SE409861B - A NEW PROCEDURE FOR PREPARING A THERAPEUTIC ACTIVE PYRIDINE ASSOCIATION - Google Patents

Description

n: 7707707-1 which is believed to be useful as an antidepressant, and a preparation thereof, comprising dehydrating an intermediate of Formula B / IIQ II \ \ C | \\ * nH e .m2 N CH3 \ \\ CH3 The main disadvantages of the known method are that the framing of the intermediate is complicated, and involves chemicals which are difficult to handle, such as butyllithium, and that only a low overall yield can be obtained.

The present invention provides a process for the preparation of a compound of the formula I characterized in that a Wittig reagent is prepared according to the following reaction scheme: PhP + BrCHCHBr ---> PhPQCHCHB B9- - 3 2 2 3 2 2 FP 'f G) 9 [PhBP CH2CH2B1¶ Br + 2HN (CH3) 2 ___; [Ph3 | = ® (_: I- | ZCHZN (CH3) Z] 5,9 + G §3 + (cH3J2NH2er where Ph represents Phenyl, and reacted with 4-bromo-Phenyl-3-pyridyl ketone ~ in the presence of sodium methylate according to : 77077074 Ph gt: C e Br / 3 H2 H2N [CH3] 2 Br + NaÜCH3 + I, / I _- \ i, \ / \ N u? (III) Qíf) The latter reaction is conveniently carried out in a solvent such as dimethyltormamide, hexamethyl ¥ osFortriamide or dimethyl sulfoxide.

The new method of preparing the wittig reagent has surprisingly been found to be functional and is technically cumbersome. A further advantage of the new process is that the simple reagent sodium methylate can be used as a base instead of butyllithium which is often used in similar reactions. Butyllithium is, as mentioned, difficult to handle and should if possible be avoided in production on a technical scale due to its strong reactivity, which b1.a. may cause self-ignition.

A hese-related therapeutically active compound having the formula VI can be obtained by replacing the dimethylamine with monomethylamine in the preparation of the wittig reagent.

The therapeutically active final compound I as well as the related compound VI exist in two stereoisomeric forms, a Z-form and an * E-worm according to the IUPAC nomenclature. The preferred isomer of each compound is the Z isomer. which has, for compound I, the configuration H / kcH-N / CHB NH The preferred isomer can be obtained by isolation from a 3 isomer mixture of the final compound I.

The invention is further illustrated by the following examples: Step 1. Preparation of [Ph3PCH2CH2Br] BOTH A mixture of triphenylphosphine [26.2 g, Dl minor and 1,2-dibromoethane (1B, 8 g, D, 1 mol] in xylene (40 ml] was boiled gently for about two hours. A precipitate formed during this time. After cooling to room temperature, the mixture was filtered and the crystals were washed with xylene to give 29.2 g (55%) of the product. C) Step 2. Preparation of [Ph3PCH2CH2NMe2] Br A solution of 2-bromomethylenetriphenylphosphonium bromide {13.5 g, D, D3 mol] in acetonitrile (2DD ml] was treated in the cold with dimethylamine (ZD g, D, 44 mol) in 50 ml of acetonitrile. temperature overnight and Filtered, the crystals were washed with acetone to give the product, mp ZDD-ZDBÜC.

Step 3. N, N-Dimethyl-3- [4-bromo-phenyl] -3- (3-pyridyl) -alylamine-dihydrochloride To D, 14 g (2.5 mmol) of sodium methylate in 1 ml of dimethyl-ormamide was added a suspension of 1.4 g (2.5 mmol) of dimethylaminoethyltriphenylphosphonium bromide in 2 ml of dimethylformamide. After stirring for a few minutes, D, B5 g (2.5 mmol] of 3-pyridyl-4-bromophenyl ketone in 2 ml of dimethylformamide were added. A brown solution formed. The mixture was stirred at 7 DEG-707 DEG C. at room temperature overnight and poured. The oily number was extracted with ether and the ether phase was washed with water and evaporated. The residue was stirred with ether / petroleum ether 1: 2 and triphenyltosphine oxide crystallized. The crystals were filtered off and the mother liquor was evaporated. The residue was extracted with ), and to the hexane solution was added 1 ml of concentrated hydrochloric acid.

