JP6057257B2 - 光学活性カルボン酸エステルの製造方法 - Google Patents
光学活性カルボン酸エステルの製造方法 Download PDFInfo
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- JP6057257B2 JP6057257B2 JP2013519521A JP2013519521A JP6057257B2 JP 6057257 B2 JP6057257 B2 JP 6057257B2 JP 2013519521 A JP2013519521 A JP 2013519521A JP 2013519521 A JP2013519521 A JP 2013519521A JP 6057257 B2 JP6057257 B2 JP 6057257B2
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- Prior art keywords
- carboxylic acid
- optically active
- group
- nmr
- cdcl
- 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.)
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- 238000004519 manufacturing process Methods 0.000 title claims description 27
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 title 1
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 54
- 150000008065 acid anhydrides Chemical class 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 239000011982 enantioselective catalyst Substances 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000000962 organic group Chemical group 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 150000001721 carbon Chemical group 0.000 claims description 9
- 230000003287 optical effect Effects 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 150000002989 phenols Chemical class 0.000 claims description 8
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 6
- 150000001735 carboxylic acids Chemical class 0.000 claims description 6
- 125000005561 phenanthryl group Chemical group 0.000 claims description 6
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 4
- 229960003184 carprofen Drugs 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 229960002373 loxoprofen Drugs 0.000 claims description 2
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 claims 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 claims 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims 1
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 claims 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 claims 1
- 229960001419 fenoprofen Drugs 0.000 claims 1
- 229960002390 flurbiprofen Drugs 0.000 claims 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims 1
- 229960004187 indoprofen Drugs 0.000 claims 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims 1
- 229960000991 ketoprofen Drugs 0.000 claims 1
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 claims 1
- 229960002009 naproxen Drugs 0.000 claims 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims 1
- 229960003101 pranoprofen Drugs 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 141
- 239000011734 sodium Substances 0.000 description 68
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 45
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 43
- 238000004128 high performance liquid chromatography Methods 0.000 description 40
- 238000004896 high resolution mass spectrometry Methods 0.000 description 37
- -1 9-phenanthryl group Chemical group 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 27
- 150000001875 compounds Chemical class 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000002798 polar solvent Substances 0.000 description 12
- 239000000758 substrate Substances 0.000 description 11
- YGCWPCVAVSIFLO-LBPRGKRZSA-N (2r)-2-phenyl-1,2-dihydroimidazo[2,1-b][1,3]benzothiazole Chemical compound C1([C@@H]2CN3C4=CC=CC=C4SC3=N2)=CC=CC=C1 YGCWPCVAVSIFLO-LBPRGKRZSA-N 0.000 description 10
- 230000006340 racemization Effects 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 230000032050 esterification Effects 0.000 description 8
- 238000005886 esterification reaction Methods 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- NHIXQVYVFRYTOB-UHFFFAOYSA-N dinaphthalen-1-ylmethanol Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4C=CC=3)O)=CC=CC2=C1 NHIXQVYVFRYTOB-UHFFFAOYSA-N 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 5
- 239000005711 Benzoic acid Substances 0.000 description 5
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 229960001680 ibuprofen Drugs 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-M ibuprofen(1-) Chemical compound CC(C)CC1=CC=C(C(C)C([O-])=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-M 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 229960001614 levamisole Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- YYEROYLAYAVZNW-UHFFFAOYSA-N 2-methyl-2-phenylpropanoic acid Chemical class OC(=O)C(C)(C)C1=CC=CC=C1 YYEROYLAYAVZNW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- OUBORTRIKPEZMG-UHFFFAOYSA-N INT-2 Chemical compound Nc1c(ncn1-c1ccc(F)cc1)C(=N)C#N OUBORTRIKPEZMG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 101000767160 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Intracellular protein transport protein USO1 Proteins 0.000 description 1
- 101001060278 Xenopus laevis Fibroblast growth factor 3 Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 125000005082 alkoxyalkenyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000005018 aryl alkenyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005015 aryl alkynyl group Chemical group 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- HEFNNWSXXWATRW-JTQLQIEISA-N dexibuprofen Chemical compound CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-JTQLQIEISA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 125000004447 heteroarylalkenyl group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005312 heteroarylalkynyl group Chemical group 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical class CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0241—Imines or enamines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/49—Esterification or transesterification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
Description
本発明の製造方法で用いられるラセミのカルボン酸は、特に限定されるものではないが、下記式(g)のようにカルボキシル基のα位に不斉炭素を有するものが好ましい。
本発明の製造方法で用いられるアルコールは、下記式(a)で表される。
本発明の製造方法で用いられるフェノール誘導体は、下記式(b)で表される。
本発明の製造方法で用いられる酸無水物は、脱水縮合剤として作用する。酸無水物としては、安息香酸、フェニル基にアルキル基、アルコキシ基、アミノ基、アルコキシアルキル基等の電子供与性基が結合した安息香酸、又はα位が4級炭素である多置換カルボン酸から得られるものが好ましく、安息香酸、炭素数1〜3のアルキル基又はアルコキシ基が結合した1〜3置換の安息香酸、ピバル酸、2−メチルー2−フェニルプロピオン酸、又は2,2−ジフェニルプロピオン酸から得られるものがより好ましい。
本発明の製造方法で用いられる不斉触媒は、特に限定されるものではないが、下記式(c)〜(f)で表されるものが好ましい。
本発明の製造方法で用いられる極性溶媒は、双極子モーメントが3.0以上である。このような極性溶媒としては、アセトニトリル、N−メチルピロリドン、N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、1,3−ジメチル−2−イミダゾリジノン、ジメチルスルホキシド等が挙げられる。双極子モーメントが3.0以上の極性溶媒を用いることによって、光学活性カルボン酸のラセミ化が起こりやすくなる。
光学活性カルボン酸エステルの製造は、極性溶媒中に、ラセミのカルボン酸、アルコール又はフェノール誘導体、酸無水物、及び不斉触媒を添加することによって行われるが、反応系内に塩基を添加することが好ましい。この塩基としては、求核性を有さない有機塩基が好ましく、トリメチルアミン、トリエチルアミン、ジイソプロピルエチルアミン等が挙げられる。極性溶媒中への添加順序は任意であるが、ラセミのカルボン酸と酸無水物とを含む溶液中に、アルコール又はフェノール誘導体、有機塩基、不斉触媒を順次加えることが好ましい。
s値は、Kaganらの方法(Top.Stereochem.,1988,vol18,p249−330)によって、以下のように算出した。
s=[ln(1−C)(1−回収アルコールのee)]/[ln(1−C)(1+回収アルコールのee)]。
変換率C(%)=[回収アルコールのee]/[(回収アルコールのee)+(生成したエステルのee)]
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=12.6min(4.7%),tR=23.1min(95.3%);
IR(neat):3036,1735,1599,1512,782,679cm−1;
1H NMR(CDCl3):δ
8.29(s,1H),
8.02−7.93(m,1H),
7.85−7.60(m,5H),
7.47−7.26(m,3H),
7.24−7.02(m,6H),
7.00−6.88(m,3H),
3.74(q,J=7.1Hz,1H),
2.38(d,J=7.1Hz,2H),
1.78(tqq,J=7.1,6.6,6.6Hz,1H),
1.43(d,J=7.1Hz,3H),
0.84(d,J=6.6Hz,6H);
13C NMR(CDCl3):δ173.7,140.6,137.2,134.9,134.7,133.8,133.7,131.2,130.9,129.3,129.1,128.8,128.7,128.6,127.5,126.7,126.34,126.25,125.8,125.6,125.2,125.0,123.5,123.4,70.9,45.3,45.0,30.2,22.4,18.1;
HR MS:calcd for C34H32O2Na(M+Na+)495.2295, found 495.2276.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane/TFA=1/100/0.1,flow rate=1.0mL/min):
tR=30.5min(86.0%),tR=34.0min(14.0%);
1H NMR(CDCl3):δ
10.30(br s,1H,COOH),
7.14(d,J=7.9Hz,2H),
7.02(d,J=7.9Hz,2H),
3.63(q,J=7.3Hz,1H),
2.37(q,J=7.3Hz,2H),
1.77(tqq,J=7.3,6.5,6.5Hz,1H),
1.42(d,J=7.3Hz,3H),
0.82(d,J=6.5Hz,6H);
13C NMR(CDCl3):δ181.0,140.8,136.9,129.4,127.3,45.0,44.9,30.2,22.4,18.1.
