SU497775A3 - The method of obtaining derivatives of tetrazole - Google Patents

Description

one

The invention relates to a process for the preparation of novel tetrazole derivatives with pharmacological action.

The method is based on the known reaction of the interaction of nitriles with hydrazoic acid.

A process for the preparation of tetrazole derivatives of the formula

Js

I)

: N 1

where RI and Kz - independently of each other - hydrogen, methyl, ethyl or halogen atom;

R2 is a hydrogen atom, methyl or ethyl, a halogen atom or a trifluoromethyl group;

iR4 is methyl, ethyl, n-propyl or -butyl,

or their salts, consisting in the fact that substituted 2- (o-anilinophenyl) -acetonitrile General formula

CHj-CN

N-R4

RI

R,

ten

where R4 is a hydrogen atom, an alkyl or alkanoyl with a straight chain and no more than 4 carbon atoms;

Ri, Ra and Rs are as defined above, are reacted with a minimum of a molar amount of hydrazoic acid or azide, the resulting tetrazole derivative is either isolated, or in the case of Ri, lower alkanoyl,

they are successively hydrolyzed and alkylated, or in the case of R4, a hydrogen atom, alkylated and the desired product is isolated, or it is salted in a known manner.

Example 1. 1, (a, 1a, a-Trifluoro-.i-toluidino) -benzyl-tetrazole.

To a solution of 41.6 g of a-cyano-M- (a, a, a, -trifluoro-tolyl) -aceto-o-toluidine in 350 ml of dimethylformamide, 13.9 g of sodium azide and 11.1 g of ammonium chloride are added. The suspension is boiled under reflux for 16 hours.

Then the mixture is evaporated to dryness at 60 ° C and a residual pressure of 0.01 Torr. The residue is in the form of a brown (brown) oil, shaken with a mixture of 1500 ml of cold water and 50 ml of 2N. hydrochloric acid. The aqueous phase is decanted, and the organic phase is dissolved in 100 ml of ether. The ether solution is extracted with 200 ml of water, separated, dried over magnesium sulphate, evaporated to dryness under a residual pressure of 11 Torr. crude N- o- (o-tetrazolylmethyl) -phenyl-a, and, atrifluoroaceto-lg-toluidide, remains.

The resulting crude product (raw) is dissolved in 40 ml of ethanol and 70 ml of 2N. of condensed sodium, after which the solution is refluxed for 16 hours, cooled, then evaporated at 40 ° C under vacuum (residual pressure of 11 Torr) to dryness. The residue is dissolved in 300 ml of water. The aqueous solution was extracted with 100 ml of ether, separated, acidified with 2N. hydrochloric acid. The oil that is isolated is dissolved in 300 ml of ether. The ether solution is extracted with 300 ml of 0.1N. solution of potassium carbonate (potassium bicarbonate), 300 ml 1 n. solution of potassium bicarbonate and 100 ml 2 n. sodium carbonate solution. The latter extract, sodium carbonate extract is acidified with 2N. hydrochloric acid. The separated oil is dissolved in 200 ml of ether, the ether solution is separated, dried over magnesium sulphate, evaporated to dryness under a pressure of 3 Torr. The remaining raw material is recrystallized from ethanol - water and then from ether - petroleum ether. The resulting (a, a, a-trifluoro -. / And - toluidino) benzyl tetrazole; m.p. 138--139 ° C.

Example 2. (2,6-dichloroanilino) -benzyl-tetrazole.

In a solution of 23.0 g of o- (2-6-dichloroanilino) phenyl-acetonitrile in 195. Ml abs. 7.7 g of sodium azide and 6.2 g of ammonium chloride are introduced into dimethylformamide. The mixture is heated for 16 hours at a temperature of 160 ° C under reflux. SaTe.vi mixture is evaporated to dryness at 60 ° C and 0.01 Torr. The residue is treated with 100 ml of water and 200 ml of ether. The ether solution is separated, and the aqueous solution is extracted three times with 200 ml of ether in portions. The combined ethereal solutions are heated with activated carbon and filtered. The filtrate is extracted three times with 100 ml portions of 2 n. sodium carbonate solution. The soda extract is extracted with 50 ml of ether, separated and acidified with 2N. hydrochloric acid to pH 4.0. The precipitated crystals are dissolved in 300 ml of ether. The undissolved part is filtered off, the filtrate is dried over magnesium sulphate and then evaporated to dryness at 11 Torr. The residue is recrystallized from ethyl acetate. The resulting (2,6-dichloroanilino) benzyl tetrazole melts at 186-188 ° C.

The nitrile used as starting material is obtained as follows.

