CN1022829C - 用金属化合物合成β-内酰胺 - Google Patents
用金属化合物合成β-内酰胺 Download PDFInfo
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- CN1022829C CN1022829C CN88100703A CN88100703A CN1022829C CN 1022829 C CN1022829 C CN 1022829C CN 88100703 A CN88100703 A CN 88100703A CN 88100703 A CN88100703 A CN 88100703A CN 1022829 C CN1022829 C CN 1022829C
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- Prior art keywords
- alkyl
- hydrogen
- phenyl
- general formula
- formula
- Prior art date
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- 150000003952 β-lactams Chemical class 0.000 title description 16
- 230000015572 biosynthetic process Effects 0.000 title description 5
- 238000003786 synthesis reaction Methods 0.000 title description 4
- 150000002736 metal compounds Chemical class 0.000 title description 3
- 150000002466 imines Chemical class 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- -1 cycloalkyl ester Chemical class 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000011701 zinc Substances 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 11
- 230000007062 hydrolysis Effects 0.000 claims description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims description 11
- 229910052725 zinc Inorganic materials 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 10
- 229910000765 intermetallic Inorganic materials 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 239000011592 zinc chloride Substances 0.000 claims description 10
- 235000005074 zinc chloride Nutrition 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000004471 Glycine Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 150000001340 alkali metals Chemical class 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- 239000004411 aluminium Substances 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 229910052721 tungsten Inorganic materials 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052728 basic metal Inorganic materials 0.000 claims description 3
- 150000003818 basic metals Chemical class 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims 1
- 125000002425 furfuryl group Chemical group C(C1=CC=CO1)* 0.000 claims 1
- UEXCJVNBTNXOEH-UHFFFAOYSA-N phenyl acethylene Natural products C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 125000001544 thienyl group Chemical group 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 abstract description 8
- 239000002184 metal Substances 0.000 abstract description 8
- 239000000543 intermediate Substances 0.000 abstract description 6
- 238000006482 condensation reaction Methods 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 51
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 25
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 24
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 19
- 239000007787 solid Substances 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 235000019270 ammonium chloride Nutrition 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 10
- UWRZIZXBOLBCON-UHFFFAOYSA-N 2-phenylethenamine Chemical compound NC=CC1=CC=CC=C1 UWRZIZXBOLBCON-UHFFFAOYSA-N 0.000 description 9
- 125000003710 aryl alkyl group Chemical group 0.000 description 9
- 229940043279 diisopropylamine Drugs 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 239000010410 layer Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000005837 enolization reaction Methods 0.000 description 5
- 150000002085 enols Chemical class 0.000 description 5
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- DPBGIOZNDXKTKW-UHFFFAOYSA-L [Cl-].[Zn+2].C(C)[Li].[Cl-] Chemical compound [Cl-].[Zn+2].C(C)[Li].[Cl-] DPBGIOZNDXKTKW-UHFFFAOYSA-L 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XJIXNJVAOFTYDJ-UHFFFAOYSA-N 2-cyclopentylethyl acetate Chemical compound CC(=O)OCCC1CCCC1 XJIXNJVAOFTYDJ-UHFFFAOYSA-N 0.000 description 2
