WO2012062036A1 - 一种含培南类侧链的双环中间体的制备方法及其应用 - Google Patents
一种含培南类侧链的双环中间体的制备方法及其应用 Download PDFInfo
- Publication number
- WO2012062036A1 WO2012062036A1 PCT/CN2011/001588 CN2011001588W WO2012062036A1 WO 2012062036 A1 WO2012062036 A1 WO 2012062036A1 CN 2011001588 W CN2011001588 W CN 2011001588W WO 2012062036 A1 WO2012062036 A1 WO 2012062036A1
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- WIPO (PCT)
- Prior art keywords
- compound
- formula
- chloride
- reaction
- sulfide
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- -1 penem side chain compound Chemical class 0.000 claims abstract description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 13
- 150000007530 organic bases Chemical class 0.000 claims abstract description 9
- 150000001412 amines Chemical class 0.000 claims abstract description 7
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000012190 activator Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 8
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- 150000003335 secondary amines Chemical class 0.000 claims description 4
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 4
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical group [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- RYXNTTXRPACDJA-UHFFFAOYSA-N sulfanyl carbonochloridate Chemical compound SOC(Cl)=O RYXNTTXRPACDJA-UHFFFAOYSA-N 0.000 claims description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical group ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- WIFCKLPZYYALGY-UHFFFAOYSA-N 1h-pyrrole-2,3-dione Chemical compound O=C1NC=CC1=O WIFCKLPZYYALGY-UHFFFAOYSA-N 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- 150000003141 primary amines Chemical class 0.000 claims description 3
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical group CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical group CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims description 2
- DPLVEEXVKBWGHE-UHFFFAOYSA-N potassium sulfide Chemical compound [S-2].[K+].[K+] DPLVEEXVKBWGHE-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004593 Epoxy Substances 0.000 claims 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- 150000001454 anthracenes Chemical class 0.000 claims 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 claims 1
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 claims 1
- 230000004913 activation Effects 0.000 abstract description 7
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 238000003385 ring cleavage reaction Methods 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 0 *N(C[C@@](C1)O)[C@@]1C(O)=O Chemical compound *N(C[C@@](C1)O)[C@@]1C(O)=O 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 3
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-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
- 229960000583 acetic acid Drugs 0.000 description 2
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- XFDUHJPVQKIXHO-UHFFFAOYSA-N 3-aminobenzoic acid Chemical compound NC1=CC=CC(C(O)=O)=C1 XFDUHJPVQKIXHO-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- XHZYVDPKJZQKHJ-RQJHMYQMSA-N C=CCOC(N(C[C@@H](C1)O)[C@@H]1C(O)=O)=O Chemical compound C=CCOC(N(C[C@@H](C1)O)[C@@H]1C(O)=O)=O XHZYVDPKJZQKHJ-RQJHMYQMSA-N 0.000 description 1
- XIPFMBOWZXULIA-UHFFFAOYSA-N CC(C)(C)C(N)=O Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 1
- JOUFQMJLIBTEJR-SFYZADRCSA-N CC(C)C(OC([C@H](C1)NC[C@@H]1OC)=O)=O Chemical compound CC(C)C(OC([C@H](C1)NC[C@@H]1OC)=O)=O JOUFQMJLIBTEJR-SFYZADRCSA-N 0.000 description 1
- MRKBREIVNTVBSG-SFYZADRCSA-N CC(C)C(OC([C@H](C1)NC[C@@H]1OS(C)(=O)=O)=O)=O Chemical compound CC(C)C(OC([C@H](C1)NC[C@@H]1OS(C)(=O)=O)=O)=O MRKBREIVNTVBSG-SFYZADRCSA-N 0.000 description 1
