(19)
(11)EP 3 256 482 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
27.11.2019 Bulletin 2019/48

(21)Application number: 16722707.3

(22)Date of filing:  09.02.2016
(51)Int. Cl.: 
C07H 1/00  (2006.01)
C07D 309/10  (2006.01)
(86)International application number:
PCT/IN2016/050048
(87)International publication number:
WO 2016/128995 (18.08.2016 Gazette  2016/33)

(54)

PROCESS FOR THE PREPARATION OF SGLT INHIBITOR COMPOUNDS

VERFAHREN ZUR HERSTELLUNG VON SGLT-INHIBITOR-VERBINDUNGEN

PROCÉDÉ DE PRÉPARATION DE COMPOSÉS INHIBITEURS DE SGLT


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 09.02.2015 IN 417MU2015
27.04.2015 IN 1683MU2015

(43)Date of publication of application:
20.12.2017 Bulletin 2017/51

(73)Proprietor: Indoco Remedies Limited
Mumbai 400 098 MAH (IN)

(72)Inventors:
  • NAIR, Ranjeet
    Navi Mumbai 400701 (IN)
  • RAMESAN, Palangat Vayalileveetil
    Navi Mumbai 400701 (IN)
  • DESHMUKH, Sandip Kacharu
    Navi Mumbai 400701 (IN)
  • PANANDIKAR, Aditi Milind
    Mumbai 400098 (IN)

(74)Representative: Rees, Kerry 
WP Thompson 138 Fetter Lane
London EC4A 1BT
London EC4A 1BT (GB)


(56)References cited: : 
EP-A1- 1 609 785
WO-A1-2006/108842
WO-A1-2016/041470
WO-A1-2005/092877
WO-A1-2006/120208
CN-A- 105 440 025
  
  • PRASHANT P. DESHPANDE ET AL: "A Practical Stereoselective Synthesis and Novel Cocrystallizations of an Amphiphatic SGLT-2 Inhibitor", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 16, no. 4, 20 April 2012 (2012-04-20) , pages 577-585, XP055278964, US ISSN: 1083-6160, DOI: 10.1021/op200306q
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

FIELD OF THE INVENTION:



[0001] The present invention relates to a novel process for preparing sodium glucose transporters 2 (SGLT2) inhibitor compounds of Formula IX.

Wherein, R is halogen, alkyl or alkoxy group; and

Ar is aryl group, substituted or unsustituted monocyclic polycyclic or heterocyclic ring selected from the residues A, B, C or D as given below.


BACKGROUND AND PRIOR ART:



[0002] 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 β 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 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.

[0003] Currently various SGLT2 inhibitor drugs have been approved or in clinical phase for treatment of type 2 diabetes. A significant numbers of SGLT2 are β-C-arylglucosides derived drug candidates, most of which comprises a central 1-deoxyglucose ring moiety that is arylated at C1. Among β-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:









[0004] 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 2006120208, WO 2006108842, 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. Deshpande et al. (Organic Process Research & Development 2012,16,577-585) disclose a process for the preparation of SGLT2 inhibitors starting from a protected glucose which is further oxidized in the corresponding gluconolactone, then isolated and purified.

[0005] 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.

[0006] 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.

[0007] 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.

[0008] The drawbacks of the above prior arts are:
  1. 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. 2. The lack of stereoselectivity during formation of β-C-aryl glucoside reduces the yield of the product.
  3. 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. 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.


[0009] In view of the above, there remains a need for stereoselective, more efficient and economic process for the preparation of β-C-arylglucosides. The present inventors 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:



[0010] The objective of the present invention is to develop a rigid and cost effective process for the preparation of sodium glucose transporters 2 (SGLT2) compound of Formula IX,

wherein, R and Ar are as defined above

[0011] Another 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 β-C-arylglucosides as sodium glucose transporters 2 (SGLT2) inhibitors,

wherein, Bn is Benzyl group; R1 is hydrogen or methyl; and R and Ar are as defined above.

[0012] Yet another objective of the present invention is to prepare β-C-arylglucosides with stereoselective orientation to prepare more of β anomer.

[0013] Yet another objective of the present invention is to carry out debenzylation using easily available cost effective reagent.

[0014] Yet another objective of the present invention is to prepare intermediate compound of Formula VIII

wherein, Bn, Ar and R are same as defined above.

[0015] Yet another objective of the present invention is to prepare intermediate compound of Formula VIIIa

wherein, Bn, Ar and R are same as defined above.

SUMMARY OF THE INVENTION:



[0016] Accordingly the present invention provides a process for the preparation of the of SGLT2 compound of Formula IX,

wherein R is halogen, alkyl or alkoxy group; and

Ar is aryl group, substituted or unsustituted monocyclic, polycyclic or heterocyclic ring selected from the residues A, B, C or D as given below,

which process comprises,
  1. a) 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 sodium hypochlorite solution, a strong base and organic solvent at a temperature in the range of -80°C to 0°C to isolate an intermediate compound of Formula I,

    wherein Bn is Benzyl group;

    R1 is hydrogen or methyl; and R and Ar are as defined above.

  2. b) reacting the intermediate compound of Formula I with a reducing reagent and boron trifluoride-diethyl etherate in presence of solvent to obtain the intermediate compound of Formula VIII.

    where R and Ar are as defined above
  3. c) purifying the compound of formula VIII from a solvent to obtain compound of formula VIIIa; and

    wherein, R, Ar and Bn are same as previously defined,
  4. d) deprotecting the intermediate compound of Formula VIII to isolate compound of Formula IX.


[0017] In another aspect, the present invention provides the compound of Formula VIII

wherein, R and Ar are as defined above

[0018] In a further aspect, the present invention provides the process for the preparation of the compound canagliflozin of Formula II.

Accordingly, the process comprising the steps of,
  1. a) reacting the compound 2,3,4,6-tetra-O-benzyl-D-glucopyranose of Formula VI,

    with aryl halide compound of Formula VII

    wherein, X is any halogen group selected from Cl, Br or I; R is methyl; and Ar is 5-(4-fluorophenyl)thiophen-2-yl of Formula of residue A;
    in presence of sodium hypochlorite solution, a strong base and organic solvent at a temperature in the range of -80°C to 0°C to isolate an intermediate compound (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 of Formula Ia,

  2. b) reacting the intermediate compound of Formula Ia with a reducing reagent and boron trifluoride-diethyl etherate in presence of solvent and further purifying to obtain the intermediate 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 of Formula VIIIb.

