JPH02104581A - Alpha-hydroxymethyl-beta-lactone derivative - Google Patents
Alpha-hydroxymethyl-beta-lactone derivativeInfo
- Publication number
- JPH02104581A JPH02104581A JP63256486A JP25648688A JPH02104581A JP H02104581 A JPH02104581 A JP H02104581A JP 63256486 A JP63256486 A JP 63256486A JP 25648688 A JP25648688 A JP 25648688A JP H02104581 A JPH02104581 A JP H02104581A
- Authority
- JP
- Japan
- Prior art keywords
- hydroxy
- methyl
- acid
- formula
- lactone
- 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.)
- Pending
Links
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- -1 hydroxy-3-methylglutaryl Chemical group 0.000 abstract description 19
- 150000001875 compounds Chemical class 0.000 abstract description 18
- 239000002253 acid Substances 0.000 abstract description 15
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 abstract description 11
- 238000002360 preparation method Methods 0.000 abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- 125000006239 protecting group Chemical group 0.000 abstract description 6
- 150000002148 esters Chemical class 0.000 abstract description 5
- 102000005870 Coenzyme A Ligases Human genes 0.000 abstract 1
- 102000003960 Ligases Human genes 0.000 abstract 1
- 108090000364 Ligases Proteins 0.000 abstract 1
- 108010011449 Long-chain-fatty-acid-CoA ligase Proteins 0.000 abstract 1
- ALRHLSYJTWAHJZ-UHFFFAOYSA-N beta-hydroxy propionic acid Natural products OCCC(O)=O ALRHLSYJTWAHJZ-UHFFFAOYSA-N 0.000 abstract 1
- 230000008030 elimination Effects 0.000 abstract 1
- 238000003379 elimination reaction Methods 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000012156 elution solvent Substances 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000003180 beta-lactone group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 238000007273 lactonization reaction Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- WVYBBOXJKXXXOY-UHFFFAOYSA-N methyl 12-hydroxydodecanoate Chemical compound COC(=O)CCCCCCCCCCCO WVYBBOXJKXXXOY-UHFFFAOYSA-N 0.000 description 2
- QFZLQCAXDXMEFE-UHFFFAOYSA-N methyl 12-oxododecanoate Chemical compound COC(=O)CCCCCCCCCCC=O QFZLQCAXDXMEFE-UHFFFAOYSA-N 0.000 description 2
- YDJZXHZRXDLCEH-UHFFFAOYSA-N methyl 6-hydroxyhexanoate Chemical compound COC(=O)CCCCCO YDJZXHZRXDLCEH-UHFFFAOYSA-N 0.000 description 2
- FDNFXHCDOASWAY-UHFFFAOYSA-N methyl 6-oxohexanoate Chemical compound COC(=O)CCCCC=O FDNFXHCDOASWAY-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- ODCZJZWSXPVLAW-UHFFFAOYSA-N (2'R,3'R,7R)-(E,E)-11-[3'-(hydroxymethyl)-4'-oxo-2'-oxetanyl]-3,5,7-trimethyl-2,4-undecadienoic acid Natural products OC(=O)C=C(C)C=C(C)CC(C)CCCCC1OC(=O)C1CO ODCZJZWSXPVLAW-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 229940123239 Cholesterol synthesis inhibitor Drugs 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108010000775 Hydroxymethylglutaryl-CoA synthase Proteins 0.000 description 1
- 102100028888 Hydroxymethylglutaryl-CoA synthase, cytoplasmic Human genes 0.000 description 1
- ODCZJZWSXPVLAW-KXCGKLMDSA-N Hymeglusin Chemical compound OC(=O)/C=C(\C)/C=C(C)/C[C@H](C)CCCC[C@H]1OC(=O)[C@@H]1CO ODCZJZWSXPVLAW-KXCGKLMDSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000005641 Methyl octanoate Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical class [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- KKQKUWIVJQYGCW-UHFFFAOYSA-N methyl 2-formylpentanoate Chemical compound CCCC(C=O)C(=O)OC KKQKUWIVJQYGCW-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229960000380 propiolactone Drugs 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- GIZSHQYTTBQKOQ-UHFFFAOYSA-N threo-Syringoylglycerol Chemical compound COC1=CC(C(O)C(O)CO)=CC(OC)=C1O GIZSHQYTTBQKOQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Epoxy Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明の次の一般式（Ｉ）
（式中、Ｒは水素原子又は低級アルキを基を、ｎは４〜
１０の整数を示し、２及び３の配位はシス又はトランス
である）
で表わされる新規なα−ヒドロキシメチル−β−ラクト
ン誘導体及びその塩に関する。Detailed Description of the Invention [Industrial Application Field] The following general formula (I) of the present invention (wherein R is a hydrogen atom or a lower alkyl group, and n is 4 to 4)
The present invention relates to a novel α-hydroxymethyl-β-lactone derivative represented by the formula (integer 10, the coordination of 2 and 3 being cis or trans) and salts thereof.
従来、微生物の代謝産物である次式
で表わされる抗生物質１２３３Ａが強いコレステロール
生合成阻害作用を有し、高脂血症治療剤として有用なこ
とが知られている（％開昭６３−１４７２２号）。It has been known that antibiotic 1233A, which is a metabolite of microorganisms and is expressed by the following formula, has a strong cholesterol biosynthesis inhibitory effect and is useful as a therapeutic agent for hyperlipidemia. ).
そこで、本発明者は、α−ヒドロキシメチル−β−ラク
トンの種々の誘導体を合成し、その薬理作用を検討した
結果、上記０）式で表わされるα−ヒドロキシメチル−
β−ラクトン誘導体が優れたヒドロキシ−３−メチルグ
ルタリル・コエンザイムムシンテース（以下、ＨＭＧ
−Ｃｏ人シンテースと称する）阻害活性を有することを
見出し、本発明を完成した。Therefore, as a result of synthesizing various derivatives of α-hydroxymethyl-β-lactone and examining their pharmacological effects, the present inventors found that α-hydroxymethyl-β-lactone represented by the above formula 0)
Hydroxy-3-methylglutaryl coenzyme synthase (hereinafter referred to as HMG) is an excellent β-lactone derivative.
The present invention has been completed based on the discovery that the compound has an inhibitory activity (referred to as -Co human synthesis).
すなわち、本発明は、（Ｉ）式で表わされるα−ヒドロ
キシメチル−β−ラクトン誘導体及びその塩を提供する
ものである。That is, the present invention provides an α-hydroxymethyl-β-lactone derivative represented by formula (I) and a salt thereof.
本発明の式（Ｉ）において、Ｒの低級アルキル基として
は、メチル基、エチル基、ｎ−ゾロビル基、五−ゾロピ
ル基等が挙げられる。また塩としては、ナトリウム、カ
リウム等のアルカリ金属塩、マグネシウム、カルシウム
等のアルカリ土類金属塩が挙げられる。In formula (I) of the present invention, examples of the lower alkyl group for R include a methyl group, an ethyl group, an n-zorobyl group, and a 5-zoropyl group. Examples of the salt include alkali metal salts such as sodium and potassium, and alkaline earth metal salts such as magnesium and calcium.
本発明化合物（Ｉ）は、例えば次の反応式に従って、３
−ヒドロキシゾロピオン酸エステル（Ｉ）にω−ホルミ
ルカルゴン酸エステル（Ｉ）を反応せしめてジカルボン
酸エステル（ｆｆ） ドアＴｈ Ｌ、次いでこの一級水
酸基のみを保護して化合物（Ｖ）とした後、２個のエス
テルの一方又は両方を脱エステル化して化合物（Ｖｌ）
となし、次いでラクトン化して化合物（■）とし、更に
一級水酸基の保護基を脱離することによシ製造される。Compound (I) of the present invention can be prepared by, for example, 3 according to the following reaction formula.
-Hydroxyzolopionic acid ester (I) is reacted with ω-formylcargonic acid ester (I) to form a dicarboxylic acid ester (ff), and then only this primary hydroxyl group is protected to form a compound (V), Compound (Vl) is obtained by deesterifying one or both of the two esters.
It is then produced by lactonization to give compound (■), and further removing the protecting group of the primary hydroxyl group.
（Ｉ） 儂）
ＣＣＶ）
（■）
（式中、Ｒ，ｆｉカルゴキシル保護基を、Ｒ２は低級ア
ルキル基を、Ｒ３はヒドロキシ保護基を示し、Ｒは前記
と同じものを示す）
本方法の原料化合物（Ｉ）はβ−ゾロビオラクトンにベ
ンシルアルコール等のアルコールを水素化す） ＩＪウ
ムの存在下反応させることによシ製造される。また原料
化合物（Ｉ）は、例えば炭素環式ケトンをメタクロロ過
安息香酸及び三フフ化ホウ素ゾエチルエーテル錯体でラ
−ケトン化した後アルコール中で加溶媒分解すること
によって得られるヒドロキシ脂肪酸アルキルエステルに
ジメチルスルホキシド及びオキザリルクロリドを反応せ
しめることによ ・シ製造される。(I) I) CCV) (■) (In the formula, R, fi carboxyl protecting group, R2 is a lower alkyl group, R3 is a hydroxy protecting group, R is the same as above) Raw materials for this method Compound (I) is produced by reacting β-zorobiolactone with an alcohol such as benzyl alcohol in the presence of hydrogen. In addition, the starting compound (I) can be converted into a hydroxy fatty acid alkyl ester obtained by, for example, ar-ketonizing a carbocyclic ketone with metachloroperbenzoic acid and boron trifluoride zoethyl ether complex, and then solvolyzing it in alcohol. It is produced by reacting dimethyl sulfoxide and oxalyl chloride.
