Producing Z-isomer of hydrogen bromide salt of 2-aminothiazole derivative
a technology of hydrogen bromide salt and 2-aminothiazole, which is applied in the direction of organic active ingredients, organic chemistry, heterocyclic compound active ingredients, etc., can solve the problems of inability to reproduce the particulars of how to control the exothermic reaction, and the process is not always satisfactory as an industrial production method
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production example 1
of Methyl 2-propylidene-4-bromoacetoacetate
[0242] Into a solution obtained by dissolving 35.6 g (593 mmol) of acetic acid in 369 g of 1-chlorobutane, three components, including 253.5 g (1300 mmol) of methyl 4-bromoacetoacetate, 172.2 g (2964 mmol) of propionaldehyde and 12.6 g (148 mmol) of piperidine, were added separately in parallel over a period of 6 hours at -25 to -30.degree. C. After being held at that temperature for 2 hours, the reaction mixture was poured into 378 g of a 1.4% aqueous hydrochloric acid. The mixture was heated to 5.degree. C. and separated into an aqueous and organic layer. The organic layer was washed with 426 g of an aqueous sodium hydrogensulfite solution (40.7 g in terms of sulfurous acid gas) at 0 to 5.degree. C., and the oil layer separated was further washed with 363 g of water to give 732 g of a solution containing 267 g (1135 mmol, 87% yield) of methyl 2-propylidene-4-bromoacetoacetate in 1-chlorobutane.
example 1
[0243] To 18.7 g of the solution containing methyl 2-propylidene-4-bromoac-etoacetate in 1-chlorobutane obtained in Production Example 1, which solution contains (6.79 g, 28.9 mmol of pure methyl 2-propylidene-4-bromoacetoacetate), 9.8 g of 1-chlorobutane and 9.8 g of acetone were added, and the mixture was cooled to -30.degree. C. To the resulting solution, a solution obtained by dissolving 2.49 g (32.8 mmol) of thiourea in 10.3 g of N,N-dimethylformamide was poured quickly and stirred at 20.degree. C. for 5 minutes. The mixture was poured into 9.1 g of 1-chlorobutane which had been cooled to -10.degree. C. to give 60.2 g of a solution containing 5.08 g (17.3 mmol, 59.9% yield) of a hydrogen bromide salt of methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate and 2.40 g (8.2 mmol, 28.4% yield) of a hydrogen bromide salt of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoate. (The E / Z ratio was 32 / 68.)
examples 2 to 12
[0244] The results shown in Table 1 were obtained by carrying out the reaction in the same manner as Example 1 except that the reaction temperature and the reaction time were set to the values provided in Table 1.
1 TABLE 1 Reaction Reaction Z-isomer temperature time yield E / Z (.degree. C.) (minute) (%) ratio Example 2 20 10 57.9 33 / 67 Example 3 20 15 57.0 34 / 66 Example 4 20 20 56.0 35 / 65 Example 5 25 5 58.9 33 / 67 Example 6 25 7.5 58.3 33 / 67 Example 7 25 10 58.2 34 / 66 Example 8 30 3.5 57.7 33 / 67 Example 9 30 5 57.5 34 / 66 Example 10 30 7.5 56.5 35 / 65 Example 11 35 2 56.4 34 / 66 Example 12 35 5 55.5 36 / 64
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