A.- (2,6-dichloroanilino) -benzyl alcohol. In 100 ml absol. ether suspended 30.0 g

lithium aluminum hydride and with stirring cooled to 5 ° C. Under a nitrogen atmosphere, a solution of 65.0 g of K- (2,6-dichlorophenyl) anthranilic acid in 500 ml absol is slowly poured. ether and 100 ml abs. tetrahydrofuran. Thereafter, the mixture is refluxed for 15 hours. In a solution cooled to 5 ° C, 30 ml of water, 30 ml of a 15% aqueous solution of caustic soda and another 90 ml of water are added dropwise. Then the reactionary

the mixture is filtered, the filtrate is evaporated to dryness at 40 ° C and 11 torr. The residue is recrystallized from ether - petroleum ether. The resulting o- (2,6-dichloroanilino) benzyl alcohol melts at PO-112 ° C.

B. a-chloro-y- (2,6-dichlorophenyl) -o-toluidine. A solution of 37.5 g of o- (2,6-dichlorapylino) -benzyl alcohol in 560 ml of absol. ether and 56 ml absol. pyridine is quickly poured to a solution of 56 ml of chloride cooled to 0 ° C

thionyl and 56 ml of pentane. After that, the mixture was stirred for 30 min at 0 ° C. Add ice II and the mixture was extracted with succession but 100 ml of 2N. hydrochloric acid, 100 ml 2 n. caustic soda and 100 ml of the node. Organic

the phase is filtered from the undissolved part. The filtrate is dried over calcined potash and evaporated to dryness at 11 Torr. Untreated a-chloro-N- (2,6-dichlorophenyl) -otoluidine is used directly for

further reaction.

B. (2,6-Dichloroanilino) -phenyl-acetonitrile.

16.0 g of sodium cyanide in 100 ml of dimethyl sulfoxide are poured into a suspension at

40 ° C and stirring a solution of 21.0 g of a-chloro-1 - (, 2,6-dichlorophenyl) -o-toluidine in 100 ml of dimethylsulfoxide. The mixture is then stirred for 15 hours at 40 ° C and diluted with 2000 ml of ice-cold water. The solution is extracted four times with 1000 ml of ethyl acetate. The combined ethyl acetate solutions (extracts) are washed with 200 ml of 6N. hydrochloric acid and then 100 ml of water, then dried over magnesium sulphate and evaporated at 11 torr and 40 ° C. The residue is chromatographed on 500 g of neutral alumina. Fractions 1-3, aluminized with ether - petroleum ether (1: 1) contain o- (2,6-dichloro anilino) -phenyl-acetonitrile.

They are combined and distilled under high vacuum. Nitrile boils at 140-145 ° C (0.005 Torr) and melts after recrystallization from ether-petroleum ether at 71--72 ° C.

Froze

1. In the same way as described in Example 2, (6-chloro-o-toluidino) -benzyl tetrazole is obtained with a mp. 189-192 ° C (from methanol), starting from 22.8 g of o- (6-chloro-o-toluidino) -phenyl-acetonitrile; m.p. 73-74 ° C.

II. Similarly to that described in Example 2, (2,6-xylidino) -benzyl-tetrazole is obtained; T. PL.173-17b ° C (from ethyl acetate - petroleum ether), starting from 48.5 g of o- (2,6xylidino) -phenyl-acetonitrile; mp 92-95 ° C.

III. Similarly to that described in Example 2, (2,6-diethylanilino) -benzyl tetrazole is obtained; m.p. 196-198 ° C (from benzene), starting from 12.5 g of o- (2,6-diethylanilino) -phenyl acetonitrile; m.p. 135 ° C (0.01 Torr).

Starting materials are prepared as follows.

Similarly as described in example 2, And get o- (6-chloro-o-toluidin) benzyl alcohol; m.p. PO-111 ° C (from cyclohexane), starting from 13 g of M- (6-chloro-o-tolyl) -anthranilic acid; m.p. 213-216 ° C.

Also receive (2,6-xylidino) -benzyl alcohol; m.p. 91-92 ° C (from ether - petroleum ether), starting from 130 g of N- (2,6 xylyl) -anthranilic acid; m.p. 205-208 ° C.

O- (2,6-diethylanilino) benzyl alcohol is also prepared; m.p. 88-89 ° C (from ether - petroleum ether), starting from 269 g of N- (2,6 diethylphenyl) -anthranilic acid; m.p. 176-178 ° C.

Chlorine-N- (6-chloro-o-tolyl) -o-toluidine. A solution of 19.7 g of o- (6-chloro-o-toluidino) -benzyl alcohol in 600 ml abs. benzene is slowly heated to reflux in a nitrogen atmosphere. At 60 ° C (internal temperature), 2 ml of abs is poured. pyridine and dropwise, with thorough stirring, a solution of 5.85 ml of thionyl chloride in 50 ml of abs. benzene. The mixture is then boiled for 30 minutes under reflux, cooled and evaporated at 40 ° C. 11 Torr. The residue is dissolved in 200 ml of ether. The ether phase is extracted with 50 ml of 1N. soda solution and 50 ml of water, dried over sodium sulfate and evaporated to dryness at 11 torr. The residue is recrystallized from ether - petroleum ether. The a-chloro-N- (6-chloro-o-tolyl) -o-toluidine obtained melts at 89-91 ° C.

Similarly, a-chloro-L- (2,6-xylyl) -o-toluidine (oil) is obtained, starting from o- (2,6-xylidino) -benzyl alcohol.

