JPH0341066A - 2-substituted aminocarbonyl-4-mercaptopyrrolidine derivative - Google Patents
2-substituted aminocarbonyl-4-mercaptopyrrolidine derivativeInfo
- Publication number
- JPH0341066A JPH0341066A JP2178208A JP17820890A JPH0341066A JP H0341066 A JPH0341066 A JP H0341066A JP 2178208 A JP2178208 A JP 2178208A JP 17820890 A JP17820890 A JP 17820890A JP H0341066 A JPH0341066 A JP H0341066A
- Authority
- JP
- Japan
- Prior art keywords
- group
- mercaptopyrrolidine
- nitrobenzyloxycarbonyl
- proline
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 2-substituted aminocarbonyl-4-mercaptopyrrolidine Chemical class 0.000 title claims abstract description 68
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical class N* 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 18
- 150000001875 compounds Chemical class 0.000 abstract description 16
- 239000002904 solvent Substances 0.000 abstract description 15
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 12
- FKCMADOPPWWGNZ-YUMQZZPRSA-N [(2r)-1-[(2s)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O FKCMADOPPWWGNZ-YUMQZZPRSA-N 0.000 abstract description 6
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 abstract description 3
- 125000002252 acyl group Chemical group 0.000 abstract description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 abstract description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- 230000000845 anti-microbial effect Effects 0.000 abstract 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical class C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 238000000034 method Methods 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229960002429 proline Drugs 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical class CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 4
- 229960002591 hydroxyproline Drugs 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000010446 mirabilite Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- BDPKOVUGSUGVKQ-MJGOQNOKSA-N 2-o-[(4-methoxyphenyl)methyl] 1-o-[(4-nitrophenyl)methyl] (2s,4r)-4-hydroxypyrrolidine-1,2-dicarboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)[C@H]1N(C(=O)OCC=2C=CC(=CC=2)[N+]([O-])=O)C[C@H](O)C1 BDPKOVUGSUGVKQ-MJGOQNOKSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- PMMYEEVYMWASQN-QWWZWVQMSA-N cis-4-hydroxy-D-proline Chemical compound O[C@H]1C[NH2+][C@@H](C([O-])=O)C1 PMMYEEVYMWASQN-QWWZWVQMSA-N 0.000 description 3
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- PMMYEEVYMWASQN-IMJSIDKUSA-N trans-4-Hydroxy-L-proline Natural products O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QCLMPSJWFJZBIJ-SFTDATJTSA-N (4-methoxyphenyl)methyl (2s,4s)-4-acetylsulfanyl-2-(benzylcarbamoyl)pyrrolidine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)N1[C@H](C(=O)NCC=2C=CC=CC=2)C[C@H](SC(C)=O)C1 QCLMPSJWFJZBIJ-SFTDATJTSA-N 0.000 description 2
- ZPIWQEIXWZVLOP-KBPBESRZSA-N (4-nitrophenyl)methyl (2s,4s)-4-ethoxycarbonylsulfanyl-2-(methylcarbamoyl)pyrrolidine-1-carboxylate Chemical compound C1[C@@H](SC(=O)OCC)C[C@@H](C(=O)NC)N1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 ZPIWQEIXWZVLOP-KBPBESRZSA-N 0.000 description 2
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical class OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- DHRVMGXRSHMILI-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(=O)C1NCC(C1)S Chemical compound C(C1=CC=CC=C1)NC(=O)C1NCC(C1)S DHRVMGXRSHMILI-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 101150102523 cdc12 gene Proteins 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- FRLLRVMCQFOWFC-UHFFFAOYSA-N n,n-dimethyl-4-sulfanylpyrrolidine-2-carboxamide Chemical compound CN(C)C(=O)C1CC(S)CN1 FRLLRVMCQFOWFC-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000002829 nitrogen Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 2
- SOZQAONWQPHCPN-NSHDSACASA-N (2s)-1-benzylpyrrolidine-2-carboxamide Chemical compound NC(=O)[C@@H]1CCCN1CC1=CC=CC=C1 SOZQAONWQPHCPN-NSHDSACASA-N 0.000 description 1
- JMJMJDNHVXYAOC-MNOVXSKESA-N (2s,4r)-4-hydroxy-1-[(4-nitrophenyl)methoxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1[C@H](O)C[C@@H](C(O)=O)N1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 JMJMJDNHVXYAOC-MNOVXSKESA-N 0.000 description 1
- DXQHKYRVYYIYPO-AAEUAGOBSA-N (2s,4s)-4-acetyl-1-[(4-nitrophenyl)methoxycarbonyl]pyrrolidine-2-carbothioic s-acid Chemical compound C1[C@@H](C(=O)C)C[C@@H](C(O)=S)N1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 DXQHKYRVYYIYPO-AAEUAGOBSA-N 0.000 description 1
- SUQHNDGLACBBOE-LSDHHAIUSA-N (4-nitrophenyl)methyl (2r,4s)-4-acetylsulfanyl-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate Chemical compound CN(C)C(=O)[C@H]1C[C@H](SC(C)=O)CN1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 SUQHNDGLACBBOE-LSDHHAIUSA-N 0.000 description 1
- SUQHNDGLACBBOE-GJZGRUSLSA-N (4-nitrophenyl)methyl (2s,4s)-4-acetylsulfanyl-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate Chemical compound CN(C)C(=O)[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 SUQHNDGLACBBOE-GJZGRUSLSA-N 0.000 description 1
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 1
- BDULRHCUNZSLSK-VQTJNVASSA-N 2-o-[(4-methoxyphenyl)methyl] 1-o-[(4-nitrophenyl)methyl] (2r,4s)-4-formyloxypyrrolidine-1,2-dicarboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)[C@@H]1N(C(=O)OCC=2C=CC(=CC=2)[N+]([O-])=O)C[C@@H](OC=O)C1 BDULRHCUNZSLSK-VQTJNVASSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 1
- LOHFTLLGWCUFDL-UHFFFAOYSA-N 3-sulfanylpyrrolidine-1-carboxamide Chemical class NC(=O)N1CCC(S)C1 LOHFTLLGWCUFDL-UHFFFAOYSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical compound SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- KPVWDKBJLIDKEP-UHFFFAOYSA-L dihydroxy(dioxo)chromium;sulfuric acid Chemical compound OS(O)(=O)=O.O[Cr](O)(=O)=O KPVWDKBJLIDKEP-UHFFFAOYSA-L 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
- VYSRWEZGKYVHQG-UHFFFAOYSA-N ethyl carboniodidate Chemical compound CCOC(I)=O VYSRWEZGKYVHQG-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 1
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JQZIKLPHXXBMCA-UHFFFAOYSA-N triphenylmethanethiol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(S)C1=CC=CC=C1 JQZIKLPHXXBMCA-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は一般式CI)
〔式中、R1は水素原子を、R2は水素原子またはアミ
ノ基の保護基を、R2は水素原子、低級アルキル基、低
級アルケニル基、アラルキル基、もしくは置換低級アル
キル基を、およびR4は低級アルキル基、低級アルケニ
ル基、アラルキル基、もしくは置換低級アルキル基を、
あるいはR1およびR4は互いに結合せるアルキレン鎖
または酸素原子、硫黄原子もしくは低級アルキル置換窒
素原子を介するアルキレン鎖を表して隣接する窒素原子
とともに4〜7員環の環状アミノ基を示す。Detailed Description of the Invention The present invention relates to the general formula CI) [wherein R1 is a hydrogen atom, R2 is a hydrogen atom or a protecting group for an amino group, and R2 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aralkyl group] group, or a substituted lower alkyl group, and R4 is a lower alkyl group, a lower alkenyl group, an aralkyl group, or a substituted lower alkyl group,
Alternatively, R1 and R4 represent an alkylene chain bonded to each other or an alkylene chain via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom, and together with the adjacent nitrogen atom, represent a 4- to 7-membered cyclic amino group.
〕
で表される新規な2−置換アミノカルボニル−4−メル
カプトピロリジン誘導体に関する。] It is related with the novel 2-substituted aminocarbonyl-4-mercaptopyrrolidine derivative represented by these.
前記一般式(I)中、R2におけるアミノ基の保護基と
しては、好適には例えばtert−ブチルオキシカルボ
ニルのような低級アルコキシカルボニル基、例えば2−
ヨウ化エチルオキシカルボニル2.2.2−)リクロロ
エチルオキシカルボニルのようなハロゲノアルコキシカ
ルボニル基、例えばベンジルオキシカルボニル、p−メ
トキシベンジルオキシカルボニル、0−ニトロベンジル
オキシカルボニル、p−ニトロベンジルオキシカルボニ
ルのようなアラルキルオキシカルボニル基、例えばトリ
メチルシリル、tert−ブチルジメチルシリルのよう
なトリアルキルシリル基である。In the general formula (I), the protecting group for the amino group in R2 is preferably a lower alkoxycarbonyl group such as tert-butyloxycarbonyl, for example 2-
Ethyloxycarbonyl iodide 2.2.2-) Halogenoalkoxycarbonyl groups such as 2-)lichloroethyloxycarbonyl, e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 0-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl aralkyloxycarbonyl groups such as, for example, trialkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl.
R1またはR4における低級アルキル基としては例えば
メチル、エチル、n−プロピル、イソプロピル、n−ブ
チル等の炭素数1〜4の低級アルキル基を、低級アルケ
ニル基としては例えばプロペニル、ブテニル等の炭素数
2〜4のアルケニル基を、アラルキル基としては例えば
ベンジル、置換ベンジル、フェネチル等のフェニル基も
しくは置換フェニル基で置換された炭素数1〜3のアル
キル基を、置換低級アルキル基としては例えば水酸基、
ジ低級アルキルアミノ基、カルバモイル基等で置換され
たメチル、エチル、n−プロピル等の炭素数1〜4の低
級アルキル基を挙げることができる。Examples of lower alkyl groups in R1 or R4 include lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, and n-butyl, and examples of lower alkenyl groups include 2 carbon atoms such as propenyl and butenyl. -4 alkenyl group, the aralkyl group is, for example, a phenyl group such as benzyl, substituted benzyl, phenethyl, or an alkyl group having 1 to 3 carbon atoms substituted with a substituted phenyl group, and the substituted lower alkyl group is, for example, a hydroxyl group,
Examples include lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, and n-propyl substituted with a di-lower alkylamino group or a carbamoyl group.
