Esterification hydrochloride

Ethyl nicotiiiate may be prepared either by direct esterification of the acid with ethanol and sulphuric acid, followed by pouring into water and rendering ammoiilacal or by interaction of the acid with thionyl chloride, followed by reaction of nlcotiiiyl chloride hydrochloride with ethanol and subsequent neutralisation. 

The study of these fluorine-containing salts was then extended, and we prepared other new compounds in this series, e.g. 2-fluoroethyl glycine hydrochloride and 2-fluoroethyl betaine hydrochloride (that is, carbofluoroethoxy-methyl trimethyl ammonium chloride). The first of these was readily prepared by the Fischer-Speier esterification of glycine with fluoro-ethyl alcohol ... 

A tetrahydropyrido[3,4-/)]pyrazine nucleus was constructed from 2,3-dimethylpyrazine 687 by chlorination with A-chlorosuccinimide (NCS) to give 2,3-bis(chloromethyl)pyrazine 688, followed by cyclization with diethyl acet-amidomalonate to pyridopyrazine 689. Hydrolysis and decarboxylation of 689 in hydrochloric acid, then esterification by action of thionyl chloride in methanol gave methyl 5,6,7,8-tetrahydropyrido[3,4-. ]pyrazine-7-carboxylate hydrochloride 690 (Scheme 32) <2003BMC433>. 

Macrolactonization The original conditions of Steglich esterification are ineffective for lactonization of co-hydroxy carboxylic acids. However, addition of a soluble amine hydrochloride as a proton-transfer agent results in a useful method... 

Functional group protection. The NH— group in proline is protected by acylation in the usual Schotten-Baumann manner with benzyl chloroformate to yield the benzyloxycarbonyl derivative (42). Correspondingly the —C02H group in glycine is protected by esterification in ethanol to form the ethyl ester, obtained as the hydrochloride (43) under Fischer-Speier conditions. 

Ethyl p-aminobenzoate (esterification of p-aminobenzoic acid). Place 80ml of absolute ethanol in a 250-ml two-necked flask equipped with a double surface reflux condenser and a gas inlet tube. Pass dry hydrogen chloride (Section 4.2.38, p. 438) through the alcohol until saturated - the increase in weight is about 20 g - remove the gas inlet tube, introduce 12 g (0.088 mol) of p-aminobenzoic acid and heat the mixture under reflux for 2 hours. Upon cooling, the reaction mixture sets to a solid mass of the hydrochloride of ethyl p-aminobenzoate. It is better, however, to pour the hot solution into c. 300 ml of water (no hydrochloride separates) and add solid sodium carbonate carefully to the clear solution until it is neutral to litmus. Filter off the precipitated ester at the pump and dry in the air. The yield of ethyl p-aminobenzoate, m.p. 91 °C, is 10 g (69%). Recrystallisation from rectified (or methylated) spirit does not affect the m.p. 

Equimolecular quantities of 4-butylaminobenzoic acid and the hydrochloride of p-dimethylaminoethanol are suspended in 10 times their joint weight of toluene. The mixture is saturated with hydrochloric acid gas and heated in an oil bath at about 150°C while a current of hydrochloric acid, gas is slowly passed through the mixture so that toluene slowly distils. Along with toluene the water produced by the esterification distils. After heating for about 10 hours the mixture is cooled and water is added until the salt is dissolved. The layer of toluene is separated and the ester base precipitated from the aqueous solution by means of a solution of sodium carbonate. By dissolving the base in ether, drying the ether solution separated over potassium carbonate and adding alcoholic hydrochloric acid, to the solution until it is neutral to litmus, the monohydrochloride is obtained in the form of a colorless crystalline powder which, when recrystallized from alcohol, melts at 147-148°C. 

Pyridylmethylphosphinates can be accessed, albeit in low isolated yield, by palladium-catalyzed cross-coupling of 2- and 3-pyridylmethyl chlorides with anilinium hypophosphites <2005T6315>. For example, 3-chloromethylpyr-idine hydrochloride reacts with anilinium hypophosphite in the presence of Pd(OAc>2, dppf, 1,4-diazabicy-clo[2.2.2]octane (DABCO), and (BuOTSi as esterification agent to give butyl (pyridine-3-ylmethyl)phosphinate 53 in 46% yield (Equation 37). This transformation proceeds in 24% yield when performed on 2-chloromethylpyridine. 

Esterification with higher diazoalkanes [205] has also been suggested. A 2-ml volume of 50% potassium hydroxide solution was added to 5 ml of diethyl ether in a small flask. N-n-Butyl(or propyl)-N-nitrosoguanidine (1 g) was suspended in diethyl ether and added to the flask through a separating funnel. The reaction was carried out in a water-bath at 45°C. The diazo compound have been passed through a cooler, was trapped in diethyl ether. Hydrochlorides of amino acids (about 5 mg) were dissolved in 4 ml of methanol... 

In most of their reactions, the pyridine- and azinecarboxylic acids and their derivatives behave as any other acid (cf. Scheme 86). However, some acid chlorides can be obtained only as hydrochlorides, and we must also consider decarboxylation. Esterification of pyridine carboxylic acids can be usefully achieved via in situ generation of the acid fluoride. For example, treatment of picolinic acid with a stoichiometric amount of N,N,N,A-tetramethylfluoroformami-dinium hexafluorophosphate (TFFH) in dichloromethane and triethylamine leads to generation of the acid fluoride, which reacts with (3-methyloxetan-3-yl)methanol to give the corresponding ester in 95% yield <2004S2485>. 

In view of the rapid reaction of carbodiimides with water they are often used in dehydration reactions. Major examples are the intra- and intermolecular esterification reactions of carboxylic acids, and the formation of peptides from carboxylic acids and protected amino acids. Especially, dicyclohexylcarbodiimide (DCC) or diisopropylcar-bodiimide (DIPCD) are often used in carbodiimide mediated reactions because the corresponding urea byproducts are insoluble in most organic solvents and water, and therefore are readily removed by filtration. Also, water soluble carbodiimides, such as N-ethyl-N -(3-dimethylamino)propylcarbodiimide (EDC) or its hydrochloride (EDCCl, sometimes referred to as EDAC) are often used in these reactions. EDC reacts with carboxyl groups at pH of 4.0-6.0, but loses its reactivity at lower pH. Sometimes solid phase reactions are conducted using carbodiimide terminated linear or crosslinked polymers. 

Amino acid methyl esters are fairly simple to prepare. The classical method uses a suspension of amino acid hydrochloride in MeOH and gaseous HCl as catalyst b° l di-carboxylic acids yield the dimethyl esters.Hydrolytic and alcoholytic cleavage of side-chain amide groups of glutamine and asparagine as well as peptide bond cleavage prevents the use of this method for the esterification of peptide fragments. 

The esterification can be also performed by treating tropine hydrochloride with (-)-acetyltropyl chloride in nitrobenzene (24). 

Cycloserine has been synthesized by several workers including Stammer and Evans. The method of Evans will be briefly described. Evans reported cycloserine can be synthesized by converting DL-Serine to its methyl ester hydrochloride by Fischer esterification. 

Smooth esterification of 5-hydroxymethylpyrazol-3-one 71 was possible with A -Zcrt-butoxycarbonyl glycine 72 in 1,2-dichloromethane in the presence of DMAP and DCC to yield pyrazol-3-one ester 73 (02EJP121) (Scheme 18). Compound 71 was also esterified with 2-(6-methoxy-2-naphthyl)propionic acid 74 in DMF and in the presence of CDI to give pyrazol-3-one ester 75. Coupling of 5-aminomethylpyrazol-3-one hydrochloride 76 with trityloxyacetic acid 77 in DMF containing triethylamine and (benzotriazol-l-yloxy)trw(dimethylamino) phosphonium hexafluorophosphate (BOP) afforded pyrazol-3-one amide 78. 

The first preparation (Scheme 2) of enantiomerically pure (2R,2 R)-(+)-Z/zreo-methylphenidate hydrochloride (1) was reported by R. Rometsch of former Ciba Pharmaceuticals (now Novartis).Enantiomerically pure L-eryZ/zro-2-phenyl-2-(2-piperidyl)aceta-mide (12), obtained by the resolution of ( )-erythro-2-phenyl-2-(2-piperidyl)acetamide (11) with d-(-)-tartaric acid in 96% ethanol, was subjected to epimerization to the desired (2R,2 R)-Z/zreo-2-phenyl-2-(2-pi-peridyl)acetamide (13) with aqueous KOH. (2R,2 R)-Z/zz eo-2-Phenyl-2-(2-piperidyl)acetamide (13), thus obtained, was converted to the desired (2R,2 R)-(+)-Z/zz eo-methylphenidate hydrochloride (1) by hydrolysis and esterification. This approach has recently been further optimized by Ramaswamy and Kheta-... 

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