JP2004359583A - Chain lactic acid oligomer derivative and its production method - Google Patents
Chain lactic acid oligomer derivative and its production method Download PDFInfo
- Publication number
- JP2004359583A JP2004359583A JP2003158248A JP2003158248A JP2004359583A JP 2004359583 A JP2004359583 A JP 2004359583A JP 2003158248 A JP2003158248 A JP 2003158248A JP 2003158248 A JP2003158248 A JP 2003158248A JP 2004359583 A JP2004359583 A JP 2004359583A
- Authority
- JP
- Japan
- Prior art keywords
- group
- lactic acid
- acid oligomer
- oligomer derivative
- formula
- 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 title claims abstract description 290
- 239000004310 lactic acid Substances 0.000 title claims abstract description 144
- 235000014655 lactic acid Nutrition 0.000 title claims abstract description 144
- 238000004519 manufacturing process Methods 0.000 title claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 30
- 125000003118 aryl group Chemical group 0.000 claims abstract description 20
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 14
- -1 trichlorophenyl group Chemical group 0.000 claims description 43
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 13
- 150000003997 cyclic ketones Chemical class 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 150000004820 halides Chemical class 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 5
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 abstract description 38
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000009833 condensation Methods 0.000 description 21
- 230000005494 condensation Effects 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000013638 trimer Substances 0.000 description 8
- OZGSEIVTQLXWRO-UHFFFAOYSA-N 2,4,6-trichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=C(Cl)C=C1Cl OZGSEIVTQLXWRO-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 description 4
- ZLUIDXRFWSPPCC-UHFFFAOYSA-N 6-phenyl-1h-pyridin-2-one Chemical compound OC1=CC=CC(C=2C=CC=CC=2)=N1 ZLUIDXRFWSPPCC-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 3
- 125000003373 pyrazinyl group Chemical group 0.000 description 3
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 125000004306 triazinyl group Chemical group 0.000 description 3
- TVZDIFXOIOIPJG-UHFFFAOYSA-N 2,3,4-trichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C(Cl)=C1Cl TVZDIFXOIOIPJG-UHFFFAOYSA-N 0.000 description 2
- JBLIDPPHFGWTKU-UHFFFAOYSA-N 2,6-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=CC=C1Cl JBLIDPPHFGWTKU-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000004437 phosphorous atom Chemical group 0.000 description 2
- 229910052698 phosphorus Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical class NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 description 1
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- IICQXOJPUDICND-UHFFFAOYSA-N 1,2,4-triazole-3,5-dione Chemical class O=C1NC(=O)N=N1 IICQXOJPUDICND-UHFFFAOYSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WTSADDANMFUXAU-UHFFFAOYSA-N 1,4-dihydroindol-2-one Chemical class C1=CCC2=CC(=O)NC2=C1 WTSADDANMFUXAU-UHFFFAOYSA-N 0.000 description 1
- SRFIRLBHIAWIGZ-UHFFFAOYSA-N 1-methoxy-4-(4-methoxybutoxy)butane Chemical compound COCCCCOCCCCOC SRFIRLBHIAWIGZ-UHFFFAOYSA-N 0.000 description 1
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 1
- CDULGHZNHURECF-UHFFFAOYSA-N 2,3-dimethylaniline 2,4-dimethylaniline 2,5-dimethylaniline 2,6-dimethylaniline 3,4-dimethylaniline 3,5-dimethylaniline Chemical class CC1=CC=C(N)C(C)=C1.CC1=CC=C(C)C(N)=C1.CC1=CC(C)=CC(N)=C1.CC1=CC=C(N)C=C1C.CC1=CC=CC(N)=C1C.CC1=CC=CC(C)=C1N CDULGHZNHURECF-UHFFFAOYSA-N 0.000 description 1
- GRJZPAXRRYCPHK-UHFFFAOYSA-N 2,4,6-tribromobenzoyl bromide Chemical compound BrC1=C(C(=O)Br)C(=CC(=C1)Br)Br GRJZPAXRRYCPHK-UHFFFAOYSA-N 0.000 description 1
- VMXQXCLQDZMXFB-UHFFFAOYSA-N 2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,4-dihydroxy-3-oxopentanoic acid Chemical compound O([Si](C)(C)C(C)(C)C)CC(C(=O)O)(O)C(C(O)C)=O VMXQXCLQDZMXFB-UHFFFAOYSA-N 0.000 description 1
- YMFNNQMIMKHAJE-UHFFFAOYSA-N 2-[tert-butyl(dimethyl)silyl]oxy-2-hydroxypropanoic acid Chemical compound CC(C)(C)[Si](C)(C)OC(C)(O)C(O)=O YMFNNQMIMKHAJE-UHFFFAOYSA-N 0.000 description 1
- FXWFZIRWWNPPOV-UHFFFAOYSA-N 2-aminobenzaldehyde Chemical class NC1=CC=CC=C1C=O FXWFZIRWWNPPOV-UHFFFAOYSA-N 0.000 description 1
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical class NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-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
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- LAQJGAKLLZAETL-UHFFFAOYSA-N 2h-pyrazin-3-one Chemical class O=C1CN=CC=N1 LAQJGAKLLZAETL-UHFFFAOYSA-N 0.000 description 1
- XYVMOLOUBJBNBF-UHFFFAOYSA-N 3h-1,3-oxazol-2-one Chemical class OC1=NC=CO1 XYVMOLOUBJBNBF-UHFFFAOYSA-N 0.000 description 1
- NJAKCIUOTIPYED-UHFFFAOYSA-N 4-iodobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(I)C=C1 NJAKCIUOTIPYED-UHFFFAOYSA-N 0.000 description 1
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- MCQKBMADKGMVDE-UHFFFAOYSA-N 4-methyl-6-phenyl-1h-pyridin-2-one Chemical compound N1C(=O)C=C(C)C=C1C1=CC=CC=C1 MCQKBMADKGMVDE-UHFFFAOYSA-N 0.000 description 1
- QHUKZSBVVXZUKQ-UHFFFAOYSA-N 6-(2-methylphenyl)-1h-pyridin-2-one Chemical compound CC1=CC=CC=C1C1=CC=CC(=O)N1 QHUKZSBVVXZUKQ-UHFFFAOYSA-N 0.000 description 1
- NEXYFEYISMLKMD-UHFFFAOYSA-N 6-benzyl-1h-pyridin-2-one Chemical compound OC1=CC=CC(CC=2C=CC=CC=2)=N1 NEXYFEYISMLKMD-UHFFFAOYSA-N 0.000 description 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
