CS195682B2 - Process for preparing new derivatives of phenylglycine - Google Patents

Description

The present invention relates to a method of the invention; new amino acids. In particular, it relates to amino acids which are suitable for introducing side chains into position 7 of cephalosporin antibiotics and to a process for their preparation.

To date, a large number of cephalosporin compounds have been produced. However, only a few of these compounds are practically used and there remains a need to find new, practically useful cephalosporin antibiotics.

After extensive study, it has now been found that cephalosporin compounds which contain the acylamino group of formula (A) at the 7-position.

CH-CONH '(AJ where

R 1 represents a hydrogen atom or a hydroxy group,

R2 is C1-C6 lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl),

R 3 is hydrogen or C 1 -C 6 alkanesulfonyl (for example, methanesulfonyl, ethanesulfonyl, and

Y represents a group of formula -SO2- or -NHSO2, where R5 represents hydrogen when Y represents a group of formula -NHSO2-, show a strong antimicrobial effect against a wide variety of microorganisms, including gram-positive and gram-negative bacteria. It is particularly noteworthy that in some species of pathogenic microorganisms, their antimicrobial activity is superior to that of cephalexin, which is one of the well known cephalosporin antibiotics. It is also noteworthy that when administered orally to mammals, their antibiotic effect is maintained at a high level for a long time. Therefore, they are useful as long-acting antibiotics that can be orally administered. The amino acids of formula (I) used to introduce the acylamino group of formula (A) at position 7 of the cephalosporin nucleus can be represented by formula (I).

CH’COOH

Κ <IJ where

R1, R2, R1 and Y are as defined above.

When R @ 1 is lower alkanesulfonyl, R @ 2 --Y-- is as defined.

The present invention relates to a process for the preparation of amino acids of the formula I and their derivatives

The term "derivative" is used herein in the broader sense. 'Derivatives' include any modified forms of amino acids of formula I which are used to increase the reactivity of a carboxyl group (i.e., reactive derivatives) or which are used to protect the carboxyl group and / or the .alpha.-amino group of these compounds from the effects of any Examples of carboxy-modified derivatives include salts, ethers, halides, amides, anhydrides, etc. Examples of altered-amine derivatives include salts, acylamino compounds, Schiff bases, etc. ,

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of novel phenylglycine derivatives of the formula I and derivatives thereof with a modified carboxy group, for example salts and / or a modified N-amino group, for example N-C 1 -C 6 alkoxycarbonyl- or N-C 1 -C 6 alkoxycarbones. leaving a compound of formula II

CH-COOH where (H)

R1 is as hereinbefore defined, in free form or with a protected carboxy and / or N-amino group, to react with an acylating agent of formula III

R 2 -Y-Z (H 1) wherein

Z represents halogen and

R2 and Y are as defined above.

When the N-amino group is protected, one or two of its hydrogen atoms may be replaced by, for example, acyl groups, such as a substituted or unsubstituted benzyloxycarbonyl group (e.g., benzyloxycarbonyl-,

4-nitrobenzoyloxycarbonyl-,

4-bromobenzyloxycarbonyl-, 4-methoxybenzyloxycarbonyl-,

3,4- dimeoxyberisyloxycarbonyl- ,, · ..

4- (phenylazo) benzyloxycarbonyl-,

4- (4-methoxyphenylazo) benzyloxycarbones (1),

substituted or unsubstituted alkoxycarbonyl- or cycloalkoxycarbonyl- [e.g., tert-butoxycarbonyl-, t -pentyloxycarbonyl-, isopropoxycarbonyl-, diphenylmethoxycarbonyl-,

2-pyridylmethoxycarbonyl-,

2.2.2- trichloroethoxycarbonyl-

2.2.2- Tribromoethoxycarbonyl-

1-cyclopropetylethoxycarbonyl-,

3-iodopropoxycarbonyl-,

2-furfuryloxycarbonyl-

1-adamantyloxycarbonyl], (heter ocyclyl J oxycarbonyl [e.g.

8-quinolyloxycarbonyl], or substituted alkanoyl [for example trifluoroacetyl J, trityl, trialkylsilyl [for example trimethylsilyl, triethylsilyl]], substituted phenylthio [for example].

