CN1015104B - 烯丙基酯类和醚类的脱保护方法 - Google Patents
烯丙基酯类和醚类的脱保护方法Info
- Publication number
- CN1015104B CN1015104B CN86103521A CN86103521A CN1015104B CN 1015104 B CN1015104 B CN 1015104B CN 86103521 A CN86103521 A CN 86103521A CN 86103521 A CN86103521 A CN 86103521A CN 1015104 B CN1015104 B CN 1015104B
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- Prior art keywords
- mole
- milliliters
- palladium
- allyl ester
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 238000010511 deprotection reaction Methods 0.000 title claims abstract description 7
- 125000000746 allylic group Chemical group 0.000 title abstract description 7
- 150000002170 ethers Chemical class 0.000 title abstract description 4
- -1 allyl ester Chemical class 0.000 claims abstract description 36
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 21
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 16
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 10
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000003197 catalytic effect Effects 0.000 claims abstract description 5
- 239000003446 ligand Substances 0.000 claims abstract description 5
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 59
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 5
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 claims description 5
- 238000005336 cracking Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 150000003952 β-lactams Chemical class 0.000 claims description 2
- 230000008929 regeneration Effects 0.000 claims 1
- 238000011069 regeneration method Methods 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 2
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- 239000000203 mixture Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 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 7
- 239000002253 acid Substances 0.000 description 7
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical class COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 238000013019 agitation Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 235000014347 soups Nutrition 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 3
- 229930195708 Penicillin V Natural products 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 229940056360 penicillin g Drugs 0.000 description 3
- 229940056367 penicillin v Drugs 0.000 description 3
