JPH01228946A - Synthesis of beta-hydroxyphenetylamines - Google Patents
Synthesis of beta-hydroxyphenetylaminesInfo
- Publication number
- JPH01228946A JPH01228946A JP5535988A JP5535988A JPH01228946A JP H01228946 A JPH01228946 A JP H01228946A JP 5535988 A JP5535988 A JP 5535988A JP 5535988 A JP5535988 A JP 5535988A JP H01228946 A JPH01228946 A JP H01228946A
- Authority
- JP
- Japan
- Prior art keywords
- lower alkyl
- iii
- group
- formula
- added
- 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
- 230000015572 biosynthetic process Effects 0.000 title abstract description 15
- 238000003786 synthesis reaction Methods 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims abstract description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims abstract description 8
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 8
- 229910000365 copper sulfate Inorganic materials 0.000 claims abstract description 6
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims abstract description 6
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims abstract description 6
- 125000005042 acyloxymethyl group Chemical group 0.000 claims abstract description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 5
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims abstract description 5
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract 4
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 claims abstract 2
- 229910000360 iron(III) sulfate Inorganic materials 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical class NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 13
- RKCRKDKQUDBXAU-JAMMHHFISA-N (2s)-2-amino-3-hydroxy-3-(4-hydroxyphenyl)propanoic acid Chemical class OC(=O)[C@@H](N)C(O)C1=CC=C(O)C=C1 RKCRKDKQUDBXAU-JAMMHHFISA-N 0.000 abstract description 7
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 abstract description 4
- 229910001863 barium hydroxide Inorganic materials 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
- 239000011261 inert gas Substances 0.000 abstract description 2
- IMPPGHMHELILKG-UHFFFAOYSA-N 4-ethoxyaniline Chemical class CCOC1=CC=C(N)C=C1 IMPPGHMHELILKG-UHFFFAOYSA-N 0.000 abstract 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 2
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000003076 neurotropic agent Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000001228 spectrum Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 238000002329 infrared spectrum Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- -1 acetoxymethyl group Chemical group 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 229910000358 iron sulfate Inorganic materials 0.000 description 3
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- ULSIYEODSMZIPX-UHFFFAOYSA-N phenylethanolamine Chemical class NCC(O)C1=CC=CC=C1 ULSIYEODSMZIPX-UHFFFAOYSA-N 0.000 description 3
- 230000001766 physiological effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 150000003667 tyrosine derivatives Chemical class 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 2
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960002179 ephedrine Drugs 0.000 description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 2
- 210000003127 knee Anatomy 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 230000002276 neurotropic effect Effects 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- CAILUIWIXZDVSZ-SNVBAGLBSA-N (2r)-2-azaniumyl-2-(4-methoxyphenyl)propanoate Chemical compound COC1=CC=C([C@@](C)(N)C(O)=O)C=C1 CAILUIWIXZDVSZ-SNVBAGLBSA-N 0.000 description 1
- CNBUSIJNWNXLQQ-NSHDSACASA-N (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-NSHDSACASA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- CFCNTIFLYGKEIO-UHFFFAOYSA-N 2-isocyanoacetic acid Chemical compound OC(=O)C[N+]#[C-] CFCNTIFLYGKEIO-UHFFFAOYSA-N 0.000 description 1
- UHZCPBRALDCPOD-UHFFFAOYSA-N 4-(2-isocyanatoethyl)phenol Chemical compound OC1=CC=C(CCN=C=O)C=C1 UHZCPBRALDCPOD-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 description 1
- 108700018454 CDC15 Proteins 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DZGWFCGJZKJUFP-UHFFFAOYSA-N Tyramine Natural products NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 101150081467 cdc15 gene Proteins 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- MXXMJJSIJDMYJZ-UHFFFAOYSA-N n-(2-phenylethyl)hydroxylamine Chemical class ONCCC1=CC=CC=C1 MXXMJJSIJDMYJZ-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229960001576 octopamine Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- XYWJNTOURDMTPI-UHFFFAOYSA-N procodazole Chemical compound C1=CC=C2NC(CCC(=O)O)=NC2=C1 XYWJNTOURDMTPI-UHFFFAOYSA-N 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- ILNOTKMMDBWGOK-UHFFFAOYSA-N tert-butyl n-[2-(4-hydroxyphenyl)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCC1=CC=C(O)C=C1 ILNOTKMMDBWGOK-UHFFFAOYSA-N 0.000 description 1
- WEPYXLCLPJGRDP-UHFFFAOYSA-N tert-butyl n-[2-(4-methoxyphenyl)ethyl]carbamate Chemical compound COC1=CC=C(CCNC(=O)OC(C)(C)C)C=C1 WEPYXLCLPJGRDP-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960003986 tuaminoheptane Drugs 0.000 description 1
- VSRBKQFNFZQRBM-UHFFFAOYSA-N tuaminoheptane Chemical group CCCCCC(C)N VSRBKQFNFZQRBM-UHFFFAOYSA-N 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 229960003732 tyramine Drugs 0.000 description 1
- DZGWFCGJZKJUFP-UHFFFAOYSA-O tyraminium Chemical compound [NH3+]CCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-O 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、チロシン誘導体またはフェネチルアミン誘導
体のβ位に立体選択的に水酸基が導入された化合物を合
成する方法に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for synthesizing a compound in which a hydroxyl group is stereoselectively introduced into the β-position of a tyrosine derivative or a phenethylamine derivative.
本発明の方法により得られる化合物は、向神経作用など
の生理活性を有するβ−ヒドロキシチロシン類またはそ
の類縁の新規化合物の合成出発物質として有用である。The compounds obtained by the method of the present invention are useful as starting materials for the synthesis of β-hydroxytyrosines or novel compounds related to them, which have physiological activities such as neurotropic activity.
（従来の技術）
エフェドリン、エフェドリンに代表される一群のβ−ヒ
ドロキシフェネチルアミン類は、向神経作用等の種々の
生理作用を示すものが多く、そのためβ−ヒドロキシチ
ロシン誘導体を含む一連のフェネチルアミン系誘導体に
ついて、医薬品開発に向は現在も活発な研究活動が行わ
れている。(Prior art) A group of β-hydroxyphenethylamines represented by ephedrine and ephedrine often exhibit various physiological effects such as neurotropic effects. Therefore, a series of phenethylamine derivatives including β-hydroxytyrosine derivatives have been developed. Currently, active research activities are being carried out in the direction of drug development.
β−ヒドロキシチロシン類の合成法としては、通常アリ
ルアルデヒドとグリシンを縮合し、生成するＤＬ−スレ
オ及びＤＬ−エリスロ体を分割する方法がとられてきた
。近年になり、立体選択的な手法によるβ−ヒドロキシ
チロシン類の合成方法の開発が盛んになり、例えば、検
出らはアミノケトンのキラルな還元法（Ｊ、 Ａｍ、
Ｃｈｅｗ、 Ｓｏｅ、。Conventional methods for synthesizing β-hydroxytyrosine have been to condense allylaldehyde and glycine and separate the resulting DL-threo and DL-erythro forms. In recent years, the development of methods for synthesizing β-hydroxytyrosines using stereoselective methods has become active.
Chew, Soe.
１０６巻、４６２９頁、１９８４年）を、また伊藤らは
不斉金属錯体を用いたアリルアルデヒドとイソシアノ酢
酸エステルとの縮合法（ｊ、 Ａｍ、 Ｃｈｃｍ。106, p. 4629, 1984), and Ito et al. described a condensation method of allylaldehyde and isocyanoacetate using an asymmetric metal complex (j, Am, Chcm.
Ｓｏｃ、、 １０８巻、６４０５頁、１９８６年）を報
告している。Soc, Vol. 108, p. 6405, 1986).
しかし、これまで報告されているβ−ヒドロキシチロシ
ン類化合物は、いずれもβ位に水酸基ではなく一旦アル
デヒドやカルボン酸基を導入し、この誘導体から更に水
酸基に導くものであった。However, all of the β-hydroxytyrosine compounds that have been reported so far have introduced an aldehyde or carboxylic acid group at the β-position instead of a hydroxyl group, and this derivative is further led to a hydroxyl group.
しかも、ある場合にはラセミ分割が必要であっｔ；。Moreover, in some cases racemic division is necessary.
（発明が解決しようとする課題）
チロシンをはじめとしてフェネチルアミン誘導体は天然
物として光学活性体が容易に入手でき、それらのベンジ
ル位への水酸基の導入はβ−ヒドロキシフェネチルアミ
ン類を合成する上で利点が大きい。そこで、本発明はフ
ェネチルアミン誘導体のベンジル位に効率の良い反応に
より、且つ立体選択的に水酸基を導入する方法を提供す
ることを目的とする。(Problems to be Solved by the Invention) Optically active forms of phenethylamine derivatives such as tyrosine are easily available as natural products, and the introduction of a hydroxyl group to their benzyl position is advantageous in synthesizing β-hydroxyphenethylamines. big. Therefore, an object of the present invention is to provide a method for stereoselectively introducing a hydroxyl group into the benzyl position of a phenethylamine derivative by an efficient reaction.
