Phenylglycines

Phenylglycine analogs, generically represented by 2, have been described and characterized as potentiators of various CFTR mutants (wt, F508del, G551D, G1349D) [49]. Compound 3, the most potent compound 

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On acetylation it gives acetanilide. Nitrated with some decomposition to a mixture of 2-and 4-nitroanilines. It is basic and gives water-soluble salts with mineral acids. Heating aniline sulphate at 190 C gives sulphanilic add. When heated with alkyl chlorides or aliphatic alcohols mono- and di-alkyl derivatives are obtained, e.g. dimethylaniline. Treatment with trichloroethylene gives phenylglycine. With glycerol and sulphuric acid (Skraup s reaction) quinoline is obtained, while quinaldine can be prepared by the reaction between aniline, paraldehyde and hydrochloric acid. 

It is an important dyestuffs intermediate. It condenses with chloroethanoic acid to give phenylglycine-o-carboxylic acid for the synthesis of indigo. It can be diazotized and used as a first component in azo-dyes it condenses also with chloroanthraquinones to give intermediates for anthraquinone dyes. 

It is an important intermediate in the indigo industry. When phenylglycine is fused with sodamide a good yield of indoxyl is obtained. The indoxyl is easily oxidized to indigo. 

Phenylglycine-o-carboxylic acid. In a 750 ml. round-bottomed flask, fitted with a reflux condenser, place 14 g. of anthranilic acid (Section IV,170), 10 g. of chloroacetic acid, 20 g. of anhydrous sodium carbonate and 200 ml. of water. Reflux the mixture for. 3 hours, then pour into a beaker, cool, render shghtly acid with concentrated hy dro-chloric acid, and allow to stand overnight. Filter off the crude acid and wash it with water. Recrystalhse from hot water with the aid of a little decolourising carbon, and dry the acid at 100°. The yield of phenyl-glycine-o-carboxyhc acid, m.p. 208°, is 12 g. 

Chloroacetic acid can be esterified and aminated to provide useful chemical intermediates. Amphoteric agents suitable as shampoos have been synthesized by reaction of sodium chloroacetate with fatty amines (4,5). Reactions with amines (6) such as ammonia, methylamine, and trimethylamine yield glycine [66-40-6J, sarcosine [107-97-17, and carhoxymethyltrimethylammonium chloride, respectively. Reaction with aniline forms /V-phenylglycine [103-01 -5] a starting point for the synthesis of indigo (7). 

Enzymatic Process. Chemically synthesized substrates can be converted to the corresponding amino acids by the catalytic action of an enzyme or the microbial cells as an enzyme source, t - Alanine production from L-aspartic acid, L-aspartic acid production from fumaric acid, L-cysteine production from DL-2-aminothiazoline-4-catboxyhc acid, D-phenylglycine (and D-/> -hydtoxyphenylglycine) production from DL-phenyUiydantoin (and DL-/)-hydroxyphenylhydantoin), and L-tryptophan production from indole and DL-serine have been in operation as commercial processes. Some of the other processes shown in Table 10 are at a technical level high enough to be useful for commercial production (24). Representative chemical reactions used ia the enzymatic process are shown ia Figure 6. 

N-carbamyl-D-phenylglyc DL-5-phenylglycine hydantoin hydantoinase Pseud, putida ... 

Most methods used for the production of the commercially important a-amino penicillins, such as ampicillin and amoxicillin, are based on modifications of an enamine process employing the appropriate phenylglycine and methylacetoacetate followed by coupling with 6-APA (64). Other aspects of the fermentation, strain maintenance, equipment, inoculum development, media, and procedures used in the production of penicillin are well covered in previous editions of the Enyclopedia. Developments in these areas have been reviewed (65). 

Based on this observation, K. Heumann treated N-phenylglycine [103-01 -5] with alkali and obtained indoxyl (38) (keto form), which on aerial oxidation converted to indigotin ... 

This was the process used by BASF and Floechst for about 30 years. Later, a variation of the original Fleumann process was made aniline, formaldehyde, and hydrogen cyanide react to form phenylglycinonitrile (40) which is hydrolyzed to phenylglycine. This is the most widely used process for manufacturing indigotin. 

The greatest improvement in the manufacture of indigotin came when sodamide was used with alkali in the conversion of phenylglycine to indoxyl (125). Not only was the fusion temperature lowered from about 300°C to 200°C, but also the reaction was made practically anhydrous by the sodamide... 

Phenylglycine-o-carboxylic acid [612-42-0] M 195.2, m 208°. Crystd from hot water (charcoal). 

Chlorophenylacetic acid has been prepared from mandeloni-trile and hydrochloric acid in a sealed tube, from mandelic acid and hydrochloric acid in a sealed tube/ from a-nitrostyrene and hydrochloric acid in a sealed tube, from phenylglycine, hydrochloric acid, and sodium nitrite, from mandelic acid and phosphorus pentachloride (to give the acid chloride which is then hydrolyzed), and, in poor yield, from mandelic acid and thionyl chloride. In the method described, ethyl mandelate is prepared according to Fischer and Speier. The conversion to the chloroester and the acid hydrolysis step are modifications of a preparation described by McKenzie and Barrow. ... 

Synthetic chiral adsorbents are usually prepared by tethering a chiral molecule to a silica surface. The attachment to the silica is through alkylsiloxy bonds. A study which demonstrates the technique reports the resolution of a number of aromatic compoimds on a 1- to 8-g scale. The adsorbent is a silica that has been derivatized with a chiral reagent. Specifically, hydroxyl groups on the silica surface are covalently boimd to a derivative of f -phenylglycine. A medium-pressure chromatography apparatus is used. The racemic mixture is passed through the column, and, when resolution is successful, the separated enantiomers are isolated as completely resolved fiactions. Scheme 2.5 shows some other examples of chiral stationary phases. 

Double cyclization of the phenylglycine o-carboxylic acids 611 (R = H) with acetic or benzoic anhydride by heating gave the mesoionic oxazolones 612 and 613, respectively, which upon treatment with BF3 Et20 gave 615... 

Corey et al. synthesized a chiral bis(oxazoline)Fe(III) catalyst 30, the ligand of which was prepared from chiral phenylglycine. The catalyst was formed by the reaction of the ligand with Fel3 in the presence of I2.12 greatly enhances the Lewis acidity of the catalyst owing to the formation of a cationic species [39] (Scheme 1.49). 

In an interesting analogy to the penicillin series, acylation of 7-ACA with the phenylglycine moiety affords a compound with oral activity. Thus, phenylglycine is first protected as the carbo tertiary butyloxy derivative (45). Reaction of this with isobutyloxy chloroformate affords the mixed anhydride (46). Condensation of that with 7-ACA gives the intermediate, 47. Treatment with either trifluoroacetic or formic acid provides the free amine cephaloglycin (48). ... 

A surprising use of palladium hydroxide-on-carbon in the hydrogenation of (f )-a-phenylglycine to (R)-a-cyclohexylglycine was described by Tamura... 

To a 1 liter flask containingdimethylformamideatO°C, was added 24.8 g sodium N-(2-meth-oxycarbonyl-1-methylvinyD-D-Ct-phenylglycine (prepared from sodium D-Ct-phenylgiycine and methyl acetoacetate). The mixture was cooled to -40°C and methyl chloroformate (7.5... 

D-Phenylglycine 7-Amino-cephalosporanic acid Isobutyl chloroformate... 

A 0.60 g portion of N-carbobenzoxy-D-phenylglycine is dissolved in 10 ml of dry tetra-hydrofuran. The solution is cooled in an ice-salt bath, and to it is added 0.29 ml of tri-ethylamine with stirring over a period of 10 minutes, followed by 0.29 ml of isobutyl chloroformate, after which stirring is continued for 10 minutes at -5°C. During this time,... 

In a first step, D-2-amino-2-(1,4-cyclohexadienyl)acetic acid is obtained as follows. A solution of 11.0 g (72.7 mmol) of D-phenylglycine in 900 ml distilled ammonia (which has been treated with 45 mg lithium after distillation to destroy traces of moisture) is slowly diluted with 370 ml dry tert-butyl alcohol. 

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