  3. c) deprotecting the compound of Formula VIII b to isolate compound of Formula II.


[0019] In another aspect, the present invention provides a compound of formula VIII

wherein, R is halogen, alkyl or alkoxy group; and Ar is aryl group, substituted or unsustituted monocyclic, polycyclic or heterocyclic ring selected from the residues A or B as given below.



[0020] In yet another aspect, the present invention provides the compound of Formula VIIIa.



[0021] In yet another aspect, the present invention provides the compound of Formula VIIIb.



[0022] In a further aspect, the present invention provides the compound of Formula VIIIc.


DETAIL DESCRIPTION OF THE INVENTION:



[0023] 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 sodium glucose transporters 2 (SGLT2) inhibitor compounds of Formula IX, preferably the pharmaceutically useful antidiabetic compounds such as Canagliflozin, Dapagliflozin, Empagliflozin and Ipragliflozin.

wherein, R is halogen, alkyl or alkoxy group; and

[0024] Ar is aryl group, substituted or unsustituted monocyclic, polycyclic or heterocyclic ring selected from the residues A, B, C or D as given below,



[0025] In one embodiment, the present invention provides a process for the synthesis of the compound of Formula I

wherein, Bn is Benzyl group; R1 is hydrogen or methyl; R and Ar are same as defined above.

[0026] Accordingly, the process comprises 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 sodium hypochlorite solution, a strong base and organic solvent at a temperature in the range of -80°C to 0°C.

[0027] 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 structure produces more of the required β isomer and the hydroxyl protective group is more stable during the reaction and hence protection and deprotection steps are not required to isolate the pure compound.

[0028] Another embodiment of the present invention provides in situ preparation of 2,3,4,6-tetra-O-benzyl-D-gluconolactone. The compound of Formula VI was first reacted with 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 8.0. The preferred buffer used for the reaction is sodium bicarbonate and acetic acid. The catalyst used for the reaction is 2,2,6,6-teteamethylpiperidine-1-oxyl either alone or in combination with potassium bromide.

[0029] 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 sodium hypochlorite solution in water was added by maintaining the temperature in the range of 10°C to 40°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 preferred solvent used is tetrahydrofuran.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 preferred base used was n-butyl lithium. The reaction was monitored on HPLC for the completion. The reaction was worked up by quenching with aqueous sodium bicarbonate solution and brought the temperature of the reaction mixture slowly to 20°C to 30°C. Separated the organic layer and extracted the aqueous layer with ethyl acetate. Combined the organic layer and washed the layer with brine solution. Concentrated the organic layer under reduced pressure to get residual mass of the hemiketal compound of Formula I. The residual mass was further treated with solvent mixture of ethyl acetate and methanol to isolate hemiketal compound of Formula I.

[0030] 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.

wherein R, Ar and Bn are same as previously defined.

[0031] 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 preffered reagent used are triethylsilane, phenylsilane, and tris(trimethylsilyl)silane whereas the most preferred reagents for the reduction used is triethylsilane. The solvent used for the reduction reaction was selected from the group of solvents such as dichloromethane, dichloroethane, chloroform, toluene, xylene, tetrahydrofuran, ether, ethyl acetate 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 preferred reaction temperature to carry out the reaction was -10°C to 30°C, wherein the most preferred temperature of the reaction is 10°C to 30°C. The completion of reaction was monitored on TLC / HPLC. After completion the reaction was quenched with water and neutralised the quenched mass with ammonia solution. Separated the organic layer and the aqueous layer was again extracted with ethyl acetate. The combined organic layers were washed with 10% brine solution and concentrated the solvent under vacuum at 40°C to 45°C to half. Charged methanol to the concentrated reaction mixture and heated to 64 - 65°C. The product was precipitated at 60°C to 65°C by adding additional portion of methanol and cooled to 25°C to 30°C. Filtered the precipitated crude product to get the SGPLT2 compound of Formula VIII.

[0032] The crude compound of Formula VIII thus obtained after work up was purified from the solvent selected from the group of the solvents such as methanol, ethanol, Isopropyl alcohol, butanol and ethyl acetate either alone or in combinations thereof to obtain the desired pure β isomer of Formula VIIIa. The isolated pure compound of Formula VIIIa was taken for the preparation of SGPLT 2 inhibitors compounds.

wherein R, Ar and Bn are same as previously defined.

[0033] The hemiketal compound of Formula I can also be taken for the reduction, by first methylating the hydroxy group compound at C1 and then carrying out reduction as per the above process.

[0034] Yet another embodiment of the present invention in which the reduced compound of Formula VIII or Formula VIIIa is deprotected/debenzylated using sodium iodide/boron trifluoride-diethyl etherate or Palladium/carbon or iodotrimethylsilane reagent in presence of solvent selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, diethyl ether, toluene, dichloromethane, dichloroethane, chloroform and water, either alone or in combinations thereof to yield the compound of Formula IX. The preferred deprotecting reagent used is sodium iodide/boron trifluoride-diethyl etherate. The temperature of the reaction is maintained in the range of 0°C to 40°C for 3 - 5 hours. The reaction was monitored on HPLC for the completion. After completion of the reaction the reaction mixture was quenched with triethyl amine at 25°C to 30°C and stirred for four hours, the precipitated solid mass was filtered. Charged the wet solid mass in water and made the pH acidic by using concentrated hydrochloric acid. The product was extracted using the solvent selected from the group consisting of methyl iso butyl ketone, methyl ethyl ketone and isopropyl acetate, wherein the preferred solvent used was methyl isobutyl ketone. The organic layer was washed with water. The solvent was concentrated under reduced pressure till half of the volume. The concentrated mass was precipitated by adding cyclohexane to isolate crude solid product of the compound of Formula IX.

[0035] In another embodiment of the present invention the crude compound of formula IX was purified using the solvents selected from the group consisting of ethyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, and isopropyl acetate either alone or in combinations thereof with water for dissolution of the crude compound and precipitating the pure compound adding the solvent selected from n- hexane, n-heptane, cyclohexane. The temperature range for the purification of the crude compound is maintained between 25°C to 45°C.

