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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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

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WO 2016147197, DAPAGLIFLOZIN, NEW PATENT, HARMAN FINOCHEM LIMITED


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Dapagliflozin structure.svg

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

HARMAN FINOCHEM LIMITED [IN/IN]; 107, Vinay Bhavya Complex 159-A, C.S.T. Road Kalina, Mumbai 400098 Maharashtra (IN)

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KADAM, Vijay Trimbak; (IN).
SAIKRISHNA; (IN).
CHOUDHARE, Tukaram Sarjerao; (IN).
MINHAS, Harpreet Singh; (IN).
MINHAS, Gurpreet Singh; (IN)

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CHAIRMAN

HARPREET SINGH MINHAS

HARPREET SINGH MINHAS

Owner, HARMAN FINOCHEM LIMITED

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(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is sodium dependent glucose transporter (SGLT) which is currently under investigation for the treatment of type-2 diabetes. (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is marketed under the tradename Farxiga or Forxiga.

(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is also known as D-glucitol, l,5-anhydro-l-C-[4-chloro-3-[(4ethoxyphenyl)methyl]phenyl]-, (I S). (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3, 4,5 -triol is a white to off-white powder with a molecular formula of C2iH25C106 and a molecular weight of 408.87

Formula-I

US 6,515,117 B2 discloses (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and its pharmaceutically acceptable salts. US 6,515,117 B2 also describes process for preparation of (2S,3R,4R,5S,6R)-2-[4- chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol which comprises reaction of 5-bromo-2-chloro-4′-ethoxydiphenylmethane with 2,3,4,6-tetra-O-trimethylsilyl- -D-glucolactone in presence of THF/Toluene, methansulfonic acid to yield o-methylglucoside product which further reacts with Et3SiH, BF3Et20 in presence of MDC and acetonitrile to yield yellow solidified foam which is dissolved in MDC, pyridine and followed by acetylation with acetic anhydride, DMAP to yield tetra acetylated- β-C-glucoside as a white solid which is further deprotected with LiOH H20 in presence of THF/MeOH/H20 to get (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

The drawback of said prior art is having multiple process steps which makes the process very lengthy and tedious. Moreover the process discloses use of hazardous chemicals like pyridine which is not applicable to industry.

Process for preparation of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenylJ-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is disclosed in US 7,375,213 B2 and J.Med.Chem.2008, 51, 1145-1149. The preparation process is depicted in Scheme-I.

Scheme-1

Prior art US’213 describes reaction of 2-chloro-5-bromo-4′-ethoxy-diphenylmethane with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, n-BuLi in presence of THF and Heptane. After basification with TEA, the oily residue of methyl- l-C-(2-chloro-4′- ethoxy-diphenylmethan-3-yl)-a-D-glucopyranose obtained as solid compound after workup. This compound reacts with acetic anhydride in presence of THF, DIPEA and DMAP to get oily residue of methyl-2,3,4,6 tetra-0-acetyl-l-C-(2-chloro-4′-ethoxydiphenylmethan-3-yl)-a-D-glucopyranose which further undergoes reduction reaction in presence of acetonitirle, t riethylsilane, boron trifluoride etherate to yield 2,3,4,6-tetra-0-acetyl-l-C-(2-chloro-4′-ethoxydi henylmethan-3-yl)-β-D-glucopyranose which is further deprotected by reacting with LiOH monohydrate in presence of THF/MeOH/H20 to get (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

The said prior art describes multiple, time consuming process steps which involves getting the intermediate products as oily residue at various stages of the process, which is difficult to purify and handle for further process step. More over the workup involves multiple evaporation of product which may result in decomposition. Another drawback of the process is that the process describes n-BuLi reaction with two pot reaction. It is very difficult to transfer the material from one reactor to second reactor at -78 °C at industrial level with highly moisture sensitive reaction mass. This makes process uneconomical, cumbersome and commercially not viable. Further when practically the said method followed, a-Isomer of the final product is formed in the range of 6-8% along ith Des-bromo impurity formed in the range of 7-9 %, which increases after addition of n-butyllithium and kept the mass for overnight reaction. Moreover lactone ring cleavage is also observed in the range of 3-4% after addition of Methanesulphonic Acid/Methanol and maintained overnight for reaction completion, the removal of which is difficult from the final product.

WO 2008002824 A 1 discloses crystalline forms of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol comprising (S)-propylene glycol (PG), (R)-PG, EtOH, ethylene glycol (EG), 1 :2 L-proline, 1 : 1 L-proline, 1 : 1 L-proline hemihydrate, 1 : 1 L-phenylalanine and its preparation process.

In the light of the above drawbacks, it is necessitated to provide economical, robust, safe and commercially viable process for preparing (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

Accordingly, it is an objective of the present invention to provide a commercially viable process for the preparation of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxyb.enzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, prepared via riovel intermediates which gives higher yield and purity and facilitates easy recovery of the final compound. The purification process does not involve any costly technique/equipment, however, carried out with solvents which are industrially feasible. More over the present invention discloses the n-BuLi insitu reaction that makes the present invention cost-effective over the teachings of prior art.

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Scheme-II

Formula-Ill Formula-IV

Formula-V where R1= allyl, prop-2-ynyl,isopropyl

Scheme-Ill

where R = allyl, prop-2-ynyl

Scheme-IV

Scheme-V

Examples:

Example-1: Preparation of 3,4,5-Tris-trimethylsiIanyloxy-6-trimethylsiIanyloxymethyl-tetrahydro-pyran-2-one

To 750 cc of dry THF added 1.12 mole 3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-one at ambient temperature and stirred for 20 min. To the reaction mass added 9.0 mole N-Methyl morpholine and stirred for another 30.0 min at ambient temperature. Reaction mass was cooled to -5 °C to 0 °C and stirred for 30.0 min. Added 18.0 mole Trimethyl sillyl chloride at the temp -5 °C to 0 °C and stirred for 30.0 min. Temperature was raised to 25 °C to 30 °C and maintained for 18-20hrs. After reaction complies by GC, the reaction mass was cooled to -5 deg to 0 deg. Added Sat.Sodium bicarbonate solution to obtain the pH 7-8 and stirred for 1 hr at 0 °C. Added 500 cc toluene and stirred for lhr. Reaction mass was settled down for 30.0 min and layers were separated. To the Aqueous layer added 250 cc of toluene and stirred for 30.0 min. Layers separated and both the organic layers mixed and back washed with sat.brine solution. Organic layer was distilled under reduced pressure at a temperature of about 40 – 48 deg. Unload the oily mass . Purity: 92-96 %