Similarly, alpha-chloro-M- (2,6-diethylphenyl) -o-toluidine (oil) is obtained starting from o- (2,6-diethylanilino) -benzyl alcohol.

In the same way as described in Example 2. O- (6-chloro-o-toluidino) -phenyl-acetonitrile is obtained; m.p. 73-74 ° С (from ether - petroleum ether), starting from 10 g a-chloro-M - (- 6 chloro-o-tolyl) -o-toluidine; m.p. 89-91 ° C.

In the same way as described in Example 2, o- (2,6-xylidino) -phenyl-acetonitrile is obtained; m.p. 92-95 ° C (from ether - petroleum ether), starting from 80 g a-chloro-L- (2,6 xylyl) -o-toluidine (oil).

Similarly to the previous, o- (2,6-diethylanilino) -phenyl-acetonitrile is obtained; m.p.

135 ° C (0.01 Torr), starting from 20 g of a-chloro-N (2,6-diethyl-phenyl) -o-toluidine (oil).

Example 4. (M-methyl-a, a, OS-trifluoro-and-tolupdino) -benzyl-tetrazole. 2.5 g of sodium azide and 2.0 g of ammonium chloride are charged into a solution of 7.0 g of o- (K-methyl-a, a, a; α-trifluorine-toluidino) -phenyl-acetonitrile in 80 ml of dimethylformamide. The suspension is boiled under reflux for 16 hours. The mixture is then evaporated to dryness at 60 ° C and 0.01 Torr. The residue is dissolved in 200 ml of ether. The ether solution is extracted with 100 ml of 2N. sodium carbonate (soda) solution and 100 ml of water. The soda extract is acidified with 2N. hydrochloric acid and the oil which is separated out are dissolved in 200 ml of ether. The ether solution is separated, washed with 30 ml of water, dried over magnesium sulphate and evaporated to dryness at 11 Torr. The residue is recrystallized

from ether - petroleum ether. The resulting (K-methyl-a, a, a-trifluoro-l-toluidino) benzyl-tetrazole melts at 128-130 ° C.

The nitriles used as starting materials are prepared as follows.

A. Methyl ester of N-methyl-K- (a, a, a-trifluorotyltin) antranilic acid.

To a solution of 159.0 g of K- (a, a, a-trifluoro-w-tolyl) -anthranilic acid in 60 ml of dimethylformamide, 54.0 g of a 50% dispersion are added.

sodium hydride in paraffin oil at room temperature. The reaction mixture is heated for 1 hour at 80 ° C without access of moisture. Then at room temperature and stirring, 162 g of methyl iodide are added,

the mixture is stirred for 1 hour at room temperature and 17 hours at 70 ° C. Then it is poured onto 2500 ml of ice water. Brown oil is released. It is dissolved in 2500 ml of a mixture of ether and ethyl acetate (1: 1). The resulting ethyl acetate solution was extracted twice with 250 ml portions of 2N. sodium carbonate solution, then washed with 200 ml of water, dried over magnesium sulphate and evaporated at 40 ° C and 11 torr. The remaining methyl ester .Y-methyl-M- (a, a, a-trifluoro-g-tolyl) -anthranilic acid is subjected to fractional distillation; m.p. 125 ° C (0.01 torr).

B. o- (M-methyl-, a, a, a-trifluoro-w-toluidino) benzyl alcohol.

10.6 g of sodium borohydride and 24.25 g of lithium bromide are introduced into 750 ml of dimethyl ether of diethylene glycol and stirred for 30 minutes at room temperature. A solution of 86.0 g of methyl ester of M-methyl-M- (a, a, a-trifluoro-L4-tolyl) anthranilic acid in 490 ml of diethylene glycol dimethyl ether is poured into the suspension. Then the mixture is heated for 6 hours at 90-100 ° C. After cooling, the reaction mixture is poured, with stirring, into a solution of 89 ml of concentrated hydrochloric acid in 1300 ml of ice-water and the resulting mass is extracted twice with 2000 ml of ether. The ether solution is washed with dilute sodium bicarbonate solution, dissolved over sodium sulfate and dissolved.

the body is distilled off. The residue is subjected to fractional distillation. The obtained o- (N-Methyl-1a, a, a-trifluoro-l-toluidino) - benzyl alcohol boils at 105 ° С (0.001 Torr),

C. a-bromo-y-methyl-y- (a, a, cc - trifluoro-l-tolyl) -o toluidine.

In a solution of 44.0 g of o- (K-methyl-ss, a, a-trifluor m-toluidino) -benzyl alcohol in 100 ml of abs. benzene is poured, but drops at O- 10 ° C, 216 ml of trichromic phosphorus. The mixture is then stirred for 20 hours at room temperature and poured onto 3000 ml of ice water. The oil that has been isolated is dissolved in 2000 ml of ether. The ether solution is washed with 400 ml of 1N. potassium bicarbonate and 200 ml of a solution of sodium chloride, then dried over magnesium sulfate and evaporated at 40 ° C and AND Torr. A-bromo-M-methyl-L- (a, a, atrifoor-lg-tolyl) -o-toluidine remains as a yellow oil.

