JPH0129786B2 - - Google Patents
Info
- Publication number
- JPH0129786B2 JPH0129786B2 JP55121747A JP12174780A JPH0129786B2 JP H0129786 B2 JPH0129786 B2 JP H0129786B2 JP 55121747 A JP55121747 A JP 55121747A JP 12174780 A JP12174780 A JP 12174780A JP H0129786 B2 JPH0129786 B2 JP H0129786B2
- Authority
- JP
- Japan
- Prior art keywords
- reaction
- acid
- mmol
- derivative
- glycine
- 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
Links
- -1 N-(substituted methylene)glycine ester Chemical class 0.000 claims description 17
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- VZSTVUJXUYNIOQ-UHFFFAOYSA-N alpha-amino-gamma-cyanobutanoic acid Chemical class OC(=O)C(N)CCC#N VZSTVUJXUYNIOQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 239000003444 phase transfer catalyst Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 3
- 239000012965 benzophenone Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- SKMPRICWLXUMRY-UHFFFAOYSA-N ethyl 2-(benzhydrylideneamino)-4-cyanobutanoate Chemical compound C=1C=CC=CC=1C(=NC(CCC#N)C(=O)OCC)C1=CC=CC=C1 SKMPRICWLXUMRY-UHFFFAOYSA-N 0.000 description 3
- QUGJYNGNUBHTNS-UHFFFAOYSA-N ethyl 2-(benzhydrylideneamino)acetate Chemical compound C=1C=CC=CC=1C(=NCC(=O)OCC)C1=CC=CC=C1 QUGJYNGNUBHTNS-UHFFFAOYSA-N 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 239000008346 aqueous phase Substances 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
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 description 2
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229960003104 ornithine Drugs 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 description 2
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 description 2
- PRKYCJOUCXKCHY-UHFFFAOYSA-N 2-amino-2-cyanobutanoic acid Chemical class CCC(N)(C#N)C(O)=O PRKYCJOUCXKCHY-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ABHPLOWOQDGWMV-UHFFFAOYSA-N ethyl 2-(benzylideneamino)-4-cyanobutanoate Chemical compound CCOC(=O)C(CCC#N)N=CC1=CC=CC=C1 ABHPLOWOQDGWMV-UHFFFAOYSA-N 0.000 description 1
- PRQUMJAKVLLZHP-UHFFFAOYSA-N ethyl 2-(benzylideneamino)acetate Chemical compound CCOC(=O)CN=CC1=CC=CC=C1 PRQUMJAKVLLZHP-UHFFFAOYSA-N 0.000 description 1
- ASILPPKRZQUBAH-UHFFFAOYSA-N ethyl 2-amino-4-cyanobutanoate Chemical compound CCOC(=O)C(N)CCC#N ASILPPKRZQUBAH-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- PQTOLHHWLUCKSB-UHFFFAOYSA-N methyl 2-(benzhydrylideneamino)acetate Chemical compound C=1C=CC=CC=1C(=NCC(=O)OC)C1=CC=CC=C1 PQTOLHHWLUCKSB-UHFFFAOYSA-N 0.000 description 1
- UKLXOVLDIFDCED-UHFFFAOYSA-N methyl 4-cyanobutanoate Chemical compound COC(=O)CCCC#N UKLXOVLDIFDCED-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は、アミノ酸製造用中間体の一種である
2−アミノ−4−シアノ酪酸誘導体の製法に関す
るものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a 2-amino-4-cyanobutyric acid derivative, which is a type of intermediate for producing amino acids.
従来からアミノ酸を製造する方法として種々の
方法が提案されているがその多くは、種々の中間
体を経由する方法である。これらの方法は相応の
効果をあげてはいるが、なお次の点において限り
ない改良が望まれている。即ち(イ)中間体乃至は目
的物の合成ステツプを簡素化すべきであること、
(ロ)収率の向上をはかるべきであること、(ハ)反応条
件を、より緩和にして反応を安定化させること、
(ニ)操作を簡単にすること、(ホ)副生物を有効に利用
できるプロセスであることを及び(ヘ)省資源的ない
しは省エネルギー的プロセスであること等の改良
が望まれているのである。 Various methods have been proposed to date to produce amino acids, and most of them involve various intermediates. Although these methods have achieved a certain degree of effectiveness, endless improvements are desired in the following respects. That is, (a) the steps for synthesizing intermediates or target products should be simplified;
(b) The yield should be improved; (c) The reaction conditions should be made more relaxed to stabilize the reaction;
Improvements are desired such as (d) simplification of operation, (e) process that can effectively utilize by-products, and (f) resource- or energy-saving process.
