JPS63148990A - Production of fluorine-containing phenylalanine derivative by aminoacylase - Google Patents
Production of fluorine-containing phenylalanine derivative by aminoacylaseInfo
- Publication number
- JPS63148990A JPS63148990A JP29669586A JP29669586A JPS63148990A JP S63148990 A JPS63148990 A JP S63148990A JP 29669586 A JP29669586 A JP 29669586A JP 29669586 A JP29669586 A JP 29669586A JP S63148990 A JPS63148990 A JP S63148990A
- Authority
- JP
- Japan
- Prior art keywords
- fluorine
- formula
- phenylalanine
- acetyl
- aminoacylase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 22
- 239000011737 fluorine Substances 0.000 title claims abstract description 22
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims abstract description 21
- ULGJWNIHLSLQPZ-UHFFFAOYSA-N 7-[(6,8-dichloro-1,2,3,4-tetrahydroacridin-9-yl)amino]-n-[2-(1h-indol-3-yl)ethyl]heptanamide Chemical compound C1CCCC2=NC3=CC(Cl)=CC(Cl)=C3C(NCCCCCCC(=O)NCCC=3C4=CC=CC=C4NC=3)=C21 ULGJWNIHLSLQPZ-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 108010003977 aminoacylase I Proteins 0.000 title claims abstract description 11
- 150000002993 phenylalanine derivatives Chemical class 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 108090000790 Enzymes Proteins 0.000 claims abstract description 6
- 102000004190 Enzymes Human genes 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 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 claims abstract description 3
- 239000003456 ion exchange resin Substances 0.000 claims abstract description 3
- 229920003303 ion-exchange polymer Polymers 0.000 claims abstract description 3
- GJUCNUIUIXPERB-UHFFFAOYSA-N 2-[acetyl(trifluoromethyl)amino]-3-phenylpropanoic acid Chemical compound CC(=O)N(C(F)(F)F)C(C(O)=O)CC1=CC=CC=C1 GJUCNUIUIXPERB-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 10
- OOHQXLBZBXABCV-QMMMGPOBSA-N (2s)-3-phenyl-2-(trifluoromethylamino)propanoic acid Chemical compound FC(F)(F)N[C@H](C(=O)O)CC1=CC=CC=C1 OOHQXLBZBXABCV-QMMMGPOBSA-N 0.000 claims description 6
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 2
- 238000006911 enzymatic reaction Methods 0.000 claims 1
- 239000012452 mother liquor Substances 0.000 claims 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 claims 1
- 241000228212 Aspergillus Species 0.000 abstract description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 2
- LIEWWHLIOGAFTL-UHFFFAOYSA-N 2-acetamido-3-(2,3,4,5,6-pentafluorophenyl)propanoic acid Chemical compound C(C)(=O)NC(CC1=C(C(=C(C(=C1F)F)F)F)F)C(=O)O LIEWWHLIOGAFTL-UHFFFAOYSA-N 0.000 abstract 1
- 239000003905 agrochemical Substances 0.000 abstract 1
- 239000004599 antimicrobial Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 4
- -1 2-acetyl-3- Trifluoromethylphenyl-2-propenoic acid Chemical compound 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FQRURPFZTFUXEZ-MRVPVSSYSA-N (2s)-2,3,3,3-tetrafluoro-2-(n-fluoroanilino)propanoic acid Chemical compound OC(=O)[C@](F)(C(F)(F)F)N(F)C1=CC=CC=C1 FQRURPFZTFUXEZ-MRVPVSSYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000102542 Kara Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical class CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 1
- CBQJSKKFNMDLON-UHFFFAOYSA-N N-acetylphenylalanine Chemical compound CC(=O)NC(C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-UHFFFAOYSA-N 0.000 description 1
- 101710150975 N-acyl-L-amino acid amidohydrolase Proteins 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- RJCQBQGAPKAMLL-UHFFFAOYSA-N bromotrifluoromethane Chemical compound FC(F)(F)Br RJCQBQGAPKAMLL-UHFFFAOYSA-N 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は酵素を用いて光学活性な含フッ素フェニルアラ
ニン誘導体を製造する方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an optically active fluorine-containing phenylalanine derivative using an enzyme.
トリフルオロメチルフェニルアラニンは公知であり、化
学合成法で製造しろる化合物である。Trifluoromethylphenylalanine is a well-known compound that can be produced by chemical synthesis.