D. (o- (L-methyl-a, a, a-trifluoro-and-toluidino) -phenyl-aetonitrile.

In a solution of 100 ° C ha-bromo-M-methyl-L- (a, a, atriftora-w-tolyl) -o-toluidine in 300 ml abs. dimethyl sulfoxide slowly poured a solution of 20 g of cyanic sodium in 400 ml of absol. dimethyl sulfoxide, and the temperature of the solution should not exceed 40 ° C. The mixture is then stirred for 20 hours at 40 ° C, cooled and poured onto 3500 ml of ice water. The aqueous mixture is extracted three times with portions of 2000 ml of ethyl acetate. The ethyl acetate extracts are washed with 200 ml of 6N. hydrochloric acid and 300 ml of water. Combine the ethyl acetate extracts, dry over magnesium sulfate, and evaporate to dryness at 40 ° C / 11 Torr. In the residue, o- (L-methyl-a, (x, a-trifluoro-m-toluidino) -phenyl-aetonitrile as a yellow oil.

Example 5

I. Lithium salt (a, a, a-trifluoro-w-toluidino) -benzyl-tetrazole.

Dissolve 4.0 g of 5- (o- (a, a, a-trifluoro- ./i-tolu didino) -benzyl-tetrazole in 12.5 ml of 1N caustic lithium, pH of the solution 7.0. The solution is extracted 10 ml of ether and evaporated to dryness at 50 ° C and 11 Torr. The residue is treated three times with 20 ml portions of benzene and each time it is evaporated to dryness at I Torr. The last residue is dissolved in 100 ml of ether, the ether solution is filtered and evaporated to dryness at 11 Torr. The residue is recrystallized from ethyl acetate.

The resulting lithium salt of (a, a, a-trifluoro-lg-toluidino) -benzyl-tetrazole melts at 200-202 ° C.

P. Lithium salt of (3-chloro-o-toluidino) -benzyl-tetrazole.

3.0 g of (3-chloro-o-toluidino) benzyl tetrazole is dissolved in 10.0 ml of 1N. caustic lithium. The solution is extracted with 10 ml of ether and then evaporated to dryness at 50 ° C and 11 torr. The residue is treated with 30 ml of abs. benzene and evaporated to dryness at 11 torr. The residue is dissolved in ethyl acetate. Ethyl acetate solution

filtered and evaporated at 11 torr. The addition of petroleum ether crystallizes (from petroleum ether) the lithium salt of (3-chloro-o-toluidino) -benzyl-tetrazole; m.p. 225-230 ° C. Example 6

I. Similarly to the one described in Example 4, A, 5-o- (Mn-butyl-a, a, a-trifluoro-ltoluidino) -benzyl-tetrazole is obtained; m.p. 92-93 ° C (from ether and diclohexane), starting from 14.4 g of o- (Mn-butyl-a, a, 1a-trifluoro-l "-toluidino) -phenyl-acetonitrile; m.p. 126-130 ° C, / 0.005 torr.

P. As described in Example 4, A

get (M-ethyl-a, a, a-trifluoro- / "- toluidino) -benzyl-tetrazole; m.p. 140-142 ° C

(from ether and petroleum ether), based on

6.0 g of o- (L-ethyl-a, a, a-trifluoro-w-toluidino) phenyl-aetonitrile; m.p. 134-136 ° C /

/ 0.01 torr.

Iii. In the same manner as in Example 4, A, 5-o- (N-ethyl-3-chloro-o-toluidino) benzyl-tetrazole is obtained; m.p. 159-161 ° C (from benzene), starting from 8.4 g (o- (L-ethyl-3-chloro-otoluidino) -phenyl-acetonitrile; mp 96-97 ° C.

Baseline items are obtained as follows.

Methyl ester of M- (n-butyl) -M- (a, a, "- trifluoro-l-tolyl) -anthranilic acid.

In a solution of 255 g of methyl N- (a, a, atrifluoro-lg-tolyl) -anthranilic acid in 1500 ml absol. dimethylformamide was added in portions of 41.5 g of sodium hydride dispersion in mineral oil (50%) at room temperature. The reaction mixture is heated for 1 hour to 80 ° C in the absence of moisture. Then when int. At a temperature of 20 ° C, 119 g of nbutilbromide are added dropwise with stirring. The mixture is heated for 3 hours at 50 ° C, cooled and poured into 700 ml of ice water. The oil that has been isolated is extracted with 3000 ml of ether. The ether solution is separated, washed with 800 ml of water and 800 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness at 11 Torr. The residual N (n-butyl) -Y- (a, a, a-trifluoro-l "- tolyl) -anthranilic acid methyl ester is subjected to fractional distillation; m.p. 117-119 ° C / 0.01 torr.

