JPH0215095A - Preparation of n-protected-alpha-l-aspartyl-l-phenylalanine methyl ester - Google Patents
Preparation of n-protected-alpha-l-aspartyl-l-phenylalanine methyl esterInfo
- Publication number
- JPH0215095A JPH0215095A JP63162593A JP16259388A JPH0215095A JP H0215095 A JPH0215095 A JP H0215095A JP 63162593 A JP63162593 A JP 63162593A JP 16259388 A JP16259388 A JP 16259388A JP H0215095 A JPH0215095 A JP H0215095A
- Authority
- JP
- Japan
- Prior art keywords
- methyl ester
- phenylalanine methyl
- protected
- anhydride
- aspartic acid
- 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.)
- Granted
Links
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 45
- VSDUZFOSJDMAFZ-VIFPVBQESA-N methyl L-phenylalaninate Chemical compound COC(=O)[C@@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 claims abstract description 39
- 229960005261 aspartic acid Drugs 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 150000007942 carboxylates Chemical class 0.000 claims abstract description 18
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 14
- 239000011707 mineral Substances 0.000 claims abstract description 14
- 229910052751 metal Inorganic materials 0.000 claims abstract description 12
- 239000002184 metal Substances 0.000 claims abstract description 12
- 150000002739 metals Chemical class 0.000 claims abstract description 11
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000001099 ammonium carbonate Substances 0.000 claims abstract description 10
- 235000012501 ammonium carbonate Nutrition 0.000 claims abstract description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 9
- -1 oxides Chemical class 0.000 claims description 21
- 229910052783 alkali metal Inorganic materials 0.000 claims description 14
- 150000001340 alkali metals Chemical class 0.000 claims description 14
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 10
- 150000004679 hydroxides Chemical class 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 8
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 abstract description 20
- 150000008064 anhydrides Chemical class 0.000 abstract description 6
- 235000003599 food sweetener Nutrition 0.000 abstract description 3
- 239000003765 sweetening agent Substances 0.000 abstract description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract description 2
- 235000005911 diet Nutrition 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract 2
- 239000003513 alkali Substances 0.000 abstract 1
- 150000001734 carboxylic acid salts Chemical class 0.000 abstract 1
- 230000037213 diet Effects 0.000 abstract 1
- 238000000034 method Methods 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000013078 crystal Substances 0.000 description 14
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 13
- 150000001342 alkaline earth metals Chemical class 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 235000010755 mineral Nutrition 0.000 description 11
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 9
- 235000011054 acetic acid Nutrition 0.000 description 9
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 9
- 239000001632 sodium acetate Substances 0.000 description 9
- 235000017281 sodium acetate Nutrition 0.000 description 9
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 150000001735 carboxylic acids Chemical class 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 4
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 4
- 235000003704 aspartic acid Nutrition 0.000 description 4
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- GWKOSRIHVSBBIA-REOHCLBHSA-N (3s)-3-aminooxolane-2,5-dione Chemical compound N[C@H]1CC(=O)OC1=O GWKOSRIHVSBBIA-REOHCLBHSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- OZPYEGOBGWQOSZ-VIFPVBQESA-N benzyl n-[(3s)-2,5-dioxooxolan-3-yl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)N[C@H]1CC(=O)OC1=O OZPYEGOBGWQOSZ-VIFPVBQESA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- MRJNSMBULLCBBR-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;sulfuric acid Chemical compound OS(O)(=O)=O.COC(=O)[C@@H](N)CC1=CC=CC=C1 MRJNSMBULLCBBR-FVGYRXGTSA-N 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 125000004044 trifluoroacetyl group Chemical class FC(C(=O)*)(F)F 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical compound ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 description 1
- NTFULCXLYCSQIW-REOHCLBHSA-N (2s)-2-[(2,2,2-trifluoroacetyl)amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)C(F)(F)F NTFULCXLYCSQIW-REOHCLBHSA-N 0.000 description 1
- WYYUBJAMROQJSF-QWRGUYRKSA-N (3s)-4-[[(1s)-1-carboxy-2-phenylethyl]amino]-3-formamido-4-oxobutanoic acid Chemical compound OC(=O)C[C@H](NC=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 WYYUBJAMROQJSF-QWRGUYRKSA-N 0.000 description 1
- YSCNREZXFSZAQO-ROUUACIJSA-N (3s)-4-[[(2s)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino]-4-oxo-3-(phenylmethoxycarbonylamino)butanoic acid Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H](CC(O)=O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 YSCNREZXFSZAQO-ROUUACIJSA-N 0.000 description 1
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OTCCIMWXFLJLIA-UHFFFAOYSA-N N-acetyl-DL-aspartic acid Natural products CC(=O)NC(C(O)=O)CC(O)=O OTCCIMWXFLJLIA-UHFFFAOYSA-N 0.000 description 1
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 description 1
- MQUUQXIFCBBFDP-VKHMYHEASA-N N-formyl-L-aspartic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC=O MQUUQXIFCBBFDP-VKHMYHEASA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 239000002585 base Substances 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
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- OZPYEGOBGWQOSZ-SECBINFHSA-N benzyl n-[(3r)-2,5-dioxooxolan-3-yl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)N[C@@H]1CC(=O)OC1=O OZPYEGOBGWQOSZ-SECBINFHSA-N 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 description 1
- 229910000020 calcium bicarbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 1
- 229940071257 lithium acetate Drugs 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- DFTMVZIUYVECNW-VKHMYHEASA-N n-[(3s)-2,5-dioxooxolan-3-yl]formamide Chemical compound O=CN[C@H]1CC(=O)OC1=O DFTMVZIUYVECNW-VKHMYHEASA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical class O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 description 1
- 229960004109 potassium acetate Drugs 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Landscapes
- Peptides Or Proteins (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、Ｎ−保護−Ｌ−アスパラギン酸を有機カルボ
ン酸中、無水酢酸と反応させた後、Ｎ保護−Ｌ−アスパ
ラギン酸無水物を単離することなく、引き続きアルカリ
金属、アルカリ土類金属またはこれらの金属の水酸化物
、酸化物、炭酸塩、重炭酸塩もしくは有機カルボン酸塩
、あるいは炭酸アンモニウム、有機カルボン酸アンモニ
ウムを添加して１、−フェニルアラニンメチルエステル
鉱酸塩と反応させることを特徴とするＮ−保護−α−Ｌ
−アスパルチル−Ｌ−フェニルアラニンメチルエステル
（以下、Ｎ−保護−α−ＡＰＭと略記する）を製造する
方法に関する。Detailed Description of the Invention [Industrial Application Field] The present invention provides a method for reacting N-protected-L-aspartic acid with acetic anhydride in an organic carboxylic acid, and then reacting N-protected-L-aspartic acid anhydride with acetic anhydride. Without isolation, by subsequent addition of alkali metals, alkaline earth metals or hydroxides, oxides, carbonates, bicarbonates or organic carboxylates of these metals, or ammonium carbonate, ammonium organic carboxylates. 1. N-protected-α-L characterized by reacting with -phenylalanine methyl ester mineral acid salt
- A method for producing aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as N-protected-α-APM).
