FI68043B - N-HALOGENACYLPROLINDERIVAT VILKA AER MELLANPRODUKTER VID FRAMSTAELLNING AV THERAPEUTISKT ANVAENDBARA PROLINDERIVAT - Google Patents

Description

1,68043 N-haloacylproline derivatives which are intermediates in the preparation of therapeutically useful proline derivatives 5 Separated by division of patent application No. 770437

The invention relates to compounds which are therapeutically useful proline derivatives in the preparation of intermediates and have the formula 10 wherein 1 is hydroxy or lower alkoxy, R 1 is X- (CH-) -CH-CO-N-COR (V) 15 hydrogen, lower alkyl or phenyl-lower alkyl or phenyl, X is chlorine, bromine or iodine and n is 1 or 2.

Therapeutically useful proline derivatives which can be prepared from the compounds of formula V are the compounds described in FI application 770437 having the general formula 25 - R - S- (CHO) -CH-CO-N-1 -COR (I) wherein R is hydroxy or lower alkoxy, R 1 represents hydrogen, lower alkyl, phenyl-lower alkyl or phenyl, R 2 is hydrogen, lower alkyl, phenyl-lower alkyl, triphenylmethyl or R 1 CO R ,. is lower alkyl, phenyl or phenyl-lower alkyl and n is 1 or 2.

35 2 68043

Compounds of formula (I) in which R 1a represents hydrogen may be prepared, in particular when R 2 is R 1 --CO-, by first coupling an acid or ester of formula (II).

H1S ——— -COR (II) haloalkanoic acid of formula 10 R.

X- (CH-) -CH-COOH (IIIa) 2 n wherein X is halogen, preferably chlorine or bromine. This can be accomplished using any known method in which the acid purple is activated prior to reaction with acid II, comprising the formation of a mixed anhydride, symmetrical anhydride, acid chloride or active ester, or Woodward reagent K, EEDQ (N-ethoxycarbonyl-2-ethoxy). 1,2-dihydroxyquinoline) or a similar use.

The product obtained in this reaction is a compound of the invention of formula I X - (CH2) n - CH - CO - N-1-COR (V). 25 The compound of formula V is reacted with a thioic acid anion of formula r2-sh, (i.e. R2s ~) to give a compound of formula R "- S - (CH_) - CH - CO - N-1 - COR (I) 2 2 n 35 3 68043

When 1 * 2 is R 1 CO, this compound can then be converted to 5 μl HS- (CH 2) n -CH-CO-N-COR (Ia) by ammonolysis.

According to a particularly preferred embodiment, the acid or ester of formula II is acylated with a haloalkanoyl halide of formula t1

X- (CH 2) -CH-COX

& * n wherein each X is independently halogen, preferably chlorine or bromine, R 1 is hydrogen, lower alkyl, phenyl-lower alkyl or phenyl and n is 1 or 2. This reaction is carried out in an alkaline medium, e.g. dilute alkali metal hydroxide solution, alkali metal in a bicarbonate or alkali metal carbonate solution at a reduced temperature, e.g. about 0-15 ° C. The reaction product is also subjected to a substitution reaction using the thio-25 or thioic acid anion described above also in an alkaline medium, preferably an alkali metal carbonate solution, and then treated in a conventional manner. The compound obtained in the reaction in which the substituent R 1 in the formula I is R -CO,

Δ O

is converted to a compound in which R 2 is hydrogen by ammonolysis, e.g. by means of alcoholic ammonia or concentrated ammonium hydroxide solution or by alkaline hydrolysis using e.g. a metal hydroxide solution. When an acid of formula II is used as a starting material, the final product is obtained as a free carboxylic acid, which can then be converted to an ester, e.g. or the like.

4,68043

The following examples illustrate the invention.

Example 1 1- (3-Bromopropionyl) -L-proline L-proline (11.5 g) is dissolved in 100 ml of 1N aqueous sodium hydroxide solution and cooled to 0 ° C. An additional 25 mL of 2N aqueous sodium hydroxide solution is added followed by 17 g of 3-bromopropionyl chloride. The mixture is stirred for 4 hours and during stirring 2N sodium hydroxide (6 ml in total) is added to maintain the pH at about 8. The mixture is extracted with ether (the extract is discarded) and then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated to dryness to give an oily residue which, on trituration with ethyl acetate, gives a crystalline product, m.p. 84-86 ° C.

Example 2 1- (3-Bromo-2-methylpropionyl) -L-proline

To a stirred solution of 5.75 g of L-proline in 50 ml of 1N aqueous sodium hydroxide solution is added 25 ml of 2N sodium hydroxide solution and then 9.28 g of 3-bromo-2-20 methylpropionyl chloride. Stirring is continued for 4 hours, after which the reaction mixture is extracted with ether (the extract is poured off) and acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated to dryness to give an oily residue.

The residue is triturated with a sufficient amount of petroleum ether to dissolve the residue. When allowed to stand in the refrigerator overnight, 2.3 g of product are obtained, m.p. 64-69 ° C.

Claims (2)

N-haloacylproline derivatives which are intermediates useful in the preparation of therapeutically useful proline derivatives described in FI patent application 770437 and having the formula (I) R 2 -S- (CH 2) n -CH-CO-N - COR (I) wherein R is hydroxy or lower alkoxy, R 1 is hydrogen, lower alkyl, phenyl-lower alkyl or phenyl, R 2 is hydrogen, lower alkyl, phenyl-lower alkyl, triphenylmethyl or R 1 CO, where R 1 is lower alkyl, phenyl or phenyl-lower alkyl, and n is 1 or 2, characterized in that these intermediates have the formula (V) X-tCH 2 -CH-CO-N-1-COR (V) wherein R is hydroxy or lower alkoxy, R 1 is hydrogen, lower alkyl, phenyl-lower alkyl or phenyl, X is chlorine, bromine or iodine and n is 1 or 2. N-haloacylproline derivatives according to Claim 1, characterized in that they have the formula X-CH 2 -CH-CO-N-COOH (Vb) in which X is chlorine, bromine or iodine.