JPH0795960B2 - Process for producing L-amino acid compound alkyl ester - Google Patents
Process for producing L-amino acid compound alkyl esterInfo
- Publication number
- JPH0795960B2 JPH0795960B2 JP60083136A JP8313685A JPH0795960B2 JP H0795960 B2 JPH0795960 B2 JP H0795960B2 JP 60083136 A JP60083136 A JP 60083136A JP 8313685 A JP8313685 A JP 8313685A JP H0795960 B2 JPH0795960 B2 JP H0795960B2
- Authority
- JP
- Japan
- Prior art keywords
- amino acid
- acid compound
- alkyl ester
- protected
- reaction
- 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
- 238000000034 method Methods 0.000 title claims description 13
- -1 N-protected-amino Chemical group 0.000 claims description 24
- 235000001014 amino acid Nutrition 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 12
- 102000004157 Hydrolases Human genes 0.000 claims description 11
- 108090000604 Hydrolases Proteins 0.000 claims description 11
- 108010027597 alpha-chymotrypsin Proteins 0.000 claims description 9
- 150000001413 amino acids Chemical class 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 5
- 125000005907 alkyl ester group Chemical group 0.000 claims description 5
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 4
- 108010067372 Pancreatic elastase Proteins 0.000 claims description 4
- 102000016387 Pancreatic elastase Human genes 0.000 claims description 4
- 235000004279 alanine Nutrition 0.000 claims description 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 108090000787 Subtilisin Proteins 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 108010035972 myxobacter alpha-lytic proteinase Proteins 0.000 claims description 3
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 6
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 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 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- RRONHWAVOYADJL-HNNXBMFYSA-N (2s)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 RRONHWAVOYADJL-HNNXBMFYSA-N 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- DCAUNIBIBOKWOZ-LBPRGKRZSA-N butyl (2s)-2-amino-3-(4-hydroxyphenyl)propanoate Chemical compound CCCCOC(=O)[C@@H](N)CC1=CC=C(O)C=C1 DCAUNIBIBOKWOZ-LBPRGKRZSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- HMSHFXBDVHMCRC-SFHVURJKSA-N decyl (2s)-2-amino-3-phenylpropanoate Chemical compound CCCCCCCCCCOC(=O)[C@@H](N)CC1=CC=CC=C1 HMSHFXBDVHMCRC-SFHVURJKSA-N 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 150000003138 primary alcohols Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- MCRMUCXATQAAMN-HNNXBMFYSA-N (2s)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(O)C=C1 MCRMUCXATQAAMN-HNNXBMFYSA-N 0.000 description 1
- FLGYJBNDDWLTQR-INIZCTEOSA-N (2s)-3-phenyl-2-[[2-(phenylmethoxycarbonylamino)acetyl]amino]propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)CNC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 FLGYJBNDDWLTQR-INIZCTEOSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 102000035101 Aspartic proteases Human genes 0.000 description 1
- 108091005502 Aspartic proteases Proteins 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- USPFMEKVPDBMCG-LBPRGKRZSA-N N-benzyloxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000002820 allylidene group Chemical group [H]C(=[*])C([H])=C([H])[H] 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- YUXJLYBUNGKOOQ-LBPRGKRZSA-N decyl (2s)-2-aminopropanoate Chemical compound CCCCCCCCCCOC(=O)[C@H](C)N YUXJLYBUNGKOOQ-LBPRGKRZSA-N 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- LISDEHQPDTXACN-FQEVSTJZSA-N dodecyl (2s)-2-amino-3-phenylpropanoate Chemical compound CCCCCCCCCCCCOC(=O)[C@@H](N)CC1=CC=CC=C1 LISDEHQPDTXACN-FQEVSTJZSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
- TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- LEYORBXXAFPSGY-KRWDZBQOSA-N octyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@H](N)C(=O)OCCCCCCCC)=CNC2=C1 LEYORBXXAFPSGY-KRWDZBQOSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
【発明の詳細な説明】 ［産業上の利用分野］ 本発明は、Ｌ−アミノ酸系化合物アルキルエステルの製
法に関する。さらに詳しくは、Ｎ−保護−アミノ酸系化
合物と炭素数４〜16のアルコールとをタンパク質加水分
解酵素を用いて反応させたのち、保護基を除去してＬ−
アミノ酸系化合物アルキルエステルをうる方法に関す
る。TECHNICAL FIELD The present invention relates to a method for producing an L-amino acid compound alkyl ester. More specifically, an N-protected-amino acid compound is reacted with an alcohol having 4 to 16 carbon atoms using a protein hydrolase, and then the protecting group is removed to remove L-.
