DE1801305A1 - 7-chloro-2 3-dihydro-1-methyl-5-o-trifluoromethyl - Google Patents

Abstract

(A) Process:- (I) can be isolated as the free base or as an acid addition salt. (B) The intermediates (IV) (claimed) and (III) (not claimed) (I) is a sedative and anticonvulsant; ED50 in anti-pentetrazole test in mice is 0.85mg/kg and LD50 (mice) is 65 mg/kg (i.v.) or 1100 mg/kg(oral). Process gives improved yield and is suitable for use on technical scale. (II) is heated with an equivalent or practically equivalent amount of (III). The reaction can be carried out in the absence of a solvent. (IV) is obtained in 85-95% yield. Without further purification, (IV) can be converted into (I) by heating (pref. at >= 100 deg.C for 20 mins. to 5 hrs.) in the presence of a condensation agent such as POCl3 and/or P2O5 or polyphosphoric acid.

Description

Description of the patent application process for the production of 7-Chloro-2,3-dihydro-imethyl-5-o-trifluoromethylphenyl-1H-1,4-benzodiazpine The present The invention relates to an improved process for the preparation of 7-chloro-2,3-dihydro-1-methyl-5-o-trifluoromethylphenyl-1H-1,4-benzodiazepine in high yields and under conditions suitable for production in technical Scales are suitable, as well as the starting material used in this process.

The above connection or analog connections are made according to the previously known procedures obtained in fairly low yields, some of which the N-alkylations occurring during production are to be traced back.

In one process, for example, the N-alkylation of the one unsubstituted in the 1-8 position 2,3-Dihydro-5-phenyl-1H-1t4-benzodiazepine is the limiting factor with regard to the yield.

Another method is to use the 1-alkyl substituted 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine although in very good yields by reacting the corresponding substituted benzophenone obtained with ammonia under ring base eur diazepine structure, but that during manufacture of the substituted benzophenone used as the starting substance N-alkylations act as a limiting factor here.

It has now been found that these disadvantages can be overcome with the method according to the invention. According to the invention, N-methyl-Np-chlorophenyl-N'-o-trifluoromethylbenzoyl-ethylenediamine went out; this compound is heated in the presence of a condensing agent such as phosphorus oxychloride and / or phosphorus pentoxide or polyphosphoric acid and then the 7-chloro-2,3-dihydro-1-methyl-5-o-trifluoromethylphenyl-1H-1,4-benzodiazepine obtained as such or isolated in the form of one of its salts with acids. The reaction is carried out during the time required for the ring base. High yields of the desired compound are obtained when the reaction is carried out at temperatures of 100 ° C. or above; in this case, heating is preferably carried out for 20 minutes to 5 hours.

The starting material of the formula I used according to the invention is a hitherto unknown compound which is obtained by reacting N-methyl-p-chloroaniline with the hitherto unknown compound no-trifluoromethylbenioyl-aziridine of the formula implements. In this reaction, a mixture of equivalent amounts or practically equivalent amounts of the two compounds is heated and N-methyl-Np- [chlorophenyl-Xt-o-trifluoromethylbenzoyl-ethylenediamine is obtained directly in yields of 85-95% of theory.

The preparation of the starting compound of the formula I. in the absence of a solvent or reaction medium; This feature is the basis for a good implementation of the process according to the invention, in which the starting substance is prepared as described above and then converted into 7-chloro-2,3-dihydro-1-methyl-5 in a further process step in the same device without further purification -o-trifluoromethylphenyl-1H-1,4-benzodiazepine is converted.

The trifluoromethyl group bound to an aromatic nucleus very reactive and can, for example, be defluorinated or oxidized if it is mixed with Condensation center, etc. is brought into contact.

It was therefore surprising that 7-chloro-2,3-dihydro-1-methyl-5-o-trifluoromethylphenyl-1H-1,4-benzodiazepine according to the above procedure, in which cheap and easily available starting substances are used, is obtained in excellent yields.

7-chloro-2,3-dihydro-1-methyl-5-o-trifluoromethylphenyl-1H-1,4-benzodiazepine is a known compound, but its pharmacological effectiveness is not yet known has been described.

In those performed in connection with the present invention Animal experiments with mice have shown that the close to the invention Process produced compound valuable calming and antispasmodic effects exercises as shown in the table below. In this table are the activity and the toxicity as ED50. and LD50 value indicated. With the antipentetrazole test (Pentametbylene-1,5-tetrazole, Cardiazole) has been shown to be the one in question Compound offers protection against those caused by administration of pentotrazole Convulsive states.

Antipentotazole test ED50 LD50 mg / kg mg / kg i.v. oral 7-chloro-2,3-dihydro-1-methyl-5-o-trifluoromethylphenyl-1H-1,4-benzodiazepine 0.85 65 1 10 The invention will now be illustrated by the following examples explained in more detail0 Example 1 a) N-o-Trifluoromethylbenzoyl-aziridine.

