JPH0426661A - Preparation of 3-(n-benzyl-n-alkoxycarbonylalkylamino) propionic acid ester - Google Patents
Preparation of 3-(n-benzyl-n-alkoxycarbonylalkylamino) propionic acid esterInfo
- Publication number
- JPH0426661A JPH0426661A JP13195490A JP13195490A JPH0426661A JP H0426661 A JPH0426661 A JP H0426661A JP 13195490 A JP13195490 A JP 13195490A JP 13195490 A JP13195490 A JP 13195490A JP H0426661 A JPH0426661 A JP H0426661A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- acid ester
- propionic acid
- lower alkyl
- 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.)
- Granted
Links
- 150000003151 propanoic acid esters Chemical class 0.000 title claims description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims abstract description 16
- -1 halogeno carboxylic acid Chemical class 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 6
- QRDUQWYMGXZIKM-UHFFFAOYSA-N 3-(benzylamino)propanoic acid Chemical compound OC(=O)CCNCC1=CC=CC=C1 QRDUQWYMGXZIKM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 229910052751 metal Inorganic materials 0.000 claims abstract description 4
- 239000002184 metal Substances 0.000 claims abstract description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- 125000001302 tertiary amino group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 abstract description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 abstract description 4
- FKCMADOPPWWGNZ-YUMQZZPRSA-N [(2r)-1-[(2s)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O FKCMADOPPWWGNZ-YUMQZZPRSA-N 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 abstract description 3
- 239000002243 precursor Substances 0.000 abstract description 3
- 150000003512 tertiary amines Chemical class 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 235000015320 potassium carbonate Nutrition 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 5
- 239000011521 glass Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GKQHIYSTBXDYNQ-UHFFFAOYSA-M 1-dodecylpyridin-1-ium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+]1=CC=CC=C1 GKQHIYSTBXDYNQ-UHFFFAOYSA-M 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 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
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 description 1
- HCTJHQFFNDLDPF-UHFFFAOYSA-N ethyl 3-(benzylamino)propanoate Chemical compound CCOC(=O)CCNCC1=CC=CC=C1 HCTJHQFFNDLDPF-UHFFFAOYSA-N 0.000 description 1
- JWYHGTSTWMQTHS-UHFFFAOYSA-N ethyl 3-[benzyl-(2-ethoxy-2-oxoethyl)amino]propanoate Chemical compound CCOC(=O)CCN(CC(=O)OCC)CC1=CC=CC=C1 JWYHGTSTWMQTHS-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 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
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【発明の詳細な説明】
〈産業上の利用分野〉
本発明は、−形式（Ｉ）
Ｃ式中、Ｒ１及びＲ４は低級アルキル基を示す。Ｒ２及
びＲ３は水素原子又は低級アルキル基を示す。）
で表わされる３−（Ｎ−ベンジル−Ｎ−アルコキシカル
ボニルアルキルアミノ）プロピオン酸エステルの製法に
関する。DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention is directed to -Form (I) In the formula C, R1 and R4 represent a lower alkyl group. R2 and R3 represent a hydrogen atom or a lower alkyl group. ) It relates to a method for producing 3-(N-benzyl-N-alkoxycarbonylalkylamino)propionic acid ester.
本発明の方法で得られる一般式（Ｉ）の化合物は医薬の
合成中間体であるピロリジン誘導体の前駆体として有用
なものである。The compound of general formula (I) obtained by the method of the present invention is useful as a precursor of a pyrrolidine derivative, which is a synthetic intermediate for pharmaceuticals.
（以下余白）
〈従来技術〉
形式（Ｉ）
の化合物の製法に関する従来方法
としては、
（式中、Ｒ２，Ｒ８及びＲ４は前記に同じ。）で表わさ
れるＮ−ベンジルアミノ酸エステルとアクリル酸エステ
ルとを反応させて製造する方法がある（特開昭５１−５
６４１８号）。(The following is a blank space) <Prior art> As a conventional method for producing a compound of type (I), an N-benzyl amino acid ester and an acrylic ester represented by (wherein R2, R8 and R4 are the same as above) are used. There is a method of manufacturing by reacting (JP-A-51-5
No. 6418).
