WO2025088634A1 - A process for the preparation of gliflozin aglycones - Google Patents
A process for the preparation of gliflozin aglycones Download PDFInfo
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- WO2025088634A1 WO2025088634A1 PCT/IN2024/052131 IN2024052131W WO2025088634A1 WO 2025088634 A1 WO2025088634 A1 WO 2025088634A1 IN 2024052131 W IN2024052131 W IN 2024052131W WO 2025088634 A1 WO2025088634 A1 WO 2025088634A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Definitions
- the present invention relates to a process for the preparation of gliflozin aglycones.
- the present invention particularly relates to a process for the preparation of gliflozin aglycone through a telescopic approach using ortho-lithiation of 1,4-dihalobenzene followed by reacting with corresponding aromatic or heteroaromatic aldehydes to produce intermediates as the key step and reduction of the intermediate to obtain gliflozin aglycone.
- gliflozins consist of two fragments, sugar and aglycone, and some representative gliflozins are depicted in Scheme 1, such as Dapagliflozin (1), Sotagliflozin (2), Ertugliflozin (3), Empagliflozin (4), Bexagliflozin (5), and Ipragliflozin (6) (W02010022313A2, W02009026537A1).
- 5-bromo-2-chloro-4'-ethoxydiphenylmethane of a compound of Formula la is a key intermediate for the preparation of several gliflozins (Scheme 1).
- CN 108752184 A discloses the preparation of aglycone of Formula la starting from 5-bromo- 2-chlorobenzoic acid, converting it to corresponding acyl chloride and reacting with fluorobenzene using Friedel-Crafts reaction as the key step (Scheme 3).
- CN 113121476 A discloses the preparation of aglycone of Formula lb and Formula Ic using Friedel-Crafts reaction as a key step (Scheme 4).
- CN108623558 A discloses the preparation of aglycone of Formula Id, involving deprotonation of heterocyclic compound (benzothiophene) using n-BuLi followed by reacting with an aromatic aldehyde, and reduction of the resulted secondary alcohol (Scheme 5).
- the main aim of the present invention is to provide a cost-effective, scalable process in a reduced number of steps for the preparation of the gliflozin aglycone of Formula I, which serves as a key intermediate for the synthesis of several gliflozins.
- the main objective of the present invention is to provide gliflozin aglycone through ortho- lithiation of 1,4-dihalobenzene, followed by reacting with corresponding aromatic or heteroaromatic aldehydes and reduction of the resulted intermediate (Formula II).
- Yet another objective is to provide gliflozin aglycone through a telescopic approach using ortho-lithiation of 1,4-dihalobenzene followed by reacting with aromatic or heteroaromatic aldehydes and reduction of the intermediate to yield gliflozin aglycone.
- the present invention provides a process for preparation of gliflozin aglycones compound of formula I,
- Ri is selected from and
- R2 is selected from the group consisting of Me, Et, iPr, Bu, and comprising the steps of:
- the gliflozin aglycone compound of formula I is prepared without isolating the intermediate compound of formula (II).
- the base used in step (i) is selected from the group consisting of LITMP (lithium tetramethylpiperidide), LiHMDS (lithium hexamethyldisilazide), KHMDS (potassium hxamethyldisilazide), NaHMDS (sodium hexamethyldisilazide), and LDA (lithium diisopropylamide).
- LITMP lithium tetramethylpiperidide
- LiHMDS lithium hexamethyldisilazide
- KHMDS potassium hxamethyldisilazide
- NaHMDS sodium hexamethyldisilazide
- LDA lithium diisopropylamide
- the base is LDA.
- the solvent is selected from the group consisting of toluene, ether, THF, DCE, and DCM.
- the acid is selected from Bronsted or Lewis acid; selected from the group consisting of BFsOEti, TFA, acetic acid, H2SO4, HC1, TiCL, FeCL, citric acid, benzoic acid.
- the acid is BF3OEt2.
- the reducing agent is selected from EtsSiH and McsSiH.
- the reducing agent is EtsSiH.
- the solvent used in step (ii) is selected from DCE and DCM.
- halo refers to the present invention of F, Cl, Br, and I.
- ortho-lithiation refers to the present invention removal of the proton using base by differentiating acidifying effects of protons adjacent to halogen/ortho to halogen, preferably adjacent to F and Cl.
- ortho-lithiation is carried out at lower temperatures, such as -78 °C to -10 °C and using lithium bases.
- aryl refers to the present invention as an optionally substituted aromatic ring system, preferably substituted benzene.
- heteroaryl refers to the present invention as an aryl having at least one heteroatom selected from nitrogen, oxygen or sulfur in the ring structure.
