Method for preparing dapagliflozin and intermediate thereof

Abstract

The invention relates to a method for preparing dapagliflozin and an intermediate thereof, which comprises the following steps: reacting a compound as shown in a formula II with a compound as shown in a formula III in an organic solvent under the action of organic metal lithium, dropwise adding reaction liquid into water after the reaction is finished, and quenching to obtain a compound as shown in a formula IV, and reacting the compound as shown in the formula IV with methanol under an acidic condition to obtain a compound as shown in a formula V. The method provided by the invention has the advantages of mild conditions, few byproducts, short time consumption and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of chemical pharmacy, and more specifically, to a method for preparing dapagliflozin and its intermediates. Background Art

[0002] Dapagliflozin is a sodium-glucose co-transporter 2 inhibitor used to treat type 2 diabetes. Its chemical name is (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxyphenyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, and has the following chemical structure:

[0003]

[0004] The compound shown in Formula I is a key intermediate for the preparation of dapagliflozin, and its chemical name is (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyltetrahydro-2H-pyran-3,4,5-triyl triacetate

[0005]

[0006] WO2004 / 063209 discloses a method for preparing dapagliflozin, wherein the compound represented by formula II and the compound represented by formula III are subjected to addition reaction under the action of butyl lithium, and then methanol and methanesulfonate solution are added to react to obtain a compound represented by formula V; compound V is reduced to obtain a crude product of dapagliflozin, which is a mixture of α and β diastereomers of dapagliflozin (i.e., a mixture of compound VI and compound IX). Since the α and β diastereomers of dapagliflozin are difficult to separate, they are acetylated in one step to obtain compound I by crystallization, and the acetyl group of compound I is further removed to obtain a purified β-isomer compound VI. The route is as follows:

[0007]

[0008] In the above process, a large amount of α-C glucoside IX and furan isomer X exist in the product of the reduction step, so the yield of tetraacetylated β-C glucoside (compound I) obtained in the crystallization step is only 37%, and the mother liquor contains tetraacetylated α-C glucoside XI and tetraacetylated furan isomer XII, which affects the yield of the entire route.

[0009] Summary of the invention

[0010] The first aspect of the present invention provides a method for preparing a compound represented by formula V,

[0011] It includes the following steps:

[0012] (a) reacting a compound represented by formula II with a compound represented by formula III in an organic solvent under the action of an organic metal lithium,

[0013]

[0014] After the reaction is completed, the reaction solution is added dropwise into water to quench the reaction to obtain a compound represented by formula IV.

[0015]

[0016] (b) reacting the compound of formula IV obtained in step (a) with methanol under acidic conditions, and after the reaction is completed, quenching the reaction to obtain the compound of formula V.

[0017] In some embodiments of the present invention, the organometallic lithium in step (a) is selected from n-butyllithium, tert-butyllithium or n-hexyllithium; preferably n-butyllithium;

[0018] In some embodiments of the present invention, the organic solvent in step (a) is selected from toluene, tetrahydrofuran, methyltetrahydrofuran, hexane, heptane, dioxane, dimethyl sulfoxide, dichloromethane or any mixture thereof;

[0019] In some embodiments of the present invention, the reaction in step (a) is carried out at -90°C to -60°C, preferably at -90°C to -78°C; the reaction time is generally 2 to 4 hours;

[0020] In some embodiments of the present invention, the reaction of step (a) is operated by dropping a solution containing the compound of formula II into a solution containing organic metal lithium to form a mixture, and then dropping a solution containing the compound of formula III into the above mixture;

[0021] In some embodiments of the present invention, the quenching operation of step (a) is to slowly add the reaction solution into water, the water is preferably pre-cooled to 0-5°C, and the quenching temperature is controlled at 0-10°C;

[0022] In some embodiments of the present invention, step (a) further comprises the following steps: heating the mixed solution obtained after quenching to 20-30° C. under stirring, separating the organic phase and the aqueous phase, and then concentrating the organic phase to obtain the compound represented by formula IV;

[0023] In some embodiments of the present invention, the acid in step (b) is selected from methanesulfonic acid, toluenesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid and hydrochloric acid, preferably hydrochloric acid;

[0024] In some embodiments of the present invention, the reaction temperature in step (b) is 0°C to 40°C; preferably 25 to 30°C;

[0025] In some embodiments of the present invention, the quenching operation of step (b) is: cooling the reaction solution and then dropping it into a pre-cooled alkaline solution for quenching, and controlling the quenching temperature at 0 to 10°C; preferably, the reaction solution is cooled to 0 to 5°C, and preferably, the alkaline solution is a sodium bicarbonate solution; preferably, the pre-cooling is pre-cooling to 0 to 5°C;

[0026] In some embodiments of the present invention, further, the step of extracting and concentrating to separate compound V is included after quenching.

[0027] Compared with the prior art in which methanol and acid are directly added to the reaction solution in step (a) for quenching and methylation or water is directly added for quenching, the operating method of the present invention has a more controllable temperature, a short post-treatment time, and can reduce the generation of by-products, especially less residual intermediate hemiketal impurities (Formula VII) and furan isomers (Formula VIII) in the product. The impurity structures of the hemiketal impurities (Formula VII) and furan isomers (Formula VIII) of the present invention are as follows:

[0028]

[0029] The second aspect of the present invention provides a composition comprising a compound of formula V, wherein the HPLC purity of the compound of formula V is ≥80%, preferably ≥90%; more preferably ≥93%, such as 93-95%, such as 93%, 93.5%, 94%, 94.5%, 95% or any value or range therebetween;

[0030] Furthermore, the composition further comprises a compound of formula VII, wherein the HPLC content of the compound of formula VII is ≤5%, preferably ≤3%, more preferably ≤1%, such as 0.1-0.6%, such as 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.57%, 0.6% or any value or range therebetween;

[0031]

[0032] Furthermore, the composition further comprises a compound represented by formula VIII, wherein the HPLC content thereof is ≤5%, preferably ≤2%, such as 0.5-1.5%, such as 0.5%, 0.9%, 0.95%, 1.0%, 1.06%, 1.1%, 1.2%, 1.5% or any value or range therebetween;

[0033]

[0034] Furthermore, the composition is prepared by the aforementioned method.

[0035] The HPLC purity and HPLC content mentioned herein both refer to the ratio of the peak area corresponding to each substance to the total peak area in the HPLC spectrum.

[0036] The third aspect of the present invention provides a method for preparing a compound represented by formula VI, comprising the following steps:

[0037] (c) The composition of the second aspect of the present invention can be obtained by reacting a reducing agent in an organic solvent in the presence of a Lewis acid.

[0038] In some embodiments of the present invention, in step (c), the Lewis acid is selected from aluminum trichloride, boron trifluoride etherate or boron trifluoride tetrahydrofuran, preferably aluminum trichloride;

[0039] In some embodiments of the present invention, the molar ratio of the Lewis acid to compound II is 1 to 5:1, preferably 1.2 to 3:1, such as 1.2:1, 1.5:1, 2:1, 3:1 or any value or range therebetween;

[0040] Further, the reducing agent is selected from triethylsilane, triphenylsilane, trimethylsilane or tetramethyldisiloxane, preferably triethylsilane;

[0041] Further, the organic solvent is selected from dichloromethane, chloroform, acetonitrile or any mixture thereof;

[0042] In some embodiments of the present invention, the reaction temperature of step (c) is 0 to 40°C, preferably 20 to 30°C;

[0043] In some embodiments of the present invention, the operation of step (c) is as follows: slowly dropwise add the mixture of compound V and the organic solution into the mixture containing Lewis acid, reducing agent and organic solvent; after the dropwise addition is completed, the temperature is raised to 20-30° C. and stirred to complete the reaction. In some embodiments, after the temperature is raised, the reaction is completed after 1-1.5 hours of reaction.

[0044] In some embodiments, after the reaction in step (c) is completed, the reaction is cooled to 0-10° C. and quenched by adding water.

[0045] The method of step (c) of the present invention has a high reduction yield, and the product contains less compound IX and compound X. The reduction reaction does not require the addition of water, and the operation is simple.

[0046] The fourth aspect of the present invention provides a composition comprising a compound of formula VI and a compound of formula IX, wherein the content ratio of the compound of formula VI to the compound of formula IX is ≥10:1, preferably ≥50:1, more preferably ≥80:1, more preferably 82:1 to 90:1, for example 82:1, 83:1, 84:1, 85:1, 86:1, 87:1, 88:1, 89:1, 90:1 or any value or range therebetween. The content ratio is the ratio of the peak areas of the respective substances detected by the HPLC method;

[0047]

[0048] Furthermore, wherein the compound represented by formula X is further included, preferably, the content ratio of the compound represented by formula VI to the compound represented by formula X is ≥10:1, preferably ≥15:1, for example, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 25:1, 30:1, 100:1 or any value or range therebetween,

[0049]

[0050] Furthermore, the composition is prepared according to the method according to the third aspect of the present invention.

[0051] The fifth aspect of the present invention provides a method for preparing a compound of formula I,

[0052]

[0053] It includes the following steps:

[0054] (a) In an organic solvent, the compound shown in formula II

[0055]

[0056] React with the compound shown in formula III under the action of organometallic lithium

[0057]

[0058] After the reaction is completed, the reaction solution is added dropwise into water to quench, to obtain a compound shown in formula IV.

[0059]

[0060] (b) reacting the compound of formula IV obtained in step (a) with methanol under acidic conditions, and after the reaction is completed, quenching to obtain a compound of formula V,

[0061]

[0062] (c) reacting the compound of formula V obtained in step (b) with a reducing agent in an organic solvent in the presence of a Lewis acid to obtain a compound of formula VI,

[0063]

[0064] (d) acetylation of the compound of formula VI obtained in step (c) to obtain a compound of formula I

[0065] The sixth aspect of the present invention provides a method for preparing dapagliflozin.

[0066]

[0067] It includes the following steps:

[0068] (a) reacting a compound represented by formula II with a compound represented by formula III in an organic solvent under the action of an organic metal lithium,

[0069]

[0070] After the reaction is completed, the reaction solution is added dropwise into water to quench, to obtain a compound represented by formula IV.

[0071]

[0072] (b) reacting the compound of formula IV obtained in step (a) with methanol under acidic conditions, and after the reaction is completed, adding the reaction solution dropwise into an alkaline solution to quench the reaction and obtain a compound of formula V;

[0073]

[0074] (c) reacting the compound of formula V obtained in step (b) with a reducing agent in an organic solvent in the presence of a Lewis acid to obtain a compound of formula VI;

[0075]

[0076] (d) acetylation of the compound of formula VI obtained in step (c) to obtain a compound of formula I

[0077]

[0078] (e) removing the acetyl group from the compound I obtained in step (d) by conventional methods in the art to obtain a compound represented by formula VI, i.e., high-purity dapagliflozin.

[0079] In some embodiments of the present invention, after the reaction in step (a) is quenched, the reaction solution is heated, allowed to stand, separated, and evaporated under reduced pressure to obtain a soluble organic phase residue that can be directly used in the next reaction.

[0080] In some embodiments of the present invention, after the reaction in step (b) is quenched, cyclohexane is added to the reaction solution, stirred, allowed to stand, and separated, the aqueous phase is taken, methanol is evaporated under reduced pressure, toluene is added for extraction, the organic phase is taken, and washed with water; the organic phase is concentrated to dryness, and the residue can be dissolved and directly used in the next reaction.

[0081] In some embodiments of the present invention, after the reaction in step (c) is quenched, the mixed solution is heated to 20-30° C., stirred, allowed to stand, and separated. The aqueous phase is extracted with dichloromethane, and the organic phases are combined and evaporated to dryness. The residue can be dissolved and used directly in the next step.

[0082] In some embodiments of the present invention, steps (a) to (c) can be used for the next reaction without complicated purification steps (such as column chromatography, recrystallization, etc.), and the operation is simple.

[0083] The acetylation in step (d) can be performed by a commonly used acetylation method in the art, for example, by reacting with an acetylation agent in an organic solvent under the action of a base. The acetylation can also be performed under the action of a catalyst.

[0084] The acetylating agent may be an acetylating agent commonly used in the art; the base may be a base commonly used in the art, including an organic base or an inorganic base.

[0085] In some embodiments of the present invention, the molar ratio of the acetylating agent in step (d) to the molar ratio of compound II is 3.5 to 6.0:1, preferably 4.0 to 5.0:1; the molar ratio of the base in step (d) to the molar ratio of compound II is 3.5 to 6.0:1, preferably 4.0 to 5.0:1;

[0086] In some embodiments of the present invention, in step (d), the acetylating agent is acetic anhydride; further, in step (d), the base is selected from triethylamine, diisopropylethylamine, pyridine, 2-methylpyridine, N-methylmorpholine, sodium carbonate or potassium carbonate, preferably N-methylmorpholine or sodium carbonate.

[0087] In some embodiments of the present invention, the catalyst for the acetylation in step (d) is 4-dimethylaminopyridine.

[0088] The dosage of the acetylation reaction alkali and acetic anhydride provided by the invention is significantly reduced.

[0089] The compound I prepared by the method provided by the present invention has a high yield and contains less compound XI and compound XII.

[0090] The compound I prepared by the method provided by the present invention can be subjected to conventional methods in the art to remove the acetyl group to obtain a high-purity compound represented by formula VI.

[0091] The seventh aspect of the present invention provides use of the composition described in the second aspect and the fourth aspect of the present invention in the preparation of dapagliflozin.

[0092] Beneficial effects:

[0093] The crude product of dapagliflozin obtained by the preparation method of the present invention has a high content of β-dimer, few impurities and is easy to purify.

[0094] The reaction conditions are mild, the reaction time is short, the product purity is high, the impurities are few, and it is easy to purify.

[0095] In the preparation method of the present invention, the amounts of alkali and acetic anhydride used in the acetylation reaction are significantly reduced, and the purity of the product compound I is high.

[0096] The whole route has few purification steps, and the total yield of the final product compound I reaches 70%, with high yield and high purity.

[0097] The overall reaction conditions are mild and easy to control, which is conducive to industrial production. DETAILED DESCRIPTION

[0098] The present invention is further described below in conjunction with specific embodiments.

[0099] In the present invention, unless otherwise specified, the scientific and technical terms used in the present invention have the meanings commonly understood by those skilled in the art. In addition, the laboratory operation steps used in the present invention are all conventional steps widely used in the corresponding fields.

[0100] The terms “having”, “including” and “comprising” should be interpreted as open ended, indicating the presence of the listed elements but not excluding the existence, presence or addition of any other one or more elements that are not listed.

[0101] All ranges recited herein include those endpoints of the range between the two values ​​recited. All values ​​recited herein, whether or not stated, include the expected degree of experimental error, technical error, and instrumental error for the given technique used to measure the value.

[0102] In the present invention, unless otherwise specified, % is a percentage of weight / weight (w / w).

[0103] Unless otherwise indicated, any numerical value, such as the amount of solvent used or the range of solvent used described in the present invention, should be understood as being modified by the term "about" in all cases, indicating that such value can vary within a certain range. When there is no range (such as a range of error or the standard deviation of the average value given in a graph or data table), the term "about" should be understood to mean a larger range including the value described, and in the case of considering significant figures, the range included by rounding to the number, and the range including plus or minus 10% of the value described.

[0104] The following synthesis examples serve to illustrate the preparation of compounds I. They are to be regarded merely as illustrations of possible methods without restricting the invention to their content.

[0105] HPLC method for compound V:

[0106]

[0107]

[0108] HPLC method for compound VI:

[0109]

[0110] HPLC method for compound I:

[0111]

[0112] In the present invention, the "HPLC content", "HPLC purity", "purity" and "content" of the main product and impurities in each step of the reaction all refer to the ratio of the peak area corresponding to each peak to the total peak area in the HPLC spectrum. The "content ratio" of the present invention refers to the ratio of the peak area corresponding to each peak in the HPLC spectrum.

[0113] Example 1

[0114] Step 1: Preparation of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Compound V)

[0115]

[0116] Under N2 protection, tetrahydrofuran (650 mL) was placed in a four-necked flask and cooled to -85°C. Maintain -90~-80℃, add n-butyl lithium (hexane solution, 2.5mol / L, 460mL); control -90~-80℃ to add a toluene (1300mL) solution of compound II (325.6g); after the dropwise addition, control -90~-80℃ and stir for 1~1.5h; control -90~-80℃ to add a toluene (325mL) solution of compound III (536.9g); after the dropwise addition, control -90~-80℃ and stir for 1.5~2.5h; control the temperature at 0~10℃, add the reaction solution dropwise to 1650mL of water precooled to 0~5℃ to quench; after the quenching is completed, heat to 20~25℃ and stir for 0.5h, let stand for 0.5~1h; separate the liquids, evaporate the organic phase under reduced pressure; under N2 protection, dissolve the residue in methanol (1650mL); add HCl methanol solution (2 43.1g), stirred at 25-30°C for 3-4h; the reaction solution was cooled to 0-5°C; the temperature was controlled to <10°C, and the reaction solution was added dropwise to a 7% sodium bicarbonate solution (1650mL) precooled to 0-5°C; cyclohexane (650mL) was added and stirred for 0.5h, and allowed to stand for 0.5-1h; the liquids were separated and the cyclohexane phase was discarded; the methanol was evaporated from the aqueous phase under reduced pressure; toluene (1650mL) was added for extraction; the aqueous phase was extracted with toluene (820mL) again, the organic phases were combined, and washed with water once; the organic phase was concentrated to dryness, dichloromethane (900mL) was added and mixed, and the yield was calculated as 100% and used directly in the next step. HPLC showed that the purity of the main product (compound V) was 93.9%, the content of hemiketal impurity (compound VII) was 0.25%, and the content of furan isomer (compound VIII) was 1.06%.

[0117] Step 2: Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-methoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound VI)

[0118]

[0119] Under N2 protection, aluminum chloride (400.0 g) and dichloromethane (880 mL) were put into a four-necked flask and cooled to 10-15°C; acetonitrile (880 mL) was added dropwise while maintaining 10-30°C; triethylsilane (174.4 g) was added dropwise while controlling 10-20°C; the dichloromethane solution of compound V prepared in step 1 was slowly added dropwise while continuing to control 10-20°C; after the addition was completed, the temperature was raised to 25-30°C and stirred for 60-90 min; the mixture was cooled to 0-10°C, and water (2200 mL) was added dropwise while controlling <30°C to quench; the mixture was heated to 40°C and stirred for 2 hours. The mixture was heated to 20-30° C. and stirred for 30 minutes, and allowed to stand for 30 minutes; the mixture was separated, and the aqueous phase was extracted once with dichloromethane (880 mL). The organic phases were combined and evaporated to dryness, and dichloromethane (2200 mL) was added to dissolve the mixture to obtain a solution of compound VI. The solution was directly used in the next step according to the yield calculated as 100%. HPLC showed that the purity of the main product (compound VI) was 86.92%, the content of α-isomer (compound IX) was 1.04%, and the content of the five-membered ring isomer (compound X) was 4.48%. The water content was detected, and the final water content (KF) was <0.5%.

[0120] Step 3: Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyltetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound I)

[0121]

[0122] Under N2 protection, the solution of compound VI prepared in step 2, N-methylmorpholine (422.2 g) and 4-dimethylaminopyridine (2.5 g) were added into a flask, stirred, and cooled to 0-10°C; the temperature was controlled at 0-10°C, and acetic anhydride (459.4 g) was added dropwise; after the addition, the temperature was raised to 15-25°C, and the mixture was stirred and reacted for 1-2 hours; the temperature was lowered to 0-10°C, and water (2200 ml) was added dropwise to control the internal temperature <15°C to quench; after the addition, the temperature was raised to 20-25°C, stirred for 30 min, and allowed to stand for 30 min; the aqueous phase was separated by dichloromethane (1 100mL) was extracted once, and the organic phases were combined; the organic phase was evaporated under reduced pressure; methanol (3500mL) was added to the residue, the temperature was raised to 60-70°C, stirred and dissolved; the temperature was lowered to 0-10°C, stirred and kept warm for 2-3 hours, and filtered; methanol (3500mL) was added to the filter cake again, the temperature was raised to 60-70°C, stirred and dissolved; the temperature was lowered to 0-10°C, stirred and kept warm for 2-3 hours; filtered, and the filter cake was vacuum dried to obtain compound I (off-white powder, 403.9g, HPLC showed that the purity of the main product was 99.82%), and the total yield of 3 steps was 70%.

[0123] Example 2

[0124] Step 1: Preparation of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Compound V)

[0125]

[0126] Under N2 protection, tetrahydrofuran (260 L) was added into the reaction kettle and cooled to -90 to -80°C. Maintain -90~-80℃, add n-butyl lithium (hexane solution, 2.5mol / L, 120kg) dropwise; control -90~-80℃ to add a toluene (500L) solution of compound II (126kg) dropwise; after the dropwise addition, control -90~-80℃ and stir for 1~1.5h; control -90~-80℃ to add a toluene (200L) solution of compound III (206kg) dropwise; after the dropwise addition, control -90~-80℃ and stir for 1.5~2.5h; control the temperature at 0~10℃, add the reaction solution dropwise to 640L of water precooled to 0~5℃ to quench; after the quenching is completed, heat to 20~25℃ and stir for 0.5h, let stand for 0.5~1h; separate the liquids, evaporate the organic phase under reduced pressure; under N2 protection, dissolve the residue in methanol (630L); add HCl methanol solution (47k g), stirred at 25-30°C for 3-4h; the reaction solution was cooled to 0-5°C; the temperature was controlled to <10°C, and the reaction solution was added dropwise to a 7% sodium bicarbonate solution (700L) precooled to 0-5°C; n-heptane (250L) was added and stirred for 0.5h, and allowed to stand for 0.5-1h; the liquids were separated and the n-heptane phase was discarded; the methanol was evaporated from the aqueous phase under reduced pressure; toluene (630L) was added for extraction; the aqueous phase was extracted twice with toluene (320L), the organic phases were combined, and washed once with water; the organic phase was concentrated to dryness, dichloromethane (680L) was added and mixed, and the yield was calculated as 100% and used directly in the next step. HPLC showed that the purity of the main product (Compound VI) was 93.61%, the content of hemiketal impurity (Compound VII) was 0.57%, and the content of furan isomer (Compound VIII) was 0.95%.

[0127] Step 2: Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-methoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound VI)

[0128]

[0129] Under N2 protection, aluminum chloride (155kg) and dichloromethane (340L) were added into the reactor and cooled to 10-15°C; acetonitrile (540L) was added dropwise while maintaining 10-30°C; triethylsilane (81kg) was added dropwise while controlling 10-20°C; the dichloromethane solution of compound V prepared in step 1 was slowly added dropwise while continuing to control 10-20°C; after the addition was completed, the temperature was raised to 25-30°C and stirred for 60-90min; the temperature was cooled to 0-10°C and added dropwise to water (850L) The mixture was quenched in water; the mixture was heated to 20-30° C. and stirred for 30 minutes, and allowed to stand for 30 minutes; the mixture was separated, the aqueous phase was extracted once with dichloromethane (340 L), the organic phases were combined and evaporated to dryness, and dichloromethane (850 L) was added to dissolve to obtain a solution of compound VI, wherein HPLC showed that the purity of the main product (compound VI) was 87.91%, the content of α-isomer (compound IX) was 1.07%, and the content of the five-membered ring isomer (compound X) was 4.26%, and the water content was detected, and KF<0.5%.

[0130] Step 3: Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyltetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound I)

[0131]

[0132] Under N2 protection, the compound VI solution prepared in step 2, sodium carbonate (184kg), and 4-dimethylaminopyridine (1kg) were put into the reaction kettle with stirring, and the temperature was lowered to 0-10°C; the temperature was controlled at 0-10°C, and acetic anhydride (178kg) was added dropwise; after the addition was completed, the temperature was raised to 15-25°C, and the mixture was stirred and reacted for 1-2 hours; the temperature was lowered to 0-10°C, and the internal temperature was controlled to be <15°C, and water (850L) was added dropwise to quench; after the addition was completed, the temperature was raised to 20-25°C, stirred for 30min, and allowed to stand for 30min; the liquid was separated, and the aqueous phase was treated with dichloromethane (42 0L) was extracted once, and the organic phases were combined; the organic phase was evaporated under reduced pressure; methanol (1300L) was added to the residue, the temperature was raised to 60-70°C, stirred and dissolved; the temperature was lowered to 0-10°C, stirred and dissolved for 2-3 hours, filtered, methanol (1300L) was added to the filter cake, the temperature was raised to 60-70°C, stirred and dissolved; the temperature was lowered to 0-10°C, stirred and dissolved for 2-3 hours; filtered, and the filter cake was vacuum dried to obtain compound I (off-white powder, 154kg, HPLC showed that the purity of the main product was 99.71%), and the total yield of 3 steps was 69%.

[0133] Comparative Example 1:

[0134] Compound V was prepared by referring to the method described on page 54 of the specification of Chinese patent CN100391963C (see comparative example 1) and the method of compound D described on page 33 of the specification of CN100534997C (see comparative example 2), and the products thereof were compared with the products obtained in the present invention, and the results are shown in Table 1. As can be seen from Table 1, the preparation method of the present invention has mild quenching conditions and few by-products; and the mixed solution can achieve the purpose of separating the product from the water phase and removing excess alkali and inorganic impurities after heating, and the quenching and heating time are short, which is suitable for industrial production.

[0135] Table 1 Comparison of operation modes and quality of formula V obtained by various preparation methods

[0136]

[0137] Comparative Example 2:

[0138] Compound VI was prepared by referring to the method described on page 30 of the specification of Chinese patent CN100534997C, and the reaction solution before purification was compared with the reaction solution obtained in the present invention. The results are shown in Table 2.

[0139] Table 2 Comparison of the quality of the reaction solution of formula VI obtained by each preparation method

[0140]

[0141]

[0142] Comparative Example 3:

[0143] Compound I was prepared by referring to the method on page 30 of the specification of Chinese patent CN100534997C, and the reaction solution before purification was compared with the reaction solution obtained in the present invention. The results are shown in Table 3.

[0144] Table 3 Comparison of the quality of the reaction solution of formula I obtained by each preparation method

[0145]

Claims

1. A method for preparing a compound of formula V, It includes the following steps: (a) reacting a compound represented by formula II with a compound represented by formula III in an organic solvent under the action of an organic metal lithium, After the reaction is completed, the reaction solution is added dropwise into water to quench the reaction to obtain a compound represented by formula IV. (b) reacting the compound of formula IV obtained in step (a) with methanol under acidic conditions, and after the reaction is completed, quenching to obtain a compound of formula V.

2. The method according to claim 1, wherein: The organometallic lithium in step (a) is selected from n-butyllithium, tert-butyllithium or n-hexyllithium; preferably n-butyllithium; The organic solvent in step (a) is selected from toluene, tetrahydrofuran, methyltetrahydrofuran, hexane, heptane, dioxane, dimethyl sulfoxide, dichloromethane or any mixture thereof; The reaction in step (a) is carried out at -90°C to -60°C, preferably at -90°C to -78°C; The operation mode of the reaction in step (a) is: adding dropwise a solution containing the compound represented by formula II to a solution containing organic metal lithium to form a mixture, and then adding dropwise a solution containing the compound represented by formula III to the above mixture; The quenching operation of step (a) is to slowly add the reaction solution into water, wherein the water is preferably pre-cooled to 0-5°C, and the quenching temperature is controlled at 0-10°C; Step (a) further comprises the following steps: heating the mixed solution obtained after quenching to 20-30° C. under stirring, separating the organic phase and the aqueous phase, and then concentrating the organic phase to obtain the compound represented by formula IV; The acid in step (b) is selected from methanesulfonic acid, toluenesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid and hydrochloric acid, preferably hydrochloric acid; The reaction temperature in step (b) is 0°C to 40°C; preferably 25 to 30°C; The quenching operation of step (b) is: cooling the reaction solution and then dropping it into a pre-cooled alkaline solution for quenching, and controlling the quenching temperature to be between 0 and 10° C.; preferably, the reaction solution is cooled to 0 to 5° C., preferably, the alkaline solution is a sodium bicarbonate solution; preferably, the pre-cooling is pre-cooling to 0 to 5° C.; Further, after quenching, compound V is isolated by extraction and concentration.

3. A composition comprising a compound of formula V, wherein: The HPLC purity of the compound represented by formula V is ≥80%, preferably ≥90%; more preferably ≥93%, such as 93-95%; Furthermore, the composition further comprises a compound of formula VII, wherein the HPLC content of the compound of formula VII is ≤5%, preferably ≤3%, more preferably ≤1%, such as 0.1-0.6%, Furthermore, the composition further comprises a compound represented by formula VIII, the HPLC content of which is ≤5%, preferably ≤2%, for example 0.5-1.5%, Furthermore, the composition is prepared by the method according to claim 1 or 2, The HPLC purity and HPLC content mentioned herein both refer to the ratio of the peak area corresponding to each substance to the total peak area in the HPLC spectrum.

4. A method for preparing a compound of formula VI, It includes the following steps: (c) reacting the composition of claim 3 with a reducing agent in an organic solvent in the presence of a Lewis acid to obtain a compound of formula VI.

5. The method according to claim 4, wherein in step (c), the Lewis acid is selected from aluminum chloride, boron trifluoride etherate or boron trifluoride tetrahydrofuran, preferably aluminum chloride; Further, the molar ratio of the Lewis acid to the compound II is 1 to 5:1, preferably 1.2 to 3:1, such as 1.2:1, 1.5:1, 2:1, 3:1 or any value or range therebetween; Further, the reducing agent is selected from triethylsilane, triphenylsilane, trimethylsilane or tetramethyldisiloxane, preferably triethylsilane; Further, the organic solvent is selected from dichloromethane, chloroform, acetonitrile or any mixture thereof; The reaction temperature of step (c) is 0 to 40°C, preferably 20 to 30°C; The operation method of step (c) is as follows: slowly dropwise add the mixture of compound V and organic solution into the mixture of Lewis acid, reducing agent and organic solvent; after the dropwise addition is completed, the temperature is raised to 20-30° C. and stirred to complete the reaction.

6. A composition comprising a compound of formula VI and a compound of formula IX, wherein: The content ratio of the compound represented by formula VI to the compound represented by formula IX is ≥10:1, preferably ≥50:1, more preferably ≥80:1, more preferably 82:1 to 90:1, Furthermore, wherein the compound represented by formula X is further included, preferably, the content ratio of the compound represented by formula VI to the compound represented by formula X is ≥10:1, preferably ≥15:1, The content ratio is the ratio of the peak areas of the various substances detected by the HPLC method; Furthermore, the composition is prepared according to the method according to claim 4 or 5.

7. A method for preparing a compound of formula I, It includes the following steps: (a) in an organic solvent, the compound shown in formula II React with the compound shown in formula III under the action of organometallic lithium After the reaction is completed, the reaction solution is added dropwise into water to quench the reaction, thereby obtaining a compound represented by formula IV. (b) reacting the compound of formula IV obtained in step (a) with methanol under acidic conditions, and after the reaction is completed, quenching to obtain a compound of formula V, (c) reacting the compound of formula V obtained in step (b) with a reducing agent in an organic solvent in the presence of a Lewis acid to obtain a compound of formula VI, (d) acetylation of the compound of formula VI obtained in step (c) to obtain the compound of formula I.

8. A method for preparing dapagliflozin, It includes the following steps: (a) reacting a compound represented by formula II with a compound represented by formula III in an organic solvent under the action of an organic metal lithium, After the reaction is completed, the reaction solution is added dropwise into water to quench, to obtain a compound represented by formula IV. (b) reacting the compound of formula IV obtained in step (a) with methanol under acidic conditions, and after the reaction is completed, adding the reaction solution dropwise into an alkaline solution to quench the reaction and obtain a compound of formula V; (c) reacting the compound of formula V obtained in step (b) with a reducing agent in an organic solvent in the presence of a Lewis acid to obtain a compound of formula VI; (d) acetylation of the compound of formula VI obtained in step (c) and purification to obtain a compound of formula I, (e) removing the acetyl group from the compound of formula I obtained in step (d) by conventional methods in the art to obtain a compound of formula VI.

9. The method according to claim 7 or 8, wherein in step (d), the acetylation method is to react with an acetylating agent in an organic solvent under the action of a base; The molar ratio of the acetylating agent to the compound II is 3.5 to 6.0:1, preferably 4.0 to 5.0:1; the molar ratio of the base in step (d) to the compound II is 3.5 to 6.0:1, preferably 4.0 to 5.0:1; In step (d), the acetylating agent is acetic anhydride; further, in step (d), the base is selected from triethylamine, diisopropylethylamine, pyridine, 2-methylpyridine, N-methylmorpholine, sodium carbonate or potassium carbonate, preferably N-methylmorpholine or sodium carbonate.

10. Use of the composition according to claim 3 or 6 in the preparation of dapagliflozin.

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