A process for the preparation of a sitagliptin chiral intermediate

Abstract

The application discloses a preparation method of an empagliflozin chiral intermediate. A reactant I is subjected to a Davis oxaziridine oxidation reaction to obtain a chiral alcohol compound II, then the chiral alcohol compound II is subjected to a reaction with a compound III fluorobenzene to obtain a compound IV, and the compound IV is reduced to obtain a compound V. The application has the advantages that the chiral alcohol compound is obtained through the oxidation reaction, the chiral product can be obtained at a high yield, the reaction selectivity is good, the yield is high, and the loss of raw materials is reduced; the expensive chiral compound (S)-(+) -hydroxytetrahydrofuran can be avoided through the reaction, the production cost is effectively reduced, the synthesis process is simple, the synthesis steps of (S)-(+) -hydroxytetrahydrofuran are effectively reduced, and the problem that the cost is excessively high due to too many synthesis steps of (S)-(+) -hydroxytetrahydrofuran is avoided.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical intermediates, in particular to a preparation method of a chiral intermediate of empagliflozin. BACKGROUND

[0002] Empagliflozin (EBI-10773), CAS No.: [864070-43-9], the Chinese name of which is (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol, is jointly developed by Boehringer Ingelheim and Eli Lilly Company, and was approved by the US Food and Drug Administration (FDA) in August 2014. It is the third new drug for treating diabetes with a new mechanism of action of inhibiting SGLT 2, after the approval of Invokana (canagliflozin) of Johnson & Johnson on March 29, 2013 and Farxiga (dapagliflozin) 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, the molecular formula is C23H27ClO7, and the molecular weight is 450.91. The chemical structural formula is as follows:

[0004] .

[0005] US7579449B2, US7713938B2, US7745414B2, WO2006120208A, US7776830B2, CN102574829A, CN102549005A and other documents disclose a synthesis method of (S)-3-[4-(5-iodo-2-chlorobenzyl)phenoxy]tetrahydrofuran compound, which comprises the following steps: taking 2-chloro-5-iodobenzoic acid as a starting material, reacting with oxalyl chloride under the catalysis of fluorobenzene and DMF to generate 2-chloro-5-iodobenzoyl chloride, then performing a Friedel-Crafts reaction with fluorobenzene to generate (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone compound 1, then performing a substitution reaction with (S)-3-hydroxytetrahydrofuran to generate an intermediate compound, and finally reducing the carbonyl group to obtain the (S)-3-[4-(5-iodo-2-chlorobenzyl)phenoxy]tetrahydrofuran compound.

[0006] This method is still widely used in the synthesis of empagliflozin in the industry, but the reaction steps are more, and the Friedel-Crafts acylation reaction is easy to produce fluorine ortho impurities. The final fluorine ortho substituted intermediate impurity mixture and the product have poor reaction selectivity, and the impurities and the product have similar properties, which are difficult to separate. The key intermediate compound synthesis route is as follows:

[0007] Route one

[0008]

[0009] Organic Letters, 16(16), 4090-4093; 2014, PCT Int. Appl., 2006120208

[0010] The literature discloses a synthesis method (such as route two), which has a slightly shorter route, but the docking of phenol and (R)-3-hydroxytetrahydrofuran requires Mitsunobu reaction, which generates more urea compounds and triphenyl phosphine oxide, and the reaction post-processing is troublesome, which is not conducive to process amplification. The method of the subsequent steps in the route is basically consistent with the above-mentioned patent, and the selectivity and yield are low, the total yield is insufficient, the route steps are complicated, and the overall efficiency is low.

[0011] The synthesis process of (3S)-3-[4-[(2-chloro-5-iodophenyl) methyl] phenoxy] tetrahydrofuran is shown as follows:

[0012] Route two

[0013]

[0014] In the above routes, (S)-(+)-hydroxytetrahydrofuran is used as a chiral structure introduction method. Since (S)-(+)-hydroxytetrahydrofuran is relatively expensive, the production cost is high, and the cost of large-scale production is difficult to reduce. SUMMARY

[0015] In view of the above, the present application aims to provide a preparation method of empagliflozin chiral intermediate, which introduces chiral alcohol hydroxyl group at the alpha position of carbonyl group through Davis oxidation reaction of cheap gamma-butyrolactone, then reacts with fluorobenzene to obtain intermediate compound IV, and then further reduces to obtain the target intermediate compound V, and the compound can be continuously synthesized by route two to finally synthesize empagliflozin, and the reaction route of the present application is as follows:

[0016]

[0017] The present application is a preparation method of empagliflozin chiral intermediate, comprising the following steps,

[0018] In the first step, the reactant I is dissolved in an organic solvent, an oxidizing agent, a catalyst, a base reagent and a chiral inducer are added, the mixture is stirred, and the reaction is carried out at low temperature for 12-16 hours, and then the product is separated to obtain compound II.

[0019] In the second step, the reactant compound II is dissolved in an organic solvent under nitrogen protection, compound III is added, a catalyst is added, and the reaction is carried out at room temperature for 6-8 hours, and then the product is separated to obtain compound IV.

[0020] In the third step, compound IV is dissolved in an organic solvent, a reducing agent is added to the solution, and the reaction is carried out by heating, and then the product is separated to obtain empagliflozin chiral intermediate compound V.

[0021] Further, the solvents used in the first step reaction, the second step reaction and the third step reaction are all tetrahydrofuran.

[0022] Further, the catalyst used in the first step reaction is 2-arylsulfonyl-3-aryloxyaziridine, and the amount of the catalyst used is 10-15 mol% of compound I, and the chemical formula of the catalyst is as follows,

[0023]

[0024] Further, the oxidizing agent used in the first step reaction is benzenecarboperoxoic acid MCPBA, and the amount of the oxidizing agent used is 1.0 eq of compound I.

[0025] Further, the catalyst used in the second step reaction is sodium hydride, and the amount of the catalyst used is 1.0-1.2 eq of reactant II.

[0026] Further, the reducing agent used in the third step is lithium aluminum hydride.

[0027] Further, the chiral inductor of the first step reaction is camphorsulfonic acid, the chiral inductor used in the first step reaction is in an amount of 0.5-1 mol% of the reactant I,

[0028] Further, the molar ratio of compound II to compound III in the second step reaction is 1:1.

[0029] Further, the molar ratio of the third step reducing agent to compound IV is 1:1.

[0030] Further, the base reagent used in the first step reaction is NaHMDS, and the amount of the base reagent is 1.0-2.0 eq of compound I.

[0031] The beneficial effects of the present application are: the present application can obtain chiral alcohol compounds through oxidation reaction, and can obtain chiral products with high yield, good reaction selectivity, high yield, and reduced loss of raw materials. Through the reaction, the expensive chiral compound (S)-(+)-hydroxytetrahydrofuran can be avoided to be purchased, the production cost is effectively reduced, the simple synthesis process effectively reduces the synthesis steps of (S)-(+)-hydroxytetrahydrofuran, and the problem of high cost caused by too many steps of synthesizing (S)-(+)-hydroxytetrahydrofuran is avoided. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 Route one of the present application is a schematic diagram of the flow chart;

[0033] Figure 2 Route two of the present application is a schematic diagram of the flow chart;

[0034] Figure 3 The reaction route of the present application is a schematic diagram of the flow chart;

[0035] Figure 4 The present application is a schematic diagram of the chemical formula structure of empagliflozin. DETAILED DESCRIPTION

[0036] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the embodiments of the present application and the drawings. Obviously, the described embodiments are only part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0037] The first step reaction, 8.6 g (0.1 mol) of compound I is dissolved in 250 ml of organic solvent tetrahydrofuran, 0.1 mol of base reagent NaHMDS is added, and the temperature is reduced to -20°C, 0.1 mol of oxidant benzoic acid peroxide MCPBA is added, 0.01 mol of catalyst 2-arylsulfonyl-3-aryloxyaziridine is added, 0.001 mol of chiral inducer camphor sulfonic acid is added, and the reaction is stirred at -78°C for 24 h. TLC tracking shows that the reaction is complete. The solvent is recovered by reduced pressure fractionation. After fractionation, 100 ml of dichloromethane is added, and the pH value is adjusted to about 7.0 with dilute acid water. Stirring is carried out until it is fully dissolved. The layers are separated, and the water layer is extracted with dichloromethane. The combined organic layers are washed with saturated brine, and the organic layer is removed by reduced pressure until it is dry. 40 ml of toluene is added for recrystallization. Filtration and drying are carried out to obtain 9.1 g of compound II, with a yield of 89.2% and a purity of 97.5%.

[0038] The second step, under nitrogen protection, 10.2 g (0.1 mol) of compound II, a catalyst of 0.11 mol of sodium hydride, is dissolved in 200 ml of tetrahydrofuran, and 0.1 mol of fluorobenzene is slowly added dropwise under water bath control at 25°C or below. Stirring is carried out at room temperature for 6-8 h. After HPLC detection, the reaction liquid is added to 3 L of water, and stirring is carried out at room temperature for 1 h to precipitate the solid. Filtration and washing with water are carried out, and drying is carried out to obtain 16.8 g of compound IV, with a yield of 94.4% and a purity of 95.5%.

[0039] The third step, under nitrogen protection, 17.8 g (0.1 mol) of the dried compound IV obtained in the second step is dissolved in 250 ml of dry organic solvent tetrahydrofuran, 0.10 mol of reducing agent lithium aluminum hydride (THF solution) is added, and heating is carried out at 30-40°C for 4-5 h. After HPLC detection, water is added at 0°C to quench the excess lithium aluminum hydride, and stirring and filtration are carried out. Tetrahydrofuran is washed 2-3 times, and the solvent is removed by reduced pressure. The product is dissolved in 100 ml of dichloromethane and 100 ml of water. The organic phase is washed with saturated brine 2-3 times, and the solvent is removed by reduced pressure. The product is recrystallized with 50 ml of toluene to obtain 15.3 g of compound V, with a yield of 93.2% and a purity of 97.8%.

[0040] The first step reaction, 8.6g (0.1mol) of compound I is dissolved in 250ml organic solvent tetrahydrofuran, 0.2mol of base reagent NaHMDS is added, and the temperature is reduced to-20℃, 0.1mol of oxidant benzoic acid peroxide MCPBA is added, 0.01mol of catalyst 2-arylsulfonyl-3-aryloxyaziridine is added, 0.001mol of chiral inducer camphorsulfonic acid is added, and the reaction is stirred at-78℃ for 24h. TLC tracking shows that the reaction is complete. The solvent is recovered by reduced pressure distillation. After the distillation is completed, 100ml of dichloromethane is added, and the pH value is adjusted to about 7.0 with dilute acid water. Stirring is carried out until it is fully dissolved. The layers are separated, and the water layer is extracted with dichloromethane. The combined organic layers are washed with saturated brine. The organic layer is dried to dryness under reduced pressure. 40ml of toluene is added for recrystallization. Filtration and drying give 9.2g of compound II with a yield of 90.2% and a purity of 97.8%.

[0041] The first step reaction, 8.6g (0.1mol) of compound I is dissolved in 250ml organic solvent tetrahydrofuran, 0.2mol of base reagent NaHMDS is added, and the temperature is reduced to-20℃, 0.1mol of oxidant benzoic acid peroxide MCPBA is added, 0.01mol of catalyst 2-arylsulfonyl-3-aryloxyaziridine is added, 0.001mol of chiral inducer camphorsulfonic acid is added, and the reaction is stirred at-78℃ for 24h. TLC tracking shows that the reaction is complete. The solvent is recovered by reduced pressure distillation. After the distillation is completed, 100ml of dichloromethane is added, and the pH value is adjusted to about 7.0 with dilute acid water. Stirring is carried out until it is fully dissolved. The layers are separated, and the water layer is extracted with dichloromethane. The combined organic layers are washed with saturated brine. The organic layer is dried to dryness under reduced pressure. 40ml of toluene is added for recrystallization. Filtration and drying give 9.2g of compound II with a yield of 90.2% and a purity of 97.8%.

[0042] The first step reaction, 8.6g (0.1mol) of compound I is dissolved in 250ml organic solvent tetrahydrofuran, 0.2mol of base reagent NaHMDS is added, and the temperature is reduced to-20℃, 0.1mol of oxidant benzoic acid peroxide MCPBA is added, 0.01mol of catalyst 2-arylsulfonyl-3-aryloxyaziridine is added, 0.001mol of chiral inducer camphorsulfonic acid is added, and the reaction is stirred at-78℃ for 24h. TLC tracking shows that the reaction is complete. The solvent is recovered by reduced pressure distillation. After the distillation is completed, 100ml of dichloromethane is added, and the pH value is adjusted to about 7.0 with dilute acid water. Stirring is carried out until it is fully dissolved. The layers are separated, and the water layer is extracted with dichloromethane. The combined organic layers are washed with saturated brine. The organic layer is dried to dryness under reduced pressure. 40ml of toluene is added for recrystallization. Filtration and drying give 9.2g of compound II with a yield of 90.2% and a purity of 97.8%.

[0043] Second step, under nitrogen protection, 10.2g (0.1mol) compound II, catalyst 0.10mol sodium hydride, dissolved in 200mL tetrahydrofuran, water bath temperature control 25℃ or less slowly drop in 0.1mol fluorobenzene, room temperature stirring 6-8 hours, HPLC detection reaction complete, the reaction liquid is added to 3L water, room temperature stirring 1 hour to precipitate solid, filtration, washing with water, drying to get 16.5g compound IV, yield 92.6%, purity 95.0%.

[0044] Second step, under nitrogen protection, 10.2g (0.1mol) compound II, catalyst 0.10mol sodium hydride, dissolved in 200mL tetrahydrofuran, water bath temperature control 25℃ or less slowly drop in 0.1mol fluorobenzene, room temperature stirring 6-8 hours, HPLC detection reaction complete, the reaction liquid is added to 3L water, room temperature stirring 1 hour to precipitate solid, filtration, washing with water, drying to get 16.5g compound IV, yield 92.6%, purity 95.0%.

[0045] It is obvious to those skilled in the art that the present application is not limited to the details of the above-described exemplary embodiments, and the present application can be implemented in other specific forms without departing from the spirit or essential characteristics of the present application. Therefore, the embodiments should be considered in all respects as illustrative and not restrictive, the scope of the present application being defined by the appended claims and not by the above description, and it is intended to encompass all changes falling within the meaning and range of equivalents of the essential elements of the claims. Any reference signs in the claims should not be considered as limiting the claims to which they relate.

[0046] In addition, it should be understood that although the present specification is described in terms of embodiments, not every embodiment contains only one independent technical solution, and the description of the specification is only for the sake of clarity, those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that those skilled in the art can understand.

Claims

1. A process for the preparation of a chiral intermediate of empagliflozin, characterized in that The method comprises the following steps: In the first step, the reactant I is dissolved in an organic solvent, an oxidant is added, and a catalyst 2-arylsulfonyl-3-aryloxyaziridine is added, which has the following chemical formula , adding a base reagent and a chiral inducer camphor sulfonic acid, stirring and mixing, reacting for 12-16 h at low temperature, separating the product to obtain compound II; In the second step, the reactant compound II is dissolved in an organic solvent under nitrogen protection, compound III is added, and a catalyst sodium hydride is added, and the reaction is carried out at room temperature for 6-8 hours; after the reaction is completed, the product is separated to obtain compound IV; In the third step, compound IV is dissolved in an organic solvent, a reducing agent is added to the solution, and the reaction is heated; after the reaction is completed, the product is separated to obtain the chiral intermediate compound V of empagliflozin.

2. A process for the preparation of a chiral intermediate of empagliflozin according to claim 1, characterized in that: The organic solvent used in the first step, the second step and the third step is tetrahydrofuran.

3. A process for the preparation of a chiral intermediate of empagliflozin according to claim 1, characterized in that: The amount of the catalyst used in the first step is 10-15 mol% of compound I.

4. A process for the preparation of a chiral intermediate of empagliflozin according to claim 1, characterized in that: The oxidant used in the first step is benzenecarboperoxoic acid MCPBA, and the amount of the oxidant is 1.0 eq of compound I.

5. A process for the preparation of a chiral intermediate of empagliflozin according to claim 1, characterized in that: The amount of the catalyst used in the second step is 1.0-1.2 eq of the reactant II.

6. A process for the preparation of a chiral intermediate of empagliflozin according to claim 1, characterized in that: The reducing agent used in the third step is lithium aluminum hydride.

7. A process for the preparation of a chiral intermediate of empagliflozin according to claim 1, characterized by: The amount of the chiral inducer used in the first step is 0.5-1 mol% of the reactant I.

8. A process for the preparation of a chiral intermediate of empagliflozin according to claim 1, characterized in that: The molar ratio of compound II to compound III in the second step is 1:

1.

9. A process for the preparation of a chiral intermediate of empagliflozin according to claim 1, characterized in that: The amount of the reducing agent used in the third step is 1.0-1.2 eq of compound IV.

10. A process for the preparation of a chiral intermediate of empagliflozin according to claim 1, characterized in that: The base reagent used in the first step is NaHMDS, and the amount of the base reagent is 1.0-2.0 eq of compound I.

Images