Example-2: Preparation of 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyI-tetrahydro-pyran-3,4,5-triol

To the mixture of 10 cc THF and 10 cc Toluene added 0.138 mole 4-(5-bromo-2-chlorobenzyl)phenyl ethyl ether at ambient temperature and stirred for 15 min. Cooled to -70 to -80°C in dry ice /acetone bath and stirred for 15 min. Added a solution of 0.014 mole n-Butyl lithium (1.9M in hexanes) at -70 to -80°C. and stirred for lhr. Added solution of 3, 4, 5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80°C and stirred for 2 to 3hrs. After the compliance of the reaction, reaction mass was quenched with Methane sulphonic acid and Allyl alcohol mixture at -70 to -80°C. Temperature was raised to ambient temperature and stirred overnight. Reaction mass was quenched with 30 cc sat.sodiumbicarbonate solution to bring the pH neutral to alkaline and stirred for 30.0 min. Layers separated and aqueous layer was extracted with 10 cc of Toluene. Organic layer was combined and washed with 30cc water and 50 cc sat. brine solution. Organic layer was distilled under reduced pressure to recover toluene. Solid compound was dissolved in 50cc of toluene and quenched in n-Hexane to obtain 83 % the compound as crystalline solid.

HPLC purity: 88 – 91 %

I R data:

Anomeric C-0 stretching: 1242 cm“1

Allylic C- O stretching: 1 177 cm“1

Allylic C- H stretching: 3010 – 3120 cm“1

Aromatic C- CI stretching: 820 cm“1

Lactones O – H stretching: 3240 – 3380 cm“1

Lactones C – 0 stretching: 1045 – 1092 cm“1

Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm“1

Alkane C – H stretching: 2877,2866, 2956, 2958, 2962 cm“1

Aromatic C – H stretching: 3050 – 3090 cm“1

Dip-Mass

(M+Na) 487.19 m/z

(M+K) 503.17 m/z

Example 3: Preparation of 2-prop-2ynyl-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To the mixture of 10 cc THF and 10 cc Toluene added 0.138 mole 4-(5-bromo-2-chlorobenzyl)phenyl ethyl ether at ambient temperature and stirred for 15 min. Cooled to -70 to -80°C in dry ice /acetone bath and stirred for 15 min. Added a solution of 0.014 mole n-Butyl lithium (1.9M in hexanes) at -70 to -80°C. and stirred for lhr. Added solution of 3, 4, 5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80°C and stirred for 2 to 3hrs. After the compliance of the reaction, the reaction mass was quenched with Methane sulphonic acid and propargyl alcohol mixture at -70 to -80°C. Temperature was raised to ambient temperature and stirred overnight. Reaction mass was quenched with 30 cc sat.sodiumbicarbonate solution to bring the pH neutral to alkaline. Reaction mass stirred for 30.0 min. Layers separated and aqueous layer was extracted with 10 cc of Toluene. Organic layer were combined and washed with 30cc water and 50 cc sat. brine solution. Organic layer was distilled under reduced pressure to recover toluene. Solid compound dissolved in 50cc of toluene and quenched in n-Hexane to obtain 75 – 80 % the compound as crystalline solid.

HPLC purity: 88 – 93 %

IR data:

Anomeric C-0 stretching: 1242 cm“1

Propargyl ~c CH stretching: 2125 cm“1

Propargyl C- H stretching : 3010 – 3120 cm“1

Aromatic C- CI stretching: 820 cm“1

Lactones O – H stretching: 3240 – 3380 cm“1

Lactones C – 0 stretching: 1045 – 1092 cm“1

Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm“1

Alkane C – H stretching: 2877, 2866,2956,2958,2962 cm“1

Aromatic C – H stretching: 3050 – 3090 cm“1

Dip-Mass

(M+Na) 485.25 m/z

(M+K) 501.25 m/z

Example-4: Preparation of 2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyI-tetrahydro-pyran-3,4,5-trioI

To the mixture of 20 cc (1 : 1 MDC + ACN) added 0.1 1 mole 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol under argon atmosphere, and stirred the reaction mass for 30.0 min. Cooled the reaction mass to -40 to -55°C in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Triethylsilane at -40 to -55°C and stirred the reaction mass for 30.0 min at -50 to -55°C. Slowly added Borontrifloride in diethyl ether solution at -40 to -55°C and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to -55°C . and stirred the reaction mass for 30.0 min. Slowly raised the temperature to 25 to 30°C. Settled down the reaction mass and separated the layers, extracted the aqueous layer with 100 cc of MDC. Combined the organic layer and wash with 500 cc water. Washed the organic layer with 500 cc of sat. Brine solution. Distilled out the MDC under reduced pressure below 40°C. to get 85 %the light yellow solid.

HPLC purity: 92-95 %

Example 5: Preparation of 2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To the mixture of 20 cc (1 :1 MDC + ACN) added 0.11 mole 2-prop-2-ynyl-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol under argon

atmosphere. Stirred the reaction mass for 30.0 min. Cooled the reaction mass to -40 to -55°C in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Triethylsilane at -40 to -55°C and stirred the reaction mass for 30.0 min at -50 to -55°C. Slowly added Borontrifloride in diethyl ether solution at -40 to -55°C and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to -55°C and Stirred the reaction mass for 30.0 min. Slowly raised the temperature to 25 to 30°C. Settled down the reaction mass and separated the layers, extracted the aqueous layer with 100 cc of MDC. Combined the organic layer and washed with 500 cc water. Washed the organic layer with 500 cc of sat. Brine solution. Distilled out the MDC under reduced pressure below 40°C. to get 85%the light yellow solid.

