DESC:FIELD OF THE INVENTION:
The present invention reports improved process for preparation of Ertugliflozin L-Pyroglutamate and its Intermediates.
BACKGROUND OF THE INVENTION:
Ertugliflozin (trade name Steglatro) is a drug for treatment of type 2 diabetes. In the United States, it was approved by the Food and Drug Administration for use as a monotherapy and as a fixed dose combination with either sitagliptin or with metformin. In Europe, it was approved in March 2018 for use as a monotherapy or combination therapy. Ertugliflozin is a sodium/glucose cotransporter 2 (SGLT2) inhibitor and is in the class of drugs known as gliflozins. A combination with metformin is marketed as Segluromet.
Adverse effects in studies that were significantly more common under Ertugliflozin than under placebo included mycosis of the genitals in both men and women, vaginal itch, increased urination, thirst, hypoglycaemia (low blood sugar), and weight loss under the higher dosing scheme. A rare but life-threatening side effect of gliflozins is ketoacidosis; it occurred in three patients (0.1%) in Ertugliflozin studies. As with many diabetes drugs, combining Ertugliflozin with insulin or insulin secretagogues (such as sulfonylureas) may result in an increased risk for low blood sugar. Combination with diuretics may result in a higher risk for dehydration and low blood pressure. No clinically relevant pharmacokinetic interactions have been found in studies.
After oral intake, Ertugliflozin is practically completely absorbed from the gut and undergoes no relevant first-pass effect. Highest blood plasma concentrations are reached after one hour. When in circulation, 93.6% of the substances are bound to plasma proteins. Ertugliflozin is metabolized mainly to glucuronides by the enzymes UGT1A9 and UGT2B7. Cytochrome P450 enzymes play only a minor role in its metabolism.
The elimination half-life is estimated to be 17 hours. 40.9% are eliminated via the feces (33.8% in unchanged form and 7.1% as metabolites) and 50.2% via the urine (1.5% unchanged and 48.7% as metabolites). The high proportion of unchanged substance in the feces is probably due to hydrolysis of the metabolites back to the parent substance.
US patent number 8,080,580 discloses processes for preparation of Ertugliflozin which involves protecting the primary alcohol moiety of an intermediate compound with a trityl group in the presence of pyridine and subsequent deprotection with p-toluenesulfonic acid. This patent also discloses conversion of the Ertugliflozin to Ertugliflozin L- pyroglutamic acid.
PCT publication number WO 2014/159151 discloses a process for preparation of Ertugliflozin and its conversion to Ertugliflozin L-pyroglutamic acid. PCT publication number WO 2014/159151 discloses a process for preparation of Ertugliflozin and its conversion to Ertugliflozin-L-pyroglutamic acid (1: 1) co-crystal using excess L-pyroglutamic acid.
The deprotection of the trityl group in the presence of an acid catalyst leads to low purity and yield of the product. Also, pyridine is a hazardous chemical and its use for the manufacture of a drug product is not advisable.
OPRD Article titled “Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin” gives the development and optimization of a scalable synthesis of sodium-dependent glucose cotransporter 2 inhibitor, Ertugliflozin, for the treatment of type-2 diabetes. Highlights of the chemistry are a concise, four-step synthesis of a structurally complex API from known intermediate 4 via persilylation-selective monodesilylation, primary alcohol oxidation, aldol-crossed-Cannizzaro reaction, and solid-phase acid-catalyzed bicyclic ketal formation. The final API was isolated as the L-Pyroglutamic acid Co-crystal.
Organic Letters article titled “Stereoselective Synthesis of a Dioxabicyclo[3.2.1]Octane SGLT2 Inhibitor”, a promising class of SGLT2 inhibitors bearing a unique dioxabicyclo[3.2.1]Octane motif was recently disclosed. An improved stereoselective synthesis providing efficient access to one of the most potent and selective compounds from this class is reported. A one-pot deprotection/ cyclization was used as the key step to form the dioxabicyclo[3.2.1]Octane motif with full control of stereochemistry. Using an appropriately substituted aryl group, the route enables the synthesis of any given compound from the class.