そこで、本発明者らは上記改良を目的にアミノ
酸、特にオルニチン製造用中間体の製法を鋭意研
究したところ、極めて特異な中間体の製法を見い
出し本発明に到達した。 Therefore, the present inventors conducted intensive research on the production method of an intermediate for producing amino acids, particularly ornithine, with the aim of making the above improvements, and discovered a very unique production method of the intermediate, resulting in the present invention.
そして本発明の上記目的は、具体的には、
次の一般式()
(式中、R1はH、CH3またはアリール基を示し、
φはフエニル基を示し、U2は炭素原子数1〜4
のアルキル基を示す。)
で示されるN−(置換メチレン)グリシンエステ
ルとアクリロニトリルとを反応させて次の一般式
()
(式中、R1、φおよびR2は上記と同じものを示
す。)
で示される2−アミノ−シアノ酪酸誘導体を得る
ことによつて達成されるとの事実を見い出した。 Specifically, the above object of the present invention is as follows: (In the formula, R 1 represents H, CH 3 or an aryl group,
φ represents a phenyl group, and U 2 has 1 to 4 carbon atoms.
represents an alkyl group. ) by reacting N-(substituted methylene)glycine ester with acrylonitrile to form the following general formula () (In the formula, R 1 , φ and R 2 are the same as above.) It has been found that this can be achieved by obtaining a 2-amino-cyanobutyric acid derivative represented by the following formula.
更に上記の方法によつて得られた2−置換アミ
ノ−4−シアノ酪酸エステルを酸またはアルカリ
の存在下で加水分解することによつて、よりアミ
ノ酸製造に有利な中間体が得られる。 Further, by hydrolyzing the 2-substituted amino-4-cyanobutyric acid ester obtained by the above method in the presence of an acid or an alkali, an intermediate more advantageous for producing amino acids can be obtained.
以下、本発明法を詳述する。 The method of the present invention will be explained in detail below.
まず本発明に使用される出発原料を用意する。 First, starting materials used in the present invention are prepared.
上記一般式で示されるN−(置換メチレン)グ
リシンエステルはグリシンと炭素原子数1〜4の
アルコール等との反応によつて得られたグリシン
エステルと、ケトン類及び/又はアルデヒド類と
の脱水反応によつて得られる。 N-(substituted methylene)glycine ester represented by the above general formula is a dehydration reaction between glycine ester obtained by the reaction of glycine with an alcohol having 1 to 4 carbon atoms, etc., and ketones and/or aldehydes. obtained by.
ケトン類としてはアセトン、メチルエチルケト
ン、シクロヘキサノン、アセトフエノン、ベンゾ
フエノン等が選ばれ、またアルデヒド類としては
ホルムアルデヒド、アセトアルデヒド、プロピオ
ンアルデヒド、ベンズアルデヒド等が選ばれる
が、本発明の目的を効果的に達成するには、実際
的にはベンゾフエノン、ベンズアルデヒド、アセ
トフエノンが選ばれる。特にこれらのアルデヒド
やケトンは後述の反応において副生した副生物を
再び原料として使用可能であるだけでなく、クロ
ーズドシステム形成に有効である。 As the ketones, acetone, methyl ethyl ketone, cyclohexanone, acetophenone, benzophenone, etc. are selected, and as the aldehydes, formaldehyde, acetaldehyde, propionaldehyde, benzaldehyde, etc. are selected, but in order to effectively achieve the object of the present invention, Practically speaking, benzophenone, benzaldehyde, and acetophenone are selected. In particular, these aldehydes and ketones not only allow the by-products produced in the reactions described below to be used again as raw materials, but are also effective in forming a closed system.
他方アクリロニトリルは、それ自体周知の方法
によつて得られる。 Acrylonitrile, on the other hand, is obtained by methods known per se.