HPLC purity: 90%

Example 6: Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

To the solid obtained from example 4 charged 500cc of n-heptane and stirred for ½hrs at ambient temperature. Heated the reaction mass to 55-60°C and stirred it for 2-3 hrs.; cooled to room temperature and maintained for 4-5 hrs. Filtered the solid and washed the, cake with 100 cc n-heptane. Dried at 40-45°C under vacuum to get 85% amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

HPLC purity: 91-93%

Example 7: Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

To the solid obtained from example 5 charged 500cc of n-heptane and stirred for ½ hrs at ambient temperature. Heated the reaction mass to 55-60°C and stirred it for 2-3 hrs., cooled to room temperature and maintained for 4-5 hrs. Filtered the solid and washed the cake with 100 cc n-heptane. Dried at 40-45 °C under vacuum to get 85-88% amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

HPLC purity: 89-91%

Example 8: Preparation of L-proline – (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyI]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol co crystal

To the 10 cc of Ethyl acetate charged 1.0 mole (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol under argon atmosphere at ambient temperature and stirred for 30.0 min to get clear solution. Slowly heated the reaction mass to 60 – 65°C and stirred for 1 hr. Slowly added L-proline at 60 -65°C and maintained for 1 hr. Slowly added 15 cc n-Heptane to the reaction mass at 60 -65°C and stirred the mass for 2.5 hrs. Cooled the mass to ambient temperature for 3-4 hrs and maintained for 5 hrs. Filtered the mass under argon atmosphere. Washed the cake with 10 cc n-Heptane. Dried the cake at 50-55°C under reduced pressure to get 92% titled compound.

HPLC purity: 99%

Example 9: Preparation of L-proline – (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolco crystal

To the 10 cc of acetone charged 1.0 mole (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol under argon atmosphere at ambient temperature and stirred for 30.0 min to get clear solution. Slowly heated the reaction mass to 60 – 65°C and stirred for 1 hr. Slowly added proline at 60 -65°C and maintained for 1 hr. Slowly added 15 cc n-Heptane to the reaction mass at 60 -65°C and stirred the mass for 2.5 hrs. Cooled the mass to ambient temperature for 3-4 hrs and maintained for 5 hrs. Filtered the mass under argon atmosphere. Washed the cake with 10 cc n-Heptane. Dried the cake at 50-55°C under reduced pressure to get 93-95% titled compound.

HPLC purity: 98-99%

Example 10: Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

To the 15 cc ethyl acetate added (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol at ambient temperature and stirred for 30.0 min. Slowly added 5- 8 cc sat. sodium bicarbonate solution at ambient temperature and stirred for 1.5 hr to get the clear solution. Settled down and separated layers. Extracted the aqueous layer with 25 cc ethyl acetate.

Combined the organic layers and washed the ethyl acetate layer with 50 cc sat. Sodium chloride solution. Distilled out ethyl acetate under reduced pressure at 40 – 45°C to get fluffy solid. Charged 50 cc n-Heptane and stirred for 5 hrs to get 70-78% the title compound as Amorphous soild.

HPLC purity: 99.8-99.95 %

Example 11: Preparation of 2-chloro -4′- ethoxydiphenylmethane (impurity)

To the 20 cc THF and 20 cc Toluene added 0.25 mole 2-ehloro-5-bromo-4′- ethoxydiphenylmethane under argon atmosphere. Cooled the reaction mass to – 78° C. Slowly added n-Butyl lithium (1.9 M in hexane) at – 78° C and stirred for 30 min. Slowly added 20 % Ammonium chloride solution to the reaction mass. Brought the reaction mass to ambient temperature and stirred for 30 min. Settled and separated layers. Extracted the aqueous layer with 50 cc toluene. Washed the combined organic layer with 500 cc brine solution. Distilled out the toluene and charged heptanes, stirred for 2 – 3 hrs at ambient temperature. Filtered the product and dried the product at 45 – 50°C under reduced pressure to get 93 % titled compound.

Mass: (m+1) 247 m/z found 247.1 1

HPLC purity: 96.33 %

SHENDRA AURANGABAD, MAHARASHTRA, INDIA

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Bhupinder Singh Manhas

 

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////////WO 2016147197, DAPAGLIFLOZIN, NEW PATENT, HARMAN FINOCHEM LIMITED

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WO 2016018024, DAPAGLIFLOZIN, HANMI FINE CHEMICAL CO., LTD, NEW PATENT


 

Dapagliflozin structure.svg

 

(S) – propylene glycol and water, 1: 1 crystalline complex

 

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)

KIM, Ki Lim; (KR).
PARK, Chulhyun; (KR).
LEE, Jaeheon; (KR).
CHANG, Young-kil; (KR)

The present invention relates to a crystalline composite comprising dapagliflozin and a method for preparing the same. More specifically, the present invention provides a novel crystalline composite comprising dapagliflozin, which is an SGLT2 inhibitor, and a preparing method capable of economically preparing the novel crystalline composite at high purity.

long period of time, there is a problem with secretion of insulin in diabetes is a problem with the function of insulin, or the two compounds problems of the disease that is to say maintaining a high blood sugar. Insulin helps the one that sends glucose into cells in order to replace the nutrients such as glucose that is in a hormone secreted by the beta cells of the pancreas blood into energy. However, if there is insufficient action of insulin, glucose accumulates in the blood does not enter the cell and cause the muscles and blood sugar, sugar in the urine is out. When these two long-standing high blood sugar will cause a number of microvascular complications. Not cut due to such complications, such as may result in blindness.

 

Worldwide diabetes has become one of the major causes of death in adults, an increasing number of diabetes patients may sharply with the increase of obesity population.

 

In diabetic patients SGLT2 (Sodium-Glucose linked transporter 2) selective inhibition of significant gastrointestinal side effects without increasing the emissions of glucose in the urine, thereby improving insulin sensitivity and delay the onset of diabetes complications by the normalization of plasma glucose can be there.

 

Bristol-to US Patent No. 6,515,117 of Myers Squibb Company of formula It discloses a binary) to dapa glyphs.

 

[Formula 1]

 

While preparing the material of Formula 1 in the above patent, the desired compound was obtained as an oil form, here was added to the chloroform under vacuum to reprocess getting the desired compound as a solid in a viscous that contains ethyl acetate. Compounds of the formula I obtained by the above method of production must be carried out the purification using a column, etc. because it can not remove the impurities of the desired compound, which is not suitable as an industrial method.
In addition, Bristol-to the US Patent 7,919,598 of Myers Squibb Company No. discloses a compound of formula 2.

 

[Formula 2]
Compounds of Formula 2 are the compounds of formula 1, (S) – propylene glycol and water, 1: 1 crystalline complex: 1. The compound of Formula 2 can be conveniently used in medicine to use by crystallizing the compound of formula 1 with low crystallinity and are also useful in the purification of the compounds of formula (I).

 

However, the compound of formula 2 is (S), the price is very expensive – and the use of propylene glycol, which results in increasing the production cost. This is very disadvantageous In the eyes of people with diabetes need to take the long-term.

 

In addition, European Patent No. 2597090 of Sandoz is disclosed of the formula monohydrate. Of the formula monohydrate is then stirred as a compound of the sugar alcohol and the formula of the glycol, glycerol, arabitol, xylitol, etc. in water obtained the seed (seed), by using this discloses a method for preparing the monohydrate in water, and have.

