All about Drugs, live, by DR ANTHONY MELVIN CRASTO, Worldpeaceambassador, Worlddrugtracker, OPEN SUPERSTAR Helping millions, 100 million hits on google, pushing boundaries,2.5 lakh plus connections worldwide, 40 lakh plus VIEWS on this blog in 227 countries, 7 CONTINENTS ……A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, With death on the horizon, I have lot to acheive
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 AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was
with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc
He has total of 32 International and Indian awards
launched 2012, as forxiga in EU, FDA 2014, JAPAN PMDA 2014
Dapagliflozin propanediol monohydrate was first approved by European Medicine Agency (EMA) on November 12, 2012, then approved by the U.S. Food and Drug Administration (FDA) on January 8, 2014, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on March 24, 2014. It was co-developed and co-marketed as Forxiga® by Bristol-Myers Squibb and AstraZeneca in EU.
Dapagliflozin propanediol monohydrate is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Forxiga® is available as tablet for oral use, containing 5 mg or 10 mg of free Dapagliflozin. The recommended starting dose is 5 mg once daily in the morning.
Dapagliflozin propanediol is a solvate containing 1:1:1 ratio of the dapagliflozin, (S)-(+)-1,2-propanediol, and water.
US——-In 2011, the product was not recommended for approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. In 2011, the FDA assigned a complete response letter to the application. A new application was resubmitted in 2013 by Bristol-Myers Squibb and AstraZeneca in the U.S
AstraZeneca (NYSE:AZN) and Bristol-Myers Squibb Company (NYSE:BMY) today announced the U.S. Food and Drug Administration’s (FDA) Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 13-1 that the benefits of dapagliflozin use outweigh identified risks and support marketing of dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The Advisory Committee also voted 10-4 that the data provided sufficient evidence that dapagliflozin, relative to comparators, has an acceptable cardiovascular risk profile.
The FDA is not bound by the Advisory Committee’s recommendation but takes its advice into consideration when reviewing the application for an investigational agent. The Prescription Drug User Fee Act (PDUFA) goal date for dapagliflozin is Jan. 11, 2014.
Dapagliflozin is being reviewed by the FDA for use as monotherapy, and in combination with other antidiabetic agents, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It is a selective and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2) that works independently of insulin to help remove excess glucose from the body. Dapagliflozin, an investigational compound in the U.S., was the first SGLT2 inhibitor to be approved anywhere in the world. Dapagliflozin is currently approved under the trade name [Forxiga](TM) for the treatment of adults with type 2 diabetes, along with diet and exercise, in 38 countries, including the European Union and Australia.
1. A process for the preparation of dapagliflozin in amorphous form, the process comprising:
(a) reducing a compound of formula II to a compound of formula ΠΙ in the presence of a Lewis acid;
(b) silylating a compound of formula IV with hexamethyldisilazane to form a compound of formula V;
(c) reacting the compound of formula III with the compound of formula V in the presence of a strong base followed by treatment with an acid in the presence of an alcohol to prepare a compound of formula VII, wherein R is an alkyl group selected from C1-5 alkyl;
(d) converting the compound of formula VII to dapagliflozin;
(e) acetylating dapagliflozin to give D-glucitol, l ,5-anhydro-l -C-[4-chloro-3-[(4- ethoxyphenyl)methyl] phenyl]-, 2,3,4,6-tetraacetate, (IS)-, a compound of formula VIII;
(f) optionally, purifying the compound of formula VIII with a solvent selected from halogenated hydrocarbons, alcohols, ethers, or mixtures thereof; (g) hydrolyzing the compound of formula VIII obtained in step (f) to give dapagliflozin;
EXAMPLE 1: Preparation of 5-bromo-2-chlorobenzoyl chloride
To a suspension of 5-bromo-2-chiorobenzoic acid (lOg) in methylene di chloride (40niL), dimethylformamide (0.2g) and thionyl chloride were added and the reaction mixture was refluxed for about 2h. After completion of reaction, the solvent was distilled out. The mass obtained was degassed under vacuum followed by stripping with cyclohexane to give crude 5-bromo-2-chlorobenzoyl chloride (10.8g).
[0189] EXAMPLE 2: Preparation of 5-bromo-2-chloro-4′-ethoxybenzophenone (compound of Formula II)
5-bromo-2-chlorobenzoyl chloride (10.7g) was dissolved in methylene dichloride (40mL) and the reaction mixture was cooled to about -8°C to about -12°C under inert atmosphere. Aluminum chloride (5.65g) was added to the reaction mixture followed by addition of a solution of ethoxybenzene in methylene dichloride. The reaction mixture was stirred for about lh at about -8°C to -12°C and then quenched in dilute hydrochloric acid followed by extraction with methylene dichloride. The organic layer was washed with sodium bicarbonate solution and concentrated. The residue obtained was crystallized from methanol to give 5-bromo-2-chloro-4′-ethoxybenzophenone (8.5g). HPLC purity: 99.34%
[0190] EXAMPLE 3: Preparation of 5-bromo-2-chloro-4′-ethoxydiphenylmethane (compound of formula III)
To a mixture of 5-bromo-2-chloro-4′-ethoxybenzophenone (lOg) and methylene dichloride (50mL), cooled to about 0°C to about 5°C, triethylsilane (11.98g) and titanium chloride (22.3g) were added. The reaction mixture was stirred for about 3h at about 10°C to about 15°C. The reaction mixture was quenched into chilled water. The organic layer was separated, washed with water and sodium bicarbonate solution and concentrated under vacuum followed by stripping with toluene. The residue obtained was stirred with methanol, filtered and dried to give 5-bromo-2-chloro-4′-ethoxydiphenylmethane (9g). HPLC purity: 99.4%
[0191] EXAMPLE 4: Preparation of 2,3,4,6-tetra-0-(trimethylsilyl)-D-glucono-l,5- lactone (compound of Formula V)
To a mixture of D-glucono- 1,5 -lactone (lOg) and iodine (0.28g) in methylene dichloride (80mL), hexamethyldisilazane (36.1g) was added and the reaction mixture was refluxed. After completion of reaction, the reaction mixture was concentrated and degassed to give 2,3,4,6-tetra-0-(trimethylsilyl)-D-glucono-l,5-lactone as liquid (25g). HPLC purity: 95%
[0192] EXAMPLE 5: Preparation of D-glucopyranoside, methyl l-C-[4-chloro-3-[(4- ethoxyphenyl)methyl] phenyl] (compound of Formula VII wherein R is methyl)
To a mixture of 2,3,4,6-tetra-0-(trimethylsilyl)-D-glucono-l ,5-lactone (25g) and 5- bromo-2-chloro-4′-ethoxydiphenylmethane (8.7g) in tetrahydrofuran (174mL), cooled to about -75°C to about -88 °C under nitrogen atmosphere, n-butyl lithium in hexane (50mL) was slowly added. The reaction mixture was stirred at about the same temperature and then mixture of methanol and methanesulphonic acid was added to it. The reaction mixture was quenched into sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated sodium chloride solution and concentrated under vacuum to obtain a residue. The residue was purified with a mixture of toluene and cyclohexane. Yield: 1 lg as thick mass with 80-85% HPLC purity.
reacting the compound of formula III with the compound of formula V in the presence of a strong base followed by treatment with an acid in the presence of an alcohol to prepare a compound of formula VII, wherein R is an alkyl group selected from C1-5 alkyl;
[0193] EXAMPLE 6: Preparation of D-glucitol, l,5-anhydro-l-C-[4-chloro-3-[(4- ethoxyphenyl) methyl] phenyl]
To a mixture of D-glucopyranoside, methyl l -C-[4-chloro-3-[(4- ethoxyphenyl)methyl] phenyl] in methylene di chloride (40mL) and acetonitrile (40mL), cooled to about -40°C to about -45°C, triethylsilane (8.74g) was added followed by addition of boron trifluoride etherate (10.67g) maintaining the temperature at about -40°C to about -45°C. The reaction mixture was quenched in sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, concentrated and degassed under vacuum to give title compound (1 lg) as thick residue with 80-85% HPLC purity.
[0194] EXAMPLE 7: Preparation of D-Glucitol, l,5-anhydro-l-C-[4-chloro-3-[(4- ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (lS)-
To a cooled solution of D-glucitol, l,5-anhydro-l -C-[4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl]- (l lg) in methylene dichloride (55mL) at about 0°C to about 5°C, diisopropylethylamme, dmiethylaminopyridine and acetic anhydride were added and the reaction mixture was stirred. After completion of reaction, the reaction mixture was quenched by adding water. The aqueous layer was separated and extracted with methylene dichloride. The organic layer was separated, washed with sodium bicarbonate solution and concentrated under vacuum to obtain residue which was stripped out with methanol. The residue was purified with methanol and charcoal, followed by diisopropyl ether and methanol crystallization. Yield: lOg; HPLC purity: 99.6%
acetylating dapagliflozin to give D-glucitol, l ,5-anhydro-l -C-[4-chloro-3-[(4- ethoxyphenyl)methyl] phenyl]-, 2,3,4,6-tetraacetate, (IS)-, a compound of formula VIII;
[0195] EXAMPLE 8: Preparation of D-glucitol, l,5-anhydro-l-C-[4-chloro-3-[(4- ethoxyphenyl)methyl] phenyl] (Dapagliflozin)
To a stirred solution of D-glucitol, l,5-anhydro-l-C-[4-chloro-3-[(4- ethoxyphenyl)methyl] phenyl]-, 2,3,4,6-tetraacetate, (IS)-, (lOg) in THF: methanol: water mixture (50mL: 50mL:30mL), sodium hydroxide was added and the reaction mixture was stirred. After completion of reaction, the solvents were distilled out under vacuum and the residue obtained was dissolved in methylene dichloride and washed with water and brine and dried over sodium sulfate. The reaction mixture was concentrated and degassed to give off- white to white solids of D-glucitol, l,5-anhydro-l-C-[4-chloro-3-[(4- ethoxyphenyl)methyl] phenyl]- (dapagliflozin) Yield: 7g (XRD matches with amorphous form) HPLC purity: 99.8%
[0197] EXAMPLE 10: Preparation of D-Glucitol, l,5-anhydro-l-C-[4-chloro-3-[(4- ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (IS)- from D-glucono-1,5- lactone (One-pot Synthesis)
To a mixture of D-glucono-l,5-lactone (lOg) in methylene dichloride (80mL), hexamethyldisilazane (36. lg) was added and the reaction mixture was refluxed. After completion of reaction, the reaction mixture was concentrated and degassed. The residue obtained was dissolved in tetrahydrofuran. 5-Bromo-2-chloro-4′-ethoxydiphenylmethane (8.7g) was added to the reaction mixture which was cooled to about -75°C to about-85°C under nitrogen atmosphere. n-Butyl lithium in hexane (50mL) was slowly added to the reaction mixture maintaining the temperature between -75°C to about -85°C. The reaction mixture was stirred at about the same temperature and then mixture of methanol and methanesulphonic acid was added to it. The reaction mixture was quenched into sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated sodium chloride solution and concentrated under vacuum to obtain a residue. This residue was purified by a mixture of toluene and cyclohexane. To the product obtained, methylene dichloride and acetonitrile were added and the reaction mixture was cooled to about -40°C to about -45°C. Triethylsilane (8.74g) was added to the reaction mixture followed by addition of boron trifluoride etherate (10.67g) maintaining temperature at about -40°C to about -45°C. The reaction mixture was quenched in sodium bicarbonate solution. The aqueous layer was separated and extracted with ethyl acetate. The organic layer was separated, concentrated and degassed under vacuum. The thick residue obtained was dissolved in methylene dichloride and cooled to about 0°C to about 5°C. Diisopropylethylamine, dimethylaminopyridine and acetic anhydride were added to the reaction mixture which was stirred. After completion of reaction, the reaction mixture was quenched by adding water. The aqueous layer was separated and extracted with methylene dichloride. The organic layer was separated, washed with sodium bicarbonate solution and concentrated under vacuum to obtain residue which was stripped out with methanol The residue obtained was recrystallized with methanol and charcoal to give title compound (iOg) with 99.7% HPLC purity.
The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Therefore, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of NO donor and SGLT2 inhibitor were design to achieve dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the preferred hybrid 2 exhibited moderate SGLT2 inhibitory effects and anti-platelet aggregation activities, and its anti-platelet effect mediated by NO was also confirmed in the presence of NO scavenger. Moreover, compound 2 revealed significantly hypoglycemic effects and excretion of urinary glucose during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 2, is expected as a potential candidate for the intervention of cardiovascular complications in T2DM.
Graphical abstract
Scheme 1. Synthesis of target compounds 1-3. Reagents and conditions: (a) TMSCl, NMM, THF, 35 °C; (b) (COCl)2, CH2Cl2, DMF, then phenetole, AlCl3, 0 °C; (c) Et3SiH, BF3·OEt2, CH2Cl2, CH3CN, 25 °C; (d) n-BuLi, THF, toluene, -78 °C, then 2a followed by MeOH, CH3SO3H; (e) Et3SiH, BF3·OEt2, CH2Cl2, CH3CN, -10 °C; (f) Ac2O, pyridine, CH2Cl2, DMAP;
Dapagliflozin, also known as SGLT2 inhibitor, chemical name is (2S,3R,4R,5S,6R)-2-[3-(4-ethoxybenzyl)-4-chlorophenyl]-6- Hydroxymethyltetrahydro-2H-pyran-3,4,5-triol, a sodium-glucose cotransporter 2 inhibitor, announced by the U.S. Food and Drug Administration (FDA) on January 8, 2014 , approved the use of dapagliflozin for the treatment of type 2 diabetes, the specific structural formula is as follows:
Dapagliflozin works by inhibiting sodium-glucose transporter 2 (SGLT2), a protein in the kidney that allows glucose to be reabsorbed into the blood. This allows excess glucose to be excreted through the urine, thereby improving blood sugar control without increasing insulin secretion.
At present, there are two main methods for synthesizing dapagliflozin. One uses 5-bromo-2-chlorobenzoic acid as the starting material, which is chlorinated, Falk acylated, reduced, and then combined with 2,3,4 ,6-tetra-0-trimethylsilyl-D-glucopyranosic acid 1,5-lactone is condensed, methyl etherified, and demethoxylated to obtain dapagliflozin. The specific process route is as follows:
The method has expensive starting materials and too many process steps, so it is not suitable for industrial production, and dangerous n-butyllithium needs to be used in the reaction process, so the requirements for experimental conditions are too high;
Another method is to use o-toluidine as the starting material, undergo bromination, diazotization, chlorination, and alkylation reactions, and then react with 2,3,4,6-tetra-0-trimethylsilyl -D-glucopyranosic acid 1,5-lactone is condensed, then methyl etherified and demethoxylated to obtain dapagliflozin. The specific process route is as follows:
AIBN will be used in this reaction, which will produce highly toxic cyanide, which will seriously pollute the environment, and also requires the use of n-butyllithium, which requires high experimental conditions and is dangerous to operate, and is not suitable for large-scale production.
Example 1
Weigh 16g (0.8mol) of activated magnesium, add two iodine pellets, heat to 35°C under nitrogen protection, then add 500mL of anhydrous THF to it, without magnesium, and then add 200mL of 10% iodobenzene to it 2000mL of THF solution (total 2000mL: 20g iodobenzene (0.53mol)+2000mL THF), after the color of the solution subsided, add the remaining iodobenzene solution dropwise, react for 5h, and filter to obtain the Grignard reagent THF solution of iodobenzene.
433.4g (1.1mol) of peracetyl sugar and 1500mL of dichloromethane were added, cooled to 0°C in an ice-water bath, 545.5mL of 33% hydrogen bromide in acetic acid solution (2.2mol) was added dropwise to the reaction flask, and the mixture was gradually heated up The mixture was heated to 25° C. and stirred for 1.5 h. Saturated sodium bicarbonate solution was added to quench the reaction. The aqueous solution was extracted with dichloromethane, dried, and concentrated by rotary evaporation. 423.6 g of white solid were obtained, which was 2,3,4,6-tetraacetyl bromoglucose, and the yield was 93%.
Weigh 217.83g of 2,3,4,6-tetraacetyl bromoglucose (0.53mol) and dissolve it in 2500mL of toluene, then add 5.6g of europium oxide (3mol%) to it, under nitrogen protection, reduce the temperature to – 20°C, dropwise add the prepared iodobenzene Grignard reagent to it, and control the temperature at -20～-15°C. After the dropwise addition, the temperature is raised to 5°C for reaction for 2h, vacuum concentrated to an oily substance, and then added to it. 2000mL of toluene was dissolved, extracted twice with saturated aqueous sodium chloride solution, the organic phase was dried, concentrated in vacuo to an oily substance, and 1000mL of 3:1 n-hexane/ethyl acetate solution was added to it, heated to dissolve, cooled, and a solid was precipitated out, filtered , and dried to obtain 259.49 g of solid with a yield of 85%.
