SU552028A3 - The method of obtaining derivatives of diazepine or their 5-oxides or their salts - Google Patents

Description

Rings L and B MOiyi be replaced as indicated by faHt), iKuiHepiawT interacts with gadraein with trace release of the desired product in free form or as its 5-oxide, or as a). GS of the general formula I, their 5-oxides and 01) the corresponding salts with inorganic or organic acids possess valuable pharmacological properties. The reaction can be carried out in a lower alkanol, e.g. methanol or ethanol, to which more hydrogen halide, e.g. chloroform, is preferably added from room temperature to the boiling point of the reaction mixture, preferably at 20-60 ° C. To improve the solubility. As oxidative agents when preparing the S-OKKO compounds of formula I, it is preferable to use hydrogen peroxide or peracid at O-70 ° C. The peracidic acid approach is peracetic acid or benzoic acid. Oxidizing agents are preferably used in a solution {for example, peracetic acid in acetic acid and benzoic acid in halohydrocarbons, nap {1mer in methyl chloride or chloroform. Formula salts use nonorganic and organic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, perchloric, methanesulfonic, ethanesulfonic, or hydrated salts. Preferably, the salt-forming compound is carried out in the presence of a solvent, for example acetone, methanol, ethanol, ether, or mixtures thereof. PRI me R 1. To a solution of $ 5.4 g (0.01 mol) N, M-diethd-1- (2-6enzonl-4-chlorophenyl) - 5- (phthalium schometal) -1H-1, 2,4-triazole-3-carbsnissaMide in 150 ml of ethanol was added 1.05 g (0.021 mol) of 1 Phasic hydrate and the reaction mixture was stirred for 16 hours at a temperature of 60 ° C for another 5 hours. The hydrazd phthalic acid is filtered and || The residue is evaporated in vacuo to dryness. Ice water was added to the residue and extracted twice with ethyl acetate. The organic phase is dried a day. a solution of hydroxy sodium, once with an icy solution of hydrochloric acid and two times with water. After drying the solution over sodium sulfate solution | 1 h is sharpened in vacuum. After recrystallization from benzoylcyclohexane, the residue gives N, N-diethyl-6-phenyl-8-chloro-3H-S-triazolo (1,5-a) (1,4) benodiazepin-2-carboxamide with m. Pl. 175-177 °. In a similar way, a preparation is obtained, starting with 5.75 g (0.01 mol) of N, M-diethyl-2- (o-chlorobioeoyl) -4-chloroferyl-5- (phthalimidomethyl) -1H-1,2,4-triaol - 3-carboxamide N, L-; shethyl-6- (o-chlorophenyl) -8-chloro-4H-5-triazolo (1,5-a) (1,4) -benzodiazepine-2-carboxamide with 1.pl. 156-158 ° (from isopropanol); starting from 4.31 g (0.0 mol) of N, M-dimethyl-1 (2-o-fluorobenzoyl) -4-chloro-1-hl-5- (phthalimidomethyl) -1H-1,2,4-triazole-3-carboxamnd N, N - psmetnp - 6 - (o - phorphenyl) - 8 - chlorine - 4H - S triazolo (1,5-a) (1,4) benzodiazepine-2-carboxamide with m. Pl. 180-182 ° (from propanol); starting from, 4.13 g (0.0 mol) N, N - dimethyl - I-2 - {benzoyl - 4 - chlorphene; - 5 - (phthalimidomethyl) -.-IH-1,2,4-triaol-3-carboxamnd N, N-dimethyl-6-fegal-8-chloro-4H-5-triazolo (, 5-a) (1, 4) benzodiazepin-2-carboxamide with m. Pl. 135-137 ° C (from methylshiridahexane); starting from 4.48 g (0.01 mol) of N, N-dimethyl- - (2- (o-xlq) 5-enzoyl) -4-chlorophenyl-5- (ft imidomethyl) -1 H -1,2,4 - triazole - 3 - carxamide N, N - dimethyl 6 - (o - hls phenyl) - 8 - chloro 4H - S triazolo (1,5-a) (1,4) benzodiazepine - 2- carboxMID with so pl. 142-145 ° (from isogophopanol); Starting from 3.95 g (0.01 mol) of 1 -2-benzoyl-4-chlorophenyl) 5 - (phthalimidomethyl) -1H -1,2,4-t | 1aeol-3-carboxamide 6-phenyl-8-chloro-4HS-triazolo (1,5-a) (1,4) benzodiazepia-2-carboxal "d with t. Pl. 252-254 °; starting from 4.17 g (0.01 mol) of M-methyl-12- (o-fluorobenzoyl) -4-chlorophenyl) -5- (phthalimidomethyl) -1H-1,2,4-triazole-3-carboxamide N- methyl - 6 - (o - fluorofesh) - 8 - chlorine - 4H - S - triazolo; fl, 5-a) (1,4) benzodiazepine-2 - carboxamide with m. pl. 202-203 °; starting from 4.34 g (0.01 mol) of N-methyl-l-12- (o-chlorobenzoyl) -4-chlorfesh1l) -5- (phthalimidomethyl) -1H-1,2,4-triazole-3-carboxamide N-methyl-6 (o-chlorophenyl) -8-chloro-4H-S triazolo (1,5-a) (1,4) benzodiazepine-2-carboxamide with m. Pl. 211-213 ° (from isopropanol). The starting materials are prepared as follows: a) a solution of 58.0 g (0.25 mol) of 2-amino-5-chlorobenzophenone in 310 ml of glacial acetic acid (4: 1) revacum hydrochloric acid ends diazotize the mixture at a temperature of pereikskanii with 50ml (0.25 mol) of an aqueous solution of strta 1a1t. To the obtained solution of the dialazoin p {I salt, 150 g of ice and quickly, dropwise, a solution of 52.4 g (0.208 mol) of diethyl acid (2-chloroacetamido) -malonic acid in 600 ml of aUieTOHa. A solution of 276.0 g (2 mol) of potassium carbonate in 500 ml of water is then added dropwise over a period of 5-10 ° C, stirring is continued for an hour, and benzene and a saturated solution of sodium chloride are added. The benzene solution is separated, rinsed with a saturated solution of chloride, dissolved over sodium sulfate and ground. Obtain 121 g of crude diethyl zfir (2-chloroacetamido) - (2-benzoyl-4-chlorfe slaeo) - mung bean) new acid; b) obtained according to a) the crude diethyl ether is dissolved in 1.5 liters of dioxane. To received

