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With sodium methylate; In N-methyl-acetamide; methanol; water;
EXAMPLE 8 Synthesis 2-hydroxymethyl-4-Methoxy-3,5-Lutidine In a round bottom flask equipped with a stirrer, a condenser and a nitrogen bubbler, <strong>[150054-50-5]4-Chloro-2-hydroxymethyl-3,5-Lutidine</strong> (1 eq.) was dissolved in Dimethylformamide (3-9 volumes) and Methanol (1.5-4.5 volumes). Sodium methoxide (4 eq.) was added and the temperature was raised to (95-100.image. C.). At the end of the reaction the solvent was distilled under vacuum. Water (2 volumes) was added to the residue and the product was extracted with dichloromethane (2*4 volumes). The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product, 2-hydroxymethyl-4-Methoxy-3,5-lutidine, was obtained in 55percent yield. In another work-up method, after evaporation of the dimethylformamide/methanol, water (2 volumes was added to the residue and the product was extracted with toluene (3*4 volumes). The organic extracts were combined and while cooling and stirring HCl gas (1.2 eq.) was bubbled into solution. The product 2-hydroxymethyl-4-Methoxy-3,5-lutidine hydrochloride salt was filtered and washed with toluene. The crude product was obtained as a white solid in 50percent yield.
Pyrmethyl alcohol (8.8 g, 52.6 mmol) was dissolved in toluene (75 [ML,] water content 0.12 mg/ml) moistened with water [(180 GEL,] 10 mmol) at room temperature. To the stirred solution, at [25-30 °C,] thionyl chloride (8.15 g, 68.5 mmole) was added slowly over 60 min. (flow rate of 0.083 ml/min). Conversion of the reaction was analysed with HPLC as in Example 1. Conversion over 99.5percent. Water (2.3 ml) was added to quench any excess of thionyl chloride. An alkaline (13.5 g, 168.3 mmol 50 percent w/w sodium hydroxide) aqueous (80 ml) solution of metmercazole (9.8 g, 54.2 mmol) was added followed by additional sodium hydroxide (8.8 g, 110.5 mmol, 50 percent w/w sodium hydroxide) to reach pH>12.5. The temperature was allowed to increase to 45 °C during the additions. The reaction mixture was left with vigorous stirring for approximately two hours at [45 °C.] The agitating was interrupted and the phases were left to separate. The aqueous phase was discarded. The organic phase, comprising pyrmetazole, was washed with water and was analysed for residues of pyrmethyl alcohol (less than 0.1 percent mol).; Example 5 Pyrmethyl alcohol (8.8 g, 52.6 mmol) was dissolved in toluene (75 ml, water content 0.12 mg/ml) moistened with water [(375) J. I,] 20.8 mmol) at room temperature. To the stirred solution, at [25-35 °C,] thionyl chloride (9.33 g, 78.4 mmol) was added slowly over 60 min. (flow rate of 0.095 ml/min). Conversion of the reaction was analysed with HPLC as in Example 1. Conversion over 99.5 percent. The synthesis continued in the same way as described in Example 4. The product phase, comprising pyrmetazole, was analysed for residue of pyrmethyl alcohol (less than 0.1 percent mol).
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