RU1679760C - 1r,3s-2,2- dimethyl -3(2-methyl -2- oxypropyl) -cyclopropanecarbonitrile as intermediate compound in synthesis of pyrethroide insecticide - deltametrine and method for producing intermediate compound - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: synthesis is carried out by reaction of appropriate nitrile with excess of methylmagnesium iodide. Initially the process is carried out at 0-5 C, then it takes place at room temperature and finally by boiling with the help of reflux condenser. Thus prepared oxynitrile is dissolved in lower alkanol and then is treated at 30-40 C by hydrogen peroxide, the process is carried out in the presence of aqueous alkali solution. Thus prepared product is treated with hypobromite of alkali metal in the presence of quaternary ammonium salt being used as phase transfer catalyst. Mentioned above treatment is initially carried out at room temperature and then by boiling with the help of reflux condenser. Prepared raw material is chromatographed on silica gel, diethyl ether being used as elutriator. Desired product having essential formula C₁₀H₁₇NO,[α] $\genfrac{}{}{0ex}{}{\text{2}}{\text{n}}$ ¹ = +5,72^°(c=5,59,CCl₄) is prepared by yield 70 %. Said intermediate compound increases yield of deltametrine from 58 to 81 %, decreases number of stages from 6 to 5 and excludes ozonolysis. EFFECT: produces novel useful product using novel method. 3 cl

Description

который может найти применение в качестве промежуточного соединения в синтезе пиретроидного инсектицида дельтаметрина и новый способ получения промежуточного соединения I.A new chemical substance 1R, 3S-2,2-dimethyl-3- (2-methyl-2-hydroxypropylcyclopropanecarbonitrile of the formula I is proposed

which may find application as an intermediate in the synthesis of deltamethrin pyrethroid insecticide and a new method for the preparation of intermediate I.

 The aim of the invention is the search for a new derivative of oxycarbonitrile as an intermediate for the synthesis of deltamethrin and the development of a new method for producing intermediate I, which is carried out by a simpler technology compared to the method for producing the known intermediate for the synthesis of deltamethrin in high yield.

10 г (+)-3-карена, выделенного при ректификации соснового скипидара и имеющего [α] _D ²⁵ + 15,6^o (в чистом виде), растворяют в 20 мл хлористого метилена, охлаждают до -10^оС и, поддерживая температуру -10-0^оС, при перемешивании пропускают ток хлористого нитрозила до исчезновения карена (контроль тонкослойная хроматография на пластинках Силуфол при элюировании петролейным эфиром, после опрыскивания концентрированной серной кислотой карен (II) проявляется в виде оранжевого пятна с R_f 0,8). После этого, поддерживая температуру в указанном интервале, при перемешивании к реакционной смеси прибавляют сначала 100 мл метанола, затем 40 мл 33%-ного водного раствора диметиламина. Реакционную массу оставляют самопроизвольно нагреваться до комнатной температуры, после чего кипятят до растворения осадка (около 20 мин). После охлаждения реакционной смеси до комнатной температуры органический слой отделяют, промывают его насыщенным водным раствором хлористого натрия (30 мл), сушат безводным сульфатом натрия (5 г), упаривают в вакууме и получают 13,3 г (86% от теоретического) оксима 3-N,N-диметиламинокаран-4-она формулы

в виде желтоватого масла, кристаллизующегося при стоянии. Перекристаллизация из метанола дает аналитический образец с т.пл. 118^оС и [α]_D ²⁵ + 104,6^o (c 12,1, хлороформ).PRI me R 1. Obtaining from 3-Karen ketonitrile formula

