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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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澳格列汀, SP2086, Retagliptin

Figure imgb0068 Figure imgb0002   澳格列汀, SP2086, Retagliptin 1174122-54-3(Retagliptin), 1174038-86-8 (Retagliptin Hydrochloride), 1256756-88-3(Retagliptin Phosphate) (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7, 8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester Methyl (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo [1,5-a]pyrazine-1-carboxylate, DPP-4 inhibitor Type II diabetes

Jiangsu Hengrui Medicine Co., Ltd

  Nanjing Changao Pharmaceutical 澳格列汀 is a novel DPP-4 inhibitor (gliptin) for the treatment of type II diabetes. Because Shanghai Sun Sail Pharmaceutical, a wholly owned subsidiary of Nanjing Changao Pharmaceutical, has filed two patents to protect DPP-4 inhibitors (WO2011147207 and CN101786978), it is unknown which one covers this drug. Relevant data’s from WHO showed morbidity rate, disability rate, death rate of diabetes mellitus and overall health level of diabetes mellitus patients have already ranked the third place in non-infectious diseases, diabetes, together with tumors and cardiovascular diseases were the three main diseases which threats human health. Diabetes mellitus is usually classified into type 1 and type 2, there are more than 240 million diabetes patients, and 90% of them are suffering from type 2 diabetes, which also has a 1% growth rate every year, so, type 2 diabetes will be the main new growth point of diabetes drug market. The incidence of diabetes in China is about 5%, the number of patients of which ranks second place in the world just behind India. There are many antidiabetic drugs on the market, insulin injection, metformin, rosiglitazone, pioglitazone are representations of them. However, there is no drug alone can keep the HbA1c level of type 2 diabetes patients within the aimed range in a long term. Even though used in combination, the effect of the drugs will go down year by year after 3-4 years. Adverse reaction is one of the problems of many hypoglycemic drugs, wherein the fatal hypoglycemia is most worried by clinicians; secondly, many oral hypoglycemic drugs, such as sulfonylureas, α-glycosidase inhibitors and thiazolidinediones may all induce weight gain to patients, some of the drugs may also induce cardiovascular diseases. Therefore, developing new type hypoglycemic drugs with brand new mechanism of action, higher safety and effectiveness is an important task that should be completed quickly for the scientists. In the process of constantly finding new methods endocrine hormones were found to play an important role in the pathology and physiology of type 2 diabetes. Dipeptidyl peptidase-IV (DPP-IV) is an important enzyme related to diabetes, inhibiting the action of which to treat type 2 diabetes is a new method with good prospect. DPP-IV inhibitors can indirectly stimulate the secretion of insulin, the action of which is generated by inhibit DPP-IV to stabilize endocrine hormones such as incretin hormones, glucagons-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). GLP-1 is a production expressed by glucagon protogene after eating, and mainly secreted by intestinal mucosa L-cell, and it can stimulate the secretion of insulin by pancreatic β-cells, which plays a significant role in the stability of blood sugar. Experiments prove that GLP-1 has physiological functions as following: acting on pancreatic β-cells in a glucose-dependent manner, facilitating the transcription of insulin genes, increasing the biosynthesis and secretion of insulin, stimulating the proliferation and differentiation of β-cells, inhibiting the apoptosis of β-cells to increasing the number of pancreatic β-cells; inhibiting the secretion of glucagon; inhibiting the appetite and food intake; retarding the emptying of gastric contents, etc., all of these functions are helpful to reduce blood sugar after food intake and to keep blood sugar within constant level. In addition, it won’t cause the danger of severe hypoglycemia. GLP-1 well controlled the blood sugar of type 2 diabetes animal models and patients by multiple mechanisms. However, GLP-1 may lose biological activity through quick degradation by DPP-IV, and the half life of it is shorter than 2 minutes, which utterly limits the clinical use of GLP-1. It was found in researches that DPP-IV inhibitors can totally protect endogenous and even extraneous GLP-1 from inactivation by DPP-IV, improve activated GLP-llevel, and reduce the antagonistic effect of GLP-1 metabolites. Moreover, DPP-IV inhibitors can also delay the incidence of diabetes through stimulating the regeneration of pancreatic β-cells and the improving the glucose tolerance and insulin sensitivity. Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a novel class of agents that are being developed for the treatment or improvement in glycemic control in patients with Type 2 diabetes. For reviews on the application of DPP-IV inhibitors for the treatment of Type 2 diabetes, reference is made to the following publications: (1) al. “Type 2 diabetes-Therapy with dipeptidyl peptidase IV inhibitors“, Biochim.Biophvs. Acta. 1751:33-44 (2005) and (2) K.Augustyns. et al. “Inhibitors of proline-specific dipeptidyl peptidases: DPP4 inhibitors as a novel approach for the treatment of Type 2 diabetes“, Expert Opin. Ther. Patents, 15:1387-1407 (2005). At present, some DPP-IV inhibitors have been disclosed ( US5462928 , US5543396 , WO9515309 ,WO2003004498 , WO2003082817 , WO2004032836 , WO2004085661 ), including MK-0431 as an DPP-IV inhibitor made by Merck which showed good inhibition activity and selectivity, and which has been on the market by 2006.

    • Figure imgb0001sitagliptin

      (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7, 8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester of the following formula is compound A, the code of which is SP2086.

      Figure imgb0002

恒瑞医药旗下1.1类口服降糖药物瑞格列汀的制备方法 Synthesis of Hengrui Medicine’s diabetes drug Retagliptin courtesy yaopha see enlarged image at …………………………………………………………..

                  Example 1. Preparation of hydrochloride of compound A (SP2086-HCL)
                  (R)-7-[3-t-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester (SM2086-15) (1.35kg, 2.40mol), HCL-ethyl acetate (greater than 2M) (12.3kg) were added into a 100L reaction kettle and stirred to dissolved. The mixture was reacted for more than 2 hours at normal temperature. Detected with TLC to reaction completely before evaporated and pumped to dryness with oil pump to give 1.15∼1.20kg of white to light yellow solid product with [α]


                -28.0∼-33.0° (C=1, methanol), yield 96.0∼100%. The product was hydrochloride of (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7, 8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester (SP2086-HCL). (TLC detection: silica gel GF254plate; developing reagent: chloroform: methanol: ammonia= 40: 1: 0.1; raw material 15: Rf=0.80, product 1: Rf=0.50; ultraviolet visualization).

Example 2. Preparation of phosphate of compound A (SP2086-HPO4)

    • SP2086-HCL(1.20kg, 2.40mol) was added into 100L reaction kettle, and dissolved in dichloromethane (15.2kg), then washed with saturated sodium bicarbonate solution (5.8kg). The aqueous layer was extracted once with dichloromethane ( 6.0 kg). The organic layers were combined and washed once with water (5kg), dried with anhydrous sodium sulphate. The mixture was filtrated and concentrated to dryness under reduced pressure at 40°C to give 1.12 kg of oil. The oil was stirred and dissolved with 30 times amount of isopropanol (26.0kg). A solution of 85% phosphoric acid (305.2g, 2.65mol) in isopropanol (1.22kg) was added immidiately after the oil completely dissolved. The solid was separated out, filtered after stirring for 2 hours and washed with cold isopropanol. The wet product was dried under reduced pressure at 40°C to give 1.16∼1.24kg of white to light yellow solid with a yield of 86.0∼92.0% (the wet product could be directly suspended in isopropanol without drying).

……………………………………… Example 1(R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride

        • Figure imgb0068
          Figure imgb0069

Step 1

        • 2,2-Dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione 2,2-Dimethyl-[1,3]dioxane-4,6-dione (5.69 g, 39.5 mmol) was dissolved in 400 mL of dichloromethane under stirring, followed by addition of (2,4,5-trifluoro-phenyl)-acetic acid 1a (7.15 g, 37.6 mmol) and 4-dimethylaminopyridine (7.35 g, 60.2 mmol) in an ice-water bath. Then a suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.28 g, 43.2 mmol) in 250 mL of dichloromethane was added dropwise slowly. After stirring at room temperature for 36 hours, the reaction mixture was washed with the solution of 5% potassium bisulfate (250 mL×7) and saturated brine (250 mL×2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 2,2-dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione 1b (11.4 g, yield 96%) as a white solid. MS m/z (ESI): 315.5 [M-1]

Step 23-Oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester

        • 2,2-Dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione 1b (15.72 g, 49.6 mmol) was dissolved in 280 mL of ethanol under stirring, then the reaction mixture was heated to 70 °C in an oil bath overnight. After cooling, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 3-oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1c (12 g, yield 88%) as a yellow oil. MS m/z (ESI): 259 [M-1]

Step 33-Amino-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester

        • 3-Oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1c (24.6 g, 94.5 mmol) was dissolved in 240 mL of methanol, and ammonium acetate (36.4 g, 473 mmol) was added to the solution. The reaction mixture was heated to reflux for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure, then 100 mL of water was added to the residue. The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a light yellow solid. The resulting solid was dissolved in 50 mL of ethyl acetate at 80 °C, then 50 mL of n-hexane and seed-crystal were added to the solution. The mixture was cooled to room temperature, half an hour later, 100 mL of n-hexane was added. The mixture was stored in refrigerator overnight and then filtered under reduced pressure to obtain the title compound 3-amino-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester 1d(19.5 g, yield 80%) as a white solid. MS m/z (ESI): 260.1 [M+1]Step 43-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester
        • 3-Amino-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester 1d (4.1 g, 15.8 mmol) was added into an autoclave, followed by addition of 70 mL of methanol, di-tert-butyl dicarbonate (3.8 g, 17.4 mmol), chloro(1, 5-cyclooctadiene)rhodium( I ) dimer (32 mg, 0.0632 mmol) and (R)-1-[(S)-2-(diphenyl phosphino)ferrocenyl]-ethyl-tert-butylphosphine (68 mg, 0.126 mmol). The reaction mixture was hydrogenated for 24 hours under 6.67 atmosphere at 30 °C. The mixture was filtered and the filtrate was concentrated under reduced pressure. Then 34 mL of methanol was added to the residue at 50 °C, followed by addition of 12 mL of water until all dissolved. After cooling to room temperature, the mixture was stored in the refrigeratory overnight and then filtered. The solid product was washed with the solvent mixture of methanol/water (v:v = 3:2), dried in vacuo to obtain the title compound 3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (4 g, yield 70%) as a light yellow solid. MS m/z (ESI): 362.4 [M+1]Step 5(R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid
        • 3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1 mmol) were dissolved in the solvent mixture of 100 mL of methanol and 50 mL of water under stirring. The reaction mixture was reacted at 40-45 °C for 1-1.5 hours, then part of the solution was evaporated under reduced pressure. The residue was added with some water, then pH was adjusted to 2-3 with 1 N hydrochloric acid in an ice-water bath. The mixture was extracted with ethyl acetate (200 mLx3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then recrystallized from ethyl acetate/n-hexane to obtain the title compound (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (9.2 g) as a white solid, which was directly used in the next step. MS m/z (ESI): 332.3 [M-1] Reference: Tetrahedron Asymmetry, 2006, 17(2), 205-209

