CN112375076A - Novel method for synthesizing canagliflozin - Google Patents

Novel method for synthesizing canagliflozin Download PDF

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CN112375076A
CN112375076A CN202011322931.5A CN202011322931A CN112375076A CN 112375076 A CN112375076 A CN 112375076A CN 202011322931 A CN202011322931 A CN 202011322931A CN 112375076 A CN112375076 A CN 112375076A
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canagliflozin
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杨小龙
裴啤兵
杨铁波
陈潜
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Huanggang Luban Pharmaceutical Co ltd
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract

The invention discloses a new route for synthesizing canagliflozin. 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl]Thiophene (compound of formula 2) reacts with boronic acid pinacol ester to prepare a compound of formula 3; the compound shown in the formula 3 is coupled with 2,3,4, 6-tetra-O-acetyl-a-D-bromo glucopyranose to obtain a compound shown in the formula 4; the compound of formula 4 is hydrolyzed under basic conditions to produce canagliflozin (the compound of formula 1). The preparation method is simple and easy to control, the conversion rate of the product is high, the reaction condition is mild, and the industrial production is facilitated.

Description

Novel method for synthesizing canagliflozin
Technical Field
The invention belongs to the field of medicine and fine chemical engineering. In particular, the invention relates to a novel synthesis method of canagliflozin.
Background
There are about 2 billion patients with type 2 diabetes caused by obesity worldwide, and diabetes is the third largest killer which threatens human life. At present, clinically, the medicines for treating diabetes mainly comprise insulin and oral hypoglycemic drugs. The rapid development of oral hypoglycemic agents has made great progress in the treatment of type 2 diabetes in recent years. Clinically applied oral hypoglycemic agents can be divided into insulin secretion promoters, insulin sensitizers, alpha-glucosidase inhibitors, glucose uptake utilization promoters, glucagon-like peptide-1 (GLP-1) analogues, dipeptidyl peptidase-IV (DPP-IV) inhibitors, sodium-glucose cotransporter 2(SGLT2) inhibitors and the like. SGLT2 inhibitors are of great interest to the commercial, pharmaceutical and academic communities because of their unique mechanism of action, good clinical efficacy and broad market prospects.
Canagliflozin (Canagliflozin), trade name: Invokana, was developed by Possen pharmaceutical Inc., under Qiangsheng, and was approved by the U.S. Food and Drug Administration (FDA) for treatment of adult patients with type 2 diabetes mellitus on 29 months 3 and 2013 for improved glycemic control. Invokana (Canagliflozin) is a new class of sodium-glucose cotransporter 2(SGLT2) inhibitor drugs, also the first SGLT2 class of diabetes drugs approved in the United states. The drug was also approved by the european union committee at 11/15 in 2013. The structure is as follows:
Figure BDA0002793480990000011
canagliflozin (Canagliflozin)
Patent document WO2013068850 describes a synthesis method of canagliflozin, and the synthesis route is shown as follows:
Figure BDA0002793480990000021
according to the method, 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methylthiophene 5 is used as a starting material, a Grignard reagent of a compound of a formula 5 is prepared firstly, then the Grignard reagent reacts with the compound of the formula 5 to prepare a compound of a formula 8, and the obtained compound of the formula 8 is subjected to tert-butyl diphenyl silicon group removal protection under the condition of tetrabutylammonium fluoride to obtain a product of canagliflozin. The route uses butyl lithium, needs low temperature operation at minus 78 ℃, has strict operation requirements and has large reaction risk coefficient.
Another synthesis method is described in patent document cn200880106239.x, and its specific synthesis route is shown below:
Figure BDA0002793480990000022
the route also takes 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methylthiophene formula 2 as a raw material to react with trimethylsilyl protected gluconolactone under the action of trimethylsilyl methyllithium to obtain a formula 9; reducing and removing hydroxyl in a formula 9 under the action of triethylsilane boron trifluoride diethyl etherate to obtain a crude product of the formula 1 (canagliflozin); the compound is subjected to acetyl protection and deprotection of hydroxyl to obtain pure product canagliflozin.
However, the experimental conditions of this route still require low temperatures and are relatively severe. In addition, the reaction still requires a large amount of alkyllithium reagent, which is highly dangerous. In addition, the crude product of the formula 1 obtained by the method needs to be protected by acetyl group, then deprotected and purified to obtain the compound shown in the formula 1, thereby increasing the reaction steps.
Therefore, there is a need in the art for a new synthetic method for synthesizing canagliflozin that is low in cost, simple and convenient to operate, safe, and friendly to personnel and environment.
Disclosure of Invention
The invention aims to provide a novel synthesis method of canagliflozin. The method has the advantages of simple and convenient operation, low cost, high yield and the like; meanwhile, the method also has the advantages of safety and friendliness to personnel and environment and the like.
In a first aspect, the present invention provides a method of synthesizing canagliflozin, the method having the formula:
Figure BDA0002793480990000031
the method comprises the following steps:
1) reacting the compound shown in the formula 2 with a diboron acid pinacol ester to obtain a compound shown in a formula 3;
2) reacting the compound shown in the formula 3 with a 2,3,4, 6-tetra-O-acetyl-a-D-bromo glucopyranose compound to obtain a compound shown in a formula 4; and
3) hydrolyzing the compound of formula 4 to produce the compound of formula 1, canagliflozin.
