Method for preparing glucopyranosyl derivatives and intermediates thereof

Patent metadata

Field	Value
Publication number	US-2023250121-A1
Application number	US-202118015138-A
Country	US
Kind code	A1
Filing date	Jul 7, 2021
Priority date	Jul 8, 2020
Publication date	Aug 10, 2023
Grant date	—

Abstract

A method for preparing glucopyranosyl derivatives as sodium dependent glucose cotransporter (SGLT) inhibitors, an intermediate thereof, and a method for preparing the intermediate.

First claim

1 - 72 . (canceled)

73 . A method for preparing compound (Va), comprising the step of:
reacting compound (VIa) with methylating reagent 1 through an addition reaction in the presence of isopropyl titanate to obtain compound (Va),

wherein, the methylating reagent 1 is methylmagnesium bromide, methylmagnesium chloride, methyllithium, trimethylaluminum or dimethyl zinc;
R 3a is C 2-8 alkyl, C 4-8 alkenyl, allyl, phenyl, benzyl, p-toluenesulfonyl, benzenesulfonyl, 4-bromobenzenesulfonyl, 4-nitrophenyl, 1,3-dichlorophenyl, tert-butoxycarbonyl, triphenylmethyl, bis(4-methoxyphenyl)(phenyl)methyl, diphenylmethyl, N,N-diphenylaminoacyl, pyridyl, benzylsulfonyl, imidazolyl, N,N-dimethylaminosulfonyl, N,N-dimethylaminoacyl or

74 . The method according to claim 73 , wherein the reaction is optionally carried out in the presence of a chiral ligand 1, and the chiral ligand 1 is a dihydroxy chiral ligand or a metal ligand.

75 . The method according to claim 74 , wherein the dihydroxy chiral ligand is R-1,1′-Bi-2-naphthol, (4R,5R)-2,2-dimethyl-a,a,a′,a′-tetraphenyl-1,3-dioxolane-4,5-dimethanol, (S)-(−)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-2-naphthol or Salen ligand;
the metal ligand is metal-Salen ligand, metal-BINOL ligand or (1R,2R)-(+)-N,N′-Di-p-toluenesulfonyl-1,2-cyclohexanediamine-metal ligand.

76 . The method according to claim 75 , wherein the amount of substance of R-1,1′-Bi-2-naphthol is 0.01 to 0.9 times that of compound (VIa); preferably, the amount of substance of R-1,1′-Bi-2-naphthol is 0.05 to 0.2 times that of compound (VIa);
the amount of substance of Salen ligand is 1.0 time or less that of compound (VIa); preferably, the amount of substance of Salen ligand is 0.2 times or less that of compound (VIa).

77 . The method according to claim 73 , wherein the amount of substance of isopropyl titanate is 0.5 to 8.0 times that of compound (VIa); preferably, the amount of substance of isopropyl titanate is 1.0 to 5.0 times that of compound (VIa); preferably, the amount of substance of isopropyl titanate is 1.4 to 4.0 times that of compound (VIa); preferably, the amount of substance of isopropyl titanate is 1.4 to 2.0 times that of compound (VIa); preferably, the amount of substance of isopropyl titanate is 2.0 to 4.0 times that of compound (VIa); preferably, the amount of substance of isopropyl titanate is 3.9 times that of compound (VIa); preferably, the amount of substance of isopropyl titanate is 1.4, 2.0, 3.0 or 4.0 times that of compound (VIa).

78 . The method according to claim 73 , wherein the amount of substance of methylating reagent 1 is 3.0 to 6.0 times that of compound (VIa); preferably, the amount of substance of methylating reagent 1 is 4.0 to 6.0 times that of compound (VIa).

79 . The method according to claim 78 , wherein the amount of substance of dimethyl zinc is 3.0 to 6.0 times that of compound (VIa); preferably, the amount of substance of dimethyl zinc is 4.0 to 6.0 times that of compound (VIa);
the amount of substance of methylmagnesium bromide is 3.0 to 6.0 times that of compound (VIa); preferably, the amount of substance of methylmagnesium bromide is 4.0 to 6.0 times that of compound (VIa); preferably, the amount of substance of methylmagnesium bromide is 4.0 to 5.0 times that of compound (VIa).

80 . The method according to claim 73 , wherein the reaction of compound (VIa) and the methylating reagent 1 is carried out in an organic solvent, and the organic solvent is dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, o-xylene, p-xylene, meta-xylene or any combination thereof.

81 . The method according to claim 73 , wherein the reaction temperature of the reaction of compound (VIa) and the methylating reagent 1 is 10° C.˜ 40° C.; preferably, the reaction temperature is 20° C.˜ 35° C.; preferably, the reaction temperature is 20° C.˜32° C.;
preferably, the reaction temperature is 20° C.˜30° C.

82 . The method according to claim 73 , wherein, in the reaction of compound (VIa) and the methylating reagent 1, compound (VIa) is added by dropping, wherein the temperature of the reaction system during the dropping process is −20° C.˜ 25° C.; preferably, the temperature of the reaction system during the dropping process is −10° C. 0° C.; preferably, the temperature of the reaction system during the dropping process is −5° C.˜0° C.

83 . The method according to claim 73 , wherein the compound (VIa) can be prepared by the following method:
step a: reacting compound (VIIIa) in the presence of alkaline reagent 1 through a hydrolysis reaction to obtain compound (VIIa),

step b: reacting compound (VIIa) in the presence of oxidant 1 through an oxidation reaction to obtain compound (VIa),

84 . The method according to claim 83 , wherein the alkaline reagent 1 in step a is sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, bicarbonate sodium, sodium hydroxide or potassium hydroxide;
the solvent used in step a is dichloromethane, toluene, dichloroethane, methyl tert-butyl ether, xylene, dimethyl sulfoxide, methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran or any combination thereof; the reaction temperature in step a is −15° C.˜30° C.; preferably, the reaction temperature in step a is −15° C.˜5° C.; preferably, the reaction temperature in step a is −15° C.˜0° C.

85 . The method according to claim 83 , wherein in step a, the alkaline reagent 1 is sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the solvent is toluene or a mixed solvent of toluene and dimethyl sulfoxide; the reaction temperature is −15° C.˜0° C.

86 . The method according to claim 85 , wherein the solvent used in step a is a mixed solvent of toluene and dimethyl sulfoxide, wherein the volume ratio of toluene and dimethyl sulfoxide is (20:1)˜(25:1).

87 . The method according to claim 84 , wherein the oxidant 1 in step b is sodium hypochlorite, 2,2,6,6-tetramethylpiperidine oxide, sulfur trioxide pyridine, oxygen, ozone, Dess-Martin oxidizer, iron nitrate, 2-iodoyl benzoic acid or iodine;
the solvent used in step b is toluene, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, dichloromethane, dichloroethane or any combination thereof; the reaction temperature of step b is −10° C.˜30° C.; preferably, the reaction temperature of step b is −5° C.˜5° C.; preferably, the reaction temperature of step b is −5° C., −5° C.˜0° C. or 0° C.˜5° C.

88 . The method according to claim 84 , wherein step b is optionally carried out in the presence of an alkaline reagent b, and the alkaline reagent b is N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene or tetramethylethylenediamine.

89 . The method according to claim 84 further comprises a purification method of compound (VIIIa), wherein the purification method comprises: adding the material containing compound (VIIIa) into solvent A, and then adding solvent B to precipitate a solid compound (VIIIa);
wherein, the solvent A is methano

Assignees

• Sunshine Lake Pharma Co Ltd

Inventors

• Gu Zheng
• Qu Tong
• Wu Wuyong
• Huang Weiming
• Chen Daoqian
• Zhang Zongyuan
• Qin Haoxiong
• Li Zheng
• Yuan Weihui
• Niu Shijie
• Peng Fei
• Wu Tianyun

Classifications

• C07H1/00 Primary

  Processes for the preparation of sugar derivatives · CPC title

• C07D295/108 Primary

  to an acyclic saturated chain · CPC title

• C07D295/26

  Sulfur atoms · CPC title

• C07D317/22

  etherified · CPC title

• C07D295/185 Primary

  from aliphatic carboxylic acids · CPC title