Pyridines methyl-, pure

The easier elimination of pyridine compared to quinoline-4 may be related to the pK value of 4-methylthiazole, which is between those of lepidine and 2-picoline (25. 55). This reaction explains also why a neutrodimethine cyanine is obtained with such good yields when reacting together a quaternary salt, ketomethylene, and o-ester in a basic medium. As the reaction proceeds, the trimethine cyanine is attacked by the ketomethylene. The resulting 2-methyl quaternary salt is transformed into trimethine cyanine, consuming the totality of the ketomethylene (1, p. 512 661). The mesosubstituted neutrodimethine cyanine is practically pure. 

Preparation of 9, 11 -Epoxy-17a-21 -Dihydroxy-16 -Methyl-4-Pregnene-3 0-Dione 21-Acetate To a stirred solution of 100 mg of the 9a-bromo-11(3,17a,2Ttrihydroxy-16 3-methyl-4-pregnene-3,20-dione 21-acetate in 3 ml of tetrahydrofuran and 1 ml of methanol under nitrogen was added 1.02 ml of 0.215 N methanolic sodium methoxide. After 10 minutes at 25°C, 0.2 ml of acetic acid was added and the methanol removed in vacuo. The residue was acetylated with 1.00 ml of pyridine and 0.5 ml of acetic anhydride at 60°C for 70 minutes. The mixture was taken to dryness in vacuo, water added, and the product extracted into chloroform. The residue was crystallized from ether-acetone to give pure 9(3,11 (3-epoxy-17a,21-dihydroxy-16(3-methyl-4-pregnene-3,20-dione 21-acetate. 

Preparation of 3-(N-Formyl-N-Methyl)-Aminopropyl Chloride 50 grams of 3-(N-formyl-N-methyl)-aminopropanol-1 obtained above is dissolved in a mixture of 100 ml of chloroform and 25 grams of pyridine. 40 grams of thionyl chloride is then slowly added while maintaining the temperature below 65°C. After 6 hours of refluxing, the mixture is washed with water, then with sodium bicarbonate solution and again with water and then dried over magnesium sulfate and the solvent distilled off in vacuo. Fractional distillation at 1 mm pressure yields substantially pure 3-(N-formyl-N-methyl)-aminopropyl chloride. 

In a i-l. three-necked flask fitted with a fetirrer and thermometer are placed 93 g. (0.5 mole) of dodecanol (Note 1) and 158 g. (2 moles) of pyridine. The flask is surrounded by a water bath sufficiently cold to lower the temperature of the mixture to io°. At this temperature 105 g. (0.55 mole) of />-toluenesul-fonyl chloride is added in portions over a twenty- to thirty-minute period, or at such a rate that the temperature does not exceed 20° at any time. The mixture is then stirred for three hours at a temperature below 20°, after which it is diluted with 300 cc. of hydrochloric acid (sp.gr. 1.19) in 11. of ice water. The ester which crystallizes is collected on a chilled Buchner funnel and sucked as dry as possible. The solid is transferred to a 600-cc. beaker, 250--300 cc. of methyl alcohol is added, and the mixture is warmed on the steam bath until the ester melts. It is then cooled in a freezing mixture while being stirred continuously the ester separates in a fairly fine state. It is then collected on a chilled funnel and allowed to dry in the air, preferably at a temperature, below 20°. The yield of ester is 152-156 g. (88-90 per cent of the theoretical amount based upon the dodecanol used). It melts at 20-250 (Note 2) and is sufficiently pure for most purposes. 

Sodium borohydride, even in a very large excess, reduced methyl 2-none-noate and methyl cinnamate incompletely to mixtures of saturated esters, unsaturated alcohols and saturated alcohols [1061]. On the other hand, a,p-unsaturated esters of pyridine and pyrimidine series were converted predominantly and even exclusively to saturated alcohols. Methyl 3-(7-pyri-dyl)acrylate gave, on refluxing for 1-2 hours in methanol with 10 mol of sodium hydride per mol of the ester, 67% of 3-(y-pyridyl)propanol and 6% of 3-(y-pyridyl)-2-propenol methyl 3-(6-pyrimidyl)acrylate gave 77% of pure 3-(6-pyrimidyl)propanol [1061]. 

The C-hydroxylation of benzoquinolizinium ions is easier and, although the position of the attack on benzo[a]quinolizinium (2) salts is not known, it has been demonstrated (67JOC733) that hydroxylation of the acridizinium (benzo[6]quinolizinium, 3) ion must occur at position 6 (Scheme 8). It was not possible to obtain a pure sample of the pseudobase (17) or the 2-(2-formylbenzyl)pyridine (18) in equilibrium with it, but oxidation of the mixture with ferricyanide afforded a small amount of benzo[Z>]quinolizinone (19) (62CI(L)1292), while reaction with hydroxylamine afforded a good yield of 2-(2.-pyridyl-methyl)benzaldoxime (20) (67JOC733). 

Sulfmyl hydrazones, such as 68, reacting as 1-azabuta-l,3-dienes, undergo cycloaddition reactions with A -methyl-maleimide (NMM), to form tetrahydropyrrolo[3,4-. ]pyridine derivatives in low yield. The reaction occurs to form enantiomerically pure adduct 69 with complete endo- and facial selectivities (Equation 14) <200382241 >. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

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. 

Thermally induced isomerization of the benzocyclobutane (83) gives the pyrroloisoquino-line (84), the pyridine ring of which can be aromatized with iron(III) chloride (Scheme 29). Similarly, the aldehyde (85 X = 0) or its O-methyl oxime (85 X = NOMe) gives the cis-trans mixture (86). If p- toluenesulfonic acid is included in the reaction mixture the pure cis compounds are obtained (72AG(E)l03l). 

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