a solution / shoxam was added .6 g ((), I mol) iTiUpt) OKHCH sodium, dissolved in 2 l of water, the mixture was stirred for 30 min and / juxane then evaporated in vacuo. The residue is diluted with 500 ml of water, 20 g of activated carbon is added to the carbon, the mixture is vigorously stirred and filtered through the diatomaceous earth. With vigorous stirring, 2 n are added to the filtrate. hydrochloric acid to produce an acidic reaction according to the Congo, the carboxylic acid which has been drawn off is sucked off, rinsed in water and recrystallized from hot methanol. The resulting 1- (2-benzoyl-4-chlorophenyl) -5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid is sintered at 137-138 ° and melted with decomposition at. The crystals contain an excess amount of methanol.

Similarly, a) and b) are obtained using 66.5 g (0.25 mol) of 2-amino-2, 5-dichlorobenzophenone 1 - 2- (o - chlorobenzoyl) - 4 - chlorophenyl - 5 - (chloromethyl) - 1 H- 1,2,4-triaole-3-carboxylic acid with m. Pl. 170-175 ° (decomposition; the substance is precipitated from solution in aqueous ammonia using 2 and. Hydrochloric acid);

when using 62.5 g (0.25 mol) of 2-amino5-lor-2 fluorobenzophenone (oforbenzoyl) - 4-chlorophenyl 1-5- (chloromethyl) - 1H-1,2,4-triazole-3-carboxylic acid (hardened foam ); c) on 11.7 g (0.031 mol) of 1- (2-benzoyl-4-chloro-phenyl) -S- (chloromethyl) -1H-1,2,4-trpazole-3-carboxylic acid (see Appendix 1a and b) 60 ml of oxalyl chloride was poured and boiled under a halod for about an hour, the yellow solution was clarified at 40 ° under vacuum and 100 ml of benzene was added to the residue and again boiled to remove oxalyl chloride.

The resulting crude 1- (2-benzoyl-4-chlorophenyl) 5- (chloromethyl) - ItH, 2,4-triaol-3-carbonyl chloride is dissolved in 400 ml of dioxane and a solution of 4.55 is added dropwise over 90 minutes at room temperature. g (0.062 mol) diishlamish in 100 ml of dioxane. At the same time, diethylamine hydrochloride is gradually injected. The reaction mixture in Vacuum is evaporated to dryness. Iced water and ether were added to the residue, the organic phase was separated and it was first cooled with cold 1N. hydrochloric acid, then cold 1 and. sodium hydroxide and saturated soluble sodium chloride. After drying over sodium sulphate {iv and tariwa 1ch under vacuum, crude N, M-diethyl-1- (2-beisoyl-4-chlorophenyl) -5- (chloromethyl) -1H-1,2,4-trtazol-3-carboxamide is obtained, which melts after recrystallization from isopropanol at 118-119.