[0036] The precipitated pure solid mass filtered to isolate the required pure SGPLT2 compound of 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,



[0037] Another embodiment of the present invention provides the compound of Formula VIII b.



[0038] In yet another embodiment, the present invention provides the compound of Formula VIII c



[0039] 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



[0040] Charged water (175 ml) and sodium bicarbonate (14 gm) in RB flask (RBF) and stirred. It was cooled to 0 to 5°C and 10% sodium hypochlorite solution (34.5 gm) was added. By maintaining the temperature between (0 to 5°C), pH was adjusted with acetic acid to 7.0-7.5 (solution 1).

[0041] In another 500ml 4 neck RBF, 2,3,4,6-tetra-O-benzyl-D-glucopyranose (25 gm, 0.0046 mol) dissolved in a 1:1 mixture of dichloromethane: toluene (150 ml) and charged water (50 ml). The compound 2,2,6,6-tetramethylpiperidine-1-oxyl (0.1 gm) was then added to this mixture. To the above solution, 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 (11.25 gm 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 (2 x 75 ml) and separated. The combined organic layer was washed with water (3 x 150 ml). The organic layer (275 ml) was then dried over anhydrous sodium sulphate and concentrated under reduced pressure till to attain one third of its volume.

[0042] 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).

[0043] 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



[0044] In 250 ml 4-neck 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 (15 gm, 0.01829 mole) 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 (8.6 ml, 0.0543 mol), 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 (60 ml) and charged ethyl acetate (60 ml). 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 (14.0 gm, 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]:



[0045] 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 (10 gm, 0.0124 moles) and dichloromethane (100 ml). 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%).

Example 2: Preparation of (2S,3R,4R,5S,6R)-2-(3-[(5-(4-flourophenyl)thiophene-2-yl)methyl]-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [Canagliflozin]



[0046] In 4 neck 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 (50 gm, 0.0621moles), dichloromethane (400 ml) and acetonitrile (300 ml), sodium iodide (100 gm, 0.667 moles), boron trifluoride-diethyl etherate (94.41gm, 0.667 mole) at 25-30°C along with acetonitrile (100 ml). The reaction mixture was stirred at room temperature for 4 - 5 hours. After reaction completion, the reaction mixture was quenched by 5% bicarbonate solution (400 ml) at 25 - 30°C. Separated the organic layer and aqueous layer was further extracted with dichloromethane (2 x 250 ml). Combined organic layer was washed with 5% thiosulfate solution and dried over anhydrous sodium sulphate. Filtered and the solvent was concentrated under reduced pressure. The residue was precipitated in cyclohexane (250 ml) to isolate crude (2S,3R,4R,5S,6R)-2-(3-[(5-(4-flourophenyl)thiophene-2-yl)methyl]-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. The crude compound was further purified by dissolving in mixture of solvents ethyl acetate (100 ml) and water (2.0ml). To the solution slowly charged n-hexane (100ml) in reaction and stirred at 25°C - 30°C for 12 hours and filtered the solid to isolate pure (2S,3R,4R,5S,6R)-2-(3-[(5-(4-flourophenyl)thiophene-2-yl)methyl]-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Canagliflozin) (22 gm, 80%).

Example 3: In situ preparation of (2S,3R,4R,5S,6R)-2-(3-[(5-(4-flourophenyl)thiophene-2-yl)methyl]-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [Canagliflozin]:



[0047] In a 250 ml 4-neck RBF under nitrogen atmosphere charged (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-2-ol (50 gm, 0.0609 mole) and dichloromethane (200 ml). The reaction mass was cooled to -30°C and charged triethylsilane (28.66 ml, 0.181mole) followed by a slow addition of boron trifluoride-diethyl etherate (24.00 ml, 0.191 moles) maintaining the temperature at -40°C to 0°C. After the addition was complete the ice bath was removed and the resulting mixture was stirred at room temperature, for 1.0 - 2.0 hrs monitoring the reaction progress by TLC.

[0048] After reaction completion, sodium iodide (100 gm, 0.667moles) and boron trifluoride-diethyl etherate (94.41 gm, 0.667 mole) were added to the reaction mass at 25°C - 30°C along with acetonitrile (200 ml). The reaction mixture was stirred at room temperature for 4 - 5 hours and reaction progress was monitored by TLC. After reaction completion it was quenched by 5% sodium bicarbonate solution (400 ml) at 25°C - 30°C. Separated the organic layer and aqueous layer was extracted with additional dichloromethane (2 x 250 ml). The combined organic layer was washed with 5% sodium thiosulfate solution and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure. The residue was precipitated in cyclohexane (250 ml) to isolate the crude (2S,3R,4R,5S,6R)-2-(3-[(5-(4-flourophenyl)thiophene-2-yl)methyl]-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. The crude compound was further purified by dissolving in mixture of solvents ethyl acetate (100 ml) and water (2.0ml). To the solution slowly charged n-hexane (100ml) in reaction and stirred at 25°C - 30°C for 12 hours and filtered the solid to isolate pure (2S,3R,4R,5S,6R)-2-(3-[(5-(4-flourophenyl)thiophene-2-yl)methyl]-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Canagliflozin) (22 gm, 80%).

Example 4:


Stage1: Synthesis of (3R,4R,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.



[0049] In 3.0 lit round bottom flask charged water (400 ml) and sodium bicarbonate (53.44 gm) at room temperature stirred for 30 minutes and charged acetic acid (26.63 gm) and potassium bromide (1.6 gm) under stirring for 15 minutes. The solution of 2, 3, 4, 6-tetra-O-benzyl-D-glucopyranose (200gm, 0.37 mole) in dichloromethane (1000 ml) was added to the reaction solution. Reaction mass was cooled to 20°C to 25°C. The compound 2, 2, 6, 6,-tetramethylpiperidine-1-oxyl (0.8 gm.) was added to the reaction mass and charged slowly 10% sodium hypochlorite (325 gm (0.436) solution maintaining the temperature between 20°C to 35°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 (50gm in 200ml water) solution. Reaction mixture was stirred for 30 minutes. Separated the organic layer and extracted the aqueous layer with Dichloromethane (400ml). The combined organic layer was washed twice with 10% brine solution. Distilled out the solvent under reduced pressure by maintaining the temperature below 45°C to get the residual mass.

