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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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OLMESARTAN
Mol. mass 558.585 g/mol
Olmesartan medoxomil (trade names: Benicar in the US, Olmetec in EU, Canada and Japan, WinBP, Golme in India, Erastapex in Egypt) is an angiotensin II receptor antagonist used to treat high blood pressure.
Olmesartan is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.[1] The U.S. Food and Drug Administration (FDA) has determined that the benefits of Benicar continue to outweigh its potential risks when used for the treatment of patients with high blood pressure according to the drug label.[2]
Angiotensin-II receptor antagonists should be used with caution in renal artery stenosis. Monitoring of plasma-potassium concentration is advised, particularly in the elderly and in patients with renal impairment; lower initial doses may be appropriate in these patients. Angiotensin-II receptor antagonists should be used with caution in aortic or mitral valve stenosis and in hypertrophic cardiomyopathy. Those with primary aldosteronism, and Afro-Caribbean patients (particularly those with left ventricular hypertrophy), may not benefit from an angiotensin-II receptor antagonist.
Structure
The olmesartan molecule includes one tetrazole group (a 5-member heterocyclic ring of four nitrogen and one carbon atom) and one imidazole group (a 5-membered planar heterocyclic aromatic ring of two nitrogen and three carbon atoms, classified as an alkaloid).
Olmesartan as the starting material can be easily produced according to the method described in Japanese Examined Patent Application (Kokoku) No. Hei 7-121918 (Japanese Patent No. 2082519 ; US Patent No. 5616599 ) or the like
Olmesartan is a prodrug that works by blocking the binding of angiotensin II to the AT1 receptors in vascular muscle; it is therefore independent of angiotensin II synthesis pathways, unlike ACE inhibitors. By blocking the binding rather than the synthesis of angiotensin II, olmesartan inhibits the negative regulatory feedback on renin secretion. As a result of this blockage, olmesartan reduces vasoconstriction and the secretion of aldosterone. This lowers blood pressure by producing vasodilation, and decreasing peripheral resistance.
The usual recommended starting dose of olmesartan is 20 mg once daily. The dose may be increased to 40 mg after two weeks of therapy, if further reduction in blood pressure is desirable. Doses above 40 mg do not appear to have greater effect, and twice-daily dosing offers no advantage over the same total dose given once daily.[1] No adjustment of dosage is typically necessary for advanced age, renal impairment, or hepatic dysfunction. For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics), olmesartan should be initiated with caution; consideration should be given to use of a lower starting dose in such cases.[1] If blood pressure is not controlled by Benicar alone, a diuretic may be added. Benicar may be administered with other antihypertensive agents. Benicar may be administered with or without food.[1]
Olmesartan and Sevikar HCT is marketed worldwide by Daiichi Sankyo, in India by Abbott Healthcare Pvt. Ltd. under the trade name WinBP, by Zydus Cadila under the trade name Olmy, by Ranbaxy Laboratories Ltd. under the trade name Olvance, and in Canada by Schering-Plough as Olmetec. Benicar HCT is the brand name of a medication containing olmesartan medoxomil in combination with hydrochlorothiazide, a thiazide diuretic. Three dosage combinations are available: 20 mg or 40 mg of olmesartan medoxomil combined with 12.5 mg of hydrochlorothiazide, or 40 mg of olmesartan medoxomil combined with 25 mg of hydrochlorothiazide. Benitec H, another medication containing olmesartan medoxomil and hydrochlorothiazide, is marketed by GlaxoSmithKline in India. In Poland as Olesartan Medoxomil by TEVA, Olimestra and Co-Olimestra (with HCTZ) by Miklich Lab., Elestar (with amlodipine) and Elestar HCT (with amlodipine, HCTZ) by Menarini, Sevikar HCT (with amoldipine, HCTZ) by Aiichi Sankyo.
Research
Two clinical studies (MORE [6] and OLIVUS [7])[8] report that Benicar reduced arterial plaque during therapy for high-blood pressure (hypertension).
- RxList Inc. (5 July 2007). “Benicar (olmesartan medoxomil)”. RxList Inc. Retrieved 22 July 2010.
- “FDA Alert: Benicar (olmesartan): Ongoing Safety Review”. Drugs.com. Retrieved 2013-06-27.
- Angiotensin II receptor blocker induced fetopathy: 7 cases. Hünseler C, Paneitz A, Friedrich D, Lindner U, Oberthuer A, Körber F, Schmitt K, Welzing L, Müller A, Herkenrath P, Hoppe B, Gortner L, Roth B, Kattner E, Schaible T. Klin Padiatr. 2011 Jan;223(1):10-4. Epub 2011 Jan 26.
- “BENICAR Prescribing Information”. Retrieved 2011-01-20.
- Rubio-Tapia, Alberto; Herman, Margot L.; Ludvigsson, Jonas F.; Kelly, Darlene G.; Mangan, Thomas F.; Wu, Tsung-Teh; Murray, Joseph A. (NaN undefined NaN). “Severe Spruelike Enteropathy Associated With Olmesartan”. Mayo Clinic Proceedings 87 (8): 732–738. doi:10.1016/j.mayocp.2012.06.003.
- as referenced in http://www.medicalnewstoday.com/releases/91285.php “Olmetec(R) Is First Angiotensin Receptor Blocker (ARB) To Suggest Atherosclerosis Regression (In Hypertensives With Cardiovascular Risk), UK”
- Cardiovascular Research Foundation (2008, October 16). Drug May Reduce Coronary Artery Plaque. ScienceDaily. Retrieved January 5, 2013, from http://www.sciencedaily.com /releases/2008/10/081012121318.htm
- (Review) R Preston Mason, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, and Elucida Research, Beverly, MA, USA. Vascular Health and Risk Management, Dovepress, Published Date June 2011 Volume 2011:7 Pages 405 – 416. Optimal therapeutic strategy for treating patients with hypertension and atherosclerosis: focus on olmesartan medoxomil. Retrieved January 5, 2013, from http://www.dovepress.com/optimal-therapeutic-strategy-for-treating-patients-with-hypertension-a-peer-reviewed-article-VHRM
4-Isopropenyl-2-propyl-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid [olmesartan dehydrate, compound 34b described in J. Med. Chem., 39, 323-338 (1996)]
- Daiichi-Sankyo Benicar page
- Benicar HCT from RXlist.com
- Mayo Clinic Proceedings vol.87 Issue 8, pages 732-738
-
Olmesartan medoxomil is known by two names,
- (a)(5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-(2(tetrazole-5yl)phenyl]phenyl]methylimidazole-5-carboxylate
- (b)4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazol-5-carboxylic acid (5-methyl-2-oxo-1,-3 dioxol-4-yl)methyl ester, and has a CAS No. [144689-63-4].
-
The structural formula is represented below:
Olmesartan medoxomil, which is an angiotensin II receptor antagonist, is useful as an active ingredient in medicaments for treatment and prophylaxis of hypertension (for example, Patent documents 1 to 5 or Non-patent document 1 and 2). Techniques for producing high-purity olmesartan medoxomil are necessary for use of olmesartan medoxomil as a medicament. -
Olmesartan medoxomil is produced from olmesartan by the steps described below, but there is the problem that olmesartan which is a starting material, olmesartan medoxomil dehydrate which is a by-product, or the like, is present as an impurity.
-
- Patent document 1: Japanese Examined Patent Application (Kokoku) No. Hei 7-121918 (Japanese Patent No. 2082519 )
- Patent document 2: US Patent No. 5616599
- Patent document 3: International Patent Publication No. WO2006/029056
- Patent document 4: International Patent Publication No. WO2006/029057
- Patent document 5: International Patent Publication No. WO2006/073519
-
- Non-patent document 1: J. Med. Chem., 39, 323-338 (1996)
- Non-patent document 2: Annu. Rep. Sankyo Res. Lab. (Sankyo Kenkyusho Nempo) 55, 1-91 (2003)
-
The prior art synthetic methods involve coupling reaction between the substituted imidazole and substituted biphenyl methyl bromide. J. Med. Chem. 1996 vol. 39 No.1, page 323-38 describes the synthesis of Olmesartan medoxomil as follow. [Scheme-1 ]
-
US 5616599 describes a process for the preparation of olmesartan medoxomil as follows.
-
[0006]4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5carboxylic acid is reacted with 5-methyl-2-oxo-1, 3-dioxolene-4-yl)methyl chloride using N,N-diisopropylethyl amine as base in N,N-dimethyl acetamide at 60°C to give (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl imidazole-5-carboxylate. The resulting product is coupled with N-(triphenylmethyl)-5-[4′-(bromomethyl)biphenyl-2-yl]tetrazole [herein referred to as TTBB] at 60°C in N, N-dimethyl acetamide using potassium carbonate as base to give protected olmesartan medoxomil. The protected olmesartan medoxomil is deprotected using 75 % acetic acid to give olmesartan medoxomil.
-
This process involves column chromatographic purification of intermediates which is not desirable on commercial scale operation.
-
US 5616599 describes another process for the preparation of olmesartan Medoxomil which involves addition of methyl Magnesium chloride on diethyl 2-propylimidazole-4, 5-dicarboxylate in tetrahydrofuran at -30 to -20°C to give ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole -5-carboxylate, which is coupled with TTBB using sodium hydride as base in N, N-dimethylformamide at 60°C to give ethyl-4-(1-hydroxy-1-methylethyl)2-propyl-1-[[2′-[2-(triphenylmethyl)-2H-tetrazol-. 5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate. The product thus formed is hydrolyzed using lithium hydroxide monohydrate as base in 1,4-dioxane at 5-10°C to give lithium salt of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2′-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, which is then coupled with 5-methyl-2-oxo-(1,3-dioxolene-4-yl)methyl chloride using K2CO3 as base in N,N-dimethylacetamide at 50°C to give trityl protected olmesartan medoxomil which on deprotection using 75% acetic acid gives Olmesartan Medoxomil.
-
During the condensation of ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole -5-carboxylate, with TTBB using sodium hydride as base in N, N-dimethylformamide, various impurities are formed, and isolation of the product involves extractive workup.
, Ian R. Baxendale, Steven V. Ley and Nikzad Nikbin Corresponding author emailThe structurally related imidazole core of olmesartan is formed in a different fashion (Scheme 36). Condensation between diaminomaleonitrile and trimethyl orthobutyrate furnishes the trisubstituted imidazole 181 in high yield [53,54]. Acid-mediated nitrile hydrolysis followed by esterification results in the corresponding diester unit 182. Treatment of 182 with four equivalents of methylmagnesium chloride in a mixture of diethyl ether and dichloromethane selectively provides tertiary alcohol 183. In subsequent steps this imidazole is alkylated with the tetrazole containing biphenyl appendage, followed by ester hydrolysis and alkylation of the resulting carboxylate with 4-(chloromethyl)-5-methyl-2-oxo-1,3-dioxole to yield olmesartan (Scheme 36).