10 g of (+) - 3-carene highlighted while distillation of turpentine and pine having [α] _D ²⁵ + 15,6 ^o (neat) was dissolved in 20 ml of methylene chloride, cooled to ^-10 ° C and maintaining the temperature -10-0 ^C., with stirring current is passed nitrosyl chloride until disappearance carene (control TLC on Silufol plates by elution with petroleum ether, after spraying with concentrated sulfuric acid carene (II) appears as an orange spot with R _f 0,8). After that, while maintaining the temperature in the indicated range, with stirring, first 100 ml of methanol are added to the reaction mixture, then 40 ml of a 33% aqueous solution of dimethylamine. The reaction mass is left to spontaneously warm to room temperature, after which it is boiled until the precipitate dissolves (about 20 minutes). After the reaction mixture was cooled to room temperature, the organic layer was separated, washed with a saturated aqueous solution of sodium chloride (30 ml), dried with anhydrous sodium sulfate (5 g), evaporated in vacuo, and 13.3 g (86% of theory) of oxime 3- were obtained. N, N-dimethylaminocaran-4-one of the formula

in the form of a yellowish oil crystallizing upon standing. Recrystallization from methanol gives an analytical sample with so pl. 118 ^{° C} and [α] _D ²⁵ + 104,6 ^o (c 12,1, chloroform).

To a solution of 6 g of the indicated amino oxime in 40 ml of chloroform, 3 g of crushed sodium carbonate was added, and with vigorous stirring at room temperature, 4 ml of acetic anhydride was added dropwise. After completion of the addition of acetic anhydride, the reaction mixture was kept under stirring for about 1 h, then it was filtered, the filtrate was evaporated in a vacuum of a water-jet pump in a water bath, the residue was heated in vacuum (residual pressure 5 mm Hg, bath temperature 100 ^о С) half an hour to remove dimethylacetamide and get 4.5 g (yield 96% based on amino oxime and 81% based on 3-karen) ketonitrile (II).

 PRI me R 2. Obtaining oxynitrile (I) from ketonitrile (II).

в виде желтого масла. Аналитический образец получают хроматографированием сырого продукта на силикагеле, элюэнт диэтиловый эфир.To a solution of Grignard reagent prepared from 1.08 g of magnesium and 6.5 g of methyl iodide in 250 ml of absolute ether, a solution of 5 g of ketonitrile (II) in 20 ml of ether is added with stirring and cooling in an ice bath. The reaction mass is stirred for 1 h while cooling, 1 h at room temperature and boiled for 3 hours. After cooling the mixture to room temperature, 30 ml of water and 50 ml of a 1M hydrochloric acid solution are added dropwise with vigorous stirring. The ether layer was separated, and the aqueous layer was extracted with an additional 50 ml of ether. The combined ether extract was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, and after evaporation of the solvent, 4.8 g of oxynitrile of the formula
HO

in the form of a yellow oil. An analytical sample is obtained by chromatography of a crude product on silica gel, eluent diethyl ether.

IR (CHCl ₃ ): 3600, 2260 cm ^-1 .

NMR- ¹ H (CDCl ₃ ): 0.97, 1.11 s, 3H each; 1.24 s, 6H; 1.42 d, 2H; 2.24 d, 2H.

NMR- ¹³ C (CDCl ₃ ): 21.58 d, 37.37 t, 70.39 s, 119.53 s, 13.35 t, 22.00 d, 17.29 s, 29.60 k, 14 , 51 k, 28.70 k, 28.12 k.

 Mass spectrometer, m / z (%): 108 (20), 99 (25), 59 (100), 43 (22).

 Found, C, 71.7; H 10.3; N, 7.7.

C ₁₁ H ₁₉ NO
Calculated, C 71.9; H 10.6; N, 7.7.

[α] _D ²⁷ + 18.5 ^° (c, 8.42, chloroform).

в виде вязкого желтого масла, кристаллизующегося при стоянии. Аналитический образец получают перекристаллизацией сырого продукта из эфира гексана, т.пл. 103-104^оС.The crude oksinitril in an amount of 4.78 g was dissolved in 35 ml of methanol was added 22 ml of 10% aqueous KOH solution, and with stirring was added dropwise 33 ml of 30% hydrogen peroxide, maintaining the reaction temperature 30-40 ° ^C. Then solid sodium chloride is added until the aqueous methanol solution is saturated, and after cooling the reaction mixture, the product is extracted with chloroform (four times 50 ml). The chloroform extract is dried with anhydrous sodium sulfate and, after removal of the solvent, 4.5 g of oxyamide of the formula are obtained

in the form of a viscous yellow oil that crystallizes upon standing. An analytical sample is obtained by recrystallization of the crude product from hexane ether, mp. 103-104 ^about S.

