A new process for synthesizing empagliflozin intermediate compounds

Abstract

The present invention discloses a novel process for synthesizing an empagliflozin intermediate compound, wherein α-methyl glucoside is used as a raw material, carbonyl protection is performed, the configuration is flipped by SN2 reaction, and then a Friedel-Crafts alkylation reaction is performed to obtain an empagliflozin intermediate compound. The beneficial effects of the present invention are as follows: the present invention provides a novel synthesis process by selectively synthesizing new raw materials and obtaining chiral products by SN2 configuration flipping, thereby avoiding the use of expensive chiral reagents, while reducing the reaction steps of the overall route, and being able to effectively reduce the generation of reaction by-products; in addition, the synthesis method of the present invention is simple to operate, the raw materials are easily available, the product yield is high, the reaction selectivity is good and the purity is high, and it is suitable for industrial expansion production.

Description

Technical Field

[0001] The present invention relates to the technical field related to the synthesis of pharmaceutical intermediates, and in particular to a new synthesis process of an empagliflozin intermediate compound. Background Art

[0002] Empagliflozin (EBI-10773), CAS No.: [864070-43-9], Chinese chemical name: (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol, was jointly developed by Boehringer Ingelheim and Eli Lilly Company, and was approved by the U.S. Food and Drug Administration (FDA) in August 2014. It is the third new diabetes treatment drug with a new mechanism of action of inhibiting SGLT 2 after the FDA approved canagliflozin (Invokana) of Johnson & Johnson Pharmaceuticals on March 29, 2013 and dapagliflozin (Farxiga) of AstraZeneca on January 8, 2014.

[0003] The chemical name of empagliflozin is (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol, molecular formula: C23H27ClO7, molecular weight: 450.91, and its chemical structure is as follows: .

[0004] At present, according to the published literature, a key step in the synthesis of empagliflozin is the coupling of gluconolactone with a halogenated aromatic hydrocarbon intermediate compound. The current methods for synthesizing empagliflozin mainly include the following methods for coupling gluconolactone with a halogenated aromatic hydrocarbon compound: Route 1 (PCT patent WO2006120208A publicly reports the preparation method of empagliflozin and its key intermediates) At present, most domestic and foreign patents and literature have adopted similar methods to this route, but the overall route of this method is too long and the process cost is high. This route is through the key intermediate (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran and gluconolactone coupling under the action of n-butyl lithium (n-BuLi), nucleophilic addition with sugar, followed by methyl etherification, reduction with Et3SiH / BF3·Et2O system to eliminate the hydroxyl group on the anomeric carbon, and then nucleophilic substitution reaction with (R)-3-toluenesulfonic acid tetrahydrofuran ester to obtain the final product empagliflozin. The addition reaction of the key intermediate with TMS-protected gluconolactone requires strict low temperature and low yield. The stereoselectivity of the reaction is poor. In the subsequent reaction, the product needs to be purified by introducing protective groups such as acetyl to improve the crystallinity of the product, which adds additional process steps; the Grignard addition product needs to be reduced with triethylsilyl hydrochloride to eliminate the methoxy group at the benzyl position, which increases the difficulty of reaction operation and processing.

[0005] Route 2 (CN106905305B discloses a method for synthesizing empagliflozin and its key intermediates) (wherein, X is bromine or iodine, LG is chlorine, bromine, methanesulfonyloxy or p-toluenesulfonyloxy, and PG is acetyl, tert-butyryl or benzoyl) In this method, the gluconolactone derivative 6 and the key intermediate (S)-3-(4-(5-bromo(iodo)-2-chlorobenzyl)phenoxy)tetrahydrofuran 5 are docked by a format exchange reaction to obtain the protecting group-protected empagliflozin intermediate compound 7, and the compound is deprotected to obtain empagliflozin. In this route, compound 6 needs to be prepared in advance, which increases the reaction steps and makes the operation cumbersome.

[0006] Route 3 (CN106117192B discloses a method for synthesizing empagliflozin) The route uses 2,3,4,6-tetra-O-benzyl-D-pyranoglucono-1,5-lactone and p-chloroiodobenzene as raw materials to prepare an intermediate (1-hydroxy-1-p-chlorophenyl-2,3,4,6-tetra-O-benzyl-D-pyranoglucono-1,5-lactone, and p-chloroiodobenzene, and then uses triethylsilane and aluminum trichloride as reducing agents to remove the anomeric carbon. The synthetic route is short, the materials used in the reaction are easy to obtain, the intermediate is easy to purify, the entire reaction process is simple to operate, and has a high total yield. There is no need to use an Et3SiH / BF3·Et2O reduction system (BF3 has high toxicity), which is very beneficial to environmental protection and industrialization. The reaction route still has the problems of insufficient selectivity and a large number of by-products in connecting glucono-lactone with halogenated aromatics. Summary of the invention

[0007] In view of the above shortcomings, the present invention aims to provide a new process for synthesizing an empagliflozin intermediate compound, which uses α-methyl glucoside as a raw material, undergoes carbonyl protection, and then reverses the configuration through an SN2 reaction, and then undergoes a Friedel-Crafts alkylation reaction to obtain an empagliflozin intermediate compound. The specific technical scheme is as follows: A novel process for synthesizing an empagliflozin intermediate compound comprises the following steps: In the first step, reactant I is dissolved in an organic solvent, a protective agent and a catalyst are added, and the mixture is stirred at 30 to 40° C. for 4 to 6 hours. After the reaction is completed, the product is separated to obtain compound II; The second step is to dissolve the reactant compound II in an organic solvent, add a nucleophilic reagent, add a catalyst, and react at room temperature for 6 to 8 hours. After the reaction is completed, separate the product to obtain compound III; In the third step, compound III is dissolved in an organic solvent, chlorobenzene is added to the solution, a catalyst is added, and the reaction is heated. After the reaction is completed, the product is separated to obtain the chiral intermediate compound IV of empagliflozin.

[0008] Furthermore, the protective agent used in the first step reaction is BnCl.

[0009] Furthermore, the solvent used in the one-step reaction is dichloromethane or carbon tetrachloride.

[0010] Furthermore, the amount of the protective agent used in the first step reaction is 5 to 6 eq of compound I.

[0011] Furthermore, the second step reaction solvent is benzene or xylene.

[0012] Furthermore, the catalysts used in the first step, the second step and the third step are all aluminum chloride AlCl3.

[0013] Furthermore, the amount of catalyst used in the first step is 10-15wt% of compound I, the amount of catalyst used in the second step is 10-20mol% of compound II, and the amount of catalyst used in the third step is 1-2eq of compound III.

[0014] Furthermore, the molar ratio of compound II to the nucleophilic reagent in the second step reaction is 1:1.

[0015] Furthermore, the amount of the alkaline reagent used in the third step reaction is 2 to 3 eq of compound III, and the molar ratio of chlorobenzene to compound III in the third step is 1:1.0 to 1.05.

[0016] Furthermore, the reaction temperature of the third step is 40-60°C.

[0017] The beneficial effects of the present invention are: 1. The present invention provides a new synthesis process through the selective synthesis of new raw materials and the SN2 configuration inversion to obtain chiral products, thereby avoiding the use of expensive chiral reagents and reducing the reaction steps of the overall route, which can effectively reduce the generation of reaction by-products; 2. In addition, the synthesis method of the present invention is simple to operate, the raw materials are easily available, the product yield is high, the reaction selectivity is good and the purity is high, and it is suitable for industrial expansion production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is a reaction route flow chart of the present invention; Figure 2 This is a schematic diagram of the chemical structure of Engelhardt; Figure 3 This is a reaction route flow chart of route 1 of the present invention; Figure 4 This is a reaction route flow chart of route 2 of the present invention; Figure 5 The figure is a flow chart of the reaction route of route 3 of the present invention. DETAILED DESCRIPTION

[0019] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0020] In the first step, 19.4 g (0.01 mol) of reactant Ⅰ was dissolved in 200 ml of dichloromethane, an organic solvent, and a protective agent of 0.05 mol of BnCl and a catalyst of 1.94 g of AlCl3 were added. The mixture was stirred at 30-40°C for 4-6 hours. After the reaction was completed, saturated brine was added for washing 2-3 times. The organic phase was separated, the solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain 52.2 g of compound Ⅱ, with a yield of 94.2% and a purity of 97.9%. In the second step, 27.7 g (0.05 mol) of the reactant compound II obtained in the previous step was dissolved in 200 ml of the organic solvent dichloromethane, 0.05 mol of the nucleophilic reagent sodium bromide and 0.005 mol of the catalyst AlCl3 were added, and the reaction was carried out at room temperature for 6 to 8 hours. After the reaction was completed, saturated brine was added for washing 2 to 3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 40 ml of anisole to obtain 28.3 g of compound III with a yield of 93.9% and a purity of 97.7%; In the third step, under nitrogen protection, 30.2 g (0.05 mol) of compound III obtained in the previous step was dissolved in 250 ml of organic solvent toluene, 0.05 mol of chlorobenzene, 0.05 mol of catalyst AlCl3, and 0.1 mol of triethylamine were added to the solution, heated to react, saturated brine was added to wash 2 to 3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 50 ml of xylene to obtain 29.8 g of chiral intermediate compound IV of empagliflozin, with a yield of 93.7% and a purity of 97.9%.