![[1860-5397-7-57-i36]](https://i0.wp.com/beilstein-journals.org/bjoc/content/inline/1860-5397-7-57-i36.png)
- 53…….Yanagisawa, H.; Fujimoto, K.; Amemiya, Y.; Shimoji, Y.; Kanazaki, T.; Koike, H.; Sada, T. Angiotensin II Antagonist 1-Biphenylmethylimidazole Compounds and their Therapeutic Use. U.S. Patent 5,616,599, April 1, 1997.
Return to citation in text: [1] - 54……….Yanagisawa, H.; Amemiya, Y.; Kanazaki, T.; Shimoji, Y.; Fujimoto, K.; Kitahara, Y.; Sada, T.; Mizuno, M.; Ikeda, M.; Miyamoto, S.; Furukawa, Y.; Koike, H. J. Med. Chem. 1996, 39, 323–338. doi:10.1021/jm950450f
Return to citation in text: [1]
Reacting ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate with N-(Triphenylmethyl)-5-[4′-(bromomethyl)biphenyl-2- yl]tetrazole in an organic solvent in presence of a base and a phase transfer catalyst in non-aqueous system to give after workup, ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2′-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate, which is further processed, by following improved reaction conditions in three steps to provide substantially pure [HPLC purity 99.3 to 99.7 %] olmesartan medoxomil.
-
To a 3M solution of MeMgCl(55.86 g, 0.74 mol) in tetrahydrofuran was added a solution of diethyl 2-propyl imidazole- 4,5-dicarboxylate (50 g,0.19 mol) in tetrahydrofuran (200 ml) at -10 to 0°C under N2 atmosphere. The mixture was stirred at -5 to 0°C for 10 minutes. Reaction mass was quenched into 400 ml 25 % ammonium chloride solution followed by extraction with ethyl acetate (300 ml). The organic phase was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo to give a syrup, which was crystallized using diisopropyl ether.
Yield: 85-90 %,
Purity by HPLC: 88-93 %.
1H-NMR (CDCl3) δ: 7.8-8.1 (s, 1H), 5.8(s, 1H)., 4.35(q, 2H), 2.68(t, 2H), 1.78(m, 2H), 1.61(s, 6H), 1.36(t, 3H), 0.96(t, 3H).
Example-2Preparation of Ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2′-[2-(triphenylaiethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole
- -5-
carboxylate
-
Mixture of Ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole -5-carboxylate (41 g, 0.17 mol), potassium carbonate (47g, 0.34 mol) and tetrabutylammonium bromide (4.9 g, 0.01 mol) in acetone was stirred at room temperature for 1hr. Then TTBB (93% Purity, 92.89g, 0.15 mol) was charged, refluxed for 14hrs. Potassium salts were filtered off from the reaction mass and the filtrate was charcoalised for 1hr. It was filtered over celite bed and the filtrate was distilled off completely to get a semi solid mass. 250 ml of Methanol was added to the residue and stirred for 2-3 hrs to give a solid product, which was filtered and washed with chilled methanol and dried.
Yield: 80-85%,
Purity by HPLC: 85-90%.
1H-NMR (CDCl3) δ: 7.8-8.1 (m, 1H), 6.7-7.61 (m, 22H), 5.78 (bs, 1H), 5.38(s, 2H), 4.12 (q, 2H), 2.52 (t, 2H), 1.64(s, 6H), 1.5-1.8(m, 2H), 1.08(t, 3H), 0.88(t, 3H).
Example-3Preparation of lithium salt of 4-(1-hydroxy-1-methylethyl) 2-propyl-1-[[2′-[2-(triphenylmethyl)-2H-tetrazol-5yl] biphenyl-4-yl] methyl] imidazole -5-carboxylic acid
-
To a solution of Ethyl-4-(1-hydroxy-1-methylethyl) 2-propyl- 1-[[2′-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate (105 g, 0.14 mol) in tetrahydrofuran , was added LiOH.H2O (7.8 g, 0.18 mol) solution below 10°C. The reaction mixture was stirred at room temperature for 15 hours. Reaction mass was concentrated under vacuum at 35°C to 1/4 th of its volume. 300 ml of ethyl acetate and NaCl (130 g) were added to the residue under stirring. The organic phase was separated, dried over sodium sulphate and concentrated under vacuum to get the product. The crude product was taken as such to the next stage.
Example-4Preparation of trityl protected olmesartan medoxomil
-
To the solution of lithium salt of 4-(1-hydroxy-1-methylethyl) 2-propyl- 1-[[2′-[2-(triphenylmethyl)-2H-tetrazol-5yl] biphenyl-4-yl] methyl] imidazole -5-carboxylic acid , (97 g, 0.13 mol) in N, N-dimethyl acetamide(200 ml) was added triethylamine(12.7 g, 0.12 mol), stirred at room temperature for 0.5 hours. 5-methyl-2-oxo-(1,3-dioxolene-4-yl)methyl chloride (85% purity, 37.3 g, 0.25 mol) was added below 10°C. The mixture was stirred at 50-55°C for 4 hours, checked TLC. Dichloromethane (400 ml) and chilled water (500 ml) were added under stirring. The organic phase was separated, given brine wash (50 ml), dried over sodium sulphate and concentrated under vacuum to get a residue. To the residue methanol was added, stirred for 1hr, cooled to 5-10°, filtered and washed with chilled methanol and dried.
Yield: 75-80%,
Purity by HPLC: 96-98%.
1H-NMR (CDCl3) δ: 7.87(d, 1H), 6.90-7.52(m, 20H), 6.68(d, 2H), 5.61(s, 1H), 5.3(s, 2H), 4.7(s, 2H), 2.54(t, 2H), 1.97(s, 3H), 1.6-1.75(m, 2H), 1.62(s, 6H), 0.87(t, 3H).
Example-5Preparation of olmesartan medoxomil
-
To the suspension of trityl protected olmesartan medoxomil (50g, 0.06 mol) in 250 ml 75% acetic acid was stirred at 50-55°C for 1.5hrs and cooled to 5-10°C. The by-product trityl alcohol was filtered off and washed with 75% acetic acid. The filtrate was concentrated under vacuum to get syrup, which was crystallized using isopropyl alcohol.
Yield: 85-88%,
Purity by HPLC: 95-98%.
The material was further purified with ethyl methyl ketone. It was filtered and washed with ethyl methyl ketone and dried to give substantially pure olmesartan medoxomil.
Yield: 70-75%,
Purity by HPLC: 99.3-99.7%.
1H-NMR (CDCl3) δ: 7.81(dd, 1H), 7.43-7.6(m, 3H), 7.09d, 2H), 6.79(d, 2H), 5.41(s, 1H),4.95(s, 1H), 2.56(t, 3H), 2.17(s, 3H), 1.58-1.69(m, 2H), 1.58(s, 6H), 0.92(t,3H).
Ipragliflozin
Ipragliflozin
ASP-1941 , 1(S)-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-1-deoxy-beta-D-glucopyranose L-proline cocrystal
Kotobuki (Originator)
| (1S)-1,5-Anhydro-1-C-[3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl]-D-glucitol |
| Molecular Formula | C21H21FO5S | |
| Molecular Weight | 404.45 | |
| CAS Registry Number | 761423-87-4 |
Ipragliflozin (formerly ASP1941) has been filed in Japan on the back of phase III trials which showed that it could provide significant reductions in glycated haemoglobin levels (HbA1c) levels – a marker of glucose control over time – compared to placebo
According to Astellas’ latest R&D pipeline update in February 2013, Astellas is developing ipragliflozin only in Japan. The same document in August 2012 indicated it was also carrying out phase II studies with the drug in the US and Japan.
Astellas Pharma Inc.: Submits Application for Marketing Approval of
Ipragliflozin (ASP1941), SGLT2 Inhibitor for Treatment of
Type 2 Diabetes, in Japan
TOKYO, March 13, 2013 – Astellas Pharma Inc. (“Astellas”; Tokyo:4503; President and CEO:
Yoshihiko Hatanaka) announced today that it has submitted a market authorization application for aSGLT2 inhibitoripragliflozin (generic name; development code: ASP1941) to the Ministry of Health, Labour and Welfare in Japan seeking an approval forthe indication of type 2 diabetes.
Ipragliflozin is a selective SGLT2 (sodium-glucose co-transporter 2)inhibitor discovered through research collaboration with Kotobuki Pharmaceutical Co., Ltd. SGLTs are membrane proteins that
exist on the cell surface and transfer glucose into cells. SGLT2 is a subtype of the sodium-glucose co-transporters and plays a key role in the reuptake of glucose in the proximal tubule of the kidneys.
Ipragliflozin reduces blood glucose levels by inhibiting the reuptake of glucose.
In the Phase III pivotal study in monotherapy for type 2 diabetesin Japan, ipragliflozin
demonstrated significant decreases of HbA1c, an index of glycemic control, in change from baseline compared to placebo. Based on the safety resultsin this study, ipragliflozin was safe and well tolerated. Patients with type 2 diabetes generally need combination therapy, so it is important
for a novel oral hypoglycemic agent to be safe to use with existing diabetes therapies. In this regard, Astellas has conducted six Phase III studies to investigate the safety and efficacy of ipragliflozin
used in combination with other hypoglycemic agentsfor a long term period. In these Phase IIIstudies, effectiveness and favorable safety of ipragliflozin was confirmed even in combination with
other hypoglycemic agents.
Astellas expects to provide an additional therapeutic option and further contribute to the treatment of type 2 diabetes by introducing ipragliflozin, an oral hypoglycemic agent with a novel mechanism
of action, into the Japanese market.
About Type 2 Diabetes
Diabetes (medically known as diabetes mellitus) is a disorder in which the body has difficulty regulating its blood glucose (sugar) level. There are two major types of diabetes: type 1 and type 2.
Type 2 diabetes (formerly called non-insulin-dependent diabetes mellitus or adult-onset diabetes) is a disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Patients are instructed to increase exercise and diet restrictions, but most
require treatment with an anti-diabetic agent to control blood glucose.
structure:
The compound and methods of its synthesis are described in WO 2004/080990, WO 2005/012326 and WO 2007/114475 for example.
The gluconolactone method: In 1988 and 1989 a general method was reported to prepare C-arylglucosides from tetra-6>-benzyl protected gluconolactone, which is an oxidized derivative of glucose (see J. Org. Chem. 1988, 53, 752-753 and J. Org. Chem. 1989, 54, 610- 612). The method comprises: 1) addition of an aryllithium derivative to the hydroxy-protected gluconolactone to form a hemiketal (a.k.ci., a lactol), and 2) reduction of the resultant hemiketal with triethylsilane in the presence of boron trifluoride etherate. Disadvantages of this classical, but very commonly applied method for β-C-arylglucoside synthesis include:
1) poor “redox economy” (see J. Am. Chem. Soc. 2008, 130, 17938-17954 and Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN- 10: 0120594757); pg 38)— that is, the oxidation state of the carbon atom at CI, with respect to glucose, is oxidized in the gluconolactone and then following the arylation step is reduced to provide the requisite oxidation state of the final product. 2) due to a lack of stereospecificity, the desired β-C-arylglucoside is formed along with the undesired a-C-arylglucoside stereoisomer (this has been partially addressed by the use of hindered trialkylsilane reducing agents (see Tetrahedron: Asymmetry 2003, 14, 3243-3247) or by conversion of the hemiketal to a methyl ketal prior to reduction (see J. Org. Chem. 2007, 72, 9746-9749 and U.S. Patent 7,375,213)).
Oxidation Reduction
Glucose Gluconoloctone Hemiketal a-anomer β-anomer
R = protecting group
The metalated glucal method: U.S. Patent 7,847,074 discloses preparation of SGLT2 inhibitors that involves the coupling of a hydroxy-protected glucal that is metalated at CI with an aryl halide in the presence of a transition metal catalyst. Following the coupling step, the requisite formal addition of water to the C-arylglucal double bond to provide the desired C-aryl glucoside is effected using i) hydroboration and oxidation, or ii) epoxidation and reduction, or iii) dihydroxylation and reduction. In each case, the metalated glucal method represents poor redox economy because oxidation and reduction reactions must be conducted to establish the requisite oxidation states of the individual CI and C2 carbon atoms.
U.S. Pat. Appl. 2005/0233988 discloses the utilization of a Suzuki reaction between a CI -boronic acid or boronic ester substituted hydroxy-protected glucal and an aryl halide in the presence of a palladium catalyst. The resulting 1- C-arylglucal is then formally hydrated to provide the desired 1- C-aryl glucoside skeleton by use of a reduction step followed by an oxidation step. The synthesis of the boronic acid and its subsequent Suzuki reaction, reduction and oxidation, together, comprise a relatively long synthetic approach to C-arylglucosides and exhibits poor redox economy. Moreover, the coupling catalyst comprises palladium which is toxic and therefore should be controlled to very low levels in the drug substance.
R = protecting group; R’ = H or alkyl
The glucal epoxide method: U.S. Patent 7,847,074 discloses a method that utilizes an organometallic (derived from the requisite aglycone moiety) addition to an electrophilic epoxide located at C1-C2 of a hydroxy-protected glucose ring to furnish intermediates useful for SGLT2 inhibitor synthesis. The epoxide intermediate is prepared by the oxidation of a hydroxy- protected glucal and is not particularly stable. In Tetrahedron 2002, 58, 1997-2009 it was taught that organometallic additions to a tri-6>-benzyl protected glucal-derived epoxide can provide either the a-C-arylglucoside, mixtures of the a- and β-C-arylglucoside or the β-C-arylglucoside by selection of the appropriate counterion of the carbanionic aryl nucleophile (i.e., the
organometallic reagent). For example, carbanionic aryl groups countered with copper (i.e., cuprate reagents) or zinc (i.e., organozinc reagents) ions provide the β-C-arylglucoside, magnesium ions provide the a- and β-C-arylglucosides, and aluminum (i.e., organoaluminum reagents) ions provide the a-C-arylglucoside.
or Zn
The glycosyl leaving group substitution method: U.S. Patent 7,847,074, also disclosed a method comprising the substitution of a leaving group located at CI of a hydroxy-protected glucosyl species, such as a glycosyl halide, with a metalated aryl compound to prepare SGLT2 inhibitors. U.S. Pat. Appl. 2011/0087017 disclosed a similar method to prepare the SGLT2 inhibitor canagliflozin and preferably diarylzinc complexes are used as nucleophiles along with tetra- >-pivaloyl protected glucosylbromide.
Glucose Glucosyl bromide β-anomer
Methodology for alkynylation of 1,6-anhydroglycosides reported in Helv. Chim. Acta. 1995, 78, 242-264 describes the preparation of l,4-dideoxy-l,4-diethynyl^-D-glucopyranoses (a. La., glucopyranosyl acetylenes), that are useful for preparing but-l,3-diyne-l,4-diyl linked polysaccharides, by the ethynylating opening (alkynylation) of partially protected 4-deoxy-4-C- ethynyl-l,6-anhydroglucopyranoses. The synthesis of β-C-arylglucosides, such as could be useful as precursors for SLGT2 inhibitors, was not disclosed. The ethynylation reaction was reported to proceed with retention of configuration at the anomeric center and was rationalized (see Helv. Chim. Acta 2002, 85, 2235-2257) by the C3-hydroxyl of the 1,6- anhydroglucopyranose being deprotonated to form a C3-0-aluminium species, that coordinated with the C6-oxygen allowing delivery of the ethyne group to the β-face of the an oxycarbenium cation derivative of the glucopyranose. Three molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6-anhydroglucopyranose. The
ethynylaluminium reagent was prepared by the reaction of equimolar (i.e., 1:1) amounts of aluminum chloride and an ethynyllithium reagent that itself was formed by the reaction of an acetylene compound with butyllithium. This retentive ethynylating opening method was also applied (see Helv. Chim. Acta. 1998, 81, 2157-2189) to 2,4-di-<9-triethylsilyl- 1,6- anhydroglucopyranose to provide l-deoxy-l-C-ethynyl- -D-glucopyranose. In this example, 4 molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6- anhydroglucopyranose. The ethynylaluminium regent was prepared by the reaction of equimolar (i.e., 1: 1) amounts of aluminum chloride and an ethynyl lithium reagent that itself was formed by reaction of an acetylene compound with butyllithium.
It can be seen from the peer-reviewed and patent literature that the conventional methods that can be used to provide C-arylglucosides possess several disadvantages. These include (1) a lack of stereoselectivity during formation of the desired anomer of the C- arylglucoside, (2) poor redox economy due to oxidation and reduction reaction steps being required to change the oxidation state of CI or of CI and C2 of the carbohydrate moiety, (3) some relatively long synthetic routes, (4) the use of toxic metals such as palladium, and/or (5) atom uneconomic protection of four free hydroxyl groups. With regard to the issue of redox economy, superfluous oxidation and reduction reactions that are inherently required to allow introduction of the aryl group into the carbohydrate moiety of the previously mention synthetic methods and the subsequent synthetic steps to establish the required oxidation state, besides adding synthetic steps to the process, are particular undesirable for manufacturing processes because reductants can be difficult and dangerous to operate on large scales due to their flammability or ability to produce flammable hydrogen gas during the reaction or during workup, and because oxidants are often corrosive and require specialized handling operations (see Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN-10: 0120594757); pg 38 for discussions on this issue).
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The C-glycoside derivative represented by the formula (1) and its salt [hereinafter, they are referred to as “compound (1)” or “compound of formula (1)” in some cases] is known to be useful for treatment and prevention of diabetes such as insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes) and the like and various diabetes-related diseases including insulin-resistant diseases and obesity (Patent Literature 1).
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The method for producing the C-glycoside derivative represented by the formula (1), described in the Patent Literature 1 is understood to be represented by the below-shown reaction formula (I), by referring to the Examples and Reference Examples, described in the Patent Literature 1. Roughly explaining, it is a method which comprises reacting [1-benzothien-2-yl(5-bromo-2-fluorophenyl)methoxy]tert-butyl)dimethylsilane (synthesized in accordance with Reference Example 37 of the Literature) in a manner shown in Example 65 of the Literature, to obtain (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol and then reacting the obtained compound in accordance with Example 100 of the Literature to synthesize intended (1S)-1,5-anhydro-1-C-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol.
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However, the method for producing the C-glycoside derivative of the formula (1), disclosed in the Patent Literature 1 is not industrially satisfactory in yield and cost, as is seen in later-shown Reference Example 1 of the present Description.
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For example, as described later, the method includes a step of low product yield (for example, a step of about 50% or lower yield) and the overall yield of the C-glycoside derivative (final product) represented by the formula (1) from the compound (8) (starting raw material) is below 7%; therefore, the method has problems in yield and cost from the standpoint of medicine production and has not been satisfactory industrially. In addition, the method includes an operation of purification by column chromatography which uses chloroform as part of purification solvents; use of such a solvent poses a problem in environmental protection and there are various restrictions in industrial application of such an operation; thus, the method has problems in providing an effective medicine.
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Also, an improved method of conducting an addition reaction with trimethylsilyl carbohydrate instead of benzyl carbohydrate and then conducting deprotection for acetylation, is known for a compound which has a structure different from that of the compound of the formula (1) but has a structure common to that of the compound of the formula (1) (Patent Literature 2). It is described in the Patent Literature 2 that the improved method enhances the overall yield to 6.2% from 1.4%. Even in the improved method, however, the yield is low at 6.2% which is far from satisfaction in industrial production.
- Patent Literature 1: WO 2004/080990 Pamphlet
- Patent Literature 2: WO 2006/006496 Pamphlet
http://www.google.com/patents/EP2105442A1
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Into a tetrahydrofuran (20 ml) solution of benzo[b]thiophene (5.0 g) was dropwise added a n-hexane solution (25 ml) of n-butyl lithium (1.58 M) at -78°C in an argon atmosphere, followed by stirring at -78°C for 10 minutes. Into this solution was dropwise added a tetrahydrofuran (80 ml) solution of 5-bromo-2-fluorobenzaldehyde (8.0 g), followed by stirring at -78°C for 2.5 hours. The temperature of the reaction mixture was elevated to room temperature. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol (10.5 g, yield: 83.6%).
1H-NMR (CDCl3): δ
2.74 (1H, d), 6.35 (1H, d), 6.93 (1H, dd), 7.14 (1H, s), 7.27-7.38 (2H, m), 7.39 (1H, m), 7.68 (1H, dd), 7.74 (2H, m)
- First step: synthesis of 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol
Second step: synthesis of [1-benzothien-2-yl(5-bromo-2-fluorophenyl)methoxy](tert-butyl)dimethylsilane
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To a dimethylformamide (20 ml) solution of 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol (5.0 g) were added imidazole (1.3 g), a catalytic amount of 4-(dimethylamino)pyridine and tert-butyldimethylchlorosilane (2.7 g), followed by stirring at room temperature for 7 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain [1-benzothien-2-yl(5-bromo-2-fluorophenyl)methoxy](tert-butyl)dimethylsilane (5.22 g, yield: 78.0%).
MS: 451 (M+)
1H-NMR (CDCl3): δ
0.05 (3H, s), 0.11 (3H, s), 0.95 (9H, s), 6.34 (1H, s), 6.91 (1H, t), 7.08 (1H, d), 7.23-7.38 (2H, m), 7.64-7.68 (1H, m), 7.75-7.28 (2H, m)
Third step: Synthesis of 1-C-[3-(1-benzothien-2-yl{[tert-butyl-(dimethyl)silyloxy}methyl)4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose
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Into a tetrahydrofuran (15 ml) solution of [1-benzothien-2-yl(5-bromo-2-fluorophenyl)methoxy](tert-butyl)dimethylsilane (1.5 g) was dropwise added a n-hexane solution (2.2 ml) of n-butyl lithium (1.58 M) in an argon atmosphere at -78°C, followed by stirring at -78°C for 30 minutes. Into the solution was dropwise added a tetrahydrofuran (20 ml) solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (1.9 g), followed by stirring at -78°C for 15 minutes and then at 0°C for 1.5 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/chloroform/acetone) to obtain 1-C-[3-(1-benzothien-2-yl{[tert-butyl-(dimethyl)silyloxy}methyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose (1.52 g, yield: 50.2%). MS: 933 (M+Na)
Fourth step: Synthesis of 1-C-{3-[1-benzothien-2-yl(hydroxy)methyl]-4-fluorophenyl}-2,3,4,6-tetra-O-benzyl-D-glucopyranose
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To a tetrahydrofuran (15 ml) solution of 1-C-[3-(1-benzothien-2-yl{[tert-butyl-(dimethyl)silyloxy}methyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose (1.52 g) was added a tetrahydrofuran solution (2.0 ml) of tetrabutylammonium fluoride (1.0 M), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated per se. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-C-{3-[1-benzothien-2-yl(hydroxy)methyl]-4-fluorophenyl}-2,3,4,6-tetra-O-benzyl-D-glucopyranose (0.99 g, yield: 74.7%). MS: 819 (M+Na), 779 (M+H-H2O)
Fifth step: Synthesis of (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol
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To an acetonitrile (5.0 ml) solution of 1-C-{3-[1-benzothien-2-yl(hydroxy)methyl]-4-fluorophenyl}-2,3,4,6-tetra-O-benzyl-D-glucopyranose (500 mg) were added triethylsilane (175 mg) and boron trifluoride-diethyl ether complex (196 mg) in an argon atmosphere at -20°C, followed by stirring at -20°C for 5 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol (150 mg, yield: 30.2%) MS: 787 (M+Na)
1H-NMR (CDCl3): δ
3.42-3.48 (1H, m), 3.55-3.58 (1H, m), 3.72-3.78 (4H, m), 3.83 (1H, d), 4.14-4.30 (3H, m), 4.39 (1H, d), 4.51-4.67 (4H, m), 4.83-4.94 (2H, m), 6.86-6.90 (1H, m), 6.98 (1H, brs), 7.06-7.37 (24H, m), 7.57-7.60 (1H, m), 7.66-7.69 (1H, m)
Sixth step: Synthesis of (1S)-1,5-anhydro-1-C-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol
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To a dichloromethane (10 ml) solution of (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol (137 mg) were added pentamethylbenzene (382 mg) and a n-heptane solution (0.75 ml) of boron trichloride (1.0 M) in an argon atmosphere at -78°C, followed by stirring at -78°C for 3 hours. Methanol was added to the reaction mixture, the temperature of the resulting mixture was elevated to room temperature, and the mixture was concentrated per se. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain (1S)-1,5-anhydro-1-C-[3-(1-benzothiophene-2-ylmethyl)-4-fluorohenyl]-D-glucitol OR IPRAGLIFLOZIN (63 mg, yield: 87.8%).
1H-NMR (CD3OD): δ
3.29-3.48 (4H, m), 3.68 (1H, dd), 3.87 (1H, dd), 4.11 (1H, d), 4.20-4.29 (2H, m), 7.03 (1H, s), 7.08 (1H, dd), 7.19-7.29 (2H, m), 7.35 (1H, m), 7.42 (1H, dd), 7.64 (1H, d), 7.72 (1H, d)
(1S)-1,5-anhydro-1-C-[3-(1-benzothiophene-2-ylmethyl)-4-fluorohenyl]-D-glucitol OR IPRAGLIFLOZIN
Empagliflozin
Empagliflozin
BI-10773
(2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol
M.Wt: 450.91
: C23H27ClO7
Sponsor/Developer: Eli Lilly and Boehringer Ingelheim
Mechanism of action: SGLT 2 inhibitor
Indication (Phase): Oral treatment of adults with type 2 diabetes (Phase III, expected to conclude by year’s end); Oral treatment of adults with type 2 diabetes plus high blood pressure (Phase IIb; trial results released Oct. 2)
NDA, MAA filings planned for 2013
Empagliflozin is a potent, selective sodium glucose co-transporter-2 inhibitor that is in development for the treatment of type 2 diabetes. Empagliflozin is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), which is found almost exclusively in the proximal tubules of nephronic components in the kidneys. SGLT-2 accounts for about 90 percent of glucose reabsorption into the blood. Blocking SGLT-2 causes blood glucose to be eliminated through the urine via the urethra. The Empagliflozin phase III clinical trial program will include about 14,500 patients. The program consists of twelve ongoing international phase III clinical trials, including a large cardiovascular outcomes trial.
Empagliflozin is a novel SGLT2 inhibitor that is described for the treatment or improvement in glycemic control in patients with type 2 diabetes mellitus, for example in WO 05/092877, WO 06/117359, WO 06/120208, WO 2010/092126, WO 2010/092123, WO 2011/039107, WO 2011/039108. The use of a SGLT2 inhibitor in a method for treating obesity is described in WO 08/116,195
WO2005/092877
WO2006/117359 MP 149 DEG CENT
Empagliflozin is drug which is being investigated in clinical trials for the oral treatment oftype 2 diabetes by Boehringer Ingelheim and Eli Lilly and Company.[1][2] It is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), which is found almost exclusively in theproximal tubules of nephronic components in the kidneys. SGLT-2 accounts for about 90 percent of glucose reabsorption into the blood. Blocking SGLT-2 causes blood glucose to be eliminated through the urine via the urethra.[3][4]
SGLT-2 inhibitors such as empagliflozin reduce blood glucose by blocking glucose reabsorption in the kidney and thereby excreting glucose (i.e., blood sugar) via the urine.[5]
As of December 2013, empagliflozin is in phase III clinical trials.[2]
When taken in dosages of 10 or 25 mg once a day, the incidence of adverse events was similar to placebo. However, there was a higher frequency of genital infections at both the 10 mg and the 25 mg dosages.
1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene of the formula
as described for example in WO 2005/092877. Methods of synthesis are described in the literature, for example WO 06/120208 and WO 2011/039108. According to this invention, it is to be understood that the definition of empagliflozin also comprises its hydrates, solvates and polymorphic forms thereof, and prodrugs thereof. An advantageous crystalline form of empagliflozin is described in WO 2006/117359 and WO 2011/039107 which hereby are incorporated herein in their entirety. This crystalline form possesses good solubility properties which enables a good bioavailability of the SGLT2 inhibitor. Furthermore, the crystalline form is physico-chemically stable and thus provides a good shelf-life stability of the pharmaceutical composition. Preferred pharmaceutical compositions, such as solid formulations for oral administration, for example tablets, are described in WO 2010/092126,
http://www.google.com/patents/WO2011039108A2
Example 1 : Synthesis of the fluoride VIII.1
Oxalylchloride (176kg; 1386mol; 1 ,14eq) is added to a mixture of 2-chloro-5-iodo benzoic acid (343kg; 1214mol) (compound IX.1 ), fluorobenzene (858kg) and N,N-dimethylformamide (2kg) within 3 hours at a temperature in the range from about 25 to 30°C (gas formation). After completion of the addition, the reaction mixture is stirred for additional 2 hours at a temperature of about 25 to 30°C. The solvent (291 kg) is distilled off at a temperature between 40 and 45°C (p=200mbar). Then the reaction solution (91 1 kg) is added to aluminiumchloride AICI3 (181 kg) and fluorobenzene (192kg) at a temperature between about 25 and 30°C within 2 hours. The reaction solution is stirred at the same temperature for about an additional hour. Then the reaction mixture is added to an amount of 570 kg of water within about 2 hours at a temperature between about 20 and 30°C and stirred for an additional hour. After phase separation the organic phase (1200kg) is separated into two halves (600kg each). From the first half of the organic phase solvent (172kg) is distilled off at a temperature of about 40 to 50°C (p=200mbar). Then 2-propanole (640kg) is added. The solution is heated to about 50°C and then filtered through a charcoal cartouche (clear filtration). The cartouche may be exchanged during filtration and washed with a
fluorobenzene/2-propanole mixture (1 :4; 40kg) after filtration. Solvent (721 kg) is distilled off at a temperature of about 40 to 50°C and p=200mbar. Then 2-propanole (240kg) is added at a temperature in the range between about 40 to 50°C. If the content of fluorobenzene is greater than 1 % as determined via GC, another 140kg of solvent are distilled off and 2- propanole (140kg) is added. Then the solution is cooled from about 50°C to 40°C within one hour and seeding crystals (50g) are added. The solution is further cooled from about 40°C to 20°C within 2 hours. Water (450kg) is added at about 20°C within 1 hour and the suspension is stirred at about 20°C for an additional hour before the suspension is filtered. The filter cake is washed with 2-propanole/water (1 :1 ; 800kg). The product is dried until a water level of <0.06%w/w is obtained. The second half of the organic phase is processed identically. A total of 410kg (94%yield) of product which has a white to off-white crystalline appearance, is obtained. The identity of the product is determined via infrared spectrometry.
Example 2: Synthesis of the ketone VII.1
To a solution of the fluoride VIII.1 (208kg), tetrahydrofuran (407kg) and (S)-3- hydroxytetrahydrofuran (56kg) is added potassium-ie f-butanolate solution (20%) in tetrahydrofuran (388kg) within 3 hrs at 16 to 25°C temperature. After completion of the addition, the mixture is stirred for 60min at 20°C temperature. Then the conversion is determined via HPLC analysis. Water (355kg) is added within 20 min at a temperature of 21 °C (aqueous quench). The reaction mixture is stirred for 30 min (temperature: 20°C). The stirrer is switched off and the mixture is left stand for 60 min (temperature: 20°C). The phases are separated and solvent is distilled off from the organic phase at 19 to 45°C temperature under reduced pressure. 2-Propanol (703kg) is added to the residue at 40 to 46°C temperature and solvent is distilled off at 41 to 50°C temperature under reduced pressure. 2-Propanol (162kg) is added to the residue at 47°C temperature and solvent is distilled off at 40 to 47°C temperature under reduced pressure. Then the mixture is cooled to 0°C within 1 hr 55 min. The product is collected on a centrifuge, washed with a mixture of 2- propanol (158kg) and subsequently with ie f.-butylmethylether (88kg) and dried at 19 to 43°C under reduced pressure. 227kg (91 ,8%) of product are obtained as colourless solid. The identity of the product is determined via infrared spectrometry.
Example 3: Synthesis of the iodide V.1
To a solution of ketone VII.1 (217,4kg) and aluminium chloride (AICI3; 81 ,5kg) in toluene (366,8kg) is added 1 ,1 ,3,3-tetramethyldisiloxane (TMDS, 82,5kg) within 1 hr 30 min
(temperature: 18-26°C). After completion of the addition, the mixture is stirred for additional 1 hr at a temperature of 24°C. Then the conversion is determined via HPLC analysis.
Subsequently the reaction mixture is treated with acetone (15,0kg), stirred for 1 hr 5 min at 27°C temperature and the residual TMDS content is analyzed via GC. Then a mixture of water (573kg) and concentrated HCI (34kg) is added to the reaction mixture at a temperature of 20 to 51 °C (aqueous quench). The reaction mixture is stirred for 30 min (temperature:
51 °C). The stirrer is switched off and the mixture is left stand for 20 min (temperature: 52°C). The phases are separated and solvent is distilled off from the organic phase at 53-73°C temperature under reduced pressure. Toluene (52,8kg) and ethanol (435,7kg) are added to the residue at 61 to 70°C temperature. The reaction mixture is cooled to 36°C temperature and seeding crystals (0,25kg) are added. Stirring is continued at this temperature for 35 min. Then the mixture is cooled to 0 to 5°C and stirred for additional 30 min. The product is collected on a centrifuge, washed with ethanol (157kg) and dried at 15 to 37°C under reduced pressure. 181 kg (82,6%) of product are obtained as colourless solid. The identity of the product is determined via the HPLC retention time.
Example 4: Synthesis of the lactone IV.1
A suspension of the D-(+)-gluconic acid-delta-lactone IVa.1 (42,0kg), tetrahydrofuran (277,2kg), 4-methylmorpholine (NMM; 152,4kg) and 4-dimethylaminopyridine (DMAP;
1 ,44kg) is treated with chlorotrimethylsilane (TMSCI; 130,8kg) within 50 min at 13 to 19°C. After completion of the addition stirring is continued for 1 hr 30 min at 20 to 22°C and the conversion is determined via HPLC analysis. Then n-heptane (216,4kg) is added and the mixture is cooled to 5°C. Water (143kg) is added at 3 to 5°C within 15 min. After completion of the addition the mixture is heated to 15°C and stirred for 15 min. The stirrer is switched off and the mixture is left stand for 15 min. Then the phases are separated and the organic layer is washed in succession two times with water (143kg each). Then solvent is distilled off at 38°C under reduced pressure and n-heptane (130kg) is added to the residue. The resulting solution is filtered and the filter is rinsed with n-heptane (63kg) (filter solution and product solution are combined). Then solvent is distilled off at 39 to 40°C under reduced pressure. The water content of the residue is determined via Karl-Fischer analysis (result: 0,0%).
1 12,4kg of the product is obtained as an oil (containing residual n-heptane, which explains the yield of >100%). The identity of the product is determined via infrared spectrometry.
Example 5a: Synthesis of the glucoside 11.1
To a solution of the iodide V.1 (267kg) in tetrahydrofuran (429kg) is added Turbogrignard solution (isopropylmagnesium chloride/lithium chloride solution, 14 weight-% iPrMgCI in THF, molar ratio LiCI : iPrMgCI = 0,9 – 1 .1 mol/mol) (472kg) at -21 to -15°C temperature within 1 hr 50 min. On completion of the addition the conversion is determined via HPLC analysis. The reaction is regarded as completed when the area of the peak corresponding to the iodide V.1 is smaller than 5,0% of the total area of both peaks, iodide V.1 and the corresponding desiodo compound of iodide V.1 . If the reaction is not completed, additional Turbogrignard solution is added until the criterion is met. In this particular case the result is 3,45%. Then the lactone IV.1 (320kg) is added at -25 to -18°C temperature within 1 hr 25 min. The resulting mixture is stirred for further 1 hr 30 min at -13 to -18°C. On completion the conversion is determined via HPLC analysis (for information). On completion, a solution of citric acid in water (938L; concentration: 10 %-weight) is added to the reaction mixture of a volume of about 2500L at -13 to 19°C within 1 hr 25 min.
The solvent is partially distilled off from the reaction mixture (residual volume: 1816-1905L) at 20 to 30°C under reduced pressure and 2-methyltetrahydrofuran (532kg) is added. Then the stirrer is switched off and the phases are separated at 29°C. After phase separation the pH value of the organic phase is measured with a pH electrode (Mettler Toledo MT HA 405 DPA SC) or alternatively with pH indicator paper (such as pH-Fix 0-14, Macherey and Nagel). The measured pH value is 2 to 3. Then solvent is distilled off from the organic phase at 30 to 33°C under reduced pressure and methanol (1202kg) is added followed by the addition of a solution of 1 ,25N HCI in methanol (75kg) at 20°C (pH = 0). Full conversion to the acetale 111.1 is achieved by subsequent distillation at 20 to 32°C under reduced pressure and addition of methanol (409kg).
Completion of the reaction is obtained when two criteria are fulfilled:
1 ) The ratio of the sum of the HPLC-area of the alpha-form + beta-form of intermediate 111.1 relative to the area of intermediate llla.1 is greater or equal to 96,0% : 4,0%. 2) The ratio of the HPLC-area of the alpha-form of intermediate 111.1 to the beta-form of 111.1 is greater or equal to 97,0% to 3,0%.
In this particular case both criteria are met. Triethylamin (14kg) is added (pH = 7,4) and solvent is distilled off under reduced pressure, acetonitrile (835kg) is added and further distilled under reduced pressure. This procedure is repeated (addition of acetonitrile: 694kg) and methylene chloride (640kg) is added to the resulting mixture to yield a mixture of the acetale 111.1 in acetonitrile and methylene chloride. The water content of the mixture is determined via Karl Fischer titration (result: 0,27%).
The reaction mixture is then added within 1 hr 40 min at 10 to 19°C to a preformed mixture of AICI3 (176kg), methylene chloride (474kg), acetonitrile (340kg), and triethylsilane (205kg). The resulting mixture is stirred at 18 to 20°C for 70 min. After completion of the reaction, water (1263L) is added at 20 to 30°C within 1 hr 30 min and the mixture is partially distilled at 30 to 53°C under atmospheric pressure and the phases are separated. Toluene (698kg) is added to the organic phase and solvent is distilled off under reduced pressure at 22 to 33°C. The product is then crystallized by addition of seeding crystals (0,5kg) at 31 °C and water (267kg) added after cooling to 20°C. The reaction mixture is cooled to 5°C within 55 min and stirred at 3 to 5°C for 12 hrs. Finally the product is collected on a centrifuge as colourless, crystalline solid, washed with toluene (348kg) and dried at 22 to 58°C. 21 1 kg (73%) of product are obtained. The identity of the product is determined via the HPLC retention time.
Example 5b: Synthesis of the glucoside 11.1
To a solution of the iodide V.1 (30g) in tetrahydrofuran (55ml_) is added Turbogrignard solution (isopropylmagnesium chloride/lithium chloride solution, 14 weight-% iPrMgCI in THF, molar ratio LiCI : iPrMgCI = 0,9 – 1 .1 mol/mol) (53g) at -14 to -13°C temperature within 35 min. On completion of the addition the conversion is determined via HPLC analysis. The reaction is regarded as completed when the area of the peak corresponding to the iodide V.1 is smaller than 5,0% of the total area of both peaks, iodide V.1 and the corresponding desiodo compound of iodide V.1 . If the reaction is not completed, additional Turbogrignard solution is added until the criterion is met. In this particular case the result is 0,35%. Then the lactone IV.1 (36g) is added at -15 to -6°C temperature within 15 min. The resulting mixture is stirred for further 1 hr at -6 to -7°C. On completion, the conversion is determined via HPLC analysis (for information). On completion, a solution of citric acid in water (105mL;
concentration: 10 %-weight) is added to the reaction mixture at -15 to 10°C within 30 min. The solvent is partially distilled off from the reaction mixture (residual volume: 200mL) at 20 to 35°C under reduced pressure and 2-methyltetrahydrofuran (71 mL) is added. Then the mixture is stirred for 25min at 30°C. Then the stirrer is switched off and the phases are separated at 30°C. After phase separation the pH value of the organic phase is measured with a pH electrode (Mettler Toledo MT HA 405 DPA SC) or alternatively with pH indicator paper (such as pH-Fix 0-14, Macherey and Nagel). The measured pH value is 3. Then solvent is distilled off from the organic phase at 35°C under reduced pressure and methanol (126ml_) is added followed by the addition of a solution of 1 ,25N HCI in methanol (10,1 ml_) at 25°C (pH = 1 -2). Full conversion to the acetale 111.1 is achieved by subsequent distillation at 35°C under reduced pressure and addition of methanol (47ml_).
Completion of the reaction is obtained when two criteria are fulfilled:
1 ) The ratio of the sum of the HPLC-area of the alpha-form + beta-form of intermediate 111.1 relative to the area of intermediate llla.1 is greater or equal to 96,0% : 4,0%. In this particular case the ratio is 99,6% : 0,43%.
2) The ratio of the HPLC-area of the alpha-form of intermediate 111.1 to the beta-form of III.1 is greater or equal to 97,0% to 3,0%. In this particular case the ratio is 98,7% : 1 ,3%.
Triethylamin (2,1 mL) is added (pH = 9) and solvent is distilled off at 35°C under reduced pressure, acetonitrile (120ml_) is added and further distilled under reduced pressure at 30 to 35°C. This procedure is repeated (addition of acetonitrile: 102ml_) and methylene chloride (55ml_) is added to the resulting mixture to yield a mixture of the acetale 111.1 in acetonitrile and methylene chloride. The water content of the mixture is determined via Karl Fischer titration (result: 0,04%).
The reaction mixture is then added within 1 hr 5 min at 20°C to a preformed mixture of AICI3 (19,8g), methylene chloride (49ml_), acetonitrile (51 mL), and triethylsilane (23g). The resulting mixture is stirred at 20 to 30°C for 60 min. After completion of the reaction, water (156mL) is added at 20°C within 25 min and the mixture is partially distilled at 55°C under atmospheric pressure and the phases are separated at 33°C. The mixture is heated to 43°C and toluene (90mL) is added and solvent is distilled off under reduced pressure at 41 to 43°C. Then acetonitrile (1 OmL) is added at 41 °C and the percentage of acetonitrile is determined via GC measurement. In this particular case, the acetonitrile percentage is 27%- weight. The product is then crystallized by addition of seeding crystals (0,1 g) at 44°C and the mixture is further stirred at 44°C for 15min. The mixture is then cooled to 20°C within 60min and water (142mL) is added at 20°C within 30min. The reaction mixture is cooled to 0 to 5°C within 60 min and stirred at 3°C for 16 hrs. Finally the product is collected on a filter as colourless, crystalline solid, washed with toluene (80mL) and dried at 20 to 70°C. 20, 4g (62,6%) of product are obtained. The identity of the product is determined via the HPLC retention time.
- Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P (January 2012). “Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors”. Diabetes Obes Metab 14 (1): 83–90. doi:10.1111/j.1463-1326.2011.01517.x. PMID 21985634.
- “Empagliflozin”. clinicaltrials.gov. U.S. National Institutes of Health. Retrieved 22 September 2012.
- Nair S, Wilding JP (January 2010). “Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus”. J. Clin. Endocrinol. Metab. 95 (1): 34–42. doi:10.1210/jc.2009-0473. PMID 19892839.
- Bays H (March 2009). “From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus”. Curr Med Res Opin25 (3): 671–81. doi:10.1185/03007990802710422. PMID 19232040.
- Abdul-Ghani MA, DeFronzo RA (September 2008). “Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus”. Endocr Pract 14 (6): 782–90. PMID 18996802.
[1]. Grempler R, Thomas L, Eckhardt M et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012 Jan;14(1):83-90.
Abstract
AIMS: Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed pharmacological properties of empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors. METHODS: [(14)C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [(14)C]-mannose and [(14)C]-myo-inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with [(3)H]-labelled empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker diabetic fatty (ZDF) rats. RESULTS: Empagliflozin has an IC(50) of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approximately 1 h). Compared with other SGLT-2 inhibitors, empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high. CONCLUSIONS: Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes.
[2]. Thomas L, Grempler R, Eckhardt M et al. Long-term treatment with empagliflozin, a novel, potent and selective SGLT-2 inhibitor, improves glycaemic control and features of metabolic syndrome in diabetic rats. Diabetes Obes Metab. 2012 Jan;14(1):94-6.
Abstract
Empagliflozin is a potent, selective sodium glucose co-transporter-2 inhibitor that is in development for the treatment of type 2 diabetes. This series of studies was conducted to assess the in vivo pharmacological effects of single or multiple doses of empagliflozin in Zucker diabetic fatty rats. Single doses of empagliflozin resulted in dose-dependent increases in urinary glucose excretion and reductions in blood glucose levels. After multiple doses (5 weeks), fasting blood glucose levels were reduced by 26 and 39% with 1 and 3 mg/kg empagliflozin, respectively, relative to vehicle. After 5 weeks, HbA1c levels were reduced (from a baseline of 7.9%) by 0.3 and 1.1% with 1 and 3 mg/kg empagliflozin, respectively, versus an increase of 1.1% with vehicle. Hyperinsulinaemic-euglycaemic clamp indicated improved insulin sensitivity with empagliflozin after multiple doses versus vehicle. These findings support the development of empagliflozin for the treatment of type 2 diabetes.
[3]. Luippold G, Klein T, Mark M, Grempler R. Empagliflozin, a novel potent and selective SGLT-2 inhibitor, improves glycaemic control alone and in combination with insulin in streptozotocin-induced diabetic rats, a model of type 1 diabetes mellitus. Diabetes Obes Metab. 2012 Jul;14(7):601-7.
Abstract
AIM: Sodium glucose cotransporter-2 (SGLT-2) is key to reabsorption of glucose in the kidney. SGLT-2 inhibitors are in clinical development for treatment of type 2 diabetes mellitus (T2DM). The mechanism may be of value also in the treatment of type 1 diabetes mellitus (T1DM). This study investigated effects of the SGLT-2 inhibitor, empagliflozin, alone and in combination with insulin, on glucose homeostasis in an animal model of T1DM. METHODS: Sprague-Dawley rats were administered a single intraperitoneal injection of streptozotocin (STZ; 60 mg/kg). Acutely, STZ rats received two doses of insulin glargine with or without empagliflozin, and blood glucose was measured. In a subchronic study, STZ rats received empagliflozin alone, one or two insulin-releasing implants or a combination of one implant and empagliflozin over 28 days; blood glucose and HbA(1c) were measured. RESULTS: In the acute setting, empagliflozin in combination with 1.5 IU insulin induced a similar glucose-lowering effect as 6 IU insulin. Both interventions were more efficacious than monotherapy with 1.5 IU insulin. In the subchronic study, 12-h blood glucose profile on day 28 in the combination group was lower than with one implant, and similar to two implants. Plasma HbA(1c) was improved in the combination group and in animals with two implants. CONCLUSIONS: Empagliflozin reduced blood glucose levels in a T1DM animal model. Empagliflozin combined with low-dose insulin showed comparable glucose-lowering efficacy to treatment with high-dose insulin. Our data suggest that empagliflozin is an efficacious adjunctive-to-insulin therapy with the clinical potential for the treatment of T1DM.
[4]. Macha S, Rose P, Mattheus M et al. Lack of drug-drug interaction between empagliflozin, a sodium glucose cotransporter-2 inhibitor, and warfarin in healthy volunteers. Diabetes Obes Metab. 2012 Oct 24. doi: 10.1111/dom.12028. [Epub ahead of print]
Abstract
AIM: To investigate potential drug-drug interactions between empagliflozin and warfarin. MATERIALS AND METHODS: Healthy subjects (n=18) received empagliflozin 25 mg qd for 5 days (treatment A), followed by empagliflozin 25 mg qd for 7 days (days 6-12) with a single 25 mg dose of warfarin on day 6 (B), and a single 25 mg dose of warfarin alone (C), in an open-label, crossover study. Subjects received treatments in sequence AB_C or C_AB with a washout period of ≥14 days between AB and C or C and AB. RESULTS: Warfarin had no effect on empagliflozin area under concentration-time curve or maximum plasma concentration at steady-state (AUC(τ) (,ss) or C(max,ss) ): geometric mean ratios (GMRs) (90% confidence intervals [CI]) were 100.89% (96.86, 105.10) and 100.64% (89.79, 112.80), respectively. Empagliflozin had no effect on AUC from 0 hours to infinity (AUC(0) (-∞) ) or C(max) for R-warfarin or S-warfarin (GMRs [90% CI] for AUC(0) (-∞) : 98.49% [95.29, 101.80] and 95.88% [93.40, 98.43], respectively; C(max) : 97.89% [91.12, 105.15] and 98.88% [91.84, 106.47], respectively). Empagliflozin had no clinically relevant effects on warfarin’s anticoagulant activity (international normalised ratio [INR]) (GMR [95% CI] for peak INR: 0.87 [0.73, 1.04]; area under the effect-time curve from 0 to 168 hours: 0.88 [0.79, 0.98]. No drug-related adverse events were reported for empagliflozin after monotherapy or combined administration. The combination of empagliflozin and warfarin was well tolerated. CONCLUSIONS: No drug-drug interactions were observed between empagliflozin and warfarin, indicating that empagliflozin and warfarin can be co-administered without dosage adjustments of either drug.
[5]. Sarashina A, Koiwai K, Seman LJ et al. Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of Empagliflozin, a Sodium Glucose Cotransporter-2 (SGLT-2) Inhibitor, in Healthy Japanese Subjects. Drug Metab Pharmacokinet. 2012 Nov 13. [Epub ahead of print]
Abstract
This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 hours; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 hours. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 hours following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose-proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with placebo, and increased with empagliflozin dose.
…………………………….
formula A
Example I
(5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone
38.3 ml oxalyl chloride and 0.8 ml of dimethylformamide are added to a mixture of
100 g of 5-bromo-2-chloro-benzoic acid in 500 ml dichloromethane. The reaction mixture is stirred for 14 h, then filtered and separated from all volatile constituents in the rotary evaporator. The residue is dissolved in 150 ml dichloromethane, the solution is cooled to -5 0C, and 46.5 g of anisole are added. Then 51.5 g of aluminum trichloride are added batchwise so that the temperature does not exceed 5 0C. The solution is stirred for another 1 h at 1 to 5 0C and then poured onto crushed ice. The organic phase is separated, and the aqueous phase is extracted another three times with dichloromethane. The combined organic phases are washed with aqueous 1 M hydrochloric acid, twice with aqueous 1 M sodium hydroxide solution and with brine. Then the organic phase is dried, the solvent is removed and the residue is recrystallised in ethanol. Yield: 86.3 g (64% of theory)
Mass spectrum (ESI+): m/z = 325/327/329 (Br+CI) [M+H]+
Example Il
4-bromo-1-chloro-2-(4-methoxy-benzyl)-benzene
A solution of 86.2 g (5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone and 101.5 ml triethylsilane in 75 ml dichloromethane and 150 ml acetonitrile is cooled to 1O0C. Then with stirring 50.8 ml of boron trifluoride etherate are added so that the temperature does not exceed 2O0C. The solution is stirred for 14 h at ambient temperature, before another 9 ml triethylsilane and 4.4 ml boron trifluoride etherate are added. The solution is stirred for a further 3 h at 45 to 5O0C and then cooled to ambient temperature. A solution of 28 g potassium hydroxide in 70 ml of water is added, and the resulting mixture is stirred for 2 h. Then the organic phase is separated off and the aqueous phase is extracted another three times with diisopropylether. The combined organic phases are washed twice with aqueous 2 M potassium hydroxide solution and once with brine and then dried over sodium sulfate. After the solvent has been removed the residue is washed in ethanol, separated again and dried at 6O0C. Yield: 50.0 g (61 % of theory)
Mass spectrum (ESI+): m/z = 310/312/314 (Br+CI) [M+H]+
Example III
4-(5-bromo-2-chloro-benzyl)-phenol
A solution of 14.8 g 4-bromo-1-chloro-2-(4-methoxy-benzyl)-benzene in 150 ml dichloromethane is cooled in an ice bath. Then 50 ml of a 1 M solution of boron tribromide in dichloromethane are added, and the solution is stirred for 2 h at ambient temperature. The solution is then cooled in an ice bath again, and saturated aqueous potassium carbonate solution is added dropwise. At ambient temperature the mixture is adjusted with aqueous 1 M hydrochloric acid to a pH of 1 , the organic phase is separated, and the aqueous phase is extracted another three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, and the solvent is removed completely. Yield: 13.9 g (98% of theory) Mass spectrum (ESI ): m/z = 295/297/299 (Br+CI) [M-HV
Example IV
r4-(5-bromo-2-chloro-benzyl)-phenoxyl-tert-butyl-dimethyl-silane
A solution of 13.9 g 4-(5-bromo-2-chloro-benzyl)-phenol in 140 ml dichloromethane is cooled in an ice bath. Then 7.54 g tert-butyldimethylsilylchlorid in 20 ml dichloromethane are added followed by 9.8 ml triethylamine and 0.5 g 4- dimethylaminopyridine. The solution is stirred for 16 h at ambient temperature and then diluted with 100 ml dichloromethane. The organic phase is washed twice with aqueous 1 M hydrochloric acid and once with aqueous sodium hydrogen carbonate solution and then dried over sodium sulfate. After the solvent has been removed the residue is filtered through silica gel (cyclohexane/ethyl acetate 100:1 ). Yield: 16.8 g (87% of theory) Mass spectrum (El): m/z = 410/412/414 (Br+CI) [M]+
Example V
2.3.4.6-tetrakis-O-(trimethylsilyl)-D-glucopyranone
A solution of 20 g D-glucono-1 ,5-lactone and 98.5 ml Λ/-methylmorpholine in 200 ml of tetrahydrofuran is cooled to -5 0C. Then 85 ml trimethylsilylchloride are added dropwise so that the temperature does not exceed 5 0C. The solution is then stirred for 1 h at ambient temperature, 5 h at 35 0C and again for 14 h at ambient temperature. After the addition of 300 ml of toluene the solution is cooled in an ice bath, and 500 ml of water are added so that the temperature does not exceed 100C. The organic phase is then separated and washed in each case once with aqueous sodium dihydrogen phosphate solution, water and brine. The solvent is removed, the residue is taken up in 250 ml of toluene, and the solvent is again removed completely. Yield: 52.5 g (approx. 90% pure)
Mass spectrum (ESI+): m/z = 467 [M+H]+
Example Vl
1-chloro-4-(β-D-qlucopyranos-1-yl)-2-(4-hvdroxybenzyl)-benzene
A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-te/Tf-butyl-dimethyl-silane in 42 ml dry diethyl ether is cooled to -800C under argon. 11.6 ml of a 1.7 M solution of te/if-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80 0C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g
2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethyl ether chilled to – 80 0C. The resulting solution is stirred for 3 h at -78 0C. Then a solution of 1.1 ml methanesulphonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralised with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution, and the resulting mixture is extracted four times with ethyl acetate. The organic phases are dried over sodium sulphate and evaporated down. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane and the solution is cooled to -10 0C. After the addition of 4.4 ml triethylsilane 2.6 ml boron trifluoride etherate are added dropwise so that the temperature does not exceed -5 0C. After the addition is complete the solution is stirred for another 5 h at -5 to -10 0C and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated, and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed, and the residue is purified by chromatography on silica gel (dichoromethane/methanol 1 :0->3:1 ). The product then obtained is an approx. 6:1 mixture of β/α which can be converted into the pure β-anomer by global acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallization of the product from ethanol. The product thus obtained is converted into the title compound by deacetylation in methanol with aqueous 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory)
Mass spectrum (ESI+): m/z = 398/400 (Cl) [M+H]+
Preparation of the compound A:
1-chloro-4-(β-D-qlucopyranos-1-yl)-2-r4-(<fS)-tetrahvdrofuran-3-yloxy)-benzyll- benzene
0.19 g (f?)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran are added to a mixture of 0.20 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.29 g cesium carbonate in 2.5 ml dimethylformamide. The mixture is stirred at 75 0C for 4 h, before another 0.29 g caesium carbonate and 0.19 g (f?)-3-(4-methylphenyl- sulfonyloxy)-tetrahydrofuran are added. After an additional 14 h stirring at 75 0C the mixture is cooled to ambient temperature and brine is added. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1 :0 -> 5:1 ). Yield: 0.12 g (49% of theory) Mass spectrum (ESI+): m/z = 451/453 (Cl) [M+H] +
TOFOGLIFLOZIN » All About Drugs
TOFOGLIFLOZIN » All About Drugs
CLICK ABOVE for full article
ALSO same article at
SEE……..http://apisynthesisint.blogspot.in/2015/12/tofogliflozin.html
SEE ALL FLOZINS AT
EG, Dapagliflozin, canagliflozin and all
http://medcheminternational.blogspot.in/p/flozin-series.html
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
Dapagliflozin propanediol is a solvate containing 1:1:1 ratio of the dapagliflozin, (S)-(+)-1,2-propanediol, and water.
US——-In 2011, the product was not recommended for approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. In 2011, the FDA assigned a complete response letter to the application. A new application was resubmitted in 2013 by Bristol-Myers Squibb and AstraZeneca in the U.S
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.
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
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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]
- Statement on a nonproprietory name adopted by the USAN council
- Efficacy and Safety of Dapagliflozin, Added to Therapy of Patients With Type 2 Diabetes With Inadequate Glycemic Control on Insulin, ClinicalTrials.gov, April 2009
- Trial Details for Trial MB102-020, Bristol-Myers Squibb, May 2009
- “FDA panel advises against approval of dapagliflozin”. 19 July 2011.
- Prous Science: Molecule of the Month November 2007
- UEndocrine: Internet Endocrinology Community
- Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2008/2009
- more1) Pal, Manojit et al; Improved Process for the preparation of SGLT2 inhibitor dapagliflozin via glycosylation of 5-bromo-2-Chloro-4′-ethoxydiphenylmethane with Gluconolactone ;. Indian Pat Appl,. 2010CH03942 , 19 Oct 20122) Lemaire, Sebastien et al; Stereoselective C-Glycosylation Reactions with Arylzinc Reagents ;Organic Letters , 2012, 14 (6), 1480-1483;3) Zhuo, Biqin and Xing, Xijuan; Process for preparation of Dapagliflozin amino acid cocrystals ;Faming Zhuanli Shenqing , 102 167 715, 31 Aug 20114) Shao, Hua et al; Total synthesis of SGLT2 inhibitor Dapagliflozin ; Hecheng Huaxue , 18 (3), 389-392; 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 .
formula 1
WO 03/099836 A1 discloses a route of synthesis on pages 8-10, whereby one major step is the purification of a compound of formula 2
formula 2
The compound of formula 2 provides a means of purification for providing a compound of formula 1 since it crystallizes. Subsequently the crystalline form of the compound of formula 2 can be deprotected and converted to dapagliflozin. Using this process, dapagliflozin is obtained as an amorphous glassy off-white solid containing 0.1 1 mol% of EtOAc. Crystallization of a pharmaceutical drug is usually advantageous as it provides means for purification also suitable for industrial scale preparation. However, for providing an active pharmaceutical drug a very high purity is required. In particular, organic impurities such as EtOAc either need to be avoided or further purification steps are needed to provide the drug in a
pharmaceutically acceptable form, i.e. substantially free of organic solvents. Thus, there is the need in the art to obtain pure and crystalline dapagliflozinwhich is substantially free of organic solvents.
WO 2008/002824 A1 discloses several alternative solid forms of dapagliflozin, such as e.g. solvates containing organic alcohols or co-crystals with amino acids such as proline and phenylalanine. For instance, the document discloses crystalline
dapagliflozin solvates which additionally contain water molecules (see e.g.
Examples 3-6), but is silent about solid forms of dapagliflozin which do not contain impurities such as organic alcohols. As described above, it is desirable to provide the pharmaceutical active drug in a substantially pure form, otherwise triggering further expensive and time-consuming purification steps. In contrast, the document relates to dapagliflozin solvates where an alcohol and water are both incorporated into the crystal lattice. Hence, there is the need in the art to obtain pure and crystalline dapagliflozin suitable for pharmaceutical production.
WO 2008/1 16179 A1 refers to an immediate release pharmaceutical composition comprising dapagliflozin and propylene glycol. Propylene glycol is a chiral
substance and (S)-propylene glycol used is very expensive. Consequently, also the immediate release pharmaceutical composition is more expensive.
Crystalline forms (in comparision to the amorphous form) often show desired different physical and/or biological characteristics which may assist in the manufacture or formulation of the active compound, to the purity levels and uniformity required for regulatory approval. As described above, it is desirable to provide the pharmaceutical active drug in a substantially pure form, otherwise triggering further expensive and time-consuming purification steps.
…..
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.
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
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 ……………………..
……..
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).
Perampanel
Perampanel
5′-(2-cyanophenyl)-1′-phenyl-2,3′-bipyridinyl-6′(1’H)-one
cas no 380917-97-5
FDA-approved drug to treat epilepsy. Trade name Fycompa, Eisai (Eisai) research and development.
FYCOMPA tablets contain perampanel, a non-competitive AMPA receptorantagonist. Perampanel is described chemically as 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile hydrate (4:3).
The molecular formula is C23H15N3O •3/4H2O and the molecular weight is 362.90 (3/4 hydrate). The chemical structure of perampanel is:
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Perampanel is a white to yellowish white powder. It is freely soluble in N-methylpyrrolidone, sparingly soluble in acetonitrile and acetone, slightly soluble in methanol, ethanol and ethyl acetate, very slightly soluble in 1-octanol and diethyl ether and practically insoluble in heptane and water.
Perampanel (INN/USAN, trade name Fycompa) is an antiepileptic drug developed by Eisai Co. that acts as a selective noncompetitive antagonist of AMPA receptors, the major subtype of ionotropic glutamate receptors.[1][2]
Perampanel was found to be effective in the treatment of refractory partial-onset seizures in three pivotal (Phase 3) clinical trials[3][4] and has been approved for marketing under the brand name Fycompa by the European Medicines Agency.[5] The minimum effective dose is 4 mg once daily; doses of 8 mg and 12 mg daily provide a greater therapeutic benefit with a corresponding increase in adverse events. Dizziness and somnolence/sedation/fatigue are the most frequent dose-related adverse events. The drug is currently approved, for the control of partial-onset seizures, in those of both sexes who suffer from epilepsy and who are 12 years of age and older, by the Food and Drug Administration, and is considered to be a scheduled drug (an agent with the potential for addiction). Perampanel has been studied in other clinical indications includingParkinson’s disease.[6][7]
It has high potency (IC50 in vitro in functional studies of about 100-250 nM) and a prolonged terminal half-life in humans of approximately 105 hours. The drug is 95% bound to plasma protein. Its primary route of metabolism is by CYP3A4. It does not induce or inhibit P450 enzymes. About 70% of the dose is excreted in the feces and 30% in the urine; less than 2% of the dose is excreted unchanged into the urine.
In clinical trials, perampanel was generally well tolerated although the incidence of adverse events increased in a dose-dependent fashion. There was no increase in serious adverse events compared with placebo. According to the Food and Drug Administration, most common adverse reactions reported by patients receiving Fycompa in clinical trials include dizziness, drowsiness, fatigue, irritability, falls, upper respiratory tract infection,weight increase, vertigo, loss of muscle coordination (ataxia), gait disturbance, balance disorder, anxiety, blurred vision, stuttering (dysarthria), weakness (asthenia), aggression, and excessive sleep (hypersomnia).[8]
Fycompa’s label has a boxed warning to alert prescribers and patients about the risk of serious neuropsychiatric events. Some of these events were reported as serious and life-threatening. Violent thoughts or threatening behavior (including homicidal ideation) was also observed in a few patients. Patients and caregivers should alert a health care professional immediately if changes in mood or behavior that are not typical for the patient are observed. Health care professionals should closely monitor patients during the titration period when higher doses are used.[9]
- Rogawski, M. A. (2011). “Revisiting AMPA Receptors as an Antiepileptic Drug Target”. Epilepsy Currents 11 (2): 56–63. doi:10.5698/1535-7511-11.2.56. PMC 3117497. PMID 21686307. edit
- Rogawski MA, Hanada T. Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand 2013;127 (Suppl. 197): 19–24.Rogawski, M. A.; Kaukinen, T.; Collin, P.; Krekelä, I.; Patrikainen, H.; Tillonen, J.; Nyrke, T.; Laurila, K.; Haimila, K.; Partanen, J.; Valve, R.; Mäki, M.; Luostarinen, L. (2013). “Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist”. Acta Neurologica Scandinavica 127 (1): 19–25. doi:10.1111/ane.12100. PMID 22494246. edit
- Krauss, G. L.; Serratosa, J. M.; Villanueva, V.; Endziniene, M.; Hong, Z.; French, J.; Yang, H.; Squillacote, D.; Edwards, H. B.; Zhu, J.; Laurenza, A. (2012). “Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures”. Neurology 78 (18): 1408–1415.doi:10.1212/WNL.0b013e318254473a. PMID 22517103. edit
- French, J. A.; Krauss, G. L.; Biton, V.; Squillacote, D.; Yang, H.; Laurenza, A.; Kumar, D.; Rogawski, M. A.; Campanille, V.; Floridia, J.; Ilari, R.; Consalvo, D. E.; Thomson, A.; Sfaello, I.; Pociecha, J.; Nieto, F.; Firstenfeld, A.; Zuin, D.; Mesri, J.; Silva, W.; Nofal, P.; Cristalli, D.; Clement, J. F.; Hwang, P.; McLachlan, R.; Pillay, N.; Lasso, J.; Peralta, B. L.; Hernandez, M. L.; Tenhamm, E. (2012). “Adjunctive perampanel for refractory partial-onset seizures: Randomized phase III study 304”. Neurology 79 (6): 589–596. doi:10.1212/WNL.0b013e3182635735. PMC 3413761. PMID 22843280. edit
- “European Medicines Agency Report on Perampanel”.
- Gottwald MD, Aminoff MJ (July 2008). “New frontiers in the pharmacological management of Parkinson’s disease”. Drugs Today 44 (7): 531–45.doi:10.1358/dot.2008.44.7.1217105. PMID 18806903.
- http://www.webmd.com/epilepsy/news/20121024/epilepsy-drug-fycompa-approved
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm325038.htm
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm325038.htm
Perampanel structure is formed by the coupling of an aromatic ring . Pyridone centrally located, surrounded by connecting two benzene rings and a pyridine ring. The synthesis of 2,5 – dibromopyridine (1) Start with sodium methoxide to produce 2-substituted, and an organic tin compound occurs Stille Coupling 3 4 4 HBr generated after acid hydrolysis and coupling of benzyl bromide with NBS to give 5,5. After 6 coupling of boronic ester and get Perampanel.
Perampanel is a pharmaceutically active agent, currently in clinical phase 3. It can be used to treat Parkinson’s disease, epilepsy and multiple sclerosis.
Perampanel, having the following chemical formula
is also known as E 2007, ER 155055-90 and 3-(2-cyanophenyl)-1-phenyl-5-(2-pyridil)-1,2-dihydropyridin-2-one
Various methods of synthesis of such molecules are known, such as those reported in EP1300396, EP 1465626, EP 1772450, EP 1764361 and EP 1970370.
Many of the methods of synthesis of such active substances reported by the prior art use the key intermediate 5-(2-pyridil)-1,2-dihydropyridin-2-one also known as 2,3′-bipyridin-6′(1′H)-one having the following chemical formula:
Other methods use the synthetic precursor of this intermediate known as 2-methoxy-5-(pyridin-2-yl)pyridine or 6′-methoxy-2,3′-bipyridine having the formula:
2,3′-bipyridin-6′(1′H)-one. it is in fact prepared by simple acid-catalysed demethylation of the 6′-methoxy-2,3′-bipyridine as is reported in the prior art.
Various ways of synthesising 2-methoxy-5-(pyridin-2-yl)pyridine are known. The process summarised in Diagram (I) below is described in WO 2001096308:
Such process highlights clear disadvantages such as the need to operate in cryogenic conditions (T=−78° C.) using special equipment and the need to isolate boronic acid via work-up. In addition the use of 2-Bromopyridine is required, which exacerbates the production of waste compared to 2-chloropyridine.
Another process described in WO 2004009553 is summarised in Diagram (II):
Disadvantages of this process include the use of high molecular weight benzene-sulfonyl pyridine entailing a scarce atom-economy of the process and the need to operate at low temperature T (−78° C.) using special equipment.
Lastly, a completely different process is described in WO20087093392 for the preparation of 2,3′-bipyridin-6′(1′H)-one (Diagram (III)) which however does not include the preparation of the intermediate precursor 2-methoxy-5-(pyridin-2-yl)pyridine:
Perampanel and other 1 ,2-dihydropyridine compounds which possess antagonistic action against AMPA receptor and/or inhibitory action against kainate receptor are described in WO 01/96308. Example 7 in WO 01/96308 discloses a process for producing perampanel by reacting 3-(2-cyanophenyl)-5-(2-pyridyl)-2(lH)-pyridone with phenyl boronic acid, copper acetate and triethylamine in methylene chloride, followed by addition of concentrated aqueous ammonia, water and ethyl acetate. After work-up (phase separation, washing the organic phase and drying over magnesium sulfate), the solvent was concentrated in vacuo and the residue was purified by a silica gel column chromatography (ethyl acetate:hexane=l :2) to give the title product as pale yellow powder. There is no disclosure regarding the polymorphic nature of the product.
A new crystalline or amorphous form of a compound may possess physical properties that differ from, and are advantageous over, those of other crystalline or amorphous forms. These include, packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and filtration properties. Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use.
EP 1764361 (US 2010/324297) discloses three anhydrous crystalline forms ofperampanel, designated Form I, Form III and Form V and a hydrate form ofperampanel. Anhydrous Form I is prepared in accordance with Example Dl by dissolving perampanel in ethyl acetate (EtOAc) under reflux, cooling the solution, seeding with anhydrous perampanel crystals, continued cooling and collecting the precipitated crystals. Anhydrous Form V is prepared in accordance with Example CI, by dissolving perampanel in acetone, heating to reflux and concentrating the solution to solidification, dissolving the solids in acetone-water, refluxing then cooling and collecting the precipitate. The hydrate form is prepared in accordance with Example Bl by dissolving perampanel in acetone-water, heating, cooling the solution, seeding with perampanel hydrate crystals, continued cooling and collecting the precipitated crystals. US 2009/0088574 discloses a crystalline form of perampanel designated Form IV, which is prepared by slurring perampanel in an acetone/water mixture.
US 7,803,818 discloses an amorphous form of perampanel which is prepared by spray drying perampanel from an acetone solution.
US 7,718,807 discloses acid addition salts of perampanel or a hydrate thereof, wherein the acid is selected from the group consisting of benzenesulfonic acid, p- toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, fumaric acid, tartaric acid, succinic acid and benzoic acid.
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Perampanel aromatic ring structure is made of highly coupled. Pyridone centrally located, surrounded by connecting two benzene ring and a pyridine ring. The synthesis of 2,5 – dibromo pyridine ( 1) Start (Synthesis, 2012, 57), sodium methoxide instead of generating 2 , and organotin compounds 3 Stille Coupling occurs to generate 4 . 4 in HBr phenylboronic acid after hydrolysis and coupling to get 5 , 5 after bromination with NBS and borate 6 coupled to get Perampanel.
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A Practical, Laboratory-Scale Synthesis of Perampanel
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updated info
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Perampanel is a pharmaceutical active substance, currently in clinical phase 3, used to treat Parkinson’s disease, epilepsy and multiple sclerosis.
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[0003]Perampanel, having the following chemical formula
is also known as E 2007, ER 155055-90 and 3-(2-cyanophenyl)-1-phenyl-5-(2-pyridil)-1,2-dihydropyridin-2-one
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[0004]Various methods of synthesis of such molecule are known, such as those reported in the patent publications EP1300396 , EP1465626 ,EP1772450 , EP1764361 and EP 1970370 .
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[0005]Many of the methods of synthesis of such active substance reported by the prior art use the key intermediate 5-(2-pyridil)-1,2-dihydropyridin-2-one also known as 2,3′-bipyridin-6′(1’H)-one having the following chemical formula:
or use the synthetic precursor thereof named 2-methoxy-5-(pyridin-2-yl)pyridine or 6′-methoxy-2,3′-bipyridine having the formula:
2,3′-bipyridin-6′(1’H)-one is in fact prepared by simple acid-catalysed demethylation of the 6′-methoxy-2,3′-bipyridine as thoroughly reported in the prior art.
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[0006]Various ways of synthesising 2-methoxy-5-(pyridin-2-yl)pyridine are known. The process summarised in the diagram (I) below is described in the publication WO 2001096308 :
Diagram (I)
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[0007]
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[0008]Such process highlights clear disadvantages such as the need to operate in cryogenic conditions (T=-78°C) using special equipment and the need to isolate the boronic acid via work-up; in addition the use of 2-Bromopyridine is envisaged, which is less convenient as regards the production of waste compared to 2-chloropyridine.
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[0009]Another process described in WO 2004009553 is summarised in the diagram (II) :
Diagram (II)
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[0010]
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[0011]It presents clear disadvantages such as the use of high molecular weight benzenesulfonyl pyridine entailing a scarce atom-economy of the process and the need to operate at low temperature T (-78°C) using special equipment.
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[0012]Lastly, a completely different process is described in WO20087093392for the preparation of 2,3′-bipyridin-6′(1’H)-one which however does not include the preparation of the intermediate precursor named 2-methoxy-5-(pyridin-2-yl)pyridine, process shown in the diagram (III) :
diagram (III)
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[0013]
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