化合物（Ｉ）と偵）の反応は、リチウムゾイソプ−ｔ２
ヒルアミドの存在下、テトラヒドロフラン等の不活性溶
媒中、低温、好ましくは一２０℃以下の温度で実施され
る。The reaction between compound (I) and
It is carried out in the presence of hiramide in an inert solvent such as tetrahydrofuran at low temperature, preferably at a temperature below -20°C.
斯くして得られる化合物（ｆｆ）の−級水酸基のみを選
択的に保護する。当該保護基としては、例えばトリチル
基、メトキシエチルオキシメチル基、ペンシル基等が挙
げられる。トリチル基で保護するには、トリエチルアミ
ン、４−ジメチルアミノピリジン等の塩基の存在下、ト
リチルクロライドを反応させることによシ行われ、他の
保護基の場合もほぼ同様にして行われる。化合物（Ｖ）
はシアステレオマ−の混合物として得られ、これはカラ
ムクロマトグラフィーによって容易に分離することがで
きる。Only the -class hydroxyl group of the compound (ff) thus obtained is selectively protected. Examples of the protecting group include a trityl group, a methoxyethyloxymethyl group, and a pencil group. Protection with a trityl group is carried out by reacting trityl chloride in the presence of a base such as triethylamine or 4-dimethylaminopyridine, and protection with other protecting groups is carried out in substantially the same manner. Compound (V)
is obtained as a mixture of theastereomers, which can be easily separated by column chromatography.
化合物（Ｖ）の脱エステル化は、アルカリ加水分解、接
触還元等の常法によって行われる。Deesterification of compound (V) is carried out by conventional methods such as alkaline hydrolysis and catalytic reduction.
化合物（■）のラクトン化は、ＤＣＣｌ ベンゼンスル
ホニルクロリド、ノＱラドルエンスルホニルクロリド等
の脱水剤を用いて常法によシ行われる。Lactonization of the compound (■) is carried out in a conventional manner using a dehydrating agent such as DCCl benzenesulfonyl chloride or NO-Qradluenesulfonyl chloride.
化合物（■〕の脱保護基は、β−ラクトンが開裂しない
ような緩和な条件、例えばｎ−ゲタノール中トリフルオ
ロ酢酸、酢酸、ギ酸等の有機酸で処理する方法、ノＱラ
ゾウム炭素１、ｅラジウム、二酸化白金等を用いる接触
還元等によって行われる。The deprotecting group of compound (■) can be removed under mild conditions such that the β-lactone is not cleaved, such as by treatment with an organic acid such as trifluoroacetic acid, acetic acid, or formic acid in n-getanol. This is carried out by catalytic reduction using radium, platinum dioxide, etc.
上記方法における中間体及び目的化合物（Ｉ）は、有機
合成化学で通常採用されている抽出、再結晶、シリカゲ
ルクロマトグラフィー等の手段によって単離精製するこ
とができる。The intermediate and target compound (I) in the above method can be isolated and purified by extraction, recrystallization, silica gel chromatography, and other means commonly employed in organic synthetic chemistry.
本発明のα−ヒドロキシメチル−β−ラクトン誘導体（
Ｉ）のＨＭＧ −Ｃｏムシンテースに対ｔ−ル阻害活性
をＣ１１ｎｋｅｎｂｅａｒｄらの方法（Ｊ、Ｂｌｏｌ。α-Hydroxymethyl-β-lactone derivatives of the present invention (
I) The inhibitory activity against HMG-Co mucintase was determined by the method of C11kenbeard et al. (J, Blol.
Ｃｈ＠ｍ、 ２５０ 、３１０８ （Ｉ９７５） ）
に従って測定した結果は第１表の通シである。Ch@m, 250, 3108 (I975))
The results measured according to the method are shown in Table 1.
以下余白
第１表から明らかな如く、本発明化合物（Ｉ）は、強い
ＨＭＧ −ＣｏＡシンテース阻害活性を有し、新しいコ
レステロール合成阻害薬として有用である。As is clear from Table 1 below, the compound (I) of the present invention has strong HMG-CoA synthase inhibitory activity and is useful as a new cholesterol synthesis inhibitor.
次に参考例及び実施例を挙げて説明する。 Next, reference examples and examples will be given and explained.
参考例１
３−ヒドロキシグロビオン酸ベンゾルノ製造：
ベンゾルアルコール（７０Ｍ１）Ｋ６０％油状水素化ナ
トリウム（２２４ＩＩｇ）を少量ずつ加工、ペンシルア
ルコキシドのペンシルアルコール溶液を調製し、この溶
液を０℃に冷却し、β−プロピオラクトン（７ｄ）を１
０分間かけ滴下した。滴下後、更１ｃ３０分間攪拌を続
け、次いで２Ｎ塩酸で反応溶液を酸性にしてから、クロ
ロホルムに希釈し、水で洗浄した。有機層を無水硫酸ナ
トＩＪウムで乾燥後、減圧下濃縮し、残渣をシリカゲル
カラムクロマトグラフィー〔溶出溶媒：ヘキサンー酢酸
エチル（３：１））にて精製して、３−ヒドロキシグロ
ピオン酸ベンシルの油状物質１２．７ｆ（収率８３％）
を得た。Reference Example 1 Production of benzorno 3-hydroxyglobionic acid: Benzol alcohol (70M1) K60% oily sodium hydride (224IIg) was processed little by little to prepare a pencil alcohol solution of pencil alkoxide, and this solution was cooled to 0°C. , β-propiolactone (7d) at 1
The mixture was added dropwise over 0 minutes. After the dropwise addition, stirring was continued for another 30 minutes, and then the reaction solution was made acidic with 2N hydrochloric acid, diluted with chloroform, and washed with water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (3:1)] to obtain benzyl 3-hydroxyglopionate. Oily substance 12.7f (yield 83%)
I got it.
Ｅｌ−ＭＳ（ｎ＋／ｘ）：１８０（Ｍ ）ＩＲ（ＣＨＣ
ｊ３）シ：３５００，１７２０ｍ−’ＩＨ−ＮＭＲ（Ｃ
ＤＣｊ、 ）δｐｐｍ：２．６１（ｔ、Ｊ＝５．６Ｈｚ
。El-MS (n+/x): 180 (M) IR (CHC
j3) C: 3500, 1720m-'IH-NMR (C
DCj, )δppm: 2.61 (t, J=5.6Hz
.
２Ｈ）、３．８８（ｔ、Ｊ＝５．６Ｈｚ、２１１１）、
５．１５（ｓ 、 ２Ｈ） 、 ７．３５（ｍ 、 ５
Ｈ）参考例２
５−ホルミルペンタン酸メチルの製造：ε−カグロラク
トン（Ｉ５Ｓ’）をメタノール（３００ｄ ）に溶解し
、濃硫酸（Ｉ，５ｄ）を加え、２時間加熱還流した。反
応溶液を減圧上濃縮し、残渣をクロロホルムに希釈し、
飽和炭酸水素ナトリウム水溶液、つづいて水で洗浄した
。有機層を無水硫酸ナトリウムで乾燥後、減圧上濃縮し
、６−ヒドロキシヘキサン酸メチルの粗生成物を得た。2H), 3.88 (t, J=5.6Hz, 2111),
5.15 (s, 2H), 7.35 (m, 5
H) Reference Example 2 Production of methyl 5-formylpentanoate: ε-caglolactone (I5S') was dissolved in methanol (300d), concentrated sulfuric acid (I, 5d) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with chloroform.
Washed with saturated aqueous sodium bicarbonate solution and then water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of methyl 6-hydroxyhexanoate.
次に、オキザリルクロリド（Ｉ８ｄ ）のジクロロメタ
ン（Ｉ８０ｄ）溶液を一３５℃に冷却し、これにジメチ
ルスルホキシド（２９ｄ）を１０分間で滴下し、更に、
先の６−ヒドロキシヘキサン酸メチルの粗生成物のジク
ロロメタン（Ｉ００ｍｌ）溶液を１０分間かけ滴下した
。次いで１５分間攪拌を続けた後、トリエチルアミン（
９５ｗｌ ）を加え、５分間攪拌し、反応溶液を室温に
戻した。この反応溶液を水で洗浄し、有機層を無水硫酸
す） ＩＪウムで乾燥後、減圧上濃縮し、残渣をシリカ
ゲルカラムクロマトグラフィー〔溶出溶媒：ヘキサンー
酢酸エチル（５：１））にて精製し、５−ホルミルペン
タン酸メチルの油状物質１７ｔ（収率８９％）を得た。Next, a dichloromethane (I80d) solution of oxalyl chloride (I8d) was cooled to -35°C, dimethyl sulfoxide (29d) was added dropwise thereto over 10 minutes, and further,
A solution of the crude product of methyl 6-hydroxyhexanoate in dichloromethane (100 ml) was added dropwise over 10 minutes. After continued stirring for 15 minutes, triethylamine (
95 wl) was added, stirred for 5 minutes, and the reaction solution was returned to room temperature. This reaction solution was washed with water, and the organic layer was dried with anhydrous sulfuric acid.) After drying with IJum, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (5:1)]. , 17 tons (yield: 89%) of an oily substance of methyl 5-formylpentanoate was obtained.
