Synthesis of Ethyl 4-hydroxy

Synthesis of Ethyl 4-hydroxy-3,5-bis(((2-hydroxyethyl) (pyridin-2-ylmethyl)amino)methyl)benzoate (COzEtHsLl)... 

The synthesis of 4-alkyl-y-butyrolactones 13 and 5-alkyl-<5-valerolactones 14 can be achieved in high enantiomeric excess by alkylation of ethyl 4-oxobutanoate and ethyl 5-oxopentanoate (11, n = 2, 3). The addition of diethylzinc, as well as dimethylzinc, leads to hydroxy esters 12 in high optical purity. When methyl esters instead of ethyl esters are used as substrates, the enantioselectivity of the addition reaction is somewhat lower. Alkaline hydrolysis of the hydroxy esters 12, followed by spontaneous cyclization upon acidification, leads to the corresponding y-butyro- and -valerolactones32. 

Some developments have been carried out for the enantioselective synthesis of biologically active compounds. One such example is the synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate, an important intermediate for the angiotensinconverting enzyme (ACE) inhibitor benazepril, or for coenzyme A, using the NORPHOS ligand (Scheme 33.9) [21]. 

Jew and Park achieved a highly enantioselective synthesis of (2S)-a-(hydroxy-methyljglutamic acid, a potent metabotropic receptor ligand, through the Michael addition of 2-naphthalen-l-yl-2-oxazoline-4-carboxylic acid tert-butyl ester 72 to ethyl acrylate under phase-transfer conditions [38]. As shown in Scheme 5.36, the use of BEMP as a base at —60 °C with the catalysis of N-spiro chiral quaternary ammonium bromide le appeared to be essential for attaining an excellent selectivity. 

Synthesis of 9-oxo-la,15a-bis-(2-tetrahydropyranyloxy)-16,16-dimethyl-prosta-trans-2, trans-13-dienoic acid 4 g of ethyl 9a-hydroxy-llal5a-bis-(2-tetrahydropyranyloxy)-16,16-dimethyl-prosta-trans-2,trans-13-dienoate were dissolved in 130 ml of a mixture of ethanol-water (3 1), mixed with 3.9 g of potassium hydroxide and stirred at 25°C for 2 hours. The reaction mixture was acidified with aqueous solution of oxalic acid to pH 5, and diluted with 100 ml of water, extracted with ethyl acetate. The extracts were washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 3.88 g of 9a-hydroxy-lla,15a-bis-(2-tetrahydropyranyloxy)-16,16-dimethyl-prosta-trans-2,trans-13dienoic acid. 

When the enantioselective reduction of ethyl 4-chloroacetoacetate was carried out with alcohol dehydrogenase from Candida parapsilosis, the other enantiomer was produced ethyl (P)-4-chloro-3-hydroxybutanoate [134]. This product is a key intermediate in a synthesis of (R)-carnitine. In this case a substrate coupled approach was chosen. The enzyme also has a strong oxidation activity for 2-propanol, which was therefore selected as the cosubstrate. The situation is depicted in Fig. 3.50. Under optimized conditions, the yield of (R)-ethyl-4-chloro-3-hydroxy-butanoate reached 36.6 g L-1 (> 99% ee, 95% yield) on a 30 L scale. 

Zhou Y, Kijima T, Kuwahara S et al (2008) Synthesis of ethyl 5-cyano-6-hydroxy-2-methyl-4-(l-naphthyl)-nicotinate. Tetrahedron Lett 49 3757-3761... 

Ethyl l-hydroxy-l//-l,2,3-triazole-4-carboxylate (20) has been investigated as an additive to carbodiinoides particularly for solid-phase peptide synthesis. No racemization was observed when Fmoc-protected anoino acids were coupled to the resin-bound peptides, except for histidine residues which under these reaction conditions racenoized extensively unless the activation time was kept to one minute and three equivalents of ethyl 1-hydroxy-1//-1,2,3-triazole-4-carboxylate (20) were added. Under the latter conditions no racemization was detected.The efficiency of this newly developed method has been well documented by the successful synthesis of deglycosylated human erythropoietin.t ... 

For the synthesis of ethyl 2,4-dimethyl-3-hydroxyoctanoate from 2-methylhexanal and ethyl a-bromopropionate, Rinehart and Perkins used frt.shly sandpapered zinc foil which had been cut into narrow strips and rolled loosely. With a ratio of zinc ibromoester aldehyde of 3 3 1, the yield of hydroxy ester was 87% when the ratio was reduced to 2 3 1 the yield was owered to 68%. 

Chlorination of aromatics. Although benzene is sufficiently inert to sulfuryl chloride to be used as a solvent (see above), the reagent dichlorinates ethyl 4-hydroxy-benzoate under mild conditions. The reaction is the first step in a synthesis of 2,6-dichlorophenol. 

The hydrogenation of 2,4-diketo acid derivatives to the corresponding 2-hydroxy compounds with cinchona-modified Pt catalysts as depicted in Figure 2.4 can be carried out with chemoselectivities more than 99% and enantioselectivities up to 87% (R) and 68% (S), respectively [30a]. Enrichment to more than 98% ee was possible for several substrates by recrystallization, giving rise to an efficient technical synthesis of (R)-2-hydroxy-4-phenyl butyric acid ethyl ester [30b], a building block for several ACE (angiotensin-converting enzyme) inhibitors, as well as some enantio-merically enriched a-hydroxy and a-amino acid esters (see below) [30c]. 

The synthesis of 2(2-hydroxy-5-methy lphenyl)2H-4 -vinyl-benzo-triazole was accomplished (31) by a sequence of reactions similar to those which gave 2H5V. The starting material for this synthesis was, however, not o-nitroaniline but 4-ethyl-o-nitroaniline. After diazo-tiation, the diazonium compounds were allowed to react with p-cresol the condensation product gave 2(2-hydroxy-5-methylphenyl)2H-4-ethyl-benzotriazole after reductive cyclization. This compound was acetyl-ated, brominated, dehydrobrominated, and hydrolyzed to 2(2-hydroxy-5-methylphenyl)2H-4 —viny1-benzotriazole. 

This hydroxy functionalized ionic hquid [49], [2-(OH)EMIM][Bp4] was prepared under microwave irradiation via methylimidazolium, chlorohydrin and sodium tetrafluoroborate as materials. A microwave assisted solution phase parallel synthesis of 3,4-dihydropyridones was developed using [2-(OH)EMIM][BF4] as a soluble support. First, the [2-(0H) EMIM][BF4] was reacted with ethyl acetoacetate to obtain IL-bound acetoacetate, then this intermediate was reacted with Meldrum s acid. 

Representative procedure synthesis of ( )-(3R,4R)-l-berzyl-3-ethyl-4-hydroxy-4-methylpiperidin-2-on ... 

The initial observation of substituent effects on the pyridine derivative (4) was demonstrated by the introduction of a hydroxyl group at the C-3 position to yield (16) [11]. This hydroxylation increased tumour-inhibitory activity significantly and at the same time reduced toxicity 25-fold. Formation of the ethyl ether of (16), however, diminished anticancer potency. The increased activity of the 3-hydroxy isomer prompted the synthesis of the 5-hydroxy derivative (17)... 

Ethyl 4-chloro-6,7-dimethoxyquinoIine-3-carboxyIate and dimethyl sulfoxide heated 2 hrs. on a steam bath ethyl 4-hydroxy-6,7-dimethoxyquinoline-3-carboxylate. Y 87%. F. e. and limitations s. N.D. Harris, Synthesis 1972, 625 a-oxo-N-heterocyclics, also in the presence of Nal, cf. R. E. Lyle and M. J. Kane, J. Org. Chem. 38, 3740 (1973). 

As a typical example of tridepside synthesis, the preparation of 5-0-methylhiascic acid (227) is depicted in Scheme 35 122). Persulfate oxidation of ethyl 4-benzyloxy-2-hydroxy-6-methylbenzoate (273) in potassium hydroxide solution gave the corresponding 5-hydroxy derivative (274) from which 2,4-dibenzyloxy-5-methoxy-6-methylbenzoic acid (275) was prepared. Condensation of this acid with benzyl lecanorate (276) gave the... 

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