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- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 240000006162 Chenopodium quinoa Species 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 125000005422 alkyl sulfonamido group Chemical group 0.000 description 1
- 125000004422 alkyl sulphonamide group Chemical group 0.000 description 1
- ZIXLDMFVRPABBX-UHFFFAOYSA-N alpha-methylcyclopentanone Natural products CC1CCCC1=O ZIXLDMFVRPABBX-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000009876 antimalignant effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000005421 aryl sulfonamido group Chemical group 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000005521 carbonamide group Chemical group 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 125000006003 dichloroethyl group Chemical group 0.000 description 1
- 125000004188 dichlorophenyl group Chemical group 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical class O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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Abstract
Description
【０００１】
【発明の技術分野】
本発明は、鎖状乳酸オリゴマー誘導体およびその製造方法に関する。より詳しくは、本発明は、新規な鎖状オリゴ乳酸エステルおよびその製造方法に関する。
【０００２】
【発明の技術的背景】
環状乳酸オリゴマーは、その抗悪性腫瘍作用や血糖低下作用などの薬効が期待され、近年、医薬品開発の対象として注目されている化合物である。
【０００３】
このような環状乳酸オリゴマーは、従来、さまざまな縮合度（すなわち、異なる鎖長）を有する環状乳酸オリゴマーの混合物、あるいはさらに鎖状乳酸オリゴマーを含む混合物として得られていたが、特定鎖長を有する単一の環状乳酸オリゴマーを得ることは困難であった。
【０００４】
たとえば、減圧下で段階的に乳酸の脱水縮合反応を行うことにより、縮合度３〜１９の鎖状および／または環状の乳酸オリゴマー混合物が得られたことが報告されている（特許文献１参照）。しかしながら、この方法で得られる環状乳酸オリゴマーの組成を制御することは容易でなく、分子量分布の広い、鎖状および環状の乳酸重合体混合物が得られるに過ぎなかった。
【０００５】
また、本発明者らは、鎖状乳酸オリゴマーを含まない環状乳酸オリゴマーを得る製造方法を既に提案している（特許文献２および３参照）。この方法によれば、触媒の種類を選択することにより、実質的に環状乳酸オリゴマーのみを選択的に得ることが可能である。しかしながら、この方法によっても得られる環状乳酸オリゴマーは、乳酸単位数が２，３，４・・・と連続する鎖長の環状乳酸オリゴマーの混合物であった。
【０００６】
また、固相上で目的とする鎖長まで鎖状乳酸オリゴマーを逐次合成し、最後に環化することによって、特定鎖長を有する単一の環状オリゴマーを得ようとする試みも提案されている（非特許文献１参照。）。しかしながら、この方法では、鎖状乳酸オリゴマーの官能基の保護を含め、その操作が極めて煩雑であり、しかも最終収率が低いため、実用性に欠けるという問題点があった。
【０００７】
本発明者らは、このような実情に鑑み鋭意研究した結果、公知の分離手段を課すことで、容易に所望の環状乳酸オリゴマーを単一化合物として与えうる特異な環状乳酸オリゴマー混合物の合成原料となる鎖状乳酸オリゴマー誘導体を得て、本発明を完成するに至った。
【０００８】
【特許文献１】
特開平９−２２７３８８号公報
【特許文献２】
国際公開第０１／２１６１３Ａ１号パンフレット
【特許文献３】
国際公開第０１／２１６１２Ａ１号パンフレット
【非特許文献１】
Ｏ．Ｋｕｉｓｌｅ， Ｅ．Ｑｕｉｎｏａ， Ｒ．Ｒｉｇｕｅｒａ， Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９９年、６４巻、Ｐ．８０６３
【０００９】
【発明の目的】
本発明は、環状乳酸オリゴマーの合成中間体として有用な鎖状乳酸オリゴマー誘導体およびその製造方法を提供することを目的としている。
【００１０】
【発明の概要】
本発明に係る乳酸オリゴマー誘導体は、下記一般式（Ｉ）で示される。；
【００１１】
【化３】
式（Ｉ）中、ｍは２以上の整数であり、Ｙは−ＣＯＲ１または−Ｒ２を表し、Ｒ１は置換されていてもよい、脂肪族基、アリール基、またはヘテロ環基を表し、Ｒ２は置換されていてもよいヘテロ環基を表す。
【００１３】
本発明の乳酸オリゴマー誘導体においては、前記Ｒ１は、好ましくは、置換されていてもよい炭素原子数６〜２４のアリール基であり、より好ましくは、ハロゲン置換フェニル基であり、さらに好ましくは、ジクロロあるいはトリクロロフェニル基である。
【００１４】
また、本発明の乳酸オリゴマー誘導体においては、前記Ｒ２は、好ましくは、置換されていてもよい窒素原子含有へテロ芳香環基であり、より好ましくは、置換されていてもよいピリジル基であり、さらに好ましくは、フェニルピリジル基である。
【００１５】
本発明に係る前記乳酸オリゴマーの製造方法は、下記一般式（ＩＩ）で示される乳酸オリゴマーと、
【００１６】
【化４】
（式（ＩＩ）中、ｍは式（Ｉ）と同じである。）
Ｒ１ＣＯＸ ［ここで、Ｒ１は式（Ｉ）と同じであり、Ｘは水酸基、ハロゲン原子、−ＯＣＯＲ４（Ｒ４はＲ１と同じであっても異なってもよく、置換されていてもよい、脂肪族基、アリール基、またはヘテロ環基を表す。）を表す。］ で示されるカルボン酸またはカルボン酸誘導体、あるいは、
Ｒ３＝Ｏ［ここで、Ｒ３はカルボニル基に隣接するヘテロ原子を有するヘテロ環基（置換基を有していてもよい）を表す。］で示される環状ケトンとを
反応させることを特徴としている。
【００１８】
さらに、本発明の製造方法では、前記反応を塩基存在下で行うことが好ましい。
【００１９】
なお、前記Ｒ１ＣＯＸで示されるカルボン酸誘導体は、酸ハロゲン化物であることが好ましい。
【００２０】
【発明の具体的説明】
以下、本発明について具体的に説明する。
【００２１】
≪乳酸オリゴマー誘導体≫
本発明に係る乳酸オリゴマー誘導体は、下記一般式（Ｉ）で示される鎖状乳酸オリゴマー誘導体である。；
【００２２】
【化５】
式（Ｉ）中、ｍは２以上の整数であり、Ｙは−ＣＯＲ１または−Ｒ２を表し、Ｒ１は置換されていてもよい、脂肪族基、アリール基、またはヘテロ環基を表し、Ｒ２は置換されていてもよいヘテロ環基を表す。
【００２４】
このように本発明の乳酸オリゴマー誘導体は、任意の鎖長を有する鎖状乳酸オリゴマーのカルボキシル末端がＹとエステル結合した構造を有している。
【００２５】
本発明において、前記乳酸オリゴマー誘導体の鎖長は、出発原料となる鎖状乳酸オリゴマーの鎖長に依存しており、前記式（Ｉ）中、ｍは通常２以上、たとえば２〜３０、好ましくは３〜２０、より好ましくは３〜１５、さらに好ましくは３〜１０、特に好ましくは３〜６の整数である。なお、この場合、ｍは乳酸オリゴマー誘導体の縮合度、すなわち、乳酸オリゴマー部分の繰り返し単位である乳酸単位の個数を表しており、たとえば、ｍ＝２の場合には２量体を、ｍ＝３の場合には３量体をそれぞれ表している。
【００２６】
また、本発明の乳酸オリゴマー誘導体においては、前記式（Ｉ）中、Ｙが−ＣＯＲ１を表す場合、Ｒ１は、置換されていてもよい、脂肪族基、アリール基、またはヘテロ環基を表す。
【００２７】
置換されていてもよい脂肪族基としては、たとえば、低級アルキル基、低級アルケニル基または低級アルキニル基、低級ハロアルキル基、低級アルコキシ基、低級アルコキシアルキル基、低級アルコキシカルボニル基、低級アルキルチオ基、低級アルキルスルフィニル基、低級アルキルスルホニル基などが挙げられる。前記脂肪族基の炭素原子数は、特に限定されないが、通常１〜１０であり、好ましくは１〜６であり、より好ましくは１〜４である。また、その鎖型も特に限定されず、直鎖、分岐鎖、環状鎖またはこれらの組み合わせのいずれでもよい
より具体的には、たとえば、低級アルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基など；低級アルケニル基としては、ビニル、プロペニル、ブテニル基など（さらに後二者の基では、二重結合の位置による異性体である基なども含む。）；低級アルキニル基としては、エチニル基、プロピニル基、ブチニル基、これらの異性体である基など；低級シクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクタニル基など；低級ハロアルキル基としては、フルオロメチル基、ジフルオロメチル基、ジクロロエチル基、ブロモプロピル基など；低級アルコキシ基としては、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基など；低級ハロアルコキシ基としては、モノフルオロメトキシ、クロロプロポキシ基、これらの異性体である基など；アルコキシカルボニル基としては、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基など；アルキルチオ基としては、メチルチオ基、エチルチオ基、プロピルチオ基、ブチルチオ基、これらの異性体である基；アルキルスルフィニル基としては、メチルスルフィニル基、エチルスルフィニル基、プロピルスルフィニル基、ブチルスルフィニル基、これらの異性体である基など；アルキルスルホニル基としては、メチルスルホニル基、エチルスルホニル基、プロピルスルホニル基、ブチルスルホニル基、これらの異性体である基などが挙げられる。
【００２８】
置換されていてもよいアリール基とは、炭素原子数６〜２４、好ましくは６〜１２のアリール基であり、このアリール基は１個以上の置換基を有していてもよい。このようなアリール基の具体例としては、たとえば、フェニル基、トリール基、ナフチル基、ベンジル基、フェネチル基、フェノキシ基、メシチル基、ｐ−メトキシフェニル基などが挙げられる。
【００２９】
置換されていてもよいヘテロ環基とは、酸素原子、窒素原子、硫黄原子またはリン原子などを１個以上含有する５〜１０員環の飽和もしくは不飽和の単環もしくは縮合環を有する官能基である。このようなヘテロ環基の具体例としては、たとえば、ピリジル基、イミダゾリル基、キノリル基、イソキノリル基、ピリミジニル基、ピラジニル基、フタラジニル基、トリアジニル基、フリル基、チエニル基、ピロリル基、オキサゾリル基、イソキサゾリル基、チアゾリル基、チアジアゾリル基、トリアゾリル基、ベンズイミダゾリル基、ピロリジノ基、モルホリノ基、ピラゾロリル基などが挙げられる。これらのヘテロ環基は、１個以上の置換基を有していてもよい。
【００３０】
前記脂肪族基、アリール基またはヘテロ環基が有していてもよい置換基の例としては、たとえば、ハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子）、シアノ基、ニトロ基、アミノ基、アルキル基、ハロアルキル基、アルキルチオ基、アルキルスルフィニル基、アルキルスルホニル基、アシル基、アルコキシ基、アルコキシアルキル基、アルコキシカルボニル基、カルバモイル基、アリール基、アリールオキシ基、アリールオキシカルボニル基、アリールチオ基、アリールスルホニル基、カルボンアミド基、アルキルスルホンアミド基、アリールスルホンアミド基、スルファモイル基などが挙げられる。
【００３１】
これらのうちでは、前記Ｒ１としては、置換されていてもよい炭素原子数６〜２４のアリール基が好ましく、置換されていてもよい炭素原子数６〜１２のアリール基がより好ましく、ハロゲン置換フェニル基がさらに好ましい。
【００３２】
ハロゲン置換フェニル基としては、具体的には、たとえば、２，６−ジクロロフェニル基、２，４，６−トリクロロフェニル基、４−ヨードフェニル基、２，４，６−トリブロモフェニル基などが挙げられ、これらのうちでは、２，６−ジクロロフェニル基、２，４，６−トリクロロフェニル基などのジクロロフェニル基あるいはトリクロロフェニル基がより好ましい。
【００３３】
