CLIAMS:N/A ,TagSPECI:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“PROCESS FOR THE PREPARATION OF SGLT INHIBITOR COMPOUNDS”

2. APPLICANT:

(a) NAME: INDOCO REMEDIES LIMITED

(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East),
Mumbai – 400 098, Maharashtra, India.


3.PREAMBLE TO THE DESCRIPTION:

The following specification describes the invention.

Field of the invention:
The present invention relates to a novel process for preparing an intermediate represented by general Formula I, useful for the preparation of sodium glucose transporters 2 (SGLT2) inhibitor compounds.

Formula I
Background and Prior Art:
Chronic hyperglycaemia is a defining feature of diabetes mellitus, and consequent glucotoxicity most likely accounts for the associated microvascular disease, and contributes to premature macrovascular disease. Hence early and effective glycaemic control is fundamental to therapeutic intervention. There are two types of diabetes more prevalent viz. type 1 diabetes and type 2 diabetes. In type 1 diabetes, hyperglycaemia is due to complete or almost complete loss of insulin-secreting ß cells from the pancreatic islets of Langerhans. In type 2 diabetes, however,
hyperglycaemia indicates insulin resistance coupled with abnormalities of insulin production and secretion and other endocrinopathies that collectively cause a highly heterogeneous and progressive disorder. Treatment of type 2 diabetes is often complicated by coexistent obesity,
which further impairs insulin action and aggravates hypertension, dyslipidemia, inflammation, and other pathogenic factors that promote cardiovascular risk. New types of glucose-lowering drugs are needed, preferably offering complementary and additional effectiveness to existing drugs, along with benefits against any of the common accompanying disorders such as obesity and cardiovascular disease.

Sodium–glucose cotransporters 2 inhibitors (SGLTs), such as SGLT1 and SGLT2 inhibitors provide new therapeutic targets to reduce hyperglycaemia in patients with diabetes. SGLT1 enables the small intestine to absorb glucose and contributes to the reabsorption of glucose filtered by the kidney. SGLT2 is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors with varying specificities for these transporters can slow the rate of intestinal glucose absorption and increase the renal elimination of glucose into the urine.

Currently various SGLT2 inhibitor drugs have been approved or in clinical phase for treatment of type 2 diabetes. A significant numbers of SGLT2 are ß-C-arylglucosides derived drug candidates, most of which comprises a central 1-deoxyglucose ring moiety that is arylated at C1. Among ß-C-arylglucosides the pharmaceutically valuable drugs that are now being marketed are Canagliflogin (Formula II), Dapagliflogin (Formula III), Empagliflogin (Formula IV), whereas Ipragliflogin (Formula V) is approved for marketing in Japan. The structures of these compounds are as given below:

Formula II

Formula III

Formula IV

Formula V

The intermediate compound of Formula I is useful for the preparation of the newly developed SGLT2 inhibitors,

Formula I
wherein Bn is Benzyl group;
R is halogen, alkyl or alkoxy group;
R1 is hydrogen or methyl; and
Ar is aryl group selected from 5-(4-fluorophenyl)thiophen-2-yl, 4-ethoxyphenyl, 4-((S)-tetrahydrofuran-3-yloxy)phenyl or benzothiophen-2-yl.
There are various patents and patent applications viz., US 6,515,117, US 7,579,449, US 7,772,407, US 7,943,788, WO 2009035969, WO 2004063209, WO 2010022313, WO 2010043682, WO 2011047113, and WO 2013152476 which discloses the process for the preparation of these SGLT2 inhibitors. Most of these processes involve glucose or glucono lactone moiety for the preparation of the required compound.

In one of the prior art processes, hydroxyl group of the gluconolactone moiety is protected with trimethylsilane. The process discloses the reaction where after the C-C bond formation the resultant hemiketal formed is methylated using methanesulphonic acid. During the process the trimethylsilyl groups are hydrolysed and get removed. The demethylation of the methoxy group requires again protection with acetyl group followed by deacetylation to isolate the required compound that results in increased number of steps.