In a specific embodiment, in step 1), 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene (compound of formula 2) and pinacol borate are reacted in a solvent of S1 at a temperature of T1 under the action of a base B1 and a catalyst C1 to obtain a compound of formula 3.
In particular embodiments, the solvent S1 is selected from toluene, dioxane, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl pyrrolidone (NMP); preferably dioxane; and/or
The base B1 is selected from N, N-Diisopropylethylamine (DIEPA), potassium tert-butoxide, potassium acetate and potassium phosphate; preferably potassium acetate; and/or
The dosage of the alkali B1 is as follows: 1eq to 6 eq; preferably 3eq to 4 eq; and/or
The catalyst C1 is a palladium metal compound or a nickel metal compound; preference is given to nickel chloride, 1' -bisdiphenylphosphinoferrocene nickel dichloride (dppfNiCl)2) Tetrakistriphenylphosphine nickel, palladium chloride, tetrakistriphenylphosphine palladium, 1' -bisdiphenylphosphinoferrocene palladium dichloride (dppfpdCl)2) (ii) a Preferably dppfppdcl2(ii) a And/or
The dosage of the catalyst C1 is as follows: 0.5 mol% -5 mol%; preferably 1.5 mol% to 2.5 mol%; and/or
The temperature T1 is 20-150 ℃; preferably 40-60 ℃.
In a particular embodiment, in step 2), the compound of formula 3 is reacted with 2,3,4, 6-tetra-O-acetyl-a-D-bromoglucopyranose in the presence of a base B2 and a catalyst C2 in a solvent S2 at a temperature T2 to give the compound of formula 4.
In specific embodiments, the base B2 is triethylamine, potassium carbonate, potassium acetate, or potassium phosphate; potassium phosphate is preferred; and/or
The dosage of the alkali B2 is as follows: 1eq to 6 eq; preferably 2eq to 4 eq; and/or
The catalyst C2 is a palladium metal compound or a nickel metal compound; preference is given to nickel chloride, 1'Bis diphenylphosphinoferrocene nickel dichloride (dppfNiCl)2) Tetrakistriphenylphosphine nickel, palladium chloride, tetrakistriphenylphosphine palladium, 1' -bisdiphenylphosphinoferrocene palladium dichloride (dppfpdCl)2) (ii) a Preferably palladium tetratriphenylphosphine; and/or
The dosage of the catalyst C2 is as follows: 0.05 mol% -5 mol%; preferably 2.5 mol% to 3.5 mol%; and/or
The solvent S2 is selected from tetrahydrofuran, dioxane, N-Dimethylformamide (DMF); preferably DMF; and/or
The temperature T2 is 20-150 ℃; preferably 70-90 deg.C.
In a specific embodiment, in step 3), deprotection of the compound of formula 4 in solvent with base B3 and S3 provides the product compound of formula 1, canagliflozin.
In specific embodiments, the base B3 is lithium hydroxide, sodium hydroxide, potassium hydroxide, or potassium tert-butoxide; preferably sodium hydroxide; and/or
The solvent S3 is methanol, ethanol or isopropanol; methanol is preferred.
In a second aspect, the present invention provides a compound represented by formula 3
Figure BDA0002793480990000051
In a preferred embodiment, the compound of formula 3 is prepared by: reacting 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene (compound shown in formula 2) with pinacol borate in a solvent S1 under the action of a base B1 and a catalyst C1 at a temperature of T1 to obtain the compound shown in formula 3.
In a preferred embodiment, the solvent S1 is selected from toluene, dioxane, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl pyrrolidone (NMP); preferably dioxane; and/or
The base B1 is selected from N, N-Diisopropylethylamine (DIEPA), potassium tert-butoxide, potassium acetate and potassium phosphate; preferably potassium acetate; and/or
The dosage of the alkali B1 is as follows: 1eq to 6 eq; preferably 3eq to 4 eq; and/or
The catalyst C1 is a palladium metal compound or a nickel metal compound; preference is given to nickel chloride, 1' -bisdiphenylphosphinoferrocene nickel dichloride (dppfNiCl)2) Tetrakistriphenylphosphine nickel, palladium chloride, tetrakistriphenylphosphine palladium, 1' -bisdiphenylphosphinoferrocene palladium dichloride (dppfpdCl)2) (ii) a Preferably dppfppdcl2(ii) a And/or
The dosage of the catalyst C1 is as follows: 0.5 mol% -5 mol%; preferably 1.5 mol% to 2.5 mol%; and/or
The temperature T1 is 20-150 ℃; preferably 40-60 ℃.
In a third aspect, the present invention provides the use of a compound of formula 3 in the preparation of canagliflozin
Figure BDA0002793480990000052
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows a mass spectrum of a compound of formula 3;
FIG. 2 shows a HNMR map of a compound of formula 3;
FIG. 3 shows a mass spectrum of Canagliflozin formula 1; and
fig. 4 shows a HNMR map of canagliflozin formula 1.