Similar to that described in Example 4, A, an ethyl ester of N-ethyl-M- (a, a, a-trifluoro-w-tolyl) -anthranilic acid is obtained; m.p. 126 ° C / 0.01 Torr, based on 150 g of M- (a, a, a-trifluoro- / 14-tolyl) -anthranyl ki-slot.

In the same manner as described in Example 4, A, M-ethyl-M- (3-chlorotolyl) -anthranilic acid ethyl ester is obtained; m.p. 134-136 ° C / 0.001 Torr, based on 261 g of M- (3-chloro-otolyl) -anthranilic acid.

(n-butyl) -a, ss, and - trifluoro-g - toluidino) -benzyl alcohol.

In solution 1), 89 g of N- (H-6-methyl) -Y- (a, a, a-trifluoro-m-tolyl) methyl ester) - anthranilic acid B 3000 ml abs. benzene is poured in a nitrogen atmosphere at a concentration of 624 ml of a 0.43 M solution of lithium aluminum hydride in ether. The reaction mixture is stirred for 16 hours at 5 ° C under a nitrogen atmosphere. Then, 16.5 ml of water, 16.5 ml of a 15% sodium hydroxide solution and another 50 ml of water are added dropwise. Then the reaction mixture is filtered, the filtrate is evaporated to dryness at 40 ° C and 11 Torr. The residue is chromatographed on 2400 g of neutral alumina. Fractions 1-5, eluted with 1000 ml portions of ether, are combined and evaporated to dryness at 11 Torr. Fractions 7-14, eluted with 1000 ml portions of ether and petroleum ether (4: 6), are combined and distilled. (n-butyl) a, a., a - trifluoro-f - toluidino) - benzyl alcohol boils at 126-130 ° C / 0.005 torr.

In the same way as described in Example 4, B is obtained with o- (L-ethyl-a, a, a-trifluoro-w-toluidino) benzyl alcohol; m.p. 120 ° C / 0.001 Torr, based on 90 g of methyl ester of N-ethyl- (a, a, a-trifluoro-w-tolyl) -anthranilic acid; m.p. 126 ° C / 0.01 torr.

In the same way as described in Example 4, B is prepared with o- (N-ethyl-3-chloro-o-toluidino) benzyl alcohol; m.p. 138-140 ° C / 0.001 Torr, so pl. 66-68 ° C (from ether - petroleum ether), starting from 31.8 g of ethyl ester of Nethyl-N- (3-chloro-o-tolyl) -anthranilic acid; m.p. 134-136 ° C / 0.001 torr.

Similarly as described in example 4, C get a-bromo-N- (n-butyl) -N- (a, a, a-trifluoro.-And-tolyl), o-toluidine (oil), starting from 16 g (n -butyl) -o: ,, a, a-trifluoro-L4 - toluidino benzyl alcohol; m.p. 126-130 ° C / / 0.005 torr.

In the same way as described in Example 4, C is prepared with a-bromo-N - ethyl-N - (a, a, a - trifluoro-tolyl) -o-toluidine (oil), starting from 10.9 g of o- (L-ethyl- a, a, a-trifluoro-w-toluidino) - benzyl alcohol; m.p. 120 ° C / 0.001 torr.

In the same manner as described in Example 4, C is prepared with bromo-M-ethyl-M- (3-chloro-o-tolyl) -o-toluidine (oil), starting from 18 g of o- (N-ethyl-Zchloro-o-toluidino) -benzyl alcohol, t. Kip. 136-140 ° С / 0.001 torr.

In the same manner as described in Example 4, D, o- (L-n-butyl-a, a, a-trifluoro.l-toluidino) -phenyl-acetonitrile are obtained; m.p. 126-130 ° C / 0.005 Torr, based on 14.5 g of a-bromo-N (n-butyl) -M- (a, a, a-trifluoro -. / And -tolyl) -o-toluidino (oil) .

In the same way as described in Example 4, D, o- (M-ethyl-a, a, a-trifluoro-l-toluidino) -phenyl-acetonitrile is obtained; m.p. 134-135 ° C / / 0.01 Torr, starting from 8.9 a-bromo-L-ethyl-M- (a, a, a-trifluoro-.m-tolyl) -o-toluidine (oil).

In the same way as described in Example 4, D, o- (L-ethyl-3-chloro-o-toluidino) -phenyl-acetonitrile is obtained; m.p. 96-97 ° C (from ethanol), starting from 15.5 g of a-bromo-N-ethyl-N- (3-chloro-o-tolyl) -o-toluidine (oil).

Example 7. (3-chloro-o-toluidino) -benzyl-tetrazole.

A solution of 2.3 g of 5-N-formyl-o- (3-chloro-o-toluidino) -benzyl tetrazole in 50 ml of 7% ethanolic solution of potassium hydroxide is boiled for 3 hours under reflux, cooled and evaporated to dryness at 40 ° C and 11 torr. The residue is dissolved in 150 ml of water. The aqueous solution was extracted with 50 ml of ether, separated, acidified with 2N. hydrochloric acid. The oil that is recovered is extracted with 100 ml of ether.