Another process discloses the protection of hydroxyl group of the gluconolactone moiety with acetyl group using controlled substance acetic anhydride. The protected gluconolactone is not available commercially and has to be prepared before the reaction.
Yet another process disclosed in the prior art, where the protection of hydroxyl group of the glucose moiety is carried out with pivaloyl chloride to get the compound pivaloyl-D-glucopyranose. Before the C-C bond formation, the pivaloyl-D-glucopyranose is reacted with bromine reagent to yield pivaloyl glucopyranosyl bromide compound which increases the number of steps and handling of bromine reagent.

The drawbacks of the above prior arts are:
1. The compounds glucose or gluconolactone when protected with pivaloyl, acetyl or trimethylsilyl groups need to be freshly prepared as the resultant compounds are unstable and not available on commercial scale.
2. The lack of stereoselectivity during formation of ß-C-aryl glucoside reduces the yield of the product.
3. The process requires couple of protection and deprotection of the glucose moiety, which increases the number of steps and loss in yield of the final compound making the process uneconomical and cumbersome.
4. The glucose compound when protected with pivaloyl group requires the pivaloyl-D-glucopyranose compound to react with bromine reagent which increases the process cost and the number of steps and also involves the problem of handling of bromine reagent.

In view of the above, there remains a need for stereoselective, more efficient and economic process for the preparation of ß-C-arylglucosides. The present inventers ameliorates the prior art drawbacks by using the commercially available and stable Benzyl-D-glucopyranose moiety for the C-C bond formation reaction in the presence of strong alkali.

Objective of the Invention:
The objective of the present invention is to develop a rigid and cost effective process for the preparation of an intermediate compound of Formula I, useful for the preparation of sodium glucose transporters 2 (SGLT2) ß-C-arylglucosides,

Formula I
Wherein, Bn is Benzyl group;
R is halogen, alkyl or alkoxy group;
R1 is hydrogen or methyl; and
Ar is aryl group selected from 5-(4-fluorophenyl)thiophen-2-yl, 4-ethoxyphenyl, 4-((S)-tetrahydrofuran-3-yloxy)phenyl or benzothiophen-2-yl.
Yet another objective of the present invention is to prepare ß-C-arylglucosides with stereoselective orientation to prepare more of ß anomer.

Summary of the Invention:
The present invention provides a novel process for the preparation of an intermediate of Formula I useful for the preparation of sodium glucose transporters 2 (SGLT2) inhibitor compounds, preferably the pharmaceutically useful antidiabetic compounds such as Canagliflozin, Dapagliflozin, Empagliflozin and Ipragliflozin.
In one aspect of the present invention there is provided a process for the preparation of an intermediate represented by general Formula I, useful for preparing sodium glucose transporters 2 (SGLT2) inhibitors,

Formula I
wherein Bn is Benzyl group;
R is halogen, alkyl or alkoxy group;
R1 is hydrogen or methyl; and
Ar is aryl group selected from the residues A, B, C or D as given below,


which process comprises of treating the compound 2,3,4,6-tetra-O-benzyl-D-glucopyranose of Formula VI with aryl halide compound of Formula VII where Ar and R is as previously defined and X is any halogen group selected from Cl, Br, or I in presence of neutral sodium hypochlorite solution, a strong base and organic solvent at a temperature in the range of 0°C to -80°C.

Formula VI Formula VII

Detail Description of the Invention:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows:

The present invention discloses a novel process for preparation of an intermediate of formula I, useful for the preparation of sodium glucose transporters 2 (SGLT2) inhibitor compounds, preferably the pharmaceutically useful antidiabetic compounds such as Canagliflozin, Dapagliflozin, Empagliflozin and Ipragliflozin.
In one embodiment, the present invention provides a process for the synthesis of the compound of Formula I

Formula I
wherein, Bn is Benzyl group; R is halogen, alkyl or alkoxy group; R1 is hydrogen or methyl; and
Ar is aryl group selected from the residues A, B, C or D as given below,


comprising treating the compound 2,3,4,6-tetra-O-benzyl-D-glucopyranose of Formula VI with aryl halide compound of Formula VII wherein Ar and R is as previously defined and X is any halogen group selected from Cl, Br, or I in presence of neutral sodium hypochlorite solution, a strong base and organic solvent at a temperature in the range of 0°C to -80°C.