Detailed Description
The inventors have conducted extensive and intensive studies and unexpectedly found a novel process for synthesizing canagliflozin by using an intermediate having a novel structure. By adopting the process to synthesize canagliflozin, the occurrence of side reactions can be reduced, the reaction yield is improved, and the reaction condition is mild, thereby being beneficial to industrial production. The present invention has been completed based on this finding.
The synthesis method of canagliflozin
The inventor finds that the method for synthesizing canagliflozin in the prior art has a plurality of defects which are not beneficial to industrial production, such as harsh operating conditions, extremely low temperature, utilization of liquid reagents which have spontaneous combustion danger in air, such as alkyl lithium reagents such as n-butyl lithium and the like, and a plurality of reaction steps. In view of the above, the present inventors provide a novel synthetic route for canagliflozin, which utilizes an intermediate having a novel structure, thereby avoiding the use of dangerous reaction reagents, enabling the reaction to be carried out under mild conditions, and having a few reaction steps, thereby being very advantageous for industrial production of canagliflozin.
In a specific embodiment, the synthesis method of canagliflozin of the present invention is as follows:
Figure BDA0002793480990000061
in the method, a compound shown in a formula 2 reacts with pinacol diboron to obtain a compound shown in a formula 3, the compound shown in the formula 3 reacts with a 2,3,4, 6-tetra-O-acetyl-a-D-bromo-glucopyranose compound to obtain a compound shown in a formula 4, and the compound shown in the formula 4 is hydrolyzed under alkaline conditions to obtain canagliflozin (a compound shown in the formula 1).
Based on the new method for synthesizing canagliflozin, the inventor further optimizes the process conditions of related reactions, thereby not only reducing the occurrence of side reactions and improving the reaction yield, but also having milder reaction conditions and being beneficial to industrial production.
In the canagliflozin synthesis method, the compound in the formula 3 is a compound with a brand-new structure, and the chemical name of the compound is 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborane.
In a specific embodiment, the compound of formula 2 is reacted with boronic acid pinacol ester in S1 solvent under the action of base B1 and catalyst C1 at a temperature of T1 to give the compound of formula 3.
In the synthesis of the compound of formula 3, the solvent S1 is selected from toluene, dioxane, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl pyrrolidone (NMP); preferably dioxane; and/or
The base B1 is selected from N, N-Diisopropylethylamine (DIEPA), potassium tert-butoxide, potassium acetate and potassium phosphate; preferably potassium acetate; and/or
The dosage of the alkali B1 is as follows: 1eq to 6 eq; preferably 3eq to 4 eq; and/or
The catalyst C1 is a palladium metal compound or a nickel metal compound; preference is given to nickel chloride, 1' -bisdiphenylphosphinoferrocene nickel dichloride (dppfNiCl)2) Tetrakistriphenylphosphine nickel, palladium chloride, tetrakistriphenylphosphine palladium, 1' -bisdiphenylphosphinoferrocene palladium dichloride (dppfpdCl)2) (ii) a Preferably dppfppdcl2(ii) a And/or
The dosage of the catalyst C1 is as follows: 0.5 mol% -5 mol%; preferably 1.5 mol% to 2.5 mol%; and/or
The temperature T1 is 20-150 ℃; preferably 40-60 ℃.
In the method for synthesizing canagliflozin, a compound shown as a formula 3 and 2,3,4, 6-tetra-O-acetyl-a-D-bromo glucopyranose react in a solvent S2 under the action of a base B2 and a catalyst C2 at a temperature T2 to obtain a compound shown as a formula 4.
In the synthesis of the compound of formula 4, the base B2 is triethylamine, potassium carbonate, potassium acetate or potassium phosphate; potassium phosphate is preferred; and/or
The dosage of the alkali B2 is as follows: 1eq to 6 eq; preferably 2eq to 4 eq; and/or
The catalyst C2 is a palladium metal compound or a nickel metal compound; preference is given to nickel chloride, 1' -bisdiphenylphosphinoferrocene nickel dichloride (dppfNiCl)2) Tetrakistriphenylphosphine nickel, palladium chloride, tetrakistriphenylphosphine palladium, 1' -bisdiphenylphosphinoferrocene palladium dichloride (dppfpdCl)2) (ii) a Preferably palladium tetratriphenylphosphine; and/or
The dosage of the catalyst C2 is as follows: 0.05 mol% -5 mol%; preferably 2.5 mol% to 3.5 mol%; and/or
The solvent S2 is selected from tetrahydrofuran, dioxane, N-Dimethylformamide (DMF); preferably DMF; and/or
The temperature T2 is 20-150 ℃; preferably 70-90 deg.C.
In the canagliflozin synthesis method of the invention, the compound of formula 4 is deprotected in a base B3 and S3 solvent to obtain the final product canagliflozin.
In this step, the base B3 may be lithium hydroxide, sodium hydroxide, potassium hydroxide or potassium tert-butoxide; preferably sodium hydroxide; and/or
The solvent S3 may be methanol, ethanol or isopropanol; methanol is preferred.
The main advantages of the invention include:
1. the synthesis method of canagliflozin does not need to utilize dangerous reaction reagents;
2. the synthesis method of canagliflozin has mild reaction conditions;
3. the synthesis method of canagliflozin has simple and convenient process and few synthesis steps;
4. the synthesis method of canagliflozin has less side reaction and high reaction yield, thereby being beneficial to industrial scale-up production; and
5. the synthesis method of canagliflozin is friendly to operators and environment.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Example 1: synthesis of Compounds of formula 3
40.8g of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene (formula 2), 38.2g of pinacol diboron and 50g of potassium tert-butoxide are sequentially added into a reactor under the protection of nitrogen. After the catalyst of 2g of palladium tetratriphenylphosphine and DMF400ml are added, the reaction is started for 8 hours when the internal temperature of the reaction rises to 70 ℃. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was washed with saturated brine, separated into layers, dried and concentrated to obtain 25.1g of a residue (formula 3) in a yield of 61.5% and a HPLC purity: 93.4 percent.
ESI-MS:431.16[M+Na]+,409.19[M+H]+。
1H-NMR(400MHz,CDCl3)δ：1.22～1.43(m,12H),2.36(s,3H),3.91-4.20(m,2H),6.65～7.75(m,9H)。
Example 2: synthesis of Compounds of formula 3
Comparison of different catalysts C1
Respectively adding 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl into six reaction flask reaction bottles in a parallel reactor under the protection of nitrogen]20.42g of thiophene (formula 2), 250 ml of dioxane, 19.1g of pinacol diboron ester and 32g of potassium phosphate. Then adding 0.18g of palladium chloride into a No. 1 reaction bottle, adding 0.18g of nickel chloride into a No. 2 reaction bottle, adding 0.5g of tetratriphenylphosphine nickel into a No. 3 reaction bottle, adding 0.5g of tetratriphenylphosphine palladium into a No. 4 reaction bottle, and adding dppfpdCl into a No. 5 reaction bottle20.18g, No. 6 reaction flask is added with dppfNiCl20.35 g. After the addition, the temperature of six reaction bottles is raised to the internal temperature of 60 ℃ under parallel heating modules for reaction for 10 hours, the temperature is reduced to room temperature after the reaction is finished, the reaction bottles are filtered, ethyl acetate is added into the filtrate, the filtrate is washed by saturated saline solution for delamination, and the organic layer is dried and concentrated to obtain a residue (formula 3).
TABLE 1
Figure BDA0002793480990000091
Example 3: synthesis of Compounds of formula 3
Comparative study of catalyst amount
Respectively adding 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl into three reaction flask reaction bottles in a parallel reactor under the protection of nitrogen]20.42g of thiophene (formula 2), 250 ml of dioxane, 19.1g of pinacol diboron ester and 32g of potassium phosphate. Then adding dppfPdCl into a No. 1 reaction bottle21.5 mol% (0.13g) reaction flask No. 2 was charged with dppfPdCl22.5 mol% (0.22g) of No. 3 reaction flask was charged with dppfPdCl catalyst 25 mol% (0.44 g). Heating the 3 reaction bottles in parallel with heating modules to the internal temperature of 60 ℃ for reaction for 10 hours, cooling to room temperature after the reaction is finished, filtering, adding dichloromethane into the filtrate, washing with saturated saline solution, layering,the organic layer was dried and concentrated to give a residue (formula 3).
TABLE 2
Figure BDA0002793480990000101
Example 4: synthesis of Compounds of formula 3
Comparative study of different solvents S1
Adding 250 ml of dioxane into a No. 1 reaction bottle, 250 ml of NMP into a No. 2 reaction bottle, 250 ml of DMSO into a No. 3 reaction bottle, 250 ml of DMF into a No. 4 reaction bottle in a parallel reactor under the protection of nitrogen, and respectively adding 2- (4-fluorophenyl) -5- [ (5-iodine-2-methylphenyl) methyl group into the four reaction bottles under stirring after the addition is finished]20.42g of thiophene (formula 2) as a catalyst dppfpdCl22.5 mol% (0.22g), pinacol diboron ester 19.1g, potassium phosphate 32 g. After the addition, the temperature of 4 reaction bottles is raised to the internal temperature of 60 ℃ under the condition that heating modules are arranged in parallel, the reaction is carried out for 10 hours, the temperature is reduced to room temperature after the reaction is finished, the filtration is carried out, dichloromethane is added into the filtrate, saturated saline solution is used for washing and demixing, and the organic layer is dried and concentrated to obtain a residue (formula 3).
TABLE 3
Figure BDA0002793480990000102
Example 5: synthesis of Compounds of formula 3
Comparative study of different bases B1
Respectively adding 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl into four reaction flask reaction bottles in a parallel reactor under the protection of nitrogen]20.42g of thiophene (formula 2), 250 ml of dioxane, 19.1g of pinacol diboron and a catalyst dppfPdCl22.5 mol% (0.22 g). Then 32g of potassium acetate was added to reaction flask No. 1, 32g of potassium phosphate was added to reaction flask No. 2, 32g of DIEPA was added to reaction flask No. 3, and 32g of potassium tert-butoxide was added to reaction flask No. 4. Heating the four reaction bottles to an internal temperature of 60 ℃ under parallel heating modules after the addition, reacting for 10 hours, cooling to room temperature after the reaction is finished, filtering, adding dichloromethane into the filtrate, and adding saturated saline solutionAfter washing, the layers were separated, and the organic layer was dried and concentrated to give a residue (formula 3).