イブプロフェン(1)を基質とする不斉エステル化による動的速度論的光学分割において、反応条件を検討した。
イブプロフェンを基質とする不斉エステル化による動的速度論的光学分割において、溶媒の効果を検討した。
不斉エステル化による動的速度論的光学分割において、基質の芳香環上の置換基の効果を検討した。
N,N−ジメチルホルムアミド溶媒0.2モル中に、各種ラセミのカルボン酸1a〜iの1当量に対して、ピバル酸無水物を2.4当量、ジ(1−ナフチル)メタノールを1.2当量、ジイソプロピルエチルアミン4.8当量、(+)−ベンゾテトラミソールを5モル%加え、化学式に従って室温で48時間反応させた。反応系を0℃に冷却後、1規定塩酸を加え反応を停止した。有機層を分取後、水層を酢酸エチルで抽出した。有機層を合わせ、無水硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して粗生成物を得た。生成した光学活性エステルをシリカゲル薄層クロマトグラフィにより分離し、目的物を得た。
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=14.1min(8.2%),tR=19.7min(91.8%);
IR(neat):3051,1733,1598,1512,801,777,732cm−1;
1H NMR(CDCl3):δ
8.27(s,1H),
7.98−7.91(m,1H),
7.83−7.76(m,1H),
7.72(t,J=8.2Hz,2H),
7.66(d,J=8.2Hz,1H),
7.62(d,J=8.6Hz,1H),
7.44−7.36(m,1H),
7.31(t,J=7.5Hz,1H),
7.22−7.14(m,2H),
7.13−7.01(m,4H),
6.97(d,J=7.9Hz,2H),
6.92(d,J=7.5Hz,1H),
3.72(q,J=7.0Hz,1H),
2.25(s,3H),
1.42(d,J=7.0Hz,3H);
13C NMR(CDCl3):δ173.7,137.0,136.7,134.9,134.6,133.8,133.7,131.2,130.9,129.2,129.1,128.8,128.7,128.6,128.3,127.6,126.7,126.3,126.2,125.8,125.6,125.3,125.2,125.0,123.5,123.3,71.1,45.2,21.0,18.2;
HR MS:calcd for C31H26O2Na(M+Na+)453.1825,found 453.1816.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=14.4min(4.6%),tR=18.0min(95.4%);
1H NMR(CDCl3):δ
8.40−8.36(m,1H),
8.09−8.00(m,1H),
7.92−7.82(m,1H),
7.86−7.75(m,2H),
7.73(dd,J=8.4,8.4Hz,1H),
7.54−7.34(m,3H),
7.32−7.11(m,5H),
7.09−6.98(m,4H),
3.88−3.74(m,1H),
2.22(s,3H),
1.51(dd,J=6.9,1.8Hz,3H);
13C NMR(CDCl3):δ173.6,139.9,138.2,134.8,134.5,133.8,133.6,131.2,130.8,129.1,128.8,128.7,128.6,128.4,128.3,127.9,126.7,126.33,126.27,125.8,125.6,125.3,125.2,125.0,124.8,123.5,123.3,71.0,45.5,21.3,18.2;
HR MS:calcd for C31H26O2Na(M+Na+)453.1825, found 453.1817;
Analytical data on racemic compound:Mp:120−121℃(hexane);IR(KBr):3055,2970,2931,1597,1241,1157,779,741,710cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/50,flow rate=0.5mL/min):
tR=21.6min(4.1%),tR=34.0min(94.9%);
IR(neat):3057,1599,1510,752,730cm−1;
1H NMR(CDCl3):δ
8.31(s, 1H),
8.02−7.96(m, 1H),
7.83−7.78(m, 1H),
7.73(t,J=8.0Hz,2H),
7.69−7.62(m,2H),
7.45−7.39(m,2H),
7.34−7.30(m,1H),
7.23−7.17(m,2H),
7.14−7.00(m,6H),
6.88(d,J=8.0Hz,1H),
4.00(q,J=7.0Hz,1H),
2.16(s,3H),
1.43(d,J=7.0Hz,3H);
13C NMR(CDCl3):δ173.7,138.5,135.9,134.9,134.6,133.8,133.7,131.2,130.9,130.5,129.1,128.9,128.7,128.6,127.0,126.9,126.7,126.34,126.30,126.28,125.8,125.6,125.3,125.2,125.0,123.5,123.4,71.0,41.4,19.7,17.6;
HR MS:calcd for C31H26O2Na(M+Na+)453.1825,found 453.1813.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=22.7min(6.4%),tR=28.8min(93.6%);
IR(neat):3059,1733,1608,1512,783,733cm−1;
1H NMR(CDCl3):δ
8.26(s,1H),
7.97−7.89(m,1H),
7.85−7.58(m,5H),
7.46−7.04(m,9H),
6.93(d,J=6.9Hz,1H),
6.75−6.67(m,2H),
3.78−3.68(m,4H),
1.42(d,J=6.9Hz,3H);
13C NMR(CDCl3):δ173.7,158.7,134.8,134.6,133.8,133.6,132.1,131.2,130.9,129.1,128.83,128.76,128.71,128.6,128.3,126.7,126.3,126.2,125.8,125.6,125.3,125.2,125.0,123.5,123.3,113.9,71.0,55.3,44.8,18.2;
HR MS:calcd for C31H26O2Na(M+Na+)469.1774,found 469.1754.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=21.3min(4.5%),tR=35.6min(95.5%);
IR(neat):3055,2978,1736,1597,1250,1157,779,764,702cm−1;
1H NMR(CDCl3):δ
