RU2026857C1 - Method of synthesis of 2-methoxyisobutylisocyanide - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: 2-methoxyisobutylisocyanide. Reagent 1: CHCl₃. Reagent 2: CH₃COCH₃. Reagent 3: alkali hydroxide. Conditions: medium - methanol, temperature of reagents addition is 0 C (not above) following by spontaneous temperature increase to 45 C (not above) and exposition at the room temperature. Prepared solid precipitate is treated with CH₃OH in the presence of acid catalyst. Reaction mass is treated with ammonia and methanol and then - with alumohydride in the medium of diethyl ether. Prepared amine is treated with chloroform and alkali in the medium of organic solvent. M. p. is 72-73 C/65 mm mercury column, n $\genfrac{}{}{0ex}{}{\text{2}}{\text{D}}$ ⁰ = 1.4182-88, d $\genfrac{}{}{0ex}{}{\text{2}}{\text{4}}$ ⁰ = 0.9020-24, R_D: found 31.61, calculated 31.92. EFFECT: simplified process of synthesis.

Description

 The invention relates to an improved method for producing 2-methoxyisobutyl isocyanide, which in the form of a technetium complex is used in medicine.

N

(CH₃)

(CH₃)

NH₂ _____→

(CH₃)

NHCHO

(CH₃)

NC
Также известен способ получения 2-метоксиизобутилизоцианида, заключающийся в том, что труднодоступный 2,2-диметилазиридин подвергают взаимодействию с метанолом в присутствии комплекса трехфтористого бора с метанолом. При этом с выходом 35% образуется трудноразделяемая смесь 1-метокси-2-метилпропил-2-амина и 2-метоксиизобутиламина, из которой выделяют 2-метоксиизобутиламин. Дальнейшее превращение 2-метоксиизобутиламина в целевой продукт идет через стадии формилирования и дегидратации.A known method of producing 2-methoxyisobutyl isocyanide, which consists in the fact that acetone cyanohydrin is reacted with absolute methanol in the presence of freshly calcined zinc chloride. Resulting in a yield of 51% 2-metoksiizobutironitril reduced with lithium aluminum hydride in ether, and the thus obtained 2-metoksiizobutilamin (82%) of ethyl formate is formylated in the presence of catalytic amounts of n-toluenesulfonic acid followed by dehydration with diphosgene in the presence of triethylamine at a temperature ^(-40 ° C) target product with a yield of 67%. The total yield based on the starting acetone cyanohydrin is 26%. The disadvantage of this method is the use in the synthesis of toxic compounds such as acetone cyanohydrin, diphosgene, and conducting the final stage of the process at a temperature (-40 ° ^C), difficult to achieve in industry. The process is carried out according to the scheme:
(CH ₃ )

N

(CH ₃ )

(CH ₃ )

NH ₂ _____ →

(CH ₃ )

NHCHO

(CH ₃ )

NC
Also known is a method of producing 2-methoxyisobutyl isocyanide, which consists in the fact that inaccessible 2,2-dimethylaziridine is reacted with methanol in the presence of a complex of boron trifluoride with methanol. With a yield of 35%, a difficultly separated mixture of 1-methoxy-2-methylpropyl-2-amine and 2-methoxyisobutylamine is formed, from which 2-methoxyisobutylamine is isolated. Further conversion of 2-methoxyisobutylamine to the target product proceeds through the formylation and dehydration stages.

C(CH₃)

CH₃OCH₂C(CH₂)₂NH₂+ (CH₃)

NH₂
Наиболее близким предлагаемому способу является способ получения 2-метоксиизобутилизоцианида, заключающийся в том, что метиловый эфир 2-гидроксиизомасляной кислоты подвергают взаимодействию с йодистым метилом в присутствии гидрида натрия в смеси тетрагидрофурана с диметилформамидом. При этом с выходом 61% получают сольват метилового эфира 2-метоксиизомасляной кислоты с диметилформамидом, который после обработки концентрированным водным раствором аммиака с выходом 79% дает соответствующий амид. Амид 2-метоксиизомасляной кислоты восстанавливают алюмогидридом лития в тетрагидрофуране и образовавшийся с выходом 58% 2-метоксиизобутиламин формилируют муравьиной кислотой в уксусном ангидриде. Полученный с выходом 94% формамид дегидратируют дифосгеном в присутствии триэтиламина. Целевой продукт получают по этому способу с выходом 31%. Выход 2-метоксиизобутилизоцианида в расчете на исходный метиловый эфир 2-гидроксиизомасляной кислоты составляет около 8%. Способ осуществляют по схеме:
(CH₃)

