Methyl pyridines, purification

Methyl -propyl ketone, 340 Methyl pyridines, purification of, 177-179 N-Methylpyrrole, 837, 838 Methyl red, 621, 625 sodium salt of, 626 Methyl salicylate, 780,782 Methyl sulphite, 304 2-Methylthiophene, 836 Methyl p-toluenesulphonate, 825 Methylurea, 968, 969 Methylene bromide, 300 Methylene chloride, purification of, 176 3 4-Methylenedioxycinnamic acid, 711, 719... 

The N-oxide function has proved useful for the activation of the pyridine ring, directed toward both nucleophilic and electrophilic attack (see Amine oxides). However, pyridine N-oxides have not been used widely ia iadustrial practice, because reactions involving them almost iavariably produce at least some isomeric by-products, a dding to the cost of purification of the desired isomer. Frequently, attack takes place first at the O-substituent, with subsequent rearrangement iato the ring. For example, 3-picoline N-oxide [1003-73-2] (40) reacts with acetic anhydride to give a mixture of pyridone products ia equal amounts, 5-methyl-2-pyridone [1003-68-5] and 3-methyl-2-pyridone [1003-56-1] (11). 

A mixture of 50 g of betamethasone, 50 cc of dimethylformamide, 50 cc of methyl orthobenzoate and 1.5 g of p-toluenesulfonicacid Is heated for 24 hours on oil bath at 105°C while a slow stream of nitrogen is passed through the mixture and the methanol produced as a byproduct of the reaction is distilled off. After addition of 2 cc of pyridine to neutralize the acid catalyst the solvent and the excess of methyl orthobenzoate are almost completely eliminated under vacuum at moderate temperature. The residue Is chromatographed on a column of 1,500 g of neutral aluminum oxide. By elution with ether-petroleum ether 30 g of a crystalline mixture are obtained consisting of the epimeric mixture of 170 ,21 -methyl orthobenzoates. This mixture is dissolved without further purification, in 600 cc of methanol and 240 cc of methanol and 240 cc of aqueous 2 N oxalic acid are added to the solution. The reaction mixture is heated at 40°-50°C on water bath, then concentrated under vacuum. The residue, crystallized from acetone-ether, gives betamethasone 17-benzoate, MP 225°-231°C. 

Turanose Phenylosazone. A mixture of 4 g. of turanose, 2 ec. of water, and 1 co. of phenylhydrazine was warmed on the steam-bath until solution was complete. To the cooled solution was added 3.5 cc. of phenylhydrazine and 4 cc. of glacial acetic acid, and the mixture returned to the steam-bath for one hour. At the expiration of this time, 40 cc. of warm 60% alcohol was added and, upon cooling, a rapid crystallization of the osazone occurred. The osazone was recovered by filtration and washed with absolute alcohol followed by ether to yield 4.2 g. (69%) of lemon-yellow needles. The osazone is soluble in hot water and separates on cooling as jelly-like particles, but water is not a satisfactory solvent for its purification. It was recrystallized from 15 parts of 95% alcohol with good recovery, as needles which melted with decomposition at 200-205° and rotated [ ]d +24.5° - +33.0° (24 hours, constant value c, 0.82) in a mixture of 4 parts of pyridine, by volume, and 6 parts of absolute ethyl alcohol. In methyl cellosolve (ethylene glycol monomethyl ether) solution it rotated C< 3d" + 44.3°— + 48.5° (24 hours, constant value c, 0.80). 

The ease with which dissolution of the acetylated products can be achieved is affected by the method of isolation. In the author s experience, drying of the acetate with alcohol and ether results in apparent insolubility (even though the product was soluble at one stage of the purification process), and should be avoided. Drying, under diminished pressure, of the product precipitated by petroleum ether is sufficient. Chloroform is probably the best solvent. Nitroethane, tetrachlorethane, 2,4-pentanedione, pyridine, methyl acetate, ethyl acetate, and benzene, which have also been suggested, have disadvantages in that either they are unstable or they may cause aggregation in solution.44,116 116... 

Wang resin was purchased from Advanced ChemTech (1% DVB, 0.70mmol/g substitution, 100-200 mash, Cat. SA5009). Anhydrous tetrahydrofuran (THF), A/A-dimcthyl-formamide (DMF), methanol, dichloromethane, pyridine, 1,1 -carbonyldiimidazole (CDI), piperazine, homopiperazine, trans-1,4-diaminocyclohexane, 4-(dimethylamino)pyridine (DMAP), succinic anhydride, diglycolic anhydride, 3-methyl-glutaric anhydride, 2-aminophenol, 2-amino-p-cresol, 2-amino-4-tert-butyl phenol, /V-methylmorpholine (NMM), triphenylphosphine, diethyl azodicarboxylate (DEAD), and trifluoroacetic acid (TFA) were purchased from Aldrich Chemical Company, Inc. and used without further purification. PyBOP was purchased from Novabiochem. 

