Example 1, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Preparation fluorophenyl] glucitol (compound 3) –
Zinc bromide (0.676 g) and lithium bromide (0.261 g) was added n-butyl ether (8mL), stirred and heated to 50 deg.] C 2h, cooling backup. Under nitrogen, was added 2- (5-iodo-2-fluorobenzyl) benzothiophene (2.21g) in toluene (5mL), n-butyl ether (5mL), cooled to -25 deg.] C, was slowly added dropwise 1.6mol / L n-hexyl lithium hexane solution (4.13 ml), to control the internal temperature does not exceed -10 deg.] C, after the addition was complete the reaction was incubated at -20 ℃ 0.5h, a solution of n-butyl ether was added to the backup lithium bromide and zinc bromide, at 10 ℃ reaction was stirred 3h. Was added 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (3.48 g of) in toluene (10 mL) solution and heated to 80 deg.] C the reaction was stirred 6h, TLC analysis after completion of the reaction, was added 1mol / L dilute hydrochloric acid (7mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, concentrated, and n-heptane (5mL) and methanol (15mL) recrystallized 3.452g 3 of solid compound, yield: 77.65%. Purity: 99.45%. Melting point: 128.9 ~ 130.5 ℃. 1 the H-NMR (CDCl 3 ): [delta] 7.72 (IH, D), 7.64 (IH, D), 7.21-7.30 (4H, m), 7.04 (IH, T), 6.96 (IH, S), 5.40 ( 1H, t), 5.27 (2H , m), 4.36 (1H, d), 4.08-4.21 (4H, m), 3.82 (1H, dd), 1.19 (9H, s), 1.16 (9H, s), 1.11 (9H, s), 0.85 ( 9H, s).
Example 2, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Preparation fluorophenyl] glucitol (compound 3) –
Zinc bromide (0.676 g) and lithium bromide (0.261 g) was added n-butyl ether (8mL), stirred and heated to 50 deg.] C 2h, cooling backup. Under nitrogen, was added 2- toluene (5mL) (5- iodo-2-fluorobenzyl) benzothiophene (2.21g) in n-butyl ether (5mL), cooled to – 50 ℃, was slowly added dropwise 2.5mol / L n-butyllithium hexane solution (2.64 mL), controlling the internal temperature does not exceed -30 deg.] C, 6h after the addition was complete the reaction was kept at -50 deg.] C, was added a solution of n-butyl ether in said auxiliary zinc bromide and lithium bromide, the reaction was stirred 8h at -20 ℃. Was added 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (6.954g) in toluene (12mL) solution, heated to 25 deg.] C the reaction was stirred 24h, after completion of the reaction by TLC, was added 1mol / L dilute hydrochloric acid (8mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, concentrated, and n-heptane (5mL) and methanol (15mL) recrystallized 3.237g 3 of solid compound, yield: 72.81%. Purity: 99.36%.
Example 3, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Preparation fluorophenyl] glucitol (compound 3) –
Zinc iodide (1.915g) and lithium iodide (0.803 g) in n-butyl ether was added (10mL), stirred and heated to 50 deg.] C 1.5h, cool reserve. Under nitrogen, was added 2- (5-iodo-2-fluorobenzyl) benzothiophene (2.21g) in toluene (9mL), n-butyl ether (3mL), cooled to -30 deg.] C, was slowly added dropwise 1.6mol / L n-hexyl lithium hexane solution (4.13mL), controlling the internal temperature does not exceed -20 ℃, n-butyl ether solution after the addition was complete the reaction was kept at -30 ℃ at 5h, zinc iodide was added to the backup and lithium iodide the mixture was stirred at 25 ℃ reaction 1h. After addition of 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (4.346g) in toluene (10 mL) solution, the reaction was heated to reflux for 145 ℃ 0.5h, TLC detection completion of the reaction , was added 1mol / L dilute hydrochloric acid (8mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, concentrated, and n-heptane (5mL) and methanol (15mL) recrystallized 3.552 3 g of a solid compound in a yield of 79.9%. Purity: 99.41%.
Example 4, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Preparation fluorophenyl] glucitol (compound 3) –
Zinc bromide (0.676 g) and lithium bromide (0.261 g) was added n-butyl ether (7mL), stirred and heated to 50 deg.] C 2h, cooling backup. Under nitrogen atmosphere, 2- (5-bromo-2-yl) benzothiophene (1.927g) was added toluene (6mL), n-butyl ether (4mL), cooled to -30 deg.] C, was slowly added dropwise 2.5mol / L n-butyllithium hexane solution (2.88 mL), controlling the internal temperature does not exceed -20 deg.] C, 3h after the addition was complete the reaction was kept at -30 deg.] C, was added a solution of n-butyl ether in said auxiliary zinc bromide and lithium bromide, the reaction was kept at -5 ℃ 4h, was added 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (4.346g) in toluene (7mL) solution, stirred and heated to 120 ℃ The reaction 4h, after completion of the reaction by TLC, was added 1mol / L dilute hydrochloric acid (8mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, and concentrated under reduced pressure, n-heptane (5mL ) and methanol (15mL) recrystallized 2.783g solid compound 3, yield: 62.6%. Purity: 99.29%.
