JPS62230775A - Production of intermediate for statine and related compound thereof - Google Patents
Production of intermediate for statine and related compound thereofInfo
- Publication number
- JPS62230775A JPS62230775A JP7379086A JP7379086A JPS62230775A JP S62230775 A JPS62230775 A JP S62230775A JP 7379086 A JP7379086 A JP 7379086A JP 7379086 A JP7379086 A JP 7379086A JP S62230775 A JPS62230775 A JP S62230775A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- compound
- general formula
- fluorine
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- DFVFTMTWCUHJBL-BQBZGAKWSA-N statine Chemical compound CC(C)C[C@H](N)[C@@H](O)CC(O)=O DFVFTMTWCUHJBL-BQBZGAKWSA-N 0.000 title abstract 3
- -1 t-butyldiphenylsilyl Chemical group 0.000 claims abstract description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 9
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 8
- 239000011737 fluorine Substances 0.000 claims abstract description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006197 hydroboration reaction Methods 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 229940096017 silver fluoride Drugs 0.000 claims abstract description 4
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 claims abstract description 4
- 239000013543 active substance Substances 0.000 claims abstract description 3
- DRNXZGJGRSUXHW-UHFFFAOYSA-N silyl carbamate Chemical class NC(=O)O[SiH3] DRNXZGJGRSUXHW-UHFFFAOYSA-N 0.000 claims abstract 3
- AKZWRTCWNXHHFR-PDIZUQLASA-N [(3S)-oxolan-3-yl] N-[(2S,3S)-4-[(5S)-5-benzyl-3-[(2R)-2-carbamoyloxy-2,3-dihydro-1H-inden-1-yl]-4-oxo-3H-pyrrol-5-yl]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound NC(=O)O[C@@H]1Cc2ccccc2C1C1C=N[C@](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)(Cc2ccccc2)C1=O AKZWRTCWNXHHFR-PDIZUQLASA-N 0.000 claims abstract 2
- 125000004122 cyclic group Chemical group 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 12
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 7
- 150000002500 ions Chemical class 0.000 claims description 7
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 claims description 4
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical group C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 claims description 2
- 125000005948 methanesulfonyloxy group Chemical group 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 239000004332 silver Substances 0.000 claims description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 4
- 150000001639 boron compounds Chemical class 0.000 abstract description 3
- 239000007864 aqueous solution Substances 0.000 abstract description 2
- 229910052801 chlorine Inorganic materials 0.000 abstract description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 101000856746 Bos taurus Cytochrome c oxidase subunit 7A1, mitochondrial Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000003276 anti-hypertensive effect Effects 0.000 description 3
- 229940030600 antihypertensive agent Drugs 0.000 description 3
- 239000002220 antihypertensive agent Substances 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 229950000964 pepstatin Drugs 0.000 description 3
- 108010091212 pepstatin Proteins 0.000 description 3
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical class NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 108090000783 Renin Proteins 0.000 description 2
- 102100028255 Renin Human genes 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- KTKVOCOSCNLKQX-UHFFFAOYSA-N 2,2-dimethylpropyl methyl carbonate Chemical group COC(=O)OCC(C)(C)C KTKVOCOSCNLKQX-UHFFFAOYSA-N 0.000 description 1
- CQCAYWAIRTVXIY-UHFFFAOYSA-N 2-(triphenyl-$l^{5}-phosphanylidene)acetaldehyde Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC=O)C1=CC=CC=C1 CQCAYWAIRTVXIY-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 102100028138 F-box/WD repeat-containing protein 7 Human genes 0.000 description 1
- 101001060231 Homo sapiens F-box/WD repeat-containing protein 7 Proteins 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- AOMOJFWVOHXBTN-UHFFFAOYSA-N [tert-butyl(diphenyl)silyl] trifluoromethanesulfonate Chemical compound C=1C=CC=CC=1[Si](OS(=O)(=O)C(F)(F)F)(C(C)(C)C)C1=CC=CC=C1 AOMOJFWVOHXBTN-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- HVFZJOMDCCKYSV-UHFFFAOYSA-N dichloromethane;2,6-dimethylpyridine Chemical compound ClCCl.CC1=CC=CC(C)=N1 HVFZJOMDCCKYSV-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- PXLIDIMHPNPGMH-UHFFFAOYSA-N sodium chromate Chemical compound [Na+].[Na+].[O-][Cr]([O-])(=O)=O PXLIDIMHPNPGMH-UHFFFAOYSA-N 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- RQSBRFZHUKLKNO-VIFPVBQESA-N tert-butyl n-[(2s)-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C RQSBRFZHUKLKNO-VIFPVBQESA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は一般式（Ｔ）
（式中Ｒは炭素原子数１〜乙のアルキル基、フェニル基
またはベンジル基を表わす）
を有するスタチン及びその関連化合物の中間体の製造方
法に関する。Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a statin having the general formula (T) (wherein R represents an alkyl group having 1 to 2 carbon atoms, a phenyl group, or a benzyl group) and its The present invention relates to a method for producing intermediates of related compounds.
さらに詳しく説明すれば、本発明の前記式（Ｉ）の中間
体を弱塩基により加水分解すれば一般式囚（式中Ｒ＃−
を前記定義の通りである）を有するスタチン（Ｒはイソ
ブチルである）及びその関連化合物とすることができる
。スタチンはプロテアーゼ（ａａｐａｒｔｉｃ ｐｒｏ
ｔｅｉｎａｓｅｓ）の阻害剤として有名なペプスタチン
の構成アミノ酸であり、医薬、特に降圧剤としての利用
が考えられ、すでにレニン阻讐活性を持つ降圧剤として
の利用が見い出されている。More specifically, if the intermediate of the formula (I) of the present invention is hydrolyzed with a weak base, the intermediate of the general formula (in the formula R#-
as defined above) (R is isobutyl) and related compounds thereof. Statins are proteases (aapartic pro
It is a constituent amino acid of pepstatin, which is famous as an inhibitor of Pepstatin, and is considered to be used as a medicine, especially as an antihypertensive agent, and has already been found to be used as an antihypertensive agent with renin antihypertensive activity.