- RWHJNVBAMZWRIF-ZJUUUORDSA-N CC(C)C(OC([C@H](C[C@H](C1)O)N1C(OCC=C)=O)=O)=O Chemical compound CC(C)C(OC([C@H](C[C@H](C1)O)N1C(OCC=C)=O)=O)=O RWHJNVBAMZWRIF-ZJUUUORDSA-N 0.000 description 1
- ICFOHHBTRMLBNS-YUMQZZPRSA-N C[C@@H](C[C@H]1C(S)=O)CN1C(OCC=C)=O Chemical compound C[C@@H](C[C@H]1C(S)=O)CN1C(OCC=C)=O ICFOHHBTRMLBNS-YUMQZZPRSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- KTRFZWJCHOQHMN-UHFFFAOYSA-N chloromethanethioic s-acid Chemical compound SC(Cl)=O KTRFZWJCHOQHMN-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 229960002770 ertapenem Drugs 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000135 prohibitive effect Effects 0.000 description 1
- QQKDTTWZXHEGAQ-UHFFFAOYSA-N propyl carbonochloridate Chemical compound CCCOC(Cl)=O QQKDTTWZXHEGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007100 recyclization reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 150000004763 sulfides Chemical class 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/08—Bridged systems
-
- 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
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
-
- 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- the invention relates to a preparation method and application of a key intermediate containing a Pein-type side chain.
- Carbapenem antibiotics such as Mer 0 p e nem and Ertapenem are structurally all pyrrolidine side chains which are substituted by the parental core of the Penan and 2,4 positions. ) formed by chemical condensation. Therefore, a general method for synthesizing the above-mentioned pyrrolidine side chaining II) was found for the synthetic Peinan antibiotic
- a method for preparing a bicyclic intermediate containing a perindal side chain, the structural formula of the bicyclic intermediate is as shown in the following formula (I): an organic base
- the preparation method is as follows: 1) A compound of the formula ( ⁇ ) is reacted with a carboxyl activator under the action of an organic base to form a compound of the formula (IV) at a reaction temperature of -30 to 5 ° C, a reaction time of 0.5 to 2 h, a carboxyl activator and a formula (III).
- the ratio of the substance of the compound is 2.0 to 1.2: 1;
- R 3 is a protecting group on pyrrole quinone N, selected from the group consisting of t-butoxycarbonyl (t-BOC), p-nitrobenzyloxycarbonyl (PNZ), benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, allylic oxygen Carbonyl (AOC), benzyloxycarbonyl (Cbz), diisopropylphosphoryl (DIPP), etc.;
- the carboxyl activator is a sulfonyl chloride compound, a sulfonic acid anhydride, a mercapto chloroformate, a mercaptocarbonyl chloride compound, N, N-carbonyldiimidazole (CDI), a bicyclohexylcarbodiimide (DCC), a chloroformic acid.
- Isopropyl ester or pivaloyl chloride preferably isopropyl chloroformate and pivaloyl chloride.
- the sulfonyl chloride compound is methanesulfonyl chloride, p-toluenesulfonyl chloride or benzenesulfonyl chloride;
- the sulfonic anhydride is methanesulfonic anhydride or p-toluenesulfonic anhydride;
- the mercapto chloroformate is ethyl chloroformate or chloroformic acid Propyl ester or tert-butyl chloroformate;
- the acid chloride compound is oxalyl chloride or pivaloyl chloride.
- the organic base is triethylamine, diisopropylethylamine, pyridine, picoline, imidazole or quinoline.
- the sulfides are sodium sulfide, sodium hydrosulfide and potassium sulfide.
- the solvent used in each reaction step is selected from the group consisting of ethers, halogenated hydrocarbons, acetonitrile, toluene, ethyl acetate or the ethers are oxirane, diethyl ether or tetrahydrofuran; the halogenated alkane is dichloromethane , chloroform or 1,2-dichloroethane.
- the amine is any primary or secondary amine, such as N3 ⁇ 4PhC0 2 H, NHBSO2NH2, etc.; the secondary amine is HN(CH 3 ) 2 , HN(CH 3 )C 2 H 5 and the like.