Ｎ−保護−α−ＡＰＭは、甘味剤として使用されるａ−
Ｌ−アスパルチル−Ｌ−フェニルアラニンメチルエステ
ル（以下、α−ＡＰＭと略記する）の中間体として重要
な化合物である。α−ＡＰＭはジペプチド系の甘味料と
して広く知られており、良質な甘味特性ならびに蔗糖の
２００倍近い高甘味度を有し、ダイエツト甘味剤として
その需要が大きく伸長しているものである。N-protected-α-APM is a-
It is an important compound as an intermediate for L-aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as α-APM). α-APM is widely known as a dipeptide-based sweetener, and has good sweetness characteristics and a sweetness level nearly 200 times that of sucrose, and its demand as a dietary sweetener is rapidly increasing.
〔従来の技術および解決しようとする課題〕α−ＡＰＭ
は、Ｌ−アスパラギン酸とＬ−フェニルアラニンメチル
エステルとからなるジペプチド化合物であり、その製法
に関しては化学的製造法を中心に既に多数の方法が知ら
れている。[Conventional technology and problems to be solved] α-APM
is a dipeptide compound consisting of L-aspartic acid and L-phenylalanine methyl ester, and many methods for its production are already known, mainly chemical production methods.
その方法はＮ−保護−Ｌ−アスパラギン酸無水物を出発
原料とするのが一般的であり、例えば、Ｎ−保護−Ｌ−
アスパラギン酸無水物とＬ−フェニルアラニンメチルエ
ステルを１ｒ機溶剤中で縮合させた後、常法によって保
護基を脱離させて創造する方法（米国特許筒３．７８６
，０３９号）、反応原料としてＬ−フェニルアラニンメ
チルエステルを用い、Ｎ−保護−Ｌ−アスパラギン酸無
水物と不活性反応媒体中で反応させる方法（特開昭４６
−１３７０号）などが知られている。The method generally uses N-protected-L-aspartic acid anhydride as a starting material, for example, N-protected-L-aspartic acid anhydride.
A method of condensing aspartic acid anhydride and L-phenylalanine methyl ester in a 1R organic solvent and then removing the protecting group by a conventional method (U.S. Pat. No. 3,786)
, No. 039), a method of reacting L-phenylalanine methyl ester as a reaction raw material with N-protected-L-aspartic acid anhydride in an inert reaction medium (JP-A-46
-1370) etc. are known.
この方法によると、Ｎ−ベンジルオキシカルボニル−し
−アスパラギン酸無水物の酢酸エチル溶液およびＬ−フ
ェニルアラニンメチルエステル塩酸塩の酢酸エチル溶液
を混合し、この酢酸エチル溶液にＩＮ炭酸ナトリウム水
溶液を加え、Ｌ−フェニルアラニンメチルエステルの塩
酸塩を中和しながら反応させている。According to this method, an ethyl acetate solution of N-benzyloxycarbonyl-di-aspartic acid anhydride and an ethyl acetate solution of L-phenylalanine methyl ester hydrochloride are mixed, an IN sodium carbonate aqueous solution is added to the ethyl acetate solution, and L - The hydrochloride of phenylalanine methyl ester is reacted while being neutralized.
Ｌ−フェニルアラニンメチルエステルヲ用いない方法と
しては、Ｎ−ホルミル−し−アスパラギン酸無水物とＬ
−フェニルアラニンとを酢酸中で縮合させた後、ハロゲ
ン化水素酸との共存下に脱ホルミル化し、水、アルコー
ルおよびハロゲン化水素酸と処理する事によりエステル
化を行い、α−ＡＰＭをハロゲン化水素酸として単離す
る方法（特公昭５５−２６１３３号）が知られている。A method that does not use L-phenylalanine methyl ester is to use N-formyl-aspartic anhydride and L-phenylalanine methyl ester.
- Phenylalanine is condensed in acetic acid, then deformylated in the coexistence of hydrohalic acid, and esterified by treatment with water, alcohol, and hydrohalic acid to convert α-APM into hydrogen halide. A method of isolating it as an acid (Japanese Patent Publication No. 55-26133) is known.
また、不活性有機溶媒中、Ｎ−ベンジルオキシカルボニ
ル−し−アスパラギン酸無水物とＬ−フェニルアラニン
メチルエステル塩酸塩とを塩基の存在下に反応させる方
法（特開昭４６−７０６８号）も知られ、具体的にはＮ
−ベンジルオキシカルボニル−Ｌ−アスパラギン酸無水
物とＬ−フェニルアラニンメチルエステルの塩酸塩を酢
酸エチルに溶解し、次いで該溶液に炭酸ナトリウムある
いは炭酸カリウム水溶液を加えながら反応を行う方法で
ある。Also known is a method in which N-benzyloxycarbonyl-d-aspartic acid anhydride and L-phenylalanine methyl ester hydrochloride are reacted in the presence of a base in an inert organic solvent (Japanese Patent Application Laid-open No. 7068/1983). , specifically N
-Benzyloxycarbonyl-L-aspartic acid anhydride and L-phenylalanine methyl ester hydrochloride are dissolved in ethyl acetate, and then a reaction is carried out while adding an aqueous sodium carbonate or potassium carbonate solution to the solution.
この反応に際して有機塩基として３級アミンも用いられ
ている。しかしながら、これらの場合もＬ−フェニルア
ラニンメチルエステルの塩酸塩を使用し有ａ溶媒中、ア
ルカリ水溶液等で中和させながら反応を行うため、Ｌ−
フェニルアラニンメチルエステル
加水分解、さらにはＬ−フェニルアラニンメチルエステ
ルが特にアルカリ性条件下や、３級アミン類等の塩基性
条件下で自己環化して副生ずるジケトピペラジン化合物
の生成、、Ｎ−保護−Ｌ−アスパラギン酸無水物の水に
よる開環反応等が生じる欠点は避けることができない。Tertiary amines are also used as organic bases in this reaction. However, in these cases as well, the hydrochloride of L-phenylalanine methyl ester is used and the reaction is carried out in a solvent while being neutralized with an aqueous alkaline solution, etc.
