | 2005-05-16 |
KR20050023444A (ko) | 2005-03-09 |
PT1546096E (pt) | 2006-12-29 |
KR100919145B1 (ko) | 2009-09-28 |
EP1546096A1 (en) | 2005-06-29 |
US6872836B2 (en) | 2005-03-29 |
AU2003258536A1 (en) | 2004-02-23 |
AU2003258536C1 (en) | 2009-12-17 |
HK1080472A1 (en) | 2006-04-28 |
DE60308204D1 (de) | 2006-10-19 |
CA2491133A1 (en) | 2004-02-12 |
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