Step 6C-Pyrazin-2-yl-methylamine

        • Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane under stirring, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was hydrogenated for 8 hours under 40 atmosphere at 60 °C, filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methylamine 1h (10.7 g, yield 98%) as a brown oil. MS m/z (ESI): 110 [M+1]

Step 72,2,2-Trifluoro-N-pyrazin-2-ylmethyl-acetamide

        • C-Pyrazin-2-yl-methylamine 1h (10.9 g, 100 mmol) was added into a reaction flask, then 20 mL of trifluoroacetic anhydride was added dropwise slowly within an hour at 0 °C in an ice-water bath. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. Then it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2,2,2-trifluoro-N-pyrazin-2-ylmethyl-acetamide 1i (21.0 g) as a brown oil. MS m/z (ESI): 206.1 [M+1]

Step 83-Trifluoromethyl-imidazo[1,5-a]pyrazine

        • 2,2,2-Trifluoro-N-pyrazin-2-ylmethyl-acetamide 1i (21.0 g, 100 mmol) was added into a reaction flask at room temperature, followed by addition of 100 mL of phosphorus oxychloride. After stirring at room temperature for 30 minutes, phosphorous pentoxide (17.8 g, 125 mmol) was added to the solution. The reaction mixture was heated to reflux for 5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. Phosphorus oxychloride was removed, and the reaction system was quenched with deionized water. The mixture was adjusted to pH 5-6 with 20% sodium hydroxide solution in an ice-water bath. The mixture was extracted with ethyl acetate (250 mL×4), and the combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 3-trifluoromethyl-imidazo[1,5-a]pyrazine 1j (12.0 g, yield 65%) as a yellow solid. MS m/z (ESI): 188.0 [M+1] 1H NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 8.06 (d, 1H), 7.92 (s, 1H), 7.81 (d, 1H)

Step 93-Trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine

        • 3-Trifluoromethyl-imidazo[1,5-a]pyrazine 1j (12.0 g, 64.2 mmol) was dissolved in 150 mL of anhydrous ethanol under stirring, then 10% Pd/C (500 mg) was added to the solution. The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The reaction solution was filtered through a pad of coarse silica gel and concentrated under reduced pressure to obtain the title compound 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1k (12.2 g, yield 99%) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 6.84 (s, 1H), 4.10 (m, 4H), 3.26 (m, 2H), 1.81 (s, 1H)

Step 10(R)-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo [1,5-a]pyrazin-7-yl)-propyl]-carbamic acidtert-butyl ester

        • Under a nitrogen atmosphere, 3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1k (8.6 g, 45 mmol) and 9.4 mL of triethylamine were dissolved in 300 mL of dichloromethane under stirring. After stirring at room temperature for 5 minutes, 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1f (15.0 g, 45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (17.1 g, 67.3 mmol) were added to the solution successively. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 1l (20.0 g, yield 88%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.25 (m, 1H), 7.11 (m, 1H), 7.032 (s, 1H), 4.93 (m, 2H), 4.35 (m, 3H), 4.05 (m, 2H), 2.99 (m, 2H), 2.73 (m, 2H), 1.34 (s, 9H)

Step 11(R)-[3-(1-Bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acidtert-butyl ester

        • (R)-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 11 (20.0 g, 39.6 mmol) was dissolved in 300 mL of anhydrous ethanol under stirring, and 1-bromo-2,5-pyrolidinedione (14.1 g, 79.2 mmol) was then added to the solution at room temperature. After stirring for an hour, potassium carbonate (10.9 g, 79.2 mmol) and di-tert-butyl dicarbonate (8.6 g, 39.6 mmol) were added to the mixture, and the mixture was stirred for an hour and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was filtered through a pad of coarse silica gel to remove potassium carbonate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-i midazo [1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 1m (20.0 g, yield 86%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.063 (m, 1H), 6.88 (m, 1H), 4.72 (s, 1H), 4.56 (s, 1H), 4.13 (m, 3H), 3.88 (m, 2H), 2.94 (m, 2H), 2.62 (m, 2H), 1.36 (s, 9H)

Step 12(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester

      • Octacarbonyldicobalt (4.02 g, 11.76 mmol), ethyl chloroacetate (0.71 g, 5.88 mmol), potassium carbonate (1.62 g, 11.76 mmol) and 50 mL of methanol were added into the reaction flask. After stirring for 5 minutes, (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acidtert-butyl ester 1m (2.3 g, 3.92 mmol) was added. The reaction mixture was reacted at 60 °C in an oil bath, and the colour of the reaction mixture turned from puce to purple. 2 hours later, Electro-Spray Ionization (ESI) mass spectrometry showed the starting material disappeared. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 1n (1.1 g, yield 50%) as a white solid. MS m/z (ESI): 565.0 [M+1] Reference: Journal of Organometallic Chemistry, 1985, 285(1-3), 293-303

Step 13(R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride

  • [0064]
    (R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 1n (0.12 g, 2.12 mmol) was added to a solution of 2.2 N hydrochloric acid in 5 mL of ethyl acetate. The reaction mixture was reacted at room temperature for 5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride 1 (0.12 g, yield 94.3%) as a light yellow solid. MS m/z (ESI): 465.2 [M+1] 1H NMR (400 MHz, CD3OD): δ 7.101-7.08 (m, 1H), 6.906-6.864 (m, 1H), 5.343-4.995 (m, 2H), 4.221-4.093 (m, 5H), 3.954 (s, 3H), 2.978-2.937 (m, 2H), 2.71-2.643 (m, 2H), 2.061 (s, 2H)
EP2230241A1 * Nov 27, 2008 Sep 22, 2010 Jiangsu Hengrui Medicine Co., Ltd. Tetrahydro-imidazoý1,5-a¨pyrazine derivatives, preparation methods and medical uses thereof
WO2003004498A1 * Jul 5, 2002 Jan 16, 2003 Merck & Co Inc Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2005003135A1 * Jun 18, 2004 Jan 13, 2005 Alex Minhua Chen Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor

FDA Approves Trulicity (dulaglutide) for Type 2 Diabetes

FDA Approves Trulicity (dulaglutide) for Type 2 Diabetes


PRONUNCIATION doo” la gloo’ tide
THERAPEUTIC CLAIM Treatment of type II diabetes
1. 7-37-Glucagon-like peptide I [8-glycine,22-glutamic acid,36-glycine] (synthetic
human) fusion protein with peptide (synthetic 16-amino acid linker) fusion protein with immunoglobulin G4 (synthetic human Fc fragment), dimer
2. [Gly8,Glu22,Gly36]human glucagon-like peptide 1-(7-37)-peptidyltetraglycyl-Lseryltetraglycyl-L-seryltetraglycyl-L-seryl-L-alanyldes-Lys229-[Pro10,Ala16,Ala17]human immunoglobulin heavy constant γ4 chain H-CH2-CH3 fragment, (55-55′:58-58′)-bisdisulfide dimer


  • Dulaglutide
  • LY 2189265
  • LY-2189265
  • LY2189265


GLP-1 immunoglobulin G (IgG4) Fc fusion protein with extended activity; a hypoglycemic agent.
  • 7-37-Glucagon-like peptide I (8-glycine,22-glutamic acid,36-glycine) (synthetic human) fusion protein
    with peptide (synthetic 16-amino acid linker) fusion protein with immunoglobulin G4 (synthetic human Fc fragment), dimer


sept 18 2014

The US Food and Drug Administration (FDA) has approved dulaglutide (Trulicity, Eli Lilly & Co), as a once-weekly injection for the treatment of type 2 diabetes.

A member of the glucagon-like peptide-1 receptor agonist class, dulaglutide joins liraglutide (Victoza, Novo Nordisk), exenatide (Byetta, AstraZeneca/Bristol-Myers Squibb), and albiglutide (Tanzeum, GlaxoSmithKline), on the US market.

Once-weekly dulaglutide was approved based on 6 clinical trials involving a total of 3342 patients who received the drug. It was studied as a stand-alone therapy and in combination withmetformin, sulfonylurea, thiazolidinedione, and prandial insulin.

In one trial the once-weekly dulaglutide was non-inferior to daily liraglutide and in another it topped the oral dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (Januvia, Merck).

The most common side effects observed in patients treated with dulaglutide were nausea, diarrhea, vomiting, abdominal pain, and decreased appetite.

Dulaglutide should not be used to treat people with type 1 diabetes, diabetic ketoacidosis, or severe abdominal or intestinal problems, or as first-line therapy for patients who cannot be managed with diet and exercise.

As with others in its class, dulaglutide’s label will include a boxed warning that thyroid C-cell tumors have been observed in rodents but the risk in humans is unknown. The drug should not be used in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2.

The FDA is requiring Lilly to conduct the following postmarketing studies for dulaglutide:

•  A clinical trial to evaluate dosing, efficacy, and safety in children

•  A study to assess potential effects on sexual maturation, reproduction, and central nervous system development and function in immature rats

•  An MTC case registry of at least 15 years duration to identify any increase in MTC incidence with the drug

•  A clinical trial comparing dulaglutide with insulin glargine on glycemic control in patients with type 2 diabetes and moderate or severe renal impairment

•  A cardiovascular outcomes trial to evaluate the drug’s cardiovascular risk profile in patients with high baseline risk for cardiovascular disease.

The FDA approval also comes with a Risk Evaluation and Mitigation Strategy, including a communication plan to inform healthcare professionals about the serious risks associated with the drug.



Disulfide bridges location
55-55′ 58-58′ 90-150 90′-150′ 196-254 196′-254′

MANUFACTURER Eli Lilly and Company

LY2189265 (dulaglutide), a glucagon-like peptide-1 analog, is a biologic entity being studied as a once-weekly treatment for type 2 diabetes.

Dulaglatuide works by stimulating cells to release insulin only when blood sugar levels are high.

Gwen Krivi, Ph.D., vice president, product development, Lilly Diabetes, said of the drug, “We believe dulaglutide, if approved, can bring significant benefits to people with type 2 diabetes.”

In fact, it might help to control both diabetics’ blood sugar and their high blood pressure.

Eli Lilly CEO John Lechleiter believes the drug has the potential to be a blockbuster. Lilly could be ready to seek approval by 2013.

For more information on dulaglutide clinical studies, click here.




Data Preseted at 49th EASD Annual Meeting Show Treatment with Lilly’s Investigational Dulaglutide Resulted in Improved Patient-Reported Health Outcomes – September 26, 2013

Lilly’s Investigational GLP-1 Receptor Agonist, Dulaglutide, Showed Superior Glycemic Control Versus Comparators in Patients with Type 2 Diabetes – June 22, 2013

Lilly Announces Positive Results of Phase III Trials of Dulaglutide in Type 2 Diabetes – April 16, 2013

Lilly Diabetes Announces Positive Results of Phase III Trials of Dulaglutide in Type 2 Diabetes
 – October 22, 2012

Lilly Diabetes Presents Phase II Blood Pressure and Heart Rate Data on Investigational GLP-1 Analog Candidate, Dulaglutide, in Patients with Type 2 Diabetes at the 27th American Society of Hypertension Scientific Meeting – May 22, 2012

FDA approves Jardiance to treat type 2 diabetes



For synthesis see

August 1, 2014

The U.S. Food and Drug Administration today approved Jardiance (empagliflozin) tablets as an addition to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Type 2 diabetes affects approximately 26 million people and accounts for more than 90 percent of diabetes cases diagnosed in the United States. Over time, high blood sugar levels can increase the risk for serious complications, including heart disease, blindness, and nerve and kidney damage.

“Jardiance provides an additional treatment option for the care of patients with type 2 diabetes,” said Curtis J. Rosebraugh, M.D., M.P.H., director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research. “It can be used alone or added to existing treatment regimens to control blood sugar levels in the overall management of diabetes.”

Jardiance is a sodium glucose co-transporter 2 (SGLT2) inhibitor. It works by blocking the reabsorption of glucose (blood sugar) by the kidney, increasing glucose excretion, and lowering blood glucose levels in diabetics who have elevated blood glucose levels. The drug’s safety and effectiveness were evaluated in seven clinical trials with 4,480 patients with type 2 diabetes receiving Jardiance. The pivotal trials showed that Jardiance improved hemoglobin A1c levels (a measure of blood sugar control) compared to placebo.

Jardiance has been studied as a stand-alone therapy and in combination with other type 2 diabetes therapies including metformin, sulfonylureas, pioglitazone, and insulin. Jardiance should not be used: to treat people with type 1 diabetes; in those who have increased ketones in their blood or urine (diabetic ketoacidosis); and in those with severe renal impairment, end stage renal disease, or in patients on dialysis.

The FDA is requiring four postmarketing studies for Jardiance:

  • Completion of an ongoing cardiovascular outcomes trial.
  • A pediatric pharmacokinetic/pharmacodynamic study.
  • A pediatric safety and efficacy study. As part of the safety and efficacy study, the effect on bone health and development will be evaluated.
  • A nonclinical (animal) juvenile toxicity study with a particular focus on renal development, bone development, and growth.

Jardiance can cause dehydration, leading to a drop in blood pressure (hypotension) that can result in dizziness and/or fainting and a decline in renal function. The elderly, patients with impaired renal function, and patients on diuretics to treat other conditions appeared to be more susceptible to this risk.

The most common side effects of Jardiance are urinary tract infections and female genital infections.

Jardiance is distributed by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.



synthesis see

Luseogliflozin, TS 071…………. strongly inhibited SGLT2 activity,

An antidiabetic agent that inhibits sodium-dependent glucose cotransporter 2 (SGLT2).



Taisho Pharmaceutical Co., Ltd

Taisho (Originator), PHASE 3

Click to access 2013041801-e.pdf


Taisho Pharmaceutical Holdings Co. Ltd.
Description Oral sodium-glucose cotransporter 2 (SGLT2) inhibitor


WO 2010119990


TS-071, an SGLT-2 inhibitor, is in phase III clinical development at Taisho for the oral treatment of type 1 and type 2 diabetes

In 2012, the product was licensed to Novartis and Taisho Toyama Pharmaceutical by Taisho in Japan for comarketing for the treatment of type 2 diabetes.

Diabetes is a metabolic disorder which is rapidly emerging as a global health care problem that threatens to reach pandemic levels. The number of people with diabetes worldwide is expected to rise from 285 million in 2010 to 438 million by 2030. Diabetes results from deficiency in insulin because of impaired pancreatic β-cell function or from resistance to insulin in body, thus leading to abnormally high levels of blood glucose.

Diabetes which results from complete deficiency in insulin secretion is Type 1 diabetes and the diabetes due to resistance to insulin activity together with an inadequate insulin secretion is Type 2 diabetes. Type 2 diabetes (Non insulin dependent diabetes) accounts for 90-95 % of all diabetes. An early defect in Type 2 diabetes mellitus is insulin resistance which is a state of reduced responsiveness to circulating concentrations of insulin and is often present years before clinical diagnosis of diabetes. A key component of the pathophysiology of Type 2 diabetes mellitus involves an impaired pancreatic β-cell function which eventually contributes to decreased insulin secretion in response to elevated plasma glucose. The β-cell compensates for insulin resistance by increasing the insulin secretion, eventually resulting in reduced β-cell mass. Consequently, blood glucose levels stay at abnormally high levels (hyperglycemia).

Hyperglycemia is central to both the vascular consequences of diabetes and the progressive nature of the disease itself. Chronic hyperglycemia leads to decrease in insulin secretion and further to decrease in insulin sensitivity. As a result, the blood glucose concentration is increased, leading to diabetes, which is self-exacerbated. Chronic hyperglycemia has been shown to result in higher protein glycation, cell apoptosis and increased oxidative stress; leading to complications such as cardiovascular disease, stroke, nephropathy, retinopathy (leading to visual impairment or blindness), neuropathy, hypertension, dyslipidemia, premature atherosclerosis, diabetic foot ulcer and obesity. So, when a person suffers from diabetes, it becomes important to control the blood glucose level. Normalization of plasma glucose in Type 2 diabetes patients improves insulin action and may offset the development of beta cell failure and diabetic complications in the advanced stages of the disease.

Diabetes is basically treated by diet and exercise therapies. However, when sufficient relief is not obtained by these therapies, medicament is prescribed alongwith. Various antidiabetic agents being currently used include biguanides (decrease glucose production in the liver and increase sensitivity to insulin), sulfonylureas and meglitinides (stimulate insulin production), a-glucosidase inhibitors (slow down starch absorption and glucose production) and thiazolidinediones (increase insulin sensitivity). These therapies have various side effects: biguanides cause lactic acidosis, sulfonylurea compounds cause significant hypoglycemia, a-glucosidase inhibitors cause abdominal bloating and diarrhea, and thiazolidinediones cause edema and weight gain. Recently introduced line of therapy includes inhibitors of dipeptidyl peptidase-IV (DPP-IV) enzyme, which may be useful in the treatment of diabetes, particularly in Type 2 diabetes. DPP-IV inhibitors lead to decrease in inactivation of incretins glucagon like peptide- 1 (GLP-1) and gastric inhibitory peptide (GIP), thus leading to increased production of insulin by the pancreas in a glucose dependent manner. All of these therapies discussed, have an insulin dependent mechanism.

Another mechanism which offers insulin independent means of reducing glycemic levels, is the inhibition of sodium glucose co-transporters (SGLTs). In healthy individuals, almost 99% of the plasma glucose filtered in the kidneys is reabsorbed, thus leading to only less than 1% of the total filtered glucose being excreted in urine. Two types of SGLTs, SGLT-1 and SGLT-2, enable the kidneys to recover filtered glucose. SGLT-1 is a low capacity, high-affinity transporter expressed in the gut (small intestine epithelium), heart, and kidney (S3 segment of the renal proximal tubule), whereas SGLT-2 (a 672 amino acid protein containing 14 membrane-spanning segments), is a low affinity, high capacity glucose ” transporter, located mainly in the S 1 segment of the proximal tubule of the kidney. SGLT-2 facilitates approximately 90% of glucose reabsorption and the rate of glucose filtration increases proportionally as the glycemic level increases. The inhibition of SGLT-2 should be highly selective, because non-selective inhibition leads to complications such as severe, sometimes fatal diarrhea, dehydration, peripheral insulin resistance, hypoglycemia in CNS and an impaired glucose uptake in the intestine.

Humans lacking a functional SGLT-2 gene appear to live normal lives, other than exhibiting copious glucose excretion with no adverse effects on carbohydrate metabolism. However, humans with SGLT-1 gene mutations are unable to transport glucose or galactose normally across the intestinal wall, resulting in condition known as glucose-galactose malabsorption syndrome.

Hence, competitive inhibition of SGLT-2, leading to renal excretion of glucose represents an attractive approach to normalize the high blood glucose associated with diabetes. Lower blood glucose levels would, in turn, lead to reduced rates of protein glycation, improved insulin sensitivity in liver and peripheral tissues, and improved cell function. As a consequence of progressive reduction in hepatic insulin resistance, the elevated hepatic glucose output which is characteristic of Type 2 diabetes would be expected to gradually diminish to normal values. In addition, excretion of glucose may reduce overall caloric load and lead to weight loss. Risk of hypoglycemia associated with SGLT-2 inhibition mechanism is low, because there is no interference with the normal counter regulatory mechanisms for glucose.