Another OPRD article titled “Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin” gives a practical synthesis of SGLT2 inhibitor candidate Ertugliflozin has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxabicyclo[3.2.1]Octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-D-glucose, with nucleophilichydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate. A co-crystalline complex of the amorphous solid 1 with L-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.
US patent 7,919,598 provides a novel method for a crystalline (S)-propylene glycol ((S)-PG) solvate compound Ia (form SC-3) of Ertugliflozin. A process of preparing crystalline compound Ia (form SC-3)

comprising:
treating compound A

in an organic solvent with base and (S)-propylene glycol, optionally adding seeds of (S)-PG crystalline compound Ia (form SC-3), to provide (S)-PG crystalline compound Ia (form SC-3).
Journal of Medicinal Chemistry titled “Discovery of a Clinical Candidate from the Structurally Unique Dioxabicyclo[3.2.1]Octane Class of Sodium-Dependent Glucose Cotransporter 2 Inhibitors” basically gives the method synthesis of Ertugliflozin as depicted in the scheme below:

The present invention relates to the novel process for the preparation of (2S,3S,4S,5R)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-carbaldehyde intermediate and its use for the preparation of Ertugliflozin L-Pyroglutamate.

SUMMARY OF THE INVENTION:
The present invention relates to the novel process for preparation of (2S,3S,4S,5R)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-carbaldehyde intermediate and its further use for preparation of Ertugliflozin L-Pyroglutamate.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a novel process for preparation of (2S,3S,4S,5R)-6-(4-chloro-3-(4-ethoxybenzyl) phenyl)-3,4,5-trihydroxy-6-methoxy tetra hydro-2H-pyran-2-carbaldehyde is disclosed which comprises:
1. a solution of methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-tris-O-(trimethylsilyl)-a-D-Glucopyranoside in methylene dichloride and dimethylsulphoxide at 10-20°C is taken;
2. triethylamine is added to it;
3. further added sulphur trioxide pyridine complex with stirring at 10-20°C till reaction completion;
4. water is added, the pH is adjusted with hydrochloric acid to 2.0-2.5 and layer separation;
5. complete recovery of methylene chloride to get residue containing a mixture of two major compounds;
6. residue of step 5. dissolved in methylene dichloride (250 ml);
7. trifluoroacetic acid added to it at 0-10°C and stirred till completion of the reaction;
8. water is added and pH is adjusted to 6.5-7.0 using aqueous sodium bicarbonate solution;
9. layer separation and washing of methylene dichloride layer with 10% sodium chloride solution; and
10. complete recovery of methylene dichloride layer and isolating (2S,3S,4S,5R)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-carbaldehyde for use in the preparation of Ertugliflozin L-Pyroglutamate.
According to the second embodiment of the present invention, a novel process for purification of (1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-Ethoxybenzyl) phenyl)-1-(hydroxymethyl)-6,8-dioxa bicyclo-[3.2.1]Octane-2,3,4-triol L-Pyroglutamate or Ertugliflozin L-Pyroglutamate is disclosed which comprises:
1. adding crude (1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-Ethoxybenzyl)phenyl)-1-(hydroxy methyl)-6,8-dioxa bicyclo-[3.2.1]Octane-2,3,4-triol L-Pyroglutamate or Ertugliflozin L-Pyroglutamate in aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof with or without water;
2. heating and stirring the reaction mass at 70-80°C for 1-2 hours to ensure complete dissolution;
3. cooling the reaction mass to 0-10°C;
4. stirring for 2-3 hours at this temperature;
5. isolation of product as wet cake by routine filtration;
6. running washing with the C1-C4 alcohol as used in step 1. above with or without water; and
7. drying the wet cake at 35-45°C for 8-16 hours to get desired pure (1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-Ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo-[3.2.1] Octane-2,3,4-triol L-Pyroglutamate or Ertugliflozin L-Pyroglutamate.