OOCH₃

(CH₃)

CH

(CH₃)

H₂____→

(CH₃)

NH

(CH₃)

NHCHO __→ (CH₃)

NC
Недостатками известного способа является использование в качестве исходного продукта труднодоступного метилового эфира 2-гидроксиизомасляной кислоты, а также на последней стадии высокотоксичного дифосгена. К недостаткам известного способа относится использование сухих растворителей, особенно тетрагидрофурана, делающих способ трудно осуществимым в промышленности.The disadvantage of this method is the use of highly toxic 2,2-dimethylaziridine and the formation of a difficultly separated mixture of 1-methoxy-2-methylpropyl-2-amine and 2-methoxyisobutylamine. The process is carried out according to the scheme
H ₂ c

C (CH ₃ )

CH ₃ OCH ₂ C (CH ₂ ) ₂ NH ₂ + (CH ₃ )

NH ₂
The closest to the proposed method is a method for producing 2-methoxyisobutyl isocyanide, which consists in the fact that methyl ester of 2-hydroxyisobutyric acid is reacted with methyl iodide in the presence of sodium hydride in a mixture of tetrahydrofuran with dimethylformamide. At the same time, in 61% yield, a 2-methoxyisobutyric acid methyl ester solvate with dimethylformamide is obtained, which after treatment with concentrated aqueous ammonia in 79% yield gives the corresponding amide. The 2-methoxyisobutyric acid amide is reduced with lithium aluminum hydride in tetrahydrofuran, and 2-methoxyisobutylamine formed in 58% yield is formed with formic acid in acetic anhydride. Obtained in 94% yield, formamide was dehydrated with diphosgene in the presence of triethylamine. The target product is obtained by this method with a yield of 31%. The yield of 2-methoxyisobutylisocyanide based on the starting methyl ester of 2-hydroxyisobutyric acid is about 8%. The method is carried out according to the scheme:
(CH ₃ )

OOCH ₃

(CH ₃ )

CH

(CH ₃ )

H ₂ ____ →

(CH ₃ )

NH

(CH ₃ )

NHCHO __ → (CH ₃ )

NC
The disadvantages of this method is the use as a starting product of inaccessible methyl ester of 2-hydroxyisobutyric acid, as well as in the last stage of highly toxic diphosgene. The disadvantages of this method include the use of dry solvents, especially tetrahydrofuran, making the method difficult to implement in industry.

 The aim of the invention is to simplify the process.

The goal is achieved by a method for producing 2-metoksiizobutilizotsianida reacting chloroform, acetone and caustic alkali in methanol at a temperature not exceeding ⁰ ° C, followed by a spontaneous temperature increase of 45 ^{° C} and holding at room temperature followed by treatment with methanol in the presence of an acidic catalyst to obtain a reaction mass containing methyl ester of 2-methoxyisobutyric acid, which is directly subjected to ammonolysis, to form the corresponding amide, gave its amide reduction is carried out in diethyl ether, in the presence of LiAlH ₄ and the resulting 2-methoxyisobutylamine is treated with caustic alkali, mainly finely divided potassium hydroxide, and chloroform in an inert organic solvent, mainly benzene, when the reaction mixture is boiled, possibly in the presence of a catalyst phase transfer.

The distinctive features of the proposed method is to obtain 2-metoksiizobutilizotsianida interaction, are linked chloroform, acetone and caustic alkali in methanol at a temperature of not higher than ⁰ ° C, followed by spontaneous rise in temperature no higher than 45 ^{° C} and holding at room temperature followed by treatment with methanol in the presence of an acid catalyst to obtain a reaction mass containing methyl ester of 2-methoxyisobutyric acid, which is directly subjected to ammonolysis, amide reduction medium diethyl ether and the thus obtained amine is treated with chloroform and alkali in an organic solvent under reflux of the reaction medium.

 The invention is further illustrated by the following examples.