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000007738 vacuum evaporation Methods 0.000 description 3
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 2
- 210000005252 bulbus oculi Anatomy 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000003672 processing method Methods 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-N trans-cinnamic acid Chemical class OC(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-N 0.000 description 2
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 description 1
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- KCMITHMNVLRGJU-CMDGGOBGSA-N Allyl cinnamate Chemical compound C=CCOC(=O)\C=C\C1=CC=CC=C1 KCMITHMNVLRGJU-CMDGGOBGSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000675108 Citrus tangerina Species 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 239000012456 homogeneous solution Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- POSICDHOUBKJKP-UHFFFAOYSA-N prop-2-enoxybenzene Chemical compound C=CCOC1=CC=CC=C1 POSICDHOUBKJKP-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D477/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- 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
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
-
- 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)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及烯丙基酯类和醚类脱保护作用的方法。该方法包括羧酸的烯丙基酯和苯酚的烯丙基醚与吡咯烷或哌啶和催化量的有机溶剂可溶的有配位膦配位体的钯配合物反应，裂解烯丙基并再生成羧酸或苯酚。
Description
本发明是关于钯催化下烯丙基酯类和醚类的脱保护方法。
用烯丙氧羰基作为羧酸的保护基这是大家熟悉的，即用烯丙醇酯化羧酸并在起到保护作用后再去掉烯丙基使羧基复原。例如，Ohtani等人在Journal of Organic Chemistry 1984，第49卷5271-5272页上报导，在碳代青霉烯（carbapenems）合成中一个关键步骤是C-3酯的最后脱保护步骤，而且举了一个由于钯（0）的作用使烯丙酯基裂解的例子。
Jeffrey在Journal of OrganicChemistry，1982，第47卷587-590页中，美国专利NO.4，314，942中;1984年4月26日公开的英国专利申请GB.2128，187A例21中，都揭示了在催化量的四（三苯膦）-钯（0）和三苯膦存在下应用2-乙基己酸钾，在羰基保护的β-内酰胺衍生物，如青霉素，头孢菌素和碳代青霉烯中烯丙氧羰基的裂解作用。;KUNZ等人在Angew，Chem，Int.Ed.Engl，1984，第23卷，71-72页报导了应用烯丙基去掉不稳定的O-糖肽合成时的羧基保护基。这篇文章报导，在四氢呋喃中氩气氛下并在过量十倍的吗啉作为接受体亲核试剂情况下，通过与约10%摩尔的四（三苯膦）-钯（0）反应裂解烯丙基酯。
本发明的目的是提供一种烯丙基酯类和酚醚类的脱烯丙基方法，这种方法产生的相应羰酸和苯酚的产率比以前的工艺方法要高。
本发明的进一步目的是提供一种和以前工艺方法相比，可以在较低温度和较短时间条件下进行的方法，所以，这种方法可以在反应条件下，包括在较高温度和较长时间条件下分解那些有敏感结构的烯丙基酯类。
本发明通过包括羧酸的烯丙基酯或苯酚的烯丙基醚与吡咯烷或
啶和催化量的有机溶剂可溶的有配位膦配位体的裂解烯丙基的钯配合物反应达到了目的。反应后回收羧酸或苯酚。
本发明的方法可用于任何羧酸的烯丙基酯或苯酚的烯丙基醚的脱烯丙基，例如，烯丙基苯醚，苯甲酸烯丙基酯，肉桂酸烯丙基酯等等。根据本发明可以优先脱去保护的烯丙基酯类是β-内酰胺烯丙基酯类，例如青霉素，头孢菌类，和碳代青霉烯，特别是碳代青霉烯衍生物的烯丙基酯类，该衍生物的特征在于具有如下2-取代的化学式
其中A代表C1-C6直链或支链亚烷基;R1代表任意取代的脂族基，环脂基，环族基-脂肪基，芳基，芳脂基，杂芳基，杂芳脂基，杂环基或杂环基-脂族基，而