ＥＩ−ＭＳ（ｎ＋／ｚ）：１４３（Ｍ−１）ＩＲ（ＣＨ
Ｃｊ、）シ：１７２５，１７１０（ｍ−’’Ｈ−ＮＭＲ
（ＣＤＣＪｓ ）δｐｐｍ：２．３３（ｔ、Ｊ＝５．４
Ｈｚ、２Ｈ）。EI-MS (n+/z): 143 (M-1) IR (CH
Cj, ) 1725, 1710 (m-''H-NMR
(CDCJs) δppm: 2.33 (t, J=5.4
Hz, 2H).
２．４１（ｄｔ、Ｊ ＝６．９Ｈｚ、−１，８Ｈｚ２Ｈ
）、３．６７ （ｓ 、 ３Ｈ） 。2.41 (dt, J = 6.9Hz, -1,8Hz2H
), 3.67 (s, 3H).
９．７７ （ｔ 、 Ｊ＝１．８ Ｈｚ 、 ＩＨ）参
考例３
シクロドデカノリドの製造ニ
ジクロドデカノン（９，１ｆ ）を、クロロホルム（５
０１！Ｌりに溶解し、ｍ−クロロ過安息香酸（Ｉ７，３
Ｆ ）と三フッ化ホウ素−ゾエチルエーテル錯体（６，
２ｄ）を加え、６０℃にて１６時間加熱した。反応溶液
を室温に戻し、析出してくる沈澱物をろ別し、ろ液をク
ロロホルムに希釈して、飽和炭酸水素ナトリウム水溶液
ついで水で順次洗浄した。有機層を無水硫酸ナトリウム
で乾燥後、減圧上濃縮したものをシリカゲルカラムクロ
マトグラフィー〔溶出溶媒：ヘキサンー酢酸エチル（２
ｏ：１）〕にて精製し、シクロドデカノリドの油状物質
８．７１ ｆ （収率８８％）を得た。9.77 (t, J=1.8 Hz, IH) Reference Example 3 Production of cyclododecanolide Nidiclododecanone (9,1f) was dissolved in chloroform (5
01! m-chloroperbenzoic acid (I7,3
F ) and boron trifluoride-zoethyl ether complex (6,
2d) was added and heated at 60°C for 16 hours. The reaction solution was returned to room temperature, and the precipitate that had separated out was filtered off. The filtrate was diluted with chloroform and washed successively with a saturated aqueous sodium bicarbonate solution and then with water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography [elution solvent: hexane-ethyl acetate (2
o:1)] to obtain 8.71 f (88% yield) of an oily substance of cyclododecanolide.
ＥＩ−ＭＳ（ｒｒ＋／ｚ） ：１９８（Ｍ ）ＩＲ（Ｃ
Ｈ＋ｊ３ ）ｙ ： １７１５ｃＩｎ−’ＩＨ−ＮＭＲ
（ＣＤＣＪｓ）δｐｐｍ：２．３７（ｔ、Ｊ＝６．１Ｈ
ｚ、２Ｈ）。EI-MS(rr+/z): 198(M)IR(C
H+j3)y: 1715cIn-'IH-NMR
(CDCJs) δppm: 2.37 (t, J=6.1H
z, 2H).
４．１６（ｔ、Ｊ＝５．０Ｈｚ、２Ｈ）参考例４
１１−ホルミルウンデカン酸メチルの製造：シクロドデ
カノリド（８，７９）をメタノール（２６０ｄ）に溶解
し、濃硫酸（Ｉｄ）を加えて、２時間加熱還流した。反
応溶液を減圧上濃縮し、残渣をクロロホルムに希釈し、
飽和炭酸水素す） ＩＪウム水溶液つづいて水で洗浄し
た。有機層を無水硫酸ナトリウムで乾燥後、減圧上濃縮
し、１２−ヒドロキシドデカン酸メチルの粗生成物を得
た。4.16 (t, J=5.0Hz, 2H) Reference Example 4 Production of methyl 11-formylundecanoate: Dissolve cyclododecanolide (8,79) in methanol (260d), add concentrated sulfuric acid (Id) In addition, the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with chloroform.
Saturated hydrogen carbonate) IJum aqueous solution and then washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of methyl 12-hydroxydodecanoate.
オキザリルクロリド（８ｄ）のジクロロメタン（Ｉ００
ｍ）溶液を、−３５℃に冷却し、これにジメチルスルホ
キシド（Ｉ５ｍ／）ｌ、１０分間かけ滴下した。更に先
の１２−ヒドロキシドデカン酸メチルの粗生成物のジク
ロロメタン（４０ｓｕ）溶液を、１０分間で滴下した後
、１５分間攪拌した。次いで、トリエチルアミン（６０
ｉｕ）を加え、５分間攪拌した後、室温に戻した。この
反応溶液を水で洗浄し、有機層を無水硫酸ナトリウムで
乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラ
ムクロマトグラフィー〔溶出溶媒：ヘキサンー酢酸エチ
ル（２０：１））にて精製し、１１−ホルミルウンデカ
ン酸メチルの油状物質９．７ ｔ （収率９３％）を得
た。Oxalyl chloride (8d) in dichloromethane (I00
m) The solution was cooled to −35° C., and 5 ml/l of dimethyl sulfoxide (I) was added dropwise thereto over 10 minutes. Furthermore, a dichloromethane (40 su) solution of the crude product of methyl 12-hydroxydodecanoate was added dropwise over 10 minutes, followed by stirring for 15 minutes. Then triethylamine (60
iu) was added, stirred for 5 minutes, and then returned to room temperature. This reaction solution was washed with water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (20:1)] to obtain 9.7 t (93% yield) of an oily substance of methyl 11-formylundecanoate.
Ｅｒ−ＭＳ（ｍ、／ｚ）：２２７（Ｍ −１）Ｉ Ｒ（
ＣＨ（Ｊ３）シ：１７２５，１７１０α−１ＩＨ−ＮＭ
Ｒ（ＣＤＣｌ５）δｐｐｒｎ ： ２．３０（ｔ、Ｊ＝
６Ｈｚ、２Ｈ）。Er-MS (m, /z): 227 (M -1) I R (
CH (J3): 1725, 1710α-1IH-NM
R(CDCl5)δpprn: 2.30(t, J=
6Hz, 2H).
２．４１（ｄｔ、Ｊ＝６．９Ｈｚ、１．８Ｈｚ、２Ｈ）
。2.41 (dt, J=6.9Hz, 1.8Hz, 2H)
.
３−６６（ｓ、３Ｈ）９
９．７６（ｔ、Ｊ＝１．８Ｈｚ、ＩＨ）実施例１
３−ヒドロキシ−２−（ヒドロキシメチル）オクタンニ
酸 １−ベンシル ８−メチルの製造：
ジイソゾロビルアミン（４，９５ｘｉ ）の乾燥テトラ
ヒドロ７ラン（２０ｄ ）溶液を窒素雰囲気下、ドライ
アイス−アセトン浴にて、−７８℃に冷却した。この溶
液を攪拌しながら、１９．５Ｍｌのｎ−ジチルリチウム
のヘキサン溶液（Ｉ，６４Ｍ）を滴下して、リチウムジ
インゾロビルアミドのテトラヒドロフラン溶液を調製し
、さらにこの溶液中に２．４ｔの３−ヒドロキシノロピ
オン酸ベンシルのテトラヒドロフラン（７，５ｄ ）溶
液を、５分間で滴下した。１０分間放置後、反応液を一
２０℃に昇温し、５分間−２０℃に保持した後、再び一
７８℃に冷却し、１０分間保持した後、２．１２の５−
ホルミルペンタン酸メチルのテトラヒドロフラン（Ｉ３
ｍ）溶液を、１５分間かけて滴下した。５０分間放置後
、反応溶液に飽和塩化アンモニウム水溶液を加え、反応
を中止した。生成物をエーテルで抽出し、抽出液を無水
硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣
をシリカゲルのカラムクロマトグラフィー〔溶出溶媒：
ヘキサンー酢酸エチル（Ｉ０：１））にて精製し、３−
ヒドロキシ−２−（ヒドロキシメチル）オクタンニ酸
１−ベンシル ８−メチルの油状物質３．０７ ｆ （
収率７１％）を得た。3-66(s, 3H)9 9.76(t, J=1.8Hz, IH) Example 1 Production of 1-benzyl 8-methyl 3-hydroxy-2-(hydroxymethyl)octanioate: Diisozorovir A solution of the amine (4,95xi) in dry tetrahydro7rane (20d) was cooled to -78°C in a dry ice-acetone bath under a nitrogen atmosphere. While stirring this solution, 19.5 ml of a hexane solution (I, 64 M) of n-dityl lithium was added dropwise to prepare a tetrahydrofuran solution of lithium diinzolobylamide, and further into this solution was added 2.4 t of 3 A solution of benzyl-hydroxynoropionate in tetrahydrofuran (7,5d) was added dropwise over 5 minutes. After standing for 10 minutes, the reaction solution was heated to -20°C, held at -20°C for 5 minutes, cooled again to -78°C, held for 10 minutes, and then heated to -20°C.
Tetrahydrofuran (I3) of methyl formylpentanoate
m) The solution was added dropwise over a period of 15 minutes. After standing for 50 minutes, a saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. The product was extracted with ether, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography [elution solvent:
Purified with hexane-ethyl acetate (I0:1)), 3-
Hydroxy-2-(hydroxymethyl)octanedioic acid
1-Benzyl 8-methyl oil 3.07 f (
A yield of 71% was obtained.