またR2およびR4が互いに結合せるアルキ1./ン鎖
または酸素原子、硫黄原子もしくは低級アルキル置換窒
素原子を介するアルキレン鎖を表して、隣接する窒素原
子と共に4〜7員環の環状アミノ基を示す場合としては
、例えばアゼチジノ基、ピペリジノ基、ピロリジノ基、
モルホリノ基、チオモルホリノ基、N−メチルピペラジ
ノ基等を挙げることができる。Also, alkyl 1.R2 and R4 are bonded to each other. When representing an alkylene chain via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom, and representing a 4- to 7-membered cyclic amino group together with the adjacent nitrogen atom, examples include an azetidino group, a piperidino group, pyrrolidino group,
Examples include a morpholino group, a thiomorpholino group, and an N-methylpiperazino group.
なお、前記一般式(1)で示される化合物は2位および
4位の不斉炭素に基く光学異性体および立体異性体が存
在し、これらの異性体が便宜上すべて単一の式で示され
ているが、これによって本発明の記載の範囲は限定され
るものではない。しかしながら、好適には、(2S、4
S)配位、〔2R,4R)配位の化合物を挙げることが
できる本発明者らは前記一般式CI)で示される本発明
化合物が優れた抗菌活性を有するペネムあるいはカルバ
ペネム化合物の重要な合成中間体として有用な化合物で
あることを見い出し本発明を完成した。The compound represented by the general formula (1) has optical isomers and stereoisomers based on the asymmetric carbon atoms at the 2- and 4-positions, and for convenience, all of these isomers are represented by a single formula. However, the scope of the present invention is not limited thereby. However, preferably (2S, 4
S) coordination and [2R,4R) coordination compounds.The present inventors have found that the compound of the present invention represented by the general formula CI) is an important synthesis of penem or carbapenem compounds having excellent antibacterial activity. The present invention was completed by discovering that the compound is useful as an intermediate.
本発明によって得られる前記一般式(1)を有する化合
物としては、例えば以下に記載する化合物を挙げること
ができる。Examples of the compound having the general formula (1) obtained by the present invention include the compounds described below.
(1)2−メチルアミノカルボニル−4−メルカプトピ
ロリジン
(2)2−エチルアミノカルボニル−4−メルカプトピ
ロリジン
(3)2−n−プロピルアミノカルボニル−4−メルカ
プトピロリジン
(4)2−イソプロピルアミノカルボニル−4−メルカ
プトピロリジン
(5)2−n−ブチルアミノカルボニル−4−メルカプ
トピロリジン
(6)2−イソブチルアミノカルボニル−4−メルカプ
トピロリジン
(7)2−ジメチルアミノカルボニル−4−メルカプト
ピロリジン
(8)2−ジエチルアミノカルボニル−4−メルカプト
ピロリジン
(9)2−ジ−n−ブチルアミノカルボニル−4−メル
カプトピロリジン
(10) 2−ジイソプロピルアミノカルボニル−4−
メルカプトピロリジン
(11) 2−ジ−n−ブチルアミノカルボニル−4−
メルカプトピロリジン
(12) 2−ジイソブチルアミノカルボニル−4−メ
ルカプトピロリジン
(13) 2−エチルメチルアミノカルボニル−4−メ
ルカブトビロリジン
(14)2−n−ブチルメチルアミノカルボニル−4−
メルカプトピロリジン
(15)2−n−ブチルエチルアミノカルボニル−4−
メルカプトピロリジン
(16) 2− (2−ヒドロキシルエチル)アミノカ
ルボニル−4−メルカプトピロリジン
(17)2−(3−ヒドロキシルプロピル)アミノカル
ボニル−4−メルカプトピロリジン
(18)2−(2−ヒドロキシルプロピル)アミノカル
ボニル−4−メルカプトピロリジン
(19)2−(2−ヒドロキシ−l−メチルエチル)ア
ミノカルボニル−4−メルカプト−ピロリジン
(20)2−(2−ジメチルアミノエチル)アミノカル
ボニル−4−メルカプトピロリジン
(21)2−(2−ジエチルアミノエチル)アミノカル
ボニル−4−メルカプトピロリジン
(22) 2− (3−ジメチルアミノプロピル)アミ
ノカルボニル−4−メルカプトピロリジン(23)
(24)
(25)
(26)
2−(3−ジエチルアミノプロピル)アミノカルボニル
−4−メルカプトピロリジン2−(2−ジメチルアミノ
エチル)エチルアミノカルボニル−4−メルカプト−ピ
ロリジン
2−(2−ジエチルアミノエチル)エチルアミノカルボ
ニル−4−メルカプト−ピロリジン
2−(2−カルバモイルメチル)アミノカルボニル−4
−メルカプトピロリジン
(27)
2−(2−カルバモイルエチル)アミノカルボニル−4
−メルカプトピロリジン
(28)
2−ベンジルアミノカルボニル−4−メルカプトピロリ
ジン
(29)
(30)
(31)
2−(2−ヒドロキシルエチル)メチルアミノカルボニ
ル−4−メルカプトピロリジン2−(2−ヒドロキシル
エチル)エチルアミノカルボニル−4−メルカプトピロ
リジン2−(2−ジメチルアミノエチル)メチルアミノ
カルボニル−4−メルカプトピロリジン32) 2−ベ
ンジルメチルアミノエルボニル−4−メルカプトピロリ
ジン
(33) 2−ベンジルエチルアミノカルボニル−4−
メルカプトピロリジン
(34)2−(1−アゼチジノ力ルボニル)−4−メル
カプトピロリジン
(35)2−(1−ピロリジノカルボニル)−4−メル
カプトピロリジン
(36)2−(1−ピペリジノカルボニル)−4−メル
カプトピロリジン
(37)2−(1−モルホリノカルボニル)−4−メル
カプトピロリジン
(38)2−(1−チオモルホリノカルボニル)−4−
メルカプトピロリジン
(39) 2− (1−N−メチルピペラジノカルボニ
ル)−4−メルカプトピロリジン
(40)2−(1−N−エチルピペラジノカルボニル)
−4−メルカプトピロリジン
本例示化合物においては前述したように立体異性体か存
在し、単一の名称であげたが、それによって何ら限定さ
れるものではない。しかしながら好適なものとして、(
2S、43)、(2R,4R)配位を有するものを挙げ
ることかできる。(1) 2-Methylaminocarbonyl-4-mercaptopyrrolidine (2) 2-ethylaminocarbonyl-4-mercaptopyrrolidine (3) 2-n-propylaminocarbonyl-4-mercaptopyrrolidine (4) 2-isopropylaminocarbonyl- 4-mercaptopyrrolidine (5) 2-n-butylaminocarbonyl-4-mercaptopyrrolidine (6) 2-isobutylaminocarbonyl-4-mercaptopyrrolidine (7) 2-dimethylaminocarbonyl-4-mercaptopyrrolidine (8) 2- Diethylaminocarbonyl-4-mercaptopyrrolidine (9) 2-di-n-butylaminocarbonyl-4-mercaptopyrrolidine (10) 2-diisopropylaminocarbonyl-4-
Mercaptopyrrolidine (11) 2-di-n-butylaminocarbonyl-4-
Mercaptopyrrolidine (12) 2-diisobutylaminocarbonyl-4-mercaptopyrrolidine (13) 2-ethylmethylaminocarbonyl-4-mercaptopyrrolidine (14) 2-n-butylmethylaminocarbonyl-4-
Mercaptopyrrolidine (15) 2-n-butylethylaminocarbonyl-4-
Mercaptopyrrolidine (16) 2-(2-hydroxylethyl)aminocarbonyl-4-mercaptopyrrolidine (17) 2-(3-hydroxylpropyl)aminocarbonyl-4-mercaptopyrrolidine (18) 2-(2-hydroxylpropyl)amino Carbonyl-4-mercaptopyrrolidine (19) 2-(2-hydroxy-l-methylethyl)aminocarbonyl-4-mercapto-pyrrolidine (20) 2-(2-dimethylaminoethyl)aminocarbonyl-4-mercaptopyrrolidine (21 ) 2-(2-diethylaminoethyl)aminocarbonyl-4-mercaptopyrrolidine (22) 2-(3-dimethylaminopropyl)aminocarbonyl-4-mercaptopyrrolidine (23) (24) (25) (26) 2-( 3-diethylaminopropyl)aminocarbonyl-4-mercaptopyrrolidine 2-(2-dimethylaminoethyl)ethylaminocarbonyl-4-mercapto-pyrrolidine 2-(2-diethylaminoethyl)ethylaminocarbonyl-4-mercapto-pyrrolidine 2-( 2-Carbamoylmethyl)aminocarbonyl-4
-Mercaptopyrrolidine (27) 2-(2-carbamoylethyl)aminocarbonyl-4
-Mercaptopyrrolidine (28) 2-benzylaminocarbonyl-4-mercaptopyrrolidine (29) (30) (31) 2-(2-hydroxylethyl)methylaminocarbonyl-4-mercaptopyrrolidine 2-(2-hydroxylethyl)ethyl Aminocarbonyl-4-mercaptopyrrolidine 2-(2-dimethylaminoethyl)methylaminocarbonyl-4-mercaptopyrrolidine 32) 2-Benzylmethylaminoerbonyl-4-mercaptopyrrolidine (33) 2-Benzylethylaminocarbonyl-4-
Mercaptopyrrolidine (34) 2-(1-azetidinocarbonyl)-4-mercaptopyrrolidine (35) 2-(1-pyrrolidinocarbonyl)-4-mercaptopyrrolidine (36) 2-(1-piperidinocarbonyl)- 4-Mercaptopyrrolidine (37) 2-(1-morpholinocarbonyl)-4-mercaptopyrrolidine (38) 2-(1-thiomorpholinocarbonyl)-4-
Mercaptopyrrolidine (39) 2-(1-N-methylpiperazinocarbonyl)-4-mercaptopyrrolidine (40) 2-(1-N-ethylpiperazinocarbonyl)
-4-Mercaptopyrrolidine As mentioned above, stereoisomers exist in this exemplified compound, and although a single name has been given, this is not intended to be limiting in any way. However, as a preferred option (
Examples include those having 2S, 43) and (2R, 4R) coordinations.