It relates to a method for obtaining an amino acid compound alkyl ester.
本発明の方法によりえられたＬ−アミノ酸系化合物アル
キルエステルは界面活性機能を有しているが、一般に界
面活性剤に比べ皮膚刺激性が少ない、毒性が低い、生分
解性が良いなどの特徴を有するので、化粧品を中心とす
る用途に好適に利用されうる。The L-amino acid compound alkyl ester obtained by the method of the present invention has a surface-active function, but is generally characterized by less skin irritation, less toxicity, and better biodegradability than surfactants. Therefore, it can be suitably used for applications centered on cosmetics.
［従来の技術］ アミノ酸系化合物であるアミノ酸またはペプチドのアル
キルエステルの製法として、アミノ酸またはペプチドと
塩化水素飽和アルコールとを反応させてエステル化する
方法、あるいはアミノ酸またはペプチドとアルコールと
をｐ−トルエンスルフォン酸の存在下、四塩化炭素中で
煮沸還流して生成する水を共沸混合物として除いてエス
テル化し、要すれば保護基を除去してアミノ酸アルキル
エステルまたはペプチドアルキルエステルにする方法な
どが知られている。[Prior Art] As a method for producing an alkyl ester of an amino acid or a peptide that is an amino acid compound, a method of reacting an amino acid or a peptide with a saturated hydrogen chloride alcohol for esterification, or an amino acid or a peptide and an alcohol with p-toluenesulfone A known method is to remove water generated by boiling under reflux in carbon tetrachloride in the presence of an acid as an azeotropic mixture for esterification, and if necessary remove a protecting group to give an amino acid alkyl ester or peptide alkyl ester. ing.
［発明が解決しようとする問題点］ しかし前記の方法は、反応中に熱を発生したり、高温で
反応させなければならず、またアミノ酸系化合物として
DL体を用いると、生成するアミノ酸系化合物アルキルエ
ステルにはＤ体とＬ体とが含まれ、Ｌ体のみをえたいと
きには分割工程が必要で、コスト的に高くつくという欠
点がある。[Problems to be Solved by the Invention] However, in the above-mentioned method, heat must be generated during the reaction or the reaction must be performed at a high temperature.
When the DL-form is used, the resulting amino acid compound alkyl ester includes the D-form and the L-form, and when it is desired to obtain only the L-form, a step of resolution is required, which has the disadvantage of being costly.
本発明は、原料としてDL体アミノ酸系化合物を用いてア
ルキルエステルを生成させるばあいでも、Ｄ体アミノ酸
アルキルエステルの生成を防止し、低コストでＬ−アミ
ノ酸またはＬ−ペプチドのアルキルエステルをうる方法
を提供するためになされたものである。The present invention is a method for obtaining an alkyl ester of L-amino acid or L-peptide at low cost by preventing the formation of D-amino acid alkyl ester even when an alkyl ester is produced using a DL-amino acid compound as a raw material. It was made to provide.
［問題点を解決するための手段］ 本発明は、Ｎ−保護−アミノ酸系化合物と炭素数４〜16
のアルコールとをタンパク質加水分解酵素の存在下で反
応させてＮ−保護−Ｌ−アミノ酸系化合物アルキルエス
テルとし、保護基を除去してＬ−アミノ酸系化合物アル
キルエステルをうることを特徴とするＬ−アミノ酸系化
合物アルキルエステルの製法に関する。[Means for Solving Problems] The present invention provides an N-protected-amino acid compound and a carbon number of 4 to 16
L-amino acid compound alkyl ester by removing the protecting group by reacting with the alcohol in the presence of a protein hydrolase to give an N-protected-L-amino acid compound alkyl ester. The present invention relates to a method for producing an amino acid compound alkyl ester.