（課題を解決するための手段）
本発明者らは、チロシン誘導体を含むフェネチルアミン
誘導体のベンジル位に水酸基を立体選択的に導入すべく
鋭意研究を重ねた結果、Ｎ−ｔ−ブトキシカルボニル誘
導体に硫酸銅及び過硫酸カリウムを作用させると立体選
択的に環状カルバメートを形成し、これを利用してβ位
にヒドロキシ基を有する７エネチルアミン類を合成する
ことが可能であるという知見を得、本発明を完成した。(Means for Solving the Problems) As a result of intensive research to stereoselectively introduce a hydroxyl group into the benzyl position of phenethylamine derivatives including tyrosine derivatives, the present inventors found that We have obtained the knowledge that when copper and potassium persulfate are reacted, a cyclic carbamate is stereoselectively formed, and that it is possible to synthesize 7-enethylamines having a hydroxyl group at the β-position by using this, and the present invention has been developed. completed.
本発明は、−最大（ＩＩ）：
（式中 Ｒ１は低級アルキル基、低級アルコキシカルボ
ニル基、アシルオキシメチル基または水素原子であり；
Ｒ２は水素原子または低級アルキル基であり；Ｒ３は低
級アルキル基であり；Ｘは水素原子、低級アルキル基、
低級アルコキシ基またはハロゲン原子であり；ｎは１ま
たは２である）で表されるフェネチルアミン誘導体に硫
酸銅、塩化鉄（Ｉ［Ｉ）、硫酸鉄（Ｉ［）もしくは酢酸
銅及び過硫酸カリウムもしくは四酢酸銅を作用させて一
般式（）：
（式中、Ｒ１、Ｒ２、Ｒ３、Ｘ及びｎは前記の定義と同
じである）で表される化合物とし、続いて、この式（Ｉ
Ｉ［）の環状カルバメートをアルカリ加水分解すること
により一般式（Ｉ）：
Ｈ
（式中、Ｒ１、Ｒ２、Ｒ３、Ｘ及びｎは前記の定義と同
じである）で表されるβ位にヒドロキシ基を有するフェ
ネチルアミン類を合成する方法を提供する。The present invention provides - maximum (II): (wherein R1 is a lower alkyl group, a lower alkoxycarbonyl group, an acyloxymethyl group or a hydrogen atom;
R2 is a hydrogen atom or a lower alkyl group; R3 is a lower alkyl group; X is a hydrogen atom, a lower alkyl group,
lower alkoxy group or halogen atom; n is 1 or 2), copper sulfate, iron chloride (I[I), iron sulfate (I[) or copper acetate and potassium persulfate or A compound represented by the general formula (): (wherein R1, R2, R3,
By alkaline hydrolysis of the cyclic carbamate of I[), hydroxyl is added to the β-position represented by the general formula (I): H (wherein R1, R2, R3, X and n are the same as defined above). Provided are methods for synthesizing phenethylamines having groups.
本発明の以下の方法により製造することができる式（Ｉ
）で表されるフェネチルアミン誘導体において、 Ｒｌ
は、低級アルキル基としてはメチル、エチル、ｎ−プロ
ピル、ｎ−ブチルもしくはバレリルが好ましく、低級ア
ルコキシカルボニル基としてはメトキシカルボニルもし
くはエトキシカルボニル基が好ましく、また、アシルオ
キシメチル基としてはアセトキシメチル基もしくはペン
ゾイルオキンメチル基が好ましく：Ｒ２は、低級アルキ
ル基としてはメチル、エチル、ｎ−プロピルもしくはｎ
−ブチル基が好ましく；Ｒ３は、低級アルキル基として
はメチル、エチル、ｎ−プロピルもしくはｎ−ブチル基
が好ましく、低級アルコキノ基としてはメトキシ基もし
くはエトキシ基が好ましく；Ｘは、低級アルキル基とし
てはメチル、エチル、ｎ−プロピルもしくはｎ−ブチル
基が好ましい。Formula (I) can be produced by the following method of the present invention
) in the phenethylamine derivative represented by Rl
The lower alkyl group is preferably methyl, ethyl, n-propyl, n-butyl or valeryl, the lower alkoxycarbonyl group is preferably methoxycarbonyl or ethoxycarbonyl group, and the acyloxymethyl group is preferably acetoxymethyl group or penzoyl group. Oquinemethyl group is preferred: R2 is lower alkyl group such as methyl, ethyl, n-propyl or n
-butyl group is preferred; R3 is preferably a methyl, ethyl, n-propyl or n-butyl group as a lower alkyl group, and a methoxy or ethoxy group is preferred as a lower alkokino group; Methyl, ethyl, n-propyl or n-butyl groups are preferred.
本発明の方法は、以下のようにして実施することができ
る。即ち、式（ＩＩ）で表されるフェネチルアミン誘導
体を不活性溶媒、好ましくはアセトニトリルに溶解し、
不活性ガス（例えば、アルゴンガス、窒素ガス等）雰囲
気下で過硫酸カリウム水溶液もしくは四酢酸鉛水溶液及
び硫酸銅水溶液、塩化鉄（ＩＩＩ）水溶液、硫酸鉄（ｎ
Ｉ）水溶液もしくは酢酸銅水溶液を加え、室温ないし８
０°Ｃで０．５〜５時間撹拌して反応させる。この際、
加える過硫酸カリウム及び硫酸銅等の量は、特に限定さ
れないが、好ましくは７工ネチルアミン誘導体に対して
それぞれ約２当量及び０．２当量である。The method of the present invention can be carried out as follows. That is, a phenethylamine derivative represented by formula (II) is dissolved in an inert solvent, preferably acetonitrile,
Under an inert gas (e.g. argon gas, nitrogen gas, etc.) atmosphere, potassium persulfate aqueous solution or lead tetraacetate aqueous solution, copper sulfate aqueous solution, iron (III) chloride aqueous solution, iron sulfate (n
I) Add aqueous solution or copper acetate aqueous solution and heat from room temperature to 8
Stir and react at 0°C for 0.5-5 hours. On this occasion,
The amounts of potassium persulfate, copper sulfate, etc. to be added are not particularly limited, but are preferably about 2 equivalents and 0.2 equivalents, respectively, relative to the heptamine netylamine derivative.
反応液を適当な溶媒（例えば、酢酸エチル、クロロホル
ム等）で抽出し、カラムクロマトグラフィー（例えば、
シリカゲルを充填したカラムに付し、エーテル、酢酸エ
チルもしくはアセトニトリルなどで溶出する）等の通常
の方法を用いて精製することにより式（ＩＩＩ）で表さ
れる環状カルバメートを得る。The reaction solution was extracted with an appropriate solvent (e.g., ethyl acetate, chloroform, etc.) and subjected to column chromatography (e.g.,
The cyclic carbamate represented by formula (III) is obtained by purification using a conventional method such as applying to a column packed with silica gel and eluting with ether, ethyl acetate or acetonitrile.
この環状カルバメートを反応に関与しない溶媒、例えば
エタノールに溶解し、アルカリ、好ましくは水酸化バリ
ウム水溶液を加え、５０〜９０°Ｃで加水分解する。反
応液を中和後、必要に応じて官能基を保護したのち（例
えば、アミノ基をｔ−ブトキンカルボニル基で保護する
）、溶媒抽出し、カラムクロマトグラフィー等の通常の
方法により精製することにより式（Ｉ）で表されるβ−
ヒドロキシフェネチルアミン誘導体又はその保護化合物
を得ることができる。This cyclic carbamate is dissolved in a solvent that does not participate in the reaction, such as ethanol, and an alkali, preferably an aqueous barium hydroxide solution, is added and hydrolyzed at 50 to 90°C. After neutralizing the reaction solution and protecting the functional groups as necessary (for example, protecting the amino group with a t-butquine carbonyl group), solvent extraction is performed, and purification is performed by a conventional method such as column chromatography. β- represented by formula (I)
Hydroxyphenethylamine derivatives or protected compounds thereof can be obtained.
本発明で使用する式（ｎ）の出発物質は、公知化合物で
あるが、以下の参考例の記載に従って合成できるもので
ある。The starting material of formula (n) used in the present invention is a known compound, but it can be synthesized according to the description in the following reference examples.
以下実施例及び参考例を以て本発明をより詳細に説明す
るが、本発明は実施例に限定されるものではない。The present invention will be explained in more detail below using Examples and Reference Examples, but the present invention is not limited to the Examples.