[0050] To the residual mass under nitrogen, charged solution of (5- Iodo-2-methylbenzyl)-2-(4-fluoro-phenyl)thiophene (131gm, 0.320 mole) dissolved in tetrahydrofuran (786 ml) and stirred. Applied cooling to the resulting mixture and brought the temperature to -70°C. Charged n-butyl lithium in hexane 1.6M (262ml, 0.417 moles) maintaining the temperature between -70°C to -30°C. The reaction progress was monitored by HPLC. After the reaction completion, reaction was quenched with (10%) sodium bicarbonate solution (393 ml) and allowed the temperature to rise slowly to 25°C to 30°C. Separated the organic layer and the aqueous layer was extracted with ethyl acetate (260 ml). The combined organic layer was washed with (10%) brine solution. Organic layer was concentrated under reduced pressure. The residue was dissolved in 1:1 mixture of solvent methanol and ethyl acetate at 50-55°C. The product was precipitated by adding methanol (4.0 Vol) at 50-55°. The reaction mass was cooled to 25-30°C.the solid was filtered to get (184gm 70.2%) (3R, 4R, 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.

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)-4-methylphenyl] tetrahydro-2H-pyran.



[0051] In a 2.0 lit RBF charged (3R, 4R, 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 (150gm, 0.1829mole) and ethyl acetate (900ml) under nitrogen atmosphere .Maintaining the nitrogen atmosphere and stirring the reaction mass was cooled to 20°C to 25°C. Triethyl silane (25.5gm 0.21mol) was added followed by a slow addition of boron trifluoride diethyl etherate (31.1gm, 0.219 moles). After addition was complete, the reaction mixture was stirred maintaining the temperature at 25°C to 30°C, for1.0 to 2.0 hours. The reaction progress was monitored on TLC. After completion, the reaction mass was quenched with water (300ml) and adjusted the pH between 7 - 10 using ammonia solution (25%). Separated the organic layer and aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with 10% brine solution, Organic layer was concentrated under vacuum below 45°C to make the volume half. Charged methanol (3 vol) and heated the reaction mixture to 64°C to 65°C to get the clear solution. Precipitated the product by adding additional four volume methanol and cooled to 25°C to 30°C. The solid product was filtered to get (105gm 71.42 %) (2R, 3R, 4R, 5S, 6S)-3, 4, 5-tris (benzyloxy)-2-((benzyloxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)-4-methyl-phenyl]-tetrahydro-2H-pyran compound.

Stage-3: Preparation of (2S, 3R, 4R, 5S, 6R)-2-(3-[(5-(4-flourophenyl) thiophene-2-yl) methyl]-4methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [Canagliflozin]



[0052] In 2.0lit RBF charged (2R,3R, 4R, 5S, 6S)-3, 4, 5-tris (benzyloxy)-2-((benzyloxy methyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)-4-methylphenyl]tetrahydro-2H-pyran (100 gm, 0.124moles), acetonitrile (600 ml), sodium iodide (200 gm,1.335 moles), water (25 ml), boron trifluoride diethyletherate (226 gm,1.592 moles) maintaining temperature between 25°C to 35°C and flushed with acetonitrile (100 ml). The reaction mixture was stirred maintaining temperature at 25°C to 35°C for three hours. After reaction completion by TLC, the reaction mixture was quenched using triethyl amine (250 ml) and maintained under stirring at 25°C to 30°C for four hours. Filtered the solid mass and the wet cake was taken in water (500 ml). Adjusted the pH between 2 - 3 using concentrated hydrochloric acid. The product was extracted with Methyl Iso butyl ketone (500 ml), aqueous layer was once more extracted with Methyl Iso butyl ketone (200 ml). The combined organic layer was washed with water and concentrated under reduced pressure to bring the volume to half. To the concentrated volume charged cyclohexane (300 ml) to precipitate the crude product (40 gm) (2S, 3R, 4R, 5S, 6R)-2-(3-[(5-(4-flourophenyl) thiophene-2-yl) methyl]-4methylphenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Crude Canagliflozin).

Purification of Crude Canagliflozin:



[0053] In 250 ml round bottom flask, crude Canagliflozin (40 gm) was dissolved in mixture of 2:1 ratio methyl isobutyl ketone and methanol at 25°C to 30°C. After dissolving the solid charged activated charcoal (2.0 gm) and stirred for 30 minutes. Filtered the charcoal through hyflo bed. The filtrate was distilled under reduced pressure to obtain an oily residue. To this residue, charged methyl isobutyl ketone (160 ml), water (1.6 ml). The temperature of the reaction mass was raised to 30°C to 35°C and stirred for 30 minutes. Charged slowly cyclohexane (80 ml) maintaining the temperature at 30°C to 35°C. After addition was completed reaction mass stirred for 3 hrs at same temperature then cooled to 25°C to 30°C. The solid was filtered to obtain (35.2 gm), 88% of pure crystalline Canagliflozin.

Example 5: Preparation of (2S, 3R, 4R, 5S, 6R)-2-(3-[(5-(4-flourophenyl) thiophene-2-yl) methyl]-4methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [Canagliflozin]



[0054] In a 2.0 lit RBF charged (3R, 4R, 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 (150gm, 0.1829mole) and ethyl acetate (900ml) under nitrogen atmosphere .The reaction mass cooled to 20°C to 25°C under stirring. Triethyl silane (25.5gm 0.21mol) was added followed by a slow addition of boron trifluoride diethyl etherate (31.1gm, 0.219 moles). After complete addition the reaction mixture was maintained under stirring at 25°C to 30°C, for 1.0 - 2.0 hours. The reaction progress was monitored on TLC. After reaction completion Ethyl acetate was distilled out completely under reduced pressure.