Methyl 2-pyridyl ketoxime. A solution of 2-acetylpyridine (3, Acros, 27.2 g, 0.225 mole) and hydroxylamine hydrochloride (18.0 g, 0.259 mole) in 100 mL of pyridine is stirred magnetically and heated to reflux in a 250-mL, round-bottomed flask fitted with a water-cooled reflux condenser for 6 h. After removing the solvent on a rotary evaporator, 400 mL of HzO is added, resulting in precipitation of the oxime in the form of a white precipitate which is isolated by vacuum filtration. The filtrate is extracted three times with 100 mL of ether. The white solid is dissolved in ether and combined with the extracts, and then dried with Na2S04. The solvent is evaporated using a rotary evaporator. The crude product (30.0 g, 97%) is used directly in the next step without further purification. 

The preparation of conjugated dienes from pyridines is exemplified by the transformation of 2-picoline into the sex pheromone (669) of Lobesia botrana, a major pest of vineyards (Scheme 154) (80TL67). Thus, the lithio salt of 2-picoline was alkylated by 2-(5-chloropentyl-oxy)tetrahydropyran, the resulting pyridine (665) N-methylated, and the pyridinium salt reduced by sodium borohydride. Quaternization of the 1,2,3,6-tetrahydropyridine (666) and Hofmann elimination gave the (7 , 9Z)-undecadien-l-ol (667) as the sole isomer. Protection of the alcohol and treatment of the corresponding ammonium salt (668) of the amine with lithium dimethylcuprate gave pure (669) after hydrolysis, acetylation and HPLC purification. 

To a stirred solution of the glycosyl donor la (24 mg, 0.037 mmol), 18 mg (0.056 mmol) of methyl 2,3,4-tri-O-acetyl-a-D-glucopyranoside 4 in 1 mL of Et20 was added 7.4 p,L of 1 M MeOTf in CH3N02 and the mixture was stirred at room temperature for 20 h. After addition of 1 drop of pyridine, concentration followed by purification by flash chromatography on silica gel (EtOAc-hexane, 1 2) gave 20 mg of a mixture of a- and p-anomers in 64% yield (ot/p, 5.1 1). 

S-(0-Methyl)mandelic acid chloride was prepared (14-h reflux in 5 mL of benzene) from the S-(0-methyl)mandelic acid (0.33 g, 2.0 mmol) and oxalyl chloride (0.34 mL, 4.0 mmol). The chloride was added to a solution of 3 (0.56 g, 2.0 mmol) and dry pyridine (0.33 mL, 4.0 mmol) in dry toluene (20 mL) at — 10°C. The mixture was then allowed to attain 0°C. After 14 h, toluene was added, and the mixture was washed with water (20 mL). Toluene solution was dried (MgS04) and concentrated to dryness to yield 4 (0.84, 98%), which was used in the next step without purification. 

Cumming s Modification.—(J. S. 0.1., 41, 20.)—A convenient apparatus for the estimation of methoxyl groups by the Zeisel method consists of a long-necked round-bottomed flask attached by a ground-glass joint to a bulbed U-tube. The methyl iodide generated by the interaction of hydriodic acid and the methoxyl group is absorbed in alcoholic silver nitrate. Pyridine may also be used as absorbent. (J. C. S., 117, 193.) For purification of hydriodic acid, see p. 506. 

Pyridine-2,6 dicarboxylate 33.4 g was added to the product from Step 4 (17g) dissolved in 400ml of acetonitrile/water, 7 3, followed by (NH4)2Ce(N03)g (llOg) dissolved in 400 ml acetonitrile/water, 1 1. The mixture was stirred 20 minutes at 0°C and 10 minutes at ambient temperature, poured into 400 ml water and extracted with methyl chloride. The organic layer was dried, concentrated, and 14 g of red crystals isolated after chromatographic purification on silica gel using hexane/EtOAc, 20 1, mp = 59 °C. 

To a cooled solution of 3-methoxy-2-pyridyl 2-azido-2-deoxy-P-D-galactopyranoside (1.5 g, 4.8 mmol), in 20 mL of pyridine, 1.2 mL (5.23 mmol) of t-butyldimethylsilyl tri-fluoromethanesulfate was added dropwise at 0°C over 30 min. The mixture was stirred for 30 min, AcjO (2 mL) was then added. The. solution was kept at 0°C for 15 h. The reaction mixture was poured into ice-water and extracted with CHjClj. The extraction was processed as usual. Purification by flash chromatography on silica gel using 2 1 (v/v) hexane-EtOAc as the irrigant gave 3-methyl-2-pyridyl 3,4-di-0-acetyl-fi-0-t-butyldimethylsilyl-2-azido-2-deoxy-p-D-galactopyranoside as a colorless syrup (2.21 g, 90%) —0.62°... 

Here the biotransformation (Fig. 19-6) is preferred over the chemical reduction with commercially available asymmetric catalysts (BH3- or noble-metal-based), since with the chemocatalysts the desired high enantiomeric excess (ee > 98%, 99.8% after purification) is not achievable. Since the ketone has only a very low solubility in the aqueous phase, 1 kg ketone is added as solution in 4 L 0.9 M H2SO4 to the bioreactor. The bioreduction is essentially carried out in a two-phase system, consisting of the aqueous phase and small droplets made up of substrate and product. The downstream processing consists of multiple extraction steps with methyl ethyl ketone and precipitation induced by pH titration of the pyridine functional group (pfCa = 4.66) with NaOH. The (R)-amino alcohol is an important intermediate for the synthesis of (1-3-agonists that can be used for obesity therapy and to decrease the level of associated type II diabetes, coronary artery disease and hypertension. 

---