 

However, the European patent is described that the hydrate should be obtained stirred for three days at low temperature in order to obtain after obtaining the actual seed crystals, although not yield is mentioned is expected to be very low. For this reason, because of the situation in the research and development of novel crystalline complexes THE dapa glyphs are continually required.

 

Best Mode for Carrying out the Invention

Hereinafter, the present invention will be described in detail.
Crystalline complex according to the invention is for lowering the production cost by obtaining a product of high purity without the need for further purification, it has the structure of formula (3).
[Formula 3]

The crystalline complex is in the X- ray diffraction pattern of 9.7, 17.3, 20.0, 20.4, and may comprise a characteristic peak at a 2θ of 21.4 ± 0.2 °, preferably 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 43.9 ± 0.2 °, and can include a peak at 2θ of teukjeongjik, it may be most preferably having a powder X-ray diffraction pattern is shown in Fig.
It was confirmed that the heat-absorption peak appears at about 163 ℃, to refer to the thermal analysis by; (DSC differential scanning calorimetr) The crystalline complex is differential scanning calorimetry of FIG.
The crystalline complex is the measured moisture content in accordance with the Karl-Fischer method can be 2-5%, preferably be 2.1 ~ 3.5%.
In addition, the present invention includes a mixture of 1), mannitol and the solvent to prepare a mannitol solution; 2) preparing an alcohol solution by mixing the alcohol with the glyph dapa gin; 3) mixing the mannitol solution and the alcohol solution, heating to 50 ~ 100 ℃; And 4) cooling the heated solution to 0 ~ 15 ℃ provides a method for preparing the crystalline complex comprising the steps of obtaining a composite having a crystalline structure of Formula 3.
It describes a method for producing crystalline complex according to the present invention;
Step 1: Mannitol solution prepared
Step 1 of the manufacturing method according to the present invention is a step in which a mixture of mannitol and a solvent to prepare a mannitol solution.
The mannitol is suitable for the manufacture of a therapeutic agent for diabetes to be taking a long period of time as a material that is widely used like medicine, food, with high stability and low price. Furthermore, mannitol is used in reducing the edema by osmotic action, and thus the material to promote diuresis. This is mannitol is determined to be helpful to the action Qin dapa glyphs used as SGLT-2 inhibitors.
The mannitol is typically so long that can be purchased and / or synthesis is not particularly limited, preferably the D- mannitol, L- and D · mannitol may include one or more of the group consisting of L- mannitol , and it can be most preferably D- Magny-tolyl.
The solvent as long as it can dissolve the mannitol is not particularly limited, and may preferably be water.
The Mani mixing ratio of the toll and the solvent. If the amount that can be dissolve the mannitol, the solvent is not particularly restricted, the preferably mannitol and solvent 1: 8-20 weight ratio or 1: 1 may be mixed with 10 to 15 weight .
Step 2: Preparation of an alcohol solution
Step 2 of the manufacturing method according to the invention by mixing the alcohol with Jean dapa glyph is a step for preparing the alcoholic solution.
In the glyph binary dapa may be prepared by the method described in commercially available, and arc carried US Patent 6,515,117 example G.
The alcohol is long as it can dissolve the THE dapa glyph is not particularly limited, preferably the C 1 ~ C 4 alcohol may comprise at least one of (a lower alcohol), and most preferably ethanol .
The dapa If the mixing ratio of the pictures and alcohol as a glyph is content that can be dissolved in THE dapa glyph to alcohol is not particularly limited, preferably the gin alcohol dapa glyphs 1: 3-8 or 1: a volume ratio of 6-7 It may be mixed.
Step 3: heat-up phase
Step 3 of the manufacturing method according to the present invention is a step in which the mani mixing and heating the solution and the alcohol solution toll.
The step is a process for producing a crystalline complex containing THE dapa glyphs included in mannitol as an alcohol solution that is included in the mannitol solution, the mixing ratio of the mixed solution and the alcohol solution is mannitol and the pro pageul a binary 1: 0.5-2 or 1: it is preferable to mix in 1.0 to 1.5 molar ratio.
The heating may preferably be carried out at 50 ~ 100 70 ~ 90 ℃ or ℃.
Step 4: obtained crystalline complexes
Step 4 according to the present invention is by cooling the heated solution to obtain a crystalline complex having the structure of Formula 3.
The cooling is preferably at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃.
Further, according to the embodiment of the present invention, in order to improve the speed of determining the crystalline complex to be obtained, the cooling after seeding may further include a (seeding) and further comprising cooling. The further cooling can preferably be carried out at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃ for 5 to 24 hours, or 7 ~ 15 hours.
The production method of the present invention as described above, dapa glyphs to binary and mannitol for the crystalline complex has the advantage that can be produced in more than 99.0% pure without further purification, including, of high purity at a low manufacturing cost crystalline It has the advantage of producing the composite.

Mode for the Invention

Hereinafter the present invention will be described in more detail by examples. However, these examples are for the purpose of illustrating the invention by way of example, but the scope of the present invention is limited to these Examples.
Example 1. Preparation of the crystalline complex
The D- mannitol 0.98g (5.4mmol) was dissolved in purified water to prepare a mannitol 12㎖. On the other hand, amorphous THE dapa glyphs (purity:> 94%, U.S. Patent No. 6,515,117 prepared by the method described in of Example G) was dissolved in 2g (4.9mmol) in ethanol to give the alcohol 13 ㎖ solution. After the mannitol solution at room temperature to give the mixed solution is added to the alcohol solution. The mixed solution was heated under reflux for 3 hours so that the 80 ℃. After the cooling the solution obtained through the reflux slowly to 10 ℃ for 2 hours and then added to camp in the dapa glyph to 4 wt% solution total weight compared to the seeding (seeding) for 12 hours at 200 rpm at 4 ℃ cooling and stirring was added. After Buchner funnel (Buchner funnel) and filtered with a filter paper 55 ㎜ and dried for 8 hours under nitrogen and 20 ℃ to obtain a crystalline complex 1.3g (45%).
Experimental Example 1. Structural analysis
Nuclear magnetic resonance spectrum (NMR) (400MHz FT-NMR Spectrometer (Varian, 400-MR)) of a crystalline complex obtained in Example 1 by using 1 yielded a H NMR spectrum, and the results, and in Fig. 1 It exhibited.
1 H NMR (400㎒, DMSO-d 6 ): δ 7.37-7.35 (d, 1H), 7.32-7.31 (d, 1H), 7.24-7.21 (dd, 1H), 7.10-7.08 (d, 2H), 6.83-6.81 (d, 2H), 4.97-4.95 (dd, 2H), 4.84-4.83 (d, 1H), 4.48-4.44 (t, 1H), 4.42-4.40 (d, 1H), 4.34-4.31 (t , 1H), 4.14-4.12 (d, 1H), 4.02-3.92 (m, 5H), 3.71-3.67 (m, 1H), 3.67-3.58 (m, 1H), 3.56-3.52 (t, 1H), 3.46 -3.35 (m, 3H), 3.28-3.07 (m, 4H), 1.31-1.27 (t, 3H)
The first through the results of 1 H NMR, and also, to the structure of a crystalline complex obtained in Example 1, it was confirmed that the formula (4).
[Formula 4]