- WSZGYCUJTYMCTB-UHFFFAOYSA-N 3-amino-1-methyl-4-phenylazetidin-2-one Chemical compound NC1C(=O)N(C)C1C1=CC=CC=C1 WSZGYCUJTYMCTB-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 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
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000002027 dichloromethane extract Substances 0.000 description 2
- YNLAOSYQHBDIKW-UHFFFAOYSA-M diethylaluminium chloride Chemical compound CC[Al](Cl)CC YNLAOSYQHBDIKW-UHFFFAOYSA-M 0.000 description 2
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical group CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- ORRQJZMYQQDYDX-UHFFFAOYSA-N ethyl 2-(diethylamino)acetate Chemical compound CCOC(=O)CN(CC)CC ORRQJZMYQQDYDX-UHFFFAOYSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000005298 paramagnetic effect Effects 0.000 description 2
- 239000003579 shift reagent Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000002769 thiazolinyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WSZGYCUJTYMCTB-IUCAKERBSA-N (3s,4s)-3-amino-1-methyl-4-phenylazetidin-2-one Chemical compound N[C@@H]1C(=O)N(C)[C@H]1C1=CC=CC=C1 WSZGYCUJTYMCTB-IUCAKERBSA-N 0.000 description 1
- AXQVKDQRBAXYBP-UHFFFAOYSA-N 2-aminoethanimidic acid Chemical compound NCC=N AXQVKDQRBAXYBP-UHFFFAOYSA-N 0.000 description 1
- IBKRTBANUKZHRD-UHFFFAOYSA-N 3-amino-4-phenylazetidin-2-one Chemical compound N1C(=O)C(N)C1C1=CC=CC=C1 IBKRTBANUKZHRD-UHFFFAOYSA-N 0.000 description 1
- GCBWDZYSLVSRRI-UHFFFAOYSA-N 3-aminoazetidin-2-one Chemical compound NC1CNC1=O GCBWDZYSLVSRRI-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- SGXDXUYKISDCAZ-UHFFFAOYSA-N N,N-diethylglycine Chemical compound CCN(CC)CC(O)=O SGXDXUYKISDCAZ-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- CPQHOTXYSJSUMB-UHFFFAOYSA-L S(=O)(=O)([O-])[O-].[Na+].C(Cl)Cl.[Na+] Chemical compound S(=O)(=O)([O-])[O-].[Na+].C(Cl)Cl.[Na+] CPQHOTXYSJSUMB-UHFFFAOYSA-L 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- LRMBRFABGNDSDR-UHFFFAOYSA-N [Li].CCOCC Chemical compound [Li].CCOCC LRMBRFABGNDSDR-UHFFFAOYSA-N 0.000 description 1
- QKNDAUTYSODFJV-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;sodium Chemical compound [Na].C[Si](C)(C)N[Si](C)(C)C QKNDAUTYSODFJV-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- ANUZKYYBDVLEEI-UHFFFAOYSA-N butane;hexane;lithium Chemical compound [Li]CCCC.CCCCCC ANUZKYYBDVLEEI-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical class CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- HXTGGPKOEKKUQO-UHFFFAOYSA-N n-methyl-1-phenylmethanimine Chemical compound CN=CC1=CC=CC=C1 HXTGGPKOEKKUQO-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 235000019353 potassium silicate Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- 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
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/06—Zinc compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Adhesives Or Adhesive Processes (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
- Manufacture And Refinement Of Metals (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
新型中间体一金属烯醇化物和合适的亚胺缩合反应,制得反式-β-内酰胺,产率几乎是定量的。一些新型金属烯醇化物作为中间体被提供。
Description
本发明涉及某些反式-β-内酰胺类化合物及其新的中间体的新的制备方法。
本发明涉及通式Ⅰ的反式-β-内酰胺化合物的制备方法。
式中
R2和R3各自为氢,烷基,芳基或芳烷基,并可任意取代有烷基,芳基或芳烷基,或者是
其中R6,R7和R8各自为烷基,芳基或芳烷基,每个基团又可任意取代;R6,R7和R8可以相同或不同,和
R2,R3可以相同或不同,但R2和R3不能同时为甲基或苄基,或者
R2,R3与氮原子一起连接为最大到八元环,并且每个基可任意取代有烷基,芳基或芳烷基;
R1是氢,卤素,烷基,烯基,烷氧基,芳基或芳烷基,或者是
其中R9,R10和R11各自为烷基,芳基,芳烷
基,每个基又可任意取代,而R9,R10和R11可以相同或不同,
R4是烷基,羟基,卤素,磺酰基,烷氧基,烯基,炔基或芳基,这些基团还可任意被取代,或者是
,其中,R5是烷基。
本发明还涉及通式Ⅱ的新金属化合物,
Ⅱ
式中
R2′和R3′是上面R2和R3代表的基团,但不为氢,
R12是烷基,芳基或芳烷基,每个基团可任意被烷基,芳基或芳烷基取代,
M是锌,铝,锆,硼,锡或钛,
P是碱金属,
W,X,Y和Z是烷基,芳基,卤素,烷氧基,烷硫基,
triflate或任何其它取代磺酰基或任何其它适宜的阴离子基团,W,X,Y和Z可以相同或不同;a,b,c和m为0或1,n=1-6的整数。
本发明还涉及通式Ⅰa的S-反-β-内酰胺的制备方法,
式中R1,R2,R3和R4的定义同上。
为了寻找或合成新的β-内酰胺和开发合成已知β-内酰胺(2-氮杂环丁烷酮)的新方法,已经进行了许多研究。这是因为,这些化合物是强力的抗生素,对于人类有很好的耐受性。这些β-内酰胺是四元环酰胺,是青霉素和头孢菌素的主要结构单元。