Phenylalanine methyl ester hydrolysis, and furthermore, L-phenylalanine methyl ester self-cyclizes under alkaline conditions or basic conditions such as tertiary amines to form diketopiperazine compounds as by-products, N-protected-L - The disadvantage of ring-opening reaction of aspartic anhydride with water cannot be avoided.
一方、Ｎ−ホルミル−し−アスパラギン酸無水物とＬ−
フェニルアラニンメチルエステルとの反応を溶媒中、酢
酸あるいはギ酸の存在下に行う方法（特開昭６２−１４
９６６９号）が知られている。On the other hand, N-formyl-shi-aspartic anhydride and L-
A method in which the reaction with phenylalanine methyl ester is carried out in a solvent in the presence of acetic acid or formic acid (Japanese Unexamined Patent Publication No. 62-14
No. 9669) is known.
しかし、この方法は酢酸あるいはギ酸の存在下に有機溶
媒中でＬ−フェニルアラニンメチルエステルを反応させ
る方法であって、使用する原料は単離したＬ−フェニル
アラニンメチルエステル溶液を用いるため中和したのち
、抽出、脱水処理など操作が繁５１である。また、単離
したＬ−フェニルアラニンメチルエステル
で、上記の方法と同様な欠点を有している。However, this method involves reacting L-phenylalanine methyl ester in an organic solvent in the presence of acetic acid or formic acid, and since the raw material used is an isolated L-phenylalanine methyl ester solution, it is neutralized. There are 51 operations such as extraction and dehydration. It is also an isolated L-phenylalanine methyl ester, which has the same drawbacks as the above method.
また、特開昭６１−２６７６００号においては、Ｎ−ベ
ンジルオキシカルボニル−し−アスパラギン酸をトルエ
ン中、無水酢酸で無水物化した後、Ｌ−フェニルアラニ
ンメチルエステルを含有するトルエン溶液を添加し、反
応させている。Furthermore, in JP-A No. 61-267600, after N-benzyloxycarbonyl-di-aspartic acid was anhydrified with acetic anhydride in toluene, a toluene solution containing L-phenylalanine methyl ester was added and reacted. ing.
このように、従来知られているＮ−保護 Ｌ−アスパラ
ギン酸無水物とＬ−フェニルアラニンメチルエステルと
の反応においては、一般にＮ−保護−Ｌ−アスパラギン
酸無水物を単離して用いている。そのため、この無水物
の吸湿により開環物を生じるおそれがあった。また、反
応において副生ずるＮ−保護−β−アスパルチル−し−
フェニルアラニンメチルエステル（以下、Ｎ−保護−β
−ＡＰＭと略記する）の分離およびＮ−保護−αＡＰＭ
の単離の必要性があった。Thus, in the conventionally known reaction between N-protected L-aspartic acid anhydride and L-phenylalanine methyl ester, N-protected L-aspartic acid anhydride is generally isolated and used. Therefore, there was a risk that ring-opened products would be generated due to moisture absorption of this anhydride. In addition, N-protected-β-aspartyl- which is a by-product in the reaction
Phenylalanine methyl ester (hereinafter referred to as N-protected-β
- APM) separation and N-protection - αAPM
There was a need for isolation.
本発明の目的は上記の従来方法の欠点を除去したＮ−保
護−Ｌ−アスパラギン酸を出発原料とする工業的に優れ
たＮ−保護−α−ＡＰＭの製造方法を提供することにあ
る。An object of the present invention is to provide an industrially superior method for producing N-protected-α-APM using N-protected-L-aspartic acid as a starting material, which eliminates the drawbacks of the above-mentioned conventional methods.
本発明者らは、Ｎ−保護−Ｌ−アスパラギン酸を出発原
料としたα−異性体比を減少させず、また上記のような
従来法の欠点がない、しかも工業的製造法として満足で
きる方法について鋭意検討した結果、有機カルボン酸中
、Ｎ−保護−Ｌ−アスパラギン酸を無水物化した後、引
き続きＬ−フェニルアラニンメチルエステルとの反応に
おいて、Ｌ−フェニルアラニンメチルエステルを鉱酸塩
の形態で、すなわち、従来の方法のように該鉱酸塩を中
和、抽出、脱水等の処理を行ってＬ−フェニルアラニン
メチルエステルとして単離することなく、しかも有機カ
ルボン酸中、アルカリ金属、アルカリ土類金属、または
これら金属の水酸化物、酸化物、炭酸塩、重炭酸塩もし
くは有機カルボン酸塩、あるいは炭酸アンモニウム、有
機カルボン酸アンモニウムを添加してＮ−保護−Ｌ−ア
スパラギン酸無水物と縮合反応させて、Ｎ−保護−α−
ＡＰＭを製造する方法を見出し、本発明を完成した。The present inventors have developed a method that does not reduce the α-isomer ratio using N-protected-L-aspartic acid as a starting material, does not have the drawbacks of the conventional methods described above, and is also satisfactory as an industrial production method. As a result of intensive studies, we found that after anhydrifying N-protected L-aspartic acid in an organic carboxylic acid, in the subsequent reaction with L-phenylalanine methyl ester, L-phenylalanine methyl ester was obtained in the form of a mineral acid salt, i.e. , without having to isolate the mineral salt as L-phenylalanine methyl ester by neutralization, extraction, dehydration, etc. as in conventional methods, and in addition, in organic carboxylic acids, alkali metals, alkaline earth metals, Alternatively, hydroxides, oxides, carbonates, bicarbonates, or organic carboxylates of these metals, or ammonium carbonate or ammonium organic carboxylates are added to cause a condensation reaction with N-protected-L-aspartic anhydride. , N-protected-α-
We have discovered a method for manufacturing APM and completed the present invention.
