FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of intermediate of dapagliflozin, a SGLT2 inhibitor used for the treatment of diabetes. The present invention further relates to process for the preparation of dapagliflozin.

BACKGROUND OF THE INVENTION

Approximately 100 million people worldwide suffer from type II diabetes (NIDDM), which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes for which are still unknown. Hyperglycemia is considered to be the major risk factor for the development of diabetic complications, and is likely to contribute directly to the impairment of insulin secretion seen in advanced NIDDM. Normalization of plasma glucose in NIDDM patients would be predicted to improve insulin action, and to offset the development of diabetic complications. An inhibitor of the sodium-dependent glucose transporter SGLT2 in the kidney would be expected to aid in the normalization of plasma glucose levels, and perhaps body weight, by enhancing glucose excretion.

The development of novel, safe, and orally active antidiabetic agents is also desired in order to complement existing therapies, including the sulfonylureas, thiazolidinediones, metformin, and insulin, and to avoid the potential side effects associated with the use of these other agents.

Ninety percent of glucose reuptake in the kidney occurs in the epithelial cells of the early SI segment of the renal cortical proximal tubule, and SGLT2 is likely to be the major transporter responsible for this reuptake. SGLT2 is a 672 amino acid protein containing 14 membrane-spanning segments that is predominantly expressed in the early S1 segment of the renal proximal tubules. The substrate specificity, sodium dependence, and localization of SGLT2 are consistent with the properties of the high capacity, low affinity, sodium-dependent glucose transporter previously characterized in human
cortical kidney proximal tubules. In addition, hybrid depletion studies implicate SGLT2 as the predominant Na.sup. + / glucose co-transporter in the S1 segment of the proximal tubule, since virtually all Na-dependent glucose transport activity encoded in mRNA from rat kidney cortex is inhibited by an antisense oligonucleotide specific to rat SGLT2. SGLT2 is a candidate gene for some forms of familial glucosuria, a genetic abnormality in which renal glucose reabsorption is impaired to varying degrees. None of these syndromes investigated to date map to the SGLT2 locus on chromosome 16. However, the studies of highly homologous rodent SGLTs strongly implicate SGLT2 as the major renal sodium-dependent transporter of glucose and suggest that the glucosuria locus that has been mapped encodes an SGLT2 regulator. Inhibition of SGLT2 would be predicted to reduce plasma glucose levels via enhanced glucose excretion in diabetic patients.

SGLT1, another Na-dependent glucose co-transporter that is 60% identical to SGLT2 at the amino acid level, is expressed in the small intestine and in the more distal S3 segment of the renal proximal tubule. Despite their sequence similarities, human SGLT1 and SGLT2 are biochemically distinguishable. For SGLT1, the molar ratio of Na.sup.+ to glucose transported is 2:1, whereas for SGLT2, the ratio is 1:1. The K.sub.m for Na.sup.+ is 32 and 250-300 mM for SGLT1 and SGLT2, respectively. K.sub.m values for uptake of glucose and the nonmetabolizable glucose analog .alpha.-methyl-D-glucopyranoside (AMG) are similar for SGLT1 and SGLT2, i.e. 0.8 and 1.6 mM (glucose) and 0.4 and 1.6 mM (AMG) for SGLT1 and SGLT2 transporters, respectively. However, the two transporters do vary in their substrate specificities for sugars such as galactose, which is a substrate for SGLT1 only.

Administration of phlorizin, a specific inhibitor of SGLT activity, provided proof of concept in vivo by promoting glucose excretion, lowering fasting and fed plasma glucose, and promoting glucose utilization without hypoglycemic side effects in several diabetic rodent models and in one canine diabetes model. No adverse effects on plasma ion balance, renal function or renal morphology have been observed as a consequence of phlorizin treatment for as long as two weeks. In addition, no hypoglycemic or other adverse effects have been observed when phlorizin is administered to normal animals,
despite the presence of glycosuria. Administration of an inhibitor of renal SGLTs for a 6-month period (Tanabe Seiyaku) was reported to improve fasting and fed plasma glucose, improve insulin secretion and utilization in obese NIDDM rat models, and offset the development of nephropathy and neuropathy in the absence of hypoglycemic or renal side effects.