The ether solution is extracted with 20 ml of water, dried over sodium sulfate and evaporated to dryness at 11 Torr. The residue is recrystallized from ether - petroleum ether. The resulting 5-o- (3-chloro-o-toluidino) benzyl tetrazole melts at 153-155 ° C.

Similarly receive (2,3-xylidino) benzyl-tetrazole; m.p. 169-171 ° C (from ether-petroleum ether), starting from 2 g of 5-N-formyl-o - (2,3-xylidino) -benzyl-tetrazole.

Baseline items are obtained as follows.

A. o- (3-chloro-o-toluidino) - benzyl alcohol.

A suspension of 18.15 g of lithium aluminum hydride in 200 ml of abs is prepared. tetrahydrofuran and cooled with stirring to 5 ° C. Under nitrogen, a solution of 50 g of (3-chloro-o-tolyl) -anthranilic acid is slowly poured.

200 ml abs. tetrahydrofuran. The mixture is then boiled for 2 hours under reflux, cooled to 5 ° C, and 18.2 ml of water, 18.2 ml of a 15% sodium hydroxide solution and another 54.5 ml of water are added dropwise. Then the reaction mixture is filtered, the filtrate is evaporated to dryness at 40 ° and 11 Torr. The residue is dissolved in 400 ml of ether. The ether solution is washed with 50 ml of water, 150 ml of 2N. sodium carbonate solution and 50 ml of water, dried over

sodium sulfate, evaporated at 40 ° C and 11 Torr. The residue is distilled under a deep vacuum, o- (3-chloro-o-toluidino) -benzyl alcohol boils at 160 ° C / 0.01 Torr., T. Pl. 51-52 ° С (from ether - petroleum ether).

Similarly as described in example 7, And get o- (2,3 - zsilidino) - benzyl alcohol; m., pl. 74-7: 5 ° C (from ether - petroleum ether), starting from 250 g of M- (2,3-Xylol) anthranilic acid.

B. a-chloro-N- (3-chloro-o-tolyl) -o-toluidine.

In a solution of 6 g of o- (3-chloro-o-toluidino) -benzyl alcohol in 50 ml of abs. ether poured 100 ml of 5 n. ethereal hydrochloric acid solution. The mixture is shaken for 5 minutes, while

the precipitated crystals go into solution. Pour another 200 ml of abs. ether, shaken for another 15 minutes, evaporated at 40 ° C and 11 Torr. The residue is treated with a small amount of ether - petrolainoto ether

(1: 1). The precipitated crystals are filtered off and treated with 30 ml of water and 200 ml of ether. The mixture is agitated, the ether solution is separated, washed with 30 ml of water, dried over sodium sulfate, evaporated at 11 Torr.

-Understated α-chloro- (3-chloro-about-11) ester

lil) - 0-toluidine can be used directly for further reaction.

Similarly, on the cannon in nimer 7, B, a-chloro- (2,3-xylene) -o-toluidine is obtained, starting from 15 g of o- (2,3-xylidino) -benzyl residue.

C. o- (3-chloro-o-toluidino) -phenyl-acetonitrile.

1.3 g sodium cyanide suspension in 80 ml of dimethyl sulfoxide is poured into a suspension at 40 ° C and the stirrer is added to a gstzor of crude crude c-chloro- (3-chloro-o-tolyl) -o-tolu 1-dine in 20 ml of dimethyl alkyl q-hydroxide. The mixture was stirred for 90 minutes at 40 ° C and diluted with 800 ml of ice-cold water. The solution is extracted three times with 400 ml portions of ethyl acetate. The ethyl acetate solutions are washed in portions in 100 ml of water and 100 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated at 40 ° C and 11 torr. The residue is dissolved in 50 ml of ether. The ether solution is filtered through a layer of neutral alumina. The filtrate is evaporated to dryness at II Torr. The residue is recrystallized from ether - petroleum ether. The resulting o- (3-chloro-o-toluidino) -phenyl - acetonitrnl melts at 86-88 ° C.

Similarly, o- (2,3-xylidino) phenyl-acetonitrile is prepared; m.p. 95-96 ° C (from ether-petroleum ether), starting from 9 g of chloro- (2,3-xylyl) -o-toluidine.

D. a-cyano-N- (3-chloro-o-tolyl) -o-formo-toluidide.

A mixture of 8.5 ml of formic acid and 17.5 ml of acetic anhydride is stirred for 1 hour at 40-50 ° C. Then, 2.4 g of o- (3Hlar-o-toluidino) -phenyl-acetonitrile are introduced in portions and the mixture is stirred for 6 hours at 40 ° C. Then the solution with stirring, poured into 100 ml of warm water (40 ° C), stirred for 20 minutes and the mixture poured onto ice. The oil that is recovered is extracted with ether. The ether layer is separated, washed with water, dried over sodium sulfate and filtered through a layer of neutral alumina. The filtrate is evaporated to dryness with a torus. The residue is recrystallized from ether - petroleum ether.

The resulting a-cyano-N- (3-chloro-o-tolyl) o-formo toluidide melts at 114-116 ° C (114-116 ° C).