〈発明が解決しようとする課題〉
しかしながら、この従来方法は一般式（Ｉ）の化合物の
収率が満足できるものではなく、さらに出発物質である
Ｎ−ベンジルアミノ酸エステルが比較的高価なアミノ酸
エステルから得られるものであり、工業的に有利な方法
とは言い難い製法である。<Problems to be Solved by the Invention> However, this conventional method does not provide a satisfactory yield of the compound of general formula (I), and furthermore, the starting material, N-benzyl amino acid ester, is difficult to obtain from a relatively expensive amino acid ester. This is a manufacturing method that cannot be said to be industrially advantageous.
本発明の目的は比較的安価な出発物質から収率よ＜−形
式（Ｉ）の化合物を製造する方法を提供することにある
。It is an object of the present invention to provide a method for producing compounds of the form (I) in high yields from relatively inexpensive starting materials.
〈課題を解決するための手段〉
本発明は、−形式（ＩＩ）：
で表わされる３−（Ｎ−ベンジルアミノ）プロピオン酸
エステルを、脱酸剤の存在下、−形式％式％）
（式中、Ｒ２，Ｒ３及びＲ４は前記に同じ。<Means for Solving the Problems> The present invention provides a method for treating a 3-(N-benzylamino)propionic acid ester represented by -Form (II): in the presence of an acid absorbing agent in the form of -Form %Formula%) (Formula %Formula %) Inside, R2, R3 and R4 are the same as above.
Ｘｌはハロゲン原子を示す。）
で表わされるハロカルボン酸エステルと反応させること
を特徴とする一般式（Ｉ）の化合物の製法に関するもの
である。Xl represents a halogen atom. ) The present invention relates to a method for producing a compound of general formula (I), which is characterized by reacting the compound with a halocarboxylic acid ester represented by the formula (I).
形式（Ｉ）、（ＩＴ ）及び（ＩＩＩ ）において、Ｒ
＋ 、Ｒ２、Ｒ３及びＲ４で表わされる低級アルキル基
としては、メチル基、エチル基、プロピル基、イソプロ
ピル基、ブチル基、イソブチル基、ｔｅｒｔ−ブチル基
等の炭素数１〜４のアルキル基が挙げられる。In forms (I), (IT) and (III), R
Examples of the lower alkyl group represented by +, R2, R3 and R4 include alkyl groups having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, and tert-butyl group. It will be done.
−ＡＧ式（ｎ［）においてＸｌで表わされるハロゲン原
子としては、塩素、臭素、ヨウ素等の原子が挙げられる
。Examples of the halogen atom represented by Xl in the -AG formula (n[) include atoms such as chlorine, bromine, and iodine.
本発明の出発物質である一般式（ＴＩ）の化合物は、ベ
ンジルアミンとアクリル酸エステルとを反応させること
により容易に得ることができる。The compound of general formula (TI), which is a starting material of the present invention, can be easily obtained by reacting benzylamine with an acrylic ester.
本発明の脱酸剤としては第３級アミン及び炭酸金属塩が
好適である。第３級アミンとしては、トリメチルアミン
、トリエチルアミン、ｌ−メチルピペリジン、ピリジン
、ジメチルアニリン等が挙げられる。炭酸金属塩として
は、炭酸ナトリウム、炭酸カリウム等の炭酸アルカリ金
属塩が挙げられる。As the deoxidizing agent of the present invention, tertiary amines and metal carbonates are suitable. Examples of the tertiary amine include trimethylamine, triethylamine, l-methylpiperidine, pyridine, dimethylaniline, and the like. Examples of metal carbonate include alkali metal carbonate such as sodium carbonate and potassium carbonate.
本発明の方法を実施するにあたっては、本発明の反応に
不活性な溶媒を使用することができる。In carrying out the method of the invention, solvents that are inert to the reaction of the invention can be used.
溶媒の具体例としては、ベンゼン、トルエン、キシレン
等の芳香族炭化水素、メチルエチルケトン、メチルイソ
ブチルケトン等のケトン類、エチルアルコール、イソプ
ロピルアルコール等のアルコール類、テトラハイドロフ
ラン、ジオキサン等のエーテル類などを挙げることがで
きる。Specific examples of solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, ketones such as methyl ethyl ketone and methyl isobutyl ketone, alcohols such as ethyl alcohol and isopropyl alcohol, and ethers such as tetrahydrofuran and dioxane. can be mentioned.