[0055] To the residue charged acetonitrile (600 ml), sodium iodide (200 gm, 1.335 moles), purified water (25 ml), boron trifluoride diethyletherate (226 gm, 1.592 moles) at 25°C to 30°C and flushed with acetonitrile (100 ml). The reaction mixture was stirred at 30°C to 35° C for 3 hours. After reaction completion by TLC, the reaction mixture was quenched with triethyl amine (250 ml) and stirred for at 25°C to 30°C 4 hours. The solid mass was filtered and the wet cake taken in water (500 ml). Adjusted the pH between 2 - 3 using concentrated hydrochloric acid. The product was extracted with Methyl Iso butyl ketone (500 ml) and separated the layer. Extracted the aqueous layer with Methyl Iso butyl ketone (200 ml). Then combined organic layer was washed with purified water. The solvent was concentrated under reduced pressure to make the volume to half. Charged cyclohexane (300 ml) to the concentrated solution to precipitate (40 gm), crude (2S, 3R, 4R, 5S, 6R)-2-(3-[(5-(4-flourophenyl) thiophene-2-yl) methyl]-4methylphenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Canagliflozin).

Purification of Crude Canagliflozin:



[0056] In 250 ml round bottom flask, crude Canagliflozin (40 gm) was dissolved in mixture of 2:1 ratio methyl isobutyl ketone and methanol at 25°C to 30°C. After dissolving the solid charged activated charcoal (2.0 gm) and stirred for 30 minutes. Filtered the charcoal through hyflo bed. The filtrate was distilled under reduced pressure to obtain an oily residue. To this residue,charged methyl isobutyl ketone (160 ml), water (1.6 ml). The temperature of the reaction mass was raised to 30°C to 35°C and stirred for 30 minutes. Charged slowly cyclohexane (80 ml) maintaining the temperature at 30°C to 35°C. After addition was completed reaction mass stirred for 3 hrs at same temperature then cooled to 25°C to 30°C. The solid was filtered to obtain (35.2 gm), 88% of pure crystalline Canagliflozin.


Claims

1. A process for the preparation of compound of Formula IX,

wherein R is halogen, alkyl or alkoxy group; and Ar is aryl group, substituted or unsustituted monocyclic, polycyclic or heterocyclic ring selected from the residues A, B, C or D as given below,

which process comprises,

a) 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 sodium hypochlorite solution, a strong base and organic solvent at a temperature in the range of -80°C to 0°C to isolate an intermediate compound of Formula I;

wherein Bn is Benzyl group; R1 is hydrogen or methyl; and

R and Ar are as defined above.

b) reacting the intermediate compound of Formula I with a reducing reagent and boron trifluoride-diethyl etherate in presence of solvent to obtain the intermediate compound of Formula VIII;

where R and Ar are as defined above.

c) purifying the compound of formula VIII from a solvent to obtain compound of formula VIIIa; and

wherein R, Ar and Bn are same as previously defined

d) deprotecting the intermediate compound of Formula VIIIa to isolate compound of Formula IX.


 
2. The process according to claim 1, wherein, the organic solvent used in step a) is selected from the group consisting of ether, diethyl ether, dibutyl ether, toluene, xylene and tetrahydrofuran either alone or in combinations thereof.
 
3. The process according to claim 1, wherein, the base used in step a) is selected from the group consisting of organometallic reagents such as n-butyl lithium, sec-butyl lithium or mixture of n-hexyl lithium and (trimethylsilyl)methyl lithium.
 
4. The process according to claim 1, wherein, the reducing agent used in step b) is selected from the group of reagents, phenylsilane, tri-n-propylsilane, dimethylphenylsilane, triethylsilane, tris(trimethylsilyl)silane, triisobutylsilane, triphenylsilane, tert-butyldimethylsilane, triisopropylsilane and diisobutylaluminium hydride.
 
5. The process according to claim 4, wherein, the reducing agent is selected from triethylsilane, phenylsilane, and tris(trimethylsilyl)silane.
 
6. The process according to claim 1, wherein, the solvent used in step b) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, toluene, xylene tetrahydrofuran, ether, ethyl acetate and acetonitrile either alone or in combinations thereof.
 
7. The process according to claim 1, wherein, the reaction of step b) is carried out at temperature in the range of -45°C to 30°C.
 
8. The process according to claim 1, wherein, the purification of the compound of Formula VIII is carried out in the solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, butanol and ethyl acetate either alone or in combinations thereof to obtain compound of Formula VIIIa.
 
9. The process according to claim 1, wherein, the deprotection of formula VIIIa is conducted in presence of a reducing agent and a solvent at a temperature range of 0°C to 40°C.
 
10. The process according to claim 9, wherein, the reducing agent is selected from the group consisting of sodium iodide/boron trifluoride-diethyl etherate or Palladium/carbon or iodotrimethylsilane reagent and the solvent is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, diethyl ether, toluene, dichloromethane, dichloroethane, chloroform and water, either alone or in combinations thereof.
 
11. The process according to claim 1, wherein, the compound of formula IX is purified using the solvents selected from the group consisting of ethyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, and isopropyl acetate either alone or in combinations thereof with water for dissolution and precipitating the pure compound adding the solvent selected from n-hexane, n-heptane, cyclohexane.
 
12. The process according to claim 11, wherein, the purification of the crude compound is maintained at a temperature of 25°C to 45°C.
 
13. The process according to claim 1, wherein, the compound of formula IX is selected from the group of compounds consisting of

a) (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 of Formula II;

b) (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol of formula III;

c) (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol of formula IV; and

d) (2S,3R,4R,SS,6R)-2-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-6-(hydroxymethyl)oxane-3,4,5-triol of compound of formula V.


 
14. The process according to claim 1, wherein, the process for the preparation of the compound (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 of Formula II,

comprising the steps of,

a) reacting the compound 2,3,4,6-tetra-O-benzyl-D-glucopyranose of Formula VI,

with aryl halide compound of Formula VII

wherein X is any halogen group selected from Cl, Br or I; R is methyl; and Ar is 5-(4-fluorophenyl)thiophen-2-yl of Formula of residue A;
in presence of sodium hypochlorite solution, a strong base and organic solvent at a temperature in the range of -80°C to 0°C to isolate an intermediate compound (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 of Formula la;

b) reacting the intermediate compound of Formula Ia with a reducing reagent and boron trifluoride-diethyl etherate in presence of solvent and further purifying to obtain the intermediate 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 of Formula VIIIb; and

c) deprotecting the compound of Formula VIIIb to isolate compound of Formula II.

d) Purifying the compound of Formula II in solvents selected from the group consisting of ethyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, and isopropyl acetate either alone or in combinations thereof with water for dissolution and precipitating the pure compound adding the solvent selected from n-hexane, n-heptane, cyclohexane.