ＥＩ−ＭＳ（ｍ／ ｚ ） ： ３２４ （Ｍ ）ＩＲ
（ＣＨＣｊ３）シ：３５００．１７２５ｃｒ！Ｌ″″ｌ
ＩＨ−ＮＭＲ（ＣＤＣｊ、 ）δｐｐ＋１１：２．３０
（ｔ、Ｊ＝６．６Ｈｚ、２Ｈ）。EI-MS (m/z): 324 (M)IR
(CHCj3) Shi: 3500.1725cr! L″″l
IH-NMR (CDCj, )δpp+11:2.30
(t, J=6.6Hz, 2H).
２．７（ｒｎ、ＩＨ）。2.7 (rn, IH).
３．６５（ｓ、３Ｈ）。3.65 (s, 3H).
３、９ （ｍ 、 Ｉ Ｈ）。3, 9 (m, IH).
３．９６（ｄ、Ｊ＝３．１Ｈｚ、ＩＨ）。3.96 (d, J=3.1Hz, IH).
４．０２（ｄ 、 Ｊ＝２．５Ｈｚ 、 ＩＨ）。4.02 (d, J=2.5Hz, IH).
５．１２ （ｓ 、 ２Ｈ）。5.12 (s, 2H).
７．３５（ａ、５Ｈ）
実施例２
３−ヒドロキシ−２−（）リフェニルメトキシメチル）
オクタンニ酸 １−ベンシル８−メチルの製造：
３−ヒドロキシ−２−（ヒドロキシメチル）オクタンニ
酸 １−ベンシル ８−ｊチル（３，５９）を、ジクロ
ロメタン（３５ｄ）に溶解し、４−ジメチルアミノピリ
ジン（６５１１９）、トリエチルアミン（２，３ｍ／
）およびトリフェニルメチルクロリド（３，３ｆ ）を
加え、室温で２３時間反応せしめた。反応溶液を、ジク
ロロメタンに希釈し、飽和炭酸水素ナトリウム水溶液、
次いで水で洗浄した。有機層を無水硫酸ナトリウムで乾
燥後、溶媒を減圧下留去した。残渣をシリカゲルカラム
クロマイグラフィー〔溶出溶媒：ヘキサンー酢酸エチル
（５：１））にて精製し、エリトロ−３−ヒドロキシ−
２−（）リフェニルメトキシメチル）オクタンニ酸 １
−ベンシル ８−メチル１．４２ ｔ （収率２３％）
と、ヒレオー３−ヒドロキシ−２−（トリフェニルメト
キシメチル）オクタンニ酸 １−ベンシル ８−メチル
２．６６ ｔ （収率４４％）の油状物質を得た。7.35(a,5H) Example 2 3-hydroxy-2-()liphenylmethoxymethyl)
Production of 1-bensyl 8-methyl octanoate: 3-hydroxy-2-(hydroxymethyl)octanoate 1-benzyl 8-j thyl (3,59) was dissolved in dichloromethane (35d), and 4-dimethylaminopyridine was dissolved. (65119), triethylamine (2,3m/
) and triphenylmethyl chloride (3,3f) were added and reacted at room temperature for 23 hours. The reaction solution was diluted with dichloromethane, saturated aqueous sodium hydrogen carbonate solution,
It was then washed with water. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromography [elution solvent: hexane-ethyl acetate (5:1)], and erythro-3-hydroxy-
2-()liphenylmethoxymethyl)octanedioic acid 1
-bensyl 8-methyl 1.42 t (yield 23%)
Then, 2.66 t (yield 44%) of an oily substance of 1-benzyl 8-methyl filleo-3-hydroxy-2-(triphenylmethoxymethyl)octanioate was obtained.
エ リ ト ロ 形
ＥＩ−ＭＳ（ｍ／ｚ）：５ ６６（Ｍ ）ｒｎ（ｃｍ
ｃｔ３ ）ｐ：３５００，１７２５ ｃｌｒＬ−’ＩＨ
−ＮＭＲ（ＣＤＣｊ３ ）δ ｐ ｐＩ’ｎ：２．２３
（ｔ、Ｊ＝６．１Ｈｚ、２Ｋ）。Elitro EI-MS (m/z): 5 66 (M) rn (cm
ct3) p:3500,1725 clrL-'IH
-NMR (CDCj3) δ p pI'n: 2.23
(t, J=6.1Hz, 2K).
２．６７（ｍ、 ＩＨ）、３．５２ （ｄ 、
Ｊ ＝６．１Ｈｚ、’２Ｈ） 。2.67 (m, IH), 3.52 (d,
J = 6.1Hz, '2H).
３．６４（４，３Ｈ）、３．９（ｍ、ＩＨ）、５．１８
（ｓ、２Ｈ）トレオ形
ＥＸ−ＭＳ（＋ｎ／ｚ ）：５６６ （Ｍ ）ＩＲ（Ｃ
ＨＣ）、 ）ν ：３５００．１７２５ｃｍ−’ｌＨ
−ＮＭＲ（ＣＤＣｊ３ ）δｐｐｍ ：２．２３（ｔ
、Ｊ＝６．１Ｈｚ、２Ｈ）、２．６７（ｍ、ＩＨ）。3.64 (4,3H), 3.9 (m, IH), 5.18
(s, 2H) Threo type EX-MS (+n/z): 566 (M) IR (C
HC), )ν: 3500.1725cm-'lH
-NMR (CDCj3) δppm: 2.23 (t
, J=6.1Hz, 2H), 2.67(m, IH).
３．５２（ｄ、Ｊ＝６．１Ｈｚ 、２Ｈ）、３．６４（
ｓ、３Ｈ）。3.52 (d, J=6.1Hz, 2H), 3.64 (
s, 3H).
３．９（ｎｏ、ＩＨ）、５．１８（Ｉ１，２Ｈ）実施例
３
トランス−６−ヒトロキシー７−（トリフェニルメトキ
シメチル）オクタンニ酸 ８゜６−ラクトンの製造：
５６６１１ｆ／のヒレオー３−ヒドロキシ−２−（トリ
フェニルメトキシメチル〕オクタンニ酸 １−ベンシル
８−メチルをエタノール−水混合液（２：１）（Ｉ５
１Ｅ／）に溶解し、水酸化カリウム（２８０１Ｒｇ）を
加え、室温で４時間反応せしめた。反応後減圧下、エタ
ン−ルを留去し、残渣を飽和炭酸水素ナトリウム水溶液
で希釈し、エーテルにて洗浄した。3.9 (no. 1-Benzyl 8-methyl hydroxy-2-(triphenylmethoxymethyl)octanioate was added to an ethanol-water mixture (2:1) (I5
1E/), potassium hydroxide (2801Rg) was added, and the mixture was reacted at room temperature for 4 hours. After the reaction, ethane was distilled off under reduced pressure, and the residue was diluted with a saturated aqueous sodium bicarbonate solution and washed with ether.
水層を９Ｎ塩酸で酸性にし、生成物をエーテルで抽出し
、抽出液を無水硫酸ナトリウムで乾燥し、減圧下溶媒を
留去して、ジカルボン酸の粗生成物を得た。この粗生成
物をビリシン（９ｄ）に溶解し、水冷下、水酸化カリウ
ム（９０１Ｑ）と、Ｐ−トルエンスルホニルクロリド（
６１ｍ＋？）を加えた後、３℃にて１３時間放置した。The aqueous layer was made acidic with 9N hydrochloric acid, the product was extracted with ether, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude dicarboxylic acid product. This crude product was dissolved in bilicin (9d), and under water cooling, potassium hydroxide (901Q) and P-toluenesulfonyl chloride (
61m+? ) was added and then left at 3°C for 13 hours.
メタノール（５ｄ）を加え、室温に３０分間放置した後
、減圧下濃縮し、残渣をジクロロメタンに溶かし、飽和
食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥
後、溶媒を減圧下留去し、残渣をシリカゲルカラムクロ
マトグラフィー〔溶出溶媒：クロロホルム−メタノール
（２０：１））Ｋて精製してトランス−６−ヒトロキシ
ー７−（トリフェニルメトキシメチル）オクタンニ酸
８゜６−ラクトンの無色結晶性物質２１２報（収率４８
％）を得た。Methanol (5d) was added and the mixture was allowed to stand at room temperature for 30 minutes, then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: chloroform-methanol (20:1)] to obtain trans-6-hydroxy-7- (triphenylmethoxymethyl)octanedioic acid
Colorless crystalline substance of 8゜6-lactone 212 reports (yield 48
%) was obtained.