参考例１
（２Ｓ）−２−（Ｎ−ｔ−ブトキシカルボニル）アミノ
−３−（ｐ−メトキシフェニル）プロパツールアセテー
トの合成
Ｎ−ｔ−ブトキシカルボニル−ｐ−メトキシ−Ｌ−フェ
ニルアラニンメチルエステル１．００ ｇ（３，２３鳳
ｍａｔ）をテトラヒドロフラン（以下ＴＨＦと略す）５
０ｍｌｌに溶かした溶液を、水素化リチウムアルミニウ
ム１８４鳳ｔｃ４．８Ｓ謙ｍｏｌ）のＴＨＦ懸濁液（５
０＠ｌｌ）中に滴下した。室温で１時間撹拌して後、水
冷下で氷片を加えて過剰の試薬を分解した。硫酸マグネ
シウムを加えて濾過し、濾液を濃縮し、残渣をエーテル
に溶かして、１０％酒石酸溶液および水で洗浄した。有
機層を乾燥後濃縮し油状のアルコール体７ｃ＋ｏｍｇ（
収率８６゜９％）を得た。アルコール体３９０ｍｔ（１
，３９ｍ履ｏ１）をピリジン２ａｌｌに溶かし、無水酢
酸１９５μｆｆ１（２，０７ｍｍｏｌ）を加えて室温で
３時間撹拌した。メタノールで過剰の試薬を分解後、エ
ーテルおよび水を加えて抽出し、エーテル層を濃縮して
、残渣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（２： ｌ） ）で精製して標記化合物４
０（ｌｎ（収率９１．３％）を無色結晶として得た。Reference Example 1 Synthesis of (2S)-2-(N-t-butoxycarbonyl)amino-3-(p-methoxyphenyl)propatur acetate N-t-butoxycarbonyl-p-methoxy-L-phenylalanine methyl ester 1. 00 g (3,23 mat) in tetrahydrofuran (hereinafter abbreviated as THF) 5
The solution dissolved in 0 ml was added to a THF suspension (5 mol) of lithium aluminum hydride 184
0@ll). After stirring at room temperature for 1 hour, excess reagent was decomposed by adding ice chips while cooling with water. It was filtered by adding magnesium sulfate, the filtrate was concentrated, the residue was dissolved in ether and washed with 10% tartaric acid solution and water. The organic layer was dried and concentrated to give an oily alcohol 7c+omg (
A yield of 86.9%) was obtained. Alcohol body 390mt (1
, 39mol o1) was dissolved in 2all pyridine, 195μff1 (2.07mmol) of acetic anhydride was added, and the mixture was stirred at room temperature for 3 hours. After decomposing excess reagent with methanol, extraction was performed by adding ether and water, the ether layer was concentrated, and the residue was purified by silica gel column chromatography (ether/hexane (2: l)) to obtain the title compound 4.
0(ln (yield 91.3%)) was obtained as colorless crystals.
性状：無色結晶
融点：９８．５〜９９．５℃
’Ｈ−ＮＭＲスペクトル（ｌ ＯＯＭＨｚＳ ＣＤＣｌ
３、δｐｐ■）：
１．４４ （９Ｈ，ｓ）、２．１０ （３Ｈ，ｓ）。Properties: Colorless crystal Melting point: 98.5-99.5°C 'H-NMR spectrum (l OOMHZS CDCl
3, δpp■): 1.44 (9H, s), 2.10 (3H, s).
２．７９ （２Ｈ，ｍ）、３．８０ （３Ｈ，ｓ）。2.79 (2H, m), 3.80 (3H, s).
４．０２ （２Ｈ，ｂｓ）、４．０５ （ＩＨ，ｍ）。4.02 (2H, bs), 4.05 (IH, m).
４．６０ （ＩＨ，ｂｓ）。4.60 (IH, bs).
６．８４ （２Ｈ，ｄ、Ｊ・１０Ｈｚ）。6.84 (2H, d, J・10Hz).
７．１１ （２Ｈ，ｄ、Ｊ・ＩＱＨｚ）ＩＲスペクトル
（ｙｅｓ−’）： ３３６４，２９Ｂ８゜１７２６．１
６９４，１２６２．１２４６［ａｌ ”： −１２，
７° （ｃ・１．００． ＣＨＣＩＬｓ）参考例２
Ｎ−ｔ−ブトキシカルボニル−Ｌ−ｐ−メトキシフェニ
ルアラニンメチルエステルの合成Ｎ−ｔ−ブトキシカル
ボニル−し−チロシン１０．０ ｇ （３５，５ｍ ＋
ａｏｌ）をエーテル１００ｍＡに溶かし、ジアゾメタン
のエーテル溶液を発泡しなくなるまで加えた。反応溶液
を乾燥後、減圧濃縮し、得られた残渣をジメチルホルム
アミド（以下ＤＭＦと略す）（２００ｍｌ）に溶かし、
水冷下−１？大過剰のヨウ化メチルと水素化ナトリウム
１．６ｇ （５３，３ｍ １＠Ｉ）を加えて、水冷下で
１時間、さらに室温で１時間撹拌した。反応終了後、ニ
ーチルと塩化アンモニウム水溶液を加えて抽出し、エー
テル層を１０％クエン酸水溶液および水で洗浄した。硫
酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲ
ルカラムクロマトグラフィー（エーテル／ヘキサン（１
： Ｄ ）で精製して標記化金物ｘｏ、＋ｇ（収率９４
．７％）を得た。7.11 (2H, d, J・IQHz) IR spectrum (yes-'): 3364,29B8°1726.1
694,1262.1246 [al ”: -12,
7° (c・1.00.CHCILs) Reference Example 2 Synthesis of N-t-butoxycarbonyl-L-p-methoxyphenylalanine methyl ester N-t-butoxycarbonyl-tyrosine 10.0 g (35,5m +
aol) was dissolved in 100 mA of ether, and an ethereal solution of diazomethane was added until no more foaming occurred. After drying the reaction solution, it was concentrated under reduced pressure, and the resulting residue was dissolved in dimethylformamide (hereinafter abbreviated as DMF) (200 ml),
Under water cooling -1? A large excess of methyl iodide and 1.6 g (53.3 m 1@I) of sodium hydride were added, and the mixture was stirred for 1 hour under water cooling and then for 1 hour at room temperature. After the reaction was completed, nityl and ammonium chloride aqueous solution were added for extraction, and the ether layer was washed with 10% citric acid aqueous solution and water. After drying over magnesium sulfate, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ether/hexane (1
:D) to obtain the labeled metal compound xo, +g (yield 94
．． 7%).
性状：無色の油状物
’Ｈ−ＮＭＲスペクトル（１００Ｍ Ｈｚ ＳＣＤ Ｃ
１ｓ、δｐｐｍ） ：
１．４３ （９Ｂ、ｓ）。Properties: Colorless oil 'H-NMR spectrum (100MHz SCD C
1s, δppm): 1.43 (9B, s).
３．０１ （２Ｈ，ｄ、Ｊ寡６Ｈｚ）。3.01 (2H, d, J low 6Hz).
３．７１ （３Ｈ，Ｓ）、３．７８ （３Ｈ，Ｓ）。3.71 (3H, S), 3.78 (3H, S).
４．５２ （ＩＨ，ｍ）、４．９０ （ＩＨ，ｂ）。4.52 (IH, m), 4.90 (IH, b).
６．８０ （２Ｂ、ｄ、ＪｉＨｚ）。6.80 (2B, d, JiHz).
７．０２ （２Ｈ，ｄ、Ｊ−９Ｈ２）
ＩＲスペクトル（ｙ ｃｍ−つ ：３４５２，２９８４
゜１７４８．１７１８，１２５２．１２１８［ｇｌ ”
ニー２７．１’ （ｃ・２．ｏＯ，ＣＨＣＬ）参考例３
Ｎ−ｔ−ブトキシカルボニル−２−（ｐ−メトキシフェ
ニル）エチルアミンの合成
チラミン３０ （ｌａｗ （２，１８ｉｚ ｉｄｏ＋）
をメタノール１０鳳ｌに溶かしジーｔ−ブチル−ジカル
ポキシラート５ｏｏｘｘ（２，ｓｘｍ＋＋ｕｌ）を加え
て１６時間撹拌した。反応溶液を濃縮し、酢酸エチルお
よび水を加えて抽出した。有機層を１０％クエン酸水溶
液および水で洗浄後、乾燥し、減圧濃縮し残液をシリカ
ゲルカラムクロマトグラフィー（エーテル／ヘキサン（
３： １） ）で精製してＮ−ｔ−ブトキシカルボニル
チラミン４９６１ｇ（収率９５゜９％）を得た。7.02 (2H, d, J-9H2) IR spectrum (y cm-t: 3452, 2984
゜1748.1718, 1252.1218 [gl ”
27.1' (c・2.oO, CHCL) Reference Example 3 Synthesis of Nt-butoxycarbonyl-2-(p-methoxyphenyl)ethylamine Tyramine 30 (law (2,18iz ido+)
was dissolved in 10 liters of methanol, 5ooxx (2, sxm++ ul) of di-t-butyl-dicarpoxylate was added, and the mixture was stirred for 16 hours. The reaction solution was concentrated and extracted with ethyl acetate and water. The organic layer was washed with 10% citric acid aqueous solution and water, dried, concentrated under reduced pressure, and the remaining liquid was purified by silica gel column chromatography (ether/hexane).
