JP2019199446A - Method of producing s-ica ribosylhomocysteine - Google Patents
Method of producing s-ica ribosylhomocysteine Download PDFInfo
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- JP2019199446A JP2019199446A JP2018095270A JP2018095270A JP2019199446A JP 2019199446 A JP2019199446 A JP 2019199446A JP 2018095270 A JP2018095270 A JP 2018095270A JP 2018095270 A JP2018095270 A JP 2018095270A JP 2019199446 A JP2019199446 A JP 2019199446A
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- 238000000034 method Methods 0.000 title claims abstract description 13
- BQEWHRSAWRKDTH-IQMFPIFPSA-N (2s)-2-[[(3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]amino]-4-sulfanylbutanoic acid Chemical compound OC[C@H]1OC(N[C@@H](CCS)C(O)=O)[C@H](O)[C@@H]1O BQEWHRSAWRKDTH-IQMFPIFPSA-N 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 125000006239 protecting group Chemical group 0.000 claims abstract description 16
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 claims description 8
- 229960004452 methionine Drugs 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- FFEARJCKVFRZRR-SCSAIBSYSA-N D-methionine Chemical compound CSCC[C@@H](N)C(O)=O FFEARJCKVFRZRR-SCSAIBSYSA-N 0.000 claims description 3
- 229930182818 D-methionine Natural products 0.000 claims description 3
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 claims description 3
- 229930195722 L-methionine Natural products 0.000 claims description 3
- 125000000393 L-methionino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(SC([H])([H])[H])([H])[H] 0.000 claims description 2
- 238000010586 diagram Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 44
- -1 p-methoxybenzyl Chemical group 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- 239000007810 chemical reaction solvent Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- ZZWRZHMATCAGEF-YWTNHNAXSA-N 1-[(2R,3R,4R,5S)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-(iodomethyl)oxolan-2-yl]imidazole-4-carboxamide Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1[C@H](O[C@H]([C@@H]1O[Si](C)(C)C(C)(C)C)N2C=C(N=C2)C(=O)N)CI ZZWRZHMATCAGEF-YWTNHNAXSA-N 0.000 description 4
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 3
- SXNMHJMWHQTRMH-YWTNHNAXSA-N 1-[(2R,3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-(hydroxymethyl)oxolan-2-yl]imidazole-4-carboxamide Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1[C@H](O[C@H]([C@@H]1O[Si](C)(C)C(C)(C)C)N2C=C(N=C2)C(=O)N)CO SXNMHJMWHQTRMH-YWTNHNAXSA-N 0.000 description 3
- WMAHJTUDRMMGCJ-GBEXAXCTSA-N 1-[(2R,3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-[[tert-butyl(dimethyl)silyl]oxymethyl]oxolan-2-yl]imidazole-4-carboxamide Chemical compound CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=C(N=C2)C(=O)N)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C WMAHJTUDRMMGCJ-GBEXAXCTSA-N 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- HIVMLHRDNLMYGX-SOAMZJECSA-N [(2R,3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-(4-carbamoylimidazol-1-yl)oxolan-2-yl]methyl methanesulfonate Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1[C@H](O[C@H]([C@@H]1O[Si](C)(C)C(C)(C)C)N2C=C(N=C2)C(=O)N)COS(=O)(=O)C HIVMLHRDNLMYGX-SOAMZJECSA-N 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
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 235000010288 sodium nitrite Nutrition 0.000 description 3
- KKIWUCRMXKEDTH-RFNSYMJRSA-N (2R)-4-[[(2S,3S,4R,5R)-5-(4-carbamoylimidazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](CCSC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=C(N=C2)C(=O)N)O)O)C(=O)O KKIWUCRMXKEDTH-RFNSYMJRSA-N 0.000 description 2
- NMIZONYLXCOHEF-UHFFFAOYSA-N 1h-imidazole-2-carboxamide Chemical compound NC(=O)C1=NC=CN1 NMIZONYLXCOHEF-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 125000005947 C1-C6 alkylsulfonyloxy group Chemical group 0.000 description 1
- 102000004867 Hydro-Lyases Human genes 0.000 description 1
- 108090001042 Hydro-Lyases Proteins 0.000 description 1
- ZTVZLYBCZNMWCF-WDSKDSINSA-N L,L-homocystine zwitterion Chemical compound OC(=O)[C@@H](N)CCSSCC[C@H](N)C(O)=O ZTVZLYBCZNMWCF-WDSKDSINSA-N 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical class OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005002 aryl methyl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 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
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000006257 n-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])OC(*)=O 0.000 description 1
- 125000006256 n-propyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC(*)=O 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Saccharide Compounds (AREA)
Abstract
【課題】Ｓ−ＩＣＡリボシルホモシステインの製造方法に係る新規な技術を提供する。【解決手段】式（１）で表される化合物又はその塩の製造方法であって、式（２）で表される化合物と、式（３）で表される化合物とを反応させて式（４）で表される化合物を生成させ、得られた式（４）で表される化合物に対し保護基の除去処理を行うことを含む、式（１）で表される化合物の製造方法。【選択図】 なしPROBLEM TO BE SOLVED: To provide a novel technique relating to a method for producing S-ICA ribosylhomocysteine. A method for producing a compound represented by formula (1) or a salt thereof, comprising reacting a compound represented by formula (2) with a compound represented by formula (3), A method for producing a compound represented by formula (1), which comprises producing a compound represented by 4) and subjecting the obtained compound represented by formula (4) to a protective group removal treatment. [Selection diagram] None
Description
本発明は、Ｓ−ＩＣＡリボシルホモシステインの製造方法に関する。 The present invention relates to a method for producing S-ICA ribosylhomocysteine.
核酸などのメチル化を司るＳ−ａｄｅｎｏｓｙｌｍｅｔｈｉｏｎｉｎｅ（ＳＡＭ）が知られており、変形性関節炎やうつ病の治療薬として使用されているほか、例えば該ＳＡＭを含む関節の痛みの改善用組成物が提案されている（特許文献１）。
また、ＳＡＭの脱メチル体（ＳＡＨ）も、ＳＡＨヒドラーゼ活性や抗ウイルスや腫瘍活性など多彩な生物活性を有することから医薬品のリードとして大きく期待されている。
S-adenosylationine (SAM) that controls methylation of nucleic acids and the like is known and used as a therapeutic agent for osteoarthritis and depression. For example, a composition for improving joint pain containing the SAM is proposed. (Patent Document 1).
In addition, demethylated SAM (SAH) is highly expected as a pharmaceutical lead because it has various biological activities such as SAH hydrase activity and antiviral and tumor activity.
本発明は、Ｓ−ＩＣＡリボシルホモシステインの製造方法に係る新規な技術の提供を目的とする。 An object of this invention is to provide the novel technique which concerns on the manufacturing method of S-ICA ribosyl homocysteine.
コムラサキシメジより単離された新規植物成長促進物質（フェアリー化合物）のイミダゾールカルボキサミド（ＩＣＡ）を稲に投与後の抽出物より、式（１）で表される化合物（Ｓ−ＩＣＡリボシルホモシステイン）が単離された。
発明者は、Ｓ−ＩＣＡリボシルホモシステインにも多彩な生物活性が期待できると考え、合成研究に着手し、本発明を完成させた。
From an extract after administration of imidazole carboxamide (ICA), a novel plant growth promoting substance (fairy compound) isolated from Komura Saxi Mediji, to a rice plant, a compound represented by formula (1) (S-ICA ribosyl homocysteine) is obtained. Isolated.
The inventor considered that S-ICA ribosylhomocysteine can also be expected to have various biological activities, and started synthetic research to complete the present invention.
本発明の要旨は以下のとおりである。
［１］ 式（１）：
式（２）：
式（３）：
得られた前記式（４）で表される化合物に対し保護基の除去処理を行うことを含む、前記式（１）で表される化合物の製造方法。
［２］ 前記式（２）で表される化合物を光学活性メチオニンから変換することにより得ることをさらに含む、［１］に記載の製造方法。
［３］ 前記光学活性メチオニンがＬ−メチオニンまたはＤ−メチオニンである［１］に記載の製造方法。
The gist of the present invention is as follows.
[1] Formula (1):
Formula (2):
Formula (3):
The manufacturing method of the compound represented by the said Formula (1) including performing the removal process of a protecting group with respect to the compound represented by the obtained said Formula (4).
[2] The production method according to [1], further comprising obtaining the compound represented by the formula (2) by converting it from optically active methionine.
[3] The production method according to [1], wherein the optically active methionine is L-methionine or D-methionine.
