PREPARATION METHOD FOR SGLT2 INHIBITOR INTERMEDIATE V

Abstract

Disclosed is a preparation method for an SGLT2 inhibitor intermediate V, the method comprising: adding a compound IV to a solvent, and in the presence of a catalytic reagent, carrying out heat preservation reaction with a fluorination reagent. The preparation process for the intermediate V is simple in operations, mild in reaction conditions and high in safety, facilitates quality control and is suitable for industrial production. In addition, the intermediate V prepared by the method is high in purity, has few side reaction product monofluoro-impurity shown as structural Formula V, is easy to purify, and is applicable to quality research on active pharmaceutical ingredients and preparations of the SGLT2 inhibitor.

Claims

1. A preparation method for an SGLT2 inhibitor intermediate V, comprising subjecting a compound of Formula IV to a substitution reaction with a fluorination reagent in the presence of a catalytic reagent, ##STR00011## wherein: R.sub.1 is benzyl, p-methoxybenzyl, triphenylmethyl, acetyl, benzoyl, pivaloyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tri-iso-propylsilyl, 2-tetrahydropyranyl, methoxymethyl or 2-ethoxyethyl, and R.sub.2 is methyl, ethyl, methoxy, ethoxy or (tetrahydrofuran-3-yl)oxy.

2. The preparation method according to claim 1, wherein the compound of Formula IV is dissolved in a solvent, and subjected to a heat-preservation substitution reaction with a fluorination reagent in the presence of a catalytic reagent, to obtain the SGLT2 inhibitor intermediate V.

3. The preparation method according to claim 1, wherein the catalytic reagent is one or more of methanol, anhydrous ethanol, iso-propanol, n-propanol or n-butanol.

4. The preparation method according to claim 1, wherein the amount of the catalytic reagent is 2-6 wt of the amount of the compound of Formula IV.

5. The preparation method according to claim 2, wherein the solvent is one or more selected from dichloromethane, acetonitrile, isopropyl ether, tetrahydrofuran, methyl tert-butyl ether, n-heptane and ethyl acetate.

6. The preparation method according to claim 2, wherein the amount of the solvent is (0-10) ml/g relative to the weight of the compound of Formula IV.

7. The preparation method according to claim 1, wherein the fluorination reagent is one selected from diethylaminosulfur trifluoride, 1-fluoropyridinium tetrafluoroborate, anhydrous hydrogen fluoride, anhydrous potassium fluoride, DAST fluoroborate, selective fluorination reagent II (CAS No. 159269-48-4,1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane;ditetrafluoroborate), bis(2-complex.

8. The preparation method according to claim 1, wherein the molar amount of the fluorination reagent is 2-30 times of the molar amount of the compound of Formula IV.

9. The preparation method according to claim 1, wherein the temperature of the heat-preservation substitution reaction is 10-70 C.

10. The preparation method according to claim 1, wherein the time of the heat-preservation substitution reaction is 10-98 hrs.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG. 1 is a .sup.1H NMR spectrum of a monofluoro-impurity V;

[0026] FIG. 2 is a .sup.13C NMR spectrum of the monofluoro-impurity V;

[0027] FIG. 3 is an IR spectrum of the monofluoro-impurity V;

[0028] FIG. 4 is an UV spectrum of the monofluoro-impurity V;

[0029] FIG. 5 is a LC-MS spectrum of the monofluoro-impurity V; and

[0030] FIG. 6 is an HPLC chromatogram of the monofluoro-impurity V.

DETAILED DESCRIPTION

[0031] Specific embodiments of the present invention are provided below to show possible implementation processes, but not to limit the present invention. To make the objects, the technical solution, and advantages of the present invention clearer, the present invention is described in further detail with reference to examples. It should be understood that the specific embodiments described herein are merely used to explain the present invention but are not intended to limit the present invention.

[0032] Unless otherwise specified, the monofluoro-impurity mentioned in the following examples is a monofluoro-impurity of Formula V below:

##STR00005## [0033] where R1 and R2 have the same definitions as those for the compound V in specific embodiments.

Example 1

##STR00006##

[0034] (2R,3R,4R,5S,6S)-3,4,5-tri(benzyloxy)-2-((benzyloxy)methyl)-6-(4-chloro-3-(4-ethoxyb enzyl)phenyl)cyclohexanone (5.0 g, 6.4 mmol, 1.0 eq), dichloromethane (25 mL), diethylaminosulfur trifluoride (15.4 g, 95.5 mmol, 15.0 eq), and anhydrous ethanol (0.01 g, 2 M.sub.SM) were added to a reaction flask, heated to 20 C. and reacted for 72 hrs. The reaction solution was quenched with iced water, and alkalized. The organic phase was separated, dried, and concentrated to obtain a crude product of Formula V (5.04 g, purity 93.2%, monofluoro-impurity 1.3%, yield 98.0%).

[0035] The structure characterization data of the monofluoro-impurity V is shown in FIGS. 1-6 and Table 1.

TABLE-US-00001 TABLE 1 Structure characterization data of monofluoro-impurity V Item Feature data Feature attribution .sup.1H NMR 7.381-7.397 (d, 1H, J = 8 Hz), 7.233-7.299 (m, Phenyl ring proton (D6-DMSO, 14H), 7.112-7.184 (m, 6H), 7.009-7.025 (d, 2H, ppm), J = 12 Hz), 6.783-6.798(d, 2H, J = 7.5 Hz), 500 MHz 6.697-6.713 (d, 2H, J = 8 Hz) 4669-4.808 (m, 4H), 4354-4478 (m, 4H), / 4.246-4.268 (d, 1H, J = 11 Hz), 3.975 (m, 2H), 3.946 (s, 2H), 3.659 (m, 1H), 3.615 (m, 1H), 2.953 (m, 1H) 3.866-3.908 (q, 2H), 1.251(t, 3H, J = 7 Hz) Ethyl proton .sup.13C NMR 156.96, 138.50, 138.25, 138.18, 138.11, 133.00, Carbon in unsaturated (D6-DMSO, 131.93, 131.87, 131.63, 131.22, 129.61, 129.04, region ppm), 128.70, 128.39, 128.34, 128.12, 128.03, 127.95, 125 MHz 127.89, 127.81, 127.71, 127.64, 127.58, 127.41, 127.35, 127.28, 114.34 81.39, 78.32, 78.25, 75.44, 75.37, 73.62, 72.30, Carbon in partially 71.35, 71.06, 64.85 saturated region 62.96, 14.74 Ethyl carbon of ethoxy 43.78, 43.62 Allylic methylene carbon 37.61 Benzyl carbon of ethoxybenzyl LCMS m/z = 806 M + Na.sup.+ IR 3064.349, 3032.850 CH stretching vibration of benzene ring 2980.017, 2908.216, 2879.754 Methyl/methylene stretching vibration 1613.972, 1511.005, 1476.198 Benzene ring skeleton vibration 1245.794, 1162.449, 1116.391 Stretching vibration in ether 733.970, 695.902 CH bending vibration of benzene ring UV 230.00 K band 193.50 E band

Example 2

##STR00007##

[0036] (2R,3R,4R,5S,6S)-3,4,5-tris(trimethylsilyloxy)-2-((trimethylsilyloxy)methyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)cyclohexanone (5.0 g, 7.0 mmol, 1.0 eq), acetonitrile (18 mL), diethylaminosulfur trifluoride (7.4 g, 45.9 mmol, 6.56 eq), and anhydrous ethanol (0.03 g, 6 M.sub.SM) were added to a reaction flask, heated to 23 C. and reacted for 68 hrs. The reaction solution was quenched with iced water, and alkalized. The organic phase was separated, dried, and concentrated to obtain a crude product of Formula V (4.98 g, purity 91.6%, monofluoro-impurity 2.1%, yield 97.1%).

Example 3

##STR00008##

[0037] (2R,3R,4R,5S,6S)-3,4,5-tris(p-methoxybenzyloxy)-2-((p-methoxybenzyloxy)methyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)cyclohexanone (5.0 g, 5.6 mmol, 1.0 eq), isopropyl ether (20 mL), DAST fluoroborate (10.5 g, 45.8 mmol, 8.18 eq), and methanol (0.015 g, 3 M.sub.SM) were added to a reaction flask, heated to 25 C. and reacted for 65 hrs. The reaction solution was quenched with iced water, and alkalized. The organic phase was separated, dried, and concentrated to obtain a crude product of Formula V (4.62 g, purity 90.3%, monofluoro-impurity 0.9%, yield 89.3%).

Example 4

##STR00009##

(2R,3R,4R,5S,6S)-3,4,5-tris(methoxymethyloxy)-2-((methoxymethyloxy)methyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)cyclohexanone (5.0 g, 8.4 mmol, 1.0 eq), dichloromethane (16 mL), selective fluorination reagent II (6.8 g, 21.3 mmol, 2.54 eq), and methanol (0.01 g, 2 M.sub.SM) were added to a reaction flask, heated to 20 C. and reacted for 70 hrs. The reaction solution was quenched with iced water, and alkalized. The organic phase was separated, dried, and concentrated to obtain a crude product of Formula V (4.52 g, purity 90.7%, monofluoro-impurity 2.3%, yield 86.9%).

Example 5

##STR00010##

[0038] (2R,3R,4R,5S,6S)-3,4,5-tris(2-tetrahydropyranyloxy)-2-((2-tetrahydropyranyloxy)methyl )-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)cyclohexanone (5.0 g, 6.6 mmol, 1.0 eq), tetrahydrofuran (20 mL), bis(2-methoxyethyl)aminosulfur trifluoride (5.2 g, 23.5 mmol, 3.56 eq), and n-propanol (0.01 g, 2 M.sub.SM) were added to a reaction flask, heated to 19 C. and reacted for 65 hrs. The reaction solution was quenched with iced water, and alkalized. The organic phase was separated, dried, and concentrated to obtain a crude product of Formula V (4.73 g, purity 92.1%, monofluoro-impurity 1.7%, yield 92.0%).

[0039] The above embodiments are merely preferred embodiments of the present invention, and the scope of the present invention is not limited thereto. Any insubstantial changes and substitutions made by those skilled in the art based on the present invention fall within the protection scope of the present invention.