以下に本発明化合物の製造方法について詳細に述べる。The method for producing the compound of the present invention will be described in detail below.
(式中、R2、R1およびR4は前述と同し意味を、R
1はアセチル、プロピオニル、ベンゾイル、フェニルア
セチル等のアシル基、あるいはエトキシカルボニル基を
示す。)
で表されるピロリジン誘導体を加水分解反応または加溶
媒分解反応に付すことにより一般式(I)で表される2
−置換アミノカルボニル−4−メルカプトピロリジン誘
導体を製造することができる本反応は水酸化ナトリウム
、水酸化カリウム、ナトリウムメトキシド、ナトリウム
エトキシド、リチウムメトキシド、リチウムエトキシド
、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム
等の塩基の存在下で行う。(In the formula, R2, R1 and R4 have the same meanings as above, R
1 represents an acyl group such as acetyl, propionyl, benzoyl, or phenylacetyl, or an ethoxycarbonyl group. ) by subjecting the pyrrolidine derivative represented by formula (I) to a hydrolysis reaction or solvolysis reaction.
-Substituted aminocarbonyl-4-mercaptopyrrolidine derivatives can be produced by this reaction: sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, lithium methoxide, lithium ethoxide, sodium hydrogen carbonate, sodium carbonate, It is carried out in the presence of a base such as potassium carbonate.
本反応で使用する不活性溶媒としてはメタノール、エタ
ノール、アセトニトリル、テトラヒドロフラン、ジオキ
サン、アセトン、塩化メチレンなどの有機溶媒およびこ
れらの有機溶媒の混合溶媒、水、およびさきの有機溶媒
と水との混合溶媒を挙げることかできる。Inert solvents used in this reaction include organic solvents such as methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane, acetone, and methylene chloride, mixed solvents of these organic solvents, water, and mixed solvents of the aforementioned organic solvents and water. I can list the following.
反応温度は特に限定はないが、副反応を抑制するため一
20°C〜40°Cの範囲で実施することが好ましい。Although the reaction temperature is not particularly limited, it is preferably carried out within a range of -20°C to 40°C in order to suppress side reactions.
反応終了後は通常の有機化学的手法によって成績体を取
り出すことができる。例えば、反応混合物を塩酸、硫酸
、リン酸、酢酸などの酸により中和し、水と分離する有
機溶媒にて抽出、水洗の後、溶媒を留去することにより
得ることができる。After the reaction is complete, the resultant can be taken out using conventional organic chemistry techniques. For example, it can be obtained by neutralizing the reaction mixture with an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, extracting with an organic solvent that separates from water, washing with water, and then distilling off the solvent.
なお、原料のピロリジン誘導体(II)は各種の方法に
よって製造することが可能であるが、例えば以下に示す
方法によって、トランス−4−ヒドロキシ−L−プロリ
ンよを原料化合物として2S配位を有するピロリジン誘
導体(IIa)、 (IIb〕、あるいは(I[c)
を製造することができる。The raw material pyrrolidine derivative (II) can be produced by various methods, but for example, by the method shown below, pyrrolidine having a 2S coordination can be produced using trans-4-hydroxy-L-proline as a raw material compound. Derivative (IIa), (IIb] or (I[c)
can be manufactured.
(IIa)
(IIb)
(Irb)
〔式中、R3、R4およびRsは前述と同じ意味を有す
る。R1はアミノ基の保護基を示し、R7はカルボキシ
ル基の保護基を示す。〕
A工程 一般によく用いられる各種公知のアミノ酸のア
ミノ基の保護反応によって容易に達成することができ、
例えば塩基の存在下でアリールメチルオキシカルボニル
クロリド等と反応させる方法、あるいはS−アシル−4
,6−ジメチル−2−メルカプトピリミジン等を用いる
方法等を挙げることができる。(IIa) (IIb) (Irb) [wherein R3, R4 and Rs have the same meanings as above. R1 represents an amino group-protecting group, and R7 represents a carboxyl group-protecting group. ] Step A can be easily achieved by a commonly used amino group protection reaction of various known amino acids,
For example, a method of reacting with arylmethyloxycarbonyl chloride etc. in the presence of a base, or a method of reacting with S-acyl-4
, 6-dimethyl-2-mercaptopyrimidine, and the like.
B工程 カルボン酸よりエステルを得る各種の公知の方
法が可能であるが、例えば塩基の存在下でカルボン酸2
を各種のアルキルハライドあるいはアラルキルハライド
等と反応させることにより達成することができる。Step B: Various known methods for obtaining an ester from a carboxylic acid are possible; for example, in the presence of a base, a carboxylic acid
This can be achieved by reacting with various alkyl halides or aralkyl halides.
C工程 水酸基を保護されたチオール基に変換する各種
の公知方法か可能であるが、例えば水酸基の活性エステ
ル体に誘導後、チオ酢酸、チオ安息香酸、トリチルメル
カプタン等の各種のチオ化試薬と塩基存在下で反応させ
ることにより達成することができる。Step C: Various known methods are possible for converting a hydroxyl group into a protected thiol group; for example, after derivation of a hydroxyl group into an active ester form, various thiolating reagents such as thioacetic acid, thiobenzoic acid, trityl mercaptan, etc. and a base are used. This can be achieved by reacting in the presence of
また本工程はアルコール誘導体をトリフェニルホスフィ
ン、ジエチルアゾジカルボキシレートの存在下に、テト
ラヒドロフラン等の不活性溶媒中、チオ酢酸等のチオ化
試薬と反応させても得ることかできる。This step can also be obtained by reacting an alcohol derivative with a thiolating reagent such as thioacetic acid in the presence of triphenylphosphine and diethyl azodicarboxylate in an inert solvent such as tetrahydrofuran.
D工程 エステルをカルボキシル基に変換する各種公知
の方法が可能であるが、例えばアルカリ加水分解、トリ
フルオロ酢酸、臭化水素酸等を用いる酸による方法、ま
たは亜鉛を用いる還元的方法によって行うことができる
。Step D Various known methods for converting esters into carboxyl groups are possible; for example, alkaline hydrolysis, an acid method using trifluoroacetic acid, hydrobromic acid, etc., or a reductive method using zinc. can.
C工程 カルボン酸をアミド基に変換する各種の公知の
方法が可能であるが、例えばカルボン酸基をハロゲン化
剤、アシル化剤等によって、活性エステル誘導体とし、
一般式
で表されるアミンと処理する方法によって達成される。Step C Various known methods are possible for converting carboxylic acid into an amide group, but for example, converting a carboxylic acid group into an active ester derivative using a halogenating agent, an acylating agent, etc.
This is achieved by a method of treating an amine represented by the general formula.
F工程 水酸基をカルボニル基に変換する各種公知の酸
化反応が可能であるが、例えばアセトン中クロム酸−硫
酸等の酸化反応によって達成することができる。Step F Various known oxidation reactions for converting hydroxyl groups into carbonyl groups are possible, and this can be achieved, for example, by oxidation reactions such as chromic acid-sulfuric acid in acetone.
C工程 カルボニル基を水酸基に変換する各種公知の還
元反応が可能であるが、例えば水素化ホウ素ナトリウム
等で処理することにより化合物見とユの水酸基の立体が
異なる化合物見の混合物を得ることができる。Step C Various known reduction reactions for converting carbonyl groups into hydroxyl groups are possible, but for example, by treating with sodium borohydride etc., a mixture of compounds with different steric hydroxyl groups can be obtained. .
なお、之と旦の生成比は条件によって異なるか、それぞ
れの化合物は再結晶、クロマトグラフィー等の精製によ
り単一化合物として得ることができる。Incidentally, the production ratio of these and tanning differs depending on the conditions, or each compound can be obtained as a single compound by purification such as recrystallization or chromatography.
4位水酸基の異性化は上記FおよびC工程を経て達成す
ることができるか、次に述べるHおよび■工程を経る方
法によっても達成することかできる。Isomerization of the hydroxyl group at the 4-position can be achieved through the steps F and C described above, or it can also be achieved through the steps H and (2) described below.
H・■工程 アルコール誘導体をトリフェニルホスフィ
ン、ジエチルアゾジカルボキシレートの存在下に、テト
ラヒドロフラン等の不活性溶媒中でギ酸と反応させホル
ミルオキシ誘導体世とした後、アルカリ加水分解等の方
法により、ホルミル基をを除去することによって達成す
ることかできるJ工程 一般によく用いられる各種公知
のアミン基の脱保護法が可能であるが、例えばトリフル
オロ酢酸や臭化水素酸等の酸を用いる方法、亜鉛やりチ
ウム−液体アンモニア等を用いる還元的方法、あるいは
接触還元等によって達成することができる。H・■Step The alcohol derivative is reacted with formic acid in an inert solvent such as tetrahydrofuran in the presence of triphenylphosphine and diethyl azodicarboxylate to form a formyloxy derivative, and then formyloxy derivative is obtained by a method such as alkaline hydrolysis. J step can be achieved by removing the group. Various commonly used and well-known deprotection methods for amine groups are possible, such as methods using acids such as trifluoroacetic acid or hydrobromic acid, This can be achieved by a reductive method using halium-liquid ammonia or the like, or by catalytic reduction.
また2R体のピロリジン誘導体(II)の製造にあたっ
ては原料化合物としてシス−4−ヒドロキシ−D−プロ
リンを用いる前述の2S体の製造法に準じて、すなわち
、23体の製造で述べた諸反応を組合せることによって
製造することかできる以上の方法で得られた本発明の化
合物CI)は下記の反応式に示す方法により、優れた抗
菌活性を有するペネム、あるいはカルバペネム化合物に
〔式中、R,、R,、R,およびR1は前述と同じ意味
を有する。R1は水酸基の保護基を示す。In addition, the production of the 2R-form pyrrolidine derivative (II) was carried out in accordance with the method for producing the 2S-form described above using cis-4-hydroxy-D-proline as a raw material, that is, the various reactions described in the production of the 23-form were carried out. The compound CI) of the present invention obtained by the above methods can be produced by combining penem or carbapenem compounds with excellent antibacterial activity by the method shown in the reaction formula below [in the formula, R, , R, , R, and R1 have the same meaning as above. R1 represents a hydroxyl protecting group.
〕 次に実施例、参考例をあげて本発明をさらに具体的
に説明するが、本発明はもちろんこれらによって何ら限
定されるものではない。] Next, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is of course not limited to these in any way.