次に、この二種の原料を反応させる。反応方法
としては均一溶媒系で反応させる方法と水相と有
機相との間で反応させる方法の2種があるが、操
作及び単離が簡単であるという理由で後者の反応
法が好ましい。 Next, these two types of raw materials are reacted. There are two reaction methods: a method in which the reaction is carried out in a homogeneous solvent system and a method in which the reaction is carried out between an aqueous phase and an organic phase, and the latter reaction method is preferred because it is easy to operate and isolate.
均一溶媒系で反応させる場合、溶媒としてエタ
ノールなどのアルコール類、ジクロルメタンなど
のハロゲン化炭化水素類、エーテル類、ベンゼン
などの炭化水素類、ジメチルホルムアミドおよび
ジメチルスルホキシドなどを単独、または2種以
上混合して使用する。塩基としては水酸化カリウ
ムなどのアルカリ金属酸化物、ナトリウムエチラ
ートなどのアルカリアルコラート、1,8−ジア
ザビシクロ(5,4,0)ウンデセン−7などの
有機塩基等が用いられる。この時の塩基の添加量
は通常、N−(置換メチレン)グリシンエステル
1モルに対し、0.01〜6モル当量である。この反
応は0℃以上、溶媒沸点、好ましくは50℃以下で
反応液を撹拌すれば円滑に進行する。 When reacting in a homogeneous solvent system, alcohols such as ethanol, halogenated hydrocarbons such as dichloromethane, ethers, hydrocarbons such as benzene, dimethylformamide and dimethyl sulfoxide may be used alone or in combination of two or more. and use it. As the base, an alkali metal oxide such as potassium hydroxide, an alkali alcoholate such as sodium ethylate, an organic base such as 1,8-diazabicyclo(5,4,0)undecene-7, etc. are used. The amount of base added at this time is usually 0.01 to 6 molar equivalents per mole of N-(substituted methylene)glycine ester. This reaction proceeds smoothly if the reaction solution is stirred at a temperature above 0°C and at the boiling point of the solvent, preferably below 50°C.
2相間溶媒系で反応させる場合、反応溶媒とし
て、ハロゲン化炭化水素類、エーテル類、炭化水
素類等の有機溶媒と水との混合溶媒を用いる。こ
の場合、塩基としては水酸化ナトリウム、炭酸ナ
トリウム、炭酸水素ナトリウムなどのアルカリ金
属の水酸化物、炭酸塩、炭酸水素塩などを用い
る。この反応で使用する塩基の量は、通常、N−
(置換メチレン)グリシンエステル1モルに対し
て、0.01〜6モル当量である。この時の反応温度
は使用する溶媒によつて多少異なるが、一般的に
は0〜80℃、通常は0〜40℃で反応を行なう。 When the reaction is carried out in a two-phase solvent system, a mixed solvent of water and an organic solvent such as halogenated hydrocarbons, ethers, or hydrocarbons is used as the reaction solvent. In this case, the base used is an alkali metal hydroxide, carbonate, hydrogen carbonate, etc., such as sodium hydroxide, sodium carbonate, or sodium hydrogen carbonate. The amount of base used in this reaction is usually N-
The amount is 0.01 to 6 molar equivalents per mole of (substituted methylene)glycine ester. The reaction temperature at this time varies somewhat depending on the solvent used, but the reaction is generally carried out at 0 to 80°C, usually 0 to 40°C.
2相間溶媒系で反応させる場合、相間移動触媒
を使用しなくても反応が進むが、より好ましくは
N−(置換メチレン)グリシンエステル1モル当
り0.01〜1.0モル当量の相間移動触媒を用いる。
相間移動触媒としては、たとえば、テトラブチル
アンモニウム硫酸水素塩、ベンジルトリメチルア
ンモニウムクロライド、ベンジルトリメチルアン
モニウムヒドロキシド、セシルトリメチルアンモ
ニウムブロマイド、ドデシルトリメチルアンモニ
ウムクロライド、テトラエチルアンモニウムヒド
ロキシドなどの4級アンモニウム塩、より好まし
くはテトラブチルアンモニウム硫酸水素塩、ベン
ジルトリメチルアンモニウムヒドロキシド、テト
ラエチルアンモニウムヒドロキシドが用いられ
る。 When the reaction is carried out in a two-phase solvent system, the reaction proceeds without using a phase transfer catalyst, but it is more preferable to use a phase transfer catalyst in an amount of 0.01 to 1.0 molar equivalent per mole of N-(substituted methylene)glycine ester.
