JPH04108768A - Production of amino acid ester - Google Patents
Production of amino acid esterInfo
- Publication number
- JPH04108768A JPH04108768A JP22894090A JP22894090A JPH04108768A JP H04108768 A JPH04108768 A JP H04108768A JP 22894090 A JP22894090 A JP 22894090A JP 22894090 A JP22894090 A JP 22894090A JP H04108768 A JPH04108768 A JP H04108768A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- lower alkyl
- amino acid
- 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.)
- Pending
Links
- -1 amino acid ester Chemical class 0.000 title claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 7
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 238000010306 acid treatment Methods 0.000 claims abstract 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 4
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical class O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 abstract description 11
- 150000001413 amino acids Chemical class 0.000 abstract description 7
- 239000002253 acid Substances 0.000 abstract description 5
- 239000002585 base Substances 0.000 abstract description 3
- 150000002081 enamines Chemical class 0.000 abstract description 3
- 125000005843 halogen group Chemical group 0.000 abstract description 3
- 150000008065 acid anhydrides Chemical class 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 12
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 10
- 229960002510 mandelic acid Drugs 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-O Piperidinium(1+) Chemical compound C1CC[NH2+]CC1 NQRYJNQNLNOLGT-UHFFFAOYSA-O 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-O diethylammonium Chemical compound CC[NH2+]CC HPNMFZURTQLUMO-UHFFFAOYSA-O 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、アミノ酸とマンデル酸とからアミノ酸エステ
ルを製造する方法に関する。DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing amino acid esters from amino acids and mandelic acid.
本発明により得られるアミノ酸エステルはペニシリンあ
るいはセファロスポリン系抗生物質のアンル基として有
用である。The amino acid ester obtained according to the present invention is useful as an anchor group in penicillin or cephalosporin antibiotics.
従来の技術
アミノ酸とマンデル酸とからアミノ酸エステルを製造す
る方法としては、（Ａ）７ミノ基を保護したアミノ酸と
カルボキシル基を保護したマンデル酸とを反応させた後
、アミノ基およびカルボキシル基の保護基をそれぞれ除
去する方法（ＮＯ８５１０１０４６）、 （Ｂ）アミノ
基を保護したアミノ酸とマンデル酸とを、ビルスマイヤ
ー試薬、スルホニルハライド類またはハロゲン化リン化
合物などの活性化剤の存在下に反応させる方法（特開昭
６１−１４８１４６号公報）が開示されている。Conventional technology A method for producing an amino acid ester from an amino acid and mandelic acid includes (A) reacting an amino acid with a 7-mino group protected with mandelic acid with a protected carboxyl group, and then protecting the amino group and the carboxyl group. (B) A method of reacting an amino acid with a protected amino group with mandelic acid in the presence of an activator such as a Vilsmeier reagent, sulfonyl halides, or a halogenated phosphorus compound (NO85101046). JP-A-61-148146) is disclosed.
発明が解決しようとする課題
前記（Ａ）法では、工程数が長いこと、高価な保護基（
例えば、ｔ−ブトキシカルボニル）の使用、加水素分解
による保護基（例えば、ペンジルオ牛ジカルボニル、ベ
ンジルエステル）の除去工程での水素ガス使用時の装置
、安全性など、工業的規模での製造法として必ずしも好
ましいものではない。また（Ｂ）法では、刺激性の活性
化剤の使用、上記と同様高価な保護基の使用など、該方
法も工業的製法として必ずしも有利な方法ではない。Problems to be Solved by the Invention The above method (A) requires a long number of steps and requires expensive protecting groups (
Production methods on an industrial scale, such as the use of hydrogen gas (e.g., t-butoxycarbonyl), equipment and safety when using hydrogen gas in the step of removing protecting groups by hydrolysis (e.g., pendyloxycarbonyl, benzyl ester) is not necessarily preferable. In addition, method (B) uses an irritating activator, uses an expensive protecting group as mentioned above, etc., and is not necessarily an advantageous method as an industrial production method.
課Ｕを解決するための手段
本発明によれば、脱保護が容易なエナミンとしてアミノ
基を保護したアミノ酸と無保護のマンデル酸とからアミ
ノ酸エステルを良好な収率で、工業的に有利な方法で実
施可能な製造法が提供される。Means for Solving Section U According to the present invention, an industrially advantageous method for producing an amino acid ester in good yield from an amino acid whose amino group is protected as an enamine that is easy to deprotect and unprotected mandelic acid. A manufacturing method that can be carried out is provided.