TABLE 4
Figure BDA0002793480990000111
Example 6: synthesis of Compounds of formula 3
Base dosage comparison study
Respectively adding 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl into four reaction flask reaction bottles in a parallel reactor under the protection of nitrogen]20.42g of thiophene (formula 2), 250 ml of dioxane, 19.1g of pinacol diboron and a catalyst dppfPdCl22.5 mol% (0.22 g). Then, 4.9g (1eq) of potassium acetate was added to reaction flask # 1, 9.8g (2eq) of potassium acetate was added to reaction flask # 2, 19.6g (4eq) of potassium acetate was added to reaction flask # 3, and 29.4g (6eq) of potassium acetate was added to reaction flask # 4. After the addition, the four reaction bottles are heated to the internal temperature of 60 ℃ under parallel heating modules for reaction for 10 hours, the temperature is reduced to room temperature after the reaction is finished, the reaction bottles are filtered, dichloromethane is added into the filtrate, saturated saline solution is used for washing and demixing, and the organic layer is dried and concentrated to obtain a residue (formula 3).
TABLE 5
Figure BDA0002793480990000112
Example 7: synthesis of Compounds of formula 3
Comparative study of solvent dosage
Under the protection of nitrogen, 102.1 ml of dioxane was added into a reaction bottle No. 1, 204.2 ml of dioxane was added into a reaction bottle No. 2, and 306.3 ml of dioxane was added into a reaction bottle No. 3 in a parallel reactor. After the addition, 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl group was added to each of 3 reaction flasks under stirring]20.42g of thiophene (formula 2) as a catalyst dppfpdCl22.5 mol% (0.22g), pinacol ester diboron (formula 5)19.1g, and potassium acetate 19.6 g. Heating the 3 reaction bottles in parallel with heating modules to an internal temperature of 60 ℃ for reaction for 10 hours, cooling to room temperature after the reaction is finished, filtering, adding methylene dichloride into the filtrateThe alkyl group was washed with saturated brine, and the layers were separated, and the organic layer was dried and concentrated to obtain a residue (formula 3).
TABLE 6
Figure BDA0002793480990000121
Example 8: synthesis of Compounds of formula 3
Comparative study of different temperatures T1
Respectively adding 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl into 4 reaction bottles in a parallel reactor under the protection of nitrogen]20.42g of thiophene (formula 2), 205 ml of dioxane, 19.1g of pinacol diboron and 19.6g of potassium acetate. Catalyst dppfPdCl22.5 mol% (0.22g), then setting the temperature of No. 1 reaction flask at 20 ℃, the temperature of No. 2 reaction flask at 40 ℃, the temperature of No. 3 reaction flask at 60 ℃ and the temperature of No. 3 reaction flask at 80 ℃. After the setting is finished, starting reaction for 10 hours after the temperature in 4 reaction bottles reaches the requirement, cooling to room temperature after the reaction is finished, filtering, adding dichloromethane into filtrate, washing with saturated saline solution, demixing, drying an organic layer, and concentrating to obtain a residue (formula 3).
TABLE 7
Figure BDA0002793480990000122
Figure BDA0002793480990000131
Example 9: synthesis of Compound of formula 3 (optimum conditions after screening)
2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl is sequentially added into the reactor under the protection of nitrogen]408.4g of thiophene (formula 2), 382g of pinacol diboron and 392g of potassium acetate. Catalyst dppfPdCl24.4g of dioxane 4084ml, and after the addition, the reaction was started for 10 hours when the internal temperature of the reaction reached 60 ℃. Cooling to room temperature after reaction, filtering, adding dichloromethane into the filtrate, washing with saturated saline solution, demixing, drying the organic layer, and concentrating to obtainTo 406.7g of residue (formula 3), yield 99.6%, HPLC purity: 93.8 percent.
Example 10: synthesis of Compound of formula 4
Comparison of different catalysts C2
Under the protection of nitrogen, 20.42g of the compound of formula 3, 250 ml of dioxane, 20.55g of 2,3,4, 6-tetra-O-acetyl-alpha-D-bromo glucopyranose and 32g of potassium phosphate are respectively added into six reaction bottles in parallel reactors, then 0.18g of palladium chloride is added into a reaction bottle No. 1, 0.18g of nickel chloride is added into a reaction bottle No. 2, 0.5g of tetratriphenylphosphine nickel is added into a reaction bottle No. 3, 0.6g of tetratriphenylphosphine palladium is added into a reaction bottle No. 4, and dppfNiCl is added into a reaction bottle No. 520.35g, 6 # reaction flask with dppfPdCl20.22 g. After the addition, the temperature of six reaction bottles is raised to the internal temperature of 70 ℃ under parallel heating modules for reaction for 12 hours, the temperature is reduced to room temperature after the reaction is finished, the reaction bottles are filtered, dichloromethane is added into the filtrate, saturated saline solution is used for washing and demixing, and an organic layer is dried and concentrated to obtain a light yellow solid (formula 4).
TABLE 8
Figure BDA0002793480990000132
Example 11: synthesis of Compound of formula 4
Comparative study of catalyst C2 dosage
Under the protection of nitrogen, 20.42g of the compound of the formula 3, 250 ml of dioxane, 20.55g of 2,3,4, 6-tetra-O-acetyl-a-D-bromo glucopyranose and 32g of potassium phosphate are respectively added into three reaction bottles in a parallel reactor. Then, in reaction flask No. 1, 1.5 mol% (0.867g) of palladium tetratriphenylphosphine was added, reaction flask No. 2, 2.5 mol% (1.445g) of palladium tetratriphenylphosphine was added, and reaction flask No. 3, 3.5 mol% (2.023g) of palladium tetratriphenylphosphine was added. After the addition, the temperature of 3 reaction bottles is raised to the internal temperature of 70 ℃ under the condition that heating modules are arranged in parallel, the reaction is carried out for 12 hours, the temperature is reduced to room temperature after the reaction is finished, the filtration is carried out, dichloromethane is added into the filtrate, the saturated saline solution is used for washing and layering, the organic layer is dried and concentrated to obtain a light yellow solid (formula 4).
TABLE 9
Figure BDA0002793480990000141
Example 12: synthesis of Compound of formula 4
Comparative study of different solvents S2
250 ml of dioxane is added into a No. 1 reaction bottle, 250 ml of tetrahydrofuran is added into a No. 2 reaction bottle, 250 ml of DMSO is added into a No. 3 reaction bottle, 250 ml of DMF is added into a No. 4 reaction bottle, and after the addition is finished, 20.42g of the compound of the formula 3, 1.445g of palladium tetratriphenylphosphine, 20.55g of 2,3,4, 6-tetra-O-acetyl-alpha-D-bromoglucopyranose and 32g of potassium phosphate are respectively added into the four reaction bottles under stirring. Heating the 4 reaction bottles in parallel by heating modules to the internal temperature of 70 ℃ for carrying out a reaction for 12 hours, cooling to the room temperature after the reaction is finished, filtering, adding dichloromethane into the filtrate, washing with saturated saline solution, layering, drying the organic layer, and concentrating to obtain a light yellow solid (formula 4).
Watch 10
Figure BDA0002793480990000142
Example 13: synthesis of Compound of formula 4
Comparative study of base B2
Under the protection of nitrogen, 20.42g of the compound of the formula 3, 250 ml of DMF, 1.445g of palladium tetratriphenylphosphine and 20.55g of 2,3,4, 6-tetra-O-acetyl-a-D-bromoglucopyranose are respectively added into four reaction bottles in a parallel reactor. Then, 21g (3eq) of potassium carbonate was added to reaction flask # 1, 32g (3eq) of potassium phosphate was added to reaction flask # 2, 15.2g (3eq) of triethylamine was added to reaction flask # 3, and 15g (3eq) of potassium acetate was added to reaction flask # 4. Heating the 4 reaction bottles in parallel by heating modules to the internal temperature of 70 ℃ for reaction for 12 hours, cooling to the room temperature after the reaction is finished, filtering, adding dichloromethane into the filtrate, washing with saturated saline solution, layering, drying the organic layer, and concentrating to obtain a light yellow solid (formula 4).
TABLE 11
Figure BDA0002793480990000151
Example 14: synthesis of Compound of formula 4
Comparative study of base B2 dosage
Under the protection of nitrogen, 20.42g of the compound of the formula 3, 250 ml of DMF, 1.445g of palladium tetratriphenylphosphine and 20.55g of 2,3,4, 6-tetra-O-acetyl-a-D-bromoglucopyranose are respectively added into four reaction bottles in a parallel reactor. Then, 5g (1eq) of potassium phosphate was added to reaction flask # 1, 10.7g (1eq) of potassium phosphate was added to reaction flask # 2, 21.4g (2eq) of potassium phosphate was added to reaction flask # 2, 42.8g (4eq) of potassium phosphate was added to reaction flask # 3, and 64.2g (6eq) of potassium phosphate was added to reaction flask # 4. . Heating the 4 reaction bottles in parallel by heating modules to 70 ℃ to react for 12 hours, cooling to room temperature after the reaction is finished, filtering, adding dichloromethane into the filtrate, washing with saturated saline solution, demixing, drying the organic layer, and concentrating to obtain a light yellow solid (formula 4).
TABLE 12
Figure BDA0002793480990000152
Figure BDA0002793480990000161
Example 15: synthesis of Compound of formula 4
Comparative study of solvent dosage
Under the protection of nitrogen, 102.1 ml of DMF was added into a reaction bottle No. 1, 204.2 ml of DMF was added into a reaction bottle No. 2 and 306.3 ml of DMF was added into a reaction bottle No. 3 in parallel reactors. After the addition, 20.42g of the compound of formula 3, 1.445g of palladium tetratriphenylphosphine, 20.55g of 2,3,4, 6-tetra-O-acetyl-a-D-bromoglucopyranose and 32g of potassium phosphate are added into four reaction bottles under stirring. After the addition, the temperature of 3 reaction bottles is raised to 70 internal temperature under the condition that heating modules are arranged in parallel, reaction is carried out for 15 hours, the temperature is reduced to room temperature after the reaction is finished, filtration is carried out, dichloromethane is added into filtrate, saturated saline solution is used for washing and layering, an organic layer is dried and concentrated to obtain a light yellow solid (formula 4).