IR (CHCl ₃ ): 3600, 3520, 3410, 1680, 1590 cm ^-1 .

¹ H NMR (CDCl ₃ ): 0.91, 1.09 s, 3H each; 1.22 s, 6H; 1.41 m, 2.16 m.

¹³ C NMR (acetone-d ₆ ): 22.63 d, 38.42 t, 70.08 s, 175.73 s, 31.75 t, 23.00 d, 16.96 s, 28.91 k, 15.56 k, 29.07 k, 30.48 k.

 Mass spectrum, m / z (%): 140 (57), 83 (22), 59 (100), 55 (24), 43 (29).

 Found, C, 66.9; H 11.1; N, 6.5.

C ₁₁ H ₂₁ NO ₂
Calculated, C 66.3; H 10.6; N, 7.0.

[α] _D ²¹ 2.4 (c 3.74, chloroform).

 To a solution of 13.5 g of potassium hydroxide in 30 ml of water, 4.16 ml of bromine are added dropwise with stirring while cooling in an ice bath, after which 0.3 g of triethylbenzylammonium chloride and a solution of 4 g of the crude indicated oxyamide in 30 ml of methylene chloride are added. The mixture was stirred for 1 h at room temperature, then refluxed for 1.5 h with vigorous stirring, cooled to room temperature and the organic layer was separated. The aqueous phase is extracted with 20 ml of methylene chloride, the combined extract is washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and, after evaporation of the solvent, 3.08 g of crude oxynitrile (I) are obtained in the form of a yellow oil. The yield of oxy nitrile (I) based on ketonitrile (II) is 70%. An analytical sample of oxy nitrile (I) is obtained by chromatography of the crude product on silica gel, diethyl ether eluent.

IR (CCl ₄ ): 3620, 2240 cm ^-1 .

NMR ¹ H (CCl ₄ ): 1.17 s, 6H; 1.22, 1.26 s, 3H each; 1.57 d, 2H; 2.62 s, 1H.

¹³ C NMR (CDCl ₃ ): 26.35 d, 38.90 t, 70.45 s, 119.29 s, 14.24 d, 23.05 s, 26.40 k, 16.59 k, 29, 17 to, 28.79 to.

 Mass spectrum, m / z (%): 94 (27), 82 (30), 59 (100), 56 (21), 43 (53), 41 (22).

 Found, C, 71.0; H 10.1; N, 8.1.

C ₁₀ H ₁₇ NO
Calculated, C 71.8; H 10.3; N, 8.4.

[α] _D ²¹ + 5, 72 ^o (c 5.59, chloroform).

К раствору 0,16 г оксинитрила (I), полученного по примеру 2, в 2 мл этанола прибавляют раствор 0,75 г едкого кали в 2 мл воды. Смесь кипятят с обратным холодильником 24 ч, после чего подкисляют 1М раствором соляной кислоты до рН 1-2, насыщают раствор твердым хлористым натрием и экстрагируют продукт эфиром (две порции по 30 мл). Эфирный раствор упаривают, к остатку прибавляют 10 мл 10%-ного раствора едкого калия. Щелочной раствор промывают эфиром (две порции по 10 мл), подкисляют 1М раствором соляной кислоты и экстрагируют эфиром (три порции по 20 мл). Эфирный экстракт высушивают безводным сульфатом магния и упаривают растворитель. Остаток растворяют в 3 мл бензола, прибавляют 0,05 г n-толуолсульфокислоты и кипятят смесь 1 ч с обратным холодильником, после чего промывают 2 мл 0,5 н. раствора карбоната натрия, высушивают безводным сульфатом магния и после удаления растворителя получают 0,11 г указанного лактона (используемого в процессе получения дельтаметрина), кристаллизующегося при стоянии. Выход лактона в расчете на оксинитрил 68% Для получения аналитического образца лактон перекристаллизовывают из эфира гексана, т.пл. 83^оС.PRI me R 3. Obtaining from oxynitrile (I) 1R-chrysanthemolactone of the formula