3:1)) to obtain 4961 g of N-t-butoxycarbonyltyramine (yield: 95.9%).
性状：無色結晶（エーテル／ヘキサンから再結晶）この
Ｎ−ｔ−ブトキンカルボニルチラミン２００Ｂ （０，
８４３ｍ ｍｏｌ）をＤＭＦ５鳳ｆｆｉに溶かして大過
剰のヨウ化メチル、水素化ナトリウム３ｏ諺ｇ（１，０
１ｍｍｏｌ）を加えて室温で１時間撹拌した。Properties: Colorless crystals (recrystallized from ether/hexane) This Nt-butquine carbonyltyramine 200B (0,
Dissolve 843 m mol) in DMF 5 ffi to obtain a large excess of methyl iodide and 30 g of sodium hydride (1,0
1 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour.
塩化アンモニウム水溶液および酢酸エチルを加えて抽出
し、有機層を水洗、乾燥後、減圧濃縮し残渣をシリカゲ
ルカラムクロマトグラフィー（エーテル／ヘキサン（３
： ｌ） ）で精製して標記化合物２０３ｍｇ （９５
，８％）を得た。Extraction was performed by adding an aqueous ammonium chloride solution and ethyl acetate, and the organic layer was washed with water, dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ether/hexane (3
: l)) to give 203 mg of the title compound (95
, 8%).
性状：無色結晶
融点：５８．５〜５９．０℃
’Ｈ−ＮＭＲスペクトル（１００ＭＨｚＳ ＣＤＣｌ５
、δｐｐｍ） ：
１．４４３ （（ｌ）Ｉ、ｓ）。Properties: Colorless crystal Melting point: 58.5-59.0°C 'H-NMR spectrum (100MHzS CDCl5
, δppm): 1.443 ((l)I,s).
２．７４ （２Ｈ，ｔ、Ｊ・７Ｈｚ）。2.74 (2H, t, J・7Hz).
３．３５ （２Ｈ，ｑ、Ｊ・７Ｈｚ）。3.35 (2H, q, J・7Hz).
３．８０ （３Ｈ，Ｓ）、４．５０ （ＩＨ，ｂｓ）。3.80 (3H, S), 4.50 (IH, bs).
６．８４ （２Ｈ，ｄ、Ｊ−８Ｈ２）。6.84 (2H, d, J-8H2).
７．１２ （２Ｈ，ｄ、Ｊ・８Ｈｚ）
ＩＲスペクトル（ｙｃｍ−’）： ３３６８，２９９６
゜１６Ｂ２． １５３２． １５１６． １２９２参考
例４
（２Ｓ）−２−（ｔ−ブトキシカルボニル）アミ’３−
（３，４−ジメトキシフェニル）プロパツールアセテー
トの合成
Ｏ
Ｌ−ドーパ５００腸ｇ（２，５４飄飄◎ｌ）を水とジオ
キサン（ｌ：ｌ）混合液１０ｍｆｆ１に溶かし、０．５
Ｎ水酸化ナトリウム水溶液およびジーｔ−プチルージ力
ルポキシラートを加えて１６時間撹拌した。7.12 (2H, d, J・8Hz) IR spectrum (ycm-'): 3368,2996
゜16B2. 1532. 1516. 1292 Reference Example 4 (2S)-2-(t-butoxycarbonyl)ami'3-
Synthesis of (3,4-dimethoxyphenyl) propazole acetate 500 g (2,54 ◎l) of L-dopa was dissolved in 10 mff1 of a mixture of water and dioxane (l:l), and 0.5
N aqueous sodium hydroxide solution and di-t-butyl hydroxylate were added, and the mixture was stirred for 16 hours.
反応溶液をエーテルで洗浄し、水層をＩＮ塩酸でｐＨ２
にして酢酸エチルで抽出した。有機層を飽和食塩水で洗
浄し、乾燥後、減圧濃縮した。残渣をエーテル５＠１に
溶かしジアゾメタンのエーテル溶液を発泡が止まるまで
加えた。反応溶液を乾燥後、減圧濃縮しＤＭＦ７ｍＡに
溶かして水冷下で過剰のヨウ化メチルと水素化ナトリウ
ム９５ｓＢ（３，１８ｍ ｍｏｌ）を加え、室温で３０
分撹拌した。The reaction solution was washed with ether, and the aqueous layer was adjusted to pH 2 with IN hydrochloric acid.
and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was dissolved in ether 5@1 and an ethereal solution of diazomethane was added until bubbling stopped. After drying, the reaction solution was concentrated under reduced pressure, dissolved in DMF 7 mA, and added with excess methyl iodide and 95 sB (3.18 mmol) of sodium hydride under water cooling.
Stir for 1 minute.
エーテルと塩化アンモニウム水溶液を加えて抽出した。Ether and aqueous ammonium chloride solution were added for extraction.
エーテル層を水洗、乾燥し、減圧濃縮し、残渣をＴＨＦ
（５ｍｇ）に溶かした。これを水素化リチウムアルミニ
ウム（８３ｍｔ）のＴＨＦ懸濁液（５ｍｆｆ１）中に０
°Ｃで滴下して後、室温で３０分撹拌した。再び氷冷し
、氷片を加えて過剰の試薬を分解した後、エーテルで希
釈し、硫酸マグネシウムを加えて濾過した。濾液をＩＮ
塩酸および水で洗浄後、乾燥し、減圧濃縮した。残渣を
ピリジン３ｍＱに溶かし、無水酢酸５００μｌ加えて１
６時間撹拌した。メタノールで過剰の試薬を分解後、減
圧濃縮し、残渣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（１： １） ）で精製して標記
化合物２６８Ｂ（収率３１．２％）を得Ｉこ 。The ether layer was washed with water, dried, concentrated under reduced pressure, and the residue was dissolved in THF.
(5 mg). This was added to a THF suspension (5mff1) of lithium aluminum hydride (83mt).
After the dropwise addition at °C, the mixture was stirred at room temperature for 30 minutes. The mixture was cooled on ice again, ice chips were added to decompose excess reagent, diluted with ether, magnesium sulfate was added, and the mixture was filtered. Insert the filtrate
After washing with hydrochloric acid and water, it was dried and concentrated under reduced pressure. Dissolve the residue in 3 mQ of pyridine, add 500 μl of acetic anhydride, and
Stirred for 6 hours. After decomposing excess reagent with methanol, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ether/hexane (1:1)) to obtain the title compound 268B (yield 31.2%).
性状：無色結晶
融点：８０〜８３°Ｃ
’Ｈ−ＮＭＲスペクトル（１００ＭＨ２，ＣＤＣｌ３、
δｐｐｍ） ：
１．４４ （９Ｈ，ｓ）、２．０９ （３Ｈ，ｓ）。Properties: Colorless crystal Melting point: 80-83°C 'H-NMR spectrum (100MH2, CDCl3,
δppm): 1.44 (9H, s), 2.09 (3H, s).
２．７８ （２Ｈ，ｍ）、３．８７ （６Ｈ，ｓ）。2.78 (2H, m), 3.87 (6H, s).
４．０４ （２Ｈ，ｓ）。4.04 (2H, s).
３．９−４．２ （ＩＨ，ｍ）。3.9-4.2 (IH, m).
４．６３ （ＩＨ，ｂ）。4.63 (IH, b).
６．６−７．０ （３Ｈ，ｍ）
ＩＲスペクトル（ｙ ｃｍ−’ ） ： ３３７２
＋ ２９８４ ＋１７４６．１７１４．１２４２
［ａｌ ”ニー８．２° （ｃｍｌ、ｏｏ、ＣＨＣｌ５
）実施例１
（２３，３Ｒ）−２−（Ｎ−ｔ−ブトキシカルボニル）
−３−（４−メトキシフェニル）セリンの製造
（１）（４Ｒ，５Ｒ）−４−アセトキシメチル−５−（
４−メトキシフェニル）−２−オキサゾリトンの合成
参考例１の化合物（２Ｓ） −２−（Ｎ−ｔ−ブトキシ
カルボニル）アミノ−３−（ｐ−メトキシフェニル）グ
ロパノールアセテート２００醜！（０゜６１８鳳園ｏ１
）のア七トニトリル溶液（５鳳ｌ）に過硫酸カリウム３
３４鳳（（１，２４ｍ■・ｌ）を含む水溶液（５Ｉ）と
硫酸銅２０ａｔ （０，１２４ｍ ｍ＠ｌ）を含む水溶
液１鵬直を加え、窒素気流下、７０”Ｏで１．５時間撹
拌した。反応液を酢酸エチルで抽出し、有機層を水洗、
乾燥後、濃縮し、シリカゲルクロマトグラフィー（エー
テルにて溶出）で精製して標記化合物１１４Ｂ（収率６
９．２％）を得た。6.6-7.0 (3H, m) IR spectrum (y cm-'): 3372
+ 2984 +1746.1714.1242 [al “knee 8.2° (cml, oo, CHCl5
) Example 1 (23,3R)-2-(N-t-butoxycarbonyl)
Production of -3-(4-methoxyphenyl)serine (1) (4R,5R)-4-acetoxymethyl-5-(
Synthesis of 4-methoxyphenyl)-2-oxazolitone Compound (2S) of Reference Example 1 -2-(N-t-butoxycarbonyl)amino-3-(p-methoxyphenyl)glopanol acetate 200 Ugly! (0゜618 Hoen o1
) of potassium persulfate (5 liters)
An aqueous solution (5I) containing 34 tungsten ((1,24 ml) and an aqueous solution 1 sulfuric acid containing 20 at (0,124 m m@l) were added, and the mixture was heated at 70"O under a nitrogen stream for 1.5 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with water.