为合成有兴趣的1,2-二氨基乙烷,1-氨基-2亚氨基乙烷,α-羟基亚胺和有关的有机化合物而发展了新方法[(M.R.P.Van Vliet,G.van Koten,J.T.B.H.Jastrzebski,K.Vrieze和A.L.Spek,J.Organometal.Chem,251,C17(1983);M.R.P.van Vliet,Ph.D.Thesis,Amsterdam(1987);M.R.P.van Vliet,G.van Koten,P.Buysingh,J.T.B.H.Jastrzebski和A.L.Spek,Organometallics,6,537(1987)],该方法中,金属前体配合物被形成,其中包括ZnWX和AlWXY。
再有,从α-亚氨酸酯Ra-N=C(H)C(ORb)=O(其中Ra是烷基,Rb是烷基)和二乙基锌形成的金属配合物可以合成反-β-内酰胺,如程式Ⅰ所描述。
所形成的β-内酰胺的反式立体构型通过Ra为叔丁基,Rb为甲基的β-内酰胺化合物的X-射线结晶结构测定而被清楚地证实(M.R.P.van Vliet,J.T.B.H.Jastrzebski,W.J.Klaver,K.Goubitz和G.van Koten,RecL.Trav.Chim.Pays-Bas,100,137(1987)。这种β-内酰胺的制备方法的严重缺点是,取代基的变化范围太小,Ra只能是叔丁基或异丙基和Rb只能是甲基或乙基,而且,只能用二伯烷基锌化合物形成β-内酰胺。
程式Ⅰ描述的反应的最新研究揭示,首先,形成的有机锌配合物大概转化成烯醇锌,接着,再与第二当量的亚氨酸酯反应转化成反式-β-内酰胺(见程式Ⅱ)。
程式Ⅱ
烯醇锌化合物已经被分离出,并经X-射线测定证实了它固态的结构。
最新研究指出,所假定的中间体烯醇锌(见程式Ⅱ)和其它金属烯醇化物可以通过另一途径由碱金属烯醇化物与适宜的金属化合物反应就地制备。此反应以程式Ⅲ描述,所有的可改变的取代基的含义如上面所规定。
程式Ⅲ
如此得到的金属烯醇化物显示一种独特的反应活性,在与适合的亚胺作用物反应时,完全得到定量的反式-β-内酰胺。这种新奇的反应性是意想不到的,因为涉及烯醇盐的现有路线仅仅得到顺式-β-内酰胺或顺式-和反式-β-内酰胺的混合物。
许多β-内酰胺的合成是已知的,例如“杂环化学”第二部分第Ⅱ章中,关于β-内酰胺各种合成方法的综合评述,John Wiley和Sons出版的“The Synthesis of the β-lactam function”G.A.Koppel(1983)。然而,通过醇醛缩合继之闭环,合成带1-H(或可水解基团),3-NH2和4-烷基取代基的反式-β-内酰胺的合成路线则没有叙述。
P.Andreoli等在“Tetrahedron Lett”,27(15),1695-1698(1986)中报导了,在锂化合物和三甲基氯硅烷存在下,腈与甘氨酸酯的反应。然而,分离出的3,4-二取代的氮杂环丁烷酮,主要是顺式构型。
在欧洲专利申请No180398中叙述了,从腈和甘氨酸酯就地生成的甲醛亚胺可合成4-取代的β-内酰胺。
在二异丙基胺锂存在下,从N-三甲基硅烷基醛亚胺和烯醇酯已经制备了N-未取代的2-氮杂环丁烷酮[D.J.Hart等,J.Amer.Chem.Soc,48,289(1983)]。这些2-氮杂环丁烷酮在3-位上没有(被取代的)氮原子。
本发明意想不到地容易地和选择性地合成了1,3,4-三取代的反式-2-氮杂环丁烷酮,在此分子中连接于C-3碳原子的原子是氮原子,如果需要,1-位的取代基经水解可容易地除去。从新的中间体氨基金属烯醇化物和适合的亚胺的缩合反应已经得到至少含90%反式构型的所需化合物,产率几乎是定量的。这在现有文献中没有报导。
使一种立体对映体显著过量的合成方法也已经发现。通过选择甘氨酸烷酯的合适对映体做原料,可以合成富反式-β-内酰胺对映体。这里合适的甘氨酸烷酯对映体是指适宜于制备所需的反式-β-内酰胺对映体。
本发明的一个目的提供制备通式Ⅰ的反式-β-内酰胺(其中R1,R2,R3,R4的定义如前)的方法,该方法的特征是,通式Ⅱ的化合物与通式Ⅳ的亚胺反应,
式Ⅱ中R12,M,P,W,X,Y,R,a,b,c,m和n的定义同上;R2′和R3′分别与R2和R3相同,不过,当R2和R3为氢时,R2′和R3′与氮原子连在一起形成通式Ⅲ的环,
式Ⅲ中R12,R14,R15,R16,R17,R18,R19和R20各自为烷基,芳基,芳烷基,并且R12,R14,R15,R16,R17,R18,R19和R20可以相同也可以不同,
式Ⅳ中R4的定义同上,R1′与R1相同,不过,当R1为氢时,R1′为
式中R6,R7和R8的定义同上,并且在反应后该基团被酸或碱水解;和当R2和R3都为氢时,反应后经酸或碱催化水解,通式Ⅲ的环被除去。
本发明的另一个目的是,提供上面描述的通式为Ⅱ的化合物,式中R2′和R3′分别与R2和R3相同,不过,二者不能同时为氢,R12,M,P,W,X,Y,Z,a,b,c,m和n的定义同上。
此外,本发明还提供了制备前面定义的通式Ⅱ化合物的方法。该方法的特征是,碱金属碱与R2′R3′N-甘氨酸烷酯和具有通式为MW(X)a(Y)b(Z)c的金属化合物反应,其中R2′,R3′,M,W,X,Y,Z,a,b,c,m和n的定义同上。
本发明还提供了一锅法制备上面定义的通式Ⅰ的反式-β-内酰胺的方法。该方法的特征是,在碱金属碱和通式为MW(X)a(Y)b(Z)c(其中M,W,X,Y,Z,a,b,和c的定义同上)的金属化合物存在下,R2′R3′N-甘氨酰烷酯(其中R2′和R3′的定义同上)与定义如上的通式Ⅳ的亚胺反应,不过,当R2,R3为氢时,反应后经酸或碱催化水解,以除去通式Ⅲ的环。
最后,本发明提供了制备通式为Ⅰa的(3S)-反式-β-内酰胺(其中R1,R2,R3和R4的定义同上)的方法。该方法的特征是,将R2′R3′N-甘氨酸烷酯的合适对映体(其中R2′和R3′的定义同上)加以转化,不过,当R2′和R3′都是氢时,反应后,需通过酸或碱催化水解以除去通式Ⅲ的环。
优先使用的碱金属碱是二异丙基胺锂或六甲基二硅氮烷钠。在金属化合物MW(X)a(Y)b(Z)c中优选的M是锌或铝,而a,b和c的值取决于M的价数。
以一锅法合成反式-β-内酰胺确是可能的。例如,首先在室温下,加一当量正丁基锂的正己烷溶液于二异丙胺的苯溶液中,得到二异丙基胺锂,接着,再加Et2NCH2COOEt。所得的烯醇锂在反应期间部分地结晶。然后,加一当量干燥的二氯化锌(得到一种透明溶液),最后,加一当量N-(亚苄基)甲胺,回流反应混合物半小时,按照这一方法,使用适合的亚胺,可以合成各种各样的反式-β-内酰胺。然而,如果不加金属化合物MW(X)a(Y)b(Z)c(M,W,X,Y,Z,a,b,和c的定义同上),就不生成β-内酰胺。
该化合物在具有施光活性的顺磁位移试剂的CDCl2中的1HNMR试验指出,两种对映体以1∶2摩尔比存在,这表明一种对映体超过33%。
所有这些反应最好在惰性的,非极性的或弱极性的溶剂中进行,例如戊烷,苯和乙醚。此外,这些反应中使用的金属化合物MW(X)a(Y)b
(Z)c(其中M,W,X,Y,Z,a,b和c的定义同上)基本上是无水的,这一点也很重要。当有少量水存在时,产率降低,立体选择性也降低。
下面的一些非限制性实例用来进一步阐明本发明。
一般方法
所有反应采用标准Schlenk技术在干燥氮气保护下进行[“空气敏感化合物的处理”。D.F.Shriver,出版者Mc.Graw Hill,纽约(1969)]。所有溶剂在使用前用钠干燥后重蒸。乙醛酸N-叔丁基亚氨基乙酯和乙醛酸N-异丙基亚氨基甲酯经缩合反应制备;参考;叔丁胺和异丙胺分别与乙醛酸乙酯和乙醛酸甲酯的反应。2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊烷-1-乙酸乙酯已经叙述于“Tetrahedron Lett”。22,1787(1981)。正丁基锂的正己烷溶液和二乙基锌的正己烷溶液市场上可以买到。
应用干燥的金属化合物制备金属烯醇化物是非常重要的。因此,例如二氯化锌或者由乙醚中的锌和干燥氯化氢制备,或者从市场上买二氯化锌后在亚硫酰氯中回流脱水。
实例Ⅰ
N,N-二乙基甘氨酸乙酯的烯醇化乙基锌氯化锂配合物的合成
于0℃下,加13.33ml(1.5mol)正丁基锂己烷溶液(等于20m mol正丁基锂)于含2.02g(20m mol)二异丙基胺的30ml乙醚溶液中。反应混合物的温度升至室温并搅拌10分钟。在搅拌下,向所得二异丙基氨化锂溶液中加3.18g(20m mol)N,N-二乙基甘氨酸乙酯,立即生成N,N-二乙基甘氨酸乙酯的烯醇锂白色悬浮液。继续搅拌反应混合物30分钟后,冷却至-35℃。在此温度并搅拌下,加含2.6g(20m mol)氯化乙基锌的15ml乙醚溶液,在无色溶液中形成浓厚沉淀。于-35℃下,搅拌反应混合物30分钟,然后,升温至25℃,并再搅拌30分钟。
从沉淀中滗去溶液,用正戊烷洗涤沉淀三次,每次15ml。最后的产物在25℃下真空干燥,得到4.5g(76.3%)N,N-二乙基甘氨酸乙酯的烯醇化乙基锌氯化锂配合物,为空气敏感的白色固体:1HNMR(60MHz,C6D6)δ:3.70(S,1H,C=CH),3.60(m,2H,OCH2CH3),2.65(m,4H,NCH2CH3),1.55(t,3H,ZnCH2CH3),1.15(m,9H,CH2CH3和OCH2CH3),0.50(m,2H,ZnCH2CH3).