代表以环碳原子连接到亚烷基A上的含氮芳香杂环并由取代基R1季铵化。这类衍生物在英国专利申请GB2128 187A中详细叙述过，这里一起提出供参考。
优先选用于本发明方法的有机溶剂可溶的钯配合物催化剂是四（三苯膦）钯（o），而最好是在游离的三苯膦存在下应用。每摩尔烯丙基酯或醚最好用0.01到0.1摩尔的催化剂。每摩尔四（三苯膦钯最好用1.5到5摩尔的三苯膦。
在反应中每摩尔烯丙基酯或醚最好用1.0到1.5摩尔的吡咯烷或哌啶。
脱烯丙基反应最好是在惰性溶剂例如二氯甲烷，氯仿，***，苯，甲苯，乙酸乙酯，乙睛等中进行。而反应最好在温度从-5℃到30℃，时间从10分钟到4小时条件下进行。
下面的实例具体说明实施本发明的最佳方案。
实例1
把三氟甲磺酸甲酯（1.05当量）加到冰冷的悬浮于乙睛中的化合物Ⅰ中，化合物Ⅰ是由英国专利申请GB2128187A实例21步骤F制得。20分钟以后，加入三苯膦（5%摩尔），四（三苯膦）-钯（o）（2.5%摩尔）和吡咯烷（1.05当量）。迅速发生沉淀并在0℃下搅拌所得浆状物10分钟。加入丙酮后析出粗制固体，用甲醇重结晶得到所需要的产物Ⅱ，产率70%，纯度90-93%。
当用2-乙基己酸钾代替例Ⅰ中的吡咯烷时，得不到产物。
实例2
在6毫升干燥乙腈中加化合物Ⅲ（0.350克，0.936毫摩尔）所得烯丙基酯溶液在-5℃下冷却并用三氟甲磺酸甲酯（0.111毫升，0.983毫摩尔）处理。15分钟后，加入四（三苯膦）钯（o）（0.027克，2.5%摩尔）和三苯膦（0.027克）溶液，搅拌反应混合物约5分钟后，滴加吡咯烷（0.082毫升，0.983毫摩尔）。固体慢慢地开始从所得的棕色溶液中析出。在0℃下激烈搅拌此混合物约20分钟，然后慢慢加入15毫升冷的（0℃）丙酮并在0℃继续搅拌约20分钟。过滤出悬浮物并用冷的丙酮洗涤残留物，然后真空干燥得到0.345克米色粉末。以少量的PH7的磷酸盐缓冲液（0.05摩尔）溶解这种物质并用短的反相色谱（C18Bondapak）柱分离。用水洗脱和冷冻干燥有关馏份得到0.255克淡黄色固体。这种物质按以前作法，再次用色谱法提纯，给出（冷冻干燥以后）纯的化合物Ⅳ（0.195克，产率60%）为淡黄色固体：
1Hnmr（D2O）δ8.58，7.83（ABq，J＝
6.4Hz，2H），7.87（s，1H），4.32-3.95（m，2H），4.22（s，2H），4.17（s，3H），3.32（dd，J1＝2.6Hz，J2＝6.1Hz，1H），3.06-2.93（m，2H），2.74（s，3H），1.22（d，J＝6.4Hz，3H）;ir（KBr）1757，1590cm-1;uv（磷酸盐缓冲液，PH7.4）296nm（ε7446）。
实例3
化合物Ⅴ（0.582克，0.0015摩尔）在15毫升干燥乙腈中的烯丙基酯溶液，在氮气氛下-5℃用三氟甲磺酸甲酯（0.178毫升，1.575毫摩尔）处理。15分钟后，把在1毫升二氯甲烷中的四（三苯膦）钯（0.035克，2摩尔%）和三苯膦（0.035克）加入，5分钟后加入0.131毫升（1.575毫摩尔）吡咯烷。生成的混合物在0℃搅拌约20分钟，然后加入30毫升冷的（0℃）丙酮。在0℃激烈搅拌该混合物约15分钟，此后过滤收集沉淀物，用冷丙酮洗涤并真空干燥，得到0.520克米色粉末。用***烯释滤液，另外得到0.041克粗产物。合并这些固体并溶解在少量PH7.4的磷酸盐缓冲液（0.05M）中并用于做反相（C18Bondapak）柱，用水然后用2%乙腈-水洗脱，冷冻干燥，得到黄色固体化合物Ⅵ（0.413克，产率76%）：1Hnmr（D2O）σ8.55，7.76（ABq，J＝6.3Hz，2H），7.81（s，1H），4.4-3.7（m，2H），4.19（s，2H），4.16（s，3H），3.47-3.14（m，2H），2.73（s，3H），1.24（d，J＝6.4Hz，3H），1.16（d，J＝7.3Hz，3H，ir（KBr）1750，1595cm-1;uv（磷酸盐缓冲液，PH7.4）293nm（ε7170）。
实例4
把三氟甲磺酸甲酯（3.17毫升，28.05毫摩尔）加到100毫升乙腈与化合物Ⅶ（10.00克，26.7毫摩尔）组成的冰冷的烯丙酯悬浮液中。生成的均匀的黄色溶液在20℃下搅拌。依次加三苯膦（350毫克，1.33毫摩尔）和在20毫升二氯甲烷中的四（三苯膦）钯（770毫克，0.66毫摩尔），此混合物被搅拌5分钟，然后在5分钟内加入在15毫升乙腈中的吡咯烷（2.4毫升，28.05毫摩尔）溶液。出现结晶并把生成的浆状物在0℃搅拌约10分钟。加入预先冷冻的丙酮（150毫升），此混合物搅拌15分钟。收集生成的黄色固体，用60毫升丙酮洗两次。
干燥后，黄色固体在50毫升冷（0℃）甲醇中研磨约30分钟。过滤生成的米色浆状物，稍加干燥后溶解在20毫升冷水中。迅速过滤生成的混合物，加入100毫升冷乙醇。在0℃搅拌约10分钟以后，出现结晶，搅拌生成的混合物1.3小时以上。收集固体，在高真空下下干燥约3小时得到化合物Ⅷ4.82克，产率51.8%。
实例5
在0°-5℃和氮气下，滴加三氟甲磺酸甲酯（4.055毫升，35.349毫摩尔）于124毫升乙腈与化合物Ⅸ（12.63克，33.707毫摩尔）组成的烯丙酯溶液中。透明的黄色反应混合物在0-5℃下搅拌约15分钟。在0-5℃下把三苯膦（429.44毫克，1.661毫摩尔）一次加到此反应混合物中，接着再加入在33毫升二氯甲烷中的四（三苯膦）钯（959.56毫克，0.831毫摩尔）溶液。透明的橙色反应混合物在0-5℃下搅拌约5分钟。然后滴加在乙腈（41.3毫升）中的吡咯烷（3.03毫升，33.707毫摩尔）溶液。在0-5℃搅拌5分钟，分批地并在激烈搅拌下把冰冷丙酮（250毫升）加到这种透明的深橙色反应混合物中，再加入无水***（150毫升）。在0-5℃继续搅拌5分钟，然后在氮气下