8.36(s,1H),
8.08−7.98(m,1H),
7.92−7.84(m,1H),
7.81(d,J=7.5Hz,1H),
7.79(d,J=8.1Hz,1H),
7.75(d,J=8.1Hz,1H),
7.72(d,J=8.7Hz,1H),
7.53−7.43(m,2H),
7.40(dd,J=7.5,7.5Hz,1H),
7.32−7.12(m,5H),
7.01(d,J=6.9Hz,1H),
6.87−6.71(m,3H),
3.82(q,J=7.2Hz,1H),
3.62(s,3H),
1.52(d,J=7.2Hz,3H);
13C NMR(CDCl3):δ173.4,159.7,141.4,134.7,134.5,133.8,133.6,131.2,130.8,129.5,129.1,128.8,128.7,128.6,126.7,126.4,126.3,125.8,125.6,125.3,125.2,125.0,123.4,123.3,120.1,113.1,112.9,71.1,55.1,45.6,18.1;
HR MS:calcd for C31H26O3Na(M+Na+)469.1774,found 469.1766.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=17.8min(1.5%),tR=30.0min(98.5%);
1H NMR(CDCl3):δ
8.35(s,1H),
8.13−7.95(m,1H),
7.82−7.53(m,5H),
7.46−7.32(m,3H),
7.30−7.07(m,7H),
6.79(td,J=7.6,1.2Hz,1H),
6.68(dd,J=8.1,1.2Hz,1H),
4.08(q,J=7.2Hz,1H),
3.39(s,3H),
1.42(d,J=7.2Hz,3H);
13C NMR(CDCl3):δ174.1,156.8,135.2,135.0,133.8,133.7,131.2,131.0,128.9,128.8,128.74,128.67,128.61,128.3,128.1,126.6,126.4,126.2,125.8,125.7,125.6,125.14,125.06,123.7,123.6,120.5,110.3,70.8,55.0,39.6,16.8;
HR MS:calcd for C31H26O3Na(M+Na+)469.1774,found 469.1770;
Analytical data on racemic compound:Mp:160−161℃(CHCl3/petroleum ether);IR(KBr):3060,1730,1600,1494,778,758cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=17.9min(6.6%),tR=20.3min(93.4%);
IR(neat):3052,1737,1599,1510,837,777cm−1;
1H NMR(CDCl3):δ
8.26(d,J=3.0Hz,1H),
7.90(dd,J=7.5,3.0Hz,1H),
7.81(d,J=7.5Hz,1H),
7.75(t,J=8.5Hz,2H),
7.70(d,J=8.0Hz,1H),
7.62(dd,J=8.5,3.0Hz,1H),
7.45−7.32(m,3H),
7.26−7.04(m,8H),
6.93(dd,J=7.0,3.0Hz,1H),
3.73(qd,J=8.5,1.5Hz,1H),
1.45−1.41(m,3H);
13C NMR(CDCl3):δ173.1,138.4,134.5,134.4,133.8,133.7,133.0,131.1,130.8,129.2,129.1,128.9,128.7,128.6,128.3,126.7,126.4,126.1,125.9,125.7,125.3,125.2,124.5,123.3,123.2,71.4,45.0,18.0;
HR MS:calcd for C30H23O2ClNa(M+Na+)473.1279,found 473.1284.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=12.7min(6.3%),tR=16.9min(93.7%);
IR(neat):3055,2978,1736,1589,1242,1165,787,756cm−1;
1H NMR(CDCl3):δ
8.37(s,1H),
8.00(d,J=8.5Hz,1H),
7.91−7.87(m,1H),
7.82(dd,J=7.5,7.5Hz,2H),
7.77(d,J=8.0Hz,1H),
7.73(d,J=8.5Hz,1H),
7.52−7.45(m,2H),
7.42(dd,J=7.5,7.5Hz,1H),
7.33−7.27(m,2H),
7.26−7.17(m,4H),
7.14(dd,J=7.5,7.5Hz,1H),
7.09(d,J=7.5Hz,1H),
7.04(d,J=8.0Hz,1H),
3.81(q,J=7.0Hz,1H),
1.51(d,J=7.0Hz,3H);
13C NMR(CDCl3):δ172.9,141.9,134.6,134.4,134.4,133.8,133.7,131.2,130.9,129.8,129.2,128.9,128.9,128.7,127.9,127.4,126.8,126.4,126.2,126.0,125.9,125.8,125.4,125.2,125.0,123.34,123.25,71.4,45.3,18.1;
HR MS:calcd for C30H23ClO2Na(M+Na+)473.1279,found 473.1298.
HPLC(CHIRALPAK IC,i−PrOH/hexane=1/50,flow rate=1.0 mL/min):
tR=8.7min(6.0%),tR=10.8min(94.0%);
1H NMR(CDCl3):δ
8.35(s,1H)
8.12−7.96(m,1H)
7.83−7.65(m,5H),
7.42−7.38(m,2H),
7.34(t,J=7.5Hz,1H)
7.30−7.21(m,3H),
7.19−7.12(m,3H),
7.10−6.98(m,3H),
4.29(q,J=7.5Hz,1H),
1.43(d,J=7.5Hz,3H);
13C NMR(CDCl3):δ173.1,137.8,134.8,134.5,133.83,133.81,133.7,131.2,130.9,129.5,129.1,128.9,128.8,128.7,128.5,128.3,127.0,126.7,126.4,126.3,125.8,125.7,125.6,125.2,125.0,123.6,123.4,71.4,42.1,17.4;
HR MS:calcd for C30H23O2ClNa(M+Na+)473.1279,found 473.1261;
Analytical data on racemic compound:Mp:143−144℃(petroleum ether);IR(KBr):3067,1718,1598,1509,795,764cm−1.