To a solution of 0.16 g of oxynitrile (I) obtained in Example 2 in 2 ml of ethanol is added a solution of 0.75 g of caustic potassium in 2 ml of water. The mixture is refluxed for 24 hours, after which it is acidified with 1M hydrochloric acid to pH 1-2, the solution is saturated with solid sodium chloride and the product is extracted with ether (two portions of 30 ml). The ether solution was evaporated, 10 ml of 10% potassium hydroxide solution was added to the residue. The alkaline solution is washed with ether (two portions of 10 ml), acidified with 1M hydrochloric acid and extracted with ether (three portions of 20 ml). The ether extract was dried with anhydrous magnesium sulfate and the solvent was evaporated. The residue was dissolved in 3 ml of benzene, 0.05 g of n-toluenesulfonic acid was added, and the mixture was refluxed for 1 h, after which it was washed with 2 ml of 0.5 N. a solution of sodium carbonate, dried with anhydrous magnesium sulfate, and after removing the solvent, 0.11 g of the indicated lactone (used in the process of obtaining deltamethrin) is obtained, which crystallizes upon standing. The yield of lactone based on oxy nitrile 68%. To obtain an analytical sample, the lactone is recrystallized from hexane ether, mp. 83 ^about S.

IR (CCl ₄ ): 1730, 1270, 1200 cm ^-1 .

NMR ¹ H (CCl4): 1.06, 1.21, 1.42, 1.32 s, 3H each.

¹³ C NMR (CCl ₄ -CDCl ₃ ): 21.91 d, 29.38 t, 81.93 s, 169.10 s, 23.60 d, 25.03 s, 28.14 k, 15.21 k , 26.31 q, 26.63 q.

 Mass spectrum, m / z (%): 168 (18), 124 (37), 110 (63), 109 (100), 95 (81), 67 (77), 43 (64).

 Found, C, 71.4; H 9.93.

C ₁₀ H ₁₆ O ₂
Calculated, C 71.4; H 10.6.

[α] _D ²¹ + 84 ^° C (c 1.40, chloroform).

К раствору 2 г КОН в 20 мл метанола прибавляют 4 г указанного оксиэфира и кипятят смесь 3 ч, после чего подкисляют и экстрагируют 3,5 г образовавшейся соответствующей кислоты формулы

которую растворяют в 10 мл толуола, содержащего 50 мг n-толуолсульфокислоты, смесь кипятят 30 мин и выделяют 3 г указанного хризантемолактона. Выход продукта в расчете на указанный оксиэфир 89%
П р и м е р 5. Получение дельтаметрина из указанного хризантемолактона осуществляют по следующей схеме:

__→
К 1 г шестиводного бромида магния прибавляют 0,65 мл пиридина и 1 г хризантемолактона (II). Смесь выдерживают 14 ч при 125^оС, охлаждают и добавляют смесь 2М соляной кислоты с эфиром. Выпавший осадок комплекса бромида магния с цис-хризантемовой кислотой отфильтровывают и высушивают, после чего разлагают смесью 5М соляной кислоты и диоксана 1:1 и выделяют 0,49 г (49%) 1R-цис-хризантемовой кислоты (III, R OH).PRI me R 4. Obtaining the specified lactone from a known intermediate compound of the formula

To a solution of 2 g of KOH in 20 ml of methanol, 4 g of the indicated hydroxyether are added and the mixture is boiled for 3 hours, then acidified and extracted with 3.5 g of the corresponding corresponding acid of the formula

which is dissolved in 10 ml of toluene containing 50 mg of n-toluenesulfonic acid, the mixture is boiled for 30 minutes and 3 g of the indicated chrysanthemolactone is isolated. The product yield calculated on the specified hydroxyether 89%
PRI me R 5. Obtaining deltamethrin from the specified chrysanthemolactone is carried out according to the following scheme:

__ →
0.65 ml of pyridine and 1 g of chrysanthemolactone (II) are added to 1 g of magnesium hydrogen bromide. The mixture is kept 14 hours at 125 ^{° C,} the mixture was cooled and 2M hydrochloric acid and ether. The precipitate of the complex of magnesium bromide with cis-chrysanthemum acid is filtered off and dried, after which it is decomposed with a mixture of 5M hydrochloric acid and dioxane 1: 1 and 0.49 g (49%) of 1R-cis-chrysanthemum acid (III, R OH) is isolated.