即ち本発明は式（１）
式（１）
（式中、Ｒ’は水素、低級アルキルまたは置換もしくは
非置換のベンジルを表わし、Ｒ２は低級アルキルを表わ
し、Ｒ３は水素または低級アルキルを表わし、Ｒ４は低
級アルキルまたは低級アルコキシを表わし、Ｒ５は水素
、アルカリ金属またはアンモニウムを表わす）
で表わされる化合物と、式（Ｉｆ）
Ｘ−Ｃｏｏ−Ｒ’ （ｎ）
（式中、Ｘはハロゲン原子を表わし、Ｒ６は低級アルキ
ルを表わす）
で表わされる化合物とを反応させて得られた反応混合物
と、式（ＩＶ）
口Ｈ
（式中、Ｒ７は、水素、低級アルキルまたは低級アルコ
キシを表わし、Ｒ６は水素、アルカリ金属またはアンモ
ニウムを表わす）
で表わされる化合物とを加えて反応を行わせ、（式中、
Ｒ’〜Ｒ′、Ｒ７およびＲ６は前記と同義である）で表
わされる化合物を得た後、次いで酸処理することを特徴
とする式（ＶＴ）
（式中、Ｒ’、 Ｒ’は前記と同義である）で表わされ
るアミノ酸エステルまたはその塩の製造法に関する。That is, the present invention provides formula (1) formula (1) (wherein R' represents hydrogen, lower alkyl, or substituted or unsubstituted benzyl, R2 represents lower alkyl, R3 represents hydrogen or lower alkyl, and R4 represents lower alkyl or lower alkoxy, R5 represents hydrogen, alkali metal or ammonium) and a compound represented by the formula (If) X-Coo-R' (n) (wherein, X represents a halogen atom, R6 represents lower alkyl) and a reaction mixture obtained by reacting a compound represented by the formula (IV) H (wherein R7 represents hydrogen, lower alkyl or lower alkoxy, R6 represents hydrogen, (representing an alkali metal or ammonium) is added to carry out the reaction, (in the formula,
After obtaining a compound represented by the formula (VT) (R' to R', R7 and R6 are as defined above), the compound is then treated with an acid. This invention relates to a method for producing an amino acid ester or a salt thereof represented by (synonymous).
ここで、Ｒ１〜Ｒ４、Ｒ＠およびＲ７の定義中、低級ア
ルキルおよび低級アルコキシのアルキル部分は、炭素数
１〜４の直鎮または分岐状のアルキル、具体的には、メ
チル、エチル、プロピル、イソプロピル、ブチル、イソ
ブチル、５ｅｃ−ブチルおよびｔｅｒｔ−ブチルを包含
する。Ｒ１の定義中、置換ベンジルの置換基は、ヒドロ
キシなどを包含する。Here, in the definitions of R1 to R4, R@ and R7, the alkyl moiety of lower alkyl and lower alkoxy is a straight or branched alkyl having 1 to 4 carbon atoms, specifically, methyl, ethyl, propyl, Includes isopropyl, butyl, isobutyl, 5ec-butyl and tert-butyl. In the definition of R1, substituents of substituted benzyl include hydroxy and the like.
Ｒ５、Ｉｔ”の定義中、アルカリ金属は、ナトリウム、
カリウムを包含し、またアンモニウムは、シンクロヘキ
シルアンモニウム、ジエチルアンモニウム、トリエチル
アンモニウム、ピペリジニウム、Ｎ−メチルピペリジニ
ウム、Ｎ−メチルモルホリニウムなどの置換または環状
のアンモニウムを包含スる。In the definition of "R5, It", the alkali metal is sodium,
Potassium is included, and ammonium also includes substituted or cyclic ammonium such as synchrohexylammonium, diethylammonium, triethylammonium, piperidinium, N-methylpiperidinium, N-methylmorpholinium, and the like.
また、式（旧においてＸで示されるハロゲン原子は、塩
素、臭素、ヨウ素を包含する。In addition, the halogen atom represented by X in the formula (old) includes chlorine, bromine, and iodine.
化合物（ＶＩ）の塩は、例えば塩酸塩、フマル酸塩、メ
タンスルホン酸塩、パラトルエンスルホン酸塩などが挙
げられる。Examples of the salts of compound (VI) include hydrochloride, fumarate, methanesulfonate, and paratoluenesulfonate.
以下、本発明について詳細に説明する。The present invention will be explained in detail below.
