Phenylacetic acid derivatives synthesis

From a commercial point of view, organic halides are in principle a less attractive feedstock for the synthesis of alkanoic or benzoic acid derivatives compared with alkenes or toluenes, which can lead to the corresponding acids via hydroformyla-tion and oxidation, hydrocarboxylation, or direct air oxidation, respectively. Thus, apart from methanol, an economically viable carbonylation of C-X compounds is restricted to the synthesis of higher-value fine chemicals in cases where alternative starting materials are not easily accessible, e. g., phenylacetic acid derivatives (cf. Section 2.1.2.1). 

Tolmetin sodium is a NSAID, which decreases inflammation, pain, and fever, probably through inhibition of cyclooxygenase activity and prostaglandin synthesis. It is indicated in the treatment of chronic and acute rheumatoid arthritis and osteoarthritis and juvenile rheumatoid arthritis. Tolmetin and ketoroiac are structurally related heteroaryl acetic acid derivatives with different pharmacological features. Diclofenac is a phenylacetic acid derivative that was developed specifically as an antiinflammatory agent. 

Synthesis of repaglinide involves condensation of an appropriately substituted and chi-rally pure benzylamine derivative with an appropriately substituted phenylacetic acid derivative (7) followed by saponification. The reported process for the key intermediate (7) described a five-step process with an overall yield of about 30% of theory (Scheme 23.4) We undertook development of an alternative synthetic strategy to prepare 7 and developed an efficient and commercially feasible synthesis starting from 2-hydroxy-4-methylbenzoic acid (9) in two steps. Thus, 9 was first alkylated with ethyl bromide in a polar aprotic solvent and in the presence of an inorganic base to afford ethyl 2-ethoxy-4-methylbenzoate... 

The synthesis and metabolism of trace amines and monoamine neurotransmitters largely overlap [1]. The trace amines PEA, TYR and TRP are synthesized in neurons by decarboxylation of precursor amino acids through the enzyme aromatic amino acid decarboxylase (AADC). OCT is derived from TYR. by involvement of the enzyme dopamine (3-hydroxylase (Fig. 1 DBH). The catabolism of trace amines occurs in both glia and neurons and is predominantly mediated by monoamine oxidases (MAO-A and -B). While TYR., TRP and OCT show approximately equal affinities toward MAO-A and MAO-B, PEA serves as preferred substrate for MAO-B. The metabolites phenylacetic acid (PEA), hydroxyphenylacetic acid (TYR.), hydroxymandelic acid (OCT), and indole-3-acetic (TRP) are believed to be pharmacologically inactive. 

Phenylacetic acid Used in the chemical and pharmaceutical industries for the manufacture of phenylacetate esters, amphetamine and some derivatives used for the synthesis of penicillins used in fragrance applications and cleaning solutions. 

Historically, this represents the first thiophene synthesis, when Laurent obtained tetraphenylthiophene by heating polymeric thiobenzaldehyde in 1844. Almost any aromatic methyl derivative can be converted to tetraphenylthiophene, which is thermodynamically the most stable thiophene, by heating with sulfur. Toluene, phenylacetic acid, benzyl alcohol, benzyl sulfide or disulfide, benzyl sulfonate or even sodium thiobenzoate have been converted to tetraphenylthiophene under these conditions (52HC(3)l). 

In most indigo syntheses the indole structure is built up by ring closure of appropriate benzene derivatives by C-N or C-C bond formation. Examples of C-N bond formation include von Baeyer s 1878 synthesis from phenylacetic acid (3) via oxindole (4). 

Enholm [13] has also described the synthesis of soluble designer supports by the ring-opening metathesis polymerization (ROMP) of norbornyl derivatives. Reduction of norbornene-l-carboxaldehyde 88 to the corresponding alcohol 89, followed by treatment with either 2-bromopropionic acid or 2-bromo-2-phenylacetic acid in the presence of DCC, provided the esters 90 or 91 respectively (Scheme 19). Polymerization of 90 and 91 was carried out with Grubbs catalyst and halted after 25 s by capping with excess ethyl vinyl ether to give polymers 92 and 93 respectively. 

Simple benzannelation of benzene leads to naphthalene. Related to our synthesis, a great number of benzene derivatives with an acidified methylene group that are ready for condensation with (7), e.g., desoxybenzoin (activated by carbonyl), benzyl-phenylsulphones (activated by sulphonyl), esters of phenylacetic acids, and best-suited, the phenylacetonitriles (activated by cyano) can easily be transformed to arylaminobutadienes 54) and cyclized to naphthalenes (56) ... 

Increasing the temperature to 350 °C results in decarbonylation of the phenylpyruvic acid methyl ester derivatives and the phenyl acetic ester is formed with a ratio of 65 % a-ketoester to 35 % acetic acid ester. Until now the industrial process for the synthesis of phenylacetic acid ester has started from benzyl chloride, which is converted to benzyl cyanide by KCN, followed by hydrolysis. Every step of this reaction must be performed in a separate reactor and special measures must be taken for handling large amounts of toxic KCN. The new route is certainly an environmentally benign alternative [8,27]. 

Penicillin Formation by Penicillium Chrysogenum. The first reactions of the penicillin biosynthetic pathway are identical to the ones in A. chrysogenum (Figure 1.1-1). IPN, however, is not epimerized to penicillin N instead it is converted to 6-aminopenicillanic acid (6-APA) by removal of the L-a-aminoadipic acid side chain, which is substituted by a hydrophobic acyl group. Both steps are catalyzed by the same enzyme, the acyl coenzyme A IPN acyltransferase (IAT). The enzymatic activity of lAT is believed to be the result of the processing of a 40-kD monomeric precursor into a dimeric form consisting of two subunits with MWs of 11 and 29 kD. Due to the broad substrate specifity of lAT, various penicillin derivatives are synthesized naturally by attachment of different acyl-CoA derivatives to the 6-APA-core. For industrial purposes, to facilitate extraction by organic solvents, synthesis usually is directed to the less hydrophilic penicillin V or penicillin G. This is by addition of phenoxyacetic acid or phenylacetic acid, respectively, as precursors to the culture broth. 

A one-pot two-step synthesis of hydroxystilbenes with trans selectivity was developed through a modified Perkin reaction between benzaldehydes and phenylacetic acids bearing 4- or 2-hydroxy substitution at the aromatic ring [67]. The reaction was performed under mild conditions in the presence of piperidine-methylimidazole and polyethylene glycol under microwave irradiation. As a result, 71% yield of ( )-4-chloro-4 -hydroxy-3 -methoxystilbene from 4-hydroxy-3-methoxybenzaldehyde and 4-chlorophenylacetic acid was obtained. A microwave-induced one-pot process for the preparation of arylethenes has been patented [118]. For the preparation of a series of arylethenes (I R -R = H, OH, OMe, AcO, halo, NO2 R, R, R = OH, AcO R= H, substituted aryl), reaction of 2- or 4-hydroxy substituted cinnamic adds or derivatives in the presence of a base, under reflux or microwave irradiation, has been used. For example, a mixture of a-phenyl-4-hydroxy-3-methoxycinnamic acid, NaHC03, methylimidazole, and polyethylene glycol was microwaved at 200 W and 180 °C for 10 min to give 96% 4-hydroxy-3-methoxystilbene. 

A related agent, g1icetanile sodiurn (42), is made by a variant of this process. Methyl phenylacetate is reacted with chlorosulfonic acid to give which itself readily reacts with ami nopyrimidine derivative 39 to give sulfonamide Saponification to acid is followed by conversion to the acid chloride and amide formation with 5-chloro-2-methoxyaniline to complete the synthesis of the hypoglycemic agent glicetanile (42). ... 

Atropine can be synthesized from tropi-none and tropic acid as starting materials. Tropinone can be prepared by Robinson s synthesis (68) and reduced under proper conditions to tropine. ( )-Tropic acid can be prepared from ethyl phenylacetate (69, 70) or acetophenone (71). The 0-acetyl derivative of tropyl chloride reacts with tropine to yield O-acetyl of atropine hydrochloride, from which the acetyl group hydrolyzes spontaneously in aqueous solution (72). 

Guimond N, Fagnou K (2009) Isoquinoline synthesis via rhodium-catalyzed oxidative cross-coupling/cyclization of aryl aldimines and alkynes. J Am Chem Soc 131 12050-12051 Booth BL, CoUis A (1989) One-step synthesis of A -(l-benzylisoquinohn-3-yl)phenylacet-amidinium trifluoromethanesulphonate derivatives from phenylacetonitiiles and trifluoro-methanesulphonic Acid. J Chem Res Synop 304-305... 

---