試験例4で最適化した条件のもとで、基質1j−1〜28の不斉エステル化による動的速度論的光学分割において、一般性の検討をした。
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/50,flow rate=1.0mL/min):
tR=14.8min(4.1%),tR=19.8min(95.9%);
1H NMR(CDCl3):δ
8.29(s,1H),
7.99−7.94(m,1H),
7.84−7.79(m,1H),
7.74(t,J=7.0Hz,2H),
7.68(d,J=8.0Hz,1H),
7.63(d,J=8.5Hz,1H),
7.45−7.38(m,2H),
7.35−7.31(m,1H),
7.23−7.14(m,7H),
7.11(t,J=7.5Hz,1H),
7.06(d,J=7.5Hz,1H),
6.90(d,J=7.0Hz,1H),
3.77(q,J=7.0Hz,1H),
1.45(d,J=7.0Hz,3H);
13C NMR(CDCl3):δ173.5,140.0,134.8,134.6,133.8,133.7,131.2,130.8,129.1,128.9,128.7,128.64,128.57,127.8,127.2,126.7,126.4,126.3,125.9,125.6,125.2,125.0,123.5,123.3,71.1,45.6,18.2;
HR MS:calcd for C30H24O2Na(M+Na+)439.1669,found 439.1668;
Analytical data on racemic compound:Mp:128℃(i−PrOH/hexane);IR(KBr):3067,1728,1600,1509,776,699cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=19.0min(4.3%),tR=32.7min(95.7%);
1H NMR(CDCl3):δ
8.33(s,1H),
7.97−7.83(m,2H),
7.83−7.56(m,7H),
7.46−6.92(m,11H),
6.85(d,J=7.2Hz,1H),
4.54(q,J=6.9Hz,1H),
1.60(d,J=6.9Hz,3H);
13C NMR(CDCl3):δ174.0,136.0,134.7,134.4,133.9,133.8,133.7,131.4,131.2,130.9,129.0,128.82,128.80,128.7,128.6,128.3,127.8,126.7,126.4,126.22,126.16,125.8,125.7,125.6,125.4,125.1,124.9,124.8,123.5,123.4,123.3,71.3,41.6,17.9;
HR MS:calcd for C34H26O2Na(M+Na+)489.1825,found 489.1809;
Anallytical data on racemic compound:Mp:152−153℃(CHCl3/petroleum ether);IR(KBr):3055,1735,1599,1494,778,757cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=25.3min(5.6%),tR=53.0min(94.4%);
IR(neat):3060,1737,1599,1509,755cm−1;
1H NMR(CDCl3):δ
8.30(s,1H),
7.95(d,J=7.6Hz,1H),
7.86−7.52(m,8H),
7.45−7.31(m,4H),
7.30−7.11(m,4H),
7.10−7.00(m,2H),
6.92(dd,J=7.8,7.5Hz,1H),
6.87(dd,J=8.1,6.9Hz,1H),
3.92(q,J=6.9Hz,1H),
1.53(d,J=6.9Hz,3H);
13C NMR(CDCl3):δ173.5,137.5,134.7,134.5,133.8,133.6,133.4,132.6,131.2,130.8,129.1,128.8,128.7,128.6,128.3,128.2,127.8,127.5,126.7,126.4,126.3,126.04,125.98,125.84,125.77,125.6,125.3,125.2,125.0,123.4,123.3,71.3,45.8,18.3;
HR MS:calcd for C34H26O2Na(M+Na+)489.1825,found 489.1815.
HPLC(CHIRALPAK IC,i−PrOH/hexane=1/50,flow rate=1.0mL/min):
tR=14.7min(2.6%),tR=23.9min(97.4%);
1H NMR(CDCl3):δ
8.62(d,J=8.4Hz,1H),
8.55(d,J=8.1Hz,1H),
8.38(s,1H),
7.79−7.87(m,2H),
7.82−7.22(m,14H),
7.20−7.05(m,2H),
7.01−6.90(m,3H),
4.54(q,J=6.9Hz,1H),
1.66(d,J=6.9Hz,3H);
13C NMR(CDCl3):δ174.0,134.6,134.4,134.3,133.8,133.7,131.4,131.2,130.9,130.8,130.7,130.4,129.9,129.0,128.83,128.76,128.6,128.3,126.8,126.7,126.6,126.4,126.3,126.2,125.82,125.80,125.72,125.65,125.1,125.0,123.9,123.5,123.3,123.2,122.3,71.4,42.0,17.8;
HR MS:calcd for C38H28O2Na(M+Na+)539.1982,found 539. 1968;
Analytical data on racemic compound:Mp:115−117℃(CHCl3/petroleum ether);IR(KBr):3058,1733,1599,1509,779,747,726cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=1.0mL/min):
tR=15.1min(6.4%),tR=31.1min(93.6%);
IR(neat):3055,2978,1728,1242,1157,1041,787,733cm−1;
1H NMR(CDCl3):δ
8.34(s,1H),
8.00(d,J=8.5Hz,1H),
7.91−7.86(m,1H),
7.82(dd,J=8.0,8.0Hz,2H),
7.77(d,J=8.0Hz,1H),
7.72(d,J=9.0Hz,1H),
7.48(dddd,J=15.0,7.5,7.5,2.0Hz,2H),
7.44−7.38(m,1H),
7.33−7.27(m,2H),
7.25(dd,J=8.0,8.0Hz,1H),
7.19(d,J=7.5Hz,1H),
7.08(d,J=7.5Hz,1H),
6.74−6.72(m,1H),
6.69−6.67(m,1H),
5.90(s,2H),
3.75(q,J=7.0Hz,1H),
1.48(d,J=7.0Hz,3H);
13C NMR(CDCl3):δ173.5,147.7,146.7,134.7,134.5,133.8,133.74,133.69,131.2,130.9,129.1,128.84,128.81,128.6,126.7,126.3,126.2,125.8,125.6,125.4,125.2,125.0,123.5,123.3,120.1,108.20,108.16,100.9,71.2,45.2,18.2;
HR MS:calcd for C31H24O4Na(M+Na+)483.1567,found 483.1574.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/4,flow rate=0.5mL/min):
tR=17.6min(8.1%),tR=19.7min(91.9%);
IR(neat):3055,2939,1728,1597,1258,1158,787,733cm−1;
1H NMR(CDCl3):δ
8.35(s,1H),
8.01(d,J=7.5Hz,1H),
7.92−7.85(m,1H),
7.83(d,J=7.2Hz,1H),
7.81(d,J=7.5Hz,1H),
7.76(d,J=8.1Hz,1H),
7.70(d,J=8.7Hz,1H),
7.54−7.37(m,3H),
7.33−7.14(m,4H),
7.03(d,J=7.2Hz,1H),
6.82−6.71(m,2H),
6.67(d,J=1.5Hz,1H),
3.87(s,3H),
3.79(q,J=6.9Hz,1H),
3.58(s,3H),
1.52(d,J=6.9Hz,3H);
