CS246872B1 - Preparation method of 1-(2,6-dimethylphenoxy)-2-propanon - Google Patents
Preparation method of 1-(2,6-dimethylphenoxy)-2-propanon Download PDFInfo
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- CS246872B1 CS246872B1 CS719184A CS719184A CS246872B1 CS 246872 B1 CS246872 B1 CS 246872B1 CS 719184 A CS719184 A CS 719184A CS 719184 A CS719184 A CS 719184A CS 246872 B1 CS246872 B1 CS 246872B1
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- XDJULAUHYAJQBU-UHFFFAOYSA-N 1-(2,6-dimethylphenoxy)propan-2-one Chemical compound CC(=O)COC1=C(C)C=CC=C1C XDJULAUHYAJQBU-UHFFFAOYSA-N 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title description 4
- NXXYKOUNUYWIHA-UHFFFAOYSA-N 2,6-Dimethylphenol Chemical compound CC1=CC=CC(C)=C1O NXXYKOUNUYWIHA-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 238000009835 boiling Methods 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- -1 alkali metal 2,6-dimethylphenolate Chemical class 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 229910001516 alkali metal iodide Inorganic materials 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 235000009518 sodium iodide Nutrition 0.000 claims description 6
- 230000003197 catalytic effect Effects 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 2
- 150000001983 dialkylethers Chemical class 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- VQFAIAKCILWQPZ-UHFFFAOYSA-N bromoacetone Chemical compound CC(=O)CBr VQFAIAKCILWQPZ-UHFFFAOYSA-N 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 150000003739 xylenols Chemical class 0.000 description 3
- VLPIATFUUWWMKC-SNVBAGLBSA-N (2r)-1-(2,6-dimethylphenoxy)propan-2-amine Chemical compound C[C@@H](N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-SNVBAGLBSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 229960003404 mexiletine Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- WEFSXBPMNKAUDL-UHFFFAOYSA-N 1-iodopropan-2-one Chemical compound CC(=O)CI WEFSXBPMNKAUDL-UHFFFAOYSA-N 0.000 description 1
- NXXYKOUNUYWIHA-UHFFFAOYSA-M 2,6-dimethylphenolate Chemical compound CC1=CC=CC(C)=C1[O-] NXXYKOUNUYWIHA-UHFFFAOYSA-M 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- ZTPAYGILGMXFAV-UHFFFAOYSA-M potassium;2,6-dimethylphenolate Chemical compound [K+].CC1=CC=CC(C)=C1[O-] ZTPAYGILGMXFAV-UHFFFAOYSA-M 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- UGPKJFUWKPOBIQ-UHFFFAOYSA-M sodium;2,6-dimethylphenolate Chemical compound [Na+].CC1=CC=CC(C)=C1[O-] UGPKJFUWKPOBIQ-UHFFFAOYSA-M 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
Riešenie sa týká spósobu přípravy 1-(2,6-dimetylfenoxy)-2-propanónu, ktorý sa používá ako medziprodukt pri výrobě antiarytmika mexiletinu.The present invention relates to a process for the preparation of 1- (2,6-dimethylphenoxy) -2-propanone which is used as an intermediate in the manufacture of the antiarrhythmic drug mexiletine.
Zlúčenina připravuje reakciou 2,6-dimetylfenolu a 1-chlor- alebo 1-brómaceténom a sol'ou slabej kyseliny a silné) zásady, alebo reakciou 2,6-dimetylfenolátom alkalického kovu s 1-chlór- alebo 1-hrómacetónom, za katalytického pósobenia jodidu alkalického kovu, zahrievaním vo vhodnom organickom rozpúšťadle, alebo za podmienok medzifázovei katalÝzv.The compound is prepared by reaction of 2,6-dimethylphenol and 1-chloro- or 1-bromoacetene and a weak acid and strong base salt, or by reaction of an alkali metal 2,6-dimethylphenolate with 1-chloro- or 1-bromoacetone under catalytic action. an alkali metal iodide, by heating in a suitable organic solvent, or under interfacial catalysis conditions.
Vynález sa týká spůsobu přípravy 1-(2,6-dimetylfenoxyj-2-propanónu vzorca I,The invention relates to a process for the preparation of 1- (2,6-dimethylphenoxy) -2-propanone of the formula I,
ktorý sa používá ako medziprodukt pri výrobě antiarytmika mexiletinu.which is used as an intermediate in the production of the antiarrhythmic drug mexiletine.