Watch 13
Figure BDA0002793480990000162
Example 16: synthesis of Compound of formula 4
Comparative study of different temperatures T2
Under the protection of nitrogen, 20.42g of the compound of the formula 3, 204.2 ml of DMF, 1.445g of palladium tetratriphenylphosphine, 20.55g of 2,3,4, 6-tetra-O-acetyl-a-D-bromoglucopyranose and 32g of potassium phosphate are respectively added into four reaction bottles in a parallel reactor. Then, the heating temperature is set to 50 ℃ of the internal temperature in the No. 1 reaction flask, the heating temperature is set to 70 ℃ of the internal temperature in the No. 2 reaction flask, the heating temperature is set to 90 ℃ of the internal temperature in the No. 3 reaction flask, and the heating temperature is set to 110 ℃ of the internal temperature in the No. 4 reaction flask. And (3) reacting for 12 hours after the temperature in the four reaction bottles is reached, cooling to room temperature after the reaction is finished, filtering, adding dichloromethane into the filtrate, washing with saturated saline solution, layering, drying the organic layer, and concentrating to obtain a light yellow solid (formula 4).
TABLE 14
Figure BDA0002793480990000171
Example 17: synthesis of Compound of formula 4 (optimum conditions after screening)
408.3g of (formula 3), 4000ml of DMF, 28.9g of palladium tetratriphenylphosphine, 410g of 2,3,4, 6-tetra-O-acetyl-a-D-bromoglucopyranose and 640g of potassium phosphate are added into a reaction bottle under the protection of nitrogen. Then the reaction flask was heated to an internal temperature of 70 ℃ and the reaction was timed for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was washed with saturated brine, separated into layers, and the organic layer was dried and concentrated to obtain 573.5g of a pale yellow solid (formula 4) with a yield of 93.6%. HPLC purity: 96.5 percent.
Example 18: synthetic canagliflozin
Comparative study of different bases B3
12.3g of the compound of formula 4 and 15 ml of methanol are respectively added into four reaction bottles in a parallel reactor to be dissolved, and then 10g of 20% lithium hydroxide solution is added into a reaction bottle No. 1, 20g of 20% sodium hydroxide solution is added into a reaction bottle No. 2, 28g of 20% potassium hydroxide solution is added into a reaction bottle No. 3, and 56g of 20% potassium tert-butoxide methanol solution is added into a reaction bottle No. 4. After the addition, four reaction bottles react at 25 ℃ for one hour by TLC/HPLC until the raw material formula 4 is reacted completely, then four reactions are carried out to adjust the pH of the reaction liquid to be neutral by using dilute hydrochloric acid, the reaction liquid is distilled to remove methanol, the residue is dissolved by ethyl acetate and then washed by saturated saline, an organic layer is dried by sodium sulfate, and a solid is obtained by recrystallization by using an ethyl acetate-n-hexane mixture (ethyl acetate: n-hexane ═ 1:3) after filtration and concentration, so that solid canagliflozin is obtained.
Watch 15
Figure BDA0002793480990000172
Example 19: synthetic canagliflozin
Comparative study of different reaction solvents S3
Adding 12.3g of a compound of formula 4 into four reaction bottles in parallel reactors respectively, adding 150ml of methanol into a reaction bottle No. 1 for dissolving, adding 150ml of ethanol into a reaction bottle No. 2 for dissolving, adding 150ml of isopropanol into a reaction bottle No. 3 for dissolving, adding 20% sodium hydroxide solution into three reaction bottles after dissolving, reacting for one hour at 25 ℃ by TLC/HPLC until the reaction of the raw material formula 4 is finished, adjusting the pH of a reaction solution to be neutral by using diluted hydrochloric acid in three reactions, distilling the reaction solution to remove the methanol, dissolving the residue by using ethyl acetate, washing by using saturated saline, drying an organic layer by using sodium sulfate, filtering and concentrating to obtain a solid, and recrystallizing by using an ethyl acetate-n-hexane mixture (the ethyl acetate: n-hexane is 1:3) to obtain the solid canagliflozin.
Watch 15
Figure BDA0002793480990000181
Example 20: synthetic Canagliflozin (formula 1)
61.3g of the compound of formula 4 synthesized in example 24 was taken and charged into a reaction flask, and then 65ml of methanol was added to dissolve it, and after dissolving it, 100g of 20% sodium hydroxide solution was added. After the completion of the addition, TLC/HPLC was carried out at 25 ℃ for 1 hour until the reaction of the starting material of formula 4 was completed, followed by adjusting the pH of the reaction solution to neutral with dilute hydrochloric acid, distilling off methanol from the reaction solution, dissolving the residue with ethyl acetate, followed by washing with saturated brine, drying the organic layer with sodium sulfate, filtering and concentrating to obtain a solid, recrystallizing with an ethyl acetate-n-hexane mixture (ethyl acetate: n-hexane 1:3) to obtain 40.2g of a solid in a yield of 90.4%, and having an HPLC purity: 98.1 percent.