As the phase transfer catalyst, for example, quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, benzyltrimethylammonium hydroxide, ceyltrimethylammonium bromide, dodecyltrimethylammonium chloride, and tetraethylammonium hydroxide, more preferably Tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium hydroxide, and tetraethylammonium hydroxide are used.
上記いずれの反応も、原則として化学量論量の
出発物質が使用されるが、好ましくはN−(置換
メチレン)グリシンエステル1モルにつき0・9
〜1・1モルの割合のアクリロニトリルが使用さ
れる。 In any of the above reactions, a stoichiometric amount of starting material is used in principle, preferably 0.9 per mole of N-(substituted methylene)glycine ester.
Acrylonitrile is used in a proportion of ˜1·1 mol.
反応は、常圧、加圧、減圧と種々の圧力下で可
能であるが、好ましくは常圧下で行なわれる。 The reaction can be carried out under various pressures such as normal pressure, increased pressure, and reduced pressure, but is preferably carried out under normal pressure.
反応には、回分式、連続式又は半連続式の任意
の方式が採用される。回分式で反応を行なわせる
場合、通常5〜60分で反応は終了する。 Any system such as batch, continuous or semi-continuous can be used for the reaction. When the reaction is carried out batchwise, the reaction is usually completed in 5 to 60 minutes.
反応終了後生成物を公知の方法で分取すると次
式で示されるα−(置換メチレン)アミノ−4−
シアノラク酸エステル(以下単に誘導体()と
称する)が得られる。 After the reaction is completed, the product is collected using a known method to obtain α-(substituted methylene)amino-4-
A cyanolac acid ester (hereinafter simply referred to as a derivative ()) is obtained.
反応終了後、生成物を分離する方法としては公
知の方法が採用される。 After the reaction is completed, a known method is employed to separate the product.
たとえば、相間移動触媒を使用して2相間で反
応させる場合、反応後水相と分離された有機相か
ら溶媒を除去し、残留物をシリカゲルを充填した
カラムに通す。この場合相間移動触媒を含む一部
不純物がカラムに吸着されるので溶媒で洗浄後、
全流出液から溶媒を減圧除去すると精製された誘
導体()が得られる。 For example, when a phase transfer catalyst is used to cause a reaction between two phases, the solvent is removed from the aqueous phase and the separated organic phase after the reaction, and the residue is passed through a column packed with silica gel. In this case, some impurities including phase transfer catalyst are adsorbed on the column, so after washing with solvent,
Removal of the solvent from the total effluent under reduced pressure yields the purified derivative ().
本発明においては更に分取された精製誘導体
()を、又は、前記反応で得た誘導体()を
含む反応混合物を酸またはアルカリの存在下で加
水分解反応に処する。 In the present invention, the fractionated purified derivative () or a reaction mixture containing the derivative () obtained in the above reaction is further subjected to a hydrolysis reaction in the presence of an acid or an alkali.
酸で加水分解する場合、酸として硫酸、塩酸リ
ン酸等の鉱酸や、酢酸、プロピオン酸、クエン
酸、シユウ酸等の有機カルボン酸またはスルホン
酸基を有するイオン交換樹脂等を選んで、水の存
在下で、温度0〜50℃好ましくは20〜30℃で0.5
〜10時間、好ましくは1〜3時間反応させる。こ
のとき酸は、誘導体()1モルにつき少なくと
も1モル以上使用される。 When hydrolyzing with an acid, select mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid, etc., organic carboxylic acids such as acetic acid, propionic acid, citric acid, oxalic acid, or ion exchange resins having sulfonic acid groups as the acid. 0.5 at a temperature of 0-50℃, preferably 20-30℃ in the presence of
Allow to react for ~10 hours, preferably 1-3 hours. At this time, at least 1 mol or more of the acid is used per 1 mol of the derivative ().