After drying, it was concentrated and purified by silica gel chromatography (eluting with ether) to obtain the title compound 114B (yield: 6
9.2%).
性状：無色結晶
融点：９９．５〜１００．０℃
’Ｈ−ＮＭＲスペ’） トル（３６０ＭＨｚ、ＣＤＣ１
５、ａｐｐ醜） ：
２．１１ （３Ｈ，Ｓ）、３．８３ （３Ｈ，Ｓ）。Properties: Colorless crystal Melting point: 99.5-100.0℃ 'H-NMR spectrum') (360MHz, CDC1
5, app ugly): 2.11 (3H,S), 3.83 (3H,S).
３．９７ （ＩＨ，ｄｄｄｄ、Ｊ−１，０，４，２゜５
．９，６．３Ｈｚ）。3.97 (IH, dddd, J-1, 0, 4, 2゜5
．． 9,6.3Hz).
４．１２ （ＩＨ，ｄｄ、Ｊ＠５．９，１１．６Ｈｚ）
。4.12 (IH, dd, [email protected], 11.6Hz)
.
４．３３ （ＩＨ，ｄｄ、Ｊ・４．２．１１．６Ｈｚ）
。4.33 (IH, dd, J・4.2.11.6Hz)
.
５．２２ （ＩＨ，ｄ、Ｊ□６．３Ｈｚ）。5.22 (IH, d, J□6.3Hz).
５．７９ （ＩＨ，ｂｓ）。5.79 (IH, bs).
６．９４ （２Ｈ，ｄ、Ｊ諺９Ｈｚ）。6.94 (2H, d, J proverb 9Hz).
７．３０ （２Ｈ，ｄ、Ｊ・９Ｈｚ）
ＩＲスペクトル（ｙｃｌｌ−’）： ３３１６，２９４
８゜１７６４．１７４４．１２５２
［ｉｒ］ ”： ＋５８．８ ’ （ｃ−１，００，Ｃ
ＨＣｌ５）（２）（２Ｒ，３Ｒ）−２−（Ｎ−ｔ−ブト
キシカルボニル）アミノ−３−（ｐ−メトキシフェニル
）−１，３−プロパンジオールの合成０〜
Ｈ
上記（１）の化合物（４Ｒ，ＳＲ） −４−アセトキシ
メチル−５−（４−メトキシフェニル）−２−オキサゾ
リドン２００ａｔ （０，７５４ｍ ｍｏｌ）のエタノ
ール溶液（５鳳１）に０．５Ｎ水酸化バリウム水溶液４
．５鳳１を加えて８０℃で４時間撹拌した。希硫酸で中
和後、沈澱を濾去し、濾液を炭酸水素ナトリウムでｐＨ
９にした。ジーｔ−プチル−ジカルポナート２０ ｏＪ
ｉ （ｏ、ｓ ７ｍ ｍｏｌ）とジオキサン３鳳ｉを加
えて室温で１６時間撹拌した。7.30 (2H, d, J・9Hz) IR spectrum (ycll-'): 3316,294
8゜1764.1744.1252 [ir] ”: +58.8' (c-1,00,C
HCl5) (2) Synthesis of (2R,3R)-2-(N-t-butoxycarbonyl)amino-3-(p-methoxyphenyl)-1,3-propanediol 0-H Compound (1) above ( 4R, SR) -4-acetoxymethyl-5-(4-methoxyphenyl)-2-oxazolidone 200 at (0,754 mmol) in ethanol solution (5 1) 0.5N barium hydroxide aqueous solution 4
．． 5 and 1 were added, and the mixture was stirred at 80°C for 4 hours. After neutralizing with dilute sulfuric acid, the precipitate was filtered off, and the filtrate was adjusted to pH with sodium hydrogen carbonate.
I made it 9. Di-t-butyl-dicarponate 20 oJ
7 mmol of dioxane and dioxane were added, and the mixture was stirred at room temperature for 16 hours.
酢酸エチルで抽出後、有機層を水洗、乾燥、減圧濃縮し
、シリカゲルカラムクロマトグラフィーにより精製して
標記化合物１９１ｍｇ（収率６６％）を得た。After extraction with ethyl acetate, the organic layer was washed with water, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 191 mg (yield: 66%) of the title compound.
性状：無色の油状物
’Ｈ−ＮＭＲスペクトル（１００Ｍ Ｈｚ 、 ＣＤ
Ｃｌ ｓ、δ ｐｐ鳳） ：
１．３７ （９Ｈ，ｓ）、２．４２ （ＩＨ，ｂｓ）。Properties: Colorless oil 'H-NMR spectrum (100MHz, CD
Cl s, δ pp Otori): 1.37 (9H, s), 2.42 (IH, bs).
３．６５−３．８５ （３Ｈ）。3.65-3.85 (3H).
３．７９ （３Ｈ，ｓ）。3.79 (3H, s).
４．９０ （ＩＨ，ｄ、Ｊ・４Ｈｚ）。4.90 (IH, d, J, 4Hz).
５．１ａ （ｉＨ，ｂｓ）。5.1a (iH, bs).
６．８６ （２Ｈ，ｄ、Ｊ尊９Ｈｚ）。6.86 (2H, d, Json 9Hz).
７．２８ （２８，ｄ、ＪＩＨｚ）
（３）（２Ｓ、３Ｒ）−Ｎ−ｔ−ブトキシカルボニル−
３−（４−メトキシフェニル）セリンの合成
０Ｈ
二酸化白金３０ＩＣを水４ｍｌに懸濁し、水素雰囲気下
で１５分撹拌した後、上記（２）の化合物（２Ｒ，３Ｒ
） −２−（Ｎ−ｔ−ブトキシカルボニル）アミノ−３
−（ｐ−メトキシフェニル）−１，３＝プロパンジオ一
ル５０鳳ｇ（０，１６８ｍ１拳■）のジオキサン溶液（
４ａｌｌ）を加え、５５℃で酸素ガスを吹き込みながら
１７時間撹拌した。触媒を濾去し、濾液に炭酸水素ナト
リウムを加えてエーテルで洗浄した。水層をＩＮ塩酸で
ｐＨ１にし、酢酸エチルで抽出し、有機層を水洗、乾燥
後、減圧濃縮して標記化合物２４■ｇ（収率４６％）を
油状物として得た。7.28 (28, d, JIHz) (3) (2S, 3R)-N-t-butoxycarbonyl-
Synthesis of 3-(4-methoxyphenyl)serine After suspending 0H platinum dioxide 30IC in 4 ml of water and stirring under hydrogen atmosphere for 15 minutes, the compound (2R, 3R
) -2-(N-t-butoxycarbonyl)amino-3
-(p-Methoxyphenyl)-1,3=Dioxane solution of 50 g (0,168 ml) of propanediol (
4all) was added thereto, and the mixture was stirred at 55° C. for 17 hours while blowing oxygen gas. The catalyst was removed by filtration, sodium hydrogen carbonate was added to the filtrate, and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with IN hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water, dried, and concentrated under reduced pressure to obtain 24 g (yield: 46%) of the title compound as an oil.
性状：無色の油状物
’Ｈ−ＮＭＲスペクトル（１００ＭＨｚ、ＣＤＣＤＣ１
５１ａｐｐ：
１．３２ （９Ｈ，Ｓ）、３．７８ （３Ｈ，８）。Properties: Colorless oil 'H-NMR spectrum (100MHz, CDCDC1
51app: 1.32 (9H, S), 3.78 (3H, 8).
４．５３ （ＬＨ，ｄ、Ｊ−８Ｈｚ）。4.53 (LH, d, J-8Hz).
５．２９ （ＩＨ，ｄ、Ｊ・２Ｈｚ）。5.29 (IH, d, J・2Hz).
５．４７ （ＩＨ，ｄ、Ｊ・８Ｈｚ）。5.47 (IH, d, J, 8Hz).
６．４２ （２Ｈ，ｂｓ）。6.42 (2H, bs).