トリフルオロメチルフェニルアラニンは、医薬、農薬、
坑薗剤、試薬、それらの中間原料等として有用である。Trifluoromethylphenylalanine is used in pharmaceuticals, pesticides,
It is useful as a reagent, a reagent, an intermediate raw material for these, etc.
化学合成法によるトリフルオロメチルフェニルアラニ
ンとして１例えばブロモベンシトリフルオライドからト
リフルオロメチルブロマイドを経て合成する方法が知ら
れている（Ｊ、Ｏｒｇ、Ｃｂｅｍ、λ互、７３３（１９
６０）参照）。As trifluoromethylphenylalanine by a chemical synthesis method, for example, a method of synthesizing from bromobencytrifluoride via trifluoromethyl bromide is known (J, Org, Cbem, λ Mutual, 733 (19
60)).
従来、化学合成で得られる含フッ累マエニルアラニンｌ
ｎはラセミ体であって、より有用な光学活性体を得るに
はラセミ分スリを必要とし。Conventionally, fluorine-containing enylalanine obtained by chemical synthesis
n is a racemate, and racemic separation is required to obtain a more useful optically active form.
しかもこのラセミ分割は通常容具ではない。Moreover, this racemic division is not a normal case.
本発明者らは、トリフルオロメチルフェニルアラニンや
ペンタフルオロフェニルアラニンなどの光学活性な含フ
ッ素フェニルアラニン誘導体を製造する方法について検
討した結果、特定の含フッ素化合物をアミノアシラーゼ
により加水分解を行ない光学活性な含フッ素フェニルア
ラニン誘導体に変換する方法を見出し１本発明に到達し
た。The present inventors investigated methods for producing optically active fluorine-containing phenylalanine derivatives such as trifluoromethylphenylalanine and pentafluorophenylalanine, and found that a specific fluorine-containing compound was hydrolyzed with aminoacylase to produce optically active fluorine-containing derivatives. The present invention was achieved by discovering a method for converting into phenylalanine derivatives.
〔式［！］におけるＸ、 Ｙ、 ｒｎ、 １１は上ｉｔ
！５ｔ、 ［電］電こ同じ］本発明において、アミノア
シラーゼの甚１１として９７ましいのは２式［＋１で裏
さ１１る含）・ソ累化合物の中で、フルオロ、メチル基
やフ・ン緊↓℃の入ったＮ−アレチノし−１・１ノフル
ン（゛ロメチル−（ＯＬ ’）−フェニルアラニンやＮ
−アセチル−ペンタフルオロ−（ＤＬ）−フェニルアラ
ニンがｌＴましい。〔formula[! ], X, Y, rn, 11 are above it
! 5t, [electron] same] In the present invention, the most preferable aminoacylase is the 2 formula [+1 with 11 reversed], N-aretino-1,1-noflune (゛romethyl-(OL')-phenylalanine and N containing ↓℃)
-acetyl-pentafluoro-(DL)-phenylalanine is preferred.
本反応に使用するアミノアシラーぜはアスペルギルス属
、ペニシリウム届に属する菌１１の生産するアシラーゼ
や咄乳類のγ１’ｌＡｆ山来のものが便用出来る。 ア
スペルギルス由来のアシラーゼは豚の７ｒｒＪ複由来の
ものよりも１式［１１で表される含フッ素化合物に月す
る反応性は良好であった。As the aminoacylase used in this reaction, acylase produced by bacteria 11 belonging to the genus Aspergillus and Penicillium, and γ1'lAf Yamaki from mammals can be conveniently used. Acylase derived from Aspergillus had better reactivity towards the fluorine-containing compound represented by formula 1 [11] than that derived from pig 7rrJ complex.
後述する実施１５１１に示すように、アミノアシラーゼ
による含フッ欝フェニルアラニン誘１算１４：の生成速
度は下記の回向にあった。As shown in Example 1511 described below, the production rate of fluorine-containing phenylalanine derivative 14: by aminoacylase was in the following direction.
