CS244255B1 - Method of 5-methylisoxazole-3-carboxyl acid's amide production - Google Patents
Method of 5-methylisoxazole-3-carboxyl acid's amide production Download PDFInfo
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- CS244255B1 CS244255B1 CS848663A CS866384A CS244255B1 CS 244255 B1 CS244255 B1 CS 244255B1 CS 848663 A CS848663 A CS 848663A CS 866384 A CS866384 A CS 866384A CS 244255 B1 CS244255 B1 CS 244255B1
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- methylisoxazole
- carboxylic acid
- methyl
- reaction mixture
- amide
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- 238000000034 method Methods 0.000 title claims abstract description 9
- 150000001408 amides Chemical class 0.000 title claims description 4
- 239000002253 acid Substances 0.000 title description 3
- 238000004519 manufacturing process Methods 0.000 title description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000011541 reaction mixture Substances 0.000 claims abstract description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 11
- KBOSIRPMGVGOEP-UHFFFAOYSA-N 5-methyl-1,2-oxazole-3-carboxamide Chemical compound CC1=CC(C(N)=O)=NO1 KBOSIRPMGVGOEP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000002955 isolation Methods 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 238000001816 cooling Methods 0.000 claims description 7
- 238000006386 neutralization reaction Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- 159000000000 sodium salts Chemical group 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 238000000354 decomposition reaction Methods 0.000 claims description 3
- 150000002443 hydroxylamines Chemical class 0.000 claims description 3
- KLPASEZGNSBTBD-UHFFFAOYSA-N 4,5-dimethyl-1,2-oxazole-3-carboxylic acid Chemical compound CC=1ON=C(C(O)=O)C=1C KLPASEZGNSBTBD-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- OMHOEQINEXASKE-UHFFFAOYSA-N methyl 2,4-dioxopentanoate Chemical compound COC(=O)C(=O)CC(C)=O OMHOEQINEXASKE-UHFFFAOYSA-N 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- BELORUTWNZRKML-UHFFFAOYSA-N methyl 1,2-oxazole-3-carboxylate Chemical compound COC(=O)C=1C=CON=1 BELORUTWNZRKML-UHFFFAOYSA-N 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 abstract description 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 abstract description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 4
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 abstract description 3
- MVHHQOCEOUNTID-UHFFFAOYSA-N methyl 5-methyl-1,2-oxazole-3-carboxylate Chemical compound COC(=O)C=1C=C(C)ON=1 MVHHQOCEOUNTID-UHFFFAOYSA-N 0.000 abstract description 2
- LKZDZYHULMRBPU-UHFFFAOYSA-M sodium;2,4-dioxopentanoate Chemical compound [Na+].CC(=O)CC(=O)C([O-])=O LKZDZYHULMRBPU-UHFFFAOYSA-M 0.000 abstract description 2
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940127089 cytotoxic agent Drugs 0.000 abstract 1
- 238000007865 diluting Methods 0.000 abstract 1
- 230000033444 hydroxylation Effects 0.000 abstract 1
- 238000005805 hydroxylation reaction Methods 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 3
- BNMPIJWVMVNSRD-UHFFFAOYSA-N 5-methyl-1,2-oxazole-3-carboxylic acid Chemical compound CC1=CC(C(O)=O)=NO1 BNMPIJWVMVNSRD-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- -1 acetylpyruvic acid ester Chemical class 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- UNRQTHVKJQUDDF-UHFFFAOYSA-N acetylpyruvic acid Chemical compound CC(=O)CC(=O)C(O)=O UNRQTHVKJQUDDF-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- ARYKRXSKOTZGQO-UHFFFAOYSA-N diethyl oxalate propan-2-one Chemical compound CC(C)=O.CCOC(=O)C(=O)OCC ARYKRXSKOTZGQO-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- YERWBBMSDMSDKT-UHFFFAOYSA-N ethyl 2-oxopentanoate Chemical compound CCCC(=O)C(=O)OCC YERWBBMSDMSDKT-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Způsob výroby amidu 5-methylisoxazol -3-karboxylové kyseliny, který slouží k přípravě účinného chemotherapeutika 3- -sulfanilamido-5-methylisoxazolu (sulfa- methaxazolu). Jeho přípravu lze provést způsobem v jednom sledu, bez izolace meziproduktů, prakticky v jednom reaktoru. Známým způsobem vyrobena sodná sůl met- hyleeteru kyseliny acetylpyrohroznové se rozloží při snížené teplote kyselinou sírovou zředěnou methanolem a současně se převede reakční směs do mírně kyselé reakce, ve které probíhá velice dobře cy- klizace působením hydroxylaminhydrochlo- ridu. Methylester 5-tnettiylisoxazol-3-ka- rboxylové kyseliny se převede na amid 5-methylisoxazol-3-karboxylové kyseliny oddestilováním rozpouštědel, zředěním vodou a přidáním vodného amoniaku.Process for the preparation of 5-methylisoxazole-3-carboxylic acid amide, which is used for the preparation of an effective chemotherapeutic agent of 3-sulfanilamido-5-methylisoxazole (sulfa- methaxazole). It can be prepared in a single-sequence manner, without isolation of the intermediates, in virtually one reactor. The acetylpyruvic acid sodium salt of sodium methoxide is known to be decomposed at a reduced temperature with sulfuric acid diluted with methanol and at the same time the reaction mixture is converted into a slightly acidic reaction in which hydroxylation with hydroxylamine hydrochloride proceeds very well. 5-Methyl-isoxazole-3-carboxylic acid methyl ester is converted to 5-methyl-isoxazole-3-carboxylic acid amide by distilling off the solvents, diluting with water and adding aqueous ammonia.
Description
Vynález se týká výroby amidu 5-methylisoxazol-3-karboxylové kyseliny, který slouží jako meziprodukt účinného chemotherapeutika 3-sulfanilamido-5-methylisoxazolu (sulfamethoxazolu).The present invention relates to the preparation of 5-methylisoxazole-3-carboxylic acid amide, which serves as an intermediate of the active chemotherapeutic 3-sulfanilamido-5-methylisoxazole (sulfamethoxazole).
Dosavadní způsob vychází z čs AO č. 175 335 a čs AO Č. 182 117 to jest z přípravy esteru acetylpyrohroznové kyseliny Claisenovou kondenzací esteru kyseliny šíavelové s acetonem a methoxidem nebo ethoxidem sodným. Sodná sůl acetylpyrohroznové kyseliny se po izolaci rozloží methanolickým roztokem kyseliny sírové na methylester kyseliny acetylpyrohroznové, který se cyklizuje působením soli hydroxylaminu na methylester 5-methylisoxazol-3-karboxylové kyseliny. Vyizolovaný produkt se převede na amid 5-methylisoxazol-3-karboxylové kyseliny vodným amoniakem v ethanolu. Nevýhodou těchto postupů je dvojí izolace meziproduktů. U obou izolací odpadají matečné louhy s organickými rozpouštědly, které je nutno dále zpracovat.The prior art process is based on AO No. 175 335 and AO No. 182 117, i.e., from the preparation of an acetylpyruvic acid ester with Claisen by condensation of a oxalic acid ester with acetone and sodium methoxide or ethoxide. After isolation, the acetylpyruvic acid sodium salt is decomposed with methanolic sulfuric acid to give methyl acetylpyruvic acid ester, which is cyclized by treatment with a hydroxylamine salt to 5-methylisoxazole-3-carboxylic acid methyl ester. The isolated product was converted to 5-methylisoxazole-3-carboxylic acid amide with aqueous ammonia in ethanol. The disadvantage of these processes is the double isolation of intermediates. In both insulations, mother liquors with organic solvents are eliminated and must be further processed.
•Uvedené nevýhody odstraňuje způsob vynálezu, jehož podstata je v tom, že se surová sodná sůl methylesterů kyseliny acetylpyrohroznové rozloží v molárním poměru 1 : ji,05 až 1,1 methanolickóu kyselinou sírovou o koncentraci 16 až 20 % obj. při hodnotě pH reakční směsi 5 až 2 za teploty 7 až 15 3C a vzniklá reakční směs se cyklizuje působením sol-i hydroxylaminu na methylester kyseliny 5-methylisoxazol-3-karboxylové. Ten se po neutralizaci reakční směsi hydrogenuhličitanem sodným, oddestilování rozpouštědla a doplněním reakční směsi vodou na troj-až čtyřnásobek objemu bez izolace převede amoniakem na amid 5-methyl-3-isoxazolkarboxylové kyseliny. Ten se po ochlazení reakční směsi na 10 až 15 °C izoluje filtrací a promytím se zbaví anorganických solí. To znamená, že se po Claisenově kondenzaci diethyloxalátu a acetonem v prostředí methoxidu sodného provede rozklad sodné soli enolformy a současné neutralizace s konečnou úpravouThe above-mentioned disadvantages are overcome by the method of the invention, which is characterized in that the crude sodium salt of methyl esters of acetylpyruvic acid is decomposed in a molar ratio of 1: 1, 0.5 to 1.1 methanolic sulfuric acid at a concentration of 16 to 20% by volume. 5-2 at 7-15 C 3 and the reaction mixture is cyclized with hydroxylamine sol and the methyl 5-methylisoxazole-3-carboxylic acid. After neutralization of the reaction mixture with sodium bicarbonate, distilling off the solvent and making up the reaction mixture with water to three to four times the volume without isolation, ammonia is converted into 5-methyl-3-isoxazolecarboxylic acid amide. After cooling the reaction mixture to 10-15 ° C, this is isolated by filtration and washed to remove inorganic salts. This means that after Claisen condensation of diethyl oxalate and acetone in sodium methoxide, the decomposition of enolform sodium salt and simultaneous neutralization with final treatment
- 2 244 2SS reakčního prostředí na mírnou kyselost (pH 2 až 5) kyselinou sírovou zředěnou methanolem. Příprava methanolického roztoku kyseliny sírové se provádí za chlazení do teploty 15 °C. Rozklad a neutralizace probíhá rovněž za chlazení v uvedeném rozmezí 7 až 15 °C, s výhodou 8 až 10 °C.. Za těchto podmínek nedochází k vedlejším destrukčním reakcím. Po míchání se přidá k reakční směsi hydroxylaminhydrochlorid nebo síran. Cyklizace se udržuje 6 až 7 hodin při teplotě 35 až 40 °C. Po neutralizaci hydrogenuhličitanem sodným nebo jiným alkalickým činidlem, se oddestiluje za atmosférického tlaku převážná část organického rozpouštědla. V laboratoři lze provést destilaci tří čtvrtin rozpouštědla bez neutralizace za atmosférického tlaku. Zbytek se zahustí ve vakuu. Odparek se zředí stanoveným množstvím vody a po rozmíchání se přidá vodný amoniak. Reakce se udržuje za míchání 5 hodin při teplotě 25 až 30 °C.- 2 244 2SS of the reaction medium to moderate acidity (pH 2-5) diluted with methanolic sulfuric acid. The methanolic sulfuric acid solution is prepared under cooling to 15 ° C. The decomposition and neutralization also take place with cooling in the range of 7 to 15 ° C, preferably 8 to 10 ° C. Under these conditions, no destructive side reactions occur. After stirring, hydroxylamine hydrochloride or sulfate is added to the reaction mixture. The cyclization is maintained at 35-40 ° C for 6-7 hours. After neutralization with sodium bicarbonate or other alkaline reagent, most of the organic solvent is distilled off at atmospheric pressure. Three quarters of the solvent can be distilled in the laboratory without neutralization at atmospheric pressure. The residue was concentrated in vacuo. The residue is diluted with a specified amount of water and, after stirring, aqueous ammonia is added. The reaction is maintained at 25-30 ° C with stirring for 5 hours.
Po zchlazení na 10 až 15 °C se získaný amid 5-methylisoxazol-3-karboxylové kyseliny odsaje a promyje vodou vychlazenou na 10 až 15 °C do ztráty síranů a chloridů. Získá se světlá krystalická látka vyhovující kvality s nepatrnou stopou izomeru. Výtěžnost na výchozí diethyloxalát je 63,7 % theorie.After cooling to 10 to 15 ° C, the 5-methylisoxazole-3-carboxylic acid amide obtained is suction filtered and washed with water cooled to 10 to 15 ° C until loss of sulphates and chlorides. A pale crystalline material of satisfactory quality with a slight trace of isomer is obtained. The yield on starting diethyl oxalate is 63.7% of theory.
Podstatnou výhodou způsobu podle vynálezu je snížení pracnosti, neboT odpadá dvojí izolace meziproduktů, jak vyplývá z následujícího srovnání blokových schémat přípravy:An essential advantage of the process according to the invention is the reduction of labor, since the double isolation of intermediates is eliminated, as follows from the following comparison of the flow diagrams:
Dosavadní stav d iethyloxalát aceton lfeOCH^ sodná sůl enolátu methylesteru kys. 1) HpS04 iacetylpyrohroznovéJ2)^0/„CT > methylester kys.'“BACKGROUND iethyloxalát acetone d ^ lfeOCH sodium enolate acid methyl ester. 1) p H 2 S0 4 iacetylpyrohroznovéJ) ^ 0 / "T C> acid methyl ester. '"
5-methylisoxazol3-karbox.ylové izolace izolace jr amid kyseliny5-methylisoxazole-3-carboxyl isolation isolation of the acid amide
5-methylisoxazol “3-karboxylové izolace5-methylisoxazole-3-carboxylic acid isolation
Způsob podle vynálezu d iethyloxalát acetonThe process of the invention is diethyl oxalate acetone
3odné sůl enolátu nethylesteru kys. ic etylpyrohroznové methylester kys.3-ethyl ester of ethylpyruvic acid ethyl ester enolate
l)Hj>SOÁ k 5-methylisoxazol —-3-karboxylovél) Hj> SO and 5-methylisoxazole-carboxylic --3
NaOCH3 NaOCH 3
2)NHpOH.HCl2) NHpOH.HCl
- 3 244 255- 3,244,255
Výrobu amidu 5-methylisoxazol-3-karboxylové kyseliny lze provést v jednom reaktoru bez přerušení. Reakce probíhají v prostředí methanolu až na amidaci, která probíhá ve vodném prostředí. Následující příklad provedení způsob podle vynálezu pouze dokládá, ale nijak neomezuje:The production of 5-methylisoxazole-3-carboxylic acid amide can be carried out in one reactor without interruption. The reactions take place in methanol medium except for the amidation which takes place in aqueous medium. The following exemplary embodiment illustrates the method of the invention but does not limit it in any way:
Ke směsi 750 ml methanolického roztoku methoxidu sodného o obsahu 26,7 % a 1 750 methanolu se během 1 hodiny přikape směs 400 g diethyloxalétu a 200 ml acetonu do teploty 35 °C.To a mixture of 750 ml of methanolic sodium methoxide solution containing 26.7% and 1750 methanol was added dropwise a mixture of 400 g of diethyl oxalate and 200 ml of acetone dropwise over 1 hour to a temperature of 35 ° C.
Reakční směs se míchá 5 hodin při 30 až 35 °C. Poté se směs ochladí na 8 až 10 °C a zvolna se připouští vychlazený roztok 110 ml kyseliny sirové o koncentraci 98 % obj. v 500 ml methanolu. Po míchání a zvýšení teploty reakční směsi na 25 až 30 °C se přidá 180 g hydroxylaminhydrochloridu. Reakční směs se míchá 7 hodin při teplotě 35 až 40 °C. Po ochlazení na 20 °C se přidá 190 g hydrogenuhličitanu sodného během 30 až 50 minut. Za atmosférického tlaku se oddestiluje 2 až 2,2 litrů methanolu. Zbytek se ve vakuu zahustí na celkový objem 500 až 600 ml. Obsah se zředí 21 vody a vodným amoniakem se reakční směs zneutralizuje. K převedení esteru na amid se přidá do reakční směsi 800 ml koncentrovaného vodného amoniaku (25%). Reakční směs se míchá 5 hodin při teplotě 25 až 30 °C.The reaction mixture was stirred at 30-35 ° C for 5 hours. The mixture is then cooled to 8-10 ° C and a cooled solution of 110 ml of 98% v / v sulfuric acid in 500 ml of methanol is slowly added. After stirring and raising the temperature of the reaction mixture to 25-30 ° C, 180 g of hydroxylamine hydrochloride are added. The reaction mixture was stirred at 35-40 ° C for 7 hours. After cooling to 20 ° C, 190 g of sodium bicarbonate are added over a period of 30 to 50 minutes. 2 to 2.2 liters of methanol are distilled off at atmospheric pressure. The residue is concentrated in vacuo to a total volume of 500 to 600 ml. The contents were diluted with water and neutralized with aqueous ammonia. To convert the ester to the amide, 800 mL of concentrated aqueous ammonia (25%) was added to the reaction mixture. The reaction mixture was stirred at 25-30 ° C for 5 hours.
Po ochlazení na 10 až 15 °C se vyloučený amid 5-methylisoxazol-3-karboxylové kyseliny odsaje, promyje vodou vychlazenou na 8 až 10 °C do ztráty síranů a chloridů.After cooling to 10-15 ° C, the precipitated 5-methylisoxazole-3-carboxylic acid amide is filtered off with suction, washed with water cooled to 8-10 ° C until loss of sulphates and chlorides.
Získá se 220 g bezbarvého nebo mírně nažloutlého amidu 5-methylisoxazol-3-karboxylové kyseliny o t.t. 167 až 169 °C, který podle plynové chromatografie obsahuje jen nepatrné stopy izomeru a vedlejších látek.220 g of colorless or slightly yellowish 5-methylisoxazole-3-carboxylic acid amide of m.p. 167 DEG -169 DEG C. which, according to gas chromatography, contains only slight traces of isomer and by-products.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS848663A CS244255B1 (en) | 1984-11-13 | 1984-11-13 | Method of 5-methylisoxazole-3-carboxyl acid's amide production |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS848663A CS244255B1 (en) | 1984-11-13 | 1984-11-13 | Method of 5-methylisoxazole-3-carboxyl acid's amide production |
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| Publication Number | Publication Date |
|---|---|
| CS866384A1 CS866384A1 (en) | 1985-09-17 |
| CS244255B1 true CS244255B1 (en) | 1986-07-17 |
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| CS848663A CS244255B1 (en) | 1984-11-13 | 1984-11-13 | Method of 5-methylisoxazole-3-carboxyl acid's amide production |
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- 1984-11-13 CS CS848663A patent/CS244255B1/en unknown
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| CS866384A1 (en) | 1985-09-17 |
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