６．８３ （２Ｈ，ｄ、ＪＩＩ９Ｈｚ）。6.83 (2H, d, JII 9Hz).
７．２７ （２Ｈ，ｄ、Ｊ・９Ｈｚ）
ＩＲスペクトル（ｙ ｃｍ−リ ：３４０４，２９８４
゜１６９６．１２５０
［ａ］ ”ニー１５．０” （ｃＯ，５０，ＣＨＣｌ３
）実施例２
Ｎ−ｔ−ブトキシカルボニルーオクトバミンの製造
（１）５− （４−メトキシフェニル）−２−オキサシ
リドンの合成
参考例３の化合物Ｎ−ｔ−ブトキシカルボニル−２−（
ｐ−メトキシフェニル）エチルアミン５０３１！ （２
，０ｍ ｍｏｌ）のアセトニトリル溶液（ｌｏ＠１ｌ）
ｉ：過硫酸カリウム１．０８ｇ（４，０ｒｍ ｍｏｌ）
ヲ含む水溶液（１０ｍＤとｆＥｒａ銅６４−ｇ（０，
４ｍ＠ｏｌ）を含む水溶液３ｍｆｆ１を加え、窒素気流
下で脱気した。５５°Ｃで４時間撹拌した後、反応液を
酢酸エチルで抽出した。有機層を水洗、乾燥後、濃縮し
、シリカゲルクロマトグラフィー（エーテル及び酢酸エ
チルにて溶出）で精製して標記化合物２８８１１１（収
率７４．７％）を得た。7.27 (2H, d, J・9Hz) IR spectrum (y cm-li: 3404, 2984
゜1696.1250 [a] "Knee 15.0" (cO,50,CHCl3
) Example 2 Production of N-t-butoxycarbonyl-octobamine (1) Synthesis of 5-(4-methoxyphenyl)-2-oxacylidone Compound of Reference Example 3 N-t-butoxycarbonyl-2-(
p-methoxyphenyl)ethylamine 5031! (2
,0m mol) in acetonitrile solution (lo@1l)
i: Potassium persulfate 1.08g (4.0rm mol)
An aqueous solution containing (10 mD and fEra copper 64-g (0,
3mff1 of an aqueous solution containing 4m@ol) was added and degassed under a nitrogen stream. After stirring at 55°C for 4 hours, the reaction solution was extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated, and purified by silica gel chromatography (eluted with ether and ethyl acetate) to obtain the title compound 288111 (yield 74.7%).
性状：無色結晶
融点：１１６．Ｏ〜１１６．５℃
’Ｈ−ＮＭＲスペクトル（１００ＭＨｚ −ＣＤ Ｃｉ
ｓ１δ ｐｐｍ） ：
３．５４ （１）１．ｄｄｄ、Ｊ−１，８，８，８Ｈｚ
）。Properties: Colorless crystal Melting point: 116. O~116.5℃'H-NMR spectrum (100MHz-CD Ci
s1δ ppm): 3.54 (1)1. ddd, J-1,8,8,8Hz
).
３．８３ （３１−１，Ｓ）。3.83 (31-1, S).
３．９２ （ＩＨ，ｄｄｄ、Ｊ・１，８，８．８Ｈｚ）
。3.92 (IH, ddd, J・1,8,8.8Hz)
.
５．５６ （１１（、ｔ、Ｊ−８Ｈ２）。5.56 (11(, t, J-8H2).
５．９０ （ＩＨ，ｂ）。5.90 (IH, b).
６．９０ （２Ｈ，ｄ、ＪｉＨｚ）。6.90 (2H, d, JiHz).
７．３０ （２Ｈ，ｄ、ＪｉＨｚ）
ＩＲスペクトル（ｙｅｓ−’）：３２６８，３１６４゜
１７５６．１７２４．１２５４
（２）ｌ−（４−メトキシフェニル）−２−（Ｎ−ｔ−
ブトキシカルボニル）アミノエタノールの合成
０Ｈ
上記（１）の化合物５−（４−メトキシフェニル）−２
−オキサシリドン２００ｍｇ（１，０４鳳朧ｏ１）のエ
タノール溶液（５朧＆）に０．５Ｎ水酸化バリウム水溶
液４．２量直を加えて７０℃で５時間撹拌した。希硫酸
で中和後、沈澱を濾去し、濾液を炭酸水素ナトリウムで
ｐＨ９にした。ジーｔ−ブチル−ジカルポナート３６０
μｌ（１，５７重鳳・ｌ）とジオキサン５ｍｌを加えて
室温で１６時間撹拌した。酢酸エチルで抽出後、有機層
を水洗、乾燥、減圧濃縮し、シリカゲルカラムクロマト
グラフ（−（エーテル／ヘキサン（３： ｌ）で溶出）
により精製して標記化合物２２７Ｂ（収率８２％）を得
た。7.30 (2H, d, JiHz) IR spectrum (yes-'): 3268, 3164° 1756.1724.1254 (2) l-(4-methoxyphenyl)-2-(N-t-
Synthesis of butoxycarbonyl)aminoethanol 0H Compound 5-(4-methoxyphenyl)-2 of (1) above
- To an ethanol solution (5 Oboro) of 200 mg (1,04 Oboro o1) of oxacilidone was added 4.2 volumes of a 0.5 N barium hydroxide aqueous solution, and the mixture was stirred at 70°C for 5 hours. After neutralization with dilute sulfuric acid, the precipitate was filtered off, and the filtrate was adjusted to pH 9 with sodium hydrogen carbonate. Di-t-butyl dicarponate 360
μl (1,57 liters) and 5 ml of dioxane were added and stirred at room temperature for 16 hours. After extraction with ethyl acetate, the organic layer was washed with water, dried, concentrated under reduced pressure, and subjected to silica gel column chromatography (-(eluted with ether/hexane (3: l)).
Purification was performed to obtain the title compound 227B (yield 82%).
性状：無色結晶
’Ｈ−ＮＭＲスペクトル（１００ＭＨｚ、ＣＤＣ１５、
δｐｐ■）：
１．４４ （９Ｈ，ｓ）。Properties: Colorless crystal 'H-NMR spectrum (100MHz, CDC15,
δpp■): 1.44 (9H, s).
２．５０ （ＩＨ，ｂｓ）。2.50 (IH, bs).
３．１５−３．４５ （２Ｈ，ｍ）。3.15-3.45 (2H, m).
３．７８ （３Ｈ，ｓ）。3.78 (3H, s).
４．７４ （ＩＨ，ｄｄ、Ｊ□４，８Ｈｚ）。4.74 (IH, dd, J□4,8Hz).
４．９０ （ＩＨ，ｂ）。4.90 (IH, b).
６．８５ （２Ｈ，ｄ、Ｊ・９Ｈｚ）。6.85 (2H, d, J・9Hz).
７．２５ （２Ｈ，ｄ、Ｊ□９Ｈｚ）
ＩＲスペクトル（ｙｃ＋ａ−’）： ３４２４．２９８
０゜（３）Ｎ−ｔ−ブトキシ力ルポニルーオクトパミン
の合成
上記（２）の化合物１−（４−メトキシフェニル）−２
−（Ｎ−ｔ−７’トキシカルボニル）アミノエタノール
１４０鳳ｒ（０，５４２ｍｍ・１）の塩化メチレン溶液
（１５ｍｌ）に−１０℃の水冷下で三臭化ホウ素の１Ｍ
塩化メチレン溶液（２，６ｍＤを加えた。−１０℃で１
時間撹拌後、室温に戻しＮ。7.25 (2H, d, J□9Hz) IR spectrum (yc+a-'): 3424.298
0゜(3) Synthesis of N-t-butoxyluponyl-octopamine Compound 1-(4-methoxyphenyl)-2 of above (2)
-(N-t-7'toxycarbonyl)aminoethanol 140 ml (0,542 mm 1) in methylene chloride solution (15 ml) under water cooling at -10°C with 1M boron tribromide.
Methylene chloride solution (2.6 mD was added. 1 at -10 °C
After stirring for an hour, return to room temperature and add N.
Ｎ−ジメチルアセトアミドを白濁が無くなるまで（約１
ｍｌ）加えて、さらに２時間撹拌した。反応終了後塩
化アンモニウム水溶液とエーテルを加えた。水層を炭酸
水素ナトリウムでｐＨ９に調整し、大過剰のジーｔ−プ
チルージカルボナートとジオキサンを加えて室温で１６
時間撹拌した。酢酸エチルで抽出し、有機層を水洗、乾
燥後に減圧濃縮した。残渣をシリカゲルカラムクロマト
グラフィー（エーテルで溶出）で精製して標記化合物４
５重ｇ（収率３４％）を得た。Add N-dimethylacetamide until the cloudiness disappears (approximately 1
ml) and further stirred for 2 hours. After the reaction was completed, an aqueous ammonium chloride solution and ether were added. The aqueous layer was adjusted to pH 9 with sodium hydrogen carbonate, and a large excess of di-t-butyl-dicarbonate and dioxane were added, and the mixture was heated to 16 mL at room temperature.
Stir for hours. The organic layer was extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ether) to obtain the title compound 4.
5 g (yield: 34%) was obtained.
性状：無色結晶
融点＝１４４〜１４５℃
’Ｈ−ＮＭＲスペクトル（１００ＭＨｚ、ＣＤ３０ＤＳ
ａ ｐｐｍ） ：
１．４４ （９Ｈ，ｓ）。Properties: Colorless crystal Melting point = 144-145°C 'H-NMR spectrum (100MHz, CD30DS
a ppm): 1.44 (9H, s).
３．１−３．３ （２Ｈ，ｍ）。3.1-3.3 (2H, m).
４．５８ （ＩＨ，ｔ、Ｊ・６Ｈｚ）。4.58 (IH, t, J・6Hz).
６．７４ （２Ｈ，ｄ、Ｊ−９Ｈ２）。6.74 (2H, d, J-9H2).
７．１６ （２Ｈ，ｄ、Ｊ・９Ｈｚ）
！Ｒスペクトル（ｙ ｃ＋ｓ−つ ：３４１６，３２８
０゜２９８０．１６５０
実施例３
（２Ｓ、３Ｒ）−Ｎ−ｔ−ブトキシカルボニル−３−（
３，４−ジメトキシフェニル）セリンの製（１）（４Ｒ
，５Ｒ）−４−アセトキシメチル−５−（３，４−ジメ
トキシ）フェニル−２−オキサゾリドンの合成
参考例４の化合物（２Ｓ） −２−（ｔ−ブトキシカル
ボニル）−アミノ−３−（３，４−ジメトキシフェニル
）プロパツールアセテート２００膳ｇ（０，５６６ｍｍ
ｏｌ）のアセトニトリル溶液（５ａｔ）に過硫酸カリウ
ム３０６鳳ｇ（１−１３鳳鳳・ｌ）を含む水溶液（５鳳
０と硫酸鋼１８鳳（（０，１１３ｍｎｏ １）を含む水
溶液１ｍｌを加え、窒素気流下で脱気した。７０℃で５
時間撹拌した後、反応液を酢酸エチルで抽出した。有機
層を水洗、乾燥後、濃縮し、シリカゲルクロマトグラフ
ィー（エーテルおよび酢酸エチルにて溶出）で精製して
標記化合物７３鳳ｇ（収率４３．５％）を得た。7.16 (2H, d, J・9Hz)! R spectrum (yc+s-t:3416,328
0°2980.1650 Example 3 (2S,3R)-Nt-butoxycarbonyl-3-(
Production of 3,4-dimethoxyphenyl)serine (1) (4R
,5R) -4-acetoxymethyl-5-(3,4-dimethoxy)phenyl-2-oxazolidone Compound (2S) of Reference Example 4 -2-(t-butoxycarbonyl)-amino-3-(3, 4-dimethoxyphenyl) propatool acetate 200 servings (0,566 mm
To the acetonitrile solution (5at) of potassium persulfate, add 1 ml of an aqueous solution containing 306 g (1-13 mno 1) of potassium persulfate (5 0 and 18 ml of sulfuric acid steel (0,113 mno 1), Degassed under nitrogen stream. 5 at 70°C.
After stirring for an hour, the reaction solution was extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated, and purified by silica gel chromatography (eluted with ether and ethyl acetate) to obtain 73 g (yield: 43.5%) of the title compound.
性状：無色の油状物
’Ｈ−ＮＭＲスペクトル（１００ＭＨｚ、ＣＤＣｌ５−
δｐｐｍ） ：
２．１２ （３Ｈ，ｓ）、３．９２ （６Ｈ，ｓ）。Properties: Colorless oil 'H-NMR spectrum (100MHz, CDCl5-
δppm): 2.12 (3H, s), 3.92 (6H, s).
３．８−４．１ （ＩＨ，ｍ）。3.8-4.1 (IH, m).
４．０４−４．２５ （２）１．ｍ）。4.04-4.25 (2) 1. m).
５．２２ （ＩＨ，ｄ、Ｊ寓６Ｈｚ）。5.22 (IH, d, J 6Hz).
６．２１ （ＩＨ，ｓ）、６．８９ （３Ｈ，５）ＩＲ
スペクトル（ｙ ｃｍ−つ ：３３５２，３０２３゜１
７５４．１２６６．１２３８
［ｇ］ ！Ｄ’：＋４３．４” （ｃ−１，ｏＯ，ＣＨ
Ｃら）（２）上記（１）で得たオキサゾリドンは実施例
１または実施例２の方法により容易に加水分解され（２
Ｓ、３Ｒ）−Ｎ−ｔ−ブトキシカルボニル−３−（３，
４−ジメトキシフェニル）セリンが得られた。6.21 (IH,s), 6.89 (3H,5)IR
Spectrum (ycm-t:3352,3023゜1
754.1266.1238 [g]! D': +43.4" (c-1, oO, CH
C et al.) (2) The oxazolidone obtained in (1) above is easily hydrolyzed by the method of Example 1 or Example 2 (2)
S, 3R)-N-t-butoxycarbonyl-3-(3,
4-dimethoxyphenyl)serine was obtained.
実施例４
（２５，３Ｒ）−Ｎ−ｔ−ブトキシカルボニル−３−（
４−メトキシフェニル）セリンの製造（１）（４Ｓ、Ｓ
Ｒ） −４−メトキシカルボニル−５−（４−メトキシ
）フェニル−２−オキサゾリドンの合成
参考例２の化合物Ｎ−ｔ−ブトキシカルボニル−１，−
ｐ−メトキシフェニルアラニンメチルエステル２３０■
ｇ（０，７４４鳳鳳・ｌ）のアセトニトリル溶液（５ｍ
ｌ）に過硫酸カリウム３８５鳳ｇ（１゜４２■鳳・ｌ）
を含む水溶液（５ｔｉ）と硫酸鋼２３鳳ｇ（０，１４２
鳳鳳・Ｉ）を含む水溶液１ｍｌを加え、窒素気流下で脱
気した。７０”Ｏで２時間撹拌した後、反応液をエーテ
ルで抽出した。エーテル層を水洗、乾燥後、濃縮し、シ
リカゲルクロマトグラフィー（エーテルにて溶出）で精
製して標記化合物６９．９鳳ｇ（収率３９．１％）を得
た。Example 4 (25,3R)-Nt-butoxycarbonyl-3-(
Production of 4-methoxyphenyl)serine (1) (4S,S
R) Synthesis of -4-methoxycarbonyl-5-(4-methoxy)phenyl-2-oxazolidone Compound N-t-butoxycarbonyl-1,- of Reference Example 2
p-methoxyphenylalanine methyl ester 230■
acetonitrile solution (5 m
l) 385g of potassium persulfate (1°42cm/l)
(5ti) and sulfuric acid steel 23g (0,142g)
1 ml of an aqueous solution containing Hoho I) was added, and the mixture was degassed under a nitrogen stream. After stirring at 70"O for 2 hours, the reaction solution was extracted with ether. The ether layer was washed with water, dried, concentrated, and purified by silica gel chromatography (eluted with ether) to yield 69.9 g of the title compound ( A yield of 39.1%) was obtained.
性状：無色結晶 融点：１０２．０−１０２．５℃ ’Ｈ−ＮＭＲスペクトル（１００ＭＨｚＳＣＤＣＩｓ。Properties: Colorless crystal Melting point: 102.0-102.5℃ 'H-NMR spectrum (100MHz SCDCIs.
ａｐｐ鳳） ： ３．５４ （３Ｈ，ｓ）、３．８６ （３Ｂ、ｓ）。app Otori): 3.54 (3H, s), 3.86 (3B, s).
４．３０ （ＩＨ，ｄ、Ｊ宿６Ｈｚ）。4.30 (IH, d, J Inn 6Hz).
５．５８ （ＩＨ，ｄ、Ｊ・６Ｈｚ）。5.58 (IH, d, J, 6Hz).
６．４２ （ＩＨ，ｂｓ）。6.42 (IH, bs).
６．９２ （２Ｈ，ｄ、Ｊ婁９Ｈｚ）。6.92 (2H, d, J 9Hz).
７．３４ （２Ｈ，ｄ、Ｊ−９Ｈｚ）
ＩＲスペクトル（ｙｅｓ−’）： ３２６８，１７５８
゜１２８０．１２２８
［ｇ］ ”： ＋８０．６＠（ｃ−１，０３，ＣＨＣｌ
５）（２）上記（１）で得たオキサゾリドンはカルポキ
シル基を還元してアルコールとした後、実施例１または
実施例２の方法により加水分解後、再び酸化することに
より容易に（２３，３Ｒ）−Ｎ−ｔ−ブトキシカルボニ
ル−３−（４−メトキシフェニル）セリンを得ることが
できる。7.34 (2H, d, J-9Hz) IR spectrum (yes-'): 3268,1758
゜1280.1228 [g] ”: +80.6@(c-1,03,CHCl
(23,3R )-Nt-butoxycarbonyl-3-(4-methoxyphenyl)serine can be obtained.