１’ｌ＋ｅ ＞ １−ＣＦ３−１’ｌ＋ｅ ＝ ｎ−Ｃ
Ｆ３４ｈｅ ＞ ｏ−ＣＦｒ−ｒｌ＋ｅアミノアシラー
ゼの加水分解反応によ）て生成した１体の含フッｌ：フ
ェニルアラニンは反応ｉαをイオン交１灸囚脂に通ずる
ことによりイオン交ＩＦＡＩＡＩ詣に吸着させ゛外見１
生成をすることが出来。1'l+e >1-CF3-1'l+e = n-C
One fluorine-containing phenylalanine produced by the hydrolysis reaction of F34he > o-CFr-rl+e aminoacylase is adsorbed to the ion exchanger IFAIAI by passing the reaction iα through the ion exchanger 1 moxibustion fat. 1
It is possible to generate.
反応１！中に残るＮ−アセチル−（Ｄし）−含フッ累フ
ェニルアラニンは、無水位酵Ｍを用いてラセミ化を行な
わせＤＬ休として、再び下記式のように反応に１１する
ことができる。Reaction 1! The N-acetyl-(D-)-fluorinated phenylalanine remaining therein can be racemized using anhydrous fermentation M and subjected to DL suspension, and then reacted again as shown in the following formula.
なお、出発物質である式［１］で表される化合物は種々
の化学的合成法で製造しうるものである。 例え４ｆ装
置１１Ｊアセチル−（Ｄ Ｌ）−フェニルアラニンは置
換ベンスアルデヒドとアセチルグリシンのｔｎ合物に無
水酢酸と酢酸すトリウムを加えて２時間還流を行ないト
ルフルオロメチルフェニルアズラクトン
アセトン−水系で一晩還流を行ない２−アセチル−３−
トルフルオロメチルフェニル−２−プロペン酸を得る．
次に．酢酸に溶解し．酸化白金触媒化水素で還元すると
Ｎ−アセチル−トリフルオロメチル−フェニルアラニン
が１１＃られる。The starting material, the compound represented by formula [1], can be produced by various chemical synthesis methods. For example, 4F Apparatus 11J Acetyl-(D L)-phenylalanine is prepared by adding acetic anhydride and sodium acetate to a tn compound of substituted benzaldehyde and acetylglycine, refluxing for 2 hours, and overnight in a trifluoromethylphenylazlactone acetone-water system. Reflux to produce 2-acetyl-3-
Trifluoromethylphenyl-2-propenoic acid is obtained.
next. Dissolve in acetic acid. Reduction with platinum oxide catalyzed hydrogen yields N-acetyl-trifluoromethyl-phenylalanine 11#.
以下，本発明を実施例により具体的に説明するが，本発
明はこれら実施例に限定されるものではない。EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.
実施例 １
前記方法で合成した、Ｎ−アセチル−（ＤＬ）ートリフ
ルオロメチルフェニルアラニンから７スペルギルス由来
のアシラーゼを使用して対応するトリフルオロメチルフ
ェニルアラニンを製造した。Example 1 From N-acetyl-(DL)-trifluoromethylphenylalanine synthesized by the above method, the corresponding trifluoromethylphenylalanine was produced using acylase derived from Hepatospergillus.
まず、・トリフルオロメチル基がオル１．メタ位，パラ
位に導入された３種のＮ−アセチル−（ＤＬ）−）リフ
ルオロメチルフェニルアラニン３．３モル（９ ０ ０
ｇ”）をそれぞれ含むリン酸緩衝液（ｐＨ ７．０
）６５Ｌに溶解させ反応液とした． これら３種の反応
ｔαにアスペルギルス由来のＬ−アミノ、アシラーゼ９
，０００Ｕを添加し、３７℃で ２４時間撹拌しながら
反応を行なわせた．（Ｌ−アミノアシラーゼの活性は単
位（Ｕ）で記載する．ＩＵはｐｌ（ Ｅｌ 。First, the trifluoromethyl group is 1. 3.3 mol (900
phosphate buffer (pH 7.0
) was dissolved in 65 L to prepare a reaction solution. Aspergillus-derived L-amino, acylase 9 is involved in these three reactions tα.
,000 U was added thereto, and the reaction was allowed to proceed at 37°C for 24 hours with stirring. (The activity of L-aminoacylase is expressed in units (U). IU is pl (El).
０、３７℃で毎分ＮーアセチルーＬーメチオニン１μｍ
ｏｌを加水分解する酵素量とする．）つぎに、これら３
種の反応液６５Ｌからイオン交換樹脂をもちいて、生成
物の分離を行なった。1μm of N-acetyl-L-methionine per minute at 0.37℃
Let ol be the amount of enzyme to hydrolyze. ) Next, these 3
The product was separated from 65 L of the seed reaction solution using an ion exchange resin.