なお以下の実施例および参考例で用いた略号の意味は次
のとおりである。The meanings of the abbreviations used in the following Examples and Reference Examples are as follows.
PNZ : p−ニトロベンジルオキシカルボニル
基PMZ : I) −メトキシベンジルオキ
ン力ルポニル基PMB : p−メトキシベンジル基
PNB : p−二トロベンジル基
Ph :フェニル基
AC=アセチル基
tBu:t−ブチル基
Me =メチル基
Et :エチル基
参考例1−1
PNZ
トランス−4−ヒドロキシ−L−プロリン(6゜55g
)、トリエチルアミン(7,51dりを水(15yrt
l)に溶解させ、これに室温で5−p−二トロペンジル
オキシカルボニル−4,6−ジメチル−2−メルカプト
ピリミジン(15,95g)のジオキサン(35rnI
)溶液を滴下し、そのまま室温で1.5時間攪拌し、−
夜装置した。反応液に水冷下2N−水酸化ナトリウム(
3Lxj’)を加えエーテルで抽出、エーテル層をIN
−水酸化ナトリウム(20−)で洗浄後アルカリ水層を
合わせ、2N−塩酸水(100rd)を用いて酸性とし
、これを酢酸エチルで抽出した。酢酸エチル層を2N−
塩酸水で順次洗浄し、芒硝乾燥、溶媒留去し、得られる
粗結晶を酢酸エチルでリパルプ精製してトランス1−(
p−二トロペンジルオキシカルボニル〉−4−ヒドロキ
シ−L−プロリンを得た。PNZ: p-nitrobenzyloxycarbonyl group PMZ: I) -methoxybenzyloxycarbonyl group PMB: p-methoxybenzyl group PNB: p-nitrobenzyl group Ph: phenyl group AC=acetyl group tBu: t-butyl group Me =Methyl group Et: Ethyl group Reference example 1-1 PNZ trans-4-hydroxy-L-proline (6°55g
), triethylamine (7,51d) and water (15yrt
5-p-nitropenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (15.95 g) was dissolved in dioxane (35 rnI
) solution was added dropwise and stirred at room temperature for 1.5 hours, -
I installed it at night. Add 2N-sodium hydroxide (
Add 3Lxj') and extract with ether, IN the ether layer
- After washing with sodium hydroxide (20-), the alkaline aqueous layers were combined, acidified using 2N-hydrochloric acid (100rd), and extracted with ethyl acetate. The ethyl acetate layer was diluted with 2N-
The crude crystals obtained were washed successively with hydrochloric acid, dried with sodium sulfate, and the solvent was distilled off. The resulting crude crystals were purified by repulping with ethyl acetate to obtain trans
p-Nitropenzyloxycarbonyl>-4-hydroxy-L-proline was obtained.
m、p、 134.3〜135.5℃IR,,,cm
−’(Nujol): 3300(br)、 1738
.1660゜16α5.1520.1340.1205
゜1172、1070.965
参考例1−2
トランス−1−(p−ニトロベンジルオキシカルボニル
)−4−ヒドロキシ−L−プロリン(15、Og))リ
エチルアミン(13,5J)を乾燥ジメチルホルムアミ
ド(150rILl)に溶解させ、窒素気流下、p−メ
トキシベンジルクロリド(12,66m1)を滴下し、
70℃で10時間攪拌した。反応液を酢酸エチル(50
0rd)で希釈し、水洗、芒硝乾燥、溶媒留去し、残渣
をエーテルから結晶化しトランス−1−(p−ニトロベ
ンジルオキシカルボニル)−4−ヒドロキシ−L−プロ
リン−p−メトキシベンジルエステルを得た。m, p, 134.3-135.5℃IR,,,cm
-' (Nujol): 3300 (br), 1738
.. 1660°16α5.1520.1340.1205
゜1172, 1070.965 Reference Example 1-2 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline (15, Og)) ethylamine (13,5J) was dissolved in dry dimethylformamide (150rILl) ), p-methoxybenzyl chloride (12.66ml) was added dropwise under a nitrogen stream,
The mixture was stirred at 70°C for 10 hours. The reaction solution was diluted with ethyl acetate (50
The residue was crystallized from ether to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline-p-methoxybenzyl ester. Ta.
m、p、 83〜85°C
IR,、、cr’(film) : 3430.173
5.1705.1510゜1340、1245.116
0
参考例1−3
トランス−1−(p−ニトロベンジルオキシカルボニル
)−4−ヒドロキシ−し−プロリン−p−メトキシベン
ジルエステル(8,6g) 、トリフェニルホスフィン
(7,86g)を乾燥テトラヒドロフラン(201nl
)に溶解し、水冷、窒素気流下、ジエチルアゾジカーボ
ネー) (5,22g)の乾燥テトラヒドロフラン(5
−)溶液を滴下しそのままで30分間攪拌した後、チオ
酢酸(2,28g)を滴下し、水冷下1時間、その後室
温で3時間攪拌し、反応液を濃縮。残渣をシリカゲルカ
ラムクロマトグラフィーに付し、シス−1−(p−ニト
ロベンジルオキシカルボニル)−4−アセチルチオ−L
−プロリン−p−メトキシベンジルエステル得た。m, p, 83-85°C IR,, cr' (film): 3430.173
5.1705.1510°1340, 1245.116
0 Reference Example 1-3 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-proline-p-methoxybenzyl ester (8.6 g) and triphenylphosphine (7.86 g) were dissolved in dry tetrahydrofuran ( 201nl
) in dry tetrahydrofuran (5.22 g) and cooled in water under a nitrogen stream.
-) The solution was added dropwise and stirred for 30 minutes, then thioacetic acid (2.28 g) was added dropwise, stirred for 1 hour under water cooling, then stirred at room temperature for 3 hours, and the reaction solution was concentrated. The residue was subjected to silica gel column chromatography to give cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L
-Proline-p-methoxybenzyl ester was obtained.
[R,、、cr’(film) : 1740(sh)
、 1715.1520゜1405、 1348. 1
12O
MR
δ(CDC1,)
: 2.31(3H,S)、3.79(3H,s)、
5、10(28,s)、5.24(2H,s)、7.4
9(2H,d、J=9.0Hz)、8.18(2H,d
、J=9.0Hz)参考例1−4
シス−1−(p−ニトロベンジルオキシカルボニル)−
4−アセチルチオ−L−プロリン−p−メトキシベンジ
ルエステル(9,76g) 、アニソール(4,32g
)をトリフロロ酢酸(35rILl)とともに30分室
温で攪拌。減圧下濃縮し残渣をシリカゲルカラムクロマ
トグラフィーに付し、シス−1−(p−ニトロベンジル
オキシカルボニル)−4−アセチルチオ−L−プロリン
を得た。[R,,,cr'(film): 1740(sh)
, 1715.1520°1405, 1348. 1
12O MR δ (CDC1,): 2.31 (3H, S), 3.79 (3H, s),
5, 10 (28, s), 5.24 (2H, s), 7.4
9 (2H, d, J = 9.0Hz), 8.18 (2H, d
, J=9.0Hz) Reference Example 1-4 cis-1-(p-nitrobenzyloxycarbonyl)-
4-acetylthio-L-proline-p-methoxybenzyl ester (9.76g), anisole (4.32g)
) was stirred with trifluoroacetic acid (35rILl) for 30 minutes at room temperature. The residue was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline.
m、p、 107〜109℃
IR,、、cm−’(Nujol) :1725.16
85.1660(sh)。m, p, 107-109°C IR,, cm-' (Nujol): 1725.16
85.1660 (sh).
1340、1180.1110
参考例1−5
ニル)−4−アセチルチオ−L−プロリン(180■)
を乾燥テトラヒドロフラン(2rd)にとかし、ジメチ
ルアミン塩酸塩(48■)、N、N−ジメチルアミンピ
リジン(78■)、ジシクロへキシルカルボジイミド(
152■)を順次加え、−夜攪拌した。不溶物を濾去し
、濾液を酢酸エチルで希釈し、希塩酸、水で順次洗浄し
、芒硝乾燥、溶媒留去し、残渣を、シリカゲルクロマト
グラフィーに付しく2S、4S)−1−(p−ニトロベ
ンジルオキシカルボニル)−2−ジメチルアミノカルボ
ニル−4−アセチルチオピロリジンを得た。1340, 1180.1110 Reference Example 1-5 Nyl)-4-acetylthio-L-proline (180■)
was dissolved in dry tetrahydrofuran (2rd), dimethylamine hydrochloride (48■), N,N-dimethylaminepyridine (78■), dicyclohexylcarbodiimide (
152■) were added one after another, and the mixture was stirred overnight. Insoluble materials were removed by filtration, the filtrate was diluted with ethyl acetate, washed successively with dilute hydrochloric acid and water, dried with sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography to obtain 2S, 4S)-1-(p- Nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine was obtained.
[R,、、cm−’(film) : 1705.16
50. 1515. 1400゜1340、 11l1
05N δ(CDCIs) : 2.32(3H
,s)、2.97(3H,s)、3、11(3H,S)
、5.21(2B、 s)、8、18(2H,d、 J
=8.5Hz)(α) !’+ 5.21 ’ (c
=0.379 Tセ) ン)以下参考例1−5と同様に
して各々対応するアミンを用いて以下のチオアセテート
を得た。[R,, cm-' (film): 1705.16
50. 1515. 1400°1340, 11l1 05N δ (CDCIs): 2.32 (3H
, s), 2.97 (3H, s), 3, 11 (3H, S)
, 5.21 (2B, s), 8, 18 (2H, d, J
=8.5Hz)(α)! '+5.21' (c
=0.379 T sen) The following thioacetates were obtained in the same manner as in Reference Example 1-5 using the corresponding amines.