Two axes were formed. A 1: 1 mixture of ethanol / ether was added dropwise until a homogeneous phase was obtained. The product then crystallized, and after cooling, 0.3 g (about 30%) of it was isolated. M.p. 178-19200. This product did not lower the melting point when mixed with an authentic sample. The NMR spectrum was identical to the spectrum of an authentic sample.

According to a modified embodiment of dry thawing, the compounds of formula I and VI above can be prepared by the following reaction route: CH / 3 @ Q HN \ R || ~ | / CH3 9 [Phsp CHzCHZÜPh] B ”'__'" -> PhsPæ-CH-CHZN of _ \ R baS / DHS ---> Ph3r == cH-cH2N \; R * CH Br Ph P = cH-cH N / 3 + / '3 2 \ l ----> R \ N fi o (111) Br' ”1 ---- § \\ + Ph3PD" ïï cH 'I CHZ i / \'. ena R. ... w- 7707707-1 wherein R represents methyl or hydrogen.

According to a further, modified embodiment of the invention, the compound of formula VII can be prepared according to the following reaction route: - Br se e / [Phae CHZCHZUH] Br + Kl Q -Eï-e - c H (III) Br '_ / n lll \ - N (/) CH3 R (v: (VII) wherein X is a leaving group selected from the halogens such as Cl, or Br, methylsulfonyl and toluenesulfonyl, introduced by reacting the compound of Formula IV with a halogenating agents such as HCl, HBr, PBr3.

PCl3, SUZIZ, PCl5 or methylsulfonyl or toluenesulfonic acid and wherein R is as defined above.

Claims (4)

7707707-'1 7 The intermediate of formula IV and its acid addition salts are new. While they are advantageous over prior art processes for the preparation of the compound of formula I, the above modified processes do not all have the advantages of the original process of the present invention. fatentkrav A novel process for the preparation of therapeutically useful compounds of the formula Br, a? * \\ 'll H VII H 2 \\ R Z'_C "J _ (' J == ('J / CH3 wherein R is methyl or hydrogen , a pure geometric isomer thereof, or a therapeutically acceptable salt of said compound or isomer, it is known, etc., that a Wittig reagent is prepared according to the following reaction scheme: PhBP + src fi zcnzx -> 1PhaF fl cHezcHzxjarg, Ph + 2HN ---> \ R CH R ae --->. Ph3P @ cH2cH2N \ B19 +> NH2xO R CH3 7787707 - 1 'B where Ph represents a phenyl group, X represents Br or ÜPh and R is as defined above, and was reacted with 4-bromophenyl-3-pyridyl ketone either directly in the presence of sodium methylate according to the following reaction scheme: @ w Bryn f. e Ph PCH CH r Br + manen + = I. _____> 3. 2 2 »3 ä; /, ¿> \ V '. \\ R re' ^ \\ _ a, / \ / N, C "n 0 (111) Hr. \ ', Y / ß \ /. \ __-___ åNaBr + cH3uH + \\ I \ \ Ü + Ph3Pu fi t fi CH3 / cH2N \ .f <(V11) or post-conversion under the influence of a base to a Wittig reagent according to the formula CH / Ph3P-CH-CH2M \ R 3 A process according to claim 1, characterized in that X represents Br and that the final product is Prepared according to the scheme - B // / f CH E \ {;:; U I ______; e 3 Ph3PcH CH N '/ B69 + NancH3 + \ * \\\ \\ 2 2 \\ R H Ü 7707707-1 ---- 7 NaBr + CH3ÜH + + Ph3PÜ_e (VII) A process according to claim 1 or 2, characterized in that the last reaction step is carried out in an organic solvent such as dimethylformamide, hexamethylphosphoric triamide or dimethylsuloxide. A process according to any one of claims 1-3, characterized by the use of starting materials which give a compound of the formula Br I '| f / Axlï ål /// QÉ / I fi ICH cH k 2 / CHQ \\ cH3 PRESENTED PUBLICATIONS: Organic reactions. Editorial board A C Cope, editor-in-chief, R Adams ... Vol. 14. New York 1965, pp. 270-490 (The wittig reaction) .-