The first known non-selective SGLT-2 inhibitor was the natural product phlorizin

(glucose, 1 -[2-P-D-glucopyranosyloxy)-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)- 1 – propanone). Subsequently, several other synthetic analogues were derived based on the structure of phlorizin. Optimisation of the scaffolds to achieve selective SGLT-2 inhibitors led to the discovery of several considerably different scaffolds.

C-glycoside derivatives have been disclosed, for example, in PCT publications

W.O20040131 18, WO2005085265, WO2006008038, WO2006034489, WO2006037537, WO2006010557, WO2006089872, WO2006002912, WO2006054629, WO2006064033, WO2007136116, WO2007000445, WO2007093610, WO2008069327, WO2008020011, WO2008013321, WO2008013277, WO2008042688, WO2008122014, WO2008116195, WO2008042688, WO2009026537, WO2010147430, WO2010095768, WO2010023594, WO2010022313, WO2011051864, WO201 1048148 and WO2012019496 US patents US65151 17B2, US6936590B2 and US7202350B2 and Japanese patent application JP2004359630. The compounds shown below are the SGLT-2 inhibitors which have reached advanced stages of human clinical trials: Bristol-Myers Squibb’s “Dapagliflozin” with Formula A, Mitsubishi Tanabe and Johnson & Johnson’s “Canagliflozin” with Formula B, Lexicon’s “Lx-421 1″ with Formula C, Boehringer Ingelheim and Eli Lilly’s “Empagliflozin” with Formula D, Roche and Chugai’s “Tofogliflozin” with Formula E, Taisho’s “Luseogliflozin” with Formula F, Pfizer’ s “Ertugliflozin” with Formula G and Astellas and Kotobuki’s “Ipragliflozin” with Formula H.

Figure imgf000005_0001

Formula G                                                                                                                  Formula H

In spite of all these molecules in advanced stages of human clinical trials, there is still no drug available in the market as SGLT-2 inhibitor. Out of the potential candidates entering the clinical stages, many have been discontinued, emphasizing the unmet need. Thus there is an ongoing requirement to screen more scaffolds useful as SGLT-2 inhibitors that can have advantageous potency, stability, selectivity, better half-life, and/ or better pharmacodynamic properties. In this regard, a novel class of SGLT-2 inhibitors is provided herein





        Example 5
    • Figure imgb0035

Synthesis of 2,3,4,6-tetra-O-benzyl-1-C-[2-methoxy-4-methyl-(4-ethoxybenzyl)phenyl]-5-thio-D-glucopyranose

    • Five drops of 1,2-dibromoethane were added to a mixture of magnesium (41 mg, 1.67 mmol), 1-bromo-3-(4-ethoxybenzyl)-6-methoxy-4-methylbenzene (0.51 g, 1.51 mmol) and tetrahydrofuran (2 mL). After heated to reflux for one hour, this mixture was allowed to stand still to room temperature to prepare a Grignard reagent. A tetrahydrofuran solution (1.40 mL) of 1.0 M i-propyl magnesium chloride and the prepared Grignard reagent were added dropwise sequentially to a tetrahydrofuran (5 mL) solution of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (0.76 g, 1.38 mmol) while cooled on ice and the mixture was stirred for 30 minutes. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate =4:1) to obtain (0.76 g, 68%) a yellow oily title compound.
      1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (t, J=6.92 Hz, 3 H) 2.21 (s, 3 H) 3.51 – 4.20 (m, 12 H) 3.85 – 3.89 (m, 3 H) 4.51 (s, 2 H) 4.65 (d, J=10.72 Hz, 1 H) 4.71 (d, J=5.75 Hz, 1 H) 4.78 – 4.99 (m, 3 H) 6.59 – 7.43 (m, 26 H)

Example 6

    • [0315]
      Figure imgb0036

Synthesis of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-1-thio-D-glucitol

    • An acetonitrile (18 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-5-thio-D-glucopyranose (840 mg, 1.04 mmol) was added sequentially with Et3SiH (0.415 mL, 2.60 mmol) and BF3·Et2O (0.198 mL, 1.56 mmol) at -18°C and stirred for an hour. After the reaction mixture was added with a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (640 mg, 77%).
      1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=6.88 Hz, 3 H) 2.21 (s, 3 H) 3.02 – 3.21 (m, 1 H) 3.55 (t,J=9.40 Hz, 1 H) 3.71 (s, 1 H) 3.74 – 3.97 (m, 10 H) 4.01 (s, 1 H) 4.45 – 4.56 (m, 3 H) 4.60 (d, J=10.55 Hz, 2 H) 4.86 (s, 2 H) 4.90 (d, J=10.55 Hz, 1H) 6.58 – 6.76 (m, 5 H) 6.90 (d, J=7.34 Hz, 1 H) 7.09 – 7.19 (m, 5 H) 7.23 – 7.35 (m, 15 H).
      ESI m/z = 812 (M+NH4).

Example 7

    • Figure imgb0037

Synthesis of (1S)-1,5-anhydro-1-[3-(4-ethoxybenzyl)-6-methoxy-4-methylphenyl]-1-thio-D-glucitol

  • A mixture of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-1-thio-D-glucitol (630 mg, 0.792 mmol), 20% palladium hydroxide on activated carbon (650 mg) and ethyl acetate (10 mL) – ethanol (10 mL) was stirred under hydrogen atmosphere at room temperature for 66 hours. The insolubles in the reaction mixture were filtered off with celite and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol =10:1) to obtain a colorless powdery title compound (280 mg, 81%) as 0.5 hydrate. 1H NMR (600 MHz, METHANOL- d4) δ ppm 1.35 (t, J=6.9 Hz, 3 H) 2.17 (s, 3 H) 2.92 – 3.01 (m, 1 H) 3.24 (t, J=8.71 Hz, 1 H) 3.54 – 3.60 (m, 1 H) 3.72 (dd, J=11.5, 6.4 Hz, 1 H) 3.81 (s, 3 H) 3.83 (s, 2 H) 3.94 (dd, J=11.5, 3.7 Hz, 1 H) 3.97 (q, J=6.9 Hz, 2 H) 4.33 (s, 1 H) 6.77 (d, J=8.3 Hz, 2 H) 6.76 (s, 1 H) 6.99 (d, J=8.3 Hz, 2 H) 7.10 (s, 1 H). ESI m/z = 452 (M+NH4+), 493 (M+CH3CO2-). mp 155.0-157.0°C. Anal. Calcd for C23H30O6S·0.5H2O: C, 62.28; H, 7.06. Found: C, 62.39; H, 7.10.




(1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol (TS-071) is a Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for Type 2 Diabetes Treatment 
(Journal of Medicinal Chemistry) Saturday March 20th 2010
Author(s): ,
GO TO: [Article]

(1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol (3p)

Compound 3p (0.281 g, 81%) was prepared as a colorless powder from 21p (0.630 g, 0.792 mmol) according to the method described for the synthesis of 3a. (Method A)
mp 155.0−157.0 °C.
 1H NMR (600 MHz, MeOH-d4) δ 1.35 (t, J = 6.9 Hz, 3 H), 2.17 (s, 3 H), 2.92−3.01 (m, 1 H), 3.24 (t, J = 8.7 Hz, 1 H), 3.54−3.60 (m, 1 H), 3.72 (dd, J = 6.4, 11.5, Hz, 1 H), 3.81 (s, 3 H), 3.83 (s, 2 H), 3.94 (dd, J = 3.7, 11.5 Hz, 1 H), 3.97 (q, J = 6.9 Hz, 2 H), 4.33 (brs, 1 H), 6.77 (d, J = 8.3 Hz, 2 H), 6.76 (s, 1 H), 6.99 (d, J = 8.3 Hz, 2 H), 7.10 (s, 1 H).
MS (ESI) m/z 452 (M+NH4).
Anal. Calcd for (C23H30O6S·0.5H2O) C, 62.28; H, 7.06. Found C, 62.39; H, 7.10.

3p is compd

cmpds R1 R2 R3 SGLT2 (nM) mean (95% CI) SGLT1 (nM) mean (95% CI) T1/T2 selectivity
1 27.8 (21.8−35.3) 246 (162−374) 8.8
3a H H OEt 73.6 (51.4−105) 26100 (20300−33700) 355
3b H OH OEt 283 (268−298) 14600 (11500−18500) 51.6
3c H OMe OEt 13.4 (11.3−15.8) 565 (510−627) 42.2
3d H F OEt 9.40 (5.87−15.0) 7960 (7180−8820) 847
3e H Me OEt 2.29 (1.76−2.99) 671 (230−1960) 293
3f H Cl OEt 1.77 (0.95−3.30) 1210 (798−1840) 684
3g OH H OEt 17.4 (15.9−19.0) 4040 (1200−13600) 232
3h OMe H OEt 37.9 (26.4−54.4) 100000 (66500−151000) 2640
3i OMe OMe OEt 10.8 (6.84−17.1) 4270 (1560−11600) 395
3j H Cl OMe 1.68 (1.08−2.60) 260 (72.5−931) 155
3k H Cl Me 1.37 (0.97−1.95) 209 (80.2−545) 153
3l H Cl Et 1.78 (0.88−3.63) 602 (473−767) 338
3m H Cl iPr 4.01 (1.75−9.17) 8160 (4860−13700) 2040
3n H Cl tBu 18.8 (11.0−32.1) 35600 (31900−39800) 1890
3o H Cl SMe 1.16 (0.73−1.85) 391 (239−641) 337
3p OMe Me OEt 2.26 (1.48−3.43) 3990 (2690−5920) 1770
3q OMe Me Et 1.71 (1.19−2.46) 2830 (1540−5200) 1650
3r OMe Me iPr 2.68 (2.15−3.34) 17300 (14100−21100) 6400
3s OMe Cl Et 1.51 (0.75−3.04) 3340 (2710−4110) 2210


