Hydrolysis ethyl esters

The first was proposed by Iraoto and Otsuji (511) and Otsuji et al (512) and concerned the pK of substituted 2-, 4-, and 5-carboxylic acids and the alkaline hydrolysis rate k of their respective ethyl esters (259, 260, and 261, where Y = Et). When Hammett cr , values were used for... 

The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

Carboxyl groups of ammo acids and peptides are normally protected as esters Methyl and ethyl esters are prepared by Fischer esterification Deprotection of methyl and ethyl esters is accomplished by hydrolysis m base Benzyl esters are a popular choice because they can also be removed by hydrogenolysis Thus a synthetic peptide protected at both... 

Section 27 16 Carboxyl groups are normally protected as benzyl methyl or ethyl esters Hydrolysis m dilute base is normally used to deprotect methyl and ethyl esters Benzyl protecting groups are removed by hydrogenolysis... 

Dichloroacetic acid is produced in the laboratory by the reaction of chloral hydrate [302-17-0] with sodium cyanide (31). It has been manufactured by the chlorination of acetic and chloroacetic acids (32), reduction of trichloroacetic acid (33), hydrolysis of pentachloroethane [76-01-7] (34), and hydrolysis of dichloroacetyl chloride. Due to similar boiling points, the separation of dichloroacetic acid from chloroacetic acid is not practical by conventional distillation. However, this separation has been accompHshed by the addition of a eotropeforming hydrocarbons such as bromoben2ene (35) or by distillation of the methyl or ethyl ester. 

Pish protein concentrate and soy protein concentrate have been used to prepare a low phenylalanine, high tyrosine peptide for use with phenylketonuria patients (150). The process includes pepsin hydrolysis at pH 1.5 ptonase hydrolysis at pH 6.5 to Hberate aromatic amino acids gel filtration on Sephadex G-15 to remove aromatic amino acids incubation with papain and ethyl esters of L-tyrosine and L-tryptophan, ie, plastein synthesis and ultrafiltration (qv). The plastein has a bland taste and odor and does not contain free amino acids. Yields of 69.3 and 60.9% from PPG and soy protein concentrate, respectively, have been attained. 

Other Methods of Preparation. In addition to the direct hydration process, the sulfuric acid process, and fermentation routes to manufacture ethanol, several other processes have been suggested. These include the hydration of ethylene by dilute acids, the hydrolysis of ethyl esters other than sulfates, the hydrogenation of acetaldehyde, and the use of synthesis gas. None of these methods has been successfilUy implemented on a commercial scale, but the route from synthesis gas has received a great deal of attention since the 1974 oil embargo. 

Hydrolysis of Ethyl Esters. The hydrolysis of esters (other than ethyl sulfates) is not a commercial route for producing ethanol. An indirect hydration of ethylene actually takes place during the proposed (153) hydrolysis of ethyl sulfite cataly2ed by silver sulfate. 

The hydrolysis of ethyl acetate, prepared by the reaction of ethylene with acetic acid under pressure (154), and the hydrolysis of the ethyl ester of chlorosulfonic acid (155) have been considered and found to be of Httie industrial importance. 

In fact, most pyrimidinecarboxylic acids are made by hydrolysis of the corresponding esters, nitriles or sometimes amides, many of which can be made more easily by primary synthesis than can the acids themselves. Thus, pyrimidine-5-carboxylic acid may be made by alkaline hydrolysis of its ethyl ester (62JOC2264) and pyrimidin-5-ylacetic acid (789 ... 

Pteridine-7-carboxylic acid, 6-oxo-synthesis, 3, 310 Pteridinecarboxylic acids structure, 3, 276-277 Pteridine-4-carboxylic acids ethyl ester hydrolysis, 3, 276 Pteridine-6-carboxylic acids properties, 3, 277 reactions, 3, 304 Pteridine-7-carboxylic acids properties, 3, 277 reactions, 3, 304 Pteridine-6,7-dicarboxylic acid properties, 3, 277 Pteridine-2,4-dione, 7-hydroxy-tautomerism, 3, 271... 

Glycine ethyl ester hydrochloride has been prepared by the action of absolute alcohol and hydrogen chloride on glycine from glycyl chloride and alcohol by the action of ammonia or hexamethylenetetramine on chloroacetic acid, and subsequent hydrolysis with alcoholic hydrochloric acid and by the action of hydrogen chloride and alcohol on methyleneamino-acetonitrile. ... 

Propionic acid [79-09-4] M 74.1, b 141 , d 0.992, n 1.3865, n25 1.3843, pK 5-6.8 (Ho scale, aq H2SO4), pK2 4.88. Dried with Na2S04 or by fractional distn, then redistd after refluxing with a few crystals of KMn04. An alternative purification uses the conversion to the ethyl ester, fractional distn and hydrolysis. [Bradbury J Am Chem Soc 74 2709 1952.] Propionic acid can also be heated for 0.5h with an amount of benzoic anhydride equivalent to the amount of water present (in the presence of Cr03 as catalyst), followed by fractional distn. [Cham and Israel 7 C/iem 5oc 96 I960.]... 

Merck and Maeder have patented the manufacture of arecaidine by loss of water from l-methyl-4-hydroxypiperidine-3-carboxylic acid. A method of producing the latter has been describd by Mannich and Veit and has been developed by Ugriumov for the production of arecaidine and arecoline. With the same objective, Dankova, Sidorova and Preobrachenski use what is substantially McElvain s process,but start by converting ethylene oxide, via the chlorohydrin and the cyanohydrin, into -chloropropionic acid. The ethyl ester of this with methylamine in benzene at 140° furnishes methylbis(2-carbethoxyethyl) amine (I) which on refluxing with sodium or sodium Moamyloxide in xylene yields l-methyl-3-carbethoxy-4-piperidone (II). The latter is reduced by sodium amalgam in dilute hydrochloric acid at 0° to l-methyl-3-carbethoxy-4-hydroxypiperidine (III) which on dehydration, and hydrolysis, yields arecaidine (IV R = H), convertible by methylation into arecoline (IV R = CH3). 

On autoxidation by aeration in tertiary butyl alcohol containing potassium tert-butyl oxide, quininone yields quininic acid (98 per cent.) and meroquinenine terf-butyl ester, CgHi N. CO. O. C4H9, b.b. 127°/20 mm., dj 0-9832, [a]o° -(- 50-0° (EtOH), identified by hydrolysis to meroquinenine (meroquinene) and eonversion of this to the better-known ethyl ester (p. 438). (Doering and Chanley.)... 

Meroquinenine, CgHjjOaN (meroquinene), formed by the oxidation of all four alkaloids and of cinchoninone or quininone and by the hydrolysis of quinenine or cinchenine (p. 489), crystallises from methyl alcohol in needles, m.p. 223-4° (dee.), [ajp -f- 27-5° (H2O). It gives a nitrosoamine, m.p. 67°, and a monoacetyl derivative, m.p. 110°, and can be esterified the ethyl ester hydrochloride has m.p. 165°. When oxidised by chromic acid it yields formic and cincboloiponic acids. On reduction with zinc dust and hydriodic acid, it adds on two atoms of hydrogen forming cincholoipon, CgH jOaN, and when heated with hydrochloric acid at 250-60° gives 3-ethyl-4-methylpyridine ()3-collidine). 

In a penicillin synthesis, the carboxyl group was protected as a / -bromophenacyl ester that was cleaved by nucleophilic displacement (PhSK, DMF, 20°, 30 min, 64% yield). Hydrogenolysis of a benzyl ester was difficult (perhaps because of catalyst poisoning by sulfur) basic hydrolysis of methyl or ethyl esters led to attack at the /3-lactam ring. ... 

Only in the case of the pyruvic acid condensation product was it possible to isolate the corresponding ethyl ester under these conditions. This, on mild hydrolysis, reverted to 1-methyl-1,2,3,4-tetrahydro-j8-carbohne-1-carboxylic acid, identical with the starting material, which therefore had the assigned structure 26 (R = CH3) and was not the SchiflF s base 25 (R = CH3). Alkaline hydrolysis of the ester was accompanied by decarboxylation. ... 

Imoto and co-workers have also studied the pA values of substituted thiazolecarboxylic acids and the alkaline hydrolysis of their ethyl esters, each in three relative positions (2-B-4-Y, 2-B-5-Y, and 5-II-2-Y). In the case of the pA values, the p-values are far from constant, varying from 0.83 to 2,35, This variation is likely to be due to the intervention of tautomeric equilibria and of hydrogen bonds. The /3-ratios for the three sets of ester hydrolyses are roughly constant (0,61-0.73), and, assuming that the introduction of two heteroatoms leads to cumulative (multiplicative) effects on the transmission, this result is of the same order of magnitude as the product of the and values discussed above, i.e. 1.0 and 0.6, respectively. The lowest value for the pA (0,83) for the 2-R-5-COOH series is also of the same order of magnitude. All the available reaction constants are summarized in Table VI. 

Estimated using p-values from piiC-values of furoic acids and the hydrolysis of their ethyl esters after correction for the difference in reaction conditions. 

The respective amide was prepared from 7-substituted 5-oxo-2,3-dihydro-5//-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acids via acid chlorides with different benzylamines (00M1P3). 6-Carboxamides were N-benzylated, and a side-chain phenolic hydroxy group was O-alkylated. 7-Aryl-5-oxo-2,3-dihydro-5//-pyrido[l, 2,3-r/e]-1,4-benzoxazine-6-carboxylic acid was obtained from the ethyl ester by alkalic hydrolysis. 

Reaction of 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l, 2,3- e]-1,4-ben-zothiazine-6-carboxylic acid and its ethyl ester with B(OH)3 in AC2O in the presence of ZnCl2 afforded 6-[(diacetoxyboryl)oxycarbonyl] derivative 323 (R = OAc)], which was reacted with primary and cyclic amines to give 10-amino-9-fluoro-7-carboxylic acid derivatives 324 (97MI41, 98MI30). 6-[(Difluoroboryl)oxycarbonyl derivative 323 (R = F) was obtained from ethyl 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazine-6-carboxylate with BF3-THF complex. Reaction of 323 (R = F) and 1-methylpiperazine in DMF at 50-60 °C and subsequent acidic hydrolysis afforded 7 (97MI1). 

Hydrolysis of ethyl 9-fluoro-10-(4-methylpiperazino)-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazine-6-carboxylate in a boiling mixture of AcOH and 35% HCl afforded 7 HCl (97USP5703233). That of (3S)-3-methyl-10-(2,6-dimethyl-4-pyridyl)-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- e]-l,4-benzothiazine-6-carboxylate gave the 6-carboxylic acid (OOMIPIO). 7-Oxo-2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazine-6-carboxylic acid was obtained from its ethyl ester by alkalic hydrolysis in 20% yield (99AP19). 

By oxidation with chromic acid, this is converted into cyclohexanone-3-carboxylic acid, in which the —CH. OH— group is converted into the —CO— group. This is converted into its ethyl ester and treated with magnesium methyl iodide, and the product, on hydrolysis, yields l-methyl-cyclohexane-l-ol-3-carboxylic acid, which is converted byhydro-bromic acid into 1-bromo-l - methyl - cyclohexane - 3 - carboxylic acid. When this is digested with pyridine, hydrobromic acid is eliminated and yields l-methyl-A -cyclohexane-3-carboxylic acid of the formula—... 

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. 

---