Methylene Methyl Ethyl Acetic Acid

Methylene Iodide, 1, 57 7, 90 0-Methyl Esculetin, 4, 45 df-METHYL Ethyl Acetic Acid, 5,75 Methyl formate, 3, 67 a-M ETHYL d-GLUCOSIDE, 6, 64... 

Methylene iodide, I, 57-59 /3-Methyl esculetin, IV, 45-46 (//-Methyl ethyl acetic acid, V, 75-77 Methyl formate, III, 67 Methyl hexyl carbinol, I, 61-66 Methyl iodide, I, 57, 59 5-Methyl isatin, V, 74 Methyl o-nitrobenzoate, III, 72 Methyl m-nitrobenzoate, III, 71-72, 73-Methyl oxalate, V, 60 Methyl Red, II, 47-51... 

Fig. 1. Ultraviolet absorption of solvents (HPLC grade unless otherwise stated). A, acetonitrile (far-UV grade) B, methyl tert-butyl ether C, acetonitrile D, 1-chlorobutane E, methylene chloride F, acetic acid (AR grade) G, ethyl acetate H, acetone I, hexane J, iso-octane K, methanol L, tetrahydro-furan M, chloroform N, diethylamine (ARgrade).

Derivatization Dissolve less than 1 mg of methyl or ethyl ester in 1 ml of freshly distilled pyrrolidine and 0.1 ml of acetic acid. Heat the mixture in a sealed or capped tube (able to withstand high temperatures) at 100° for 30 min. Cool the reaction mixture to room temperature and add 2 ml of methylene chloride. Wash the methylene chloride extract with dilute HC1, followed by ion exchange water. Dry the methylene chloride extract with anhydrous magnesium sulfate.1... 

The nitration of both 4-methyl- and 4-chloro-2,6-dinitrotoluenes (66 and 67) with mixed acid in acetic acid at subambient temperature allows the isolation of the nitramines, (68) and (69), respectively. Thermolysis of (68) and (69) in refluxing methylene chloride yields the corresponding diazophenols, (70) and (71), respectively. Scilly and co-workers isolated 2-diazo-4,6-dinitrophenol (DINOL) (53) from the thermolysis of fV,2,3,5-tetranitroaniline (73) in ethyl acetate at 60 °C. 

Heating ethyl 5-fluoro-4-[cyano(ethoxycarbonyl)methyl]-2,3-dihydro-l-methyl-7-oxo-l//,7//-pyrido[3,2,l-i7]cinnoline-8-carboxylate (83, R = COOEt) in a mixture of cone. HCl and acetic acid gave the 8-carboxy-4-acetic acid derivative (92EUP470578). The acetic acid group was decarboxylated by heating in boiling ethanol in the presence of NEts to give the 4-methyl derivative. When the 4-[cyano(tert-butoxycarbonyl)methyl]-8-carboxylate 83 (R = COOrBu) was treated with trifluoroacetic acid in methylene chloride at room temperature, the 4-cyanomethyl-8-carboxylate 83 (R = H) was obtained. 

Ethylene glycol in the presence of an acid catalyst readily reacts with aldehydes and ketones to form cyclic acetals and ketals (60). 1,3-Dioxolane [646-06-0] is the product of condensing formaldehyde and ethylene glycol. Applications for 1,3-dioxolane are as a solvent replacement for methylene chloride, 1,2-dichloroethane, 1,1,1-trichloroethane, and methyl ethyl ketone as a solvent for polymers as an inhibitor in 1,1,1-trichloroethane as a polymer or matrix interaction product for metal working and electroplating in lithium batteries and in the electronics industry (61). 1,3-Dioxolane can also be used in the formation of polyacetals, both for homopolymerization and as a comonomer with formaldehyde. Cyclic acetals and ketals are used as protecting groups for reaction-sensitive aldehydes and ketones in natural product synthesis and pharmaceuticals (62). 

To the suspension of 12.8 g of 2-methyl-3,4-dioxo-l,3,4,14b-tetrahydro-10H-pyrazino[l,2-a]pyrrolo[2,l-c][l,4]benzodiazepine in 460 ml of tetrahydrofuran, 200 ml of 1-molar diborane in tetrahydrofuran are added while stirring and cooling with ice. The mixture is refluxed for one hour, again cooled and combined with 25 ml of acetic acid. It is evaporated, the residue taken up in 50 ml of 30% aqueous sodium hydroxide and the mixture extracted with methylene chloride. The extract is dried, evaporated, the residue dissolved in diethyl ether, the solution filtered and the filtrate evaporated, to yield the crude 2-methyl-l,3,4,14b-tetrahydro-10H-pyrazino[l,2-a]pyrrolo[2,l-c][l,4]benzodiazepine. It is triturated with ethyl acetate-diethyl ether, chromatographed on 70 g of silica gel and eluted with methanol-chloroform (1 9). The eluate is evaporated and the residue salified. 

