JPS62286964A - Production of oxiracetam - Google Patents
Production of oxiracetamInfo
- Publication number
- JPS62286964A JPS62286964A JP12736886A JP12736886A JPS62286964A JP S62286964 A JPS62286964 A JP S62286964A JP 12736886 A JP12736886 A JP 12736886A JP 12736886 A JP12736886 A JP 12736886A JP S62286964 A JPS62286964 A JP S62286964A
- Authority
- JP
- Japan
- Prior art keywords
- oxiracetam
- ammonia
- reaction
- chloro
- ester
- 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
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229960001227 oxiracetam Drugs 0.000 title claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 19
- -1 4-chloro-3-hydroxybutyric acid ester Chemical class 0.000 claims abstract description 14
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000004471 Glycine Substances 0.000 claims abstract description 9
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 abstract description 23
- 125000000217 alkyl group Chemical group 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 2
- 230000004060 metabolic process Effects 0.000 abstract description 2
- 230000002490 cerebral effect Effects 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000005576 amination reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 2
- ZAJNMXDBJKCCAT-UHFFFAOYSA-N ethyl 4-chloro-3-hydroxybutanoate Chemical compound CCOC(=O)CC(O)CCl ZAJNMXDBJKCCAT-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-ZJRLKYRESA-N (2r)-2-azaniumyl-3-hydroxybutanoate Chemical compound CC(O)[C@@H](N)C(O)=O AYFVYJQAPQTCCC-ZJRLKYRESA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 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
- VFTCEPBUNAKJHC-UHFFFAOYSA-N [acetyloxy(ethyl)amino] acetate Chemical compound CC(=O)ON(CC)OC(C)=O VFTCEPBUNAKJHC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- KWFADUNOPOSMIJ-UHFFFAOYSA-N ethyl 3-chloro-3-oxopropanoate Chemical compound CCOC(=O)CC(Cl)=O KWFADUNOPOSMIJ-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
- 239000011521 glass Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- WMRINGSAVOPXTE-UHFFFAOYSA-N methyl 4-chloro-3-hydroxybutanoate Chemical compound COC(=O)CC(O)CCl WMRINGSAVOPXTE-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
６、発明の詳細な説明
〔産業上の利用分野〕
本発明は、医薬（脳代謝改善剤）として知られるオキシ
ラセタム（４−ヒドロキシ−２−オキソ−１−ピロリジ
ンアセトアミド）の製造法に関する。Detailed Description of the Invention 6. Detailed Description of the Invention [Field of Industrial Application] The present invention relates to oxiracetam (4-hydroxy-2-oxo-1-pyrrolidine acetamide), which is known as a medicine (brain metabolism improving agent). ).
従来、本発明で目的とするオキシラセタムの合成法とし
ては、（１）イミノジ酢酸エチルとエトキシカルボニル
アセチルクロリドを原料とし、５工程の反応によって得
る方法（特公昭５８−２２０３４号公報）および（２）
ｒ−アミノ−β−ヒドロキシ酪酸を原料とし、それにヘ
キサメチルジシラデンなどを反応させた後、３工程の反
応を経て得る方法（特開昭５３−１０１３６７号公報）
、が知られている。Conventionally, methods for synthesizing oxiracetam, which is the object of the present invention, include (1) a method in which ethyl iminodiacetate and ethoxycarbonylacetyl chloride are used as raw materials and obtained through a five-step reaction (Japanese Patent Publication No. 58-22034); and (2) )
A method using r-amino-β-hydroxybutyric acid as a raw material, reacting it with hexamethyldisiladene, etc., and then performing a three-step reaction (Japanese Patent Application Laid-Open No. 101367/1983).
,It has been known.
従来の方法は、いずれも、用いる原料が高価であり、ま
た、多工程の反応を要するなどの欠点を有している。All conventional methods have drawbacks such as expensive raw materials and multi-step reactions.
本発明Ｈ４−クロロ−６−ヒドロキシ酪酸エステルに、
グリシンエステル或いはその塩又はそれらの混合物を反
応させ、４−ヒドロキシ−２−オキソ−１−ピロリジン
酢酸エステルを得て、これをアンモニアによジアミノ化
することを特徴とするオキシラセタムの製造方法である
。The present invention H4-chloro-6-hydroxybutyric acid ester,
A method for producing oxiracetam, which comprises reacting glycine ester, a salt thereof, or a mixture thereof to obtain 4-hydroxy-2-oxo-1-pyrrolidine acetate, which is then diaminated with ammonia. .