参考例2−1
オキザリルクロリド(0,2ml>の乾燥塩化メチレン
(5−)溶液に−60〜−70’Cでジメチルスルホキ
シド(0,35m1)の乾燥塩化メチレン溶液(1−)
に滴下し、10分後、トランス−1−(p−ニトロベン
ジルオキシカルボニル)−4−ヒドロキシ−L−プロリ
ン p−メトキシベンジルエステル(860■)の乾燥
塩化メチレン溶液(10m0を一50°C以下で滴下し
、05分間攪拌した。次にトリエチルアミン(1,01
g)を滴下し、室温まで加温、塩化メチレンで希釈し、
希塩酸水で洗浄し、芒硝乾燥、溶媒留去、残渣をシリカ
ゲルカラムクロマトグラフィーに付し、1−(pニトロ
ベンジルオキシカルボニル)−4−オキソ−L−プロリ
ン p−メトキシベンジルエステル
rR,、、cm−’(film): 1762. 1
740. 1710. 1512゜1345、 124
5. 1155
NMRδ(CDC12) : 3.78(3H
,s)、3.95(2H,s)、5.08(2H,s)
、6.85(2H,d、 J=9H2)、8.12(2
H,d、J=9H2)参考例2−2
NZ
1−(p−ニトロベンジルオキシカルボニル)−4−オ
キソ−L−プロリン p−メトキシベンジルエステル(
650■)をエタノール(45mj’)にとかし、室温
で、水素化ホウ素ナトリウム(86■)を2回にわけて
加える。30分後、300以下で減圧濃縮し、濃縮液を
酢酸エチルで希釈し、水洗、芒硝乾燥、溶媒留去後、残
渣をシリカゲルカラムクロマトグラフィーに付し、シス
−l−<p−ニトロベンジルオキシカルボニル)−4−
ヒドロキシ−L−プロリン p−メトキシベンジルエス
テルとトランス−1−(p−ニトロベンジルオキシカル
ボニル)−4−ヒドロキシ−L−プリン p−メトキシ
ベンジルエステルを得た。Reference Example 2-1 Oxalyl chloride (0.2 ml) in dry methylene chloride (5-) solution at -60 to -70'C dimethyl sulfoxide (0.35 ml) in dry methylene chloride solution (1-)
After 10 minutes, a dry methylene chloride solution of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester (860 μm) was added dropwise to and stirred for 05 minutes.Next, triethylamine (1,01
g) was added dropwise, warmed to room temperature, diluted with methylene chloride,
Washing with dilute hydrochloric acid water, drying with Glauber's salt, evaporation of the solvent, and subjecting the residue to silica gel column chromatography to obtain 1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline p-methoxybenzyl ester rR,, cm -'(film): 1762. 1
740. 1710. 1512°1345, 124
5. 1155 NMRδ (CDC12): 3.78 (3H
, s), 3.95 (2H, s), 5.08 (2H, s)
, 6.85 (2H, d, J=9H2), 8.12 (2
H, d, J = 9H2) Reference Example 2-2 NZ 1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline p-methoxybenzyl ester (
650 ■) in ethanol (45 mj'), and sodium borohydride (86 ■) was added in two portions at room temperature. After 30 minutes, it was concentrated under reduced pressure below 300℃, the concentrated solution was diluted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off.The residue was subjected to silica gel column chromatography to obtain cis-l- carbonyl)-4-
Hydroxy-L-proline p-methoxybenzyl ester and trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-purine p-methoxybenzyl ester were obtained.
トランス体: IR,NMRは参考例1−2の化合物の
スペクトルデータと一致し
た。Trans form: IR and NMR were consistent with the spectral data of the compound of Reference Example 1-2.
シス体: [R,、、Cm−’(film): 340
0(br)、 1725゜1515、1405.135
0. 1250゜1170、112O
NMRδ(CDCIg) : 3.78(3H,s)
、5、08(2)(、s)、6.82(2H,d、 J
=9Hz)、 8.12(2)1.d、J=9Hz)参
考例2−3
シス−1−(p−ニトロベンジルオキシカルボニル)−
4−ヒドロキシ−L−プロリン p−メトキシベンジル
エステル(610■)ヲ用いて、参考例1−3および1
−4と同様の方法によりトランス−1−(p−ニトロベ
ンジルオキシカルボニル)−4−アセチルチオ−L−プ
ロリンを得たILax cm−’(f+1m)
NMR
δ(CDC13)
:〜3000. 1700. +515. 1430
1400、 1345. 1205. 1165:
2.32(3H,S)、5.20(2H,br。Cis form: [R,,, Cm-' (film): 340
0(br), 1725°1515, 1405.135
0. 1250°1170, 112O NMRδ (CDCIg): 3.78 (3H, s)
,5,08(2)(,s),6.82(2H,d,J
=9Hz), 8.12(2)1. d, J=9Hz) Reference Example 2-3 cis-1-(p-nitrobenzyloxycarbonyl)-
Reference Examples 1-3 and 1 were prepared using 4-hydroxy-L-proline p-methoxybenzyl ester (610).
ILax cm-' (f+1m) NMR δ (CDC13): ~3000. 1700. +515. 1430
1400, 1345. 1205. 1165:
2.32 (3H, S), 5.20 (2H, br.
S)、7.’ 42(2H,d、 J=9Hz)、8.
12(2H,d、J=9Hz)
参考例3−1
シス−4−ヒドロキシ−D−プロリンより参考例1−1
および1−2と同様の方法により得たシス−1−p−ニ
トロペンジル才キシカルボニルー4−ヒドロキシ−D−
プロリン−p−メトキシベンジルエステル(166■)
と、トリフェニルホスフィン(202■)を乾燥テトラ
ヒドロフラン(1,5mt’)にとかし、次にギ酸(2
7■)を加える。さらにジエチルアゾジカーボネー)(
134■)を室温窒素気流下で加え、30分攪拌後、溶
媒留去。残渣をシリカゲルクロマトグラフィーで精製し
、トランス−1−p−ニトロベンジルオキシカルボニル
−4−ホルミルオキシ−D−プロリン−p−メトキシベ
ンジルエステルを得た。S), 7. '42 (2H, d, J=9Hz), 8.
12 (2H, d, J=9Hz) Reference example 3-1 Reference example 1-1 from cis-4-hydroxy-D-proline
and cis-1-p-nitropenzyloxycarbonyl-4-hydroxy-D- obtained by the same method as 1-2.
Proline-p-methoxybenzyl ester (166■)
and triphenylphosphine (202 ■) were dissolved in dry tetrahydrofuran (1,5 mt'), then formic acid (2
Add 7■). Furthermore, diethyl azodicarbonate) (
134■) was added at room temperature under a nitrogen stream, and after stirring for 30 minutes, the solvent was distilled off. The residue was purified by silica gel chromatography to obtain trans-1-p-nitrobenzyloxycarbonyl-4-formyloxy-D-proline-p-methoxybenzyl ester.
IR=、、 am−’(film) : 1720.1
515.1402.1342゜1245、1165.1
120゜
NMRδ(CDCh) : 3.76(3H,s)
、4.50(2H,t、 J雰8Hz)、5.08(2
8,s)、
5、15(2H,ABq、 J=16Hz)、5.41
(IH,m)、7.97(IH,s)参考例3−2
NZ
NZ
トランス−t−p−二トロペンジルオキシ力ルボニルー
4−ホルミルオキシ〜D−プロリンーp−メトキシベン
ジルエステル(215■)をテトラヒドロフラン(1,
1d)にとかし、I N −Na0H(0,93d )
を加え、10分攪拌後、酢酸エチルで希釈し、飽和食塩
水で洗浄。芒硝乾燥後溶媒留去。残渣を薄層クロマトグ
ラフィーで精製し、トランス−t−p−ニトロベンジル
オキシカルボニル−4−ヒドロキシ−D−プロリン−p
−メトキシベンジルエステルを得た。IR=,, am-'(film): 1720.1
515.1402.1342゜1245, 1165.1
120°NMRδ (CDCh): 3.76 (3H, s)
, 4.50 (2H, t, J atmosphere 8Hz), 5.08 (2
8, s), 5, 15 (2H, ABq, J=16Hz), 5.41
(IH, m), 7.97 (IH, s) Reference Example 3-2 NZ NZ trans-t-p-nitropenzyloxy carbonyl-4-formyloxy-D-proline-p-methoxybenzyl ester (215 ) to tetrahydrofuran (1,
1d), I N -Na0H (0,93d)
After stirring for 10 minutes, the mixture was diluted with ethyl acetate and washed with saturated brine. After drying the Glauber's salt, the solvent was distilled off. The residue was purified by thin layer chromatography to give trans-t-p-nitrobenzyloxycarbonyl-4-hydroxy-D-proline-p
-Methoxybenzyl ester was obtained.
[R,、、cm−’(film) : 3425(br
)、 1735.1705゜1510、1400.13
40.1240゜162
NMRδ(CDCIg) : 2.33(2H,m
)、3、58(2H,d、 J=3.5Hz)、3、7
3(3H,s)、5.03(2H,s)、5、07(2
H,ABq、 J=18Hz)、6、73(2H,d、
J=9)1z)、6、77(2H,d、 J=9)1
z)、8、00(2H,d、 J=8.5Hz)、8.
07(2H,d、J=8.5Hz)参考例4−1
トランス−t−p−ニトロベンジルオキシカルボニル−
4−ヒドロキシニL−プロリン(500■)とp−ニト
ロベンジルプロミド(383■)を用い、参考例1−2
と同様の方法によりトランス−1−p−二トロベンジル
オキシカルボニル−4−ヒドロキシ−L−プロリン−p
−ニトロベンジルエステルを得た。[R,, cm-' (film): 3425 (br
), 1735.1705°1510, 1400.13
40.1240°162 NMRδ (CDCIg): 2.33 (2H, m
), 3, 58 (2H, d, J=3.5Hz), 3, 7
3 (3H, s), 5.03 (2H, s), 5, 07 (2
H,ABq, J=18Hz), 6,73(2H,d,
J=9)1z), 6, 77(2H,d, J=9)1
z), 8, 00 (2H, d, J=8.5Hz), 8.
07 (2H, d, J=8.5Hz) Reference example 4-1 trans-t-p-nitrobenzyloxycarbonyl-
Reference Example 1-2 using 4-hydroxydi-L-proline (500 ■) and p-nitrobenzyl bromide (383 ■)
trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-L-proline-p by the same method as
-Nitrobenzyl ester was obtained.
rR,、lIcm−’(CHC1*): 3380(b
r)、 1750.1705゜1520、1425.1
400.1342゜16O
NMRδ(CDCIs) + 2.20(3H,m
)、3.67(2H,d、J=3Hz)、4.60(2
H,t、 J=8Hz)、5、15(2H,s)、5.