- the solvent in the reaction is ethylene oxide, tetrahydrofuran, ethyl acetate, toluene, acetone, acetic acid or DMF; the reaction temperature is 0 to 40 ° C, and the reaction time is 30 min to 24 h.
- the bicyclic intermediate (I) compound is prepared by "one pot method", the synthesis route is short, and the operation is simple and convenient; 2.
- the method has good versatility, and the protection base for pyrrole quinone N is BOC, PNZ , AOC, Cbz, DIPP, oxycarbonyl, p-methoxybenzyloxycarbonyl, etc.; 3.
- Example 3 The pivaloyl chloride in Example 3 was replaced with 40 g (0.327 mol) of isopropyl chloroformate, and the other additions and methods were the same to obtain 60.7 g (0.284 mol, yield 93.4%) of the title compound oil (1S, 4S)-Allyloxythio-6-oxo-5-thio-2-azabicyclo[2.2.1]hept-2-ester.
- Example 7 The pivaloyl chloride in Example 7 was replaced with 40 g (0.327 mol) of isopropyl chloroformate, and the other additions were the same. The title compound was obtained as a pale yellow solid (82.6 g (0.268 mol, yield: 88%). 4S)-4-Nitrobenzyloxycarbonyl-6-oxo-5-thio-2-azabicyclo[2.2.1]hept-2-ester.
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Description
一种含培南类侧链的双环中间体的制备方法及其应用
技术领域
本发明涉及一种含培南类侧链的关键中间体的制备方法和应用。
背景技术
美罗培南 (Mer0penem)、 尔他培南 (Ertapenem)等碳青霉烯类抗生素, 从结 构上看, 都是由培南母核与 2,4位取代的吡咯烷侧链(Π ) 经化学缩合而成。 因 此, 找到一种合成上述吡咯烷侧链化 II ) 的通用的方法, 对于合成培南类 抗生
吡咯垸侧链化合物( II )的合成,研究比较多的是以 L-羟脯氨酸为起始原料, 经过 N-保护、 羧基活化、 羟基活化, 4-位发生双分子亲核取代反应 (SN2反应) 翻转构型、 活化的羧基与胺缩合、 水解反应等步骤得到 (Π )。 反应路线如下:
(XXIV)
(XVII) (XVIII) (XX)
(XIX) 这种制备方法往往合成路线过长,制备过程复杂,总收率不高,而且不是一种
通用的简便的制备方法。
为了克服传统方法的缺点, 近年来也有一些文献介绍通过先合成双环中间体 化合物(如下式(1) )来制备培南侧链化合物。 但是, 这些文献方法都不约而同 地存在一些缺陷, 如专利 US5322952A1 , 采用了通硫化氢的方法环合, 这对环 境不友好, 不适宜工业化生产; 专利 US5648501A, 对羧基的活化选用二苯基磷 酰酯, 虽然收率较高, 但是价格昂贵成本太高, 也不适宜大规模生产。
