Patent GB-1347375-A (GB)
Title: Phenylalanine derivatives and a process for the manufacture thereof
IPC: C07F5/04
Filed: 1971-10-29
Abstract: 1347375 Phenylalanine derivatives F HOFFMANN-LA ROCHE & CO AG 29 Oct 1971 [30 Oct 1970] 50335/71 Heading C2C [Also in Division A5] Novel compounds of Formula I: wherein R 1  represents a hydroxy group or an alkoxy group which may be alkenyl-, alkynyl- or phenyl-substituted, R 2  represents a hydrogen atom, a phenyl group or an alkyl group which may be alkenyl- or alkynyl-substituted, R 3  represents a hydrogen atom, an alkanoyl group which may be substituted by alkoxy or by phenyl which may be alkoxy- or halo-substituted, a benzoyl group which may be alkoxy- or halo-substituted, an alkenoyl group, an alkynoyl group, an alkoxycarbonyl group which may be phenyl-substituted, an aminocarbonyl group which may be alkyl-substituted or a phenyl-thio group which may be nitro-substituted and R 4  represents an alkanoyl group which may be substituted by alkoxy or by phenyl which may be alkoxy- or halo-substituted, a benzoyl group which may be alkoxy- or halo-substituted, an alkenoyl group, an alkynoyl group, an alkoxycarbonyl group, an aminocarbonyl group which may be alkyl-substituted, an alkylsulphonyl group, an alkoxymethyl group or an alkyl group which is substituted by alkenyl, alkynyl, alkoxyalkyl, cyano, carboxy, alkoxycarbonyl (which may be alkenyl-, alkynyl- or phenylsubstituted) or aminocarbonyl (which may be alkyl-substituted) and wherein aliphatic groups R 1  to R 4  or aliphatic portions of the groups R 1  to R 4  each contain up to 18 carbon atoms, provided that R 3  has a significance different from R 4 , and with the proviso that when R 1  is hydroxy, R 2  is hydrogen, and R 3  is hydrogen or acetyl, R 4  is not acetyl, and salts thereof are prepared by one of the following methods: (a) a compound of formula wherein R 1  is a hydroxy group when R 3  represents a hydrogen atom, or a salt thereof, after protection of an -NHR 2  group which may be present by complex-formation with a copper (II) salt, with an agent furnishing the group R<SP>1</SP> 4 , wherein R<SP>1</SP> 4  has any of the values accorded to R 4  in claim 1 except carboxyalkyl, and cleaving a copper (II) complex with the aid of an acidic agent, or (b) esterifying a free acid of Formula I wherein R 1  is OH and R 4  is not alkoxymethyl or (c) subjecting an ester of formula wherein R 2  and R 3  have the significance given above, R<SP>1</SP> 1  has any of the values accorded to R 1  above except hydroxy and R<SP>111</SP> 4  represents an alkyl-sulphonyl group, an alkoxymethyl group or an alkyl group which is substituted by alkenyl, alkynyl, alkoxyalkyl, cyano, carboxy, alkoxycarbonyl (which may be alkenyl-, alkyl- or phenyl-substituted) or aminocarbonyl (which may be alkyl-substituted), to a mild basic hydrolysis, or (d) reducing a cinnamic acid derivative of the general Formula V: wherein R<SP>11</SP> 3  is alkanoyl optionally substituted by alkoxy or by phenyl which may be alkoxy- or halo-substituted, a benzoyl group which may be alkoxy- or halo-substituted, an alkenoyl group or an alkynoyl group and R<SP>4</SP> 4  has any of the values accorded to R 4  above except carboxyalkyl or alkoxymethyl, or a salt thereof, or (e) treating a compound of Formula VI: wherein R<SP>5</SP> 4  represents an alkyl group which is substituted by alkenyl, alkynyl, alkoxyalkyl or cyano, with an alkanol which may be phenylsubstituted or with ammonia or with an alkylamine or dialkylamine, or subjecting said isocyanate of Formula VI to a hydrolysis, or (f) subjecting a malonic acid ester of the general Formula VII: wherein R<SP>1</SP> 1  is as R 1  but not OH and R<SP>111</SP> 3  is as R 3  but not nitro-substituted phenylthio and R<SP>6</SP> 4  represents an alkylsulphonyl group or an alkyl group which is substituted by alkenyl, alkynyl, cyano, alkoxycarbonyl (which may be alkenyl-, alkynyl- or phenyl-substituted) or aminocarbonyl (which may be alkyl-substituted), to a hydrolysis and subsequent decarboxylation, or (g) treating a salt of the general formula wherein A is the anion of an acid, under anhydrous conditions with an acid halide or anhydride furnishing the group R<SP>7</SP> 4  wherein R<SP>7</SP> 4  represents an alkanol group which may be substituted by alkoxy or by phenyl which may be alkoxy- or halo-substituted, a benzoyl group which may be alkoxy- or halo-substituted, an alkenoyl group, an alkynoyl group, an alkoxycarbonyl group which may be phenyl-substituted, an aminocarbonyl group which may be alkyl-substituted or an alkylsulphonyl group, or (h) treating a compound of formula under anhydrous conditions with a Lewis acid, reacting the product obtained with an acid halide or anhydride furnishing the group R<SP>7</SP> 4 , wherein R<SP>7</SP> 4  has the significance given earlier, and subjecting the product obtained to a mild hydrolysis, or (k) subjecting to hydrolysis a compound of the general Formula X: wherein R<SP>8</SP> 4  represents an alkyl group which is substituted by alkenyl, alkynyl, alkoxyalkyl, cyano, carboxy, alkoxycarbonyl (which may be alkenyl-, alkynyl- or phenyl-substituted) or aminocarbonyl (which may be alkyl-substituted) and R 5  represents a group of one of the formulµ and, if desired, subjecting a product obtained to one of the following operations: (A) cleavage of a benzyloxycarbonyl group bound to the nitrogen atom by reduction or by treatment with hydrogen bromide or trifluoroacetic acid; (B) cleavage of a t-alkoxycarbonyl group or a nitrosubstituted phenylthio group bound to the nitrogen atom by treatment with an acidic agent; (C) cleavage of an acid group R 3  which is present in a compound of Formula I in which R 4  represents an alkyl group which is substituted by alkenyl, alkynyl, alkoxyalkyl, cyano, carboxy, alkoxycarbonyl (which may be optionally alkenyl-, alkynyl- or phenyl-substituted) or aminocarbonyl (which may be alkyl-substituted) by hydrolysis; and, also if desired, converting a product obtained into a salt; in which formulµ aliphatic groups R 1  to R 4 , R<SP>1</SP> 1 , R<SP>11</SP> 3 , R<SP>111</SP>  3  and R<SP>1</SP> 4  to R<SP>8</SP> 4  or aliphatic portions of the groups R 1  to R 4 , R<SP>1</SP> 1 , R<SP>11</SP> 3 , R<SP>111</SP> 3  and R<SP>1</SP> 4  to R<SP>8</SP> 4  each contain up to 18 carbon atoms. Intermediates are prepared as in Applications Nos. 50330/71 and 50332/71.