23(2H,ABq)、7.47(4H,d、 J=8
.5Hz)、8、15(4H,d、 J=8.5Hz)
参考例4−2
トランス−t−p−ニトロベンジルオキシカルボニル−
4−ヒドロキシ−L−プロリン−p−ニトロベンジルエ
ステルを参考例1−3および実施例1と同様の方法によ
りシス−1−p−ニトロベンジルオキシカルボニル−4
−メルカプト−L−プロリン−p−ニトロベンジルエス
テルを得た。rR,,lIcm-'(CHC1*): 3380(b
r), 1750.1705°1520, 1425.1
400.1342゜16O NMRδ (CDCIs) + 2.20 (3H, m
), 3.67 (2H, d, J = 3Hz), 4.60 (2
H, t, J=8Hz), 5, 15 (2H, s), 5.
23 (2H, ABq), 7.47 (4H, d, J=8
.. 5Hz), 8, 15 (4H, d, J=8.5Hz)
Reference Example 4-2 Trans-t-p-nitrobenzyloxycarbonyl-
4-Hydroxy-L-proline-p-nitrobenzyl ester was converted to cis-1-p-nitrobenzyloxycarbonyl-4 in the same manner as in Reference Example 1-3 and Example 1.
-Mercapto-L-proline-p-nitrobenzyl ester was obtained.
IR,、、cm−’(film) : 1700.16
85.1600.1510゜1430、1400.13
40.1105参考例4−3
a) シス−t−p−ニトロベンジルオキシカルボニル
−4−メルカプト−L−7’ロリン−p−ニトロベンジ
ルエステル(115■)を乾燥テトラヒドロフラン(3
−)にとかし、トリエチルアミン(30■)を加えた後
、水冷下クロルギ酸エチル(28,5■)を滴下し、1
0分間攪拌後、酢酸エチルで希釈し、希塩酸、水で順次
洗浄し、芒硝乾燥。溶媒留去し、シス−1−p−ニトロ
ベンジルオキシカルボニル−4−エトキシカルボニルチ
オ−L−プロリン−p−ニトロベンジルエステル(13
3■)を得た。IR,, cm-' (film): 1700.16
85.1600.1510°1430, 1400.13
40.1105 Reference Example 4-3 a) Cis-t-p-nitrobenzyloxycarbonyl-4-mercapto-L-7'loline-p-nitrobenzyl ester (115) was dissolved in dry tetrahydrofuran (3
-), added triethylamine (30 µ), and added dropwise ethyl chloroformate (28,5 µ) under water cooling.
After stirring for 0 minutes, dilute with ethyl acetate, wash sequentially with dilute hydrochloric acid and water, and dry with sodium sulfate. The solvent was evaporated and cis-1-p-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline-p-nitrobenzyl ester (13
3■) was obtained.
IR,、、cm−’(film) : 1755.17
10.1610.1525゜1405、1350.11
60.1015゜50
b)上記a)で得たエステル誘導体(133■)をテト
ラヒドロフラン−水(1: 1)混液(5−)にとかし
、I N−NaOH(0,26rIdl)を加え、室温
で2.5時間攪拌後、I N −MCI (0,3−)
加え、酢酸エチルで抽出水洗、芒硝乾燥後、溶媒留去。IR,, cm-' (film): 1755.17
10.1610.1525°1405, 1350.11
60.1015゜50 b) Dissolve the ester derivative (133■) obtained in a) above in a tetrahydrofuran-water (1:1) mixture (5-), add IN-NaOH (0.26rIdl), and stir at room temperature. After stirring for 2.5 hours, I N -MCI (0,3-)
Then, extract with ethyl acetate, wash with water, dry with sodium sulfate, and evaporate the solvent.
残渣をシリカゲル薄層クロマトグラフィーに付しシス−
1−p−ニトロベンジルオキシカルボニル−4−エトキ
シカルボニルチオ−L−プロリンを得た。The residue was subjected to silica gel thin layer chromatography.
1-p-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline was obtained.
IR,、、cr’(film) : 1700.152
0.1400.1340゜1165、1145
NMRδ(CDCIg) : 1.30(3H,t
、 J=7Hz)、4、28(2H,q、 J=7H2
)、5、24(2H,s)、
7、50(2H,d、 J=9Hz)、8、17(2H
,d、 J=9Hz)
参考例4−4
シス−1−p−ニトロベンジルオキシカルボニル−4−
エトキシカルボニルチオ−L−プロリン(72■)を乾
燥テトラヒドロフラン(3−)にとかし、トリエチルア
ミン(40■〉を加えた後、水冷下、クロルギ酸エチル
(41■)を滴下し15分攪拌後、メチルアミン(40
%)水溶液(1,5mN)を滴下し、更に15分攪拌。IR,,,cr'(film): 1700.152
0.1400.1340°1165, 1145 NMRδ (CDCIg): 1.30 (3H, t
, J=7Hz), 4, 28(2H,q, J=7H2
), 5, 24 (2H, s), 7, 50 (2H, d, J=9Hz), 8, 17 (2H
, d, J=9Hz) Reference Example 4-4 Cis-1-p-nitrobenzyloxycarbonyl-4-
Ethoxycarbonylthio-L-proline (72■) was dissolved in dry tetrahydrofuran (3-), triethylamine (40■) was added, ethyl chloroformate (41■) was added dropwise under water cooling, and after stirring for 15 minutes, methyl Amine (40
%) aqueous solution (1.5 mN) was added dropwise and stirred for an additional 15 minutes.
反応液を酢酸エチルで希釈し、希塩酸、水で洗浄し芒硝
乾燥。溶媒留去し、(2S、4S)−1−p−ニトロベ
ンジルオキシカルボニル−2−メチルアミノカルボニル
−4−エトキシカルボニルチオピロリジンを得た。The reaction solution was diluted with ethyl acetate, washed with dilute hydrochloric acid and water, and dried with mirabilite. The solvent was distilled off to obtain (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-methylaminocarbonyl-4-ethoxycarbonylthiopyrrolidine.
[R,、、am−’(Nujol): 3290.17
05.1660.1520゜1425、 口05.1
345.1180゜160
: 1.30(3H,t、J−8H2)、2、80(3
H,d、 J=5H2)、4、27(2H,q、 J=
8Hz)、5、22(2H,S)、
7、48(2H,d、 J=9H2)、8、18(2H
,d、 Jf9Hz)
以下参考例4−4と同様にして各々対応するアミンを用
いて、以下のチオカーボネートを得゛た。[R,,,am-'(Nujol): 3290.17
05.1660.1520°1425, 口05.1
345.1180°160: 1.30 (3H, t, J-8H2), 2, 80 (3
H, d, J=5H2), 4, 27(2H, q, J=
8Hz), 5, 22 (2H, S), 7, 48 (2H, d, J=9H2), 8, 18 (2H
, d, Jf9Hz) The following thiocarbonates were obtained in the same manner as in Reference Example 4-4 using the corresponding amines.
NMRδ(CDCIg)
参考例5
a)トランス−4−ヒドロキシ−L−プロリン(10g
)と5−p−メトキシベンジルオキシカルボニル−4,
6−ジメチル−2−メルカプトピリミジン(23,2g
)を用い、参考例1−1と同様の方法によりトランス−
1−(p−メトキシベンジルオキシカルボニル)−4−
ヒドロキシ−L−プロリンを得た。NMRδ (CDCIg) Reference Example 5 a) Trans-4-hydroxy-L-proline (10g
) and 5-p-methoxybenzyloxycarbonyl-4,
6-dimethyl-2-mercaptopyrimidine (23.2g
) in the same manner as in Reference Example 1-1.
1-(p-methoxybenzyloxycarbonyl)-4-
Hydroxy-L-proline was obtained.
IR,、、Cm−’(film)
: 3400(br)、 1692. 1430゜
1355、 1245. 1170. 1122:
2.23(2H,m)、3.73(3H,s)、5、0
0(2H,S)、6.78(2H,d、 J=9Hz)
、7.20(2H,d、 J=9Hz)で得たプロリン
誘導体(0,57g)とNMRδ(CDCh)
b)
上記
a)
ベンジルアミン(0,215g)を用い、参考例2−1
と同様の方法によりトランス−1−p−メトキシベンジ
ルオキシカルボニル−4−ヒドロキシ−L−ベンジルプ
ロリンアミドを得た。IR,,,Cm-'(film): 3400(br), 1692. 1430°1355, 1245. 1170. 1122:
2.23 (2H, m), 3.73 (3H, s), 5, 0
0 (2H, S), 6.78 (2H, d, J=9Hz)
, 7.20 (2H, d, J=9Hz) and NMR δ (CDCh) b) Using the above a) benzylamine (0,215 g), Reference Example 2-1
Trans-1-p-methoxybenzyloxycarbonyl-4-hydroxy-L-benzylprolinamide was obtained in the same manner as above.
[R−、、cm−’(Nujol): 3375.33
00.1665. 1248゜1165、 1120.
1010
25Nδ(CDCI2) : 3.76(3H,s
)、4.35(4N、 m)、4.96(2H,s)、
6.79(2H,d、 J=9Hz)、7.20(5H
,5)
C)上記b)で得たベンジルプロリンアミド(0,5g
)を用い、参考例1−3と同様の方法により(2S、4
S)−1−p−メトキシベンジルオキシカルボニル−2
−ベンジルアミノカルボニル−4−アセチルチオピロリ
ジンを得た。[R-,, cm-' (Nujol): 3375.33
00.1665. 1248°1165, 1120.
1010 25Nδ (CDCI2): 3.76 (3H,s
), 4.35 (4N, m), 4.96 (2H, s),
6.79 (2H, d, J=9Hz), 7.20 (5H
,5) C) Benzylprolinamide obtained in b) above (0.5g
) and in the same manner as in Reference Example 1-3 (2S, 4
S)-1-p-methoxybenzyloxycarbonyl-2
-Benzylaminocarbonyl-4-acetylthiopyrrolidine was obtained.