すなわち、それぞれの反応液にＨＣｌを添加してＩ）Ｈ
ｌ．５とし、凝集沈殿物を目通によって除去し、ｔ１ｔ
αをＨ Ｉ型の強酸性カチオン交喚樹脂に通じ、残存す
るＮ−アセチル−Ｄ−）リフルオロメチルフェニルアラ
ニンは水もしくはメタノールで溶出を行ない回収した．
続いて吸着されているアミノ酸を５％のアンモニア水
で溶出し、この溶離液を減圧濃縮しメタノールにて洗浄
し結晶を得た． その結果を表１に示す。That is, by adding HCl to each reaction solution, I)
l. 5, the flocculated precipitate was removed by sieving, and t1t
α was passed through H type strongly acidic cationic exchange resin, and the remaining N-acetyl-D-)lifluoromethylphenylalanine was recovered by elution with water or methanol.
Subsequently, the adsorbed amino acids were eluted with 5% aqueous ammonia, and the eluate was concentrated under reduced pressure and washed with methanol to obtain crystals. The results are shown in Table 1.
実施例 ２
実施列１で回収したＮ−アセチル−Ｄ−トリフルオロメ
チルフェニルアラニンは減圧Ｓ縮を行ない、メタノール
を除去した後、結晶Ｎ−アセチル−Ｄ−）リアセチルメ
チルフェニルアラニンを表−１に示す量それぞれ回収を
行なった。Example 2 N-acetyl-D-trifluoromethylphenylalanine recovered in Example 1 was subjected to vacuum S condensation to remove methanol, and crystalline N-acetyl-D-)lyacetylmethylphenylalanine was obtained as shown in Table 1. Each amount was collected.
回収した原料の一部それぞれ１００ｇに水２００ｍ１．
水酸化ナトリウム１５ｇを添加し、溶解後無水酢酸４７
００ｇを５０℃、１時間で滴下しながら添加を１テない
、冷却後、析出する結晶を分離した。ラセミ化収率１０
０％、回収収率８０％でａｏｇのＮ−アセチル−ＤＬ−
）リフルオロメチルフェニルアラニンを得た。Add 200ml of water to 100g of each recovered raw material.
Add 15 g of sodium hydroxide, dissolve and then add 47 g of acetic anhydride.
00g was added dropwise at 50°C over 1 hour, and after cooling, the precipitated crystals were separated. Racemization yield 10
N-acetyl-DL- of aog with 0% recovery yield and 80% recovery yield.
) Lifluoromethylphenylalanine was obtained.
なお、Ｎ−アセチル−トリフルオロメチルフェニルアラ
ニンのラセミ化率の測定は、光学分割カラム ＣＨＩ
ＲＡＬ ＰＡＣ’Ｋ （ダイセル）を用い、移動相は
０．２ｍＭ ＣｕＳＯ４を用いた。The racemization rate of N-acetyl-trifluoromethylphenylalanine was measured using an optical resolution column CHI.
RAL PAC'K (Daicel) was used, and the mobile phase was 0.2mM CuSO4.
実施例 ３
０、ＩＮの水酸化ナトリウムｆ？ａ ｉ１１’で調製し
たＤＥＡＥ−セ’７７デツクスＡ−２５（ＯＨｆｆｌ）
ｌＥ３ｍｌにアシラーゼ５０Ｕ （２５０ｍｇ１５０ｍ
ｌ）をイオン吸着させ固定化を行なフた。Example 3 Sodium hydroxide f? DEAE-Se'77dex A-25 (OHffl) prepared in ai11'
50U of acylase (250mg150ml) in 3ml of lE
1) was ion-adsorbed and immobilized.
調製したゲル１６ｍ１をカラＪ１に詰め、Ｎ−アセチル
−ＤＬ−バラ−トリフルオロメチルフェニルアラニン
０．２Ｍを含み水酸化ナトリウムでｐＨ７，０に調製し
た溶液を５Ｖ＝５ｈ、−１で通液を行ない、カラム出口
で生成物であるバラ−トリフルオロメチル−（Ｌ）−フ
ェニルアラニンは４２ｍＭであった。Pack 16 ml of the prepared gel into Kara J1, and add N-acetyl-DL-bala-trifluoromethylphenylalanine.