2-nitrophenylthio-

2,4-dlnitrophenylthio], and d. The N-amino group may also be protected in the form of a Schiff base, in which case its two hydrogen atoms are replaced by a substituted alkylidene group [e.g.

2-hydroxybenzylidene-

2-hydroxy-5;

2-hydroxy-1-naphthylmethylene-

3-hydroxy-4-pyridylmethylene-, 1-methoxycarbonyl-2-propylldene-, 1-ethoxycarbonyl-2-propylidene-,

3-ethoxycarbonyl-2-butylidene-, 1-acetyl-2-propylidene-, 1-propionyl-2-butylidene-, 1-acetyl-2-propylidene-, 1-proplonyl-2-propylidene-, 1-benzoyl-2 -pr opyliden,

1,3-bis (ethoxycarbonyl) -2-propylidene-

1,3-bis (ethoxycarbonyl) -2-propylidene- (N-methylcarbamoyl) -2-propylidene,

1- (Ν, Ν-dimethylcarbamoyl) -2-propylidene-

1- [N- (2-methoxyphenyl) carbamoyl] -2-propylidene,

1- [N- (4-Methoxyphenyl) carbamoyl] -2-propylidene-

5 98 2

WITH

1- (N-Phenylcarbamoyl) -2-propylidene-

2-ethoxycarbonylcyclopentylidene-, 2-ethoxycarbonylcyclohexylidene-, 2-acetoxycyclohexylidene,

3,3-dimethyl-5-oxocyclohexylide] or the like.

The .alpha.-amino group may be further protected in the form of an acid addition salt, e.g. in the form of hydrochloride, hydrobromide, hydroiodide and the like.

The carboxyl group may be protected by any conventional protecting group. Of the protected carboxy groups, silylated carboxyl groups are preferably used. Silyl esters can be obtained by reaction with a silylating agent such as trialkyl halogensilane, dialkyl halogensilane.

alkyltrihalogensilane, hexaalkylcyclotrisilazane,;

octaalkylcyclotetrasilazane, trialkylsilylacetamide or;

bis (trialkylsilyl) acetamide.

Another possibility is the simultaneous protection of the α-amino group and the carboxyl group, for example in the form of a chelate using a chelating metal compound. Examples of metal compounds include any compound that can form a chelating bond with α-amino and carboxy groups, such as organic and inorganic copper, cobalt, nickel, and magnesium compounds: Specific examples include copper chloride, nitrate , sulfate, borane ,. phosphate, cyanide, formate, acetate, propionate, citrate, tartrate, benzoate, copper salicylate.

The reaction is conveniently carried out in an inert solvent. Examples of inert solvents include acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine, etc. When the solvent is water miscible, it can be used as a mixture with water. There is no particular limitation on the reaction temperature, in most cases the reaction may be carried out with cooling or at room temperature.

If the prepared amino acid of the formula I contains protecting groups, these groups can be cleaved in a known manner, whereby the product can first be &quot; optionally isolated &quot; or purified.

One typical way of cleavage of the α-amino protecting group is by acid decomposition. This method is generally applied to such groups as benzyloxycarbonyl-, substituted benzyloxycarbonyl-, substituted or unsubstituted alkoxycarbonyl-, substituted or unsubstituted aryloxycarbonyl-, adamantyloxy-, trityl-, substituted phenylthio-, substituted aralkylidene, substituted alkylidene-, substituted alkylidene-, substituted- Various substances can be used as acids, in particular those which can be easily distilled off under reduced pressure (for example, formic acid or trifluoroacetic acid) are preferred. The cleavage is sometimes carried out in an inert solvent, usually an organic solvent that is miscible with water or a mixture thereof.

Another typical procedure is. a catalytic reduction conventionally used in the case of substituted or unsubstituted benzyloxycarbonyl-. ^: 2-pyridylmethoxycarbonyl appd. The palladium catalyst is most commonly used, but any other catalyst may also be used.

Other typical processes include hydrolysis, which can be used for trifluoroacetyl, a reaction with a heavy metal (e.g., copper or zinc) in which it can be used for haloalkoxycarbonyl and -8-quinolyloxycarbonyl.