IR,、、cm−’(Nujol): 3280.16
90.1675.124ONMRδ(CDCI3)
: 2.27(3H,s)、3.82(3H,s)、
4、42(2H,d、 J=6Hz)、5、05(2H
,S)、6.87(2H,d、 J=8H2)、7.2
3(2M、 d、 J=8H2)、7、28(5H,s
)
実施例1
(2S、4S)−1−(p−ニトロベンジルオキシカル
ボニル)−2−ジメチルアミノカルボニル−4−アセチ
ルチオピロリジン(40■)をメタノール(4ml)に
とかし、I N−NaOH(0,1d)を室温15分U
!攪拌した。その後lN−1(C1(0,11mj’)
を加え、減圧下濃縮。濃縮液を酢酸エチルで希釈し、水
洗、芒硝乾燥後、溶媒留去しく2S、4S)−1−(p
−ニトロベンジルオキシカルボニル)−2−ジメチルア
ミノカルボニル−4−メルカプトピロリジンを得た。IR,, cm-' (Nujol): 3280.16
90.1675.124ONMRδ(CDCI3)
: 2.27 (3H, s), 3.82 (3H, s),
4, 42 (2H, d, J=6Hz), 5, 05 (2H
, S), 6.87 (2H, d, J=8H2), 7.2
3 (2M, d, J=8H2), 7, 28 (5H, s
) Example 1 (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine (40 ml) was dissolved in methanol (4 ml), and IN-NaOH (0 , 1d) at room temperature for 15 minutes
! Stirred. Then lN-1(C1(0,11mj')
and concentrated under reduced pressure. The concentrated solution was diluted with ethyl acetate, washed with water, dried with mirabilite, and the solvent was distilled off to give 2S, 4S)-1-(p
-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained.
IR,、、cm””(film) + 1705.16
50. 1515.1400゜1340、1165.1
1l1
05Nδ(CDC1*) : 1.90(IH,d
、、I’8Hz)、2、97(3H,S)、3.08(
3H,S)、5、19(2)1. S)、7.48(2
H,d、 J=9H2)、8.15(2H,d、 J=
9H2)実施例2
a)トランス−1−(p−ニトロベンジルオキシカルボ
ニル)−4−アセチルチオ−L−プロリン(180■)
を用い、参考例1−5と同様の方法により(2S、4R
]−1−Cp−ニトロベンジルオキシカルボニル)−2
−ジメチルアミノカJv。IR,, cm"" (film) + 1705.16
50. 1515.1400°1340, 1165.1
1l1 05Nδ (CDC1*): 1.90 (IH, d
,,I'8Hz), 2,97(3H,S), 3.08(
3H,S), 5, 19(2)1. S), 7.48 (2
H, d, J=9H2), 8.15(2H, d, J=
9H2) Example 2 a) trans-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline (180■)
(2S, 4R
]-1-Cp-nitrobenzyloxycarbonyl)-2
-Dimethylaminoka Jv.
ボニル−4−アセチルチオピロリジン(100■)を得
た。Bonyl-4-acetylthiopyrrolidine (100 .mu.) was obtained.
IR,、、cm−’(film) : 1700.16
55.1515.1400゜1340、 1115
〔α〕色’+ 32.8°(c =0.375 、アセ
トン)b)上記a)で得たチオアセテート誘導体(80
■)を実施例1と同様の方法により(23,4R)−1
−(p−ニトロベンジルオキシカルボニル)−2−ジメ
チルアミノカルボニル−4−メルカプトピロリジンを得
た。IR,, cm-' (film): 1700.16
55.1515.1400°1340, 1115 [α] Color' + 32.8° (c = 0.375, acetone) b) Thioacetate derivative obtained in a) above (80
(23,4R)-1 by the same method as in Example 1.
-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained.
[R,、、cm−’(film) : 1700. 1
650. 1510.1420゜MR
δ(CDC12’)
1400、 1340. 1120
: 1.77(lH,d、J=7H2)、2、97C
3H,S)、3.16(3)(、S)、5、22(2H
,S’)、
8、16(2H,d、 J:8.5Hz)実施例3
a)トランス−1−p−二トロベンジルオ牛ジカルボニ
ルー4−ヒドロキシ−D−プロリン−p−メトキシベン
ジルエステル(110■)を用い、参考例1−3 、
1−4および1−5と同様の方法により(2R,4R)
−t−p−ニトロベンジルオキシカルボニル−2−ジメ
チルアミノカルボニル−4−アセチルチオピロリジンを
得た。[R,, cm-' (film): 1700. 1
650. 1510.1420°MR δ (CDC12') 1400, 1340. 1120: 1.77 (lH, d, J=7H2), 2, 97C
3H,S), 3.16(3)(,S), 5,22(2H
, S'), 8, 16 (2H, d, J: 8.5 Hz) Example 3 a) Trans-1-p-nitrobenzyl-bovine dicarbonyl-4-hydroxy-D-proline-p-methoxybenzyl ester (110 ), using Reference Example 1-3,
By the same method as 1-4 and 1-5 (2R, 4R)
-tp-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine was obtained.
rR,、、cm−’(film) : 1705.16
50.1515.1435゜1340、 1115
(α) if’ 7..38°(c =0.2to
、 アセトン)b)上記a)で得たチオアセテート誘導
体(42■)を用い実施例1と同様の方法により〔2R
94R)−1−p−二トロベンジルオキシ力ルボニル−
2−ジメチルアミノカルボニル−4−メルカプトピロリ
ジンを得た。rR,, cm-' (film): 1705.16
50.1515.1435°1340, 1115 (α) if' 7. .. 38° (c = 0.2to
, acetone) b) [2R
94R)-1-p-nitrobenzyloxycarbonyl-
2-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained.
IR,、、cn+−’(film) : 1710.
1660.1525.1440゜1347、 1180
.1122
実施例4
a)
シス−4−ヒドロキシ−D−プロリ
ン
(30
0■)より参考例1−1.1−2.1−3.1−4およ
び1−5と同様の方法により(2R,4S)−1−(p
−ニトロベンジルオキシカルボニル)−2−ジメチルア
ミノカルボニル−4−アセチルチオピロリジン(45■
)を得た。IR,,,cn+-'(film): 1710.
1660.1525.1440゜1347, 1180
.. 1122 Example 4 a) From cis-4-hydroxy-D-proline (300■), (2R, 4S)-1-(p
-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine (45■
) was obtained.
[R,、、cm−’(film) : 1700.16
50.1520.1400゜1345、1120
〔α) g”−29,6°(c =0.215 、アセ
トン)b)上記a)で得たチオアセテート誘導体(30
■)を実施例1と同様の方法により(2R,4S)−1
−(p−ニトロベンジルオキシカルボニル)−2−ジメ
チルアミノカルボニル−4−メルカプトピロリジンを得
た。[R,, cm-' (film): 1700.16
50.1520.1400° 1345, 1120 [α) g”-29,6° (c = 0.215, acetone) b) Thioacetate derivative obtained in a) above (30
(2R,4S)-1 by the same method as in Example 1.
-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained.
IR,、、cm−’(film) : 1710. 1
655.1520. 1430゜実施例5
(2S、4S)−1−p−ニトロベンジルオキシカルボ
ニル−2−メチルアミノカルボニル−4−エトキシカル
ボニルチオピロリジン(82■)をメタノール:水(l
二1)混液(4mt’)にとかしI N −NaOH(
0,257nl)を加えて、室温、30分攪拌後、I
N−HCl (0,27d)を加え、酢酸エチルで抽出
し、水洗、芒硝乾燥後溶媒留去し〔2S4S)−1−p
−ニトロベンジルオキシカルボニル−2−メチルアミノ
カルボニル−4−メルカプトピロリジンを得た。IR,, cm-' (film): 1710. 1
655.1520. 1430゜Example 5 (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-methylaminocarbonyl-4-ethoxycarbonylthiopyrrolidine (82■) was dissolved in methanol:water (l
21) Dissolve the mixture (4 mt') and add I N -NaOH (
After stirring at room temperature for 30 minutes,
N-HCl (0.27d) was added, extracted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off [2S4S)-1-p.
-Nitrobenzyloxycarbonyl-2-methylaminocarbonyl-4-mercaptopyrrolidine was obtained.
IR,、、cr’(Nujol): 3280.171
0.1650. 15101340、1165
NMRδ(CDCIり : 2.79(3H,d、
J=5Hz)、4、27(2H,t、 J=8Hz)、
5、23(2H,s)、7.50(2H,d、 J=9
Hz)、8.20(2H,d、 J=9H2)以下実施
例1あるいは実施例5と同様にして以下のメルカプタン
を得た。IR,,,cr'(Nujol): 3280.171
0.1650. 15101340, 1165 NMRδ (CDCI: 2.79 (3H, d,
J=5Hz), 4, 27(2H,t, J=8Hz),
5, 23 (2H, s), 7.50 (2H, d, J=9
Hz), 8.20 (2H, d, J=9H2) The following mercaptan was obtained in the same manner as in Example 1 or Example 5.
cS
実施例1
7
a) (2S、4S)−1−p−メトキシベンジルオ
キシカルボニル−2−ベンジルアミノカルボニル−4−
アセチルチオピロリジン(177■)とアニソール(8
6■)をトリフロロ酢酸(0,5d)にとかし、室温で
30分攪拌した。反応液を減圧下濃縮し、酢酸エチルで
希釈、重曹水及び水で洗浄後、芒硝乾燥。溶媒留去し、
残渣をシリカゲル薄層クロマトグラフィーに付し、(2
S、4S〕−2−ベンジルアミノカルボニル−4−アセ
チルチオピロリジンを得た。cS Example 1 7 a) (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-benzylaminocarbonyl-4-
Acetylthiopyrrolidine (177■) and anisole (8
6) was dissolved in trifluoroacetic acid (0.5d) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous sodium bicarbonate and water, and dried with sodium sulfate. Remove the solvent,
The residue was subjected to silica gel thin layer chromatography (2
S,4S]-2-benzylaminocarbonyl-4-acetylthiopyrrolidine was obtained.