すなわち、本発明は、Ｎ−保１ｔ−Ｌ−アスパラギン酸
を有機カルボン酸中、無水酢酸と反応させた後、生成し
たＮ−保ｆｉＩ−Ｌ−アスパラギン酸無水物を単離する
ことなく、引き続きアルカリ金属、アルカリ土類金属、
またはこれら金属の水酸化物、酸化物、炭酸塩、重炭酸
塩もしくは有機カルボン酸塩、あるいは炭酸アンモニウ
ム、有８カルボン酸アンモニウムを添加してＬ−フェニ
ルアラニンメチルエステル鉱酸塩と反応させることを特
徴とするＮ−保護−α−Ｌ−アスパルチル−しフェニル
アラニンメチルエステルの製造方法である。That is, the present invention involves reacting N-L-aspartic acid with acetic anhydride in an organic carboxylic acid, and then subsequently reacting the resulting N-L-L-aspartic anhydride without isolating it. alkali metals, alkaline earth metals,
Or, it is characterized by adding hydroxides, oxides, carbonates, bicarbonates, or organic carboxylates of these metals, or ammonium carbonate, or ammonium octacarboxylate to react with the L-phenylalanine methyl ester mineral salt. This is a method for producing N-protected-α-L-aspartyl-phenylalanine methyl ester.
本発明の方法はＬ−フェニルアラニンメチルエステルの
鉱酸塩が有機カルボン酸中アルカリ金属、アルカリ土類
金属、またはこれら金属の水酸化物、酸化物、炭酸塩、
重炭酸塩、もしくは有機カルボン酸塩、あるいは炭酸ア
ンモニウム、有機カルボン酸アンモニウムを添加するこ
とによりＬ−フェニルアラニンメチルエステルとして実
質的に反応するが、Ｌ−フェニルアラニンメチルエステ
ルは、を機カルボン酸中では遊離状態にあっても自己閉
環反応、ざらにＮ−保護−Ｌ−アスパラギン酸無水物の
水分による開環反応が全く起こらない特徴を存する。The method of the present invention is characterized in that the mineral acid salt of L-phenylalanine methyl ester is an alkali metal, an alkaline earth metal, or a hydroxide, oxide, or carbonate of these metals in an organic carboxylic acid.
By adding bicarbonate, organic carboxylate, ammonium carbonate, or ammonium organic carboxylate, it substantially reacts as L-phenylalanine methyl ester, but L-phenylalanine methyl ester is free in organic carboxylic acid. It has the characteristic that no self-ring-closing reaction or ring-opening reaction due to moisture in N-protected-L-aspartic acid anhydride does not occur at all even under the conditions.
本発明の方法で用いるＮ−保護基は、ベンゾイル基、ア
セチル基、ホルミル基、ハロゲン置換アセチル基、トリ
フルオロアセチル基、トリクロロアセチル基等のアシル
型保８Ｗ基、トリフェニルメチル基、ｐ−トルエンスル
ホニルＬ ｐ−メトキシベンジルオキシカルボニル基な
どのアルコキシベンジルオキシカルボニル基、Ｐ−クロ
ルベンジルオキシカルボニル基などのハロゲノベンジル
オキシカルボニル基、ｐ−ニトロベンジルオキシカルボ
ニル基などの置換または非置換のベンジルオキシカルボ
ニル基が挙げられるが、特にホルミル基、トリフルオロ
アセチル基、ベンジルオキシカルボニル基が好ましい。The N-protecting groups used in the method of the present invention include benzoyl groups, acetyl groups, formyl groups, halogen-substituted acetyl groups, trifluoroacetyl groups, trichloroacetyl groups, etc., acyl-type protective groups, triphenylmethyl groups, p-toluene groups, etc. Sulfonyl L Alkoxybenzyloxycarbonyl group such as p-methoxybenzyloxycarbonyl group, halogenobenzyloxycarbonyl group such as P-chlorobenzyloxycarbonyl group, substituted or unsubstituted benzyloxycarbonyl group such as p-nitrobenzyloxycarbonyl group Among them, formyl group, trifluoroacetyl group, and benzyloxycarbonyl group are particularly preferred.
これらのＮ−保１−Ｌ−アスパラギン酸は種々の方法で
製造することができ、下記のような製法が採用できる。These N-1-L-aspartic acids can be produced by various methods, and the following production method can be adopted.
Ｎ−ヘンシルオキシカルボニル−し−アスパラギン酸無
水物は、Ｌ−アスパラギン酸とカルボベンゾキシクロラ
イドと反応させてＮ−ベンジルオキシカルボニル−し−
アスパラギン酸を得る公知の方法で製造しうる。さらに
、Ｎ−アセチル−しアスパラギン酸、Ｎ−トリフルオロ
アセチル−Ｌ−アスパラギン酸、Ｎ−トリクロロアセチ
ル−■、−アスパラギン酸は、Ｌ−アスパラギン酸をア
ルカリ水溶液中、無水酢酸、無水トリフルオロ酢酸、無
水トリクロロ酢酸を用いてそれぞれ反応させることによ
り容易に製造することができる。N-benzyloxycarbonyl-aspartic anhydride is produced by reacting L-aspartic acid with carbobenzoxy chloride.
It can be produced by any known method for obtaining aspartic acid. Furthermore, N-acetyl-aspartic acid, N-trifluoroacetyl-L-aspartic acid, N-trichloroacetyl-■,-aspartic acid can be obtained by preparing L-aspartic acid in an alkaline aqueous solution, acetic anhydride, trifluoroacetic anhydride, They can be easily produced by reacting each with trichloroacetic anhydride.
また、本発明に用いるＬ−フェニルアラニンメチルエス
テル鉱酸塩は、Ｌ−フェニルアラニンをメタノール中鉱
酸の存在で常法によってエステル化することにより製造
することができる。Further, the L-phenylalanine methyl ester mineral salt used in the present invention can be produced by esterifying L-phenylalanine in the presence of a mineral acid in methanol by a conventional method.
本発明の方法で使用される有機カルボン酸は、ギ酸、酢
酸、プロピオン酸のごときカルボン酸類を挙げることが
できるが、好ましくは酢酸、プロピオン酸が使用される
。The organic carboxylic acids used in the method of the present invention include carboxylic acids such as formic acid, acetic acid, and propionic acid, but acetic acid and propionic acid are preferably used.
これらのを機カルボン酸の使用量は、特に限定されるも
のではないが操作上、通常は、原料のＮ−保３９−Ｌ−
アスパラギン酸に対して２〜５０重量倍の範囲で使用す
るのが好ましい。The amount of these carboxylic acids used is not particularly limited, but for operational reasons, it is usually
It is preferably used in an amount of 2 to 50 times the weight of aspartic acid.