迅速过滤此悬浮液。固体残留物用无水***（50毫升）洗涤并真空干燥得到11.05克（33.12毫摩尔，产率96.6%）粗的黄色吸水性固体。把该固体溶解在冰冷的磷酸盐缓冲液（75毫升;PH7.0）中，用50毫升一份的***洗涤两次。水层在搅拌下抽真空45分钟，用反相色谱法提纯。提纯和冷冻干燥后得到9.63克（27.617毫摩尔，产率81.0%）的化合物Ⅹ。
实例6和实例7
以类似于实例1-5的方法进行上述反应，化合物Ⅻ的产率是72%，化合ⅪⅤ的产率是61%。
下面的实例说明在本发明中用哌啶代替吡咯烷。
实例8
在实例1中说明的反应进行如下：把三氟甲磺酸甲酯（0.121毫升，1.068毫摩尔）加到冷却到0℃由10毫升乙腈与化合物Ⅰ（350毫克，0.971毫摩尔）组成的烯丙基酯悬浮液中。生成的淡黄色混合物被搅拌1小时，加入三苯膦（25毫克，0.095毫摩尔）和在2毫升二氯甲烷中的四（三苯膦）钯（25毫克，0.0216毫摩尔）。慢慢加入哌啶（0.105毫升，1.068毫摩尔），在0℃下搅拌所生成的浅桔色混合物。15分钟以后，形成黄色沉淀，继续搅拌1.5小时。加入丙酮（10毫升），生成的浆状物被搅拌30分钟，过滤固体，用2份10毫升的丙酮洗涤并干燥。生成的产物230毫克，产率70.7%，纯度约69.4%。
下面的实例说明本发明用于头孢菌素脱烯丙基的方法。
实例9
把吡咯烷（0.161毫升，1.919毫摩尔）慢慢地加到由10毫升二氯甲烷与化合物ⅩⅤ（787毫克，1.828毫摩尔），四（三苯膦）钯（o）（53毫克，0.045毫摩尔）和三苯膦（50毫克，0.190毫摩尔）组成的冰***液中，此混合物在0℃被搅拌约25分钟，然后倾入10毫升碳酸氢钠（383毫克）烯溶液中用力搅拌之后，分离出有机相再用10毫升碳酸氢钠烯溶液萃取。把预先加入10毫升二氯甲烷的此水溶液用IN的盐酸在0℃酸化到PH2.5。分离有机相，另用10毫升二氯甲烷萃取此水溶液。干燥后真空蒸发，得到630毫克（产率88%）游离的酸，化合物ⅩⅥ。
下面的两个实例说明用于青霉素烯丙基酯脱烯丙基的方法。
实例10
把吡咯烷（0.121毫升，1.45毫摩尔）加到由10毫升二氯甲烷与青霉素-Ⅴ的烯丙基酯（540毫克，1.38毫摩尔）和四（三苯膦）钯（40毫克，0.0345毫摩尔）组成的冰冷混合物中。在0℃搅拌此混合物约30分钟，然后用10毫升碳酸氢钠
（600毫克）水溶液萃取。此溶液用5%的盐酸酸化并用3份10毫升的二氯甲烷萃取。干燥后真空蒸发，析出301毫克（产率62.3%）青霉素-Ⅴ的游离酸为白色固体。核磁共振谱与青霉素-Ⅴ游离酸的结构相一致。
实例11
把四（三苯膦）钯（112毫克，0.097毫摩尔）和三苯膦（100毫克，0.381毫摩尔）慢慢加到20毫升二氯甲烷与青霉素-G烯丙基酯（1.456克，3.889毫摩尔）组成的溶液中。搅拌此混合物几分钟以后，得到均匀的混合物。然后把此混合物冷却到0℃并慢慢地加入在5毫升二氯甲烷中的吡咯烷（0.341毫毫升，4.084毫摩尔）。生成的混合物在0℃搅拌15分钟。加入由溶解在50毫升水中的1.63克碳酸氢钠所制备的稀的碳酸氢钠溶液（25毫升）和10毫升乙酸乙酯。激烈搅拌后，收集水溶液部分。有机相用25毫升稀的碳酸氢钠萃取。合并水溶液相冷却到0℃，加入20毫升二氯甲烷并用5%盐酸（约14毫升）把混合物酸化到PH2。收集有机相，水溶液混合物用2份25毫升二氯甲烷萃取。合并有机相，干燥，然后真空浓缩得到1.22克（产率93.8%）白色固体青霉素-G游离酸。核磁共振谱与青霉素-G游离酸的结构相一致。
下面两个实例说明本发明用于简单芳香酸的脱烯丙基的方法。
实例12
把四（三苯膦）钯（178毫克，0.154毫摩尔）加到由
15毫升二氯甲烷与苯甲酸的烯丙基酯（1.00克，6.16毫摩尔）组成的冰***液中，搅拌此反应混合物直到得到均匀溶液。加入吡咯烷（0.540毫升，6.47毫摩尔），产生的混合物在0℃被搅拌20分钟，然后倒入20毫升的氢氧化钠（285毫克NaOH，7.12毫摩尔）烯溶液中。慢慢倾出有机相，水溶液用5毫升二氯甲烷洗涤。用5%的盐酸（约6毫升）酸化后用3份10毫升的二氯甲烷萃取苯甲酸产物。干燥后真空浓缩，得到苯甲酸白色固体730毫克（产率97%），熔点为122-123℃。
实例13
把吡咯烷（0.466毫升，5.58毫摩尔）加到反式肉桂酸烯丙酯（1.0克，5.31毫摩尔）和四（三苯膦）钯（o）（150毫克，0.13毫摩尔）在15毫升二氯甲烷中的冰***液中。生成的混合物在0℃搅拌约50分钟。然后把它倒入20毫升稀氢氧化钠（5.86毫摩尔NaoH）溶液中，水相用2份15毫升二氯甲烷洗涤，然后用5%稀盐酸酸化。该酸用3份10毫升二氯甲烷萃取。有机相用硫酸镁干燥，并真空蒸发，得到765毫克（产率97.%）反式肉桂酸，熔点为133-134℃。核磁共振谱与反式肉桂酸的结构相一致。
下面实例说明苯酚的烯丙基醚的脱烯丙基作用。
实例14
把四（三苯膦）钯（o）（215毫克，0.186毫摩尔），三苯膦（215毫克，0.819毫摩尔）和吡咯烷（0.684毫升，
8.198毫摩尔）加到在10毫升二氯甲烷中的烯丙基苯基醚（1.00克，7.45毫摩尔）溶液中。此混合物在室温下搅拌约4小时。用2份10毫升5%氢氧化钠水溶液萃取，萃取物用浓盐酸酸化到约PH1-2。苯酚用3份10毫升二氯甲烷萃取，用硫酸镁干燥并过滤，真空浓缩得到625毫克（产率89.1%）纯苯酚。核磁共振谱与苯酚的结构相一致。