本発明者らは、容易にかつ安価に入手し得る原料を用い
、短い工程でしかも単純な反゛応により、オキシラセタ
ムを製造する方法を見い出すべく鋭意研究を行なった。The present inventors conducted extensive research to find a method for producing oxiracetam using easily and inexpensively available raw materials, short steps, and simple reactions.
その結果、２工程でオキシラセタムが合成できることを
見い出し、本発明の方法を完成した。As a result, they discovered that oxiracetam can be synthesized in two steps, and completed the method of the present invention.
本発明を式で示せば、次のようになる。The present invention can be expressed as follows.
環化工程 ＣＨ２Ｃ０２Ｒ （Ｉｔ） （ＩＩ）（ＩＮ） 以下、各工程を詳細に説明する。Cyclization process CH2C02R (It) (II) (IN) Each step will be explained in detail below.
１、環化工程
本工程では、化合物（１）
Ｈ２Ｃ１
ＨＯＨ
ＣＨ２０ｏ２Ｒ
（式中、Ｒは低級アルキル基である。）で表わされる４
−クロロ−３−ヒドロキシ酪酸エステルに、グリシンエ
ステルあるいはその塩又は、それらの混合物を反応させ
化合物（ＩＩ）を合成する。1. Cyclization step In this step, compound (1) 4 represented by H2C1 HOH CH20o2R (wherein R is a lower alkyl group)
-Chloro-3-hydroxybutyric acid ester is reacted with glycine ester, its salt, or a mixture thereof to synthesize compound (II).
（式中 Ｈ／は低級アルキル基である。）本発明の方法
において原料となる４−クロロ−６−ヒドロキシ酪酸エ
ステルは、例えば、工業原料として安価に入手し得るエ
ピクロロヒドリンのカルボニル化反応によって容易に製
造される（４？開昭５６−６８６４４号公報）。(In the formula, H/ is a lower alkyl group.) 4-chloro-6-hydroxybutyric acid ester, which is a raw material in the method of the present invention, can be used, for example, in the carbonylation reaction of epichlorohydrin, which is inexpensively available as an industrial raw material. (4? Japanese Patent Publication No. 56-68644).
上記式（１）、（ｉｔ）のＲ，Ｒ’は低級アルキル基で
あれば特に制限はないが、製造過程で脱離していく置換
基であり、炭素数４以上では経済的でない。R and R' in the above formulas (1) and (it) are not particularly limited as long as they are lower alkyl groups, but they are substituents that are eliminated during the manufacturing process, and if they have 4 or more carbon atoms, it is not economical.
従って、炭素数１〜３が好ましい。Therefore, the number of carbon atoms is preferably 1 to 3.
本発明の方法を実施するに当っては、溶媒の使用が望ま
しく、水、メタノール、エタノール、プロパツール、ブ
タノール、２−メトキシエタノールの如きプロトン性溶
媒およびジオキサン、１゜２−ジメトキシエタン、ジグ
ライムの如きエーテル系溶媒、ならびにこれらの混合溶
媒を用いることができるが、プロトン性溶媒が望ましい
。In carrying out the process of the invention, it is desirable to use solvents, such as water, protic solvents such as methanol, ethanol, propatool, butanol, 2-methoxyethanol, and dioxane, 1.2-dimethoxyethane, diglyme, etc. Ether solvents such as ether solvents and mixed solvents thereof can be used, but protic solvents are preferable.
反応液中、ハロゲン化水素が副生じてくるが、このハロ
ゲン化水素は、反応速度を減少させるため中和剤を加え
た万が好ましい。Hydrogen halide is produced as a by-product in the reaction solution, but it is preferable to add a neutralizing agent to the hydrogen halide in order to reduce the reaction rate.
無機塩基としては、水酸化ナトリウム、水酸化カリウム
、水酸化カルシウムの如きアル−カリ金、萬またはアル
カリ土類金属の水酸化物および炭酸ナトリウム、炭酸水
素ナトリウム、炭酸カリウムの如きアルカリ金属炭酸塩
を用い得るが、収率および経済性を考慮すると、アルカ
リ金属炭酸塩が望ましく、特に炭酸ナトリウムが望まし
い。Inorganic bases include hydroxides of alkali gold, alkaline or alkaline earth metals such as sodium hydroxide, potassium hydroxide and calcium hydroxide, and alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate and potassium carbonate. However, in consideration of yield and economy, alkali metal carbonates are preferred, and sodium carbonate is particularly preferred.
有機塩基としては、アミン類たとえば、アンモニア、ト
リエチルアミン、ジメチルアニリン、グリシンエステル
が用いられる。使用量は、４−クロロ−３−ヒドロキシ
酪酸エステルに対し１当量必要であるが、グリシンエス
テルをその塩酸塩の如き酸塩として用いる場合には、更
に１当Ｎｋ必要とする。反応温度２０〜２００℃、好ま
しくは７０〜１６０°Ｃであり、反応時間は、温度その
他の条件により、１〜７０時間である。As the organic base, amines such as ammonia, triethylamine, dimethylaniline, and glycine ester are used. The amount used is 1 equivalent per 4-chloro-3-hydroxybutyric acid ester, but when glycine ester is used as an acid salt such as its hydrochloride, an additional 1 equivalent Nk is required. The reaction temperature is 20 to 200°C, preferably 70 to 160°C, and the reaction time is 1 to 70 hours depending on the temperature and other conditions.
反応液を濾過濃縮すると、生成物（Ｉｔ）を含む粘稠液
が得られる。生成物は、クロマトグラフによって分離精
製できるが、特に精製しなくとも、次のアミノ化工程に
使用できる。The reaction solution is filtered and concentrated to obtain a viscous liquid containing the product (It). The product can be separated and purified by chromatography, but it can be used in the next amination step without any particular purification.
アミン化工程
本工程では、前記化合物（ＩＩ）を含む、反応液を、ア
ンモニアと反応させ、オキシラセタム金得ル。Amination Step In this step, the reaction solution containing the compound (II) is reacted with ammonia to obtain oxiracetam gold.
アンモニアは、化合物（１１）に対して、１〜５０倍、
好ましくは、２〜１０倍モル使用される。少なすぎると
、反応速度が遅くなる。Ammonia is 1 to 50 times that of compound (11),
Preferably, it is used in an amount of 2 to 10 times the mole. If it is too small, the reaction rate will be slow.
反応温度は−１０〜１００°Ｃ１好ましくは、０〜８０
℃である。これより低温では反応が遅く、高温では選択
性が上がらない。The reaction temperature is -10 to 100°C, preferably 0 to 80°C.
It is ℃. At lower temperatures, the reaction is slow, and at higher temperatures, selectivity does not increase.
本発明は溶剤の使用が好ましい。溶剤としては特に制限
はなくアンモニア水が工業的に最も入手しやすいが、反
応後アルコールが生成するためにそれと同一の脂肪族ア
ルコール溶剤を用いた方が反応後の溶剤回収、再利用に
有利である。The present invention preferably uses a solvent. There are no particular restrictions on the solvent, and ammonia water is the easiest to obtain industrially, but since alcohol is produced after the reaction, it is more advantageous to use the same aliphatic alcohol solvent for solvent recovery and reuse after the reaction. be.
反応液より、オキシラセタムを単離する方法としては、
特に制限はないが、前記アミノ化液を脱アンモニア、濃
縮脱溶剤しオキシラセタムを析出させる事ができる。生
成物は濃縮途中で濾過するか、あるいは脱溶剤後アルコ
ールにより洗浄する事によって比較的純度の高い生成物
が得られる。The method for isolating oxiracetam from the reaction solution is as follows:
Although there are no particular limitations, the aminated solution can be deammoniated, concentrated and desolvented to precipitate oxiracetam. A product with relatively high purity can be obtained by filtering the product during concentration or by washing with alcohol after removing the solvent.
以下、実施例により更に詳しく説明する。 A more detailed explanation will be given below with reference to Examples.
実施例１
ガラス製の四ロフラスコにグリシンエチルエステル塩酸
塩（１３９，５１！１モル）炭酸ナトリウム（１０６ｇ
、１モル）および、４−クロロ−３−ヒドロキシ酪酸メ
チル（１５２，５ｇ、１モル）を仕込み、さらにメタノ
ール（１，０００，１を加、ｔ、攪拌しながら、３０時
間還流した。反応後、不溶物を除いた。濾液を取ジ、液
体クロマトグラフィー（以下、ＨＬＣと略す）で定量し
たところ環化物が６１％の収率で生成していることがわ
がった。Example 1 Glycine ethyl ester hydrochloride (139,51!1 mol) and sodium carbonate (106 g
, 1 mol) and methyl 4-chloro-3-hydroxybutyrate (152.5 g, 1 mol) were added, and methanol (1,000.1 mol) was added, and the mixture was refluxed for 30 hours while stirring. After the reaction The filtrate was analyzed by liquid chromatography (hereinafter abbreviated as HLC), and it was found that a cyclized product was produced in a yield of 61%.
又、濾液を薄層クロマトグラフィー（シリカゾル板、ク
ロロホルム −メタノール−９５：５）Ｋより、生成物
を分離精製できる。Further, the product can be separated and purified from the filtrate by thin layer chromatography (silica sol plate, chloroform-methanol-95:5).
反応液を濃縮し、１０％含アンモニア 水 溶液（５１
０，９）Ｋ溶解し、１５℃１０時間攪拌し念。The reaction solution was concentrated and a 10% ammonia-containing aqueous solution (51
0,9) K was dissolved and stirred for 10 hours at 15°C.
反応液をＨＬＣで定量したところ、オキシラセタムが５
５％（グリシンエステルに対して）生成していた。When the reaction solution was quantified by HLC, the amount of oxiracetam was 5.
5% (based on glycine ester) was produced.
実施例２ グリシンエチルエステル塩酸塩（１３９，５＆。Example 2 Glycine ethyl ester hydrochloride (139,5&.
１モル）、炭酸ナトリウム（１０６ｇ、１モル）および
、４−クロロ−３−ヒドロキシ酪酸エチル（１６６，５
Ｆ、１モル）を仕込み、さらにエタノール（１０００ｇ
）を加え、攪拌しながら、５０時間還流した。１０時間
後、３０時間後および５０時間後、ＨＬＣにより環化物
を定量したところ、それぞれ収率６５％、５９％、およ
び５７％であった。1 mol), sodium carbonate (106 g, 1 mol) and ethyl 4-chloro-3-hydroxybutyrate (166,5
F, 1 mol) and further ethanol (1000 g
) and refluxed for 50 hours while stirring. After 10 hours, 30 hours, and 50 hours, the cyclized product was quantified by HLC, and the yields were 65%, 59%, and 57%, respectively.
反応液を濃縮し、１０％含アンモニア、メタノール溶液
（５１０ｇ）に溶解し、１５°０１１０時間攪拌した。The reaction solution was concentrated, dissolved in a 10% ammonia-methanol solution (510 g), and stirred for 15 hours.
反応液をＨＬＣで定量したところ、オキシラセタムが、
５２％生成していた。When the reaction solution was quantified by HLC, oxiracetam was
It was produced at 52%.
実施例３
実施例１と同様に、環化反応を行ない、反応後、反応液
を氷水冷却しながら、アンモニアガスを通気した。５１
．９のアンモニアを溶解させ、反応液を１５°０１１０
時間攪拌した。ＨＬＣで定量したところオキシラセタム
が５９％生成していた。Example 3 A cyclization reaction was carried out in the same manner as in Example 1, and after the reaction, ammonia gas was passed through the reaction solution while cooling it with ice water. 51
．． Dissolve the ammonia in Step 9 and reduce the reaction solution to 15°0110
Stir for hours. As determined by HLC, 59% of oxiracetam was produced.
実施例４
ガラス製の四ロフラスコに、グリシ／エチルエステル塩
酸塩（６９，８、Ｆ、 ０．５モル）、グリシンエチル
エステル（５１，５Ｎ、 ０．５モル）、炭酸ナトリ
ウム（７９，５＆、０．７５モル）および、４−りｏ
ａ −３−ヒドロキシ酪酸エチルＣ１６６，５１１モル
）を仕込み、さらにエタノール（１０００ｇ）を加え、
攪拌し々から、３０時間還流した。Example 4 In a glass four-ring flask, glycine/ethyl ester hydrochloride (69,8, F, 0.5 mol), glycine ethyl ester (51,5 N, 0.5 mol), sodium carbonate (79,5&, 0.75 mol) and 4-rio
166,511 mol of ethyl a-3-hydroxybutyrate) was added, and ethanol (1000 g) was added.
The mixture was stirred frequently and refluxed for 30 hours.
ＨＬＣで定量したところ、環化物が５５％の収率で生成
していた。As determined by HLC, a cyclized product was produced in a yield of 55%.
さらに、実施例６と同様にアミノ化を行ないＨＬＣで定
量したところ、オキシラセタムが、４９％生成していた
。Further, amination was carried out in the same manner as in Example 6, and quantification by HLC revealed that 49% of oxiracetam was produced.
実施例５
ガラス製の四ロフラスコに、グリシンエチルエステル（
１０３５’、１モル）、炭酸ナトリウム（５３ｇ、０．
５モル）および４−クロロ−３−ヒドロキシ酪酸エチル
（１６６，５ｇ、１モル）全仕込み、さらにエタノール
（１０００，ｌｋ加え攪拌しながら３０時間還流した。Example 5 Glycine ethyl ester (
1035', 1 mol), sodium carbonate (53 g, 0.
5 mol) and ethyl 4-chloro-3-hydroxybutyrate (166.5 g, 1 mol) were added, and ethanol (1000 lk) was added and refluxed for 30 hours with stirring.
ＨＬＣで定量したところ環化物が５０％の収率で生成し
ていた。As determined by HLC, a cyclized product was produced in a yield of 50%.
さらに、実施例３と同様に、アミン化を行ないＨＬＣで
定量したところ、オキシラセタムが、４５チ生成してい
た。Furthermore, in the same manner as in Example 3, amination was carried out and quantitative determination by HLC revealed that 45 units of oxiracetam were produced.
本発明の方法によジ、容易に安価に入手し得る原料から
、工業的に有利にオキシラセタムを製造できる。By the method of the present invention, oxiracetam can be industrially advantageously produced from raw materials that are easily available at low cost.
Claims (1)
エステル或いはその塩又はそれらの混合物を反応させ、
４−ヒドロキシ−２−オキソ−１−ピロリジン酢酸エス
テルを得て、これをアンモニアによりアミノ化すること
を特徴とするオキシラセタムの製造方法。Reacting 4-chloro-3-hydroxybutyric acid ester with glycine ester, a salt thereof, or a mixture thereof,
A method for producing oxiracetam, which comprises obtaining 4-hydroxy-2-oxo-1-pyrrolidine acetate and aminating it with ammonia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12736886A JPS62286964A (en) | 1986-06-03 | 1986-06-03 | Production of oxiracetam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12736886A JPS62286964A (en) | 1986-06-03 | 1986-06-03 | Production of oxiracetam |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62286964A true JPS62286964A (en) | 1987-12-12 |
Family
ID=14958239
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12736886A Pending JPS62286964A (en) | 1986-06-03 | 1986-06-03 | Production of oxiracetam |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62286964A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100424393B1 (en) * | 2001-11-26 | 2004-03-24 | 한국화학연구원 | Process for the preparation of oxiracetam |
| KR100461859B1 (en) * | 2002-04-23 | 2004-12-14 | 주식회사 바이넥스 | The manufacturing method of Oxiracetam |
| CN102558014A (en) * | 2011-11-09 | 2012-07-11 | 天津市汉康医药生物技术有限公司 | Oxiracetam compound with steady crystal form |
| CN102627596A (en) * | 2012-03-16 | 2012-08-08 | 天津景寅医药生物技术发展有限公司 | Preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN103553999A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam crystal form III |
-
1986
- 1986-06-03 JP JP12736886A patent/JPS62286964A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100424393B1 (en) * | 2001-11-26 | 2004-03-24 | 한국화학연구원 | Process for the preparation of oxiracetam |
| KR100461859B1 (en) * | 2002-04-23 | 2004-12-14 | 주식회사 바이넥스 | The manufacturing method of Oxiracetam |
| CN102558014A (en) * | 2011-11-09 | 2012-07-11 | 天津市汉康医药生物技术有限公司 | Oxiracetam compound with steady crystal form |
| CN102627596A (en) * | 2012-03-16 | 2012-08-08 | 天津景寅医药生物技术发展有限公司 | Preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN102627596B (en) * | 2012-03-16 | 2016-01-27 | 天津景寅医药生物技术发展有限公司 | A kind of preparation method of Esomeprazole |
| CN103553999A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam crystal form III |
| CN103553999B (en) * | 2013-11-06 | 2015-05-27 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam crystal form III |
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