本発明の方法においてＮ−保護−Ｌ−アスパラギン酸の
無水物化に用いる無水酢酸量は、Ｎ−保７９−Ｌ−アス
パラギン酸に対して等モルあれば充分であるが、通常は
０．９〜１．５モル比の範囲である。In the method of the present invention, it is sufficient that the amount of acetic anhydride used to convert N-protected-L-aspartic acid into anhydride is equimolar to N-protected-L-aspartic acid, but it is usually 0.9 to 79-L-aspartic acid. The molar ratio is in the range of 1.5.
本発明の方法において用いるアルカリ金属、アルカリ土
類金属は、例えばナトリウム、マグネシウム等があげら
れる。Examples of the alkali metals and alkaline earth metals used in the method of the present invention include sodium and magnesium.
またアルカリ金属、アルカリ土類金属の水酸化物として
は、例えば、水酸化ナトリウム、水酸化カリウム、水酸
化リチウム、水酸化マグネシウムなどの水酸化物等があ
げられる。アルカリ金属、アルカリ土類金属の酸化物と
しては酸化カルシウム、酸化マグネシウムなどの酸化物
等があげられる。アルカリ金属、アルカリ土類金属の炭
酸塩としては炭酸リチウム、炭酸ナトリウム、炭酸カリ
ウム、炭酸カルシウム、炭酸マグネシウム等があげられ
る。アルカリ金属、アルカリ土類金属の重炭酸塩として
は、重炭酸リチウム、重炭酸ナトリウム、重炭酸カリウ
ム、重炭酸カルシウムなどの重炭酸塩があげられる。ア
ルカリ金属、アルカリ土類金属の有機カルボン酸塩とし
ては、酢酸リチウム、酢酸ナトリウム、酢酸カリウム、
酢酸カルシウム、酢酸マグネシウム、好ましくは酢酸ナ
トリウム、酢酸カリウムが使用される。炭酸アンモニウ
ムまたは有機カルボン酸アンモニウムも使用できる。Examples of the hydroxides of alkali metals and alkaline earth metals include hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and magnesium hydroxide. Examples of oxides of alkali metals and alkaline earth metals include oxides such as calcium oxide and magnesium oxide. Examples of carbonates of alkali metals and alkaline earth metals include lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate. Examples of bicarbonates of alkali metals and alkaline earth metals include bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and calcium bicarbonate. Examples of organic carboxylates of alkali metals and alkaline earth metals include lithium acetate, sodium acetate, potassium acetate,
Calcium acetate, magnesium acetate, preferably sodium acetate, potassium acetate are used. Ammonium carbonate or ammonium organic carboxylates can also be used.
アルカリ金属、アルカリ土類金属またはこれら金属の水
酸化物、酸化物、炭酸塩、重炭酸塩もしくは有機カルボ
ン酸塩、あるいは炭酸アンモニウム、有機カルボン酸ア
ンモニウムの使用量は、Ｌフェニルアラニンメチルエス
テルの鉱酸塩に対して等モル量であれば充分であるが、
通常は１．０〜３．０モル比の範囲である。The amount of alkali metals, alkaline earth metals, hydroxides, oxides, carbonates, bicarbonates, or organic carboxylates of these metals, or ammonium carbonate or ammonium organic carboxylates, is based on the mineral acid of L-phenylalanine methyl ester. It is sufficient if the amount is equimolar to the salt, but
Usually, the molar ratio is in the range of 1.0 to 3.0.
本発明の方法を実施するには、有機カルボン酸中、Ｌ−
アスパラギン酸を無水酢酸で無水物化した後、懸濁また
は溶解状態で、アルカリ金属、アルカリ土類金属、また
はこれら金属の水酸化物、酸化物、炭酸塩、重炭酸塩も
しくは有機カルボン酸塩、あるいは炭酸アンモニウム、
有機カルボン酸アンモニウムを添加した後、Ｌ−フェニ
ルアラニンメチルエステルの鉱酸塩を添加するか、ある
いはＬ−フェニルアラニンメチルエステルの鉱酸塩を添
加した後、アルカリ金属、アルカリ土類金属、またはこ
れら金属の水酸化物、酸化物、炭酸塩、重炭酸塩もしく
は有機カルボン酸塩、あるいは炭酸アンモニウム、有機
カルボン酸アンモニウムを加えてもよい。To carry out the process of the invention, L-
After anhydrification of aspartic acid with acetic anhydride, in suspended or dissolved state, alkali metals, alkaline earth metals, or hydroxides, oxides, carbonates, bicarbonates or organic carboxylates of these metals, or ammonium carbonate,
After adding the organic ammonium carboxylate, the mineral acid salt of L-phenylalanine methyl ester is added, or after the addition of the mineral acid salt of L-phenylalanine methyl ester, an alkali metal, an alkaline earth metal, or one of these metals is added. Hydroxides, oxides, carbonates, bicarbonates or organic carboxylates, or ammonium carbonate, ammonium organic carboxylates may be added.
本発明における反応温度については、Ｎ−保護−Ｌ−ア
スパラギン酸の無水物化は４０〜６５°Ｃの範囲でよく
、好ましくは５０〜６０゛Ｃの範囲である。またトノ−
保護−Ｌ−アスパラギン酸無水物とＬ−フェニルアラニ
ンメチルエステルの反応においては特に制限はなく、通
常は一１５〜８０°Ｃの範囲でよく、好ましくは−５〜
２５“Ｃの範囲である。Regarding the reaction temperature in the present invention, the anhydride of N-protected L-aspartic acid may be in the range of 40 to 65°C, preferably in the range of 50 to 60°C. Also, the tonneau
There is no particular restriction on the reaction between protected L-aspartic acid anhydride and L-phenylalanine methyl ester, and the temperature is usually in the range of -15 to 80°C, preferably in the range of -5 to 80°C.
It is in the range of 25"C.
反応時間は、いずれも通常０．５〜１０時間であれば十
分である。It is usually sufficient for the reaction time to be 0.5 to 10 hours.
反応後、一般にＮ〜Ｎ保護α−ＡＰＭは反応系内に沈澱
として析出してくる。また、副生ずるＮ保護−β−ＡＰ
Ｍは比較的有機カルボン酸に溶解するため、析出した結
晶を濾過、洗浄することにより容易に目的のＮ−保護−
α−ＡＰＭを単離することができる。After the reaction, N~N-protected α-APM generally precipitates in the reaction system. In addition, the by-product N-protection-β-AP
Since M is relatively soluble in organic carboxylic acids, the desired N-protection can be easily obtained by filtering and washing the precipitated crystals.
α-APM can be isolated.
一方、単離したＮ−保護−α−ＡＰＭに少量含有される
Ｎ−保護−β−ＡＰＭは常法により水あるいは有機溶剤
等で容易に除去される。On the other hand, N-protected-β-APM contained in a small amount in isolated N-protected-α-APM can be easily removed with water or an organic solvent by a conventional method.
本発明の方法によれば、有機カルボン酸を使用し、Ｎ−
保１−Ｌ−アスパラギン酸を無水物化した後、引き続き
各種金属または各種金属化合物等を添加し、Ｌ−フェニ
ルアラニンメチルエステルの鉱酸塩と反応させることに
よって短時間で効率よ（Ｎ−保護−α−ＡＰＭを得るこ
とができ、本発明の方法は工業的製法として価値の高い
製造方法となりうる。According to the method of the invention, an organic carboxylic acid is used and N-
1-After converting L-aspartic acid to anhydride, various metals or various metal compounds are added and reacted with the mineral acid salt of L-phenylalanine methyl ester to efficiently convert (N-protected-α) -APM can be obtained, and the method of the present invention can be a highly valuable manufacturing method as an industrial manufacturing method.
以下、実施例によって本発明の方法を詳しく説明する。 Hereinafter, the method of the present invention will be explained in detail with reference to Examples.
実施例１
酢酸６３．３ ｇにＮ−）リフルオロアセチル−し−ア
スパラギン酸２２．９ｇ （０，１モル）を加えてＱｉ
させた後、無水酢酸１０．２ｇ （０，１モル）を加え
、５５〜５５°Ｃに昇温し同温度で６時間攪拌した。反
応後、１５〜２０°Ｃに冷却し同温度で酢酸ナトリウム
９．２ｇ （０，１１モル）を加え、ついで同温度でＬ
−フェニルアラニンメチルエステルｔｉ酸塩２０．５ｇ
（０゜０９５モル）を添加した。同温度で２時間攪拌
反応させた後、析出している結晶を濾過、洗浄、乾燥す
ることによりＮ−１−リフルオロアセチル−αＬ−アス
パルチルーＬ−フェニルアラニンメチルエステルの結晶
を得た。Example 1 22.9 g (0.1 mol) of N-)lifluoroacetyl-thi-aspartic acid was added to 63.3 g of acetic acid to obtain Qi.
After that, 10.2 g (0.1 mol) of acetic anhydride was added, the temperature was raised to 55 to 55°C, and the mixture was stirred at the same temperature for 6 hours. After the reaction, it was cooled to 15-20°C, 9.2g (0.11 mol) of sodium acetate was added at the same temperature, and then L was added at the same temperature.
-Phenylalanine methyl ester tatiic acid salt 20.5g
(0°095 mol) was added. After stirring and reacting at the same temperature for 2 hours, the precipitated crystals were filtered, washed, and dried to obtain crystals of N-1-lifluoroacetyl-αL-aspartyl-L-phenylalanine methyl ester.
収量２９．３ｇ （収率７９．０％／対Ｌ−フェニルア
ラニンメチルエステル塩酸塩）
得られた結晶を高速液体クロマトグラフィーで分析の結
果、α一体のみであった。Yield: 29.3 g (yield: 79.0%/based on L-phenylalanine methyl ester hydrochloride) Analysis of the obtained crystals by high performance liquid chromatography revealed that only α was present.
融点１５０〜１５１’Ｃ
元素分析値（％） Ｃ１ｂＨ＋７ＮｚＯｂＦ３としてＣ
ＩＩ Ｎ Ｆ実測値 ４９．
１０ ４．４５ ７．１７ １４．５６計算値 ４９
．２４ ４．３９ ７．１８ １４．６０実施例２
実施例１において、を機カルボン酸と有機カルボン酸塩
として表−１に示すものを使用する以外は実施例１と同
様に行った。Melting point 150-151'C Elemental analysis value (%) C as C1bH+7NzObF3
II NF actual measurement value 49.
10 4.45 7.17 14.56 Calculated value 49
．． 24 4.39 7.18 14.60 Example 2 The same procedure as in Example 1 was carried out except that the organic carboxylic acid and the organic carboxylate shown in Table 1 were used.
結果を表−１に示す。The results are shown in Table-1.
表
実施例３
実施例１において、無水酢酸の使用量を９．７ｇ（０，
０９５モル）に代える以外は実施例１と同様に行った。Table Example 3 In Example 1, the amount of acetic anhydride used was 9.7 g (0,
The same procedure as in Example 1 was carried out except that 095 mol) was used.
収量２９．０ｇ （収率７８．２％／対Ｌ−フェニルア
ラニンメチルエステル塩酸塩）
実施例４
酢酸９５．５ｇにＮ−ベンジルオキシカルボニル−し−
アスパラギン酸２６．７ｇ （０，１モル）を加え懸濁
させた後、無水酢酸１０．２ｇ （０，１モル）を加え
、５５〜６０°Ｃに昇温し同温度で５時間攪拌した。反
応後、１５〜２０°Ｃに冷却し同温度で酢酸ナトリウム
９．２ｇ （０，１１モル）を加え、ついで同温度でし
フェニルアラニンメチルエステル［酸塩２０．５ｇ （
０，０９５モル）を添加した。同温度で４時間攪拌反応
させた後、同温度で水７５．３ｇを加え、０〜５“Ｃに
冷却した後、析出している結晶を濾過、洗浄、乾燥する
ことにより結晶を得た。Yield 29.0g (yield 78.2%/based on L-phenylalanine methyl ester hydrochloride) Example 4 N-benzyloxycarbonyl-hydrochloride was added to 95.5g of acetic acid.
After adding and suspending 26.7 g (0.1 mol) of aspartic acid, 10.2 g (0.1 mol) of acetic anhydride was added, the temperature was raised to 55-60°C, and the mixture was stirred at the same temperature for 5 hours. After the reaction, it was cooled to 15-20°C, 9.2g (0.11 mol) of sodium acetate was added at the same temperature, and then 20.5g (20.5g (acid) of phenylalanine methyl ester [acid acid] was added at the same temperature.
0,095 mol) was added. After reacting with stirring at the same temperature for 4 hours, 75.3 g of water was added at the same temperature, and after cooling to 0 to 5"C, the precipitated crystals were filtered, washed, and dried to obtain crystals.
収量２８．９ｇ （収率７１．０％／対Ｌ−フェニルア
ラニンメチルエステルＦ酸塩）
融点１２３．９〜１２４．８°Ｃ
元素分析値（％）ＣＺ□Ｉ＋、、Ｎ、Ｏ，とじてＩＩＮ
実測値 ６１．７８ ５．６８ ６．５３計算値
６１．６８ ５．６５ ６．５４このものの元素分析の
結果、Ｎ−ベンジルオキシカルボニル−α−Ｌ−アスパ
ルチルーＬ−フェニルアラニンメチルエステルに一敗し
た。Yield 28.9g (yield 71.0%/based on L-phenylalanine methyl ester F salt) Melting point 123.9-124.8°C Elemental analysis value (%) CZ□I+,, N, O, and IIN Actual value 61.78 5.68 6.53 Calculated value
61.68 5.65 6.54 As a result of elemental analysis of this product, it was defeated by N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester.
実施例５
実施例４において、Ｌ−フェニルアラニンメチルエステ
ル硫酸塩を２６．３ｇ （０，０９５モル）、酢酸ナト
リウムを１６．８ｇ （０，２１モル）使用する以外は
実施例４と同様に行った。Example 5 The same procedure as in Example 4 was carried out except that 26.3 g (0,095 mol) of L-phenylalanine methyl ester sulfate and 16.8 g (0,21 mol) of sodium acetate were used. .
収量２７．８ｇ （収率６８．３％／対Ｌ−フェニルア
ラニンメチルエステルｇ酸塩＞
実施例６
実施例４において、無水酢酸を９．７ ｇ （０，０９
５モル）使用する以外は実施例４と同様に行った。Yield 27.8 g (yield 68.3%/based on L-phenylalanine methyl ester g-acid> Example 6 In Example 4, acetic anhydride was 9.7 g (0.09
The same procedure as in Example 4 was carried out except that 5 mol) was used.
収量 ２７．７ｇ （収率６８．１％／対Ｌ−フェニル
アラニンメチルエステル硫酸塩）
実施例７
酢酸２８．６８にＮ−ホルミル−し−アスパラギン酸１
６．１ｇ （０，１モル）を加え懸濁させた後、無水酢
酸１０．２ｇ （０，１モル）を加え、５０〜５５°Ｃ
に昇温し同温度で５時間攪拌した。反応後、１５〜２０
°Ｃに冷却し同温度で酢酸ナトリウム９．２ｇ （０，
１１モル）を加え、ついで同温度でＬ−フェニルアラニ
ンメチルエステル塩酸塩２０．５ｇ （０，０９５モル
）を添加した。同温度で４時間撹拌反応させた後濃縮し
、水５７．２ｇを加え、１０〜１５°Ｃに冷却した後、
析出している結晶を濾過、洗浄、乾燥することにより２
８．２ｇの結晶を得た。Yield 27.7g (yield 68.1%/based on L-phenylalanine methyl ester sulfate) Example 7 1 N-formyl-aspartic acid in 28.68 ml of acetic acid
After adding and suspending 6.1 g (0.1 mol), 10.2 g (0.1 mol) of acetic anhydride was added and heated at 50-55°C.
and stirred at the same temperature for 5 hours. After reaction, 15-20
Cool to °C and at the same temperature 9.2 g of sodium acetate (0,
Then, at the same temperature, 20.5 g (0,095 mol) of L-phenylalanine methyl ester hydrochloride was added. After stirring and reacting at the same temperature for 4 hours, it was concentrated, 57.2 g of water was added, and the mixture was cooled to 10-15°C.
By filtering, washing and drying the precipitated crystals, 2
8.2 g of crystals were obtained.
得られた結晶を高速液体クロマトグラフィーで分析の結
果、α−異性体：β−異性体は８１．０ ： １９．０
であった。この結晶を常法によって精製し、純粋なＮ−
ホルミル−α−Ｌ−アスパルチルーＬ−フェニルアラニ
ンメチルエステルの結晶を得た。Analysis of the obtained crystals by high performance liquid chromatography revealed that the α-isomer:β-isomer was 81.0:19.0.
Met. This crystal is purified by a conventional method to obtain pure N-
Crystals of formyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained.
収量２０．８ｇ （収率６８．０％／対Ｌ−フェニルア
ラニンメチルエステル塩酸塩）
また、このものの元素分析の結果、Ｎ−ホルミル−α−
Ｌ−アスパルチル−Ｌ−フェニルアラニンメチルエステ
ルに一敗した。Yield 20.8g (yield 68.0%/based on L-phenylalanine methyl ester hydrochloride) Also, as a result of elemental analysis of this product, N-formyl-α-
I was defeated by L-aspartyl-L-phenylalanine methyl ester.
元素分析値（％） Ｃ＋ｓＨ＋ａＮｔＯａと、してＩ−
ＩＮ
実測値 ５５．８５ ５．６９ ８．６６計算イ直
５５．９０ ５．６３ ８．６９実施例
８
実施例１において、Ｌ−フェニルアラニンメチルエステ
ル塩酸塩の代わりにＬ−フェニルアラニンメチルエステ
ル６Ｍ酸塩ヲ２６．３ｇ （０，０９５モル）使用し、
また酢酸ナトリウムを１７．６ｇ （０，２１モル）使
用する以外は実施例１と同様に行って、Ｎ−トリフルオ
ロアセチルーα−Ｌ−アスパルチルＬ−フェニルアラニ
ンメチルエステルの結晶を得た。Elemental analysis value (%) C+sH+aNtOa and I-
IN Actual measurement value 55.85 5.69 8.66 Calculated directly
55.90 5.63 8.69 Example 8 In Example 1, 26.3 g (0,095 mol) of L-phenylalanine methyl ester 6M salt was used instead of L-phenylalanine methyl ester hydrochloride,
Further, the same procedure as in Example 1 was repeated except that 17.6 g (0.21 mol) of sodium acetate was used to obtain crystals of N-trifluoroacetyl-α-L-aspartyl L-phenylalanine methyl ester.
収量２９．０ｇ （収率７８，２％／対Ｌ−フェニルア
ラニンメチルエステル’ｎＲＭ塩）
実施例９
実施例４において、Ｎ−ベンジルオキシカルボニル−し
−アスパラギン酸を無水物化した後、Ｌ−フェニルアラ
ニンメチルエステル塩酸塩を添加し、その後、酢酸ナト
リウムを加える以外は実施例４と同様に行った。Yield: 29.0 g (yield: 78.2%/based on L-phenylalanine methyl ester 'nRM salt) Example 9 In Example 4, after anhydrating N-benzyloxycarbonyl-cycloaspartic acid, L-phenylalanine methyl The same procedure as in Example 4 was carried out except that the ester hydrochloride was added and then sodium acetate was added.