Claims (6)
1、一种β-内酰胺烯丙基酯的脱保护方法，该方法包括每摩尔β-内酰胺烯丙基酯与1.0-1.5摩尔吡咯烷和催化量的有机溶剂可溶解的有配位膦配位体的钯配合物于-5℃-30℃反应10分钟至4小时，裂解烯丙基并再生成β-内酰胺。
2、碳代青霉烯衍生物的烯丙基酯的脱保护方法，该碳代青霉烯衍生物的特点在于有如下2-取代的化学式，其中A代表C1-C6
直链或支链亚烷基;R1代表任意取代的脂肪基，环脂基，环脂基-脂肪基，芳基，芳脂基，杂芳基，杂芳脂肪基，杂环基或杂环基-脂肪基，而
代表以环碳原子连接到亚烷基A上的含氮的芳香杂环并以R1取代基季胺化，该方法包括每1摩尔的碳代青霉烯衍生物的烯丙基酯同1.0-1.5摩尔的吡咯烷和催化量的有机溶剂可溶解的有配位膦配位体的钯配合物于-5℃-30℃下反应10分钟到4小时，裂解烯丙基部分并生成碳代青霉烯衍生物。
3、权利要求1或2规定的方法，其中有机溶剂可溶的具有配位膦配位体的钯配合物是四（三苯膦）钯（0）。
4、权利要求3规定的方法，其中每摩尔的烯丙基酯用0.01到0.1摩尔的四（三苯膦）钯（0）。
5、权利要求3规定的方法，其中四（三苯膦）钯（0）在游离的三苯膦存在下使用。
6、权利要求5规定的方法，其中每摩尔四（三苯膦）钯（0）用1.5到5摩尔三苯膦。
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| AR (1) | AR241019A1 (zh) |
| AT (1) | AT390955B (zh) |
| BE (1) | BE904885A (zh) |
| CA (1) | CA1273630A (zh) |
| CH (1) | CH666678A5 (zh) |
| CS (1) | CS265220B2 (zh) |
| DD (1) | DD245433A5 (zh) |
| DE (1) | DE3619200C2 (zh) |
| DK (1) | DK268886A (zh) |
| EG (1) | EG18276A (zh) |
| ES (1) | ES8800684A1 (zh) |
| FI (1) | FI89486C (zh) |
| FR (1) | FR2583038B1 (zh) |
| GB (1) | GB2176478B (zh) |
| GR (1) | GR861432B (zh) |
| HU (1) | HU198167B (zh) |
| IE (1) | IE59187B1 (zh) |
| IL (1) | IL79023A (zh) |
| IT (1) | IT1190041B (zh) |
| LU (1) | LU86461A1 (zh) |
| NL (1) | NL191787C (zh) |
| NO (1) | NO165998C (zh) |
| NZ (1) | NZ216364A (zh) |
| OA (1) | OA08340A (zh) |
| PT (1) | PT82727B (zh) |
| SE (1) | SE469076B (zh) |
| SU (1) | SU1508959A3 (zh) |
| YU (1) | YU45330B (zh) |
| ZA (1) | ZA862749B (zh) |
| ZM (1) | ZM3786A1 (zh) |
| ZW (1) | ZW9286A1 (zh) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE60588B1 (en) * | 1986-07-30 | 1994-07-27 | Sumitomo Pharma | Carbapenem compound in crystalline form, and its production and use |
| JPS63154628A (ja) * | 1986-12-17 | 1988-06-27 | Nippon Zeon Co Ltd | 保護化アルコール化合物の脱保護方法 |
| EP0384732A3 (en) * | 1989-02-23 | 1991-12-04 | Merck & Co. Inc. | Deblocking process for allyl esters with regeneratable polymer supported pd (0) |
| CA2093989A1 (fr) * | 1992-04-15 | 1993-10-16 | Jean-Marie Bernard | Reactif et procede catalytique utile pour cliver une fonction protegee |
| FR2690153A1 (fr) * | 1992-04-15 | 1993-10-22 | Rhone Poulenc Chimie | Réactif et procédé catalytique utile pour cliver une fonction protégée. |
| US5587474A (en) * | 1992-06-18 | 1996-12-24 | Tanabe Seiyaku Co., Ltd. | Method for removing the protecting group for carboxyl group |