本発明によれば、Ｓ−ＩＣＡリボシルホモシステインの製造方法に係る新規な技術を提供することができる。 ADVANTAGE OF THE INVENTION According to this invention, the novel technique which concerns on the manufacturing method of S-ICA ribosyl homocysteine can be provided.
以下、本発明の実施形態の１つについて詳細に説明する。
なお、以下において、一般式が有する官能基の定義については、すでに記載した定義を引用してその説明を省略することがある。
Hereinafter, one embodiment of the present invention will be described in detail.
In the following, the definition of the functional group of the general formula may be omitted with reference to the definition already described.
なお、本明細書において、アミノ基の保護基とは、アミノ基の保護基として通常知られている保護基であれば特に制限はなく、例えばベンジル基、パラメトキシベンジル基（ｐ−メトキシベンジル基）等のアラルキル基、メトキシカルボニル基、エトキシカルボニル基、ｎ−プロピルオキシカルボニル基、イソプロピルオキシカルボニル基、ｎ−ブチルオキシカルボニル基、イソブチルオキシカルボニル基、ｔｅｒｔ−ブトキシカルボニル（Ｂｏｃ）基等のアルコキシカルボニル基、ベンジルオキシカルボニル基、ｐ−メトキシベンジルオキシカルボニル基、ｐ−ニトロベンジルオキシカルボニル基等のアラルコキシカルボニル基、メトキシメチル基、メトキシエトキシメチル基、１−（エトキシ）エチル基、メトキシイソプロピル基などの１−（アルコキシ）アルキル基、アセチル基、トリフルオロアセチル基、プロピオニル基、ブチリル基、ピバロイル基、ベンゾイル基、メチルベンゾイル基等のアシル基などが挙げられる。
また、カルボン酸の保護基もまた、カルボン酸の保護基として通常知られている保護基であれば特に制限はなく、メチル基、エチル基、イソプロピル基、ｔｅｒｔ−ブチル基、ベンジル基、ニトロベンジル基などが挙げられる。
また、ヒドロキシル基の保護基もまた、ヒドロキシル基の保護基として通常知られている保護基であれば特に制限はなく、例えば、トリメチルシリル基、ｔ−ブチルジメチルシリル（ＴＢＳ）基等のトリアルキルシリル基、ベンジル基、ジフェニルメチル基等のアリールメチル基、アセチル基、プロピオニル基等のアシル基、メトキシメチル基、エトキシメチル基等の低級アルコキシメチル基、ベンジルオキシメチル基等のアラルキルオキシメチル基、テトラヒドロピラニル基等などが挙げられる。
In the present specification, the amino-protecting group is not particularly limited as long as it is a protective group commonly known as an amino-protecting group. For example, benzyl group, paramethoxybenzyl group (p-methoxybenzyl group) ) Aralkyl groups such as methoxycarbonyl group, ethoxycarbonyl group, n-propyloxycarbonyl group, isopropyloxycarbonyl group, n-butyloxycarbonyl group, isobutyloxycarbonyl group, tert-butoxycarbonyl (Boc) group, etc. Group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, aralkoxycarbonyl group such as p-nitrobenzyloxycarbonyl group, methoxymethyl group, methoxyethoxymethyl group, 1- (ethoxy) ethyl group, methoxyisopropyl group Such as - (alkoxy) alkyl group, an acetyl group, trifluoroacetyl group, a propionyl group, a butyryl group, a pivaloyl group, a benzoyl group and an acyl group such as a methyl benzoyl group.
The carboxylic acid protecting group is not particularly limited as long as it is a protecting group generally known as a carboxylic acid protecting group, and is a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a benzyl group, or a nitrobenzyl group. Groups and the like.
The hydroxyl protecting group is not particularly limited as long as it is a protecting group commonly known as a hydroxyl protecting group. For example, a trialkylsilyl group such as a trimethylsilyl group or a t-butyldimethylsilyl (TBS) group can be used. Group, arylmethyl group such as benzyl group and diphenylmethyl group, acyl group such as acetyl group and propionyl group, lower alkoxymethyl group such as methoxymethyl group and ethoxymethyl group, aralkyloxymethyl group such as benzyloxymethyl group, tetrahydro A pyranyl group etc. are mentioned.
本実施形態に係る製造方法の一例である、以下に表す反応経路を詳細に説明する。
なお、以下の説明において、粗生成物について精製をせずにそのまま次の処理に用いている場合は、基質となる化合物が１００％の収率で生成物に変換されたとみなし、基質の使用量を生成物の使用量とみなす。
The reaction route shown below, which is an example of the production method according to the present embodiment, will be described in detail.
In the following explanation, when the crude product is used for the next treatment without purification, it is considered that the compound as a substrate has been converted to the product in a yield of 100%, and the amount of the substrate used Is regarded as the amount of product used.
当該反応経路において、Ｒ１はカルボン酸の保護基を、Ｒ２はアミノ基の保護基を、Ｘは脱離基を、Ｒ３はヒドロキシル基の保護基を示す。 In the reaction pathway, R 1 represents a carboxylic acid protecting group, R 2 represents an amino protecting group, X represents a leaving group, and R 3 represents a hydroxyl protecting group.
［工程１］
式（ii）で表される化合物は、式（i）で表される化合物であるメチオニンを酸化し、ジスルフィド結合を形成して二量体とすることにより得ることができる。
[Step 1]
The compound represented by formula (ii) can be obtained by oxidizing methionine, which is a compound represented by formula (i), to form a disulfide bond to form a dimer.
当該反応は、例えば、液体アンモニアなどの反応溶媒中、式（i）で表される化合物（メチオニン）を金属リチウムなどで処理することにより行うことができる。金属リチウム等の使用量は、式（i）で表される化合物に対し、例えば２〜１０当量とすることができる。また、反応温度は、例えば-７８〜-４０℃とすることができる。 The reaction can be performed, for example, by treating the compound (methionine) represented by the formula (i) with metallic lithium or the like in a reaction solvent such as liquid ammonia. The usage-amount of metal lithium etc. can be 2-10 equivalent with respect to the compound represented by Formula (i), for example. Moreover, reaction temperature can be made into -78--40 degreeC, for example.
［工程２］
式（iii）で表される化合物は、式（ii）で表される化合物にカルボン酸の保護基およびアミノ基の保護基を導入することにより得ることができる。
[Step 2]
The compound represented by the formula (iii) can be obtained by introducing a protecting group for a carboxylic acid and a protecting group for an amino group into the compound represented by the formula (ii).
式中、Ｒ１、Ｒ２は上記の定義に同じ。 In the formula, R 1 and R 2 are the same as defined above.
当該反応は当業者が適宜設定でき、カルボン酸、アミノ基保護基導入に係る公知の方法により行うことができる。
例えば、Ｒ１がメチル基、Ｒ２がＢｏｃ基である場合を想定する。
当該反応は、まず、メタノールなどの反応溶媒中、塩化チオニル、塩化オキサリルなどを式（ii）で表される化合物に作用させる。塩化チオニル等の使用量は、式（ii）で表される化合物に対し、例えば１〜３当量とすることができる。また、反応温度は、例えば２０〜８０℃とすることができる。
次に、得られた生成物に対し、メタノールなどの反応溶媒中、トリエチルアミン等の塩基の存在下、Ｂｏｃ２Ｏを作用させる。Ｂｏｃ２Ｏの使用量は、式（ｉｉ）で表される化合物に対し、例えば２〜４当量とすることができる。また、反応温度は、例えば２０〜４０℃とすることができる。
The reaction can be appropriately set by those skilled in the art, and can be performed by a known method related to introduction of a carboxylic acid or amino group protecting group.
For example, assume that R 1 is a methyl group and R 2 is a Boc group.
In the reaction, first, thionyl chloride, oxalyl chloride and the like are allowed to act on the compound represented by formula (ii) in a reaction solvent such as methanol. The usage-amount of thionyl chloride etc. can be 1-3 equivalent with respect to the compound represented by Formula (ii). Moreover, reaction temperature can be 20-80 degreeC, for example.
Next, Boc 2 O is allowed to act on the obtained product in a reaction solvent such as methanol in the presence of a base such as triethylamine. The amount of the boc 2 O are relative to the compound represented by formula (ii), it can be, for example, 2 to 4 equivalents. Moreover, reaction temperature can be 20-40 degreeC, for example.
［工程３］
式（２）で表される化合物は、式（iii）で表される化合物を還元してジスルフィド結合を切断し、単量体とすることにより得ることができる。
[Step 3]
The compound represented by the formula (2) can be obtained by reducing the compound represented by the formula (iii) to cleave the disulfide bond to form a monomer.