まず、アミノ基をエナミンとして保護した化合物（１）
と化合物（ＩＩ）とを好ましくは塩基の存在下、反応さ
せることにより中間に
次式（ＩＩＩ）
Ｒ’
□
１．椀、ＣＵＲ’
（式中、Ｒ’−Ｒ’およびＲ６は前記と同義である）で
示される混合酸無水物を生成させる。First, a compound (1) with an amino group protected as an enamine
By reacting compound (II) with compound (II), preferably in the presence of a base, the following formula (III) R' □ 1. A mixed acid anhydride represented by CUR' (wherein R'-R' and R6 have the same meanings as above) is produced.
化合物（ｉ）は、相当するアミノ酸と安価に入手容易な
１．３−ジカルボニル化合物より得ることができる。１
，３−ジカルボニル化合物としては、アセト酢酸メチル
、アセト酢酸エチル、アセチルアセトンなどが挙げられ
る。Compound (i) can be obtained from the corresponding amino acid and a 1,3-dicarbonyl compound that is inexpensive and easily available. 1
, 3-dicarbonyl compounds include methyl acetoacetate, ethyl acetoacetate, acetylacetone, and the like.
化合物（旧は化合物（１）に対して１．０〜２．０当量
用いられ、塩基としてはトリエチルアミン、Ｎ−メチル
モルホリン、Ｎ−メチルピペリジンなどが用いられる。1.0 to 2.0 equivalents are used with respect to the compound (formerly compound (1)), and triethylamine, N-methylmorpholine, N-methylpiperidine, etc. are used as the base.
反応溶媒としては、ジクロロメタン、クロロホルム、ジ
クロロエタン、テトラヒドロフラン、ジオキサン、ジグ
ライム、１．２−ジメトキシエタン、アセトン、酢酸エ
チルなどが用いられる。As the reaction solvent, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, dioxane, diglyme, 1,2-dimethoxyethane, acetone, ethyl acetate, etc. are used.
反応は、０℃以下で行われ、反応温度によって異なるが
、通常０．５〜２時間で完了する。The reaction is carried out at 0°C or lower and is usually completed in 0.5 to 2 hours, although it varies depending on the reaction temperature.
生成した化合物（Ｉ［［）は、通常単離することなく、
引き続いて化合物（ＩＶ）と反応させることにより化合
物（Ｖ）を得る。The generated compound (I[[) is usually not isolated,
Compound (V) is then obtained by reacting with compound (IV).
化合物（ＩＶ）は化合物（Ｉ）に対して０．５〜５．０
当量、好ましくは１．０〜２．０当量用いられる。Compound (IV) is 0.5 to 5.0 relative to compound (I)
An equivalent amount is used, preferably 1.0 to 2.0 equivalents.
反応は一５０〜５０℃、好ましくは一２０〜１０℃で行
われ、反応温度によって異なるが、通常０．５〜２時間
で完了する。The reaction is carried out at -50 to 50°C, preferably -20 to 10°C, and is usually completed in 0.5 to 2 hours, depending on the reaction temperature.
生成した化合物（Ｖ）は単離することも可能であるが、
一般には単離することなく、そのまま次工程へ進むこと
もできる。即ち、化合物（Ｖ）を含む反応液をｐ遇した
溶液あるいは直接反応液に、化合物（Ｖ）に対して０．
５〜５当量、好ましくは１．０〜２．０当量の酸を加え
、０〜５０℃、好ましくは１０〜３０℃で１〜１０時間
攪拌することにより脱保護はほぼ定量的に進行し、目的
化合物（ＶＩ）が得られる。Although the generated compound (V) can be isolated,
Generally, it is possible to proceed directly to the next step without isolation. That is, a solution containing a reaction solution containing compound (V) or a direct reaction solution is added at a concentration of 0.0% relative to compound (V).
Deprotection proceeds almost quantitatively by adding 5 to 5 equivalents, preferably 1.0 to 2.0 equivalents of acid, and stirring at 0 to 50°C, preferably 10 to 30°C, for 1 to 10 hours. The target compound (VI) is obtained.
酸としては、塩酸、メタンスルホン酸またはノくラドル
エンスルホン酸などが挙げられる。Examples of the acid include hydrochloric acid, methanesulfonic acid, and noradruenesulfonic acid.