かくして、酸の存在下で加水分解反応がなされ
ると、次式で示される2−アミノ−4−シアノ酪
酸エステルとアルデヒド類またはケトン類が得ら
れる。(以下誘導体()と称する)
加水分解反応生成物から公知の方法、例えば抽
出法により誘導体()とケトンまたはアルデヒ
ド類を分離すれば、本発明の第2の目的物と副生
物が得られる。 Thus, when the hydrolysis reaction is carried out in the presence of an acid, 2-amino-4-cyanobutyric acid ester and aldehydes or ketones represented by the following formula are obtained. (hereinafter referred to as derivative ()) The second objective product and by-product of the present invention can be obtained by separating the derivative () and ketone or aldehyde from the hydrolysis reaction product by a known method, such as an extraction method.
副生物は、公知の方法でN−(置換メチレン)
グリシンエステル製造用の原料としてリサイクル
可能となり、この点にも本発明の一特徴がある。 The by-product is converted into N-(substituted methylene) by a known method.
It can be recycled as a raw material for producing glycine ester, which is another feature of the present invention.
他方、アルカリの存在下で加水分解する場合ア
ルカリとしてNaOH、KOH、NH4、OH、
Na2CO3、CaCO3、CH3COONa等を選んで水の
存在下で、温度0〜50℃好ましくは20〜30℃、1
〜10時間、好ましくは3〜5時間反応させる。 On the other hand, when hydrolyzed in the presence of an alkali, the alkalis include NaOH, KOH, NH 4 , OH,
Select Na 2 CO 3 , CaCO 3 , CH 3 COONa, etc. in the presence of water at a temperature of 0 to 50°C, preferably 20 to 30°C, 1
Allow to react for ~10 hours, preferably 3-5 hours.
このとき、アルカリは誘導体()1モルにつ
き少なくとも1モル以上使用される。 At this time, at least 1 mol or more of the alkali is used per 1 mol of the derivative ().
反応終了すると、次式で示される2−(置換メ
チレン)−4−シアノ酪酸(以下単に誘導体()
と称する)が得られる。 Upon completion of the reaction, 2-(substituted methylene)-4-cyanobutyric acid (hereinafter simply a derivative ()) shown by the following formula
) is obtained.
反応生成混合物から公知の方法、例えば、抽出
法により誘導体()を分離取得できる。 The derivative (2) can be separated and obtained from the reaction product mixture by a known method, for example, an extraction method.
なお、加水分解反応を誘導体()の単独物を
原料とせずに、言いかえればN−(置換メチレン)
グリシンエステルへのアクリロニトリル付加反応
生成混合物をそのまま加水分解反応に供する場
合、次の処方を考慮する必要がある。 In addition, instead of using the derivative () alone as a raw material for the hydrolysis reaction, in other words, N-(substituted methylene)
When the mixture produced by the addition reaction of acrylonitrile to glycine ester is subjected to the hydrolysis reaction as it is, the following formulation must be considered.
まず酸による加水分解は反応混液から水層を除
去し、有機層に酸を加える。この場合の酸は前記
と同様である。 First, acid hydrolysis removes the aqueous layer from the reaction mixture and adds acid to the organic layer. The acid in this case is the same as above.
またアルカリによる加水分解は付加反応終了
後、更に3〜5時間反応を継続するだけでよい。 Further, for hydrolysis with an alkali, it is only necessary to continue the reaction for an additional 3 to 5 hours after the completion of the addition reaction.
反応条件、分離方法は前記と同様である。 The reaction conditions and separation method are the same as described above.
以上のように本発明法によると工業的に有利に
得られる出発原料を用いて誘導体()()又
は()を簡素化されたステツプを経て高収率で
得られるとともに、その副生物を再び出発原料製
造用原料として再使用可能である。 As described above, according to the method of the present invention, the derivative ()() or () can be obtained in high yield through simplified steps using industrially advantageously obtained starting materials, and the by-product can be recovered again. It can be reused as a raw material for producing starting materials.
本発明の誘導体()()は更に必要な反応
に供することによつて例えばオルニチン等のアミ
ノ酸に有利に変換可能となる。 The derivative ()() of the present invention can be advantageously converted into an amino acid such as ornithine by further subjecting it to a necessary reaction.