式中、Ｒ１、Ｒ２は上記の定義に同じ。 In the formula, R 1 and R 2 are the same as defined above.
当該反応は、例えば、式（iii）で表される化合物を、酢酸およびジエチルエーテルの混合液中などにおいて亜鉛等を作用させることにより行うことができる。亜鉛等の使用量は、式（iii）で表される化合物に対し、例えば２０〜１００当量とすることができる。また、反応温度は、例えば２０〜４０℃とすることができる。 The reaction can be carried out, for example, by reacting the compound represented by formula (iii) with zinc or the like in a mixed solution of acetic acid and diethyl ether. The usage-amount of zinc etc. can be 20-100 equivalent with respect to the compound represented by Formula (iii), for example. Moreover, reaction temperature can be 20-40 degreeC, for example.
［工程４］
式（４）で表される化合物は、式（２）で表される化合物と式（３）で表される化合物とを反応させることにより得ることができる。
[Step 4]
The compound represented by formula (4) can be obtained by reacting the compound represented by formula (2) with the compound represented by formula (3).
式中、Ｒ３は上記の定義に同じ。 In the formula, R 3 is the same as defined above.
式中、Ｒ１、Ｒ２、Ｒ３は上記の定義に同じ。 In the formula, R 1 , R 2 and R 3 are the same as defined above.
当該反応は、例えば、N,N-ジメチルホルムアミド（ＤＭＦ）などの反応溶媒中、塩基の存在下、式（２）で表される化合物を式（３）で表される化合物に作用させることにより行うことができる。塩基は、例えばピリジン、トリエチルアミン、ジイソプロピルエチルアミン、テトラメチルエチレンジアミン、およびＮ−メチルイミダゾールなどの有機塩基を用いることができる。塩基の使用量は、例えば式（３）で表される化合物に対し２〜１０当量とすることができる。また、反応温度は、例えば２０〜５０℃とすることができる。 The reaction is performed by, for example, reacting the compound represented by the formula (2) with the compound represented by the formula (3) in the presence of a base in a reaction solvent such as N, N-dimethylformamide (DMF). It can be carried out. As the base, for example, organic bases such as pyridine, triethylamine, diisopropylethylamine, tetramethylethylenediamine, and N-methylimidazole can be used. The usage-amount of a base can be made into 2-10 equivalent with respect to the compound represented, for example by Formula (3). Moreover, reaction temperature can be 20-50 degreeC, for example.
なお、式（３）で表される化合物は、例えば以下の工程Ａ〜Ｄを行うことにより得ることができる。 In addition, the compound represented by Formula (3) can be obtained by performing the following processes AD, for example.
当該反応経路において、Ｘ、Ｒ３は上記の定義に同じ。 In the reaction route, X and R 3 are the same as defined above.
［工程Ａ］
式（ｂ）で表される化合物は、式（ａ）で表される化合物を変換することにより得ることができる。
[Step A]
The compound represented by the formula (b) can be obtained by converting the compound represented by the formula (a).
式中、Arは2,4−ジニトロフェニル基を示し、Ｒ３は上記の定義に同じ。 In the formula, Ar represents a 2,4-dinitrophenyl group, and R 3 has the same definition as above.
式中、Ｒ３は上記の定義に同じ。 In the formula, R 3 is the same as defined above.
当該反応においては、例えば、ＤＭＦなどの反応溶媒中、式（ａ）で表される化合物に対しエチレンジアミン等をまず反応させる。エチレンジアミン等の使用量は、式（ａ）で表される化合物に対し例えば１０〜３０当量とすることができる。また、反応温度は例えば２０〜８０℃とすることができる。
次に生成物に対し、反応溶媒中、酸性条件下で亜硝酸ナトリウムを作用させて式（ｂ）で表される化合物を得る。亜硝酸ナトリウムの使用量は、反応に供する生成物に対し、例えば３〜１０当量とすることができる。反応溶媒は例えばテトラヒドロフラン（ＴＨＦ）と水の混合液とすることができる。また、反応温度は例えば０〜２０℃とすることができる。
In this reaction, for example, ethylenediamine or the like is first reacted with the compound represented by the formula (a) in a reaction solvent such as DMF. The usage-amount of ethylenediamine etc. can be 10-30 equivalent with respect to the compound represented by Formula (a). Moreover, reaction temperature can be 20-80 degreeC, for example.
Next, the product is reacted with sodium nitrite under acidic conditions in a reaction solvent to obtain a compound represented by the formula (b). The usage-amount of sodium nitrite can be 3-10 equivalent with respect to the product with which it uses for reaction. The reaction solvent can be, for example, a mixed solution of tetrahydrofuran (THF) and water. Moreover, reaction temperature can be 0-20 degreeC, for example.
なお、式（a）で表される化合物についてはOrg. Biomol. Chem., 2014, 12, 3813-3815.に基づき得ることができる。 The compound represented by the formula (a) can be obtained based on Org. Biomol. Chem., 2014, 12, 3813-3815.
［工程Ｂ］
式（ｃ）で表される化合物は、式（ｂ）で表される化合物を変換することにより得ることができる。
[Step B]
The compound represented by the formula (c) can be obtained by converting the compound represented by the formula (b).
式中、Ｒ３は上記の定義に同じ。 In the formula, R 3 is the same as defined above.
当該反応は、例えば、メタノールなどの反応溶媒中、式（ｂ）で表される化合物に対しカンファースルホン酸を作用させることにより行うことができる。カンファースルホン酸等の使用量は、例えば０．２〜２当量とすることができる。また、反応温度は例えば０〜４０℃とすることができる。 This reaction can be performed, for example, by allowing camphorsulfonic acid to act on the compound represented by the formula (b) in a reaction solvent such as methanol. The usage-amount of camphor sulfonic acid etc. can be 0.2-2 equivalent, for example. Moreover, reaction temperature can be 0-40 degreeC, for example.
［工程Ｃ］
式（ｄ）で表される化合物は、式（ｃ）で表される化合物から変換することにより得ることができる。
[Step C]
The compound represented by the formula (d) can be obtained by converting from the compound represented by the formula (c).
式中、Ｒ３は上記の定義に同じ。 In the formula, R 3 is the same as defined above.
当該反応は、例えば、塩化メチレンなどの反応溶媒中、式（ｃ）で表される化合物に対しトリエチルアミンとメシルクロライドを作用させることにより行うことができる。トリエチルアミンとメシルクロライドの使用量は、それぞれ、例えば式（ｃ）で表される化合物に対し１〜５当量とすることができる。また、反応温度は例えば０〜４０℃とすることができる。 This reaction can be performed, for example, by allowing triethylamine and mesyl chloride to act on the compound represented by the formula (c) in a reaction solvent such as methylene chloride. The usage-amount of a triethylamine and mesyl chloride can be 1-5 equivalent respectively with respect to the compound represented, for example by Formula (c). Moreover, reaction temperature can be 0-40 degreeC, for example.
［工程Ｄ］
式（３）で表される化合物は、式（ｄ）で表される化合物から変換して脱離基を導入することにより得ることができる。
[Step D]
The compound represented by the formula (3) can be obtained by converting from the compound represented by the formula (d) and introducing a leaving group.
本明細書において、脱離基とは、ハロゲン原子、Ｃ１−６アルキルスルホニルオキシ基またはアリールスルホニルオキシ基などをいう。このうち、工程４がより効率的に進行するため、脱離基としてハロゲン原子が好ましく、より好ましくはヨウ素原子である。
脱離基の導入するための処理は特に限定されず、適宜設定でき、公知の方法に基づき行うようにしてもよい。
例えば脱離基がヨウ素原子である場合を想定する。
当該反応は、アセトンなどの反応溶媒中、式（ｄ）で表される化合物に対しヨウ化ナトリウム等を作用させることにより行うことができる。ヨウ化ナトリウム等の使用量は、例えば、式（ｄ）で表される化合物に対し１〜５当量とすることができる。また、反応温度は例えば２０〜５０℃とすることができる。
In this specification, the leaving group refers to a halogen atom, a C1-6 alkylsulfonyloxy group, an arylsulfonyloxy group, or the like. Among these, since the process 4 proceeds more efficiently, a halogen atom is preferable as a leaving group, and an iodine atom is more preferable.
The treatment for introducing the leaving group is not particularly limited, can be set as appropriate, and may be performed based on a known method.
For example, assume that the leaving group is an iodine atom.
This reaction can be performed by allowing sodium iodide or the like to act on the compound represented by the formula (d) in a reaction solvent such as acetone. The usage-amount of sodium iodide etc. can be 1-5 equivalent with respect to the compound represented by Formula (d), for example. Moreover, reaction temperature can be 20-50 degreeC, for example.