 Patent Filing date Publication date Applicant Title
1 * AL-MASOUDI, NAJIM A. ET AL: “Synthesis of some novel 1-(5-thio-.beta.-D-glucopyranosyl)-6-azaur acil derivatives. Thio sugar nucleosides” NUCLEOSIDES & NUCLEOTIDES , 12(7), 687-99 CODEN: NUNUD5; ISSN: 0732-8311, 1993, XP008091463
2 * See also references of WO2006073197A1
EP2419097A1 * Apr 16, 2010 Feb 22, 2012 Taisho Pharmaceutical Co., Ltd. Pharmaceutical compositions
EP2455374A1 * Oct 15, 2009 May 23, 2012 Janssen Pharmaceutica N.V. Process for the Preparation of Compounds useful as inhibitors of SGLT
EP2601949A2 * Apr 16, 2010 Jun 12, 2013 Taisho Pharmaceutical Co., Ltd. Pharmaceutical compositions
EP2668953A1 * May 15, 2009 Dec 4, 2013 Bristol-Myers Squibb Company Pharmaceutical compositions comprising an SGLT2 inhibitor with a supply of carbohydrate and/or an inhibitor of uric acid synthesis
WO2009143020A1 May 15, 2009 Nov 26, 2009 Bristol-Myers Squibb Company Method for treating hyperuricemia employing an sglt2 inhibitor and composition containing same
WO2010043682A2 * Oct 15, 2009 Apr 22, 2010 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of sglt
WO2010119990A1 Apr 16, 2010 Oct 21, 2010 Taisho Pharmaceutical Co., Ltd. Pharmaceutical compositions
WO2013152654A1 * Mar 14, 2013 Oct 17, 2013 Theracos, Inc. Process for preparation of benzylbenzene sodium-dependent glucose cotransporter 2 (sglt2) inhibitors


  • Week in Review, Clinical Results
    Taisho Pharmaceutical Holdings Co. Ltd. (Tokyo:4581), Tokyo, Japan Product: Luseogliflozin (TS-071) Business: Endocrine/Metabolic Molecular target: Sodium-glucose cotransporter 2 (SGLT2) Description: Oral sodium-glucose…
  • Week in Review, Clinical Results
    Taisho Pharmaceutical Holdings Co. Ltd. (Tokyo:4581), Tokyo, Japan Product: Luseogliflozin (TS-071) Business: Endocrine/Metabolic Molecular target: Sodium-glucose cotransporter 2 (SGLT2) Description: Oral sodium-glucose…
  • Week in Review, Regulatory
    Taisho Pharmaceutical Holdings Co. Ltd. (Tokyo:4581), Tokyo, Japan Product: Luseogliflozin (TS-071) Business: Endocrine/Metabolic Last month, Taisho’s Taisho Pharmaceutical Co. Ltd. subsidiary submitted a regulatory …
  • BioCentury on BioBusiness, Strategy
    As sales flatten for Merck’s sitagliptin franchise and a new class of oral diabetes drugs comes to market, the pharma has tapped Pfizer and Abide to shore up its position.



New Drug Shows Promise for Type 2 Diabetes

TUESDAY Sept. 3, 2013 — An injectable drug that mimics the action of a little-known hormone may hold promise for patients with type 2 diabetes.

The experimental drug, called LY, is a copy of a hormone called fibroblast growth factor 21 (FGF21), and researchers report that it seems to help protect against obesity and may boost the action of insulin.



Fibroblast growth factor 21 is a member of the fibroblast growth factor (FGF) family. FGF21 stimulates glucose uptake in adipocytes but not in other cell types.This effect is additive to the activity of insulin. FGF21 treatment of adipocytes is associated with phosphorylation of FRS2, a protein linking FGF receptors to the Ras/MAP kinase pathway.
FGF21 injection in ob/ob mice results in an increase in Glut1 in adipose tissue. FGF21 also protects animals from diet-induced obesity when overexpressed in transgenic mice and lowers blood glucose and triglyceride levels when administered to diabetic rodents. Treatment of animals with FGF21 results in increased energy expenditure, fat utilization and lipid excretion

Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species


Type II diabetes is the most prevalent form of diabetes. The disease is caused by insulin resistance and pancreatic β cell failure, which results in decreased glucose-stimulated insulin secretion. Fibroblast growth factor (FGF) 21, a member of the FGF family, has been identified as a metabolic regulator and is preferentially expressed in the liver and adipose tissue and exerts its biological activities through the cell surface receptor composed of FGFR1c and β-Klotho on target cells such as liver and adipose tissues (WO0136640, and WO0118172).

The receptor complex is thought to trigger cytoplasmic signaling and to up-regulate the GLUT1 expression through the Ras/MAP kinase pathway.

Its abilities to provide sustained glucose and lipid control, and improve insulin sensitivity and β-cell function, without causing any apparent adverse effects in preclinical settings, have made FGF21 an attractive therapeutic agent for type-2 diabetes and associated metabolic disorders.

There have been a number of efforts towards developing therapies based on FGF21. WO2006065582, WO2006028714, WO2006028595, and WO2005061712 relate to muteins of FGF21, comprising individual amino-acid substitutions. WO2006078463 is directed towards a method of treating cardiovascular disease using FGF21. WO2005072769 relates to methods of treating diabetes using combinations of FGF21 and thiazolidinedione. WO03059270 relates to methods of reducing the mortality of critically ill patients comprising administering FGF21. WO03011213 relates to a method of treating diabetes and obesity comprising administering FGF21.

However, many of these proposed therapies suffer from the problem that FGF21 has an in-vivo half-life of between 1.5 and 2 hrs in humans. Some attempts have been made to overcome this drawback. WO2005091944, WO2006050247 and WO2008121563 disclose FGF21 molecules linked to PEG via lysine or cysteine residues, glycosyl groups and non-natural amino acid residues, respectively. WO2005113606 describes FGF21 molecules recombinantly fused via their C-terminus to albumin and immunoglobulin molecules using polyglycine linkers.

However, developing protein conjugates into useful, cost-effective pharmaceuticals presents a number of significant and oftentimes competing challenges: a balance must be struck between in vivo efficacy, in vivo half-life, stability for in vitro storage, and ease and efficiency of manufacture, including conjugation efficiency and specificity. In general, it is an imperative that the conjugation process does not eliminate or significantly reduce the desired biological action of the protein in question.

The protein-protein interactions required for function may require multiple regions of the protein to act in concert, and perturbing any of these with the nearby presence of a conjugate may interfere with the active site(s), or cause sufficient alterations to the tertiary structure so as to reduce active-site function. Unless the conjugation is through the N′ or C′ terminus, internal mutations to facilitate the linkage may be required. These mutations can have unpredictable effects on protein structure and function. There therefore continues to be a need for alternative FGF21-based therapeutics.

The reference to any art in this specification is not, and should not be taken as, an acknowledgement of any form or suggestion that the referenced art forms part of the common general knowledge.

FDA Approves Canagliflozin, Invokana – First in New Class of Type 2 Diabetes Drugs


FRIDAY March 29, 2013

The first in a new class of type 2 diabetes drugs was approved Friday by the U.S. Food and Drug Administration.

Invokana (canagliflozin) tablets are to be taken, in tandem with a healthy diet and exercise, to improve blood sugar control in adults with type 2 diabetes.

Invokana belongs to a class of drugs called sodium-glucose co-transporter 2 (SGLT2) inhibitors. It works by blocking the reabsorption of glucose (sugar) by the kidney and increasing glucose excretions in urine, the FDA said in a news release.

Canagliflozin (Invokana) is drug for the treatment of type 2 diabetes developed by Johnson & Johnson.[1][2] In March 2013, canagliflozin became the first in a new class of drugs for diabetes treatment to be approved.[3] It is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine

  1. New J&J diabetes drug effective in mid-stage study, Jun 26, 2010
  2.  Edward C. Chao (2011). “Canagliflozin”. Drugs of the Future 36 (5): 351–357. doi:10.1358/dof.2011.36.5.1590789.
  3.  “U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin”. Reuters. Mar 29, 2013. “U.S. health regulators have approved a new diabetes drug from Johnson & Johnson, making it the first in its class to be approved in the United States.”
  4. Prous Science: Molecule of the Month November 2007

The agency told drug maker Janssen Pharmaceuticals that it must conduct five post-approval studies of the drug to determine the risk of problems such as heart disease, cancer, pancreatitis, liver abnormalities and pregnancy complications.



Canagliflozin is a highly potent and selective subtype 2 sodium-glucose transport protein (SGLT2) inhibitor to CHO- hSGLT2, CHO- rSGLT2 and CHO- mSGLT2 with IC50 of 4.4 nM, 3.7 nM and 2 nM, respectively.