The above-mentioned solid was dissolved in 1000mL 2:3:1 tetrahydrofuran/ethanol/water solution, then 40g sodium hydroxide solid (1mol) was added to it, stirred overnight, vacuum concentrated to obtain oil after the reaction was finished, and then 1000mL of ethyl acetate was added thereto. The ester was dissolved, extracted twice with saturated aqueous sodium chloride solution and twice with saturated aqueous sodium thiosulfate solution, dried the organic phase, concentrated in vacuo to an oil, to which was added 200 mL of 1:3 ethyl acetate/acetonitrile solution , heated to dissolve, cooled and recrystallized to obtain 147.1 g of white rice-like crystals with a yield of 80.2% and a purity of 99.2% (determined by high performance liquid chromatography, external standard method).
Weigh 26.7g (1.33mol) of activated magnesium, add two iodine pellets, heat to 35°C under nitrogen protection, then add 500mL of anhydrous THF to it, without magnesium, and then add 200mL of 10% iodine to it The THF solution of benzene (2000mL in total: 20g iodobenzene (0.53mol)+2000mL THF), after the color of the solution subsides, add the remaining iodobenzene solution dropwise, react for 5h, and filter to obtain the Grignard reagent THF solution of iodobenzene .
433.4g (1.1mol) of peracetyl sugar and 1500mL of dichloromethane were added, cooled to 0°C in an ice-water bath, 272.75mL of 33% hydrogen bromide in acetic acid solution (1.1mol) was added dropwise to the reaction flask, and the mixture was gradually heated up The mixture was heated to 25° C. and stirred for 1.5 h. Saturated sodium bicarbonate solution was added to quench the reaction. The aqueous solution was extracted with dichloromethane, dried, and concentrated by rotary evaporation. 381.5 g of white solid were obtained, which was 2,3,4,6-tetraacetyl bromoglucose, and the yield was 83.8%.
Weigh 217.83g of 2,3,4,6-tetraacetyl bromoglucose (0.53mol) and dissolve it in 5000mL of toluene, then add 5.76g of gadolinium oxide (3mol%) to it, under nitrogen protection, reduce the temperature to – 20°C, dropwise add the prepared iodobenzene Grignard reagent to it, and control the temperature at -20～-15°C. After the dropwise addition, the temperature is raised to 5°C for reaction for 2h, vacuum concentrated to an oily substance, and then added to it. 2000mL of toluene was dissolved, extracted twice with saturated aqueous sodium chloride solution, the organic phase was dried, concentrated in vacuo to an oily substance, and 1000mL of 3:1 n-hexane/ethyl acetate solution was added to it, heated to dissolve, cooled, and a solid was precipitated out, filtered , dried to obtain solid 281.2g, yield 92.1%.
The above-mentioned solid was dissolved in 1000mL 2:3:1 tetrahydrofuran/ethanol/water solution, then 40g sodium hydroxide solid (1mol) was added to it, stirred overnight, vacuum concentrated to obtain oil after the reaction was finished, and then 1000mL of ethyl acetate was added thereto. The ester was dissolved, extracted twice with saturated aqueous sodium chloride solution and twice with saturated aqueous sodium thiosulfate solution, dried the organic phase, concentrated in vacuo to an oil, to which was added 200 mL of 1:4 ethyl acetate/acetonitrile solution , heated to dissolve, cooled and recrystallized to obtain 150.9 g of white rice-like crystals with a yield of 88.2% and a purity of 99.5% (determined by high performance liquid chromatography, external standard method).
Example 3
Weigh 37.4g (1.862mol) of activated magnesium, add two iodine pellets, heat to 35°C under nitrogen protection, then add 500mL of anhydrous THF to it, without magnesium, and then add 200mL of 10% iodine to it The THF solution of benzene (2000mL in total: 20g iodobenzene (0.53mol)+2000mL THF), after the color of the solution subsides, add the remaining iodobenzene solution dropwise, react for 5h, and filter to obtain the Grignard reagent THF solution of iodobenzene .
433.4g (1.1mol) of peracetyl sugar and 1500mL of dichloromethane were added, cooled to 0°C in an ice-water bath, 818.25mL of 33% hydrogen bromide in acetic acid solution (3.3mol) was added dropwise to the reaction flask, and the mixture was gradually heated up The mixture was heated to 25° C. and stirred for 1.5 h. Saturated sodium bicarbonate solution was added to quench the reaction. The aqueous solution was extracted with dichloromethane, dried, and concentrated by rotary evaporation. 375.3 g of white solid were obtained, which was 2,3,4,6-tetraacetyl bromoglucose, and the yield was 82.4%.
Weigh 217.83g 2,3,4,6-tetraacetyl bromoglucose (0.53mol) and dissolve it in 7500mL toluene, then add 5.6g europium oxide (3mol%) to it, under nitrogen protection, reduce the temperature to – 20°C, dropwise add the prepared iodobenzene Grignard reagent to it, and control the temperature at -20～-15°C. After the dropwise addition, the temperature is raised to 5°C for reaction for 2h, vacuum concentrated to an oily substance, and then added to it. 2000mL of toluene was dissolved, extracted twice with saturated aqueous sodium chloride solution, the organic phase was dried, concentrated in vacuo to an oily substance, and 1000mL of 3:1 n-hexane/ethyl acetate solution was added to it, heated to dissolve, cooled, and a solid was precipitated out, filtered , and dried to obtain 273.25 g of solid with a yield of 89.5%.
The above-mentioned solid was dissolved in 1000mL 2:3:1 tetrahydrofuran/ethanol/water solution, then 40g sodium hydroxide solid (1mol) was added to it, stirred overnight, vacuum concentrated to obtain oil after the reaction was finished, and then 1000mL of ethyl acetate was added thereto. The ester was dissolved, extracted twice with saturated aqueous sodium chloride solution and twice with saturated aqueous sodium thiosulfate solution, the organic phase was dried, concentrated in vacuo to an oil, to which was added 200 mL of 1:5 ethyl acetate/acetonitrile solution , heated to dissolve, cooled and recrystallized to obtain 152.7 g of white rice-like crystals with a yield of 82.9% and a purity of 99.4% (determined by high performance liquid chromatography, external standard method).
Example 4
Weigh 26.7g (1.33mol) of activated magnesium, add two iodine pellets, heat to 35°C under nitrogen protection, then add 500mL of anhydrous THF to it, without magnesium, and then add 200mL of 10% iodine to it The THF solution of benzene (2000mL in total: 20g iodobenzene (0.53mol)+2000mL THF), after the color of the solution subsides, add the remaining iodobenzene solution dropwise, react for 5h, and filter to obtain the Grignard reagent THF solution of iodobenzene .
433.4g (1.1mol) of peracetyl sugar and 1500mL of dichloromethane were added, cooled to 0°C in an ice-water bath, 545.5mL of 33% hydrogen bromide in acetic acid solution (2.2mol) was added dropwise to the reaction flask, and the mixture was gradually heated up The mixture was heated to 25° C. and stirred for 1.5 h. Saturated sodium bicarbonate solution was added to quench the reaction. The aqueous solution was extracted with dichloromethane, dried, and concentrated by rotary evaporation. 425.1 g of white solid were obtained, which was 2,3,4,6-tetraacetyl bromoglucose in 94% yield.
Weigh 217.83g of 2,3,4,6-tetraacetyl bromoglucose (0.53mol) and dissolve it in 5000mL of toluene, then add 5.76g of gadolinium oxide (3mol%) to it, under nitrogen protection, reduce the temperature to – 20°C, dropwise add the prepared iodobenzene Grignard reagent to it, control the temperature at -20～-15°C, after the dropwise addition, raise the temperature to 5°C for 2 hours, concentrate in vacuo to an oily substance, then add to it 2000mL of toluene was dissolved, extracted twice with saturated aqueous sodium chloride solution, the organic phase was dried, concentrated in vacuo to an oily substance, then 1000mL of 3:1 n-hexane/ethyl acetate solution was added to it, heated to dissolve, cooled, and a solid was precipitated out, filtered , and dried to obtain 278.6 g of solid with a yield of 91.2%.
The above-mentioned solid was dissolved in 1000mL 2:3:1 tetrahydrofuran/ethanol/water solution, then 40g sodium hydroxide solid (1mol) was added to it, stirred overnight, vacuum concentrated to obtain oil after the reaction was completed, and 1000mL of ethyl acetate was added thereto. The ester was dissolved, extracted twice with saturated aqueous sodium chloride solution and twice with saturated aqueous sodium thiosulfate solution, the organic phase was dried, concentrated in vacuo to an oil, to which was added 200 mL of 1:4 ethyl acetate/acetonitrile solution , heated to dissolve, cooled and recrystallized to obtain 155.62 g of white rice-like crystals with a yield of 84.5% and a purity of 99.7% (determined by high performance liquid chromatography, external standard method).
Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a group of oral medicines used for treating diabetes that have been approved since 2013. SGLT2 inhibitors prevent the kidneys from re-absorbing glucose back into the blood by passing into the bladder. Glucose is re-absorbed back into the blood via the renal proximal tubules. SGLT2 is a protein predominantly expressed in the renal proximal tubules and is likely to be major transporter responsible for this uptake. Glucose-lowering effect of SGLT-2 inhibitors occurs via an insulin-independent mechanism mostly through glucosuria by increasing the urinary excretion of glucose.
It has been shown that the treatment with SGLT2 inhibitors in patients with type II diabetes lowers HbAlc, reduces body weight, lowers systemic blood pressure (BP) and induces a small increase in LDL-C and HDL-C levels.
SGLT2 inhibitors inhibit the reabsorption of sodium and glucose from the tubule and hence, more sodium is delivered in the macula densa causing arteriole dilation, reduced intraglomerular pressure and decreased hyperfiltration. SGLT2 inhibitors cause natriuresis and volume depletion, and an increase in circulating levels of renin, angiotensin and aldosterone. They also reduce albuminuria and slow GFR loss through mechanisms that appear independent of glycemia.
Dapagliflozin is a highly potent and reversible SGLT2 inhibitor, which increases the amount of glucose excreted in the urine and improves both fasting and post-prandial plasma glucose levels in patients with type 2 diabetes. Dapagliflozin has also been shown to tend to reduce liver fat content in some studies in a diabetic population.
Dapagliflozin is available on the market in the form of dapagliflozin propanediol monohydrate and is sold under trade name Forxiga or Farxiga in the form of fdm-coated tablets. Further it is available on the market as a combination product with metformin hydrochloride which is sold under trade name Xigduo IR or Xigduo XR in the form of film-coated tablets. In addition, it is available on the market as a combination product with saxagliptin hydrochloride which is sold under trade name Qtem in the form of film-coated tablets. Moreover, it is available on the market as a combination product with saxagliptin hydrochloride and metformin hydrochloride which is sold under trade name Qtemmet XR in the form of film-coated tablets.
Dapagliflozin as a monotherapy and in a combination with other active substances has demonstrated its efficacy in improving glycaemic control and reducing body weight and blood pressure in a broad spectrum of patients with type II diabetes, including those with high baseline HbAlc and the elderly. A sustained reduction in serum uric acid concentration was also observed. Dapagliflozin provides significant improvement in HbAlc, reduction in insulin dose and reduction in body weight in patients with type 1 diabetes as adjunct therapy to adjustable insulin.
Dapagliflozin can be in its free form or any stereoisomer or any pharmaceutically acceptable salt or co crystal complex or a hydrate or a solvate thereof and in any polymorphic forms and any mixtures thereof.
Dapagliflozin as a substance was first disclosed in US 6,515,117. The process for the preparation of dapagliflozin involves the reaction of 4-bromo- 1 -chloro-2-(4-ethoxybenyl)benzene with 2,3,4,6-tetra-O-trimethyl silyl -D-gluconolactone, the obtained compound 3 on demethoxylation yields diastereomeric mixture of Dapagliflozin. Hie diastereomeric mixture of dapagliflozin is further acetylated with acetic anhydride in the presence of pyridine and dimethylaminopyridine yields, then recrystallized from absolute ethanol to yield the desired tetra-acetyJated b-C-glucoside as a white solid. Compound tetra-acetylated b-C-glucoside is treated with lithium hydroxide hydrate which undergoes deprotection to yield the compound dapagliflozin.
Several other documents, patents and applications disclose the process for the preparation of dapagliflozin such as for example WOO 127128, WO03099836, W02004063209, W02006034489,
Prior art documents already provided some compositions of SGLT2 inhibitor dapagliflozin.
W02008116179 discloses immediate release formulation in the form of a stock granulation or in the form of a capsule or a tablet which comprises dapagliflozin propylene glycol hydrate, one or more bulking agent, one or more binder and one or more disintegrant.
WO2011060256 describes the bilayer tablet comprising dapagliflozin having sustained release profde in one layer and metformin in another layer while WO2011060290 describes immediate release formulation of dapagliflozin and metformin.
WO2012163546 discloses the pharmaceutical composition comprising cyclodextrin and dapagliflozin.
Co-crystals of dapagliflozin with lactose are described in WO2014178040.
Solid dispersion compositions comprising amorphous dapagliflozin and at least one polymer are disclosed in W02015011113 and in WO2015128853.
CN103721261 discloses the combination of SGLT2 inhibitor with vitamins such as vitamin B.
Pharmaceutical composition preparation comprising dapagliflozin L-proline and metformin and/or DPP-IV inhibitor is disclosed in WO2018124497.
EP2252289A1 provides a combination of SGLT inhibitor with DPP4 inhibitor showing synergistic effect in increasing plasma active GLP-1 level in a patient over that provided by administration of the SGLT inhibitor or the DPP4 inhibitor alone.
EP2395983A1 relates to a pharmaceutical composition comprising a SGLT2 inhibitor, a DPP4 inhibitor and a third antidiabetic agent which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia.
Example A: HPLC method
The purity of Dapagliflozine in general may be determined with the following HPLC method: column: XBridge C18, 150×4.6mm, 3.5; flow-rate: 0.9ml/min; column temperature: 50°C, wavelength: UV 225 nm; mobile phase: eluent A: 0.1% H3PO4, Eluent B: methanol; gradient:
Sample preparation: Accurately weigh about 40mg of sample and dissolve in 50 ml of solvent. Calculation: Use area per cent method. Do not integrate solvent peaks.
Example 1: Preparation of 5-bromo-2-chlorobenzoyl chloride
5-bromo-2-chlorobenzoic acid (450 g) was suspended in dichloromethane (2.25 L) and dimethylformamide (0.74 ml). At 15 – 30°C oxalyl chloride (180.3 ml) was slowly added. During addition gas evolution of HC1 and CO2 occurred. The reaction was performed at 20-30°C. The reaction was considered to be complete if 2-chloro-5-bromobenzoic acid was below 1% (area percent purity). The mixture was concentrated at elevated temperature until oily residue was obtained.
Example 2: Preparation of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone
Dichloromethane (900 ml) was charged into reactor and then aluminum chloride (267.6 g) was added. The reaction mixture was cooled below 5°C and ethoxybenzene (256.1 ml) was slowly added. After complete addition, the mixture was gradually cooled below -5°C. In a separate reactor, 5-bromo-2-chlorobenzoyl chloride (485g) was dissolved in dichloromethane (900 ml). This solution was slowly added to the mixture of aluminum chloride and ethoxybenzene with such rate that temperature was kept below -5°C. After complete addition the mixture was stirred below -5°C until reaction was finished. The reaction was considered to be complete if methyl ester was below 1 % (the reaction mixture is sampled in methanol). After reaction was completed the reaction mixture was slowly added into cooled 1M HC1 solution and flushed with of dichloromethane (450 ml). The organic phase was separated and water phase was washed again with dichloromethane. Organic phases were combined and washed with water and NaHC03 solution. So obtained organic phase was concentrated to oily residue and dissolved in methanol ethyl acetate mixture in 10 to 1 ratio at reflux temperature. The clear solution was gradually cooled down to 35-45 °C and seeded with pure 5-bromo-2-chlorophenyl(4-ethoxyphenyl)methanone. The reaction mass was gradually cooled down to 0-10°C and stirred at that temperature up to 4 hours. The precipitate was isolated and washed with precooled methanol. The product was dried to a final LOD (Loss on drying) content of less than 1.0% with a yield of 564g (87% mass yield).
Example 3: Preparation of 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene
5-bromo-2-chlorophenyl(4-ethoxyphenyl)methanone (400g) was dissolved in 1.62L tetrahydrofuran. Into solution NaBTL (53.5g ) was added. After addition, the mixture was stirred at ambient temperature for 30-60 min followed by cooling of reaction mixture below -5°C. Aluminum chloride (314g) was added in portion and reaction mixture maintained below 5°C. After addition, the reaction mixture was gradually heated to reflux temperature and stirred until reaction was complete. Reaction mixture was cooled to ambient temperature and mixture of THF/water was slowly added into reaction mixture followed by addition of water and stirred at ambient temperature. Organic phase was collected and washed with saturated NaCl solution. Organic phase was concentrated to oily residue and dissolved in ethanol (800ml) at elevated temperature. Solution was cooled to 25-30°C and seeded with pure 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene. The reaction mass was gradually cooled to -2 to 10°C and stirred at that temperature. The product was isolated and washed with precooled ethanol and dried until final LOD (Loss on drying) content was less than 1.0%. Yield was 322 g (89%).
