JPH04187667A - Production of 2-substituted hydroxyiminopropanedinitrile - Google Patents
Production of 2-substituted hydroxyiminopropanedinitrileInfo
- Publication number
- JPH04187667A JPH04187667A JP31638090A JP31638090A JPH04187667A JP H04187667 A JPH04187667 A JP H04187667A JP 31638090 A JP31638090 A JP 31638090A JP 31638090 A JP31638090 A JP 31638090A JP H04187667 A JPH04187667 A JP H04187667A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- salt
- substituted
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- IQDSOHXLWXMDPM-UHFFFAOYSA-N 2-hydroxyiminopropanedinitrile Chemical class ON=C(C#N)C#N IQDSOHXLWXMDPM-UHFFFAOYSA-N 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- JXPDNDHCMMOJPC-UHFFFAOYSA-N 2-hydroxybutanedinitrile Chemical compound N#CC(O)CC#N JXPDNDHCMMOJPC-UHFFFAOYSA-N 0.000 claims abstract description 5
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000002152 alkylating effect Effects 0.000 claims abstract description 5
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 5
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 5
- 230000002378 acidificating effect Effects 0.000 claims abstract description 3
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 150000002642 lithium compounds Chemical class 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 150000003112 potassium compounds Chemical class 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 4
- -1 2-substituted hydroxyimino-2(5-amino-1,2,4- thiadiazol-3-yl)acetic acids Chemical class 0.000 abstract description 10
- 239000002168 alkylating agent Substances 0.000 abstract description 6
- 229940100198 alkylating agent Drugs 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 229930186147 Cephalosporin Natural products 0.000 abstract description 2
- 229940124587 cephalosporin Drugs 0.000 abstract description 2
- 150000001780 cephalosporins Chemical class 0.000 abstract description 2
- 230000000845 anti-microbial effect Effects 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- BPAUMYWBCYAMGI-UHFFFAOYSA-N 2-methoxyiminopropanedinitrile Chemical compound CON=C(C#N)C#N BPAUMYWBCYAMGI-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 150000004006 C-nitroso compounds Chemical class 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical group N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- YKUHPXMDZYYZBQ-UHFFFAOYSA-N iminomalononitrile Chemical compound N#CC(=N)C#N YKUHPXMDZYYZBQ-UHFFFAOYSA-N 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
- 239000010410 layer Substances 0.000 description 1
- 229910001416 lithium ion Inorganic materials 0.000 description 1
- IDNHOWMYUQKKTI-UHFFFAOYSA-M lithium nitrite Chemical compound [Li+].[O-]N=O IDNHOWMYUQKKTI-UHFFFAOYSA-M 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- SXUXONJXVIQGLC-UHFFFAOYSA-N oxathiirane 2,2-dioxide Chemical compound O=S1(=O)CO1 SXUXONJXVIQGLC-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 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
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000005406 washing Methods 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］
本発明は抗菌作用を有するセファロスポリン系化合物を
製造するためのア／ル化剤として有用な２−置換ヒドロ
キシイミノ−２−（５−アミノ−１．２．４−チアジア
ゾール−３−イル）酢酸又はその塩の中間原料化合物
２−置換ヒドロキンイミノプロパンジニトリルの製造法
に関する。Detailed Description of the Invention [Industrial Field of Application] The present invention provides 2-substituted hydroxyimino-2-(5- Intermediate compound for amino-1.2.4-thiadiazol-3-yl)acetic acid or its salt
The present invention relates to a method for producing 2-substituted hydroquine iminopropanedinitrile.
Ｕ従来の技術］
２−１１ヒドロキシイミノプロパンジニトリルの製造法
としては、例えば２−ンアノアセトアミドから３工程を
経て得る方法（特開昭５７−１５８７６９号公報、特開
昭６１−５０８４号公報、特開昭６３−２６４４７０号
公報、特開平１−３０８２８７号公報）および２−ヒド
ロキシイミノプロパンジニトリルのＮａ塩およびＡｇ塩
がら得る方法（特開昭５７−１５８７６９号公報、特開
昭６Ｃ）−１７２９８７号公報）が知られている。U Prior Art] As a method for producing 2-11 hydroxyiminopropanedinitrile, for example, a method of obtaining it from 2-ananoacetamide through three steps (JP-A-57-158769, JP-A-61-5084) , JP-A-63-264470, JP-A-1-308287) and a method for obtaining Na and Ag salts of 2-hydroxyiminopropanedinitrile (JP-A-57-158769, JP-A-6C) -172987) is known.