发明内容
本发明的目的在于,提供一种廉价的、适宜工业化生产的含培南侧链双环中 间体(I) 的制备方法, 以及用该中间体合成相应培南侧链化合物的方法。
以反式 -L-羟脯氨酸为起始原料, 经 N上保护后, 用 "一锅法 "进行羧基活 化、 羟基活化、 再环合得到式 (I)化合物; 式 (I)化合物与对应的胺缩合得到 保护的培南侧链化合物, 反应路线如下图所示。
一种含培南侧链的双环中间体的制备方法,所述双环中间体的结构式如下反 应路线中的式 (I)所示: 有机碱
所述制备方法如下:
1 ) 式 (ΠΙ) 化合物在有机碱作用下, 与羧基活化剂反应生成式 (IV) 化合 物, 反应温度为 -30〜- 5°C, 反应时间为 0.5〜2h, 羧基活化剂与式 (III) 化合物 的物质的量比为 2.0〜1.2: 1;
其中, R3为吡咯浣 N上的保护基, 选自叔丁氧羰基 (t-BOC)、 对硝基苄氧 羰基 (PNZ)、苄氧羰基、对甲氧基苄氧羰基、烯丙氧羰基 (AOC)、苄氧羰基 (Cbz)、 二异丙基磷酰基 (DIPP) 等;
2) 式 (IV) 化合物在有机碱作用下, 与羟基活化剂反应生成式 (V ) 化合 物, 反应温度为 -20〜- 5 °C, 反应时间为 0.5〜2h, 羟基活化剂与式 (IV ) 化合物 的物质的量比 1.5〜1.05: 1;
3 ) 式 (V ) 化合物与硫化物在低温下环合得到双环化合物( I ), 反应温度 为 -20〜0°C, 反应时间为 l〜5h, 硫化物与式 (V )化合物的摩尔比为 2〜8: 1。
所述羧基活化剂是磺酰氯化合物、磺酸酐、垸基氯甲酸酯、垸基酰氯化合物、 N, N-羰基二咪唑 (CDI)、 二环已基碳二亚胺 (DCC)、 氯甲酸异丙酯或特戊酰氯, 优选氯甲酸异丙酯和特戊酰氯。
所述磺酰氯化合物是甲烷磺酰氯、对甲苯磺酰氯或苯磺酰氯;所述磺酸酐是 甲磺酸酐或对甲苯磺酸酐;所述垸基氯甲酸酯是氯甲酸乙酯、氯甲酸异丙酯或氯 甲酸叔丁酯; 所述酰氯化合物是草酰氯或特戊酰氯。
所述有机碱是三乙胺、 二异丙基乙胺、 吡啶、 甲基吡啶、 咪唑或喹啉。 所述硫化物是硫化钠、 硫氢化钠和硫化钾。
在各反应步骤中用到的溶剂选自醚类、 卤代垸烃、 乙睛、 甲苯、 乙酸乙酯或 所述醚类是环氧乙垸、 乙醚或四氢呋喃; 所述卤代烷烃是二氯甲烷、 氯仿或 1,2-二氯乙烷。
所述式(I )化合物的应用, 其特征在于, 所述式( I )化合物与胺开环缩合得 到培南侧链化合物 (11), 反应式如下:
反应中的溶剂是环氧乙烷、四氢呋喃、乙酸乙酯、甲苯、丙酮、乙酸或 DMF; 反应温度为 0〜40°C, 反应时间为 30min〜24h。
本发明的优点: 1、 双环中间体(I )化合物由 "一锅法"制得, 合成路线简 短, 操作简单方便; 2、 该法通用性好, 对于吡咯垸 N上保护基为 BOC、 PNZ、 AOC、 Cbz 、 DIPP、 氧羰基、 对甲氧基苄氧羰基等均适用; 3、采用羧基用氯 甲酸异丙酯、特戊酰氯等活化, 然后用硫化钠环合的方法、, 原料廉价易得、 收率 高, 能极大地成本降低; 4、 该法反应条件温和、环境友好, 是一条适宜工业化 生产的路线。
具体实施方式
实施例 1
1 ) 二 (lS,4S)-6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-基磷酸酯
反应瓶中加入 90g (0.305mol) 的 (2S,4R)-1- (二异丙基磷酸基) -4-羟基吡咯烷 -2-甲酸和 430ml的二氯甲烷, 室温下加入 35g (0.347mol) 的三乙胺。 氮气保护 下降温到瓶内温度 -15°C,滴加 40.4g(0.335mol)的特戊酰氯,搅拌反应 15分钟。 再向其中加入 40g(0.396mol)的三乙胺, 滴加甲垸磺酰氯 41.7g(0.335mol), 搅拌 反应 15分钟。 温度降到 -10Ό以下后, 加入 Na2S 9H20溶液, 搅拌反应 1小时。 流加 3N HC1 200ml, 静置分相, 水层用 120ml二氯甲烷萃取一次, 合并有机相, 加入 32g(0.317mol)三乙胺,加热回流 2小时。温度降到 0°C,加入 IN HC1 200ml。 静置分相, 有机相分别用水, 5%碳酸钠水溶液和饱和盐水洗。 减压浓缩蒸干, 流加 400ml的石油醚, 降温到 0°C, 搅拌 2小时, 过滤, 晶体用 MTBE打浆, 过 滤, 40°C烘干。 得到产品 82g(0.28mol, 收率 91.8%)二异丙基(18,48)-6-氧代-5-硫