(R CH₃). 57,2 г указанного альдегида, обрабатывают раствором 16,9 г натрия в 570 мл метанола и выделяют 52,4 г лактона (R Me), который кипятят 2 ч в смеси 260 мл воды и 130 мл диоксана, после чего получают 25 г карональдегида формулы
HO

= O Выход карональдегида в расчете на хризантемовую кислоту (III, R OH) 40%
К раствору 36,8 г карональдегида в смеси 135 мл тетрагидрофурана и 27 мл бромоформа при -10^оС прикапывают 90 мл 30%-ного раствора едкого кали в метаноле за 1 ч. Смесь перемешивают 2 ч при -10^оС, после чего прибавляют 200 мл воды и перемешивают еще 0,5 ч при 25^оС. Тетрагидрофуран и метанол упаривают, водный раствор подкисляют 15%-ным раствором соляной кислоты. Выпавший осадок отфильтровывают, промывают водой и после высушивания получают 68,5 г кислоты формулы VI, которую превращают в соответствующий лактон (VII) с выходом 95% обработкой n-толуолсульфокислотой в бензоле. Полученный лактон в количестве 56,6 г растворяют в 400 мл сухого эфира, прибавляют 330 мл уксусной кислоты и при перемешивании прибавляют порциями 118 г цинковой пыли. Смесь перемешивают 2,5 ч при 25^оС, после чего отфильтровывают. Фильтрат упаривают, остаток разбавляют водой. Выпавшие кристаллы отфильтровывают, промывают водой и высушивают. После перекристаллизации из изопропанола получают 36 г (80%) дельтаметриновой кислоты формулы

OOH Выход полученной таким образом дельтаметриновой кислоты в расчете на карональдегид 65%
К раствору 29,8 г дельтаметриновой кислоты в 250 мл эфира прибавляют при 0^оС 5 капель диметилформамида и 17,9 г хлористого тионила. После удаления растворителя выделяют 31 г (98%) хлорангидрида (III, R Cl).To a solution of 73.5 g of chrysanthemum acid in 140 ml of petroleum ether add 35 ml of thionyl chloride and incubated overnight at room temperature. After removal of the solvent and excess thionyl chloride, 80 g of acid chloride (III, R Cl) is isolated, which is dissolved in 80 ml of petroleum ether and 65 ml of pyridine and 55 ml of methanol are successively added. After removal of the solvent from the reaction mixture, 75.6 g of methyl ether (III, R CH ₃ ) were isolated. The ester in an amount of 70 g was dissolved in 700 ml of methanol, the solution was cooled to -80 ^{° C} and ozone was passed into it current for 3.5 h, whereupon the mixture at -40 ^{° C} was added 79 ml dimethyl sulfide. The solvent was removed in vacuo, the residue (75.9 g) was dissolved in 560 ml of 30% acetic acid, incubated 15 min at ⁸⁰ ° C, and after alkalization solution was extracted with 53.5 g of the resulting aldehyde of formula

(R CH ₃ ). 57.2 g of the indicated aldehyde are treated with a solution of 16.9 g of sodium in 570 ml of methanol and 52.4 g of lactone (R Me) is isolated, which is boiled for 2 hours in a mixture of 260 ml of water and 130 ml of dioxane, after which 25 g of caronaldehyde are obtained formulas
HO