［発明が解決しようとする課題］
特開昭５７−１５８７６９号公報には２−置換ヒドロキ
シイミノプロパンジニトリルを製造するために２−ヒド
ロキンイミノプロパ／ジニトリルのアルカリ金属塩が用
いられている。しかし実施例ではアルカリ金属塩として
用いられているものはＮａ塩のみに限定されており、収
率も必ずしも満足すべきものとはいえない。[Problems to be Solved by the Invention] In JP-A-57-158769, an alkali metal salt of 2-hydroquiniminopropa/dinitrile is used to produce 2-substituted hydroxyiminopropanedinitrile. However, in the examples, the alkali metal salt used is limited to Na salt, and the yield is not necessarily satisfactory.
特開昭６Ｃ）−１７２９８７号公報には２−ヒドロキシ
イミノプロパンジニトリルのＡｇ塩を用いる方法が記載
されているがＡｇ塩を用いることは価格的に工業的大量
生産に適した方法とはいえず、また、Ｒ５がシクロプロ
ピルメチル基に限定されており、収率も３０％と極めて
低い。JP-A No. 6C)-172987 describes a method using Ag salt of 2-hydroxyiminopropanedinitrile, but although using Ag salt is a method suitable for industrial mass production in terms of cost. Furthermore, R5 is limited to a cyclopropylmethyl group, and the yield is extremely low at 30%.
［課題を解決するための手段］
本発明者等は、簡便な操作でしかも高収率を与えるよう
な工業的に有利な２−置換ヒドロキノイミノプロパンジ
ニトリルの製造法を見い出すべく鋭意検討した結果、２
−ヒドロキシイミノプロパンジニトリルのに塩またはＬ
ｉ塩をアル牛ル化剤でアルキル化することによりＮａ塩
よりも高収率でしかも高純度の下記−船底（＋）で表わ
される目的化合物をほぼ定量的に製造する方法を見い出
し、本発明を完成した。[Means for Solving the Problems] The present inventors have conducted extensive studies in order to find an industrially advantageous method for producing 2-substituted hydroquiniminopropanedinitrile that is easy to operate and provides a high yield. Result, 2
-Hydroxyiminopropanedinitrile salt or L
We have discovered a method for almost quantitatively producing the target compound represented by -bottom (+) in higher yield and purity than Na salt by alkylating I salt with an alkylating agent, and have achieved the present invention. completed.
すなわち、本発明は、
（１）式
［式中、Ｍはカリウムまたはリチウムを示す］で表わさ
れる化合物をアルキル化することを特徴とする式
［式中、Ｒ，は置換されていてもよい直鎖、分枝又は環
状のアルキル基を示す］で表わされる化合物の製造法お
よび
２、マロンニトリルを酸性条件下、亜硝酸またはその塩
と反応させ、次いでカリウム化合物又はリチウム化合物
と反応させて得られる化合物（ＩＩ）をアルキル化する
ことを特徴とする化合物（１）の製造法に関する。That is, the present invention provides alkylation of a compound represented by the formula (1) [wherein M represents potassium or lithium] [wherein R is an optionally substituted straight compound]. [representing a chain, branched or cyclic alkyl group] Method for producing a compound represented by [2] Malonitrile is reacted with nitrous acid or a salt thereof under acidic conditions, and then reacted with a potassium compound or a lithium compound. The present invention relates to a method for producing compound (1), which comprises alkylating compound (II).
以下に詳細な説明を行う。A detailed explanation will be given below.
化合物（ｎ）はマロンニトリルをニトロソ化反応に従わ
せることにより製造できる。Compound (n) can be produced by subjecting malonitrile to a nitrosation reaction.