-2-氮杂双环 [2.2.1]庚 -2-基磷酸酯。
Mp: 89〜90°C
1H NMR(400MHz, CDC13)
1.27(d, 3H), 1.29(d, 3H), 1.30(d, 6H), 2.02(m, 1H), 2,13(m, 1H), 3.40(m, 1H), 3.71(m: 1H), 4.09(m, 1H), 4.20(m, 1H), 4.57(m, 2H)。
实施例 2
2) 二异丙基 (lS,4S)-6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-基磷酸酯
将实施例 1中的 40.4g(0.335mol)的特戊酰氯替换为 40g(0.327mol)的氯甲酸 异丙酯, 其他加量和方法均相同, 得到 74.3g(0.253mol, 收率 91.8%)二异丙基 (lS,4S)-6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-基磷酸酯。
实施例 3
3 (1S,4S)-烯丙氧羰基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-酯的制备
将实施例 1中的 90g (0.305mol) 的 (2S,4R)-1- (二异丙基磷酸基) -4-羟基吡咯 垸 -2-甲酸替换为 65g (O.305mol)的 (2S,4R)-1-烯丙氧羰基 -4-羟基吡咯垸 -2-甲酸, 其他加量和方法均相同, 得到油状物 60.4g (0.283mol, 收率 93%) (1S,4S)-稀丙
氧羰基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-酯。
1H NMR(400MHz, CDC13)
2.18(m, 2H), 3.65(m, IH), 3.85(d, 1H), 4.14(m, IH), 4.63(d, 2H), 4.67(m, IH), 5.22(d IH), 5.32(d, 1H), 5.92(m, 1H)。
实施例 4
4) (1S,4S)-烯丙氧羰基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-酯的制备
将实施例 3 中的特戊酰氯替换为 40g(0.327mol)的氯甲酸异丙酯, 其他加量 和方法均相同, 得到标题化合物油状物 60.7g (0.284mol, 收率 93.4%) (1S,4S)- 烯丙氧驟基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-酯。
实施例 5
5) -叔丁氧羰基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-酯的制备
将实施例 1中的 90g (0.305mol) 的 (2S,4R)-1- (二异丙基磷酸基) -4-羟基吡咯 垸 -2-甲酸替换为 70.4g (O.305mol) 的 (2S,4R)-1- (叔丁氧羰基 )-4-羟基吡咯垸 -2-
甲酸, 其他加量和方法均相同, 得到白色固体 63.7g (0.278mol, 收率 91.2%)
(1S,4S)-叔丁氧羰基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-酯。
Mp: 91 °C
1H NMR(400MHz, CD2C12)
