反应详情

The thioisobutyramide resulting from Example 73A was dissolved in 70 mls THF and added slowly to a solution of (34.1 g, 0.27 mols) 1,3-dichloracetone in 40 mls THF. A 10 ml rinse of THF was used to completely transfer the thioamide. The reaction was carried out in a 250 ml flask with mechanical stirring under nitrogen atmosphere. The reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath. The bath was kept in place for 1 hour after which it was removed and the reaction stirred for 18 hours. Next this stirred chloromethyl-thiazole solution was added to 376 mls (4.37 mols) 40% aqueous methylamine solution at 15° C. in a 1liter flask. The temperature was maintained below 25° C. during addition. After half an hour the bath was removed and the reaction stirred for 3 hours at ambient temperature. The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls. The residue was then basified with 50 g 10% NaOH to pH 12 and extracted into methylene chloride (2×160 mls). The combined organics were then washed with 1×150 g of 20% ammonium chloride followed by 1×90 g of 20% ammonium chloride. The combined aqueous washes were then back extracted with 150 mls methylene chloride. The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water. This acidic product solution was then washed with 135 mls methylene chloride. Next the acidic product solution was cooled, then neutralized with 100 g 20% NaOH solution. The product was extracted from this mixture with methylene chloride (2×135 mls). The solvent was removed under vacuum to afford the desired product as an amber oil. (yield approx. 28 grams)

1. washA 10 ml rinse of THF
2. customThe reaction was carried out in a 250 ml flask
3. temperatureThe reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath
4. customafter which it was removed
5. stirringthe reaction stirred for 18 hours
6. temperatureThe temperature was maintained below 25° C. during addition
7. customAfter half an hour the bath was removed
8. stirringthe reaction stirred for 3 hours at ambient temperature
9. customThe solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls
10. extractionextracted into methylene chloride (2×160 mls)
11. washThe combined organics were then washed with 1×150 g of 20% ammonium chloride
12. extractionThe combined aqueous washes were then back extracted with 150 mls methylene chloride
13. extractionThe combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water
14. washThis acidic product solution was then washed with 135 mls methylene chloride
15. temperatureNext the acidic product solution was cooled
16. extractionThe product was extracted from this mixture with methylene chloride (2×135 mls)
17. customThe solvent was removed under vacuum