元素分析:(C10H21NO2ZnLiCL)
实测值:C,40.56;H,7.58;N,4.65;Zn,22.09
理论值:C,40.70;H,7.17;N,4.74;Zn,22.16
实例Ⅱ
1-甲基-3-取代的-4-苯基-2-氮杂环丁烷酮的合成
A.反式-1-甲基-3-二乙氨基-4-苯基-2-氮杂环烷酮的合成
于室温下,将2.95g(10m mol)N,N-二乙基甘氨酸乙酯的烯醇化乙基锌氯化锂配合物(实例Ⅰ所得产品)溶解于20ml苯中。将1.19g(10m mol)N-(亚苄基)甲胺加到此无色透明溶液中。所得溶液回流30分钟。在此期间形成一些沉淀。将反应混合物冷至室温后用25ml乙醚稀释。向此混合物中加入10ml饱和氯化铵水溶液。分出水层,有机层先用饱和氯化铵水溶液洗两次(每次10ml)后用水洗两次(每次10ml),硫酸钠干燥,减压浓缩,得到2.2g(95%)2-氮杂环丁烷酮产物,为白色固体,m.p70-71℃。1HNMR(60MH2,CDCl3)δ:7.30(m,5H,芳环),4.60(d,J=1.6Hz,1H,NCHCHPh),4.10(d,J=1.6Hz,1H,NCHCHPh),2.90(S,3H,NCH3),2.90(q,4H,NCH2CH3),1.15(t,6H,NCH2-CH3)。元素分析:(C14H20N2O)
实测值:C72.13;H8.80;N11.73
理论值:C72.38;H8.68;N12.06
B.1-甲基-3-甲苯氨基-4-苯基-2-氮杂环丁烷酮的合成
于室温和搅拌下,将10m mol正丁基锂(6.67ml 1.5mol己烷溶液)加到1.40ml(10m mol)二异丙基胺于25ml苯的溶液中。搅拌此反应混合物15分钟。然后,加1.93g(10m mol)N,N-甲基苯基甘氨酸乙酯。再搅拌此溶液10分钟。然后,加10m mol二氯化锌(10ml1.0mol乙醚溶液)。再搅拌10分钟后,加1.19g(10m mol)N-(亚苄基)甲胺并回流此反应混合物25小时。将反应混合物倾倒于20ml饱和氯化铵水溶液中。用乙醚提取水层。用硫酸镁干燥有机提取液,减压浓缩得到2.50g(94%)2-氮杂环丁烷酮
产物,为浅棕色固体。其60MHz1HNMR数据揭示,该产物是顺式-和反式-异物体(顺式/反式:2/98)的混合物。
乙醚中重结晶,得到纯的2-氮杂环丁烷酮产物,为浅黄色(反式-异物体)和棕色(顺式-异构体)结晶,可以经挑取结晶法分开。
反式异构体的性质:m.p.84℃。1HNMR(CDCl3)δ:7.44(m,3H,ArH),7.30(m,2H,ArH),7.12(t,J=7.0Hz,2H,ArH),6.76(t,J=7.0Hz,1H,ArH),6.56(d,J=7.7Hz,2H,ArH),4.75(宽,S,1H,N-CH-CH-Ph),4.50(d,J=2.2Hz,1H,N-CH-CH-Ph),3.15(S,3H,Ph-N-CH3),2.90(S,3H,N-CH3).BCNMR(CDCl3)δ:167.76(C=O),149.26,137.12,129.75,129.64,129.20,126.86,119.22,114.91(ArC),78.35(N-CH-CH-Ph),63.51(N-CH-CH-Ph),35.42(Ph-N-CH3),27.35(N-CH3).IR(KBr):1760cm-1。
顺式-异构体的性质:m.p.137℃。1HNMR(CDCl3)δ:6.40-7.44(m,10H,ArH),5.10(d,J=4.4Hz,1H,N-CH-CH-Ph),4.77(d,J=4.4Hz,1H,N-CH-CH-Ph),3.18(S,3H,Ph-N-CH3),2.70(S,3H,N-CH3)。
IR(KBr):1748cm-1。
实例Ⅲ
反式-1-(取代的)-3-二乙氨基-4-苯基-2-氮杂环丁
烷酮的合成(一锅法)
A.反式-1-甲基-3-二乙氨基-4-苯基-2-氮杂环丁烷酮的合成
将13.33ml(1.5mol)正丁基锂的己烷溶液(相当于20m mol正丁基锂)加到2.02g(20m mol)二异丙胺于25ml苯的溶液中。搅拌所得的二异丙基氨锂10分钟。然后,加3.18g(20m mol)N,N-二乙基甘氨酸乙酯,立即得到白色悬浮液。搅拌此悬浮液30分钟。然后,加2.73g(20m mol)二氯化锌于20ml乙醚的溶液,得到黄色溶液,再搅拌此溶液10分钟。真空蒸除溶液中的大部分乙醚和己烷。将2.38g(20m mol)N-(亚苄基)甲胺加到所得苯溶液中,并回流此反应混合物30分钟。在此期间,沉淀出一些固体物质。将反应混合物冷至室温后用20ml乙醚稀释。加15ml饱和氯化铵水溶液于反应混合物中。分出有机层并用饱和氯化铵水溶液洗两次,每次15ml,再用水洗两次,每次15ml,硫酸钠干燥,减压浓缩,得到4.2g(90.5%)反式-2-氮杂环丁烷酮产物,为白色固体,其性质与实例1产物相同。
B.表1示出此2-氮杂环丁烷酮和另一代表性化合物的合成示意式。
表Ⅰ
产率 顺式 反式
1)R1=甲基;R4=苯基 90% <2% >98%
2)R1=苄基;R4=苯基 92% <2% >98%
实例Ⅳ
反式-3-甲苯氨基-4-[(三甲基硅烷基)乙炔基]-2-氮杂环丁烷酮
于室温搅拌下,将10m mol正丁基锂(6.67ml1.5mol己烷溶液)加到1.40ml(10m mol)二异丙胺于25ml苯的溶液中。搅拌此反应混合物15分钟后,加1.93g(10m mol)N,N-甲基苯基甘氨酸乙酯。再搅拌此溶液10分钟后,加入10m mol二氯化锌(10ml1.0mol的乙醚溶液)。搅拌此反应混合物5分钟后,加1.98g(10m mol)N-(3-三甲基硅烷基-2-亚丙炔基)三甲基硅烷基胺,回流反应混合物8小时。将反应混合物倾倒于20ml饱和氯化铵水溶液中。用乙醚提取水层。硫酸镁干燥有机提取液,减压浓缩,得到2.70g(99%)2-氮杂环丁烷酮产物,为暗棕色固体。
乙醚/戊烷中重结晶,得到纯的反式-异构体,为灰白色结晶,m.p.136℃。1HNMR(CDCl3)δ:7.08(m,2H,ArH),6.74(m,3H,ArH),6.18(宽,S,1H,N-H),4.90(宽,S,1H,N-CH-CH-C三C),4.03(d,J=2.2Hz,1H,N-CH-CH-C三C),2.85(S,
3H,N-CH2),0.35(S,9H,SiMe2).IR(KBr):1786cm-1。
元素分析:(C15H20N2OSi):
实测值:C65.59;H7.66;N10.21
理论值:C66.13;H7.40;N10.28
实例Ⅴ
反式-3-二乙氨基-4-取代的-2-氮杂环丁烷酮的合成(一锅法)