［工程５］
式（１）で表される化合物は、式（４）で表される化合物について保護基の除去を行うことにより得ることができる。
[Step 5]
The compound represented by the formula (1) can be obtained by removing the protecting group from the compound represented by the formula (4).
当該反応は、例えば、反応溶媒中、公知の脱保護試薬を式（４）で表される化合物に対し作用させることにより行うことができ、例えば各保護基の除去に係る公知の方法を組み合わせるなどして行うことができる。
例えば、Ｒ１がメチル基、Ｒ２がＢｏｃ基、Ｒ３がＴＢＳ基である場合を想定する。
このとき、まず、式（４）で表される化合物に対し、反応溶媒中、フッ化アンモニウム等を作用させることにより、Ｂｏｃ基を除去する。フッ化アンモニウム等の使用量は、式（４）で表される化合物に対し、例えば２〜２０当量とすることができる。反応溶媒は、例えばＴＨＦとメタノールの混合溶媒とすることができる。また、反応温度は、例えば２０〜６０℃とすることができる。
次に、Ｂｏｃ基を除去した化合物に対し、反応溶媒中、水酸化リチウム等を作用させることにより、メチルエステルの加水分解を行い、メチル基を除去する。水酸化リチウム等の使用量は、当該反応に供した化合物に対し、例えば２〜２０当量とすることができる。反応溶媒は、例えばＴＨＦとすることができる。また、反応温度は、例えば２０〜６０℃とすることができる。
続いて、メチル基を除去した化合物に対し、反応溶媒中、トリフルオロ酢酸等を作用させることにより、ＴＢＳ基を除去する。トリフルオロ酢酸等の使用量は、当該反応に供した化合物に対し、例えば５０〜２００当量とすることができる。反応溶媒は、例えばメタノールとすることができる。また、反応温度は、例えば２０〜７０℃とすることができる。
The reaction can be performed, for example, by allowing a known deprotecting reagent to act on the compound represented by formula (4) in a reaction solvent, for example, combining known methods relating to the removal of each protecting group, etc. Can be done.
For example, assume that R 1 is a methyl group, R 2 is a Boc group, and R 3 is a TBS group.
At this time, first, the Boc group is removed by allowing ammonium fluoride or the like to act on the compound represented by the formula (4) in a reaction solvent. The usage-amount of ammonium fluoride etc. can be 2-20 equivalent with respect to the compound represented by Formula (4), for example. The reaction solvent can be, for example, a mixed solvent of THF and methanol. Moreover, reaction temperature can be 20-60 degreeC, for example.
Next, by reacting the compound from which the Boc group has been removed with lithium hydroxide or the like in a reaction solvent, the methyl ester is hydrolyzed to remove the methyl group. The usage-amount of lithium hydroxide etc. can be 2-20 equivalent with respect to the compound with which the said reaction was used. The reaction solvent can be, for example, THF. Moreover, reaction temperature can be 20-60 degreeC, for example.
Subsequently, the TBS group is removed by allowing trifluoroacetic acid or the like to act on the compound from which the methyl group has been removed in a reaction solvent. The usage-amount of trifluoroacetic acid etc. can be 50-200 equivalent with respect to the compound with which the said reaction was used. The reaction solvent can be methanol, for example. Moreover, reaction temperature can be 20-70 degreeC, for example.
以上、本実施形態によれば、Ｓ−ＩＣＡリボシルホモシステインの製造方法に係る新規な技術を提供することができる。本方法では、両鏡像体が入手容易なメチオニンを出発原料としている。すなわち、L−メチオニンやD−メチオニンなどの光学活性メチオニンを出発原料として用いＳ−ＩＣＡリボシルホモシステインについてＬ体とＤ体の両異性体をそれぞれ合成することができるため、非天然型のホモシステイン誘導体の合成も可能である。 As mentioned above, according to this embodiment, the novel technique which concerns on the manufacturing method of S-ICA ribosyl homocysteine can be provided. In this method, methionine, which is easily available for both enantiomers, is used as a starting material. That is, since both L-form and D-form isomers of S-ICA ribosylhomocysteine can be synthesized using optically active methionine such as L-methionine and D-methionine as starting materials, unnatural homocysteine Derivative synthesis is also possible.
以下、実施例に基づき本発明をより詳細に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example, this invention is not limited to these.
［実施例１］
dimethyl 4,4'-disulfanediyl(2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)butanoate)
[Example 1]
dimethyl 4,4'-disulfanediyl (2S, 2'S) -bis (2-((tert-butoxycarbonyl) amino) butanoate)
-78℃に冷やしたナスフラスコに約100 mLの液体アンモニアを貯め、(L)-メチオニン4.0 g, 26.8 mmolと薄く切った金属リチウム555 mg, 80.0 mmolを順次加えた後、1.5時間撹拌した。反応液に塩化アンモニウムを加え反応を停止させた後、室温まで昇温しアンモニアを揮発させた。得られた残渣を水40 mLに溶かし、pH 4-5になるまで1Mの塩酸を加えた。この水溶液を氷冷下撹拌しているところに30%過酸化水素水20 mLを加え、析出物をろ取し、減圧下乾燥させることで (2S,2'S)-ホモシスチン (1.56 g, 収率43%)を白色固体として得た。
(2S,2'S)-ホモシスチン (500 mg, 1.86 mmol)をメタノール(MeOH)18 mLに懸濁させ、塩化チオニル2.0 mL, 27.6 mmolを加え、70℃で24時間撹拌した。その後、反応液を減圧下濃縮し、688 mgの粗生成物を得た。
粗生成物200 mgをMeOH 6.8 mLに溶かし、トリエチルアミン376μL, 2.71 mmolとBoc2O 440 mg, 2.02 mmolを氷冷下加え、室温で24時間撹拌した。反応液を減圧下濃縮後、残渣に0.1 Mの塩酸と酢酸エチルを加え溶解させた。分離した有機層を炭酸ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムを加え乾燥させ、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒ヘキサン：酢酸エチル=4：1→3：2）にて精製することで、dimethyl 4,4'-disulfanediyl(2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)butanoate) (237 mg, 収率88%, 2段階) を白色固体として得た。
1H NMR (500 MHz, CDCl3, δ): 5.12 (br d, J = 7.0 Hz, 2H), 4.36 (br s, 2H), 3.72 (s, 6H), 2.68 (t, J = 7.0 Hz, 4H), 2.18-2.22 (m, 2H), 1.94-1.99 (m, 2H), 1.40 (s, 18H).
About 100 mL of liquid ammonia was stored in an eggplant flask cooled to −78 ° C., (L) -methionine (4.0 g, 26.8 mmol) and metal lithium (555 mg, 80.0 mmol) were sequentially added, followed by stirring for 1.5 hours. Ammonium chloride was added to the reaction solution to stop the reaction, and then the temperature was raised to room temperature to volatilize ammonia. The obtained residue was dissolved in 40 mL of water, and 1M hydrochloric acid was added until pH 4-5. To this stirred aqueous solution under ice-cooling, 20 mL of 30% aqueous hydrogen peroxide was added, and the precipitate was collected by filtration and dried under reduced pressure to obtain (2S, 2'S) -homomocystine (1.56 g, yield 43 %) Was obtained as a white solid.
(2S, 2 ′S) -Homocystine (500 mg, 1.86 mmol) was suspended in 18 mL of methanol (MeOH), 2.0 mL of thionyl chloride, 27.6 mmol was added, and the mixture was stirred at 70 ° C. for 24 hours. Thereafter, the reaction solution was concentrated under reduced pressure to obtain 688 mg of a crude product.
200 mg of the crude product was dissolved in 6.8 mL of MeOH, and 376 μL, 2.71 mmol of triethylamine and 440 mg, 2.02 mmol of Boc 2 O were added with ice cooling, followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and 0.1 M hydrochloric acid and ethyl acetate were added to the residue and dissolved. The separated organic layer was washed with aqueous sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane: ethyl acetate = 4: 1 → 3: 2), so that dimethyl 4,4'-disulfanediyl (2S, 2'S) -bis (2-((tert- butoxycarbonyl) amino) butanoate) (237 mg, 88% yield, 2 steps) was obtained as a white solid.
1 H NMR (500 MHz, CDCl 3 , δ): 5.12 (br d, J = 7.0 Hz, 2H), 4.36 (br s, 2H), 3.72 (s, 6H), 2.68 (t, J = 7.0 Hz, 4H), 2.18-2.22 (m, 2H), 1.94-1.99 (m, 2H), 1.40 (s, 18H).