 
15. The compound of formula VIII or its enantiomer

wherein R is halogen, alkyl or alkoxy group; and Ar is aryl group, substituted or unsustituted monocyclic, polycyclic or heterocyclic ring selected from the residues A or B as given below,

selected from the group consisting of;

a) the compound of formula VIIIa,

wherein R is halogen, alkyl or alkoxy group; and Ar is aryl group, substituted or unsustituted monocyclic, polycyclic or heterocyclic ring selected from the residues A or B as given below.

b) the compound of Formula VIIIb, and

c) the compound of Formula VIIIc.


 


Ansprüche

1. Verfahren für die Herstellung der Verbindung der Formel IX,

wobei R eine Halogen-, Alkyl- oder Alkoxygruppe ist; und Ar Folgendes ist:
Arylgruppe, substituierter oder unsubstituierter monocyclischer, polycyclischer oder heterocyclischer Ring, der aus den Resten A, B, C oder D, wie nachstehend angegeben, ausgewählt ist:

welches Verfahren Folgendes umfasst:

a) Behandeln der Verbindung 2,3,4,6-Tetra-O-benzyl-D-glucopyranose der Formel VI,

mit einer Arylhalogenidverbindung der Formel VII,

wobei Ar und R wie vorstehend definiert sind und X jedwede Halogengruppe ist, die aus Cl, Br oder I ausgewählt ist,
in Gegenwart von Natriumhypochloritlösung, einer starken Base und einem organischen Lösungsmittel bei einer Temperatur in dem Bereich von -80 °C bis 0 °C, um eine Zwischenverbindung der Formel I zu isolieren:

wobei Bn eine Benzylgruppe ist, R1 Wasserstoff oder Methyl ist und

R und Ar wie vorstehend definiert sind;

b) Reagieren der Zwischenverbindung der Formel I mit einem Reduktionsreagenz und Bortrifluoriddiethyletherat in Gegenwart eines Lösungsmittels, um die Zwischenverbindung der Formel VIII zu erhalten:

wobei R und Ar wie vorstehend definiert sind;

c) Aufreinigen der Verbindung der Formel VIII aus einem Lösungsmittel, um die Verbindung der Formel VIIIa zu erhalten:

wobei R, Ar und Bn wie vorstehend definiert sind; und

d) Entschützen der Zwischenverbindung der Formel VIIIa, um die Verbindung der Formel IX zu isolieren.


 
2. Verfahren nach Anspruch 1, wobei das organische Lösungsmittel, das im Schritt a) verwendet wird, aus der Gruppe ausgewählt ist, die aus Folgenden besteht: Ether, Diethylether, Dibutylether, Toluol, Xylol und Tetrahydrofuran, entweder allein oder in Kombinationen davon.
 
3. Verfahren nach Anspruch 1, wobei die Base, die im Schritt a) verwendet wird, aus der Gruppe ausgewählt ist, die aus metallorganischen Reagenzien besteht, wie zum Beispiel n-Butyllithium, sec-Butyllithium oder einer Mischung aus n-Hexyllithium und (Trimethylsilyl)methyllithium.
 
4. Verfahren nach Anspruch 1, wobei das Reduktionsmittel, das im Schritt b) verwendet wird, aus der Gruppe von Reagenzien ausgewählt ist: Phenylsilan, Tri-n-propylsilan, Dimethylphenylsilan, Triethylsilan, Tris(trimethylsilyl)silan, Triisobutylsilan, Triphenylsilan, tert-Butyldimethylsilan, Triisopropylsilan und Diisobutylaluminiumhydrid.
 
5. Verfahren nach Anspruch 4, wobei das Reduktionsmittel aus Triethylsilan, Phenylsilan und Tris(trimethylsilyl)silan ausgewählt ist.
 
6. Verfahren nach Anspruch 1, wobei das Lösungsmittel, das im Schritt b) verwendet wird, aus der Gruppe ausgewählt ist, die aus Folgenden besteht: Dichlormethan, Dichlorethan, Chloroform, Toluol, Xylol Tetrahydrofuran, Ether, Ethylacetat und Acetonitril, entweder allein oder in Kombinationen davon.
 
7. Verfahren nach Anspruch 1, wobei die Reaktion von Schritt b) bei einer Temperatur in dem Bereich von -45 °C bis 30 °C durchgeführt wird.
 
8. Verfahren nach Anspruch 1, wobei die Aufreinigung der Verbindung der Formel VIII in dem Lösungsmittel durchgeführt wird, das aus der Gruppe ausgewählt ist, die aus Folgenden besteht: Methanol, Ethanol, Isopropylalkohol, Butanol und Ethylacetat, entweder allein oder in Kombinationen davon, um die Verbindung der Formel VIIIa zu erhalten.
 
9. Verfahren nach Anspruch 1, wobei die Entschützung der Formel VIIIa in Gegenwart eines Reduktionsmittels und eines Lösungsmittels bei einem Temperaturbereich von 0 °C bis 40 °C ausgeführt wird.
 
10. Verfahren nach Anspruch 9, wobei das Reduktionsmittel aus der Gruppe ausgewählt ist, die aus Natriumiodid/Bortrifluoriddiethyletherat oder Palladium/Kohlenstoff oder Iodtrimethylsilan-Reagenz besteht, und das Lösungsmittel aus der Gruppe ausgewählt ist, die aus Folgenden besteht: Acetonitril, Methanol, Ethanol, Isopropanol, Tetrahydrofuran, Diethylether, Toluol, Dichlormethan, Dichlorethan, Chloroform und Wasser, entweder allein oder in Kombinationen davon.
 
11. Verfahren nach Anspruch 1, wobei die Verbindung der Formel IX unter Verwendung der Lösungsmittel, die aus der Gruppe ausgewählt sind, die aus Folgenden besteht: Ethylacetat, Methanol, Methylethylketon, Methylisobutylketon und Isopropylacetat, entweder allein oder in Kombinationen davon, mit Wasser für die Auflösung und Ausfällen der reinen Verbindung unter Zugabe des Lösungsmittels, das aus n-Hexan, n-Heptan, Cyclohexan ausgewählt ist, aufgereinigt wird.
 