本発明の反応を第４ｍアンモニウム塩及び／またはヨウ
化カリウムを共存させて実施すると、反応がより短時間
で終了し、しかもより高収率で一般式（Ｉ）の化合物を
得ることができる。したがって、第４級アンモニウム塩
またはヨウ化カリウムを共存させることは、本発明の方
法をより好適に実施せしめる。When the reaction of the present invention is carried out in the presence of a quaternary ammonium salt and/or potassium iodide, the reaction can be completed in a shorter time and the compound of general formula (I) can be obtained in a higher yield. Therefore, the coexistence of a quaternary ammonium salt or potassium iodide allows the method of the present invention to be carried out more suitably.
第４級アンモニウム塩としては、−数式（１■）バフ
（式中、Ｒ５，Ｒａ 、Ｒ７及びＲｅはアルキル基又は
アラルキル基あるいは結合している窒素原子といっしょ
になって複素環を示す。As the quaternary ammonium salt, -Buff (formula (1)) (wherein R5, Ra, R7 and Re together with an alkyl group or an aralkyl group or a bonded nitrogen atom represents a heterocycle).
ｘ２は無機酸又は有機酸の陰イオン残基を示す。）
で表わされる化合物が挙げられる。具体的には、テトラ
メチルアンモニウムクロライド、テトラエチルアンモニ
ウムクロライド、テトラブチルアンモニウムフロライド
、テトラブチルアンモニウムクロライド、テトラブチル
アンモニウムブロマイド、テトラブチルアンモニウムア
イオダイド、テトラブチルアンモニウムハイドロジエン
スルフエト、トリオクチルメチルアンモニウムクロライ
ド、ベンジルトリエチルアンモニウムクロライド、ベン
ジルトリエチルアンモニウムブロマイド、Ｎ−ラウリル
ピリジニウムクロライド、Ｎ−ラウリルビコリニウムク
ロライド等が挙げられる。x2 represents an anionic residue of an inorganic or organic acid. ) Compounds represented by: Specifically, tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride. , benzyltriethylammonium chloride, benzyltriethylammonium bromide, N-laurylpyridinium chloride, N-laurylvicolinium chloride, and the like.
一１１９式（ＩＩＩ ）の化合物及び脱酸剤の使用量は
、−数式（ＩＩ ）の化合物１モルに対して、それぞれ
０．５〜３モル好ましくは１〜２モル及び０５〜５モル
好ましくは１〜３モルである。第４級アンモニウム塩及
び／またはヨウ化カリウムは、数式（ＩＩ）の化合物１
モルに対して０．００１モル以上いくら使用してもよい
が、通常０．００１〜０．１モル使用する。The amount of the compound of formula (III) and the deoxidizing agent to be used is 0.5 to 3 mol, preferably 1 to 2 mol, and preferably 0.5 to 5 mol, respectively, per 1 mol of the compound of formula (II). It is 1 to 3 moles. The quaternary ammonium salt and/or potassium iodide is compound 1 of formula (II)
Although it may be used in an amount of 0.001 mol or more per mole, it is usually used in a range of 0.001 to 0.1 mol.
反応温度は通常５０℃〜１５０°Ｃの範囲であるが、好
ましくは７０℃〜１２０℃の範囲である。The reaction temperature is usually in the range of 50°C to 150°C, preferably in the range of 70°C to 120°C.
このようにして生成した一般式（Ｉ）の化合物は、反応
終了後の反応液から塩類を濾別して得られる濾液、又は
当該反応液に水を添加して塩類を溶解せしめ分液して得
られる有機層を濃縮することにより、単離される。また
溶媒として芳香族炭化水素を使用した場合は、溶媒を除
去することなく反応終了後の反応液をそのまま、ピロリ
ジン誘導体への原料として用いることが可能ある。The compound of general formula (I) produced in this way can be obtained from a filtrate obtained by filtering salts from the reaction solution after the completion of the reaction, or by adding water to the reaction solution to dissolve salts and separating the liquid. Isolate by concentrating the organic layer. Furthermore, when an aromatic hydrocarbon is used as a solvent, the reaction solution after the reaction can be used as it is as a raw material for a pyrrolidine derivative without removing the solvent.