- the ring structure may be monocyclic, bicyclic or tricyclic, optionally having fused rings, such as furan, thiophene, benzothiophene, pyrrole, pyridine, bipyridine, picolylimine, y-pyran, y- thiopyran, phenanthroline, pyrimidine, bipyrimidine, pyrazine, indole, coumarone, thionaphthene, carbazole, dibenzofuran, dibenzothiophene, pyrazole, imidazole, benzimidazole, oxazole, thiazole, dithiazole, isoxazole, isothiazole, quinoline, bisquinoline, isoquinoline, bisisoquinoline, acridine, chromene, phenazine
- base refers to the present invention as an organic or inorganic base such as lithium, potassium, and sodium, selected from LITMP, LiHMDS, KHMDS, NaHMDS and LDA.
- the term “acid” refers to the present invention as Bronsted or Lewis acid selected from BF 3 OEt 2 , TFA, acetic acid, H2SO4, HC1, TiCL, FeCl 3 , citric acid, benzoic acid.
- reducing agent refers to the present invention as selected from Et 3 SiH, McsSiH, NaBH 3 , NaBH(OAc) 3 , NaBH 3 CN, H 2 in the presence of Pd/C.
- solvent refers to the present invention as selected from, but not limited to "ester solvents” such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; "ether solvents” such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), 1 ,4-dioxane and the like; “hydrocarbon solvents” such as toluene, hexane, heptane, pet ether, xylene, cyclohexane and the like; “polar aprotic solvents” such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2- pyrrolidone and the like; “ketone solvents” such as acetone, methylethyl ketone, methylisobutyl ketone
- the present invention provides a process for synthesizing the gliflozin aglycone of Formula I,
- Formula I wherein Xi and X2 are selected from halo such as Cl, Br, F & I; Ri is selected from optionally substituted aryl or heteroaryl, preferably
- Ri is selected from
- R2 is selected from Me, Et, iPr, Bu,
- N- BuLi (1.6 M in hexane, 35.91 mL, 57.45 mmol, 1.1 equiv) was added to a stirred solution of N,N- diisopropylamine (8.29 mL, 57.45 mmol, l.lequiv) in THF (57.45ml) at -78 °C under argon atmosphere, the resulting solution was stirred for 45 minutes.
- Triethyl silane (4.68 mL, 29.32 mmol, 2 equiv) was slowly added to a stirred solution of the compound of Formula (Ila) (5 g, 14.66 mmol, 1 equiv) in dry DCM at -20 °C.
- 50% wt. solution of BFs.OEti (3.65 mL, 14.66 mmol, 1 equiv) was slowly added and stirred for another 20 minutes. After completion of the reaction, it was quenched with saturated aqueous NaHCCh solution and extracted 2-3 times with DCM. Combined organic layers were washed with brine solution and dried over anhydrous sodium sulphate.
- N- BuLi (1.6 M in hexane, 3.59 mL, 5.74 mmol, 1.1 equiv) was slowly added to a stirred solution of N, N-diisopropylamine (0.79 mL, 5.74 mmol, 1.1 equiv) in THF (5.2 mL) at -78 °C under argon condition, the resulting solution was stirred for 45 minutes.
- Triethylsilane (0.66 mL, 4.17 mmol, 2 equiv) was slowly added to a stirred solution of the compound of Formula (lib) (0.8 g, 2 mmol, 1 equiv) in DCM at -20 °C.
- BFs.OEti (0.26 mL, 2 mmol, lequvi) was slowly added, and stirred for 20 minutes.
- N- BuLi (1.6 M in hexane, 2.8 mL, 4.62 mmol, l.lequiv) was added to a stirred solution of N, N-diisopropylamine (0.66 mL, 4.62 mmol, 1.1 equiv) in THF (4.2 mL) at -78 °C under argon condition, the resulting solution was stirred for 45 minutes.
- Triethylsilane (0.59 mL, 3.7 mmol, 2 equiv) was slowly added to a stirred solution of the compound of Formula (lie) (0.8 g, 1.8 mmol. 1 equiv) in DCM at -20 °C.
- BFs.OEti (0.45 mL, 1.8 mmol, 1 equiv) was slowly added, and stirred for 20 minutes. After completion of the reaction, it was quenched with saturated aq. NaHCOs solution and extracted 2-3 times with DCM. Combined organic layers were washed with brine solution, dried over anhydrous sodium sulphate, solvents were evaporated under reduced pressure.
- Triethylsilane (0.473 mL, 2.96 mmol, 2 equiv) was slowly added to a stirred solution of the compound of Formula (Hd) (0.5 g, 1.48 mmol. 1 equiv) in DCM at -20 °C.
- BF 3 .OEt2 (0.370 mL, 1.48 mmol, 1 equiv) was slowly added; and stired for 20 minutes. After completion of the reaction, it was quenched with saturated aq. NaHCO 3 solution and extracted 2-3 times with DCM. Combined organic layers were washed with brine solution, dried over anhydrous sodium sulphate, and solvents were evaporated under reduced pressure.
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Abstract
The present invention relates to a novel process for the preparation of gliflozin aglycone through a telescopic approach using ortho-lithiation of 1,4-dihalobenzene followed by reacting with corresponding aromatic or heteroaromatic aldehydes and reduction of the resulted in diarylmethanol or (aryl)(heteroaryl)methanol intermediate as key steps.