Phlorizin itself is unattractive as an oral drug since it is a nonspecific SGLT1/SGLT2 inhibitor and hydrolyzed in the gut to its aglycone phloretin, which is a potent inhibitor of facilitated glucose transport. Concurrent inhibition of facilitative glucose transporters (GLUTs) is undesirable since such inhibitors would be predicted to exacerbate peripheral insulin resistance as well as promote hypoglycemia in the CNS. Inhibition of SGLT1 could also have serious adverse consequences as is illustrated by the hereditary syndrome glucose/galactose malabsorption (GGM), in which mutations in the SGLT1 co-transporter result in impaired glucose uptake in the intestine, and life-threatening diarrhea and dehydration. The biochemical differences between SGLT2 and SGLT1, as well as the degree of sequence divergence between them, allow for identification of selective SGLT2 inhibitors.

The following references disclose C-aryl glucosides SGLT2 inhibitors for treating diabetes.

WO 01/27128 discloses compounds of the structure where A is O, S, NH, or (CH2)n where n is 0-3; R1, R2 and R2a are independently

hydrogen, OH, OR5, alkyl, CF3, OCHF2, OCF3, SR5i or halogen, etc; R3 and R are independently hydrogen, OH, OR5a, Aryl, OCH2, Aryl, alkyl, cycloalkyl, CF3, --OCHF2, --OCF3, halogen, etc. These compounds are reported to be inhibitors of the SGLT2 transporter and consequently represent a mode for treatment of diabetes and complications thereof. WO 98/31697 discloses compounds of the structure
Where Ar includes, among others, phenyl, biphenyl, diphenylmethane, diphenylethane, and diphenylether, and R1 is a glycoside, R2 is H, OH, amino, halogen, carboxy, alkyl, cycloalkyl, or carboxamido, and R is hydrogen, alkyl, or acyl, and k, m, and n are independently 1-4. A subset of compounds disclosed in WO 98/31697 contains compounds of the following structures which are disclosed for use in the treatment or prevention of inflammatory diseases, autoimmune diseases, infections, cancer, and cancer metastasis, reperfusion disorders, thrombosis, ulcer, wounds, osteoporosis, diabetes mellitus and atherosclerosis, among others.

The process for the preparation of dapagliflozin is disclosed in J. Med. Chem. 2008, 51, 1145-1149 represented by Scheme 1 below (Scheme 1).

The first step of Scheme 1 was involved preparation of key intermediate 3. Accordingly, compound 1 was converted to the corresponding acid chloride and used for the Friedel-
Crafts acylation of arylether 2 to afford 3. This two-step method however, involved the use of excess A1C13 and led to the formation of environmentally harmful gaseous HC1.
Moreover, this protocol involved i) the cumbersome preparation of moisture-sensitive arylacetyl chloride, ii) the use of large volume of chlorinated solvent and iii) the generation of aluminium waste that need to be disposed. Additionally, in our hand the second step i.e. Et3SiH-mediated reduction of ketone 3 to compound 4 provided variable yields of product. Thus, there is still a need for an efficient, cost effective process for the preparation of dapagliflozin which is industrially feasible.

SUMMARY OF THE INVENTION

The main aspect of the invention relates to an improved process for the preparation of intermediate of Dapagliflozin. The present invention further relates to the process for the preparation of Dapagliflozin.

In one aspect the present invention relates to process for the preparation of benzophenone derivative, an intermediate of Dapagliflozin using a mixture of trifluoro acetic anhydride and inorganic acid optionally in presence of a suitable solvent which is further reduced using conventional reducing agents in presence of aluminium chloride. The reduced intermediate is further converted to Dapagliflozin.

DETAIL DESCRIPTION OF THE INVENTION

The present invention relates to an improved and efficient process for the preparation of compound of formula 5, an intermediate of Dapagliflozin. The present invention further relates to the process for the preparation of Dapagliflozin.

In one embodiment, the present invention relates to a process for the preparation of compound of formula 3, an intermediate of Dapagliflozin using a mixture of trifluoro acetic anhydride and inorganic acid which is further reduced using conventional reducing agents in presence of aluminium chloride to afford compound of formula 5.

In another embodiment, the present invention relates to process for the preparation of compound of formula 3, an intermediate of dapagliflozin, comprising the steps of:

a) reacting compound of formula 1 with compound of formula 2 using trifluoro
acetic anhydride and inorganic acid optionally in presence of a suitable solvent to
give compound of formula 3

b) Compound of formula 3 is then reduced to give compound of formula 5.

According to the present invention, the compound of formula 1 is reacted with compound of formula 2 in presence of trifluoroacetic anhydride and inorganic acid such as phosphoric acid optionally in presence of a solvent such as acetonitrile, tetrahydrofuran, 1,4 dioxane and the like. The reaction is carried out at 0° C to 60° C. The carbonyl group of compound of formula 3 is then reduced using conventional reducing agents such as sodium borohydride in presence of aluminium chloride and suitable solvent such as 1,4 dioxane, ether, tetrahydrofurn and the like to give compound of formula 5.

In yet another embodiment, the present invention related to process for the preparation of
Dapagliflozin.

In yet another embodiment, the process for preparation of dapagliflozin is represented by scheme 2 below.

The advantages of the present invention include:

1. The use of oxalyl chloride, aluminium chloride and a chlorinated hydrocarbon in the step 1 has been eliminated. The excess of TFAA and TFA (trifluoroacetic acid produced during the reaction) can be removed by distillation that allows the recovery of spent TFAA as TFA. Trifluoroacetic acid can be converted back to TFAA via dehydration thereby eliminating the acid waste.

2. The use of chlorinated solvent has been avoided in step 2. The use of flammable and irritant liquids such as triethylsilane and boron trifluoride etherate was replaced by less expensive reagents e.g. sodium borohydride and aluminum chloride. Being solids these reagents are easy to handle especially in large scale preparations.

The invention is described by the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention

EXAMPLES:

Preparation of 5-bromo-2-chloro-4'-ethoxybenzophenone (3)

Trifluoroacetic anhydride (TFAA) (12.83 mmol, 4 equiv) was added to 5-bromo-2-chloro benzoic acid 1 (3.2 mmol) at 0 °C. The mixture was stirred at room temperature and after 20 min all the solids were dissolved. After stirred for additional 20 min, phenetole 2 (3.52 mmol, 1.1 equiv) was added. To this mixture was added 85 % phosphoric acid (H3PO4) (0.59 mmol, 0.18 equiv) dropwise over a period of 20 min. The mixture was then stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC) the excess of trifluoroacetic acid/ Trifluoroacetic anhydride was distilled out at atmospheric pressure. The residual liquid was partitioned between chloroform (30 mL) and water (25 mL). The organic layer was separated, washed with 5% sodium hydroxide followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated to give the crude title compound. The crude product (0 and p isomers) was purified by column chromatography using 0.5% ethylacetatem-hexane;1H NMR (400 MHz, CDC13) δ 7.76 (d, y = 8.8 Hz, 2H), 7.53 (dd, J= 2.2 Hz, 8.4 Hz, 1H), 7.48 (d, J= 2.2 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.93 (d, J= 8.8 Hz, 2H), 4.11 (q, J= 7.0 Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H); 13C NMR (400 MHz, CDC13) δ 191.9, 163.8, 140.7, 133.6, 132.5, 131.5, 131.4, 130.1, 128.6, 120.4, 114.4, 63.9, 14.6; MS (ESI) m/z 339 (M+l); HRMS Calcd for C15H,3BrC102(M+H)+: 338.9787; Found 338.9787.

Preparation of 5-bromo-2-chloro-4'-ethoxydiphenylmethane (5)

A mixture ot 5-bromo-2-chloro-4 -ethoxybenzophenone 3 (2.7 mmol), sodium borohydride (NaBH4) (13.4 mmol), and anhydrous aluminium chloride (A lCl3) (7.4 mmol) in dry 1,4-dioxane (25 mL) was heated to reflux for 5 hours. The mixture was then cooled and diluted with water (10 mL) to give two clear phases. The whole mixture was extracted with ethylacetate (4 x 50 mL). The organic layers were collected, combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography using 0.25% ethylacetate:n-hexane to give the title compound;1H NMR (400 MHz, CDC13) δ 7.20-7.29 (m, 3H), 7.08 (d, J = 8.8 Hz, 2H), 6.83 (d, J= 8.8 Hz, 2H), 4.00 (q, J= 7.0 Hz, 2H), 3.96 (s, 2H), 1.40 (t, J = 7.0 Hz, 3H); 13C NMR (400 MHz, CDC13) δ 157.7, 141.3, 133.5, 133.1, 130.8, 130.5, 130.4, 129.9, 120.4, 114.6, 63.4, 38.2, 14.9.

Preparation of 2,3,4,6-tetra-O-trimethylsilyl- β-D-glucolactone (6)

To a stirred solution of gluconolactone (13 mmol) and ,N-methylmorpholine (107 mmol) at -5 °C in tetrahydrofuran (THF) under nitrogen (N2) atmosphere was added trimethylsilyl chloride (78 mmol) via a dropping funnel at a rate such that the temperature should not exceed 5°C. After 1 hour, the mixture was heated to 35°C for 5 hours; and then cool to 20 °C. The mixture was stirred overnight at the same temperature and diluted with toluene (30 mL). The mixture was then cooled to 0-5 °C and diluted with water (70 mL) at a rate so that the temperature should not exceed 10 °C. The organic layer was collected, washed with aqueous sodium phosphate (NaH2PO4), water, and brine and then concentrated under reduced pressure. The resultant light yellow oil was diluted with
toluene and concentrated to give the title compound as a colorless oil. IR (cm-1): 1759 (C=O); 1H NMR (400 MHz, CDC13) δ 4.05 (dt, J= 2.2 Hz, 7.4 Hz, 1H), 3.87 (d, J= 7.9 Hz, 1H), 3.80 (t, J= 7.4 Hz, 1H), 3.69 (dd, J= 2.2 Hz, 11.9 Hz, 1H), 3.63 (dd, J= 2.2 Hz, 11.8 Hz, 1H), 3.62 (t, J= 7.5 Hz, 1H), 0.07 (s, 9H), 0.06 (s, 9H), 0.05 (s, 9H), 0.00 (s,9H). .
Preparation of O-methoxyglucoside (7)

To a stirred solution of 5-bromo-2-chloro-4'-ethoxydiphenylmethane 5 (0.5 mmol) in 1:2 tetrahydrofuran/toluene (12 mL) at -78°C under nitrogen atomosphere was added n-butyllithium (2.5 M in hexane, 0.5 mmol) dropwise maintaining the temperature at -70°C. After 30 min, this solution was transferred by cannula to a stirred solution of 2,3,4,6-tetra-O-trimethylsilyl- β-D-glucolactone 5 (0.5 mmol) in toluene (11 mL) at -78°C at a rate that the temperature is maintained at -70°C. After 1 hour, methanesulfonic acid (0.6 N in methanol) was added; and the mixture was warmed to room temperature and stirred for 16 hours. The mixture was then quenched with saturated aqueous sodium bicarbonate. After extraction with ethyl acetate (3 x 20 mL) the organic layers were collected, combined, washed with brine, dried over sodium sulphate, filtered and concentration under reduced pressure. The residue was treated with hot toluene (15 mL), and poured into hexane (10 mL) to precipitate out methylglucoside 7. The title compound was isolated as a white solid (85%); IR (cm-1): 3388 (OH); 1H NMR (400 MHz, CD3OD) δ 7.54 (d, J= 2.2 Hz, 1H), 7.45 (dd, J= 2.2 Hz, 8.4 Hz, 1H), 7.35 (d, J= 8.4 Hz, 1H), 7.08 (d, J= 8.8 Hz, 2H), 6.79 (d, J= 8.8 Hz, 2H), 4.08 (d, J= 15.0 Hz, 1H), 3.99 (d, J = 15.0 Hz, 1H), 3.98 (q, J= 7.0 Hz, 2H), 3.92 (dd, 7= 2.2 Hz, 11.8 Hz, 1H), 3.80 (dd, J = 5.3 Hz, 11.9 Hz, 1H), 3.74 (t, J= 9.2 Hz, 1H), 3.57 (m, 1H), 3.41 (d, J= 8.8 Hz, 1H), 3.08 (d, J= 9.7 Hz, 1H), 3.06 (s, 3H), 1.35 (t, J= 7.0 Hz, 3H).

Preparation of tetra-acetylated β-C-glucoside (8)

To a stirred solution of O-methylglucoside 7 (0.3 mmol) in 1:1 dichloromethane/acetonitrile (11 mL) at -10°C was added triethylsilane (Et3SiH) (0.6 mmol) followed by BF3 . OEt2 (0.4 mmol) at a rate such that the temperature was maintained between -5 and -10°C. The solution was allowed to warm to 0 °C and stirred for 5 hours prior to quenching with saturated aqueous sodium bicarbonate (30 mL). After removal of organic volatiles under reduced pressure, the residue was partitioned between ethyl acetate (30 mL) and water (25 mL). The mixture was extracted with ethyl acetate (2 x 20 mL), The organic layers were collected, combined, washed with water followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give yellow foam like product. Peracetylation was achieved by adding AC2O (2.6 mmol) and 4-dimethylaminopyridine (DMAP) (0.13 mmol) to a solution of this residue in dichloromethane (75 mL) and pyridine (2.5 mmol). After 1.5 hours, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were collected, washed with 1.0 N hydrochloric acid and brine, dried over sodium sulphate, filtered and concentration under reduced pressure. The residue was recrystallized from absolute ethanol to give the title compound 8 (55% for two steps) as a white solid. IR (cm-1): 1754 (CO); 2H NMR (400 MHz, CDC13) δ 7.35 (d, J = 8.4, 1H), 7.19 (dd, J= 1.8 Hz, 8.4 Hz, 1H), 7.07 (d, J = 1.8 Hz, 1H), 7.05 (d, J= 8.8 Hz, 2H), 6.82 (d, J= 8.8 Hz, 2H), 5.28 (t, J= 9.2 Hz, 1H), 5.20 (t, J= 9.2 Hz, 1H), 5.05 (t, J= 9.2 Hz, 1H), 4.31 (d, J= 9.7 Hz, 1H), 4.26 (dd, J= 4.8 Hz, 12.8 Hz, 1H), 4.14 (dd, J =2.2 Hz, 12.4 Hz, 1H), 3.95-4.07 (m, 4H), 3.80 (m, 1H), 2.08 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H), 1.71 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H); 13C NMR (400 MHz, CDCI3) δ 170.6, 170.3, 169.4, 168.7, 157.5, 139.0, 135.1, 134.6, 131.0, 129.8, 125.9, 114.5, 79.5, 76.1, 74.1, 72.6, 68.5, 63.4, 62.3, 38.3, 20.7, 20.6, 20.3, 14.9; MS (ESI) m/z 599 (M + Na).

Preparation of (2S,,3R,,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-
hydroxymethyltetrahydro-2H-pyran-3,4,5-triol (9)

To a stirred solution of tetra-acetylated β-C-glucoside 8 (4.7 mmol) in 2:3:1 tetrahydrofuran/methanol/water (48 mL) was added lithiumhydroxide (LiOH-H2O) (5.5 mmol). After the mixture was stirred overnight, the volatiles were removed under reduced pressure. The residue, after dissolution in ethylacetate (30 mL), was subsequently washed with brine (15 mL), brine containing 10 mL of 5% aq potassium sulphate (KHSO4) (5 mL) and brine (5 mL) prior to drying over sodium sulphate. Filtration and removal of the volatiles under reduced pressure yielded the title compound (100%) as a glassy off-white amorphous solid.1H NMR (400 MHz, CD3OD) δ 7.33 (d, J = 6.0 Hz, 1H), 7.31 (d, J= 2.2 Hz, 1H), 7.31 (dd, J= 2.2 Hz, 6.0 Hz, 1H), 7.07 (d, J= 8.8 Hz, 2H), 6.78 (d, J= 8.8 Hz, 2H), 4.07-3.90 (m, 7H), 3.85 (d, J= 10.6 Hz, 1H), 3.69 (dd, 7= 5.3 Hz, 10.6 Hz, 1H), 3.42-3.25 (m, 4H), 1.34 (t, J= 7.0 Hz, 3H); 13C NMR (400 MHz, CD3OD)δ 158.7, 141.3, 139.9, 134.4, 132.8, 131.9, 130.8, 130.1, 128.1, 115.4, 82.8, 82.1, 79.7, 76.4, 71.8, 64.4, 63.1, 39.2, 15.2; MS (ESI) m/z 431 (M + Na).

We claim

1. A process for the preparation of compound of formula 5 comprising the steps of:

a) reacting compound of formula 1 with compound of formula 2 using an anhydride and inorganic acid optionally in presence of a suitable solvent to give compound
of formula 3

b) reducing the compound of formula 3 to give compound of formula 5.

2. The process according to claim 1, wherein the anhydride is trifluoroacetic ahnydride.

3. The process according to claim 1, wherein inorganic acid is phosphoric acid.
4. The process according to claim 1, wherein the solvent is selected from acetonitrile, 1,4 dioxane, tetrahydrofuran.

4. The process according to claim 1, wherein the process is carried out at a temperature of about 0°C to 60°C.

5. The process according to claim 1, wherein the reduction is carried out by sodium borohydride

6. The process according to claim 1, wherein the reduction is carried out in presence of aluminium chloride.

7. A process for the preparation of dapagliflozin, represented by scheme below