The above-mentioned invention is supported by the following non-limiting examples:
Example 1: Preparation of Methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-tris-O-(trimethylsilyl)-a-D-Glucopyranoside: 50g of Methyl-1-C-[4-chloro-3-[(4-ethoxy phenyl) methyl]phenyl]-D-Glucopyranoside was dissolved in toluene (100 ml) in a round bottom flask. Toluene is distilled off under vacuum at 60-80°C. The reaction mass was cooled to 20-30°C and methylene dichloride (500 ml) was added to it and stirred till complete dissolution. Then, imidazole (38 g) was added to it and further cooled to -40 to -50°C and chlorotrimethyl silane (58.50 g) was added to it and stirred till completion of the reaction. Water (250 ml) was added to it and the reaction mass was allowed to raise temperature to 20-30°C. The product was extracted with methylene dichloride (100 ml) and added solution of Pyridinium p-Toluene sulfonate (157.50 g) in water (133.50 g) to it. Washing of the organic layer is done with sodium dihydrogen phosphate (6.40 g) and disodium hydrogen phosphate (11.20 g) solution in water (250 ml) followed by washing with 10% sodium chloride solution (100 ml). Then, methylene chloride was removed completely to get 71 g of Methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-tris-O-(trimethylsilyl)-a-D-Glucopyranoside.
Example 2: Preparation of (2S,3S,4S,5R)-6-(4-chloro-3-(4-ethoxybenzyl) phenyl)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-carbaldehyde: 70g of Methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]-2,3,4-tris-O-(trimethylsilyl)-a-D-Glucopyranoside was dissolved in methylene dichloride (350ml) in a round bottom flask at 20-30°C with stirring. The reaction mass was cooled to 10-20°C and then dimethyl sulphoxide (50g) was added followed by addition of triethylamine (38 g). Addition of sulphur trioxide pyridine complex (46 g) was done and stirred till completion of reaction. Water (300ml) was added and the pH was adjusted with hydrochloric acid to 2.0-2.5 and layer separation. Methylene chloride was completely recovered to get the residue containing a mixture of two major compounds.
The residue was dissolved in methylene dichloride (250ml) and trifluoroacetic acid (50g) was added to it at 0-10°C and stirred till the completion of reaction. Water (100ml) was added and the pH adjusted to 6.5-7.0 using aqueous sodium bicarbonate solution. The organic layer was separated and complete recovery of methylene dichloride was done. Methanol was added and complete recovery for removal of traces of methylene dichloride was done; (2S,3S,4S,5R)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-carbaldehyde was isolated for use in the preparation of Ertugliflozin L-Pyroglutamate.
Example 3: Preparation of (2S,3R,4S,5S)-2-(4-chloro-3-(4-Ethoxybenzyl) phenyl)-6,6-bis(hydroxymethyl)-2-methoxy tetrahydro-2H-pyran-3,4,5-triol: 48g of (2S,3S,4S,5R)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-carbaldehyde for use in the preparation of Ertugliflozin L-Pyroglutamate was dissolved in methanol (100 ml) at 20-30°C. The reaction mass was heated to 50-60°C followed by the addition of solution of sodium methoxide (45g) in methanol (200ml). The resulting mass was stirred for 3-4 hours till the completion of the reaction. The solution of sodium bisulfite (165 g) in water (550ml) was added to it and stirred for 30-60 minutes. Methanol was recovered under vacuum at 50-60°C and the reaction mass was cooled to 25-35°C. Water (100 ml) was added and the product was extracted in methyl tert-butyl ether (250 ml). Methylene tert butyl ether was completely recovered under vacuum and the product was recrystallized in methanol (100 ml) to get (2S,3R,4S,5S)-2-(4-chloro-3-(4-Ethoxybenzyl)phenyl)-6,6-bis(hydroxymethyl)-2-methoxy tetra hydro-2H-pyran-3,4,5-triol as white solid (HPLC purity= 99.90%).
Example 4: Preparation of Ertugliflozin L-Pyroglutamate: 35g of (2S,3R,4S,5S)-2-(4-chloro-3-(4-Ethoxybenzyl) phenyl)-6,6-bis(hydroxymethyl)-2-methoxy tetrahydro-2H-pyran-3,4,5-triol was dissolved in methylene chloride (175ml) at 20-30°C. The resulting mass was cooled to 0-10°C followed by the addition of trifluoroacetic acid (18.5 g) and was stirred for 1-3 hours till the completion of the reaction. Water (74 ml) was added and the pH adjusted to 6.6-7.0 using aqueous sodium bicarbonate solution. The methylene chloride layer was separated, and its complete recovery was done to get the residue. Isopropyl alcohol (70ml) was added for complete dissolution followed by addition of L-Pyroglutamic acid (40g) and stirred for 1-2 minutes at 50-60°C. The resulting material was cooled to 20-30°C and stirred for 1-3 hours. The material was cooled to 0-10°C and stirred for 1-3 hours. The product was filtered and washed with IPA (20ml) and material was dried at 35-45°C for 8-16 hours to get 33g (1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-Ethoxybenzyl) phenyl)-1-(hydroxymethyl)-6,8-dioxa bicyclo-[3.2.1]Octane-2,3,4-triol L-Pyroglutamate or Ertugliflozin L-Pyroglutamate.

,CLAIMS:We Claim:
1. A novel process for the preparation of (2S,3S,4S,5R)-6-(4-chloro-3-(4-ethoxybenzyl) phenyl)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-carbaldehyde which comprises:
a) preparing a solution of Methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl]-2,3,4-tris-O-(trimethylsilyl)-a-D-Glucopyranoside in and aliphatic halogenated hydrocarbon selected from methylene dichloride, ethylene chloride and dimethyl sulphoxide at 10-20°C;
b) adding triethylamine and sulphur trioxide pyridine complex with stirring at 10-20°C till reaction completion;
c) adding water and adjusting the pH with hydrochloric acid to 2.0-2.5;
d) stirring and separating the layer;
e) completely recovering the solvent from organic layer to get solid residue;
f) re-dissolving solid residue in solvent of step a);
g) adding trifluoroacetic acid to it at 0-10°C and stirring for 2-3 hours;
h) adding water and adjusting pH to 6.5-7.0 by Sodium bicarbonate solution;
i) stirring and separating the layer;
j) washing the organic layer with brine solution; and
k) isolating the desired material, (2S,3S,4S,5R)-6-(4-chloro-3-(4-ethoxybenzyl) phenyl)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-carbaldehyde by complete solvent recovery under vacuum.
2. A novel process for purification of (1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-ethoxybenzyl) phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo-[3.2.1]Octane-2,3,4-triol L-Pyroglutamate or Ertugliflozin L-Pyroglutamate which comprises:
a) dissolving crude (1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-Ethoxybenzyl)phenyl)-1-(hydroxy methyl)-6,8-dioxa bicyclo-[3.2.1]Octane-2,3,4-triol L-Pyroglutamate or Ertugliflozin L-Pyroglutamate in aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof with or without water;
b) heating to 70-80°C and stirring;
c) cooling the reaction mass to room temperature;
d) further stirring at 0-10°C;
e) isolating the product as wet cake by filtration; and
f) drying the wet cake at 35-45°C for 8-16 hours to get desired pure (1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-Ethoxybenzyl)phenyl)-1-(hydroxy methyl)-6,8-dioxabicyclo-[3.2.1]Octane-2,3,4-triol-L-Pyroglutamate or Ertugliflozin L-Pyroglutamate.