Doposial' sa táto zlúčenina vyrábala z 2,6-dimetylfenolu a bromacetónu za přítomnosti bezvodého uhličitanu draselného v prostředí acetonu s výťažkami 27 — 37 % (D. S. Tarbell: J. Org. Chem. 7, 251, 1942), resp. oxidáciou l-(2,6-dimetyl)fenoxy)-2-propanolu vhodnými oxidačnými činidlami D. Hesek a kol.: Cs. AO č. 223 436).To date, this compound has been produced from 2,6-dimethylphenol and bromoacetone in the presence of anhydrous potassium carbonate in acetone medium with yields of 27-37% (D. S. Tarbell: J. Org. Chem. 7, 251, 1942), respectively. oxidation of 1- (2,6-dimethyl) phenoxy) -2-propanol with suitable oxidizing agents D. Hesek et al., Cs. AO č. 223 436).
Podstata přípravy zlúčeniny I podl'a vynálezu je založená na reakcii 1-halogénacetónu všeobecného vzorca II,The preparation of the compound I according to the invention is based on the reaction of 1-haloacetone of the formula II,
X—CHz—CO—CH3 (II) kde X = Cl, Br s 2,6-dimetylfenólom za přítomnosti soli slabé) kyseliny a silnej zásady alebo s 2,6-dimetylfenolátom alkalického kovu. Reakcia sa uskutočňuje za katalytického posohenia jodidu alkalického kovu.X - CH 2 - CO - CH 3 (II) wherein X = Cl, Br with 2,6-dimethylphenol in the presence of a weak acid salt and a strong base or with an alkali metal 2,6-dimethylphenolate. The reaction is carried out with catalytic addition of an alkali metal iodide.
Postup podlá vynálezu sa uskutočňuje tak, že sa zahrieva 1,0 mol. dielu 2,6-dimetylfenolu s 0,8 až 1,3 mol. dielu 1-halogénacetónu za přítomnosti 0,7 až 1,5 mol. dielu soli slabej kyseliny a silnej zásady, napr. uhličitanu sódneho, hydrogénuhličitanu sodného, s výhodou uhličitanu draselného, alebo sa zahrieva 1,0 mol. diel 2,6-dimetylfenolátu alkalického kovu s 0,8 až 1,3 mol. dielu 1-halogénacetonu za katalytického působenia 0,05 až 0,1 mol. dielu jodidu alkalického kovu, napr. jodidu sodného alebo jodidu draselného v prostředí vhodného organického rozpúšťadla vybraného zo skupiny zahrňujúcej N-metylpyrrolidón, dimetylacetamid, metyletylketón, dialkylétery, etylénglykoly, alebo ich zmesi, s výhodou dimetylformamid alebo aceton pri teplotách 30 °C až teplota varu použitého rozpúšťadla, alebo v uzavretej nádobě za tlaku, do 0,5 MPa pri teplote 60 až 130 °C. Potřebná reakčnú dobu možno výhodné sledovat pomocou analytických metód, napr. plynovej chromatografie.The process according to the invention is carried out by heating 1.0 mol. % of 2,6-dimethylphenol with 0.8 to 1.3 mol. % of 1-haloacetone in the presence of 0.7 to 1.5 mol. part of a weak acid salt and a strong base, e.g. sodium bicarbonate, sodium bicarbonate, preferably potassium carbonate, or heated with 1.0 mol. % of alkali metal 2,6-dimethylphenolate with 0.8 to 1.3 mol. % of 1-haloacetone with catalytic treatment 0.05 to 0.1 mol. % of an alkali metal iodide, e.g. sodium iodide or potassium iodide in a suitable organic solvent selected from the group consisting of N-methylpyrrolidone, dimethylacetamide, methyl ethyl ketone, dialkyl ethers, ethylene glycols, or mixtures thereof, preferably dimethylformamide or acetone at temperatures of 30 ° C to the boiling point of the solvent used, or at a pressure of up to 0.5 MPa at a temperature of 60 to 130 ° C. The required reaction time can advantageously be monitored by analytical methods, e.g. gas chromatography.
Pri izolácii zlúčeniny vzorca I sa oddelia anorganické soli filtráciou, odsátím alebo odstředěním, použité organické rozpúšťadlo sa odstráni destiláciou s výhodou za vákua, destilačný zvyšok sa vytrepe vodou a surová zlúčenina vzorca I sa buď oddělí, alebo vyextrahuje do organického rozpúšťadla nemiešatefného s vodou a po zahuštění sa predéstiluje za vhodného vákua.In isolating the compound of formula I, the inorganic salts are separated by filtration, suction or centrifugation, the organic solvent used is removed by distillation preferably under vacuum, the distillation residue is shaken with water and the crude compound of formula I is either separated or extracted into a water-immiscible organic solvent. the concentration is pre-distilled under a suitable vacuum.
Další postup podfa vynálezu sa uskutočňuje tak, že sa 2,6-dimetylfenol, 1-halogénacetón a sol' slabej kyseliny a silnej zásady, alebo 2,6-dimétylfénolát alkalického kovu a 1-halogénacetón za přítomnosti jodidu alkalického kovu vo vyššie uvedených vzájomných molárnych pomeroch nechá reagovat za podmienok medzifázovej katalýzy s použitím běžných katalyzátorov fázového přenosu, například kvartérnych amóniových solí s počtom atómov 4 až 35, s výhodou tetrabutylamóniumbromidu v chlorovaných uhlovodíkoch s počtom uhlíkových atómov 1 až 3, s výhodou v dichlórmetáne alebo v aromatických uhlovodíkoch s počtom uhlíkových atómov 6 až 9, s výhodou v toluéne za teploty 0°C až teploty varu použitého rozpúšťadla. Potřebná reakčná doba sa sleduje analogicky ako v prvom postupe.A further process according to the invention is carried out by treating 2,6-dimethylphenol, 1-haloacetone and a weak acid and strong base salt, or alkali metal 2,6-dimethylphenolate and 1-haloacetone in the presence of an alkali metal iodide in the abovementioned molar moieties. ratios are reacted under interfacial catalysis conditions using conventional phase transfer catalysts, for example quaternary ammonium salts having 4 to 35, preferably tetrabutylammonium bromide in chlorinated hydrocarbons having 1 to 3 carbon atoms, preferably dichloromethane or aromatic hydrocarbons having carbon numbers atoms of from 6 to 9, preferably in toluene at a temperature of 0 ° C to the boiling point of the solvent used. The reaction time required is monitored analogously to the first procedure.
Pri izolácii sa oddělí organická vrstva od vodnej, premyje vodou na odstránenie solí a spracuje sa analogicky ako u prvého postupu.For isolation, the organic layer is separated from the aqueous layer, washed with water to remove salts, and worked up analogously to the first procedure.
2,6-dimethylfenolát alkalického kovu, například 2,6-dimetylfenolát sodný alebo draselný možno připravit vopred z 2,6-dimetylfenolu působením hydroxidov, alkoxidov alebo hydridov alkalických kovov v běžných organických rozpúšťadlách, s výhodou v aprotických. V případe medzťfázovej katalýzy možno 2,6-dimethylfenolát alkalického kovu pripraviť priamo v reakčnej zmesi z 2,6-dimetylfenolu a hydroxidu alkalického kovu.An alkali metal 2,6-dimethylphenolate, for example sodium or potassium 2,6-dimethylphenolate, can be prepared in advance from 2,6-dimethylphenol by treatment with alkali metal hydroxides, alkoxides or hydrides in conventional organic solvents, preferably aprotic. In the case of interfacial catalysis, an alkali metal 2,6-dimethylphenolate can be prepared directly in the reaction mixture from 2,6-dimethylphenol and an alkali metal hydroxide.
Aj 1-hrómacetón možno pripraviť priamo v reakčnej zmesi z acetónu a brómu v chlorovaných rozpúšťadlách, alebo iba v přebytku acetónu, za přítomnosti bromovodík odnímajúcich činidiel, například solí slabých kyselin a silných zásad, bez izolácie.Also, 1-bromoacetone can be prepared directly in the reaction mixture from acetone and bromine in chlorinated solvents, or only in excess acetone, in the presence of hydrogen bromide scavengers such as salts of weak acids and strong bases, without isolation.