［実施例］ 本発明においては、Ｎ−保護−アミノ酸系化合物と炭素
数４〜16のアルコールとをタンパク質加水分解酵素の存
在下で反応させることにより、Ｎ−保護−Ｌ−アミノ酸
系化合物アルキルエステルが製造される。[Example] In the present invention, an N-protected-L-amino acid compound alkyl ester is obtained by reacting an N-protected-amino acid compound with an alcohol having 4 to 16 carbon atoms in the presence of a protein hydrolase. Is manufactured.
本明細書にいうＮ−保護−アミノ酸系化合物とは、Ｎ−
保護−アミノ酸およびＮ−保護−ペプチドを含む概念で
ある。The N-protected-amino acid compound referred to in the present specification means N-
The concept includes protection-amino acids and N-protection-peptides.
前記Ｎ−保護−アミノ酸を製造するのに用いられるアミ
ノ酸としては、たとえばチロシン、トリプトファン、フ
ェニルアラニン、ロイシン、アラニン、セリンなどが好
適な具体例としてあげられ、いずれもＬ体、DL体のいず
れを使用してもよい。As the amino acid used for producing the N-protected-amino acid, for example, tyrosine, tryptophan, phenylalanine, leucine, alanine, serine and the like are mentioned as preferable specific examples, and any of L-form and DL-form is used. You may.
また、前記Ｎ−保護−ペプチドを製造するのに用いられ
るペプチドとしては、タンパク質を酸、アルカリまたは
タンパク質加水分解酵素などで処理してえられるペプチ
ドや合成ペプチドなどがあげられるが、カルボキシル末
端がチロシン、トリプトファン、フェニルアラニン、ロ
イシン、アラニン、セリン残基などであればいずれを使
用してもよいが、反応性の点からジペプチド、トリペプ
チドのような鎖長の短いペプチドが好ましい。Examples of the peptide used for producing the N-protected peptide include a peptide obtained by treating a protein with an acid, an alkali, a protein hydrolase or the like, a synthetic peptide, and the like. , Tryptophan, phenylalanine, leucine, alanine, serine residues and the like may be used, but peptides having a short chain length such as dipeptides and tripeptides are preferable from the viewpoint of reactivity.
Ｎ−保護−アミノ酸系化合物のＮ−保護基を導入する方
法としては、たとえば「タンパク質化学１ アミノ酸・
ペプチド」（共立出版）405〜509頁に記載されているよ
うな方法があげられ、このような方法によりＮ−保護−
アミノ酸系化合物がえられる。Examples of the method for introducing an N-protecting group in an N-protected-amino acid compound include "protein chemistry 1 amino acid.
Peptides "(Kyoritsu Shuppan), pages 405 to 509, and N-protection-
Amino acid compounds can be obtained.
前記Ｎ−保護基としては、通常のペプチド合成において
使用されるウレタン型、アシル型、アルキル型、アリル
型、アリリデン型、塩型などのいずれの保護基でも使用
しうるが、反応後の保護基脱離の容易さなどの点からウ
レタン型の保護基が好ましい。As the N-protecting group, any protecting group such as urethane type, acyl type, alkyl type, allyl type, allylidene type, salt type and the like used in ordinary peptide synthesis may be used, but the protecting group after reaction is used. A urethane type protecting group is preferred from the viewpoint of ease of elimination and the like.
ウレタン型のアミノ基の保護基の具体例としては、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、ｔ−ブトキシカルボニル基などがあげら
れるが、これらのうちではベンジルオキシカルボニル基
を使用することが、保護基を容易にはずすことができ
る、信頼性の高いＮ末端の保護ができる、ラセミ化を抑
えることができるなどの点から望ましい。Specific examples of the urethane-type amino-protecting group include a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, and a t-butoxycarbonyl group. Among these, the benzyloxycarbonyl group is used. However, it is desirable in that the protecting group can be easily removed, the N-terminal can be protected with high reliability, and racemization can be suppressed.