Experimental Example 2. OK crystalline crystalline complexes
By performing an X-ray diffraction analysis and differential scanning calorimetry, it was confirmed that crystal form of the crystalline complex obtained in Example 1. More specifically, Diffraction Extensible Resource Descriptor (Brucker, USA) for use with X-ray diffraction (XRD) to perform, and differential scanning calorimetry (Differential scanning calorimeter; METTLER TOLEDO, Swiss) for use by differential scanning calorimetry (DSC) It was performed. Results of X-ray diffraction analysis results in Figure 1, the differential scanning calorimetry are shown in Fig.
Results of X-ray diffraction analysis, the crystalline complex according to an embodiment of the present invention exhibited a characteristic peak at 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 2θ of 43.9 ° .
Experimental Example 3. HPLC analysis
To a crystalline complex obtained in Example 1 under the conditions of Table 1 and Table 2 it was carried out to HPLC (high performance liquid chromatography) analysis.

TABLE 1

column Ascentis Express RP-Amide 4.6mm × 150mm (diameter × height), 2.7㎛ (Aldrich)
The mobile phase A: Formic acid 1mL/1000mL in H 2 OB: Formic acid 1mL/1000mL in Acetonitrile (ACN)
Test Solution Acetonitrile Test specimen 5mg / 10mL in 50% (ACN)
Column temperature 25 ℃
Wavelength detector UV, 220nm
Dose 3 ㎕
Flow rate 0.7 mL / min
Operating hours 40 min

Table 2

Gradient systems
Time (min) Mobile phase A (%) Mobile phase B (%)
0 75 25
0-25 35 65
25-26 30 70
26-29 30 70
29-35 75 25
35-40 75 25
As described above, the results of the HPLC analysis, the crystalline complex of Example 1, it was confirmed that the purity of 99% or more. In addition, the crystalline complex of Example 1, it was confirmed that the water content measured by Karl-Fischer method of 2.9%.

Claims

To a crystalline complex comprising a dapa THE glyph having the structure of formula 3: [Formula 3]

According to claim 1, wherein said crystalline complex is in the X- ray diffraction pattern of 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4, and the characteristic peaks at 2θ of 43.9 ± 0.2 ° containing crystalline complexes.

According to claim 1, wherein said crystalline complex is the measured moisture content in accordance with the Karl-Fischer method which is characterized in that 2 to 5%, the crystalline complex.
1) preparing a mannitol solution by mixing mannitol (mannitol) and the solvent 2) a mixture of binary (dapagliflozin) and alcohol in dapa glyph for preparing an alcohol solution; 3) wherein the mannitol solution and the alcohol mixing the solution and heated to 50 ~ 100 ℃; And 4) the production method to cool the heated solution to 0 ~ 15 ℃ comprising the step of obtaining a polycrystalline composite having a structure of formula (3), a crystalline complex: [Formula 3]
[Claim 5]
According to claim 4, wherein the solvent is the production of water, the crystalline complex.
According to claim 4, wherein the alcohol is a C 1 ~ C 4, a method of producing a crystalline complex comprising at least one kind of alcohol.
According to claim 6, wherein the alcohol is ethanol, the method of the crystalline complex prepared.

According to claim 4, wherein the mixing ratio by the spirit and mannitol dapa glyph is 1: 0.5 to 2 mole ratio, the method of producing a crystalline complex.

 

FIGURES

Figure 1 illustrates a X- ray diffraction spectrum of the crystalline complex in accordance with an embodiment of the present invention.
2 is a result of the differential scanning calorimetry of the crystalline complexes (DSC) in accordance with an embodiment of the present invention.
3 is of the crystalline complex in accordance with an embodiment of the present invention 1 shows the H-NMR measurement results.
[Figure 1]

[Figure 2]

[Figure 3]

 

CEO, YOUNG KIL CHANG

/////////WO 2016018024, DAPAGLIFLOZIN, HANMI FINE CHEMICAL CO., LTD, New patent

AstraZeneca’s Forxiga receives positive advice from Scottish Medicines Consortium


DAPAGLIFLOZIN

SYNTHESIS       https://newdrugapprovals.org/2013/12/18/dapagliflozin-sees-light/

AstraZeneca announced that the Scottish Medicines Consortium (SMC) has issued positive advice for use of its Forxiga, a selective and reversible inhibitor of sodium-glucose co-transporter-2, as part of a triple therapy regimen for type 2 diabetes.

http://www.pharmaceutical-technology.com/news/newsastrazenecas-forxiga-receives-positive-advice-scottish-medicines-consortium-4312778?WT.mc_id=DN_News

ANTHONYFLOZIN………Find one if you can in this review


find here

http://medcheminternational.blogspot.in/p/flozin-series.html

1 TOFOGLIFLOZIN
2 SERGLIFLOZIN
3 DAPAGLIFLOZIN
4 IPRAGLIFLOZIN
5 EMPAGLIFLOZIN
6 LUSEOGLIFLOZIN
7 REMOGLIFLOZIN
8 ERTUGLIFLOZIN
9 SOTAGLIFLOZON

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DAPAGLIFLOZIN…FDA approves AZ diabetes drug Farxiga


DAPAGLIFLOZIN, BMS-512148

The US Food and Drug Administration has finally approved AstraZeneca’s diabetes drug Farxiga but is insisting on six post-marketing studies, including a cardiovascular outcomes trial.

The approval was expected given that the agency’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1 last month that the benefits of Farxiga (dapagliflozin), already marketed in Europe as Forxiga, outweigh identified risks. The FDA rejected the drug in January 2012 due to concerns about possible liver damage and the potential link with breast and bladder cancer.