IR,、、cl’(film) : 3325.169
0.1510.1400゜1350、1120.95O
NMRδ(CDCI2) : 2.28(3H,s
)、3.83(2H,m)、4.42(2H,d、J=
6H2)、
7.32(5H,5)
b)上記a)で得たチオアセテート誘導体(40■)を
実施例1と同様の処理に付し、(2S、4S〕−2−ベ
ンジルアミノカルボニル−4−メルカプトピロリジンを
得た。IR,,,cl'(film): 3325.169
0.1510.1400°1350, 1120.95O NMRδ (CDCI2): 2.28 (3H, s
), 3.83 (2H, m), 4.42 (2H, d, J=
6H2), 7.32(5H,5) b) The thioacetate derivative (40■) obtained in a) above was subjected to the same treatment as in Example 1 to obtain (2S,4S]-2-benzylaminocarbonyl- 4-Mercaptopyrrolidine was obtained.
tR,、、cm−’(film) : 3250.16
85.1610.1510゜132
参考例6
−3−(ジフェニルホスホリルオキシ−6−(1−p−
ニトロベンジルオキシカルボニルオキシエチル)−1−
アザビシクロ(3,2,0)−ヘブトー2−エンー7−
オンー2−カルボキシレート(122■)を乾燥アセト
ニトリル(3mi’)にとかし、窒素気流中、水冷下に
ジイソプロピルエチルアミン(31■)を加え、次いで
(2S、4S)−1−p−二トロペンジルオキシカルボ
ニルー2−ジメチルアミノカルボニル−4−メルカプト
ピロリジン(60■)を加え、そのまま1時間攪拌した
。反応液を酢酸エチルで希釈し、水洗後、硫酸マグネシ
ウムで乾燥し溶媒留去した。残渣をシリカゲル薄層クロ
マトグラフィーにより精製しく5R,6S、8R,3’
3.5’5)−p−ニトロベンジル−3−(3−(1−
p−ニトロベンジルオキシカルボニル−5−ジメチルア
ミノカルボニル)ピロリジニルチオ)−6−(1−p−
ニトロベンジルオキシカルボニルオキシエチル)−1−
アザビシクロ(3,2,0)−ヘプト−2−エン−7−
オン−2−カルボキシレート(95■)を得た。tR,, cm-' (film): 3250.16
85.1610.1510°132 Reference Example 6 -3-(diphenylphosphoryloxy-6-(1-p-
Nitrobenzyloxycarbonyloxyethyl)-1-
Azabicyclo(3,2,0)-hebuto-2-en-7-
On-2-carboxylate (122■) was dissolved in dry acetonitrile (3mi'), diisopropylethylamine (31■) was added under water cooling in a nitrogen stream, and then (2S,4S)-1-p-nitropenzyl Oxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (60 μ) was added, and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography to obtain 5R, 6S, 8R, 3'
3.5'5)-p-nitrobenzyl-3-(3-(1-
p-nitrobenzyloxycarbonyl-5-dimethylaminocarbonyl)pyrrolidinylthio)-6-(1-p-
Nitrobenzyloxycarbonyloxyethyl)-1-
Azabicyclo(3,2,0)-hept-2-ene-7-
One-2-carboxylate (95■) was obtained.
IR,、、cm−’(film) : 1780.17
45.1705.1650゜1605、1515.13
42.1257NMRδ(CDCI+) :
1.49(3H,d、J=6Hz)、2、99(3H,
s)、3.11(3H,S)、5、25(48,S)、
5.23および5、46(2H,ABq、 J=14H
z)、7、53(4H,d、 J=8.5Hz)、7、
62(2H,d、 J=8.5Hz)、8、18(6H
,d、 J=8.5Hz)〔α) g”+ 7.7°(
c 〜0.303 、アセトン)b) (5R,6S
、 8R,3’3.5’S) −p−ニトロベンジル−
3−(3−(1−p−ニトロベンジルオキシカルボニル
−5−ジメチルアミノカルボニル)ピロリジニルチオ)
−6−(1−p−ニトロベンジルオキシカルボニルオキ
シエチル)−1−アザビシクロ(3,2,O)ヘプト−
2−エン−7−オン−2−カルボキシレート(95mg
)をジオキサン(20rnl)に溶かしモルホリノブロ
パンスホン酸緩衝液(pH=7.0 、 10rnl)
及び酸化白金(35■)を加え3.5気圧の水素圧下6
,5時間水素添加した。触媒を濾過した後、減圧下ジオ
キサンを留去し、残液を酢酸エチルで洗浄し、水層を再
度減圧下有機溶媒を留去し、残液をポリマークロマトグ
ラフィー(CHP−20P)に付すと水で溶出される部
分から(5R,6S、8R3″S、5’5)−3−(3
−(5−ジメチルアミノカルボニル)ピロリジニルチオ
)−6−(1−ヒドロキシエチル)−1−アザビシクロ
〔3,20〕ヘプト−2−エン−7−オン−2−カルボ
ン酸を得た。IR,, cm-' (film): 1780.17
45.1705.1650°1605, 1515.13
42.1257NMRδ (CDCI+):
1.49 (3H, d, J=6Hz), 2,99 (3H,
s), 3.11 (3H, S), 5, 25 (48, S),
5.23 and 5, 46 (2H, ABq, J=14H
z), 7, 53 (4H, d, J=8.5Hz), 7,
62 (2H, d, J=8.5Hz), 8, 18 (6H
, d, J=8.5Hz) [α) g”+ 7.7° (
c ~0.303, acetone)b) (5R,6S
, 8R,3'3.5'S) -p-nitrobenzyl-
3-(3-(1-p-nitrobenzyloxycarbonyl-5-dimethylaminocarbonyl)pyrrolidinylthio)
-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo(3,2,O)hept-
2-en-7-one-2-carboxylate (95 mg
) in dioxane (20rnl) and morpholinopropane sulfonic acid buffer (pH=7.0, 10rnl)
and platinum oxide (35cm) and heated under a hydrogen pressure of 3.5 atm.
, hydrogenated for 5 hours. After filtering the catalyst, dioxane was distilled off under reduced pressure, the residual liquid was washed with ethyl acetate, the organic solvent was distilled off from the aqueous layer again under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P). From the part eluted with water (5R, 6S, 8R3″S, 5’5)-3-(3
-(5-dimethylaminocarbonyl)pyrrolidinylthio)-6-(1-hydroxyethyl)-1-azabicyclo[3,20]hept-2-en-7-one-2-carboxylic acid was obtained.
UV−−g nm (HJ)
[Lax cm−’(KBr)
= 297
+ 1755. 1627. 1393. 1252
゜130
: 1.25(3H,d、J=6.4Hz)、1、8
1〜1.96(IH,III)、2、96(3H,S)
、3.03(3H,S)、3、14〜3.20(3H,
m)、
3.31〜3.41(2H,m)、
3、62〜3.72(IH,m)、
3、90〜4.00(IH,m)、
4、14〜4.26(2H,m)、
4.63(IH,t、J・8.5Hz)NMRδ(D2
0)UV--g nm (HJ) [Lax cm-' (KBr) = 297 + 1755. 1627. 1393. 1252
゜130: 1.25 (3H, d, J = 6.4Hz), 1, 8
1-1.96 (IH, III), 2, 96 (3H, S)
, 3.03 (3H, S), 3, 14-3.20 (3H,
m), 3.31-3.41 (2H, m), 3, 62-3.72 (IH, m), 3, 90-4.00 (IH, m), 4, 14-4.26 ( 2H, m), 4.63 (IH, t, J・8.5Hz) NMRδ (D2
0)
Claims (1)
アミノ基の保護基を、R_3は水素原子、低級アルキル
基、低級アルケニル基、アラルキル基、もしくは置換低
級アルキル基を、およびR_4は低級アルキル基、低級
アルケニル基、アラルキル基、もしくは置換低級アルキ
ル基を、あるいはR_3およびR_4は互いに結合せる
アルキレン鎖または酸素原子、硫黄原子もしくは低級ア
ルキル置換窒素原子を介するアルキレン鎖を表して隣接
する窒素原子とともに4〜7員環の環状アミノ基を示す
。 で表される2−置換アミノカルボニル−4−メルカプト
ピロリジン誘導体[Claims] General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R_1 is a hydrogen atom, R_2 is a hydrogen atom or a protecting group for an amino group, and R_3 is a hydrogen atom , a lower alkyl group, a lower alkenyl group, an aralkyl group, or a substituted lower alkyl group, and R_4 is a lower alkyl group, a lower alkenyl group, an aralkyl group, or a substituted lower alkyl group, or R_3 and R_4 are alkylene chains bonded to each other. Alternatively, it represents an alkylene chain via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom, and represents a 4- to 7-membered cyclic amino group together with the adjacent nitrogen atom. 2-substituted aminocarbonyl-4-mercaptopyrrolidine derivative represented by
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2178208A JPH0341066A (en) | 1990-07-04 | 1990-07-04 | 2-substituted aminocarbonyl-4-mercaptopyrrolidine derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2178208A JPH0341066A (en) | 1990-07-04 | 1990-07-04 | 2-substituted aminocarbonyl-4-mercaptopyrrolidine derivative |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP58127485A Division JPS6019787A (en) | 1983-05-09 | 1983-07-12 | Novel beta-lactam compound and its preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH0341066A true JPH0341066A (en) | 1991-02-21 |
JPH059426B2 JPH059426B2 (en) | 1993-02-04 |
Family
ID=16044471
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2178208A Granted JPH0341066A (en) | 1990-07-04 | 1990-07-04 | 2-substituted aminocarbonyl-4-mercaptopyrrolidine derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0341066A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006001841A (en) * | 2004-06-15 | 2006-01-05 | Sumitomo Chemical Co Ltd | Preparation method of nitrogen-containing heterocyclic compound |
JP2010531310A (en) * | 2007-06-28 | 2010-09-24 | ケービーピー・バイオサイエンシズ・カンパニー・リミテッド | New carbapenem derivatives |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014140467A (en) | 2013-01-23 | 2014-08-07 | Tatsuta Electric Wire & Cable Co Ltd | Drip speed measuring instrument |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5913757A (en) * | 1982-07-14 | 1984-01-24 | Sankyo Co Ltd | 3-mercaptopyprolidine derivative and its preparation |
-
1990
- 1990-07-04 JP JP2178208A patent/JPH0341066A/en active Granted
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5913757A (en) * | 1982-07-14 | 1984-01-24 | Sankyo Co Ltd | 3-mercaptopyprolidine derivative and its preparation |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006001841A (en) * | 2004-06-15 | 2006-01-05 | Sumitomo Chemical Co Ltd | Preparation method of nitrogen-containing heterocyclic compound |
JP2010531310A (en) * | 2007-06-28 | 2010-09-24 | ケービーピー・バイオサイエンシズ・カンパニー・リミテッド | New carbapenem derivatives |
Also Published As
Publication number | Publication date |
---|---|
JPH059426B2 (en) | 1993-02-04 |
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