100 g of o-trifluoromethylbenzoyl chloride was added dropwise with stirring added aziridine to a mixture of 3 aziridine in the course of 1 h at -5 - 0 ° C. after finished The addition was stirred for a further hour, then the organic phase was separated off and the aqueous layer extracted once with 125 cc of methylene chloride.

The combined organic phases were saturated with aqueous NaCl solution, dried over BaOH and evaporated in vacuo. It left behind 102 g of N-o-trifluoromethylbenzoyl "aziridine, that is sufficient for the further reaction was pure.

b) N-methyl-N-p-chlorophenyl-N'-o-trifluoromethylbenzoylethylenediamine.

A mixture of 102 g of N-o-trifluoromethylbenzoylaziridine, 67.3 g of N-methyl-p-chloroaniline and 420 cm3 of isopropanol was refluxed for 24 h. When cooling down at 40, the crystallization began and after the addition of 420 cm³ of water was the Precipitation ended. The precipitate was filtered off with aqueous isopropanol (80 cm3 isopropanol and 120 cm3 water) and dried. Yield 145 g, Mp 106-108.5 ° C. The compound was sufficiently pure for further implementation. After recrystallization from isopropanol, the Pp rose to 108-109 ° C.

c) 7-chloro-2,3-dihydro-imethyl-5-o-trtiluomethylphenyl-1H-1,4-benzodiazepine.

A mixture of 143 g of N-methyl-n-p-chlorophenyl-N'-otrifluoromethylbenzoyl-ethylenediamine, 280 cm 3 of phosphorus oxychloride and 72 g of phosphorus pentoxide were refluxed for 45 minutes heated. After cooling it was the reaction mixture into a mixture poured out of 280 cm³ of concentrated hydrochloric acid and ice water. It became enough Ice added to keep the temperature below 10 ° C. The hydrochloride fell Addition of 280 g NaCl completely finished. It was stirred for 1 hour and then the hydrochloride filtered off and washed with aqueous saturated NaCl solution. In wet hydrochloride was dissolved in 560 cm³ of methanol and treated with 25% aqueous ammonia until the color of the solution changed to yellow. The base was made by adding 850 cm³ Water precipitated, filtered off, washed with water and dried; Yield 122 g, pp 96-97 ° C.

Example 2 7-chloro-2,3-dihydro-1-methyl-5-o-trifluoromethylphenyl-1H-1,4-benzodiazepine hydrochloride.

A mixture of 6 g of N-methyl-p-chloroaniline and 9.2 g of crude N-o-trifluoromethylbenzoyl-aziridine was heated on the steam bath for 16 h. then 25 cc became phosphorus oxychloride and 6 g of phosphorus pentoxide were added and the reaction mixture was refluxed for 30 min heated to boiling. After evaporation to dryness under reduced pressure it was used the residue is stirred with ice water and the pH sert by adding 2N sodium hydroxide solution set to 8.0. The compound was extracted with diethyl ether, the essential Solution dried over MgSO4 and evaporated. There remained 13 g of 7-chloro-2,3-dihydro-1-methyl-5-o-trifluoromethylphenyl-1H-1,4-benzodiazepine, which crystallized out when left to stand. The compound was dissolved in 20 cm3 of methanol dissolved and the solution was treated with 4 cm³ of 10N methanolic hydrochloric acid. The hydrochloride 7-chloro-2,3-dihydro-1-methyl-5-o-trifluoromethylphenyl-1H-1,4-benzodiazepine was precipitated by adding ether, filtered off with diethyl ether washed and dried.

Yield 10.9 g, mp 267 ° C (dec.).

Claims

Claims (2)

P a t e n t a n s p r ü c h e 1. Process for the preparation of 7-chloro-2,3-dihydro-1-methyl-5-o-triBluoromethylphenyl-1H-1,4-benzodiazepine, as a result, N-methyl-p-chloroaniline is used in a first process stage with N-o-TriBluormethylbenzoylaziridin reacted with heating and in a second Stage the obtained, crude N-methyl-N-p-chlorophenyl-N'-o-trifluoromethylbenzoyl-ethylenediamine containing reaction mixture in the presence of a condensing agent such as phosphorus oxychloride and / or phosphorus pentoxide or polyphosphoric acid further heated and finally the 7-chloro-2,3-dihydro-1-methyl-5-o-trifluoromethylphenyl-1H-1,4-benzodiazepine formed under the ring ala such or isolated in the form of its acid addition salts. 2. N-methyl-N-p-chlorophenyl-N'-o-trifluoromethylbenzoyl ethylenediamine.