Výhodou postupu podfa vynálezu je, že z 1-chlór- alebo 1-brómacetónu vzniká působením katalytického množstva jodidu alkalického kovu „in šitu“ 1-jódacetón, ktorý je podstatné reaktivnější ako východzie 1-halogénu acetony, čo má za následok niekol'konásobné zvýšenie výtažku zlúčeniny vzorca I ako u doposial' známého postupu alkylácie 2,6-dimetylfenolu.An advantage of the process according to the invention is that from 1-chloro- or 1-bromoacetone a 1-iodoacetone is formed in situ by a catalytic amount of an alkali metal iodide, which is substantially more reactive than the 1-halogen starting acetones, resulting in a multiple increase yield of the compound of formula I as in the prior art alkylation process of 2,6-dimethylphenol.
V ďalšom je predmet vynálezu popísaný v príkladoch prevedenia bez toho, že by sa iba na tieto obmedzoval.In the following, the invention is described in the examples without being limited thereto.
Příklad 1Example 1
K roztoku 12,2 g (0,1 molu) xylenolu v 50 ml dimetylformamidu sa přidá 2 g jodidu draselného a v priebehu 1 hodiny sa pri 70 až 80 °C súbežne dávkuje 13,7 g (0,1 molu) brómacetónu a 9,6 g (0,07 molu) bezvodého uhličitanu draselného. Po přidaní všetkého množstva sa teplota udržuje ešte 3 hodiny. Anorganické soli sa odsajú, filtrát sa zahustí za vákua a zbytok sa dešti246872 luje za zníženého tlaku. Získá sa 13,7 g (76 percent) látky vzorca I s teplotou varu 136 až 138 °C/2,4 kPa.To a solution of 12.2 g (0.1 mol) of xylenol in 50 ml of dimethylformamide is added 2 g of potassium iodide, and simultaneously 13.7 g (0.1 mol) of bromoacetone and 9 are added simultaneously at 70-80 ° C. 6 g (0.07 mol) of anhydrous potassium carbonate. The temperature was maintained for 3 hours after all was added. The inorganic salts are filtered off with suction, the filtrate is concentrated under vacuum and the residue is distilled under reduced pressure. 13.7 g (76%) of the compound of formula I are obtained with a boiling point of 136-138 ° C / 2.4 kPa.
Příklad 2Example 2
Postupuje sa analogicky podlá bodu 1 s tým rozdielom, že sa dimetylíormamid nahradí acetónom ako reakčné prostredie. Získá sa 11,7 až 12,6 g (65 až 70 °/o) látky vzorca I.The procedure is analogous to point 1, except that dimethylformamide is replaced by acetone as the reaction medium. 11.7 to 12.6 g (65 to 70%) of the compound of formula I are obtained.
Příklad 3Example 3
Roztok 2,6-dimetylfenolátu sodného připraveného z 12,2 g (0,1 molu] 2,6-dimetylfenolu a 2,4 g hydridu sodného v 25 ml dimetylformamidu sa počas 1 hodiny přidává k roztoku 9,3 g chlóracetónu v 25 ml dimetylformamidu a 1,5 g jodidu sodného pri 30 až 35 °C. Přidáním celého množstva sa udržuje teplota 90 až 95 °C ešte 4 hodiny. Spracovaním produktu podlá bodu 1 sa získá 9,6 g (53 °/o) látky vzorca I.A solution of sodium 2,6-dimethylphenolate prepared from 12.2 g (0.1 mol) of 2,6-dimethylphenol and 2.4 g of sodium hydride in 25 ml of dimethylformamide was added to a solution of 9.3 g of chloroacetone in 25 ml over 1 hour. dimethylformamide and 1.5 g of sodium iodide at 30-35 [deg.] C. By adding the entire amount, the temperature is maintained at 90-95 [deg.] C. for a further 4 hours. .
Příklad 4Example 4
Postupuje sa analogicky ako podlá bodu 3 s tým rozdielom, že 2,6-dimetylfenolát sa připraví reakciou 2,6-dimetylfenolu s alkoxidom v odpovedjúcom alkohole, ktorý sa vákuovo odpaří.The procedure is analogous to that in point 3, except that 2,6-dimethylphenolate is prepared by reacting 2,6-dimethylphenol with an alkoxide in the corresponding alcohol which is evaporated under vacuum.