12. Verfahren nach Anspruch 11, wobei die Aufreinigung der Rohverbindung bei einer Temperatur von 25 °C bis 45 °C aufrechterhalten wird.
 
13. Verfahren nach Anspruch 1, wobei die Verbindung der Formel IX aus der Gruppe von Verbindungen ausgewählt ist, die aus Folgenden besteht:

a) (2S,3R,4R,5S,6R)-2-(3-((5-(4-Fluorphenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol der Formel II:

b) (2S,3R,4R,5S,6R)-2-[4-Chlor-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol der Formel III:

c) (2S,3R,4R,5S,6R)-2-[4-Chlor-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxan-3,4,5-triol der Formel IV:

und

d) (2S,3R,4R,5S,6R)-2-[3-(1-Benzothiophen-2-ylmethyl)-4-fluorphenyl]-6-(hydroxymethyl)oxan-3,4,5-triol der Verbindung der Formel V:


 
14. Verfahren nach Anspruch 1, wobei das Verfahren für die Herstellung der Verbindung (2S,3R,4R,5S,6R)-2-(3-((5-(4-Fluorphenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol der Formel II,

die folgenden Schritte umfasst:

a) Reagieren der Verbindung 2,3,4,6-Tetra-O-benzyl-D-glucopyranose der Formel VI,

mit einer Arylhalogenidverbindung der Formel VII,

wobei X jedwede Halogengruppe ist, die aus Cl, Br oder I ausgewählt ist, R Methyl ist und Ar 5-(4-Fluorphenyl)thiophen-2-yl der Formel des Restes A ist,
in Gegenwart von Natriumhypochloritlösung, einer starken Base und einem organischen Lösungsmittel bei einer Temperatur in dem Bereich von -80 °C bis 0 °C, um eine Zwischenverbindung (3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorphenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-2-ol der Formel Ia zu isolieren:

b) Reagieren der Zwischenverbindung der Formel Ia mit einem Reduktionsreagenz und Bortrifluoriddiethyletherat in Gegenwart eines Lösungsmittels und weiter Aufreinigen, um die Zwischenverbindung (2R,3R,4R,5S,6S)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-6-(3-((5-(4-fluorphenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran der Formel VIIIb zu erhalten:

c) Entschützen der Verbindung der Formel VIIIb, um die Verbindung der Formel II zu isolieren; und

d) Aufreinigen der Verbindung der Formel II in Lösungsmitteln, die aus der Gruppe ausgewählt sind, die aus Folgenden besteht: Ethylacetat, Methanol, Methylethylketon, Methylisobutylketon und Isopropylacetat, entweder allein oder in Kombinationen davon, mit Wasser für die Auflösung und Ausfällen der reinen Verbindung unter Zugabe des Lösungsmittels, das aus n-Hexan, n-Heptan, Cyclohexan ausgewählt ist.


 
15. Verbindung der Formel VIII oder ihr Enantiomer,

wobei R eine Halogen-, Alkyl- oder Alkoxygruppe ist und Ar Folgendes ist: Arylgruppe, substituierter oder unsubstituierter monocyclischer, polycyclischer oder heterocyclischer Ring, der aus den Resten A oder B, wie nachstehend angegeben, ausgewählt ist:

die/das aus der Gruppe ausgewählt ist, die aus Folgenden besteht:

a) der Verbindung der Formel VIIIa,

wobei R eine Halogen-, Alkyl- oder Alkoxygruppe ist und Ar Folgendes ist: Arylgruppe, substituierter oder unsubstituierter monocyclischer, polycyclischer oder heterocyclischer Ring, der aus den Resten A oder B, wie nachstehend angegeben, ausgewählt ist:

b) der Verbindung der Formel VIIIb,

und

c) der Verbindung der Formel VIIIc,


 


Revendications

1. Procédé de préparation d'un composé de Formule IX,

dans lequel R est halogène, un groupement alkyle ou alcoxy ; et Ar est un groupement aryle, un cycle monocyclique, polycyclique ou hétérocyclique substitué ou non substitué, choisi parmi les restes A, B, C ou D tels que donnés ci-après

lequel procédé comprend

a) le traitement du composé de 2,3,4,6-tétra-O-benzyl-D-glucopyranose de Formule VI,

avec un composé d'halogénure d'aryle de Formule VII

dans lequel Ar et R sont tels que définis précédemment et X est un groupement halogène quelconque choisi parmi Cl, Br, ou I,
en présence d'une solution d'hypochlorite de sodium, d'une base forte et d'un solvant organique à une température dans la plage allant de -80°C à 0°C, afin d'isoler un composé intermédiaire de Formule I

dans lequel Bn est un groupement benzyle ; R1 est hydrogène ou méthyle ; et

R et Ar sont tels que définis ci-dessus ;

b) la réaction du composé intermédiaire de Formule I avec un réactif réducteur et du trifluorure de bore-éthérate de diéthyle en présence de solvant, afin d'obtenir le composé intermédiaire de Formule VIII

dans lequel R et Ar sont tels que définis ci-dessus,

c) la purification du composé de Formule VIII à partir d'un solvant, afin d'obtenir le composé de Formule Villa ;

dans lequel R, Ar et Bn sont tels que définis précédemment, et

d) la déprotection du composé intermédiaire de Formule VIIIa, afin d'isoler le composé de Formule IX.


 
2. Procédé selon la revendication 1, dans lequel le solvant organique utilisé dans l'étape a) est choisi dans le groupe constitué par l'éther, le diéthyl éther, le dibutyl éther, le toluène, le xylène et le tétrahydrofurane, seuls ou bien en combinaisons de ceux-ci.
 
3. Procédé selon la revendication 1, dans lequel la base utilisée dans l'étape a) est choisie dans le groupe constitué par les réactifs organométalliques tels que le n-butyllithium, le sec-butyllithium, ou un mélange de n-hexyllithium et de (triméthylsilyl)méthyllithium.
 
4. Procédé selon la revendication 1, dans lequel l'agent réducteur utilisé dans l'étape b) est choisi dans le groupe constitué par les réactifs à base de phénylsilane, de tri-n-propylsilane, de diméthylphénylsilane, de triéthylsilane, de tris(triméthylsilyl)silane, de triisobutylsilane, de triphénylsilane, de tertio-butyldiméthylsilane, de triisopropylsilane, et d'hydrure de diisobutylaluminium.
 