[0021] In the first step, 19.4 g (0.01 mol) of reactant Ⅰ was dissolved in 200 ml of dichloromethane, an organic solvent, and a protective agent of 0.06 mol of BnCl and a catalyst of 1.94 g of AlCl3 were added. The mixture was stirred at 30-40°C for 4-6 hours. After the reaction was completed, saturated brine was added for washing 2-3 times. The organic phase was separated, the solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain 52.0 g of compound Ⅱ, with a yield of 92.8% and a purity of 97.8%. In the first step, 19.4 g (0.01 mol) of reactant Ⅰ was dissolved in 200 ml of dichloromethane, an organic solvent, and a protective agent of 0.05 mol of BnCl and a catalyst of 2.91 g of AlCl3 were added. The mixture was stirred at 30-40°C for 4-6 hours. After the reaction was completed, saturated brine was added for washing 2-3 times. The organic phase was separated, the solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain 52.3 g of compound Ⅱ, with a yield of 92.9% and a purity of 97.8%. In the second step, 27.7 g (0.05 mol) of the reactant compound II obtained in the previous step was dissolved in 200 ml of the organic solvent dichloromethane, 0.05 mol of the nucleophilic reagent sodium bromide and 0.01 mol of the catalyst AlCl3 were added, and the reaction was carried out at room temperature for 6 to 8 hours. After the reaction was completed, saturated brine was added for washing 2 to 3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 40 ml of anisole to obtain 27.8 g of compound III with a yield of 92.2% and a purity of 97.5%. In the third step, under nitrogen protection, 30.2 g (0.05 mol) of compound III obtained in the previous step was dissolved in 250 ml of organic solvent toluene, 0.05 mol of chlorobenzene, 0.1 mol of catalyst AlCl3 and 0.1 mol of triethylamine were added to the solution, and heated to react. After the reaction, saturated brine was added to wash 2 to 3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 50 ml of xylene to obtain 29.5 g of chiral intermediate compound IV of empagliflozin, with a yield of 92.8% and a purity of 97.9%.

[0022] In the third step, under nitrogen protection, 30.2 g (0.05 mol) of compound III obtained in the previous step was dissolved in 250 ml of organic solvent toluene, 0.05 mol of chlorobenzene, 0.1 mol of catalyst AlCl3 and 0.15 mol of triethylamine were added to the solution, and heated to react. After the reaction, saturated brine was added to wash 2 to 3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 50 ml of xylene to obtain 29.3 g of chiral intermediate compound IV of empagliflozin with a yield of 92.2% and a purity of 97.6%.

[0023] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

[0024] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A novel process for synthesizing an intermediate compound of empagliflozin, characterized in that The following steps are involved: In the first step, reactant I is dissolved in an organic solvent, a protective agent and a catalyst are added, and the mixture is stirred at 30 to 40° C. for 4 to 6 hours. After the reaction is completed, the product is separated to obtain compound II; The second step is to dissolve the reactant compound II in an organic solvent, add a nucleophilic reagent, add a catalyst, and react at room temperature for 6 to 8 hours. After the reaction is completed, separate the product to obtain compound III; In the third step, compound III is dissolved in an organic solvent, chlorobenzene is added to the solution, a catalyst is added, and an alkaline reagent, triethylamine, is added, and the reaction is heated. After the reaction is completed, the product is separated to obtain the chiral intermediate compound IV of empagliflozin.

2. The novel process for synthesizing an empagliflozin intermediate compound according to claim 1, characterized in that: The protective agent used in the first step reaction is BnCl.

3. The novel process for synthesizing an empagliflozin intermediate compound according to claim 1, characterized in that: The solvent used in the first step reaction and the third step reaction is dichloromethane.

4. The novel process for synthesizing an empagliflozin intermediate compound according to claim 1, characterized in that: The amount of the protective agent used in the first step reaction is 5 to 6 eq of compound I.

5. The novel process for synthesizing an empagliflozin intermediate compound according to claim 1, characterized in that: The second step reaction solvent is benzene or xylene.

6. The novel process for synthesizing an empagliflozin intermediate compound according to claim 1, characterized in that: The catalysts used in the first step, the second step and the third step are all aluminum chloride AlCl3.

7. The novel process for synthesizing an intermediate compound of empagliflozin according to claim 1, characterized in that: The amount of catalyst used in the first step is 10-15wt% of compound I, the amount of catalyst used in the second step is 10-20mol% of compound II, and the amount of catalyst used in the third step is 1-2eq of compound III.

8. The novel process for synthesizing an empagliflozin intermediate compound according to claim 1, characterized in that: The molar ratio of compound II to the nucleophilic reagent in the second step reaction is 1:

1.

9. The novel process for synthesizing an empagliflozin intermediate compound according to claim 1, characterized in that: The amount of the alkaline reagent used in the third step reaction is 2 to 3 eq of compound III, and the molar ratio of chlorobenzene to compound III in the third step is 1:1.0 to 1.

05.

10. The novel process for synthesizing an intermediate compound of empagliflozin according to claim 1, characterized in that: The reaction temperature of the third step is 40-60°C.

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