按照实例Ⅲ采用的同样步骤和同样的反应条件,用N-三甲基硅烷基保护的亚胺进行反应,得到1-未取代的反式-β-内酰胺。在水溶液处理时,水解掉N-SiMe3基,而不是N-(亚苄基)甲胺。表Ⅱ给出代表性例子。
表Ⅱ
产率 顺式 反式
1)R4=苯基 94% <2% >98%
2)R4=C≡C-苯基 92% <2% >98%
3)R4=C≡C-SiMe395%< <2% >98%
实例Ⅵ
1-甲基-3-氨基-4-苯基-2-氮杂环丁烷酮的合成
A.1-甲基-3-(2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基)-4-苯基-2-氮杂环丁烷酮的合成
于-70℃并搅拌下,将10m mol正丁基锂(6.67ml1.5mol己烷溶液)加到1.40ml(10m mol)二异丙胺于25ml的乙醚溶液中。搅拌此反应混合物10分钟后,加2.45g(10m mol)2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊烷基-1-乙酸乙酯。于-70℃下,再搅拌此溶液15分钟后,加入10m mol二氯化锌(6.76ml,1.48mol乙醚溶液)。-70℃下搅拌5分钟后,开始沉淀出白色固体(LiCl)。然后,加1.19g(10m mol)N-(亚苄基)甲胺。于-70℃下再搅拌此反应混合物15分钟,然后,温热至室温并迅速加20ml饱和氯化铵水溶液以停止反应。用乙醚提取水层。乙醚提取液用水洗涤,硫酸钠干燥,减压浓缩,得到3.05g(96%)纯的2-氮杂环丁烷酮产物,为浅黄色固体,其1HNMR数据揭示,此产物是顺式-和反式-异构体(顺式/反式为8/92)的混合物。
乙醚/己烷中重结晶,得到纯的反式-异构体产物,为无色结晶。m.p.90.5-91.5℃。1HNMR(CDCl3)δ:7.17-7.44(m,5H,ArH),4.10(d,J=1.8Hz,1H,N-CH-CH-Pn),4.05(m,1H,N--CH-CH-Ph),2.75(宽,S,3H,N-CH3),0.63-0.85(m,4H,Si-CH2-CH2-Si),0.12(S,6H,Si(CH3)2),0.04(S,6H,Si(CH3)2)。13CNMR(CDCl3)δ:170.23(C=0),137.03,128.83,128.25,126.18(ArC),72.92(N-CH-CH-Pn),68.63(N-CH-CH-Pn),26.58(N-CH3),7.94(Si-CH2CH2-Si),0.59(Si(OH3)2,0.10(Si(CH3)2)。
B.直接转化为1-甲基-3-氨基-4-苯基-2-氮杂环丁烷酮
按照上述同样步骤进行,但不包括终止反应,制得的反应混合物含有1-甲基-3-(2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基)-4-苯基-2-氮杂环丁烷酮。于室温下迅速加50ml1mol的盐酸水溶液。用乙醚提取水层,然后,用固体氢氧化钾碱化至pH11并用二氯甲烷提取。用50ml饱和氯化铵水溶液洗涤二氯甲烷提取液,硫酸钠干燥,减压浓缩,得到1.28g(73%)纯的2-氮杂环丁烷酮产物,为浅黄色油状物,放置固化。
1HNMR数据揭示,此产物是顺式-和反式-异构体的混合物(顺式-/反式-为8/92)。IR(CDCl3):1740cm-1。反式异构体的1HNMR(CDCl3)δ:7.18-7.44(m,5H,ArH),4.19(d,J=1.8Hz,1H,H2N-CH-CH-Ph),3.91(m,1H,H2NCH-CH-Ph),2.76(宽,S,3H,N-CH3),1.91(宽,S,2H,NH2);顺式异构体的1HNMR(CDCl3)δ:4.75(d,J=4.9Hz,1H,H2N-CH-CH-Ph),4.47(d,J=4.9Hz,1H,H2N-CH-CH-Ph),2.83(S,3H,N-CH3)。反式异构体的13CNMR(CDCl3)δ:170.33(C=0),136.59,128.67,128.16,125.89(ArC),70.23(N-CH-CH-Ph),67.28(N-CH-CH-Ph),
26.53(N-CH3);顺式异构体的13CMR(CDCl3)δ:64.60(N-CH-CH-Ph),63.60(N-CH-CH-Ph)。
从纯的反式-1-甲基-3-(2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基)-4-苯基-2-氮杂环丁烷酮可以制得纯的反式-1-甲基-3-氨基-4-苯基-2-氮杂环丁烷酮。于室温下,向0.80g(2.5m mol)纯的反式-2-氮杂环丁烷酮于20ml乙醚的溶液中加20ml1mol的盐酸水溶液。搅拌此混合物1小时后分出乙醚层,然后,用固体氢氧化钾中和水层至pH6,并用二氯甲烷提取。
用硫酸钠干燥二氯甲烷提取液,减压浓缩,得到0.37g(84%)纯的反式1-甲基-3-氨基-4-苯基-2-氮杂环丁烷酮,为无色油状物,放置固化,m.p.51.5℃。
表Ⅲ给出制备3-氨基取代的β-内酰胺的示意式和制得的一些β-内酰胺中间体,以及它们的产率和物理数据
表Ⅲ
R1R4产率 顺式 反式
Me Ph 96% 8% 92%
SiMea 3Ph 90% 30% 70%
SiMea 3C≡CSiMe375% 8% 92%
CH2Ph Me 95% <5% >95%
a.经水解即除去三甲基硅烷基并由氢置换。
表Ⅲ附录:化合物2,3和4的物理数据。
3-(2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基)-4-苯基-2-氮杂环丁烷酮:
反式异构体:浅黄色固体,m.p.101℃。1HNMR(CDCl3)δ:7.12(S,5H,ArH),6.29(宽,S,H,NH),4.23(d,J=2.1Hz,1H,N-CH-CH-Pn),3.92(d,J=2.1Hz,1H,N-CH-CH-Ph),0.70(S,4H,Si-CH2-CH2-Si),0.13(S,6H,Si(CH3)2),0.05(S,6H,Si(CH3)2)。13C NMR(CDCl3)δ:171.65(C=0),139.34,128.76,128.13,125.51(ArC),73.61(N-CH-CH-Ph),62.76(N-CH-CH-Ph),7.97(Si-CH2-CH2-Si),0.45(Si(CH3)2)。
顺式异构体:1H NMR(CDCl3)δ:4.68(d,J=5.3Hz,1H,N-CH-CH-Ph),4.42(d,J=5.3Hz,1H,N-CH-CH-Ph)。
3-氨基-4-苯基-2-氮杂环丁烷酮:
反式异物体:浅黄色固体。1H NMR(CDCl3)δ:7.10(S,5H,ArH),6.32(宽,S,1H,NH),4.22(d,J=2.0Hz,1H,H2N-CH-CH-Ph),3.81(d,J=2.0Hz,(H,H2N-CH-CH-Ph),1.62(宽,S,2H,NH2)。13C NMR(CDCl3)δ:171.55(C=0),138.93,128.77,126.69,125.46(ArC),71.08(N-CH-CH-Ph),62.70(N-CH-CH-Ph)。IR(CDCl3):1755cm-1。
3-(2,2,5,5-四甲基-2,5-二硅杂环戊基-1-氮杂)-4-[(三甲基硅烷基)乙炔基]-2-氮杂环丁烷酮:
反式异构体:浅棕色固体。1H NMR(CDCl3)δ:7.25(宽,S,1H,NH),4.48(d,J=2.1Hz,1H,N-CH-CH-C≡CSiMe2),3.61(d,J=2.1Hz,1H,N-CH-CH-C≡CSiMe2),0.71(S,4H,Si-CH2CH2-Si),0.15(宽,S,21H,Si(CH3)2)。
1-苄基-3-(2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基)-4-苯基-2-氮杂环丁烷酮:
反式异构体:浅黄色油状物。1H NMR(CDCl3)δ:7.13(S,5H,Ar-H),4.59(d,J=15Hz,1H,N-CH2-Pn),3.96(d,J=15Hz,1H,N-CH2-Ph),3.79(d,J=2.2Hz,1H,N-CH-CH-CH3),3.24(dq,J=2.2和J=6.0Hz,1H,N-CH-CH-CH2),
1.32(d,J=6.0Hz,3H,N-CH-CH-CH3),0.74(S,4H,Si-CH2-CH2-Si),0.15(S,6H,Si(CH3)2),0.09(S,6H,Si(CH3)2)。13C NMR(CDCl3)δ:168.79(C=0),138.87,128.40,128.01,127.38(ArC),68.46(N-CH-CH-CH3),58.67(N-CH-CH-CH3),43.73(N-CH2-Ph),16.40(N-CH-CH-CH3),7.80(Si-CH2CH2-Si),0.32(Si(CH3)2),0.05(Si(CH3)2)。
实例Ⅶ
1-甲基-3-双(三甲基硅烷基)氨基-4-苯基-2-氮杂环丁烷酮的合成
于-70℃和搅拌下,将10m mol正丁基锂(6.67ml1.5mol己烷溶液)加到1.40ml(10m mol)二异丙胺于25ml乙醚的溶液中。搅拌此反应混合物10分钟,然后,加2.47g(10m mol)N,N-双(三甲基硅烷基)甘氨酸乙酯。于-70℃下再搅拌此溶液10分钟,然后加10m mol二氯化锌(6.76ml,1.48mol乙醚溶液)。于-70℃下反应5分钟后,开始沉淀出白色固体(LiCl)。加1.19g(10m mol)N-(亚苄基)甲胺。于-70℃下再搅拌反应混合物15分钟,在温热至室温后,迅速加20ml饱和氯化铵水溶液以终止反应。用乙醚提取水层。用水洗涤乙醚提取液,硅酸钠干燥,减压浓缩,得到2.41g(75%)反式-氮杂环丁烷酮产物,为浅黄色油状物。1H NMR(CDCl3)δ:7.08-7.42(m,5H,ArH),4.18(d,J=1.8Hz,1H,N-CH-CH-Ph),4.09(m,1H,N-CH-CH-Ph),2.73(宽,S,3H,N-CH3),0.20(S,18H,Si(CH2)2)。13C NMR(CDCl3)δ:171.57(C=0),136.92,128.78,128.11,125.76(ArC),75.25(N-CH-CH-Ph),68.61(N-CH-CH-Ph),26.59(N-CH3),2.39(Si(CH3)3)。IR(CDCl3):1742cm-1。
实例Ⅷ
使用二乙基氯化铝作金属源合成1-甲基-3-(2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基)-4-苯基-2-氮杂环丁烷酮
在-70℃和搅拌下,加10m mol正丁基锂(6.67ml1.5mol己烷溶液)于1.40ml(10m mol)二异丙胺于25ml乙醚的溶液中。搅拌此反应混合物10分钟,然后,加2.45g(10m mol)2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基-1-乙酸乙酯。于-70℃下再搅拌此溶液15分钟,然后,加20m mol二乙基氯化铝(20.00ml 1.0mol己烷溶液)。立即沉淀出白色固体。加1.19g(10m mol)N-(亚苄基)甲胺。于-70℃下再搅拌此反应混合物15分钟。温热至室温后,迅速加20ml饱和氯化铵水溶液以终止反应。猛烈地放出乙烷。用乙醚提取水层。用水洗涤乙醚提取液,硫酸钠干燥,减压浓缩,得到2.86g(90%)纯的2-氮杂环丁烷酮产物,为浅黄色固体,其物理性质与实例ⅥA所得的产物相同。1H NMR数据揭示,该产物为顺式-和反式异构体的混合物(顺式/反式为10/90)。
实例Ⅸ
富对映异构的反式-1-甲基-3-二乙氨基-4-苯基-2-氮杂环丁烷酮的合成
将13.33ml1.5mol正丁基锂的己烷溶液(相当于20m mol正丁基锂)加到2.02g(20m mol)二异丙胺于25ml苯的溶液中。搅拌所得二异丙氨基锂溶液10分钟。加3.18g(20m mol)相应纯对映异构的N,N-二乙基甘氨酸
酯,反应放热。搅拌此溶液30分钟。然后,加2.73g(20m mol)二氯化锌于20ml乙醚的溶液,反应物呈黄色溶液。搅拌此溶液10分钟。减压蒸出溶液中的大部分乙醚和己烷。加2.38g(20m mol)N-(亚苄基)甲胺于所得苯溶液中,然后,回流此反应混合物70分钟。在此期间,沉淀出一些固体物质。将反应混合物冷却至室温,并用20ml乙醚稀释。加15ml饱和氯化铵水溶液于反应混合物中。分出有机相,用饱和氯化铵水溶液洗两次,每次15ml,再水洗两次,每次15ml。用4mol盐酸水溶液提取有机相两次,每次20ml。酸性水相用2醚洗三次,每次20ml。用浓氨水将水相调至碱性,并用乙醚提取三次,每次20ml。用硫酸钠干燥有机提取液,减压浓缩,得到3.5g(75%)2-氮杂环丁烷酮产物,为白色固体,其性质与实例ⅡA所述化合物相同。
在施光活性顺磁位移试剂(Eu(TFC)2)存在下其1H NMR(60MH2,CDCl2)揭示,两种对映体的H3分别在5.30和5.50PPm比值为1∶2,这表明一种对映体超过33%。在同样条件下,
实例ⅡA所得2-氮杂环丁烷酮,两种比值为1∶1。
没有外加金属化合物的试验
于-70℃下按实例Ⅵ所述方法制备2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基-1-乙酸乙酯的烯醇化锂乙醚溶液。不同于实例Ⅵ的方法,不加金属化合物MW(X)a(Y)b(Z)c(M,W,X,Y,Z,a,b和c的定义同前),而是在-70℃,在25ml乙醚中的烯醇化锂直接与1.19g(10m mol)N-(亚苄基)甲胺反应。在-70℃下搅拌2小时后,经1HNMR检定,没有生成β-内酰胺。
Claims (11)
1、通式为Ⅰ的反式-β-内酰胺化合物的制备方法,
式中R2和R3各自为氢,C1-6烷基,苯基或(C1-6)烷基苯基,或是三[(C1-6)烷基]甲硅烷基,或R2,R3与相连的氮原子一起形成通式为Ⅲ的环,
通式Ⅲ中R13、R14、R15、R16、R17、R18、R19和R20各自为C1-6烷基,或R17、R18、R19和R20各自为氢;
R1是氢,C1-6烷基,苯基或C1-6烷基苯基,或是三[(C1-6)烷基]甲硅烷基,
R4是C1-6烷基,C3-6烷基,C3-6炔基,每个基团又可任意被苯基或三[(C1-6)烷基]甲硅烷基取代,C1-6烷基任意取代的亚氨基;苯基;[(C1-6)烷基]甲硅烷基,噻吩基,糠基或吡啶基;
该方法的特征是,通式为Ⅱ的化合物与通式Ⅳ的亚胺反应;
式中R12是C1-6烷基,或(C1-6)烷基C4-8环烷基,
M是锌,铝或硼,
P是碱金属,
W,X,Y,和Z是C1-6烷基或卤素,并且W,X,Y和Z可以相同或不同,
a,b,c和m为0或1,n=1-6的整数,
R′ 2和R′ 3分别为R2和R3,条件是,当R2和R3是氢时,R′ 2和R′ 3与相连的氮原子一起形成通式为Ⅲ的环,
式中R4的定义同上,R′ 1是R1代表的基团,条件是当R1为氢时,R′ 1为三[(C1-6)烷基]甲硅烷基,
反应后用酸或碱水解该基团,并且当R2和R3都是氢时,反应后经酸或碱催化水解使通式Ⅲ的环转化为NH2或[(C1-6)烷基]甲硅烷基转化为氢。
2、权利要求1的方法,其中通式为Ⅱ的化合物中,R2′和R3′分别是R2和R3,不过,不同时为氢,R12,M,P,W,X,Y,Z,a,b,c,m和n的定义同权利要求1。
3、权利要求2的方法,其中通式为Ⅱ的化合物的制备方法是,R2′R3′N-甘氨酸乙酯与碱金属碱和通式为MW(X)a(Y)b(Z)c的金属化合物反应,式中R2′,R3′,M,P,W,X,Y,Z,a,b,c,m和n的定义同权利要求2。
4、制备权利要求1规定的通式为Ⅰ的反式-β-内酰胺的一锅法,其特征是在碱金属碱和通式为MW(X)a(Y)b(Z)c(其中M,W,X,Y,Z,a,b和c的定义同权利要求1)的存在下,R2′R3′N-甘氨酸烷基酯(其中R2′R3′的定义同权利要求1)与权利要求1规定的通式为Ⅳ的亚胺反应,条件是,当R2和R3为氢时,反应后,经酸或碱催化水解除去通式Ⅲ的环。
5、按照权利要求1或4的方法制备通式为1a的(3S)-反式-β-内酰胺,
Ⅰa
式中R1,R2,R3和R4的定义同权利要求1或4中的定义,
其特征是R2′R3′N-甘氨酸(C1-6)烷基或(C1-6)烷基(C4-8)环烷基酯的相应对映体(其中R2′和R3′的定义同权利要求1)被转化,条件是,当R2,R3是氢时,反应后,经酸或碱催化水解除去通式为Ⅲ的环。
6、权利要求1或4的方法,其特征是合成权利要求1规定的通式Ⅰ的反式-β-内酰胺,其中R1是甲基,R4是苯基,
R2,R3是甲基或
R2,R3是乙基或
R2,R3与氮原子一起连接成2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基或者
R2,R3是氢或
R2,R3是三甲基硅烷基或
R2是甲基,R3是苯基或
R1是苄基,R4是苯基和
R2,R3是乙基或
R2,R3与氮原子连成2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基,或
R2,R3是氢或
R1是氢,R4是苯乙炔基和
R2,R3是乙基或
R1是氢,R4是三甲基硅烷基乙炔基和
R2,R3是乙基或
R2,R3与氮原子一起连成2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基或R2,R3是氢或
R2是甲基,R3是苯基或
R1是三甲基硅烷基,或氢,R4是苯基和
R2,R3是乙基或
R2,R3与氮原子一起连成2,2,5,5-四甲基-1-氮杂-2,5-二硅杂环戊基或R2,R3是氢。
7、权利要求1,3或4规定的方法,其中M是锌或铝。
8、权利要求3,4,5,6或7规定的方法,其中,碱金属碱是二异丙基氨锂。
9、权利要求7规定的方法,其中M是锌。
10、权利要求2规定的方法,其中R2,R3是乙基,M是锌,X,Y是乙基,P是锂,W是卤素,n是2。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP87200185.4 | 1987-02-06 | ||
EP87200185 | 1987-02-06 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN88100703A CN88100703A (zh) | 1988-08-17 |
CN1022829C true CN1022829C (zh) | 1993-11-24 |
Family
ID=8197576
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN88100703A Expired - Fee Related CN1022829C (zh) | 1987-02-06 | 1988-02-05 | 用金属化合物合成β-内酰胺 |
Country Status (15)
Country | Link |
---|---|
US (1) | US4898955A (zh) |
EP (1) | EP0281177B1 (zh) |
JP (1) | JPS63301859A (zh) |
KR (1) | KR880009920A (zh) |
CN (1) | CN1022829C (zh) |
AT (1) | ATE93848T1 (zh) |
AU (1) | AU611666B2 (zh) |
DE (1) | DE3883559T2 (zh) |
DK (1) | DK59488A (zh) |
ES (1) | ES2059487T3 (zh) |
FI (1) | FI880497A (zh) |
HU (1) | HU910055D0 (zh) |
NO (1) | NO880499L (zh) |
NZ (2) | NZ235457A (zh) |