13C NMR(CDCl3):δ173.6,148.8,148.1,134.7,134.5,133.8,133.6,132.4,131.1,130.8,129.1,128.8,128.7,128.6,126.7,126.3,126.2,125.8,125.7,125.3,125.2,125.0,123.4,123.3,119.8,111.0,110.5,71.1,55.9,55.6,45.2,18.2;
HR MS:calcd for C32H28O4Na(M+Na+)499.1880,found 499.1877.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/4,flow rate=0.5mL/min):
tR=14.8min(5.0%),tR=18.2min(95.0%);
IR(neat):3055,2939,1736,1604,1157,1057,787,741cm−1;
1H NMR(CDCl3):δ
8.37(s,1H),
8.03(d,J=8.0Hz,1H),
7.92−7.86(m,1H),
7.82(dd,J=9.0,9.0Hz,2H),
7.77(d,J=8.5Hz,1H),
7.73(d,J=8.5Hz,1H),
7.53−7.44(m,2H),
7.42(dd,J=7.5,7.5Hz,1H),
7.33−7.20(m,3H),
7.18(d,J=7.0Hz,1H),
7.07(d,J=7.0Hz,1H),
6.38−6.34(m,3H),
3.78(q,J=7.0Hz,1H),
3.62(s,6H),
1.51(d,J=7.0Hz,3H);
13C NMR(CDCl3):δ173.2,160.8,142.2,134.7,134.5,133.8,133.7,131.2,130.9,129.1,128.9,128.7,128.6,126.7,126.4,126.3,125.9,125.7,125.4,125.2,125.0,123.5,123.3,105.6,99.6,71.2,55.2,45.9,18.1;
HR MS:calcd for C32H28O4Na(M+Na+)499.1880,found 499.1886.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/4,flow rate=0.5mL/min):
tR=14.9min(5.2%),tR=17.7min(94.8%);
1H NMR(CDCl3):δ
8.37(s,1H),
8.01(d,J=8.0Hz,1H),
7.90(d,J=7.0Hz,1H),
7.83(dd,J=8.5,8.5Hz,2H),
7.78(d,J=8.0 Hz,1H),
7.71(d,J=8.5Hz,1H),
7.55−7.44(m,2H),
7.43(dd,J=7.5,7.5Hz,1H),
7.35−7.22 (m,3H),
7.18(d,J=7.0Hz,1H),
7.06(d,J=7.0Hz,1H),
6.42−6.37(m,2H),
3.85(s,3H),
3.82−3.75(m,1H),
3.62(s,6H),
1.53(d,J=7.0Hz,3H);
13C NMR(CDCl3)δ173.3,153.2,135.5,135.5,134.6,134.5,133.8,133.7,131.2,130.9,129.2,128.9,128.8,128.7,126.7,126.4,126.3,125.9,125.7,125.4,125.2,125.0,123.5,123.3,104.6,71.3,60.8,55.9,45.9,18.1;
HR MS:calcd for C33H30O5Na(M+Na+)529.1985,found 529.1964;
Analytical data on racemic compound:Mp:85−86℃(CHCl3/petroleum ether);IR(KBr):3055,2939,1728,1589,1242,1134,787cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=12.3min(5.4%),tR=15.2min(94.6%);
IR(neat):3055,2978,1728,1604,1257,1157,1072,779,756,694cm−1;
1H NMR(CDCl3):δ
8.37(s,1H),
8.01(d,J=8.0Hz,1H),
7.89(d,J=8.0Hz,1H),
7.83(dd,J=8.0,8.0Hz,2H),
7.77(d,J=8.5Hz,1H),
7.73(d,J=8.5Hz,1H),
7.53−7.45(m,2H),
7.44−7.39(m,1H),
7.32(d,J=7.5Hz,1H),
7.29(d,J=7.5Hz,1H),
7.25−7.16(m,3H),
7.00−6.91(m,4H),
3.84(q,J=7.0Hz,1H),
1.52(d,J=7.0Hz,3H);
13C NMR(CDCl3):δ172.9,162.8(d,J=246.3Hz),142.3(d,J=7.5Hz),134.6,134.4,133.8,133.7,131.1,130.8,130.0(d,J=8.1Hz),129.2,128.9,128.9,128.7,126.7,126.4,126.1,125.9,125.7,125.3,125.2,125.0,123.50,123.47,123.3(d,J=7.5Hz),114.7(d,J=21.8Hz),114.1(d,J=21.2Hz),71.3,45.3,18.0;
HR MS:calcd for C30H23FO2Na(M+Na+)457.1574,found 457.1581.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=14.7min(3.7%),tR=18.5min(96.3%);
1H NMR(CDCl3):δ
8.42(s,1H),
8.09−8.04(m,1H),
7.91−7.86(m,1H),
7.85−7.79(m,3H),
7.77(d,J=8.5Hz,1H),
7.52−7.47(m,2H),
7.42(dd,J=8.0,8.0Hz,1H),
7.33(dd,J=8.0,8.0Hz,1H),
7.31(dd,J=8.0,8.0Hz,1H),
7.27−7.16(m,4H),
7.13(d,J=7.0Hz,1H),
7.03−6.96(m,2H),
4.18(q,J=7.5Hz,1H),
1.52(d,J=7.5Hz,3H);
13C NMR(CDCl3):δ173.0,160.4(d,J=246.0Hz),134.8,134.6,133.8,133.7,131.2,130.9,129.1,128.84(d,J=7.3Hz),128.81,128.78,128.70(d,J=6.3Hz),128.67,127.3(d,J=14.4Hz),126.7,126.4,126.2,125.9,125.7,125.4,125.2,125.0,124.1(d,J=3.1Hz),123.5,123.4,115.4(d,J=22.7Hz),38.4(d,J=2.0Hz),17.3;
HR MS:calcd for C30H23FO2Na(M+Na+)457.1574,found 457.1555;
Analytical data on racemic compound:MP:127−128°C(hexane);IR(KBr):3062,1736,1188,1157,779cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=15.1min(7.6%),tR=17.6min(92.4%);
1H NMR(CDCl3):δ
8.43(s,1H),
8.12−8.05(m,1H),
7.91−7.85(m,2H),
7.86(d,J=8.5Hz,1H),
7.82(d,J=8.0Hz,1H),
7.76(d,J=8.5Hz,1H),
7.53−7.47(m,3H),
7.44−7.40(m,1H),
7.36−7.30(m,2H),
7.28−7.20(m,3H),
7.17(d,J=7.0Hz,1H),
7.14(ddd,J=7.5,7.5,1.0Hz,1H),
7.06(ddd,J=7.5,7.5,2.0Hz,1H),
4.37(q,J=7.0Hz,1H),
1.51(d,J=7.0Hz,3H);
13C NMR(CDCl3):δ173.0,139.5,134.7,134.5,133.8,133.7,131.2,130.9,129.1,128.9,128.8,128.7,128.6,127.6,126.7,126.4,126.3,125.8,125.70,125.65,125.2,125.0,124.5,123.6,123.4,71.4,44.7,17.7;
HR MS:calcd for C30H23BrO2Na(M+Na+)517.0774,found 517.0781;
Analytical data on racemic compound:Mp:138−139℃(CHCl3/petroleum ether);IR(KBr):3055,1188,787cm−1.