実施例１
１ρ容のガラス製反応器に３−（Ｎ−ベンジルアミノ）
プロピオン酸エチルエステル２０７ｇ、トルエン２０７
ｇ及びトリエチルアミン１２１ｇを仕込み、９５°Ｃに
加熱した。撹拌下クロル酢酸エチル１４７ｇを２時間で
滴下し、９５〜１０５°Ｃで１６時間反応させた。反応
終了後１反応液を５０°Ｃに冷却し、水１５０ｇ加えて
析出している塩を溶解させた。溶解後、反応液を分液し
て有機層を得た。有機層を水１００ｇで洗浄し、次いで
減圧下で濃縮して、淡褐色油状の３−（Ｎ−ベンジル−
Ｎ−エトキシカルボニルメチルアミノ）プロピオン酸エ
チルエステル２４９ｇ （収率８５％）を得た。Example 1 3-(N-benzylamino) was added to a 1ρ glass reactor.
Propionate ethyl ester 207g, toluene 207g
g and 121 g of triethylamine were charged and heated to 95°C. While stirring, 147 g of ethyl chloroacetate was added dropwise over 2 hours, and the mixture was reacted at 95 to 105°C for 16 hours. After the reaction was completed, one reaction solution was cooled to 50°C, and 150g of water was added to dissolve the precipitated salt. After dissolution, the reaction solution was separated to obtain an organic layer. The organic layer was washed with 100 g of water and then concentrated under reduced pressure to give a pale brown oil of 3-(N-benzyl-
249 g (yield: 85%) of N-ethoxycarbonylmethylamino)propionic acid ethyl ester was obtained.
実施例２
テトラブチルアンモニウムブロマイド４ｇを共存させ且
つ反応時間を６時間にした以外は、実施例１と同条件下
で反応及び後処理をして、淡褐色油状の３−（Ｎ〜ベン
ジル−Ｎ−エトキシカルボニルメチルアミノ）プロピオ
ン酸エチルエステル２８７ｇ （収率９８％）を得た。Example 2 The reaction and post-treatment were carried out under the same conditions as in Example 1, except that 4 g of tetrabutylammonium bromide was present and the reaction time was 6 hours. 287 g (yield: 98%) of -ethoxycarbonylmethylamino)propionic acid ethyl ester was obtained.
実施例３
１ρ容のガラス製反応器に３−（Ｎ−ベンジルアミノ）
プロピオン酸メチルエステル１９３ｇ、トルエン３００
ｇ、トリエチルアミン１２１ｇ及びテトラブチルアンモ
ニウムブロマイド４ｇを仕込み、９５°Ｃに加熱した。Example 3 3-(N-benzylamino) in a 1ρ glass reactor
Propionate methyl ester 193g, toluene 300
g, 121 g of triethylamine and 4 g of tetrabutylammonium bromide were charged and heated to 95°C.
撹拌下クロル酢酸メチル１３０ｇを２時間で滴下し、９
５〜ｌＯＯ℃で６時間反応させた。反応終了後、反応液
を実施例ｌと同様に処理して、３−（Ｎ−ベンジル−Ｎ
メトキシカルボニルメチルアミノ）プロピオン酸メチル
エステル２６１ｇ（収率９８５％）を得た。While stirring, 130 g of methyl chloroacetate was added dropwise over 2 hours, and 9
The reaction was carried out at 5-100° C. for 6 hours. After the reaction was completed, the reaction solution was treated in the same manner as in Example 1 to obtain 3-(N-benzyl-N
261 g (yield: 985%) of methoxycarbonylmethylamino)propionic acid methyl ester was obtained.
実施例４
２０ｆ２容のガラス製反応器に３−（Ｎ−ベンジルアミ
ノ）プロピオン酸エチルエステル１６４７ｇ、メチルエ
チルケトン２５４６ｇ、炭酸カリウム１０９８ｇ及びヨ
ウ化カリウム１６ｇを仕込み、７５℃に加熱した。撹拌
下クロル酢酸エチル９７５ｇを２時間で滴下し、７５〜
８０ ’Ｃで５時間反応させた。反応終了後、反応液を
室温まで冷却し、析出している塩を濾過し、塩類をメチ
ルエチルケトン１０００ｇで洗浄した。得られた濾液及
び洗液を減圧下で濃縮して、淡褐色油状の３（Ｎ−ベン
ジル−Ｎ−エトキシカルボニルメチルアミノ）プロピオ
ン酸エチルエステル２２３８ｇ（収率９６％）を得た。Example 4 1647 g of 3-(N-benzylamino)propionic acid ethyl ester, 2546 g of methyl ethyl ketone, 1098 g of potassium carbonate, and 16 g of potassium iodide were placed in a 20 f2 glass reactor and heated to 75°C. While stirring, 975 g of ethyl chloroacetate was added dropwise over 2 hours.