次の本発明法を実施例をもつて説明する。 The following method of the present invention will be explained using examples.
実施例 1
撹拌器を装着したフラスコに、N−(ジフエニ
ルメチレン)グリシンエチルエステル2.7g(10
ミリモル)ジクロルメタン20ml、アルリロニトリ
ル0.5g(10ミリモル)、テトラブチルアンモニウ
ム硫酸水素塩0.3g(1ミリモル)および35%水
酸化ナトリウム水溶液1.1gを仕込み、室温中に
て30分間反応させた。反応液を分液し、有機層を
1回水洗したのち溶媒を除去した。濃縮液をシリ
カゲルカラムで分離し、2−(ジフエニルメチレ
ンアミノ)−4−シアノ酪酸エチル2.9g得た。収
率は90.5%であつた。Example 1 2.7 g of N-(diphenylmethylene)glycine ethyl ester (10
20 ml of dichloromethane (mmol), 0.5 g (10 mmol) of allylonitrile, 0.3 g (1 mmol) of tetrabutylammonium hydrogen sulfate, and 1.1 g of a 35% aqueous sodium hydroxide solution were charged, and reacted for 30 minutes at room temperature. The reaction solution was separated into layers, the organic layer was washed once with water, and then the solvent was removed. The concentrated solution was separated using a silica gel column to obtain 2.9 g of ethyl 2-(diphenylmethyleneamino)-4-cyanobutyrate. The yield was 90.5%.
実施例 2
実施例1と同様の装置にN−(ジフエニルメチ
レン)グリシンメチルエステル2.5g(10ミリモ
ル)、ジクロルメタン20ml、アクリロニトリル0.5
g(10ミリモル)、テトラブチルアンモニウム硫
酸水素塩1.7g(5ミリモル)および30%水酸化
カリウム水溶液5.6gを仕込み、氷水中にて冷却
しながら1時間反応させた。反応液を実施例1と
同様に処理し、2−(ジフエニルメチレンアミノ)
4−シアノ酪酸メチル2.7g得た。収率は87.3%
であつた。Example 2 Into the same apparatus as in Example 1, 2.5 g (10 mmol) of N-(diphenylmethylene)glycine methyl ester, 20 ml of dichloromethane, and 0.5 acrylonitrile were added.
(10 mmol), 1.7 g (5 mmol) of tetrabutylammonium hydrogen sulfate, and 5.6 g of a 30% aqueous potassium hydroxide solution, and the mixture was reacted for 1 hour while cooling in ice water. The reaction solution was treated in the same manner as in Example 1, and 2-(diphenylmethyleneamino)
2.7 g of methyl 4-cyanobutyrate was obtained. Yield is 87.3%
It was hot.
実施例 3
実施例1と同様の装置にN−(ジフエニルメチ
レン)グリシンエチルエステル2.7g(10ミリモ
ル)、ベンゼン30ml、アクリロニトリル0.5g(10
ミリモル)および35%水酸化ナトリウム水溶液
3.3gを仕込み、50℃にて3時間反応させた。反
応液を実施例1と同様に処理し2−(ジフエニル
メチレンアミノ)−4−シアノ酪酸エチル1.7g得
た。収率は53.1%であつた。Example 3 Into the same apparatus as in Example 1, 2.7 g (10 mmol) of N-(diphenylmethylene)glycine ethyl ester, 30 ml of benzene, and 0.5 g (10 mmol) of acrylonitrile were added.
mmol) and 35% aqueous sodium hydroxide solution
3.3g was charged and reacted at 50°C for 3 hours. The reaction solution was treated in the same manner as in Example 1 to obtain 1.7 g of ethyl 2-(diphenylmethyleneamino)-4-cyanobutyrate. The yield was 53.1%.