MS:467.1292[M+Na]+,455.1452[M+H]+。
1H NMR(600MHz,Methanol-d4)δ7.52(dd,J＝8.8,5.2Hz,2H),7.32(d,J＝1.8Hz,1H),7.25(dd,J＝7.8,1.8Hz,1H),7.16(d,J＝7.8Hz,1H),7.10(d,J＝3.6Hz,1H),7.06(t,J＝8.8Hz,2H),6.70(d,J＝3.7Hz,1H),4.15–4.14(m,2H),4.12(d,J＝9.4Hz,1H),3.89(dd,J＝12.0,2.0Hz,1H),3.71(dd,J＝12.0,5.3Hz,1H),3.49(t,J＝8.5Hz,1H),3.45–3.38(m,3H),2.30(s,3H)。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (9)

1. A method of synthesizing canagliflozin, the method having the formula:
Figure FDA0002793480980000011
the method comprises the following steps:
1) reacting the compound shown in the formula 2 with a diboron acid pinacol ester to obtain a compound shown in a formula 3;
2) reacting the compound shown in the formula 3 with a 2,3,4, 6-tetra-O-acetyl-a-D-bromo glucopyranose compound to obtain a compound shown in a formula 4; and
3) hydrolyzing the compound of formula 4 to produce the compound of formula 1, canagliflozin.
2. The process of claim 1, wherein in step 1), 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene (compound of formula 2) is reacted with pinacol borate in S1 solvent at T1 in the presence of base B1 and catalyst C1 to give the compound of formula 3.
3. The method of claim 2, wherein the solvent S1 is selected from the group consisting of toluene, dioxane, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl pyrrolidone (NMP); preferably dioxane; and/or
The base B1 is selected from N, N-Diisopropylethylamine (DIEPA), potassium tert-butoxide, potassium acetate and potassium phosphate; preferably potassium acetate; and/or
The dosage of the alkali B1 is as follows: 1eq to 6 eq; preferably 3eq to 4 eq; and/or
The catalyst C1 is a palladium metal compound or a nickel metal compound; preference is given to nickel chloride, 1' -bisdiphenylphosphinoferrocene nickel dichloride (dppfNiCl)2) Tetrakistriphenylphosphine nickel, palladium chloride, tetrakistriphenylphosphine palladium, 1' -bisdiphenylphosphinoferrocene palladium dichloride (dppfpdCl)2) (ii) a Preferably dppfppdcl2(ii) a And/or
The dosage of the catalyst C1 is as follows: 0.5 mol% -5 mol%; preferably 1.5 mol% to 2.5 mol%; and/or
The temperature T1 is 20-150 ℃; preferably 40-60 ℃.
4. The process of claim 1 wherein in step 2) the compound of formula 3 is reacted with 2,3,4, 6-tetra-O-acetyl-a-D-bromoglucopyranose in the presence of base B2 and catalyst C2 in a solvent of S2 at a temperature of T2 to provide the compound of formula 4.
5. The process of claim 9, wherein the base B2 is triethylamine, potassium carbonate, potassium acetate, or potassium phosphate; potassium phosphate is preferred; and/or
The dosage of the alkali B2 is as follows: 1eq to 6 eq; preferably 2eq to 4 eq; and/or
The catalyst C2 is a palladium metal compound or a nickel metal compound; preference is given to nickel chloride, 1' -bisdiphenylphosphinoferrocene nickel dichloride (dppfNiCl)2) Tetrakistriphenylphosphine nickel, palladium chloride, tetrakistriphenylphosphine palladium, 1' -bisdiphenylphosphinoferrocene palladium dichloride (dppfpdCl)2) (ii) a Preferably palladium tetratriphenylphosphine; and/or
The dosage of the catalyst C2 is as follows: 0.05 mol% -5 mol%; preferably 2.5 mol% to 3.5 mol%; and/or
The solvent S2 is selected from tetrahydrofuran, dioxane, N-Dimethylformamide (DMF); preferably DMF; and/or
The temperature T2 is 20-150 ℃; preferably 70-90 deg.C.
6. The process of claim 1, wherein in step 3), deprotection of the compound of formula 4 in solvents of base B3 and S3 provides the product compound of formula 1, canagliflozin.
7. The process of claim 6, wherein the base B3 is lithium hydroxide, sodium hydroxide, potassium hydroxide or potassium tert-butoxide; preferably sodium hydroxide; and/or
The solvent S3 is methanol, ethanol or isopropanol; methanol is preferred.
8. A compound represented by the formula 3
Figure FDA0002793480980000021
9. Use of a compound of formula 3 in the preparation of canagliflozin
Figure FDA0002793480980000022
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CN106938998A (en) * 2017-04-07 2017-07-11 四川智强医药科技开发有限公司 Synthetic method of the canagliflozin about material
CN110698467A (en) * 2019-10-31 2020-01-17 黄冈鲁班药业股份有限公司 Synthetic method of engagliflozin

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CN104109157A (en) * 2014-08-04 2014-10-22 山东康美乐医药科技有限公司 Preparation method of canagliflozin
CN104557895A (en) * 2015-01-27 2015-04-29 江苏嘉逸医药有限公司 Synthesis process of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
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