| 13.5% |
With sodium hydrogencarbonate; In tetrahydrofuran; water; ethyl acetate; at 0 - 20℃; for 23h; |
A crude product of methyl azetidine-3-carboxylate hydrochloride (calculated as 1.93 g of pure product) was dissolved in water (26 ml), sodium hydrogencarbonate (3.2 g), then a solution of di-t-butyl dicarbonate (2.91 g) in tetrahydrofuran (13 ml) were added with stirring and cooling in an ice bath, followed by stirring at the same temperature for 0.5 hours. The reaction mixture was stirred at room temperature for 19.5 hours. Tetrahydrofuran in the reaction mixture was distilled off, extraction was performed with ethyl acetate. The organic layer was washed with brine (70 ml) and dried over anhydrous sodium sulfate. The concentrated organic layer and the aqueous layer were combined, and tetrahydrofuran (50 ml) was added thereto. This was stirred with cooling in an ice bath, and sodium hydrogencarbonate (3.2 g), then di-t-butyl dicarbonate (2.91 g) were again added thereto. The reaction mixture was stirred at the same temperature for 0.5 hours, then at room temperature for 2.5 days. The reaction mixture was partitioned, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1, 1:1, ethyl acetate, then ethyl acetate:methanol=10:1). The fractions containing the target compound were concentrated to give the title compound (370 mg, 13.5%) as a colorless oil.1H-NMR Spectrum (CDCl3) delta (ppm): 1.44 (9H, s), 3.35 (1H, m), 3.75 (3H, s), 4.10 (4H, d, J=7.6 Hz). |
| 13.5% |
|
(Production Example 86) Methyl 1-tert-butoxycarbonylazetidine-3-carboxylate A crude product of methyl azetidine-3-carboxylate hydrochloride (assessed as 1.93 g of a pure product) was dissolved in water (26 ml), and sodium hydrogencarbonate (3.2 g) and a solution of di-t-butyl dicarbonate (2.91 g) in tetrahydrofuran (13 ml) were added while stirring and cooling in an ice bath, followed by stirring at the same temperature for 0.5 hr. The reaction mixture was stirred at room temperature for 19.5 hr. Tetrahydrofuran in the reaction mixture was removed, and extracted with ethyl acetate. The organic layer was washed with brine (70 ml), and dried over anhydrous sodium sulfate. The concentrated organic layer and the aqueous layer were combined, and tetrahydrofuran (50 ml) was added. This was stirred while cooling in an ice bath, and sodium hydrogencarbonate (3.2 g), and di-t-butyl dicarbonate (2.91 g) were again added thereto. After stirring at the same temperature for 0.5 hr, stirring was carried out at room temperature for 2.5 days. The reaction mixture was partitioned, and the aqueous layer was extracted with ethyl acetate. The organic layer was combined and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate = 2:1, 1:1, ethyl acetate, then ethyl acetate:methanol = 10:1). Fractions containing the target compound were concentrated to provide the titled compound as a colorless oil (370 mg, 13.5 %). 1H-NMR Spectrum (CDCl3) delta (ppm): 1.44(9H, s), 3.35 (1H, m), 3.75 (3H, s), 4.10 (4H, d, J = 7.6 Hz). |
| 582 kg |
|
Triethylamine (TEA, 560 kg, 5544 mol, 2.18 eq) was added dropwise to the crudesolution of 2 at 5-10 C giving a vigorous exothermic reaction over about 7 hrs. The mixture was cooled to 5-15 C. More triethylamine was added (210 kg, 2082 mol, 0.82 eq). Di-tertbutyl dicarbonate (boc anhydride, Boc2O, CAS Reg. No. 24424-99-5 (587 kg, 2690 mol, 1.06eq.) dropwise at 5-15 C, giving a slightly exothermic reaction with gas generated for about 7 hrs. The mixture was stirred at 1 520 C for 16 hrs. Methanol was removed by evaporation at 50C over about 5 hrs. Toluene (1360 kg, 5.3 wt) and water (1750 kg, 6.8 wt) were added and stirred for 20 mm. The organic phases were separated. The water phase was extracted with toluene. The combined organic phases were washed with brine and dried over MgSO4 (150 kg, 0.58 wt) for 30 mm, and filtered. The filter cake was washed with toluene. The combined organic phases were evaporated at 50-60 C under vacuum. (vacuum: about 0.08 Mpa, about 40 hrs) to give 3 (CAS Reg. No. 610791-05-4, 582 kg 90.4 w% by qNMR assay)in 96.4% corrected yield. |
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