PRI me R 1. To a well-mixed, cooled to (-1) - (- 5) ^о С solution of 180 g (4.5 mol) of sodium hydroxide in 1 liter of methanol, a mixture of 119.5 g (1) is added dropwise. mol) of chloroform and 145 g (2.5 mol) of acetone. Upon completion of the addition the reaction mixture, accompanied by the precipitation of sodium chloride, energetically cooled so that the temperature did not exceed 45 ^C. The reaction mixture was allowed to stand overnight, 400 ml of solvent was distilled off, sodium chloride was filtered off, washed with methanol. The methanol is evaporated, the solid residue is dissolved in 100 ml of water and acidified with 10% sulfuric acid to pH 1, extracted with diethyl ether, the ether extract is dried with anhydrous magnesium sulfate, the ether is removed, and 1 l of methanol and 40 g of KU-2 resin are added to the residue. -8 in the H ⁺ form. After 20 days, the resin is filtered off, washed with methanol, methanol is evaporated, an equal volume of concentrated brine is added to the residue, the organic layer is separated and 274 ml of concentrated ammonia solution and 300 ml of methanol are added. The reaction mixture containing 2-methoxyisobutyric acid methyl ester was kept at room temperature for 48 hours and evaporated. The residue was reduced with lithium aluminum hydride (13 g) in 400 ml of dry diethyl ether. After which the excess lithium aluminum hydride is decomposed with 13 ml of water, 13 ml of a 15% sodium hydroxide solution and 40 ml of water, the precipitate is filtered off, washed with ether, the solution is dried with anhydrous magnesium sulfate and evaporated. The residue is dissolved in 19.6 ml of chloroform and 30.6 g of potassium hydroxide in 80 ml of benzene are added to the suspension. The reaction mixture is boiled under vigorous stirring for 15 hours, cooled, filtered, and the precipitate is washed with benzene. The benzene layer is washed with 5% aqueous hydrochloric acid, 1% aqueous sodium hydroxide solution, water, dried with anhydrous magnesium sulfate. Benzene is distilled off, and the residue is distilled in vacuo to obtain 4.1 g of 2-methoxyisobutylisocyanide.

T. bale. 72-73 ^about C / 65 mm Hg; n _D ²⁰ 1.4186; d ₄ ²⁰ 0.9020; MR _D found. 31.61; MR _D calc. 31.97. (Literature data: b.p. 56-59 ° ^C / 25 mm Hg .; 60-61 ° ^C / 22 mm Hg.).

EXAMPLE EXAMPLE 2 To a vigorously stirred solution of 180 g (4.5 mol) of sodium hydroxide in 1 L of methanol at a temperature of (-5) ^{° C} under cooling is added dropwise a mixture of 119.5 g (1 mol) and chloroform 145 (2.5 mol) acetone. Upon completion of the addition reaction, accompanied by precipitation of the sodium chloride precipitate vigorously cooled to the temperature of the reaction mixture did not exceed 45 ^C. The reaction mixture was allowed to stand overnight at room temperature, 400 ml of solvent was distilled off, the precipitate is filtered off, washed with methanol, the methanol solution was acidified with concentrated sulfuric acid to pH 1 and add another 40 ml of concentrated sulfuric acid. The precipitated sodium sulfate is filtered off and methanol is distilled off. A double volume of concentrated brine was added to the cold residue, the organic layer was separated, washed with concentrated brine, 177 ml of concentrated aqueous ammonia and 200 ml of methanol were added. Then they are treated analogously to example 1 and obtain 4.27 g of 2-methoxyisobutylisocyanide with so Kip. ^About 82-84 C / 85 mm Hg .; n _D ²⁰ 1, 4188; d ₄ ²⁰ 0.9024.

PRI me R 3. Analogously to example 2, the target product is obtained from 180 g of sodium hydroxide, 119.5 g of chloroform, 145 g of acetone, esterification is carried out in the presence of sulfuric acid and after filtration of sodium sulfate, distillation of methanol, washing with brine, ammonolysis 210 ml of a concentrated solution of ammonia in 230 ml of methanol and evaporation, the dry residue is restored 13 g of lithium aluminum hydride in 400 ml of dry ether, the excess reducing agent is decomposed, the organic layer is dried and evaporated. The residue is dissolved in 50 ml of methylene chloride, 1.2 g of benzyltriethylammonium chloride and 80 ml of a 50% aqueous solution of sodium hydroxide are added to the solution. A solution of 34 g (23 ml) of chloroform in 50 ml of methylene chloride was added to the reaction mixture and stirred for 1 h, then it was kept at reflux for 1 h. The organic layer was separated, the aqueous layer was extracted with methylene chloride, the extract was washed with 5% aqueous hydrochloric acid solution, 1% aqueous sodium hydroxide solution, water, dried with anhydrous sodium sulfate, methylene chloride is distilled off, and the residue is distilled in vacuum to obtain 4.3 g of the target product with so Kip. 80-81 ^about C / 80 mm Hg .; n _D ²⁰ 1.4182.