A solution containing 0.2 M and adjusted to pH 7.0 with sodium hydroxide was passed through the solution at -1 for 5 V = 5 h, and at the column outlet the product rose-trifluoromethyl-(L)-phenylalanine was 42 mM there were.
Claims (1)
り下記［II］で表される光学活性を有する含フッ素フェ
ニルアラニン誘導体に変換せしめることを特徴とする光
学活性を有する含フッ素フェニルアラニン誘導体の製造
方法。 ▲数式、化学式、表等があります▼［ I ］ 式［ I ］において、 Ｘ：０〜３の整数 Ｙ：０〜３の整数（ただし、Ｘ＋Ｙ≦３） ｍ：０〜５の整数 ｎ：０〜５の整数（ただし、ｍ＋ｎ≦５） ▲数式、化学式、表等があります▼［II］ 〔式［ I ］におけるＸ、Ｙ、ｍ、ｎ、は上記式［ I ］
に同じ〕 ２、酵素がアミノアシラーゼであることを特徴とする特
許請求の範囲１項の方法。 ３、変換を酵素および式［ I ］で表される含フッ素化
合物を含む系で行なうことを特徴とする特許請求の範囲
第１項の方法。 ４、式［ I ］で表される含フッ素化合物がＮ−アセチ
ル−トリフルオロメチル−（ＤＬ）−フェニルアラニン
であり、式［II］で表される含フッ素フェニルアラニン
誘導体がトリフルオロメチル−（Ｌ）−フェニルアラニ
ンであることを特徴とする特許請求の範囲第１項の方法
。 ５、式［ I ］で示されるラセミ体の含フッ素化合物を
アミノアシラーゼにより加水分解させ、式［II］で示さ
れるＬ体の光学活性な含フッ素アミノ酸をイオン交換樹
脂により分離し反応系から除く。母液に残存する光学活
性Ｎ−アセチル−（Ｄ）−含フッ素アミノ酸に無水酢酸
を作用せしめてラセミ化を行ない、Ｎ−アセチル−（Ｄ
Ｌ）−含フッ素アミノ酸とし、再びアシラーゼ反応の原
料とすることを特徴とする特許請求の範囲１項の方法。 ６、式［ I ］から式［II］へ酵素反応を行なう場合、
固定化アミノアシラーゼを用いることを特徴とする特許
請求の範囲第１項の方法。[Claims] 1. Having an optical activity characterized by converting a fluorine-containing compound represented by [I] below into a fluorine-containing phenylalanine derivative having an optical activity represented by [II] below using an enzyme. A method for producing a fluorine-containing phenylalanine derivative. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] In the formula [I], An integer of ~5 (however, m+n≦5) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] [X, Y, m, n in formula [I] are the above formula [I]
2. The method according to claim 1, wherein the enzyme is aminoacylase. 3. The method according to claim 1, wherein the conversion is carried out in a system containing an enzyme and a fluorine-containing compound represented by formula [I]. 4. The fluorine-containing compound represented by formula [I] is N-acetyl-trifluoromethyl-(DL)-phenylalanine, and the fluorine-containing phenylalanine derivative represented by formula [II] is trifluoromethyl-(L) - phenylalanine. 5. Hydrolyze the racemic fluorine-containing compound represented by formula [I] with aminoacylase, and separate the L-form optically active fluorine-containing amino acid represented by formula [II] using an ion exchange resin and remove it from the reaction system. . The optically active N-acetyl-(D)-fluorinated amino acid remaining in the mother liquor is racemized by the action of acetic anhydride to form N-acetyl-(D).
2. The method according to claim 1, wherein the fluorine-containing amino acid L) is used again as a raw material for the acylase reaction. 6. When performing an enzymatic reaction from formula [I] to formula [II],
The method according to claim 1, characterized in that an immobilized aminoacylase is used.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29669586A JPS63148990A (en) | 1986-12-15 | 1986-12-15 | Production of fluorine-containing phenylalanine derivative by aminoacylase |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29669586A JPS63148990A (en) | 1986-12-15 | 1986-12-15 | Production of fluorine-containing phenylalanine derivative by aminoacylase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63148990A true JPS63148990A (en) | 1988-06-21 |
Family
ID=17836887
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP29669586A Pending JPS63148990A (en) | 1986-12-15 | 1986-12-15 | Production of fluorine-containing phenylalanine derivative by aminoacylase |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63148990A (en) |
-
1986
- 1986-12-15 JP JP29669586A patent/JPS63148990A/en active Pending
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