［実施例2］
1-((2R,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide
[Example 2]
1-((2R, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydrofuran-2-yl) -1H-imidazole -4-carboxamide
5-amino-1-((2R,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-N-(2,4-dinitrophenyl)-1H-imidazole-4-carboxamide 30.4 g, 39.6 mmolをDMF 396 mLに溶かし、氷冷下エチレンジアミン66.2 mL, 991 mmolを加え、60度で8.5時間撹拌した。室温に冷却後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を1M塩酸と飽和食塩水で洗浄後、無水硫酸マグネシウムを加え乾燥した。ろ過後、ろ液を減圧濃縮し26.1 gの粗生成物を得た。
得られた粗生成物5.0 gをTHF 90 mLに溶解させ氷冷し、4.0 gの亜硝酸ナトリウムを溶かした水50 mLと酢酸90 mLを加えた後、8時間氷冷下で撹拌した。 その後、反応液に炭酸ナトリウム水溶液を加え酢酸エチルで抽出し、有機層を炭酸ナトリウム水溶液と飽和食塩水で洗浄した。有機層に無水硫酸マグネシウムを加え乾燥し、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒ヘキサン：酢酸エチル = 3：1 → 2：1）にて精製することで、1-((2R,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide (2.17g, 収率45%)をオレンジ色のアモルファスとして得た。
1H NMR (500 MHz, CDCl3, δ): 7.79 (d, J = 1.1 Hz, 1H), 7.64 (d, J =1.1 Hz, 1H), 6.92 (br s, 1H), 5.56 (d, J = 6.8 Hz, 1H), 5.30 (br s, 1H), 4.15-4.19 (m, 2H), 4.08 (br s, 1H), 3.82 (dd, J = 11, 3.4 Hz, 1H), 3.76 (dd, J = 11, 2.3 Hz, 1H), 0.95 (s, 9H), 0.93 (s, 9H), 0.82 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H), 0.10 (s, 6H), -0.06 (s, 3H), -0.30 (s, 3H).
5-amino-1-((2R, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydrofuran-2-yl) -N- (2,4-dinitrophenyl) -1H-imidazole-4-carboxamide 30.4 g, 39.6 mmol was dissolved in 396 mL of DMF, 66.2 mL, 991 mmol of ethylenediamine was added under ice cooling, and the mixture was stirred at 60 ° C for 8.5 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 26.1 g of a crude product.
5.0 g of the resulting crude product was dissolved in 90 mL of THF and ice-cooled. After adding 50 mL of water in which 4.0 g of sodium nitrite was dissolved and 90 mL of acetic acid, the mixture was stirred for 8 hours under ice-cooling. Thereafter, an aqueous sodium carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with an aqueous sodium carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue is purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 3: 1 → 2: 1) to give 1-((2R, 3R, 4R, 5R) -3,4-bis ((tert -butyldimethylsilyl) oxy) -5-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide (2.17 g, 45% yield) was obtained as an orange amorphous. .
1 H NMR (500 MHz, CDCl 3 , δ): 7.79 (d, J = 1.1 Hz, 1H), 7.64 (d, J = 1.1 Hz, 1H), 6.92 (br s, 1H), 5.56 (d, J = 6.8 Hz, 1H), 5.30 (br s, 1H), 4.15-4.19 (m, 2H), 4.08 (br s, 1H), 3.82 (dd, J = 11, 3.4 Hz, 1H), 3.76 (dd, J = 11, 2.3 Hz, 1H), 0.95 (s, 9H), 0.93 (s, 9H), 0.82 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H), 0.10 (s, 6H ), -0.06 (s, 3H), -0.30 (s, 3H).
［実施例３］
1-((2R,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide
[Example 3]
1-((2R, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide
1-((2R,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide 100 mg, 171 μmolをMeOH 1.0 mLに溶かし、カンファースルホン酸49.5 mg, 213 μmolを加え、室温下6.5時間撹拌した。その後、反応混合物にトリエチルアミンを加え酸を中和し、減圧下濃縮した。残渣に酢酸エチルと水を加え溶解させた後、有機層を分離し、飽和塩化アンモニウム水溶液と飽和食塩水にて洗浄後、無水硫酸マグネシウムを加え乾燥させた。ろ過後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒クロロホルム：メタノール = 30：1）にて精製することで、1-((2R,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide (64.4 mg, 収率80%)を白色固体として得た。
1H NMR (500 MHz, CD3OD, δ): 7.84 (s, 1H), 7.83 (s, 1H), 5.53 (d, J = 7.2 Hz, 1H), 4.27 (dd, J = 12, 5.2 Hz, 1H), 4.12-4.13 (m, 1H), 3.92-3.93 (m, 1H), 3.63 (dd, J = 12, 3.6 Hz, 1H), 3.58 (dd, J = 12, 2.8 Hz, 1H), 0.82 (s, 9H), 0.68 (s, 9H), 0.01 (s, 6H), -0.16 (s, 3H), -0.42 (s, 3H).
1-((2R, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydrofuran-2-yl) -1H-imidazole -4-carboxamide 100 mg, 171 μmol was dissolved in MeOH 1.0 mL, camphorsulfonic acid 49.5 mg, 213 μmol was added, and the mixture was stirred at room temperature for 6.5 hours. Thereafter, triethylamine was added to the reaction mixture to neutralize the acid, and the mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue for dissolution, the organic layer was separated, washed with a saturated aqueous ammonium chloride solution and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent chloroform: methanol = 30: 1) to give 1-((2R, 3R, 4R, 5R) -3,4 -bis ((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide (64.4 mg, yield 80%) was obtained as a white solid.
1 H NMR (500 MHz, CD 3 OD, δ): 7.84 (s, 1H), 7.83 (s, 1H), 5.53 (d, J = 7.2 Hz, 1H), 4.27 (dd, J = 12, 5.2 Hz , 1H), 4.12-4.13 (m, 1H), 3.92-3.93 (m, 1H), 3.63 (dd, J = 12, 3.6 Hz, 1H), 3.58 (dd, J = 12, 2.8 Hz, 1H), 0.82 (s, 9H), 0.68 (s, 9H), 0.01 (s, 6H), -0.16 (s, 3H), -0.42 (s, 3H).
［実施例４］
1-((2R,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(methanesulfonyloxymethyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide
[Example 4]
1-((2R, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (methanesulfonyloxymethyl) tetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide
1-((2R,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide (100 mg, 210 μmol) を塩化メチレン350 μLに溶かし、氷冷下トリエチルアミン64 μL, 460 μmolとメシルクロライド18 μL, 230 μmolを順次加え、氷冷下22時間撹拌した。その後、反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムを加え乾燥し、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒クロロホルム：メタノール = 10：1）にて精製することで、1-((2R,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(methanesulfonyloxymethyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide (97 mg, 収率83%)を白色固体として得た。
1H NMR (500 MHz, CDCl3, δ): 7.81 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 6.98 (br s, 1H), 5.85 (br s, 1H), 5.57 (d, J = 5.0 Hz, 1H), 4.43 (dd, J = 12, 3.5 Hz, 1H), 4.38 (dd, J = 12, 3.5 Hz, 1H), 4.23 (q, J = 3.5 Hz, 1H), 4.19 (t, J = 3.5 Hz, 1H), 4.15 (t, J = 5.0 Hz, 1H), 3.07 (s, 3H), 0.90 (s, 9H), 0.80 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), -0.03 (s, 3H), -0.21 (s, 3H).
1-((2R, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide (100 mg, 210 μmol) was dissolved in 350 μL of methylene chloride, and 64 μL and 460 μmol of triethylamine and 18 μL and 230 μmol of mesyl chloride were sequentially added under ice cooling, followed by stirring for 22 hours under ice cooling. Thereafter, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent chloroform: methanol = 10: 1) to give 1-((2R, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (methanesulfonyloxymethyl) tetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide (97 mg, 83% yield) was obtained as a white solid.
1 H NMR (500 MHz, CDCl 3 , δ): 7.81 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 6.98 (br s, 1H), 5.85 (br s, 1H), 5.57 (d, J = 5.0 Hz, 1H), 4.43 (dd, J = 12, 3.5 Hz, 1H), 4.38 (dd, J = 12, 3.5 Hz, 1H), 4.23 (q, J = 3.5 Hz, 1H), 4.19 (t, J = 3.5 Hz, 1H), 4.15 (t, J = 5.0 Hz, 1H), 3.07 (s, 3H), 0.90 (s, 9H), 0.80 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), -0.03 (s, 3H), -0.21 (s, 3H).
