A chiral synthesis process of an empagliflozin intermediate

Abstract

The application discloses a chiral synthesis process of an empagliflozin intermediate, and the process comprises the following steps: dissolving a reactant I in an organic solvent to perform chiral oxidation to alcohol, adding a protecting agent to protect, further reducing a carbonyl in an ester group in a product, and then performing deprotection to obtain a target product, a chiral intermediate compound (S)-(+) 3-hydroxytetrahydrofuran. The application has the advantages that: the chiral alcohol compound is obtained through the oxidation reaction of the relatively cheap raw material under the action of the chiral reagent, the chiral product can be obtained at a high yield, the reaction selectivity is good, the yield is high, the loss of the raw material is reduced, the expensive chiral compound (S)-(+) 3-hydroxytetrahydrofuran is avoided to purchase, the production cost is effectively reduced, meanwhile, the steps are simple, the operation is easy, the raw material is easy to obtain, the product is easy to process, and the application is suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically a chiral synthesis process for empagliflozin intermediate. Background Technology

[0002] Empagliflozin (EBI-10773), CAS No.: [864070-43-9], Chinese chemical name: (1S)-1,5-dehydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucanol, was jointly developed by Boehringer Ingelheim and Eli Lilly and Company. It received FDA approval in August 2014. It is the third new drug for the treatment of diabetes with a novel mechanism of action that inhibits SGLT2, following the FDA's approval of canagliflozin (Invokana) from Johnson & Johnson on March 29, 2013, and dapagliflozin (Farxiga) from AstraZeneca on January 8, 2014.

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

[0004] .

[0005] Documents such as US7579449B2, US7713938B2, US7745414B2, WO2006120208A, US7776830B2, CN102574829A, and CN102549005A describe a synthetic method using 2-chloro-5-iodobenzoic acid as a starting material. This method involves reacting oxalyl chloride with fluorobenzene and DMF under catalysis to generate 2-chloro-5-iodobenzoyl chloride, followed by a Friedel-Crafts reaction with fluorobenzene to generate (2-chloro-5-iodophenyl)(4-fluorophenyl)methyl ketone compound 1. This compound is then substituted with (S)-3-hydroxytetrahydrofuran to generate an intermediate compound, and finally, carbonyl reduction yields (S)-3-[4-(5-iodo-2-chlorobenzyl)phenoxy]tetrahydrofuran.

[0006] This method is still widely used in the industrial synthesis of empagliflozin. However, it involves many reaction steps, and the Friedel-Crafts acylation reaction easily generates ortho-fluorine impurities. The final product is a mixture of ortho-fluorine substituted intermediates and impurities, resulting in poor reaction selectivity. Furthermore, the impurities and products have similar properties, making separation difficult. The synthetic route for the key intermediate compound is as follows:

[0007] Route 1

[0008]

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

[0010] The literature discloses a synthetic method (such as Route 2). Although the route is slightly shorter, the docking of phenol and (R)-3-hydroxytetrahydrofuran requires the Mitsunobu reaction, which generates more urea compounds and triphenylphosphine, and the post-reaction processing is troublesome, which is not conducive to the scale-up of the process. The subsequent steps in the route are basically the same as those in the above-mentioned patent, with low selectivity and yield, insufficient overall reaction yield, cumbersome route steps, and low overall efficiency.

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

[0012] Route 2

[0013]

[0014] All of the above routes use the chiral intermediate compound (S)-(+)-3-hydroxytetrahydrofuran as the way to introduce the chiral structure. However, the synthesis of the chiral intermediate (S)-(+)-3-hydroxytetrahydrofuran often requires expensive chiral materials, resulting in high prices and increased production costs, which is not conducive to large-scale industrial production. Summary of the Invention

[0015] To address the shortcomings of the aforementioned route, which involves high raw material prices and high preparation costs for the chiral compound (S)-(+)-3-hydroxytetrahydrofuran, thus increasing the overall cost of the route, this invention aims to provide a chiral synthetic process for the empagliflozin intermediate. This process can obtain the chiral intermediate compound (S)-(+)-3-hydroxytetrahydrofuran in high yield and at low cost, effectively reducing the overall production cost of the route. The route of this invention is as follows:

[0016]

[0017] The technical solution of this invention is as follows:

[0018] A chiral synthetic process for an empagliflozin intermediate includes the following steps:

[0019] First, reactant I was dissolved in an organic solvent, and an oxidizing agent, a catalyst, a base reagent, and a chiral inducer were added. The mixture was stirred and stirred, and the reaction was carried out at room temperature for 6-8 hours. After the reaction was completed, the product was separated to obtain compound II.

[0020] In the second step, under nitrogen protection, reactant compound II was dissolved in an organic solvent, a protective agent was added, and an alkaline reagent was added. The mixture was stirred at room temperature for 6–8 hours. After the reaction was completed, the product was separated to obtain compound III.

[0021] The third step involves dissolving compound III in an organic solvent, adding a reducing agent to the solution, heating the reaction, and then separating the product after the reaction is complete to obtain compound IV.