The advantage of using 2,3,4,6-tetra-O-benzyl-D-glucopyranose over the other glucanone or glucose moiety is the stability of the compound at ambient temperature which makes the compound commercially available. The compound, 2,3,4,6-tetra-O-benzyl-D-glucopyranose due to its bulky structures produces more of the required ß isomer and the hydroxyl protective group is more stable during the reaction and hence protection and deprotection steps are not needed to isolate the pure compound.

Another embodiment of the present invention provides insitu preparation of 2,3,4,6-tetra-O-benzyl-D-gluconolactone. The compound of Formula VI was first reacted with a neutral sodium hypochlorite solution in presence of buffer and catalyst using water as solvent medium to prepare solution of 2,3,4,6-tetra-O-benzyl-D-gluconolactone by maintaining the temperature of the reaction at -5°C to 30°C and pH of the reaction at 7.0 to 7.5. The preffered buffer used for the reaction is sodium bicarbonate and acetic acid. The catalyst used for the reaction is 2,2,6,6-trimethylpiperidine-1-oxyl.

The compound 2,3,4,6-tetra-O-benzyl-D-glucopyranose was charged in solvent and the catalyst is added to the solution. To this solution neutral sodium hypochlorite solution in water was added maintaining the temperature in the range of 10°C to 30°C. The solvent used in the reaction is selected from group consisting of dichloromethane, dichloroethane, chloroform, toluene, xylene, tetrahydrofuran, ether, water either alone or in combinations thereof. The reaction completion was monitored on HPLC. The reaction mass was quenched by adding aqueous sodium thiosulphate solution. The reaction was worked up by separating the organic layer and concentrated to obtain solution of 2,3,4,6-tetra-O-benzyl-D-gluconolactone.

To the above solution under nitrogen the solution of aryl halide compound of Formula VII was charged and cooled the mixture to –70°C. The solvent used for preparing solution of the compound of Formula VII was selected from the group consisting of ether, diethyl ether, dibutyl ether, toluene, xylene and tetrahydrofuran either alone or in combinations thereof. The reaction is carried out in presence of a base selected from organometallic reagents such as n-butyl lithium, sec-butyl lithium and mixture of n-hexyl lithium and (trimethylsilyl) methyl lithium. The reaction was monitored on HPLC for the completion. The reaction was worked up by quenching with aqueous sodium bicarbonate solution and brought slowly to 20°C to 30°C. Separated the organic layer and concentrated under reduced pressure to isolate solid mass of the hemiketal compound of Formula I.

In another embodiment of the present invention, the compound of Formula I was subjected to reduction. The hemiketal compound was reduced with the reducing reagent and boron trifluoride diethyl etherate in presence of solvent to obtain the compound of Formula VIII.

Formula VIII.
The reducing reagents used for reduction of hemiketal was selected from the group of reagents, phenylsilane, tri-n-propylsilane, dimethylphenylsilane, triethylsilane, tris(trimethylsilyl)silane, triisobutylsilane, triphenylsilane, tert-butyldimethylsilane, triisopropylsilane and diisobutylaluminium hydride. The solvent used for the reduction reaction was selected from the group of solvents such as dichloromethane, dichloroethane, chloroform, toluene, xylene tetrahydrofuran, ether and acetonitrile either alone or in combinations thereof. The reaction was carried out at temperature in the range of -45°C to -30°C. The completion of reaction was monitored on HPLC. The compound obtained after work up was taken for the preparation of SGPLT 2 inhibitors.

The hemiketal compound of Formula I can be taken for the reduction, by first methylating the hydroxy group compound at C1 and then carrying out reduction as per the above process.

Yet another embodiment of the present invention in which the reduced compound of Formula VIII is deprotected/debenzylated using Palladium /carbon or iodotrimethylsilane reagent in presence of solvent selected from methanol, ethanol, isopropanol tetrahydrofuran, diethyl ether, toluene, dichloromethane , dichloroethane, chloroform either alone or in combinations thereof to yield the compound of Formula IX. The temperature of the reaction is maintained in the range of 0°C to 40°C. The reaction is monitored on TLC for the completion. The reaction mixture was concentrated under reduced pressure to obtain a residual mass. Charged solvents selected from the group consisting of n- hexane, n-heptane, cyclohexane, methanol and water either alone or in combinations thereof to the residual mass and stirred. Filtered the precipitated solid mass to isolate the required SGPLT2 compound.