実施例 4
実施例1と同様の装置にN−(フエニルメチル
メチレン)グリシンエチルエステル2.1g(10ミ
リモル)、ジクロルメタン20ml、アクリロニトリ
ル0.5g(10ミリモル)、ベンジルトリエチルアン
モニウムクロライド0.5gおよび10%水酸化ナト
リウム水溶液2gを仕込み、室温中にて1時間反
応させた。反応液を実施例1と同様に処理し2−
(ジフエニルメチルメチレンアミノ)4−シアノ
酪酸エチル1.8g得た。収率は69.7%であつた。Example 4 In an apparatus similar to Example 1, 2.1 g (10 mmol) of N-(phenylmethylmethylene)glycine ethyl ester, 20 ml of dichloromethane, 0.5 g (10 mmol) of acrylonitrile, 0.5 g of benzyltriethylammonium chloride, and 10% water were added. 2 g of an aqueous sodium oxide solution was charged, and the mixture was reacted at room temperature for 1 hour. The reaction solution was treated in the same manner as in Example 1, and 2-
1.8 g of ethyl (diphenylmethylmethyleneamino)4-cyanobutyrate was obtained. The yield was 69.7%.
実施例 5
実施例1と同様の装置にN−(モノフエニルメ
チレン)グリシンエチルエステル1.9g(10ミリ
モル)、ジクロルメタン20ml、アクリロニトリル
0.5g(10ミリモル)、ベンジルトリメチルアンモ
ニウムクロライド0.5gおよび10%水酸化ナトリ
ウム水溶液5gを仕込み氷水中にて1時間反応さ
せた。反応液を実施例1と同様に処理し、2−
(モノフエニルメチレンアミノ)−4−シアノ酪酸
エチル1.2g得た。収率は49.1%であつた。Example 5 Into the same apparatus as in Example 1, 1.9 g (10 mmol) of N-(monophenylmethylene)glycine ethyl ester, 20 ml of dichloromethane, and acrylonitrile were added.
0.5 g (10 mmol), benzyltrimethylammonium chloride, 0.5 g, and 5 g of a 10% aqueous sodium hydroxide solution were charged and reacted in ice water for 1 hour. The reaction solution was treated in the same manner as in Example 1, and 2-
1.2 g of ethyl (monophenylmethyleneamino)-4-cyanobutyrate was obtained. The yield was 49.1%.
実施例 6
実施例1と同様の装置にN−(ジフエニルメチ
レン)グリシンエチルエステル2.7g(10ミリモ
ル)エタノール20ml、ナトリウムエチラート0.5
g(10ミリモル)およびアクリロニトリル0.5g
(10ミリモル)を仕込み、室温中にて1時間反応
させた。反応液を実施例1と同様に処理し、2−
(ジフエニルメチレンアミノ)−4−シアノ酪酸エ
チル2.7g得た。収率は84.3%であつた。Example 6 In a device similar to Example 1, 2.7 g (10 mmol) of N-(diphenylmethylene)glycine ethyl ester, 20 ml of ethanol, and 0.5 sodium ethyl ester were added.
g (10 mmol) and acrylonitrile 0.5 g
(10 mmol) and reacted at room temperature for 1 hour. The reaction solution was treated in the same manner as in Example 1, and 2-
2.7 g of ethyl (diphenylmethyleneamino)-4-cyanobutyrate was obtained. The yield was 84.3%.
実施例 7
実施例1と同様の装置に2−(ジフエニルメチ
レンアミノ)−4−シアノ酪酸エチル1.0g(3.3
ミリモル)およびエタノール10mlを仕込んだ。室
温中で撹拌しながら1N塩酸6mlを加え、1時間
反応させた。冷却しながらエタノールを減圧除去
し、濃縮液にシクロルメタンを加えベンゾフエノ
ンを抽出した。水層を0.1N水酸化ナトリウムで
PH8〜9に調製し、ジクロルメタンで抽出した。
溶媒を除去すると2−アミノ−4−シアノ酪酸エ
チル0.39g得られた。収率は82.0%であつた。Example 7 Into the same apparatus as in Example 1, 1.0 g (3.3
mmol) and 10 ml of ethanol. While stirring at room temperature, 6 ml of 1N hydrochloric acid was added, and the mixture was allowed to react for 1 hour. Ethanol was removed under reduced pressure while cooling, and cyclomethane was added to the concentrate to extract benzophenone. The aqueous layer was diluted with 0.1N sodium hydroxide.
The pH was adjusted to 8-9 and extracted with dichloromethane.
Removal of the solvent yielded 0.39 g of ethyl 2-amino-4-cyanobutyrate. The yield was 82.0%.