Similarly, receive

when using 12.8 g (0.031 mol) (o-chlorobenoyl) -4-chlorophenyl 1 -5- (chloromethyl)

Hi-1,2,4-triaol-3-carboxylic acid and 4.55

(0.062 mol) daethylamine N, K1-diethyl-1- 2- (o-chlorobioeoyl) -4-chlorophenyl-5- (chloromethyl)

- 1H-1,2,4-triaol - 3 carboxamide;

p; w the use of 12.26 g (0.031 lol) ((-fluoro6ene (.yl) -4-chlorophenyl-5- (chloromethyl) -1H-1 .2,4-triazole-3-carbonic acid and 2.8 g (0.062 mol) dimethylamine N, N-dimegap-112- (o-fluorobenzoyl) -4-chlorophenyl-5- (chloromethyl) 1I-1, 2,4-triazole-3-carboxamide;

when using 11.66 g (0.031 mol) of 1- 2-benzoyl-4-chlorophenyl-5- (chloromethyl) -1H-, 2,4-triazole-3-carboxylic acid and 2.8 g (0.062 mol) of dimethylamine N N-dimethyl-1-2-benzoyl-4-chlorophenyl-5- (chloromethyl) -1H-1,2,4-triaol-3 carboxamide; d) a solution of 8.62 g (0.02 mol) of N, N-diethyl-1 (2-benzoyl-4-chlorophenyl) -5 (chloromethyl) -1H-1,2,4-triazole-3-carboxam} yes and 4.63 g (0.025 mol) of potassium phthalimide in 200 m; dilyltilformanda is stirred for 2 hours at 50 °. The reaction mixture was then poured onto ice water and extracted twice with ethyl acetate. The organic phase is washed twice with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in ethnyl acetate and the solution is chromatographed on 500 silica gel. Ethyl acetate is used as eluent. The contents of the desired product are combined. Pure, amorphous N, N-diethyl-1- (2-beneoyl-4-chlorophenyl) -5- (phthalimidomethyl) -1H-1,, 4-triazole-3-carboxamide is liquefied at 85-90 ° Similarly, receive

Starting from 9.32 g (0.02 mol) N, M-Daethyl-1- {2- (o-chlorobenzoyl) -4-chlorophenyl-5- (chloromethyl)

-Sh-1,2,4-triazo-l-3-carboxes of ha and N, M-dieshl-2- (o-chlorobenzoyl) -4-chlorophenyl-5- (phthalimidomethyl) -1H-1,2,4-triazole -3-carboxacd;

from 8.43 g (0.02 mol) of N, 4-diethyl-l-2- (o-fluorobenzoyl) -4-chlorophenyl-5- (chloromethyl) -1H-1,2,4-triaol-3- carboxamide N, M-damethyl-1- (2- (o-fluorobenzoyl) -4-chlorfei-5-phthalideldimethyl) -1H-1,2,4-griazole-3-carboxamide;

starting from 8.06 g (0.02 mol) N, M-damethyl-1-2-benzoyl-4-xporfe 1 Chl-5- (chloromethyl) -1H-, 2,4-trizol-3-carboxamide N, N- dimethyl-1 2-benzoyl-4-goq) rfesh1l-5- (phthalidadomethyl)

-Sh 1,2,4-Triazole-3-carboxamide;

ISZI) in e fe.fe g (6.02 mol) N, N-noted-1- 2- (o-chlorobenone) -4-Chlorophenyl-5- (chloromethyl) -1 H-1,2,4-triazole - 3 sa mida

N, N-dimethyl- - 12- (o-chlorobenzoyl) -4-chlorophenyl)

-5 - (phthalimidomethyl) - IH -1,2,4 - triazole - 3 - carboxamide.

Example 2. To a solution of 6.8 g (0.018 mol) of N. M-dimetz1L-6- (o-fluorofesh) -8-chloro-4№5-trnaeopo (1,5-a) (1.4) benodeodiaepin- 2-to rboxamide in 270 ml of methylene chloride was added dropwise at O a solution of 6.1 g (0.035 mol) of 75% m-chloroperox - benzoic acid in 140 ml of methylene chloride during 20 minutes. Transparent reaction

the mixture is stirred for 3 hours at 0-5 ° n for 20 hours at

room temperature. The reaction solution is evaporated to dryness in vacuo, the residue is dissolved in a small amount of methylene chloride and the ether is added to a slight turbidity. The precipitated crystals are filtered off, recrystallized from chlorine methylene / ether, dried at 100 ° for 20 hours, and 5-oxide N, N-dimethyl-b- (o-fluorophenl) -8-chloro-4H-5-t is obtained {1azolo (1,5-a) (1,4) -benzodiaeepin-2-carboxamide with t. Pl. 170-172k, ° (decomposition).

The compound contains approximately 1/2 mol of methylene chloride.

Claims (2)

1. A method for producing diazepine derivatives of & S-So-nS X N where RJ is a hydrogen atom or an alkyl group with 1-3 carbon atoms; RI and R J are a hydrogen atom or an alkyl group with 1-6 carbon atoms; eight rings A and B can be substituted by halogen to atomic number 35, alkyl or alkoxy groups with 1-6 carbon atoms each, trifluoromethyl or nitro groups, or their 5-oxides, or their salts, characterized in that the compound of the general formula / Lg N N-C C-0 where is the phthalnmides group; RI, RI and Ra have the indicated meanings; COLs A and B may be substituted as described above, subjected to interaction with hydrazine, followed by separation of the target product in free form or in the form of its 5-oxide, or in the form of its salt. 2. A method according to claim 1, characterized in that the process is carried out at 20 60 C. Sources of information taken into account U} and exp; 1. The patent of Switzerland N 463518, cl. 12 p 10/01, 1968