type ii diabetes mellitus [ non-insulin dependent diabetes mellitus (NIDDM) ] is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance. Hyperglycemia is considered to be a major risk factor for the development of diabetic complications, and is likely directly related to the decreased insulin secretion that occurs in advanced NIDDM. It is expected that sodium-dependent glucose transporter (SGLT2) inhibitors can help normalize plasma glucose levels by promoting glucose excretion in the kidney, and may help normalize body weight.

Continuous control of plasma glucose levels in diabetic patients can counteract the development of diabetic complications and beta cell loss that occur in advanced disease. It has been reported that chronic (6 month) treatment of Zucker diabetic rats with SGLT2 inhibitor increased insulin response to glycemia, increased insulin sensitivity, and delayed onset of nephropathy and neuropathy in these animals, with no kidney pathology and plasma electrolyte imbalance. It is expected that selective inhibition of SGLT2 in diabetic patients will restore normal plasma glucose levels by promoting urinary glucose excretion, because of increased insulin sensitivity, delaying the onset of diabetic complications.

Compound i is an SGLT2 inhibitor useful in the treatment or delay of onset or progression of diabetes, including diabetic complications such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and Impaired Glucose Homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood fatty acid or glycerol levels, obesity, hyperlipidemia including hypertriglyceridemia, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels.

At present, the international literature discloses a preparation method of the compound I, which mainly comprises the following steps: US7932379, US6515117 and US7919598, which can be summarized in the following routes:

the route is a long step and is not industrially scalable, and therefore it is desirable to provide a shortened step operation which minimizes the production of intermediates during the preparation of compound i to improve yield and purity. It is further desirable that such methods employ stereoselective manipulations in order to prepare substantially enantiomerically pure compounds.

Disclosure of Invention

The invention aims to solve the technical problems and provides a preparation method of dapagliflozin compound shown as a formula I, which has high purity and high yield, and comprises the following steps:

a. reacting the compound of the formula II with the compound of the formula III to obtain a compound of the formula IV,

wherein R1 is a hydroxyl protecting agent, and X is selected from bromine or iodine; preferably, R1 is a silane group, X is bromine; more preferably, R1 is trimethylsilyl;

adding the compound of the formula III into an organic solvent, cooling and protecting with nitrogen, slowly adding butyl lithium, and slowly adding the compound of the formula II after the compound of the formula III completely reacts. And after the reaction is finished, slowly adding the aqueous solution of the first acid, controlling the temperature, naturally heating to 0-40 ℃ after the addition is finished, reacting for 2-3 hours, and performing post-treatment to obtain the compound shown in the formula IV. The acid one is selected from hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid or trifluoroacetic acid, preferably trifluoroacetic acid.

Butyllithium is selected from n-butyllithium or tert-butyllithium, preferably n-butyllithium, said compound of formula III: a compound of formula II: the molar ratio of butyllithium is about 1:1.0-2.0:1.0-2.0, preferably 1:1.5: 1.3.

The reaction solvent is selected from tetrahydrofuran, benzene, toluene, xylene or diethyl ether, and preferably a mixed solvent of tetrahydrofuran and toluene;

b. the compound of the formula IV reacts to obtain a compound of the formula V,

and (3) adding ethanol into the compound of the formula V to dissolve the compound, cooling to 0-40 ℃, slowly adding an acidic alcohol solution, reacting for 5-8 hours under heat preservation, and performing post-treatment to obtain the compound of the formula V. Wherein the acidic alcohol solution is selected from ethanol solution of hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid or trifluoroacetic acid, preferably ethanol solution of hydrochloric acid.

The compound of formula v can also be purified by recrystallization from an organic solvent. Dissolving a benign solvent of the compound shown in the formula V, and adding a poor solvent for crystallization, wherein the benign solvent is selected from methanol, ethanol, n-propanol or isopropanol, and preferably n-propanol; the poor solvent is selected from n-heptane, n-hexane or cyclohexane, preferably n-heptane.

c. The compound of the formula V is subjected to reduction reaction to obtain a compound of a formula I,

the reducing agent is a mixture of silane and boron trifluoride etherate, wherein the silane is selected from triethylsilane, trimethylsilane, isopropylsilane or phenylsilane, preferably triethylsilane.

The reduction reaction temperature in the step c is-20 to-10 ℃;

the preparation method provided by the invention can be used for preparing the compound of the formula V with high yield and high purity. The compounds of formula I prepared with the highly pure compounds of formula V are of higher purity without further purification.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to specific examples. Lower part

The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention.

Example 1

Preparation of Compound 4a

Adding the compound 3a (180g, 0.55mol), tetrahydrofuran (360ml) and toluene (720ml) into a 5L three-necked bottle, stirring until the mixture is dissolved out, carrying out nitrogen protection, cooling to-80 to-70 ℃ through a dry ice-acetone bath, dropwise adding n-butyllithium solution (287ml, 0.715mol and 1.3eq), controlling the temperature in the dropwise adding process to-80 to-70 ℃, and stirring and reacting for 0.5h at-80 to-70 ℃ after the dropwise adding is finished. Dropwise adding a solution of the compound 2a (400g, 0.86mol) dissolved in toluene (360ml), controlling the temperature in the dropwise adding process to be between 80 ℃ below zero and 70 ℃ below zero, and stirring and reacting for 1 hour at 80 ℃ below zero and 70 ℃ below zero after the dropwise adding is finished.

And (3) dropwise adding a solution of trifluoroacetic acid (126g, 1.10mol) dissolved in water (600mL) into the reaction solution, controlling the temperature to be less than-20 ℃, naturally heating to 10-20 ℃ after dropwise adding, and reacting for 2-3 hours.

After completion of the reaction, water (180ml) and ethyl acetate (180ml) were added to the reaction mixture, and after stirring for 30min, the layers were separated, the aqueous layer was extracted with ethyl acetate (540ml), and the organic layers were combined. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate (720ml) and water (720ml) in this order, dried over anhydrous sodium sulfate (400g) for 2 hours, filtered, and concentrated under reduced pressure at 42 ℃ to dryness to give compound 4a (230g) in 98.4% yield.

Example 2

Preparation of Compound 4a

Adding the compound 3a (180g, 0.55mol), tetrahydrofuran (360ml) and toluene (720ml) into a 5L three-necked bottle, stirring until the mixture is dissolved out, carrying out nitrogen protection, cooling to-80 to-70 ℃ through a dry ice-acetone bath, dropwise adding n-butyllithium solution (287ml, 0.715mol and 1.3eq), controlling the temperature in the dropwise adding process to-80 to-70 ℃, and stirring and reacting for 0.5h at-80 to-70 ℃ after the dropwise adding is finished. Dropwise adding a solution of the compound 2a (385g, 0.825mol) dissolved in tetrahydrofuran (360ml), controlling the temperature in the dropwise adding process to be between 80 ℃ below zero and 70 ℃ below zero, and stirring and reacting for 1 hour at 80 ℃ below zero and 70 ℃ below zero after the dropwise adding process is finished.

After completion of the reaction, water (180ml) and ethyl acetate (180ml) were added to the reaction mixture, and after stirring for 30min, the layers were separated, the aqueous layer was extracted with ethyl acetate (540ml), and the organic layers were combined. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate (720ml) and water (720ml) in this order, dried over anhydrous sodium sulfate (400g) for 2 hours, filtered, and concentrated under reduced pressure at 42 ℃ to dryness to give compound 4a (225g) in a yield of 96.2%.

Example 3

Preparation of Compound 5a

Adding ethanol (1.3L) into the compound 4a (230g, 054mol), stirring for dissolving, cooling to 10-20 ℃, dropwise adding an ethanol solution of methanesulfonic acid (105.7g dissolved in 500ml), and reacting for 5-8 hours under heat preservation after dropwise adding. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (1.8L), water (1.8L) and ethyl acetate (1.8L) were added, the mixture was stirred for 30min and then separated, the aqueous layer was extracted with ethyl acetate (1.8L), the organic layers were combined, the organic layer was washed with a saturated aqueous sodium chloride solution (900ml), dried over anhydrous sodium sulfate (500g) for 2 hours, filtered and concentrated under reduced pressure at 42 ℃ to dryness to give compound 5a (242.7g, oil) in 99.0% yield and 95.9% purity.

Example 4

Preparation of Compound 5a

Adding ethanol (1.3L) into the compound 4a (230g, 054mol), stirring for dissolving, cooling to 10-20 ℃, dropwise adding 2mol/L ethanol hydrochloride solution, and reacting for 5-8 hours under heat preservation after dropwise adding. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (1.8L), water (1.8L) and ethyl acetate (1.8L) were added, the mixture was stirred for 30min and then separated, the aqueous layer was extracted with ethyl acetate (1.8L), the organic layers were combined, the organic layer was washed with a saturated aqueous sodium chloride solution (900ml), dried over anhydrous sodium sulfate (500g) for 2 hours, filtered and concentrated under reduced pressure at 42 ℃ to dryness to give compound 5a (242.7g, oil) in 99.0% yield and 97.4% purity.

Example 5

Purification of Compound 5a

N-propanol (720ml) was added to the compound 5a (240g) obtained in example 3, the mixture was stirred to dissolve at 40 ℃, the temperature was reduced to 10-20 ℃, n-heptane (3.6L) and water (18ml) were added to precipitate a large amount of solid, the mixture was stirred for 5 hours, filtered, and the cake was washed with n-heptane (300ml × 2). The solid was dried under vacuum at 40 ℃ for 3 hours to give compound 5a (206.6g, white solid) in 86.1% yield and 99.4% purity.

Example 6

Preparation of Compounds of formula I

Compound 4a (10.0g,22.1mmol,1.0eq) from example 5 was dissolved in dichloromethane (50mL) and acetonitrile (50mL), dried overnight by addition of activated molecular sieve (30 g).

Adding the solution into a reaction bottle, adding triethylsilane (7.7g,66.2mmol,3.0eq) under the protection of nitrogen, cooling to-20 to-10 ℃, dropwise adding boron trifluoride diethyl etherate (6.3g,44.2mmol,2.0eq), keeping the temperature and stirring for 4 hours after dropwise adding, and then heating to room temperature and stirring for 1 hour. Saturated sodium bicarbonate solution (100mL) and ethyl acetate (100mL) were added to the reaction mixture, the solution was separated, the aqueous phase was extracted once more with ethyl acetate (50mL), the organic phases were combined, washed once with water (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 8.8g of the compound of formula I in 97.3% yield, 99.8% purity, and 0.03% maximum single impurity.

Spectral data:

¹H NMR(400MHz,CDCl₃)δ(ppm)1.75(s,3H),1.77(s,3H),1.85-1.87(d,3H),5.12(br,2H),6.06-6.10(q,J＝6.4Hz,1H),6.99(s,1H),7.04-7.07(m,1H),7.28-7.31(m,1H),7.40-7.43(m,1H),7.44-7.53(m,2H),7.85(s,1H)。

IR(KBr):3478,3268,3081,2982,1627,1514,1483,1551,1455,1427,1397,1189,1274,1096,860,819,775cm^-1。MS(m/z)：471.06031[M+H]⁺。

comparative example 1

Preparation of Compounds of formula I

Compound 4 a' (10.0g,22.1mmol,1.0eq, 90.2% pure) was dissolved in dichloromethane (50mL) and acetonitrile (50mL), dried overnight by addition of activated molecular sieve (30 g).

Adding the solution into a reaction bottle, adding triethylsilane (7.7g,66.2mmol,3.0eq) under the protection of nitrogen, cooling to-20 to-10 ℃, dropwise adding boron trifluoride diethyl etherate (6.3g,44.2mmol,2.0eq), keeping the temperature and stirring for 4 hours after dropwise adding, and then heating to room temperature and stirring for 1 hour. To the reaction solution were added a saturated sodium bicarbonate solution (100mL) and ethyl acetate (100mL), the solution was separated, the aqueous phase was extracted once more with ethyl acetate (50mL), the organic phases were combined, washed once with water (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 7.4g of the compound of formula i, with a yield of 83.1% and a purity of 85.0%.

Comparative example 2

Purifying the compound of formula 5 a': methyl-1-C- (2-chloro-4' -ethoxydiphenylmethane-3-yl) -alpha-D-glucopyranose

The compound of formula 5 a' was prepared with a purity of 89.1% following exactly the procedure of example 17 of patent CN 200810088495.2.

Adding n-propanol (30ml) into the compound 5 a' (10g) obtained in the previous step, stirring and dissolving at 40 ℃, cooling to 10-20 ℃, adding n-heptane (150mlL) and water (75 mu l), precipitating a large amount of solid, continuing stirring for 5 hours, filtering, and washing a filter cake with n-heptane (5 ml). The solid was dried under vacuum at 40 ℃ for 3 hours to give compound 5 a' (7.6g, white solid) in 76.1% yield and 89.2% purity.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and decorations can be made without departing from the concept of the present invention, and these modifications and decorations should also be regarded as being within the protection scope of the present invention.

Claims

1. A process for the preparation of a compound of formula i, comprising the steps of:

b. the compound of the formula IV reacts to obtain a compound of the formula V,

wherein R1 is trimethylsilyl, and X is selected from bromine;

in step a, the acid I is trifluoroacetic acid;

in the step b, the acidic alcohol solution is hydrochloric acid ethanol solution; the method also comprises the steps of recrystallizing and purifying the compound of the formula V by using an organic solvent, dissolving the compound of the formula V by using a benign solvent, and adding a poor solvent for crystallization, wherein the benign solvent is selected from methanol, ethanol, n-propanol or isopropanol, and the poor solvent is selected from n-heptane, n-hexane or cyclohexane.

2. The method according to claim 1, wherein in step c, the reducing agent is a mixture of silane and boron trifluoride etherate.

3. The method of claim 2, wherein the silane is selected from triethylsilane, trimethylsilane, isopropylsilane, and phenylsilane.