Ｎ−保護−アミノ酸系化合物と反応せしめられる炭素数
４〜16のアルコールとしては、第１級アルコール、第２
級アルコールなどの脂肪族アルコールがあげられるが、
反応性の点から第１級アルコールを用いることが好まし
い。Examples of the alcohol having 4 to 16 carbon atoms which is reacted with the N-protected amino acid compound include primary alcohols and secondary alcohols.
Aliphatic alcohols such as high grade alcohol can be mentioned,
From the viewpoint of reactivity, it is preferable to use a primary alcohol.
本発明に用いるタンパク質加水分解酵素としては、たと
えばセリンプロテアーゼ、システインプロテアーゼ、金
属プロテアーゼ、アスパルティックプロテアーゼなどが
あげられるがこれらに限定されるものではなく、Ｎ−保
護−アミノ酸系化合物と炭素数４〜16のアルコールとか
らＮ−保護−Ｌ−アミノ酸系化合物アルキルエステルを
合成するものであれば、とくに制限なく使用しうる。こ
れらのうちで好ましいものとしては、セリンプロテアー
ゼのα−キモトリプシン、サブチリシン、エラスター
ゼ、α−リチックプロテアーゼなどがあげられ、用いら
れる原料の種類によって適宜選択して用いればよい。Examples of the protein hydrolase used in the present invention include, but are not limited to, serine protease, cysteine protease, metalloprotease, and aspartic protease. N-protected-amino acid compounds and C4 to C4 Any compound can be used without particular limitation as long as it can synthesize an N-protected-L-amino acid compound alkyl ester from 16 alcohols. Of these, preferred are serine protease α-chymotrypsin, subtilisin, elastase, α-lytic protease and the like, which may be appropriately selected and used depending on the type of raw material used.
たとえばＮ−保護−アミノ酸系化合物のカルボキシル末
端が、チロシン、トリプトファン、フェニルアラニンま
たはロイシン残基であるばあいには、タンパク質加水分
解酵素がα−キモトリプシンまたはサブチリシンである
ことが好ましく、カルボキシ末端がアラニンまたはセリ
ン残基であるばあいには、タンパク質加水分解酵素がエ
ラスターゼまたはα−リチックプロテアーゼであること
が好ましい。For example, when the carboxyl terminus of the N-protected-amino acid compound is a tyrosine, tryptophan, phenylalanine or leucine residue, the proteolytic enzyme is preferably α-chymotrypsin or subtilisin, and the carboxy terminus is alanine or When it is a serine residue, it is preferable that the protein hydrolase is elastase or α-lytic protease.
Ｎ−保護−Ｌ−アミノ酸系化合物アルキルエステルは、
Ｎ−保護−アミノ酸系化合物と炭素数４〜16のアルコー
ルとを水と混合しない有機溶媒とタンパク質加水分解酵
素を含んだ水性液、好ましくは緩衝液との２相系で激し
く攪拌しながら反応させることによってえられる。The N-protected-L-amino acid compound alkyl ester is
The N-protected-amino acid compound and the alcohol having 4 to 16 carbon atoms are reacted with stirring in a two-phase system comprising an organic solvent immiscible with water and an aqueous solution containing a protein hydrolase, preferably a buffer solution. It can be obtained.
前記有機溶媒としては、たとえばクロロホルム、酢酸エ
チル、ベンゼン、四塩化炭素、ジエチルエーテルなどが
あげられ、水と混和しないかぎりとくに制限なく使用し
うる。これらのうちではクロロホルムが反応の進みやす
さの点から好ましい。Examples of the organic solvent include chloroform, ethyl acetate, benzene, carbon tetrachloride, diethyl ether and the like, which can be used without particular limitation as long as they are not miscible with water. Of these, chloroform is preferable from the viewpoint of easy reaction.
前記水性液としては、反応時のpHを一定に保つという点
からトリス−塩酸緩衝液などを用いることが好ましい
が、これらに限定されるものではない。水性液として緩
衝液を用いるばあいの濃度は、通常１〜７重量％、好ま
しくは３〜５重量％である。As the above-mentioned aqueous liquid, it is preferable to use Tris-hydrochloric acid buffer solution or the like from the viewpoint of keeping the pH constant during the reaction, but it is not limited thereto. When a buffer solution is used as the aqueous solution, the concentration is usually 1 to 7% by weight, preferably 3 to 5% by weight.
