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EP-4739697-A1 - PROCESS FOR THE PREPARATION OF DAPAGLIFLOZIN

EP4739697A1EP 4739697 A1EP4739697 A1EP 4739697A1EP-4739697-A1

Abstract

The present invention relates to a process for the preparation of dapagliflozin, comprising the reaction of 4-(5-bromo-2-chlorobenzyl)phenyl ethyl ether starting material with an alkyl-lithium compound (step a); subsequent reaction of the obtained product with a trimethylsilyl-protected gluconolactone (step b); subsequent reaction of the obtained product with an acid in methanol to obtain the methyl C-aryl glycoside (V) (step c); and a last step, wherein the obtained product is converted to dapagliflozin, or a pharmaceutically acceptable salt or solvate thereof (step d). The selection of specific ratios and/or amounts of solvents in steps a) and c) provides an improved process, with improved overall purity with less purification steps.

Inventors

  • KAMI SKA, Ewelina
  • PUNDA, Pawe

Assignees

  • Zaklady Farmaceutyczne Polpharma S.A.

Dates

Publication Date
20260513
Application Date
20240705

Claims (15)

  1. 1. A process for the preparation of dapagliflozin of formula (VI): or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps: a) reacting a compound of formula (I): with an alkyl-lithium compound, in a mixture of solvents comprising solvent A and solvent B, to provide a compound of formula (II): b) reacting the compound of formula (II) with a compound of formula (III): to provide a compound of formula (IV) c) treating the compound of formula (IV) with an acid, in methanol, to provide a compound of formula (V) and d) converting the compound of formula (V) to dapagliflozin, or a pharmaceutically acceptable salt or solvate thereof; wherein in step a) the solvent A is selected from tetrahydrofuran and 2- methyltetrahydrofuran, solvent B is toluene, and the volume ratio A: B is from 1 :4 to 1 :6, and wherein the amount of methanol in step c) is of from 8 to 18 litres per kg of starting compound of formula (I).
  2. 2. Process according to claim 1 , wherein the alkyl-lithium compound in step a) is selected from methyl lithium, n-butyl lithium and t-butyl lithium, and preferably is n-butyl lithium.
  3. 3. Process according to claims 1 or 2, wherein solvent A in step a) is 2- methy Itetrahyd rof u ran .
  4. 4. Process according to any one of claims 1 to 3, wherein the volume ratio A:B is from 1 :4.5 to 1 :5.5, and preferably is about 1 :5.
  5. 5. Process according to any one of claims 1 to 4, wherein the amount of the mixture of solvents A+B used in step a), is from 5 to 14 litres per kg of compound of formula (I).
  6. 6. Process according to any one of claims 1 to 5, wherein the acid in step c) is selected from hydrochloric acid, sulphuric acid, methanesulfonic acid, phosphoric acid, hydrobromic acid and nitric acid.
  7. 7. Process according to claim 6, wherein the acid is hydrochloric acid.
  8. 8. Process according to any one of claims 1 to 7, wherein the pH of the reaction solution in step c) is comprised between 0 and 3.5, preferably comprised between 0 and 3, more preferably comprised between 0 and 2.5, and still more preferably comprised between 0 and 2.
  9. 9. Process according to any one of claims 1 to 8, wherein the amount of methanol in step c) is from 9 to 16 litres, preferably from 9.5 to 14 litres, and more preferably from 10 to 13 litres per kg of compound of formula (I).
  10. 10. Process according to any one of claims 1 to 9, wherein step d) comprises the following steps: d1) converting the compound of formula (V) to dapagliflozin, d2) converting dapagliflozin to dapagliflozin acetate of formula (VII): '") , and d3) converting dapagliflozin acetate of formula (VII) to dapagliflozin or a pharmaceutically acceptable salt or solvate thereof.
  11. 11. Process according to claim 10, wherein, before step d3), the compound of formula (VII) is recrystallized from ethanol.
  12. 12. Process according to claims 10 or 11 , wherein in step d3) dapagliflozin is obtained as amorphous dapagliflozin, by precipitation from a mixture of a solvent and an antisolvent.
  13. 13.- Process according to claim 12, wherein the solvent is selected from methyl tert-butyl ether, methanol, ethanol, dichloromethane, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofuran, and mixtures thereof; and the antisolvent is selected from an n- alkane, such as n-pentane, n-hexane, n-heptane or n-octane, and cyclohexane; preferably the solvent is methyl tert-butyl ether and the antisolvent is n-heptane.
  14. 14. Process according to claims 10 or 11 , wherein in step d3) dapagliflozin obtained as crystalline dapagliflozin propanediol monohydrate, by precipitation from a mixture of an organic solvent, water and (S)-1 ,2-propanediol.
  15. 15. Process according to claim 14, wherein the organic solvent is selected from ethyl acetate, isopropyl acetate, n-propyl acetate, butyl acetate, methyl tert-butyl ether, and mixtures thereof.