この反応に使用されるニトロソ化剤は活性メチレン化合
物と反応してＣ−ニトロソ化合物を生成しうる慣用のも
ので、例えば亜硝酸またはアルカリ金属亜硝酸塩（例え
ば亜硝酸ナトリウム、亜硝酸カリウム、亜硝酸リチウム
等）のごとき耶硝酸塩なとが含まれる。The nitrosating agents used in this reaction are those conventionally capable of reacting with active methylene compounds to form C-nitroso compounds, such as nitrous acid or alkali metal nitrites (e.g. sodium nitrite, potassium nitrite, lithium nitrite). etc.) and other nitrates.
ニトロン化剤として亜硝酸の塩を使用した場合、この反
応は通常塩酸、硫酸、酢酸などのごとき無機または有機
酸の存在で実施される。When a salt of nitrous acid is used as the nitroning agent, the reaction is usually carried out in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, acetic acid, etc.
この反応は通常水、酢酸、アルコール（例えばエタノー
ル、メタノール等）、エーテル、テトラヒドロフランの
ごとき溶媒、あるいは反応に悪影響を与えない他の溶媒
中で実施される。反応温度は特に限定されず、反応は通
常冷却下ないしは加熱下で実施される。This reaction is usually carried out in a solvent such as water, acetic acid, alcohol (eg, ethanol, methanol, etc.), ether, tetrahydrofuran, or other solvent that does not adversely affect the reaction. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.
このようにして得られたニトロン体はカリウム化合物又
はリチウム化合物（例えば炭酸カリウム、炭酸リチウム
、水酸化カリウム、水酸化リチウム等）を添加すること
により、化合物（ＩＩ）に変換することかできる。添加
するカリウム化合物又はリチウム化合物の量は１〜３倍
モル量 好ましくは１〜２倍モル量である。反応は通常
室温でよい。The nitrone compound thus obtained can be converted into compound (II) by adding a potassium compound or a lithium compound (eg, potassium carbonate, lithium carbonate, potassium hydroxide, lithium hydroxide, etc.). The amount of the potassium compound or lithium compound to be added is 1 to 3 times the molar amount, preferably 1 to 2 times the molar amount. The reaction can usually be carried out at room temperature.
本発明者等はこの化合物（ＩＩ）を効率的に単離精製す
る方法として溶媒抽出方法を開発した。The present inventors developed a solvent extraction method as a method for efficiently isolating and purifying this compound (II).
すなわち通常ニトロン化反応は水系で行われるため、化
合物（ＩＩ）は水系で存在する。この状態において下記
に述べる適当な溶媒を加え抽出すれば化合物（Ｉｔ）か
高純度で有機層側に抽出精製できる。That is, since the nitronation reaction is usually carried out in an aqueous system, compound (II) exists in an aqueous system. In this state, if an appropriate solvent described below is added and extracted, compound (It) can be extracted and purified with high purity into the organic layer side.
抽出溶媒としてはメチルエチルケトン、アセトニトリル
、ジメチルホルムアミド、酢酸エチル、テトラヒドロフ
ラン等が実施できるが、特に抽出効率および次工程のメ
チル化反応で用いる溶媒との共通化を考えるとメチルエ
チルケトンが最適である。As the extraction solvent, methyl ethyl ketone, acetonitrile, dimethylformamide, ethyl acetate, tetrahydrofuran, etc. can be used, but methyl ethyl ketone is most suitable, especially considering extraction efficiency and commonality with the solvent used in the methylation reaction in the next step.
化合物（１）は化合物（ＩＩ）をヒドロキンイミノ基上
に置換基（Ｒ１）を導入する反応（アルキル化反応）に
従わせることにより製造できる。Compound (1) can be produced by subjecting compound (II) to a reaction (alkylation reaction) of introducing a substituent (R1) onto the hydroquinimino group.
Ｒ１で示される直鎖、分枝又は環状のアルキル基として
は炭素数１〜１０のアルキル基かあげられ、例えばメチ
ル、エチル、プロピル、イソプロピル、ブチル、イソブ
チル、ｔ−ブチル、ペンチル、ｔ−ペンチル、ヘキシル
、ヘプチル、オクチル、ノニル、デンルなどのほかシク
ロプロピル。The straight chain, branched or cyclic alkyl group represented by R1 includes alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, t-pentyl. , hexyl, heptyl, octyl, nonyl, denyl, etc. as well as cyclopropyl.
シクロブチル、シクロペンチル、／クロヘキシル。Cyclobutyl, cyclopentyl, /chlorhexyl.
シクロペンチルなどがあげられる。これらは、１〜３個
の置換基を有していてもよい。それらの置換基としては
例えば、ハロゲン（例、塩素、臭素、フッ素等）、 水
酸Ｍ、ｃ、、アルコキ７基、シアン基＋ Ｃｌ ＠アル
フキジカルボニル基、カルボキシル基１式−ＣＯＯＲ’
（Ｒ’は置換されていてもよいＣ３＠アルキル基又は
置換されていてもよいＣ７Ｉ！アラルキル基を示す）で
表わされるエステル化されたカルボキシ基等が挙げられ
る。Examples include cyclopentyl. These may have 1 to 3 substituents. Examples of these substituents include halogen (e.g., chlorine, bromine, fluorine, etc.), hydroxyl M, c, 7 alkoxy groups, cyan group + Cl @alfkidicarbonyl group, carboxyl group 1 formula -COOR'
Examples include esterified carboxy groups represented by (R' represents an optionally substituted C3@alkyl group or an optionally substituted C7I!aralkyl group).
Ｒ１で表わされるＣ１０のアルキル基としては、Ｒ’に
ついて述へたようなＣ＋ａアルキル基か好ましく、これ
らアルキル基はＣ１，アルコキシ基（メトキ／、エトキ
ノ、プロピルチオン）、Ｃ，、アルキルチオ基（メチル
チオ、エチルチオ、プロピルチオ）、ハロゲン、シアン
等で置換されていてもよい。又Ｒ２で表わされる、置換
されていてもよいＣ７１，アラルキル基としては、ハロ
ゲン、ニトロ、ＣＩ３アルキル基等で置換されていても
よいベンジル、フェネチル等が挙げられる。The C10 alkyl group represented by R1 is preferably a C+a alkyl group as described for R'; , ethylthio, propylthio), halogen, cyan, etc. Further, the optionally substituted C71, aralkyl group represented by R2 includes benzyl, phenethyl, etc. which may be substituted with halogen, nitro, CI3 alkyl group, etc.
Ｒ３て示される置換されていてもよい直鎖、分枝又は環
状のアルキル基のうち、好ましくは置換されていてもよ
い炭素数１〜６の直鎖または分枝状アルキル基である。Among the optionally substituted linear, branched or cyclic alkyl groups represented by R3, preferred is an optionally substituted linear or branched alkyl group having 1 to 6 carbon atoms.
ヒドロキンイミノ基上に置換基を導入する反応に使用さ
れる試薬（アルキル化剤）としては−船底％式％（［［
）
［式中、Ｒ，は前記の定義と同じで、Ｙは酸残基を示す
］の化合物か使用される。The reagent (alkylating agent) used in the reaction to introduce a substituent onto the hydroquinimino group is - bottom% formula% ([[
) [wherein R is the same as defined above and Y represents an acid residue] is used.
適当な酸残基としてはハロゲン化水素酸（例えば塩酸、
臭化水素酸、ヨウ化水素酸等）、硫酸、アルキル硫酸（
例えばメチル硫酸、エチル硫酸等）、スルホン酸（例え
ばメタノスルホン酸、ｐ−トルエンスルホン酸等）のご
とき酸の残基か含まれる。Suitable acid residues include hydrohalic acids (e.g. hydrochloric acid,
hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, alkyl sulfuric acid (
Examples include residues of acids such as methyl sulfate, ethyl sulfate, etc.), sulfonic acids (eg, methanosulfonic acid, p-toluenesulfonic acid, etc.).
化合物（Ｉ［Ｉ）を用いた反応は通常水、メチルエチル
ケトン、アセトニトリル、アセトン、エタノール、エー
テル、エチルアセテート、ジメチルホルムアミドのごと
き溶媒または反応に影響を与えないその他の溶媒中で実
施される。また、化合物（ＩＩ）の抽出後、そのまま同
じ溶媒を用いて次反応に付してもよい。The reaction using compound (I[I) is usually carried out in a solvent such as water, methyl ethyl ketone, acetonitrile, acetone, ethanol, ether, ethyl acetate, dimethylformamide, or other solvents that do not affect the reaction. Alternatively, after extraction of compound (II), the same solvent may be used as it is for the next reaction.
アルキル化剤の使用量は０．５から３倍モル量、好まし
くは０５から２倍モル量用いる。反応温度は通常冷却下
で行い、アルキル化剤滴下後室温にもとす。反応時間は
温度濃度等の反応条件との関係において適宜設定できる
が通常５分から５時間好ましくは５分から３時間の範囲
である。目的化合物は自体公知の手段、たとえば洗浄、
濃縮、減圧蒸留により単離・精製することかできる。The amount of the alkylating agent used is 0.5 to 3 times the molar amount, preferably 0.5 to 2 times the molar amount. The reaction temperature is usually carried out under cooling and is brought to room temperature after the alkylating agent is added dropwise. The reaction time can be appropriately set depending on the reaction conditions such as temperature and concentration, but is usually in the range of 5 minutes to 5 hours, preferably 5 minutes to 3 hours. The target compound can be obtained by methods known per se, such as washing,
It can be isolated and purified by concentration and vacuum distillation.
上記方法によって得られた化合物（１）はさらに下記に
示す方法により式（ＩＶ）で表わされる２−置換ヒドロ
ヰシイミ／−２−（５−アミ／−１，２゜４−チアンア
ゾール−３−イル）酢酸又はその塩に導くことができる
。式（ＩＶ）の化合物は各種のすぐれた抗菌活性を有す
るセファロスポリンやペニンリンを得るべくそれぞれ７
位或は６位にア／ル基を導入する場合のアンル化剤とし
て有用である。Compound (1) obtained by the above method is further converted to 2-substituted hydrocyimy/-2-(5-ami/-1,2゜4-thianazol-3-yl) represented by formula (IV) by the method shown below. ) can lead to acetic acid or its salts. The compound of formula (IV) was used to obtain various cephalosporins and peninrins having excellent antibacterial activity.
It is useful as an unlying agent when introducing an aryl group into the 6-position or the 6-position.
［方 法〕 の塩 ＼ ＯＲ。[Method〕 salt \ OR.
（ＴＶ）またはその塩
［式中、Ｒ３は前記の意義通りで、Ｍ′はアルカリ金属
を示す］
［実施例］
実施例１
水（６０ｄ）中のマロンニトリル（２０ｇ、 ０．３０
ｍｏｌ）および酢酸（３４、６−、０，６０ｍｏｌ）の
混合物に水浴中で冷却しかつ撹拌しながら１０ないし１
５°Ｃで亜硝酸ナトリウム（３］、８ｇ、０．４５ｍｏ
ｌ）の水溶液（６０ｄ）を滴下し、撹拌を冷却下で３時
間続けた。次いで炭酸カリウム（４１，５ｇ、０゜３０
ｍｏｌ）または炭酸リチウム（２２，１７ｇ、 ０．３
Ｑ ｍｏｌ）および水（５０ｄ）を加えメチルエチルケ
トン（１００ｙｘ５）で抽出した。このメチルエチルケ
トン抽出液中の金属イオンを定量する時、カリウムまた
はリチウムイオンがそれぞれ０．３０モル含まれ、かつ
ナトリウムイオンはほとんど検出されない。このメチル
エチルケトン溶媒を１／３に濃縮した後、水浴中で冷却
し、かつ撹拌しながら、ジメチル硫酸（３２，８−，０
，３３ｍｏｌ）を滴下し、撹拌を冷却下で５分さらに室
温で１時間撹拌した。反応混合物に水（３００ｄ）およ
び塩化ナトリウム（２０ｇ）を加え、有機層を分離した
。水層をメチルエチルケトン（１００ｄ）で抽出し先は
との有機層と混合した。このメチルエチルケトン抽出液
について ２−メトキンイミノプロパンジニトリルのＨ
ＰＬＣ分析による定量を行った。炭酸カリウムを使用の
場合、すなわち２−ヒドロキンイミノプロパンジニトリ
ルのＫａ塩を経由する反応では８４％、炭酸リチウムを
使用の場合、すなわち２−ヒドロキシイミノプロパンジ
ニトリルのＬｉ塩を経由する反応では９４％の収率で２
−メトキシイミノプロパンジニトリルが得られた。次い
で溶媒を減圧留去すると濃紫色の油状物が得られ、これ
を減圧蒸留にて精製し純度９０％の２−メトキシイミノ
プロパンジニトリルを２２．１ｇ得た。 （ｂｐ、 ２
８〜ｂ
１η豊ユ
実施例１の炭酸カリウムまたは炭酸リチウムの代わりに