（従来技術）
スタチンはペプスタチン（ｐｅｐｓｔａｔｉｎ、 ジ
ャーナル・オン・アンチビオティックス（Ｊ、Ａｎｔｉ
ｂｉｏ−ｔｉｅｓ）、 １９７０年、２３巻、２５９頁
〕を構成する最も重要なアミノ酸として悔涙らによって
見い出され、近年レニン阻害活性を持つ抗高血圧作用が
注目されている化合物である。(Prior art) Statin is pepstatin (Journal on Antibiotics).
Bio-ties), 1970, Vol. 23, p. 259] was discovered by Hanai et al., and is a compound that has recently attracted attention for its antihypertensive action with renin inhibitory activity.
降圧作用は例えば、ボジャー（Ｂｏｇｅｒ）らネイチャ
ー（Ｎａｔｕｒｅ） 、 １９８３年、３０６巻、８１
頁およびリッチ、ディー、エッチ（ｇｉ ａｈ、 Ｄ、
Ｈ，）ジャーナル・オプ・メディカルケミストリー（
Ｊ、Ｍｅｄ。The antihypertensive effect is described, for example, by Boger et al., Nature, 1983, vol. 306, 81.
Page and Rich, Dee, Ecchi (gi ah, D,
H,) Journal of Medical Chemistry (
J, Med.
Ｃｈｅｍ−）、 １９８５年、２８巻、２８３頁に述べ
られているＣ又、スタチンを含む合成ペプチドを降圧剤
として利用する試みもメツツク社のグループで行なわれ
ている。Chem-), 1985, vol. 28, p. 283. Also, the Metsuku Group is attempting to utilize synthetic peptides containing statins as antihypertensive agents.
これらは、特開昭第５９−１５５３４５号および第６
（１−２３１，６９５号などに開示されている。These are JP-A No. 59-155345 and No. 6
(Disclosed in No. 1-231,695, etc.
このスタチンの合成も数多く報告されている。例えば、
エッチ・モリシマ（Ｈ−ＪＭｏｒｉ ｓｈｉｍａ）らジ
ャーナル・オン・アンチビオチックス（Ｊ、’Ａｎｔｉ
ｂｉｏ−ｔｔｃｓ）＊ １９７３年、２６巻、１１５頁
、ダブリュー・−ニス・リュー（Ｗ、 −８，Ｌｉ ｕ
）ら ジャーナル・オプ・オーガニックケミストリー
（Ｊ、 Ｏｒｇ、 Ｃｈｅｍ） 。Numerous reports have also been made on the synthesis of statins. for example,
H-JMorishima et al. Journal on Antibiotics (J, 'Anti
bio-ttcs) * 1973, vol. 26, p. 115, W. -8, Li u
) et al. Journal of Organic Chemistry (J, Org, Chem).
１９７８年、４３巻、７５４頁、ピー・ダブリュー・ケ
ー・ウー（Ｐ、Ｗ、 Ｋ、 Ｗｏ ｏ ）テトラヘドロ
ンレターズ（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅｒｓ
） 、 ２６巻、２９７３頁等に記載されているが、今
だに安価に工業的生産に耐え得る光学活性体の製造法は
ない。1978, Volume 43, Page 754, P, W, K, Wo o Tetrahedron Letters
), vol. 26, p. 2973, etc., but there is still no method for producing optically active substances at low cost that can withstand industrial production.
（解決すべき問題点）
本発明者は天然界に存在する異常アミノ酸の役割に注目
し、その光学活性体の簡便な合成法を検討していた過程
で、１，２−及び１，３−不斉誘導の新しい方法を見い
出した。(Problems to be Solved) The present inventor focused on the role of abnormal amino acids that exist in nature, and in the process of investigating a simple method for synthesizing optically active forms thereof, discovered that 1,2- and 1,3- We have discovered a new method for asymmetric induction.
そこで、本発明者が新たに見い出した１、２−不斉誘導
反応を用いることによりスタチンなどのアミノアルコー
ル類を容易に入手出来るアミノ酸を原料として、効率よ
く合成する方法を見い出し本発明を完成した。Therefore, by using the newly discovered 1,2-asymmetric induction reaction, the present inventors discovered a method for efficiently synthesizing amino alcohols such as statins using readily available amino acids as raw materials, and completed the present invention. .
（問題点を解決する手段）
以前、本発明者はアミノ酸、ペプチド化学の分野で広く
用いられているアミン基の保護基であるｔ−ブチルジメ
チルオキシカルボニル基（以下、Ｂｏａと略す）を含ん
だアミノ酸にｔ−プチルジメチルシリルトリフレート（
以下、ＴＢＤＭＳＯＴｆと略す）を作用させると、Ｎ−
ｔ−ブチルジメチルシリルオキシカルボニル化合物が得
られることを見い出した。以下にこの反応を反応式で示
す。(Means for Solving the Problems) Previously, the present inventors discovered a method containing a t-butyldimethyloxycarbonyl group (hereinafter abbreviated as Boa), which is a protecting group for amine groups widely used in the fields of amino acid and peptide chemistry. Amino acids include t-butyldimethylsilyl triflate (
(hereinafter abbreviated as TBDMSOTf), N-
It has been found that a t-butyldimethylsilyloxycarbonyl compound can be obtained. This reaction is shown below using a reaction formula.