= O The yield of caronaldehyde calculated on chrysanthemum acid (III, R OH) 40%
To a solution of 36.8 g karonaldegida in a mixture of 135 ml tetrahydrofuran and 27 ml of bromoform at ^-10 ° C was added dropwise 90 ml of 30% strength potassium hydroxide solution in methanol for 1 h. The mixture was stirred for 2 hours at ^-10 ° C after which was added 200 ml of water and stirred for another 0.5 h at 25 ^about C. Tetrahydrofuran and methanol are evaporated, the aqueous solution is acidified with 15% hydrochloric acid solution. The precipitate formed is filtered off, washed with water, and after drying, 68.5 g of the acid of formula VI are obtained, which is converted to the corresponding lactone (VII) in 95% yield by treatment with n-toluenesulfonic acid in benzene. The resulting lactone in an amount of 56.6 g is dissolved in 400 ml of dry ether, 330 ml of acetic acid are added and 118 g of zinc dust are added in portions. The mixture was stirred for 2.5 hours at ²⁵ ° C, then filtered. The filtrate was evaporated, the residue was diluted with water. The precipitated crystals are filtered off, washed with water and dried. Recrystallization from isopropanol gives 36 g (80%) of deltamethric acid of the formula

OOH Yield of deltamethric acid thus obtained, calculated on caronaldehyde 65%
To a solution of 29.8 g deltametrinovoy acid in 250 ml of ether was added at 0 ^C. 5 drops dimethylformamide and 17.9 g of thionyl chloride. After removal of the solvent, 31 g (98%) of the acid chloride (III, R Cl) are isolated.

To a flask containing 10 ml of n-heptane, 1 ml of water, 1.98 g phenoxybenzaldehyde, 22 ml diazabicyclo (2.2.2) octane and 0.59 g of sodium cyanide was added at ²⁰ ° C, the solution 3.32 g of acid chloride deltametrinovoy 10 ml of n-heptane, stirred for 2 hours, and then filtered. The filter cake was washed with 30 ml of ether, the filtrate was dried with magnesium sulfate and, after evaporation of the solvent, 4.4 g (96%) of ether (IX) were obtained as a mixture of two diastereomers.

To a solution of 600 g of a mixture of esters of diastereomers in 1200 ml of isopropyl alcohol was added 90 ml of aqueous ammonia, the mixture was cooled ^to 0 ° C and stirred for 48 hours at this temperature, whereupon the precipitate is filtered, washed on the filter with 300 ml of isopropyl alcohol, cooled to minus 20 ^about C and after drying get 485 g of deltamethrin (81%).

получают с выходом 31% в расчете на 3-карен.Thus, the desired product, the oxy nitrile product for the synthesis of deltamethrin, is obtained with a yield of 70% based on ketonitrile or 57% based on 3-karen, while the known intermediate is an oxyester of the formula

receive with a yield of 31% per 3-karen.

The yield of deltamethrin using the proposed intermediate is 3.8% based on 3-karen, while using the known intermediate 2.6%
Furthermore, the proposed process for preparing intermediate is a simpler (the number of process steps five instead of six in a known manner) and does not require stages ozonolysis and maintaining low temperatures (-68 ^{° C),} which took place in the ozonation, long duration of the process (step methylation by a known method is carried out for a week).

Claims (2)

1.1R, 3S-2,2-Dimethyl-3- (2-methyl-2-hydroxypropyl) cyclopropanecarbonitrile of the formula

as an intermediate in the synthesis of pyrethroid insecticide - deltamethrin. 2. The method of obtaining 1R, 3S-2,2-dimethyl-3- (2-methyl-2-hydroxypropyl) cyclopropanecarbonitrile of the formula

characterized in that the ketonitrile formula

treated with an excess of methylmagnesium iodide, first at 0 5 ^o C, and then at room temperature and boiling under reflux, the resulting oxynitrile of the formula

dissolved in lower aliphatic alcohol and treated with hydrogen peroxide in the presence of an aqueous solution of caustic alkali at 30 40 ^o C, the resulting oxyamide of the formula

treated with in situ alkali metal hypobromite in the presence of a quaternary ammonium salt interfacial transfer catalyst, first at room temperature and then at reflux.