前記式（Ｉ）においてＹが−ＣＯＲ１である場合に、Ｒ１がこのような官能基であると、得られる乳酸オリゴマー誘導体の末端が活性化され、後述する環化反応の際に−ＯＹ（すなわち、−ＯＣＯＲ１）が都合よく脱離して、環状乳酸オリゴマーを与えるため望ましい。
【００３４】
また、本発明の乳酸オリゴマー誘導体においては、前記式（Ｉ）中、Ｙが−Ｒ２を表す場合、Ｒ２は、置換されていてもよいヘテロ環基を表す。
【００３５】
前記置換されていてもよいヘテロ環基とは、酸素原子、窒素原子、硫黄原子またはリン原子などを１個以上含有する５〜１０員環の飽和もしくは不飽和の単環もしくは縮合環を有する官能基である。このようなヘテロ環基の具体例としては、たとえば、ピリジル基、イミダゾリル基、キノリル基、イソキノリル基、ピリミジニル基、ピラジニル基、フタラジニル基、トリアジニル基、フリル基、チエニル基、ピロリル基、オキサゾリル基、イソキサゾリル基、チアゾリル基、チアジアゾリル基、トリアゾリル基、ベンズイミダゾリル基、ピロリジノ基、モルホリノ基、ピラゾロリル基などが挙げられる。なお、これらのヘテロ環基は、１個以上の置換基を有していてもよい。
【００３６】
前記ヘテロ環基が有していてもよい置換基の例としては、たとえば、ハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子）、シアノ基、ニトロ基、アミノ基、アルキル基、ハロアルキル基、アルキルチオ基、アルキルスルフィニル基、アルキルスルホニル基、アシル基、アルコキシ基、アルコキシアルキル基、アルコキシカルボニル基、カルバモイル基、アリール基、アリールオキシ基、アリールオキシカルボニル基、アリールチオ基、アリールスルホニル基、カルボンアミド基、アルキルスルホンアミド基、アリールスルホンアミド基、スルファモイル基などが挙げられる。
【００３７】
これらのうちでは、前記Ｒ２は、好ましくは、置換されていてもよい窒素原子含有へテロ芳香環基であり、該窒素原子含有へテロ芳香環基としては、たとえば、ピリジル基、ピリミジニル基、ピラジニル基、フタラジニル基、トリアジニル基などが挙げられる。
【００３８】
これらのうちでは、置換されていてもよいピリジル基、さらには置換されていてもよい２−ピリジル基がより好ましく、具体的には、たとえば、６−フェニル−２−ピリジル基、４−メチル−６−フェニル−２−ピリジル基、６−ベンジル−２−ピリジル基、６−トリル−２−ピリジル基などが挙げられる。
【００３９】
これらのうちでは、６−フェニル−２−ピリジル基、４−メチル−６−フェニル−２−ピリジル基などのフェニルピリジル基がさらに好ましい。
【００４０】
式（Ｉ）中のＹが−Ｒ２である場合に、Ｒ２がこのような官能基であると、得られる乳酸オリゴマー誘導体の末端が活性化され、後述する環化反応の際に−ＯＹ（すなわち、−ＯＲ２）が都合よく脱離して、所望の環状乳酸オリゴマーを与えるため望ましい。
【００４１】
具体的には、このような本発明の乳酸オリゴマー誘導体を用いて、好ましくはアミノピリジン、芳香族スルホン酸などの触媒存在下で環化反応させることにより、該乳酸オリゴマー誘導体の縮合度の整数倍の縮合度を有する環状乳酸オリゴマーの混合物を得ることができる。たとえば、触媒存在下、溶媒が還流する条件において、ｎ個（ｎは１以上の整数）の鎖状乳酸オリゴマー誘導体（縮合度ｍ）の末端から−ＯＹが脱離し、１以上の鎖状乳酸オリゴマー残基が環化することによって、主として、縮合度＝ｍｎの環状乳酸オリゴマーを含む環状乳酸オリゴマー混合物が生成する。
【００４２】
生成した環状乳酸オリゴマーの混合物の縮合度ｍｎは、合成中間体である本発明の鎖状乳酸オリゴマー誘導体の縮合度の影響を受ける。すなわち、上述したように合成中間体である鎖状乳酸オリゴマー誘導体の縮合度ｍが３であれば、生成する環状乳酸オリゴマーは、その縮合度が、３，６，９・・・３ｎ（ｎは１以上の整数）の混合物となる。したがって、得られる環状乳酸オリゴマーの混合物の縮合度ｍｎは、合成中間体である鎖状乳酸オリゴマー誘導体の縮合度ｍによっても異なるが、平均して３〜６０、好ましくは３〜２４のものを合成することができる。
【００４３】
すなわち、前記環状乳酸オリゴマーの混合物は、その縮合度が本発明の鎖状乳酸オリゴマー誘導体の縮合度の整数倍である、特定の環状乳酸オリゴマーの集団となる。したがって、本発明の鎖状乳酸オリゴマー誘導体の縮合度、ひいては該誘導体の出発原料である鎖状乳酸オリゴマーの縮合度を選択することにより、所望の環状乳酸オリゴマーおよび他の環状乳酸オリゴマー（縮合度は整数倍に変化している）を含む混合物を得ることができる。
【００４４】
このように比較的単純な組成の混合物を、カラムクロマトグラフィー、高速液体クロマトグラフィーなどの従来公知の方法で分離することによって、容易に所望の鎖長（縮合度）を有する環状乳酸オリゴマーを単一の化合物として得ることができる。
【００４５】
なお、本発明の乳酸オリゴマー誘導体には、不斉炭素原子が含まれており、立体異性体が存在する。しかしながら、すべての可能な異性体および２種以上の該異性体を任意の比率で含む混合物も本発明の乳酸オリゴマー誘導体に含まれる。具体的には、光学活性体、ラセミ体、ジアステレオマーなどの各種光学異性体およびこれらの混合物も本発明の乳酸オリゴマー誘導体に含まれる。
【００４６】
また、本発明の乳酸オリゴマー誘導体およびその出発原料たる鎖状乳酸オリゴマーは、金属塩（たとえば、ナトリウム塩、カリウム塩、マグネシウム塩、カルシウム塩、アルミニウム塩、亜鉛塩など）、水和物、溶媒和物、結晶多形などの各種形態をとりうる。
【００４７】
≪乳酸オリゴマー誘導体の製造方法≫
次に、本発明の鎖状乳酸オリゴマー誘導体の好適な製造方法について、具体的に説明する。
【００４８】
前記乳酸オリゴマー誘導体は、下記一般式（ＩＩ）で示される乳酸オリゴマーと、
【００４９】
【化６】
（式（ＩＩ）中、ｍは式（Ｉ）と同じである。）
Ｒ１ＣＯＸ ［ここで、Ｒ１は式（Ｉ）と同じであり、Ｘは水酸基、ハロゲン原子、−ＯＣＯＲ４（Ｒ４はＲ１と同じであっても異なってもよく、置換されていてもよい、脂肪族基、アリール基、またはヘテロ環基を表す。）を表す。］ で示されるカルボン酸またはカルボン酸誘導体、あるいは、
Ｒ３＝Ｏ［ここで、Ｒ３はカルボニル基に隣接するヘテロ原子を有するヘテロ環基（置換基を有していてもよい）を表す。］で示される環状ケトンとを、
好ましくは塩基存在下で、反応させることにより製造することができる。
【００５１】
上記式（ＩＩ）で示される鎖状乳酸オリゴマーは、ｍ個の乳酸単位の繰り返しを有する特定鎖長の単一の化合物である。ここで、ｍは、式（Ｉ）と同じであり、具体的には、通常２以上、たとえば２〜３０、好ましくは３〜２０、より好ましくは３〜１５、さらに好ましくは３〜１０、特に好ましくは３〜６の整数を表す。
【００５２】
このような特定鎖長を有する単一の鎖状乳酸オリゴマーの製造方法については、すでに本発明者らにより提案されている（特願２００２−０４２００９号）。この方法によれば、３〜２０量体の間の一定鎖長を有する鎖状乳酸オリゴマーを単一の化合物として直接的に合成することができる。
【００５３】
具体的には、水酸基を保護した乳酸オリゴマーと、カルボキシル基を保護した乳酸または乳酸オリゴマーとを反応させ、さらに必要に応じて、得られた一定鎖長の乳酸オリゴマーにおける水酸基の保護基をフッ化水素酸で処理することにより、またカルボキシル基の保護基をトリフルオロ酢酸／塩化メチレンで処理することにより、選択的に脱保護し、特定鎖長を有する単一の鎖状乳酸オリゴマーを得ることができる。
【００５４】
より具体的には、たとえば、塩化メチレンを溶媒として、４−ジメチルアミノピリジンおよびＮ，Ｎ’−ジシクロヘキシルカルボジイミドの存在下で、ｔｅｒｔ−ブチルジメチルシロキシラクトイル乳酸とラクトイル乳酸ｔｅｒｔ−ブチルを反応させることにより、ｔｅｒｔ−ブチルジメチルシロキシ乳酸４量体ｔｅｒｔ−ブチルエステルを得る。これをフッ化水素酸で処理することにより、乳酸４量体ｔｅｒｔ−ブチルエステルを得て、さらにこの乳酸４量体ｔｅｒｔ−ブチルエステルをトリフルオロ酢酸／塩化メチレンで処理することにより鎖状乳酸オリゴマー４量体を得ることができる。
【００５５】
本発明においては、この方法を使用して、出発物質として望ましい鎖状乳酸オリゴマーを直接的に調製することができる。
【００５６】
また、前記鎖状乳酸オリゴマーと反応させるＲ１ＣＯＸ ［ここで、Ｒ１は式（Ｉ）と同じであり、Ｘは水酸基、ハロゲン原子、−ＯＣＯＲ４（Ｒ４はＲ１と同じであっても異なってもよく、置換されていてもよい、脂肪族基、アリール基、またはヘテロ環基を表す。）を表す。］ で示されるカルボン酸またはカルボン酸誘導体としては、前記鎖状乳酸オリゴマーと反応し、エステル結合を形成して、前述したＲ１を鎖状乳酸オリゴマー末端に与えることができるものであれば、特に限定はされず、カルボン酸、酸ハロゲン化物、酸無水物のいずれであってもよい。
【００５７】
前記Ｒ１ＣＯＸが、酸無水物である場合、すなわち、Ｘが−ＯＣＯＲ４である場合には、Ｒ４はＲ１と同じであっても異なってもよく、置換されていてもよい、脂肪族基、アリール基、またはヘテロ環基を表す。このような置換されていてもよい、脂肪族基、アリール基、またはヘテロ環基としては、Ｒ１として既述したものが挙げられる。
【００５８】
これらのうち、反応性が良好で収率よく乳酸オリゴマー誘導体を得られる点からは、酸ハロゲン化物を用いることが好ましい。
【００５９】
前記酸ハロゲン化物としては、酸フッ化物、酸塩化物、酸臭化物、酸ヨウ化物のいずれであってもよいが、これらのうち、取り扱いや入手容易な点からは、酸塩化物、酸臭化物が好ましく、具体的には、たとえば、２，６−ジクロロベンゾイルクロライド、２，４，６−トリクロロベンゾイルクロライド、４−ヨードベンゾイルクロライド、２，４，６−トリブロモベンゾイルブロミドなどが挙げられる。
【００６０】
さらにこれらのうちでは、反応性の点から、２，６−ジクロロベンゾイルクロライド、２，４，６−トリクロロベンゾイルクロライドなどのジクロロあるいはトリクロロベンゾイルクロライドが好ましく使用される。このジクロロあるいはトリクロロベンゾイルクロライドは、鎖状乳酸オリゴマーのカルボキシル末端を活性化させる官能基（−Ｙ）として、ジクロロあるいはトリクロロベンゾイル基を供与する。これらは、単独でまたは２以上組み合わせて用いられる。
【００６１】
また、前記鎖状乳酸オリゴマーと反応させる環状ケトンＲ３＝Ｏとしては、前記鎖状乳酸オリゴマーと反応し、エステル結合を形成して、前述したＲ２を鎖状乳酸オリゴマー末端に与えることができるものであれば、特に限定はされないが、Ｒ３は、通常、カルボニル基のカルボニル炭素に隣接するヘテロ原子を有するヘテロ環基であり、該へテロ環基は１個以上の置換基を有していてもよい。
【００６２】
すなわち、Ｒ３＝Ｏは、カルボニル基のカルボニル炭素に隣接するヘテロ原子（該へテロ原子は水素原子を有している。）を有し、該へテロ原子がカルボニル炭素と共にヘテロ環を形成している環状ケトンである。さらに、前記へテロ原子は、好ましくは窒素原子である。
【００６３】
該環状ケトンＲ３＝Ｏは、鎖状乳酸オリゴマーと反応させた際に、ケト−エノール互変異性と類似した構造変化を生じ、エノール互変異性体と類似した化合物Ｒ２ＯＨ（ここで、Ｒ２は式（Ｉ）と同じ。）となり、該化合物Ｒ２ＯＨと鎖状乳酸オリゴマー末端のカルボキシル基とが反応し、エステル結合を形成することによって本発明の乳酸オリゴマー誘導体が生成する。
【００６４】
前記環状ケトンとしては、具体的には、たとえば、２−ピリドン類、２（３Ｈ）−ピラジノン類、オキサゾロン類、２−キノロン類、イソキノロン類、ピリミジン−２，４（１Ｈ，３Ｈ）−ジオン、１，４−ジヒドロ−２Ｈ−インドール−２−オン類、１，７−ジヒドロ−６Ｈ−プリン−６−オン類、３Ｈ−１，２，４−トリアゾール−３，５（４Ｈ）−ジオン類などが挙げられる。
【００６５】
これらの化合物のうちでは、２−ピリドン類が好ましい。この２−ピリドン類は、鎖状乳酸オリゴマーのカルボキシル末端を活性化させる官能基（−ＯＹ）として、ピリジルオキシ基、好ましくは２−ピリジルオキシ基を供与する。
【００６６】
前記環状ケトンとして、より具体的には、６−フェニル−２−ピリドン、４−メチル−６−フェニル−２−ピリドン、６−ベンジル−２−ピリドン、６−トリル−２−ピリドンなどが例示される。これらは、単独でまたは２以上組み合わせて用いられる。
【００６７】
前記鎖状乳酸オリゴマーと、Ｒ１ＣＯＸで示されるカルボン酸またはカルボン酸誘導体、あるいは、Ｒ３＝Ｏで示される環状ケトンとを、反応させる際の量比は、特に限定されず、平衡点、費用などを考慮して設定できるが、そのモル比は、好ましくは１：０．７〜１：２０、より好ましくは１：１〜１：１０である。
【００６８】