| JP2847693B2 (ja) * | 1992-06-18 | 1999-01-20 | 田辺製薬株式会社 | カルボキシル基保護基の除去方法 |
| US5578740A (en) * | 1994-12-23 | 1996-11-26 | The Dow Chemical Company | Process for preparation of epoxy compounds essentially free of organic halides |
| US20060128939A1 (en) * | 2004-12-03 | 2006-06-15 | Vijayendra Kumar | One pot process for making polymeric antioxidants |
| US8361802B2 (en) * | 2009-03-09 | 2013-01-29 | University of Pittsburgh—of the Commonwealth System of Higher Education | Fluorescent ozone sensor |
| US8550716B2 (en) | 2010-06-22 | 2013-10-08 | S.C. Johnson & Son, Inc. | Tactile enhancement mechanism for a closure mechanism |
| US8974118B2 (en) | 2010-10-29 | 2015-03-10 | S.C. Johnson & Son, Inc. | Reclosable bag having a sound producing zipper |
| US9327875B2 (en) | 2010-10-29 | 2016-05-03 | S.C. Johnson & Son, Inc. | Reclosable bag having a loud sound during closing |
| US11180286B2 (en) | 2010-10-29 | 2021-11-23 | S. C. Johnson & Son, Inc. | Reclosable bag having a loud sound during closing |
| US8568031B2 (en) | 2011-02-22 | 2013-10-29 | S.C. Johnson & Son, Inc. | Clicking closure device for a reclosable pouch |
| US8469593B2 (en) | 2011-02-22 | 2013-06-25 | S.C. Johnson & Son, Inc. | Reclosable bag having a press-to-vent zipper |
| EP3004134B1 (en) * | 2013-06-04 | 2019-02-27 | The University of Sydney | Peptide ligation |
| US10294423B2 (en) | 2013-11-22 | 2019-05-21 | Polnox Corporation | Macromolecular antioxidants based on dual type moiety per molecule: structures, methods of making and using the same |
| KR102014596B1 (ko) | 2016-08-12 | 2019-10-21 | 가톨릭대학교 산학협력단 | 연조직 경화용 조성물 |
| US20180251695A1 (en) | 2017-03-01 | 2018-09-06 | Polnox Corporation | Macromolecular Corrosion (McIn) Inhibitors: Structures, Methods Of Making And Using The Same |
| CN108383848A (zh) * | 2018-03-27 | 2018-08-10 | 石家庄蒎格医药科技有限公司 | 聚乙二醇纳洛酮新杂质及其制备方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4314942A (en) * | 1979-01-10 | 1982-02-09 | Schering Corporation | Deprotection of allylic esters, carbonates and carbamates catalyzed by palladium compounds |
| US4536335A (en) * | 1982-06-18 | 1985-08-20 | Bristol-Myers Company | Carbapenem antibiotics |
| DE3443993A1 (de) * | 1984-12-01 | 1986-06-05 | Bayer Ag, 5090 Leverkusen | Verfahren zur herstellung von neuen indolderivaten und deren verwendung |
-
1985