READ ABOUT SYNTHESIS AT
 Wish You a Happy Pongal animation

DAPAGLIFLOZIN SEES LIGHT


DAPAGLIFLOZIN, BMS-512148

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

cas 461432-26-8

Molecular Formula: C21H25ClO6
Molecular Weight: 408.87

 

Bristol-Myers Squibb (Originator)
AstraZeneca

TYPE 2 DIABETES,SGLT-2 Inhibitors

launched 2012,  as forxiga in EU

Figure US20120282336A1-20121108-C00006

Dapagliflozin propanediol is a solvate containing 1:1:1 ratio of the dapagliflozin, (S)-(+)-1,2-propanediol, and water.

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002322/WC500136024.pdf

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

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM262996.pdf

WILMINGTON, Del. & PRINCETON, N.J.--(BUSINESS WIRE)--December 12, 2013--

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.

Figure imgf000002_0001

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.

http://online.wsj.com/article/PR-CO-20131212-910828.html?dsk=y

………………………………………………………………..

PATENTS

WO 2010138535

WO 2011060256

WO 2012041898

WO 2012163990

WO 2013068850

WO 2012163546

WO 2013068850

WO 2013079501

Dapagliflozin (INN/USAN,[1] trade name Forxiga) is a drug used to treat type 2 diabetes. It was developed by Bristol-Myers Squibb in partnership with AstraZeneca. Although dapagliflozin’s method of action would operate on both types of diabetes[1] and other conditions resulting inhyperglycemia, the current clinical trials specifically exclude participants with type 1 diabetes.[2][3]

In July 2011 an US Food and Drug Administration (FDA) committee recommended against approval until more data was available.[4] The Prescription Drug User Fee Act (PDUFA) date for dapagliflozin for the treatment of Type 2 diabetes was extended three months by the FDA to January 28, 2012.

In April 2012, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued a positive opinion on the drug. It is now marketed in a number of European countries including the UK and Germany.

Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine.[5] The efficacy of the this medication class has yet to be determined, but in initial clinical trials, dapagliflozin lowers HbA1c by 0.90 percentage points when added to metformin.[6]

Type II diabetes is the most common form of diabetes accounting for 90% of diabetes cases. Over 100 million people worldwide have type-2 diabetes (nearly 17 million in the U.S.) and the prevalence is increasing dramatically in both the developed and developing worlds. Type-II diabetes is a lifelong illness, which generally starts in middle age or later part of life, but can start at any age. Patients with type-2 diabetes do not respond properly to insulin, the hormone that normally allows the body to convert blood glucose into energy or store it in cells to be used later. The problem in type-2 diabetes is a condition called insulin resistance where the body produces insulin, in normal or even high amounts, but certain mechanisms prevent insulin from moving glucose into cells. Because the body does not use insulin properly, glucose rises to unsafe levels in the blood, the condition known as hyperglycemia.

Hyperglycemia, that is, elevated plasma glucose, is a hallmark of diabetes. Plasma glucose is normally filtered in the kidney in the glomerulus but is actively reabsorbed in the proximal tubule (kidney). Sodium-dependent glucose co-transporter SGLT2 appears to be the major transporter responsible for the reuptake of glucose at this site. The SGLT inhibitor phlorizin, and closely related analogs, inhibit this reuptake process in diabetic rodents and dogs, resulting in normalization of plasma glucose levels by promoting glucose excretion without hypoglycemic side effects. Long term (6 month) treatment of Zucker diabetic rats with an SGLT2 inhibitor has been reported to improve insulin response to glycemia, improve insulin sensitivity, and delay the onset of nephropathy and neuropathy in these animals, with no detectable pathology in the kidney and no electrolyte imbalance in plasma. Selective inhibition of SGLT2 in diabetic patients would be expected to normalize plasma glucose by enhancing the excretion of glucose in the urine, thereby improving insulin sensitivity and delaying the development of diabetic complications.

The treatment of diabetes is an important health concern and despite a wide range of available therapies, the epidemic continues. Type 2 diabetes (T2DM) is a progressive disease caused by insulin resistance and decreased pancreatic β-cell function. Insulin is produced by the pancreatic β-cell and mediates cellular glucose uptake and clearance. Insulin resistance is characterized by the lack of response to the actions of this hormone which results in decreased cellular clearance of glucose from the circulation and overproduction of glucose by the liver.

The currently available therapies to treat type 2 diabetes augment the action or delivery of insulin to lower blood glucose. However, despite therapy, many patients do not achieve control of their type 2 diabetes. According to the National Health and Nutrition Examination Survey (NHANES) III, only 36% of type 2 diabetics achieve glycemic control defined as a A1C<7.0% with current therapies. In an effort to treat type 2 diabetes, aggressive therapy with multiple pharmacologic agents may be prescribed. The use of insulin plus oral agents has increased from approximately 3 to 11% from NHANES II to III.

Thus, treatment of hyperglycemia in type 2 diabetes (T2DM) remains a major challenge, particularly in patients who require insulin as the disease progresses. Various combinations of insulin with oral anti-diabetic agents (OADs) have been investigated in recent years, and an increasing number of patients have been placed on these regimens. Poulsen, M. K. et al., “The combined effect of triple therapy with rosiglitazone, metformin, and insulin in type 2 diabetic patients”,Diabetes Care, 26 (12):3273-3279 (2003); Buse, J., “Combining insulin and oral agents”, Am. J. Med., 108 (Supp. 6a):23S-32S (2000). Often, these combination therapies become less effective in controlling hyperglycemia over time, particularly as weight gain and worsening insulin resistance impair insulin response pathways.

Hypoglycemia, weight gain, and subsequent increased insulin resistance are significant factors that limit optimal titration and effectiveness of insulin. (Holman, R. R. et al., “Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes”, N. Engl. J. Med., 357 (17):1716-1730 (2007)). Weight gain with insulin therapy is predominantly a consequence of the reduction of glucosuria, and is thought to be proportional to the correction of glycemia. (Makimattila, S. et al., “Causes of weight gain during insulin therapy with and without metformin in patients with Type II diabetes mellitus”, Diabetologia, 42 (4):406-412 (1999)). Insulin drives weight gain when used alone or with OADs. (Buse, J., supra). In some cases, intensive insulin therapy may worsen lipid overload and complicate progression of the disease through a spiral of caloric surplus, hyperinsulinemia, increased lipogenesis, increased adipocity, increased insulin resistance, beta-cell toxicity, and hyperglycemia. (Unger, R. H., “Reinventing type 2 diabetes: pathogenesis, treatment, and prevention”, JAMA, 299 (10):1185-1187 (2008)). Among commonly used OADs, thiazolidinediones (TZDs) and sulfonylureas intrinsically contribute to weight gain as glucosuria dissipates with improved glycemic control. Weight gain is less prominent with metformin, acting through suppression of hepatic glucose output, or with incretin-based DPP-4 inhibitors. Overall, there is a pressing need for novel agents that can be safely added to insulin-dependent therapies to help achieve glycemic targets without increasing the risks of weight gain or hypoglycemia.

A novel approach to treating hyperglycemia involves targeting transporters for glucose reabsorption in the kidney. (Kanai, Y. et al., “The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose”, J. Clin. Invest., 93 (1):397-404 (1994)). Agents that selectively block the sodium-glucose cotransporter 2 (SGLT2) located in the proximal tubule of the kidney can inhibit reabsorption of glucose and induce its elimination through urinary excretion. (Brown, G. K., “Glucose transporters: structure, function and consequences of deficiency”, J. Inherit. Metab. Dis., 23 (3):237-246 (2000)). SGLT2 inhibition has been shown in pre-clinical models to lower blood glucose independently of insulin. (Han, S. et al., “Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats”, Diabetes, 57 (6):1723-1729 (2008); Katsuno, K. et al., “Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level”, J. Pharmacol. Exp. Ther., 320 (1):323-330 (2007)).

Dapagliflozin(BMS-512148) is a potent sodium-glucose transport proteins inhibitor with IC50 of 1.1 nM and 1.4uM for SGLT2 and SGLT1, respectively. Dapagliflozin (BMS-512148) inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine. Symptoms of hypoglycaemia occurred in similar proportions of patients in the dapagliflozin (2~4%) and placebo groups (3%). Signs, symptoms, and other reports suggestive of genital infections were more frequent in the dapagliflozin groups (2•5 mg, [8%]; 5 mg, [13%]; 10 mg, [9%]) than in the placebo group ( [5%]).

Dapagliflozin (which is disclosed in U.S. Pat. No. 6,515,117) is an inhibitor of sodium-glucose reabsorption by the kidney, by inhibiting SGLT2, which results in an increased excretion of glucose in the urine. This effect lowers plasma glucose in an insulin-independent manner.

Dapagliflozin is currently undergoing clinical development for treatment of type 2 diabetes. (Han, S. et al., supra; Meng, W. et al., “Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes”, J. Med. Chem., 51 (5):1145-1149 (2008)). Phase 2a and 2b studies with dapagliflozin have demonstrated efficacy in reducing hyperglycemia either alone or in combination with metformin in patients with T2DM. (Komoroski, B. et al., “Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus”, Clin. Pharmacol. Ther., 85 (5):513-519 (2009); List, J. F. et al., “Dapagliflozin-induced glucosuria is accompanied by weight loss in type 2 diabetic patients”, 68th Scientific Sessions of the American Diabetes Association, San Francisco, Calif., Jun. 6-10, 2008, Presentation No. 0461P).

It has been found that dapagliflozin does not act through insulin signaling pathways and is effective in controlling blood sugar in patients whose insulin signaling pathways do not work well. This applies to extremes of insulin resistance, in type 2 diabetes as well as in insulin resistance syndromes, caused by, for example, mutations in the insulin receptor.

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). Dapagliflozin is also associated with hypotensive reactions.

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]

  1.  Statement on a nonproprietory name adopted by the USAN council
  2.  Efficacy and Safety of Dapagliflozin, Added to Therapy of Patients With Type 2 Diabetes With Inadequate Glycemic Control on Insulin, ClinicalTrials.gov, April 2009
  3.  Trial Details for Trial MB102-020, Bristol-Myers Squibb, May 2009
  4.  “FDA panel advises against approval of dapagliflozin”. 19 July 2011.
  5.  Prous Science: Molecule of the Month November 2007
  6.  UEndocrine: Internet Endocrinology Community
  7.  Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2008/2009
  8. 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; 2010

    5) Liou, Jason et al; Processes for the preparation of C-Aryl glycoside amino acid complexes as potential SGLT2 Inhibitors ;. PCT Int Appl,. WO2010022313

    6) Seed, Brian et al; Preparation of Deuterated benzyl-benzene glycosides having an inhibitory Effect on sodium-dependent glucose co-transporter; . PCT Int Appl,. WO2010009243

    7) Song, Yanli et al; Preparation of benzylbenzene glycoside Derivatives as antidiabetic Agents ;. PCT Int Appl,. WO2009026537

    8) 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,. WO2008002824

    10) Deshpande, Prashant P. et al; Methods of producing C-Aryl glucoside SGLT2 Inhibitors ;.. U.S. Pat Appl Publ,. 20,040,138,439

     

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 .

Figure imgf000004_0001

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

Figure imgf000004_0002

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.

…..

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

http://www.google.com/patents/US20120282336

http://www.tga.gov.au/pdf/auspar/auspar-dapagliflozin-propanediol-monohydrate-130114.pdf

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.

Figure US20120282336A1-20121108-C00006

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

………………………………

In Vitro Characterization and Pharmacokinetics of Dapagliflozin 

dmd.aspetjournals.org/content/…/DMD29165_supplemental_data_.doc

Dapagliflozin (BMS-512148), (2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)

-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol. 1H NMR (500 MHz, CD3OD) δ 7.33

(d, J = 6.0, 1H), 7.31 (d, J = 2.2, 1H), 7.31 (dd, J = 2.2, 6.0, 1H), 7.07 (d, J = 8.8, 2H),

6.78 (d, J = 8.8, 2H), 4.07-3.90 (m, 7H), 3.85 (d, J = 10.6, 1H), 3.69 (dd, J = 5.3, 10.6,

1H), 3.42-3.25 (m, 4H), 1.34 (t, J = 7.0, 3H). 13C NMR (125 MHz, CD3OD) δ 158.8,

140.0, 139.9, 134.4, 132.9, 131.9, 130.8, 130.1, 128.2, 115.5, 82.9, 82.2, 79.7, 76.4, 71.9,

64.5, 63.1, 39.2, 15.2.

HRMS calculated for C21H25ClNaO6 (M+Na)+

For C21H25ClO6: C, 61.68; H, 6.16. Found: C, 61.16; H, 6.58.

: 431.1237; found 431.1234. Anal. Calcd

SECOND SET

J. Med. Chem., 2008, 51 (5), pp 1145–1149
DOI: 10.1021/jm701272q

1H NMR (500 MHz, CD3OD) δ 7.33 (d, J = 6.0, 1H), 7.31 (d, J = 2.2, 1H), 7.31 (dd, J = 2.2, 6.0, 1H), 7.07 (d, J = 8.8, 2H), 6.78 (d, J = 8.8, 2H), 4.07–3.90 (m, 7H), 3.85 (d, J = 10.6, 1H), 3.69 (dd, J = 5.3, 10.6, 1H), 3.42–3.25 (m, 4H), 1.34 (t, J = 7.0, 3H);

13C NMR (125 MHz, CD3OD) δ 158.8, 140.0, 139.9, 134.4, 132.9, 131.9, 130.8, 130.1, 128.2, 115.5, 82.9, 82.2, 79.7, 76.4, 71.9, 64.5, 63.1, 39.2, 15.2;

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] [%] B
    0.0 25
    25.0 65
    26.0 70
    29.0 70
    29.5 25
    35.0 25

    ……………………..

    Bristol-Myers Squibb and AstraZeneca type 2 diabetes drug dapagliflozin net Dag out chemical synthesis chemical synthesis of type 2 diabetes drug Farxiga_dapagliflozin_Forxiga from Bristol-Myers Sq

……..

http://www.google.com/patents/WO2013068850A2?cl=en

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.

1H NMR (400 MHz, CDC13) δ 7.56-7.54 (m, 2H), 7.43-7.31 (m, 13H), 7.29-7.22 (m, 6H), 7.07- 7.04 (m, 2H), 7.00 (d, J= 2.0 Hz, IH), 6.87 (dd, J= 8.4, 2.0 Hz, IH), 6.83-6.81 (m, 2H), 4.18 (d, J= 9.6 Hz, IH), 4.02 (q, J= 6.9 Hz, 2H), 3.96 (d, J= 10.8 Hz, 2H), 3.86 (ddd, J= 11.3, 7.7, 1.1 Hz, IH), 3.76 (ddd, J= 8.4, 8.4, 4.8 Hz, IH), 3.56 (ddd, J= 9.0, 6.4, 2.4 Hz, IH), 3.50 (dd, J=

I I.4, 5.4 Hz, IH), 3.44 (dd, J= 9.4, 8.6 Hz, IH), 3.38 (dd, J= 8.8, 8.8 Hz, IH), 1.70 (dd, J= 7.8, 5.4 Hz, IH, OH), 1.42 (t, J= 6.8 Hz, 3H), 1.21 (d, J= 5.2 Hz, IH, OH), 1.00 (s, 9H), 0.64 (s, 9H); 13C NMR (100 MHz, CDC13) δ 157.4 (C), 138.8 (C), 137.4 (C), 136.3 (CH x2), 136.1 (CH x2), 135.2 (CH x2), 135.0 (C), 134.9 (CH x2), 134.8 (C), 134.2 (C), 132.8 (C), 132.0 (C), 131.6 (CH), 131.1 (C), 129.9 (CH x2), 129.7 (CH), 129.6 (CH), 129.5 (CH), 129.4 (CH), 129.2 (CH), 127.58 (CH x2), 127.57 (CH x2), 127.54 (CH x2), 127.31 (CH), 127.28 (CH x2), 114.4 (CH x2), 82.2 (CH), 80.5 (CH), 79.3 (CH), 76.3 (CH), 72.7 (CH), 63.4 (CH2), 62.7 (CH2), 38.2 (CH2), 27.2 (CH3 x3), 26.6 (CH3 x3), 19.6 (C), 19.2 (C), 14.9 (CH3). EXAMPLE 25 -Synthesis of dapagliflozin ((25,3R,4R,55,6/?)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (Ij))

IVj’ U

[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).

1H NMR (400 MHz, CD3OD) δ 7.37-7.34 (m, 2H), 7.29 (dd, J= 8.2, 2.2 Hz, 1H), 7.12-7.10 (m, 2H), 6.82-6.80 (m, 2H), 4.10 (d, J= 9.6 Hz, 2H), 4.04 (d, J= 9.2 Hz, 2H), 4.00 (q, J= 7.1 Hz, 2H), 3.91-3.87 (m, 1H), 3.73-3.67(m, 1H), 3.47-3.40 (m, 3H), 3.31-3.23 (m, 2H), 1.37 (t, J= 7.0 Hz, 3H);

13C NMR (100 MHz, CD3OD) δ 157.4 (C), 138.6 (C), 138.5 (C), 133.1 (C), 131.5 (C), 130.5 (CH), 129.4 (CH x2), 128.7 (CH), 126.8 (CH), 114.0 (CH x2), 80.5 (CH), 80.8 (CH), 78.3 (CH), 75.0 (CH), 70.4 (CH), 63.0 (CH2), 61.7 (CH2), 37.8 (CH2), 13.8 (CH3);

LCMS (ESI) m/z 426 (100, [M+NH4]+), 428 (36, [M+NH4+2]+), 447 (33, [M+K]+).

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

chromatography (eluting with 1 :20 EtOAc/rc-heptane) afforded 2,4-di-6>-ieri-butyldiphenylsilyl- l,6-anhydro- “D-glucopyranose (5.89 g, 81%).

1H NMR (400 MHz, CDC13) δ 7.82-7.70 (m, 8H), 7.49-7.36 (m, 12H), 5.17 (s, IH), 4.22 (d, J= 4.8 Hz, IH), 3.88-3.85 (m, IH), 3.583-3.579 (m, IH), 3.492-3.486 (m, IH), 3.47-3.45 (m, IH), 3.30 (dd, J= 7.4, 5.4 Hz, IH), 1.71 (d, J= 6.0 Hz, IH), 1.142 (s, 9H), 1.139 (s, 9H); 13C NMR (100 MHz, CDCI3) δ 135.89 (CH x2), 135.87 (CH x2), 135.85 (CH x2), 135.83 (CH x2), 133.8 (C), 133.5 (C), 133.3 (C), 133.2 (C), 129.94 (CH), 129.92 (CH), 129.90 (CH), 129.88 (CH), 127.84 (CH2 x2), 127.82 (CH2 x2), 127.77 (CH2 x4), 102.4 (CH), 76.9 (CH), 75.3 (CH), 73.9 (CH), 73.5 (CH), 65.4 (CH2), 27.0 (CH3 x6), 19.3 (C x2).

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