実施例 8
実施例1と同様の装置に2−(ジフエニルメチ
レンアミノ)−4−シアノ酪酸エチル1.0g(3.3
ミリモル)、およびエタノール1mlを仕込んだ。
室温中で撹拌しながら20%水酸化カリウム水溶液
1.5gを加え、3時間反応させた。エタノールを
減圧除去後濃縮物にジクロルメタン30mlを加え
0.1N塩酸でPH6〜7に調製してから5分間撹拌
した。ジクロルメタン層を分液後、溶媒を除去す
ると2−(ジフエニルメチレンアミノ)−4−シア
ノ酪酸が0.76g得られた。収率は82.7%であつ
た。Example 8 Into the same apparatus as in Example 1, 1.0 g (3.3
mmol) and 1 ml of ethanol.
20% aqueous potassium hydroxide solution with stirring at room temperature
1.5 g was added and reacted for 3 hours. After removing ethanol under reduced pressure, add 30 ml of dichloromethane to the concentrate.
After adjusting the pH to 6 to 7 with 0.1N hydrochloric acid, the mixture was stirred for 5 minutes. After separating the dichloromethane layer, the solvent was removed to obtain 0.76 g of 2-(diphenylmethyleneamino)-4-cyanobutyric acid. The yield was 82.7%.
Claims (1)
φはフエニル基を示し、R2は炭素原子数1〜4
のアルキル基を示す。) で示されるN−(置換メチレン)グリシンエステ
ルとアクリロニトリルとを反応させることを特徴
とする次の一般式() (式中、R1、φおよびR2は上記と同じものを示
す。) で示される2−アミノ−4−シアノ酪酸誘導体の
製法。[Claims] First-order general formula () (In the formula, R 1 represents H, CH 3 or an aryl group,
φ represents a phenyl group, and R 2 has 1 to 4 carbon atoms.
represents an alkyl group. ) The following general formula () is characterized by reacting the N-(substituted methylene)glycine ester represented by () with acrylonitrile. (In the formula, R 1 , φ and R 2 are the same as above.) A method for producing a 2-amino-4-cyanobutyric acid derivative represented by the following.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12174780A JPS5746951A (en) | 1980-09-04 | 1980-09-04 | Production of 2-amino-4-cyanobutyric derivative |
DE8181106970T DE3161839D1 (en) | 1980-09-04 | 1981-09-04 | Propylamine derivative and process of manufacturing the same |
EP81106970A EP0047516B1 (en) | 1980-09-04 | 1981-09-04 | Propylamine derivative and process of manufacturing the same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12174780A JPS5746951A (en) | 1980-09-04 | 1980-09-04 | Production of 2-amino-4-cyanobutyric derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5746951A JPS5746951A (en) | 1982-03-17 |
JPH0129786B2 true JPH0129786B2 (en) | 1989-06-14 |
Family
ID=14818877
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP12174780A Granted JPS5746951A (en) | 1980-09-04 | 1980-09-04 | Production of 2-amino-4-cyanobutyric derivative |
Country Status (2)
Country | Link |
---|---|
JP (1) | JPS5746951A (en) |
DE (1) | DE3161839D1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03104968U (en) * | 1990-02-15 | 1991-10-30 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS54125644A (en) * | 1978-02-27 | 1979-09-29 | Synthelabo | Benzylidene derivative and its manufacture |
JPS54138548A (en) * | 1978-04-14 | 1979-10-27 | Synthelabo | Benzylidene derivative and its manufacture |
-
1980
- 1980-09-04 JP JP12174780A patent/JPS5746951A/en active Granted
-
1981
- 1981-09-04 DE DE8181106970T patent/DE3161839D1/en not_active Expired
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS54125644A (en) * | 1978-02-27 | 1979-09-29 | Synthelabo | Benzylidene derivative and its manufacture |
JPS54138548A (en) * | 1978-04-14 | 1979-10-27 | Synthelabo | Benzylidene derivative and its manufacture |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03104968U (en) * | 1990-02-15 | 1991-10-30 |
Also Published As
Publication number | Publication date |
---|---|
JPS5746951A (en) | 1982-03-17 |
DE3161839D1 (en) | 1984-02-09 |
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