これは、Ｎ−ウレタン型保誦基が脱炭酸を伴うことなく
Ｎ−カルボキシラートイオ／として捕捉されたことを意
味する。また、生成し九Ｎ−シリルエステルはフッ素イ
オン処理でＮ−カルボキシラードイオンを再生する（堺
谷、大船テトラヘドロンレターズ（Ｔｅｔｒａｈｅｄｓ
ｏｎ Ｌｅｔｔｅｒｓ）、 １９８５年、５５４３頁）
。This means that the N-urethane type storage group was captured as N-carboxylate io/ without decarboxylation. In addition, the generated 9N-silyl ester can be treated with fluorine ions to regenerate N-carboxylade ions (Sakai, Ofuna Tetrahedron Letters).
on Letters), 1985, p. 5543)
.
光学活性なスタチン及びその関連化合物を合成するには
、まず、原料として容易に入手可能なアミノ酸を用いる
。To synthesize optically active statins and their related compounds, readily available amino acids are first used as raw materials.
原料の合成を簡単に説明する。The synthesis of raw materials will be briefly explained.
まず、一般式（Ｖ）
（式中ＲおよびＢｏｃは前記定義通りである）のアミノ
酸誘導体に式（ＶＩ）
で表わされるホスホランを作用させ、次いで還元するこ
とにより一般式α９
（式中ＲおよびＢｏｃは前記定義の通りでおる）を有す
るアリルアルコール体が得られる。First, an amino acid derivative of the general formula (V) (wherein R and Boc are as defined above) is treated with phosphorane represented by the formula (VI), and then reduced to give the amino acid derivative of the general formula α9 (wherein R and Boc are as defined above). is as defined above) is obtained.
このアルコール体にＮ−クロルコハク酸イミドまたはＮ
−ブロムコハク酸イミドを作用させると一般式（■α）
（式中ＲおよびＢｏａは前記定義の通りである）を有す
るアリルノ・ライド化合物となる。またα０にパラトル
エンスルホニルクロリドまたはメタンスルホニルクロリ
ドを作用させると一般式（■ｂ）および（ＶＩＩＩＣ）
（上式中ＲおよびＢｏｃは前記定義の通りである）を有
するスルホネート化合物が得られる。N-chlorosuccinimide or N
- When treated with bromosuccinimide, an allylno-ride compound having the general formula (■α) (wherein R and Boa are as defined above) is obtained. Furthermore, when α0 is reacted with paratoluenesulfonyl chloride or methanesulfonyl chloride, sulfonate compounds having the general formulas (■b) and (VIIIC) (in which R and Boc are as defined above) are obtained.
上述ノ（ＶＩＩＩＣ）、（ＶＩＩＩｂ）、（ＶＩＩＩＣ
）Ｋ１．５〜２当量のｔ−ブチルジメチルシリルトリフ
レー） （ＴＢＤＭＳＯＴｆ）またはｔ−ブチルジフェ
ニルシリルトリフレートを塩基存在下作用させることに
より一般式（ＩＶ）（式中Ｒは前記定義の通りであり、
Ａはｔ−ブチルジメチルシリル基またはｔ−ブチルジフ
ェニルシリル基を表わし、Ｘはブロム原子、クロル原子
、パラトルエンスルホニルオキシ基またはメタンスルホ
ニルオキ７基を表わす）
を有するシリルカルバメート誘導体が得られる。(VIIIC), (VIIIb), (VIIIC)
)K1.5 to 2 equivalents of t-butyldimethylsilyl triflate) (TBDMSOTf) or t-butyldiphenylsilyl triflate in the presence of a base to obtain the general formula (IV) (wherein R is as defined above). can be,
A is a t-butyldimethylsilyl group or a t-butyldiphenylsilyl group;
この化合物ＧＶ）を有機溶媒中、含フッ素イオン試薬と
処理すると、基Ｘが脱離基として働き、前述のＮ−カル
ボキシラードイオンが立体選択的に環化した本発明の一
般式（ｎ）
（式中Ｒは前記定義と同じである）
を有する環状カルバメート誘導体になる。When this compound GV) is treated with a fluorine-containing ion reagent in an organic solvent, the group X acts as a leaving group, and the above-mentioned N-carboxylald ion stereoselectively cyclizes the general formula (n) of the present invention ( In the formula, R is the same as defined above.
ここで云う、有機溶媒とは、反応に関与しないものであ
れば何でもよいが、アセトニトリル、ジメチルアセトア
ミド、ジメチルホルムアミド、トルエン、ベンゼン、キ
シレンまたはニトロメタンが好ましい。反応は室温以下
でよく、用いる含フッ素イオン試薬は例えばテトラブチ
ルアンモニウムフロリド、テトライソフロビルアンモニ
ウムフロリドなどのテトラアルキルアンモニウムフロリ
ド、フッ化銀、フッ化銅、ホウ素化テトラフルオロ銀な
どが好ましい。しかし、トリフルオロメタンスルホニル
銀などの含フッ素イオン試薬でない金属の試薬でも反応
は進行する。The organic solvent referred to herein may be any solvent as long as it does not participate in the reaction, but acetonitrile, dimethylacetamide, dimethylformamide, toluene, benzene, xylene, or nitromethane are preferred. The reaction may be carried out at room temperature or below, and the fluorine-containing ion reagents used include, for example, tetraalkylammonium fluorides such as tetrabutylammonium fluoride and tetraisofluorbylammonium fluoride, silver fluoride, copper fluoride, and tetrafluorosilver boron. preferable. However, the reaction proceeds even with a metal reagent other than a fluorine-containing ion reagent such as silver trifluoromethanesulfonyl.
基Ｘｆｌ前述したごとく、一般に用いられているｉで脱
離する基であればよいが、合成手段として常用されてい
るクロル原子、ブロム原子、パラトルエンスルホニルオ
キシ基またはメタンスルホニルオキシ基がよい。As mentioned above, the group Xfl may be any commonly used group that leaves off at i, but preferably is a chlor atom, a bromine atom, a paratoluenesulfonyloxy group, or a methanesulfonyloxy group, which are commonly used as a synthetic means.
この化合物（［１１をエーテル系溶媒中、好ましくはテ
トラヒドロフラン中、ヒドロホウ素化反応に付すことに
より一般式（１１）
（式中Ｒは前記定義通りである）を有するアルコール化
合物が得られる。ヒドロホウ素化反応は、ジポラン、ボ
ラン テトラヒドロフラン錯体、アルキルボラン、ジア
ルキルボラン等のホウ素化合物と反応させ、次いで塩素
条件下過酸化水素水と処理する方法が常用されている。By subjecting this compound ([11) to a hydroboration reaction in an ether solvent, preferably tetrahydrofuran, an alcohol compound having the general formula (11) (wherein R is as defined above) can be obtained. A commonly used method for the reaction is to react with a boron compound such as diporane, borane tetrahydrofuran complex, alkylborane, dialkylborane, etc., and then treat with hydrogen peroxide solution under chlorine conditions.
ホウ素化合物及び塩基は９−ボラビシクロ〔６゜６．１
〕 ノナンと水酸化ナトリウム水溶液が代表として掲
げられる。このアルコール化合物（ｍ）の酸化は一級ア
ルコールをカルボン酸にする一般的に用いられている方
法でよい。例えば、クロム酸、無水クロム酸を基にした
種々の酸化剤、クロム酸・硫酸・アセトン、クロム酸・
硫酸・酢酸、無水クロム酸・酢酸、無水クロム酸 ピリ
ジンなどが掲げられる。また、過マンガン酸カリウム、
酸化銀なども有用である。Boron compounds and bases are 9-borabicyclo[6゜6.1
] Representative examples include nonane and aqueous sodium hydroxide solution. The alcohol compound (m) may be oxidized by a commonly used method to convert a primary alcohol into a carboxylic acid. For example, chromic acid, various oxidizing agents based on chromic acid anhydride, chromic acid/sulfuric acid/acetone, chromic acid/
Sulfuric acid/acetic acid, chromic anhydride/acetic acid, chromic anhydride pyridine, etc. are listed. Also, potassium permanganate,
Silver oxide and the like are also useful.
斯くして得られる本発明化合物（Ｉ）は、弱塩基を用い
た加水分解反応に付すことにより容易にスタチン及びそ
の関連化合物（Ｘ）になる。The thus obtained compound (I) of the present invention is easily converted into statins and related compounds (X) by subjecting them to a hydrolysis reaction using a weak base.
この反応において、用いられる弱塩基としては、例えば
水酸化リチウム、水酸化バリウムなどが掲げられる。In this reaction, examples of the weak base used include lithium hydroxide and barium hydroxide.
（実施例）
次に実施例および参考例でもって本発明をさらに具体的
に説明するが、本発明がこれら実施例の範囲に限定され
るものでないことはいうまでもない。例中のＮＭＲスペ
クトルのデータ中、Ｓは単線、ｄは二重線、ｍは多重線
、ｂｒは巾広を意味する。(Examples) Next, the present invention will be explained in more detail with reference to Examples and Reference Examples, but it goes without saying that the present invention is not limited to the scope of these Examples. In the NMR spectrum data in the example, S means single line, d means doublet, m means multiplet, and br means width.
参考例 １
４−Ｎ−（ｔ−ブトキシカルボニル）アミノ−６−メチ
ル−２−へブチナール
既知の方法により得られたＮ−ｔ−ブトキシカルボニル
−Ｌ−ロイシナール（１，７２ｇ、８．０ミリモル）の
ベンゼン溶液（３０ｍＪ）に、ホルミルメチレントリフ
ェニルホスホラン（２，９，ｌｉ＋、９．５ミリモル）
を加え、６０℃加温下１２時間攪拌を行なった。溶媒を
留去した後、シリカゲルカラムクロマトグラフィー（エ
ーテル／ヘキサン＝１／１）に付し、標記化合物を１．
７１１！（収率８９％）得た。Reference example 1 4-N-(t-butoxycarbonyl)amino-6-methyl-2-hebutynal N-t-butoxycarbonyl-L-leucinal obtained by a known method (1,72 g, 8.0 mmol) Formylmethylenetriphenylphosphorane (2,9,li+, 9.5 mmol) was added to a benzene solution (30 mJ) of
was added and stirred for 12 hours while heating at 60°C. After distilling off the solvent, it was subjected to silica gel column chromatography (ether/hexane = 1/1) to obtain the title compound in 1.
711! (yield 89%).
性状：無色油状物質
参考例 ２
４−Ｎ−（ｔ−ブトキシカルボニル）アミノ−６−メチ
ル−２−へブテン−１−オール望素雰囲気下、−４０℃
に冷却したリチウムトリｔ−ブトキシアルミニウムヒド
リド（２，２１８，５ミリモル）のテトラヒドロフラン
溶液（１０ｍ）Ｉｃ、参考例１の化合物（１，７１，９
，７，１ミＩＪモル）のテトラヒドロ７ラン溶液（５ｄ
）を加え、２時間攪拌を行なった。メタノール（５ＴＩ
Ｌｌ）を加え反応停止後、エーテル及び無水硫酸マグネ
シウムを加えｆ過し、溶媒を減圧留去した後、得られた
油状物をシリカゲルカラムクロマトグラフィー（エーテ
ル／ヘキサン＝３／１ ”）に付すことにより標記化合
物１．１２ Ｆを得た。（収率６５％）性状：無色プリ
ズム晶
融点ニア９５〜８０．５℃（ヘキサン再結晶）ＩＲスペ
クトル（フィルム、 ｃｍ−” ） ：３３３６．１６
９４．１５３４
マススペクトル（ｍ／ｚ）：
２４４（Ｍ＋１ ）”、 １８８．１７ＯＮＭＲスペ
クトｋ （６０Ｍｉｈ、 ＣＤＣｌ３． ） ：０．
９３ （６Ｈ，ｄ 、 Ｊ＝６．０Ｈｚ）、 １．１〜
１．８（３Ｈ，ｍ）、 １．４５（９Ｈ，ｓ ）、 ３
．３６（ＩＨ，ｍ）、３．６０（ＩＨ，ｍ）、４．０８
（２Ｈ，ｍ）、４．８０（ＩＨ，ｄ、Ｊ＝８．０Ｈｚ
）、 ５．６５（２Ｈ，ｍ＞。Properties: Colorless oil reference example 2 4-N-(t-butoxycarbonyl)amino-6-methyl-2-hebuten-1-ol Under desired atmosphere, -40°C
A solution of lithium tri-t-butoxyaluminum hydride (2,218,5 mmol) in tetrahydrofuran (10 m) cooled to Ic, the compound of Reference Example 1 (1,71,9
, 7,1 mmol) in tetrahydro-7rane solution (5d
) was added and stirred for 2 hours. Methanol (5TI
After adding ether and anhydrous magnesium sulfate to stop the reaction, filtrate by adding ether and anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, and subjecting the obtained oil to silica gel column chromatography (ether/hexane = 3/1''). The title compound 1.12F was obtained. (Yield 65%) Properties: Colorless prism crystal Melting point near 95-80.5°C (hexane recrystallization) IR spectrum (film, cm-''): 3336.16
94.1534 Mass spectrum (m/z): 244 (M+1)", 188.17 ONMR spectrum k (60 Mih, CDCl3.): 0.
93 (6H, d, J=6.0Hz), 1.1~
1.8 (3H, m), 1.45 (9H, s), 3
．． 36 (IH, m), 3.60 (IH, m), 4.08
(2H, m), 4.80 (IH, d, J = 8.0Hz
), 5.65 (2H, m>.
参考例 ３
４−Ｎ−（ｔ−ブトキシカルボニル）アミノ−６−メチ
ル−２−ヘプテン−１−クロリド参考例２の化合物（２
，０，＠、８．２ミ！Ｊモル）の塩化メチレン溶液（３
０ｆｆ１７）に水冷下、トリフェニルホスフィンＣ２，
６９，９，９ミリモル）及び、Ｎ−クロロスクシンイミ
ド（１，２ｇ、９．０ミリモル）を加え、室温まで昇温
後、１時間攪拌を行なつた。溶媒を減圧留去後、得られ
た油状物をシリカゲルカラムクロマトグラフィー（ヘキ
サンおよびヘキサン／エーテル＝１／４）に付し標記化
合物２．１２ｇを得た（収率９９％）。Reference Example 3 4-N-(t-Butoxycarbonyl)amino-6-methyl-2-heptene-1-chloride Compound of Reference Example 2 (2
,0,@,8.2mi! J mol) in methylene chloride solution (3
0ff17) under water cooling, triphenylphosphine C2,
69.9.9 mmol) and N-chlorosuccinimide (1.2 g, 9.0 mmol) were added, and the mixture was heated to room temperature and stirred for 1 hour. After distilling off the solvent under reduced pressure, the obtained oil was subjected to silica gel column chromatography (hexane and hexane/ether = 1/4) to obtain 2.12 g of the title compound (yield 99%).
性状：無色油状物質
ＩＲスペクトル（フィルム、 ｃｌｒＬ−１） ：３３
４８．１６９８．１５２２
ＮＭＲスペクトル（６０ＭＨｚ 、 ＣＤＣｌ５ 、
） ：０．９１ （６Ｈ，ｄ、 Ｊ＝６．０Ｈｚ）、
１．１〜１．８（３Ｈ，ｍ）、１．４４（９Ｈ，ｓ）
、４．００（２Ｈ，ｍ）、４．１５（ＩＨ，ｍ）、４．
５９（Ｉ Ｈ，ｂｒｄ 、 Ｊ＝８．０Ｈｚ）、 ５．
６５ （２Ｈ。Properties: Colorless oily substance IR spectrum (film, clrL-1): 33
48.1698.1522 NMR spectrum (60MHz, CDCl5,
): 0.91 (6H, d, J=6.0Hz),
1.1-1.8 (3H, m), 1.44 (9H, s)
, 4.00 (2H, m), 4.15 (IH, m), 4.
59 (I H,brd, J=8.0Hz), 5.
65 (2H.
ｍ）。m).
参考例 ４
４−Ｎ−（ｔ−プチルジメチルンリルオキシカルボニル
）アミノ−６−メチル−２−へブテン−１−クロリド
参考例６の化合物（２，０ｇ、７．６ミＩＪモル）の塩
化メチレン溶液（Ｉ Ｑｄ）に、２．６−ルチジン（１
，７８１！Ｊ、 １５．！１ミリそル）およびｔ−プチ
ルジメチルシリルトリプルオロメタンスルホネー）（２
，６３ゴ、１１．５ミリモル）を加え、室温、窒素雰囲
気下１５分攪拌を行なった。飽和塩化アンモニウム水溶
液を加え、エーテル抽出し、得られた有機層に無水硫酸
マグネシウムを加え乾燥し、ｆ過し、溶媒を減圧留去し
て、標記化合物２．８ｇを得た。Reference Example 4 4-N-(t-Butyldimethyllinyloxycarbonyl)amino-6-methyl-2-hebutene-1-chloride Compound of Reference Example 6 (2.0 g, 7.6 mmol) in methylene chloride 2,6-lutidine (1
,781! J, 15. ! 1 mmol) and t-butyldimethylsilyl triple olomethane sulfone) (2
, 63g, 11.5 mmol) and stirred for 15 minutes at room temperature under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution was added and extracted with ether. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 2.8 g of the title compound.
性状：無色油状物質
ＩＲスペクトル（フィルムｅ ｍ−’） ：３３４４．
１６９６．１５０８
ＮＭＲスペクト” （６０ＭＨｚ ＊ ＣＤ Ｃ４、）
’０．２５（６Ｈ，ｓ）、０．９２（９Ｈ，ｓ）。Properties: Colorless oil IR spectrum (film e m-'): 3344.
1696.1508 NMR Spect” (60MHz * CD C4,)
'0.25 (6H, s), 0.92 (9H, s).
１．１〜１．９（３Ｈ，ｍ）、３．９４（２Ｈ，ｍ）。1.1-1.9 (3H, m), 3.94 (2H, m).
４．１５（ＩＨ，ｒｎ）、４．７０（ＩＨ，ｄ、Ｊ＝８
．０Ｈｚ）、５．６５（２Ｈ，ｍ）一実施例 １
Ａ、 ４−インブチル−５−ビニル−２−オキサゾリ
ド１
参考例４の化合物（２，８，Ｌ ７．６ ミＩＪモル）
のアセトニトリル溶液（２０ｄ）にフッ化銀（１，４６
、！ｉ＋、１１．５ミリモル）を加え、室温で４８時間
攪拌を行なった。酢酸エチルで抽出し、得られた有機層
に無水硫酸マグネシウムを加え乾燥後、溶媒留去し、得
られた油状物をシリカゲルカラムクロマトグラフィー（
エーテル）に付すことにより、４．５−）ランス体と４
．５−シス体の混合物として１．１５ ｇの標記化合物
が得られた（収率８６チ）。4.15 (IH, rn), 4.70 (IH, d, J=8
．． 0 Hz), 5.65 (2H, m) Example 1 A, 4-Inbutyl-5-vinyl-2-oxazolide 1 Compound of Reference Example 4 (2,8, L 7.6 mmol)
Silver fluoride (1,46
,! i+, 11.5 mmol) and stirred at room temperature for 48 hours. After extraction with ethyl acetate, anhydrous magnesium sulfate was added to the obtained organic layer, and after drying, the solvent was distilled off, and the obtained oil was subjected to silica gel column chromatography (
4.5-) lance isomer and 4
．． 1.15 g of the title compound was obtained as a mixture of 5-cis forms (yield: 86 g).
この混合物を、中圧のシリカゲルカラムクロマトグラフ
ィー（エーテル／ヘキサン＝３／２ ）に付すことによ
りトランス体／シス体＝５／１の割合で、それぞれ単一
な化合物として４．５−）ランス体と４．５−シス体ｔ
ｌ−得た。This mixture was subjected to medium-pressure silica gel column chromatography (ether/hexane = 3/2) at a ratio of trans isomer/cis isomer = 5/1, and the 4.5-) trans isomer was converted into a single compound. and 4.5-cis t
l-obtained.
Ｏ
（Ｉα）の物性
性状：無色細状物質
ＩＲｎスペクトルフィルム、 ｃｔｎ ）：３２８０．
１７＜Ｓｏ、１４７０．１３９ＯＮＭＲスペクトル（１
００朧、ＣＤＣｌ３． ）：０．９０ （３Ｈ，ｄ
、 Ｊ＝６．１Ｈｚ）、 ０．９２（３Ｈ，ｄ、Ｊ＝６
．１出）、１．２〜１．９（３Ｈ。Physical properties of O (Iα): colorless fine substance IRn spectrum film, ctn): 3280.
17<So, 1470.139ONMR spectrum (1
00 Oboro, CDCl3. ): 0.90 (3H, d
, J=6.1Hz), 0.92(3H,d, J=6
．． 1), 1.2-1.9 (3H.
ｍ ） 、 ３．５８ （Ｉ Ｈ，ｄｄｄｄ、 Ｊ＝６
．６．５．６゜５．６．１．０Ｈｚ ）、 ４．５０
（Ｉ Ｈ，ｄｄｄｄ、 Ｊ＝６．６．６．６．１．０．
１．０七）、 ５．２８ （ＩＨ。m ), 3.58 (I H, dddd, J=6
．． 6.5.6°5.6.1.0Hz), 4.50
(I H, dddd, J=6.6.6.6.1.0.
1.07), 5.28 (IH.
ｄｄｒｉ、 Ｊ＝１０．３．１．５．１．０Ｈｚ）、
５．３８（Ｉ Ｈ，ｄｄｄ、 Ｊ＝１７．１ 、１．５
．１．０比）。ddri, J=10.3.1.5.1.0Hz),
5.38 (I H, ddd, J=17.1, 1.5
．． 1.0 ratio).
５．９０ （ＩＩＬ ｄｄｄ、 Ｊ＝１７．１ 、１０
．３゜６．６ｆＩｚ ） 、 ６．６８ （Ｉ ｎ、
ｂｒａ ） −（Ｉｈ）の物性
性状：無色針状晶（ヘキサン再結晶）
融点：５４．５〜５６．５°Ｃ
ＩＲｎスペクトルフィルム、 ｍ−１） ：３２７２．
１７５４，１３８８．１２４８ＮＭＲスペクトル（１０
０Ｍ出、 ＣＤＣｌ３． ） ：０．８８ （３Ｈ，
ｄ、 Ｊ＝６．３Ｈｚ）、 ０．９４（３Ｈ，ｄ、Ｊ＝
６．３出）、１．１〜１．８（３Ｈ。5.90 (IIL ddd, J=17.1, 10
．． 3゜6.6fIz), 6.68 (I n,
Physical properties of (Ih): Colorless needle crystals (hexane recrystallization) Melting point: 54.5-56.5°C IRn spectrum film, m-1): 3272.
1754, 1388.1248 NMR spectrum (10
0M output, CDCl3. ): 0.88 (3H,
d, J=6.3Hz), 0.94(3H, d, J=
6.3), 1.1-1.8 (3H.
ｍ）、 ３．９４ （ＩＨ，ｄｄｄ、 Ｊ−９，５，７
，８゜４．９ ）Ｉｚ ） 、 ５．０１ （Ｉ Ｈ，
ｄｄｄｄ、 Ｊ＝７．８゜６８．１．０．１．０比）、
５．３６（ＩＨ，ａｄａ。m), 3.94 (IH, ddd, J-9, 5, 7
,8゜4.9)Iz),5.01(IH,
dddd, J=7.8゜68.1.0.1.0 ratio),
5.36 (IH, ada.
Ｊ＝１０．０．１．７．１．０比ｓ）、５．４２（ＩＨ
。J = 10.0.1.7.1.0 ratio s), 5.42 (IH
.
ｄｄｄ、 Ｊ＝１６．８．１．７．１．０比）、５．８
８（ＩＨ，ｄｄｄ、 Ｊ−１６，８，１０，０，６，８
Ｈｚ）。ddd, J=16.8.1.7.1.0 ratio), 5.8
8 (IH, ddd, J-16, 8, 10, 0, 6, 8
Hz).
５．８８ （ＩＨ，ｂｒｓ ）−
Ｂ、 ４−イソブチル−５−カルボキシメチル−２−
オキサゾリドン
窒素雰囲気下、室温で、工程Ａの化合物（工α）（４２
１η、２．５ミリモル）のテトラヒドロフラン溶液（１
５ｄ）に０．５規定の９−ボラビシクロ［３，３，１）
ノナン（９−ＢＢＮ）ヘキサン溶液（１５ｍｔ、 ７．
５ミリモル）を加え、２４時間攪拌を行なった。5.88 (IH,brs)-B, 4-isobutyl-5-carboxymethyl-2-
Oxazolidone Compound of Step A (Work α) (42
1η, 2.5 mmol) in tetrahydrofuran solution (1
5d) with 0.5 normal 9-borabicyclo[3,3,1)
Nonane (9-BBN) hexane solution (15mt, 7.
5 mmol) was added and stirred for 24 hours.
エタノ−＃（４，５ｍｌ、 ７ ＜Ｓ ミＩＪ−１１−
／Ｉ／）、６規定水酸化ナトリウム水溶液（１，５，ｄ
、９．０ミリモル）を加え、水冷後、３０％過酸化水素
水（ろ、Ｏｄ。Ethano-# (4.5ml, 7<S MiIJ-11-
/I/), 6N aqueous sodium hydroxide solution (1,5,d
, 9.0 mmol) was added, and after cooling with water, 30% hydrogen peroxide solution (Od.
２６ミリモル）をさらに加え、３０分間攪拌を行なった
。クロロホルムで抽出し、得られた有機層に無水硫酸す
） ＩＪウムを加え乾燥後、溶媒留去した。26 mmol) was further added and stirred for 30 minutes. After extraction with chloroform, anhydrous sulfuric acid (IJ) was added to the obtained organic layer, and after drying, the solvent was distilled off.
得られたアルコール化合物をアセトン（Ｉ ＱｍＡ’）
にとかし、水冷下、２規定のジョーンズ（Ｊｏｎｅｓ）
試薬（クロム酸ナトリウムと硫酸の混合物）５ｍを加え
、室温で２時間攪拌した。The obtained alcohol compound was mixed with acetone (IQmA')
Comb, under water cooling, 2-regulation Jones (Jones)
5 m of a reagent (a mixture of sodium chromate and sulfuric acid) was added, and the mixture was stirred at room temperature for 2 hours.
１）Ｈを３に（７、酢酸エチルで抽出し、つぎに有機層
を飽和炭酸水素ナトリウム水溶液で洗い、さらにこの水
層をｐＨ３にした後、再び酢酸エチルで抽出を行なった
。得られた有機層に無水硫酸マグネシウムを加え乾燥後
、溶媒を減圧下留去することＫより標記化合物３７３ｍ
９を得た（収率７４％）。1) H was diluted to 3 (7), extracted with ethyl acetate, then the organic layer was washed with a saturated aqueous sodium bicarbonate solution, the aqueous layer was adjusted to pH 3, and extracted with ethyl acetate again. Obtained After adding anhydrous magnesium sulfate to the organic layer and drying, the solvent was distilled off under reduced pressure to obtain the title compound 373m.
9 was obtained (yield 74%).
性状：無色油状物質
Ｉ ｎスペクトル（フィルム＊ ｍ−’） ：３２７２
．１７４０
マススペクトｋ （ｍ／ｚ ） ： ２０２ （Ｍ＋
１ ）”。Properties: Colorless oil I n spectrum (film * m-'): 3272
．． 1740 Mass spectrum k (m/z): 202 (M+
1)”.
ＮＭＲスペクト”（６０ＭＨｚ、ＣＤＣ４、）：０．８
８ （６Ｈ，ｄ、Ｊ＝６．０土）、１．２〜１．８（３
Ｈ，ｍ’）、２．７０（２Ｈ，ｄ、Ｊ＝７．０Ｈｚ）、
３．５５（ＩＨ，ｄｄｄ、 Ｊ＝６．０゜６．０ 、
５．０Ｈｚ ）、、 ４．４５ （Ｉ Ｈ，ｄｄｄ、
Ｊ＝７．０．７．０．５．０Ｈ２）、 ６．９０ （Ｉ
Ｈ，ｂｒｓ）。NMR spectrum” (60MHz, CDC4,): 0.8
8 (6H, d, J = 6.0 soil), 1.2-1.8 (3
H, m'), 2.70 (2H, d, J=7.0Hz),
3.55 (IH, ddd, J=6.0°6.0,
5.0Hz), 4.45 (I H, ddd,
J=7.0.7.0.5.0H2), 6.90 (I
H, brs).
１０．０ （Ｉ Ｈ，ｂｒｓ） 。10.0 (IH, brs).
参考例 ５
実施例１の化合物を過剰の１Ｎ水酸化リチウムの水溶液
にとかし、室温で一晩放置した。反応液を注意深く中和
することにより、天然のスタチンと物性が同一な化合物
が得られた。Reference Example 5 The compound of Example 1 was dissolved in an excess 1N lithium hydroxide aqueous solution and left overnight at room temperature. By carefully neutralizing the reaction solution, a compound with physical properties identical to natural statins was obtained.
Claims (5)
またはベンジル基を表わし、Ａはｔ−ブチルジメチルシ
リル基またはｔ−ブチルジフェニルシリル基を表わし、
Ｘはブロム原子、クロル原子、パラトルエンスルホニル
オキシ基またはメタンスルホニルオキシ基を表わす） を有するシリルカルバメート誘導体を含フッ素イオン試
薬で処理し、一般式 ▲数式、化学式、表等があります▼ （式中Ｒは前記定義の通りである）を有する環状カルバ
メート誘導体となし、 次いでヒドロホウ素化反応に付し、一般式 ▲数式、化学式、表等があります▼ （式中Ｒは前記定義の通りである）を有するアルコール
化合物となし、さらに酸化することを特徴とする一般式 ▲数式、化学式、表等があります▼ （式中Ｒは前記定義の通りである）を有する化合物の製
造方法。(1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents an alkyl group having 1 to 6 carbon atoms, phenyl group, or benzyl group, and A represents t-butyldimethylsilyl group or t-butyl represents a diphenylsilyl group,
A silyl carbamate derivative having a bromine atom, a chloro atom, a paratoluenesulfonyloxy group, or a methanesulfonyloxy group is treated with a fluorine-containing ion reagent to obtain the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula R is as defined above), and then subjected to hydroboration reaction to form a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R is as defined above) A method for producing a compound having the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R is as defined above), which is characterized by being further oxidized.
ムフロリド、フッ化銀、フッ化銅またはテトラフルオロ
ホウ素化銀である特許請求の範囲第１項記載の方法。(2) The method according to claim 1, wherein the fluorine-containing ion reagent is tetraalkylammonium fluoride, silver fluoride, copper fluoride, or silver tetrafluoroboride.
酸化水素水、アルキルボランと過酸化水素水またはジア
ルキルボランと過酸化水素水である特許請求の範囲第１
項記載の方法。(3) Claim 1, wherein the reagents used in the hydroboration reaction are diporan and aqueous hydrogen peroxide, alkylborane and aqueous hydrogen peroxide, or dialkylborane and aqueous hydrogen peroxide.
The method described in section.
ン酸カリウムである特許請求の範囲第１項記載の方法。(4) The method according to claim 1, wherein the oxidizing agent is chromic acid, chromic anhydride, or potassium permanganate.
、またはベンジル基を表わす） を有する環状カルバメート誘導体が光学活性体である特
許請求の範囲第１および２項記載の方法。(5) A cyclic carbamate derivative having the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a benzyl group) is an optically active substance. A method according to claims 1 and 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7379086A JPS62230775A (en) | 1986-03-31 | 1986-03-31 | Production of intermediate for statine and related compound thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7379086A JPS62230775A (en) | 1986-03-31 | 1986-03-31 | Production of intermediate for statine and related compound thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62230775A true JPS62230775A (en) | 1987-10-09 |
Family
ID=13528335
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7379086A Pending JPS62230775A (en) | 1986-03-31 | 1986-03-31 | Production of intermediate for statine and related compound thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62230775A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6288238B1 (en) * | 2000-09-19 | 2001-09-11 | Board Of Trustees Operating Michigan State University | Process for the preparation of 5-hydroxymethyl 2-oxazolidinone and novel intermediate |
-
1986
- 1986-03-31 JP JP7379086A patent/JPS62230775A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6288238B1 (en) * | 2000-09-19 | 2001-09-11 | Board Of Trustees Operating Michigan State University | Process for the preparation of 5-hydroxymethyl 2-oxazolidinone and novel intermediate |
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