Ｒ１ＣＯＸで示されるカルボン酸またはカルボン酸誘導体、とくに酸ハロゲン化物を使用する場合には、該カルボン酸またはカルボン酸誘導体（酸ハロゲン化物）は、前記鎖状乳酸オリゴマーに対し、通常１〜５当量、好ましくは１〜３当量、より好ましくは、１〜２．５当量の量で用いられる。また、環状ケトンＲ３＝Ｏを使用する場合には、該環状ケトンは、前記鎖状乳酸オリゴマーに対し、通常１〜２０当量、好ましくは５〜１２当量、より好ましくは６〜１０当量の量で用いられる。
【００６９】
本発明の鎖状乳酸オリゴマー誘導体の製造方法では、前記反応は、塩基の存在下で行われることが望ましい。おそらく該塩基は、鎖状乳酸オリゴマーの末端カルボキシル基がエステル化される際に触媒として作用すると考えられる。このような塩基としては、無機塩基または有機塩基のいずれも使用できる。
【００７０】
無機塩基としては、リチウム、ナトリウム、カリウムなどのアルカリ金属の水酸化物、水素化物、炭酸塩、炭酸水素塩；マグネシウム、カルシウムなどのアルカリ土類金属の水酸化物、水素化物、炭酸塩、炭酸水素塩；ナトリウムメチラート、ナトリウムエチラートなどのアルカリ金属アルコキシラート；酢酸ナトリウム、リン酸一水素ナトリウム、リン酸水素一カリウムなどのアルカリ金属弱酸塩などが挙げられる。
【００７１】
さらに有機塩基としては、アンモニア；ピリジン、ヨウ化２−クロロ−１−メチルピリジニウム、４−ジメチルアミノピリジンなどのピリジン誘導体；第４級アンモニウム塩；トリメチルアミン、トリエチルアミン、ジメチルエチルアミン、ジイソプロピルエチルアミン、アニリン、ナフチルアミンまたはその置換体などのアミン類；トルイジン類、キシリジン類、アミノフェノール類、アニリジン類、フェネチジン類、アミノベンズアルデヒド類、アミノベンゾニトリル類、アミノベンゾフェノン類、アミノビフェニル類などが挙げられる。
【００７２】
これらのうちでは、トリエチルアミン、ジイソプロピルエチルアミン、ヨウ化２−クロロ−１−メチルピリジニウムなどが好ましく挙げられる。これらは、単独でまたは２以上組み合わせて用いられる。
【００７３】
具体的には、２，４，６−トリクロロベンゾイルクロライドなどの酸ハロゲン化物（Ｒ１ＣＯＸ）を使用する場合に用いられる塩基としては、トリエチルアミン、ジイソプロピルエチルアミンなどのアミン類が好ましい。該アミン類は、通常、鎖状乳酸オリゴマーに対し、１〜３０当量、好ましくは１〜１０当量、より好ましくは、１〜３当量の量で用いられる。
【００７４】
他方、６−フェニル−２−ピリドンなどの環状ケトン（Ｒ３＝Ｏ）を使用する場合に用いられる塩基としては、トリエチルアミンなどのアミン類、ピリジニウム塩などのピリジン誘導体（ピリジンも含む）が好ましく、これらを組み合わせて用いることがより好ましい。該アミン類およびピリジニウム塩はそれぞれ、通常、鎖状乳酸オリゴマーに対し、１〜３０当量、好ましくは、１〜１５当量、より好ましくは１〜１０当量の量で用いられる。
【００７５】
また、前記反応は、通常、常圧で行われ、その反応温度は、通常４〜４０℃、好ましくは室温であり、さらに反応溶媒の存在下で行われることが望ましい。
【００７６】
反応溶媒としては、原料を溶解することができ、反応に不活性な溶媒であれば特に限定されない。このような反応溶媒として、具体的には、アセトン、メチルエチルケトン、シクロペンタノン、シクロヘキサノンなどのケトン系溶媒；アセトニトリルなどのニトリル系溶媒；ヘキサン、ベンゼン、アルキルベンゼン、トルエンまたはキシレンなどの炭化水素系溶媒；Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドンなどのアミド系溶媒；ジエチルエーテル、ジメトキシエタン、メトキシエチルエーテル、テトラヒドロフラン、１，４−ジオキサン、１，３−ジオキサン、ビス［２−（メトキシエチル）］エーテル、ビス［２−（メトキシエトキシ）エチル］エーテルなどのエーテル系溶媒；酢酸エチル、酢酸ブチルなどのエステル系溶媒；ジメチルスルホキシド、ジメチルスルホン、スルホラン、１−メチル−２−ピロリジノン、１，３−ジメチル−２−イミダゾリジノン、テトラメチル尿素、フェノール、クロロフェノール、クレゾール、アニソール、クロロホルム、ジクロロメタン、ジクロロエチレン、トリクロロエチレンなどが例示される。これらの溶媒は、単独でまたは２以上組み合わせて用いられる。
【００７７】
また、前記反応は、アルゴンおよび／または窒素雰囲気下で行われることが好ましい。反応時間は、特に限定されないが、生産効率の点からは、通常２〜２０時間、好ましくは２〜１２時間である。
【００７８】
【発明の効果】
本発明によれば、新規な鎖状乳酸オリゴマー誘導体およびその製造方法を提供することができる。さらに、該誘導体を合成中間体として、該誘導体の縮合度の整数倍となる縮合度を有する環状乳酸オリゴマーの混合物を得ることができる。この環状乳酸オリゴマーの混合物を分離することによって、所望の縮合度（鎖長）を有する環状乳酸オリゴマーを単一化合物として容易に得ることが可能である。
【００７９】
【実施例】
以下、実施例に基づいて本発明をさらに具体的に説明するが、本発明はこれらの実施例に限定されるものではない。
【００８０】
【実施例１】乳酸オリゴマー（３量体）誘導体の合成
【００８１】
【化７】
窒素雰囲気下、室温において、鎖状乳酸３量体９．０ｍｇ（０．０３８４ｍｍｏｌ）の重クロロホルム（ＣＤＣｌ３） ０．３ｍｌ溶液をＮＭＲ用サンプルチューブ内に入れ、ジイソプロピルエチルアミン１８．７ｍｇ（２．０ｅｑ）の重クロロホルム（ＣＤＣｌ３） ０．１５ｍｌ溶液を加え、さらに２，４，６−トリクロロベンゾイルクロリド９．９ｍｇ（２．０ｅｑ）を０．１５ｍｌの重クロロホルム（ＣＤＣｌ３）に溶解して加え、ＮＭＲのプローブ内で１時間反応させた。その後、鎖状乳酸３量体の２，４，６−トリクロロベンゾイル酸無水物をＮＭＲにより確認した。
【００８３】
【実施例２】乳酸オリゴマー（４量体）誘導体の合成
【００８５】
【化８】
アルゴン雰囲気下、室温において、鎖状乳酸４量体５９．２ｍｇ（０．１９３３ｍｍｏｌ）の重クロロホルム（ＣＤＣｌ３） ０．３ｍｌ溶液をＮＭＲ用サンプルチューブ内に入れ、ジイソプロピルエチルアミン５１．６ｍｇ（２．１ｅｑ）の重クロロホルム（ＣＤＣｌ３） ０．１５ｍｌ溶液を加え、さらに２，４，６−トリクロロベンゾイルクロリド９７．６ｍｇ（２．１ｅｑ）を０．１５ｍｌの重クロロホルム（ＣＤＣｌ３）に溶解して加え、４℃に冷却した超音波洗浄器で５分間撹拌した。ＮＭＲのプローブ内で１時間反応させた後、鎖状乳酸４量体の２，４，６−トリクロロベンゾイル酸無水物をＮＭＲにより確認した。
【００８７】
【実施例３】乳酸オリゴマー（５量体）誘導体の合成
【００８９】
【化９】
窒素雰囲気下、室温において、鎖状乳酸５量体３６．６ｍｇ（０．０９６７ｍｍｏｌ）の重クロロホルム（ＣＤＣｌ３） ０．３ｍｌ溶液をＮＭＲ用サンプルチューブ内に入れ、ジイソプロピルエチルアミン２５．８ｍｇ（２．１ｅｑ）の重クロロホルム（ＣＤＣｌ３） ０．１５ｍｌ溶液を加え、さらに２，４，６−トリクロロベンゾイルクロリド４８．８ｍｇ（２．１ｅｑ）を０．１５ｍｌの重クロロホルム（ＣＤＣｌ３）に溶解して加え１時間反応させた後、鎖状乳酸５量体の２，４，６−トリクロロベンゾイル酸無水物をＮＭＲにより確認した。
【００９１】
【実施例４】乳酸オリゴマー（６量体）誘導体の合成
【００９３】
【化１０】
窒素雰囲気下、室温において、鎖状乳酸６量体４３．０ｍｇ（０．０９６ｍｍｏｌ）の重クロロホルム（ＣＤＣｌ３） ０．３５ｍｌ溶液をＮＭＲ用サンプルチューブ内に入れ、ジイソプロピルエチルアミン２９ｍｇ（２．４ｅｑ）の重クロロホルム（ＣＤＣｌ３） ０．１７ｍｌ溶液を加え、さらに２，４，６−トリクロロベンゾイルクロリド５０．５ｍｇ（２．２ｅｑ）を０．１３ｍｌの重クロロホルム（ＣＤＣｌ３）に溶解して加え１時間反応させた後、鎖状乳酸６量体の２，４，６−トリクロロベンゾイル酸無水物をＮＭＲにより確認した。
【００９５】
【実施例５】乳酸オリゴマー（３量体）誘導体の合成
【００９７】
【化１１】
アルゴン雰囲気下、室温において、６−フェニル−２−ピリドン０．２７８８ｇ（１．６２８ｍｍｏｌ）とヨウ化２−クロロ−１−メチルピリジニウム０．４０７８ｇ（１．５９６ｍｍｏｌ）、トリエチルアミン０．１６３２ｇ（１．６１２ｍｍｏｌ）とを溶解したトルエン溶液３０ｍｌを１時間攪拌し、この溶液を６０℃に保ち、自動滴下装置を用いて該溶液中に、鎖状乳酸３量体０．０５１９ｇ（０．２２１６ｍｍｏｌ）とトリエチルアミン０．０２４０ｇ（０．２３７２ｍｍｏｌ）とを溶解したトルエン溶液１８ｍｌを９時間以上かけて滴下し、滴下後３０分間その温度を保ち、次いで、室温に冷却した。得られた反応混合物を濃縮し、カラムクロマトグラフィー（溶出液；ジクロロメタン：メタノール＝１００：３）で単離し、鎖状乳酸３量体ピリジルエステルを得た（０．６７３ｇ、収率８６％）。構造はＮＭＲにより確認した。
【００９９】
【実施例６】乳酸オリゴマー（４量体）誘導体の合成
【０１０１】
【化１２】
アルゴン雰囲気下、室温において、６−フェニル−２−ピリドン０．３８１１ｇ（２．２２６ｍｍｏｌ）とヨウ化２−クロロ−１−メチルピリジニウム０．５７７５ｇ（２．２６０ｍｍｏｌ）、トリエチルアミン０．２２８６ｇ（２．２５９ｍｍｏｌ）とをジクロロメタン５ｍｌで溶解し、トルエン５０ｍｌで希釈した溶液を１時間攪拌し、この溶液を７５℃に保ち、自動滴下装置を用いて該溶液中に、鎖状乳酸４量体０．０８８３ｇ（０．２８８３ｍｍｏｌ）とトリエチルアミン０．０３７０ｇ（０．３６５６ｍｍｏｌ）とをジクロロメタン５ｍｌで溶解しトルエンで希釈した溶液３０ｍｌを９時間以上かけて滴下し、滴下後３０分間その温度を保ち、次いで、室温に冷却した。得られた反応混合物を濃縮し、カラムクロマトグラフィー（溶出液；ジクロロメタン：メタノール＝１００：３）で単離し、鎖状乳酸４量体ピリジルエステルを得た（０．１０４６ｇ、収率８２％）。構造はＮＭＲにより確認した。
【０１０３】
【参考例１】環状乳酸オリゴマー混合物の合成
【０１０５】
【化１３】
アルゴン雰囲気下、室温において、鎖状乳酸３量体０．１１７０ｇ（０．４９９６ｍｍｏｌ）のＴＨＦ（テトラヒドロフラン）溶液５ｍｌに、トリエチルアミン０．１５３５ｍｌ（２．０ｅｑ）を加え、さらに２，４，６−トリクロロベンゾイルクロリド０．２５６１ｇ（２．０ｅｑ）のＴＨＦ溶液５ｍｌを加え、２時間攪拌した。得られた混合物をアルゴン雰囲気下でろ過した後、トルエン２５０ｍｌで希釈した。０．３６６７ｇ（６．０ｅｑ）の４−ジメチルアミノピリジン（ＤＭＡＰ）をトルエン５０ｍｌで溶かし還流を行った。高還流状態になったら、これに対して、トルエン２５０ｍｌで希釈した前記混合物を、自動滴下装置を用いて５時間以上かけて滴下した。滴下終了後３０分還流を続け、還流終了後、室温まで冷却し、濃縮した後、カラムクロマトグラフィー（溶出液；ベンゼン：酢酸エチル＝１５：４）で単離し、環状乳酸３量体、環状乳酸６量体、環状乳酸９量体、環状乳酸１２量体、環状乳酸１５量体の混合物０．０５５２ｇを得た。
【０１０７】
この環状乳酸オリゴマー混合物のマススペクトルを測定した（ＥＳＩ−ＭＳ法による）。該マススペクトルチャートを図１に示す。
【図面の簡単な説明】
【図１】図１は、参考例１で得られた環状乳酸オリゴマー混合物のマススペクトルチャートである。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a linear lactic acid oligomer derivative and a method for producing the same. More specifically, the present invention relates to a novel linear oligolactic acid ester and a method for producing the same.
[0002]
TECHNICAL BACKGROUND OF THE INVENTION
BACKGROUND ART Cyclic lactic acid oligomers are expected to have pharmacological effects such as an anti-malignant tumor effect and a blood sugar lowering effect, and have recently been attracting attention as targets for drug development.
[0003]
Such cyclic lactic acid oligomers have heretofore been obtained as a mixture of cyclic lactic acid oligomers having various degrees of condensation (that is, different chain lengths) or a mixture further containing a linear lactic acid oligomer, but have a specific chain length. It was difficult to obtain a single cyclic lactic acid oligomer.
[0004]
For example, it has been reported that a linear and / or cyclic lactic acid oligomer mixture having a degree of condensation of 3 to 19 was obtained by performing a stepwise dehydration condensation reaction of lactic acid under reduced pressure (see Patent Document 1). . However, it was not easy to control the composition of the cyclic lactic acid oligomer obtained by this method, and only a mixture of linear and cyclic lactic acid polymers having a wide molecular weight distribution was obtained.
[0005]
In addition, the present inventors have already proposed a method for producing a cyclic lactic acid oligomer containing no chain lactic acid oligomer (see Patent Documents 2 and 3). According to this method, it is possible to selectively obtain substantially only the cyclic lactic acid oligomer by selecting the type of the catalyst. However, the cyclic lactic acid oligomer obtained by this method was a mixture of cyclic lactic acid oligomers having a continuous chain length of 2, 3, 4...
[0006]
In addition, an attempt has been made to obtain a single cyclic oligomer having a specific chain length by sequentially synthesizing a linear lactic acid oligomer up to a target chain length on a solid phase and finally cyclizing the oligomer. (See Non-Patent
[0007]
The present inventors have conducted intensive studies in view of such circumstances, and as a result of imposing known separation means, can be used as a raw material for synthesizing a specific cyclic lactic acid oligomer mixture that can easily give a desired cyclic lactic acid oligomer as a single compound. Thus, the present invention was completed by obtaining a linear lactic acid oligomer derivative.
[0008]
[Patent Document 1]
JP-A-9-227388
[Patent Document 2]
International Publication No. 01 / 21613A1 pamphlet
[Patent Document 3]
WO 01 / 21612A1 pamphlet
[Non-patent document 1]
O. Kuisle, E .; Quinoa, R .; Riguera, J .; Org. Chem. , 1999, vol. 64, p. 8063
[0009]
[Object of the invention]
An object of the present invention is to provide a chain lactic acid oligomer derivative useful as a synthetic intermediate for a cyclic lactic acid oligomer and a method for producing the same.
[0010]
Summary of the Invention
The lactic acid oligomer derivative according to the present invention is represented by the following general formula (I). ;
[0011]
Embedded image
In the formula (I), m is an integer of 2 or more, and Y is -COR 1 Or -R 2 And R 1 Represents an optionally substituted aliphatic group, aryl group, or heterocyclic group; 2 Represents a heterocyclic group which may be substituted.
[0013]
In the lactic acid oligomer derivative of the present invention, the R 1 Is preferably an optionally substituted aryl group having 6 to 24 carbon atoms, more preferably a halogen-substituted phenyl group, further preferably a dichloro or trichlorophenyl group.
[0014]
Further, in the lactic acid oligomer derivative of the present invention, the R 2 Is preferably an optionally substituted nitrogen-containing heteroaromatic ring group, more preferably an optionally substituted pyridyl group, further preferably a phenylpyridyl group.
[0015]
The method for producing a lactic acid oligomer according to the present invention comprises a lactic acid oligomer represented by the following general formula (II):
[0016]
Embedded image
(In the formula (II), m is the same as the formula (I).)
R 1 COX [where R 1 Is the same as in formula (I), and X is a hydroxyl group, a halogen atom, -OCOR 4 (R 4 Is R 1 Represents an aliphatic group, an aryl group, or a heterocyclic group which may be the same or different and may be substituted. ). A carboxylic acid or a carboxylic acid derivative represented by
R 3 = O [where R 3 Represents a heterocyclic group having a hetero atom adjacent to the carbonyl group (which may have a substituent). And a cyclic ketone represented by
It is characterized by reacting.
[0018]
Furthermore, in the production method of the present invention, the reaction is preferably performed in the presence of a base.
[0019]
The above R 1 The carboxylic acid derivative represented by COX is preferably an acid halide.
[0020]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described specifically.
[0021]
<< Lactic acid oligomer derivative >>
The lactic acid oligomer derivative according to the present invention is a linear lactic acid oligomer derivative represented by the following general formula (I). ;
[0022]
Embedded image
In the formula (I), m is an integer of 2 or more, and Y is -COR 1 Or -R 2 And R 1 Represents an optionally substituted aliphatic group, aryl group, or heterocyclic group; 2 Represents a heterocyclic group which may be substituted.
[0024]
As described above, the lactic acid oligomer derivative of the present invention has a structure in which the carboxyl terminal of a linear lactic acid oligomer having an arbitrary chain length is ester-bonded to Y.
[0025]
In the present invention, the chain length of the lactic acid oligomer derivative depends on the chain length of the linear lactic acid oligomer as a starting material, and in the formula (I), m is usually 2 or more, for example, 2 to 30, and preferably 2 to 30, It is an integer of 3 to 20, more preferably 3 to 15, still more preferably 3 to 10, and particularly preferably 3 to 6. In this case, m represents the degree of condensation of the lactic acid oligomer derivative, that is, the number of lactic acid units which are repeating units of the lactic acid oligomer portion. For example, when m = 2, a dimer is represented by m = 3 In the case of, each represents a trimer.
[0026]
In the lactic acid oligomer derivative of the present invention, in the formula (I), Y is -COR. 1 R represents 1 Represents an aliphatic group, an aryl group, or a heterocyclic group which may be substituted.
[0027]
Examples of the aliphatic group which may be substituted include, for example, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, a lower haloalkyl group, a lower alkoxy group, a lower alkoxyalkyl group, a lower alkoxycarbonyl group, a lower alkylthio group, and a lower alkyl group. And a sulfinyl group and a lower alkylsulfonyl group. The number of carbon atoms of the aliphatic group is not particularly limited, but is usually 1 to 10, preferably 1 to 6, and more preferably 1 to 4. In addition, the chain type is not particularly limited, and may be any of a linear chain, a branched chain, a cyclic chain, or a combination thereof.
More specifically, for example, lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like; lower alkenyl groups include vinyl , Propenyl, butenyl group and the like (further, the latter two groups include a group which is an isomer depending on the position of a double bond.); Examples of the lower alkynyl group include an ethynyl group, a propynyl group, a butynyl group and the like. Lower cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctanyl group and the like; lower haloalkyl group includes fluoromethyl group, difluoromethyl group, Dichloroethyl group, bromopropyl group, etc .; An oxy group, an ethoxy group, a propoxy group, a butoxy group and the like; a lower haloalkoxy group such as a monofluoromethoxy, chloropropoxy group and a group that is an isomer thereof; and an alkoxycarbonyl group such as a methoxycarbonyl group and an ethoxycarbonyl group An alkylthio group such as a methylthio group, an ethylthio group, a propylthio group, and a butylthio group, and isomers thereof; and an alkylsulfinyl group such as a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, A sulfinyl group, a group that is an isomer thereof, and the like; Examples of the alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group, and a group that is an isomer thereof.
[0028]
The optionally substituted aryl group is an aryl group having 6 to 24, preferably 6 to 12 carbon atoms, and the aryl group may have one or more substituents. Specific examples of such an aryl group include, for example, a phenyl group, a tolyl group, a naphthyl group, a benzyl group, a phenethyl group, a phenoxy group, a mesityl group, and a p-methoxyphenyl group.
[0029]
The optionally substituted heterocyclic group is a functional group having a 5- to 10-membered saturated or unsaturated monocyclic or condensed ring containing at least one oxygen atom, nitrogen atom, sulfur atom or phosphorus atom. It is. Specific examples of such a heterocyclic group include, for example, pyridyl group, imidazolyl group, quinolyl group, isoquinolyl group, pyrimidinyl group, pyrazinyl group, phthalazinyl group, triazinyl group, furyl group, thienyl group, pyrrolyl group, oxazolyl group, Examples include an isoxazolyl group, a thiazolyl group, a thiadiazolyl group, a triazolyl group, a benzimidazolyl group, a pyrrolidino group, a morpholino group, and a pyrazololyl group. These heterocyclic groups may have one or more substituents.
[0030]
Examples of the substituent which the aliphatic group, aryl group or heterocyclic group may have include, for example, halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), cyano group, nitro group, amino group Group, alkyl group, haloalkyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, acyl group, alkoxy group, alkoxyalkyl group, alkoxycarbonyl group, carbamoyl group, aryl group, aryloxy group, aryloxycarbonyl group, arylthio group , Arylsulfonyl, carbonamido, alkylsulfonamido, arylsulfonamido, and sulfamoyl groups.
[0031]
Among these, the R 1 Is preferably an aryl group having 6 to 24 carbon atoms which may be substituted, more preferably an aryl group having 6 to 12 carbon atoms which may be substituted, and still more preferably a halogen-substituted phenyl group.
[0032]
Specific examples of the halogen-substituted phenyl group include a 2,6-dichlorophenyl group, a 2,4,6-trichlorophenyl group, a 4-iodophenyl group, and a 2,4,6-tribromophenyl group. Of these, a dichlorophenyl group such as a 2,6-dichlorophenyl group and a 2,4,6-trichlorophenyl group or a trichlorophenyl group is more preferable.
[0033]
In the above formula (I), Y is -COR 1 If R 1 Is such a functional group, the terminal of the resulting lactic acid oligomer derivative is activated, and during the cyclization reaction described later, -OY (that is, -OCOR) 1 ) Is desirable because it is conveniently eliminated to give cyclic lactic acid oligomers.
[0034]
In the lactic acid oligomer derivative of the present invention, in the formula (I), Y is -R 2 R represents 2 Represents a heterocyclic group which may be substituted.
[0035]
The heterocyclic group which may be substituted is a 5- to 10-membered saturated or unsaturated monocyclic or condensed ring having at least one oxygen atom, nitrogen atom, sulfur atom or phosphorus atom. Group. Specific examples of such a heterocyclic group include, for example, pyridyl group, imidazolyl group, quinolyl group, isoquinolyl group, pyrimidinyl group, pyrazinyl group, phthalazinyl group, triazinyl group, furyl group, thienyl group, pyrrolyl group, oxazolyl group, Examples include an isoxazolyl group, a thiazolyl group, a thiadiazolyl group, a triazolyl group, a benzimidazolyl group, a pyrrolidino group, a morpholino group, and a pyrazololyl group. In addition, these heterocyclic groups may have one or more substituents.
[0036]
Examples of the substituent which the heterocyclic group may have include, for example, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a cyano group, a nitro group, an amino group, an alkyl group, a haloalkyl group , Alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, carbamoyl, aryl, aryloxy, aryloxycarbonyl, arylthio, arylsulfonyl, carbonamide Groups, alkylsulfonamide groups, arylsulfonamide groups, sulfamoyl groups and the like.
[0037]
Among these, the R 2 Is preferably a nitrogen atom-containing heteroaromatic ring group which may be substituted, and examples of the nitrogen atom-containing heteroaromatic ring group include a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a phthalazinyl group, and a triazinyl group. And the like.
[0038]
Among these, a pyridyl group which may be substituted, and a 2-pyridyl group which may be further substituted are more preferable, and specifically, for example, a 6-phenyl-2-pyridyl group, 4-methyl- A 6-phenyl-2-pyridyl group, a 6-benzyl-2-pyridyl group, a 6-tolyl-2-pyridyl group, and the like.
[0039]
Among these, a phenylpyridyl group such as a 6-phenyl-2-pyridyl group and a 4-methyl-6-phenyl-2-pyridyl group is more preferred.
[0040]
Y in the formula (I) is -R 2 If R 2 Is such a functional group, the terminal of the resulting lactic acid oligomer derivative is activated, and during the cyclization reaction described later, -OY (that is, -OR) 2 ) Is desirable because it is conveniently eliminated to give the desired cyclic lactic acid oligomer.
[0041]
Specifically, by using such a lactic acid oligomer derivative of the present invention, a cyclization reaction is preferably carried out in the presence of a catalyst such as aminopyridine or aromatic sulfonic acid, thereby obtaining an integral multiple of the degree of condensation of the lactic acid oligomer derivative. Can be obtained. For example, under the condition that the solvent is refluxed in the presence of a catalyst, -OY is eliminated from the terminal of n (n is an integer of 1 or more) linear lactic acid oligomer derivatives (degree of condensation m) to form one or more linear lactic acid oligomers. Cyclization of the residue mainly produces a cyclic lactic acid oligomer mixture containing a cyclic lactic acid oligomer having a degree of condensation of mn.
[0042]
The degree of condensation mn of the resulting mixture of cyclic lactic acid oligomers is affected by the degree of condensation of the linear lactic acid oligomer derivative of the present invention, which is a synthetic intermediate. That is, as described above, if the degree of condensation m of the linear lactic acid oligomer derivative as a synthetic intermediate is 3, the resulting cyclic lactic acid oligomer has a degree of condensation of 3, 6, 9,. (An integer of 1 or more). Therefore, the degree of condensation mn of the resulting mixture of cyclic lactic acid oligomers varies depending on the degree of condensation m of the linear lactic acid oligomer derivative, which is a synthetic intermediate, but is on average 3 to 60, preferably 3 to 24. can do.
[0043]
That is, the mixture of the cyclic lactic acid oligomers is a specific cyclic lactic acid oligomer group whose degree of condensation is an integral multiple of the degree of condensation of the linear lactic acid oligomer derivative of the present invention. Accordingly, by selecting the degree of condensation of the linear lactic acid oligomer derivative of the present invention and, consequently, the degree of condensation of the linear lactic acid oligomer which is the starting material of the derivative, the desired cyclic lactic acid oligomer and other cyclic lactic acid oligomer (condensation degree (Integrally varying).
[0044]
By separating a mixture having a relatively simple composition by a conventionally known method such as column chromatography or high-performance liquid chromatography, a cyclic lactic acid oligomer having a desired chain length (condensation degree) can be easily isolated. Can be obtained.
[0045]
The lactic acid oligomer derivative of the present invention contains an asymmetric carbon atom and has a stereoisomer. However, all possible isomers and mixtures comprising two or more such isomers in any proportion are also included in the lactic acid oligomer derivatives of the invention. Specifically, various optical isomers such as optically active isomers, racemates and diastereomers, and mixtures thereof are also included in the lactic acid oligomer derivative of the present invention.
[0046]
Further, the lactic acid oligomer derivative of the present invention and the chain lactic acid oligomer as a starting material thereof may be a metal salt (eg, sodium salt, potassium salt, magnesium salt, calcium salt, aluminum salt, zinc salt, etc.), hydrate, solvate It can take various forms such as a product and a polymorph.
[0047]
<< Production method of lactic acid oligomer derivative >>
Next, a preferred method for producing the linear lactic acid oligomer derivative of the present invention will be specifically described.
[0048]
The lactic acid oligomer derivative includes a lactic acid oligomer represented by the following general formula (II):
[0049]
Embedded image
(In the formula (II), m is the same as the formula (I).)
R 1 COX [where R 1 Is the same as in formula (I), and X is a hydroxyl group, a halogen atom, -OCOR 4 (R 4 Is R 1 Represents an aliphatic group, an aryl group, or a heterocyclic group which may be the same or different and may be substituted. ). A carboxylic acid or a carboxylic acid derivative represented by
R 3 = O [where R 3 Represents a heterocyclic group having a hetero atom adjacent to the carbonyl group (which may have a substituent). And a cyclic ketone represented by the formula:
Preferably, it can be produced by reacting in the presence of a base.
[0051]
The chain lactic acid oligomer represented by the above formula (II) is a single compound having a specific chain length and having a repetition of m lactic acid units. Here, m is the same as in formula (I), and specifically, is usually 2 or more, for example, 2 to 30, preferably 3 to 20, more preferably 3 to 15, still more preferably 3 to 10, and particularly preferably 3 to 10. It preferably represents an integer of 3 to 6.
[0052]
The present inventors have already proposed a method for producing a single linear lactic acid oligomer having such a specific chain length (Japanese Patent Application No. 2002-042009). According to this method, a linear lactic acid oligomer having a constant chain length between 3 to 20 mer can be directly synthesized as a single compound.
[0053]
Specifically, a hydroxyl-protected lactic acid oligomer is reacted with a carboxyl-protected lactic acid or lactic acid oligomer, and if necessary, the hydroxyl-protecting group in the obtained lactic acid oligomer having a constant chain length is fluorinated. By treating with a hydrochloric acid and treating the carboxyl protecting group with trifluoroacetic acid / methylene chloride, it is possible to selectively deprotect and obtain a single linear lactic acid oligomer having a specific chain length. it can.
[0054]
More specifically, for example, reacting tert-butyldimethylsiloxylactoyl lactic acid with tert-butyl lactoyl lactate using methylene chloride as a solvent in the presence of 4-dimethylaminopyridine and N, N′-dicyclohexylcarbodiimide. As a result, tert-butyldimethylsiloxylactic acid tetramer tert-butyl ester is obtained. This is treated with hydrofluoric acid to obtain a lactic acid tetramer tert-butyl ester, and the lactic acid tetramer tert-butyl ester is further treated with trifluoroacetic acid / methylene chloride to obtain a linear lactic acid oligomer. A tetramer can be obtained.
[0055]
In the present invention, this method can be used to directly prepare a linear lactic acid oligomer desired as a starting material.
[0056]
Further, R which reacts with the linear lactic acid oligomer 1 COX [where R 1 Is the same as in formula (I), and X is a hydroxyl group, a halogen atom, -OCOR 4 (R 4 Is R 1 Represents an aliphatic group, an aryl group, or a heterocyclic group which may be the same or different and may be substituted. ). The carboxylic acid or carboxylic acid derivative represented by the formula (1) is formed by reacting with the linear lactic acid oligomer to form an ester bond, 1 Is not particularly limited, as long as it can give to the terminal of the chain lactic acid oligomer, and may be any of carboxylic acid, acid halide, and acid anhydride.
[0057]
The R 1 When COX is an acid anhydride, that is, X is -OCOR 4 If R 4 Is R 1 Represents an aliphatic group, an aryl group, or a heterocyclic group which may be the same or different and may be substituted. Such an optionally substituted aliphatic group, aryl group, or heterocyclic group includes R 1 As described above.
[0058]
Among these, it is preferable to use an acid halide from the viewpoint of good reactivity and obtaining a lactic acid oligomer derivative with good yield.
[0059]
The acid halide may be any of oxyfluoride, acid chloride, acid bromide, and acid iodide.Of these, from the viewpoint of easy handling and availability, acid chloride and acid bromide are used. Preferred and specific examples include 2,6-dichlorobenzoyl chloride, 2,4,6-trichlorobenzoyl chloride, 4-iodobenzoyl chloride, and 2,4,6-tribromobenzoyl bromide.
[0060]
Among them, dichloro or trichlorobenzoyl chloride such as 2,6-dichlorobenzoyl chloride and 2,4,6-trichlorobenzoyl chloride are preferably used from the viewpoint of reactivity. The dichloro or trichlorobenzoyl chloride provides a dichloro or trichlorobenzoyl group as a functional group (-Y) for activating the carboxyl terminal of the linear lactic acid oligomer. These are used alone or in combination of two or more.
[0061]
A cyclic ketone R to be reacted with the linear lactic acid oligomer; 3 = O, reacts with the linear lactic acid oligomer to form an ester bond, 2 Is not particularly limited as long as it can give the terminal of the chain lactic acid oligomer, 3 Is usually a heterocyclic group having a heteroatom adjacent to the carbonyl carbon of the carbonyl group, and the heterocyclic group may have one or more substituents.
[0062]
That is, R 3 = 0 is a cyclic ketone having a heteroatom adjacent to the carbonyl carbon of the carbonyl group (the heteroatom has a hydrogen atom), and the heteroatom forms a heterocycle with the carbonyl carbon. It is. Further, the hetero atom is preferably a nitrogen atom.
[0063]
The cyclic ketone R 3 ＯO causes a structural change similar to keto-enol tautomerism when reacted with linear lactic acid oligomers, resulting in a compound R similar to the enol tautomer 2 OH (where R 2 Is the same as in formula (I). ) And the compound R 2 OH reacts with the carboxyl group at the terminal of the chain lactic acid oligomer to form an ester bond, thereby producing the lactic acid oligomer derivative of the present invention.
[0064]
Specific examples of the cyclic ketone include 2-pyridones, 2 (3H) -pyrazinones, oxazolones, 2-quinolones, isoquinolones, pyrimidine-2,4 (1H, 3H) -dione, and the like. 1,4-dihydro-2H-indol-2-ones, 1,7-dihydro-6H-purin-6-ones, 3H-1,2,4-triazole-3,5 (4H) -diones and the like Is mentioned.
[0065]
Among these compounds, 2-pyridones are preferred. The 2-pyridones provide a pyridyloxy group, preferably a 2-pyridyloxy group, as a functional group (-OY) for activating the carboxyl terminal of the linear lactic acid oligomer.
[0066]
More specifically, examples of the cyclic ketone include 6-phenyl-2-pyridone, 4-methyl-6-phenyl-2-pyridone, 6-benzyl-2-pyridone, 6-tolyl-2-pyridone, and the like. You. These are used alone or in combination of two or more.
[0067]
The linear lactic acid oligomer, R 1 A carboxylic acid or carboxylic acid derivative represented by COX, or R 3 The amount ratio at the time of reacting with the cyclic ketone represented by ＝ O is not particularly limited, and can be set in consideration of an equilibrium point, cost, and the like. The molar ratio is preferably from 1: 0.7 to 1 : 20, more preferably 1: 1 to 1:10.
[0068]
R 1 When a carboxylic acid or a carboxylic acid derivative represented by COX, particularly an acid halide, is used, the carboxylic acid or the carboxylic acid derivative (acid halide) is usually used in an amount of 1 to 5 equivalents based on the chain lactic acid oligomer, It is preferably used in an amount of 1 to 3 equivalents, more preferably 1 to 2.5 equivalents. Also, the cyclic ketone R 3 When ＯO is used, the cyclic ketone is used in an amount of usually 1 to 20 equivalents, preferably 5 to 12 equivalents, more preferably 6 to 10 equivalents, based on the linear lactic acid oligomer.
[0069]
In the method for producing a linear lactic acid oligomer derivative of the present invention, the reaction is desirably performed in the presence of a base. Presumably, the base acts as a catalyst when the terminal carboxyl group of the linear lactic acid oligomer is esterified. As such a base, either an inorganic base or an organic base can be used.
[0070]
Inorganic bases include hydroxides, hydrides, carbonates and bicarbonates of alkali metals such as lithium, sodium and potassium; hydroxides, hydrides, carbonates and carbonates of alkaline earth metals such as magnesium and calcium Hydrogen salts; alkali metal alkoxylates such as sodium methylate and sodium ethylate; and alkali metal weak acid salts such as sodium acetate, sodium monohydrogen phosphate and monopotassium hydrogen phosphate.
[0071]
Further, as the organic base, ammonia; pyridine derivatives such as pyridine, 2-chloro-1-methylpyridinium iodide and 4-dimethylaminopyridine; quaternary ammonium salts; trimethylamine, triethylamine, dimethylethylamine, diisopropylethylamine, aniline, naphthylamine Or an amine such as a substituent thereof; toluidines, xylidines, aminophenols, anilidines, phenetidines, aminobenzaldehydes, aminobenzonitrile, aminobenzophenones, aminobiphenyls and the like.
[0072]
Of these, triethylamine, diisopropylethylamine, 2-chloro-1-methylpyridinium iodide and the like are preferred. These are used alone or in combination of two or more.
[0073]
Specifically, acid halides such as 2,4,6-trichlorobenzoyl chloride (R 1 As the base used when using (COX), amines such as triethylamine and diisopropylethylamine are preferable. The amines are generally used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, based on the linear lactic acid oligomer.
[0074]
On the other hand, cyclic ketones such as 6-phenyl-2-pyridone (R 3 As the base used when ＝ O) is used, amines such as triethylamine and pyridine derivatives (including pyridine) such as pyridinium salts are preferable, and a combination of these is more preferable. The amines and the pyridinium salts are each used in an amount of usually 1 to 30 equivalents, preferably 1 to 15 equivalents, more preferably 1 to 10 equivalents, based on the linear lactic acid oligomer.
[0075]
The reaction is usually carried out at normal pressure, the reaction temperature is usually 4 to 40 ° C., preferably room temperature, and it is desirable to carry out the reaction in the presence of a reaction solvent.
[0076]
The reaction solvent is not particularly limited as long as it can dissolve the raw materials and is inert to the reaction. Specific examples of such a reaction solvent include ketone solvents such as acetone, methyl ethyl ketone, cyclopentanone and cyclohexanone; nitrile solvents such as acetonitrile; hydrocarbon solvents such as hexane, benzene, alkylbenzene, toluene and xylene; Amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone; diethyl ether, dimethoxyethane, methoxyethyl ether, tetrahydrofuran, 1,4-dioxane, 1,3-dioxane , Bis [2- (methoxyethyl) ethyl] ether and bis [2- (methoxyethoxy) ethyl] ether; ester solvents such as ethyl acetate and butyl acetate; dimethyl sulfoxide, dimethyl sulfone, sulfora , 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, tetramethylurea, phenol, chlorophenol, cresol, anisole, chloroform, dichloromethane, dichloroethylene, trichlorethylene, and the like. These solvents are used alone or in combination of two or more.
[0077]
Further, the reaction is preferably performed in an argon and / or nitrogen atmosphere. The reaction time is not particularly limited, but is usually 2 to 20 hours, preferably 2 to 12 hours from the viewpoint of production efficiency.
[0078]
【The invention's effect】
According to the present invention, a novel linear lactic acid oligomer derivative and a method for producing the same can be provided. Further, using the derivative as a synthetic intermediate, a mixture of cyclic lactic acid oligomers having a degree of condensation that is an integral multiple of the degree of condensation of the derivative can be obtained. By separating this mixture of cyclic lactic acid oligomers, a cyclic lactic acid oligomer having a desired degree of condensation (chain length) can be easily obtained as a single compound.
[0079]
【Example】
Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited to these examples.
[0080]
Example 1 Synthesis of lactic acid oligomer (trimer) derivative
[0081]
Embedded image
At room temperature under nitrogen atmosphere, 9.0 mg (0.0384 mmol) of linear lactic acid trimer was added to deuterated chloroform (CDCl 3 ) 0.3 ml of the solution was placed in a sample tube for NMR, and 18.7 mg (2.0 eq) of diisopropylethylamine was added to chloroform (CDCl). 3 0.15 ml of a solution was added, and 9.9 mg (2.0 eq) of 2,4,6-trichlorobenzoyl chloride was further added to 0.15 ml of deuterated chloroform (CDCl 3 ), And reacted for 1 hour in an NMR probe. Thereafter, 2,4,6-trichlorobenzoyl anhydride, a linear lactic acid trimer, was confirmed by NMR.
[0083]
Example 2 Synthesis of lactic acid oligomer (tetramer) derivative
[0085]
Embedded image
At room temperature under an argon atmosphere, 59.2 mg (0.1933 mmol) of linear lactic acid tetramer in deuterated chloroform (CDCl 3 ) A 0.3 ml solution was put into a sample tube for NMR, and 51.6 mg (2.1 eq) of diisopropylethylamine was added to chloroform (CDCl). 3 A 0.15 ml solution was added, and 97.6 mg (2.1 eq) of 2,4,6-trichlorobenzoyl chloride was further added to 0.15 ml of deuterated chloroform (CDCl 3 ) And stirred for 5 minutes in an ultrasonic cleaner cooled to 4 ° C. After reacting in an NMR probe for 1 hour, 2,4,6-trichlorobenzoyl anhydride of a linear lactic acid tetramer was confirmed by NMR.
[0087]
Example 3 Synthesis of lactic acid oligomer (pentamer) derivative
[0089]
Embedded image
At room temperature under a nitrogen atmosphere, 36.6 mg (0.0967 mmol) of linear lactic acid pentamer was added to deuterated chloroform (CDCl 3 ) A 0.3 ml solution was put into a sample tube for NMR, and 25.8 mg (2.1 eq) of diisopropylethylamine was added to chloroform (CDCl). 3 0.15 ml of a solution was added, and 48.8 mg (2.1 eq) of 2,4,6-trichlorobenzoyl chloride was further added to 0.15 ml of deuterated chloroform (CDCl 3 ), And the mixture was allowed to react for 1 hour. Then, 2,4,6-trichlorobenzoyl anhydride of a linear lactic acid pentamer was confirmed by NMR.
[0091]
Example 4 Synthesis of Lactic Acid Oligomeric (Hexamer) Derivative
[0093]
Embedded image
At room temperature under a nitrogen atmosphere, 43.0 mg (0.096 mmol) of linear lactic acid hexamer in deuterated chloroform (CDCl 3 A 0.35 ml solution was placed in a sample tube for NMR, and 29 mg (2.4 eq) of diisopropylethylamine was added to chloroform (CDCl). 3 0.17 ml of a solution was added, and 50.5 mg (2.2 eq) of 2,4,6-trichlorobenzoyl chloride was added to 0.13 ml of deuterated chloroform (CDCl 3 ), And the mixture was reacted for 1 hour. Then, 2,4,6-trichlorobenzoyl anhydride of a linear lactic acid hexamer was confirmed by NMR.
[0095]
Example 5 Synthesis of lactic acid oligomer (trimer) derivative
[0097]
Embedded image
At room temperature under an argon atmosphere, 0.2788 g (1.628 mmol) of 6-phenyl-2-pyridone, 0.4078 g (1.596 mmol) of 2-chloro-1-methylpyridinium iodide, and 0.1632 g (1.612 mmol) of triethylamine ) Was dissolved for 1 hour, the solution was kept at 60 ° C., and 0.0519 g (0.2216 mmol) of linear lactic acid trimer and 0. 18240 ml (0.2372 mmol) of a toluene solution in which 0.0240 g (0.2372 mmol) was dissolved was added dropwise over 9 hours, the temperature was maintained for 30 minutes after the dropwise addition, and then cooled to room temperature. The obtained reaction mixture was concentrated and isolated by column chromatography (eluent; dichloromethane: methanol = 100: 3) to obtain a linear lactic acid trimer pyridyl ester (0.673 g, yield 86%). The structure was confirmed by NMR.
[0099]
Example 6 Synthesis of lactic acid oligomer (tetramer) derivative
[0101]
Embedded image
At room temperature under an argon atmosphere, 0.3811 g (2.226 mmol) of 6-phenyl-2-pyridone, 0.5775 g (2.260 mmol) of 2-chloro-1-methylpyridinium iodide, and 0.2286 g (2.259 mmol) of triethylamine ) Was dissolved in 5 ml of dichloromethane, and a solution diluted with 50 ml of toluene was stirred for 1 hour. The solution was kept at 75 ° C., and 0.0883 g of a linear lactic acid tetramer ( (0.2883 mmol) and triethylamine (0.0370 g (0.3656 mmol)) dissolved in dichloromethane (5 ml) and diluted with toluene (30 ml) were added dropwise over a period of 9 hours or more. did. The obtained reaction mixture was concentrated and isolated by column chromatography (eluent; dichloromethane: methanol = 100: 3) to obtain a linear lactic acid tetramer pyridyl ester (0.1046 g, yield 82%). The structure was confirmed by NMR.
[0103]
[Reference Example 1] Synthesis of cyclic lactic acid oligomer mixture
[0105]
Embedded image
At room temperature under an argon atmosphere, 0.1535 ml (2.0 eq) of triethylamine was added to 5 ml of a THF (tetrahydrofuran) solution containing 0.1170 g (0.4996 mmol) of the linear lactic acid trimer, and 2,4,6-trichloroamine was further added. 5 ml of a THF solution containing 0.2561 g (2.0 eq) of benzoyl chloride was added, and the mixture was stirred for 2 hours. The obtained mixture was filtered under an argon atmosphere, and then diluted with 250 ml of toluene. 0.3667 g (6.0 eq) of 4-dimethylaminopyridine (DMAP) was dissolved in 50 ml of toluene and refluxed. When a high reflux state was reached, the mixture diluted with 250 ml of toluene was added dropwise over 5 hours using an automatic dropping device. After the completion of the dropwise addition, reflux was continued for 30 minutes. After the completion of the reflux, the mixture was cooled to room temperature, concentrated, and then isolated by column chromatography (eluent: benzene: ethyl acetate = 15: 4). 0.0552 g of a mixture of hexamer, cyclic lactic acid 9-mer, cyclic lactic acid 12-mer and cyclic lactic acid 15-mer was obtained.
[0107]
The mass spectrum of this cyclic lactic acid oligomer mixture was measured (by ESI-MS method). The mass spectrum chart is shown in FIG.
[Brief description of the drawings]
FIG. 1 is a mass spectrum chart of the cyclic lactic acid oligomer mixture obtained in Reference Example 1.
Claims (10)
Ｙは−ＣＯＲ１または−Ｒ２を表し、
Ｒ１は置換されていてもよい、脂肪族基、アリール基、またはヘテロ環基を表し、
Ｒ２は置換されていてもよいヘテロ環基を表す。A lactic acid oligomer derivative represented by the following general formula (I);
Y represents -COR 1 or -R 2,
R 1 represents an optionally substituted aliphatic group, aryl group, or heterocyclic group;
R 2 represents an optionally substituted heterocyclic group.
Ｒ１ＣＯＸ ［ここで、Ｒ１は式（Ｉ）と同じであり、Ｘは水酸基、ハロゲン原子、−ＯＣＯＲ４（Ｒ４はＲ１と同じであっても異なってもよく、置換されていてもよい、脂肪族基、アリール基、またはヘテロ環基を表す。）を表す。］ で示されるカルボン酸またはカルボン酸誘導体、あるいは、
Ｒ３＝Ｏ［ここで、Ｒ３はカルボニル基に隣接するヘテロ原子を有するヘテロ環基（置換基を有していてもよい）を表す。］で示される環状ケトンとを
反応させることを特徴とする請求項１に記載された乳酸オリゴマー誘導体の製造方法。A lactic acid oligomer represented by the following general formula (II):
R 1 COX wherein R 1 is the same as in formula (I), X is a hydroxyl group, a halogen atom, —OCOR 4 (R 4 may be the same as or different from R 1, and may be substituted Represents an aliphatic group, an aryl group, or a heterocyclic group.). A carboxylic acid or a carboxylic acid derivative represented by
R 3 ＯO [where R 3 represents a heterocyclic group having a hetero atom adjacent to the carbonyl group (which may have a substituent). The method for producing a lactic acid oligomer derivative according to claim 1, wherein the cyclic lactone derivative is reacted with a cyclic ketone represented by the formula:
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| JP2003158248A JP4316299B2 (en) | 2003-06-03 | 2003-06-03 | Chain lactic acid oligomer derivative and method for producing the same |
| PCT/JP2004/007697 WO2004108654A1 (en) | 2003-06-03 | 2004-06-03 | Chain lactic acid oligomer derivative and process for producing the same |
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| WO2008119518A1 (en) * | 2007-03-30 | 2008-10-09 | Laccure Ab | Use of oligomers of lactic acid in the treatment of gynaecological disorders |
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| JPH0959218A (en) * | 1995-08-25 | 1997-03-04 | Shimadzu Corp | L-lactic acid oligomer derivative |
| CN1379771A (en) * | 1999-09-20 | 2002-11-13 | 天藤制药株式会社 | Process for preparation of cyclic lactic acid oligomers |
| US6861538B1 (en) * | 1999-09-20 | 2005-03-01 | Amato Pharmaceutical Products, Ltd. | Process for the preparation of cyclic lactic acid oligomer |
| JP2002275256A (en) * | 2001-03-19 | 2002-09-25 | Tendou Seiyaku Kk | Method for producing lactic acid oligomer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008119518A1 (en) * | 2007-03-30 | 2008-10-09 | Laccure Ab | Use of oligomers of lactic acid in the treatment of gynaecological disorders |
| US8425894B2 (en) | 2007-03-30 | 2013-04-23 | Laccure Ab | Use of oligomers of lactic acid in the treatment of gynaecological disorders |
| US8912232B2 (en) | 2007-03-30 | 2014-12-16 | Laccure Ab | Use of oligomers of lactic acid in the treatment of gynaecological disorders |
| US9315444B2 (en) | 2007-03-30 | 2016-04-19 | Laccure Ab | Use of oligomers of lactic acid in the treatment of gynaecological disorders |
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