Similarly, a-cyano-N- (2,3-xilyl) -o-formo-toluidide is prepared; m.p. 119-121 ° C (from ether-petroleum ether), starting from 6 g of o- (2,3-xylidino) -phenyl-acetonitrile.

E. 5-N-formyl-o- (3-chlorop-o-toluidino) benzyl-tetrazole.

1.92 g of sodium azide and 1.54 g of ammonium chloride are added to a solution of 5.9 g of a-cyano-N- (3-chloro-o-tolyl) o-formo toluidide in 60 ml of dimethylformamide. The resulting suspension was refluxed for 36 hours. The mixture is then evaporated to dryness at 60 ° C and 0.01 Torr. The residue is treated with 100 ml of ice and water. 20 ml 2n. sodium carbonate solution. Water-base solution extracted with 30 ml of ether1 7 J

pa, acidified with 2n. hydrochloric acid and the oil that is separated out are extracted with ether. The ether solution is washed with water, dried over sodium sulfate and evaporated at II Torr. 5-N-formyl-o - (3-chloro-o-toluidino) -benzyl-tetrazole (recrystallized from ethyl acetate-ether); m.p. 175-176 ° C.

5-N-formyl-o - (2,3-xylidino) - benzyl tetrazole.

A mixture of 3.38 g of azide "atri and 2.28 g of aluminum chloride in 22 ml of abs. tetrahydrofuran is refluxed for 30 minutes. A solution of 4.0 g of a-cyano-N- (2,3-xilyl) -o-formotoluidide in 8 ml of abs is added to the cooled mixture. tetrahydrofuran. The mixture was boiled under reflux for 3 days, cooled, diluted with 50 ml of ice water and evaporated at 60 ° C and 11 Torr. The residue is treated with 20 ml. 2 n. hydrochloric acid and

the mixture is extracted with 60 ml of chloroform. The chloroform solution is extracted with 20 ml of 2N. caustic soda. The aqueous alkaline solution is separated, treated with activated carbon and filtered. The filtrate is acidified with conc. hydrochloric acid. The crystals separated out are extracted with ether. The ether solution is dried over sodium sulfate and evaporated at 11 Torr. The residue is recrystallized from ether - ethyl acetate. The resulting 5-N-formyl-o- (2,3-xylidino) -benzyl tetrazole melts at 188-191 ° C. Example 8.

J. In a manner similar to that described in Example 7, I, 5- (o-aniline benzyl) -tetrazol is obtained; m.p.

141 -142 ° C (from benzene), starting from 5- (M-formyl-o-aniline benzyl) -tetrazol a.

A. o- (M-phenylformamido) -benzyl ester of formic acid. A mixture of 63 ml of formic acid and

130 ml of acetic anhydride mix

At 40 ° C. Then, 19.9 g of o-aniline benzyl alcohol are introduced in portions and the mixture is stirred for 3 hours at 40 ° C and 16 hours at room temperature. Then the solution is poured

with stirring in 1000 ml of warm water (40 ° C), stirred for 20 minutes and cooled to room temperature. The oil that is recovered is extracted with ether. The ether solution is washed three times with water, dried over

sodium sulfate and evaporated to dryness with

IIorr. The residue is distilled (in a tube with ball expansion) o- (N-phenylformamido) -benzyl ester of formic acid boils at 135-140 ° s / 0.001 Torr.

B. a-Oxy-N-phenyl-o-formomoidide.

To a solution of 8.08 g of sodium carbonate in 100 ml of water is added dropwise and stirring, at room temperature, a solution of 19.4 g of o- (N-phenyl-formamido) -benzyl ether

formic acid and 300 ml of ethanol. The mixture is stirred for 5 hours at room temperature and poured into 3000 ml of ice water. The oil that is recovered is extracted with ether. The ether solution is washed with water, dried

over sodium sulfate and evaporated at

1 W,

And torr. The residue is chromatographed on 800 g of silica gel.

Fractions 6–9, eluted with 100 ml portions of ether, contained pure a-hydroxy-L-fezyl-o-formotoluide as a yellow oil.

C. ss-chloro-y-phenyl-o-formotoluid.

A solution of 9.9 g of a-hydroxy-M-phenyl-o-formoluid in 334 ml of abs. benzene is slowly heated under nitrogen. At 50 ° C (internal temperature), 0.31 ml of pyridine and a solution of 5.65 ml of thionyl chloride and 28 ml of abs are added dropwise. benzene. Then the mixture is stirred for 30 minutes at 50 ° C and evaporated to dryness at 40 ° C and 11 torr. The residue is dissolved in 100 ml of ether. The ether solution is extracted with 40 ml of water and 40 ml of a saturated solution of sodium chloride, dried over sodium sulfate and evaporated at 11 Torr, bringing the volume to about 30 ml. An ethereal solution of a-chloro-N-phenyl-o-formotoluid is used for further reaction.