［実施例５］
1-((2R,3R,4R,5S)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(iodomethyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide
[Example 5]
1-((2R, 3R, 4R, 5S) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (iodomethyl) tetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide
1-((2R,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(methanesulfonyloxymethyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide (135 mg, 250 μmol) をアセトン1.4 mLに溶かし、ヨウ化ナトリウム147 mg, 980 μmolを加え、50度で21時間撹拌した。その後、反応混合物を減圧濃縮し、残渣に炭酸水素ナトリウム水溶液と酢酸エチルを加え溶解させた後、有機層と水層を分離した。水層は酢酸エチルで再度抽出し、合わせた有機層を炭酸水素ナトリウム水溶液と飽和食塩水で洗浄後、無水硫酸マグネシウムを加え乾燥し、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒クロロホルム：メタノール = 10：1）にて精製することで、1-((2R,3R,4R,5S)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(iodomethyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide (124 mg, 収率87%)を黄色油状物質として得た。
1H NMR (500 MHz, CDCl3, δ): 7.77 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 6.95 (br s, 1H), 5.64 (br s, 1H), 5.57 (d, J = 6.0 Hz, 1H), 4.15-4.18 (m, 1H), 4.04-4.07 (m, 2H), 3.36 (dd, J = 11, 6.0 Hz, 1H), 3.32 (dd, 11, 4.5 Hz, 1H), 0.91 (s, 9H), 0.81 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H), -0.05 (s, 3H), -0.22 (s, 3H).
1-((2R, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (methanesulfonyloxymethyl) tetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide (135 mg, 250 μmol) was dissolved in 1.4 mL of acetone, 147 mg of sodium iodide and 980 μmol were added, and the mixture was stirred at 50 degrees for 21 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution and ethyl acetate were dissolved in the residue, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent chloroform: methanol = 10: 1) to give 1-((2R, 3R, 4R, 5S) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (iodomethyl) tetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide (124 mg, yield 87%) was obtained as a yellow oily substance.
1 H NMR (500 MHz, CDCl 3 , δ): 7.77 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 6.95 (br s, 1H), 5.64 (br s, 1H), 5.57 (d, J = 6.0 Hz, 1H), 4.15-4.18 (m, 1H), 4.04-4.07 (m, 2H), 3.36 (dd, J = 11, 6.0 Hz, 1H), 3.32 (dd , 11, 4.5 Hz, 1H), 0.91 (s, 9H), 0.81 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H), -0.05 (s, 3H), -0.22 (s, 3H).
［実施例６］
methyl(tert-butoxycarbonyl)-L-homocysteinate
[Example 6]
methyl (tert-butoxycarbonyl) -L-homocysteinate
Dimethyl 4,4'-disulfanediyl(2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)butanoate) (237 mg, 477 μmol)を酢酸14.6 mLとジエチルエーテル0.8 mLに溶かして氷冷し、亜鉛粉末 1.87 g, 28.6 mmolを加えた後、室温下24時間撹拌した。反応混合物をセライトろ過して固形物を除いた後、減圧下濃縮した。残渣に0.1 M塩酸と酢酸エチルを加え溶解させた後、有機層と水層を分離した。水層は酢酸エチルで再度抽出し、合わせた有機層を0.1 M塩酸、炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムを加え乾燥し、ろ過後、ろ液を減圧濃縮した。得られたmethyl (tert-butoxycarbonyl)-L-homocysteinateを含む残渣236 mgはそのまま次の反応に用いた。 Dimethyl 4,4'-disulfanediyl (2S, 2'S) -bis (2-((tert-butoxycarbonyl) amino) butanoate) (237 mg, 477 μmol) was dissolved in 14.6 mL acetic acid and 0.8 mL diethyl ether and ice-cooled. After adding zinc powder 1.87 g, 28.6 mmol, the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through celite to remove solids, and then concentrated under reduced pressure. After 0.1 M hydrochloric acid and ethyl acetate were added to the residue and dissolved, the organic layer and the aqueous layer were separated. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was washed with 0.1 M hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue (236 mg) containing methyl (tert-butoxycarbonyl) -L-homocysteinate was directly used in the next reaction.
［実施例７］
methyl S-(((2S,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(4-carbamoyl-1H-imidazol-1-yl)tetrahydrofuran-2-yl)methyl)-N-(tert-butoxycarbonyl)-L-homocysteinate
[Example 7]
methyl S-(((2S, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (4-carbamoyl-1H-imidazol-1-yl) tetrahydrofuran-2-yl) methyl) -N- (tert-butoxycarbonyl) -L-homocysteinate
1-((2R,3R,4R,5S)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(iodomethyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide (130 mg, 224 μmol) をDMF 800 μLに溶かし、トリエチルアミン200 μL, 1.44 mmolとmethyl (tert-butoxycarbonyl)-L-homocysteinate 110 mg, ca 441 μmolを氷冷下加え、室温下24時間撹拌した。その後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムを加え乾燥し、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒ヘキサン：酢酸エチル=3：2→0：1)にて精製することで、methyl S-(((2S,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(4-carbamoyl-1H-imidazol-1-yl)tetrahydrofuran-2-yl)methyl)-N-(tert-butoxycarbonyl)-L-homocysteinate (116 mg, 74%)を白色アモルファスとして得た。
1H NMR (500 MHz, CDCl3, δ): 7.71 (s, 1H), 7.57 (s, 1H), 6.99 (br s, 1H), 6.05 (br s, 1H), 5.51 (d, J = 6.0 Hz, 1H), 5.47 (br s, 1H), 4.35 (br s, 1H), 4.14 (m, 1H), 4.09 (m, 1H), 4.01 (m, 1H), 3.68 (s, 3H), 2.70-2.79 (m, 2H), 2.57-2.63 (m, 2H), 1.85-1.91 (m, 1H), 1.34 (s, 9H), 0.87 (s, 9H), 0.77 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), -0.09 (s, 3H), -0.27 (s, 3H).
1-((2R, 3R, 4R, 5S) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (iodomethyl) tetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide (130 mg, 224 μmol) was dissolved in DMF 800 μL, triethylamine 200 μL, 1.44 mmol and methyl (tert-butoxycarbonyl) -L-homocysteinate 110 mg, ca 441 μmol were added under ice cooling, and the mixture was stirred at room temperature for 24 hours. Thereafter, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 3: 2 → 0: 1) to obtain methyl S-(((2S, 3R, 4R, 5R) -3,4-bis ( (tert-butyldimethylsilyl) oxy) -5- (4-carbamoyl-1H-imidazol-1-yl) tetrahydrofuran-2-yl) methyl) -N- (tert-butoxycarbonyl) -L-homocysteinate (116 mg, 74%) Was obtained as a white amorphous.
1 H NMR (500 MHz, CDCl 3 , δ): 7.71 (s, 1H), 7.57 (s, 1H), 6.99 (br s, 1H), 6.05 (br s, 1H), 5.51 (d, J = 6.0 Hz, 1H), 5.47 (br s, 1H), 4.35 (br s, 1H), 4.14 (m, 1H), 4.09 (m, 1H), 4.01 (m, 1H), 3.68 (s, 3H), 2.70 -2.79 (m, 2H), 2.57-2.63 (m, 2H), 1.85-1.91 (m, 1H), 1.34 (s, 9H), 0.87 (s, 9H), 0.77 (s, 9H), 0.06 (s , 3H), 0.05 (s, 3H), -0.09 (s, 3H), -0.27 (s, 3H).