Example 4: Preparation of 3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol
4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene (97.5g ) and toluene (1.46L) was charge into reactor. Solution was heated to reflux temperature and approximately half of the solvent was distilled out. Tetrahydrofuran (195 mL) was charged into the solution and mixture was cooled below -70°C. Solution of 15% «-Buli in hexane (227.5 ml) was slowly added and temperature was kept below -70°C. After complete addition solution was stirred at temperature below -70°C to complete reaction. Solution of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (182 g) in toluene (243 mL) was added into reaction mixture at temperature below -70°C. After complete addition, the mixture was stirred below -70°C, warmed to approximately -65°C and then mixture of 57.6 g methanesulfonic acid in 488 ml methanol was added. After addition, the mixture was gradually warmed to ambient temperature and stirred until reaction was complete. After reaction was finished reaction mixture was slowly added into saturated NaHCCL solution (630ml) and stirred. Into quenched mixture 975 ml of heptane and 585 ml methanol was added. The mixture was stirred for additional 15 min. Organic phase was washed with water/methanol mixture several times. Water phases were combined and distilled to remove organic solvents. Into the residual water phase, toluene was added to perform extraction. Organic phases were combined and washed with water. Organic phase was distillated at elevated temperature until oily residue was obtained.
Example 5: Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl) tetrahydro2H-pyran-3,4,5-triol – Dapagliflozin
Dichloromethane (656 mL) was charged into oily residue from step 4 and stirred at ambient temperature until clear solution was obtained. Triethysilane (122 mL) was added into the so obtained solution. Reaction mixture was cooled below -30°C and 94.2 mL of boron trifluoride etherate was slowly added at temperatures below -30°C. After complete addition, the mixture was stirred below -30°C for one hour and gradually warmed to -5 to 0°C until reaction was completed. After reaction was finished saturated NaHCCL solution (468 mL) was slowly added. Reaction mixture was distilled to remove organic solvents followed by addition ethyl acetate into the residue. Organic phase was collected and washed again with saturated NaHC03 and water. So obtained organic phase was distillated at elevated temperature until oily residue is obtained.
Example 6: Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate.
Oily residual from example 5 was dissolved in dichloromethane (602 mL) at ambient temperature followed by addition of DMAP (6.22g). Reaction mixture was cooled to 0 – 10°C and 144.3 mL of acetic anhydride was added at temperatures below 10°C. Reaction mixture was gradually warmed to ambient temperature and stirred until reaction was completed. Reaction mass was washed with water with saturated NaHC03. Organic phase was collected and concentrated to oily residue to which ethanol (1.68L) was charged and approximately 300 ml ethanol was removed by distillation. The clear solution was gradually cooled to 60-65 °C and seeded. The reaction mass was gradually cooled to 20-25 °C and product was isolated. The product was dried at 50°C in vacuum until LOD (Loss on drying) below 1.0% 123g of product was obtained with yield 71%. HPLC purity: 99.97 %.
Formula 9 Formula 2
(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (740 g) as prepared according to process described in examples 1 to 6 was charged into solution of methanol (2.27L), water (0.74L) and NaOH (23 lg) at 35-45°C and stirred at 35-45°C until reaction was completed. After reaction was finished 1M HC1 (1.63L) was slowly added. Reaction mass was distilled to remove organic solvents and product was extracted by tert-butyl methyl ether. Combined organic phases were washed with water and concentrated at elevated temperature until oily residue was obtained. Content of impurity IMP A was below 0.02%.
Example 7a: Preparation of amorphous dapagliflozin.
Oily residue as prepared according to example 7 comprising approximately 262 g of dapagliflozin was dissolved in toluene (2.5L) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (5.3L) at temperature between 10 to 15°C and stirring rate with P/V at 4 W/m3. After complete addition, the suspension was cooled to 0°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Filtration rate was 14 · 104 m/s. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of impurity IMP A was below 0.02% and residual heptane and toluene were 1673 ppm and below 89 ppm.
(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (30 g) of 4 different qualities obtained by the process known in the prior art was charged into solution of methanol (90 mL), water (30 mL) and NaOH (9.36 g) and stirred at 35-45°C until reaction was completed and sampled for HPLC analysis (Sample 1).
After reaction was finished 1M HC1 (66 mL) was slowly added. Reaction mass was distilled to remove organic solvents and product was extracted by tert-butyl methyl ether. To the combined organic phases 68ml of 1M NaOH was added and pH was set to 12.5 to 13.5. Phases were separated and organic phase is washed again with 68ml of water without pH correction. So obtained organic phase was sampled for HPLC analysis (Sample 2) and concentrated at elevated temperature until oily residue was obtained.
Oily residue comprising approximately 21 g of dapagliflozin was dissolved in toluene (210 mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (420 mL) at temperature between 10 to 15°C and stirring rate with P/V as defined in Table 1. After complete addition, the suspension was cooled to 0°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Filtration rate was as defined in Table 1. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Amorphous dapagliflozin with content of impurity IMP A as shown in Table 1 and residual heptane and toluene as shown in Table 1 was obtained for each cases.
Table 1 : Process parameters used in the preparation of four different starting materials (cases).
As it is evident from Table 2 the final amorphous dapagliflozin prepared by the extraction process according to the present invention contains less than 0.02% of impurity IMP A irrespective of the level of impurity IMP A present in the starting material.
Table 2: Content of impurity IMP A in the final amorphous dapagliflozin obtained with and without extraction.
Example 9
Oily residue, as obtained by the procedure described in example 8 case 1, containing approximately 2 g of dapagliflozin was dissolved in 1.5ml of isopropyl acetate and 6ml of tert-butyl methyl ether at temperature 50-55 °C. So prepared solution was charged into 25 mL of heptane at 0°C. After complete addition the suspension was stirred at -10 to 0°C. Suspension was isolated and washed with precooled heptane at temperatures between 25°C to 50 °C. 1.5 g of dapagliflozin was obtained with content of impurity IMP A was below 0.02%.
Example 10
Oily residue, as obtained by the procedure described in example 8 case 1, containing approximately 2 g of dapagliflozin was dissolved in 1.5ml of isopropyl acetate and 6ml of tert-butyl methyl ether at temperature 50-55 °C. So prepared solution was charged into 40 mL of heptane at 0°C. After complete addition the suspension was stirred at -10 to 0°C. Suspension was isolated and washed with precooled heptane at temperatures between 25°C to 50 °C. 1.5 g of dapagliflozin was obtained with content of impurity IMP A was below 0.02%.
Example 11
Dapagliflozin (30g) was dissolved in toluene (285mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (600mL) at 5°C and stirring rate with P/V at 16 W/m3. After complete addition, the suspension was cooled to -10°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of residual heptane and toluene were 1480 ppm and 732 ppm.
Example 12
Dapagliflozin (30g) was dissolved in toluene (285mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (600mL) at 20°C and stirring rate with P/V at 16 W/m3. After complete addition, the suspension was cooled to 5°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled hcptanc Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of residual heptane and toluene were 2873 ppm and 639 ppm.
Comparative Example 1
Dapagliflozin (30g) was dissolved in toluene (285mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (600mL) at -5°C and stirring rate with P/V at 16 W/m3. After complete addition, the suspension was cooled to -15°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of residual heptane and toluene were 1940 ppm and 1557 ppm.
Comparative Example 2
Dapagliflozin (30g) was dissolved in toluene (285mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (600mL) at 25°C and stirring rate with P V at 16 W/m3. After complete addition, the suspension was cooled to 20°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of residual heptane and toluene were 3663 ppm and 2047 ppm.
Comparative Example 3
Dapagliflozin (30g) was dissolved in toluene (285mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (600mL) at 30°C and stirring rate with P/V at 16 W/m3. After complete addition, the suspension was cooled to 15°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of residual heptane and toluene were 2425 ppm and 1812 ppm.
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Daggliflozin (English name: Dapagliflozin) is a new Sodium glucose co-transporters 2 (SGLT-2) inhibitor developed by Bristol-Myers Squibb and AstraZeneca. Approved by the European Commission on November 14, 2012, and marketed in the United States on January 8, 2014, to improve glycemic control in adult patients with type 2 diabetes by combining diet and exercise; the trade name is Farxiga, currently offering 5 mg and 10 mg tablets. At the same time, a combination of dapagliflozin and metformin hydrochloride has also been marketed.The chemical name of dapagliflozin is (2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H – pyran-3,4,5-triol, the chemical formula is C 21 H 25 ClO 6 , CAS No. 461432-26-8, the structural formula is shown as 2, clinically used as a pharmaceutical for dapagliflozin (S) -1,2-propanediol monohydrate, the structural formula is as shown in 1.
The synthesis of β-type C-aryl glycosidic bonds is a key point in the synthetic route during the preparation of dapagliflozin. At present, there are four synthetic methods for the synthesis of dapagliflozin reported in the literature and patents.Route 1: The synthetic route of dapagliflozin reported in patent WO03099836A1 is as follows:
The route uses 2-chloro-5-bromobenzoic acid (12) as raw material to react with phenethyl ether to form intermediate 11 and then triethylsilane to obtain intermediate 10; intermediate 10 and n-butyl The lithium is reacted at -78 ° C, and then subjected to a nucleophilic addition reaction with the intermediate 9, and then methoxylated to obtain the intermediate 8; the intermediate 8 is subjected to acylation reduction and deprotection to obtain the intermediate 2. The disadvantage of this method is that the β-type C-aryl glycosidic bond synthesis of the compound is carried out at a low temperature of -78 ° C, which is obviously difficult to meet the needs of industrial production; and, through nucleophilic addition, methoxylation, The five-step reaction of acetylation, reduction and hydrolysis can synthesize the β-type C-aryl glycosidic bond. The procedure is relatively long, and the purity of the intermediate 2 is only 94%.Route 2: The synthetic route of dapagliflozin reported in the literature OrgLett.2012, 14, 1480 is as follows:
The intermediate 14 of the route is reacted with di-n-butyl-n-hexylmagnesium for 48 hours at 0 ° C, and then reacted with zinc bromide to prepare an organozinc reagent by Br/Mg/Zn exchange reaction, and then with intermediate 4 Intermediate 3 was prepared by nucleophilic substitution reaction; finally, intermediate 2 was obtained by deprotection with sodium methoxide. The synthesis method is relatively novel, and the synthesis step is short. However, the research experiment is conducted only as a synthesis method, and the post treatment of the intermediate 3 is performed by column chromatography. The purity of the intermediate 2 produced was not reported. Moreover, the di-n-butyl-n-hexylmagnesium reagent used in the route is not a commonly used reagent, and is not commercially available in China. It can only be prepared by reacting dibutylmagnesium with n-hexyllithium reagent before the test, and the operation is cumbersome and difficult to mass. use.Route 3: The synthetic route of dapagliflozin reported in patent WO2013068850A2 is as follows:
The route uses 1,6-anhydroglucose (20) as a raw material, protects the 2,4-hydroxyl group by tert-butyldiphenylchlorosilane, and then protects the 3-position hydroxyl group with phenylmagnesium bromide. Intermediate 18. The intermediate 14 is subjected to an Br/Mg/Al exchange reaction to prepare an organoaluminum reagent 16, which is reacted with an intermediate 18 to form an intermediate 15, and finally, deprotected to obtain an intermediate 2. The synthesis method is very novel and is also used as a synthetic methodological study. The purification of the intermediates is carried out by column chromatography. The 1,6-anhydroglucose (20) used in the route is very expensive; and the multi-step reaction in the route uses a format reagent, a preparation format reagent or an organoaluminum reagent, which is cumbersome and cumbersome to perform, and is difficult to scale synthesis. The purity of the intermediate 2 produced was not reported.Route 4: The synthetic route of dapagliflozin reported in patent WO2013152476A1 is as follows:
The route uses 2-chloro-5-iodobenzoic acid (24) as raw material to form intermediate 22 by Friedel acylation and reduction reaction, and exchange with I-Mg at -5 ° C with isopropyl magnesium chloride lithium chloride. The intermediate 8 is obtained by nucleophilic addition and methoxylation with the intermediate 9, and then the intermediate 2 is obtained by reduction with triethylsilane, and the intermediate 2 is further purified by co-crystallizing with L-valine. Finally, The pure intermediate 2 was obtained by removing L-valine. This route is a modified route of Route 1, which replaces n-butyllithium with isopropylmagnesium chloride chloride to raise the reaction temperature of the reaction from -78 °C to -5 °C. However, the problem of a long step of synthesizing a β-type C-aryl glycosidic bond still exists. The obtained intermediate 2 is not optically pure, and needs to be purified by co-crystallizing with L-valine, and the work amount of post-treatment is increased, and finally the purity of the intermediate 2 is 99.3%.Among the four synthetic routes described above for dapagliflozin, route one and route four are commonly used synthetic methods for β-type C-aryl glycosidic bonds, and the route is long, and the optical purity of the obtained product is not high, and further purification is required. Post processing is cumbersome. Moreover, the reaction required at -78 °C in Route 1 requires high equipment and high energy consumption, which undoubtedly increases the cost. Although both Route 2 and Route 3 are new methods, most of the purification of intermediates used is column chromatography. Such a process is not suitable for scale production in factories; and some of the synthetic routes are used. Reagents are not commercially available or expensive, and there is no advantage in such route costs. Therefore, there is an urgent need to find a new method for the synthesis of dapagliflozin, and to enable industrial production, and the route has a cost advantage.Repeating the procedure reported in the literature in Equation 2, the yield of Intermediate 3 was only 46%. The organic zinc reagent is prepared by Br/Mg/Zn exchange reaction, and the exchange reaction yield is 78%; and the raw material is prepared by X/Li/Zn exchange reaction to prepare an organic zinc reagent, and the exchange reaction yield is 98.5%, which is also the two Different reaction pathways lead to the essential reason for the different yields of intermediate 3. Moreover, the price of commercially available 1.0 mol/L di-n-butyl magnesium n-heptane solution 500 mL is 1380 yuan, and the price of 1.6 mol/L n-hexyl lithium n-hexane solution 500 mL is 950 yuan, and 2.5 mol/L n-butyl lithium. The price of 500 mL of n-hexane solution is only 145 yuan. Therefore, the method for preparing dapagliflozin by preparing an organozinc reagent by X/Li/Zn and then synthesizing the β-type C-aryl glycosidic bond designed by the invention has the advantages of cost, ease of operation and industrialization. Very obvious advantage.In order to solve this problem, the original compound company uses a eutectic method in the production of dapagliflozin to make dapagliflozin together with a solvent or an amino acid compound, since the compound 2 sugar ring structure contains four hydroxyl groups and is easy to absorb moisture and deteriorate. The crystal is made into a relatively stable solid, easy to store, stable and controllable in quality, and easy to prepare. Among them, the marketed dapagliflozin forms a stable eutectic with (S)-1,2-propanediol and water (1). The original crystal form patent (CN101479287B, CN103145773B) reported that all 11 crystal forms are dapagliflozin solvate or dapagliflozin. Crystal. Among them, there are two preparation methods for the da forme (S)-1,2-propanediol monohydrate (1) having a crystal structure of type Ia:Method 1: The preparation method is as follows:
Compound 7 is deprotected with sodium hydroxide to obtain compound 2, then compound 2 is extracted with isopropyl acetate, (S)-1,2-propanediol ((S)-PG) is added, and seed crystal of compound 1 is added. Then, cyclohexane was added to crystallize and separated to obtain a eutectic of the compound (1) of the type Ia.Method 2: The preparation method is as follows:
Compound 8 is subjected to reduction of methoxy group by triethylsilane and boron trifluoride diethyl ether complex, and then the reaction solution is extracted with methyl tert-butyl ether (MTBE), and (S)-1,2-propanediol ( (S)-PG), a seed crystal of the compound 1 is added, and then cyclohexane is added to crystallize, and the mixture is separated and dried to obtain a eutectic of the compound (1) of the type Ia.The above two methods for preparing the eutectic are all used in the cyclohexane solvent, which is listed in the appendix of the 2015 edition of the Pharmacopoeia (four parts) as the second type of solvent that should be restricted, with a residual limit of 0.388%. The solvent residue of the final product obtained must reach the specified limit, and the post-treatment process is complicated, time-consuming and labor-intensive, and the production cost is correspondingly increased. The invention finds a suitable solvent on the basis of the synthetic route to prepare a medicinal crystal form, and has obvious advantages in both the method and the process operation steps.The synthetic route is as follows:
Comparative Example 1, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4- Preparation of chlorophenyl]glucosamine (Compound 3)Under nitrogen protection, 1.0 mol/L di-n-butylmagnesium-n-heptane solution (16 mL) was cooled to 0 ° C, and 1.6 mol/L n-hexane lithium n-hexane solution (10 mL) was slowly added dropwise. After the addition was completed, 0 ° C After stirring for 15 h, dry n-butyl ether (2.5 mL) was added to prepare a solution of di-n-butyl-n-hexylmagnesium lithium solution, which was calibrated with iodine and stored for use.Zinc bromide (2.7 g) and lithium bromide (1.04 g) were added with n-butyl ether (20 mL), heated to 50 ° C for 4 h, and cooled for use. 4-(2-Chloro-5-bromo-benzyl) phenyl ether (6.513 g) was added with toluene (8 mL) and n-butyl ether (5 mL) under nitrogen, cooled to 0 ° C, and 0.61 mol/L was added dropwise. n-Butyl-n-hexylmagnesium lithium solution (13.1 mL), after the addition is completed, the reaction was kept at 0 ° C for 48 h, and the above-mentioned alternate zinc bromide and lithium bromide n-butyl ether solution were added, and the reaction was kept at 0 ° C for 1 h, and added 2 , 3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (14.49 g) in toluene (25 mL), heated to 100 ° C to stir the reaction, after TLC detection reaction, add 1 mol / L diluted hydrochloric acid (60 mL), taken after stirring extraction, the organic phase was washed with water (40 mL), then washed with saturated brine (40 mL), dried over anhydrous Na 2 SO 4, concentrated under reduced pressure, column chromatography (petroleum ether / Ethyl acetate = 20:1) 10.38 g of Compound 3 as a pale yellow oil. Yield: 46%. Purity: 99.02%. The organozinc reagent prepared by the method has an iodine calibration yield of 78%.The calibration method of the concentration of the prepared organic zinc reagent: accurately weighed iodine (1 mmol), placed in a three-necked flask, replaced nitrogen, and added anhydrous 0.5 mol/L LiCl tetrahydrofuran solution (5 mL), stirred and dissolved, and cooled to 0 ° C. The prepared organozinc reagent was slowly added dropwise until the color of the brownish yellow solution disappeared.Example 2 (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)Zinc bromide (2.25 g) and lithium bromide (0.87 g) were added with n-butyl ether (30 mL), heated to 50 ° C for 2 h, and cooled for use. 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (10 mL) and n-butyl ether (10 mL) under nitrogen, cooled to -20 ° C, and slowly added dropwise 1.6 mol / L-n-hexyl lithium n-hexane solution (14mL), control the internal temperature does not exceed -10 ° C, after the completion of the addition, the temperature is incubated at -20 ° C for 0.5 h, adding the above-mentioned spare zinc bromide and lithium bromide n-butyl ether solution, The reaction was stirred at 20 ° C for 3 h. Add 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (11.59g) toluene (50mL) solution, heat to 120 ° C and stir the reaction for 4h, after TLC detection reaction, was added 1mol / L diluted hydrochloric acid (40 mL), water (20 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous Na 2 SO 4, concentrated with n-heptane (15mL) and methanol (60 mL) and recrystallized 10.8 g of Compound 3 as a white solid was obtained in a yield: 72.42%. Purity: 99.47%. Melting point: 99.5 to 101.6 °C. (The organic zinc reagent prepared by this method was iodine-calibrated in a yield of 98.5%.) ESI-MS (m/z): 767.30 [M+Na] + . 1 H-NMR (400 MHz, CDCl 3 ): δ 7.33 (1H, d), 7.14-7.17 (2H, m), 7.05 (2H, d), 6.79-6.81 (2H, dd), 5.39 (1H, t ), 5.21-5.31 (2H, m), 4.33 (1H, d), 4.17-4.20 (1H, dd), 3.94-4.11 (5H, m), 3.79-3.83 (1H, m), 1.39 (3H, t ), 1.20 (9H, s), 1.16 (9H, s), 1.11 (9H, s), 0.86 (9H, s).Example 3, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3) PrepareZinc bromide (3.38 g) and lithium bromide (1.3 g) were added with n-butyl ether (40 mL), heated to 50 ° C for 2 h, and cooled for use. 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (20 mL) and n-butyl ether (5 mL) under nitrogen, cooled to -50 ° C, and slowly added dropwise 2.5 mol / L-butyllithium hexane solution (8mL), control the internal temperature does not exceed -30 ° C, after the addition is completed, the reaction is kept at -50 ° C for 10 h, adding the above-mentioned alternate zinc bromide and lithium bromide n-butyl ether solution, The reaction was stirred at -20 ° C for 10 h. Add 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (34.77g) toluene (80mL) solution, heat to 100 ° C and stir the reaction for 24h, after TLC detection reaction, was added 1mol / L diluted hydrochloric acid (60 mL), water (50 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous Na 2 SO 4, concentrated with n-heptane (15mL) and methanol (60 mL) and recrystallized 10.854 g of Compound 3 as a white solid. Yield: 72.81%. Purity: 99.53%.Example 4, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)N-butyl ether (50 mL) was added to zinc iodide (3.19 g) and lithium iodide (1.34 g), and the mixture was heated to 50 ° C for 1.5 h, and cooled for use. 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (15 mL) and n-butyl ether (5 mL) under nitrogen, cooled to -60 ° C, and slowly added dropwise 1.6 mol / L-n-hexyl lithium n-hexane solution (13.8mL), control the internal temperature does not exceed -20 ° C, after the addition is completed, the reaction is kept at -60 ° C for 5 h, and the above-mentioned alternate zinc iodide and lithium iodide n-butyl ether solution is added. The reaction was stirred at 25 ° C for 1 h. Add 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (23.2g) toluene (50mL) solution, heat to 140 ° C reflux reaction for 0.5h, after TLC detection reaction was added 1mol / L diluted hydrochloric acid (50 mL), water (50 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous SO 4 Na 2, concentrated by weight of n-heptane (15mL) and methanol (60 mL) Crystallization gave 10.51 g of Compound 3 as a white solid, yield 70.5%. Purity: 99.41%.Example 5, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)To the zinc bromide (2.25 g) and lithium bromide (0.87 g), cyclopentyl methyl ether (30 mL) was added, and the mixture was heated to 50 ° C for 3 hours, and cooled for use. 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (10 mL) and cyclopentyl methyl ether (10 mL) under nitrogen, cooled to -5 ° C, and slowly added dropwise. Mol / L n-hexyl lithium n-hexane solution (12.5mL), control the internal temperature does not exceed 0 ° C, after the addition is completed, the reaction is kept at -5 ° C for 3 h, adding the above-mentioned spare zinc bromide and lithium bromide cyclopentyl methyl ether The solution was incubated at -5 ° C for 4 h, and a solution of 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (17.39 g) in toluene (40 mL) was added and heated to 80 ℃ reaction was stirred 6h, after completion of the reaction by TLC, was added 1mol / L diluted hydrochloric acid (50 mL), water (50 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous 2 SO 4 Na, and concentrated under reduced pressure, Recrystallization of n-heptane (15 mL) and methanol (60 mL) gave 8.15 g of Compound 3 as a white solid. Purity: 99.39%.Example 6, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)Zinc bromide (4.5 g) and lithium bromide (1.74 g) were added with n-butyl ether (60 mL), heated to 50 ° C for 3 h, and cooled for use. 4-(2-Chloro-5-bromo-benzyl) phenyl ether (6.513 g) was added with toluene (15 mL) and n-butyl ether (5 mL) under nitrogen, cooled to -30 ° C, and slowly added dropwise 2.5 mol / L-butyllithium n-hexane solution (8.4mL), control the internal temperature does not exceed -20 ° C, after the addition is completed, the reaction is kept at -30 ° C for 3 h, and the above-mentioned alternate zinc bromide and lithium bromide n-butyl ether solution is added. The reaction was incubated at -5 ° C for 4 h, and a solution of 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (14.49 g) in toluene (50 mL) was added and heated to 120 ° C for stirring. the reaction 4h, after completion of the reaction by TLC, was added 1mol / L diluted hydrochloric acid (50 mL), water (40 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous Na 2 SO 4, and concentrated under reduced pressure, n-heptyl Recrystallization of the alkane (15 mL) and methanol (60 mL) gave 10.38 g of Compound 3 as a white solid. Purity: 99.54%.Example 7, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)Methyl bromide (40 mL) was added to zinc bromide (2.25 g) and lithium bromide (0.87 g), and the mixture was heated to 50 ° C for 3 h, and cooled for use. 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (15 mL), methyl tert-butyl ether (15 mL), cooled to -40 ° C, and slowly added dropwise. 1.6mol/L n-hexyl lithium n-hexane solution (13.8mL), control the internal temperature does not exceed -30 ° C, after the addition is completed, the reaction is kept at -40 ° C for 4 h, and the above-mentioned alternate zinc bromide and lithium bromide are added. The butyl ether solution was incubated at 5 ° C for 7 h, and a solution of 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (17.39 g) in toluene (50 mL) was added and heated. to 90 deg.] C the reaction was stirred 8h, after completion of the reaction by TLC, was added 1mol / L diluted hydrochloric acid (40 mL), water (40 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous Na 2 SO 4, and concentrated under reduced pressure Recrystallization from n-heptane (15 mL) and methanol (60 mL) gave 9.41 g of Compound 3 as a white solid. Purity: 99.42%. Example 8. Preparation of dapagliflozin (S)-1,2-propanediol monohydrate eutectic (Compound 1)To the compound 3 (37.27 g), methanol (190 mL) was added, and sodium methoxide (10.8 g) was added thereto, and the mixture was heated under reflux for 3 hours. After the TLC reaction was completed, methanol was concentrated, and isopropyl acetate (100 mL) was added to the residue, and water was added. (60 mL), extracted with stirring and the organic phase washed with water (50 mL). (S)-1,2-propanediol (3.8g) and water (0.9g) were added to the organic phase, stirred until it was dissolved, and n-heptane (200 mL) was added, and the mixture was stirred for 2 hours under ice-cooling, suction filtration, filter cake Washing with n-heptane and drying at 30 ° C gave 23.89 g of Compound 1 as a white solid. Yield: 95%. Purity: 99.79%. Melting point: 69.1 to 75.6 °C. The product obtained was subjected to KF = 3.74% (theoretical value: 3.58%). ESI-MS (m/z): 431.22 [M+Na] + . 1 H-NMR (400 MHz, CD 3 OD): δ 7.33 – 7.37 (2H, m), 7.28-7.30 (1H, dd), 7.11 (2H, d), 6.80-6.83 (2H, dd), 4.1 ( 1H, d), 3.98-4.05 (4H, m), 3.88-3.91 (1H, dd), 3.74-3.82 (1H, m), 3.68-3.73 (1H, m), 3.37-3.49 (5H, m), 3.28-3.34 (1H, m), 1.37 (1H, t), 1.15 (3H, d).The crystal form of the obtained product was subjected to thermogravimetric analysis (TGA) by a Universal V4.7A TA instrument, and the TGA curve (Fig. 1) showed a weight loss of about 18.52% from about room temperature to about 240 ° C. The original form Ia crystal form The TGA plot shows a value of 18.7%.The crystal form of the obtained product was subjected to differential scanning calorimetry (DSC) by a Universal V4.7A TA instrument, and the DSC curve (Fig. 2) showed endotherm in the range of about 60 ° C to 85 ° C. The DSC plot shows a range of approximately 50 ° C to 78 ° C.
The crystal form of the obtained product was examined by a Bruker D8advance instrument for powder X-ray diffraction (PXRD), and the 2X value of the PXRD pattern (Fig. 3) (CuKα).
There are characteristic peaks at 3.749°, 7.52°, 7.995°, 8.664°, 15.134°, 15.708°, 17.069°, 18.946°, 20.049°, which are completely consistent with the characteristic peaks of the PXRD pattern of the Ia crystal form in the original patent.In combination with the nuclear magnetic data and melting point of the prepared crystal form, the crystal form of the product (Compound 1) obtained by the present invention is consistent with the pharmaceutically acceptable crystalline form Ia reported in the original patent.
Patent Citations
Publication numberPriority datePublication dateAssigneeTitleCN101479287A *2006-06-282009-07-08布里斯托尔-迈尔斯斯奎布公司Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetesCN104496952A *2014-11-282015-04-08深圳翰宇药业股份有限公司Synthesis method of dapagliflozinCN105153137A *2015-09-172015-12-16上海应用技术学院Preparation method of empagliflozinFamily To Family CitationsCN104829572B *2014-02-102019-01-04江苏豪森药业集团有限公司Dapagliflozin novel crystal forms and preparation method thereofCN105399735A *2015-12-292016-03-16上海应用技术学院Empagliflozin intermediate, and preparation method and application thereof* Cited by examiner, † Cited by third party
Non-Patent Citations
TitleCHEN DEJIN ET AL., CHINA MASTER’S THESES FULL-TEXT DATABASE, ENGINEERING TECHNOLOGY I, vol. B016-731, no. 3, 15 March 2016 (2016-03-15) *LEMAIRE S. ET AL.: “Stereoselective C-glycosylation of furanosyl halides with arylzinc reagents”, PURE APPL. CHEM., vol. 86, no. 3, 4 March 2014 (2014-03-04), pages 329 – 333 *LEMAIRE S. ET AL.: “Stereoselective C-Glycosylation Reactions with Arylzinc Reagents”, ORGANIC LETTERS, vol. 14, no. 6, 2 March 2012 (2012-03-02), pages 1480 – 1483, XP055069093 ** Cited by examiner, † Cited by third partyCLIP
Chemical Synthesis
Dapagliflozin propanediol hydrate, an orally active sodium glucose cotransporter type 2 (SGLT-2) inhibitor, was developed by Bristol-Myers Squibb (BMS) and AstraZeneca for the once-daily treatment of type 2 diabetes. As opposed to competitor SGLT-2 inhibitors, dapagliflozin was not associated with renal toxicity or long-term deterioration of renal function in phase III clinical trials. The drug exhibits excellent SGLT2 potency with more than 1200 fold selectivity over the SGLT1 enzyme.
The IC50 for SGLT2 is less than one thousandth of the IC50 for SGLT1 (1.1 versus 1390 nmol/l), so that the drug does not interfere with the intestinal glucose absorption.[7
dapagliflozin being an inhibitor of sodiumdependent glucose transporters found in the intestine and kidney (SGLT2) and to a method for treating diabetes, especially type II diabetes, as well as hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, Syndrome X, diabetic
complications, atherosclerosis and related diseases, employing such C-aryl glucosides alone or in combination with one, two or more other type antidiabetic agent and/or one, two or more other type therapeutic agents such as hypolipidemic agents.
Approximately 100 million people worldwide suffer from type II diabetes (NIDDM – non-insulin-dependent diabetes mellitus), which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes for which are as yet unknown. Hyperglycemia is considered to be the major risk factor for the development of diabetic complications, and is likely to contribute directly to the impairment of insulin secretion seen in advanced NIDDM. Normalization of plasma glucose in NIDDM patients would be predicted to improve insulin action, and to offset the development of diabetic complications. An inhibitor of the sodium-dependent glucose transporter SGLT2 in the kidney would be expected to aid in the normalization of plasma glucose levels, and perhaps body weight, by enhancing glucose excretion.
Dapagliflozin can be prepared using similar procedures as described in U.S. Pat. No. 6,515,117 or international published applications no. WO 03/099836 and WO 2008/116179
WO 03/099836 A1 refers to dapagliflozin having the structure according to formula 1 .
formula 1
WO 03/099836 A1 discloses a route of synthesis on pages 8-10, whereby one major step is the purification of a compound of formula 2
formula 2
The compound of formula 2 provides a means of purification for providing a compound of formula 1 since it crystallizes. Subsequently the crystalline form of the compound of formula 2 can be deprotected and converted to dapagliflozin. Using this process, dapagliflozin is obtained as an amorphous glassy off-white solid containing 0.1 1 mol% of EtOAc. Crystallization of a pharmaceutical drug is usually advantageous as it provides means for purification also suitable for industrial scale preparation. However, for providing an active pharmaceutical drug a very high purity is required. In particular, organic impurities such as EtOAc either need to be avoided or further purification steps are needed to provide the drug in a
pharmaceutically acceptable form, i.e. substantially free of organic solvents. Thus, there is the need in the art to obtain pure and crystalline dapagliflozinwhich is substantially free of organic solvents.
WO 2008/002824 A1 discloses several alternative solid forms of dapagliflozin, such as e.g. solvates containing organic alcohols or co-crystals with amino acids such as proline and phenylalanine. For instance, the document discloses crystalline
dapagliflozin solvates which additionally contain water molecules (see e.g.
Examples 3-6), but is silent about solid forms of dapagliflozin which do not contain impurities such as organic alcohols. As described above, it is desirable to provide the pharmaceutical active drug in a substantially pure form, otherwise triggering further expensive and time-consuming purification steps. In contrast, the document relates to dapagliflozin solvates where an alcohol and water are both incorporated into the crystal lattice. Hence, there is the need in the art to obtain pure and crystalline dapagliflozin suitable for pharmaceutical production.
WO 2008/1 16179 A1 refers to an immediate release pharmaceutical composition comprising dapagliflozin and propylene glycol. Propylene glycol is a chiral
substance and (S)-propylene glycol used is very expensive. Consequently, also the immediate release pharmaceutical composition is more expensive.
Crystalline forms (in comparision to the amorphous form) often show desired different physical and/or biological characteristics which may assist in the manufacture or formulation of the active compound, to the purity levels and uniformity required for regulatory approval. As described above, it is desirable to provide the pharmaceutical active drug in a substantially pure form, otherwise triggering further expensive and time-consuming purification steps.
PATENT
WO 2008/ 1 16179 Al seems to disclose an immediate release formulation comprising dapagliflozin and propylene glycol hydrate. WO 2008/ 116195 A2 refers to the use of an SLGT2 inhibitor in the treatment of obesity
Example 2 Dapagliflozin (S) PGS—(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (S)-propane-1,2-diol hydrate (1:1:1)
Dapagliflozin (S) propylene glycol hydrate (1:1:1) can be prepared using similar procedures as described in published applications WO 08/002824 and WO 2008/116179, the disclosures of which are herein incorporated by reference in their entirety for any purpose. SGLT2 EC50=1.1 nM.
Example 3 Dapagliflozin (R) PGS—(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (R)-propane-1,2-diol hydrate (1:1:1)
Dapagliflozin (R) propylene glycol hydrate (1:1:1) can be prepared using similar procedures as described in WO 08/002824 and WO 2008/116179, the disclosures of which are herein incorporated by reference in their entirety for any purpose. SGLT2 EC50=1.1 nM.
WO 2008/002824 A1 discloses several alternative solid forms of dapagliflozin, such as e.g. solvates containing organic alcohols or co-crystals with amino acids such as proline and phenylalanine. For instance, the document discloses crystalline
dapagliflozin solvates which additionally contain water molecules (see e.g.
Examples 3-6), but is silent about solid forms of dapagliflozin which do not contain impurities such as organic alcohols. As described above, it is desirable to provide the pharmaceutical active drug in a substantially pure form, otherwise triggering further expensive and time-consuming purification steps. In contrast, the document relates to dapagliflozin solvates where an alcohol and water are both incorporated into the crystal lattice. Hence, there is the need in the art to obtain pure and crystalline dapagliflozin suitable for pharmaceutical production.
WO 2008/1 16179 A1 refers to an immediate release pharmaceutical composition comprising dapagliflozin and propylene glycol. Propylene glycol is a chiral
substance and (S)-propylene glycol used is very expensive. Consequently, also the immediate release pharmaceutical composition is more expensive.
Surprisingly, amorphous dapagliflozin can be purified with the process of the present invention. For instance amorphous dapagliflozin having a purity of 99,0% can be converted to crystalline dapagliflozin hydrate having a purity of 100% (see examples of the present application). Moreover, said crystalline dapagliflozin hydrate does not contain any additional solvent which is desirable. Thus, the process of purifying dapagliflozin according to the present invention is superior compared with the process of WO 03/099836 A1 .
Additionally, the dapagliflozin hydrate obtained is crystalline which is advantageous with respect to the formulation of a pharmaceutical composition. The use of expensive diols such as (S)-propanediol for obtaining an immediate release pharmaceutical composition as disclosed in WO 2008/1 16179 A1 can be avoided
HRMS calcd for C21H25ClNaO6 (M + Na)+ 431.1237, found 431.1234. Anal. Calcd for C21H25ClO6: C, 61.68; H, 6.16. Found: C, 61.16; H, 6.58.
HPLC
HPLC measurements were performed with an Agilent 1100 series instrument equipped with a UV-vis detector set to 240 nm according to the following method: Column: Ascentis Express RP-Amide 4.6 x 150 mm, 2.7 mm; Column temperature: 25 °C – Eluent A: 0.1 % formic acid in water – Eluent B: 0.1 % formic acid in acetonitrile – Injection volume: 3 mL – Flow: 0.7 mL/min – Gradient:Time [min][%] B0.02525.06526.07029.07029.52535.025……………………..
EXAMPLE 24 – Synthesis of 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(4-chloro-3-(4- ethoxybenzyl)phenyl)- -D-glucopyranoside 2,4-di-6>-TBDPS-dapagliflozin; (IVj”))
[0229] l-(5-Bromo-2-chlorobenzyl)-4-ethoxybenzene (1.5 g, 4.6 mmol) and magnesium powder (0.54 g, 22.2 mmol) were placed in a suitable reactor, followed by THF (12 mL) and 1,2- dibromoethane (0.16 mL). The mixture was heated to reflux. After the reaction had initiated, a solution of l-(5-bromo-2-chlorobenzyl)-4-ethoxybenzene (4.5 g, 13.8 mmol) in THF (28 mL) was added dropwise. The mixture was allowed to stir for another hour under reflux, and was then cooled to ambient temperature, and then titrated to determine the concentration. The above prepared 4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl magnesium bromide (31 mL, 10 mmol, 0.32 M in THF) and A1C13 (0.5 M in THF, 8.0 mL, 4.0 mmol) were mixed at ambient temperature to give a black solution, which was stirred at ambient temperature for 1 hour. To a solution of
I, 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 phenylmagnesium bromide (0.38 mL, 1.0 mmol, 2.6 M solution in Et20). 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 then PhOMe (6mL) was added. The reaction mixture was heated at 130 °C (external bath temperature) for 8 hours at which time HPLC assay analysis indicated a 51% yield of 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(4-chloro-3- (4-ethoxybenzyl)phenyl)- -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 1:30 EtOAc/77-heptane) affording the product 2,4-di-6>- ieri-butyldiphenylsilyl- 1 – -(4-chloro-3 -(4-ethoxybenzyl)phenyl)- β-D-glucopyranoside (0.30 g, 34%) as a white powder.
[0230] A solution of the 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(4-chloro-3-(4- ethoxybenzyl)phenyl)- -D-glucopyranoside (60 mg, 0.068 mmol) in THF (3.0 mL) and TBAF (3.0 mL, 3.0 mmol, 1.0 M in THF) was stirred at ambient temperature for 15 hours. CaC03 (0.62 g), Dowex^ 50WX8-400 ion exchange resin (1.86 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 filtrated 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 : 10 MeOH/DCM) affording dapagliflozin (30 mg).
Example 1 – Synthesis of l,6-anhydro-2,4-di-6>-ieri-butyldiphenylsilyl- -D-glucopyranose (II”)
III 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
WO 2016147197, DAPAGLIFLOZIN, NEW PATENT, HARMAN FINOCHEM LIMITED
LINK>>> (WO2016147197) A NOVEL PROCESS FOR PREPARING (2S,3R,4R,5S,6R)-2-[4-CHLORO-3-(4-ETHOXYBENZYL)PHENY 1] -6-(HY DROXY METHYL)TETRAHYDRO-2H-PY RAN-3,4,5-TRIOL AND ITS AMORPHOUS FORM
PATENT
PATENT
WO2016018024, CRYSTALLINE COMPOSITE COMPRISING DAPAGLIFLOZIN AND METHOD FOR PREPARING SAME
HANMI FINE CHEMICAL CO., LTD. [KR/KR]; 59, Gyeongje-ro, Siheung-si, Gyeonggi-do 429-848 (KR)
Dapagliflozin, sold under the brand name Farxiga among others, is a medication used to treat type 2 diabetes and, with certain restrictions, type 1 diabetes.[2] It is also used to treat adults with certain kinds of heart failure.[3][4][5]
It was developed by Bristol-Myers Squibb in partnership with AstraZeneca. In 2018, it was the 227th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[10][11]
Medical uses
Dapagliflozin is used along with diet and exercise to improve glycemic control in adults with type 2 diabetes and to reduce the risk of hospitalization for heart failure among adults with type 2 diabetes and known cardiovascular disease or other risk factors.[12][3] It appears more useful than empagliflozin.[13][verification needed]
In addition, dapagliflozin is indicated for the treatment of adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.[3][4][5] It is also indicated to reduce the risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression.[14]
In the European Union it is indicated in adults:
for the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise:
as monotherapy when metformin is considered inappropriate due to intolerance;
in addition to other medicinal products for the treatment of type 2 diabetes;
for the treatment of insufficiently controlled type 1 diabetes mellitus as an adjunct to insulin in patients with BMI ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy; and
for the treatment of heart failure with reduced ejection fraction.[5]
Adverse effects
Since dapagliflozin leads to heavy glycosuria (sometimes up to about 70 grams per day) it can lead to rapid weight loss and tiredness. The glucose acts as an osmotic diuretic (this effect is the cause of polyuria in diabetes) which can lead to dehydration. The increased amount of glucose in the urine can also worsen the infections already associated with diabetes, particularly urinary tract infections and thrush (candidiasis). Rarely, use of an SGLT2 drug, including dapagliflozin, is associated with necrotizing fasciitis of the perineum, also called Fournier gangrene.[15]
Dapagliflozin can cause dehydration, serious urinary tract infections and genital yeast infections.[3] Elderly people, people with kidney problems, those with low blood pressure, and people on diuretics should be assessed for their volume status and kidney function.[3] People with signs and symptoms of metabolic acidosis or ketoacidosis (acid buildup in the blood) should also be assessed.[3] Dapagliflozin can cause serious cases of necrotizing fasciitis of the perineum (Fournier gangrene) in people with diabetes and low blood sugar when combined with insulin.[3]
To lessen the risk of developing ketoacidosis (a serious condition in which the body produces high levels of blood acids called ketones) after surgery, the FDA has approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines to recommend they be stopped temporarily before scheduled surgery. Canagliflozin, dapagliflozin, and empagliflozin should each be stopped at least three days before, and ertugliflozin should be stopped at least four days before scheduled surgery.[17]
Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.[17]
Use is not recommended in patients with eGFR < 45ml/min/1.73m2, though data from 2021 shows the reduction in the kidney failure risks in people with chronic kidney disease using dapagliflozin.[18]
Mechanism of action
Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine.[19] In clinical trials, dapagliflozin lowered HbA1c by 0.6 versus placebo percentage points when added to metformin.[20]
Regarding its protective effects in heart failure, this is attributed primarily to haemodynamic effects, where SGLT2 inhibitors potently reduce intravascular volume through osmotic diuresis and natriuresis. This consequently may lead to a reduction in preload and afterload, thereby alleviating cardiac workload and improving left ventricular function.[21]
Selectivity
The IC50 for SGLT2 is less than one thousandth of the IC50 for SGLT1 (1.1 versus 1390 nmol/L), so that the drug does not interfere with intestinal glucose absorption.[22]
In July 2016, the fixed-dose combination of saxagliptin and dapagliflozin was approved for medical use in the European Union and is sold under the brand name Qtern.[28] The combination drug was approved for medical use in the United States in February 2017, where it is sold under the brand name Qtern.[29][30]
In May 2019, the fixed-dose combination of dapagliflozin, saxagliptin, and metformin hydrochloride as extended-release tablets was approved in the United States to improve glycemic control in adults with type 2 diabetes when used in combination with diet and exercise. The FDA granted the approval of Qternmet XR to AstraZeneca.[31] The combination drug was approved for use in the European Union in November 2019, and is sold under the brand name Qtrilmet.[32]
Dapagliflozin was found effective in several studies in participants with type 2 and type 1 diabetes.[5] The main measure of effectiveness was the level of glycosylated haemoglobin (HbA1c), which gives an indication of how well blood glucose is controlled.[5]
In two studies involving 840 participants with type 2 diabetes, dapagliflozin when used alone decreased HbA1c levels by 0.66 percentage points more than placebo (a dummy treatment) after 24 weeks.[5] In four other studies involving 2,370 participants, adding dapagliflozin to other diabetes medicines decreased HbA1c levels by 0.54-0.68 percentage points more than adding placebo after 24 weeks.[5]
In a study involving 814 participants with type 2 diabetes, dapagliflozin used in combination with metformin was at least as effective as a sulphonylurea (another type of diabetes medicines) used with metformin.[5] Both combinations reduced HbA1c levels by 0.52 percentage points after 52 weeks.[5]
A long-term study, involving over 17,000 participants with type 2 diabetes, looked at the effects of dapagliflozin on cardiovascular (heart and circulation) disease.[5] The study indicated that dapagliflozin’s effects were in line with those of other diabetes medicines that also work by blocking SGLT2.[5]
In two studies involving 1,648 participants with type 1 diabetes whose blood sugar was not controlled well enough on insulin alone, adding dapagliflozin 5 mg decreased HbA1c levels after 24 hours by 0.37% and by 0.42% more than adding placebo.[5]
Dapagliflozin was approved for medical use in the European Union in November 2012.[5] It is marketed in a number of European countries.[33]
Dapagliflozin was approved for medical use in the United States in January 2014.[34][14]
In 2020, the U.S. Food and Drug Administration (FDA) expanded the indications for dapagliflozin to include treatment for adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.[3] It is the first in this particular drug class, sodium-glucose co-transporter 2 (SGLT2) inhibitors, to be approved to treat adults with New York Heart Association’s functional class II-IV heart failure with reduced ejection fraction.[3]
Dapagliflozin was shown in a clinical trial to improve survival and reduce the need for hospitalization in adults with heart failure with reduced ejection fraction.[3] The safety and effectiveness of dapagliflozin were evaluated in a randomized, double-blind, placebo-controlled study of 4,744 participants.[3] The average age of participants was 66 years and more participants were male (77%) than female.[3] To determine the drug’s effectiveness, investigators examined the occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits.[3] Participants were randomly assigned to receive a once-daily dose of either 10 milligrams of dapagliflozin or a placebo (inactive treatment).[3] After about 18 months, people who received dapagliflozin had fewer cardiovascular deaths, hospitalizations for heart failure, and urgent heart failure visits than those receiving the placebo.[3]
In July 2020, the FDA granted AstraZeneca a Fast Track Designation in the US for the development of dapagliflozin to reduce the risk of hospitalisation for heart failure or cardiovascular death in adults following a heart attack.[35]
In August 2020, it was reported that detailed results from the Phase III DAPA-CKD trial showed that AstraZeneca’s FARXIGA® (dapagliflozin) on top of standard of care reduced the composite measure of worsening of renal function or risk of cardiovascular (CV) or renal death by 39% compared to placebo (p<0.0001) in patients with chronic kidney disease (CKD) Stages 2-4 and elevated urinary albumin excretion. The results were consistent in patients both with and without type 2 diabetes (T2D)[36]
In April 2021, the FDA expanded the indications for dapagliflozin (Farxiga) to include reducing the risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression.[14] The efficacy of dapagliflozin to improve kidney outcomes and reduce cardiovascular death in people with chronic kidney disease was evaluated in a multicenter, double-blind study of 4,304 participants.[14]
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Dapagliflozin is an approved drug by U.S. Food and Drug Administration (FDA). Dapagliflozin is a representative of SGLT-2 inhibitors, actively considered to cure diabetes type 2. Thus, methodology of dapagliflozin synthesis has rarely published (Ellsworth et al. 2002; Meng 2008). Scheme 1 have shown the general synthetic route for the synthesis of dapagliflozin. Gluconolactone 3 which was protected by trimethylsilyl TMS was treated with aryl lithium. Aryl lithium was obtained by reacting aryl bromide 2 (exchange of Li/Br) with n-BuLi. Methyl C-aryl glucoside 4 was produced by treatment of resulting mixture with methane sulfonic acid in the presence of methanol. Compound 4 was subjected to acetylation in the presence of Ac2O, resulted in the formation of 5 followed by reduction of 5 to 6 with the help of Et3SiH and BF3.OEt2. Finally, dapagliflozin 1 was produced via hydrolysis of 6 by LiOH (Deshpande et al. 2008; Meng 2008).
Meng W, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, Zahler R, Deshpande PP, Pullockaran A, Hagan DL, Morgan N, Taylor JR, Obermeier MT, Humphreys WG, Khanna A, Discenza L, Robertson JG, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN (2008) “Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. ” Journal of Medicinal Chemistry 51(5): 1145–1149. https://doi.org/10.1021/jm701272q
Deshpande PP, Ellsworth BA, Singh J, Denzel TW, Lai C, Crispino G, Randazzo ME, Gougoutas JZ (2008) Methods of producing C-aryl glucoside SGLT2 inhibitors, Google Patents. https://patents.google.com/patent/US7375213B2/en
Jun et al. has reported a few improvements to the scheme 1. In the improved methodology scheme 2, trimethylsilyl chloride was added to gluconolactone 7 in the presence of N-methylmorpholine and tetrahydrofuran THF (Horton et al. 1981), followed by the formation of persilyated lactone 3. After completing the reaction of aryl bromide 2 with n-BuLi, added to persilyated lactone 3. Intermediate lactol 8 was produced by treating resulting reaction mixture with trifluoroacetic acid in aqueous form. Then ethyl C-aryl glycoside 9 yielded when subsequently compound 8 was subjected to methane-sulfonic acid in ethyl alcohol. Crude product 9 in the form of oil was secured after the screening of solvents. Jun et al. proposed that more than 98% pure 9 was collected as crystalline solvate after the crystallization of crude oil from n-propanol and n-heptane mixture (Yu et al. 2019). Moreover, Wang et al. proposed that a high extent of diastereoselectivity obtained after the reduction of tetra-O-unprotected methyl C-aryl glucoside by utilizing Et3SiH and BF3.Et2O (Wang et al. 2014). The nature of active pharmaceutical ingredient is amorphous foam which is isolated after the reduction of 9. Production of cocrystalline complex facilitate the isolation and purification of API (Deng et al. 2017). It is concluded that more than 99.7% pure dapagliflozin produced in overall 79% yield, after the crystallization of a mixture consists of n-heptane and ethyl acetate (Yu et al. 2019).
Zheng et al. designed the production methodology of dapagliflozin by introducing NO donor group at the last steps of general route of dapagliflozin synthesis (scheme 1). Novel hybrids achieved by the combination of dapagliflozin and NO donor, having excellent dual characteristics of anti-hyperglycemic and anti-thrombosis. The figure 2 represent the modifiable site (4-position) of dapagliflozin.