D. a-Cyano-K1-phenyl-o-formotoluid.

In a solution of 3.06 g of cyanic sodium in 197 ml of dimethyl sulfoxide, a solution of 10 g of crude a-chloro-M-phenyl-o-formotoluid in 30 ml of ether is poured at room temperature with stirring. The mixture is then stirred for 10 minutes at room temperature and poured into 1000 ml of ice-cold water. The separated yellow oil is extracted with 800 ml of ethyl acetate. The ethyl acetate solution is washed with 200 ml of water and 200 ml of a saturated solution of sodium chloride and evaporated to dryness at 40 ° C and I Torr. Get a-Cyano-M-phenyl-oformotoluidid in the form of oil.

E. In a similar manner, 5-M-formyl-anilinobenzyl-tetrazole is obtained; m.p. 159-160 ° C (from ethyl acetate), starting from 4.5 g of a-cyanoN-phenyl-o-formotoluid.

P r and m er. 9.

I. (3-chloro-o-toluidino) -benzyl-tetrazole.

A mixture of 1.91 g of sodium azide and 1.3 g of aluminum chloride in 20 ml of abs. tetrahydrofuran is refluxed for 30 minutes, then a solution of 2.2 g of o- (3-chloro-o-toluidino-) phenyl acetonitrile in 20 ml abs is poured into the cooled solution. tetrahydrofuran. The mixture was boiled for 3 days (3 days) under reflux, cooled, diluted with 50 ml of ice water and evaporated at 60 ° C and 11 Torr to a volume of 30 ml. The aqueous mixture is treated with 20 ml of 2N. hydrochloric acid and extracted with 100 ml of chloroform. The chloroform solution is separated and extracted with water, then with 20 ml of 2N. caustic soda. Bodnop1, fir-tree solution, is separated, treated with activated charcoal, filtered. The filtrate is acidified with conc. hydrochloric acid. The crystals separated out are extracted with ether. The ether solution is dried over sodium sulfate and evaporated to dryness at 11 Torr. The residue is recrystallized from ether - petroleum ether. Received (3-chloro-o14

toluidino) -benzyl tetrazole melts at 153 -155 ° C.

Ii. Similarly, receive (2,6-dichloranilino) -benzyl-tetrazole; m.p. 186-188 ° C (from ethyl acetate), starting from 4.5 g of o-2,6-dichloroanilino) phenyl acetonitrile; m.p. 71-72 ° C. P p and measures 10.

I. (Mn-propyl-a, a, wasps) -trifluoro-.n-toluidinobenzyl-tetrazole.

In the suspension formed by 1.92 g of 50% sodium hydride dispersion (in mineral oil) in 27 ml of abs. dimethylformamide, pour in a dropwise at O-5 ° C a solution of 6.4 g, aua-trifluoro- / and - toluidino) -benzyl-tetrazole; m.p. 128-130 ° C in 27 ml abs. dimethylformamide. The suspension is stirred for 20 minutes at room temperature. Then, at 0 °, a solution of 2.46 g is poured (dropwise)

n-pripilbromida in 20 ml of dimethylformamide. Then the mixture is stirred for 2 hours at room temperature and evaporated to dryness at 60 ° C and 11 Torr. The residue is dissolved in 150 ml of water. The aqueous solution is extracted with 50 ml of ether,

are separated, acidified with conc. hydrochloric acid. The oil that is isolated is dissolved in 200 ml of ether. The ether solution is washed with water, dried over sodium sulfate and evaporated to dryness at 11 Torr. The residue is recrystallized from ether. The resulting (Mn-propyl-a, a, a-trifluoro — w-toluidino) benzyl tetrazole melts at 132-134 ° C.

II. Analogously, (L-ethyl-a, a, a-trifluoro-lg-toluidino) -benzyl-tetrazole is obtained;

m.p. 140-142 ° C, based on 6.7 g (a, ss, atriftoral-lg-toluidino) -benzene-tetrazole.

III. Similarly, (L-ethyl-3chloro-o-toluidino) -benzyl-tetrazole is obtained; m.p. 159-161 ° C, based on 7.3 g of (3-chloro-otoluidino-) benzene-tetrazole.

Subject invention

The method of obtaining derivatives of tetrazole of the formula

50

55

where RI and Ra independently of each other - hydrogen, methyl, ethyl or halogen atom;

R2 is a hydrogen atom, methyl or ethyl, a halogen atom or a trifluoromethyl group; R4 is methyl, ethyl, n-propyl or n-butyl, or their salts, characterized in that the substituted 2- (o-anilinophenyl) -acetonitrile of the general formula

15

CHj-CN

R

where R4 is a hydrogen atom, alkyl or alkanoyl with a straight chain and not more than 4 carbon atoms;

sixteen

Ri, R2 and Rs are as defined above, are reacted with a minimum of a molar amount of hydrazoic acid or azide, the resulting tetrazole derivative is either isolated, or in the case of R4, it is lower alkanol,

they are successively hydrolyzed and alkylated, or in the case of R4, a hydrogen atom, alkylated, and the desired product is isolated or salified using known techniques.