NZ210740A

NZ210740A - A process for the preparation of a cyanoethylated benzodiazepine

Info

Publication number: NZ210740A
Application number: NZ210740A
Authority: NZ
Inventors: L H Schlager
Original assignee: Gerot Pharmazeutika
Priority date: 1984-01-18
Filing date: 1985-01-04
Publication date: 1987-07-31
Also published as: ES539059A0; ATA15084A; PT79831A; PT79831B; KR910006989B1; KR850005420A; ES8601929A1; NO161672C; NO850189L; NO161672B; AT379391B

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £10740 21074 MO BM'JUIM Priory Date(s): ..l.8.r.h&.^ ^ '' ^irS3 "'•-' -^^osut-^j.^ f-'.'ti.ur.on rv.tr: ....?. I.JUL 190?, *;•..•;/• '"-'.J ~ ;-1- ;J&* NEW ZEALAND PATENTS ACT 19 5 3 COMPLETE SPECIFICATION A PROCESS FOR THE PREPARATION OF CYANOETHYLATED BENZODIAZEPINE WE, GEROT-PHARMAZEUTIKA GESELLSCHAFT m.b.H., a company organised and existing under the laws of Austria, of Arnethgasse 3, A-1171 Vienna XVI, Austria, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement;- •folio wc-ci - lex- 210740 The present invention relates to a new process for preparing cyanoethylated 3-hydroxy-1,4-benzodiazepine-2-ones known as sleeping drugs and showing therapeutical advantages compared with similar preparations. Compounds of the general formula CH2CH2.CN CH— OH (I) , in which is hydrogen, halogen, trifluoroniethyl or nitro and R2 is hydrogen or halogen, are obtained according to the Austrian patent specification 361 492 (and the corresponding British patent specification 2 043 630) by selective cyanoethylation of 3-hydroxy-1,4-benzodiazepine-2-ones of the general formula (II) , in which R1 and R2 are as defined above. The selectivity of the substitution at the NH-group is favoured by the addition of phase transfer catalysts, such as e.g. triethylbenzy1 ammoniumchloride. Without that relatively expensive additive cyanoethylation occurs also at the OH-group, resulting in the necessity to separate mono- and disub-stitution products as well as in a reduction of yield. The starting compounds of general formula (II) are obtained usually by saponification of the corresponding O—acyl 210 ."A W - 2 - precursors of the general formula tH—O.Acyl (III) , in which and R£ are as defined above and Acyl represents any acyl group, in which compounds the position 3 is protected by the acyl group against cyanoethylation. According to the invention the sleeping drugs of general formula (I) may be obtained in a single-step process already from these O-acyl precursors of formula (III) by reacting these O-acyl derivatives (III) without use of a phase transfer catalyst with compounds of the general formula ch. -CH- I y -cn (IV) , in which X is a reactive radical, such as e.g. a halogen atom or the sulfonyloxy group and Y is hydrogen or in which X together with Y represent a second atomic bond in basic medium and immediately subsequently saponifying by alkaline means the new intermediates of general formula CH -.CH-,. CN O.Acyl (V) , in which R 1 ' R2 and Acyl are as defined above. Thus, the compounds of general formula (I) may be obtained by a step-saving process and in good yield. That means, that instead of the known process comprising two steps V 210740 - 3 - III >11 (Journ. Org. Chem. 27, 1691 (1962)) and II >1 (Austrian patent specification 361 492) the single step reaction III >(V) >1 may be performed now having the additional advantages to operate with equivalent amounts of the reaction component (IV) and to be easier in technical respect and to be practically harmless for the environment. The process of the invention is surprising inasmuch as the relative rate of the two reactions proceeding in the basic medium- (canoethylation and saponification resp.) could not be expected. Also the resistance of the cyano group in the intermediate (V) against an additional saponification could not be foreseen. The following examples illustrate the invention without limiting it thereto. Example 1:1 ml of aerylonitrile and then dropwise 3 ml of 1N NaOH are added with stirring to a suspension of 5 g of 7-chloro-3-acetoxy~5-(2'-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzo-diazepine-2-one in 20 ml of acetone and 10 ml of distilled water at room temperature. At the thin layer chromatogram (silicagel 60F 254, developer: toluene/ethanol/NH^OH 25 % = 70 : 30 : 1,5) a sample of the mixture stirred over night shows a substantially complete conversion to the 1-(2-cyanoethyl)-7-chloro-3-acetoxy-5-(2'-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, a small portion thereof being already saponified to the 1-(2-cyanoethyl)-7-chloro-3-hydroxy-5-(2'-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one. The dropwise addition of 14 ml of 1N NaOH to the mixture further stirred at room temperature results in a completion of the saponification within 5 hours. Then gradually 16 ml of IN HC1 are dropped thereto, it is stirred for a further hour, the mixture is left to stand over night at 4°C, then it is sucked off and washed with water and isopropanol. The 1-(2-cyanoethyl)-7-chloro-3-hydroxy-5-(2'-fluoro-phenyl) -1,3-dihydro-2H-1,4-benzodiazepine-2-one thus obtained has after drying a weight of 4,8 g (93 % of theory) and melts after recrystallization from acetone or methanol at 190 to 193°C. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> t v I 210740 - 4 - Example 2: The cyanoethylated intermediate may be obtained in pure state e.g. as follows: 2 drops of a 40 % methanolic solution of benzyltrime-thyl-ammoniuni-hydroxide ("Triton B"-solution) are added to a stirred suspension of 5 g of 7-chloro-3-acetoxy-5-(2'-fluoro-phenyl) -1,3-dihydro-2H-1,4-benzodiazepine-2-one in 20 ml of acrylonitrile. At the thin layer chromatogram (silicagel 6OF 254, developer: chloroform/methanol 9 : 1) a sample of the mixture stirred over night shows a substantially complete conversion to the 1 -(2-cyanoethyl)-7-chloro-3-acetoxy-5-(2'-fluoro-phenyl)-1,3-dihydro-2H-1 ,4-benzodiazepine-2-one. The suspension is diluted with petroleum ether, left to stand several hours at 4°C, and then it is sucked off and washed with some isopropa-nol. Yield 5,4 g (93,7 %). After recrystallization from methanol the product melts at 200 to 202°C. - 5 - 210740 WHAT WE CLAIM IS: 1. A process for preparing cyanoethylated 3-hydroxy- 1,4-benzodiazepine-2-ones of the general formula ch2ch2.cn ch—oh (I) , in which. is hydrogen, .halogen, trifluoromethyl or nitro and and R2 is hydrogen or halogen, comprising the reaction of 3-acyl-1,4-benzodiazepine-2-ones of the general formula H N • COv £h—O.Acyl (III), in which and R£ are as defined above and Acyl represents any acyl group, with compounds of the general formula CH. -CH- I Y -CN in which X is (IV) , a halogen atom or the sulfonyloxy group and Y is hydrogen or in which X together with Y represent a second atomic bond in basic medium and immediately subsequently alkaline saponification of the intermediates of general formula W:' "V-**"'-- > .. * —'7* R. - 6 - CH0CH-.CN I 2 2 CO H—0.Acyl R, 2 10/40 (V) , in which R1, R2 and Acyl are as defined above. -PH^RMAZEUTIKA GESELLSCHAFT m.b.H. .r/Attorneys, SOU, & CAREY. </div>