JPH0530439B2 - - Google Patents
Info
- Publication number
- JPH0530439B2 JPH0530439B2 JP63190160A JP19016088A JPH0530439B2 JP H0530439 B2 JPH0530439 B2 JP H0530439B2 JP 63190160 A JP63190160 A JP 63190160A JP 19016088 A JP19016088 A JP 19016088A JP H0530439 B2 JPH0530439 B2 JP H0530439B2
- Authority
- JP
- Japan
- Prior art keywords
- reaction
- column
- immobilized
- organic solvent
- solution
- 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.)
- Expired - Lifetime
Links
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 29
- 239000000758 substrate Substances 0.000 claims description 28
- 108010016626 Dipeptides Proteins 0.000 claims description 21
- 239000000872 buffer Substances 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 108091005804 Peptidases Proteins 0.000 claims description 9
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical class OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 8
- 125000005907 alkyl ester group Chemical group 0.000 claims description 8
- 235000003704 aspartic acid Nutrition 0.000 claims description 8
- 150000001509 aspartic acid derivatives Chemical class 0.000 claims description 8
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 8
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Chemical class OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 8
- 239000004365 Protease Substances 0.000 claims description 7
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- 230000005465 channeling Effects 0.000 claims description 5
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910001424 calcium ion Inorganic materials 0.000 claims description 4
- 238000010924 continuous production Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 102000004190 Enzymes Human genes 0.000 description 15
- 108090000790 Enzymes Proteins 0.000 description 15
- 108010093096 Immobilized Enzymes Proteins 0.000 description 15
- 229940088598 enzyme Drugs 0.000 description 14
- 108090001109 Thermolysin Proteins 0.000 description 13
- 239000002994 raw material Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 229960005261 aspartic acid Drugs 0.000 description 7
- 229960005190 phenylalanine Drugs 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 4
- -1 N-substituted phenylalanine Chemical class 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000001110 calcium chloride Substances 0.000 description 4
- 229910001628 calcium chloride Inorganic materials 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000010647 peptide synthesis reaction Methods 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- CSRCBLMBBOJYEX-UHFFFAOYSA-M sodium;2-morpholin-4-ylethanesulfonic acid;hydroxide Chemical compound [OH-].[Na+].OS(=O)(=O)CCN1CCOCC1 CSRCBLMBBOJYEX-UHFFFAOYSA-M 0.000 description 4
- XYXYXSKSTZAEJW-VIFPVBQESA-N (2s)-2-(phenylmethoxycarbonylamino)butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 XYXYXSKSTZAEJW-VIFPVBQESA-N 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 235000011148 calcium chloride Nutrition 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 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 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- VSDUZFOSJDMAFZ-VIFPVBQESA-N methyl L-phenylalaninate Chemical compound COC(=O)[C@@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- YMCKXAIYXCYCGH-VWURTLBMSA-N (2s)-2-aminobutanedioic acid;(2s)-2-amino-3-phenylpropanoic acid Chemical class OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 YMCKXAIYXCYCGH-VWURTLBMSA-N 0.000 description 1
- DPEYHNFHDIXMNV-UHFFFAOYSA-N (9-amino-3-bicyclo[3.3.1]nonanyl)-(4-benzyl-5-methyl-1,4-diazepan-1-yl)methanone dihydrochloride Chemical compound Cl.Cl.CC1CCN(CCN1Cc1ccccc1)C(=O)C1CC2CCCC(C1)C2N DPEYHNFHDIXMNV-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- BPCZRKPMLRWWBV-UHFFFAOYSA-N C(#N)C1OCCN(C1)C(C)S(=O)(=O)O Chemical compound C(#N)C1OCCN(C1)C(C)S(=O)(=O)O BPCZRKPMLRWWBV-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- OHJMTUPIZMNBFR-UHFFFAOYSA-N biuret Chemical compound NC(=O)NC(N)=O OHJMTUPIZMNBFR-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011437 continuous method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Landscapes
- Apparatus Associated With Microorganisms And Enzymes (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Devices And Processes Conducted In The Presence Of Fluids And Solid Particles (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19016088A JPH0239895A (ja) | 1988-07-28 | 1988-07-28 | ジペプチドの連続製造法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19016088A JPH0239895A (ja) | 1988-07-28 | 1988-07-28 | ジペプチドの連続製造法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0239895A JPH0239895A (ja) | 1990-02-08 |
| JPH0530439B2 true JPH0530439B2 (fr) | 1993-05-10 |
Family
ID=16253424
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19016088A Granted JPH0239895A (ja) | 1988-07-28 | 1988-07-28 | ジペプチドの連続製造法 |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0239895A (fr) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20020015742A (ko) * | 2000-08-23 | 2002-03-02 | 신철수 | 단백질 가수분해효소를 이용한 아스파탐 전구체의 제조방법 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6229996A (ja) * | 1985-07-30 | 1987-02-07 | Hiroshi Ooshima | Ｎ−保護ｌ−アスパルチル−ｌ−フエニルアラニン低級アルキルエステルの製造方法 |
-
1988
- 1988-07-28 JP JP19016088A patent/JPH0239895A/ja active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6229996A (ja) * | 1985-07-30 | 1987-02-07 | Hiroshi Ooshima | Ｎ−保護ｌ−アスパルチル−ｌ−フエニルアラニン低級アルキルエステルの製造方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0239895A (ja) | 1990-02-08 |
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