Example 4. To a solution of 250 g (4.5 mol) of caustic potassium in 1 liter of methanol which was thoroughly mixed and cooled to (-1) - (- 5) ^° C, a mixture of 119.5 g (1) was added dropwise. mol) of chloroform and 145 g (2.5 mol) of acetone. Then proceed analogously to example 1 and get 4.5 g of 2-methoxyisobutylisocyanide with so Kip. 70-72 ^about C / 62 mm Hg .; n _D ²⁰ 1.4187. Chromatogram on silufol UV-254: in ethanol, one spot with R _f 0,85; in ethyl acetate, one spot with R _f 0.8; in the system ether - hexane 1: 1 one spot with R _f 0.50.

Example 5. With cooling and vigorous stirring, a solution of 150 g of 1,1,1-trichloro-tert-butanol in 300 ml of methanol is added to a solution of 223 g of potassium hydroxide in 600 ml of 20% aqueous methanol at such a rate that the temperature of the reaction mixture did not exceed ⁰ ° C, then the reaction is allowed to come to room temperature and stirring was continued for 1 hour, and to complete the reaction refluxed for 2 hours. After cooling, the potassium chloride precipitate was filtered off and washed with 100 ml of methanol. The solvent was distilled off from the filtrate, the residue was adjusted with 10% sulfuric acid to pH ≈ 1, the inorganic precipitate was separated by filtration, washed with ether, the aqueous solution was extracted 2-3 times with ether, the combined extract was dried with anhydrous sodium sulfate. The ether is evaporated, 1 l of methanol and 40 g of KU-2-8 resin are added to the residue, and then proceed analogously to example 1 using 390 ml of a concentrated solution of ammonia in 400 ml of methanol, 30 g of lithium aluminum hydride and 800 ml of dry ether are recovered. The residue after the recovery is dissolved in 30 ml of chloroform and added to a suspension of 40 g of potassium hydroxide in 120 ml of benzene to give 14.2 g ((15.6%) of 2-metoksiizobutilizotsianida bp. 80-81 ^{of the} C / 8 mmHg Art. Hg; n _D ²⁰ 1.4184.

For all experiments, an analysis was performed using gas chromatography on a LHM-8MD instrument, a stainless steel column 0.3 cm in diameter, 100 cm long, filled with 5% OV-17 on "inert super", 0.125-0.160, temperature 95 ^о С the carrier gas is helium 21 ml / min; a solution of 2-methoxyisobutyl isocyanide in benzene. The exit time of benzene is 40 s, the exit time of 2-methoxyisobutyl isocyanide is 140 s. No other peaks in the chromatograms were found. All physicochemical methods used invariably show high purity of the target product.

 As can be seen from the above examples, the proposed method is simple to implement, based on the use of available starting compounds, does not require isolation of intermediate compounds. The resulting product has a high degree of purity (more than 99%), which is confirmed by the analysis of TLC, GLC, and PMR spectra.

Claims (4)

1. METHOD FOR PRODUCING 2-METHOXYISOBUTYLISOTANIZE using 2-methoxyisobutyric acid methyl ester, including its ammonolysis to obtain 2-methoxyisobutyric acid amide, subsequent reduction of LiAlH ₄ in an organic solvent to 2-methoxyisobutylamine, characterized in that, for the purpose of, chlorine is simplified subjected to interaction with acetone in the presence of alkali in methanol at a temperature of addition of reagents not exceeding 0 ^o C, followed by a spontaneous increase in temperature not exceeding 45 ^o C and exp holding at room temperature, followed by treatment with methanol in the presence of an acidic catalyst to obtain a reaction mixture containing 2-methoxyisobutyric acid methyl ester, which is directly subjected to ammonolysis, the amide is reduced in diethyl ether and the resulting amine is treated with alkali and chloroform in an organic solvent .  2. The method according to claim 1, characterized in that benzene is used as an organic solvent.  3. The method according to claim 1, characterized in that when processing the amine, finely ground caustic potassium is used.  4. The method according to p. 1, characterized in that the processing of the amine is carried out in the presence of a phase transfer catalyst.