Příklad 5Example 5
Do tlakovej nádoby sa předloží 12,2 g (0,1 molu) 2,6-dimetylfenolu, 13,7 g (0,1 molu) brómacetónu a 10,4 g (0,075 molu) bezvodého uhličitanu sodného s 2 g jodidu sodného v 50 ml acetónu. Nádoba sa uzavrie a .pri 90 až 95 °C sa obsah mieša 3 hodiny. Po skončení reakcie sa nádoba ochladí na teplotu 20 až 25 QC, uvolněné plyny sa vypustia a ďalej sa produkt spracuje podlá příkladu 1. Získá sa tak 14,8 gramu (81 %) látky vzorca I.12.2 g (0.1 mol) of 2,6-dimethylphenol, 13.7 g (0.1 mol) of bromoacetone and 10.4 g (0.075 mol) of anhydrous sodium carbonate with 2 g of sodium iodide are introduced into a pressure vessel. 50 ml acetone. The vessel was sealed and the contents were stirred for 3 hours at 90-95 ° C. After the reaction, the vessel was cooled to 20 to 25? C, the released gas is discharged, and the product was further processed according to Example 1 to give 14.8 g (81%) compound of formula I.
Příklad 6Example 6
K miešanej zmesi 12,2 g (0,1 molu) 2,6-dimetylfenolu v 100 ml dichlórmetánu sa přidá 25 ml 40 °/o roztoku hydroxidu sodného. Po přidaní 1,6 g (0,005 molu) tetrabutylamóniumbromidu sa reakčná zmes vyhřeje na 40 °C a k roztoku sa postupné přidává 13,7 g (0,1 molu) brómacetónu v 30 ml dichlórmetánu. Priebeh reakcie sa sleduje pomocou plynovej chromatograíie. Po ukončení reakcie sa organická vrstva oddělí, premyje vodou a ďalej spracuje podlá příkladu 1. Získá sa tak 8,1 g látky vzorca I.To a stirred mixture of 2,6-dimethylphenol (12.2 g, 0.1 mol) in dichloromethane (100 mL) was added sodium hydroxide solution (40 mL, 40%). After addition of 1.6 g (0.005 mol) of tetrabutylammonium bromide, the reaction mixture is heated to 40 ° C and 13.7 g (0.1 mol) of bromoacetone in 30 ml of dichloromethane are added successively. The progress of the reaction was monitored by gas chromatography. After completion of the reaction, the organic layer was separated, washed with water and further processed as in Example 1. 8.1 g of the compound of formula I were obtained.
Příklad 7 acetónu, 1,5 g jodidu sodného a 8,4 g bezvodého uhličitanu draselného v 100 ml acetónu sa zahrieva na teplotu varu 3 až 5 hodin. Po skončení reakcie sa reakčná zmes zahustí, přidá sa 50 ml vodného amoniaku a 50 ml toluénu. Organická vrstva sa oddělí a po premyti s vodou sa vákuovo destiluje. Získá sa 10,8 až 12,6 g (60 až 70 %) látky vzorca I.Example 7 of acetone, 1.5 g of sodium iodide and 8.4 g of anhydrous potassium carbonate in 100 ml of acetone are heated to boiling for 3-5 hours. After completion of the reaction, the reaction mixture is concentrated, 50 ml of aqueous ammonia and 50 ml of toluene are added. The organic layer was separated and washed with water and vacuum distilled. 10.8 to 12.6 g (60 to 70%) of the compound of formula I are obtained.