HPLC(CHIRALPAK IC,i−PrOH/hexane=1/50,flow rate=0.5mL/min):
tR=19.0min(9.2%),tR=23.2min(90.8%);
1H NMR(CDCl3):δ
8.32(s,1H),
7.98−7.90(m,1H),
7.84−7.67(m,5H),
7.45−7.32(m,3H),
7.31−7.14(m,5H),
7.09(dd,J=7.5,1.8Hz,1H),
7.03(dd,J=7.8,1.8Hz,1H),
6.94(dd,J=7.8,7.5Hz,1H),
4.30(q,J=7.2Hz,1H),
1.43(d,J=7.2Hz,3H);
13C NMR(CDCl3):δ
172.7,140.1,134.6,134.3,133.8,133.7,133.2,131.1,130.9,129.2,129.0,128.9,128.7,128.3,127.5,127.2,126.7,126.6,126.52,126.45,126.2,125.9,125.8,125.2,125.0,123.5,123.3,71.7,43.1,17.4;
HR MS:calcd for C30H22O2Cl2Na(M+Na+)507.0889,found 507.0887;
Analytical data on racemic compound:MP:151−154°C(petroleum ether);IR(KBr):3059,1737,1598,1510,1158,778cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=13.6min(8.9%),tR=18.3min(91.1%);
1H NMR(CDCl3):δ
8.35(s,1H),
8.01−7.92(m,1H),
7.84−7.65(m,5H),
7.44−7.32(m,2H),
7.29−7.16(m,6H),
7.14−7.09(m,1H),
7.04(d,J=8.4Hz,1H),
6.97(dd,J=8.4,1.8Hz,1H),
4.35(q,J=7.2Hz,1H),
1.42(d,J=7.2Hz,3H);
13C NMR(CDCl3):δ
172.7,136.3,134.50,134.45,134.3,133.8,133.7,133.4,131.1,130.9,129.33,129.26,129.18,129.0,128.9,128.7,127.2,126.7,126.4,126.2,125.9,125.74,125.70,125.2,125.0,123.5,123.3,71.7,41.7,17.3;
HR MS:calcd for C30H22O2Cl2Na(M+Na+)507.0889,found 507.0896;
Analytical data on racemic compound:IR(neat):3060,1733,1590,1510,1474,1156,777cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=1.0mL/min):
tR=11.0min(7.6%),tR=13.4min(92.4%);
IR(neat):3055,2978,1736,1597,1242,1157,1080,779,741,694cm−1;
1H NMR(CDCl3):δ
8.34(s,1H),
7.97(d,J=8.1Hz,1H),
7.93−7.85(m,1H),
7.83(d,J=7.2Hz,1H),
7.81(d,J=8.1Hz,1H),
7.77(d,J=8.1Hz,1H),
7.72(d,J=8.7Hz,1H),
7.54−7.37(m,3H),
7.36−7.16(m,5H),
7.11−6.99(m,2H),
6.73(d,J=8.4Hz,1H),
3.85(s,3H),
3.76(q,J=6.9Hz,1H),
1.49(d,J=6.9Hz,3H);
13C NMR(CDCl3):δ173.2,154.1,134.6,134.4,133.8,133.7,133.0,131.1,130.8,129.4,129.1,128.9,128.8,128.7,127.0,126.7,126.4,126.1,125.8,125.7,125.4,125.2,125.0,123.4,123.3,122.3,111.9,71.4,56.1,44.5,18.1;
HR MS:calcd for C31H25ClO3Na(M+Na+)503.1384,found 503.1387.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/4,flow rate=1.0mL/min):
tR=13.9min(6.9%),tR=35.8min(93.1%);
IR(neat):3035,1735,1660,1599,1511,780,680cm−1;
1H NMR(CDCl3):δ
8.28(s,1H),
7.93−7.85(m,1H),
7.82−7.54(m,6H),
7.52−7.44(m,2H),
7.44−7.06(m,13H),
6.95(d,J=7.1Hz,1H),
3.81(q,J=7.1Hz,1H),
1.46(d,J=7.1Hz,3H);
13C NMR(CDCl3):δ196.3,173.0,140.1,137.8,137.3,134.5,134.4,133.8,133.7,132.4,131.6,131.1,130.8,129.9,129.5,129.2,128.93,128.91,128.86,128.7,128.6,128.3,128.2,126.7,126.4,126.1,125.9,125.7,125.4,125.2,125.0,123.2,71.4,45.5,17.9;
HR MS:calcd for C37H28O3Na(M+Na+)543.1931,found 543.1910.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/50,flow rate=1.0mL/min):
tR=21.0min(6.7%),tR=25.2min(93.3%);
IR(neat):3036,1735,1585,1484,781,679cm−1;
1H NMR(CDCl3):δ
8.28(s,1H),
7.92(d,J=8.0Hz,1H),
7.82−7.62(m,5H),
7.43−7.30(m,3H),
7.27−7.09(m,7H),
6.98−6.91(m,3H),
6.86−6.83(m,1H),
6.82−6.73(m,3H),
3.72(q,J=7.0Hz,1H),
1.42(d,J=7.0Hz,3H);
13C NMR(CDCl3):δ173.1,157.3,157.0,141.9,134.7,134.6,133.8,133.7,131.2,130.9,129.8,129.7,129.1,128.9,128.8,128.7,128.3,126.7,126.4,126.1,125.9,125.7,125.3,125.2,125.1,123.4,123.3,123.1,122.6,118.7,118.4,117.6,71.2,45.5,17.9;
HR MS:calcd for C36H28O3Na(M+Na+)531.1931,found 531.1948.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.75mL/min):
tR=10.8min(9.5%),tR=17.7min(90.5%);
IR(neat):3035,1734,1599,1513,783,679cm−1;
1H NMR(CDCl3):δ
8.29(s,1H),
7.95−7.86(m,1H),
7.80−7.72(m,1H),
7.70(d,J=8.1Hz,2H),
7.64(d,J=8.1Hz,2H),
7.46−7.04(m,13H),
7.01−6.90(m,3H),
3.74(q,J=7.0Hz,1H),
1.44(t,J=7.0Hz,3H);
13C NMR(CDCl3):δ172.9,159.6(d,J=248.2Hz),141.3,141.2,135.5,134.6,134.4,133.8,133.7,131.1,130.9,130.7(d,J=3.7Hz),129.2,128.9(d,J=3.2Hz),128.7,128.5,128.3,127.8(d,J=13.7Hz),127.7,126.7,126.4,126.1,125.9,125.7,125.4,125.2,125.0,123.8(d,J=3.1Hz),123.4,123.3,115.4(d,J=23.6Hz),71.5,45.1,17.9;
HR MS:calcd for C36H27O2FNa(M+Na+)533.1887,found 533.1865.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=1.0mL/min):
tR=13.1min(5.1%),tR=16.5min(94.9%);
IR(neat):3034,1733,1604,1508,782,679cm−1;
1H NMR(CDCl3):δ
8.29(s,1H),
8.00−7.90(m,1H),
7.82−6.96(m,17H),
6.95−6.81(m,2H),
3.86(q,J=7.0Hz,1H),
3.79(s,3H)
1.49(d,J=7.0Hz,3H);
13C NMR(CDCl3):δ173.6,157.6,135.1,134.7,134.5,133.8,133.7,133.6,131.2,130.8,129.3,129.1,128.9,128.8,128.7,128.6,128.3,127.1,126.7,126.5,126.3,126.2,125.8,125.6,125.3,125.2,125.0,123.4,123.3,118.9,105.5,71.2,55.2,45.5,18.3;
HR MS:calcd for C35H28O3Na(M+Na+)519.1931,found 519.1932.