EXAMPLE 5, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Preparation fluorophenyl] glucitol (compound 3) –
Zinc bromide (0.676 g) and lithium bromide (0.261 g) was added cyclopentyl ether (8mL), stirred and heated to 50 deg.] C 2h, cooling backup. Under nitrogen, was added 2- (5-iodo-2-fluorobenzyl) benzothiophene (2.21g) in toluene (6mL), cyclopentyl methyl ether (6mL), cooled to -30 deg.] C, was slowly added dropwise 1.6 mol / L hexane solution of n-hexyl lithium (4.5mL), controlling the internal temperature does not exceed -20 ℃, after the addition was complete the reaction was kept at -30 ℃ at 3h, added to the backup lithium bromide and zinc bromide cyclopentylmethyl the ether solution, the reaction incubated at -5 ℃ 4h, was added 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (4.346g) in toluene (8mL) solution, heated to 120 ℃ reaction was stirred 4h, after completion of the reaction by TLC, was added 1mol / L dilute hydrochloric acid (8mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, and concentrated under reduced pressure, with n-heptane dioxane (5mL) and methanol (15mL) recrystallized 2.088g solid compound 3, yield: 47%. Purity: 99.3%.
6, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Example Preparation fluorophenyl] glucitol (compound 3) –
Zinc bromide (0.676 g) and lithium bromide (0.261 g) was added methyl t-butyl ether (8mL), was heated to 50 ℃ stirred 3h, cooling backup. Under nitrogen, was added 2- toluene (6mL), methyl t-butyl ether (4mL) (5- iodo-2-fluorobenzyl) benzothiophene (2.21g), cooled to -40 deg.] C, was slowly added dropwise 1.6 mol / L n-hexyl lithium hexane solution (3.94mL), controlling the internal temperature does not exceed -30 ℃, after the addition was complete the reaction was kept at -40 ℃ at 4h, was added to the lithium bromide and zinc bromide spare methyl tert-butyl ether solution, the reaction incubated at 5 ℃ 7H, was added 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (3.48 g of) in toluene (8mL) solution, heated to 90 ℃ reaction was stirred 6h, after completion of the reaction by TLC, was added 1mol / L dilute hydrochloric acid (8mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, and concentrated under reduced pressure, with n-heptane dioxane (5mL) and methanol (15mL) recrystallized 2.792g solid compound 3, yield: 62.8%. Purity: 99.44%.
Example 7, (1S) -1,5- anhydro-1- [3- (1-methyl-thiophen-2-yl) -4-fluorophenyl] -D-glucitol (Compound 2) preparation
Compound 3 (7.41g) was added methanol (35mL), was added sodium methoxide (2.161g), heated at reflux for 5H reaction, after completion of the reaction by TLC, concentrated and the residue was added methanol (10 mL), water (10 mL), acetic acid ( 3g), was added seed crystal (0.1g), stirred at 5 ℃ crystallization, filtration, the filter cake washed with cold (methanol: (5mL) was washed with 1) solvent to give an off-white solid 3.89g compound 2: water = 1 , yield: 96.2%. Purity: 99.29%. 1 the H-NMR (the CD 3 the OD): [delta] 7.70 (IH, D), 7.63 (IH, D), 7.43 (IH, dd), 7.34-7.38 (IH, m), 7.21-7.26 (2H, m) , 7.08 (1H, t), 7.01 (1H, s), 4.18-4.28 (2H, m), 4.12 (1H, d), 3.88 (1H, dd), 3.70 (1H, dd), 3.30-3.50 (4H , m).
Example 8, (1S) -1,5- anhydro-1- [3- (1-methyl-thiophen-2-yl) -4-fluorophenyl] -D-glucitol (Compound 2) preparatio
Methanol was added (15mL) of the compound 3 (7.41g) was added sodium hydroxide (2g) in water (10 mL) solution was heated to 50 deg.] C the reaction was stirred 10h, TLC detection after completion of the reaction, water (10mL), 2mol / L hydrochloric acid (2mL), stirred at room temperature for crystallization, white solid was suction filtered, the filter cake washed with water (5mL) was washed and dried to give 3.806g of compound 2, yield: 94.1%. Purity: 99.31%.
Preparation 9, Ignatius column eutectic net L- proline (Compound 1) Example
Net Ignatius column (compound 2) (4.04g) was added ethanol (25mL), was added L- proline (1.15 g of), the reaction was heated at reflux for 1h, cooled to room temperature, filtered, the filter cake washed with cold ethanol, and dried to give white solid 4.67g of compound 1. Yield: 90%. Purity: 99.51%. Melting point: 194.0 ~ 202.1 ℃. The MS-ESI (m / Z): 427.16 [the M + of Na] + . 1 the H-NMR (the CD 3 the OD): [delta] 7.75 (IH, D), 7.67 (IH, D), 7.45 (IH, dd), 7.37 (IH, m), 7.24-7.31 (2H, m), 7.10 (1H, t), 7.07 ( 1H, s), 4.23-4.32 (2H, m), 4.13 (1H, d), 3.98 (1H, t), 3.89 (1H, d), 3.71 (1H, dd),3.31-3.50 (5H, m), 3.21-3.27 (1H, m), 2.27-2.34 (1H, m), 2.09-2.17 (1H, m), 1.95-2.02 (2H, m).
Claims
Ignatius one kind of column and net synthesis process, comprising the steps of: (1), from 4-fluoro-3- (2-benzothienyl) methyl-5-phenyl-halide as a raw material, in an appropriate solvent 5 is reacted with an alkyl lithium, followed by reaction with the zinc salt prepared organozinc reagents – bis [4-fluoro-3- (2-benzothienyl) methyl phenyl] zinc, and then with 2,3,4,6-tetra -O- pivaloyl -α-D- glucopyranose 4-bromo nucleophilic substitution reaction of intermediate net Ignatius column 3; (2), compound 3 by an organic base off pivaloyl protecting group prepared net Ignatius column 2; wherein, in the 4-fluoro-3- (2-benzothienyl) methyl-5-phenyl halide of structure X is selected from bromo or iodo; synthesis route is as follows:

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