本発明の製法において使用されるＮ−保護−アミノ酸系
化合物およびアルコールの濃度は、通常それぞれ0.1〜1
0mH、好ましくは１〜5mMおよび50〜500mM、好ましくは1
00〜200mMである。また、使用されるＮ−保護−アミノ
酸系化合物とアルコールとのモル比は、通常1:50〜1:50
0、好ましくは1:100〜1:200である。The concentrations of the N-protected amino acid compound and alcohol used in the production method of the present invention are usually 0.1 to 1 each.
0 mM, preferably 1-5 mM and 50-500 mM, preferably 1
It is from 00 to 200 mM. The molar ratio of the N-protected-amino acid compound used to the alcohol is usually 1:50 to 1:50.
It is 0, preferably 1: 100 to 1: 200.
反応時のpHは用いるアミノ酸系化合物やアルコールの種
類によって適宜選択すればよいが、通常６〜９、好まし
くは７〜８であり、反応温度は通常10〜45℃、好ましく
は30〜40℃、反応時間は通常５〜24時間、好ましくは10
〜20時間である。The pH during the reaction may be appropriately selected depending on the type of amino acid compound or alcohol used, but is usually 6 to 9, preferably 7 to 8, and the reaction temperature is usually 10 to 45 ° C, preferably 30 to 40 ° C, The reaction time is usually 5 to 24 hours, preferably 10
~ 20 hours.
タンパク質加水分解酵素の好ましい使用量はその種類に
よっても異なるが、できるだけ多い方が反応率が高くな
り好ましい。通常緩衝液中に0.1〜5mM、好ましくは0.4
〜1mM含有せしめられる。The preferred amount of the protein hydrolase varies depending on its type, but it is preferable that the amount is as large as possible because the reaction rate becomes high. Usually 0.1-5 mM in buffer, preferably 0.4
~ 1 mM is included.
２相系で攪拌させて反応させたのち、反応液を濾過し、
有機溶媒層を分取し、溶媒を除去したのち、氷酢酸中で
５〜20％パラジウム−炭素またはパラジウム黒の触媒を
加えて解放容器中、常圧下で水素添加を行なうことによ
り、ベンジルオキシカルボニル基を除去し、Ｌ−アミノ
酸系化合物アルキルエステルがえられる。他のＮ−保護
基を用いたばあいには前述の「タンパク質化学１ アミ
ノ酸・ペプチド」（共立出版）405〜509頁記載の方法な
どに従って除去すればよい。After reacting by stirring in a two-phase system, the reaction solution is filtered,
After separating the organic solvent layer and removing the solvent, benzyloxycarbonyl was obtained by adding 5 to 20% palladium-carbon or palladium black catalyst in glacial acetic acid and hydrogenating under an atmospheric pressure in an open vessel. The group is removed to give an L-amino acid compound alkyl ester. When other N-protecting group is used, it may be removed according to the method described in the above-mentioned "Protein Chemistry 1 Amino Acids / Peptides" (Kyoritsu Shuppan), pages 405 to 509.
次に本発明の方法を実施例によりさらに詳細に説明す
る。Next, the method of the present invention will be described in more detail by way of examples.
実施例１ Ｎ−ベンジルオキシカルボニル チロシン7.5mgおよび
ｎ−ブチルアルコール176mgをクロロホルム23.75mlに溶
解させたのち、α−キモトリプシン（シグマ社製の58U/
mg）12.5mgを溶解させた0.1Mトリス−塩酸緩衝液（pH7.
5）1.25mlを加え、30℃で18時間激しく攪拌しながら反
応させた。Example 1 N-benzyloxycarbonyl tyrosine (7.5 mg) and n-butyl alcohol (176 mg) were dissolved in chloroform (23.75 ml), and then α-chymotrypsin (58U / 58U manufactured by Sigma) was dissolved.