収量３０．３ｇ（収率７４，４％／対Ｌ−フェニルアラ
ニンメチルエステル塩酸塩）
実施例１０
酢酸９５．５ｇにＮ−ヘンシルオキシカルボニルし一ア
スパラギン酸２６．７ｇ （０，１モル）を加え懸濁さ
せた後、無水酢酸１０．２ｇ （０，１モル）を加え、
５５〜６０°Ｃに昇温し同温度で５時間撹拌した。反応
後、１０〜１５°Ｃに冷却し同温度でＬ−フェニルアラ
ニンメチルエステルＦ（Ｊ塩２０．５ｇ （０，０９５
モル）を添加した後、同温度で酢酸ナトリウム９．２ｇ
（０，１１モル）を加え、同温度で４時間攪拌反応させ
た後、同温度で水７５．３ ｇを加え、０〜５°Ｃに冷
却した後、析出している結晶を濾過、洗浄、乾燥するこ
とにより結晶を得た。Yield: 30.3 g (yield 74.4%/based on L-phenylalanine methyl ester hydrochloride) Example 10 To 95.5 g of acetic acid was added 26.7 g (0.1 mol) of N-hensyloxycarbonyl monoaspartic acid. After suspending, 10.2 g (0.1 mol) of acetic anhydride was added,
The temperature was raised to 55-60°C and stirred at the same temperature for 5 hours. After the reaction, it was cooled to 10-15°C and at the same temperature, L-phenylalanine methyl ester F (J salt 20.5g (0,095
9.2 g of sodium acetate at the same temperature.
(0.11 mol) was stirred and reacted at the same temperature for 4 hours, then 75.3 g of water was added at the same temperature, and after cooling to 0-5°C, the precipitated crystals were filtered and washed. , crystals were obtained by drying.
収量３０．４ｇ （収率７４．７％／対Ｌ−フェニルア
ラニンメチルエステル塩Ｍ 塩）
特許出願人 三井東圧化学株式会社Yield 30.4g (yield 74.7%/based on L-phenylalanine methyl ester salt M salt) Patent applicant Mitsui Toatsu Chemical Co., Ltd.
Claims (1)
、無水酢酸と反応させた後、生成したＮ−保護−Ｌ−ア
スパラギン酸無水物を単離することなく、引き続きアル
カリ金属、アルカリ土類金属、またはこれら金属の水酸
化物、酸化物、炭酸塩、重炭酸塩もしくは有機カルボン
酸塩、あるいは炭酸アンモニウム、有機カルボン酸アン
モニウムを添加してＬ−フェニルアラニンメチルエステ
ル鉱酸塩と反応させることを特徴とするＮ−保護−α−
Ｌ−アスパルチル−Ｌ−フェニルアラニンメチルエステ
ルの製造方法。1. After reacting N-protected-L-aspartic acid with acetic anhydride in an organic carboxylic acid, the resulting N-protected-L-aspartic anhydride is subsequently reacted with an alkali metal, alkaline earth Addition of metals, hydroxides, oxides, carbonates, bicarbonates or organic carboxylates of these metals, or ammonium carbonate or ammonium organic carboxylates to react with the L-phenylalanine methyl ester mineral salt. Featured N-Protection-α-
A method for producing L-aspartyl-L-phenylalanine methyl ester.
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16259388A JP2598467B2 (en) | 1988-07-01 | 1988-07-01 | Method for producing N-protected-α-L-aspartyl-L-phenylalanine methyl ester |
| AT89104832T ATE110740T1 (en) | 1988-03-22 | 1989-03-16 | PREPARATION OF ALPHA-1-ASPARTYL-1-PHENYLALANINE METHYLESTER WITH PROTECTED NITROGEN. |
| DE68917762T DE68917762T2 (en) | 1988-03-22 | 1989-03-16 | Production of alpha-1-aspartyl-1-phenylalanine methyl ester with a protected nitrogen atom. |
| CA000593914A CA1339658C (en) | 1988-03-22 | 1989-03-16 | Preparation of n-protected .alpha.-l-aspartyl-l-phenylalanine methyl ester |
| EP89104832A EP0334236B1 (en) | 1988-03-22 | 1989-03-16 | Preparation of n-protected alpha-l-aspartyl-l-phenylalanine methyl ester |
| BR898901324A BR8901324A (en) | 1988-03-22 | 1989-03-21 | PROCESSES FOR THE PREPARATION OF A METHYL ESTER OF ALPHA-L-ASPARTYL-L-PHENYLALANINE WITH PROTECTED N, FOR THE PREPARATION OF AN ASPARTIC ANYTHIDE WITH PROTECTED N AND FOR THE PREPARATION OF N-BENZYLOXICARBONYL-L-ASPARTIC ANIDIDE |
| NO89891243A NO891243L (en) | 1988-03-22 | 1989-03-21 | PROCEDURE FOR THE PREPARATION OF AN N-PROTECTED ALFA-L-ASPARTYL-L-PHENYLALANINE METHYL ESTER. |
| DK141289A DK141289A (en) | 1988-03-22 | 1989-03-22 | PROCEDURE FOR PREPARING AN N-PROTECTED ALFA-L-ASPARAGYL-L-PHENYLALANINE METHYL ESTER |
| AU31620/89A AU605968B2 (en) | 1988-03-22 | 1989-03-22 | Preparation of n-protected alpha-l-aspartyl-l-phenylanla- nine methyl ester |
| KR1019890003589A KR910006287B1 (en) | 1988-03-22 | 1989-03-22 | Preparation of-n-protected alpha-l-aspartyl-l-phenylalanine methyl ester |
| US07/823,538 US5302743A (en) | 1988-03-22 | 1992-01-21 | Preparation of N-protected α-L-aspartyl-L-phenylalanine methyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16259388A JP2598467B2 (en) | 1988-07-01 | 1988-07-01 | Method for producing N-protected-α-L-aspartyl-L-phenylalanine methyl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0215095A true JPH0215095A (en) | 1990-01-18 |
| JP2598467B2 JP2598467B2 (en) | 1997-04-09 |
Family
ID=15757541
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16259388A Expired - Lifetime JP2598467B2 (en) | 1988-03-22 | 1988-07-01 | Method for producing N-protected-α-L-aspartyl-L-phenylalanine methyl ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2598467B2 (en) |
-
1988
- 1988-07-01 JP JP16259388A patent/JP2598467B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2598467B2 (en) | 1997-04-09 |
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