HPLC(CHIRALPAK IA,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=23.5min(94.4%),tR=28.3min(5.6%);
1H NMR(CDCl3):δ
8.36(s,1H),
8.06−7.97(m,1H),
7.95−7.86(m,1H),
7.82(dd,J=8.1,4.2Hz,2H),
7.76(dd,J=8.9,8.9Hz,2H),
7.55−7.37(m,3H),
7.34−7.12(m,6H),
7.08−6.98(m,3H),
3.82(q,J=7.2Hz,1H),
3.14(ddd,J=13.7,3.3,3.3Hz,1H),
2.51(ddd,J=13.7,10.2,3.3Hz,1H),
2.42−2.25(m,2H),
2.19−1.88(m,3H),
1.83−1.64(m,1H),
1.51(d,J=7.2Hz,3H);
13C NMR(CDCl3):δ
220.0,173.5,138.90,138.88,137.8,134.8,134.6,133.8,133.7,131.18,131.17,130.9,129.1,129.0,128.8,128.7,128.6,127.8,126.68,126.67,126.3,126.2,126.1,125.8,125.63,125.61,125.29,125.26,125.2,124.9,123.5,123.34,123.32,71.05,71.04,51.0,45.2,38.2,35.2,35.1,29.2,29.1,20.5,18.13,18.11;
HR MS:calcd for C36H32O3Na(M+Na+)535.2244,found 535.2232;
Analytical data on racemic compound:IR(neat):2970,1736,1597,1450,779,756cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/4,flow rate=1.0mL/min):
tR=16.4min(89.2%),tR=19.6min(10.8%);
1H NMR(CDCl3):δ
8.35(s,1H),
8.23−8.14(m,1H),
8.01−7.92(m,1H),
7.91−7.82(m,1H),
7.80(dd,J=8.4,8.4Hz,2H),
7.72(dd,J=9.3,9.3Hz,2H),
7.51−7.40(m,3H),
7.39−7.16(m,5H),
7.12−6.98(m,4H),
6.95−6.89(m,1H),
3.88−3.70(m,3H),
1.52(d,J=7.2Hz,3H);
13C NMR(CDCl3):δ
173.4,158.4,150.8,146.6,138.3,135.3,134.6,134.5,133.8,133.7,131.1,130.9,129.1,128.81,128.81,128.6,127.6,127.4,126.7,126.3,126.1,125.8,125.6,125.4,125.1,125.0,123.4,123.3,119.8,119.5,117.1,115.3,71.4,44.9,27.8,18.0;
HR MS:calcd for C36H27NO3Na(M+Na+)544.1833,found 544.1880;
Analytical data on racemic compound:MP:189−190°C(i−PrOH/hexane);IR(KBr);3055,1728,1666,1427,1157,787cm−1.
HPLC(CHIRALPAK IC,i−PrOH/hexane=1/1,flow rate=1.0mL/min):
tR=13.7min(95.2%),tR=16.8min(4.8%);
1H NMR(CDCl3):δ
8.37(s,1H),
8.07−7.97(m,1H),
7.96−7.84(m,2H),
7.80(d,J=8.1Hz,2H),
7.78−7.69(m,4H),
7.62−7.43(m,5H),
7.38(dd,J=7.2,7.2Hz,1H),
7.34−7.16(m,6H),
7.07(d,J=8.4Hz,1H),
4.76(s,2H),
3.85(q,J=7.2Hz,1H),
1.53(d,J=7.2Hz,3H);
13C NMR(CDCl3):δ
173.4,167.4,140.0,138.5,135.9,134.7,134.5,133.8,133.7,133.1,132.04,132.04,131.2,130.8,129.1,128.83,128.78,128.6,128.43,128.43,128.35,126.7,126.4,126.2,125.8,125.6,125.4,125.2,125.1,124.1,123.4,123.3,122.6,119.5,71.2,50.6,45.1,18.1;
HR MS:calcd for C38H29NO3Na(M+Na+)570.2040,found 570.2018;
Analytical data on racemic compound:MP:193−194°C(i−PrOH/hexane);IR(KBr):3047,1728,1697,1458,1157,787cm−1
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/4,flow rate=1.0mL/min):
tR=9.6min(95.6%),tR=12.9min(4.4%);
1H NMR(DMSO−d6):δ
11.4(s.1H),
8.28(s,1H),
8.23(s,1H),
8.10(d,J=7.5Hz,1H),
8.07−7.94(m,2H),
7.93(d,J=8.5Hz,1H),
7.89(d,J=8.5Hz,1H),
7.81(d,J=7.0Hz,1H),
7.69(d,J=8.5Hz,1H),
7.67−7.25(m,7H),
7.24−7.00(m,3H),
6.87(d,J=7.5Hz,1H),
4.22−4.09(m,1H),
1.53(d,J=7.5Hz,3H);
13C NMR(DMSO−d6):δ
173.4,140.8,138.6,138.5,134.5,134.3,133.6,133.4,130.7,130.3,129.2,129.1,128.9.128.8,127.2,126.7,126.2,126.0,125.9,125.5,125.4,125.1,125.0,123.7,123.1,123.0,122.98,122.95,121.0,120.9,119.9,118.9,112.6,110.3,70.6,45.2,18.7;
Analytical data on racemic compound:MP:250−251°C(EtOAc/hexane);IR(KBr):3356,3062,1705,1466,1173,787cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=14.4min(93.6%),tR=16.9min(6.4%);
1H NMR(CDCl3):δ
8.41−8.34(m,1H),
8.27(d,J=8.5Hz,1H),
8.13(s,1H),
8.00(d,J=6.5Hz,1H),
7.88(s,1H),
7.84(d,J=7.5Hz,1H),
7.80−7.64(m,5H),
7.46−7.37(m,3H),
7.28−7.09(m,5H),
7.08−6.99(m,2H),
4.06−3.95(m,1H),
1.62(dd,J=7.5,2.5Hz,3H),
1.56(s,9H);
13C NMR(CDCl3):δ
173.3,150.5,139.8,138.9,137.2,134.7,134.4,133.8,133.6,131.2,130.8,129.1,128.8,128.7,128.6,128.5,126.9,126.8,126.6,126.22,126.18,125.8,125.5,125.4,125.1,124.9,123.8,123.4,123.3,123.1,119.7,119.2,117.3,115.8,84.2,71.4,46.2,28.1,18.4;
HR MS:calcd for C41H34O4NClNa(M+Na+)662.2069,found 662.2052;
Analytical data on racemic compound:IR(neat):2978,1728,1466,1157,764,741cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=14.9min(4.4%),tR=17.5min(95.6%);
1H NMR(CDCl3):δ
8.38(s,1H),
8.03−7.95(m,1H),
7.92−7.74(m,5H),
7.53−7.38(m,3H),