A solution of 3-chloroperbenzoic acid (55%) in methylene chloride is cooled in an ice bath. (5R)-(-)-Carvone are added dropwise thereto so that the temperature does not rise above 20°C. The reaction mixture is stirred at room temperature for 3.5 h, whereby a precipitate of 3-chlorobenzoic acid forms. This suspension is stirred for 30 min and cooled with ice in order to complete the precipitation. The precipitate is filtered off and washed with hexane/methylene chloride (9 1). The filtrate is evaporated carefully. The thus-obtained oil (epoxide) is suspended in ice-water and treated with 3 N sulfuric acid while cooling in an ice bath so that the temperature does not rise above 20°C. The mixture is stirred at room temperature for 15 h. The pH is adjusted to 6.5 by adding 3 N sodium hydroxide solution. A small amount of 3-chlorobenzoic acid is filtered off. The aqueous phase is cooled to 0°C, whereupon sodium (meta)periodate are added in portions over 30 min so that the temperature does not rise above 20°C. After stirring at room temperature for 2 h sodium sulfite and sodium bicarbonate are added in succession. The suspension is filtered and the filtrate is extracted three times with methylene chloride each time. The combined organic phases are dried over sodium sulfate and evaporated. There is obtained (5R)-5-acetyl-2-methyl-2-cyclohexen-l-one (crystallized from hexane/ethyl acetate at 0°C). 

D) Preparation of 2-(l-Flydroxyethyl)-3-Methyl-5-(2-Oxo-2,5-Dihydro-4-Furyl)Benzo[b]-Furan (3574 CB) 13.2 grams of compound 3556 CB of which the preparation is described in (C) are treated successively with 66 ml of methylene chloride, 27 ml of methanol and, with stirring, 1.6 grams of sodium borohydride added in stages. The reaction takes 1 hour. The mixture is poured into water acidified with a sufficient amount of acetic acid, the solvents are stripped under vacuum, the crystalline product removed, washed with water, and recrystallized from ethyl acetate. Yield 90%. MPk= 158°C. 

To a solution of 2-ethoxy-l-[[2 -(lH-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid (2.07 g) in methylene chloride (10 ml) were added trityl chloride (1.59 g) and triethylamine (0.8 ml). The mixture was stirred at room temperature for 1 hour. The mixture was washed with water and concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals 2-ethoxy-l-[[2 -(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid (2.12 g, 66%), M.P. 168-170°C. 

A solution of 23.9 g (100 mMol) of methyl 3,4-diaminobenzoate dihydrochloride and 11.7 g (110 mMol) of butyric acid chloride in 100 ml of phosphorus oxychloride is refluxed for 2 h. Then about 80 ml of phosphorus oxychloride are distilled off and the residue is mixed with about 150 ml of water. The oily crude product precipitated is extracted three times with 50 ml of ethyl acetate and after evaporation purified by column chromatography (600 g of silica gel eluant methylene chloride/methanol (30 1)). Yield of methyl-2-n-propyl-benzimidazole-5-carboxylate 15.0 g of oil (69%). 

To a 2 L, 3-neck Morton flask fitted with a thermometer, a mechanical stirrer, and an addition funnel was added the methyl 3-hydroxy-2-methylene-3-phenylpropionate (305.9 g, 1.585 mol) followed by addition of 48% HBr (505 ml, 4.46 mol) in one portion. The flask was immersed in an ice-water bath, at which time concentrated sulfuric acid (460 ml, 8.62 mol) was added dropwise over 90 min and the internal temperature of the reaction mixture was maintained at 23°-27°C throughout the addition process. After removal of the ice-water bath, the mixture was allowed to stir at room temperature overnight. The solution was then transferred to a separatory funnel and the organic layer was allowed to separate from the acid layer. The acids were drained and the organic layer was diluted with 2 L of a 1 1 ethyl acetate/hexane solution, washed with saturated aqueous sodium bicarbonate solution (1 L), dried over sodium sulfate, and concentrated to yield 400.0 g (99%) of the desired (Z)-l-bromo-2-carbomethoxy-3-phenyl-2-propene as a light yellow oil, which was used without any additional purification, boiling point 180°C (12 mm). 

Although PPE is the most efficient and inexpensive extraction technique, it is also the most nonspecific extraction procedure which is known to be susceptible to matrix effect for LC-MS/MS assay. In contrast, LLE provides a much cleaner extract. LLE, also known as solvent extraction and partitioning, separates analytes based on their relative solubility in two different immiscible solvents, usually water and an organic solvent. The most commonly used solvents for LLE are ethyl acetate (EtOAc), methyl ferf-butyl-ether (MtBE), methylene chloride (CH2C12), and hexane or the combination of the above solvents. In order to manipulate the polarity of the analytes, often a volatile acid or base such as FA or NH4OH respectively at 5-10 %... 

We can arrive at the same conclusion in a different way using an alternative analysis based on the values in Appendix C. The pK of the protons on the a carbon of ethyl acetate is 30, whereas the pK of those of methyl cyanoacetate is 12.8. Therefore, a cyano group lowers the pK of the a carbon protons by 30 - 12.8 = 17 units. The pK of the a carbon protons of an N,N-disubstituted amide, A,A-diethylacetamide, is 34.5. If we assume that the cyano group enhances the acidity of the methylene protons in the given compound by the same amount, their pK would be 34.5 - 17 = 16.5. Thus, the estimated pK of the methylene protons is at least 9 pA units lower than that of the amide proton, a factor of one billion. 

Neutral Solutes. In the reversed-phase mode, water is used as the weak solvent and acetonitrile, methanol, or THF (where applicable) is used as the strong solvent. (It is notable that the addition of acid or base to the mobile phase used for neutral molecules does not preclude separation, and, as such, the approach outlined later for ionizable components is equally viable.) In normal-phase HPLC, hexane is used as the weak solvent and isopropanol is used as the strong solvent. To change selectivity based on the strong solvent, isopropanol may be replaced (in part) with methylene chloride, methyl t-butyl ether, or ethyl acetate. However, note should be made of the relatively high UV cutoffs of these solvents when UV detection is to be used and precautions should be taken to ensure solvent miscibility across the range of the gradient. 

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