［実施例８］
S-(((2S,3S,4R,5R)-5-(4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-L-homocysteine
[Example 8]
S-(((2S, 3S, 4R, 5R) -5- (4-carbamoyl-1H-imidazol-1-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methyl) -L-homocysteine
Methyl S-(((2S,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(4-carbamoyl-1H-imidazol-1-yl)tetrahydrofuran-2-yl)methyl)-N-(tert-butoxycarbonyl)-L-homocysteinate (27 mg, 38.4 μmol) をTHFとMeOHの1:2混合溶媒0.3 mLに溶かし、フッ化アンモニウム14 mg, 384 μmolを加えて60℃で48時間撹拌した。その後、反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒クロロホルム：メタノール = 19：1→4：1)にて精製することで、methyl N-(tert-butoxycarbonyl)-S-(((2S,3S,4R,5R)-5-(4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-L-homocysteinate (8 mg, 43%)を得た。
Methyl N-(tert-butoxycarbonyl)-S-(((2S,3S,4R,5R)-5-(4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-L-homocysteinate (8 mg, 16.9 μmol) をTHF 450 μLに溶かし、水50 μLに溶解させた水酸化ナトリウム5.3 mg, 34.0 μmolを加え、室温下1時間撹拌した。反応液に酢酸を加え溶液を酸性にした後、減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒クロロホルム：メタノール = 2：1) にて精製することで、N-(tert-butoxycarbonyl)-S-(((2S,3S,4R,5R)-5-(4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-L-homocysteine (4 mg, 52%) を得た。
N-(tert-butoxycarbonyl)-S-(((2S,3S,4R,5R)-5-(4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-L-homocysteine (4 mg)を水100 μLに溶かし、トリフルオロ酢酸100 μLを加え、室温下54時間撹拌した。その後、反応液を減圧下濃縮することでS-(((2S,3S,4R,5R)-5-(4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-L-homocysteine (6 mg)を白色固体として得た。
1H NMR (500 MHz, D２O, δ): 8.33 (br s, 1H), 7.99 (br s, 1H), 5.79 (d, J = 4.5 Hz, 1H), 4.42 (t, J = 5.0 Hz, 1H), 4.20-4.26 (m, 2H), 3.87 (t, J = 6.0 Hz, 1H), 2.94 (dd, J = 15, 5.0 Hz, 1H), 2.85 (dd, J = 15, 7.0 Hz, 1H), 2.66 (t, J = 7.5 Hz, 2H), 2.03-2.15 (m, 2H).
Methyl S-(((2S, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (4-carbamoyl-1H-imidazol-1-yl) tetrahydrofuran-2-yl) Methyl) -N- (tert-butoxycarbonyl) -L-homocysteinate (27 mg, 38.4 μmol) is dissolved in 0.3 mL of a 1: 2 mixture of THF and MeOH, and 14 mg of ammonium fluoride, 384 μmol is added at 60 ° C. Stir for 48 hours. Thereafter, the reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (developing solvent chloroform: methanol = 19: 1 → 4: 1) to obtain methyl N- (tert-butoxycarbonyl) -S- ( ((2S, 3S, 4R, 5R) -5- (4-carbamoyl-1H-imidazol-1-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methyl) -L-homocysteinate (8 mg, 43%) Got.
Methyl N- (tert-butoxycarbonyl) -S-(((2S, 3S, 4R, 5R) -5- (4-carbamoyl-1H-imidazol-1-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methyl ) -L-homocysteinate (8 mg, 16.9 μmol) was dissolved in 450 μL of THF, 5.3 mg, 34.0 μmol of sodium hydroxide dissolved in 50 μL of water was added, and the mixture was stirred at room temperature for 1 hour. Acetic acid was added to the reaction solution to acidify the solution, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: chloroform: methanol = 2: 1) to give N- (tert-butoxycarbonyl)- S-(((2S, 3S, 4R, 5R) -5- (4-carbamoyl-1H-imidazol-1-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methyl) -L-homocysteine (4 mg, 52%).
N- (tert-butoxycarbonyl) -S-(((2S, 3S, 4R, 5R) -5- (4-carbamoyl-1H-imidazol-1-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methyl) -L-homocysteine (4 mg) was dissolved in 100 μL of water, 100 μL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 54 hours. Thereafter, the reaction solution was concentrated under reduced pressure to obtain S-((((2S, 3S, 4R, 5R) -5- (4-carbamoyl-1H-imidazol-1-yl) -3,4-dihydroxytetrahydrofuran-2-yl ) methyl) -L-homocysteine (6 mg) was obtained as a white solid.
1 H NMR (500 MHz, D 2 O, δ): 8.33 (br s, 1H), 7.99 (br s, 1H), 5.79 (d, J = 4.5 Hz, 1H), 4.42 (t, J = 5.0 Hz , 1H), 4.20-4.26 (m, 2H), 3.87 (t, J = 6.0 Hz, 1H), 2.94 (dd, J = 15, 5.0 Hz, 1H), 2.85 (dd, J = 15, 7.0 Hz, 1H), 2.66 (t, J = 7.5 Hz, 2H), 2.03-2.15 (m, 2H).
［実施例９］
methyl (tert-butoxycarbonyl)-D-homocysteinate
[Example 9]
methyl (tert-butoxycarbonyl) -D-homocysteinate
Dimethyl 4,4'-disulfanediyl(2R,2'R)-bis(2-((tert-butoxycarbonyl)amino)butanoate) (228 mg, 459 μmol) を酢酸15 mLとジエチルエーテル0.3 mLに溶かして氷冷し、亜鉛粉末 1.80 g, 27.5 mmolを加えた後、室温下10時間撹拌した。反応混合物をセライトろ過して固形物を除いた後、減圧下濃縮した。残渣に0.1 M塩酸と酢酸エチルを加え溶解させた後、有機層と水層を分離した。水層は酢酸エチルで再度抽出し、合わせた有機層を0.1 M塩酸、炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムを加え乾燥し、ろ過後、ろ液を減圧濃縮した。得られたmethyl (tert-butoxycarbonyl)-D-homocysteinateを含む残渣213 mgはそのまま次の反応に用いた。 Dimethyl 4,4'-disulfanediyl (2R, 2'R) -bis (2-((tert-butoxycarbonyl) amino) butanoate) (228 mg, 459 μmol) was dissolved in 15 mL acetic acid and 0.3 mL diethyl ether and ice-cooled. After adding zinc powder 1.80 g, 27.5 mmol, the mixture was stirred at room temperature for 10 hours. The reaction mixture was filtered through Celite to remove solids, and then concentrated under reduced pressure. After 0.1 M hydrochloric acid and ethyl acetate were added to the residue and dissolved, the organic layer and the aqueous layer were separated. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was washed with 0.1 M hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue (213 mg) containing methyl (tert-butoxycarbonyl) -D-homocysteinate was directly used in the next reaction.
［実施例１０］
methyl S-(((2S,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(4-carbamoyl-1H-imidazol-1-yl)tetrahydrofuran-2-yl)methyl)-N-(tert-butoxycarbonyl)-D-homocysteinate
[Example 10]
methyl S-(((2S, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (4-carbamoyl-1H-imidazol-1-yl) tetrahydrofuran-2-yl) methyl) -N- (tert-butoxycarbonyl) -D-homocysteinate
1-((2R,3R,4R,5S)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(iodomethyl)tetrahydrofuran-2-yl)-1H-imidazole-4-carboxamide (200 mg, 344 μmol) をDMF 680 μLに溶かし、トリエチルアミン142 μL, 1.02 mmolとmethyl (tert-butoxycarbonyl)-D-homocysteinate 158 mg, ca 634 μmolを氷冷下加え、室温下24時間撹拌した。その後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムを加え乾燥し、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒ヘキサン：酢酸エチル=3：2→0：1)にて精製することで、methyl S-(((2S,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(4-carbamoyl-1H-imidazol-1-yl)tetrahydrofuran-2-yl)methyl)-N-(tert-butoxycarbonyl)-D-homocysteinate (190 mg, 79%)を白色アモルファスとして得た。
1H NMR (500 MHz, CDCl3, δ): 7.71 (s, 1H), 7.58 (s, 1H), 6.97 (br s, 1H), 5.75 (br s, 1H), 5.53 (d, J = 5.5 Hz, 1H), 5.21 (br s, 1H), 4.36 (br s, 1H), 4.15 (dt, J = 6.0, 2.5 Hz, 1H), 4.00-4.08 (m, 2H), 3.70 (s, 3H), 2.75 (d, J = 6.0 Hz, 2H), 2.58-2.61 (m, 3H), 1.86-1.92 (m, 1H), 1.39 (s, 9H), 0.89 (s, 9H), 0.79 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H), -0.07 (s, 3H), -0.25 (s, 3H).
1-((2R, 3R, 4R, 5S) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (iodomethyl) tetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide (200 mg, 344 μmol) was dissolved in 680 μL of DMF, and 142 μL, 1.02 mmol of triethylamine, 158 mg of methyl (tert-butoxycarbonyl) -D-homocysteinate, and 634 μmol of ca were added under ice cooling, followed by stirring at room temperature for 24 hours. Thereafter, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 3: 2 → 0: 1) to obtain methyl S-(((2S, 3R, 4R, 5R) -3,4-bis ( (tert-butyldimethylsilyl) oxy) -5- (4-carbamoyl-1H-imidazol-1-yl) tetrahydrofuran-2-yl) methyl) -N- (tert-butoxycarbonyl) -D-homocysteinate (190 mg, 79%) Was obtained as a white amorphous.
1 H NMR (500 MHz, CDCl 3 , δ): 7.71 (s, 1H), 7.58 (s, 1H), 6.97 (br s, 1H), 5.75 (br s, 1H), 5.53 (d, J = 5.5 Hz, 1H), 5.21 (br s, 1H), 4.36 (br s, 1H), 4.15 (dt, J = 6.0, 2.5 Hz, 1H), 4.00-4.08 (m, 2H), 3.70 (s, 3H) , 2.75 (d, J = 6.0 Hz, 2H), 2.58-2.61 (m, 3H), 1.86-1.92 (m, 1H), 1.39 (s, 9H), 0.89 (s, 9H), 0.79 (s, 9H ), 0.09 (s, 3H), 0.07 (s, 3H), -0.07 (s, 3H), -0.25 (s, 3H).
［実施例１１］
methyl S-(((2S,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(4-carbamoyl-1H-imidazol-1-yl)tetrahydrofuran-2-yl)methyl)-N-(tert-butoxycarbonyl)-D-homocysteinate
[Example 11]
methyl S-(((2S, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (4-carbamoyl-1H-imidazol-1-yl) tetrahydrofuran-2-yl) methyl) -N- (tert-butoxycarbonyl) -D-homocysteinate
Methyl S-(((2S,3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(4-carbamoyl-1H-imidazol-1-yl)tetrahydrofuran-2-yl)methyl)-N-(tert-butoxycarbonyl)-D-homocysteinate (190 mg, 270 μmol)をTHFとMeOHの1:1混合溶媒2.6 mLに溶かし、フッ化アンモニウム100 mg, 2.70 mmolを加えて60 ℃で48時間撹拌した。その後、反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒クロロホルム：メタノール=19：1→4：1)にて精製することで、methyl N-(tert-butoxycarbonyl)-S-(((2S,3S,4R,5R)-5-(4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-D-homocysteinate (128 mg, quant)を白色アモルファスとして得た。
Methyl N-(tert-butoxycarbonyl)-S-(((2S,3S,4R,5R)-5-(4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-D-homocysteinate (105 mg, 221 μmol)をTHF 2 mLに溶かし、水200 μLに溶解させた水酸化リチウム26 mg, 1.09 mmolを加え、室温下20分間撹拌した。反応液に水を加え希釈した後、減圧濃縮によりTHFを除き、得られた水溶液をジエチルエーテルで洗浄した。その後、1Mの塩酸を加え溶液を酸性にし、酢酸エチルとTHFで抽出した。有機層に無水硫酸マグネシウムを加え乾燥し、ろ過後、ろ液を減圧濃縮することでN-(tert-butoxycarbonyl)-S-(((2S,3S,4R,5R)-5-(4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-D-homocysteine (88 mg, 86%)を白色固体として得た。
N-(tert-butoxycarbonyl)-S-(((2S,3S,4R,5R)-5-(4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-D-homocysteine (29 mg, 630 μmol) をMeOH 100 μLに溶かし、トリフルオロ酢酸300 μLを加え、室温下20時間撹拌した。その後、反応液を減圧下濃縮することでS-(((2S,3S,4R,5R)-5-(4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-D-homocysteine (30 mg)を白色固体として得た。
1H NMR (500 MHz, D２O, δ): 8.97 (br s, 1H), 8.14 (br s, 1H), 5.85 (d, J = 4.5 Hz, 1H), 4.40 (t, J = 5.0 Hz, 1H), 4.28 (dt, J = 6.5, 5.0 Hz, 1H), 4.17 (t, J = 5.0 Hz, 1H), 4.08 (t, J = 6.5 Hz, 1H), 2.94 (dd, J = 14, 5.0 Hz, 1H), 2.84 (dd, J = 14, 7.0 Hz, 1H), 2.69 (t, J = 7.5 Hz, 2H), 2.06-2.21 (m, 2H).
Methyl S-(((2S, 3R, 4R, 5R) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5- (4-carbamoyl-1H-imidazol-1-yl) tetrahydrofuran-2-yl) Methyl) -N- (tert-butoxycarbonyl) -D-homocysteinate (190 mg, 270 μmol) is dissolved in 2.6 mL of 1: 1 mixed solvent of THF and MeOH, and 100 mg, 2.70 mmol of ammonium fluoride is added at 60 ° C. Stir for 48 hours. Thereafter, the reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (developing solvent chloroform: methanol = 19: 1 → 4: 1) to obtain methyl N- (tert-butoxycarbonyl) -S- ( ((2S, 3S, 4R, 5R) -5- (4-carbamoyl-1H-imidazol-1-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methyl) -D-homocysteinate (128 mg, quant) Obtained as a white amorphous.
Methyl N- (tert-butoxycarbonyl) -S-(((2S, 3S, 4R, 5R) -5- (4-carbamoyl-1H-imidazol-1-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methyl ) -D-homocysteinate (105 mg, 221 μmol) was dissolved in 2 mL of THF, 26 mg, 1.09 mmol of lithium hydroxide dissolved in 200 μL of water was added, and the mixture was stirred at room temperature for 20 minutes. After diluting the reaction solution with water, THF was removed by concentration under reduced pressure, and the resulting aqueous solution was washed with diethyl ether. Thereafter, 1M hydrochloric acid was added to acidify the solution, and the mixture was extracted with ethyl acetate and THF. The organic layer is dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give N- (tert-butoxycarbonyl) -S-(((2S, 3S, 4R, 5R) -5- (4-carbamoyl -1H-imidazol-1-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methyl) -D-homocysteine (88 mg, 86%) was obtained as a white solid.
N- (tert-butoxycarbonyl) -S-(((2S, 3S, 4R, 5R) -5- (4-carbamoyl-1H-imidazol-1-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methyl) -D-homocysteine (29 mg, 630 μmol) was dissolved in 100 μL of MeOH, 300 μL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 20 hours. Thereafter, the reaction solution was concentrated under reduced pressure to obtain S-((((2S, 3S, 4R, 5R) -5- (4-carbamoyl-1H-imidazol-1-yl) -3,4-dihydroxytetrahydrofuran-2-yl ) methyl) -D-homocysteine (30 mg) was obtained as a white solid.
1 H NMR (500 MHz, D 2 O, δ): 8.97 (br s, 1H), 8.14 (br s, 1H), 5.85 (d, J = 4.5 Hz, 1H), 4.40 (t, J = 5.0 Hz , 1H), 4.28 (dt, J = 6.5, 5.0 Hz, 1H), 4.17 (t, J = 5.0 Hz, 1H), 4.08 (t, J = 6.5 Hz, 1H), 2.94 (dd, J = 14, 5.0 Hz, 1H), 2.84 (dd, J = 14, 7.0 Hz, 1H), 2.69 (t, J = 7.5 Hz, 2H), 2.06-2.21 (m, 2H).
Claims (3)
式（２）：
（式中、Ｒ１はカルボン酸の保護基であり、Ｒ２はアミノ基の保護基である。）で表される化合物と、
式（３）：
（式中、Ｘは脱離基であり、Ｒ３はヒドロキシル基の保護基である。）で表される化合物とを反応させて式（４）：
（式中、Ｒ１、Ｒ２およびＲ３は前記定義に同じ）で表される化合物を生成させ、
得られた前記式（４）で表される化合物に対し保護基の除去処理を行うことを含む、前記式（１）で表される化合物の製造方法。 Formula (1):
Formula (2):
Wherein R 1 is a protecting group for carboxylic acid and R 2 is a protecting group for amino group;
Formula (3):
(Wherein X is a leaving group and R 3 is a hydroxyl-protecting group) is reacted with a compound represented by formula (4):
(Wherein R 1 , R 2 and R 3 are the same as defined above),
The manufacturing method of the compound represented by the said Formula (1) including performing the removal process of a protecting group with respect to the compound represented by the obtained said Formula (4).
The production method according to claim 2, wherein the optically active methionine is L-methionine or D-methionine.
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| CN112239421A (en) * | 2020-11-06 | 2021-01-19 | 江苏宝众宝达药业有限公司 | Method for synthesizing L-homocystine |
| CN115746711A (en) * | 2022-11-08 | 2023-03-07 | 东莞领航电子新材料有限公司 | Aluminum alloy mirror surface polishing solution and polishing method |
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| CN112239421A (en) * | 2020-11-06 | 2021-01-19 | 江苏宝众宝达药业有限公司 | Method for synthesizing L-homocystine |
| CN115746711A (en) * | 2022-11-08 | 2023-03-07 | 东莞领航电子新材料有限公司 | Aluminum alloy mirror surface polishing solution and polishing method |
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