Ｅｌ−ＭＳ（ｎ＋／ｚ） ：４４４ （Ｍ ）ＩＲ（Ｃ
ＨＣｊ３）シ：１８２０，１７２０ｃｎＬ−１１）１−
ＮＭＲ（ＣＤＣｊ３）δｐｐｍ：２．２３（ｔ、Ｊ＝６
．１Ｈｚ、２Ｈ）、３．４（ｍ、 ＩＨ）３．６（ｍ、
２Ｈ）、４．６（ｒｂ、ＩＨ）実施例４
トランス−６−ヒトロキシー７−（ヒドロキシメチル）
オクタンニ酸 ８．６−ラクトンの製造：
６７■のトランス−６−ヒトロキシー７−（トリフェニ
ルメトキシメチル）オクタンニ酸 ８．６−ラクトンを
、ｎ−ブタノール（Ｌ２ｄ）に溶解し、攪拌しながら、
トリフルオロ酢酸（ｏ、５２ ｍｌ ）をゆつくシと滴
下した後、室温に４時間放置した。反応溶液を酢酸エチ
ルに希釈し、飽和炭酸水素ナトリウム水溶液および飽和
食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥後
、溶媒を減圧下、 留去した。残渣をシリカゲルカラム
クロマトグラフィー（溶出溶媒：クロロホルム−メタノ
ール（Ｉ０：１）〕にて精製し、トランス−６−ヒドロ
キシ〜７−（ヒドロキシメチル）オクタンニ酸 ８．６
−ラクトンの無色油状物質２４ｍｇ（収率７９％）を得
た。El-MS(n+/z):444 (M)IR(C
HCj3) C:1820,1720cnL-11)1-
NMR (CDCj3) δppm: 2.23 (t, J=6
．． 1Hz, 2H), 3.4 (m, IH) 3.6 (m,
2H), 4.6 (rb, IH) Example 4 trans-6-hydroxyloxy7-(hydroxymethyl)
Production of octanedioic acid 8.6-lactone: 67■ trans-6-hydroxyloxy7-(triphenylmethoxymethyl)octanedioic acid 8.6-lactone was dissolved in n-butanol (L2d), and while stirring,
Trifluoroacetic acid (o, 52 ml) was slowly added dropwise, and the mixture was left at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform-methanol (I0:1)) to obtain trans-6-hydroxy to 7-(hydroxymethyl)octanedioic acid 8.6
-24 mg (yield 79%) of a colorless oily substance of lactone was obtained.
ＩＩ−ＭＳ（ｒｈ／ｚ ） ： １８４（Ｍ −１８）
ｒ Ｒ（ＣＨＣ）３）ｙ：３４９０，１８２０．１７２
５ｃｍ−’ＩＨ−ＮＭＲ（ＣＤＣｊ３）δＰＰｎ１：２
．３４（ｔ 、Ｊ＝７．０Ｈｚ 、２Ｈ）、３．４（ｍ
、 １Ｈ）４．０（ｍ、２Ｈ）、４．６（ｍ、ＩＨ）実
施例５
シス−３−ヒドロキシ−２−（、トリフェニルメトキシ
メチル）オクタンニ酸 ８−メチル １，３−ラクトン
の製造：
２００１１９のエリトロ−３−ヒドロキシ−２−（トリ
フェニルメトキシメチル）オクタン二酸 １−ベンシル
８−メチルをエタノール（４ｄ）に溶解し、ノＱラゾ
ウム黒（２０■）を加え、常圧で４５分間、水素添加し
た。触媒をろ別し、ろ液を減圧上濃縮して、モノカルメ
ン酸の粗生成物を得た。この粗生成物をビリシン（３，
５ｄ ）に溶解し、水冷下、水酸化カリウム（Ｉ９ｍ９
）とｐ−トルエンスルホ、 ニルクロリド（Ｉ３２Ｒｐ
）を加えた後、３℃に１８時間放置した。メタノール（
Ｉｄ）ｔ−加え、１０分間室温に放置した後、減圧上濃
縮し、残渣をジクロロメタンに溶解し、さらに飽和食塩
水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した
後、溶媒を減圧下留去した。残渣をシリカゲルカラムク
ロマトグラフィー〔溶出溶媒：ヘキサンー酢酸エチル（
５：１））にて精製し、シス−３−ヒドロキシ−２−（
トリフェニルメトキシメチル）オクタンニ酸 ８−メチ
ル １．３−−）クトンの無色結晶性物質４４ ｍｇ
（収率２７％〕を得た。II-MS (rh/z): 184 (M-18)
r R(CHC)3)y:3490,1820.172
5cm-'IH-NMR (CDCj3) δPPn1:2
．． 34 (t, J=7.0Hz, 2H), 3.4 (m
, 1H) 4.0 (m, 2H), 4.6 (m, IH) Example 5 Production of cis-3-hydroxy-2-(, triphenylmethoxymethyl)octanioate 8-methyl 1,3-lactone : Dissolve 1-benzyl 8-methyl erythro-3-hydroxy-2-(triphenylmethoxymethyl)octanedioate of 200119 in ethanol (4d), add Norazoum black (20μ), and dissolve at normal pressure for 45 minutes. Hydrogenated for 1 minute. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product of monocarmenic acid. This crude product was mixed with bilysin (3,
5d) and dissolved in potassium hydroxide (I9m9) under water cooling.
) and p-toluenesulfo, nyl chloride (I32Rp
) was added and then left at 3°C for 18 hours. methanol(
Id) t- was added, and after standing at room temperature for 10 minutes, it was concentrated under reduced pressure, and the residue was dissolved in dichloromethane, and further washed with saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography [elution solvent: hexane-ethyl acetate (
5:1)) to give cis-3-hydroxy-2-(
44 mg of colorless crystalline substance of triphenylmethoxymethyl)octaneioate 8-methyl 1.3-)chton
(Yield 27%) was obtained.
ＥＩ −ＭＳ （ｒｎ／ｚ ） ： ４５８ （Ｍ
）ｒＲ（ＣＨｃ７３）シ：１８２０１７３０ｃｒＩｔ−
’ｌＨ−ＮＭＲ（ＣＤ（ｊ３）δｐｐｔｏ：２．２３（
ｔ、Ｊ＝６．８Ｈｚ、２Ｋ）、３．４（ｒａ、２）り。EI-MS (rn/z): 458 (M
)rR(CHc73)C:18201730crIt-
'lH-NMR(CD(j3)δppto:2.23(
t, J=6.8Hz, 2K), 3.4(ra, 2)ri.
３−６４（ａ＊３Ｈ）、３．９（ｍ、１Ｈ）、４．５（
ｍ、１Ｈ）実施例６
シスー３−ヒドロキシ−２−（ヒドロキシメチル）オク
タンニ酸 ８−メチル １，３−ラクトンの製造：
３０ｒｎｇのシス−３−ヒドロキシ−２−（トリフェニ
ルメトキシメチル）オクタンニ酸８−メチル １，３−
ラクトンを、ｎ−ブタノール（０，５４１Ｌｔ）に溶解
した溶液を、室温で攪拌しながら、これにトリフルオロ
ｆｆ［（０，１８ｄ）を滴下し、そのまま室温に３時間
放置した。この反応液を酢酸エチルに希釈し、飽和炭酸
水素す） ＩＪウム水溶液および飽和食塩水で洗浄し、
有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧下留
去した。残渣をシリカゲルカラムクロマトグラフィー〔
溶出溶媒：ヘキサンー酢酸エチル（２：１））にて精製
し、シス−３−ヒドロキシ−２−（ヒドロキシメチル）
オクタンニ酸 ８−メチル １．３−ラクトンの油状物
質１１■（収率７８％）を得た。3-64 (a * 3H), 3.9 (m, 1H), 4.5 (
m, 1H) Example 6 Preparation of cis-3-hydroxy-2-(hydroxymethyl)octanedioic acid 8-methyl 1,3-lactone: 30 rng of cis-3-hydroxy-2-(triphenylmethoxymethyl)octanedioic acid 8 -Methyl 1,3-
Trifluoro ff[(0,18d) was added dropwise to a solution of lactone dissolved in n-butanol (0,541 Lt) while stirring at room temperature, and the solution was left at room temperature for 3 hours. This reaction solution was diluted with ethyl acetate, washed with saturated hydrogen carbonate solution and saturated brine,
After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography [
Elution solvent: Purified with hexane-ethyl acetate (2:1)) to obtain cis-3-hydroxy-2-(hydroxymethyl)
An oily substance of 8-methyl 1,3-lactone octanoate (11 quartz) (yield 78%) was obtained.
ＦＡＢ−ＭＳ（ｍ／ ｚ ） ： ２１７ （ＭＨ）Ｉ
Ｒ（ＣＨＣｊ３）シ：３４９０，１８２０．１７３０Ｃ
ＭＬＩＩＨ−ＮＭＲ（ＣＤＣｊ３）δｐｐｎ＋：２．２
３ （ｔ 、 Ｊ＝６．８Ｈｚ 、 ２Ｈ） 。FAB-MS (m/z): 217 (MH)I
R (CHCj3): 3490, 1820.1730C
MLIIH-NMR (CDCj3) δppn+: 2.2
3 (t, J=6.8Hz, 2H).
３．６４（ｓ 、３Ｈ） 、３．９（ｒｎ、２Ｈ） 。3.64 (s, 3H), 3.9 (rn, 2H).
４．１２（ｒｎ、ＩＨ）、４．７３（ｒｈ、ＩＨ）実施
例７
トランスー３−ヒドロキシ−２−（トリフェニルメトキ
シメチル）オクタンニ酸 ８−メチル １．３−ラクト
ンの製造：
５５０１！ｔｇのトンオー３−ヒドロキシ−２−（トリ
フェニルメトキシメチル）オクタンニ酸 １−ペンシル
８−メチルを実施例５と同様罠処理して、トランス−
３−ヒドロキシ−２−（トリフェニルメトキシメチル）
オクタンニ酸 ８−メチル １．３−ラクトンの無色結
晶性物質３５９■（収率７７％）を得た。4.12 (rn, IH), 4.73 (rh, IH) Example 7 Preparation of trans-3-hydroxy-2-(triphenylmethoxymethyl)octanioate 8-methyl 1.3-lactone: 5501! tg of 1-pencyl 8-methyl 3-hydroxy-2-(triphenylmethoxymethyl)octanedioate was treated in the same manner as in Example 5 to obtain trans-
3-hydroxy-2-(triphenylmethoxymethyl)
359 ml of a colorless crystalline substance of 8-methyl 1,3-lactone octanioate (yield 77%) was obtained.