Příklad 8Example 8
Do zmesi 15 ml acetónu a 70 ml dichlórmetánu s kvapkou 50 % kyseliny bromovodíkovej sa za refluxu v malých dávkách, přidává 8 g brómu. Ďalšie množstvo sa přidá vždy po odfarbení zmesi. Po doreagovaní sa roztok neutralizuje hydrouhličitanom sodným, anorganické soli sa oddelia a k surovému medziproduktu po predchádzajúcom zahuštění sa přidá 10 g 2,6-dimethylfenolu v 40 ml acetónu, 6,7 g bezvodého uhličitanu draselného a 1 g jodidu draselného. Reakčná zmes sa zahrieva k varu 4 až 5 hodin. Izoláciou produktu podl'a bodu 1 sa získá 6,5 g (45 °/o) látky vzorca I. Příklad 9To a mixture of 15 ml of acetone and 70 ml of dichloromethane with a drop of 50% hydrobromic acid, 8 g of bromine are added under reflux in small portions. An additional amount is added each time the mixture is discolored. After reaction, the solution is neutralized with sodium bicarbonate, the inorganic salts are separated and 10 g 2,6-dimethylphenol in 40 ml acetone, 6.7 g anhydrous potassium carbonate and 1 g potassium iodide are added to the crude intermediate after concentration. The reaction mixture is heated to boiling for 4-5 hours. Isolation of the product of item 1 yielded 6.5 g (45%) of the compound of formula I. Example 9
Do acetónu vyhriateho na 50 °C sa pomaly prikvapkáva 8 g brómu tak, aby sa udržiaval mierny reflux reakčnej zmesi. Súčasne sa do reakčnej zmesi přidává bezvodý uhličitan draselný na vychytávanie v reakcii vznikajúceho bromovodíka. Po skončení reakcie sa anorganické soli oddelia a ďalej sa postupuje ako v příklade 8. Takýmto spósobom sa získá 7,3 g (49 %) látky vzorca I.8 g of bromine is slowly added dropwise to acetone heated to 50 ° C to maintain a slight reflux of the reaction mixture. Simultaneously, anhydrous potassium carbonate is added to the reaction mixture for uptake in the hydrogen bromide reaction. Upon completion of the reaction, the inorganic salts were separated and proceeded as in Example 8. 7.3 g (49%) of the compound of formula I were obtained in this way.
Příklad 10Example 10
Zmes 12,2 g (0,1 molu) xylenolu, 11,5 g (0,125 molu) chlóracetónu a 9,6 g (0,07 molu) bezvodého uhličitanu draselného sa zahrieva s 1,5 g jodidu draselného v 150 ml acetónu k varu počas 20 hodin. Anorganické solí sa odsajú a filtrát sa po zahuštění destiluje za zníženého tlaku. Získá sa 16,5 až 17,1 g (92 až 95 %) látky vzorca I s teplotou varu 136 až 138 °C/2,4 kPa.A mixture of 12.2 g (0.1 mol) of xylenol, 11.5 g (0.125 mol) of chloroacetone and 9.6 g (0.07 mol) of anhydrous potassium carbonate is heated with 1.5 g of potassium iodide in 150 ml of acetone to boiling for 20 hours. The inorganic salts are filtered off with suction and, after concentration, the filtrate is distilled under reduced pressure. 16.5 to 17.1 g (92 to 95%) of the compound of formula I are obtained with a boiling point of 136 to 138 ° C / 2.4 kPa.
Příklad 11Example 11
Zmes 12,2 g (0,1 molu) xylenolu, 11,5 g (0,125 molu) chlóracetónu, 10,3 g (0,075 molu) bezvodého uhličitanu draselného sa zahrieva k varu s 1,5 g jodidu sodného v 150 ml acetónu a 20 ml dimetylformamidu počas 12 až 14 hodin. Priebeh reakcie sa sleduje pomocou plynovej chromatografie. Spracovaním pódia bodu 1 sa získá 16,2 až 17 g (90 až 94 %) látky vzorca I.A mixture of 12.2 g (0.1 mol) of xylenol, 11.5 g (0.125 mol) of chloroacetone, 10.3 g (0.075 mol) of anhydrous potassium carbonate is heated to boiling with 1.5 g of sodium iodide in 150 ml of acetone and 20 ml of dimethylformamide for 12 to 14 hours. The progress of the reaction was monitored by gas chromatography. Treatment of the stage 1 yields 16.2-17 g (90-94%) of the compound of formula I.
Zmes 12,2 g 2,6-dimetylfenolu, 10 g chlór7A mixture of 12.2 g of 2,6-dimethylphenol, 10 g of chlorine7
24BS7224BS72
Claims (5)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS719184A CS246872B1 (en) | 1984-09-25 | 1984-09-25 | Preparation method of 1-(2,6-dimethylphenoxy)-2-propanon |
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| CS719184A CS246872B1 (en) | 1984-09-25 | 1984-09-25 | Preparation method of 1-(2,6-dimethylphenoxy)-2-propanon |
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| CS246872B1 true CS246872B1 (en) | 1986-11-13 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105017033A (en) * | 2015-06-10 | 2015-11-04 | 山西云鹏制药有限公司 | Process for producing mexiletine hydrochloride |
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1984
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017033A (en) * | 2015-06-10 | 2015-11-04 | 山西云鹏制药有限公司 | Process for producing mexiletine hydrochloride |
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