化合物（Ｖｌ）は、一般の濾過、再結晶などにより単離
、精製することができる。なお、より高純度の化合物（
Ｖｌ）を所望の場合は、単離した化合物（ＶＩ）へメタ
ノールを加えて懸濁させた溶液を攪拌し、不溶物を濾過
することにより、リスラリ−精製することができる。Compound (Vl) can be isolated and purified by general filtration, recrystallization, etc. In addition, higher purity compounds (
When Vl) is desired, it can be reslurry-purified by adding methanol to the isolated compound (VI), stirring the suspension, and filtering insoluble matter.
方法は、１０〜６０℃、好ましくは２０−４０℃で、０
．５〜６時間攪拌させた後、濾過することにより高純度
の化合物を高収率で得ることができる。The method involves heating at 10-60°C, preferably 20-40°C, and 0
．． After stirring for 5 to 6 hours, a highly pure compound can be obtained in high yield by filtration.
本発明の製造法で得られる化合物（ＶＴ）のうち、例え
ばＤ−０−（Ｌ−アラニル）マンデル酸はＷＯ３４１０
２２７２に言己載のセファロスポリン系抗生物質のアシ
ル基として用いられる。Among the compounds (VT) obtained by the production method of the present invention, for example, D-0-(L-alanyl)mandelic acid is
It is used as an acyl group in cephalosporin antibiotics, which are described in Japanese, No. 2272.
以下の参考例および実施例により本発明の詳細な説明す
る。The present invention will be explained in detail with reference to the following reference examples and examples.
参考例１
３− Ｃ（１−カルボキシエチル）アミノコ−２−ブテ
ン酸メチルエステルジシクロヘキシルアミン塩の合成
アセト酢酸メチル２５０ｄおよびＬ−アラニン１７８ｇ
をメタノール２．５β中へ添加し、加熱還流下ジシクロ
ヘキシルアミン４００ｇを３０分間で滴下した後、反応
混合液が均一な溶液になるまで３時間加熱還流した。反
応液を減圧濃縮し、インプロピルアルコール５００ｍ１
を加え、さらに濃縮した。濃縮液にイソプロピルアルコ
ールＩｉ！と酢酸エチル３５０ｄとを加え、６０℃まで
加熱した後３０分間攪拌後、水冷下で析出した結晶を戸
数、乾燥することにより標題化合物６５３ｇ （収率
８８．６％）を得た。Reference Example 1 Synthesis of 3-C(1-carboxyethyl)aminoco-2-butenoic acid methyl ester dicyclohexylamine salt 250 d of methyl acetoacetate and 178 g of L-alanine
was added to methanol 2.5β, and 400 g of dicyclohexylamine was added dropwise over 30 minutes while heating under reflux, followed by heating under reflux for 3 hours until the reaction mixture became a homogeneous solution. The reaction solution was concentrated under reduced pressure, and 500ml of inpropyl alcohol was added.
was added and further concentrated. Isopropyl alcohol II for the concentrate! After heating to 60° C. and stirring for 30 minutes, the precipitated crystals were dried several times under water cooling to obtain 653 g (yield: 88.6%) of the title compound.
融点：１５２〜１５３℃
〔α］、 ＝＋７２〜７３° （Ｃ・１．メタノール
）ＩＲ（ＫＢｒ錠剤）（ａｍ−’） ： ７８０．１０
６０． １１６０． １２６０゜１５８０、１６０５．
１６６０．２９９０’Ｈ−ＮＭＲ（ＣＤＣｊ）、）（ｐ
ｐｍ） ： １．４５（ｄ、３Ｈ）、 １．９４（ｓ、
３）１）。Melting point: 152-153°C [α], = +72-73° (C.1. Methanol) IR (KBr tablet) (am-'): 780.10
60. 1160. 1260°1580, 1605.
1660.2990'H-NMR (CDCj), ) (p
pm): 1.45 (d, 3H), 1.94 (s,
3)1).
３．６２（ｓ、３Ｈ）、 ４．００（ｄｔ、１）１）、
４．４３（ｓ、ＬＨ＞、 ８，９８（ｄ、１）Ｉ）、
１．１〜２．１５（ｍ、２２Ｈ）、 ３．０１（ｔ、
２Ｈ）実施例Ｉ
Ｄ−０−（Ｌ−アラニル）マンデル酸の合成参考例工で
得られる３−Ｃ（１−カルボキシエチル）アミノコ−２
−ブテン酸メチルエステルジシクロヘキシルアミン塩１
４７ｇｋよびトリエチルアミン５．５８−をジクロロエ
タン８００ｄ中へ添加し、０℃以下でクロロギ酸エチル
４２ｍをジクロロエタン８０ｍに混合した溶液を加え、
同温度で３０分間攪拌した。次いで、ジクロロエタン８
００ｄ中にＤ−マンデル！ ６６．８ｇとトリエチル
アミン６１．４ｍｌとを溶解させた溶液を冷却下漬下し
２時間攪拌した。反応液を室温まで昇温した後、析出し
た白色結晶を濾過し、Ｐ液に濃塩酸４０ｍ１を加え室温
下で４時間攪拌した。攪拌後析出した白色結晶を濾過し
た後、乾燥することにより！！！化合物８０．７ｇ（収
率９０．４％）を得た。3.62 (s, 3H), 4.00 (dt, 1) 1),
4.43 (s, LH>, 8,98 (d, 1) I),
1.1-2.15 (m, 22H), 3.01 (t,
2H) Example I Synthesis of D-0-(L-alanyl)mandelic acid Reference example 3-C(1-carboxyethyl)aminoco-2 obtained by the procedure
-Butenoic acid methyl ester dicyclohexylamine salt 1
Add 47 gk and 5.58 g of triethylamine into 800 d of dichloroethane, add a solution of 42 ml of ethyl chloroformate mixed in 80 ml of dichloroethane at below 0°C,
The mixture was stirred at the same temperature for 30 minutes. Then dichloroethane 8
D-Mandel during 00d! A solution containing 66.8 g and 61.4 ml of triethylamine was soaked under cooling and stirred for 2 hours. After the reaction solution was heated to room temperature, the precipitated white crystals were filtered, 40 ml of concentrated hydrochloric acid was added to the P solution, and the mixture was stirred at room temperature for 4 hours. By filtering the white crystals that precipitated after stirring and then drying them! ! ! 80.7 g (yield 90.4%) of the compound was obtained.
上記化合物をさらにメタノール４００ｄを用いて４０℃
で１時間リスラリ−精製することにより高純度の化合物
を得た。The above compound was further mixed with methanol 400d at 40°C.
A highly pure compound was obtained by reslurry purification for 1 hour.
融点＝１５６〜１５８℃（分解）
〔α］ ＝−１１１，１６° （ｃ＝０．２． メタ
ノール）［Ｒ（ＫＢｒ錠剤）（ａｍ−’） ：？１０．
１１９０，１２４０．１７３０．３０５０’）Ｉ−ＮＭ
Ｒ（Ｄ、０）（ｐｐｍ） ： １．３６（ｄ、３Ｈ）、
４．１２（ｑ、ＩＩＩ）。Melting point = 156-158°C (decomposition) [α] = -111,16° (c = 0.2. Methanol) [R (KBr tablet) (am-'):? 10.
1190,1240.1730.3050')I-NM
R (D, 0) (ppm): 1.36 (d, 3H),
4.12 (q, III).
５．７０（ｓ、ＩＨ）、 ７．２〜７．３（ｍ、５Ｈ
）元素分析値
理論値（％） ： Ｃ５９，１８，Ｈ５，８７，Ｎ ６
．２８実測値（％） ： Ｃ５ｇ、３７． Ｈ５，９
６，Ｎ ６．３１実施例２
Ｄ−〇−（Ｌ−アラニル）マンデル酸の合成りロロギ酸
エチルの代わりにクロロギ酸イソブチル５７．２ｍを用
いる以外は、実施例１と同様の操作を行うことにより標
題化合物７７．４ｇ （収率８６．７％）を得た。5.70 (s, IH), 7.2-7.3 (m, 5H
) Elemental analysis value Theoretical value (%): C59,18, H5,87, N6
．． 28 Actual value (%): C5g, 37. H5,9
6,N 6.31 Example 2 Synthesis of D-〇-(L-alanyl)mandelic acid Perform the same operation as Example 1 except that 57.2m of isobutyl chloroformate is used instead of ethyl chloroformate. 77.4 g (yield: 86.7%) of the title compound was obtained.
実施例３
Ｄ−０−（Ｌ−アラニル）マンデル酸塩酸塩の合成
り−０−（Ｌ−アラニル）マンデル酸７５．０ｇを酢酸
１５０−中に添加し、攪拌しながら濃塩酸２７ｍ１を加
えて溶解させた。次いで該混合液中に酢酸エチル１，６
１を加え、析出した白色結晶を一過、乾燥することによ
り標題化合物８４．１ｇ（収率９６．４％）を得た。Example 3 Synthesis of D-0-(L-alanyl)mandelic acid hydrochloride 75.0g of 0-(L-alanyl)mandelic acid was added to 150ml of acetic acid, and 27ml of concentrated hydrochloric acid was added with stirring. Dissolved. Then, 1,6 ethyl acetate was added to the mixture.