0.1 M Tris-hydrochloric acid buffer solution (pH 7.
5) 1.25 ml was added and reacted at 30 ° C. for 18 hours with vigorous stirring.
反応後、濾過して有機溶媒層を分取し、減圧濃縮により
溶媒を除去したのち、氷酢酸20ml中で５％パラジウム−
炭素100mgを触媒として用い、１時間水素ガスを通じる
接触的水素添加により保護基を除去した。After the reaction, the organic solvent layer was separated by filtration and concentrated under reduced pressure to remove the solvent, and then 5% palladium in 20 ml of glacial acetic acid was added.
The protecting groups were removed by catalytic hydrogenation with hydrogen gas for 1 hour using 100 mg of carbon as catalyst.
この反応生成物をTLC分析に供し、ｎ−ブチルアルコー
ル：酢酸：水＝4:1:2（容量比）の展開溶媒で展開し、
ニンヒドリン試薬で発色させたところ、標品のチロシン
ブチルエステルとRf値が完全に一致した。また、酸加水
分解後TLC分析に供したところ、標品のチロシンと一致
する位置にスポットを与えた。前記のようにしてチロシ
ンブチルエステルがえられていることが確認された。This reaction product is subjected to TLC analysis and developed with a developing solvent of n-butyl alcohol: acetic acid: water = 4: 1: 2 (volume ratio),
When the color was developed with ninhydrin reagent, the R f value of the sample tyrosine butyl ester was completely in agreement. In addition, when subjected to TLC analysis after acid hydrolysis, spots were provided at positions corresponding to the tyrosine of the standard. As described above, it was confirmed that tyrosine butyl ester was obtained.
実施例２ Ｎ−ベンジルオキシカルボニル トリプトファン8.0mg
およびｎ−オクチルアルコール310mgをクロロホルム24.
25mlに溶解させ、それにα−キモトリプシン7.5mgを溶
解させたリン酸緩衝液（pH7.5）0.75mlを加え、30℃で2
0時間激しく攪拌しながら反応させた。Example 2 N-benzyloxycarbonyl tryptophan 8.0 mg
And 310 mg of n-octyl alcohol in chloroform 24.
Dissolve it in 25 ml, add 0.75 ml of phosphate buffer (pH 7.5) containing 7.5 mg of α-chymotrypsin, and add 2 at 30 ℃.
The reaction was carried out for 0 hours with vigorous stirring.
反応後、実施例１と同様にして保護基を除去したのちTL
C分析に供したところ、この反応生成物は標品のトリプ
トファンオクチルエステルと完全に一致した。After the reaction, the protective group was removed in the same manner as in Example 1, and then TL
When subjected to C analysis, this reaction product was completely in agreement with the authentic tryptophan octyl ester.
実施例３ Ｎ−ベンジルオキシカルボニル ロイシン27mgおよびｎ
−デシルアルコール1.58gをクロロホルム95mlに溶解さ
せ、それにα−キモトリプシン50mgを溶解させた0.1Mト
リス−塩酸緩衝液（PH7.5）5mlを加え、30℃で18時間激
しく攪拌しながら反応させた。Example 3 N-benzyloxycarbonyl leucine 27 mg and n
-1.58 g of decyl alcohol was dissolved in 95 ml of chloroform, and 5 ml of 0.1 M tris-hydrochloric acid buffer solution (PH7.5) in which 50 mg of α-chymotrypsin was dissolved was added thereto, and the mixture was reacted at 30 ° C for 18 hours with vigorous stirring.
反応後、実施例１と同様にして保護基を除去し、TLC、G
C、GC−MS分析に供したところ、ロイシンデシルエステ
ルであることが確認された。After the reaction, the protecting group was removed in the same manner as in Example 1, and TLC, G
When subjected to C and GC-MS analysis, it was confirmed to be leucine decyl ester.
実施例４ Ｎ−ベンジルオキシカルボニル フェニルアラニン7mg
およびｎ−ラウリルアルコール440mgをクロロホルム24.