（発明の効果）
本発明の方法を使用することにより、チロシン誘導体の
β位に立体特異的に水酸基を導入することができる。得
られたβ−ヒドロキシチロシン類は、β位に水酸基を持
ちかつ立体特異性を有するので、種々の生理活性を持つ
ことが知られているβ−ヒドロキシフェネチルアミン類
化合物の合成出発物質として大変有益な化合物である。(Effects of the Invention) By using the method of the present invention, a hydroxyl group can be stereospecifically introduced into the β-position of a tyrosine derivative. The obtained β-hydroxytyrosines have a hydroxyl group at the β-position and have stereospecificity, so they are very useful as starting materials for the synthesis of β-hydroxyphenethylamine compounds, which are known to have various physiological activities. It is a compound.
手 続 補 正 書
昭和６３年４月２２日
１、事件の表示
昭和６３年特許願ＰｊＳ５５３５９号
２、発明の名称
β−ヒドロキシ７エネチルアミン類の合成法３、補−正
をする者
事件との関係 特許出願人
住所
名称 （１９０）サントリー株式会社
４、代 理 人
５、補正の対象
（別紙）
（１）［特許請求の範囲］を次のとおり補正する。Procedures Amendment Document April 22, 1988 1. Indication of the case 1988 Patent Application PjS55359 2. Name of the invention Method for synthesizing β-hydroxy 7enethylamines 3. Person making the amendment Relationship with the case Patent applicant address name (190) Suntory Ltd. 4, Agent 5, Subject of amendment (attached sheet) (1) [Scope of claims] is amended as follows.
「 下記の一般式（ＩＩ）：
に１
（式中 Ｒ１は低級アルキル基、低級アルコキシカルボ
ニル基、アシルオキシメチル基または水素原子であり：
Ｒ２は水素原子または低級アルキル基であり、Ｒ３は低
級アルキル基であり：Ｘは水素原子、低級アルキル基、
低級アルコキシ基またはハロゲン原子であり：ｎは１ま
たは２である）で表されるフェネチルアミン誘導体に硫
酸銅、塩化鉄（Ｉｌｌ）、硫酸鉄（Ｉ［［）もしくは酢
酸銅及び過硫酸カリウムもしくは四酢酸鉛を作用させて
一般式（）：
（式中、Ｒ１，Ｒ２、Ｒ３、Ｘ及びｎは前記の定義と同
じである）で表される環状カルバメートとし、続いて、
この式（ＩＩＩ）の化合物をアルカリ加水分解すること
により一般式（Ｉ）：
Ｈ
（式中、−盈２−１Ｒ３、Ｒ１、Ｘ及びｎは前記の定義
と同じである）で表されるβ位にヒドロキシ基を有する
フェネチルアミン誘導体を合成する方法。」（２）明細
書の記載を次のとおり補正する。"The following general formula (II): 1 (wherein R1 is a lower alkyl group, a lower alkoxycarbonyl group, an acyloxymethyl group, or a hydrogen atom:
R2 is a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group; X is a hydrogen atom, a lower alkyl group,
copper sulfate, iron chloride (Ill), iron sulfate (I [[) or copper acetate and potassium persulfate or tetraacetic acid]. A cyclic carbamate represented by the general formula (): (wherein R1, R2, R3, X and n are the same as defined above) by the action of lead, and then,
By alkaline hydrolysis of the compound of formula (III), β represented by the general formula (I): H (wherein -R, R, X and n are the same as defined above) A method for synthesizing a phenethylamine derivative having a hydroxy group at the position. (2) The statement in the description is amended as follows.
頁 行 誤 正目
下！ −Ｈ，ｌ＠ −ｔ１７．ｌ’
３４ １１ ３．５４（３１１，Ｓ）
３．１！（３Ｈ，Ｓ）以 上Page line error correct
under! -H,l@-t17. l'
34 11 3.54 (311,S)
3.1! (3H,S) or more
Claims (1)
ボニル基、アシルオキシメチル基または水素原子であり
；Ｒ＾２は水素原子または低級アルキル基であり；Ｒ＾
３は低級アルキル基であり；Ｘは水素原子、低級アルキ
ル基、低級アルコキシ基またはハロゲン原子であり；ｎ
は１または２である）で表されるフェネチルアミン誘導
体に硫酸銅、塩化鉄（III）、硫酸鉄（III）もしくは酢
酸銅及び過硫酸カリウムもしくは四酢酸鉛を作用させて
一般式（III）： ▲数式、化学式、表等があります▼（III） （式中、Ｒ＾１、Ｒ＾２、Ｒ＾３、Ｘ及びｎは前記の定
義と同じである）で表される環状カルバメートとし、続
いて、この式（III）の化合物をアルカリ加水分解する
ことにより一般式（ I ）： ▲数式、化学式、表等があります▼（ I ） （式中、Ｒ＾１Ｒ＾１、Ｒ＾２、Ｒ＾３、Ｘ及びｎは前
記の定義と同じである）で表されるβ位にヒドロキシ基
を有するフェネチルアミン誘導体を合成する方法。[Claims] The following general formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 is a lower alkyl group, a lower alkoxycarbonyl group, an acyloxymethyl group, or a hydrogen atom. and R^2 is a hydrogen atom or a lower alkyl group; R^
3 is a lower alkyl group; X is a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom; n
is 1 or 2) is reacted with copper sulfate, iron (III) chloride, iron (III) sulfate, copper acetate, and potassium persulfate or lead tetraacetate to obtain the general formula (III): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼(III) (In the formula, R^1, R^2, R^3, X and n are the same as the above definitions) cyclic carbamate, followed by By alkaline hydrolysis of the compound of formula (III), the general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1R^1, R^2, R^ 3. A method for synthesizing a phenethylamine derivative having a hydroxy group at the β-position represented by (X and n are the same as defined above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5535988A JPH01228946A (en) | 1988-03-09 | 1988-03-09 | Synthesis of beta-hydroxyphenetylamines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5535988A JPH01228946A (en) | 1988-03-09 | 1988-03-09 | Synthesis of beta-hydroxyphenetylamines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01228946A true JPH01228946A (en) | 1989-09-12 |
Family
ID=12996297
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5535988A Pending JPH01228946A (en) | 1988-03-09 | 1988-03-09 | Synthesis of beta-hydroxyphenetylamines |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01228946A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5739387A (en) * | 1995-05-18 | 1998-04-14 | Sumitomo Chemical Company, Limited | Process for producing threo-3-(3,4-dihydroxyphenyl)serine |
| WO1999002508A1 (en) * | 1997-07-10 | 1999-01-21 | Ube Industries, Ltd. | Process for producing 4-alkoxycarbonyl-2-oxazolidinone compounds |
| KR20000063913A (en) * | 2000-08-10 | 2000-11-06 | 하현준 | Process for preparing 1,2-diaminopropane alcohols from aziridines |
| KR20010000196A (en) * | 2000-08-10 | 2001-01-05 | 하현준 | Process for preparing alpha-amino acids and their derivatives including phenylalanine and homophenylalanine from aziridines |
| WO2003002514A1 (en) * | 2001-06-28 | 2003-01-09 | Dr. Reddy's Research Foundation | 3-aryl-alpha-amino propanoic acid derivatives and a process for their preparation |
-
1988
- 1988-03-09 JP JP5535988A patent/JPH01228946A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5739387A (en) * | 1995-05-18 | 1998-04-14 | Sumitomo Chemical Company, Limited | Process for producing threo-3-(3,4-dihydroxyphenyl)serine |
| WO1999002508A1 (en) * | 1997-07-10 | 1999-01-21 | Ube Industries, Ltd. | Process for producing 4-alkoxycarbonyl-2-oxazolidinone compounds |
| KR20000063913A (en) * | 2000-08-10 | 2000-11-06 | 하현준 | Process for preparing 1,2-diaminopropane alcohols from aziridines |
| KR20010000196A (en) * | 2000-08-10 | 2001-01-05 | 하현준 | Process for preparing alpha-amino acids and their derivatives including phenylalanine and homophenylalanine from aziridines |
| WO2002012184A1 (en) * | 2000-08-10 | 2002-02-14 | Chembionex Co., Ltd. | Process for preparing alpha-amino acids and their derivatives including phenylalanine and homophenylalanine and their intermediates |
| WO2002012185A1 (en) * | 2000-08-10 | 2002-02-14 | Chembionex Co., Ltd. | Process for preparing 2,3-diaminopropanols and synthesis of other compounds using 2,3-diaminopropanols |
| WO2003002514A1 (en) * | 2001-06-28 | 2003-01-09 | Dr. Reddy's Research Foundation | 3-aryl-alpha-amino propanoic acid derivatives and a process for their preparation |
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