- 1985-06-07 US US06/742,495 patent/US4788282A/en not_active Expired - Fee Related
-
1986
- 1986-04-10 CA CA000506363A patent/CA1273630A/en not_active Expired - Lifetime
- 1986-04-11 ZA ZA862749A patent/ZA862749B/xx unknown
- 1986-04-24 ZW ZW92/86A patent/ZW9286A1/xx unknown
- 1986-04-28 ZM ZM37/86A patent/ZM3786A1/xx unknown
- 1986-05-16 FR FR868607068A patent/FR2583038B1/fr not_active Expired
- 1986-05-23 CN CN86103521A patent/CN1015104B/zh not_active Expired
- 1986-05-28 YU YU904/86A patent/YU45330B/xx unknown
- 1986-05-30 NZ NZ216364A patent/NZ216364A/en unknown
- 1986-06-03 GR GR861432A patent/GR861432B/el unknown
- 1986-06-04 IL IL79023A patent/IL79023A/xx not_active IP Right Cessation
- 1986-06-04 FI FI862377A patent/FI89486C/fi not_active IP Right Cessation
- 1986-06-04 CS CS864119A patent/CS265220B2/cs unknown
- 1986-06-05 NO NO862237A patent/NO165998C/no unknown
- 1986-06-05 JP JP61131047A patent/JPH0637496B2/ja not_active Expired - Lifetime
- 1986-06-05 EG EG350/86A patent/EG18276A/xx active
- 1986-06-05 KR KR1019860004452A patent/KR900007246B1/ko not_active IP Right Cessation
- 1986-06-05 IT IT20691/86A patent/IT1190041B/it active
- 1986-06-06 OA OA58874A patent/OA08340A/xx unknown
- 1986-06-06 DD DD86291080A patent/DD245433A5/de not_active IP Right Cessation
- 1986-06-06 HU HU862400A patent/HU198167B/hu not_active IP Right Cessation
- 1986-06-06 IE IE151486A patent/IE59187B1/en not_active IP Right Cessation
- 1986-06-06 GB GB08613738A patent/GB2176478B/en not_active Expired
- 1986-06-06 CH CH2313/86A patent/CH666678A5/de not_active IP Right Cessation
- 1986-06-06 SU SU864027586A patent/SU1508959A3/ru active
- 1986-06-06 PT PT82727A patent/PT82727B/pt not_active IP Right Cessation
- 1986-06-06 LU LU86461A patent/LU86461A1/fr unknown
- 1986-06-06 BE BE0/216754A patent/BE904885A/fr not_active IP Right Cessation
- 1986-06-06 NL NL8601469A patent/NL191787C/xx not_active IP Right Cessation
- 1986-06-06 ES ES555840A patent/ES8800684A1/es not_active Expired
- 1986-06-06 DK DK268886A patent/DK268886A/da not_active Application Discontinuation
- 1986-06-06 AR AR304252A patent/AR241019A1/es active
- 1986-06-06 SE SE8602555A patent/SE469076B/sv not_active IP Right Cessation
- 1986-06-07 DE DE3619200A patent/DE3619200C2/de not_active Expired - Fee Related
- 1986-06-09 AT AT0155586A patent/AT390955B/de not_active IP Right Cessation
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