Formula IX
wherein R is halogen, alkyl or alkoxy group and Ar is aryl group selected from the residues A, B, C or D as given below,


The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respects as illustrative only and non restrictive to the invention.

EXAMPLES:

Example 1:
Stage 1: Synthesis of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-2-ol
Charged water (175 ml) and sodium bicarbonate (14 gm) in RBflask (RBF) and stirred. It was cooled to 0 to 5°C and 10% sodium hypochlorite solution (34.5gm) was added. By maintaining the temperature between (0- to 5°C), pH was adjusted with acetic acid to 7.0-7.5 (solution 1).

In another 500ml 4 neck RBF, 2,3,4,6-tetra-O-benzyl-D-glucopyranose (25gm, 0.0046 mol) dissolved in a 1:1 mixture of dichloromethane: toluene (150ml) and charged water (50ml). The compound 2,2,6,6-tetramethylpiperidine-1-oxyl (0.1gm.) was then added to this mixture. To the above solution, neutral sodium hypochlorite solution (solution 1) was slowly added by maintaining the temperature between 10°C to 15°C. The progress of the reaction was monitored by HPLC. After completion of the reaction the reaction mixture was quenched by adding aqueous sodium thiosulphate (11.25gm in 25 ml water) solution. The quenched reaction mixture was stirred for 10-15 minutes and the temperature of reaction mixture was raised to 25°C. The organic layer was separated. The aqueous layer was extracted with toluene (2x 75ml) and separated. The combined organic layer was washed with water (3 x 150 ml). The organic layer (275ml) was then dried over anhydrous sodium sulphate and concentrated under reduced pressure till one third of its volume.
The above toluene layer was taken in 500 ml 4-necked RBF and a solution of (5-iodo-2- methyl -benzyl)-2-(4-fluorophenyl)thiophene (12.5 gm, 0.0306 moles) in tetrahydrofuran (75 ml) was added, under nitrogen atmosphere. Applied cooling to the resulting mixture to about -40°C to -30°C, and charged n-butyl lithium in hexane 1.6M (37.5 ml, 0.0588 moles).

The reaction progress was monitored by HPLC. After the reaction completion, reaction was quenched with saturated sodium bicarbonate solution (25 ml) and was allowed to attain 25°C to 30°C. The layers were separated and the organic layer, dried over sodium sulphate was concentrated under reduced pressure to yield the compound (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methyl -phenyl) tetrahydro-2H-pyran-2-ol as a solid ( 25 gm, 65%).

Stage-2: Synthesis of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran
In 250ml 4neck RBF charged (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-2-ol (15gm, 0.01829mole) and dichloromethane (60 ml) under nitrogen atmosphere .The reaction mass cooled to -30°C under stirring. Maintaining the temperature between -40°C to -20°C charged triethylsilane (8.6ml 0.0543mol), followed by a slow addition of boron trifluoride diethyl etherate (7.2 ml, 0.0573 moles). After the addition was complete maintained the reaction mass for 30 minutes and then removed the ice bath and allowed the temperature to attain 20°C and maintained under nitrogen, for 1.0 - 2.0 hour. The reaction progress was monitored on TLC. After completion the reaction mass was quenched with cold water (60ml) and charged ethyl acetate (60ml). The layers were separated and the organic layer was washed with a saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to yield the compound (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(3-((5-(4-fluorophenyl)-thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran (14.0gm 95 %).

Stage-3: Synthesis of (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [Canagliflozin]
In 250 ml RBF charged (3R,4R,5R,6R)-3,4,5-tris (benzyloxy)-6-(benzyloxymethyl)-2-(3-[(5-(4-fluorophenyl)thiophen-2-yl)-4-methylphenyl]tetrahydro-2H-pyran (10gm, 0.0124 moles) and dichloromethane (100ml). The reaction mixture was cooled under stirring to 0°C, and charged iodotrimethylsilane (8.83 ml, 0.062 moles). Raised the temp to 25°C - 30°C and maintained for 5 - 6 hours. The reaction was monitored on TLC. The reaction mixture was concentrated under reduced pressure, charged cyclohexane to the residual mass and stirred. Filtered the precipitated compound and dried to isolate 2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol as a solid (5.0 gm 90%).

Dated this 9th day of February, 2015

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates