C-aryl glucoside SGLT2 inhibitors and method US 6515117 B2

Dapagliflozin

http://www.google.co.in/patents/US6515117

HPLC retention time: 7.08 min, 94% pure, YMC S5 C-18 4.6×50 mm column, 2.5 mL/min, detection at 220 nM; 8 min gradient 0-100% B hold 5 min at 100% B. Solvent A: 10% MeOH/H₂O+0.2% H₃PO₄. Solvent B: 90% MeOH/H₂O+0.2% H₃PO₄.

¹H NMP (500 MHz, CD₃OD) δ7.33 (d, 1H, J=6 Hz), 7.31 (d, 1H, J=2.2 Hz), 7.31 (dd, 1H, J=6 Hz, J=2.2 Hz), 7.07 (d, 2H, J=8.8 Hz), 6.78 (d, 2H, J=8.8 Hz), 4.07-3.90 (m, 7H), 3.85 (d, 1H, J=10.6 Hz), 3.69 (dd, 1H, J=5.3, 10.6 Hz), 3.42-3.25 (m, 4H) Hz), 1.34 (t, 3H, J=7 Hz).

¹³C NMP (125 MHz, CD₃OD) δ158.8, 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.

Anal Calcd for C₂₁H₂₅ClO₆ LC-MS [M+Na⁺]431; found 431.

Dapagliflozin

Systematic (IUPAC) name
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
Clinical data
Trade names	Forxiga, Farxiga
AHFS/Drugs.com	UK Drug Information
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	US: C
Legal status	UK: POM US: ℞-only
Routes	Oral
Identifiers
CAS number	461432-26-8
ATC code	A10BX09
PubChem	CID 9887712
ChemSpider	8063384
UNII	1ULL0QJ8UC
ChEMBL	CHEMBL429910
Synonyms	BMS-512148
Chemical data
Formula	C21H25ClO6
Mol. mass	408.873 g/mol

Citing Patent	Filing date	Publication date	Applicant	Title
US6774112 *	8 Apr 2002	10 Aug 2004	Bristol-Myers Squibb Company	Antidiabetic agents; cardiovascular disorders
US6936590 *	4 Oct 2002	30 Aug 2005	Bristol Myers Squibb Company	Treating diabetic with a sodium dependent glucose transporters (SGLT2) inhibitors, especially type II diabetes; use of pyran compounds including dapaglifozin
US7084124	30 Jul 2004	1 Aug 2006	Janssen Pharmaceutica, N.V.	Antidiabetic agents; insulin resistance
US7094763 *	30 Jul 2004	22 Aug 2006	Janssen Pharaceutica, N.V.	e.g., 2-(4-Ethylbenzyl)-4-( beta -D-glucopyranosyl)-1H-indole, used for the treatment or prophylaxis of diabetes and Syndrome X.
US7094764	30 Jul 2004	22 Aug 2006	Janssen Pharmaceutica N.V.	Substituted benzimidazole-, Benztriazole-, and benzimidazolone-O-glucosides
US7129220	30 Jul 2004	31 Oct 2006	Janssen Pharmaceutica N.V	Substituted indole-O-glucosides
US7169761 *	4 Aug 2003	30 Jan 2007	Astellas Pharma Inc.	Azulene derivatives and salts thereof
US7199159 *	23 May 2001	3 Apr 2007	Centre National De La Recherche Scientifique (C.N.R.S.)	Use of biguanide derivatives for making a medicine having a wound healing effect
US7238702	9 Feb 2006	3 Jul 2007	Bristol-Myers Squibb Company	Dihydroquinazolinones as 5HT modulators
US7288528 *	12 Dec 2003	30 Oct 2007	Sanofi-Aventis Deutschland Gmbh	Aromatic fluoroglycoside derivatives, medicaments containing these compounds, and the use thereof
US7371759	21 Sep 2004	13 May 2008	Bristol-Myers Squibb Company	Anticholesterol agents; reducing blood serum lipids; anticancer agents; antiarthritic agents; antiinflammatory agents; antitumor agents; immunosuppressants; obesity; hypotensive agents
US7375213	23 Dec 2003	20 May 2008	Bristol-Myers Squibb Company	inhibitors of sodium dependent glucose transporters found in the intestine and kidney (SGLT2), and more particularly to a process of producing such compounds, for example dapagliflozin
US7417032	27 Jul 2005	26 Aug 2008	Boehringer Ingelheim International Gmbh	D-xylopyranosyl-phenyl-substituted cycles, medicaments containing such compounds, their use and process for their manufacture
US7420059	15 Nov 2004	2 Sep 2008	Bristol-Myers Squibb Company	HMG-CoA reductase inhibitors and method
US7482330	15 Jun 2006	27 Jan 2009	Janssen Pharmaceutica N.V.	3-(4-Ethylbenzyl)-5-( beta -D-glucopyranosyl)-1H-indole; antidiabetic agents; insulin resistance
US7511020	15 Jun 2006	31 Mar 2009	Janssen Pharmaceutica N.V.	2-[3-(4-Ethyl-benzyl)-3H-benzoimidazol-4-yloxy]- .squ. -D-glucoglucopyranoside; sodium glucose transporter inhibitor; antidiabetic agent; Syndrome X, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis, hypertension, ischemia, stroke, heart disease, irritable bowel disorder, and cataracts
US7511021	2 Jun 2006	31 Mar 2009	Janssen Pharmaceutica N.V.	2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy} beta-D-glucopyranoside; sodium glucose transporter inhibitor; antidiabetic agent; Syndrome X, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis, hypertension, ischemia, stroke, heart disease , and cataracts
US7511022	15 Jun 2006	31 Mar 2009	Janssen Pharmaceutica N.V.	Substituted indole-O-glucosides
US7566699	24 Mar 2004	28 Jul 2009	Kissei Pharmaceutical Co., Ltd.	Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof
US7576063	30 Sep 2003	18 Aug 2009	Kissei Pharmaceutical Co., Ltd.	prevention or treatment of disease associated with hyperglycemia: diabetes, impaired glucose tolerance, impaired fasting glycemia, diabetic complications or obesity; e.g. 4-[(4-{3-[1-carbamoyl-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-3-( beta -D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
US7579449	15 Mar 2005	25 Aug 2009	Boehringer Ingelheim International Gmbh	Metabolic disorders like diabetes; inhibits sodium-dependent glucose cotransporter; 1-chloro-2-(4-cyclopentyloxybenzyl)-4-( beta -D-glucopyranos-1-yl)-benzene
US7662790	13 Apr 2006	16 Feb 2010	Boehringer Ingelheim International Gmbh	Glucopyranosyl-substituted (heteroaryloxy-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7666845	3 Dec 2007	23 Feb 2010	Janssen Pharmaceutica N.V.	Compounds having inhibitory activity against sodium-dependent glucose transporter
US7683160	29 Aug 2006	23 Mar 2010	Boehringer Ingelheim International Gmbh	1-chloro-4-( beta -D-glucopyranos-1-yl)-2-[4-((1R,2R)-2-hydroxy-cyclopent-1-yloxy)-benzyl]-benzene; metabolic disorders such as diabetes, metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia; sodium-dependent glucose cotransporter SGLT2 inhibitors
US7687469	15 Dec 2005	30 Mar 2010	Boehringer Ingelheim International Gmbh	Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7713938	19 Apr 2006	11 May 2010	Boehringer Ingelheim International Gmbh	Crystalline form of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US7723309	21 Apr 2006	25 May 2010	Boehringer Ingelheim International Gmbh	Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US7745414	14 Feb 2007	29 Jun 2010	Boehringer Ingelheim International Gmbh	Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
US7772191	3 May 2006	10 Aug 2010	Boehringer Ingelheim International Gmbh	Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
US7772378	22 Feb 2006	10 Aug 2010	Boehringer Ingelheim International Gmbh	inhibiting sodium-dependent glucose cotransporter SGLT2; diabetes mellitus, metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias, atherosclerosis, obesity, high blood pressure, chronic heart failure
US7776830	1 May 2007	17 Aug 2010	Boehringer Ingelheim International Gmbh	sodium-dependent glucose cotransporter (SGLT2) inhibitor; improved pharmacological or pharmacokinetic properties; antidiabetic agent, metabolic disorders, obesity, insulin resistance, atherosclerosis, chronic heart failure, liver fat
US7781577	27 Sep 2007	24 Aug 2010	Lexicon Pharmaceuticals, Inc.	2-[4-Chloro-3-(4-hydroxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol; 2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-piperidine-1-carboxylic acid methyl ester; (2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxytetrahydro-2H-thiopyran-3,4,5-triol; antidibetic, antiobesity agents
US7795436	24 Aug 2006	14 Sep 2010	Bristol-Myers Squibb Company	cis-6-(2,4-Dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one, used for treating metabolic disorders, nervous system disorders, headaches, gastrointestinal disorders and as analgesics
US7816328	11 Sep 2009	19 Oct 2010	Janssen Pharmaceutica Nv	such as 3-(4-Ethylbenzyl)-5-( beta -D-glucopyranosyl)-1H-indole, used for for treating diabetes, Syndrome X, or associated symptoms selected from obesity, nephropathy, neuropathy, retinopathy, atherosclerosis, polycystic ovarian syndrome, hypertension, ischemia, stroke and cardiovascula disorders
US7816330	11 Sep 2009	19 Oct 2010	Janssen Pharmaceutica Nv	Substituted benzimidazole-, benztriazole-, and benzimidazolone-O-glucosides
US7816331	22 Sep 2009	19 Oct 2010	Janssen Pharmaceutica Nv	Substituted indazole-O-glucosides
US7820630	22 Sep 2009	26 Oct 2010	Janssen Pharmaceutica Nv	Substituted indole-O-glucosides
US7838499	22 Aug 2008	23 Nov 2010	Theracos, Inc.	(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; for treating diseases assoicated with sodium glucose co-transporter inhibition (SGLT) such as diabetes, hyperglycemia, insulin resistance, metabolic syndrome, atherosclerosis
US7846945	4 Mar 2008	7 Dec 2010	Lexicon Pharmaceuticals, Inc.	2-[4-Chloro-3-(4-hydroxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol; 2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-piperidine-1-carboxylic acid methyl ester; (2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxytetrahydro-2H-thiopyran-3,4,5-triol; antidibetic, antiobesity agents
US7847074	14 Sep 2006	7 Dec 2010	Boehringer Ingelheim International Gmbh	Processes for preparing of glucopyranosyl-substituted (ethynyl-benzyl)-benzene derivatives and intermediates thereof
US7851502 *	21 Mar 2008	14 Dec 2010	Bristol-Myers Squibb Company	Pharmaceutical formulations containing an SGLT2 inhibitor
US7851602	27 Jul 2006	14 Dec 2010	Boehringer Ingelheim International Gmbh	Glucopyranosyl-substituted ((hetero)cycloalkylethynyl-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7851617	26 Jul 2007	14 Dec 2010	Mitsubishi Tanabe Pharma Corporation	Indole derivatives
US7888487	3 Aug 2009	15 Feb 2011	Kissei Pharmaceutical Co., Ltd.	Pyrazole derivative, medicinal composition containing the same, medicinal use thereof and intermediate in producing the same
US7919598 *	20 Jun 2007	5 Apr 2011	Bristol-Myers Squibb Company	Crystal structures of SGLT2 inhibitors and processes for preparing same
US7932379	19 Jun 2007	26 Apr 2011	Bristol-Myers Squibb Company	Methods of producing C-aryl glucoside SGLT2 inhibitors
US7935674	18 Jun 2009	3 May 2011	Mitsubishi Tanabe Pharma Corporation	Indole derivatives
US7943582	3 Dec 2007	17 May 2011	Mitsubishi Tanabe Pharma Corporation	Canagliflozin, a sodium-glucose transporter 2 inhibitor as antiobesity, antidiabetic agent; purity; handling characteristics; easy formulation; storage stability
US7943656	18 Apr 2008	17 May 2011	Bristol-Myers Squibb Company	Crystal forms of saxagliptin and processes for preparing same
US7943788	31 Jan 2005	17 May 2011	Mitsubishi Tanabe Pharma Corporation	Glucopyranoside compound
US8026347	17 Jul 2008	27 Sep 2011	Lexicon Pharmaceuticals, Inc.	Methods and compounds useful for the preparation of sodium glucose co-transporter 2 inhibitors
US8080580	24 Aug 2009	20 Dec 2011	Pfizer Inc.	Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
US8088743 *	21 Mar 2008	3 Jan 2012	Bristol-Myers Squibb Company	Sodium dependent glucose transporter (SGLT2); such as dapagliflozin, dapagliflozin-PGS, a C-glucoside or an O-glucoside
US8106021	1 Nov 2010	31 Jan 2012	Theracos, Inc.	Benzylbenzene derivatives and methods of use
US8129434	11 Dec 2008	6 Mar 2012	Theracos, Inc.	Benzylphenyl cyclohexane derivatives and methods of use
US8198464	20 Dec 2007	12 Jun 2012	Astellas Pharma Inc.	Method for producing C-glycoside derivative and intermediate for synthesis thereof
US8202984	13 Jan 2011	19 Jun 2012	Mitsubishi Tanabe Pharma Corporation	Glucopyranoside compound
US8221786	18 Nov 2010	17 Jul 2012	Bristol-Myers Squibb Company	Pharmaceutical formulations containing an SGLT2 inhibitor
US8222219	1 Jul 2011	17 Jul 2012	Mitsubishi Tanabe Pharma Corporation	Glucopyranoside compound
US8236847	6 Apr 2011	7 Aug 2012	Bristol-Myers Squibb Company	Crystal forms of saxagliptin and processes for preparing same
US8278268	24 Oct 2007	2 Oct 2012	Ortho-Mcneil Pharmaceutical, Inc.	Combination therapy comprising glucose reabsorption inhibitors and PPAR modulators
US8283454	21 Aug 2009	9 Oct 2012	Theracos, Inc.	Processes for the preparation of SGLT2 inhibitors
US8293878	11 Aug 2011	23 Oct 2012	Lexicon Pharmaceuticals, Inc.	Methods and compounds useful for the preparation of sodium glucose co-transporter 2 inhibitors
US8361972	21 Jun 2012	29 Jan 2013	Bristol Myers-Squibb Company	Pharmaceutical formulations containing an SGLT2 inhibitor
US8476413	18 Aug 2010	2 Jul 2013	Lexicon Pharmaceuticals, Inc.	Sulfanyl-tetrahydropyran-based compounds and methods of their use
US8501698	16 Mar 2011	6 Aug 2013	Bristol-Myers Squibb Company	Crystal structures of SGLT2 inhibitors and processes for preparing same
US8507450	7 Sep 2006	13 Aug 2013	Boehringer Ingelheim International Gmbh	Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments
US8513202	9 May 2011	20 Aug 2013	Mitsubishi Tanabe Pharma Corporation	Crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate
US8551957	15 Aug 2008	8 Oct 2013	Boehringer Ingelheim International Gmbh	Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate
US8557782	9 Jun 2010	15 Oct 2013	Boehringer Ingelheim International Gmbh	Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
US8575321	21 Dec 2011	5 Nov 2013	Theracos, Inc.	Benzylbenzene derivatives and methods of use
US8603989 *	15 May 2009	10 Dec 2013	Bristol-Myers Squibb Company	Method for treating and preventing kidney stones employing an SGLT2 inhibitor and composition containing same
US8652527	19 Mar 2013	18 Feb 2014	Upsher-Smith Laboratories, Inc	Extended-release topiramate capsules
US8669380	21 Oct 2010	11 Mar 2014	Pfizer Inc.	Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
US8685934 *	26 May 2010	1 Apr 2014	Bristol-Myers Squibb Company	Methods for treating extreme insulin resistance in patients resistant to previous treatment with other anti-diabetic drugs employing an SGLT2 inhibitor and compositions thereof
US8716251	4 Jan 2013	6 May 2014	Bristol-Myers Squibb Company	Pharmaceutical formulations containing an SGLT2 inhibitor
US8772512	8 Jul 2010	8 Jul 2014	Janssen Pharmaceutica Nv	Crystallisation process for 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene
US8785403	12 Jun 2012	22 Jul 2014	Mitsubishi Tanabe Pharma Corporation	Glucopyranoside compound
US8791077 *	15 May 2009	29 Jul 2014	Astrazeneca Ab	Method for treating hyperuricemia employing an SGLT2 inhibitor and composition containing same
US8802637	30 Sep 2013	12 Aug 2014	Theracos, Inc.	Benzylbenzene derivatives and methods of use
US8802715	27 Dec 2013	12 Aug 2014	Astrazeneca Ab	Crystal forms of saxagliptin and processes for preparing same
US8802842	28 Sep 2010	12 Aug 2014	Boehringer Ingelheim International Gmbh	Method for the preparation of a crystalline form
US20110003757 *	29 Jan 2009	6 Jan 2011	Astellas Pharma Inc.	Pharmaceutical compositions for treating fatty liver disease
US20110065658 *	15 May 2009	17 Mar 2011	Bristol-Myers Squibb Company	Method for treating hyperuricemia employing an sglt2 inhibitor and composition containing same
US20110077213 *	15 May 2009	31 Mar 2011	Bristol-Myers Squibb Company	Method for treating and preventing kidney stones employing an sglt2 inhibitor and composition containing same
US20110098240 *	15 Aug 2008	28 Apr 2011	Boehringer Ingelheim International Gmbh	Pharmaceutical composition comprising a sglt2 inhibitor in combination with a dpp-iv inhibitor
US20120041069 *	18 Apr 2011	16 Feb 2012	Nectid Inc.	Sglt2 inhibitor dosage forms
US20120071403 *	26 May 2010	22 Mar 2012	Astrazeneca Uk Limited	Methods for Treating Type 2 Diabetes in Patients Resistant to Previous Treatment with other Anti-Diabetic Drugs Employing an SGLT2 Inhibitor and Compositions Thereof
US20120077739 *	2 Dec 2011	29 Mar 2012	Bristol-Myers Squibb	Methods for treating obesity employing an sglt2 inhibitor and compositions thereof
US20130023486 *	14 Jan 2011	24 Jan 2013	Tianjin Institute Of Pharmaceutical Research	Phenyl c-glucoside derivatives, preparation methods and uses thereof
CN102167715B	7 Mar 2011	24 Apr 2013	上海惠斯生物科技有限公司	Eutectic preparation method of sodium-glucose cotransporter 2 bulk pharmaceutical chemicals
EP2308841A2	27 Sep 2007	13 Apr 2011	Lexicon Pharmaceuticals, Inc.	Phlorizin analogs as SGLT2 inhibitors
EP2455374A1	15 Oct 2009	23 May 2012	Janssen Pharmaceutica N.V.	Process for the Preparation of Compounds useful as inhibitors of SGLT
EP2457908A1	15 Oct 2009	30 May 2012	Janssen Pharmaceutica N.V.	Process for the Preparation of Compounds useful as inhibitors of SGLT
EP2457918A2	21 Jun 2007	30 May 2012	Bristol-Myers Squibb Company	Crystalline solvates and complexes of (1s)-1,5-anhydro-1-c-(3-((phenyl) methyl) phenyl)-d-glucitol derivatives with amino acids as SGLT2 inhibitors for the treatment of diabetes
EP2481726A2	18 Apr 2008	1 Aug 2012	Bristol-Myers Squibb Company	Crystal forms of saxagliptin and processes for preparing same
EP2514756A1	30 Jul 2004	24 Oct 2012	Mitsubishi Tanabe Pharma Corporation	Novel compounds having inhibitory activity against sodium-dependant glucose transporter
EP2668953A1	15 May 2009	4 Dec 2013	Bristol-Myers Squibb Company	Pharmaceutical compositions comprising an SGLT2 inhibitor with a supply of carbohydrate and/or an inhibitor of uric acid synthesis
WO2003099836A1 *	15 May 2003	4 Dec 2003	Squibb Bristol Myers Co	C-aryl glucoside sglt2 inhibitors and method
WO2004080990A1	12 Mar 2004	23 Sep 2004	Kazuhiro Ikegai	C-glycoside derivatives and salts thereof
WO2005012318A2 *	30 Jul 2004	10 Feb 2005	Janssen Pharmaceutica Nv	Substituted fused heterocyclic c-glycosides
WO2006019886A2	14 Jul 2005	23 Feb 2006	Saleem Ahmad	Pyrrolo(oxo)isoquinolines as 5ht ligands
WO2008006043A2	6 Jul 2007	10 Jan 2008	Squibb Bristol Myers Co	1,3-oxazole derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents
WO2008042688A2	27 Sep 2007	10 Apr 2008	Lexicon Pharmaceuticals Inc	Phlorizin analogs as inhibitors of sodium glucose co-transporter 2
WO2009035969A1 *	9 Sep 2008	19 Mar 2009	Janssen Pharmaceutica Nv	Process for the preparation of compounds useful as inhibitors of sglt
WO2011051864A1	21 Oct 2010	5 May 2011	Pfizer Inc.	Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
WO2011060256A2	12 Nov 2010	19 May 2011	Bristol-Myers Squibb Company	Bilayer tablet formulations
WO2011060290A2	12 Nov 2010	19 May 2011	Bristol-Myer Squibb Company	Immediate release tablet formulations
WO2011070592A2	9 Dec 2010	16 Jun 2011	Panacea Biotec Ltd.	Novel sugar derivatives
WO2011142478A1	11 May 2011	17 Nov 2011	Mitsubishi Tanabe Pharma Corporation	Canagliflozin containing tablets
WO2012031124A2	1 Sep 2011	8 Mar 2012	Astrazeneca Uk Limited	Drug formulations using water soluble antioxidants
WO2012106303A1	31 Jan 2012	9 Aug 2012	Astrazeneca Uk Limited	Pharmaceutical formulations including an amine compound

4-cyano-N methyl benzamide

Prepararation 4-cyano-N methyl benzamide.

A mixture of 4-bromo-N-ethyl-3-methylnenzamide (3.76 g, 16.5 mmol, can be synthesized according to the following reference Oxford, A. W.; et al EP 533266 (1993)), K4[Fe(CN)₆]-3H₂0 (2.09 g, 4.94 mmol), Na₂C0₃ (1.05 g, 9.89 mmol), Pd(OAc)₂ (75 mg, 0.33 mmol), l,4-diazabicyclo[2.2.2] octane (74 mg, 0.66 mmol), and DMA (20 mL) was maintained under N₂ atmosphere at 126-130°C for 7.5 hr. Afterward, the mixture was cooled to room temperature, diluted with EtOAc, stirred for 20 min, and filtered through diatomaceous earth. The filtrate was concentrated under reduce pressure, and the residue (5.52 g) was stirred in a mixture of Et₂0 (5 mL) and hexanes (10 mL). Afterward, the solid was collected by filtration, and washed with Et₂0 to form the title compound (2.53 g). The mother liquor was concentrated under reduce pressure, and the residue was stirred in a mixture of Et₂0 (2 mL) and hexanes (4 mL) to form an additional amount of the compound (0.265 g) as a solid. Both batches were combined (2.80 g, 97%). 

¾ NMR (300 MHz, CDC1₃) δ ppm 2.59 (s, 3H), 3.03 (d, J = 4.9 Hz, 3H), 6.17 (br s, 1H), 7.61 (dd, J = 8.2, 1.5 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H).

http://www.google.com/patents/WO2014117274A1?cl=en

vietnam

.


 



 
 

 
 

 

 dalat city
hanoi











//////////

3,5 difluoro-4 formyl-N-methylbenzamide.

 Preparation of 3,5 difluoro-4 formyl-N-methylbenzamide.

To an ice-cold solution of 3,5-difluoro-4-formylbenzoic acid (120 g, 645 mmol) in dichloromethane (1.5 L) and N,N-dimethylformamide (2.0 g, 27 mmol) was added oxalyl chloride (90 g, 709 mmol) drop-wise at a rate that allowed the mixture to not exceed an internal temperature of 10°C. The resulting mixture was stirred at the same temperature for 0.5 hr, warmed to room temperature, and stirred for an additional 1.5 hr. The solution was then cooled to 0°C, and aqueous methylamine (40%, 168 mL, 1.94 mol) was added drop-wise at a rate that allowed the mixture to not exceed an internal temperature of 7°C. Afterward, the mixture was quenched with aqueous HC1 (2M, 335 mL, 670 mmol) and warmed to room temperature. The organic layer was separated, washed with brine (500 mL), dried over MgSC>4, filtered, and concentrated under vacuum. The resulting residual solid was taken in MTBE (500 mL), and the resulting mixture was heated to reflux for 0.5 hr, cooled to room temperature, and stirred for 18 hr. Afterward, the mixture was cooled to 0°C, filtered, rinsed with pentane, and dried under vacuum to form the title compound (103 g, 80%) as a solid.

 ¾ NMR (300 MHz, CDC1₃) δ ppm 3.03 (d, J = 4.86 Hz, 3 H), 6.37 (br s, 1 H), 7.36-7.42 (m, 2 H), 10.36 (s, 1 H); 

MS m/z 200.06 [M+H]⁺ (ESI).

3,5-difluoro-4-formylbenzoic acid.

3,5-difluoro-4-formylbenzoic acid.

To a solution of 3,5-difluorobenzoic acid (291 g, 1.84 mol) in 2-methyltetrahydrofuran (4.35 L) was added TMEDA (604 mL, 4.03 mol) at room temperature. The resulting solution was cooled to -78°C. Afterward, /?-BuLi (2.5 M in hexane) (1.77 L, 4.43 mol) was added drop-wise, during which the temperature of the mixture remained at less than -65 °C. The mixture was then stirred at -78 °C for 1.5 hr. Anhydrous MeOCHO (239 mL, 3.88 mol) was added dropwise at a rate that allowed the temperature to be maintained at less than -65 °C. The resulting solution was allowed to warm at room temperature, and then maintained a room temperature while being stirred for 18 hr. The mixture was then cooled to 0-5°C, and excess base was quenched with 6M aqueous HC1 (2.2 L, 13.2 mol). The phases were then separated, and the aqueous layer was extracted 3 times with 2- methyltetrahydrofuran (3 x 500 mL). The combined organic phases were washed with saturated brine, dried over MgS0₄, filtered, and concentrated under vacuum. The residue was dissolved in ethyl acetate (350 mL) at reflux, and cooled to room temperature.

Hexanes (480 mL) were then added, and the resulting mixture was further cooled to -15°C. The solid was collected by filtration, rinsed with hexanes, and dried under mechanical vacuum to form the title compound (122 g, 35%) as a solid. 

H NMR (300 MHz, DMSO- d₆) δ ppm 7.63-7.70 (m, 2 H), 10.23 (s, 1 H); 

MS m/z (ESI) 187.17 [M+H]⁺.