Horton D, Priebe W (1981) “Synthetic routes to higher-carbon sugars. Reaction of lactones with 2-lithio-, 3-dithiane. ” Carbohydrate Research 94(1): 27–41. https://doi.org/10.1016/S0008-6215(00)85593-7
Yu J, Cao Y, Yu H, Wang JJ (2019) “A Concise and Efficient Synthesis of Dapagliflozin. ” Organic Process Research & Development 23(7): 1458–1461. https://doi.org/10.1021/acs.oprd.9b00141
Wang X-j, Zhang L, Byrne D, Nummy L, Weber D, Krishnamurthy D, Yee N, Senanayake CH (2014) “Efficient synthesis of empagliflozin, an inhibitor of SGLT-2, utilizing an AlCl3-promoted silane reduction of a β-glycopyranoside. ” Organic Letters 16(16): 4090–4093. https://doi.org/10.1021/ol501755h
Deng J-H, Lu T-B, Sun CC, J-M Chen (2017) “Dapagliflozin-citric acid cocrystal showing better solid state properties than dapagliflozin. ” European Journal of Pharmaceutical Sciences 104: 255–261. https://doi.org/10.1016/j.ejps.2017.04.008
Scheme 3 has shown the formation strategy of new hybrids of nitric oxide with dapagliflozin. During the synthesis process, the compound 6 was treated with BBr3 that result in the formation of phenol 10, which was further subjected to condensation with bromoalkane and then undergo hydrolysis and produce 11 intermediates. Target compound was obtained by the reacting 11 with silver nitrate in acetonitrile (Li et al. 2018).
Li Z, Xu X, Deng L, Liao R, Liang R, Zhang B, Zhang LJB (2018) Design, synthesis and biological evaluation of nitric oxide releasing derivatives of dapagliflozin as potential anti-diabetic and anti-thrombotic agents. Bioorganic & Medicinal Chemistry 26(14): 3947–3952. https://doi.org/10.1016/j.bmc.2018.06.017
Lin et al. fabricated green route (scheme 4) for the production of dapagliflozin. 5-bromo-2-chlorobenzoic acid 12 and gluconolactone were utilized to initiate the synthesis. By taking BF3.Et2O in catalytic amount to produce 13, overall yield of 76% was obtained in one-pot way via considering the Friedel-Craft acylation and ketallization. There was no need to do work-up operations to separate the diaryl ketal 13 as it was easily crystallized from the mixture. Compound 14 was produce as a result of condensation between 13 and 3. Overall yield of 68% of compound 15 was produced by the deprotection of silyl group in ethyl alcohol media. In THF presence, single crystals of 15 was achieved and characterized by XRD-analysis. High yield of dapagliflozin was obtained after the reduction of 15 that was carried out by triethylsilane in the presence of boron trifluoride diethyl etherate in dichloromethane. Upon crystallization from the mixture having heptane and ethyl acetate, greater than 98% pure dapagliflozin was produced by green synthetic pathway (Hu et al. 2019).
Hu L, Zou P, Wei W, Yuan X-M, Qiu X-L, Gou S-H (2019) “Facile and green synthesis of dapagliflozin. ” Synthetic Communications 49(23): 3373–3379. https://doi.org/10.1080/00397911.2019.1666283
PAPER
A Concise and Efficient Synthesis of Dapagliflozin
Cite this: Org. Process Res. Dev.2019, 23, 7, 1458–1461
A concise and efficient synthesis of the SGLT-2 inhibitor dapagliflozin (1) has been developed. This route involves ethyl C-aryl glycoside 9 as the key intermediate, which is easily crystallized and purified as the crystalline n-propanol solvate with high purity (>98.5%). The tetra-O-unprotected compound 9 could be directly reduced to crude dapagliflozin with high diastereoselectivity. The final pure API product 1 was isolated and purified with high purity (>99.7%). The process has been implemented on a multikilogram scale.
A general, transition-metal-free, highly stereoselective cross-coupling reaction between glycosyl bromides and various arylzinc reagents leading to β-arylated glycosides is reported. The stereoselectivity of the reaction is explained by invoking anchimeric assistance via a bicyclic intermediate. Stereochemical probes confirm the participation of the 2-pivaloyloxy group. Finally, this new method was applied to a short and efficient stereoselective synthesis of Dapagliflozin and Canagliflozin.
One study found that it had no benefit on heart disease risk or overall risk of death in people with diabetes.[37] Another study found that in heart failure with a reduced ejection fraction, dapagliflozin reduced the risk of worsening of heart failure or progression to death from cardiovascular causes, irrespective of diabetic status.[38]
^ Ptaszynska, Agata; Johnsson, Kristina M.; Parikh, Shamik J.; De Bruin, Tjerk W. A.; Apanovitch, Anne Marie; List, James F. (2014). “Safety Profile of Dapagliflozin for Type 2 Diabetes: Pooled Analysis of Clinical Studies for Overall Safety and Rare Events”. Drug Safety. 37 (10): 815–829. doi:10.1007/s40264-014-0213-4. PMID25096959. S2CID24064402.
^ Zelniker TA, Wiviott SD, Raz I, et al. (January 2019). “SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials”. Lancet. 393(10166): 31–9. doi:10.1016/S0140-6736(18)32590-X. PMID30424892. S2CID53277899. However, in patients with atherosclerotic cardiovascular disease, the effect of empagliflozin on cardiovascular death was more pro-nounced than that of canagliflozin or dapagliflozin
Clinical trial number NCT00528372 for “A Phase III Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes Who Are Not Well Controlled With Diet and Exercise” at ClinicalTrials.gov
Clinical trial number NCT00643851 for “An Efficacy & Safety Study of BMS-512148 in Combination With Metformin Extended Release Tablets” at ClinicalTrials.gov
Clinical trial number NCT00859898 for “Study of Dapagliflozin in Combination With Metformin XR to Initiate the Treatment of Type 2 Diabetes” at ClinicalTrials.gov
Clinical trial number NCT00528879 for “A Phase III Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes Who Are Not Well Controlled on Metformin Alone” at ClinicalTrials.gov
Clinical trial number NCT00660907 for “Efficacy and Safety of Dapagliflozin in Combination With Metformin in Type 2 Diabetes Patients” at ClinicalTrials.gov
Clinical trial number NCT00680745 for “Efficacy and Safety of Dapagliflozin in Combination With Glimepiride (a Sulphonylurea) in Type 2 Diabetes Patients” at ClinicalTrials.gov
Clinical trial number NCT01392677 for “Evaluation of Safety and Efficacy of Dapagliflozin in Subjects With Type 2 Diabetes Who Have Inadequate Glycaemic Control on Background Combination of Metformin and Sulfonylurea” at ClinicalTrials.gov
Clinical trial number NCT00673231 for “Efficacy and Safety of Dapagliflozin, Added to Therapy of Patients With Type 2 Diabetes With Inadequate Glycemic Control on Insulin” at ClinicalTrials.gov
Clinical trial number NCT02229396 for “Phase 3 28-Week Study With 24-Week and 52-week Extension Phases to Evaluate Efficacy and Safety of Exenatide Once Weekly and Dapagliflozin Versus Exenatide and Dapagliflozin Matching Placebo” at ClinicalTrials.gov
Clinical trial number NCT02413398 for “A Study to Evaluate the Effect of Dapagliflozin on Blood Glucose Level and Renal Safety in Patients With Type 2 Diabetes (DERIVE)” at ClinicalTrials.gov
Clinical trial number NCT01730534 for “Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58)” at ClinicalTrials.gov
Clinical trial number NCT03036124 for “Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF)” at ClinicalTrials.gov
Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2008/2009
more1) Pal, Manojit et al; Improved Process for the preparation of SGLT2 inhibitor dapagliflozin via glycosylation of 5-bromo-2-Chloro-4′-ethoxydiphenylmethane with Gluconolactone ;. Indian Pat Appl,. 2010CH03942 , 19 Oct 20122) Lemaire, Sebastien et al; Stereoselective C-Glycosylation Reactions with Arylzinc Reagents ;
Organic Letters , 2012, 14 (6), 1480-1483;3) Zhuo, Biqin and Xing, Xijuan; Process for preparation of Dapagliflozin amino acid cocrystals ;
Faming Zhuanli Shenqing , 102 167 715, 31 Aug 20114) Shao, Hua et al; Total synthesis of SGLT2 inhibitor Dapagliflozin ;
Hecheng Huaxue , 18 (3), 389-392; 20105) Liou, Jason et al; Processes for the preparation of C-Aryl glycoside amino acid complexes as potential SGLT2 Inhibitors ;. PCT Int Appl,.
WO20100223136) Seed, Brian et al; Preparation of Deuterated benzyl-benzene glycosides having an inhibitory Effect on sodium-dependent glucose co-transporter; . PCT Int Appl,.
WO20100092437) Song, Yanli et al; Preparation of benzylbenzene glycoside Derivatives as antidiabetic Agents ;. PCT Int Appl,.
WO20090265378) Meng, Wei et al; D iscovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes ;
Journal of Medicinal chemistr y, 2008, 51 (5), 1145 -1149;9) Gougoutas, Jack Z. et al; Solvates Crystalline complexes of amino acid with (1S)-1 ,5-anhydro-LC (3 – ((phenyl) methyl) phenyl)-D-glucitol were prepared as for SGLT2 Inhibitors the treatment of Diabetes ;. PCT Int Appl,.
WO200800282410) Deshpande, Prashant P. et al; Methods of producing C-Aryl glucoside SGLT2 Inhibitors ;..
The applicant Janssen-Cilag International N.V. submitted on 28 August 2012 an application for Marketing Authorisation to the European Medicines Agency (EMA) for SIRTURO, through the centralised procedure falling within the Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 21 July 2011. SIRTURO was designated as an orphan medicinal product EU/3/05/314 on 26 August 2005. SIRTURO was designated as an orphan medicinal product in the following indication: treatment of tuberculosis. The applicant applied for the following indication: SIRTURO is indicated in adults (≥ 18 years) as part of combination therapy of pulmonary tuberculosis due to multi-drug resistant Mycobacterium tuberculosis.
Disease to be treated About a third of the global population, more than 2 billion people, is infected with M. tuberculosis, of which the majority is latent. The life time risk to fall ill in overt TB is around 10% in general, but many times higher (around 10% annual risk) in untreated HIV-positive individuals. Tuberculosis is the leading cause of death in the latter population. It was estimated that a total of 8.8 million new TB cases occurred in 2010, including 1.1 million people co infected with HIV, and that about 1.45 million people died due to TB. During more recent years the burden of TB resistant to first line therapy has increased rapidly. Such multidrug resistant tuberculosis (defined later in this assessment report) has been reported in all regions of the world. Presently around 500.000 of new MDR cases are estimated to emerge every year, which is close to 5% of all new TB cases. China and India carried nearly 50% of the total burden of incident MDR-TB cases in 2008, followed by the Russian Federation (9%). The incidence of MDR-TB in US and EU was reported to be 1.1% and 2.4%, respectively. Within the EU, the incidence is much higher in certain Eastern European countries, with the largest burden in Romania, Latvia and Lithuania. MDR TB is an orphan disease in the EU, US and in Japan.
Current TB therapy and definitions Treatment of pulmonary drug susceptible TB typically takes 6 months resulting in cure rates in well over 90% of cases with good treatment adherence. The two most important drugs in this treatment are isoniazid (INH) and rifampicin (RIF). TB with resistance to at least both INH and RIF is called multidrug resistant (MDR) TB. The two most important “classes” of second-line TB drugs to be used in such cases are injectable drugs (the aminoglycosides amikacin and kanamycin, and the related agent capreomycin) and fluoroquinolones. Apart from these agents a number of miscellaneous drugs are used in addition, as part of combination therapy. The effectiveness of these latter miscellaneous drugs is generally lower, the tolerability is problematic and established breakpoints for resistance determination are lacking.
The term pre-XDR (pre-extensively drug resistant) TB is used when resistance is present also to one of the two main second-line class agents (injectables or any of the fluoroquinolones), and XDR-TB when resistance is present to INH+RIF + injectables + fluoroquinolones. The WHO standard treatment for MDR-TB is commonly divided into 2 phases: • a 4 to 6-month intensive treatment phase in which an injectable drug plus 3-4 other drugs, including a fluoroquinolone, • a continuation phase without the injectable drug and often without pyrazinamide (PZA) for a total duration of 18-24 months. Using this approach, cure rates in MDR-TB are much lower than those seen in DS-TB (ranging from less than 50% to around 75%), despite the higher number of agents and longer treatment duration. Hence, MDR TB is associated with a high mortality and is considered an important major threat to public health. More recent approaches to evaluate various MDR TB regimens have yielded somewhat more optimistic outcomes, despite shorter treatment durations. In these non-randomised studies (with low number of patients) cure rates in the range of 90% were achieved by including a fourth generation fluoroquinolone and by increasing the number of agents even further, to include up to 7 agents in the intensive phase, and still 4-5 agents in a second phase.
About the product SIRTURO (bedaquiline, formerly known as TMC 207) is a new agent of a unique class, specific for mycobacteria, and seemingly without cross-resistance to available TB agents. A large number of pre-clinical studies showed promising results for bedaquiline. For example, in animal models bedaquiline + pyrazinamide cured TB at a higher rate than the traditional first line combination, even when therapy was shortened for the former combination. The clinical program for bedaquiline has been aimed at treating MDR-TB, and data is now available from phase 2b studies of moderate size, both placebo-controlled and non-controlled studies. The treatments given in these studies were similar to those recommended by the WHO, although the number of agents used was slightly higher (five agents in the preferred background regimens). Bedaquiline (versus placebo in the controlled study) was added during the first (intensive) treatment phase, while the background regimens were generally unchanged throughout the complete course of therapy (18-24 months). On the basis of these studies, the applicant submitted an application for a conditional approval for bedaquiline, with the proposed indication: treatment of adult patients infected with pulmonary tuberculosis due to MDR M. tuberculosis, as part of combination therapy. In line with the approach in the phase 2 studies, Sirturo is only to be used during the first 6 months of therapy. However the planned pivotal study (as a specific obligation) will test for 40 weeks of bedaquiline treatment.
In 2009, the drug candidate was licensed to Global Alliance TB Drug Development by Tibotec worldwide for the treatment of tuberculosis.
Bedaquiline (INN) is chemically designated as (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4- (dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol with fumaric acid (1:1), and has the following structure:
Bedaquiline fumarate is a white to almost white powder. It contains two asymmetric carbon atoms, C-1 (R), C-2 (S) and exhibits ability to rotate the orientation of linearly polarized light (optical rotation). The substance is non-hygroscopic. It is practically insoluble in aqueous media over a wide pH range and very slightly soluble in 0.01 N HCl. The substance is soluble in a variety of organic solvents. Due to the low solubility Log KD (log P) could not be determined experimentally. In Biopharmaceutics Classification System (BCS) bedaquiline is classified as a Class 2 compound (expressing low solubility and high permeability). Bedaquiline exists in only one non-solvated crystalline form: Form A. In addition 2 pseudopoly-morphs were found: Form B and Form C. The substance can also be made amorphous. Sufficient evidence was provided to demonstrate that Form A is obtained by the employed manufacturing process of the active substance. Particle size was considered a critical quality attribute of the active substance as bedaquiline is not dissolved in the dosage form. Therefore an appropriate test on particle size determination was included in the active substance specification. The acceptance criteria are based upon the capabilities of the milling process, batch and stability data, and the known impact of the particle size on manufacturability, in-vitro release, and in-vivo performance
Bedaquiline is a bactericidal antimycobacterial drug. Chemically it is a diarylquinoline. FDA approved on December 28, 2012.
Bedaquiline is indicated as part of combination therapy in adults (≥ 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB).
Bedaquiline was approved for medical use in the United States in 2012.[1] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] The cost for six months is approximately $900 USD in low income countries, $3,000 USD in middle income countries, and $30,000 USD in high income countries.[5]
SIRTURO (bedaquiline) for oral administration is available as 100 mg strength tablets. Each tablet contains 120.89 mg of bedaquiline fumarate drug substance, which is equivalent to 100 mg of bedaquiline. Bedaquiline is a diarylquinoline antimycobacterial drug.
Bedaquiline fumarate is a white to almost white powder and is practically insoluble in aqueous media. The chemical name of bedaquiline fumarate is (1R, 2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4- (dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol compound with fumaric acid (1:1). It has a molecular formula of C32H31BrN2O2 · C4H4O4 and a molecular weight of 671.58 (555.50 + 116.07). The molecular structure of bedaquiline fumarate is the following:
SIRTURO (bedaquiline) contains the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose 2910 15 mPa.s, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, purified water (removed during processing).
As of 2013 Both the World Health Organization (WHO) and US Centers for Disease Control (CDC) have recommended (provisionally) that bedaquiline be reserved for patients with multidrug-resistant tuberculosis when an otherwise recommended regimen cannot be designed.[9][10]
Clinical trials
Bedaquiline has been studied in phase IIb studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway.[11] It has been shown to improve cure rates of smear-positive multidrug-resistant tuberculosis, though with some concern for increased rates of death (further detailed in the Adverse effects section).[12]
The most common side effects of bedaquiline in studies were nausea, joint and chest pain, and headache. The drug also has a black-box warning for increased risk of death and arrhythmias, as it may prolong the QT interval by blocking the hERG channel.[15] All patients on bedaquiline should have monitoring with a baseline and repeated ECGs.[16] If a patient has a QTcF of > 500ms or a significant ventricular arrythmia, bedaquiline and other QT prolonging drugs should be stopped.