75mlに溶解し、これにα−キモトリプシン12.5mgを溶解
させたリン酸緩衝液（pH7.5）1.25mlを加え、30℃で20
時間激しく攪拌しながら反応させた。Example 4 N-benzyloxycarbonyl phenylalanine 7 mg
And n-lauryl alcohol 440 mg chloroform 24.
Dissolve in 75 ml, add 1.25 ml of phosphate buffer (pH 7.5) in which 12.5 mg of α-chymotrypsin was dissolved, and add at 20 ℃ at 20 ℃.
The reaction was allowed to proceed with vigorous stirring for hours.
反応後、実施例１と同様にして保護基を除去し、TLC分
析に供したところ、反応生成物は標品のフェニルアラニ
ンラウリルエステルと完全に一致した。After the reaction, the protective group was removed in the same manner as in Example 1 and the product was subjected to TLC analysis. As a result, the reaction product was completely the same as the authentic phenylalanine lauryl ester.
実施例５ Ｎ−ベンジルオキシカルボニル アラニン11mgおよびｎ
−デシルアルコール0.75gをクロロホルム47.5mlに溶解
させ、それにエラスターゼ（シグマ社製の70U/mg）25mg
を溶解させたリン酸緩衝液（pH7.0）2.5mlを加え、37℃
で20時間激しく攪拌しながら反応させた。Example 5 N-benzyloxycarbonyl alanine 11 mg and n
-Dissolve 0.75 g of decyl alcohol in 47.5 ml of chloroform and add 25 mg of elastase (70U / mg manufactured by Sigma).
2.5 ml of phosphate buffer solution (pH 7.0) in which
The reaction was carried out for 20 hours with vigorous stirring.
反応後、実施例１と同様にして保護基を除去し、TLC、G
C分析に供したところ、反応生成物は標品のアラニンデ
シルエステルと完全に一致した。After the reaction, the protecting group was removed in the same manner as in Example 1, and TLC, G
When subjected to C analysis, the reaction product was in perfect agreement with the authentic alanine decyl ester.
実施例６ Ｎ−ベンジルオキシカルボニル グリシルフェニルアラ
ニン34mgおよびｎ−オクチルアルコール1.24gをクロロ
ホルム95mlに溶解させ、それにα−キモトリプシン50mg
を溶解させたリン酸緩衝液（pH7.0）5mlを加え、37℃で
20時間激しく攪拌しながら反応させた。Example 6 34 mg of N-benzyloxycarbonyl glycylphenylalanine and 1.24 g of n-octyl alcohol are dissolved in 95 ml of chloroform, and 50 mg of α-chymotrypsin is dissolved therein.
Add 5 ml of phosphate buffer (pH 7.0) in which
The reaction was carried out with vigorous stirring for 20 hours.
反応後、実施例１と同様にして保護基を除去し、TLC分
析に供したところ標品のグリシルフェニルアラニンオク
チルエステルと完全に一致した。After the reaction, the protecting group was removed in the same manner as in Example 1 and the product was subjected to TLC analysis. As a result, it was completely identical to the authentic glycylphenylalanine octyl ester.
実施例７ Ｎ−ベンジルオキシカルボニル フェニルアラニン60mg
およびｎ−デシルアルコール3.0gをクロロホルム190ml
に溶解し、これにα−キモトリプシン80mgを溶解させた
リン酸緩衝液（pH7.5）10mlを加え、30℃で24時間激し
く攪拌しながら反応させた。Example 7 N-benzyloxycarbonyl phenylalanine 60 mg
And n-decyl alcohol 3.0 g chloroform 190 ml
10 ml of a phosphate buffer (pH 7.5) in which 80 mg of α-chymotrypsin was dissolved was added thereto, and the mixture was reacted at 30 ° C. for 24 hours with vigorous stirring.
反応後、実施例１と同様にして保護基を除去した。After the reaction, the protecting group was removed in the same manner as in Example 1.