5. Procédé selon la revendication 4, dans lequel l'agent réducteur est choisi parmi le triéthylsilane, le phénylsilane, et le tris(triméthylsilyl)silane.
 
6. Procédé selon la revendication 1, dans lequel le solvant utilisé dans l'étape b) est choisi dans le groupe constitué par le dichlorométhane, le dichloroéthane, le chloroforme, le toluène, le xylène, le tétrahydrofurane, l'éther, l'acétate d'éthyle et l'acétonitrile, seuls ou bien en combinaisons de ceux-ci.
 
7. Procédé selon la revendication 1, dans lequel la réaction de l'étape b) est effectuée à une température dans la plage allant de -45°C à 30°C.
 
8. Procédé selon la revendication 1, dans lequel la purification du composé de Formule VIII est effectuée dans un solvant choisi dans le groupe constitué par le méthanol, l'éthanol, l'alcool isopropylique, le butanol et l'acétate d'éthyle, seuls ou bien en combinaisons de ceux-ci, afin d'obtenir le composé de Formule VIIIa.
 
9. Procédé selon la revendication 1, dans lequel la déprotection de la Formule VIIIa est effectuée en présence d'un agent réducteur et d'un solvant à une température dans la plage allant de 0°C à 40°C.
 
10. Procédé selon la revendication 9, dans lequel l'agent réducteur est choisi dans le groupe constitué par l'iodure de sodium/trifluorure de bore-éthérate de diéthyle ou un réactif à base de palladium sur charbon ou d'iodotriméthylsilane, et le solvant est choisi dans le groupe constitué par l'acétonitrile, le méthanol, l'éthanol, l'isopropanol, le tétrahydrofurane, le diéthyl éther, le toluène, le dichlorométhane, le dichloroéthane, le chloroforme et l'eau, seuls ou bien en combinaisons de ceux-ci.
 
11. Procédé selon la revendication 1, dans lequel le composé de Formule IX est purifié en utilisant des solvants choisis dans le groupe constitué par l'acétate d'éthyle, le méthanol, la méthyléthylcétone, la méthylisobutylcétone, et l'acétate d'isopropyle, seuls ou bien en combinaisons de ceux-ci, avec de l'eau pour la solubilisation et la précipitation du composé pur, en ajoutant un solvant choisi parmi le n-hexane, le n-heptane, le cyclohexane.
 
12. Procédé selon la revendication 11, dans lequel la purification du composé brut est maintenue à une température allant de 25°C à 45°C.
 
13. Procédé selon la revendication 1, dans lequel le composé de Formule IX est choisi dans le groupe des composés constitués par

a) le (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophényl)thiophén-2-yl)méthyl)-4-méhyl-phényl)-6-(hydroxyméthyl)tétrahydro-2H-pyran-3,4,5-triol de Formule II

b) le (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-éthoxybenzyl)phényl]-6-(hydroxy-méthyl)tétrahydro-2H-pyran-3,4,5-triol de Formule III

c) le (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphényl]méthyl]-phényl]-6-(hydroxyméthyl)oxane-3,4,5-triol de Formule IV ; et

d) le (2S,3R,4R,5S,6R)-2-[3-(1-benzothiophén-2-ylméthyl)-4-fluorophényl]-6-(hydroxyméthyl)oxane-3,4,5-triol du composé de Formule V


 
14. Procédé selon la revendication 1, dans lequel le procédé de préparation du composé de (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophényl)thiophén-2-yl)méthyl)-4-méhylphényl)-6-(hydroxyméthyl)tétrahydro-2H-pyran-3,4,5-triol de Formule II

comprenant les étapes consistant à

a) réagir le composé de 2,3,4,6-tétra-O-benzyl-D-glucopyranose de Formule VI

avec un composé d'halogénure d'aryle de Formule VII

dans lequel X est un groupement halogène quelconque choisi parmi Cl, Br ou I ;

R est méthyle ; et Ar est 5-(4-fluorophényl)thiophén-2-yle de Formule du reste A ;

en présence d'une solution d'hypochlorite de sodium, d'une base forte et d'un solvant organique à une température dans la plage allant de -80°C à 0°C, afin d'isoler un composé intermédiaire de (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)méthyl)-2-(3-((5-(4-fluorophényl)thiophén-2-yl)méthyl)-4-méhylphényl)tétrahydro-2H-pyran-2-ol de Formule la

b) réagir le composé intermédiaire de Formule la avec un réactif réducteur et du trifluorure de bore-éthérate de diéthyle en présence de solvant, et purifier davantage, afin d'obtenir le composé intermédiaire de (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)méthyl)-6-(3-((5-(4-fluorophényl)thiophén-2-yl)méthyl)-4-méhylphényl)-tétrahydro-2H-pyrane de Formule VIIIb ;

c) déprotéger le composé de Formule VIIIb afin d'isoler le composé de Formule II, et

d) purifier le composé de Formule II dans des solvants choisis dans le groupe constitué par l'acétate d'éthyle, le méthanol, la méthyléthylcétone, la méthylisobutylcétone, et l'acétate d'isopropyle, seuls ou bien en combinaisons de ceux-ci, avec de l'eau pour la solubilisation et la précipitation du composé pur, en ajoutant un solvant choisi parmi le n-hexane, le n-heptane, le cyclohexane.


 
15. Composé de Formule VIII, ou son énantiomère,

dans lequel R est halogène, un groupement alkyle ou alcoxy ; et Ar est un groupement aryle, un cycle monocyclique, polycyclique ou hétérocyclique substitué ou non substitué, choisi parmi les restes A ou B tels que donnés ci-après

choisi dans le groupe constitué par

a) le composé de Formule VIIIa

dans lequel R est halogène, un groupement alkyle ou alcoxy ; et Ar est un groupement aryle, un cycle monocyclique, polycyclique ou hétérocyclique substitué ou non substitué, choisi parmi les restes A ou B tels que donnés ci-après

b) le composé de Formule VIIIb,

et

c) le composé de Formule VIIIc


 




REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




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