Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/02—Acyclic radicals, not substituted by cyclic structures
  • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

• the invention relates to a new preparation method of the key intermediates of pharmaceutically active gliflozins, especially canagliflozin and dapagliflozin.
• the invention relates to a new preparation method of the key intermediates of structures la and lb for the synthesis of canagliflozin of formula 2a and dapagliflozin of formula 2b - SGLT2 inhibitors that are used for the treatment of diabetes [Chao, E. C. Drugs Fut. 2011, 36(5), 351; Cole, P., Vicente, M., Castaner, R. Drugs Fut. 2008, 33(9), 745]. See Diagram 1 below.
• the adduct is then deprotected and converted to the ketal of structure la, which can be isolated by precipitation.
• the ketal is then reduced in the presence of a Lewis acid, e.g. by means of triethylsilane to the respective C-glucoside.
• This methodology without the conversion to the ketal, was already generally described in the following publication (Kraus, G. A.; Molina, M. T. J. Org. Chem., 1988, 53, 752-153). With the use of this methodology the syntheses of canagliflozin (WO2005/012326A1) and dapagliflozin (WO2003/099836A1) have also been described. See Diagram 2 below.
• turbo-Grignard reagents e.g. z ' -PrMgCl*LiCl
• metalation of the iodaryl derivative prepared from the corresponding bromide is carried out at -25°C (WO2010/043682A2).
• diaryl zinc reagent prepared by a reaction of the aryl lithium 4a (Diagram 2) with zinc chloride, with bromoacetyl glucose, when a tetra-acyl derivative of canagliflozin is directly formed in the reaction (WO2011/047113).
• the invention relates to a preparation method of the intermediates of structures la (for the synthesis of canagliflozin) and lb (for the synthesis of dapaglifiozin)
• X is methyl and Ar represents 2-(5-(4-fluorophenyl)-thienyl), and in structure lb, X is chlorine and Ar represents 4-ethoxyphenyl, which comprises a reaction of the magnesate reagents of formula 6a or 6b,
• each of the groups R 1 and R 2 is independently a branched or straight Ci to C 6 alkyl
• m is an integer from 1 to 3
• n is an integer from 0 to 1
• o is an integer from 0 to 2
• magnesate reagent of type 6a or 6b is prepared through a reaction of the aryl bromide of formula 3a or 3b,
• magnesate reagents were investigated with the aim to increase the reaction temperature to facilitate industrial production.
• Magnesates are usually generated through a reaction of the respective aryl halide (Lau, S. Y. W. et al. Org. Lett. 2007, 9, 2239-2242) or heteroaryl halide (Struk, L.; Sosnicki, J. G. Synthesis 2012, 44, 735-746) and lithium trialkyl magnesate, which is generated in situ through a reaction of e.g. hexyl lithium and isopropyl magnesium chloride.
• the initial attempts on generation of a triaryl magnesate using this technique did lead to metalation, but the yield and purity of the desired intermediate were very low ( ⁇ 20%).
• magnesates with different stoichiometric compositions were optimized.
• a suitable solvent is tetrahydrofuran (THF), but also 2-methyl-THF (MeTHF).
• MeTHF 2-methyl-THF
• two addition methods were tested, i.e. A: addition of a lactone solution to a magnesate solution and B: addition of a magnesate solution to a lactone solution.
• Another key factor is the method of processing of the reaction mixture after the addition.
• the usual method i.e. addition of a solution of methanesulfonic acid in methanol, led to low yields and low purity of the desired product.
• Two three-necked flasks (100 ml and 50 ml) were dried under N 2 with a hot-air gun and left to cool down under N 2 .
• a solution of TMS-gluconolactone (4.2 g, 1.3 equiv.) in 2-MeTHF (10 ml) was prepared under nitrogen.
• Methanol (20 ml) was added to the honey-like evaporation product. Moderate heating of the mixture was used to prepare a solution into which MsOH (0.1 ml) was added under stirring. The mixture was further stirred under N 2 at the laboratory temperature (hereinafter RT only) for 20 h. Then, a 10% aqueous solution of NaHC0 3 (10 ml) was added to the reaction mixture, the mixture was evaporated, PhMe (20 ml), EtOAc (20 ml) and water (10 ml) were added to the residue. The obtained mixture was shaken, the organic layer was separated and the aqueous phase washed with PhMe (10 ml).
• Two three-necked flasks (100 ml and 50 ml) were dried under N 2 with a hot-air gun and left to cool down under N 2 .
• a solution of TMS-gluconolactone (3.39 g, 1.05 equiv.) in 2-MeTHF (10 ml) was prepared under nitrogen.
• Two three-necked flasks (100 ml and 50 ml) were dried under N 2 with a hot-air gun and left to cool down under N 2 .
• a solution of TMS-gluconolactone (3.39 g, 1.05 equiv.) in 2-MeTHF (10 ml) was prepared under nitrogen.
• the reaction mixture was then cooled down to ⁇ -25°C and adding of a solution of the lactone (3.39 g,T.05 equiv. in 10 ml of 2-MeTHF) into a solution of the magnesate was started (using a syringe pump, the needle was immersed in the cooled magnesate solution - for. approx. 1 h).
• the reaction mixture was further stirred for approx. 2 h and then a 10% aqueous solution of citric acid (30 ml) was added to it dropwise under intensive stirring.
• the reaction mixture gradually changed its color from orange to yellow, the temperature of the mixture rose to 10°C.
• the flask was then removed from the cooling bath and the obtained mixture was intensively stirred for 15 min.
• the phases were separated, the organic layer was washed with salt brine (5 ml) and evaporated on an RVE (approx. 150 mbar/41°C).
• Two three-necked flasks (100 ml and 50 ml) were dried under N 2 with a hot-air gun and left to cool down under N 2 .
• a solution of TMS-gluconolactone (3.39 g, 1.05 equiv.) in 2-MeTHF (10 ml) was prepared under nitrogen.
• the aryl bromide of formula 3a (2.5 g, 6.92 mmol) and 2-MeTHF (25 ml) were put in the other three-necked flask under N 2 and the resulting solution was cooled down under N 2 under stirring to -5°C (reaction mixture).
• a solution of i-PrMgCl in THF (2.0M, 1.14 ml, 0.33 equiv.) was added by dripping at ⁇ -5°C, the obtained mixture was further stirred for 5 min. Then, addition of a solution of n-HexLi in hexanes (2.3 M, 2.02 ml, 0.67 equiv.) was started.
• the obtained orange reaction mixture was further stirred for approx. 2 h and then a 10% aqueous solution of citric acid (30 ml) was added to the mixture drop wise under intensive stirring.
• the reaction mixture gradually changed its color from orange to yellow, the temperature of the mixture rose to 10°C.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biochemistry (AREA)
• Biotechnology (AREA)
• General Health & Medical Sciences (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Crystallography & Structural Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=57130116

Family Applications (1)

Country Status (2)

Cited By (6)

Citations (5)

• 2015
  • 2015-10-13 CZ CZ2015-729A patent/CZ2015729A3/cs unknown
• 2016
  • 2016-09-14 WO PCT/CZ2016/000103 patent/WO2017063617A1/en not_active Ceased

Patent Citations (5)

Non-Patent Citations (7)

Also Published As

Similar Documents

Legal Events