Description
A PROCESS FOR THE PREPARATION OF GLIFLOZIN AGLYCONES
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of gliflozin aglycones.
The present invention particularly relates to a process for the preparation of gliflozin aglycone through a telescopic approach using ortho-lithiation of 1,4-dihalobenzene followed by reacting with corresponding aromatic or heteroaromatic aldehydes to produce intermediates as the key step and reduction of the intermediate to obtain gliflozin aglycone.
BACKGROUND OF INVENTION
Structurally, gliflozins consist of two fragments, sugar and aglycone, and some representative gliflozins are depicted in Scheme 1, such as Dapagliflozin (1), Sotagliflozin (2), Ertugliflozin (3), Empagliflozin (4), Bexagliflozin (5), and Ipragliflozin (6) (W02010022313A2, W02009026537A1).
Scheme 1. Representative gliflozins 1-6
Generally, sugar fragment synthesis is straightforward, but aglycone’s (Formula I) synthesis is challenging and contributes substantially to the final gliflozin’s manufacturing cost. Noticeably, the synthesis of aglycone (Formula I) in a cost-effective manner directly impacts the overall production expenses. Existing synthetic routes for aglycones are lengthy and time-consuming. For example, 5-bromo-2-chloro-4'-ethoxydiphenylmethane of a
compound of Formula la (wherein Xi and X2 are selected from the group consisting of Cl, Br, F and I and Ri is selected form substituted aryl and heteroaryl groups) is a key intermediate for the preparation of several gliflozins (Scheme 1).
The prior arts, such as CN10852184A and CN107311847B, disclose the preparation of aglycone of Formula la starting from 4 -ethoxybenzaldehyde using Friedel-Crafts reaction as the key step (Scheme 2), overall in four steps.
Scheme 2.
CN 108752184 A discloses the preparation of aglycone of Formula la starting from 5-bromo- 2-chlorobenzoic acid, converting it to corresponding acyl chloride and reacting with fluorobenzene using Friedel-Crafts reaction as the key step (Scheme 3).
Scheme 3.
CN 113121476 A discloses the preparation of aglycone of Formula lb and Formula Ic using Friedel-Crafts reaction as a key step (Scheme 4).
Scheme 4.
CN108623558 A discloses the preparation of aglycone of Formula Id, involving deprotonation of heterocyclic compound (benzothiophene) using n-BuLi followed by
reacting with an aromatic aldehyde, and reduction of the resulted secondary alcohol (Scheme 5).
Scheme 5.
In addition to the above prior arts, there are prior arts such as US6414126; US6515117; US7375213; US2009/0118,201; PCT/IB2014/065726 disclose the commercially available 5-bromo-2-chlorobenzoic acid, which is first converted to 5-bromo-2-chlorobenzoyl chloride in the presence of oxalyl chloride. The subsequent, Friedel-Crafts acylation of phenetole with 5-bromo-2-chlorobenzoyl chloride furnished a mixture of regioisomers (7:1), and the required p-benzophenone is the major (J. Med. Chem. 2008, 51, 1145). Then, this p-benzophenone derivative was subjected to reduction to provide an aglycone of Formula la (Scheme 6). This synthesis involves three steps with only a 40% overall yield. Further, the Friedel-Crafts reaction generates unwanted by-products, and temperature fluctuations during the keto functionality reduction step; an acetonitrile addition is also observed, resulting in an impurity, A-acetyl-5-bromo-2-chloro-4’- ethoxydiphenylmethylamine (US 6,515,117; PCT/IB2014/065726).
Scheme 6. Synthesis of la from 5-bromo-2-chlorobenzoic acid
Another approach is to use O-methyl aniline as the starting material through bromination, diazonium chlorination, benzyl chlorination, and alkylation (Scheme 7). The process route benzylation uses AIBN, which will produce highly toxic cyanide during the reaction process, causing severe pollution and a lengthy approach, such as patent CN104478670.
Scheme 7.
In general, prior arts suggest that Friedel-Crafts acylation is a key step for synthesizing gliflozin aglycone (Formula I). It may lead to a mixture of regioisomers, low yield, lengthy steps, unwanted by-products, and toxicity. Further, the method disclosed in the prior art CN108623558 is confined to only the deprotonation of benzothiophene using n-BuLi. Therefore, synthesizing the gliflozin aglycone of Formula I in a shorter, general, safer, and economically viable synthetic route is preferred, which would intensely reduce the gliflozin's production cost.
Other references may be made to patent applications, US 7,772,191; W02006/ 120,208; US7,662,790; US 8,283,454; WO2013/152,654; US8,802,842; US9,193,751, US2005/ 233,988; W02004/080,990; W02005/012,326; W02009/022,010; CN107163092 A; WO2022116507 Al; IN2013CH06139 A; CN114380775 A; CN109456315 A; CN108276396 A; CN105481915 A; CN113121476A; CN108623558A; and research publications, J. Med. Chem. 2014, 57, 1236; and Org. Lett., 2014, 16,4090, which disclose the synthesis of other aglycones of Formula I following a similar synthetic sequence, mainly using Friedel-Crafts reaction as an inevitable step, as shown for the compound of Formula la (Scheme 6).
Therefore, synthesizing the gliflozin aglycone of Formula I in a shorter, safer, and economically viable synthetic route would intensely reduce gliflozin’s production cost.
OBJECTIVES OF THE INVENTION
In order to overcome these limitations described in the prior art, the main aim of the present invention is to provide a cost-effective, scalable process in a reduced number of steps for the preparation of the gliflozin aglycone of Formula I, which serves as a key intermediate for the synthesis of several gliflozins.
The main objective of the present invention is to provide gliflozin aglycone through ortho- lithiation of 1,4-dihalobenzene, followed by reacting with corresponding aromatic or heteroaromatic aldehydes and reduction of the resulted intermediate (Formula II).
Yet another objective is to provide gliflozin aglycone through a telescopic approach using ortho-lithiation of 1,4-dihalobenzene followed by reacting with aromatic or heteroaromatic aldehydes and reduction of the intermediate to yield gliflozin aglycone.
SUMMARY OF THE INVENTION Accordingly, the present invention provides a process for preparation of gliflozin aglycones compound of formula I,
Formula I wherein Xi and X2 are selected from the group consisting of Cl, Br, F and I; and
Ri is selected from
and
^--0 where R2 is selected from the group consisting of Me, Et, iPr, Bu, and
comprising the steps of:
(i) ortho-lithiation of 1,4-dihalobenzene (10) using a base and a solvent followed by reacting with an aldehyde of formula Ri-CHO (11), wherein Ri is selected from
to obtain the intermediate compound of formula II, wherein Xi, X2 and Ri are as defined above;
Formula II
(ii) reduction of the intermediate of Formula II using a reducing agent in the presence of an acid and a solvent to obtain gliflozin aglycone formula I,
Formula II Formula I wherein Xi, X2 and Ri are as defined above.
In an embodiment of the present invention, the gliflozin aglycone compound of formula I is prepared without isolating the intermediate compound of formula (II).
In an embodiment of the present invention, the base used in step (i) is selected from the group consisting of LITMP (lithium tetramethylpiperidide), LiHMDS (lithium hexamethyldisilazide), KHMDS (potassium hxamethyldisilazide), NaHMDS (sodium hexamethyldisilazide), and LDA (lithium diisopropylamide).
In a preferred embodiment of the present invention, the base is LDA.
In an embodiment of the present invention, the solvent is selected from the group consisting of toluene, ether, THF, DCE, and DCM.
In an embodiment of the present invention, the acid is selected from Bronsted or Lewis acid; selected from the group consisting of BFsOEti, TFA, acetic acid, H2SO4, HC1, TiCL, FeCL, citric acid, benzoic acid.
In a preferred embodiment of the present invention, the acid is BF3OEt2.
In an embodiment of the present invention, the reducing agent is selected from EtsSiH and McsSiH.
In a preferred embodiment of the present invention, the reducing agent is EtsSiH.
In a preferred embodiment the solvent used in step (ii) is selected from DCE and DCM.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
The term “halo” refers to the present invention of F, Cl, Br, and I.
The term “ortho-lithiation” refers to the present invention removal of the proton using base by differentiating acidifying effects of protons adjacent to halogen/ortho to halogen, preferably adjacent to F and Cl. In general, ortho-lithiation is carried out at lower temperatures, such as -78 °C to -10 °C and using lithium bases.
The term “aryl” refers to the present invention as an optionally substituted aromatic ring system, preferably substituted benzene.
The term “heteroaryl” refers to the present invention as an aryl having at least one heteroatom selected from nitrogen, oxygen or sulfur in the ring structure. The ring structure may be monocyclic, bicyclic or tricyclic, optionally having fused rings, such as furan, thiophene, benzothiophene, pyrrole, pyridine, bipyridine, picolylimine, y-pyran, y- thiopyran, phenanthroline, pyrimidine, bipyrimidine, pyrazine, indole, coumarone, thionaphthene, carbazole, dibenzofuran, dibenzothiophene, pyrazole, imidazole, benzimidazole, oxazole, thiazole, dithiazole, isoxazole, isothiazole, quinoline, bisquinoline, isoquinoline, bisisoquinoline, acridine, chromene, phenazine, phenoxazine, phenothiazine, triazine, thianthrene, purine, bisimidazole and bisoxazole.
The term “substituted” as used herein refers to substitution with any one or any combination of the following substituents: fluorine, chlorine, bromine and iodine; hydroxy; nitro; cyano; oxo (=0); thioxo (=S); azido; nitroso; amino; hydrazino; formyl; alkyl; alkoxy; aryl; haloalkyl groups such as trifluoromethyl, tribromomethyl and trichloromethyl; haloalkoxy groups such as -OCH2CI, -OCHF2 and -OCF3; arylalkoxy groups such as benzyloxy and phenylethoxy; cycloalkyl; -O-cycloalkyl; aryl; alkoxy; heterocyclyl; heteroaryl; alkylamino; -O-CH2-cycloalkyl; -C00Ra; -C(0)Rb; -C(S)Ra; -C(0)NRaRb; - NRaC(0)NRbRc; -N(Ra)SORb; -N(Ra)SO2Rb; -NRaC(0)0Rb; -NRaRb; -NRaC(0)Rb-; NRaC(S)Rb-; -SONRaRb-; -SO2NRaRb; -ORa; -0RaC(0)0Rb-; -0C(0)NRaRb; 0C(0)Ra; - 0C(0)NRaRb-; -RaNRbRc; -Ra0Rb-; -SRa; -SORa and -SO2Ra; Ra, Rb and Rc each independently represents hydrogen atom; substituted or unsubstituted groups selected from alkyl; aryl; arylalkyl; cycloalkyl; heterocyclyl; heteroaryl and hetero arylalkyl; Ra, Rb and Rc are also combined to form a 3-7 membered ring having 0-2 hetero atoms.
The term “alkoxy” refers to the present invention -O-alkyl group, alkyl group refers to optionally substituted Cl-10 straight or branched alkyl group and aliphatic heterocyclic compounds
The term “base” refers to the present invention as an organic or inorganic base such as lithium, potassium, and sodium, selected from LITMP, LiHMDS, KHMDS, NaHMDS and LDA.
The term “acid” refers to the present invention as Bronsted or Lewis acid selected from BF3OEt2, TFA, acetic acid, H2SO4, HC1, TiCL, FeCl3, citric acid, benzoic acid.
The term “reducing agent” refers to the present invention as selected from Et3SiH, McsSiH, NaBH3, NaBH(OAc)3, NaBH3CN, H2 in the presence of Pd/C.
The term “solvent” refers to the present invention as selected from, but not limited to "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; "ether solvents" such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), 1 ,4-dioxane and the like; "hydrocarbon solvents" such as toluene, hexane, heptane, pet ether, xylene, cyclohexane and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2- pyrrolidone and the like; "ketone solvents" such as acetone, methylethyl ketone, methylisobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "chloro solvents" such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; "nitrile solvents" such as acetonitrile, butyronitrile, isobutyronitrile and the like; "polar solvent" such as water or mixtures thereof.
The present invention provides a process for synthesizing the gliflozin aglycone of Formula I,
Formula I , wherein Xi and X2 are selected from halo such as Cl, Br, F & I; Ri is selected from optionally substituted aryl or heteroaryl, preferably
(i) ortho-lithiation of 1,4-dihalobenzene (10) using the base and suitable solvents followed by reacting with corresponding aromatic or heteroaromatic aldehyde (11) to obtain the corresponding diarylmethanol or (aryl)(heteroaryl)methanol intermediates of compound of formula II.
Formula II
(ii) reduction of the resulted in diarylmethanol or (aryl)(heteroaryl)methanol intermediate of Formula II (obtained from step-i) using reducing agents in the presence of acid in suitable solvents to obtain gliflozin aglycone of formula I. reducing agent acid
Formula II
In an embodiment of the present invention, the resulted in diarylmethanol or
(aryl)(heteroaryl)methanol intermediate compound of formula II (obtained from step -i) was reduced using reducing agents in the presence of acid in suitable solvents to obtain gliflozin
aglycone of formula I in a telescopic approach, without isolating the compound of Formula
II.
Formula II
In a preferred embodiment of the present invention, Ri is selected from
In a preferred embodiment of the present invention R2 is selected from Me, Et, iPr, Bu,
The specific embodiment of the process is represented as follows in Scheme 8.
Scheme 8
EXAMPLES:
1. 4-Bromo-l-chloro-2-(4-ethoxybenzyl) benzene (la):
N- BuLi (1.6 M in hexane, 35.91 mL, 57.45 mmol, 1.1 equiv) was added to a stirred solution of N,N- diisopropylamine (8.29 mL, 57.45 mmol, l.lequiv) in THF (57.45ml) at -78 °C under argon atmosphere, the resulting solution was stirred for 45 minutes. l-Bromo-4- chlorobenzene (10a) (10 g, 52.23 mmol, lequiv) in THF (100 mL) was slowly canulated and stirred for 45 minutes. Then, 4-ethoxybenzaldehyde (Ila) (8.77 mL, 62 mmol, 1.2 equiv) in dry THF (65 mL) was slowly cannulated to the reaction mixture, and stirred for 5 h at -78 °C. After completion of the reaction, it was quenched with aqueous NH4CI solution, extracted with EtOAc, washed with brine solution, and dried over anhydrous sodium sulphate. Organic solvents were evaporated under reduced pressure. The resulting crude oil was purified by silica gel to get a compound Ha (14 grams 78%) as a white solid. 'H NMR (400 MHz, CDCh): d 7.89 (d, J = 2.5, 0.5H), 7.72 (d, J = 2.5, 0.5H), 7.46 (d, J = 8.45, 0.5H), 7.36 (dd, J = 10.92, 8.45, 0.5H), 7.32 - 7.25 (m, 2H), 7.20 (d, J = 8.45, 0.5H), 7.15 (dd, J = 10.92, 8.45, 0.5H), 6.95 - 6.85 (m, 2H), 6.07 (d, J = 13.61, 1H), 4.04 (q, J = 7.0, 2H), 2.32 (brs, 1H)1.43 (t, J = 7.0, 3H). 13C NMR (125 MHz, CDCh): <5 158.8, 144.4,
143.1, 133.9, 133.5, 133.4, 131.5, 131.2, 130.9, 130.6, 128.9, 128.6, 128.4, 128.2, 120.9,
120.2, 114.5, 74.3, 72.2, 63.4, 14.8. IR (neat): vmax 3357, 2977, 2929, 1609, 1508, 1455, 1390, 1240, 1172, 1092, 1044, 1018, 922, 897, 807, 755, 739, 645, 628, 597, 581. HRMS (ESI) m/z calculated for C15H13B1 IO2 [M-H] +: Calcd 338.9787, found 338.9776.
Triethyl silane (4.68 mL, 29.32 mmol, 2 equiv) was slowly added to a stirred solution of the compound of Formula (Ila) (5 g, 14.66 mmol, 1 equiv) in dry DCM at -20 °C. Followed by 50% wt. solution of BFs.OEti (3.65 mL, 14.66 mmol, 1 equiv) was slowly added and stirred for another 20 minutes. After completion of the reaction, it was quenched with saturated aqueous NaHCCh solution and extracted 2-3 times with DCM. Combined organic layers were washed with brine solution and dried over anhydrous sodium sulphate.
Solvents were evaporated under reduced pressure, and the resulting crude was purified by silica gel to get a compound la (4 g 84%) as a white solid. 'H NMR (500 MHz, CDCh): d 7.32 - 7.22 (m, 3H), 7.11 (d, J = 8.7, 2H), 6.87 (d, J = 8.7, 2H), 4.04 (q, J = 7.05, 2H), 4.01 (s, 2H), 1.43 (t, J = 7.05, 3H); 13C NMR (125 MHz, CDCh): <5 157.6, 141.3,133.5, 133.1, 130.9, 130.5, 130.4, 130.0, 120.4, 114.6, 63.4, 38.2, 14.9; IR (neat): vmax 2979, 2927, 1885, 1611, 1508, 1462, 1389, 1299, 1238, 1175, 1042, 918, 806, 772, 691, 613; HRMS (ESI) m/z calculated for CisHnBrClO [M-H] +: 322.9838 found 322.9827.
2. (S)-3-(4-(5-Bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran (lb):
N- BuLi (1.6 M in hexane, 3.59 mL, 5.74 mmol, 1.1 equiv) was slowly added to a stirred solution of N, N-diisopropylamine (0.79 mL, 5.74 mmol, 1.1 equiv) in THF (5.2 mL) at -78 °C under argon condition, the resulting solution was stirred for 45 minutes. l-Bromo-4- chlorobenzene 10a (1g, 5.22 mmol, 1 equiv) in THF (10 mL) was slowly canulated and stirred for 45 minutes, (S)-4-((tetrahydrofuran-3-yl) oxy) benzaldehyde (11b) (1.20 g, 6.26 mmol, 1.2 equiv) in THF (6 mL) was slowly cannulated to the reaction mixture, and stirred for 5 h at -78 °C. After completion of the reaction, it was quenched with aqueous NH4CI solution, extracted with EtOAc, washed with brine solution, dried over anhydrous sodium sulphate, solvents were evaporated under reduced pressure. The resulting crude oil was purified by silica gel to get a compound lib in (1.34 g, 67%) as a colorless oil.
Triethylsilane (0.66 mL, 4.17 mmol, 2 equiv) was slowly added to a stirred solution of the compound of Formula (lib) (0.8 g, 2 mmol, 1 equiv) in DCM at -20 °C. Followed by BFs.OEti (0.26 mL, 2 mmol, lequvi) was slowly added, and stirred for 20 minutes. After completion of the reaction was quenched with saturated aq. NaHCOs solution and extracted 2-3 times with DCM. Combined organic layers were washed with brine solution, dried over anhydrous sodium sulphate. Solvents were evaporated under reduced pressure. The resulting crude was purified by silica gel to get a compound lb in (0.5 g, 65%) as a white solid.
'H NMR (400 MHz, CDCh): <5 7.23-7.20 (m, 1H),7.19-7.14 (m, 2H) 7.02 (d, J = 8.52 Hz, 2H), 6.74 (d, J = 8.52 Hz, 2H), 4.86-4.80 (m, 1H), 3.95-3.87 (m, 5H), 3.86-3.79 (m, 1H), 2.15-2.03 (m, 2H); 13C NMR (125 MHz, CDCh): <5 156.1, 141.2, 133.5, 133.1,130.9, 130.6, 130.0, 120.49, 115.5, 73.17, 67.2, 38.2, 33.05; IR (neat): Vmax 2927, 2859, 1611, 1508, 1383, 1240, 1179, 1089, 813, 689, 646.
3. (S)-3-(4-(2-Chloro-5-iodobenzyl)phenoxy)tetrahydrofuran (Iba):
N- BuLi (1.6 M in hexane, 2.8 mL, 4.62 mmol, l.lequiv) was added to a stirred solution of N, N-diisopropylamine (0.66 mL, 4.62 mmol, 1.1 equiv) in THF (4.2 mL) at -78 °C under argon condition, the resulting solution was stirred for 45 minutes. 1- Chloro-4-iodobenzene 10b (1 g, 4.20 mmol, 1 equiv) in THF (8 mL) was slowly canulated and stirred for 45 minutes, (S)-4-((tetrahydrofuran-3-yl)oxy) benzaldehyde 11b (0.96 g, 5.04 mmol, 1.2 equiv) in THF (6 mL) was slowly cannulated to the reaction mixture, and stirred for 5 h at -78 °C. After completion of the reaction, it was quenched with aqueous NH4CI solution, extracted with EtOAc, washed with brine solution, dried over anhydrous sodium sulphate, solvents were evaporated under reduced pressure. The resulting crude oil was purified by silica gel to get the compound lie in (1.34 g, 74%) as a yellow oil.
Triethylsilane (0.59 mL, 3.7 mmol, 2 equiv) was slowly added to a stirred solution of the compound of Formula (lie) (0.8 g, 1.8 mmol. 1 equiv) in DCM at -20 °C. Followed by BFs.OEti (0.45 mL, 1.8 mmol, 1 equiv) was slowly added, and stirred for 20 minutes. After completion of the reaction, it was quenched with saturated aq. NaHCOs solution and extracted 2-3 times with DCM. Combined organic layers were washed with brine solution, dried over anhydrous sodium sulphate, solvents were evaporated under reduced pressure. The resulting crude was purified by silica gel to get a compound of Formula Ic in (0.5 g 65%) as a white solid.
'H NMR (400 MHz, CDCh): <5 7.23 (m, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.07 (m, 1H), 6.79 (d, J = 8.8 Hz, 2H), 4.88 (m, 1H), 4.00-3.94 (m, 5H), 3.91-3.85(m, 1H), 2.22-2.10 (m, 2H); 13C NMR (400 MHz, CDCh): <5 156.1, 141.4, 139.6, 136.6,134.2, 131.2, 131.0, 130.0, 115.5, 91.6, 77.3, 73.1, 67.2, 38.0, 33.0; IR (neat): Vmax 2922, 2853, 1610, 1508, 1507, 1460, 1379, 1300, 1238, 1176, 1076, 1043, 995, 815, 807, 611, 564.
4. 2-(5-Bromo-2-fluorobenzyl)benzo[b]thiophene (Id) :
nBuLi (1.6 M in hexane, 3.92 mL, 6.28 mmol, 1.1 equiv) was slowly added to a stirred solution of N,N-diisopropylamine (0.90 mL, 6.28 mmol, 1.1 equiv) in THF (5.7 mL) at -78 °C under argon condition, the resulting solution was stirred for 45 minutes. 4- Bromofluorobenzene 10c (1 g, 5.71 mmol, 1 equiv) in THF (10 mL) was slowly canulated and stirred for 45 minutes, benzo thiophene-2-carbaldehyde 11c (1 g, 6.82 mmol, 1.1 equiv) in THF (6 mL) was slowly cannulated to the reaction mixture, and stirred for 5 h at -78 °C. After completion of the reaction, it was quenched with aqueous NH4CI solution, extracted with EtOAc, washed with brine solution, dried over anhydrous sodium sulphate, solvents were evaporated under reduced pressure. The resulting crude oil was purified by silica gel to get a compound lid in (1.3 g, 67.75%) as a yellow oil.
'H NMR (400 MHz, CDCh): <5 7.84 - 7.78 (m, 2H), 7.75 - 7.71(m, 1H), 7.48 - 7.42 (m, 1H), 7.39 - 7.30 (m, 2H), 7.20 (s, 1H), 7.02, - 6.94 (m, 1H), 6.41 (s, 1H), 2.57 (brs, 1H); 13C NMR (125 MHz, CDCh): <5 160.0, 157.5, 146.4, 139.7, 139.2, 132.6, 132.5, 132.0, 131.8, 130.5, 130.5, 124.5, 124.4, 123.8, 122.4, 121.5, 117.4, 117.2, 117.19, 66.5, 66.4; IR (neat): Vmax3358, 2921, 2851, 1711, 1478, 1338, 1247, 1166, 1108, 1013, 938, 814, 744, 725, 615, 556; HRMS (ESI) m/z calculated for Ci5Hi3BrC10 [M-H] +: 344.9541 found 344.9536.
Triethylsilane (0.473 mL, 2.96 mmol, 2 equiv) was slowly added to a stirred solution of the compound of Formula (Hd) (0.5 g, 1.48 mmol. 1 equiv) in DCM at -20 °C. Followed by BF3.OEt2 (0.370 mL, 1.48 mmol, 1 equiv) was slowly added; and stired for 20 minutes. After completion of the reaction, it was quenched with saturated aq. NaHCO3 solution and
extracted 2-3 times with DCM. Combined organic layers were washed with brine solution, dried over anhydrous sodium sulphate, and solvents were evaporated under reduced pressure. The resulting crude oil was purified by silica gel to get a compound Id in (0.31 g, 65%) as a yellow liquid. 'H NMR (400 MHz, CDCh): <57.64 (d, J = 8.00 Hz, 1H), 7.54 (d, J = 8.00 Hz, 1H), 7.28 - 7.07 (m, 4H), 6.89 (s, 1H), 6.81 (t, J = 9.0 Hz, 1H), 4.05 (s, 2H); 13C NMR (125 MHz, CDCh): <5 160.8, 158.9, 147.4, 139.8, 139.4, 129.87, 129.8, 129.7, 127.7, 127.7, 124.5, 124.5, 124.3, 123.7, 122.4, 121.2, 115.6, 115.5, 67.06, 67.03; IR (neat): vmax 3057, 2919, 2849, 1576, 1480, 1433, 1308, 1234, 1171, 1110, 1014, 857, 810, 723, 653, 618, 591, 557.MS (FAB) m/z: 322 (M+H)+, calcd for CioHisBrFS: 321.
ADVANTAGES OF THE INVENTION
The advantages of the present invention are given below.
1. An efficient and shorter route for synthesizing gliflozin aglycone. 2. Telescopic approach of gliflozin aglycones through addition and reduction.
3. Operationally simple and amenable to scaling up.
4. The purification and/or isolation are straightforward.
Claims
1. A process for preparation of gliflozin aglycones compound of formula I,
Formula I wherein Xi and X2 are selected from the group consisting of Cl, Br, F and I;
RI is selected from
^0 where R2 is selected from the group consisting of Me, Et, iPr, Bu, and
comprising the steps of:
(iii) ortho-lithiation of 1,4-dihalobenzene (10) using a base and a solvent followed by reacting with an aldehyde of formula R1-CH0 (11), wherein Ri is selected
to obtain the intermediate compound of formula II, wherein Xi, X2 and Ri are as defined above;
(iv) reduction of the intermediate of Formula II using a reducing agent in the presence of an acid and a solvent to obtain gliflozin aglycone formula I. reducing agent acid
Formula I
2. The process as claimed in claim 1, wherein the gliflozin aglycone compound of formula I is prepared without isolating the intermediate compound of formula (II).
3. The process claimed in claim 1, wherein the base is selected from the group consisting of LITMP (lithium tetramethylpiperidide), LiHMDS (lithium hexamethyldisilazide), KHMDS (potassium hexamethyldisilazide), NaHMDS (sodium hexamethyldisilazide), and LDA (lithium diisopropylamide).
4. The process claimed in claim 1, wherein the base is LDA.
5. The process claimed in claim 1, wherein the solvent used in step (i) is selected from the group consisting of toluene, ether and THF.
6. The process as claimed in claim 1, wherein the acid is selected from Bronsted or
Lewis acid; selected from the group consisting of BFsOEti, TFA, acetic acid, H2SO4, HC1, TiCL, FeCL, citric acid, benzoic acid.
7. The process as claimed in claim 1, wherein the acid is BFsOEti.
8. The process as claimed in claim 1, wherein the reducing agent is selected from EtsSiH and MesSiH.
9. The process as claimed in claim 1, wherein the reducing agent is EtsSiH.
10. The process claimed in claim 1, wherein the solvent used in step (ii) is selected from
DCE and DCM.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160280619A1 (en) * | 2013-10-31 | 2016-09-29 | Sun Pharmaceutical Industries Limited | Process for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene |
| WO2018142422A1 (en) * | 2017-02-02 | 2018-08-09 | Indoco Remedies Limited | Process for the preparation of dapagliflozin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160280619A1 (en) * | 2013-10-31 | 2016-09-29 | Sun Pharmaceutical Industries Limited | Process for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene |
| WO2018142422A1 (en) * | 2017-02-02 | 2018-08-09 | Indoco Remedies Limited | Process for the preparation of dapagliflozin |
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