7.37−7.11(m,6H),
6.93−6.87(m,2H),
4.13(q,J=7.2Hz,1H),
1.59(d.J=7.2Hz,3H);
13C NMR(CDCl3):δ
172.5,142.3,134.6,134.4,133.8,133.7,131.1,130.9,129.1,128.9,128.8,128.7,126.7,126.6,126.5,126.0,125.8,125.7,125.4,125.19,125.19,125.1,124.4,123.4,123.3,71.5,41.0,19.2;
HR MS:calcd forC28H22O2SNa(M+Na+)445.1233,found 445.1222;
Analytical data on racemic compound:MP:139−140°C(EtOAc/hexane);IR(KBr):3055,1736,1450,1173,787,702cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=17.0min(4.4%),tR=20.1min(95.6%);
1H NMR(CDCl3):δ
8.36(s,1H),
7.98(d,J=8.5Hz,1H),
7.89(d,J=7.5Hz,1H),
7.85(d,J=8.5Hz,1H),
7.82(d,J=8.5Hz,1H),
7.78(d,J=7.5Hz,1H),
7.77(d,J=7.0Hz,1H),
7.53−7.40(m,3H),
7.38−7.15(m,5H),
7.12−7.05(m,2H),
6.98(d,J=5.0Hz,1H),
3.97(q,J=7.5Hz,1H),
1.53(d,J=7.5Hz,3H);
13C NMR(CDCl3):δ
173.1,140.1,134.8,134.6,133.8,133.7,131.2,131.0,129.1,128.84.128.84,128.7,127.2,126.7,126.4,126.1,125.9,125.7,125.6,125.4,125.2,125.1,123.4,123.3,121.6,71.2,41.2,17.9;
HR MS:calcd forC28H22O2SNa(M+Na+)445.1233,found 445.1214;
Analytical data on racemic compound:MP:178−179°C(i−PrOH/hexane);IR(KBr):3055,1728,1450,1180,779cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=1.0mL/min):
tR=28.0min(98.6%),tR=34.8min(1.4%);
1H NMR(CDCl3):δ
8.41(s.1H),
7.95(d,J=8.5Hz,1H),
7.92−7.76(m,5H),
7.71(d,J=7.5Hz,2H),
7.52−7.18(m,9H),
7.11(d,J=7.5Hz,1H),
6.66(d,J=3.5Hz,1H),
6.10(d,J=3.5Hz,1H),
3.97(q.J=7.0Hz,1H),
3.75(s,3H),
2.42(s,3H),
1.60(d,J=7.0Hz,3H);
13C NMR(CDCl3):δ
185.8,171.6,141.9,140.1,137.4,134.4,134.3,133.81,133.76,131.2,131.0,130.9,129.41,129.41,129.21,129,15,128.9,128.8,128.67,128.67,126.7,126.6,125.9,125.83,125.83,125.7,125.2,125.1,123.24,123.19,122.3,107.4,71.8,37.7,33.0,21.5,16.3;
HR MS:calcd forC37H31NO3Na(M+Na+)560.2196,found 560.2191;
Analytical data on racemic compound:IR(neat):2985,1736,1620,1458,1250,1165,787,756cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/50,flow rate=0.6mL/min):
tR=27.6min(6.6%),tR=33.0min(93.4%);
1H NMR(CDCl3):δ
8.41(s,1H),
8.02(d,J=8.5Hz,1H),
7.97(d,J=10.0Hz,1H),
7.96(d,J=7.5Hz,1H),
7.83(d,J=7.5Hz,1H),
7.81(d,J=8.5Hz,1H),
7.77(d,J=9.5Hz,1H),
7.75(d,J=8.5Hz,1H),
7.46−7.14(m,11H),
6.50(s,1H),
4.69(q,J=7.0Hz,1H),
1.63(d,J=7.0Hz,3H),
1.42(s,9H);
13C NMR(CDCl3):δ
172.8,150.5,139.6,136.3,135.1,134.6,133.8,133.7,131.2,131.1,128.92,128.88,128.8,128.7,128.6,126.5,126.4,126.3,126.2,125.7,125.6,125.2,125.1,123.83,123.76,123.6,122.6,120.3,120.3,115.7,108.2,84.1,71.6,40.3,27.9,16.9;
HR MS:calcd forC37H33NO4Na(M+Na+)578.2302,found 578.2286;
Analytical data on racemic compound:IR(neat):2978,1736,1705,1458,1157,779,756cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):
tR=11.3min(0.3%),tR=21.7min(99.7%);
1H NMR(CDCl3):δ
8.37(s,1H),
8.13(d,J=8.1Hz,1H),
7.92(d,J=8.4Hz,1H),
7.88(d,J=7.8Hz,1H),
7.82(d,J=8.1Hz,1H),
7.81(d,J=8.1Hz,1H),
7.54(d,J=8.4Hz,1H),
7.51−7.34(m,5H),
7.32−7.02(m,7H),
4.07(q,J=7.2Hz,1H),
1.66−1.60(m,12H);
13C NMR(CDCl3):δ
173.3,149.6,134.6,134.4,133.8,133.7,131.1,130.9,129.0,128.9,128.8,128.6,126.6,126.4,126.0,125.8,125.71,125.71,125.1,125.0,124.45,124.45,123.43,123.38,123.17,123.17,122.4,119.47,119.41,115.1,83.6,71.6,37.1,28.2,17.0;
HR MS:calcd forC37H33NO4Na(M+Na+)578.2302,found 578.2285;
Analytical data on racemic compound:IR(neat):2978,1736,1728,1458,1157,787,756cm−1.
Claims (4)
- 動的速度論的光学分割による光学活性カルボン酸エステルの製造方法であって、
ラセミのカルボン酸と、下記式(a)で表されるアルコール又は下記式(b)で表されるフェノール誘導体とを、酸無水物と不斉触媒との存在下、双極子モーメント3.72以上の極性溶媒中で反応させ、前記ラセミのカルボン酸のうち一方のエナンチオマーを選択的にエステル化するとともに、他方のエナンチオマーをラセミ化することを含む、光学活性カルボン酸エステルの製造方法であって、
前記不斉触媒が下記式(c)〜(f)で表される光学活性カルボン酸エステルの製造方法。
- 前記ラセミのカルボン酸が下記式(g)で表される請求項1記載の光学活性カルボン酸エステルの製造方法。
- 前記式(g)中、Rg1、Rg2のいずれか一方は、多重結合を有する炭素原子を介して不斉炭素と結合する有機基であり、他方は、多重結合を有さない炭素原子を介して不斉炭素と結合する有機基である請求項2記載の光学活性カルボン酸エステルの製造方法。
- 前記ラセミのカルボン酸は、イブプロフェン、Ketoprofen、Fenoprofen、Flurbiprofen、Naproxen、Loxoprofen、Pranoprofen、Indoprofen、Carprofen又はN−Boc−Carprofenである、請求項1〜3のいずれか1項に記載の光学活性カルボン酸エステルの製造方法。
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