ＫＩ−ＭＳ（ｍ／ｚ）：４５８（Ｍ ）ＩＲ（ＣＨＣｊ
３ ）シ：１８２０，１７３０ｃｍ−”’Ｈ−ＮＭＲ（
ＣＤＣＪ３）δｐｐｍ：２．２３（ｔ 、Ｊ＝６．８Ｈ
ｚ 、２Ｈ）、３．３５（ｍ、２Ｈ）。KI-MS (m/z): 458 (M) IR (CHCj
3) C: 1820, 1730cm-”'H-NMR (
CDCJ3) δppm: 2.23 (t, J=6.8H
z, 2H), 3.35 (m, 2H).
３．５（ｍ、 １Ｈ）、３．６６ （ｓ 、３Ｈ）、４
．５（ｍ、ＩＨ）実施例８
トランス−３−ヒドロキシ−２−（ヒドロキシメチル）
オクタンニ酸 ８−１ｆル １．３−ラクトンの製造：
５０ｗ１Ｉのトランス−３−ヒドロキシ−２−（トリフ
ェニルメトキシメチル）オクタンニ酸 ８−メチル １
．３−ラクトンから実施例６と同様に処理して、トラン
ス−３−ヒドロキシ−２−（ヒドロキシメチル）オクタ
ン二酸 ８−メチル １．３−ラクトンの油状物質１６
■（収率６８％）を得た。3.5 (m, 1H), 3.66 (s, 3H), 4
．． 5(m,IH) Example 8 trans-3-hydroxy-2-(hydroxymethyl)
Octanoic acid 8-1f 1. Preparation of 3-lactone: 50w1I trans-3-hydroxy-2-(triphenylmethoxymethyl)octanoic acid 8-methyl 1
．． 3-lactone was treated in the same manner as in Example 6 to obtain an oily substance of trans-3-hydroxy-2-(hydroxymethyl)octanedioate 8-methyl 1.3-lactone 16
(68% yield) was obtained.
ＦＡＲ−ＭＳ（ｒａ／ ｔ ） ： ２１７ （ＭＨ）
ＩＲ（ＣＨＣｊ３ ）シ：３５００，１８２０．１７３
０ｃｍ−””Ｈ−ＮＭＲ（ＣＤＣＪ３）δｐｐｍ：２．
２３（ｔ、Ｊ＝＝６．８Ｈｚ、２Ｈ）、３．４１（＋ｍ
、ＩＨ）。FAR-MS (ra/t): 217 (MH)
IR(CHCj3)shi:3500,1820.173
0cm-""H-NMR (CDCJ3) δppm: 2.
23(t, J==6.8Hz, 2H), 3.41(+m
, IH).
３．６４（ａ、３Ｈ）、３．９（ｎｏ、２Ｈ）、４．５
９（ｒａ、ＩＨ）
実施例９
３−ヒトｏキシ−２−（ヒドロキシメチル）テトラドデ
カンニ酸 １−ベンシル １４−メチルの製造：
ジイソゾロビルアミン（４，８６Ｋｌ ）の乾燥テトラ
ヒドロフラン（２０ｍｌ ）溶液を窒素雰囲気下、ドラ
イアイス−アセトン浴にて一７８℃に冷却した。溶液を
攪拌しながら１７．９ｄのれ一ブチルリチウムのヘキサ
ン溶液（Ｉ，６４Ｍ）を滴下して、リチウムジイソノロ
ピルアミドのテトラヒドロフラン溶液を調製し、この溶
液に２．４ｆの３−ヒドロキシゾロピオン酸ベンシルの
テトラヒドロフラン（７，５ＭＩ）溶液を１０分間かけ
て滴下した。１０分間放置後、−２０℃に昇温し、その
ま″１５分間、−２０°Ｃに放置して、再び一７８℃に
冷却した。次いで、３ｆの１１−ポルミルウンデカン酸
メチルのテトラヒドロフラン（Ｉ２ｄ）溶液を１５分間
かけて滴下し、４０分後、反応溶液に、飽和塩化アンモ
ニウム水を加え、反応を中止した。以下、実施例１と同
様に処理し、３−ヒドロキシ−２−（ヒドロキシメチル
）テトラドデヵンニ酸 １−ベンシル１４−メチルの油
状物質３．７８ Ｆ （収率３５％）を得た。3.64 (a, 3H), 3.9 (no, 2H), 4.5
9(ra, IH) Example 9 Preparation of 1-benzyl 14-methyl 3-hydroxy-2-(hydroxymethyl)tetradodecanoate: A solution of diisozolobylamine (4,86 Kl) in dry tetrahydrofuran (20 ml). was cooled to -78°C in a dry ice-acetone bath under a nitrogen atmosphere. While stirring the solution, a hexane solution (I, 64M) of 17.9d of butyllithium was added dropwise to prepare a tetrahydrofuran solution of lithium diisonoropylamide, and 2.4f of 3-hydroxyzolopion was added dropwise to the solution. A solution of benzyl acid in tetrahydrofuran (7,5MI) was added dropwise over 10 minutes. After being left for 10 minutes, the temperature was raised to -20°C, left to stand at -20°C for 15 minutes, and then cooled to -78°C again. I2d) solution was added dropwise over 15 minutes, and after 40 minutes, saturated ammonium chloride water was added to the reaction solution to stop the reaction. An oily substance of 3.78 F (yield 35%) of 1-benzyl 14-methyl (methyl)tetradodecanoic acid was obtained.
ＥニーＭＳ（ｎｎ／ｚ ）：４０８（Ｍ″″）ＩＲ（Ｃ
ＨＣｊ３ ）ｙ：３５５０，１７２５ｃｒ！Ｌ−’ＩＨ
−ＮＭＲ（ＣＤＣｊ３ ）δｐｐｒＩＩ＋＝２．２８（
ｔ、Ｊ＝７．１Ｈｚ、２Ｈ）、２．７（ｎ＋、ＩＨ）。E knee MS (nn/z): 408 (M″″) IR (C
HCj3)y:3550,1725cr! L-'IH
-NMR(CDCj3)δpprII+=2.28(
t, J=7.1Hz, 2H), 2.7(n+, IH).
３．６３（ｓ、３Ｈ）、３．９（ｍ、ＩＨ）、３．９１
（ｄ、Ｊ＝３．０Ｈｚ、ＩＨ）、３．９８（ｄ、Ｊ＝３
．０Ｈｚ。3.63 (s, 3H), 3.9 (m, IH), 3.91
(d, J=3.0Hz, IH), 3.98 (d, J=3
．． 0Hz.
ＩＨ）、５．１５（ｓ、２Ｈ）、７．３２（ａ、５Ｈ）
実施例１０
３−ヒドロキシ−２−（トリフェニルメトキシメチル）
テトラドデカンニ［１−ベンシル １４−メチルの製造
：
２．８１の３−ヒドロキシ−２−（ヒドロキシメチル）
テトラドデカンニ酸 １−ベンシル １４−メチルをジ
クロロメタン（２８Ｍ）に溶解し、この溶液に４−ジメ
チルアミノビリジン（４２！ｎｇ）、トリエチルアミン
（Ｉ，４３ｄ）およびトリフェニルメチルクロリド（２
，１２）を加え、室温で２３時間反応せしめた。IH), 5.15 (s, 2H), 7.32 (a, 5H)
Example 10 3-hydroxy-2-(triphenylmethoxymethyl)
Preparation of tetradodecanni[1-bensyl 14-methyl: 2.81 3-hydroxy-2-(hydroxymethyl)
1-Benzyl 14-methyl tetradodecanoate was dissolved in dichloromethane (28M), and to this solution was added 4-dimethylaminopyridine (42! ng), triethylamine (I,43d) and triphenylmethyl chloride (2
, 12) were added thereto, and the mixture was allowed to react at room temperature for 23 hours.
反応溶液をジクロロメタンに希釈し、飽和炭酸水素ナト
リウム水溶液、次いで水で洗浄し、有機層を無水硫酸ナ
トリウムで乾燥後、溶媒を減圧下留去した。残渣をシリ
カゲルカラムクロマトグラフィー〔溶出溶媒：ヘキサン
ー酢酸エチル（７：１））にて精製し、エリトロ−３−
ヒドロキシ−２−（トリフェニルメトキシメチル）テト
ラドデカンニ酸 １−ベンシル １４−メチル１．０５
ｔ （収率２３％）及ヒトレオー３−ヒドロキシ−２
−（） １７フエニルメトキシメチル）テトラドデカン
ニ酸１−ベンシル １４−メチル２．２２ ｆ （収率
５０％）の油状物質を得た。The reaction solution was diluted with dichloromethane, washed with a saturated aqueous sodium bicarbonate solution and then with water, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (7:1)], and erythro-3-
Hydroxy-2-(triphenylmethoxymethyl)tetradedecanoic acid 1-benzyl 14-methyl 1.05
t (yield 23%) and human leo-3-hydroxy-2
An oily substance of 2.22 f (50% yield) of 1-benzyl 14-methyl -() 17 phenylmethoxymethyl)tetradedecanoate was obtained.
エリトロ形
Ｅｌ−ＭＳ（ｅｏ／ｚ）：６５０（Ｍ ）ＩＲ（ＣｕＣ
ｌ２）シ：３５５０．１７２５Ｃｍ−’１１−ＮＭＲ（
ＣＤＣｊ３）δｐｐｍ：２．３０（ｔ 、 Ｊ＝７．４
Ｈｚ 、２）（） 、 ２．７３（ｍ、 ＩＨ）。Erythro form El-MS (eo/z): 650 (M) IR (CuC
l2) C:3550.1725Cm-'11-NMR(
CDCj3) δppm: 2.30 (t, J=7.4
Hz, 2)(), 2.73(m, IH).
３．４５（ｄ、Ｊ＝６．４Ｈｚ、２Ｈ）、３．６５（ｓ
、３Ｈ）。3.45 (d, J=6.4Hz, 2H), 3.65 (s
, 3H).
３．８９（ｒｎ、１Ｈ）、５．１７（ｓ、２Ｈ）トレオ
形
Ｅｆ−ＭＳ（ｍ／ｚ）：６５０（Ｍ ）ＩＲ（ｃｎｃＪ
３）シ：３５５０，１７２５ｃＭＬ−’ＩＨ−ＮＭＲ（
ＣＤＣｊ３）δＰＰｍ：２．３０（ｔ、Ｊ＝７．４Ｈｚ
、２Ｈ）、２．７３（ｍ、 ＩＨ）、３．４５（ｄ、Ｊ
＝６．４Ｈｚ、２Ｈ）。3.89 (rn, 1H), 5.17 (s, 2H) threoform Ef-MS (m/z): 650 (M) IR (cncJ
3) C: 3550, 1725cML-'IH-NMR (
CDCj3) δPPm: 2.30 (t, J=7.4Hz
, 2H), 2.73 (m, IH), 3.45 (d, J
=6.4Hz, 2H).
３．６５（ａ 、 ３Ｈ） 、 ３．９０（ｍ、 １Ｈ
）、 ５．２０（ｇ、２Ｈ）実施例１１
トランス−１２−ヒドロキシ−１３−（トリフェニルメ
トキシメチル）テトラドデカン二酸 １４．１２−ラク
トンの製造＝
５００罷９のトンオー３−ヒドロキシ−２−（トリフェ
ニルメトキシメチル）ナト２ドデカンニ酸 １−ペンシ
ル １４−メチルを、エタノール−水（２：１）混合液
（７，５ｔｅ）に溶解し、水酸化カリウム（２１６■）
を加え、室温で３時間攪拌した。減圧下、エタノールを
留去し、残渣を飽和炭酸水素ナトリウム水溶液にて希釈
し、エーテルで洗浄した。3.65 (a, 3H), 3.90 (m, 1H
), 5.20 (g, 2H) Example 11 trans-12-hydroxy-13-(triphenylmethoxymethyl)tetradedecanedioic acid 14. Preparation of 12-lactone = 500 strips of 3-hydroxy-2- Dissolve 1-pencyl 14-methyl (triphenylmethoxymethyl)nato-2-dodecanoic acid in an ethanol-water (2:1) mixture (7.5 te), and dissolve potassium hydroxide (216 t).
was added and stirred at room temperature for 3 hours. Ethanol was distilled off under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution and washed with ether.
水層を９Ｎ塩酸で酸性にし、生成物をエーテルで抽出し
、抽出液を無水硫酸す） ＋７ウムで乾燥し、減圧下溶
媒を留去して、ジカルボン酸の粗生成物を得た。この粗
生成物をビリシン（７ｄ）に溶解し、水冷下、水酸化カ
リウム（３０＃）とｐ−トルエンスルホニルクロリド（
４６（Ｉ１１１９）を加えた後、３℃に２２時間放置し
た。メタノール（５ｄ）を加え、室温に３０分間放置し
た後、減圧上濃縮し、残渣をジクロロメタンに溶かし、
飽和食塩水で洗浄した。有機層を無水硫酸す） １７ウ
ムで乾燥後、溶媒を減圧下留去した。残渣をシリカゲル
カラムクロマトグラフィー〔溶出溶媒：クロロホルム−
メタノール（２０：１））にて精製し、トランス−１２
−ヒドロキシ−１３−（） ＩＪ フェニルメトキシメ
チル）テトラドデカンニ酸 １４．１２−ラクトンの油
状物質８３１Ｒｇ（収率２０％）を得た。The aqueous layer was made acidic with 9N hydrochloric acid, the product was extracted with ether, the extract was dried over sulfuric anhydride (+7 μm), and the solvent was distilled off under reduced pressure to obtain a crude dicarboxylic acid product. This crude product was dissolved in bilicin (7d), and under water cooling, potassium hydroxide (30#) and p-toluenesulfonyl chloride (
After adding 46 (I1119), the mixture was left at 3°C for 22 hours. After adding methanol (5d) and leaving it at room temperature for 30 minutes, it was concentrated under reduced pressure, and the residue was dissolved in dichloromethane.
Washed with saturated saline. After drying the organic layer over 17 um of anhydrous sulfuric acid, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [elution solvent: chloroform]
Purified with methanol (20:1)), trans-12
-Hydroxy-13-() IJ phenylmethoxymethyl)tetradedecanedioic acid 831Rg (yield 20%) of an oily substance of 14.12-lactone was obtained.
ＥＩ−ＭＳ（ｎ／ｚ）：５２８（Ｍ ）ＩＲ（ＣｕＣ
ｌ３）シ：３５００，１８２０．１７２０儂−１１Ｈ−
ＮＭＲ（ＣＤＣｊ、）δＰＰ−＊２．２４（ｔ、−Ｊ＝
７．６Ｈｚ、２Ｈ）、３．３２（ｒｂ、ＩＨ）。EI-MS (n/z): 528 (M) IR (CuC
l3) し:3500,1820.1720儂-11H-
NMR(CDCj,)δPP-*2.24(t,-J=
7.6Hz, 2H), 3.32 (rb, IH).
３．６５（ｒａ、２Ｈ）、４．４９（ｍ、ＩＨ）実施例
１２
トランス−１２−ヒドロキシ−１３−（ヒドロキシメチ
ル）テトラドデカンニ酸 １４．１２−ラクトンの製造
：
３０＃のトランス−１２−ヒドロキシ−１３−（トリフ
ェニルメトキシメチル）テトラドデカンニ酸 １４．１
２−ラクトンをｎ−ブタノール（Ｉ，７ｉｄ）に溶解し
、トリフルオロ酢酸（０，５６ｉ ）を滴下し、滴下後
２時間室温で攪拌した。反応溶液を酢酸エチルに希釈し
、飽和炭酸水素ナト’Ｊウム水溶液および飽和食塩水で
洗浄し、有機層を無水硫酸ナトリウムで乾燥後、溶媒を
減圧下留去した。3.65 (ra, 2H), 4.49 (m, IH) Example 12 Trans-12-hydroxy-13-(hydroxymethyl)tetradedecanoic acid 14. Preparation of 12-lactone: 30# trans-12 -Hydroxy-13-(triphenylmethoxymethyl)tetradedecanoic acid 14.1
2-lactone was dissolved in n-butanol (I,7id), trifluoroacetic acid (0,56i) was added dropwise, and the mixture was stirred at room temperature for 2 hours after the dropwise addition. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
残渣をシリカゲルカラムクロマトグラフィー（溶出ｇ媒
：クロロホルムーメタノール（Ｉ０：１）〕にて精製し
、トランス−１２−ヒドロキシ−１３−（ヒドロキシメ
チル）テトラドデカンニ酸 １４．１２−ラクトンの油
状物質８１１ｇ（収率４９％）を得た。The residue was purified by silica gel column chromatography (elution medium: chloroform-methanol (I0:1)) to obtain 811 g of an oily substance of trans-12-hydroxy-13-(hydroxymethyl)tetradedecanedioic acid 14.12-lactone. (yield 49%).
Ｅｌ−ＭＳ（ｍ／ ｔ ） ： ２５５ （Ｍ −３１
）ＩＲ（ＣＨ１ｊ３）シ：３５００，１８２０．１７３
０の＝ｌ’Ｈ−ＮＭＲ（ＣＤＣｊ、 ）δ、ｐ工：２．
３（ｍ、２Ｈ） 、３．４（ｎｕ、１Ｈ）、３．９（ｒ
ｎ、２Ｈ）。El-MS (m/t): 255 (M-31
)IR(CH1j3)shi:3500,1820.173
0 = l'H-NMR (CDCj, )δ, p: 2.
3 (m, 2H), 3.4 (nu, 1H), 3.9 (r
n, 2H).
４．５（ｍ、１Ｈ）
実施例１３
トランス−３−ヒドロキシ−２−（トリフェニルメトキ
シメチル）テトラドデカンニ酸１４−メチル １．３−
ラクトンの製造：２００１ｎ９のトンオー３−ヒドロキ
シ−２−（トリフェニルメトキシメチル）テトラドデカ
ンニ酸 １−ベンシル １４−メチルをエタノール（４
ｄ）に溶解し、ノ９ラゾウム黒（２０■）を加え、常圧
で４５分間水素添加した。触媒をろ別し、ろ液を減圧下
濃縮して、モノカル？ン酸の粗生成物を得た。この粗生
成物をビリシン（３ｄ）に溶解し、水冷下、水酸化カリ
ウム（Ｉ５１ｋｇ）とｐ−トルエンスルホニルクロリド
（２２０ｊｌｌｉｌ）を加えた後、３℃において１８時
間放置した。次いで、メタノール（Ｉｄ）を加え、１０
分間、室温に放置した後、減圧下濃縮し、残渣をジクロ
ロメタンに溶解し、飽和食塩水で洗浄した。有機層を無
水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去し、
残渣をシリカゲルカラムクロマトグラフィー〔溶出溶媒
：ヘキサンー酢酸エチル（５：１））にて精製し、トラ
ンス−３−ヒドロキシ−２−（トリフェニルメトキシメ
チル）テトラドデカンニ酸 ｌ４−エチル １，３−ラ
クトンの油状物質７４■（収率４５％）を得た。4.5 (m, 1H) Example 13 14-methyl trans-3-hydroxy-2-(triphenylmethoxymethyl)tetradodecanoate 1.3-
Production of lactone: Ton-oh 3-hydroxy-2-(triphenylmethoxymethyl)tetradedecanoic acid 1-benzyl 14-methyl of 2001n9 was dissolved in ethanol (4
d), No9razoum black (20 ml) was added thereto, and hydrogenation was carried out at normal pressure for 45 minutes. The catalyst is filtered off, the filtrate is concentrated under reduced pressure, and monocarboxylic acid is obtained. A crude product of phosphoric acid was obtained. This crude product was dissolved in bilicin (3d), and after adding potassium hydroxide (I51 kg) and p-toluenesulfonyl chloride (220 jllil) under water cooling, the mixture was left at 3° C. for 18 hours. Then methanol (Id) was added and 10
After being left at room temperature for a minute, it was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and washed with saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (5:1)] to obtain trans-3-hydroxy-2-(triphenylmethoxymethyl)tetradodecanoic acid l4-ethyl 1,3-lactone. 74 ml of oily substance (yield 45%) was obtained.
Ｅｌ−ＭＳ（ｒｎ／ ｚ ） ： ５４２ （Ｍ ）Ｉ
Ｒ（ＣＨＣｊ３）ｙ：１８２０，１７３０ｃＩＩＬ−’
ＩＨ−ＮＭＲ（ＣＤ（ｊ３）δｐｐｍ：２．３１（ｔ、
Ｊ＝６．８Ｈｚ、２Ｈ）、３．３（ｍ、２Ｈ）。El-MS (rn/z): 542 (M)I
R(CHCj3)y:1820,1730cIIL-'
IH-NMR (CD (j3) δppm: 2.31 (t,
J=6.8Hz, 2H), 3.3(m, 2H).
３．５（ｍ、ｉＨ）、３．６６（ａ、３Ｈ）、４．５８
（ｅｎ、ＩＨ）実施例１４
トランス−３−ヒドロキシ−２−（ヒドロキシメチル）
テトラドデカンニ酸 １４−メチル １．３−ラクトン
の製造：
５４■のトランス−３−ヒドロキシ−２−（トリフェニ
ルメトキシメチル）テトラドデカンニ酸 １４−メチル
１，３−ラクトンを、ｎ−ブタノール（Ｉ，３ｍ）に
溶解し、溶液を室温で攪拌しながら、トリフルオロ酢酸
（０，５４ｙ）を滴下し、滴下後、そのまま室温に２時
間放置し九。反応溶液を酢酸エチルに希釈し、飽和炭酸
水素ナトリウム水溶液および飽和食塩水で洗浄し、有機
層を無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し
た。3.5 (m, iH), 3.66 (a, 3H), 4.58
(en, IH) Example 14 trans-3-hydroxy-2-(hydroxymethyl)
Production of 14-methyl tetradodecanoate 1,3-lactone: 54 ■ trans-3-hydroxy-2-(triphenylmethoxymethyl) 14-methyl tetradodecanoate 1,3-lactone was mixed with n-butanol ( Trifluoroacetic acid (0,54y) was added dropwise while stirring the solution at room temperature, and after the dropwise addition, it was left to stand at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
残渣をシリカグルカラムクロマトグラフイー〔溶出溶媒
：ヘキサンー酢酸エチル（２： １ ））にて精製し、
トランス−３−ヒドロキシ−２−（ヒドロキシメチル）
テトラドデカンニ酸１４−メチル １．３−ラクトンの
油状物質１８■（収率６０％）を得た。The residue was purified by silica glu column chromatography [elution solvent: hexane-ethyl acetate (2:1)],
trans-3-hydroxy-2-(hydroxymethyl)
18 quartz (yield: 60%) of an oily substance of 14-methyl 1,3-lactone tetradodecanoate was obtained.
ＥＩ−ＭＳ（ｒＩＩ／ｘ）：３００（Ｍ ）ＩＲ（ＣＨ
（Ｊ３ ）シ：３６００ 、１８２０ 、１７３０ｃｒ
ｎ−”ＩＨ−ＮＭＲ（ＣＤＣｊ、 ）δｐｐｍ：２．３
１ （ｔ 、 Ｊ＝７．４Ｈｙｃ 、 ２Ｈ） 、 ３
．３９（ｎｎ、１Ｈ）。EI-MS (rII/x): 300 (M) IR (CH
(J3) Shi: 3600, 1820, 1730cr
n-”IH-NMR (CDCj, )δppm: 2.3
1 (t, J=7.4Hyc, 2H), 3
．． 39 (nn, 1H).
３．６６（ａ、３Ｋ）、３．９８（ｎｓ、２Ｈ）、４．
５８（ｍ、ｉＨ）
以上3.66 (a, 3K), 3.98 (ns, 2H), 4.
58 (m, iH) or more
Claims (1)
１０の整数を示し、２及び３の配位はシス又はトランス
である） で表わされるα−ヒドロキシメチル−β−ラクトン誘導
体又はその塩。[Claims] 1. The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ (I) (In the formula, R is a hydrogen atom or a lower alkyl group, and n is 4 to
an integer of 10, and the coordination of 2 and 3 is cis or trans) or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63256486A JPH02104581A (en) | 1988-10-12 | 1988-10-12 | Alpha-hydroxymethyl-beta-lactone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63256486A JPH02104581A (en) | 1988-10-12 | 1988-10-12 | Alpha-hydroxymethyl-beta-lactone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02104581A true JPH02104581A (en) | 1990-04-17 |
Family
ID=17293308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63256486A Pending JPH02104581A (en) | 1988-10-12 | 1988-10-12 | Alpha-hydroxymethyl-beta-lactone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02104581A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9698552B2 (en) | 2013-08-09 | 2017-07-04 | Autonetworks Technologies, Ltd. | Connector |
-
1988
- 1988-10-12 JP JP63256486A patent/JPH02104581A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9698552B2 (en) | 2013-08-09 | 2017-07-04 | Autonetworks Technologies, Ltd. | Connector |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6573378B1 (en) | Antiviral guanine derivatives | |
| Katagiri et al. | Highly stereoselective total synthesis of. beta.-ribofuranosylmalonate | |
| JP2002509926A (en) | Novel ascorbic acid derivative and preparation method thereof | |
| JPS6146462B2 (en) | ||
| Nakamura et al. | Total synthesis of sphingofungin E from D-glucose derivative | |
| KR100980379B1 (en) | Process for the preparation of optically active 5-hydroxy-3-oxoheptanoate derivatives | |
| JPH02104581A (en) | Alpha-hydroxymethyl-beta-lactone derivative | |
| KR0144684B1 (en) | Mono esters of dicarboxylic acids and their prepartion and use | |
| Allevi et al. | A simple and convenient transformation of l-lysine into pyridinoline and deoxypyridinoline, two collagen cross-links of biochemical interest | |
| EP0585104B1 (en) | A method of preparing a saturated monocyclic hydrocarbon compound and an intermediate therefor | |
| US5091595A (en) | Reduction of diethyl phenylmalonate to 2-phenyl-1,3-propanediol | |
| HU183655B (en) | Process for preparing 2,9-dioxo-tricyclo/4.3.1.0 3.7/ decane derivatives | |
| JP2896946B2 (en) | Production method of neocardilines | |
| HU176688B (en) | Process for preparing 2,9-dioxa-tricyclo/4,3,1,0 high 3,7/decanes | |
| US11434217B2 (en) | Method for synthesis of lobaric acid and analog thereof | |
| JPH03123780A (en) | 2h-benzo(b)quinolidine derivative | |
| Berque et al. | Enantioselective Synthesis of a C1-C9 Moiety of Tylonolide, Tylosin Aglycon | |
| JP2869745B2 (en) | Optically active dichlorlactone compound, method for producing the same, and method for producing optically active diol compound using the same | |
| Kongkathip et al. | An efficient synthesis and regioselective hydrogenolysis of dioxolane-type of carbohydrates | |
| JPH05155813A (en) | Production of hydroxyalkyl monoacrylate and its intermediate | |
| JP3263377B2 (en) | Method for producing 3,5-dihydroxy-6-oxohexanoate derivative | |
| JP2504934B2 (en) | 1,6,7-Triacylforskolin derivative | |
| JP2971966B2 (en) | Method for producing 3,5,6-trihydroxyhexanoate derivative | |
| JP3020980B2 (en) | Optically active valerolactone derivative | |
| JP2718546B2 (en) | Stereoselective production of cyclopentenone derivatives |