Methyl ester formation, methanol

Quininone, the most readily available member of the series, was used for the autoxidation studies. The Doering autoxidation procedure,4 that employs only tert-BuOH, was modified to include a THF tert-BuOH (4 1) mixture as the solvent. Likewise, the pressurized Parr bottle setup as described4 was replaced with a simple subsurface gas addition the solvent was presaturated with O2 gas, (compressed air could also be used as the O2 source) followed by t-BuOK addition and continued O2 gas purge. The autoxidations could likewise be conducted in the presence of ethanol or methanol, thereby producing the corresponding ethyl or methyl esters. Formation of these esters could occur via the reactive intermediate bicyclic lactam.4... 

Schiff s base formation occurs by condensation of the free amine base with aldehyde A in EtOAc/MeOff. The free amine base solution of glycine methyl ester in methanol is generated from the corresponding hydrochloride and triethylamine. Table 4 shows the reaction concentration profiles at 20-25°C. The Schiffs base formation is second order with respect to both the aldehyde and glycine ester. The equilibrium constant (ratio k(forward)/ k(reverse)) is calculated to be 67. 

Effect of Composition of Isooctane-Methanol Solutions on Methyl Ester Formation In Polymer B Aged 30 Days at 80 C... 

Simple methyl ester formation can be accomplished by exposure of the sample to methanolic HCl. In the case of peptides all free carboxyl groups (COOH) are converted to methyl esters. As a result, the hydrogen bonding capacity of the compound is substantially reduced and hydrophobicity and surface activity typically increase. In addition to increasing the FAB performance of the compound, the resulting mass shift is diagnostic of the number of free carboxyl groups present in the analyte. 

The traditional batch process follows the route in Figure 2.8. The catalyst, used in catalytic proportions, can be washed out at the end of the process. The excess methyl ester and methanol formed as the esterification proceeds is distilled off as a mixture. Separation of this mixture is usually not straightforward and recycle of the excess methyl ester is therefore difficult and expensive. Byproduct formation, leading to undesirable impurities which have to be removed, is also likely as reagents and end products, in the presence of a catalyst, exist together for extended periods at elevated temperatures. 

An important application of the above strategy is illustrated by the use of O-trimethylsilyl-protected amino acid hydrogen chlorides to produce half-acid/half-ester urea dipeptides in 45-49% yield [322], which represent starting materials for a variety of pharmacologically active compounds. Addition of the selected O-trime-thylsilyl-protected amino acid hydrogen chloride to a solution of triphosgene in chloroform in the presence of DIEA results in the formation of the isocyanate intermediate, which is converted in situ to the urea dipeptide upon reaction of a second amino acid methyl ester in methanol. 

The silylenol ether formed from (47) and trimethylchlorosilane was cyclized in situ, and the reaction mixture was worked up under acidic conditions to give the ketone (558). This was subjected to reduction with sodium borohydride, acid-catalyzed elimination of water, and oxidation with dichlorodicyanobenzoquinone (DDQ) to give the bicyclic ester (560). Introduction of a methoxy substituent into the retinoid structure (560) was likewise effected via the ketone (558). When this ketone was ketalized with methyl o-formate, methanol was eliminated and the product was oxidized, its six-membered ring system undergoing aromatization to form a substituted phenyl group. 

AcCl, MeOH, 95-100% yield. This is a convenient method for generating anhydrous HCl in methanol. These conditions are also used to prepare methyl esters from carboxylic acids and for the formation of amine hydrochlorides. ... 

Pyridone IV was converted to its sodium salt by treatment with an equimolar amount of sodium methoxide in methanol (see procedure below under formation of the 3-phenyl-2(lH)pyridone sulfonates). The sodium salt was next treated with the methyl ester of a-bromo-p-toluic acid, obtained by treatment of the acid with BF3 etherate. 

When 10 (R configuration about phosphorus) was treated with ribo-nuclease in aqueous methanol, nucleophilic attack by methanol in the enzyme-catalyzed process led to formation of a methyl ester, 11, which has been shown by X-ray analysis to be the isomer with the R configuration about the phosphorus (60) ... 

In our first experiment we decided to test the conversion of sunflower oil into biodiesel (16). Treatment of sunflower oil (1) with NaOMe in MeOH results in formation of a mixtme of fatty acid methyl esters (FAME), also known as biodiesel, and glycerol (2) (Figme 4.3). The reaction was performed with a six-fold molar excess of methanol with respect to sunflower oil at elevated temperatures (60°C) using a basic catalyst (NaOMe, 1% w/w with respect to sunflower oil). The CCS was equipped with a heating jacket to ensure isothermal conditions. The sunflower oil was preheated to 60°C and was pumped at 12.6 ml/min into one entrance of the CCS. Subsequently, a solution of NaOMe in MeOH was introduced through the other entrance at a flow rate of 3.1 ml per minute. After about 40 minutes, the system reaches steady state and the FAME containing some residual sunflower oil is coming... 

The treatment of 1,4-di hydro-2 7/-pyrido[ 2,3-< [ 1,2,4]triazine-3-thione 82 with dimethyl acetylenedicarboxylate (DMAD) in methanol at room temperature leads to the formation of 5-oxo-8,8a,9,10-tetrahydro-5//-4,4b,9,10-tetra-azaphenanthrene-7-carboxylic acid methyl ester 83 <1998IJH303> (Equation 5). 

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

An intEiesting variant on the Wilgerodt reaction offers a simple three-step procedure that avoids the wastage involved in the schemes above, which require the incorporation of an extra carbon atom that must later be eliminated. The sequence starts with the acylation of isobutylbenzene (49-1) with propionyl chloride to give propiophenone (49-2). Reaction of that with thallium 111 nitrate and methyl ortho-formate in methanol leads in high yield to the methyl ester (49-3) of ibuprofen [50]. This would be the method of choice for preparing the dmg but for two unfortunate facts the extreme toxicity of thallium and the very high sensitivity of analytical methods for the detection of metals. It proved to be virtually impossible, in practice, to produce samples that showed zero residues of thallium. 

Completely different results from those obtained in the photooxidation of 2.4.6-tri-tert-butyl-X phosphorin 24 (p. 54) are obtained in the photooxidation of 1.1-dimethoxy-2.4.6-tri-tert-butyl-X -phosphorin 183, as Schaffer has found. In this case the 2-hydroxy-endoxy-phosphinic acid methyl ester 213 can be isolated in about 20% yield. Its formation can be explained by assuming normal 1.4-addition to 212 as the primary product which is transformed to 213 by hydrolytic ring cleavage of the peroxide bridge, followed by loss of methanol. 

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