There is considerable controversy over the approval for the drug, as one of the largest studies to date had more deaths in the group receiving bedaquiline that those receiving placebo.[17] 10 deaths occurred in the bedaquiline group out of 79, while 2 occurred in the placebo group, out of 81.[12] Of the 10 deaths on bedaquiline, 1 was due to a motor vehicle accident, 5 were judged as due to progression of the underlying tuberculosis and 3 were well after the patient had stopped receiving bedaquiline.[17] However, there is still significant concern for the higher mortality in patients treated with bedaquiline, leading to the recommendation to limit its use to situations where a 4 drug regimen cannot otherwise be constructed, limit use with other medications that prolong the QT interval and the placement of a prominent black box warning.[17][11]
Drug interactions
Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4, the hepatic enzyme responsible for oxidative metabolism of the drug.[16] Co-administration with rifampin, a strong CYP3A4 inducer, results in a 52% decrease in the AUC of the drug. This reduces the exposure of the body to the drug and decreases the antibacterial effect. Co-administration with ketoconazole, a strong CYP3A4 inhibitor, results in a 22% increase in the AUC, and potentially an increase in the rate of adverse effects experienced[16]
Since bedaquiline can also prolong the QT interval, use of other QT prolonging drugs should be avoided.[9] Other medications for tuberculosis that can prolong the QT interval include fluoroquinolones and clofazimine.
Mode of action
Bedaquiline blocks the proton pump for ATP synthase of mycobacteria. ATP production is required for cellular energy production and its loss leads to cell death, even in dormant or nonreplicating mycobacteria.[18] It is the first member of a new class of drugs called the diarylquinolines.[18] Bedaquiline is bactericidal.[18]
Resistance
The specific part of ATP synthase affected by bedaquiline is subunit c which is encoded by the gene atpE. Mutations in atpE can lead to resistance. Mutations in drug efflux pumps have also been linked to resistance.[19]
History
Bedaquiline was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting, after the drug had been in development for over seven years.[20] It was discovered by a team led by Koen Andries at Janssen Pharmaceutica.[21]
Bedaquiline was approved for medical use in the United States in 2012.[1]
It is manufactured by Johnson & Johnson (J&J), who sought accelerated approval of the drug, a type of temporary approval for diseases lacking other viable treatment options.[22] By gaining approval for a drug that treats a neglected disease, J&J is now able to request expedited FDA review of a future drug.[23]
When it was approved by the FDA on the 28th December 2012, it was the first new medicine for TB in more than forty years.[24][25]
Bedaquiline, formally called (1R, 2S)-1-(6-Bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthyl)-1-phenyl-2-butanol in chemistry and known as Sirturo in commercial, is a new anti-mycobacterial medicine of diarylquinolines. It impinges on the
ATP synthesis of Mycobacterium tuberculosis by inhibiting the activity of proton pump on the cell’s ATP synthetase, and thereby eliminates M. tuberculosis (TB). It’s used for adult multi-drug resistant tuberculosis (MDR-PTB).
The chemical name of beidaquinoline is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-dimethylamino-2-(1-naphthyl)-1 -Phenyl-2-butanol, the first drug developed by Johnson & Johnson in the United States to inhibit mycobacterium adenosine triphosphate (ATP) synthetase, was first introduced in the United States in December 2012 for the treatment of adult multidrug-resistant tuberculosis. The trade name is Sirturo. Beidaquinoline shows strong selectivity for Mycobacterium tuberculosis ATP synthase. Its novel mechanism of action makes it not cross-resistance with other anti-tuberculosis drugs, which will greatly reduce the drug resistance of Mycobacterium tuberculosis. It shows good activity against MDR-TB in macrophages, suggesting that it has the effect of shortening treatment time.
The synthesis of beidaquinoline has been reported in the literature. The specific synthesis route is as follows:
The patent WO2004011436 mentions the use of column chromatography to separate and purify the crude product, but this method is not conducive to industrialization; in addition, a method for isolating and purifying beraquinoline diastereomer A is disclosed in Step C of the Example of WO2006125769. . However, although the purity of the diastereomer A obtained by the separation and purification method disclosed in this patent is 82%, it is actually only possible to achieve the reaction conversion rate of more than 80%. The actual study found that due to the difficult control of the reaction conditions for the preparation of bedaquino, the control conditions for water, temperature, and drip rate are harsh and the reaction is unstable, and it cannot be ensured that the conversion rate reaches more than 80% per batch, and the conversion is usually When the rate is between 60-80%, the ratio of diastereomer B to diastereomer A obtained by this method is between 1:1 and 1:3, and the next step is chiral separation. It has an impact; even the conversion rate is sometimes as low as about 50%. When the conversion rate is as low as 50%, since the amount of the product in the reaction liquid is small, as in the method using patent WO 2006125769, the isolated product can hardly be purified even if the product is separated and purified by the purification method disclosed in this patent. The resulting diastereomer A is also of low purity.
Example 1
Reaction material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA (20g) reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 56%. After quenching the reaction, n-heptane (40 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 0° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 50% acetic acid aqueous solution to remove 3-dimethylamino-1-(naphthalene-5-yl)acetone as a raw material, and 15% hydrochloric acid aqueous solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by layering the filtrate, adjusted to alkaline with aqueous ammonia, extracted with toluene and free, and then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure to obtain a product that is not correct. Enantiomer A (4.9 g), purity 89%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetylene (40 ml), DMSO (4.9 ml), and R-binaphthol phosphate (2.62 g) were added to diastereomer A (4.9 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitates are separated out; at room temperature, the filter cake is washed with acetone and dried under vacuum at 50-60° C. to give a resolution salt (2.07 g);
Split salt (2.07g), toluene (37ml), potassium carbonate (1.51g) and water (13ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, organic layer was treated with 10% potassium carbonate aqueous solution ( (5ml) was washed once, at this time organic layer TLC monitoring; washed with purified water to neutral pH (20ml × 3 times); organic layer was concentrated under reduced pressure to give a colorless oil (1.5g); add toluene (1ml) to heat the whole Dissolve, add ethanol (12ml) and stir at room temperature for 0.5h. Precipitate the solid, and stir in ice water bath for 1h. Filter and wash the filter cake with ethanol. Dry it in vacuo at 50-60°C to give bedaquinoline (1.07g). The HPLC purity is >99%. .
Example 2
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 65%. After quenching the reaction, diisopropyl ether (160 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 5° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 10% aqueous formic acid to remove 3-dimethylamino-1-(naphthalene-5-yl)acetone as a raw material, and 5% aqueous sulfuric acid solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. Filtration, filtration of the filtrate, the product was transferred to the aqueous layer, the raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer, and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. The product was diastereoisomer A (5.7 g), purity 92%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (45 ml), DMSO (5.7 ml), and R-binaphthol phosphate (3.04 g) were added to diastereomer A (5.7 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. Cooling, precipitated salt precipitation; filtered at room temperature, washed with acetone cake, 50-60 ° C vacuum drying salt (2.6g);
The resolved salt (2.41 g), toluene (39 ml), potassium carbonate (1.58 g) and water (14 ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, the organic layer was treated with 10% aqueous potassium carbonate solution ( (5ml) was washed once, washed with purified water until the pH was neutral (20ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.6g); toluene was added (1ml) to heat the solution and ethanol was added (12ml) The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedalquinoline (1.19 g) with an HPLC purity of >99%.
Example 3
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 75%. After quenching the reaction, diisopropyl ether (400 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 2° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 60% aqueous solution of propionic acid to remove 3-dimethylamino-1-(naphthalen-5-yl)acetone as a raw material, and 40% methanesulfonic acid aqueous solution was added to the organic layer for stirring to make the product salified. Precipitated in the water layer. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (6.0 g), purity 94%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (48 ml), DMSO (6.0 ml), and R-binaphthol phosphate (3.09 g) were added to diastereomeric A (6.0 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give the resolved salt (2.59 g).
The resolved salt (2.59g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved; while hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5 ml) was washed once, washed with purified water until the pH was neutral (20 ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.7 g); toluene (1 ml) was added and heated to complete dissolution, and ethanol (12 ml) was added. The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedaquinoline (1.20 g) with an HPLC purity of >99%.
Example 4
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one step reaction to obtain the racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 70%. After quenching the reaction, petroleum ether (16 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 3° C. and filtered to remove diastereoisomer B. The obtained filtrate was washed with 30% acetic acid aqueous solution to remove 3-methylamino-1-(naphthalen-5-yl)acetone as a raw material, and 25% phosphoric acid aqueous solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be slightly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, and then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (5.72 g), purity 88%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetylene (45 ml), DMSO (5.7 ml), and R-binaphthol phosphate (3.04 g) were added to diastereomer A (5.72 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated out; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give a resolution salt (2.43 g);
Split salt (2.43g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5 ml) was washed once, washed with purified water until the pH was neutral (20 ml x 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.5 g); toluene (1 ml) was added for heating and ethanol was added (12 ml) The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, and the filter cake was washed with ethanol. Drying in vacuo at 50-60° C. gave bedaquinoline (1.16 g) with an HPLC purity of >99%.
Example 5
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one step reaction to obtain the racemic bedaquiline reaction solution. The conversion of this reaction was 80% by HPLC analysis. After quenching the reaction, n-hexane (80 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 1° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 40% aqueous acetic acid to remove 3-dimethylamino-1-(naphthalen-5-yl)acetone as starting material, and 20% aqueous hydrochloric acid solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (6.1 g), purity 96%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (48 ml), DMSO (6.1 ml), and R-binaphthol phosphate (3.09 g) were added to diastereomer A (6.1 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated out; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give the resolution salt (2.69 g).
The resolved salt (2.69g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved; while hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5ml) was washed once, washed with purified water until the pH was neutral (20ml×3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.8g); toluene (1ml) was added to heat to dissolve and ethanol (12ml) was added. The precipitated solid was stirred for 0.5 h at room temperature, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedalquinoline (1.28 g) with an HPLC purity of >99%.
⊥ Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.
Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.
The first asymmetric synthesis of a very promising antituberculosis drug candidate, R207910, was achieved by developing two novel catalytic transformations; a catalytic enantioselective proton migration and a catalytic diastereoselective allylation of an intermediate α-chiral ketone. Using 2.5 mol % of a Y-catalyst derived from Y(HMDS)3 and the new chiral ligand 9, 1.25 mol % of p-methoxypyridine N-oxide (MEPO), and 0.5 mol % of Bu4NCl, α-chiral ketone 3 was produced from enone 4 with 88% ee. This reaction proceeded through a catalytic chiral Y-dienolate generation via deprotonation at the γ-position of 4, followed by regio- and enantioselective protonation at the α-position of the resulting dienolate. Preliminary mechanistic studies suggested that a Y: 9: MEPO = 2: 3: 1 ternary complex was the active catalyst. Bu4NCl markedly accelerated the reaction without affecting enantioselectivity. Enantiomerically pure 3 was obtained through a single recrystallization. The second key catalytic allylation of ketone 3 was promoted by CuF•3PPh3•2EtOH (10 mol %) in the presence of KOtBu (15 mol %), ZnCl2 (1 equiv), and Bu4PBF4 (1 equiv), giving the desired diastereomer 2 in quantitative yield with a 14: 1 ratio without any epimerization at the α-stereocenter. It is noteworthy that conventional organometallic addition reactions did not produce the desired products due to the high steric demand and a fairly acidic α-proton in substrate ketone 3. This first catalytic asymmetric synthesis of R207910 includes 12 longest linear steps from commercially available compounds with an overall yield of 5%.
Dr.Chandrasekhar S Director CSIR-Indian Institute of Chemical Technology (Council of Scientific and Industrial Research)
Ministry of Science & Technology, Government of India
Tarnaka, Hyderabad-500007, Telangana, INDIA
(1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)- 2-(naphthalen-1-yl)-1-phenylbut-an-2-ol (3a): A solution of 16a and 16b (6.0 g, 10.2 mmol) in Me2NH (200 mL, 8.0 m in THF) was stirred at 45 °C for 24 h. The solution was filtered and the filtrate concentrated under reduced pressure to afford the crude product which on purification by silica gel column chromatography (eluent: ethyl acetate/hexane = 1:6) furnished 3a and 3b as white solids (4.8 g, 90%) (1:1 w/w).
Jump up^Diacon AH, Pym A, Grobusch M, et al. (2009). “The diarylquinoline TMC207 for multidrug-resistant tuberculosis”. N Engl J Med. 360 (23): 2397–405. doi:10.1056/NEJMoa0808427. PMID19494215.
^ Jump up to:abCenters for Disease Control and Prevention (2013-10-25). “Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis”. MMWR. 62 (RR-09): 1–12. ISSN1545-8601. PMID24157696.
Jump up^de Jonge MR, Koymans LH, Guillemont JE, Koul A, Andries K (June 2007). “A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910”. Proteins. 67 (4): 971–80. doi:10.1002/prot.21376. PMID17387738.
Naloxegol (INN; PEGylated naloxol;[1] trade names Movantik and Moventig) is a peripherally–selectiveopioid antagonistdeveloped by AstraZeneca, licensed from Nektar Therapeutics, for the treatment of opioid-induced constipation.[2] It was approved in 2014 in adult patients with chronic, non-cancer pain.[3] Doses of 25 mg were found safe and well tolerated for 52 weeks.[4] When given concomitantly with opioid analgesics, naloxegol reduced constipation-related side effects, while maintaining comparable levels of analgesia.[5]
Naloxegol Oxalate was approved by the U.S. Food and Drug Administration (FDA) on Sept 16, 2014, then approved by European Medicine Agency (EMA) on Dec 8, 2014. It was developed and marketed as Movantik®(in the US)/Moventig®(in EU) by AstraZeneca.
Naloxegol oxalate is an antagonist of opioid binding at the mu-opioid receptor. It is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.
Movantik® is available as tablets for oral use, containing 12.5 mg or 25 mg of free Naloxegol. The recommended dose is 25 mg once daily (reduce to 12.5 mg if not tolerated).
Chemically, naloxegol is a pegylated (polyethylene glycol-modified) derivative of α-naloxol. Specifically, the 5-α-hydroxyl group of α-naloxol is connected via an ether linkage to the free hydroxyl group of a monomethoxy-terminated n=7 oligomer of PEG, shown extending at the lower left of the molecule image at right. The “n=7” defines the number of two-carbon ethylenes, and so the chain length, of the attached PEG chain, and the “monomethoxy” indicates that the terminal hydroxyl group of the PEG is “capped” with amethyl group.[6] The pegylation of the 5-α-hydroxyl side chain of naloxol prevents the drug from crossing the blood-brain barrier(BBB).[5] As such, it can be considered the antithesis of the peripherally-acting opiate loperamide which is utilized as an opiate-targeting anti-diarrheal agent that does not cause traditional opiate side-effects due to its inability to accumulate in the central nervous system in normal subjects.
Naloxegol was previously a Schedule II drug in the United States because of its chemical similarity to opium alkaloids, but was recently reclassified as a prescription drug after the FDA concluded that the impermeability of the blood-brain barrier to this compound made it non-habit-forming, and so without the potential for abuse — specifically, naloxegol was officially decontrolled on 23. January 2015. [7]
As an opiate antagonist, it is not expected to be capable of inducing the euphoria and anxiolytic effects which are generally cited as the desirable effects of commonly abused opiates (all of which are opiate agonists) if it were to cross the BBB; it would in fact reverse the effects of opiate drugs of abuse if it entered the central nervous system.
Naloxegol is an oral polyethylene glycol (PEG) derivative of naloxone, a peripherally acting µ-opioid receptor antagonist (PAMORA) with limited potential for interfering with centrally mediated opioid analgesia. The incorporation of a polyethylene glycol moiety aims at inhibiting naloxone’s capacity to cross the blood-brain barrier, while preserving the affinity for the µ-opioid receptor [1].
Opioid-induced bowel dysfunction (OIBD) represents a broad spectrum of symptoms that result from the actions of opioids on the CNS as well as the gastrointestinal tract. The majority of gastrointestinal effects seem to be mediated by the high number of µ-receptors that are expressed in the enteric nervous system. Naloxegol was more effective than placebo in increasing the number of spontaneous bowel movements in patients with opioid-induced constipation, including those with an inadequate response to laxatives.
Recognition of Naloxegol as a useful option in the treatment of opioid-induced constipation resulted in its approval by US-FDA for adult patients with chronic, non-cancer pain in 2014.
Naloxegol oxalate (XXI) is a peripherally acting l-opioid receptor antagonist that was approved in the USA and EU for the treatment of opioid-induced constipation in adults with chronic non-cancer pain. The drug, a pegylated version of naloxone, has significantly reduced central nervous system (CNS) penetration and works by inhibiting the binding of opioids in the gastrointestinal tract.152–154 Naloxegol oxalate was developed by Nektar and licensed to AstraZeneca. Although we were unable to find a single report in the primary or patent literature that describes the exact experimental procedures to prepare naloxegol oxalate, there havebeen reports on the preparation of closely related analogs155 with specific reports on improving the selectivity of the reduction step156 and the salt formation of the final drug substance.157 Taken together, the likely synthesis of naloxegol oxalate (XXI) is
described in Scheme 28. Naloxone (180) was treated with methoxyethyl chloride in the presence of Hunig’s base to give the protected ketone 181. Reduction of the ketone with potassium trisec-butylborohydride exclusively provided the a-alcohol 182 in 85% yield. Alternatively, sodium trialkylborohydrides could also be used to provide similar a-selective reduction in high yield.
Deprotonation of the alcohol with sodium hydride followed by alkylation with CH3(OCH2CH2)7Br (183) provided the pegylated intermediate 184 in 88% yield. Acidic removal of the methoxyethyl ether protecting group followed by treatment with oxalic acid and crystallization provided naloxegol oxalate (XXI) in good yield.
152. Corsetti, M.; Tack, J. Expert Opin. Pharmacol. 2015, 16, 399.
153. Garnock-Jones, K. P. Drugs 2015, 75, 419.
154. Leonard, J.; Baker, D. E. Ann. Pharmacother. 2015, 49, 360.
155. Bentley, M. D.; Viegas, T. X.; Goodin, R. R.; Cheng, L.; Zhao, X. US Patent
2005136031A1, 2005.
156. Cheng, L.; Bentley, M. D. WO Patent 2007124114A2, 2007.
157. Aaslund, B. L.; Aurell, C.-J.; Bohlin, M. H.; Sebhatu, T.; Ymen, B. I.; Healy, E. T.;
Jensen, D. R.; Jonaitis, D. T.; Parent, S. WO Patent 2012044243A1, 2012.
158. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm4183
US20050136031A1: The patent reports detailed synthetic procedures to manufacture gram quantities of Naloxegol. The synthesis starts with Naloxone which was treated with methoxyethyl chloride in the presence of Hunig’s base to give the protected ketone. Reduction of the ketone with potassium tri-sec-butylborohydride exclusively provided the α-alcohol in 85% yield. Deprotonation of the alcohol with sodium hydride followed by alkylation with CH3(OCH2CH2)7Br provided the pegylated Naloxone in 88% yield.
EXAMPLE 4 SYNTHESIS OF PEG 3-NALθxoL [0211] The structure of the naloxol, an exemplary small molecule drug, is shown below.
Naloxol [0212] This molecule was prepared (having a protected hydroxyl group) as part of a larger synthetic scheme as described in Example 5.
EXAMPLE 5
[0213] α,β-PEGι-naloxol was prepared. The overview of the synthesis is provided below.
(3)
(4)
5.A. Synthesis of 3-MEM-naloxone
[0214] Diisopropylethylamine (390 mg, 3.0 mmole) was added to a solution of naloxone ■ HCl • 2H2O (200 mg, 0.50 mmole) in CH2C12 (10 mL) with stining. Methoxyethyl chloride (“MEMCl,” 250 mg, 2.0 mmole) was then added dropwise to the above solution. The solution was stined at room temperature under N2 overnight.
[0215] The crude product was analyzed by HPLC, which indicated that 3-
MEM-O-naloxone (1) was formed in 97% yield. Solvents were removed by rotary evaporation to yield a sticky oil.
5.B. Synthesis of α and β epimer mixture of 3-MEM-naloxoI (2)
[0216] 3 mL of 0.2 N NaOH was added to a solution of 3-MEM-naloxone
(1) (obtained from 5.A. above, and used without further purification) in 5mL of ethanol. To this was added a solution of NaBHLt (76 mg, 2.0 mmole) in water (1 mL) dropwise. The resulting solution was stined at room temperature for 5 hours. The ethanol was removed by rotary evaporation followed by addition of a solution of 0.1 N HCl solution to destroy excess NaBKj and adjust the pH to a value of 1. The solution was washed with CHC13 to remove excess methoxyethyl chloride and its derivatives (3 x 50 mL), followed by addition of K2OO3 to raise the pH of the solution to 8.0. The product was then extracted with CHC13 (3 x 50 mL) and dried over Na2SO4. The solvent was removed by evaporation to yield a colorless sticky solid (192 mg, 0.46 mmole, 92% isolated yield based on naloxone • HCl • 2H2O).
[0217] HPLC indicated that the product was an α and β epimer mixture of
3-MEM-naloxol (2).
5.C. Synthesis of α and β epimer mixture of 6-CH3-OCH2CH2-O-3-MEM- naloxol (3a).
[0218] NaH (60% in mineral oil, 55 mg, 1.38 mmole) was added into a solution of 6-hydroxyl-3-MEM-naloxol (2) (192 mg, 0.46 mmole) in dimethylformamide (“DMF,” 6 mL). The mixture was stined at room temperature under N2 for 15 minutes, followed by addition of 2-bromoethyl methyl ether (320 mg, 2.30 mmole) in DMF (1 mL). The solution was then stirred at room temperature under N2 for 3 hours.
[0219] HPLC analysis revealed formation of a mixture of α- and β-6-CH3-OCH2CH2-0-3-MEM-naloxol (3) in about 88% yield. DMF was removed by a rotary evaporation to yield a sticky white solid. The product was used for subsequent transformation without further purification.
5.D. Synthesis of α and β epimer mixture of 6-CH3-OCH2CH2-naloxoI (4)
[0220] Crude α- and β-6-CH3-OCH2CH2-O-3-MEM-naloxol (3) was dissolved in 5 mL of CH2C12 to form a cloudy solution, to which was added 5 mL of trifluoroacetic acid (“TFA”). The resultant solution was stined at room temperature for 4 hours. The reaction was determined to be complete based upon HPLC assay. CH2C12 was removed by a rotary evaporator, followed by addition of 10 mL of water. To this solution was added sufficient K2OO3 to destroy excess TFA and to adjust the pH to 8. The solution was then extracted with CHC13 (3 x 50 mL), and the extracts were combined and further extracted with 0.1 N HCl solution (3 x 50 mL). The pH of the recovered water phase was adjusted to a pH of 8 by addition of K2CO3>followed by further extraction with CHC13 (3 x 50 mL). The combined organic layer was then dried with Na2SO4. The solvents were removed to yield a colorless sticky solid.
[0221] The solid was purified by passage two times through a silica gel column (2 cm x 30 cm) using CHCl3/CH3OH (30:1) as the eluent to yield a sticky solid. The purified product was determined by 1H NMR to be a mixture of α- and β epimers of 6-CH3-OCH2CH2-naloxol (4) containing ca. 30% α epimer and ca. 70% β epimer [100 mg, 0.26 mmole, 56% isolated yield based on 6-hydroxyl-3-MEM- naloxol (2)].
[0222] 1H NMR (δ, ppm, CDC13): 6.50-6.73 (2 H, multiplet, aromatic proton of naloxol), 5.78 (1 H, multiplet, olefinic proton of naloxone), 5.17 (2 H, multiplet, olefinic protons of naloxol), 4.73 (1 H, doublet, C5 proton of α naloxol), 4.57 (1 H, doublet, C5 proton of β naloxol), 3.91 (1H, multiplet, C6 proton of naloxol), 3.51-3.75 (4 H, multiplet, PEG), 3.39 (3 H, singlet, methoxy protons of PEG, α epimer), 3.36 (3 H, singlet, methoxy protons of PEG, β epimer), 3.23 (1 H, multiplet, C6 proton of β naloxol), 1.46-3.22 (14 H, multiplet, protons of naloxol).
Naloxol-polyethylene glycol conjugates are provided herein in solid phosphate and oxalate salt forms. Methods of preparing the salt forms, and pharmaceutical compositions comprising the salt forms are also provided herein. ACKGROUND
Effective pain management therapy often calls for an opioid analgesic. In addition to the desired analgesic effect, however, certain undesirable side effects, such as bowel dysfunction, nausea, constipation, among others, can accompany the use of an opioid analgesic. Such side effects may be due to opioid receptors being present outside of the central nervous system, principally in the gastrointestinal tract. Clinical and preclinical studies support the use of mPEG7-0-naloxol, a conjugate of the opioid antagonist naloxol and polyethylene glycol, to counteract undesirable side effects associated with use of opioid analgesics. When administered orally to a patient mPEG7-0-naloxol largely does not cross the blood brain barrier into the central nervous system, and has minimal impact on opioid- induced analgesia. See, e.g., WO 2005/058367; WO 2008/057579; Webster et al., “NKTR-118 Significantly Reverses Opioid-Induced Constipation,” Poster 39, 20th AAPM Annual Clinical Meeting (Phoenix, AZ), October 10, 2009.
To move a drug candidate such as mPEG7-O-naloxol to a viable pharmaceutical product, it is important to understand whether the drug candidate has polymorphic forms, as well as the relative stability and interconversions of these forms under conditions likely to be encountered upon large-scale production, transportation, storage and pre-usage preparation. Solid forms of a drug substance are often desired for their convenience in formulating a drug product. No solid form of mPEG7-O-naloxol drug substance has been made available to date, which is currently manufactured and isolated as an oil in a free base form. Exactly how to accomplish this is often not obvious. For example the number of pharmaceutical products that are oxalate salts is limited. The free base form of mPEG7-0-naloxol has not been observed to form a crystalline phase even when cooled to -60 °C and has been observed to exist as a glass with a transition temperature of
approximately -45 °C. Furthermore, mPEG7-0-naloxol in its free base form can undergo oxidative degradation upon exposure to air. Care can be taken in handling the free base, for example, storing it under inert gas, to avoid its degradation. However, a solid form of mPEG7-0-naloxol, preferably one that is stable when kept exposed to air, is desired
a naloxol-polyethlyene glycol conjugate oxalate salt, the salt comprising ionic species of mPEG7-0-naloxol and oxalic acid. The formulas of mPEG7-0-naloxol and oxalic acid are as follows:
In certain embodiments, the methods provided comprise dissolving mPEG7-0- naloxol free base in ethanol; adding methyl t-butyl ether to the dissolved mPEG?–
O-naloxol solution; adding oxalic acid in methyl t-butyl ether to the dissolved mPEG7-0-naloxol over a period of at least 2 hours to produce a slurry; and filtering the slurry to yield the naloxol-polyethlyene glycol conjugate oxalate salt in solid form.
In certain embodiments, the methods provided comprise dissolving mPEG7-0- naloxol free base in acetonitrile; adding water to the dissolved mPEG7-0-naloxol solution; adding oxalic acid in ethyl acetate to the dissolved mPEG7-0-naloxol over a period of at least 2 hours to produce a slurry; and filtering the slurry to yield the naloxol-polyethlyene glycol conjugate oxalate salt in solid form.
In some embodiments, the solid salt form of mPEG7-0-naloxol is a crystalline form.
In certain embodiments a solid crystalline salt provided herein is substantially pure, having a purity of at least about 80%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.
In certain embodiments, the solid salt form of mPEG7-0-naloxol is a phosphate salt.
In other embodiments, the solid mPEG7-0-naloxol salt form is an oxalate salt. For instance, in some embodiments of solid oxalate salt forms provided herein, the solid mPEG7-0-naloxol oxalate salt form is in Form A, as described herein. As another example, in some embodiments of solid oxalate salt forms provided herein, the solid mPEG7-0-naloxol oxalate salt form is in Form B, as described herein. In yet other embodiments, an oxalate salt of mPEG7-0-naloxol in solid form prepared according to the methods described herein is provided.
In yet other embodiments, an dihydrogenphosphate salt of mPEG7-0-naloxol in solid form prepared according to the methods described herein is provided.
In certain embodiments of a solid mPEG7-0-naloxol oxalate salt Form B provided herein, the salt form exhibits a single endothermic peak on differential scanning calorimetry between room temperature and about 150 °C. The single endothermic peak can occur, for instance, between about 91 °C to about 94 °C. For example, in some embodiments the endothermic peak is at about 92 °C, about 92.5 °C, or about93 °C.
“Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation.”. Aliment Pharmacol Ther. 40: 771–9. Oct 2014.doi:10.1111/apt.12899. PMID25112584.
^ Jump up to:abGarnock-Jones KP (2015). “Naloxegol: a review of its use in patients with opioid-induced constipation”. Drugs. 75 (4): 419–425. doi:10.1007/s40265-015-0357-2.
Technically, the molecule that is attached via the ether link is O-methyl-heptaethylene glycol [that is, methoxyheptaethylene glycol, CH3OCH2CH2O(CH2CH2O)5CH2CH2OH], molecular weight 340.4, CAS number 4437-01-8. See Pubchem Staff (2016). “Compound Summary for CID 526555, Pubchem Compound 4437-01”. PubChem Compound Database. Bethesda, MD, USA: NCBI, U.S. NLM. Retrieved 28 January2016.
Naloxegol oxalate (MovantikTM, Moventig)
Naloxegol oxalate (XXI) is a peripherally acting l-opioid receptor antagonist that was approved in the USA and EU for the treatment of opioid-induced constipation in adults with chronic non-cancer pain. The drug, a pegylated version of naloxone, has significantly reduced central nervous system (CNS) penetration and works by inhibiting the binding of opioids in the gastrointestinal tract.152–154 Naloxegol oxalate was developed by Nektar and licensed to AstraZeneca. Although we were unable to find a single report in the primary or patent literature that describes the exact experimental procedures to prepare naloxegol oxalate, there have been reports on the preparation of closely related analogs155 with specific reports on improving the selectivity of the reduction step156 and the salt formation of the final drug substance.157 Taken together, the likely synthesis of naloxegol oxalate (XXI) is described in Scheme 28. Naloxone (180) was treated with methoxyethyl chloride in the presence of Hunig’s base to give the protected ketone 181. Reduction of the ketone with potassium trisec-butylborohydride exclusively provided the a-alcohol 182 in 85% yield. Alternatively, sodium trialkylborohydrides could also be used to provide similar a-selective reduction in high yield.
Deprotonation of the alcohol with sodium hydride followed by alkylation with CH3(OCH2CH2)7Br (183) provided the pegylated intermediate 184 in 88% yield. Acidic removal of the methoxyethyl ether protecting group followed by treatment with oxalic acid and crystallization provided naloxegol oxalate (XXI) in good yield.
152. Corsetti, M.; Tack, J. Expert Opin. Pharmacol. 2015, 16, 399.
153. Garnock-Jones, K. P. Drugs 2015, 75, 419.
154. Leonard, J.; Baker, D. E. Ann. Pharmacother. 2015, 49, 360.
155. Bentley, M. D.; Viegas, T. X.; Goodin, R. R.; Cheng, L.; Zhao, X. US Patent
2005136031A1, 2005.
156. Cheng, L.; Bentley, M. D. WO Patent 2007124114A2, 2007.
157. Aaslund, B. L.; Aurell, C.-J.; Bohlin, M. H.; Sebhatu, T.; Ymen, B. I.; Healy, E. T.;
Jensen, D. R.; Jonaitis, D. T.; Parent, S. WO Patent 2012044243A1, 2012.
Regulators in Europe have given the green light to Eli Lilly’s Trulicity, its once-weekly glucagon-like peptide-1 receptor agonist for type 2 diabetes.
Dulaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 agonist) for the treatment of type 2 diabetes that can be used once weekly.[1][2]GLP-1 is a hormone that is involved in the normalization of level of glucose in blood (glycemia). The FDA approved dulaglutide for use in the United States in September 2014.[3] The drug is manufactured by Eli Lilly under the brand name Trulicity.[3]
Mechanism of action
Dulaglutide binding to glucagon-like peptide 1 receptor, slows gastric emptying and increases insulin secretion by beta cells in the pancreas. Simultaneously the compound reduces the elevated glucagon secretion by alpha cells of the pancreas, which is known to be inappropriate in the diabetic patient. GLP-1 is normally secreted by L cells of the gastrointestinal mucosa in response to a meal.[4]
Medical uses[
The compound is indicated for adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control. Dulaglutide is not indicated in the treatment of subjects with type 1 diabetes mellitus or patients with diabetic ketoacidosis. Dulaglutide can be used either stand-alone or in combination with other medicines for type 2 diabetes, in particular metformin, sulfonylureas, thiazolidinediones, and insulin taken concomitantly with meals.[5]
The compound is contraindicated in subjects with hypersensitivity to active principle or any of the product’s components. As a precautionary measure patients with a personal or family history of medullary thyroid carcinoma or affected by multiple endocrine neoplasia syndrome type 2 should not take dulaglutide, because for now it is unclear whether the compound can increase the risk of these cancers.[9]
Nauck M, Weinstock RS, Umpierrez GE, Guerci B, Skrivanek Z, Milicevic Z (August 2014). “Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5)”. Diabetes Care37 (8): 2149–58.doi:10.2337/dc13-2761. PMID24742660.
Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E (February 2014). “Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials”. Diabetes Res. Clin. Pract.103 (2): 269–75. doi:10.1016/j.diabres.2014.01.010.PMID24485345.
Patients with the incurable blood cancers chronic lymphocytic leukaemia (CLL) and follicular lymphoma (FL) have gained access to a new treatment option in Europe with the approval of Gilead’s Zydelig (idelalisib).
For CLL, the drug can now be used alongside Rituxan (rituximab) in patients who have received at least one prior therapy, and it has also been green lighted for first-line use in those carrying a 17p deletion or TP53 mutation who are unsuitable for chemo-immunotherapy.
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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