1 was added, and the precipitated white crystals were temporarily dried to obtain 84.1 g (yield: 96.4%) of the title compound.
融点：１８１℃ （分解）
ＩＲ（ＫＢｒ錠剤）（ａｍ−’） ： １１７０．１４
９０．１７４５．３０００’ ｌ（−ＮＭＲ（島の（ｐ
ｐｍ） ： １．３８（ｄ、３Ｈ）、 ４．托（ｑ、１
．）Ｉ）。Melting point: 181°C (decomposition) IR (KBr tablet) (am-'): 1170.14
90.1745.3000'l(-NMR(island(p
pm): 1.38 (d, 3H), 4. q, 1
．． )I).
５、９２ （ｓ、 ＩＨ） 、 ？、２７〜７．３３
（ｍ、 ５Ｈ）発明の効果
本発明によりアミノ酸エステルを簡便な操作で良好な収
率で得ることができる。5,92 (s, IH), ? , 27-7.33
(m, 5H) Effects of the Invention According to the present invention, amino acid esters can be obtained in good yields with simple operations.
Claims (1)
は非置換のベンジルを表わし、Ｒ＾２は低級アルキルを
表わし、Ｒ＾３は水素または低級アルキルを表わし、Ｒ
＾４は低級アルキルまたは低級アルコキシを表わし、Ｒ
＾５は水素、アルカリ金属またはアンモニウムを表わす
） で表わされる化合物と、式（II） Ｘ−ＣＯＯ−Ｒ＾６（II） （式中、Ｘはハロゲン原子を表わし、Ｒ＾６は低級アル
キルを表わす） で表わされる化合物とを反応させて得られた反応混合物
と、式（IV） ▲数式、化学式、表等があります▼（IV） （式中、Ｒ＾７は、水素、低級アルキルまたは低級アル
コキシを表わし、Ｒ＾８は水素、アルカリ金属またはア
ンモニウムを表わす） で表わされる化合物とを加えて反応を行わせ、式（Ｖ） ▲数式、化学式、表等があります▼（Ｖ） （式中、Ｒ＾１〜Ｒ＾４、Ｒ＾７およびＲ＾８は前記と
同義である）で表わされる化合物を得た後、次いで酸処
理することを特徴とする式（VI） ▲数式、化学式、表等があります▼（VI） （式中、Ｒ＾１、Ｒ＾７は前記と同義である）で表わさ
れるアミノ酸エステルまたはその塩の製造法。[Claims] Formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents hydrogen, lower alkyl, or substituted or unsubstituted benzyl, and R^2 represents lower represents alkyl, R^3 represents hydrogen or lower alkyl, R
^4 represents lower alkyl or lower alkoxy, R
^5 represents hydrogen, alkali metal or ammonium) and a compound represented by the formula (II) The reaction mixture obtained by reacting the compound represented by the formula (IV) with the compound represented by the formula (IV) ▲Mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R^7 is hydrogen, lower alkyl, or lower (represents alkoxy and R^8 represents hydrogen, alkali metal or ammonium) and reacts with the compound represented by the formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) , R^1 to R^4, R^7 and R^8 have the same meanings as above), and then acid treatment is performed. Formula (VI) ▲ Numerical formula, chemical formula, There are tables, etc. ▼(VI) A method for producing an amino acid ester or its salt represented by the formula (wherein R^1 and R^7 have the same meanings as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22894090A JPH04108768A (en) | 1990-08-30 | 1990-08-30 | Production of amino acid ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22894090A JPH04108768A (en) | 1990-08-30 | 1990-08-30 | Production of amino acid ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04108768A true JPH04108768A (en) | 1992-04-09 |
Family
ID=16884239
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP22894090A Pending JPH04108768A (en) | 1990-08-30 | 1990-08-30 | Production of amino acid ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04108768A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008139539A1 (en) * | 2007-04-27 | 2008-11-20 | Ajinomoto Co., Inc. | Process for producing valacyclovir |
-
1990
- 1990-08-30 JP JP22894090A patent/JPH04108768A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008139539A1 (en) * | 2007-04-27 | 2008-11-20 | Ajinomoto Co., Inc. | Process for producing valacyclovir |
| JP5152180B2 (en) * | 2007-04-27 | 2013-02-27 | 味の素株式会社 | Method for producing valaciclovir |
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