M.Wt: 444.52
CAS No: 842133-18-0

Canagliflozin Hemihydrate
(1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hydrate (2:1)

Canagliflozin (INN, trade name Invokana) is a drug of the gliflozin class, used for the treatment of type 2 diabetes.[1][2] It was developed by Mitsubishi Tanabe Pharma and is marketed under license by Janssen, a division of Johnson & Johnson.[3]
U.S. Patent No, 7,943,788 B2 (the ‘788 patent) discloses canagliflozin or salts thereof and the process for its preparation.
U.S. Patent Nos. 7,943,582 B2 and 8,513,202 B2 discloses crystalline form of 1 -(P-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate and process for preparation thereof. The US ‘582 B2 and US ‘202 B2 further discloses that preparation of the crystalline form of hemi-hydrate canagliflozin typically involves dissolving in a good solvent (e.g. ketones or esters) crude or amorphous compound prepared in accordance with the procedures described in WO 2005/012326 pamphlet, and adding water and a poor solvent (e.g. alkanes or ethers) to the resulting solution, followed by filtration.
U.S. PG-Pub. No. 2013/0237487 Al (the US ‘487 Al) discloses amorphous dapagliflozin and amorphous canagliflozin. The US ‘487 Al also discloses 1:1 crystalline complex of canagliflozin with L-proline (Form CS1), ethanol solvate of a 1: 1 crystalline complex of canagliflozin with D-proline (Form CS2), 1 :1 crystalline complex of canagliflozin with L-phenylalanine (Form CS3), 1:1 crystalline complex of canagliflozin with D-proline (Form CS4).
The US ‘487 Al discloses preparation of amorphous canagliflozin by adding its heated toluene solution into n-heptane. After drying in vacuo the product was obtained as a white solid of with melting point of 54.7°C to 72.0°C. However, upon repetition of the said experiment, the obtained amorphous canagliflozin was having higher amount of residual solvents. Therefore, the amorphous canagliflozin obtained by process as disclosed in US ‘487 Al is not suitable for pharmaceutical preparations.
The US ‘487 Al further discloses that amorphous canagliflozin obtained by the above process is hygroscopic in nature which was confirmed by Dynamic vapor sorption (DVS) analysis. Further, it was observed that the amorphous form underwent a physical change between the sorption/desorption cycle, making the sorption/desorption behavior different between the two cycles. The physical change that occurred was determined to be a conversion or partial conversion from the amorphous state to a crystalline state. This change was supported by a change in the overall appearance of the sample as the humidity increased from 70% to 90% RH.
The canagliflozin assessment report EMA/718531/2013 published by EMEA discloses that Canagliflozin hemihydrate is a white to off-white powder^ practically insoluble in water and freely soluble in ethanol and non-hygroscopic. Polymorphism has been observed for canagliflozin and the manufactured Form I is a hemihydrate, and an unstable amorphous Form II. Form I is consistently produced by the proposed commercial synthesis process. Therefore, it is evident from the prior art that the reported amorphous form of canagliflozin is unstable and hygroscopic as well as not suitable for pharmaceutical preparations due to higher amount of residual solvents above the ICH acceptable limits.
Medical use

    1. Canagliflozin is an antidiabetic drug used to improve glycemic control in people with type 2 diabetes. In extensive clinical trials, canagliflozin produced a consistent dose-dependent reduction in HbA1c of 0.77% to 1.16% when administered as monotherapy, combination with metformin, combination with metformin & Sulfonyulrea, combination with metformin & pioglitazone and In combination with insulin from a baselines of 7.8% to 8.1%, in combination with metformin, or in combination with metformin and a sulfonylurea. When added to metformin Canagliflozin 100mg was shown to be non-inferior to both Sitagliptin 100mg and glimiperide in reductions on HbA1c at one year, whilst canagliflozin 300mg successfully demontrated statistical superiority over both Sitagliptin and glimiperide in HbA1c reductions. Secondary efficacy endpoint of superior body weight reduction and blood pressure reduction (versus Sitagliptin and glimiperide)) were observed as well. Canagliflozin produces beneficial effects on HDL cholesterol whilst increasing LDL cholesterol to produce no change in total cholesterol.[4][5]


      Canagliflozin has proven to be clinically effective in people with moderate renal failure and treatment can be continued in patients with renal impairment.

      Adverse effects

      Canagliflozin, as is common with all sglt2 inhibitors, increased (generally mild) urinary tract infections, genital fungal infections, thirst,[6] LDL cholesterol, and was associated with increased urination and episodes of low blood pressure.
      There are concerns it may increase the risk of diabetic ketoacidosis.[7]
      Cardiovascular problems have been discussed with this class of drugs.[citation needed] The pre-specified endpoint for cardiovascular safety in the canagliflozin clinical development program was Major Cardiovascular Events Plus (MACE-Plus), defined as the occurrence of any of the following events: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina leading to hospitalization. This endpoint occurred in more people in the placebo group (20.5%) than in the canagliflozin treated group (18.9%).
      Nonetheless, an FDA advisory committee expressed concern regarding the cardiovascular safety of canagliflozin. A greater number of cardiovascular events was observed during the first 30 days of treatment in canagliflozin treated people (0.45%) relative to placebo treated people (0.07%), suggesting an early period of enhanced cardiovascular risk. In addition, there was an increased risk of stroke in canagliflozin treated people. However none of these effects were seen as statistically significant. Additional cardiovascular safety data from the ongoing CANVAS trial is expected in 2015.[8]


      The drug may increase the risk of dehydration in combination with diuretic drugs.
      Because it increases renal excretion of glucose, treatment with canagliflozin prevents renal reabsorption of 1,5-anhydroglucitol, leading to artifactual decreases in serum 1,5-anhydroglucitol; it can therefore interfere with the use of serum 1,5-anhydroglucitol (assay trade name, GlycoMark) as a measure of postprandial glucose excursions.[9]

      Mechanism of action

      Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the renal glucose reabsorption (SGLT1 being responsible for the remaining 10%). Blocking this transporter causes up to 119 grams of blood glucose per day to be eliminated through the urine,[10] corresponding to 476 kilocalories. Additional water is eliminated by osmotic diuresis, resulting in a lowering of blood pressure.
      This mechanism is associated with a low risk of hypoglycaemia (too low blood glucose) compared to other antidiabetic drugs such as sulfonylurea derivatives and insulin.[11]


      On July 4, 2011, the European Medicines Agency approved a paediatric investigation plan and granted both a deferral and a waiver for canagliflozin (EMEA-001030-PIP01-10) in accordance with EC Regulation No.1901/2006 of the European Parliament and of the Council.[12]
      In March 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States.[13]



Canagliflozin is an API that is an inhibitor of SGLT2 and is being developed for the treatment of type 2 diabetes mellitus.[0011] The IUPAC systematic name of canagliflozin is (25,,3/?,4i?,55′,6 ?)-2-{3-[5-[4-fluoro- phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol, and is also known as (15)-l,5-anhydro-l-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4- methylphenyl]-D-glucitol and l-( -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene. Canagliflozin is a white to off-white powder with a molecular formula of C24H25F05S and a molecular weight of 444.52. The structure of canagliflozin is shown as compound B.

Compound B – Canagliflozin
[0012] In US 2008/0146515 Al, a crystalline hemihydrate form of canagliflozin (shown as Compound C) is disclosed, having the powder X-ray diffraction (XRPD) pattern comprising the following 2Θ values measured using CuKa radiation: 4.36±0.2, 13.54±0.2, 16.00±0.2, 19.32±0.2, and 20.80±0.2. The XRPD pattern is shown in Figure 24. A process for the preparation of canagliflozin hemihydrate is also disclosed in US 2008/0146515 Al.

Compound C – hemihydrate form of canagliflozin
[0013] In US 2009/0233874 Al, a crystalline form of canagliflozin is disclosed.


WO 2005/012326 pamphlet discloses a class of compounds that are inhibitors of sodium-dependent glucose transporter (SGLT) and thus of therapeutic use for treatment of diabetes, obesity, diabetic complications, and the like. There is described in WO 2005/012326 pamphlet 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene of formula (I):

Example 1 Crystalline 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene was prepared in a similar manner as described in WO 2005/012326.

(1) To a solution of 5-bromo-1-[5-(4-fluorophenyl)-2-thienylmethyl]-2-methylbenzene (1, 28.9 g) in tetrahydrofuran (480 ml) and toluene (480 ml) was added n-butyllithium (1.6M hexane solution, 50.0 ml) dropwise at −67 to −70° C. under argon atmosphere, and the mixture was stirred for 20 minutes at the same temperature. Thereto was added a solution of 2 (34.0 g) in toluene (240 ml) dropwise at the same temperature, and the mixture was further stirred for 1 hour at the same temperature. Subsequently, thereto was added a solution of methanesulfonic acid (21.0 g) in methanol (480 ml) dropwise, and the resulting mixture was allowed to warm to room temperature and stirred for 17 hours. The mixture was cooled under ice—water cooling, and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with brine and dried over magnesium sulfate. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was triturated with toluene (100 ml)—hexane (400 ml) to give 1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]-benzene (3) (31.6 g). APCI-Mass m/Z 492 (M+NH4).
(2) A solution of 3 (63.1 g) and triethylsilane (46.4 g) in dichloromethane (660 ml) was cooled by dry ice-acetone bath under argon atmosphere, and thereto was added dropwise boron trifluoride•ethyl ether complex (50.0 ml), and the mixture was stirred at the same temperature. The mixture was allowed to warm to 0° C. and stirred for 2 hours. At the same temperature, a saturated aqueous sodium hydrogen carbonate solution (800 ml) was added, and the mixture was stirred for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate twice. The organic layer was washed with water twice, dried over magnesium sulfate and treated with activated carbon. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 ml), and thereto were added diethyl ether (600 ml) and H2O (6 ml). The mixture was stirred at room temperature overnight, and the precipitate was collected, washed with ethyl acetate-diethyl ether (1:4) and dried under reduced pressure at room temperature to give 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (33.5 g) as colorless crystals.
mp 98-100° C. APCI-Mass m/Z 462 (M+NH4). 1H-NMR (DMSO-d6) δ 2.26 (3H, s), 3.13-3.28 (4H, m), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.3 Hz), 4.10, 4.15 (each 1H, d, J=16.0 Hz), 4.43 (1H, t, J=5.8 Hz), 4.72 (1H, d, J=5.6 Hz), 4.92 (2H, d, J=4.8 Hz), 6.80 (1H, d, J=3.5 Hz), 7.11-7.15 (2H, m), 7.18-7.25 (3H, m), 7.28 (1H, d, J=3.5 Hz), 7.59 (2H, dd, J=8.8, 5.4 Hz).
Anal. Calcd. for C24H25FO5S.0.5H2O: C, 63.56; H, 5.78; F, 4.19; S, 7.07. Found: C, 63.52; H, 5.72; F, 4.08; S, 7.00.
Figure US07943582-20110517-C00001

Example 2An amorphous powder of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (1.62 g) was dissolved in acetone (15 ml), and thereto were added H2O (30 ml) and a crystalline seed. The mixture was stirred at room temperature for 18 hours, and the precipitate was collected, washed with acetone—H2O (1:4, 30 ml) and dried under reduced pressure at room temperature to give 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (1.52 g) as colorless crystals. mp 97-100° C.


there are a significant number of other β-C-arylglucoside derived drug candidates, most of which differ only in the aglycone moiety (i.e., these compounds comprise a central 1-deoxy-glucose ring moiety that is arylated at CI). It is this fact that makes them attractive targets for a novel synthetic platform technology, since a single methodology should be able to furnish a plurality of products. Among β-C-arylglucosides that possess known SGLT2 inhibition also currently in clinical development are canagliflozin, empagliflozin, and ipragliflozin.

Dapagliflozin                             Canagliflozin

Ipragliflozin …………………Empagliflozin
[0007] A series of synthetic methods have been reported in the peer-reviewed and patent literature that can be used for the preparation of β-C-arylglucosides. These methods are described below and are referred herein as the gluconolactone method, the metalated glucal method, the glucal epoxide method and the glycosyl leaving group substitution method.
[0008] The gluconolactone method: In 1988 and 1989 a general method was reported to prepare C-arylglucosides from tetra-6>-benzyl protected gluconolactone, which is an oxidized derivative of glucose (see J. Org. Chem. 1988, 53, 752-753 and J. Org. Chem. 1989, 54, 610- 612). The method comprises: 1) addition of an aryllithium derivative to the hydroxy-protected gluconolactone to form a hemiketal (, a lactol), and 2) reduction of the resultant hemiketal with triethylsilane in the presence of boron trifluoride etherate. Disadvantages of this classical, but very commonly applied method for β-C-arylglucoside synthesis include:
1) poor “redox economy” (see J. Am. Chem. Soc. 2008, 130, 17938-17954 and Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN- 10: 0120594757); pg 38)— that is, the oxidation state of the carbon atom at CI, with respect to glucose, is oxidized in the gluconolactone and then following the arylation step is reduced to provide the requisite oxidation state of the final product. 2) due to a lack of stereospecificity, the desired β-C-arylglucoside is formed along with the undesired a-C-arylglucoside stereoisomer (this has been partially addressed by the use of hindered trialkylsilane reducing agents (see Tetrahedron: Asymmetry 2003, 14, 3243-3247) or by conversion of the hemiketal to a methyl ketal prior to reduction (see J. Org. Chem. 2007, 72, 9746-9749 and U.S. Patent 7,375,213)).
Oxidation Reduction

Glucose Gluconoloctone Hemiketal a-anomer β-anomer
R = protecting group
[0009] The metalated glucal method: U.S. Patent 7,847,074 discloses preparation of SGLT2 inhibitors that involves the coupling of a hydroxy-protected glucal that is metalated at CI with an aryl halide in the presence of a transition metal catalyst. Following the coupling step, the requisite formal addition of water to the C-arylglucal double bond to provide the desired C-aryl glucoside is effected using i) hydroboration and oxidation, or ii) epoxidation and reduction, or iii) dihydroxylation and reduction. In each case, the metalated glucal method represents poor redox economy because oxidation and reduction reactions must be conducted to establish the requisite oxidation states of the individual CI and C2 carbon atoms.
[0010] U.S. Pat. Appl. 2005/0233988 discloses the utilization of a Suzuki reaction between a CI -boronic acid or boronic ester substituted hydroxy-protected glucal and an aryl halide in the presence of a palladium catalyst. The resulting 1- C-arylglucal is then formally hydrated to provide the desired 1- C-aryl glucoside skeleton by use of a reduction step followed by an oxidation step. The synthesis of the boronic acid and its subsequent Suzuki reaction, reduction and oxidation, together, comprise a relatively long synthetic approach to C-arylglucosides and exhibits poor redox economy. Moreover, the coupling catalyst comprises palladium which is toxic and therefore should be controlled to very low levels in the drug substance.

R = protecting group; R’ = H or alkyl
[0011] The glucal epoxide method: U.S. Patent 7,847,074 discloses a method that utilizes an organometallic (derived from the requisite aglycone moiety) addition to an electrophilic epoxide located at C1-C2 of a hydroxy-protected glucose ring to furnish intermediates useful for SGLT2 inhibitor synthesis. The epoxide intermediate is prepared by the oxidation of a hydroxy- protected glucal and is not particularly stable. In Tetrahedron 2002, 58, 1997-2009 it was taught that organometallic additions to a tri-6>-benzyl protected glucal-derived epoxide can provide either the a-C-arylglucoside, mixtures of the a- and β-C-arylglucoside or the β-C-arylglucoside by selection of the appropriate counterion of the carbanionic aryl nucleophile (i.e., the
organometallic reagent). For example, carbanionic aryl groups countered with copper (i.e., cuprate reagents) or zinc (i.e., organozinc reagents) ions provide the β-C-arylglucoside, magnesium ions provide the a- and β-C-arylglucosides, and aluminum (i.e., organoaluminum reagents) ions provide the a-C-arylglucoside.

or Zn[0012] The glycosyl leaving group substitution method: U.S. Patent 7,847,074, also disclosed a method comprising the substitution of a leaving group located at CI of a hydroxy-protected glucosyl species, such as a glycosyl halide, with a metalated aryl compound to prepare SGLT2 inhibitors. U.S. Pat. Appl. 2011/0087017 disclosed a similar method to prepare the SGLT2 inhibitor canagliflozin and preferably diarylzinc complexes are used as nucleophiles along with tetra- >-pivaloyl protected glucosylbromide.

Glucose Glucosyl bromide β-anomer
[0013] Methodology for alkynylation of 1,6-anhydroglycosides reported in Helv. Chim. Acta. 1995, 78, 242-264 describes the preparation of l,4-dideoxy-l,4-diethynyl^-D-glucopyranoses (a. La., glucopyranosyl acetylenes), that are useful for preparing but-l,3-diyne-l,4-diyl linked polysaccharides, by the ethynylating opening (alkynylation) of partially protected 4-deoxy-4-C- ethynyl-l,6-anhydroglucopyranoses. The synthesis of β-C-arylglucosides, such as could be useful as precursors for SLGT2 inhibitors, was not disclosed. The ethynylation reaction was reported to proceed with retention of configuration at the anomeric center and was rationalized (see Helv. Chim. Acta 2002, 85, 2235-2257) by the C3-hydroxyl of the 1,6- anhydroglucopyranose being deprotonated to form a C3-0-aluminium species, that coordinated with the C6-oxygen allowing delivery of the ethyne group to the β-face of the an oxycarbenium cation derivative of the glucopyranose. Three molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6-anhydroglucopyranose. The
ethynylaluminium reagent was prepared by the reaction of equimolar (i.e., 1:1) amounts of aluminum chloride and an ethynyllithium reagent that itself was formed by the reaction of an acetylene compound with butyllithium. This retentive ethynylating opening method was also applied (see Helv. Chim. Acta. 1998, 81, 2157-2189) to 2,4-di-<9-triethylsilyl- 1,6- anhydroglucopyranose to provide l-deoxy-l-C-ethynyl- -D-glucopyranose. In this example, 4 molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6- anhydroglucopyranose. The ethynylaluminium regent was prepared by the reaction of equimolar (i.e., 1: 1) amounts of aluminum chloride and an ethynyl lithium reagent that itself was formed by reaction of an acetylene compound with butyllithium.
[0014] It can be seen from the peer-reviewed and patent literature that the conventional methods that can be used to provide C-arylglucosides possess several disadvantages. These include (1) a lack of stereoselectivity during formation of the desired anomer of the C- arylglucoside, (2) poor redox economy due to oxidation and reduction reaction steps being required to change the oxidation state of CI or of CI and C2 of the carbohydrate moiety, (3) some relatively long synthetic routes, (4) the use of toxic metals such as palladium, and/or (5) atom uneconomic protection of four free hydroxyl groups. With regard to the issue of redox economy, superfluous oxidation and reduction reactions that are inherently required to allow introduction of the aryl group into the carbohydrate moiety of the previously mention synthetic methods and the subsequent synthetic steps to establish the required oxidation state, besides adding synthetic steps to the process, are particular undesirable for manufacturing processes because reductants can be difficult and dangerous to operate on large scales due to their flammability or ability to produce flammable hydrogen gas during the reaction or during workup, and because oxidants are often corrosive and require specialized handling operations (see Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN-10: 0120594757); pg 38 for discussions on this issue).
[0015] In view of the above, there remains a need for a shorter, more efficient and
stereoselective, redox economic process for the preparation of β-C-arylglucosides. A new process should be applicable to the industrial manufacture of SGLT2 inhibitors and their prodrugs,
EXAMPLE 22 – Synthesis of 2,4-di-0-feri-butyldiphenylsUyl-l-C-(3-((5-(4- fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside (2,4-di-6>-TBDPS- canagliflozin; (IVi”))

[0227] 2-(5-Bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (1.5 g, 4.15 mmol) and magnesium powder (0.33 g, 13.7 mmol) were placed in a suitable reactor, followed by THF (9 mL) and 1,2-dibromoethane (95 μί). The mixture was heated to reflux. After the reaction was initiated, a solution of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (2.5 g, 6.92 mmol) in THF (15mL) was added dropwise. The mixture was stirred for another 2 hours under reflux, and was then cooled to ambient temperature and titrated to determine the concentration. The thus prepared 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl magnesium bromide (0.29 M in THF, 17 mL, 5.0 mmol) and A1C13 (0.5 M in THF, 4.0 mL, 2.0 mmol) were mixed at ambient temperature to give a black solution, which was stirred at ambient temperature for 1 hour. To a solution of l ,6-anhydro-2,4-di-6>-ieri-butyldiphenylsilyl- -D-glucopyranose (0.64 g, 1.0 mmol) in PhOMe (3.0 mL) at ambient temperature was added rc-BuLi (0.4 mL, 1.0 mmol, 2.5 M solution in Bu20). After stirring for about 5 min the solution was then added into the above prepared aluminum mixture via syringe, followed by additional PhOMe (1.0 mL) to rinse the flask. The mixture was concentrated under reduced pressure (50 torr) at 60 °C (external bath temperature) to remove low-boiling point ethereal solvents, and PhOMe (6 mL) was then added. The remaining mixture was heated at 150 °C (external bath temperature) for 5 hours at which time HPLC assay analysis indicated a 68% yield of 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5- (4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside. After cooling to ambient temperature, the reaction was treated with 10% aqueous NaOH (1 mL), THF (10 mL) and diatomaceous earth at ambient temperature, then the mixture was filtered and the filter cake was washed with THF. The combined filtrates were concentrated and the crude product was purified by silica gel column chromatography (eluting with 1 :20 MTBE/rc-heptane) to give the product 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)- -D-glucopyranoside (0.51 g, 56%) as a white powder.
1H NMR (400 MHz, CDC13) δ 7.65 (d, J= 7.2 Hz, 2H), 7.55 (d, J= 7.2 Hz, 2H), 7.48 (dd, J= 7.6, 5.6 Hz, 2H), 7.44-7.20 (m, 16H), 7.11-6.95 (m, 6H), 6.57 (d, J= 3.2 Hz, IH), 4.25 (d, J= 9.6 Hz, IH), 4.06 (s, 2H), 3.90-3.86 (m, IH), 3.81-3.76 (m, IH), 3.61-3.57 (m, IH), 3.54-3.49 (m, 2H), 3.40 (dd, J= 8.8, 8.8 Hz, IH), 2.31 (s, 3H), 1.81 (dd, J= 6.6, 6.6 Hz, IH, OH), 1.19 (d, J= 4.4 Hz, IH, OH), 1.00 (s, 9H), 0.64 (s, 9H); 13C NMR (100 MHz, CDC13) δ 162.1 (d, J= 246 Hz, C), 143.1 (C), 141.4 (C), 137.9 (C), 136.8 (C), 136.5 (C), 136.4 (CH x2), 136.1 (CH x2), 135.25 (C), 135.20 (CH x2), 135.0 (CH x2), 134.8 (C), 132.8 (C), 132.3 (C), 130.9 (d, J= 3.5 Hz, C), 130.5 (CH), 130.0 (CH), 129.7 (CH), 129.5 (CH), 129.4 (CH), 129.2 (CH), 127.6 (CH x4), 127.5 (CH x2), 127.2 (CH x2), 127.1 (d, J= 8.2 Hz, CH x2), 127.06 (CH), 126.0 (CH), 122.7 (CH), 115.7 (d, J= 21.8 Hz, CH x2), 82.7 (CH), 80.5 (CH), 79.4 (CH), 76.3 (CH), 72.9 (CH), 62.8 (CH2), 34.1(CH2), 27.2 (CH3 x3), 26.7 (CH3 x3), 19.6, (C), 19.3 (CH3),19.2 (C); LCMS (ESI) m/z 938 (100, [M+NH4]+), 943 (10, [M+Na]+).
EXAMPLE 23 – Synthesis of canagliflozin (l-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)- 4-methylphenyl)- -D-glucopyranoside; (Ii))

[0228] A mixture of the 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5-(4-fluorophenyl)thiophen- 2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside (408 mg, 0.44 mmol) and TBAF (3.5 mL, 3.5 mmol, 1.0 M in THF) was stirred at ambient temperature for 4 hours. CaC03 (0.73 g), Dowex 50WX8-400 ion exchange resin (2.2 g) and MeOH (5mL) were added to the product mixture and the suspension was stirred at ambient temperature for 1 hour and then the mixture was filtered through a pad of diatomaceous earth. The filter cake was rinsed with MeOH and the combined filtrates was evaporated under vacuum and the resulting residue was purified by column chromatography (eluting with 1 :20 MeOH/DCM) affording canagliflozin (143 mg, 73%).

1H NMR (400 MHz, DMSO-J6) δ 7.63-7.57 (m, 2H), 7.28 (d, J= 3.6 Hz, 1H), 7.23-7.18 (m, 3H), 7.17-7.12 (m, 2H), 6.80 (d, J= 3.6 Hz, 1H), 4.93 (br, 2H, OH), 4.73 (br, 1H, OH), 4.44 (br,IH, OH), 4.16 (d, J= 16 Hz, 1H), 4.10 (d, J= 16 Hz, 1H), 3.97 (d, J= 9.2 Hz, 1H), 3.71 (d, J=I I.6 Hz, 1H), 3.47-3.43 (m, 1H), 3.30-3.15 (m, 4H), 2.27 (s, 3H);

13C NMR (100 MHz, DMSO- d6) δ 161.8 (d, J= 243 Hz, C), 144.1 (C), 140.7 (C), 138.7 (C), 137.8 (C), 135.4 (C), 131.0 (d, J= 3.1 Hz, C), 130.1 (CH), 129.5 (CH), 127.4 (d, J= 8.1 Hz, CH x2), 126.8 (CH), 126.7 (CH), 123.9 (CH), 116.4 (d, J= 21.6 Hz, CH x2), 81.8 (CH), 81.7 (CH), 79.0 (CH), 75.2 (CH), 70.9 (CH), 61.9 (CH2), 33.9 (CH2), 19.3 (CH3);

LCMS (ESI) m/z 462 (100, [M+NH4]+), 467 (3, [M+Na]+).

Example 1 – Synthesis of l,6-anhydro-2,4-di-6>-ieri-butyldiphenylsilyl- -D-glucopyranose (II”)

[0206] To a suspension solution of l,6-anhydro- -D-glucopyranose (1.83 g, 11.3 mmol) and imidazole (3.07 g, 45.2 mmol) in THF (10 mL) at 0 °C was added dropwise a solution of TBDPSC1 (11.6 mL, 45.2 mmol) in THF (10 mL). After the l,6-anhydro-P-D-gJucopyranose was consumed, water (10 mL) was added and the mixture was extracted twice with EtOAc (20 mL each), washed with brine (10 mL), dried (Na2S04) and concentrated. Column
chromatography (eluting with 1 :20 EtOAc/rc-heptane) afforded 2,4-di-6>-ieri-butyldiphenylsilyl- l,6-anhydro- “D-glucopyranose (5.89 g, 81%).
1H NMR (400 MHz, CDC13) δ 7.82-7.70 (m, 8H), 7.49-7.36 (m, 12H), 5.17 (s, IH), 4.22 (d, J= 4.8 Hz, IH), 3.88-3.85 (m, IH), 3.583-3.579 (m, IH), 3.492-3.486 (m, IH), 3.47-3.45 (m, IH), 3.30 (dd, J= 7.4, 5.4 Hz, IH), 1.71 (d, J= 6.0 Hz, IH), 1.142 (s, 9H), 1.139 (s, 9H); 13C NMR (100 MHz, CDCI3) δ 135.89 (CH x2), 135.87 (CH x2), 135.85 (CH x2), 135.83 (CH x2), 133.8 (C), 133.5 (C), 133.3 (C), 133.2 (C), 129.94 (CH), 129.92 (CH), 129.90 (CH), 129.88 (CH), 127.84 (CH2 x2), 127.82 (CH2 x2), 127.77 (CH2 x4), 102.4 (CH), 76.9 (CH), 75.3 (CH), 73.9 (CH), 73.5 (CH), 65.4 (CH2), 27.0 (CH3 x6), 19.3 (C x2).

FIG. 1:
X-ray powder diffraction pattern of the crystalline of hemihydrate of the compound of formula (I).
FIG. 2:
Infra-red spectrum of the crystalline of hemihydrate of the compound of formula (I).
FIGS. 3 and 4 provide the XRPD pattern and IR spectrum, respectively, of amorphous canagliflozin.
Systematic (IUPAC) name
Clinical data
Trade names Invokana
AHFS/ entry
  • US:C (Risk not ruled out)
Legal status
Routes of
Pharmacokinetic data
Bioavailability 65%
Protein binding 99%
Metabolism Hepaticglucuronidation
Biological half-life 11.8 (10–13) hours
Excretion Fecal and 33% renal
CAS Registry Number 842133-18-0 Yes
ATC code A10BX11
PubChem CID: 24812758
DrugBank DB08907 Yes
ChemSpider 26333259 
UNII 6S49DGR869 
ChEBI CHEBI:73274 
Synonyms JNJ-28431754; TA-7284; (1S)-1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol
Chemical data
Formula C24H25FO5S
Molecular mass 444.52 g/mol


  1. “U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin”. Reuters. Mar 29, 2013. U.S. health regulators have approved a new diabetes drug from Johnson & Johnson, making it the first in its class to be approved in the United States.
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CAS 1672658-93-3
C24 H25 F O6 S, 460.52
D-Glucopyranose, 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-
CAS 1809403-04-0
C24 H25 F O6 S, 460.52
D-Glucose, 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-


(2R,3S,4R,5R)-1-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one    12

From the FT-IR spectra of 12 contain a signal at 1674 cm–1, this signal is strongly indicative of a carbonyl ketone being present in 12

In 13C NMR and HMBC correlations spectra, the chemical shift at 199.75 ppm was observed. Analysis of the NMR data  confirmed that the structure of 12 is a ring-opened keto form

Synthesis of (2R,3S,4R,5R)-1-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one 12

title compound 12 (84.23% yield) and having 99.4% purity by HPLC;
DSC: 160.84–166.44 °C;
Mass: m/z 459 (M+–H);
IR (KBr, cm–1): 3313, 2982, 1674.7, 1601, 1507.5, 1232.7;
1H NMR (600 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.80 (dd, J = 1.8 Hz, 1H), 7.61–7.58 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.21–7.18 (m, 2H), 6.84 (d, J = 3.6 Hz, 1H), 5.17 (dd, J = 3.6, 3.0 Hz, 1H), 5.02 (d, J = 6.6 Hz, 1H), 4.57 (d, J = 4.8 Hz, 1H), 4.43–4.39 (m, 3H), 4.22 (s, 2H), 4.02–4.01 (m, 1H), 3.53–3.51 (m, 3H), 3.38–3.37 (m, 1H), 2.35 (s, 3H);
13C NMR (101 MHz, DMSO-d6) δ 199.7, 162.6, 160.2, 142.8, 142.1, 140.5, 138.8, 133.3, 130.5, 130.4, 130.4, 129.3, 127.2, 127.0, 127.0, 126.7, 123.5, 116.0, 115.8, 75.2, 72.3, 71.8, 71.3, 63.2, 33.2, 19.2.
HRMS (ESI): calcd m/zfor [C24H25FO6S + Na]+ = 483.1248, found m/z 483.1244.
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00281


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