METHOD FOR PREPARING GLUCOPYRANOSYL DERIVATIVES AND INTERMEDIATES THEREOF

Abstract

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

Claims

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), ##STR00095## wherein, the methylating reagent 1 is methylmagnesium bromide, methylmagnesium chloride, methyllithium, trimethylaluminum or dimethyl zinc; R.sup.3a is C.sub.2-8 alkyl, C.sub.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 ##STR00096##

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), ##STR00097## step b: reacting compound (VIIa) in the presence of oxidant 1 through an oxidation reaction to obtain compound (VIa), ##STR00098##

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 methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetone, toluene, xylene, ethyl acetate, dichloromethane, methyl tert-butyl ether, diethyl ether, isopropyl ether, anisole or any combination thereof; and the solvent B is n-heptane, n-hexane, cyclohexane, petroleum ether, water or any combination thereof.

90. The method according to claim 89, wherein the solvent A is toluene, and the solvent B is n-heptane; or the solvent A is toluene, and the solvent B is n-hexane; or the solvent A is ethanol, and the solvent B is water; or the solvent A is isopropanol, and the solvent B is water; or the solvent A is tert-butanol, and the solvent B is water; or the solvent A is acetone, and the solvent B is water; or the solvent A is ethanol, and the solvent B is n-heptane; or the solvent A is ethanol, and the solvent B is n-hexane; or the solvent A is ethanol, and the solvent B is cyclohexane; or the solvent A is ethyl acetate, and the solvent B is n-heptane; or the solvent A is ethyl acetate, and the solvent B is n-hexane; or the solvent A is methyl tert-butyl ether, and the solvent B is n-heptane.

91. The method according to claim 90, wherein the volume ratio of toluene and n-heptane is (1:3)˜(1:8); preferably, the volume ratio of toluene and n-heptane is (1:3)˜(1:5); the volume ratio of toluene and n-hexane is (1:3)˜(1:8); preferably, the volume ratio of toluene and n-hexane is (1:5)˜(1:8); the volume ratio of ethyl acetate and n-heptane is (1:1)˜(1:5); the volume ratio of ethyl acetate and n-heptane is (1:2)˜(1:3); the volume ratio of the methyl tert-butyl ether and n-heptane is (1:1)˜(1:5); the volume ratio of the methyl tert-butyl ether and n-heptane is (1:2)˜(1:3); the volume ratio of acetone and water is (1:1)˜(10:1); preferably, the volume ratio of acetone and water is (4:1)˜(6:1); the volume ratio of ethanol and water is (1:1)˜(3:1); the volume ratio of isopropanol and water is (1:1)˜(3:1); the volume ratio of ethanol and n-heptane is (1:1)˜(3:1); the volume ratio of ethanol and n-hexane is (1:1)˜(3:1); the volume ratio of ethanol and cyclohexane is (1:1)˜(3:1).

92. The method according to claim 89, wherein the crystallization temperature of the solid compound (VIIIa) is 40° C.˜10° C.; preferably, the crystallization temperature of the solid compound (VIIIa) is 30° C.˜10° C.

93. A method for preparing compound (Vc) comprising: reacting compound (VIb) with methylating reagent 1 through an addition reaction in the presence of isopropyl titanate to obtain compound (Vb); and continuing to react compound (Vb) to remove the tert-butoxycarbonyl protecting group to obtain the compound (Vc); ##STR00099## wherein the amount of substance of isopropyl titanate is 1.0 to 5.0 times that of compound (VIb); or the amount of substance of isopropyl titanate is 1.4 to 4.0 times that of compound (VIb); or the amount of substance of isopropyl titanate is 2.0 to 4.0 times that of compound (VIb); in the addition reaction, compound (VIb) is added by dropping, and the temperature of the reaction system during the dropping process is −10° C.˜0° C.; the method for removing the tert-butoxycarbonyl group comprises: directly increasing the temperature of the addition reaction to 25° C.˜50° C.; preferably, directly increasing the temperature of the addition reaction to 30° C.˜40° C.; preferably, directly increasing the temperature of the addition reaction to 30° C.˜35° C.

94. The method according to claim 93, wherein the methylating reagent 1 is methylmagnesium bromide or dimethyl zinc; wherein the amount of substance of methylmagnesium bromide is 4.0 to 5.0 times that of compound (VIb); and the amount of substance of dimethyl zinc is 4.0 to 6.0 times that of compound (VIb).

95. The method according to claim 93, wherein the amount of substance of isopropyl titanate is 2.0 to 4.0 times that of compound (VIb), the methylating reagent 1 is methylmagnesium bromide, and the amount of substance of methylmagnesium bromide is 4.0 to 5.0 times that of compound (VIb); or the amount of substance of isopropyl titanate is 1.4 to 2.0 times that of compound (VIb), the methylating reagent 1 is dimethyl zinc, and the amount of substance of dimethyl zinc is 4.0 to 6.0 times that of compound (VIb).

96. The method according to claim 93, wherein the solvent of the addition reaction of compound (VIb) and methylating reagent 1 is dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, o-xylene, p-xylene, meta-xylene or any combination thereof.

97. The method according to claim 93, wherein the addition reaction is optionally carried out in the presence of a chiral ligand 1; wherein the chiral ligand 1 is R-1,1′-Bi-2-naphthol, Salen ligand, metal-Salen ligand or metal-BINOL ligand; the amount of substance of R-1,1′-Bi-2-naphthol is 0.05 to 0.2 times that of compound (VIb); the amount of substance of Salen ligand is 0.2 times or less that of compound (VIb).

98. A method for preparing compound (I) comprising the steps of: step (A): reacting compound (III) or a salt thereof with compound (IV) through a coupling reaction to obtain compound (II), ##STR00100## step (B): reacting compound (II) through hydrogenation reduction and ring closure under acidic condition to obtain compound (I), ##STR00101## wherein, X is Cl, Br or I; R.sup.3 is benzyl, C.sub.2-8 alkyl, C.sub.4-8 alkenyl, allyl, phenyl, p-toluenesulfonyl, benzenesulfonyl, 4-bromobenzenesulfonyl, 4-nitrophenyl, 1,3-dichlorophenyl, triphenylmethyl, bis(4-methoxyphenyl) (phenyl) methyl, diphenylmethyl, N,N-diphenylaminoacyl, pyridyl, benzylsulfonyl, imidazolyl, N,N-dimethylaminosulfonyl, N,N-dimethylaminoacyl or ##STR00102## and each R.sup.1 and R.sup.2 is independently benzyl, triphenylmethyl, p-methoxybenzyl, tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, triethyl silyl, triisopropylsilyl, benzyloxycarbonyl, 2-(trimethylsilyl)ethoxymethyl, dihydropyranyl, bromopropenyl, ethylformyl, acetyl or benzoyl; or, R.sup.1 and R.sup.2 together with —OCHCHO— to which they are attached form ##STR00103##

99. The method according to claim 98, wherein the acidic condition in step (B) refers to the reaction reacts in the presence of an acid, and the acid is hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, formic acid or acetic acid; the hydrogenation reduction in step (B) is carried out in the presence of a catalyst, and the catalyst is palladium/carbon, palladium hydroxide/carbon, platinum/carbon, Raney nickel or palladium chloride; wherein, the mass ratio of the catalyst and compound (II) is (0.02:1)˜(0.8:1); preferably, the mass ratio of the catalyst and compound (II) is (0.1:1)˜(0.6:1); preferably, the mass ratio of the catalyst and compound (II) is (0.05:1) to (0.2:1).

100. The method according to claim 98, wherein, in step (A), the amount of substance of compound (IV) is 1.0 to 1.5 times that of compound (III) or a salt thereof; preferably, in step (A), the amount of substance of compound (IV) is 1.1 to 1.3 times that of compound (III) or a salt thereof; the reaction solvent in step (A) is tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, dichloromethane or any combination thereof; the reaction temperature in step (A) is 10° C.˜ 40° C.; preferably, the reaction temperature in step (A) is 20° C.˜ 30° C.

101. The method according to claim 98, wherein compound (III) is prepared by the following method A or method B, method A, ##STR00104## wherein, the method A includes the step of: reacting compound (V) or a salt thereof with hydroxyl protecting reagent 1 to obtain compound (III); method B, step 1: reacting compound (Vc) with acid 1 to obtain compound (Vd), ##STR00105## step 2: reacting compound (Vd) with hydroxyl protecting reagent 2 to obtain compound (Ve), ##STR00106## step 3: reacting compound (Ve) in the presence of acid 2 to obtain compound (Vf), ##STR00107## step 4: reacting compound (Vf) with compound R.sup.3X.sup.1 to obtain compound ##STR00108## wherein, X.sup.1 is Cl, Br or I; and each acid 1 and acid 2 is independently sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, oxalic acid, pivalic acid, methanesulfonic acid, acetic acid, formic acid, benzoic acid, p-toluenesulfonic acid, citric acid, cinnamic acid, tartaric acid, malic acid, salicylic acid, succinic acid or caffeic acid.

102. The method according to claim 101, wherein the acid 1 is used to adjust the pH of the solution; wherein after acid 1 is added, the pH of the solution is 1.0˜7.0; preferably, after acid 1 is added, the pH of the solution is 3.0˜ 7.0; preferably, after acid 1 is added, the pH of the solution is 5.5˜ 7.0; the hydroxyl protecting reagent 1 and the hydroxyl protecting reagent 2 are each independently 2,2-dimethoxypropane, benzaldehyde dimethyl acetal, trimethylchlorosilane or tert-butyldimethylchlorosilane; the reaction solvent of the method A and the reaction solvent in step 2 of method B are each independently toluene, 1,2-dichloroethane, dichloroethane, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or any combination thereof; and the reaction temperature of the method A and the reaction temperature of step 2 of the method B are each independently 0° C.˜ 40° C.; preferably, the reaction temperature of the method A and the reaction temperature of step 2 of the method B are each independently 10° C.˜ 40° C.; preferably, the reaction temperature of the method A and the reaction temperature of step 2 of the method B are each independently 8° C.˜ 30° C.; the amount of substance of acid 2 is 0.5 to 2.0 times that of compound (Ve); preferably, the amount of substance of acid 2 is 0.5 to 1.2 times that of compound (Ve).

103. The method according to claim 101, wherein the reactions of the method A and the step 2 of the method B are each independently and optionally carried out in the presence of methanesulfonic acid.

104. A compound having one of the following structures or a salt thereof: ##STR00109## wherein, each R.sup.a, R.sup.b and R.sup.c is independently H, C.sub.2-8 alkyl, C.sub.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 ##STR00110## each R.sup.1 and R.sup.2 is independently benzyl, triphenylmethyl, p-methoxybenzyl, tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, triethyl silyl, triisopropylsilyl, benzyloxycarbonyl, 2-(trimethylsilyl)ethoxymethyl, dihydropyranyl, bromopropenyl, ethylformyl, acetyl or benzoyl, or, R.sup.1 and R.sup.2 together with —OCHCHO— to which they are attached form ##STR00111##

105. A method for preparing compound (VIII) comprising the step of: reacting compound (IX) and the Grignard reagent obtained by the Grignard exchange of iodomethyl pivalate and isopropyl magnesium chloride lithium chloride through an addition reaction to obtain compound (VIII), ##STR00112## wherein, R is H, ethyl, n-propyl, n-butyl, tert-butyl, 2,2-dimethylpropyl, allyl, phenyl, benzyl, p-toluenesulfonyl, benzenesulfonyl, 4-bromobenzenesulfonyl, 4-nitrophenyl, 1,3-dichlorophenyl, tert-butoxycarbonyl, triphenylmethyl, bis(4-methoxyphenyl)benzyl, diphenylmethyl, N,N-diphenylaminoacyl, pyridyl, benzylsulfonyl, imidazolyl, N,N-dimethylaminosulfonyl, N,N-dimethylaminoacyl or ##STR00113## wherein, the method comprises a purification method of compound (VIII), and the purification method comprises: adding the material containing compound (VIII) into solvent A, and then adding solvent B to precipitate a solid compound (VIII); wherein the solvent A is methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetone, toluene, xylene, ethyl acetate, dichloromethane, methyl tert-butyl ether, diethyl ether, isopropyl ether, anisole or any combination thereof; and the solvent B is n-heptane, n-hexane, cyclohexane, petroleum ether, water or any combination thereof.

106. The method according to claim 105, wherein the solvent A is toluene, the solvent B is n-heptane, and the volume ratio of toluene and n-heptane is (1:3)˜(1:10); preferably, the volume ratio of toluene and n-heptane is (1:3)˜(1:8); preferably, the volume ratio of toluene and n-heptane is (1:3)˜(1:5); preferably, the volume ratio of toluene and n-heptane is (1:5)˜(1:8); or the solvent A is acetone, and the solvent B is water, wherein the volume ratio of acetone and water is (1:1)˜(10:1); preferably, the volume ratio of acetone and water is (2:1)˜(8:1); preferably, the volume ratio of acetone and water is (4:1)˜(6:1); or the solvent A is ethyl acetate, and the solvent B is n-heptane, wherein the volume ratio of ethyl acetate and n-heptane is (1:1)˜(1:10); preferably, the volume ratio of ethyl acetate and n-heptane is (1:1)˜ (1:5); preferably, the volume ratio of ethyl acetate and n-heptane is (1:2)˜ (1:3); or the solvent A is methyl tert-butyl ether, and the solvent B is n-heptane, wherein the volume ratio of the methyl tert-butyl ether and n-heptane is (1:3)˜ (1:10).

107. Crystal form A of compound (VIIIb), ##STR00114## wherein the X-ray powder diffraction pattern of the crystal form A has diffraction peaks at the following 2θ angles: 6.52°+0.2°, 6.89°+0.2°, 9.25°+0.2°, 9.66°±0.2°, 16.18°±0.2°, 18.44°±0.2°, 18.56°±0.2°, 21.87°±0.2°, 27.58°±0.2°; or the X-ray powder diffraction pattern of the crystal form A has diffraction peaks at the following 2θ angles: 6.52°+0.2°, 6.89°+0.2°, 9.25°±0.2°, 9.66°±0.2°, 13.72°±0.2°, 16.18°±0.2°, 18.44°±0.2°, 18.56°±0.2°, 18.86°±0.2°, 19.33°±0.2°, 20.53°±0.2°, 21.39°±0.2°, 21.87°±0.2°, 23.52°±0.2, 23.95°±0.2°, 24.38°±0.2°, 26.07°±0.2°, 27.58°±0.2°; or the X-ray powder diffraction pattern of the crystal form A has diffraction peaks at the following 2θ angles: 6.52°+0.2°, 6.89°+0.2°, 9.25°+0.2°, 9.66°+0.2°, 13.72°±0.2°, 14.44°±0.2°, 14.97°±0.2°, 15.30°±0.2°, 16.18°±0.2°, 16.95°±0.2°, 17.19°±0.2°, 18.21°±0.2°, 18.44°±0.2°, 18.56°±0.2°, 18.86°±0.2°, 19.33°±0.2°, 19.56°±0.2°, 20.13°±0.2°, 20.53°±0.2°, 20.98°±0.2°, 21.39°±0.2°, 21.87°±0.2°, 22.38°±0.2°, 22.67°±0.2°, 23.12°±0.2°, 23.52°±0.2, 23.95°±0.2°, 24.38°±0.2°, 24.88°±0.2°, 26.07°±0.2°, 27.58°±0.2°, 29.11°±0.2°, 30.54°±0.2°, 31.07°±0.2°, 31.74°±0.2°, 32.76°±0.2°, 34.69°±0.2°, 35.06°±0.2°, 39.58°±0.2°, 39.89°±0.2°, 40.51°±0.2°; or the crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1.

Description

DESCRIPTION OF THE DRAWINGS

[0299] FIG. 1 is an X-ray powder diffraction pattern of the crystal form A of the compound (VIIIb) of the present invention.

EXAMPLES

[0300] The examples of the present invention provide the methods for preparing optically pure (1R,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl)-1-[(1R)-1-hydroxyethyl]-6,8-dioxbicyclo[3.2.1]octane-2,3,4-triol (I). Skilled in the art can learn from this invention to properly improve the process parameters to implement the preparation method. Of particular note is that all similar substitutions and modifications to the skilled person is obvious, and they are deemed to be included in the present invention. Related person can clearly realize and apply the techniques disclosed herein by making some changes, appropriate alterations or combinations to the methods without departing from spirit, principles and scope of the present disclosure.

[0301] In order to further understand the invention, it is detailed below through examples.

EXAMPLES

Example 1

tert-butyl 4-[(2R,3S,4S,5R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-6-(2,2-dimethyl propionyloxy)-5-hydroxy-hexanoyl]piperazine-1-carboxylate

[0302] ##STR00066##

Step 1 (3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)tetrahydropyran-2-one

[0303] ##STR00067##

[0304] The compound 2,3,4,6-tetra-O-benzyl-D-glucopyranose (100.0 kg, 185.0 mol, purity: 99.0%) was dissolved in dichloromethane (466 kg), and then saturated solution of sodium bicarbonate (31.08 kg, 370 mol) in water (312 kg) was added into the solution, the mixture was cooled to 0° C. To the mixture were added potassium bromide (13.2 kg, 111 mol) and TEMPO (2.9 kg, 18.6 mol). After stirring for 1 min, NaClO solution (426 kg, 481 mol, available chlorine 4.0 mass %) was added in a whole, the resulting mixture was then further stirred for 1 h. The mixture was separated. The organic layer was washed with saturated brine (200 kg), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a yellow oil (99.6 kg, 185 mol, product content: 97.3%, yield: 100%).

Step 2 tert-butyl 4-[(2R,3S,4R,5R)-2,3,4,6-tetrabenzyloxy-5-hydroxy-hexanoyl]piperazine-1-carboxylate

[0305] ##STR00068##

[0306] At room temperature, (3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl) tetrahydropyran-2-one (99.6 kg, 185 mol, purity: 97.3%) was dissolved in toluene (520 kg), N-Boc piperazine (86 kg, 462.5 mol) was added dropwise slowly into the solution under N.sub.2, the mixture was kept at 30° C. and stirred for 12 h. After the reaction was complete, citric acid (53.8 kg) aqueous solution (498 kg) was added into the reaction mixture slowly. After the addition, the mixture was stirred for 20 min, stood and separated. The upper toluene solution was retained and washed with saturated brine (348.6 kg).

[0307] At room temperature, to the above toluene solution was added n-hexane (599.6 kg) dropwise, and then the mixture was stirred for 6 h. White solid was precipitated out slowly in the solution, and then the mixture was centrifuged. The filter cake was rinsed with n-hexane (99.6 kg), and the wet product was dried at 50° C. under vacuum to obtain the title compound as an off-white solid (97.9 kg, 135.1 mol, product content: 94.7%, yield: 73.0%).

Step 3 Tert-butyl 4-[(2R,3S,4S)-2,3,4,6-tetrabenzyloxy-5-oxohexanoyl]piperazine-1-carboxylate

[0308] ##STR00069##

[0309] Tert-butyl 4-[(2R,3S,4R,5R)-2,3,4,6-tetrabenzyloxy-5-hydroxy-hexanoyl]piperazine-1-carboxylate (50.0 kg, 69.0 mol, purity: 94.7%) was dissolved in toluene (129.9 kg), then DMSO (110 kg) and DIPEA (62.5 kg, 483 mol) were added into the solution. The mixture was cooled to 0° C. under N.sub.2. Sulfur trioxide pyridine (40.0 kg, 241.5 mol) was added in batches at 0° C.˜5° C. After the addition, the mixture was stirred at 0° C.˜5° C. for 1 h. The resulting mixture was diluted with methyl tert-butyl ether (105 kg), and washed with drinking water (125 kg), and then separated. The upper organic phase was retained and washed with saturated brine (200 kg×3), and concentrated under reduced pressure to obtain the title compound as a brown oil (49.9 kg, 69.0 mol, purity: 93.8%).

Step 4 tert-butyl 4-[(2R,3S,4S,5R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-6-(2,2-dimethylpropionyloxy)-5-hydroxy-hexanoyl]piperazine-1-carboxylate

[0310] ##STR00070##

[0311] Iodomethyl pivalate (23.3 kg, 96.6 mol) was dissolved in anhydrous tetrahydrofuran (58.3 kg), and the mixture was cooled to −78° C. under N.sub.2. Tetrahydrofuran solution of i-PrMgCl-LiCl (93.7 kg, 125.6 mol, 1.3 mol/L) was added dropwise to the mixture for about 1 h. After the addition, the mixture was further stirred at −78° C. for 1 h to obtain (2,2-dimethylpropionyloxymethyl)magnesium chloride. To the reactor was added a solution of tert-butyl 4-[(2R,3S,4S)-2,3,4,6-tetrabenzyloxy-5-oxohexanoyl]piperazine-1-carboxylate (49.9 kg, 69.0 mol, product content: 93.8%) in tetrahydrofuran (149.7 kg) dropwise. After the addition, the resulting mixture was further stirred at −78° C. for 0.5 h. To the reaction solution was added a solution of glacial acetic acid (16.5 kg) in tetrahydrofuran (40 kg) dropwise to quench the reaction, then drinking water (99.8 kg) was added. The temperature of the system was controlled at 10° C. The mixture was stirred for 10 min and separated, then washed with 10% brine (300 kg). To the mixture was added methyl tert-butyl ether (25.0 kg) and stirred evenly, then n-heptane (75 kg) was added. The resulting mixture was stirred for 3 h and then centrifuged. The filter cake was rinsed with n-heptane (25 kg) and dried under vacuum at 45° C. for 6 h to obtain the title product as an off-white solid (35.3 kg, 42.1 mol, product content: 98.7%, the total yield of step 3 and step 4 is: 61%).

[0312] Other purification methods of the title compound in Step 4:

[0313] At r.t., solvent A was added into a reaction flask containing the crude product of the title compound in step 4 or its tetrahydrofuran solution, the mixture was stirred to dissolve/uniform at a certain temperature, and then solvent B was added dropwise. The resulting mixture was stirred at r.t., and an off-white solid was precipitated out. The mixture was further stirred for 3 h, and the solid precipitated out completely. The resulting mixture was filtered with suction to obtain the purified title compound as an off-white solid.

[0314] Solvent A, solvent B, the volume ratio (solvent A/solvent B), dissolution temperature, precipitation temperature, precipitation time and the test results of Tests 1-11 are listed in table 1.

TABLE-US-00002 TABLE 1 volume Dissolu- ratio tion Test results (solvent A: Tem- Product Test Solvent A Solvent B solvent B) perature content Yield  1 toluene n-heptane 1:4 r.t. 96.5% 79.0%  2 toluene n-heptane 1:5 r.t. 95.5% 80.5%  3 toluene n-heptane 1:3 r.t. 97.7% 75.7%  4 toluene n-heptane 1:8 r.t. 92.6% 84.0%  5 toluene n-hexane 1:5 r.t. 95.0% 81.1%  6 ethyl acetate n-heptane 1:3 60° C. 97.0% 71.2%  7 ethyl acetate n-heptane 1:2 60° C. 97.1% 76.4%  8 ethyl acetate n-hexane 1:2 60° C. 97.0% 77.0%  9 methyl tert- n-heptane 1:3 r.t. 96.1% 83.0% butyl ether 10 acetone water 6:1 35° C. 98.4% 76.2% 11 acetone water 4:1 35° C. 98.7% 74.6% Note: The yield in Table 1 refers to the total yield of step 3 and step 4.

Test 12:

[0315] To the crude product (10 g, 11.93 mmol) of the title compound in step 4 was added ethyl acetate (30 g) and the temperature of the mixture was raised to 65° C. The mixture was cooled to r.t. when the product was dissolved. n-heptane (30 g) was added, and the mixture was stirred for 3 h and then centrifuged. The filter cake was rinsed with a mixed solvent of n-heptane (6 g) and ethyl acetate (3 g), the resulting product was dried under vacuum at 45° C. to obtain the product as off-white solid (7.42 g, 8.85 mol, product content: 99.1%, total yield of step 3 and step 4: 74.2%).

[0316] Specifically, the obtained product is crystal form A; the identification method of the crystal form A is as follows:

[0317] X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero background sample holder with a transflective sample stage. The used radiation source was (Cu, kα, Kα1 (A): 1.540598; Kα2 (Å): 1.544426; Kα2/Kα1 intensity ratio: 0.50), wherein the voltage was set at 45 KV and the current was set at 40 mA. The beam divergence of X-rays, i.e., the effective size of the X-ray confinement on the sample, was 10 mm. The θ-θ continuous scanning mode was adopted to obtain an effective 2θ range of 3°˜60°. An appropriate amount of powdered sample was placed in the circular groove of the zero background sample holder under about 18° C.˜32° C., the sample was lightly pressed with a clean glass slide to obtain a flat surface. The zero background sample frame was fixed. The sample to be tested was used to generate a traditional XRPD pattern within the range of 2θ±0.2° of 3-60° with a scanning step of 0.0168°. Use Data Collector software to collect data, HighScore Plus software to process data, Data Viewer software to read data.

[0318] The product obtained in Test 12 is crystal form A, which has diffraction peaks at the following 2θ angles: 6.52°+0.2°, 6.890 0.2°, 9.25°±0.2°, 9.66°±0.2°, 13.72°±0.2°, 14.44°±0.2°, 14.97°±0.2°, 15.30°±0.2°, 16.18°±0.2°, 16.95°±0.2°, 17.19°±0.2°, 18.21°±0.2°, 18.44°±0.2°, 18.56°±0.2°, 18.86°±0.2°, 19.33°±0.2°, 19.56°±0.2°, 20.13°±0.2°, 20.53°±0.2°, 20.98°±0.2°, 21.39°±0.2°, 21.87°±0.2°, 22.38°±0.2°, 22.67°±0.2°, 23.12°±0.2°, 23.52°±0.2, 23.95°±0.2°, 24.38°±0.2°, 24.88°±0.2°, 26.07°±0.2°, 27.58°±0.2°, 28.65°±0.2°, 29.11°±0.2°, 30.08°±0.2°, 30.54°±0.2°, 31.07°±0.2°, 31.74°±0.2°, 32.76°±0.2°, 33.57°±0.2°, 34.11°±0.2°, 34.69°±0.2°, 35.06°±0.2°, 36.76°±0.2°, 38.05°±0.2°, 38.74°±0.2°, 39.58°±0.2°, 39.89°±0.2°, 40.51°±0.2°, 41.75°±0.2°, 43.31°±0.2°, 44.87°±0.2°, 45.59°±0.2°, 46.74°±0.2°, 48.15°±0.2°, 48.85°±0.2°, 50.06°±0.2°, 51.15°±0.2°, 52.95°±0.2°, 53.80°±0.2°. Specifically, the crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1.

Example 2

tert-butyl 4-[(2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5-hydroxy-6-oxo-hexanoyl]piperazine-1-carboxylate

[0319] ##STR00071##

Step 1 tert-butyl 4-[(2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-hexanoyl]piperazine-1-carboxylate

[0320] ##STR00072##

Test 1:

[0321] tert-butyl 4-[(2R,3S,4S,5R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-6-(2,2-dimethylpropionyloxy)-5-hydroxy-hexanoyl]piperazine-1-carboxylate (2.0 kg, 2.38 mol, purity: 98.7%) prepared according to the method of Example 1, toluene (10.0 L) and dimethyl sulfoxide (0.4 L) were added into a reaction kettle. The mixture was cooled to −8° C., and sodium methoxide (0.16 kg, 2.86 mol) was added in a whole. Then the mixture was stirred at −8° C. for 2 h. After the reaction was complete, saturated ammonium chloride solution (3.2 L) was added to the reaction solution. The resulting mixture was stirred for 30 min and then separated. The organic phase was washed with water (8.0 L) and saturated brine (2.4 L) in sequence, and concentrated under reduced pressure to obtain the title compound as a light yellow oil (1.80 kg, 2.38 mol, product content: 96.1%, yield: 100%).

Tests 2-7:

[0322] tert-butyl 4-[(2R,3S,4S,5R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-6-(2,2-dimethylpropionyloxy)-5-hydroxy-hexanoyl]piperazine-1-carboxylate (purity: 96.3%) was added to a suitable solvent (6 mL/g), and the mixture was cooled to −8° C. Alkaline reagent was added in a whole. The mixture was reacted at a certain temperature. After the reaction was complete, referring to the work-up of Test 1 of this step 1, the title compound as a pale yellow oil was obtained.

[0323] Alkaline reagent, solvent, reaction temperature, reaction time and the test results of Tests 2-7 are listed in Table 2. Wherein, the amount of alkaline reagent is a molar equivalent calculated based on the reaction substrate tert-butyl 4-[(2R,3S,4S,5R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-6-(2,2-dimethylpropionyloxy)-5-hydroxy-hexanoyl]piperazine-1-carboxylate. For example, in Test 2, when the amount of the reaction substrate is 1 mol, the amount of the alkaline reagent sodium methoxide is 1.2 mol.

TABLE-US-00003 TABLE 2 Test results The amount of Raw Alkaline Alkaline Reaction Reaction Product material Test reagent reagent Solvent Temperature Time content residue 2 Sodium 1.2 eq Toluene/dimethyl  −8° C. 1.5 h 93.43% 2.02% methoxide sulfoxide (V/V) = 20/1 3 Sodium 1.5 eq Toluene/dimethyl  −8° C. 1.5 h 92.63% 1.38% methoxide sulfoxide (V/V) = 20/1 4 Sodium 1.5 eq Toluene/dimethyl −15° C. 1.5 h 93.14% 1.22% methoxide sulfoxide (V/V) = 20/1 5 Sodium 1.5 eq Toluene/dimethyl  5° C. 1.5 h 86.71% 0.70% methoxide sulfoxide (V/V) = 20/1 6 Sodium 1.5 eq Toluene/dimethyl  −8° C. 1.5 h 89.42% 1.29% ethoxide sulfoxide (V/V) = 20/1 7 Sodium 1.5 eq toluene  −8° C.  20 h 86.3% 8.70% methoxide

Step 2

Tert-butyl [(2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5-hydroxy-6-oxo-hexanoyl]piperazine-1-carboxylate

[0324] ##STR00073##

[0325] tert-butyl 4-[(2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-hexanoyl]piperazine-1-carboxylate (1.80 kg, 2.38 mol, purity: 96.1%) prepared in test 1 of step 1 of Example 2 was dissolved in a mixed solvent of toluene (5.4 L) and dimethyl sulfoxide (3.6 L), N,N-diisopropylethylamine (2.16 kg, 16.69 mol) was added to the mixture under N.sub.2. The mixture was cooled to −5° C. Sulfur trioxide pyridine complex (1.22 kg, 7.2 mol) was added in batches, and then the mixture was reacted at −5° C. for 1 h. After the reaction was complete, water (9.0 L) was added to the reaction mixture and the resulting mixture was warmed to r.t. The organic phase was washed with saturated brine (3.9 L×3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain the title compound as a pale yellow sticky (1.79 kg, 2.38 mol, product content: 87.8%, yield: 100%).

Example 3

(2R,3S,4S,5R,6R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-1-(piperazin-1-yl) heptan-1-one

[0326] ##STR00074##

Test 1:

[0327] At room temperature, dichloromethane (10.74 kg) was added to a reaction kettle, and then isopropyl titanate (2.70 kg, 9.52 mol) was added under N.sub.2. The mixture was cooled to −10° C. To the mixture a solution of methylmagnesium bromide in 2-methyltetrahydrofuran (3.81 kg, 10.39 mol, 3 mol/L) was added dropwise, and the resulting mixture was cooled to −10° C. A solution of tert-butyl [(2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5-hydroxy-6-oxo-hexanoyl]piperazine-1-carboxylate (1.79 kg, 2.38 mol, purity: 87.8%) prepared by step 2 of Example 2 in dichloromethane (10.74 kg) was added dropwise to the mixture. The temperature in the reaction kettle was controlled at −10° C.˜0° C. during the dropping process. After the addition, the mixture was continued to stir for 20 min and then heated to 25±5° C. The mixture was further stirred for 12 h, heated up to 32° C., and then further stirred for 24 h. The resulting mixture was cooled to −15° C. and slowly added to a mixed solution of concentrated hydrochloric acid (3.58 kg) and water (8.95 kg) that had been cooled to 2° C. in advance. The resulting mixture was stirred for 1 h and then separated. The organic layer was washed with dilute hydrochloric acid (concentrated hydrochloric acid 1.79 kg, and water 8.95 kg) and saturated sodium bicarbonate solution (7.5 kg) in sequence. Saturated sodium bicarbonate solution (7.5 kg) was added to the organic layer, and the resulting mixture was stirred for 10 h and then separated. The organic layer was washed with saturated brine (3.4 kg), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown sticky (1.59 kg, 2.38 mol, product content: 86.3%, yield: 100%, ee value: 93.3%).

Tests 2-21

[0328] At room temperature, to a mixture of a suitable solvent (6.0 L/kg) and (R)-BINOL were optionally added isopropyl titanate under N.sub.2, the resulting mixture was cooled to −10° C., then methylating reagent was added. tert-butyl [(2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5-hydroxy-6-oxo-hexanoyl]piperazine-1-carboxylate was dissolved in a solvent and the mixture was added dropwise to the methylating reagent solution prepared above at −10° C. After the addition, the mixture was continued to stir for 20 min and then further stirred at a certain reaction temperature (such as 25±5° C.) for 12 h. The reaction temperature was raised to 32° C. and the mixture was stirred for 12 h. After the reaction was complete, the title compound was obtained as a brown sticky referring to the work-up of Test 1.

[0329] The solvent, methylating reagent, the amount of methylating agent, the amount of isopropyl titanate, the amount of (R)-BINOL and the test results of Tests 2-21 are listed in table 3. Wherein, the amount of reagent is a molar equivalent calculated based on the reaction substrate tert-butyl [(2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5-hydroxy-6-oxo-hexanoyl]piperazine-1-carboxylate.

TABLE-US-00004 TABLE 3 the amount of The amount of (R)-BINOL Test results isopropyl methylating methylating The ee Product Reaction Test Solvent titanate agent agent amount of value content status  1 toluene 1.4 eq Zn(Me).sub.2 4.0 eq  0.2 eq 88.3% 76.1% complete  2 DCM 1.4 eq Zn(Me).sub.2 4.0 eq  0.1 eq 89.5% 77.5% complete  3 DCM 2.0 eq Zn(Me).sub.2 4.0 eq  0.1 eq 92.0% 71.8% complete  4 toluene 2.0 eq Zn(Me).sub.2 4.0 eq  0.1 eq 91.1% 74.2% complete  5 tetrahydrofuran 1.4 eq Zn(Me).sub.2 4.0 eq  0.1 eq 80.3% 69.0% complete  6 toluene 1.4 eq Zn(Me).sub.2 4.0 eq 0.05 eq 88.5% 75.3% complete  7 toluene 1.4 eq Zn(Me).sub.2 4.0 eq  0.2 eq 88.4% 80.2% complete  8 DCM 1.4 eq Zn(Me).sub.2 4.0 eq  0.1 eq 89.3% 83.3% complete  9 toluene 1.4 eq Zn(Me).sub.2 5.0 eq  0.1 eq 89.5% 83.2% complete 10 toluene 1.4 eq Zn(Me).sub.2 6.0 eq 0.05 eq 83.5% 78.9% complete 11 methyl tert-butyl ether 1.4 eq Zn(Me).sub.2 4.0 eq  0.1 eq 80.2% 80.5% complete 12 toluene 2.0 eq MeMgBr 5.0 eq — 74.2% 65.4% complete 13 DCM 1.0 eq MeMgBr 5.0 eq — 69.3% 64.5% complete 14 DCM 2.0 eq MeMgBr 5.0 eq — 87.3% 74.2% complete 15 DCM 3.0 eq MeMgBr 5.0 eq — 90.1% 84.8% complete 16 DCM 4.0 eq MeMgBr 5.0 eq — 93.4% 86.3% complete 17 DCM — MeMgBr 5.0 eq —  2.0% 46.6% complete 18 tetrahydrofuran 4.0 eq MeMgBr 5.0 eq — 51.2% 58.2% complete 19 2-methyltetrahydrofuran 4.0 eq MeMgBr 5.0 eq — 60.0% 62.1% complete 20 toluene 4.0 eq MeMgBr 5.0 eq 73.1% 67.1% complete 21 methyl tert-butyl ether 4.0 eq MeMgBr 5.0 eq — 70.5% 64.2% complete Note: In Table 3, “—” means no addition or absence; MeMgBr refers to 3 mol/L methylmagnesium bromide tetrahydrofuran solution; Zn(Me).sub.2 refers to 1.0 mol/L dimethylzinc n-hexane solution; “complete” refers to the reaction substrate tert-butyl [(2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5-hydroxy-6-oxo-hexanoyl]piperazine-1-carboxylate was completely consumed.

Example 4

(2R,3S,4S,5R,6R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-1-(piperazine-1-yl)heptan-1-one methanesulfonate

[0330] ##STR00075##

[0331] Ethyl acetate (5.74 kg) and methyl tert-butyl ether (2.35 kg) were added to a reaction kettle containing (2R,3S,4S,5R,6R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-1-(piperazin-1-yl)heptan-1-one (1.59 kg, 2.38 mol, product content: 86.3%). The mixture was stirred until dissolution. Methanesulfonic acid was added to the mixture to adjust pH to 5.5˜7.0. After the addition, the mixture was stirred for 12 h and centrifuged. The wet product was rinsed with ethyl acetate/methyl tert-butyl ether (V/V=2/1, 2.77 kg) and heptane (3.18 kg). The wet product was returned to the reaction kettle, and n-heptane (3.50 kg) was added. The resulting mixture was stirred for 12 h, centrifuged to dryness, and dried under vacuum at 35±5° C. to obtain an off-white solid (1.17 kg, 1.51 mol, product content: 95.55) %, yield: 64.0%).

Example 5

(2R,3S,4S)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl)-1-(piperazin-1-yl)butane-1-one oxalate

[0332] ##STR00076##

[0333] The (2R,3S,4S,5R,6R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-1-(piperazin-1-yl)-heptan-1-one methanesulfonate (1.17 kg, 1.51 mol, product content: 95.55%) prepared in Example 4 was dissolved in toluene (4.68 kg), then 2,2-dimethoxypropane (4.18 kg) was added, and the mixture was cooled to 8° C. Methanesulfonic acid (0.03 kg) was added, and the mixture was stirred at 8° C. for 2 h. After the reaction, the mixture was washed with saturated sodium bicarbonate solution (4.0 kg) and water (4.68 kg) in sequence. The organic phase was directly concentrated under reduced pressure without drying to obtain a brown syrup. Methyl tert-butyl ether (3.51 kg) was added to the syrup, the mixture was heated to 50° C. and stirred to dissolution, then cooled to 20° C. Anhydrous oxalic acid (0.14 kg) was added to the mixture. After the addition, the mixture was further stirred for 12 h and centrifuged. The filter cake was rinsed with methyl tert-butyl ether (1.17 L) and dried at 35±5° C. for 12 h to obtain an off-white solid (0.92 kg, purity: 95.58%, yield: 76.3%).

[0334] The methanesulfonic acid of Example 4 can be replaced with other acids, such as sulfuric acid, citric acid, oxalic acid, etc. The compound (2R,3S,4S)-2,3,4-tris(benzyloxy)-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl)-1-(piperazin-1-yl)butane-1-one oxalate can also be prepared according to the methods of Examples 4 and 5.

Example 6

(2R,3S,4S)-1-(4-allylpiperazin-1-yl)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl)butan-1-one

[0335] ##STR00077##

[0336] (2R,3S,4S)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl)-1-(piperazin-1-yl)butane-1-one oxalate (0.92 kg, purity: 95.58%) prepared according to the method of Example 5 was dissolved in methyl tert-butyl ether (3.68 kg), to the mixture were added water (2.48 kg) and 3-bromopropene (0.15 kg) in sequence. The mixture was stirred at 25° C. for 18 h, then stood and separated. The upper organic phase was retained and washed with water (2.76 kg) and saturated brine (1.06 kg) in sequence, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown syrup (0.86 kg, 1.15 mol, product content: 94.04%, yield: 100%).

Example 7

(2R,3S,4S)-1-(4-benzylpiperazin-1-yl)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl)butan-1-one

[0337] ##STR00078##

[0338] (2R,3S,4S)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl)-1-(piperazin-1-yl)butane-1-one oxalate (4.1 g, 5.14 mmol, purity: 95.58%) prepared according to the method of Example 5 was dissolved in methyl tert-butyl ether (16.4 g), to the mixture were added water (11.07 g) and benzyl bromide (0.97 g, 5.65 mmol) in sequence. The mixture was stirred at 25° C. for 12 h, then stood and separated. The upper organic phase was retained and washed with water (12.3 g) and saturated brine (4.7 g) in sequence, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown syrup (4.11 g, 5.14 mmol, product content: 92.31%, yield: 100%).

Example 8

(2R,3S,4S)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxopent-4-yl]-1-[4-(p-toluenesulfonyl)piperazin-1-yl]butan-1-one

[0339] ##STR00079##

Step 1 (2R,3S,4S,5R,6R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-1-[4-(p-toluene sulfonyl)piperazin-1-yl)heptan-1-one

[0340] ##STR00080##

[0341] (2R,3S,4S,5R,6R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-1-(piperazin-1-yl)heptan-1-one (17.4 g, 26.0 mmol) prepared according to the method of Example 3 and triethylamine (7.2 mL, 52 mmol) were dissolved in dichloromethane (100 mL), the mixture was cooled to 0° C., and 4-methylbenzenesulfonyl chloride was added to the mixture. The resulting mixture was moved to r.t. and stirred for 10 min, then washed with water (100 mL) and saturated sodium chloride solution (100 mL) in sequence, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/2-1/1) to obtain a white foamy solid (7.6 g, 9.2 mmol, yield: 35%, ee value: 93.4%).

Step 2 (2R,3S,4S)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-13-dioxolan-4-yl]-1-[4-(p-toluenesulfonyl)piperazin-1-yl]butan-1-one

[0342] ##STR00081##

[0343] (2R,3S,4S,5R,6R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-1-(4-(p-toluenesulfonyl))piperazin-1-yl)heptan-1-one (0.85 g, 1.0 mmol) was dissolved in toluene (5 mL), to the solution were added 2,2-dimethoxypropane (0.50 mL, 4.1 mmol) and methanesulfonic acid (0.04 mL, 0.6 mmol). The mixture was moved to r.t. and stirred for 20 min. The resulting mixture was washed with saturated sodium bicarbonate solution (5 mL) and saturated brine (5 mL) in sequence, and concentrated under reduced pressure to obtain a white foamy solid (0.89 g, 1.0 mmol, yield: 100%).

Example 9

(2R,3S,4S,5R)-3,4,5-tribenzyloxy-2-(benzyloxymethyl)-2-hydroxy-6-oxo-6-(4-triphenylmethyl-piperazin-1-yl)hexyl pivalate

[0344] ##STR00082##

Step 1 (2R,3S,4R,5R)-2,3,4,6-tetra(benzyloxy)-5-hydroxy-1-(piperazin-1-yl)hexan-1-one

[0345] ##STR00083##

[0346] The compound (3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl) tetrahydrofuran-2-one (50.0 g, 92.8 mmol) was dissolved in DMSO (200 mL), to the solution was added piperazine (24 g, 278.6 mmol), and the mixture was stirred at r.t. for 10 h. Toluene (400 mL) was added to dilute the mixture. The resulting mixture was washed with water (400 mL×3) and saturated sodium chloride solution (400 mL) in sequence, concentrated under reduced pressure to about 100 mL of the remaining mixture. Then n-heptane (200 mL) was added dropwise with stirring. After the addition, the mixture was stirred overnight at r.t. The upper layer was separated and removed, and the lower mixture was dried under vacuum to obtain a pale yellow syrup (34.0 g, 54.4 mmol, yield: 58.6%).

Step 2 (2R,3S,4R,5R)-2,3,4,6-tetra(benzyloxy)-5-hydroxy-1-(4-tritylpiperazine-1-yl)hexan-1-one

[0347] ##STR00084##

[0348] Triethylamine (281 mL, 1820 mmol) was added to a solution of (2R,3S,4R,5R)-2,3,4,6-tetra(benzyloxy)-5-hydroxy-1-(piperazin-1-yl)hexan-1-one (379.5 g, 607.4 mmol) in dichloromethane (1900 mL), [chloro(diphenyl)methyl]benzene (203.2 g, 728.8 mmol) was added with stirring, and the mixture was stirred at r.t. Water (1.5 L) was added to the mixture, and then the mixture was stirred for 10 min, stood and separated. The lower organic phase was washed once with 15% sodium chloride aqueous solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (EA/PE, volume ratio 10%-33%) to obtain a yellow oil (451 g, purity: 90.0%, 520.1 mmol, yield: 85.63%).

Step 3 (2R,3S,4S)-2,3,4,6-tetrakis(benzyloxy)-1-(4-tritylpiperazin-1-yl)hexan-1,5-dione

[0349] ##STR00085##

[0350] (2R,3S,4R,5R)-2,3,4,6-tetra(benzyloxy)-5-hydroxy-1-(4-tritylpiperazin-1-yl)hexan-1-one (451.0 g, 520.1 mmol) was dissolved in n-heptane (1353 mL) and DMSO (32 mL, 450 mmol), To the mixture was added N,N-diisopropylethylamine (604 mL, 3640 mmol). The mixture was cooled to 5° C. under N.sub.2, a solution of sulfur trioxide pyridine (295.7 g, 1821 mmol) and DMSO (1353 mL, 19000 mmol) was added dropwise. After the addition, the mixture was kept the temperature and stirred for 2 h, then stood and separated. The lower layer was washed with n-heptane (1000 mL×2) and then slowly poured into ice water (200 g). To the mixture was added methyl tert-butyl ether (2.0 L), and the resulting mixture was stirred for 10 minutes. After standing, the organic phase was washed with saturated aqueous sodium chloride solution (2000 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound as an off-white solid (394 g, 455.4 mmol, yield: 87.56%).

Step 4 (2,2-dimethylpropionyloxymethyl)magnesium chloride

[0351] ##STR00086##

[0352] Iodomethyl pivalate (70.0 g, 289 mmol) was dissolved in anhydrous tetrahydrofuran (210 mL) and the solution was cooled to −40° C. under N.sub.2. A solution of isopropylmagnesium chloride lithium chloride in tetrahydrofuran (230 mL, 300 mmol, 1.3 mol/L) was added dropwise to the solution for about 30 min, and the temperature was controlled at −40° C.˜−30° C. After the addition, the mixture was stirred while gradually cooled to −70° C. to obtain a gray-black liquid (50.6 g, 289 mmol, yield: 100%). The obtained Grignard reagent was directly used in the subsequent reaction (yield was calculated as 100%).

Step 5 (2R,3S,4S,5R)-3,4,5-tribenzyloxy-2-(benzyloxymethyl)-2-hydroxy-6-oxo-6-(4-trityl piperazine-1-yl)hexyl pivalate

[0353] ##STR00087##

[0354] (2R,3S,4S)-2,3,4,6-tetra(benzyloxy)-1-(4-tritylpiperazin-1-yl)hexan-1,5-dione (70.0 g, 80.9 mmol) was dissolved in anhydrous tetrahydrofuran (120 mL), and then the mixture was added dropwise to the anhydrous tetrahydrofuran solution containing (2,2-dimethylpropionyloxymethyl) magnesium chloride (49.4 g, 282 mmol) prepared in the previous step at −70° C. The temperature of the system was controlled at −70° C.˜−60° C. After the addition, the resulting mixture was stirred at this temperature for 1 h. A solution of glacial acetic acid (20 mL) in tetrahydrofuran (60 mL) was added to the mixture to quench the reaction. Petroleum ether (100 mL) was added to dilute the mixture. The resulting mixture was washed with saturated sodium bicarbonate solution (300 mL) and saturated brine (300 mL) in sequence, concentrated under reduced pressure to obtain the title compound as a yellow oil (80.0 g, 81.5 mmol, yield: 100%).

Example 10

(2R,3S,4S,5R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-1-(4-tritylpiperazine-1-yl) hexan-1-one

[0355] ##STR00088##

[0356] (2R,3S,4S,5R)-3,4,5-tribenzyloxy-2-(benzyloxymethyl)-2-hydroxy-6-oxo-6-(4-tritylpiperazine-1-yl)hexyl pivalate (80 g, 82 mmol) was dissolved in toluene (300 mL) and the solution was cooled to 0° C. under N.sub.2, then solid sodium methoxide (6.6 g, 120 mmol) was added to the solution. The resulting mixture was stirred at 0° C. for 12 h. The mixture was washed with saturated sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL) in sequence, and concentrated under reduced pressure to obtain a yellow foamy product (73 g, 82 mmol).

Example 11

(2S,3S,4S,5R)-3,4,5-tribenzyloxy-2-(benzyloxymethyl)-2-hydroxy-6-oxo-6-(4-tritylpiperazine-1-yl)hexanal

[0357] ##STR00089##

[0358] (2R,3S,4S,5R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-1-(4-tritylpiperazine-1-yl)hexan-1-one (17.0 g, 18.9 mmol) was dissolved in toluene (80 mL), to the solution were added DMSO (24 mL) and DIPEA (27 mL, 150 mmol), and the mixture was cooled to −10° C. under N.sub.2, then to the mixture was added sulfur trioxide pyridine complex (10.6 g, 66.6 mmol). The resulting mixture was stirred at 0° C.˜5° C. for 1 h, then washed with water (100 mL) and saturated brine (100 mL×2) in sequence, and concentrated under reduced pressure to obtain a dark yellow syrup (17.0 g, 19.0 mmol, yield: 100%).

Example 12

(2R,3S,4S,5R,6R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-1-(4-tritylpiperazin-1-yl)heptan-1-one

[0359] ##STR00090##

[0360] Salen (5.0 g, 9.1 mmol) was dissolved in dichloromethane (500 mL), and tetraisopropyl titanate (150 mL, 480 mmol, 95 mass %) was added to the solution under N.sub.2. The mixture was cooled to −20° C. Then methyl magnesium bromide tetrahydrofuran solution (610 mL, 610 mmol, 1.0 mol/L) was added dropwise to the mixture for about 30 min and the temperature was controlled at −5° C.˜0° C. After the addition, the mixture was stirred for 5 min, and then a solution of (2S,3S,4S,5R)-3,4,5-tribenzyloxy)-2-(benzyloxymethyl-2-hydroxy-6-oxo-6-(4-tritylpiperazin-1-yl)hexanal (110 g, 123 mmol) in dichloromethane (300 mL) was add dropwise for about 30 minutes while the temperature was controlled at −5° C.˜0° C. The resulting mixture was moved to r.t. and stirred for 14 h, then poured into ice water containing ammonium chloride (about 400 g). To the mixture was added methyl tert-butyl ether (1.0 L), and the mixture was stirred for 5 min, and then filtered with suction. The organic phase was separated from the filtrate and washed with water (1.0 L) and saturated sodium chloride solution (1.0 L) in sequence and concentrated under reduced pressure to obtain a yellow foamy solid (112 g, 122.9 mmol, yield: 100%, ee value: 93.4%).

Example 13

(2R,3S,4S)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-cyclopent-4-yl)-1-(4-triphenylmethylpiperazin-1-yl)butan-1-one

[0361] ##STR00091##

[0362] (2R,3S,4S,5R,6R)-2,3,4-tribenzyloxy-5-(benzyloxymethyl)-5,6-dihydroxy-1-(4-triphenylmethylpiperazin-1-yl)heptan-1-one (4.5 g, 4.9 mmol) was dissolved in toluene (25 mL) and the mixture was cooled to 0° C. To the mixture were added 2,2-dimethoxypropane (2.4 mL, 20 mmol) and methanesulfonic acid (0.16 mL, 2.5 mmol), and the mixture was moved to r.t. and stirred for 40 min, then washed with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL) in sequence, and concentrated under reduced pressure to obtain a pale yellow syrup (4.7 g, 4.9 mmol, yield: 100%). The crude product was used directly in the next step.

Example 14: [4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]magnesium bromide

[0363] ##STR00092##

[0364] Magnesium chips (0.041 kg, 1.71 mol) and iodine pellets (0.23 g) were added into a 5 L four-neck bottle. To the mixture was added 100 mL of a solution of 5-bromo-2-chloro-4′-ethoxydiphenylmethane (0.534 kg, 1.64 mol) in anhydrous tetrahydrofuran (1.81 L), and the mixture was heated until the reaction started. Then the remaining solution of 5-bromo-2-chloro-4′-ethoxydiphenylmethane in anhydrous tetrahydrofuran was added dropwise to the mixture for about 40 min. After the addition, the mixture was further stirred for 50 min, and then cooled to r.t. to obtain a gray-black solution (1.39 mol, product purity: 91.60%, yield is calculated as 85%). The obtained Grignard reagent was directly used in the next reaction.

Example 15

(2R,3S,4S)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl]-1-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]butan-1-one

[0365] ##STR00093##

[0366] Method One:

[0367] (2R,3S,4S)-1-(4-allylpiperazin-1-yl)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl)butan-1-one (0.74 kg, 0.99 mol, product purity: 91.98%) prepared according to the method of Example 6 was dissolved in anhydrous tetrahydrofuran (2.00 kg), and the mixture was cooled to −20° C. under N.sub.2. A solution of [4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]magnesium bromide (1.39 mol, purity: 91.60%) in tetrahydrofuran (1.81 L) was added dropwise to the mixture for about 20 min. After the addition, the mixture was stirred at −20° C. for 30 min, and then moved to r.t. and further stirred for 2 h. After the reaction, to the mixture was added dilute hydrochloric acid solution (made from concentrated hydrochloric acid (0.41 kg) and water (1.48 kg)) to quench the reaction. The resulting mixture was extracted with n-heptane (2.00 kg), and the organic phase was washed with saturated brine (2.20 L) and concentrated under reduced pressure. Then n-heptane (13.33 L) was added to the concentrate, and the resulting mixture was stirred for 20 min and then washed with a mixed solution of methanol and water (m/m=6/1, 1.38 kg). To the n-heptane phase was added column chromatography silica gel (0.14 kg), and the mixture was stirred for 8 h and filtered with suction. The filtrate was concentrated under reduced pressure to obtain a brown oil (0.687 kg, product content: 92.4%, yield: 80.0%).

[0368] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.07 (s, 1H), 7.95 (d, 1H), 7.42 (t, 6H), 7.36-7.28 (m, 10H), 7.08 (dt, 5H), 6.93 (d, 2H), 6.82 (d, 2H), 5.27 (d, 1H), 4.91 (dd, 2H), 4.70-4.50 (m, 6H), 4.44 (dd, 2H), 4.20 (d, 1H), 4.13-3.93 (m, 6H), 3.84 (dd, 2H), 1.49 (s, 3H), 1.42 (dd, 6H), 1.25 (s, 3H).

[0369] Method Two:

[0370] (2R,3S,4S)-1-(4-benzylpiperazin-1-yl)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl]butan-1-one (4.11 g, 5.14 mmol, purity: 92.31%) prepared according to the method of Example 7 was dissolved in anhydrous tetrahydrofuran (13.1 mL) and the mixture was cooled to −20° C. under N.sub.2. To the mixture was added dropwise a solution of [4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]magnesium bromide in tetrahydrofuran (13.7 mL, 6.68 mmol, 0.50 mol/L, the preparation method refers to Example 14) for about 5 min. After the addition, the mixture was stirred at −20° C. for 20 min and then moved to r.t. and further stirred for 2 h. The mixture was cooled to 0° C., and then diluted hydrochloric acid solution (21 mL, 1 mmol/mL) was added. The resulting mixture was extracted with n-heptane (30 mL), and the organic phase was washed with saturated brine (15 mL) and concentrated under reduced pressure. The obtained residue was dissolved in n-heptane (60 mL), washed with methanol/water (v/v=8/1, 10 mL), and concentrated under reduced pressure to obtain a colorless oil (4.02 g, 4.63 mmol, product content: 73.0%, yield: 90%).

[0371] Method Three:

[0372] (2R,3S,4S)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolpan-4-yl]-1-[4-(p-toluenesulfonyl)piperazin-1-yl]butan-1-one (0.89 g, 1.0 mmol) prepared according to the method of Example 8 was dissolved in anhydrous tetrahydrofuran (4 mL) and the mixture was cooled to −20° C. under N.sub.2. To the mixture was added dropwise [4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]magnesium bromide (2.6 mL, 1.3 mmol, 0.50 mol/L, the preparation method refers to Example 14) for about 1 min. After the addition, the mixture was moved to r.t. and stirred for 30 min. To the mixture was added saturated ammonium chloride solution (5 mL) to quench the reaction. The resulting mixture was extracted with petroleum ether (10 mL). The organic phase was washed with saturated sodium chloride solution (10 mL). To the mixture was added concentrated hydrochloric acid (1.0 mL), and then the mixture was stirred for 3 h and separated. The organic phase was washed with saturated sodium bicarbonate solution (5 mL) and concentrated under reduced pressure. The residue was filtered through silica gel to obtain a colorless oil (0.50 g, 0.58 mmol, yield: 56%).

[0373] Method Four:

[0374] (2R,3S,4S)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-cyclopent-4-yl)-1-(4-triphenylmethylpiperazin-1-yl)butan-1-one (4.7 g, 4.9 mmol) prepared according to the method of Example 13 was dissolved in anhydrous tetrahydrofuran (20 mL) and the mixture was cooled to −20° C. under N.sub.2. To the mixture was added dropwise bromo-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]magnesium (14 mL, 6.4 mmol, 0.46 mol/L) prepared according to the method of Example 14 for about 2 min. After the addition, the mixture was stirred at −20° C. for 10 min and then moved to r.t. and further stirred for 20 min. To the mixture was added saturated ammonium chloride solution (30 mL) to quench the reaction, and then the resulting mixture was extracted with petroleum ether (40 mL), and the organic phase was washed with saturated brine (50 mL) and concentrated under reduced pressure. The residue was filtered through silica gel to obtain a colorless oil (3.0 g, 3.5 mmol, yield: 70%).

Example 16

(1R,2S,3S,4R,5S)-5-(3-(4-ethoxybenzyl)-4-chlorophenyl)-1-((1R)-1-hydroxyethyl)-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol

[0375] ##STR00094##

[0376] (2R,3S,4S)-2,3,4-tribenzyloxy-4-[(4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl]-1-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]butane-1-one (0.687 kg, 0.79 mol, purity: 92.4%) prepared according to method one of Example 15 was dissolved in tetrahydrofuran (0.53 kg). To the mixture were added methanol (1.63 kg), concentrated hydrochloric acid (0.31 kg, 36 mass %) and palladium/carbon (0.14 kg, 10 mass %), and the resulting mixture was stirred for 12 h under H.sub.2. After the reaction, the mixture was filtered with suction and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (4.12 kg), washed with water (2.75 kg), saturated sodium bicarbonate solution (1.47 kg) and saturated brine (1.37 kg) in sequence, and then concentrated under reduced pressure. The residue was recrystallized from ethanol (0.29 kg) and n-heptane (0.26 kg) to obtain a white solid (0.263 kg, 0.52 mol, product purity: 99.27%, ee value: 99%, yield: 67.1%).

[0377] MS (ESI, pos. ion) m/z: 451.2 [M+H].sup.+;

[0378] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 7.41 (dd, 2H), 7.35-7.29 (m, 1H), 7.11 (d, 2H), 6.84 (d, 2H), 5.30 (d, 1H), 5.01 (d, 1H), 4.92 (d, 1H), 4.64 (d, 1H), 4.03-3.95 (m, 5H), 3.85 (p, 1H), 3.78 (d, 1H), 3.59-3.53 (m, 1H), 3.44 (dd, 1H), 3.38 (m, 1H), 1.30 (t, 3H), 1.18 (d, 3H).

[0379] The compound of Example 16 can also be prepared by other similar methods. For example, The substituents (allyl, benzyl, trityl or p-toluenesulfonyl) of piperazine in the intermediate compounds of Examples 6-8 or 13 can be replaced with other substituents, such as phenyl, diphenylmethyl, bis(4-methoxyphenyl)(phenyl)methyl, benzenesulfonyl, 4-bromobenzenesulfonyl, pyridyl, benzylsulfonyl, imidazolyl or N,N-dimethylaminosulfonyl; and then the target product can be obtained according to the method of Examples 15-16 of the present invention. The replaced intermediate compound can be prepared according to the preparation method of the intermediate compound of the present invention with appropriate adjustments, or can be prepared by a suitable synthetic method selected according to the structural characteristics of the intermediate compound.

[0380] Reference throughout this specification to “an embodiment,” “some embodiments,” “one embodiment”, “another example,” “an example,” “a specific example,” or “some examples,” means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the above terms throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments, examples or the features of them as long as they are not contradictory to one another.

[0381] Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.