When the .alpha.-amino group is protected in the form of an acid addition salt, the cleavage can be carried out by treatment with an organic base (for example, trimethylamine, triethylamine, N-methylpiperazine, Ν, Ν-dimethylaniline or pyridine) or inorganic. bases (e.g. sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate or ammonium carbonate).

If the α-amino group together with the carboxy group is protected in the form of a chelate, the removal of the metal compound used to form the chelate can be carried out in a conventional manner, for example by treatment with hydrogen sulfide or an ion exchange resin.

The elimination of the silyl ester group ppi releasing the carboxy group is very easily carried out in the presence of water. For example, when a reaction mixture containing an amino acid of formula I in which a carboxy group is protected by forming a silyl ester is treated in the presence of water, the silyl group is readily cleaved. Therefore, it is usually not necessary to cleave the silyl group in a separate step.

When the carboxy group is protected in any manner other than by forming a sllyl ester, the deprotection of the protecting group may be accomplished by any conventional means.

How. however, the amino acid of the formula I is suitable for introducing the acylamino group into the 7-cephalosporin compound position and, if it is to be used in this way, it is usually not necessary to remove the α-amino protecting group.

The amino group of formula (I) may be present in the form of the D-isomer or the L-Isomer, or in racemic form. When obtained in racemic form, the racemate can be resolved at any stage of production.

The following examples serve to illustrate the invention in more detail, but do not limit the scope of the invention in any way.

195882

He did

I (1)

N-tert-butoxycarbonyl-2- (3-aminophenyl) -D-glycine (8.7 g) and N-trimethylsilylacetamide (13.1 g) were added to methylene chloride (166 ml) and the resulting mixture was stirred for 1.5 hours. at room temperature. To the resulting mixture was added dropwise pyridine (13.1 g) under ice-cooling, and then a solution of methanesulfonyl chloride (8.45 g) in methylene chloride (35 ml) was added dropwise at a temperature of 3-5 ° C. The reaction mixture was stirred at the same temperature for thirty minutes and then at room temperature for four hours. The reaction mixture was shaken with an aqueous citric acid solution, washed with water, and then the methylene chloride layer was separated. The methylene chloride layer was shaken with 5% aqueous sodium bicarbonate and the aqueous layer was separated. The aqueous layer was adjusted to pH 5 with aqueous citric acid and salted out _; resinous substance. The resin was extracted with methylene chloride, the extract was washed with dilute aqueous sodium chloride solution, dried and concentrated in vacuo. Ntorc, butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine (6.3 g) was obtained as an amorphous powder.

NMR (DMSO-dB) <5 ppm ·:. - '

1.38 (9H, s);

2.99 (3 H, s),

5.09 (1H, d, J = 7.5Hz),

7.00-7.60 (4 H, m).

(2).

The thus prepared N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine (4.0 g) was dissolved in formic acid (100 ml), the solution was stirred at room temperature for one hour, and then the solvent was distilled off under reduced pressure. Dissolve in 10% aqueous acetonitrile (10 mL) and filter, acetonitrile (10 mL) is added to the filtrate, and the precipitated crystals are collected by filtration and dried to give 2- (3-mesylaminophenyl) -D-glycine (2). (7) in the form of colorless chips.

Melting point 196-198 ° C.

IC (nujol)

W ppm:

3240,2580,1616,1147.

NMR (D 2 O-DCI) δppm:

3.18 (3H, s);

5.32 (1H s),

7.47 (4H, m).

Example 2

Using the procedure described in Example 1, the sodium salt of D-N- (3-mesylaminophenyl) -N- (1-methoxycarbonyl-1-propen-2-yl) glycine ^; by reacting D - (N - 3-aminophenyl) -N- (1-methoxycarbonyl-1-propyn-2-yl) glycine sodium salt with methanesulfonyl chloride.

M.p. 141-143 ° C. '

IC. ^? (nujol) in cm ^-1 : '

3250, 1650, 1610, 1150. ' '’

NMR (DMSO-d 6).

. í ppm:

1.68 (3H, s).

2.92 (3 H, s),

3.52 (3 H, s),

4.31 (1 H, s),

4.78 (1H, d, J = 5.6 Hz),

6.90-7.25 (4H, ia,

9.58 (1H, d, I = 5.6Hz).

Example 3

To a solution of D- (3-aminophenyl) -N-tert-butoxycarbonyl glycol (1.34 g) and sodium bicarbonate (924 mg) in water (25 mL) cooled to -2 ° C was added methanesulfonyl chloride dropwise over ten minutes. (860 mg) and the resulting mixture was stirred at the same temperature for one hour. Sodium bicarbonate (164 mg) was then added and the mixture was further stirred at the same temperature for two hours and then at room temperature for one hour. The reaction mixture was washed twice with ether (30 times each) and traces of insoluble matter were filtered off. The pH of the filtrate was adjusted to 3.0 with 10% hydrochloric acid, and the product was salted out and extracted twice with ethyl acetate (40 ml each). The extract was washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. and concentrated under reduced pressure. Α- (3-mesylaminophenyl) -N-tert-butoxycarbonylglycine (1.4 g) was obtained. [Α] D = -96 ° (hiethanol, c = 1).

Example 4 (1)

To a solution of N-tert-butoxycarbonyl-2- (3-aminophenyl) -D-glycine (5.325 g in methylene chloride (100 mL)) was added N, N, N, bS (trimethylsilyl) acetamide (8) at room temperature with stirring. 20 g) The mixture was stirred at room temperature for one hour, then pyridine (3.165 g) was added under ice-cooling (to 2 to -B 4 C), followed by the dropwise addition of a solution of methanesulfone chloride over 30 minutes under ice-cooling. (4.58 g) in methylene chloride (25 ml), the mixture was stirred for thirty minutes under ice-cooling and then at room temperature for three hours, the reaction mixture was concentrated under reduced pressure and the residue was shaken with ethyl acetate (100 ml) and 2M. citric acid solution (50 mL) The ethyl acetate layer was separated and washed with 2 M citric acid solution (50 mL). The wash was extracted with ethyl acetate (30 mL): The extract was combined with the ethyl acetate layer and the mixture was washed with saturated aqueous sodium chloride solution. and three times extr The extracts were combined, washed with ethyl acetate (50 mL), adjusted to pH 4 with a 2 M citric acid solution, and then salted with sodium chloride. The precipitate was extracted four times with ether (50 mL). The extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give N-tert-butoxycarbonyl-2-mesylaminophenyl) -D-glycine (6.15 g) as a powder.

NMR (DMSO-d6) &gt;

• 5 ppm: 1, <40 (9H, s).

3.00 (3H, s),.

5.11 (1H, d, J = 8Hz);

7.00-7.60 (5 H, m). / (2), - ·

2- (3-Mesylaminophenyl) -D-glycine was obtained from the N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine thus obtained as described in Example 1 (2).

Example 5

D-2- (3-aminophenyl) glycine (16.6 g) was dissolved in N sodium hydroxide solution (100 ml) and dioxane (40 ml) was added. To the resulting solution was added a solution of copper sulfate pentahydrate (26.2 g) in water (50 mL) at room temperature, and stirring was continued for 40 minutes. The pH of the resulting mixture was adjusted to 7.0 with 20% sodium hydroxide, and then a solution of methanesulfonyl chloride (17.1 g) in dioxane (20 mL) was added dropwise over one hour at 26-28 ° C while adding methanesulfonyl chloride also dropwise. sodium hydroxide solution (47 mL) to maintain the pH of the mixture at 6.0 to 6.5. The reaction mixture was stirred at room temperature for 1 hour and then adjusted to pH 3.0 with 10% hydrochloric acid. After removal of the organic solvent by distillation under reduced pressure, 2R (3-ihesylaminophenyl) -D, -glycellic copper is obtained which is adsorbed onto an ion exchange resin ("Aniberlite TR 120 B", manufactured by Rohm and Haas Co.) and The column is washed with water until the eluate is neutral. Then the ion exchange resin is eluted with dilute aqueous ammonia [water: 30% aqueous ammonia =. 14: 1 (w / w)]. The eluate was concentrated under reduced pressure. The residue was dissolved in a small amount of methanolic hydrochloric acid and the solution was adjusted to pH 5 with methanolic ammonia. The resulting slurry was allowed to stand overnight. The precipitated crystals are filtered off and dried. 2- (3-dimethylaminophenyl) -D-glycine (15.6 g) was obtained as light brown needles. · '·

Melting point: 186.5 - 187'C.

IR.

(nujol). in cm * '·:

. 1605 (broad), 1150. . ^;

NMR-. . . . - (DC1 4 -D 2 O) δ ppm:,. ·

3.17 (3H, s);

5.16 (1 H, s),.

7.43 (4 H, m).

Example.

A solution of methanesulfonyl chloride (27.5 g) in dioxane (27 mL) was added dropwise to the mixture obtained using D-2- (3-amnophenyl) glycine (16.6 g) and copper sulfate pentahydrate (26.2 g) according to the procedure of Example 5. The methanesulfonyl chloride was added at 26-28 ° C for one hour while maintaining the pH at 8-9 by dropwise addition of a 20% sodium hydroxide solution, and the reaction mixture was worked up as described in Example 5. 2- (3-Dimesylaminophenyl) - D-glycine in the form of colorless prisms.

Melting point 171-173 ° C.

IC (nujol ¹ ) in cm ^-1 :

· 1650, 1160,

NMR · (DC1 + D 2 O). Δ ppm: 3.50 (6H, s);

5.33 (1H, s),

7.6i (4H / mj:>)

Example 7 ·.,.

. D- (4-aminophenyl) -N-tert-butoxycarbonylglycine (5 g) and bis (trimethylsilyl) acetamide (11.0 g) in methylene chloride (120 mL) were stirred at room temperature for two hours and then added at room temperature. Pyridine (2.85 g) and a solution of methanesulfonyl chloride (4.12 g) in methylene chloride (40 mL) were stirred at 2-3 ° C for thirty minutes, and the resulting mixture was stirred at the same temperature for thirty minutes and then allowed to stand overnight at After removal of the solvent under reduced pressure, ethyl acetate and 1M citric acid solution were added to the residue, and the ethyl acetate layer was separated and washed with aqueous citric acid solution, and the washings and the aqueous layer were combined and extracted with ethyl acetate. The layers were combined, washed with water and shaken with an aqueous saturated sodium bicarbonate solution, and the aqueous layer was separated, adjusted to pH 4 with 2M citric acid solution, and extracted with EtOAc. The ethyl acetate extract was washed with saturated aqueous sodium chloride solution and dried. The solvent was distilled off under reduced pressure and the resulting oil (6.0 g) was converted to a powder using ether and isopropyl ether; D-α- (4-mesylaminophenyl) -N-tert-butoxycarbonylglycine (5.5 g) was obtained as crystals.

Mp 165-183 ° C.

IR (nujol) υ ^cm-1:.

3325, 3125, 1747, 1673.

NMR · ((CDsbCO) < 5 ppm):

1.32 (9H, s);

2.84 (3 H, s),

5.0 (1 H, d),

6.90-7.3 (4H, m).

Example 8

N-tert-butoxycarbonyl-2- (3-aminophenyl) -D-glycine (3.99 g) and N, N-bis (trimethylsilyl) acetamide (6.12 g) were added to methylene chloride (40 mL). Pyridine (2.4 g) and ethanesulfonyl chloride (3.84 g) were added dropwise under ice-cooling, and the mixture was stirred at 0-5 ° C for two hours. The reaction mixture was washed successively with 2% hydrochloric acid (20 ml each), twice with water (20 ml each) and once with an aqueous saturated sodium chloride solution, and the methylene chloride layer was separated and dried over sodium sulfate. The residue was recrystallized from diisopropyl ether to give Nt-butoxycarbonyl-2- (3-ethanesulfonamidophenyl) -D-glyine (4.4 g) as a powder.

ie (film) ·; · · in cm ^-1 : 3230, 1720 ,. 1680.

NMR (CDCl3). í ppm:

1.18 (3H, t, J = 7.5 Hz),

136 (9H, s).

3.05 (q, J = 7.5Hz)

3.16 (1H, broad s),

7.23 (4 H, s),

7.71 (1H, broad s),

8.59 (1H, broad s).

Example 9

A solution of N- (3-amnophenyl) -N-tert-butoxycarbonylglycine (0.5 g) and bis (trimethylsilyl) acetamide (1.15 g) in methylene chloride (20 mL) was stirred at room temperature for 2 hours and then cooled to 2 ° C. to 3 ^e C. and sec therein dropwise pyridine (0.3 g) and a solution ethylaminosulfonylchloridu (0.54 g) in methylene chloride (6 ml). the resulting mixture was stirred for thirty minutes at the same temperature and then for fifteen hours at room temperature. After removal of the solvent, ethyl acetate and 1M citric acid solution were added to the residue, and the ethyl acetate layer was separated and washed with aqueous citric acid solution, the washings and the aqueous layer were combined, salted and extracted with ethyl acetate. The aqueous layer was separated, washed with ethyl acetate, adjusted to pH 4 with 2M citric acid, and extracted with ethyl acetate. The ethyl acetate extract was washed with an aqueous saturated sodium chloride solution and dried. After removal of the solvent by distillation under reduced pressure, Da- (3-ethylaminosulfonamidophenyl) -N-tert-butoxycarbonylglycine (0.54 g) was obtained in oily form.

IR (film) in cm ^-1 :

3250, 1700 (wide).

NMR (CDCl3)

S ppm:

9.97 (3 H, t),. 1.35 (9H, s);

3.80 (2H, q) &gt;.

5.20 (1H, broad s),

7.20 (4 H, m).

Example 10

To a solution of Da- (3-amino-4-hydroxy-phenyl) -N-tert-butoxycarbonylglycine (8.0 gj in methylene chloride (150 mL) was added bisftrtrimethylsilyl] acetamide (11.5 g) and the resulting solution was stirred at room temperature for After cooling with ice, pyridine (4.5 g) was added to the resulting mixture, and methanesulfonyl chloride (6.5 g) was added dropwise, stirring was continued under ice-cooling for thirty minutes, followed by stirring at room temperature for two hours. After concentrating under reduced pressure, ethyl acetate and water were added to the residue, the mixture was acidified with phosphoric acid and the ethyl acetate layer was separated from the aqueous layer, and the ethyl acetate layer was extracted back into aqueous sodium bicarbonate solution, the aqueous layer separated, acidified with phosphoric acid and reextracted. The ethyl acetate extract was washed with water, dried and treated with charcoal, and the resulting solution was concentrated to give Da- (3-mesylamino-). 4-hydroxyphenyl] -N-tert-butoxycarbonylglycine (6.0 g.

IC (chloroform) in cm ^-1 :

1730 (inflection), 1715.

NMR (D 2 O - NaHCO 3) ppm:

1.4 (PH, s),

3.05 (3H, s).

4.83 (1 H, s),

6.87 (1H, d, J = 8Hz).

Claims (3)

SUBJECT VYNALEZU Process for the preparation of novel phenylglycine derivatives of the general formula I CH-COOH AND NH, (i) where ' R1 is hydrogen or hydroxy; R 2 is C 1 -C 6 alkyl, R 3 is hydrogen or C 1 -C 6 alkanesulfonyl; and Y is -SO 2 - or -NH-SO 2 - wherein R 1 is hydrogen when Y is -NHSO 2, and their modified carboxy derivatives, e.g., salts and / or modified and an amino group, for example an N-C 1 -C 6 alkoxycarbonyl- or N-C 1 -C 6 alkoxycarbonylalkylidene derivative, characterized in that a compound of the general formula II is left in which: R 1 is as defined above, or the corresponding carboxy- and / or α-amino-protected compound is reacted with a compound of formula III / R 2 -Y-Z (ΙΙΓ), wherein: Z represents halogen and R2 and Y are as defined above. 2. A process according to claim 1 for the preparation of compounds of formula I, wherein R1 is hydrogen, R2 is C1-C6 alkyl, R3 is hydrogen and Y is -SO2-, characterized in that the compound of formula II is wherein R 1 is hydrogen and as compounds of formula III, wherein R 2 is C 1 -C 6 alkyl, Y is -SO 2 - and Z is as defined above. 3. The process of claim 2 wherein the reaction is carried out in the presence of a metal compound capable of forming a chelated with substituted phenylglycine, for example in the presence of a copper, nickel, cobalt or magnesium compound.