Description

“Process for the preparation of dapagliflozin” Technical Field The present invention relates to a process for the preparation of the SGLT2 inhibitor dapagliflozin. Technical Background Dapagliflozin is a reversible and highly selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). It is used in the treatment of type 2 diabetes mellitus, and it is also indicated for the treatment of heart failure and chronic kidney disease. Due to the high hygroscopicity of dapagliflozin in free form, the solid form of dapagliflozin currently used in the marketed tablets is the propanediol monohydrate, which is a solvate that consists of dapagliflozin compounded with (S)-(+)-1 ,2-propanediol and water in a 1 :1 :1 ratio. The preparation of dapagliflozin was first disclosed in the international patent application WO03/099836-A1. The synthetic route disclosed therein remains the most widely used for the preparation of dapagliflozin (Wang et al., Org. Process Res. Dev., doi: 10.1021/acs.oprd.2c00389) and it is summarized in Scheme I: (VII) (VI, Dapagliflozin) SCHEME I According to this method, aryl bromide (I) undergoes sequential Br/Li exchange with n-butyllithium (n-BuLi) at -78 °C, C-arylation with trimethylsilyl (TMS)- protected gluconolactone (III), and methoxylation with a methanol solution of methanesulfonic acid to obtain methyl C-aryl glycoside (V). Next, triethylsilane (EtaSiH) and BFa EtaO are used to reduce the compound of formula (V) to dapagliflozin (VI). The reduction reaction generally produces impurities, which are difficult to remove, so it is usually necessary to further improve the purity of dapagliflozin by acetylation and deacetylation, as the acetylated product (VII) is easier to crystallize. The base originally used in the last deacetylation step was LiOH, while this strong base has been substituted in subsequent prior art documents with NaOH, for example, as disclosed in W02008/002824-A1. Additionally, for example, other alternative acids have been disclosed to substitute the methanesulfonic acid used in the methoxylation step. Despite the improvements described so far in the prior art, the above depicted multi- step process involves the formation of different impurities along the process and, consequently, requires tedious purification procedures and results in poor yield. For large-scale chemical syntheses, to achieve an optimisation in the purification requirements is particularly useful, as it would allow to spare resources and processing time, which would result in significant cost reduction. However, practical achievement of such optimisation is not straightforward. Therefore, there is the need to provide an improved method for the preparation of dapagliflozin that can afford this substance in good yield and with low levels of impurities, and reducing the need of purification steps along the process. Object of the invention The object of the present invention is a process for the preparation of dapagliflozin. Detailed description of the invention The object of the present invention is a process for the preparation of dapagliflozin of formula (VI): or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps: a) reacting a compound of formula (I): with an alkyl-lithium compound, in a mixture of solvents comprising solvent A and solvent B, to provide a compound of formula (II): b) reacting the compound of formula (II) with a compound of formula (III): to provide a compound of formula (IV) c) treating the compound of formula (IV) with an acid, in methanol, to provide a compound of formula (V) and d) converting the compound of formula (V) to dapagliflozin, or a pharmaceutically acceptable salt or solvate thereof. wherein in step a) the solvent A is selected from tetrahydrofuran and 2- methyltetrahydrofuran, solvent B is toluene, and the volume ratio A: B is from 1 :4 to 1 :6, and wherein the amount of methanol in step c) is of from 8 to 18 litres per kg of starting compound of formula (I). The authors of the present invention have surprisingly found that by modifying the ratio of the solvents used in the lithiation step a), combined with an increase in the amount of methanol used in the methoxylation step c), a significant increase in the purity of dapagliflozin intermediate (V) is achieved. Without wishing to be bound to any theory, it is believed that, by these changes in the proportion of solvents, a change of polarity is achieved which allows a more efficient work-up, so that the formed compound of formula (V) and the impurities remain in different phases, and can be efficiently separated by simple phase separation. Along the present description, as well as in the claims, the singular expressions, generally preceded by the articles “a”, “an” or “the”, are meant to include also the plural forms, unless the context clearly indicates otherwise. Furthermore, numeric values preceded by the term “about” are meant to include the exact st