えられた反応液を調製用TLCに帯状にスポットし、ｎ−
ブタノール：酢酸：水＝4:1:2（容量比）の展開溶媒で
展開し、フェニルアラニンデシルエステルの部分をかき
とり、エーテルで抽出後26mgの溶液状物質をえた。えら
れた溶液状物質はGCおよびGC−MS分析の結果、標品のフ
ェニルアラニンデシルエステルと完全に一致した。The obtained reaction solution is spotted on a preparative TLC in a strip shape and n-
It was developed with a developing solvent of butanol: acetic acid: water = 4: 1: 2 (volume ratio), the portion of phenylalanine decyl ester was scraped off, and extracted with ether to obtain 26 mg of a solution substance. As a result of GC and GC-MS analysis, the obtained solution substance was completely in agreement with the authentic phenylalanine decyl ester.
［発明の効果］ 本発明の製法は化学的合成法に比べて、反応が30〜40℃
という温和な条件で行なえ、またＬ体のみ必要なばあい
でも原料にはDL体を使用することができるため、低コス
トでＬ−アミノ酸系化合物アルキルエステルを製造する
ことができる。[Effect of the Invention] Compared with the chemical synthesis method, the reaction of the present invention has a reaction temperature of 30 to 40 ° C.
In this case, the L-amino acid compound alkyl ester can be produced at low cost because the DL-form can be used as a starting material even when only the L-form is required.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 昭47−35194（ＪＰ，Ａ) 特公 昭58−49160（ＪＰ，Ｂ２) 特公 昭57−35956（ＪＰ，Ｂ２) ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP 47-35194 (JP, A) JP 58-49160 (JP, B2) JP 57-35956 (JP, B2)
Claims (4)
16のアルコールとをタンパク質加水分解酵素の存在下で
反応させてＮ−保護−Ｌ−アミノ酸系化合物アルキルエ
ステルとし、保護基を除去してＬ−アミノ酸系化合物ア
ルキルエステルをうることを特徴とするＬ−アミノ酸系
化合物アルキルエステルの製法。1. An N-protected-amino acid compound and a carbon number of 4 to 4.
L is characterized by reacting 16 alcohols in the presence of a protein hydrolase to give an N-protected-L-amino acid compound alkyl ester, and removing the protecting group to give an L-amino acid compound alkyl ester. -A method for producing an alkyl ester of an amino acid compound.
ル末端が、チロシン、トリプトファン、フェニルアラニ
ンまたはロイシン残基であり、タンパク質加水分解酵素
がα−キモトリプシンまたはサブチリシンである特許請
求の範囲第１項記載の製法。2. The carboxyl terminal of the N-protected amino acid compound is a tyrosine, tryptophan, phenylalanine or leucine residue, and the protein hydrolase is α-chymotrypsin or subtilisin. Manufacturing method.
ル末端が、アラニンまたはセリン残基であり、タンパク
質加水分解酵素がエラスターゼまたはα−リチックプロ
テアーゼである特許請求の範囲第１項記載の製法。3. The process according to claim 1, wherein the carboxyl terminus of the N-protected amino acid compound is an alanine or serine residue, and the protein hydrolase is elastase or α-lytic protease.
ドである特許請求の範囲第１項記載の製法。4. The method according to claim 1, wherein the amino acid compound is an amino acid or a peptide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60083136A JPH0795960B2 (en) | 1985-04-18 | 1985-04-18 | Process for producing L-amino acid compound alkyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60083136A JPH0795960B2 (en) | 1985-04-18 | 1985-04-18 | Process for producing L-amino acid compound alkyl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61239894A JPS61239894A (en) | 1986-10-25 |
| JPH0795960B2 true JPH0795960B2 (en) | 1995-10-18 |
Family
ID=13793785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60083136A Expired - Lifetime JPH0795960B2 (en) | 1985-04-18 | 1985-04-18 | Process for producing L-amino acid compound alkyl ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0795960B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU7863394A (en) * | 1993-10-20 | 1995-05-08 | Tokyo Tanabe Company Limited | Novel arylethanolamino(aryl)propanol compound |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5735956A (en) * | 1980-08-13 | 1982-02-26 | Toshiba Corp | Atomizer |
| JPS5849160A (en) * | 1981-09-17 | 1983-03-23 | 三洋電機株式会社 | Local heating of living body |
-
1985
- 1985-04-18 JP JP60083136A patent/JPH0795960B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61239894A (en) | 1986-10-25 |
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