1.42(s, 9H), 2.07(dt, 1H), 2.13(m, 1H), 3.48-3.53(m, 1H), 3.74(m, 1H), 4.11(m, 1H); 4.42-4.53(d, 1H)。
实施例 6
6) (1S,4S)-叔丁氧羰基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-酯的制备
将实施例 5中的特戊酰氯替换为 41.3g(0.337mol)的氯甲酸异丙酯,三乙胺用 相当量的二异丙基乙胺代替,其他反应方式相同,得到标题化合物白色固体 65.6g (0.286mol,收率 94%) (1S,4S)-叔丁氧羰基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2- 酯。
实施例 7
7) (lS,4S)-4-硝基苄氧羰基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-酯的制备
将实施例 1中的 90g (0.305mol) 的 (2S,4R)-1- (二异丙基磷酸基) -4-羟基吡咯 垸 -2-甲酸替换为 94.5g (0.305mol)的 (2S,4R)小 ((4-硝基苄氧)羰基) -4-羟基吡咯垸 -2-甲酸, 三乙胺用相应当量的 DIPEA替代, 其他加量和方法均相同, 得到浅黄 色固体 79.4g (0.258mol, 收率 84.5%) (lS,4S)-4-硝基苄氧羰基 -6-氧代 -5-硫 -2- 氮杂双环 [2.2.1]庚 -2-酯。
Mp: 102〜103°C
1H NMR(400MHz, CDC13)
2.11-2.27(m, 2H), 3.67-3.72(m, 1H), 3.85-3.90(m, 1H), 4.15-4.19(m, 1H), 4.62-4.70(m, 1H), 5.21(d, 1H), 5.3 l(d, 1H), 7.54(d, 2H), 8.23(d, 2H)=
实施例 8
8) (lS,4S)-4-硝基苄氧羰基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-酯的制备
将实施例 7中的特戊酰氯用为 40g(0.327mol)氯甲酸异丙酯替代, 其他加量 和反应方法相同, 得到标题化合物浅黄色固体 82.6g ( 0.268mol, 收率 88% ) (lS,4S)-4-硝基苄氧羰基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-酯。
实施例 9
9) 3-((3S,5S)-l- (二异丙基磷酰基) -3-巯基吡咯垸 -5-甲酰胺基)苯甲酸的制备
将 45.3g(0.148mol) 二异丙基 (IS, 4S)-6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-基 磷酸酯和 22.7g (0.164mol)间氨基苯甲酸溶于 250ml冰醋酸中,室温下反应 16h,
向其中加入 600ml 二氯甲垸和 300ml 1M盐酸, 抽提有机层, 浓缩, 用乙酸乙酯 和环己垸重结晶, 得白色晶体 59.2g (0.138mol, 收率 93%) 3-((3S,5S)-l- (二异丙 基磷酰基) -3-巯基吡咯烷 -5-甲酰胺基)苯甲酸。
Mp: 95〜96°C
1H NMR(400MHz, CDC13)
1.16(s, 12H), 1.50(s, 1H), 2.07-2.32(m, 2H), 2.65-2.76(m, IH), 2.90-2.94(m, IH), 3.06-3.10(m, IH), 3.57-3.65(m, 2H), 3.71-3.74(m, IH), 7.45-7.48(m, 1H), 7.87-8.0(m; 3H), 8.50-8.53(m, 1H), 10.9(S, 1H)。
实施例 10
10) ( -4-硝基苄基 2- (二甲基氨基甲酰基 )-4-巯基吡咯垸小甲酸酯的制备