The reaction was carried out at 80'C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the precipitated salts were filtered, and the salts were washed with 1000 g of methyl ethyl ketone. The obtained filtrate and washing liquid were concentrated under reduced pressure to obtain 2238 g (yield 96%) of ethyl 3(N-benzyl-N-ethoxycarbonylmethylamino)propionate as a light brown oil.
実施例５
２℃容のガラス製反応器に３−（Ｎ−ベンジルβ−アミ
ノ）プロピオン酸エチルエステル２０７ｇ、キシレン３
００ｇ、トリエチルアミン１２１ｇ及びテトラブチルア
ンモニウムブロマイド４ｇを仕込み、９３°Ｃに加熱し
た。撹拌下２−ブロムプロピオン酸エチル２７１ｇを３
時間で滴下し、９５〜１０５°Ｃで９時間反応させた。Example 5 In a 2°C glass reactor, 207 g of 3-(N-benzyl β-amino)propionic acid ethyl ester and 3 xylene were added.
00g, triethylamine 121g and tetrabutylammonium bromide 4g were charged and heated to 93°C. While stirring, 271 g of ethyl 2-bromopropionate was added to 3
The mixture was added dropwise at 95 to 105°C for 9 hours.
反応終了後、反応液を実施例１と同様に処理して、３−
［Ｎ−ベンジル−Ｎ−（１−エトキシカルボニルエチル
）アミノコプロピオン酸エチルエステル３０６ｇ（収率
９９，７％）を得た。After the reaction was completed, the reaction solution was treated in the same manner as in Example 1 to obtain 3-
[306 g (yield 99.7%) of N-benzyl-N-(1-ethoxycarbonylethyl)aminocopropionic acid ethyl ester was obtained.
〈発明の効果〉
本発明方法によれば、従来方法にくらべて、より安価な
出発物質を用いて容易により高収率で一般式（Ｉ）の化
合物を得ることができる。<Effects of the Invention> According to the method of the present invention, the compound of general formula (I) can be easily obtained in a higher yield using cheaper starting materials than in the conventional method.
Claims (3)
る３−（Ｎ−ベンジルアミノ）プロピオン酸エステルを
、脱酸剤の存在下、一般式（III）： ▲数式、化学式、表等があります▼（III） （式中、Ｒ＿２及びＲ＿３は水素原子又は低級アルキル
基を、Ｒ＿４は低級アルキル基を示す。 Ｘ＿１はハロゲン原子を示す。） で表わされるハロカルボン酸エステルと反応させること
を特徴とする一般式（ I ）： ▲数式、化学式、表等があります▼（ I ） （式中、Ｒ＿１、Ｒ＿２、Ｒ＿３及びＲ＿４は前記に同
じ。） で表わされる３−（Ｎ−ベンジル−Ｎ−アルコキシカル
ボニルアルキルアミノ）プロピオン酸エステルの製法。(1) General formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, R_1 represents a lower alkyl group.) 3-(N-benzylamino)propionic acid ester , in the presence of a deoxidizing agent, general formula (III): ▲Mathematical formula, chemical formula, table, etc.▼(III) (In the formula, R_2 and R_3 represent a hydrogen atom or a lower alkyl group, and R_4 represents a lower alkyl group. (X_1 represents a halogen atom.) General formula (I) characterized by reacting with a halocarboxylic acid ester represented by R_3 and R_4 are the same as above.) A method for producing 3-(N-benzyl-N-alkoxycarbonylalkylamino)propionic acid ester.
を共存させることを特徴とする請求項１記載の製法。(2) The method according to claim 1, characterized in that a quaternary ammonium salt and/or potassium iodide are present.