[0022] In the fourth step, compound IV was dissolved in an organic solvent, a deprotecting agent was added, and after the deprotecting group was removed, the product was separated to obtain the final chiral intermediate compound V.

[0023] Furthermore, the solvents used in the above reactions are all tetrahydrofuran (THF).

[0024] Furthermore, the oxidant used in the first step reaction is benzoic acid peroxide (MCPBA), and the amount of the oxidant is 1.0 to 1.1 eq of compound I.

[0025] Furthermore, the base reagent used in the first step reaction is NaHMDS, and the amount of base reagent used in the first step reaction is 2 to 3 eq of compound I.

[0026] Furthermore, the chiral inducer for the first step reaction is camphor sulfonic acid, and the amount of the chiral inducer used is 0.8 to 1 mol of reactant I.

[0027] Furthermore, the base reagent used in the second step reaction is triethylamine, and the amount of base reagent used in the second step is 1.0 eq of compound II.

[0028] Furthermore, the protecting agent used in the second step reaction is trimethylchlorosilane, and the molar ratio of the amount of aminomethylchlorosilane to compound II is 1:1.

[0029] Furthermore, the reducing agent used in the third step is lithium aluminum hydride, and the ratio of the reducing agent to reactant compound III is 1:1.

[0030] Furthermore, the amount of reducing agent used in the third step is 1.0 eq of compound IV in molar ratio.

[0031] Furthermore, the deprotecting agent used in the fourth step reaction is a 1 mol / L methanol solution of sodium hydroxide.

[0032] The beneficial effects of this invention are: 1. This invention obtains chiral alcohol compounds through oxidation reactions of relatively inexpensive raw materials under the action of chiral reagents, achieving high yields of chiral products, good reaction selectivity, high yield, and reduced raw material loss; 2. This invention provides a method for the chiral carbon structure of the chiral compound (S)-(+)-3-hydroxytetrahydrofuran, effectively reducing the production costs required for procurement; 3. This invention has simple steps, is easy to operate, uses readily available raw materials, and is easy to process, making it suitable for large-scale industrial production. Attached Figure Description

[0033] Figure 1 This is a schematic diagram of the route one of the present invention;

[0034] Figure 2 This is a schematic diagram of the second route of the present invention;

[0035] Figure 3 This is a schematic diagram of the reaction route of the present invention;

[0036] Figure 4 This is a schematic diagram of the Engel's chemical formula of the present invention. Detailed Implementation

[0037] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments and accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0038] In the first step, 12.8 g (0.1 mol) of compound I was dissolved in 250 ml of the organic solvent tetrahydrofuran, 0.2 mol of the base reagent NaHMDS was added, along with 0.1 mol of the oxidant benzoic acid peroxide MCPBA and 0.001 mol of the chiral inducer camphorsulfonic acid. The reaction was stirred at room temperature for 6–8 h. TLC monitoring showed that the reaction was complete. The solvent was recovered by fractional distillation under reduced pressure. After fractionation, 100 ml of dichloromethane was added, and the pH was adjusted to approximately 7.0 with dilute acid water. The mixture was stirred until completely dissolved, and the layers were separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined and washed with saturated brine. The organic layer was desolvated under reduced pressure until dry. The product was recrystallized with 40 ml of toluene to obtain 9.3 g of compound II, with a yield of 91.1% and a purity of 96.5%.

[0039] In the second step, 0.1 mol of trimethylchlorosilane and 0.1 mol of triethylamine were added to 10.2 g (0.1 mol) of compound II tetrahydrofuran. The mixture was reacted at room temperature for 6–8 h. The solvent was evaporated, and 100 ml of water and 100 ml of dichloromethane were slowly added to dissolve the product. The product was neutralized to neutrality with dilute hydrochloric acid. The organic phase was separated and washed 2–3 times with saturated brine. The organic phase was separated again, the solvent was evaporated, and the product was recrystallized from 30 ml of toluene to yield 16.8 g of compound III, with a yield of 96.5% and a purity of 96.8%.

[0040] In the third step, under nitrogen protection, 17.4 g (0.1 mol) of compound III obtained in the second step was dissolved in 250 ml of dry organic solvent tetrahydrofuran, and 0.10 mol of reducing agent lithium aluminum hydride was added. The mixture was heated at 30-40 °C for 4-5 h. After the reaction was completed by HPLC, excess lithium aluminum hydride was removed by quenching with water at 0 °C. The mixture was stirred and filtered, washed 2-3 times with tetrahydrofuran, and dissolved under reduced pressure. The product was dissolved in 100 ml of dichloromethane and 100 ml of water. The organic phase was washed 2-3 times with saturated brine. The solvent was evaporated, and the product was recrystallized from 50 ml of toluene to obtain 15.3 g of compound IV, with a yield of 15.3% and a purity of 96.9%.

[0041] In the fourth step, 16.0 g (0.1 mol) of compound IV obtained in the third step was added to 100 ml of tetrahydrofuran, and 100 ml of a methanol solution of sodium hydroxide (1 mol / L) was added. The mixture was stirred and mixed. After the reaction was detected by HPLC, dilute hydrochloric acid was added dropwise to neutralize the reaction until neutral. The mixture was evaporated to dryness, and 50 ml of dichloromethane and 50 ml of water were added to dissolve it. The product was extracted with dichloromethane 2-3 times and washed with saturated brine 2-3 times. The organic phase was separated and distilled under reduced pressure to obtain 8.5 g of compound V, with a yield of 96.6% and a purity of 97.3%.

[0042] In the first step, 12.8 g (0.1 mol) of compound I was dissolved in 250 ml of the organic solvent tetrahydrofuran, 0.3 mol of the base reagent NaHMDS was added, along with 0.1 mol of the oxidant benzoic acid peroxide MCPBA and 0.001 mol of the chiral inducer camphorsulfonic acid. The reaction was stirred at room temperature for 6–8 h. TLC monitoring showed that the reaction was complete. The solvent was recovered by fractional distillation under reduced pressure. After fractionation, 100 ml of dichloromethane was added, and the pH was adjusted to approximately 7.0 with dilute acid water. The mixture was stirred until completely dissolved, and the layers were separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined and washed with saturated brine. The organic layer was desolvated under reduced pressure until dry. The product was recrystallized with 40 ml of toluene to obtain 9.2 g of compound II, with a yield of 90.2% and a purity of 96.3%.

[0043] In the first step, 12.8 g (0.1 mol) of compound I was dissolved in 250 ml of the organic solvent tetrahydrofuran, 0.1 mol of the base reagent NaHMDS was added, along with 0.11 mol of the oxidant benzoic acid MCPBA and 0.001 mol of the chiral inducer camphorsulfonic acid. The reaction was stirred at room temperature for 6–8 h. TLC monitoring showed that the reaction was complete. The solvent was recovered by fractional distillation under reduced pressure. After fractionation, 100 ml of dichloromethane was added, and the pH was adjusted to approximately 7.0 with dilute acid water. The mixture was stirred until completely dissolved, and the layers were separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined and washed with saturated brine. The organic layer was desolvated under reduced pressure until dry. The product was recrystallized with 40 ml of toluene to obtain 9.0 g of compound II, with a yield of 88.2% and a purity of 96.3%.

[0044] In the first step, 12.8 g (0.1 mol) of compound I was dissolved in 250 ml of the organic solvent tetrahydrofuran, 0.2 mol of the base reagent NaHMDS was added, along with 0.1 mol of the oxidant benzoic acid peroxide MCPBA and 0.0008 mol of the chiral inducer camphorsulfonic acid. The reaction was stirred at room temperature for 6–8 h. TLC monitoring showed that the reaction was complete. The solvent was recovered by fractional distillation under reduced pressure. After fractionation, 100 ml of dichloromethane was added, and the pH was adjusted to approximately 7.0 with dilute acid water. The mixture was stirred until completely dissolved, and the layers were separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined and washed with saturated brine. The organic layer was desolvated under reduced pressure until dry. The product was recrystallized with 40 ml of toluene to obtain 9.2 g of compound II, with a yield of 88.2% and a purity of 96.4%.

[0045] It will be apparent to those skilled in the art that the present 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 its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0046] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for 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 can be understood by those skilled in the art.

Claims

1. A chiral synthesis process of an empagliflozin intermediate, 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, a catalyst is added, a base reagent and a chiral inducer are added, the mixture is stirred, and the reaction is carried out at room temperature for 6-8 hours; after the reaction is completed, the product is separated, and compound II is obtained; In the second step, under the protection of nitrogen, the reactant compound II is dissolved in an organic solvent, a protection reagent is added, a base reagent is added, the reaction is stirred at room temperature for 6-8 hours; after the reaction is completed, the product is separated, and compound III is obtained; In the third step, compound III 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, and compound IV is obtained; In the fourth step, compound IV is dissolved in an organic solvent, a deprotection reagent is added, and after the deprotection group is removed, the product is separated, and the final chiral intermediate compound V is obtained; The solvents used in the above reactions are all tetrahydrofuran (THF); the oxidant used in the first step is benzenecarboperoxoic acid (MCPBA), and the amount of the oxidant is 1.0-1.1 eq of compound I; the base reagent used in the first step is NaHMDS, and the amount of the base reagent used in the first step is 2-3 eq of compound I; the chiral inducer used in the first step is camphor sulfonic acid, and the amount of the chiral inducer used is 0.8-1 mol% of the reactant I; the base reagent used in the second step is triethylamine, and the amount of the base reagent used in the second step is 1.0 eq of compound II; the protection reagent used in the second step is trimethylchlorosilane, and the molar ratio of the amount of trimethylchlorosilane to compound II is 1:1; the reducing agent used in the third step is lithium aluminum hydride, and the molar ratio of the amount of the reducing agent to the reactant compound III is 1:1; the amount of the reducing agent used in the third step is 1.0 eq of compound IV; and the deprotection reagent used in the fourth step is a 1 mol / L methanol solution of sodium hydroxide.

Images