反应瓶中加入 300ml丙酮和 50g(0.162mol) (1S,4S 4-硝基苄氧羰基 -6-氧代 -5-硫 -2-氮杂双环 [2.2.1]庚 -2-酯, 溶清。 降温至 10°C, 加入 19.8g (0.244mol) 的 二甲胺盐酸盐。 控制温度在 15~20°C, 滴加 24.6g三乙胺, 在相同温度下反应 30 分钟后,减压浓缩丙酮。 向其中加入 410ml乙酸乙酯和 IN HC1, 静置分相。 向 有机相中加入 2,79g三丁基膦、 180ml的 10%盐水, 180ml的饱和盐水, 浓缩有 机相, 有大量晶体析出。 离心过滤, 真空烘干, 得白色晶体 52.2g(0.148mol,收率 87%) (2S,4S)-4-硝基苄基 2- (二甲基氨基甲酰基 )-4-巯基吡咯垸 -1-甲酸酯。
Mp: 117-119°。
1H NMR(400MHz, CDC13)
1.56(d, 1H), 1.96-2.2 l(m, 2H), 2.65-2.71(m, 1H), 2.97(s, 3H), 3.08(s, 3H), 3.48-3.73(m, 2H),4.29-4.31(m, IH), 5.19(s, 2H), 7.48(d, 2H), 8.15(d, 2H)。
Claims
1、 一种合成培南侧链的双环中间体的制备方法, 其特征在于, 所述双环中间体 的结构式
所述制备方法如下-
1 ) 式 (ΠΙ) 化合物在有机碱作用下, 与羧基活化剂反应生成式 (IV ) 化合 物, 反应温度为 -30〜- 5 °C, 反应时间为 0.5〜2h, 羧基活化剂与式 (III) 化合物 的物质的量比为 2.0〜1.2: 1;
其中, R3为吡咯垸 N上的保护基, 选自叔丁氧羰基、 对硝基苄氧羰基、 苄 氧羰基、 对甲氧基苄氧羰基、 烯丙氧羰基、 苄氧羰基或二异丙基磷酰基;
2) 式 (IV) 化合物在有机碱作用下, 与羟基活化剂反应生成式 (V ) 化合 物, 反应温度为 -20〜- 5 °C, 反应时间为 0.5〜2h, 羟基活化剂与式 (IV) 化合物 的物质的量比 1.5〜1.05: 1;
3) 式 (V ) 化合物与硫化物在低温下环合得到双环化合物( I ), 反应温度 为 -20〜0°C , 反应时间为 l〜5h, 硫化物与式 (V )化合物的摩尔比为 2〜8: 1。
2、 根据权利要求 1所述的制备方法, 其特征在于, 所述羧基活化剂是磺酰氯化 合物、 磺酸酐、 垸基氯甲酸酯、 垸基酰氯化合物、 N, N-羰基二咪唑或二环已基 碳二亚胺、 特戊酰氯或氯甲酸异丙酯。
3、 根据权利要求 2所述的制备方法, 其特征在于, 所述磺酰氯化合物是甲垸磺 酰氯、对甲苯磺酰氯或苯磺酰氯; 所述磺酸酐是甲磺酸酐或对甲苯磺酸酐; 所述 垸基氯甲酸酯是氯甲酸乙酯、氯甲酸异丙酯或氯甲酸叔丁酯;所述酰氯化合物是 草酰氯或特戊酰氯。
4、 根据权利要求 1所述的制备方法, 其特征在于, 所述有机碱是三 胺、 二异 丙基乙胺、 吡啶、 甲基吡啶、 咪唑或喹啉。
5、 根据权利要求 1所述的制备方法, 其特征在于, 所述硫化物是硫化钠、 硫氢 化钠或硫化钾。
6、 根据权利要求 1所述的制备方法, 其特征在于, 在各反应步骤中用到的溶剂 选自醚类、 卤代垸烃、 乙睛、 甲苯、 乙酸乙酯或 DMF。
7、 根据权利要求 6所述的制备方法, 其特征在于, 所述醚类是环氧乙垸、 乙醚 或四氢呋喃; 所述卤代垸烃是二氯甲垸、 氯仿或 1,2-二氯乙烷。
8、 权利要求 1所述式(I )化合物的应用, 其特征在于, 所述式(I )化合物与胺开 环缩合得到培南侧链化合物 (11), 反应式如下:
(I) (II)
所述胺是任意一级胺或二级胺;
反应中的溶剂是环氧乙垸、四氢呋喃、乙酸乙酯、甲苯、丙酮、乙酸或 DMF; 反应温度为 0〜40°C, 反应时间为 30min〜24h。
9、 根据权利要求 8 所述式(I )化合物的应用, 其特征在于, 所述一级胺是 NH2PhC02H或 NHBS02NH2; 所述二级胺是 HN(CH3)2或 HN(CH3)C2H5 。
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