Yield: 67%

Reaction Conditions:

Stage #1:di-tert-butyl-[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl}-oxy]methyl phosphate with hydrogenchloride;water in methanol at -20 - 0; for 5.23 h;
Stage #2: with potassium phosphate;dipotassium hydrogenphosphate;disodium hydrogenphosphate in methanol;water;ethyl acetate
Stage #3:ethanol;L-lysine with hydrogenchloride;acetic acidProduct distribution / selectivity;more than 3 stages;

Steps:

6; 7; 8; 9
Example 6; Lysine [(1R,2R)-2-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl}-oxy]methyl dihydrogen phosphate ethanol (1/1/1); A crude product containing 96g (0.14 mol) net of di-tert-butyl-{[(1R,2R)-2-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl methyl)propyl}-oxy]methyl phosphate synthesized similarly to Example 1 was dissolved by adding 195mL of methanol and cooled at a bath temperature of -20°C. Over 14 minutes, 334mL of concentrated hydrochloric acid was added dropwise thereto, reaction was carried out for 5 hours at 0°C. To the reaction solution was added a mixed solution of 253g of K₂HPO₄ and 206g of Na₂HPO₄ in 1909mL of aqueous solution and 660mL of ethyl acetate. The upper layer was separated, washed with 1.2L of 5% sodium chloride water, and then extracted with 10% K₃PO₄ water (1145mL) twice separately. The K₃PO₄ extracted layer was transferred to a 3L flask, 555mL of butyl acetate was added thereto, and 227mL of an aqueous solution of 5N HCl was added dropwise under stirring. At this moment, the pH of the aqueous layer was 2.2. Next, the organic layer was washed with 555mL of 5% sodium chloride water. A 100mL aqueous solution in which 35.4g of lysine had been dissolved, 55mL of ethanol and 278mL of heptane were added thereto. To the aqueous layer obtained by fractionating the lower layer was added 95mL of ethanol to obtain 313g (A solution). An amount of 78g of A solution was weighed out, 11 mL of acetic acid, 9.1 mL of water and 343mL of ethanol were added, 130mg of seed crystal was added thereto, stirring was carried out for 40 minutes at 40°C followed by stirring for 48 hours at 25°C. The produced crystal was then recovered by filtration. The crystal was washed with 50mL of ethanol and dried for 2 hours at a bath temperature of 50°C to obtain 17.4g of the title compound (yield: 67%) as a faint yellowish white crystal. The obtained crystal was verified to be the same as in Example 2 by NMR data.; Example 7; Lysine [(1R,2R)-2-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl}-oxylmethyl dihydrogen phosphate ethanol (1/1/1); An amount of 78g of the A solution obtained in Example 6 was weighed out, 11 mL of acetic acid, 8.6mL of water and 301 mL of ethanol were added thereto, 130mg of seed crystal was further added, stirring was carried out for 40 minutes at 40°C followed by stirring for 48 hours at 25°C. The produced crystal was then recovered by filtration. The crystal was washed with 50mL of ethanol and dried for 2 hours at a bath temperature of 50°C to obtain 18.7g of the title compound (yield: 72%) as a faint yellowish white crystal. The obtained crystal was verified to be the same as in Example 2 by NMR data.; Example 8; Lysine [(1R,2R)-2-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl}-oxy]methyl dihydrogen phosphate ethanol (1/1/1); An amount of 78g of the A solution obtained in Example 6 was weighed out, 11 mL of acetic acid, 4.6mL of water and 265mL of ethanol were added thereto, 130mg of seed crystal was further added, stirring was carried out for 40 minutes at 40°C followed by stirring for 48 hours at 25°C. The produced crystal was then recovered by filtration. The crystal was washed with 50mL of ethanol and dried for 2 hours at a bath temperature of 50°C to obtain 17.3g of the title compound (yield: 67%) as a faint yellowish white crystal. The obtained crystal was verified to be the same as in Example 2 by NMR data.; Example 9; Lysine [(1R,2R)-2-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl}-oxy]methyl dihydrogen phosphate ethanol (1/1/1); An amount of 78g of the A solution obtained in Example 6 was weighed out, 14.5mL of acetic acid, 11.29mL of water and 470mL of ethanol were added thereto, 130mg of seed crystal was further added, stirring was carried out for 40 minutes at 40°C followed by stirring for 48 hours at 25°C. The produced crystal was then recovered by filtration. The crystal was washed with 50mL of ethanol and dried for 2 hours at a bath temperature of 50°C to obtain 19.4g of the title compound (yield: 75%) as a faint yellowish white crystal. The obtained crystal was verified to be the same as in Example 2 by NMR data.

References:

Eisai R&D Management Co., Ltd. EP1964843, 2008, A1 Location in patent:Page/Page column 19-20