PT (1) | PT86710B (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5300252A (en) * | 1987-03-13 | 1994-04-05 | Fmc Corporation | Ether free organometallic amide compositions |
IE880319L (en) * | 1988-08-04 | 1988-08-06 | Univ Utrecht | Preparing trans-beta-lactam compounds |
AU637109B2 (en) * | 1989-06-22 | 1993-05-20 | Rijksuniversiteit Utrecht | Improved synthesis of beta-lactams using a metal compound |
EP0442576A1 (en) * | 1990-02-13 | 1991-08-21 | Rijksuniversiteit Utrecht | Synthesis of cis-beta-lactams with the aid of an alkali metal compound |
JP4758907B2 (ja) * | 2004-10-15 | 2011-08-31 | 三井化学株式会社 | チタン化合物及び光学活性シアノヒドリン類の製造法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1205982A (en) * | 1967-07-05 | 1970-09-23 | Fahlberg List Veb | Organic tin compounds with fungicidal properties |
EP0180398A1 (en) * | 1984-10-26 | 1986-05-07 | The Regents Of The University Of California | Synthesis of beta-lactam |
-
1988
- 1988-02-03 FI FI880497A patent/FI880497A/fi not_active IP Right Cessation
- 1988-02-04 NO NO880499A patent/NO880499L/no unknown
- 1988-02-05 HU HU9155A patent/HU910055D0/hu not_active IP Right Cessation
- 1988-02-05 AT AT88200209T patent/ATE93848T1/de not_active IP Right Cessation
- 1988-02-05 EP EP88200209A patent/EP0281177B1/en not_active Expired - Lifetime
- 1988-02-05 CN CN88100703A patent/CN1022829C/zh not_active Expired - Fee Related
- 1988-02-05 NZ NZ235457A patent/NZ235457A/en unknown
- 1988-02-05 PT PT86710A patent/PT86710B/pt not_active IP Right Cessation
- 1988-02-05 NZ NZ223416A patent/NZ223416A/en unknown
- 1988-02-05 DK DK059488A patent/DK59488A/da not_active Application Discontinuation
- 1988-02-05 DE DE88200209T patent/DE3883559T2/de not_active Expired - Fee Related
- 1988-02-05 ES ES88200209T patent/ES2059487T3/es not_active Expired - Lifetime
- 1988-02-06 KR KR1019880001102A patent/KR880009920A/ko not_active Application Discontinuation
- 1988-02-06 JP JP63026421A patent/JPS63301859A/ja active Pending
- 1988-02-08 AU AU11405/88A patent/AU611666B2/en not_active Ceased
- 1988-12-12 US US07/283,194 patent/US4898955A/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
NZ235457A (en) | 1992-04-28 |
ES2059487T3 (es) | 1994-11-16 |
NO880499L (no) | 1988-08-08 |
DE3883559D1 (de) | 1993-10-07 |
FI880497A0 (fi) | 1988-02-03 |
EP0281177A1 (en) | 1988-09-07 |
KR880009920A (ko) | 1988-10-05 |
HUT45974A (en) | 1988-09-28 |
HU910055D0 (en) | 1991-08-28 |
PT86710A (pt) | 1988-03-01 |
US4898955A (en) | 1990-02-06 |
HU202490B (en) | 1991-03-28 |
AU611666B2 (en) | 1991-06-20 |
DE3883559T2 (de) | 1994-01-20 |
DK59488A (da) | 1988-08-07 |
NO880499D0 (no) | 1988-02-04 |
DK59488D0 (da) | 1988-02-05 |
AU1140588A (en) | 1988-08-11 |
JPS63301859A (ja) | 1988-12-08 |
EP0281177B1 (en) | 1993-09-01 |
PT86710B (pt) | 1992-04-30 |
ATE93848T1 (de) | 1993-09-15 |
CN88100703A (zh) | 1988-08-17 |
FI880497A (fi) | 1988-08-07 |
NZ223416A (en) | 1992-04-28 |
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