炭酸水素ナトリウム（２５，２ｇ、０゜３０−）を使用
する以外はすべて実施例１と同様の方法で抽出した２−
ヒドロキシイミノプロパンジニトリルのＮａ塩のメチル
エチルケトン溶液を濃縮後、アセトニトリルを加えて、
実施例１と同様の方法でメチル化を行った結果、７０％
の収率て２−メトキンイミノプロパンジニトリルを得た
。(TV) or a salt thereof [wherein R3 is as defined above and M' represents an alkali metal] [Examples] Example 1 Malonitrile (20 g, 0.30 g in water (60 d))
mol) and acetic acid (34,6-,0.60 mol) while cooling in a water bath and stirring.
Sodium nitrite (3), 8g, 0.45mo at 5°C
An aqueous solution of l) (60d) was added dropwise and stirring continued under cooling for 3 hours. Next, potassium carbonate (41.5g, 0°30
mol) or lithium carbonate (22.17g, 0.3
Q mol) and water (50d) were added, and the mixture was extracted with methyl ethyl ketone (100yx5). When quantifying the metal ions in this methyl ethyl ketone extract, 0.30 moles of potassium or lithium ions are each contained, and almost no sodium ions are detected. After concentrating this methyl ethyl ketone solvent to 1/3, it was cooled in a water bath and dimethyl sulfate (32,8-,0
, 33 mol) was added dropwise, and the mixture was stirred for 5 minutes under cooling, and further stirred for 1 hour at room temperature. Water (300d) and sodium chloride (20g) were added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with methyl ethyl ketone (100d) and mixed with the organic layer. About this methyl ethyl ketone extract H of 2-methquiniminopropanedinitrile
Quantification was performed by PLC analysis. When potassium carbonate is used, i.e., the reaction via the Ka salt of 2-hydroxyiminopropanedinitrile, it is 84%, and when lithium carbonate is used, i.e., the reaction via the Li salt of 2-hydroxyiminopropanedinitrile, it is 84%. 2 in 94% yield
-methoxyiminopropanedinitrile was obtained. Then, the solvent was distilled off under reduced pressure to obtain a deep purple oil, which was purified by distillation under reduced pressure to obtain 22.1 g of 2-methoxyiminopropanedinitrile with a purity of 90%. (bp, 2
8-b 1η Fengyu 2- Extracted in the same manner as in Example 1 except that sodium hydrogen carbonate (25.2 g, 0°30-) was used instead of potassium carbonate or lithium carbonate in Example 1.
After concentrating the methyl ethyl ketone solution of Na salt of hydroxyiminopropanedinitrile, acetonitrile was added,
As a result of methylation performed in the same manner as in Example 1, 70%
2-methquiniminopropanedinitrile was obtained with a yield of .
［発明の効果］
本発明は上記実施例からもわかるように２−ヒドロキン
イミノプロパンジニトリルのに塩またはＬｉ塩をアルキ
ル化するという簡単な操作で高収率かつ高純度の目的化
合物を得ることかでき、工業的に極めて有利な方法であ
る。[Effects of the Invention] As can be seen from the above examples, the present invention can obtain the target compound in high yield and purity by a simple operation of alkylating a salt or a Li salt of 2-hydroquiniminopropanedinitrile. This is an industrially extremely advantageous method.
Claims (1)
れる化合物をアルキル化することを特徴とする式 ▲数式、化学式、表等があります▼（ I ） ［式中、Ｒ＿１は置換されていてもよい直鎖、分枝又は
環状のアルキル基を示す］で表わされる化合物の製造法
。 ２、マロンニトリルを酸性条件下、亜硝酸またはその塩
と反応させ、次いでカリウム化合物又はリチウム化合物
と反応させて得られる式 ▲数式、化学式、表等があります▼（II） ［式中、Ｍはカリウムまたはリチウムを示す］で表わさ
れる化合物をアルキル化することを特徴とする式 ▲数式、化学式、表等があります▼（ I ） ［式中、Ｒ＿１は置換されていてもよい直鎖、分枝又は
環状のアルキル基を示す］で表わされる化合物の製造法
。[Scope of Claims] 1. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) Formula ▲ Mathematical formula characterized by alkylating a compound represented by [In the formula, M represents potassium or lithium] , chemical formulas, tables, etc. ▼ (I) A method for producing a compound represented by [In the formula, R_1 represents an optionally substituted linear, branched, or cyclic alkyl group]. 2. The formula obtained by reacting malonitrile with nitrous acid or its salt under acidic conditions, and then with a potassium compound or lithium compound ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, M is There are formulas, chemical formulas, tables, etc. that are characterized by alkylating a compound represented by [representing potassium or lithium]. or a cyclic alkyl group].
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31638090A JPH04187667A (en) | 1990-11-20 | 1990-11-20 | Production of 2-substituted hydroxyiminopropanedinitrile |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31638090A JPH04187667A (en) | 1990-11-20 | 1990-11-20 | Production of 2-substituted hydroxyiminopropanedinitrile |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04187667A true JPH04187667A (en) | 1992-07-06 |
Family
ID=18076443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP31638090A Pending JPH04187667A (en) | 1990-11-20 | 1990-11-20 | Production of 2-substituted hydroxyiminopropanedinitrile |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04187667A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014203855A2 (en) | 2013-06-21 | 2014-12-24 | イハラケミカル工業株式会社 | Manufacturing method for 2-amino-2-hydroxyimino-n-alkoxy acetoimidoyl cyanide, and manufacturing intermediate thereof |
| US10544092B2 (en) | 2015-12-25 | 2020-01-28 | Shenyang Sinochem Agrochemicals R&D Co., Ltd. | Malononitrile oxime ether compound and use thereof |
-
1990
- 1990-11-20 JP JP31638090A patent/JPH04187667A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014203855A2 (en) | 2013-06-21 | 2014-12-24 | イハラケミカル工業株式会社 | Manufacturing method for 2-amino-2-hydroxyimino-n-alkoxy acetoimidoyl cyanide, and manufacturing intermediate thereof |
| WO2014203855A3 (en) * | 2013-06-21 | 2015-01-29 | イハラケミカル工業株式会社 | Manufacturing method for 2-amino-2-hydroxyimino-n-alkoxy acetoimidoyl cyanide, and manufacturing intermediate thereof |
| CN105377812A (en) * | 2013-06-21 | 2016-03-02 | 庵原化学工业株式会社 | Manufacturing method for 2-amino-2-hydroxyimino-n-alkoxy acetoimidoyl cyanide, and manufacturing intermediate thereof |
| JPWO2014203855A1 (en) * | 2013-06-21 | 2017-02-23 | イハラケミカル工業株式会社 | Process for producing 2-amino-2-hydroxyimino-N-alkoxyacetimidoylcyanide and its intermediate |
| CN105377812B (en) * | 2013-06-21 | 2018-09-18 | 组合化学工业株式会社 | The preparation method of 2- amino -2- oximido-N- alkoxy acetimidoyl cyanides and its prepare intermediate |
| US10544092B2 (en) | 2015-12-25 | 2020-01-28 | Shenyang Sinochem Agrochemicals R&D Co., Ltd. | Malononitrile oxime ether compound and use thereof |
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