項１記載の製法。(3) The method according to claim 1, wherein the deoxidizing agent is a tertiary amine or a metal carbonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13195490A JP3167705B2 (en) | 1990-05-21 | 1990-05-21 | Method for producing 3- (N-benzyl-N-alkoxycarbonylalkylamino) propionic acid ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13195490A JP3167705B2 (en) | 1990-05-21 | 1990-05-21 | Method for producing 3- (N-benzyl-N-alkoxycarbonylalkylamino) propionic acid ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0426661A true JPH0426661A (en) | 1992-01-29 |
| JP3167705B2 JP3167705B2 (en) | 2001-05-21 |
Family
ID=15070095
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13195490A Expired - Fee Related JP3167705B2 (en) | 1990-05-21 | 1990-05-21 | Method for producing 3- (N-benzyl-N-alkoxycarbonylalkylamino) propionic acid ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3167705B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011523658A (en) * | 2008-06-02 | 2011-08-18 | シプラ・リミテッド | Synthetic method of alformoterol |
| KR20160089542A (en) | 2014-06-25 | 2016-07-27 | 미츠비시 쥬고교 가부시키가이샤 | Labyrinth seal device for axial-flow turbine and exhaust gas turbocharger equipped with same |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6116749A (en) | 1998-06-03 | 2000-09-12 | Spaulding Lighting, Inc. | Canopy luminaire assembly |
| USD614338S1 (en) | 2009-07-14 | 2010-04-20 | Abl Ip Holding Llc | Light fixture |
| USD611642S1 (en) | 2009-07-14 | 2010-03-09 | Abl Ip Holding Llc | Light fixture |
-
1990
- 1990-05-21 JP JP13195490A patent/JP3167705B2/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011523658A (en) * | 2008-06-02 | 2011-08-18 | シプラ・リミテッド | Synthetic method of alformoterol |
| US9029421B2 (en) | 2008-06-02 | 2015-05-12 | Cipla Limited | Process for the synthesis of arformoterol |
| KR20160089542A (en) | 2014-06-25 | 2016-07-27 | 미츠비시 쥬고교 가부시키가이샤 | Labyrinth seal device for axial-flow turbine and exhaust gas turbocharger equipped with same |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3167705B2 (en) | 2001-05-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH0426661A (en) | Preparation of 3-(n-benzyl-n-alkoxycarbonylalkylamino) propionic acid ester | |
| Sundberg et al. | Improved procedures for preparation of 4-hydroxy-and 2-amino-4-methoxy-2-aminopyridines | |
| JPH07267931A (en) | Production of sulfonamide derivatives | |
| JPS63258442A (en) | Production of tetrafluorophthalic acid | |
| JPH06166683A (en) | Production of o,o'-diacyltartaric acid anhydride | |
| JPH01228946A (en) | Synthesis of beta-hydroxyphenetylamines | |
| JPS5931731A (en) | Novel method for preparing carboxylic acid derivative | |
| JP2743198B2 (en) | Cyclopentanes | |
| JPH04360866A (en) | Production of 3-aminopyrrolidines | |
| JP3486922B2 (en) | Method for producing acid amide | |
| JP3013760B2 (en) | Method for producing 4-hydroxy-2-pyrrolidone | |
| JP2773627B2 (en) | Process for producing O, O'-diacyltartaric anhydride | |
| JPH0446175A (en) | Production of 5-hydroxy-3,4-methylenedioxybenzoic acid derivative | |
| JPH0491075A (en) | Organic peracid salt and its production | |
| JPH04108768A (en) | Production of amino acid ester | |
| JPS61158962A (en) | Production of 1,4-dihydropyridine derivative | |
| JPS58216160A (en) | Production of quinoline derivative | |
| JPH10287650A (en) | Production of 1-chlorocarbonyl-4-piperidinopiperidine, or hydrochloride salt thereof | |
| JPH0235746B2 (en) | 33CHIKANTETORAFURUOROINDOORUJUDOTAI | |
| JPH0320265A (en) | Aminothiazoleacetic acid derivative and its production | |
| JP2001328993A (en) | Optically active phosphine compound | |
| JPH0272140A (en) | Optically active carboxylic acid esters and production thereof | |
| JPS6284067A (en) | Production of thiazolidine-2-one derivative | |
| JPH04103589A (en) | 3'-alkyl or aryl silyloxybenzoxazinorifamycin derivative | |
| JPH0812658A (en) | Production of sydnones |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |