CN104109157B - The preparation method that Ka Gelie is clean - Google Patents

Abstract

The present invention relates to the technical field of canagliflozin preparation, in particular to a preparation method of canagliflozin <b>:</b> using tetrapivaloyl-alpha-D-bromoglucopyranose as raw material and diboronic acid The electrophilic substitution reaction of pinacol ester generates compound IV; with 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene as raw material under catalyst action and Compound IV is reacted to generate compound VI; compound VI is hydrolyzed under alkaline conditions, and the protecting group is deprotected to obtain canagliflozin. The method for preparing canagliflozin of the present invention greatly shortens the synthetic route, only has three steps, simplifies the operation process, the reaction conditions are relatively mild, the post-treatment is simple and easy, and it is more suitable for industrial production requirements, which not only saves production time and labor costs , and reduced production cost, greatly improved the yield of reaction, and the total yield of this route reaches more than 60%.

Description

The preparation method of canagliflozin

technical field

The invention relates to the technical field of canagliflozin preparation, in particular to a preparation method of canagliflozin.

Background technique

Canagliflozin, whose trade name is Invokana, is a new SGLT2 inhibitor developed by Johnson & Johnson for the treatment of type 2 diabetes. On March 29, 2013, the US FDA approved Johnson & Johnson Invokana tablets (canagliflozin) for the treatment of Adult patients with type 2 diabetes; In September 2013, canagliflozin was approved by the European Medicines Agency (EMA) for the treatment of type 2 diabetes in adults. In addition, canagliflozin has also been approved in Australia. Canagliflozin is one of Johnson & Johnson's most promising drug candidates. Johnson & Johnson's Janssen division has the right to sell the drug in North America, South America, Europe, the Middle East, Africa, Australia, New Zealand and some Asian countries.

The chemical name of canagliflozin is (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methanol phenyl]-D-glucitol, the CAS number is 842133-18-0, and the structural formula is shown in I.

(I)

Canagliflozin is the first SGLT2 inhibitor approved by the FDA, which belongs to a new class of selective sodium-glucose co-transporter 2 (SGLT2) inhibitors, a sodium-glucose co-transporter is a glucose transporter with two Subtypes, SGLT2 is one of the subtypes, expressed near the renal tubules, and participates in the reabsorption of glucose filtered in most of the lumens. Canagliflozin can inhibit SGLT2, so that the glucose in the renal tubules cannot be absorbed smoothly. Lowers the renal glucose threshold (RTG), thereby lowering blood glucose concentrations. Clinically used for type Ⅱ diabetes. Canagliflozin is the first SGLT2 inhibitor on the market. It can achieve hypoglycemic effect once a day, has good tolerance, low drug interaction, and has broad clinical application prospects. It is currently available in several countries.

At present, the preparation method of canagliflozin has been reported in the literature at home and abroad, and WO2005012326 discloses that 5-bromo-2-methylbenzaldehyde is used as a starting material, and reacted with 2-chlorothiophene, and 2,3, 4,6-Tetra-O-trimethylsilyl-D-glucono-1,5-lactone was reacted, and then reacted with methanol solution of methanesulfonic acid to obtain crude methyl ether compound, and then reacted with trimethylsilane and boron trifluoride ether solution reaction to obtain the target product I,

Concrete synthetic route is as follows:

WO2009035969 and WO2012140120 disclose that p-fluorobromobenzene is used as a starting material, and magnesium powder is used to form a Grignard reagent, and then reacted with 2-bromothiophene to obtain 2-(4-fluorophenyl)-thiophene, which is reacted with 5-iodo- 2-Methylbenzoyl chloride reaction, the product obtained, after reduction to remove the carbonyl group, react with 2,3,4,6-O-tetrapivaloyl-alpha-D-glucopyranose bromide, and hydrolyze the deprotection group to obtain Target product I, the specific synthetic route is as follows:

The synthetic methods for the preparation of canagliflozin disclosed in the above prior art are relatively complicated, the steps are long, the production cycle is prolonged, the reaction conditions are relatively harsh, the post-treatment is relatively cumbersome, and the total yield of the route is not high.

Contents of the invention

In order to solve the above existing problems in the preparation of canagliflozin in the prior art, such as relatively long reaction steps, cumbersome process, harsh reaction conditions, complicated post-treatment, and low overall yield of the route, the present invention provides a method with shorter reaction steps and higher yield. A new method for preparing canagliflozin with high yield.

The present invention is achieved through the following measures:

A preparation method of canagliflozin, comprising the following steps

(1) Using tetrapivaloyl-alpha-D-glucopyranose bromide (II) as a raw material and biboronic acid pinacol ester (III) undergoes an electrophilic substitution reaction to generate compound (IV);

(2) Using 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene (Ⅴ) as a raw material, the compound obtained in step (1) under the action of a catalyst (IV) react to generate compound (VI);

(3) The compound (VI) obtained in step (2) is hydrolyzed under alkaline conditions, and the protecting group is deprotected to obtain compound (I), namely canagliflozin.

The whole reaction process is as follows:

The new method for preparing canagliflozin provided by the present invention, wherein the palladium catalyst used in step (1) can be one of the following reagents: palladium chloride, palladium hydroxide, palladium acetate, palladium nitrate, allyl chloride Palladium dimer, bis(benzonitrile)palladium chloride, bis(dibenzylideneacetone)palladium, 1,1'-bis(diphenylphosphino)ferrocene]palladium chloride, bis (Triphenylphosphine)ferrocenepalladium chloride, tetrakis(triphenylphosphino)palladium, tris(dibenzylideneacetone)dipalladium, bis(1,2-bis(diphenylphosphine)ethane) Palladium, dichlorobis(tricyclohexylphosphine)palladium, trans-dichlorobis(tri-O-tolylphosphine)palladium, (1,5-cyclooctadiene)palladium dichloride, sodium chloropalladate, tris( Dibenzylideneacetone) dipalladium-chloroform adduct, triphenylphosphine palladium acetate, bis(acetonitrile)palladium chloride, [1,3-bisdiphenylphosphopropane]palladium chloride, tetrakis(triphenyl Phosphine) Palladium etc. Preference is given to 1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (PdCl2(dppf)). Wherein, the molar ratio of halogenated aromatic hydrocarbon and biborpinamate is 1:1-1:2, and the molar ratio of halogenated aromatic hydrocarbon and palladium catalyst is 20:1-100:1.

The reaction solvent in step (1) is one or two of DMF, dioxane, tetrahydrofuran, DMSO, methylene chloride, chloroform (chloroform), toluene, acetone, and a mixed solvent of multiple above-mentioned reagents. The reaction temperature may be 0°C-160°C, preferably 20°C-60°C, and the reaction time may be 30 minutes to 24 hours depending on the complete reaction. The alkaline reagent used in step (1) is one of the following reagents: organic bases, such as sodium methylate, sodium ethylate, sodium acetate, potassium acetate, sodium amide, sodium trityl, potassium tert-butoxide, pyridine, piperidine Pyridine, trimethylamine, triethylamine, tripropylamine or diisopropylethylamine, etc.; inorganic bases, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, preferably alkaline The reagent is potassium acetate, and the molar ratio of halogenated aromatic hydrocarbon to potassium acetate is 1:1-1:3.

The method for preparing canagliflozin provided by the present invention, wherein the raw material compound (V) used in step (2) can be one of the following: 2-(4-fluorophenyl)-5-[(5-iodo-2 -methylphenyl)methyl]thiophene, 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene.

The alkaline reagent used in step (2) is one of the following reagents: organic bases, such as sodium methylate, sodium ethylate, sodium acetate, potassium acetate, sodium amide, sodium trityl, potassium tert-butoxide, pyridine, piperidine pyridine, trimethylamine, triethylamine, tripropylamine or diisopropylethylamine, etc.; inorganic bases, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, compound (Ⅴ ) to the amount of alkali in a molar ratio of 1:1-1:3.

The reaction solvent in step (2) is one or two of DMF, dioxane, tetrahydrofuran, DMSO, dichloromethane, chloroform (chloroform), toluene, acetone, and a mixed solvent of multiple above-mentioned reagents. The reaction temperature can be 0°C-200°C, preferably the reaction temperature is 0°C-60°C, and the reaction time can be 30 minutes to 24 hours depending on the complete reaction.

A preparation method of canagliflozin provided by the present invention, wherein the alkaline reagent used in step (3) is one of the following: organic bases, such as sodium methoxide, sodium ethoxide, sodium acetate, potassium acetate, sodium amide, three Sodium benzyl, potassium tert-butoxide, pyridine, piperidine, trimethylamine, triethylamine, tripropylamine or diisopropylethylamine, etc.; inorganic bases, such as potassium carbonate, sodium carbonate, potassium bicarbonate, bicarbonate Sodium, sodium hydroxide, potassium hydroxide, preferably the alkaline agent is sodium methoxide.

Wherein the reaction solvent of step (3) is methanol, ethanol, isopropanol, n-butanol, tert-butanol, dichloromethane, ethyl acetate, butyl acetate, ether, methyl tert-butyl ether, isopropyl ether, One or two kinds of chloroform (chloroform), acetone, etc. and a mixed solvent of more than one of the above reagents. The reaction temperature may be 0°C-200°C, preferably 20°C-80°C, and the reaction time may be 30 minutes to 24 hours depending on the completeness of the reaction.

Advantages of the present invention:

(1) The method for preparing canagliflozin of the present invention adopts palladium catalyst catalyzed synthesis technology, and the synthetic route is greatly shortened, with only three steps, which simplifies the operation process, the reaction conditions are relatively mild, the post-treatment is simple and easy, and it is more suitable for industrialization Production requirements, not only saving production time and labor costs, but also reducing production costs, greatly improving the yield of the reaction, the total yield of this route reaches more than 60%;

(2) In the preparation of compound (Ⅵ), this route adopts the substitution reaction of compound (Ⅱ) tetrapivaloyl-alpha-D-glucopyranose bromide and biboronic acid pinacol ester to obtain compound (Ⅳ ) The boric acid pinacol ester group is easier to leave, which improves the reaction yield;

(3) In the process of obtaining compound (VI) from compound (II), this route adopts a two-step reaction method in the same reaction system. After compound (II) is reacted with biboronic acid pinacol ester to obtain compound IV , without post-treatment, compound (Ⅵ) is directly added to the original reaction system for reaction to obtain compound (Ⅵ), which simplifies the operation process, shortens the production cycle, and is easy to perform after-treatment, improves the yield of the reaction, and reduces the production cost , the catalyst used in the route is easy to remove after the reaction, and is more suitable for large-scale industrial production.

detailed description:

The following examples are further illustrations of the present invention, including but not limited to the following examples. The present invention is described in detail below with reference to the examples, but those skilled in the art should understand that the present invention is not limited to these examples and the preparation method used. Moreover, those skilled in the art can perform equivalent replacement, combination, improvement or modification of the present invention according to the description of the present invention, but these will all be included in the scope of the present invention.

Example 1

(1) Preparation of tetrapivaloyl-alpha-D-glucopyranose borate pinacol ester (Ⅳ)

Under nitrogen protection, in a 50ml reaction flask, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (PdCl2(dppf)) (0.22g, 0.3mmol), potassium acetate ( 3.0g, 30mmol) and pinacol diboronate (2.8g, 10mmol) were dissolved in 12ml of DMSO, and tetrapivaloyl-alpha-D-bromoglucopyranose (5.8g, 10mmol) was added, and the temperature was controlled at 80 ℃, react for 8 hours, the reaction is complete, no post-treatment is required, and the next step reaction is directly carried out;

(2) Tris(2,2-dimethylpropanoic acid)-(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl) Preparation of methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl ester (Ⅵ)

In the reaction solution of the above reaction, compound (Ⅴ) 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene (4.9g, 12mmol) was added to control Warm at 15°C, react for 4 hours, after the reaction is complete, extract with ethyl acetate/water (V/V=1:1), wash the aqueous layer twice with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate The total yield of compound (VI) (7.7g) was 85%;

(3) (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]- Preparation of D-glucitol (canagliflozin)

In a 50ml reaction bottle, add compound VI (4.0g, 5mmol) and 20ml methanol, stir at room temperature, dissolve, add sodium methoxide (28% methanol solution), control the temperature at 60°C, react for 16 hours, cool to room temperature, and get Add 7ml of water and seed crystals to the pale yellow solution, stir at -5°C for 1 hour, and filter to obtain the target compound canagliflozin (1.8g), with a yield of 88% and a purity of 94%. mp:105-107℃;ESI-MS:445(MH ⁺ ). ¹ HNMR(CD3OD)δ7.5(m,2H),7.3(m,1H),7.25(d,1H,J=7.8Hz), 7.15(d,1H,J=7.8Hz),7.0(m,3H),6.7(m,1H),4.9(s,4H),4.2(s,2H),4.1(m,1H),3.9(d ,1H,J=12.0Hz),3.7(d,1H,J=12.0Hz),3.45(m,4H),2.3(s,3H).

Example 2

(1) Preparation of tetrapivaloyl-alpha-D-glucopyranose borate pinacol ester (Ⅳ)

Under nitrogen protection, in a 50ml reaction flask, bis(triphenylphosphine) ferrocene palladium chloride (0.21g, 0.3mmol), potassium carbonate (4.1g, 30mmol) and diboronic acid pinacol ester (2.8 g, 10mmol) was dissolved in 12ml of DMF, and tetrapivaloyl-alpha-D-bromoglucopyranose (5.8g, 10mmol) was added, the temperature was controlled at 80°C, and the reaction was carried out for 10 hours. carry out the next reaction;

(2) Tris(2,2-dimethylpropanoic acid)-(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl) Preparation of methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl ester (Ⅵ)

In the reaction solution of the above reaction, compound (Ⅴ) 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene (4.9g, 12mmol) was added to control Warm at 20°C, react for 8 hours, after the reaction is complete, extract with dichloromethane/water (V/V=1:1), wash the aqueous layer twice with dichloromethane, combine the organic layers, dry over anhydrous magnesium sulfate, and concentrate Obtain compound (Ⅵ) (7.0g), total yield: 75%;

(3) (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]- Preparation of D-glucitol (canagliflozin)

In a 50ml reaction bottle, add compound VI (4.0g, 5mmol) and 20ml methanol, stir at room temperature to dissolve it, add sodium methoxide (28% methanol solution), control the temperature at 60°C, react for 16 hours, and cool to room temperature , the obtained pale yellow solution was added with 7ml of water and seed crystals, stirred at -5°C for 1 hour, and filtered to obtain the target compound canagliflozin (1.7g), with a yield of 85% and a purity of 90%. mp:105-107℃;ESI-MS:445(MH ⁺ ). ¹ HNMR(CD3OD)δ7.5(m,2H),7.3(m,1H),7.25(d,1H,J=7.8Hz), 7.15(d,1H,J=7.8Hz),7.0(m,3H),6.7(m,1H),4.9(s,4H),4.2(s,2H),4.1(m,1H),3.9(d ,1H,J=12.0Hz),3.7(d,1H,J=12.0Hz),3.45(m,4H),2.3(s,3H).

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the embodiment, and any other changes, modifications, combinations, substitutions, and simplifications that do not deviate from the spirit and principles of the present invention All should be equivalent replacements, and all are included in the protection scope of the present invention.

Claims (2)

1. a preparation method of canagliflozin, is characterized in that comprising the following steps: (1) Preparation of tetrapivaloyl-alpha-D-glucopyranose borate pinacol ester Under the protection of nitrogen, in a 50ml reaction flask, put [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride 0.22g or 0.3mmol, potassium acetate 3.0g or 30mmol and biboronic acid pina Dissolve 2.8g or 10mmol of alcohol ester in 12ml of DMSO, add 5.8g or 10mmol of tetrapivaloyl-alpha-D-bromoglucopyranose, control the temperature at 80°C, and react for 8 hours. carry out the next reaction; (2) Tris(2,2-dimethylpropanoic acid)-(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl) Preparation of methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl ester In the reaction solution of step (1), add 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene 4.9g, namely 12mmol, and control the temperature at 15 ℃, reacted for 4 hours, the reaction was completed, extracted with ethyl acetate and water V/V=1:1, the aqueous layer was washed twice with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain tri(2, 2-Dimethylpropionic acid)-(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methanol phenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl ester 7.7g, total yield: 85%; (3) (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]- Preparation of D-glucitol In a 50ml reaction flask, add tris(2,2-dimethylpropanoic acid)-(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophene- 2-yl)methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl ester 4.0g or 5mmol and 20ml Methanol, stirred at room temperature, dissolved, added 28% methanol solution of sodium methoxide, controlled temperature at 60°C, reacted for 16 hours, cooled to room temperature, added 7ml of water and seed crystals to the obtained light yellow solution, stirred at -5°C for 1 hour, Filtration obtained 1.8 g of the target compound canagliflozin, with a yield of 88% and a purity of 94%. 2. a preparation method of canagliflozin, is characterized in that comprising the following steps: (1) Preparation of tetrapivaloyl-alpha-D-glucopyranose borate pinacol ester Under nitrogen protection, in a 50ml reaction flask, 0.21g (0.3mmol) of bis(triphenylphosphine) ferrocenepalladium chloride, 4.1g (30mmol) of potassium carbonate and 2.8g (10mmol) of pinacol borate were dissolved in In 12ml of DMF, add 5.8g of tetrapivaloyl-alpha-D-glucopyranose bromide (10mmol), control the temperature at 80°C, and react for 10 hours. After the reaction is completed, there is no need for post-treatment, and the next step of reaction is directly carried out; (2) Tris(2,2-dimethylpropanoic acid)-(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl) Preparation of methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl ester In the reaction solution of step (1), add 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene 4.9g, namely 12mmol, and control the temperature at 20 ℃, reacted for 8 hours, the reaction was completed, extracted with dichloromethane and water V/V=1:1, the aqueous layer was washed twice with dichloromethane, the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain tri(2, 2-Dimethylpropionic acid)-(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methanol phenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl ester 7.0g, total yield: 75%; (3) (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]- Preparation of D-glucitol In a 50ml reaction flask, add tris(2,2-dimethylpropanoic acid)-(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophene- 2-yl)methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl ester 4.0g or 5mmol and 20ml In methanol, stir at room temperature to dissolve it, add 28% methanol solution of sodium methoxide, control the temperature at 60°C, react for 16 hours, cool to room temperature, add 7ml of water and seed crystals to the obtained light yellow solution, and stir at -5°C for 1 Hour, filtered to obtain target compound canagliflozin 1.7g, yield 85%, purity 90%.