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FDA Accepts Eliquis sNDA
FDA Accepts For Review ELIQUIS® (apixaban) Supplemental New Drug Application for the Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), and for the Reduction in the Risk of Recurrent DVT and PE
PRINCETON, N.J. & NEW YORK, December 19, 2013–(BUSINESS WIRE)–Bristol-Myers Squibb Company (NYSE:BMY) and Pfizer Inc. (NYSE:PFE) today announced that the U.S. Food and Drug Administration (FDA) has accepted for review a Supplemental New Drug Application (sNDA) for ELIQUIS® (apixaban) for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the reduction in the risk of recurrent DVT and PE. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is August 25, 2014.
MARAVIROC
MARAVIROC
UK-427857; Selzentry; Celsentri
376348-65-1 CAS NO
Maraviroc M.Wt: 513.67
Maraviroc Formula: C29H41F2N5O
Maraviroc (brand-named Selzentry, or Celsentri outside the U.S.) is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor. It also appeared to reduce graft-versus-host disease in patients treated withallogeneic bone marrow transplantation for leukemia, in a phase 1/2 study.[3][4]
Maraviroc is an entry inhibitor. Specifically, maraviroc is a negative allosteric modulator of the CCR5 receptor, which is found on the surface of certain human cells. The chemokine receptor CCR5 is an essential co-receptor for most HIV strains and necessary for the entry process of the virus into the host cell. The drug binds to CCR5, thereby blocking the HIV protein gp120 from associating with the receptor. HIV is then unable to enter humanmacrophages and T-cells.[5] Because HIV can also use other coreceptors, such as CXCR4, an HIV tropism test such as a trofile assay must be performed to determine if the drug will be effective.[6]
Development and approval
Maraviroc, originally designated UK-427857, was developed by the drug company Pfizer in its UK labs located in Sandwich. On April 24, 2007 the U.S. Food and Drug Administration advisory panel reviewing maraviroc’s New Drug Application unanimously recommended approval for the new drug,[7] and the drug received full FDA approval on August 6, 2007 for use in treatment experienced patients.[8]
On September 24, 2007, Pfizer announced that the European Commission approved maraviroc. Industry experts forecast annual maraviroc sales of $500 million by 2011.[9]
SELZENTRY (maraviroc) is a selective, slowly reversible, small moleculeantagonist of the interaction between human CCR5 and HIV-1 gp120. Blocking this interaction prevents CCR5-tropic HIV-1 entry into cells.
SELZENTRY is available as film-coated tablets for oral administration containing either 150 or 300 mg of maraviroc and the following inactive ingredients: dibasic calcium phosphate (anhydrous), magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The film coat (Opadry® II Blue [85G20583]) contains FD&C blue #2 aluminum lake, soya lecithin, polyethylene glycol (macrogol 3350), polyvinyl alcohol, talc, and titanium dioxide.
Maraviroc is chemically described as 4,4-difluoro-#-((15′)-3-[exo-3-(3-isopropyl-5- methyl-4#-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1- phenylpropyl} cycl ohexanecarboxamide.
The molecular formula is C29H41F2N5O and the structural formula is:
 |
Maraviroc is a white to pale-colored powder with a molecular weight of 513.67. It is highly soluble across the physiological pH range (pH 1.0 to 7.5).
Two randomized, placebo-controlled clinical trials, known as MOTIVATE 1 & 2, compared 209 patients receiving optimized therapy plus a placebo to 426 patients receiving optimized therapy plus 150 mg maraviroc once daily and 414 patients receiving optimized therapy plus 150 mg maraviroc twice daily. At 48 weeks, 55% of participants receiving maraviroc once daily and 60% of participants receiving the drug twice daily achieved a viral load of less than 400 copies/mL compared with 26% of those taking placebo; about 44% of the once-daily and 45% of the twice-daily maraviroc group had a viral load of less than 50 copies/mL compared with about 23% of those who received placebo. In addition, those who received the entry inhibitor had a mean increase in CD4 cells of 110 cells/µL in the once-daily group, 106 cells/µL in the twice-daily group, and 56 cells/µL in the placebo group.[10][11][12]
The MOTIVATE trials showed no clinically relevant differences in safety between the maraviroc and placebo groups. However, researchers question the long-term safety of blocking CCR5, a receptor whose function in the healthy individual is not fully understood.[10]
- Abel S, Russell D, Whitlock LA, Ridgway CE, Nedderman AN, Walker DK (April 2008). “Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects”. British Journal of Clinical Pharmacology 65 (Suppl 1): 60–7. doi:10.1111/j.1365-2125.2008.03137.x. PMC 2311408. PMID 18333867.
- Abel S, Back DJ, Vourvahis M (2009). “Maraviroc: pharmacokinetics and drug interactions”. Antiviral Therapy 14 (5): 607–18. PMID 19704163.
- http://www.uphs.upenn.edu/news/News_Releases/2012/07/hiv/
- Blocade of lymphocyte chemotaxis in visceral graft-versus-host disease, Ran Reshef et al., New England Journal of Medicine, 367:135 (July 12, 2012)
- Levy JA (January 2009). “HIV pathogenesis: 25 years of progress and persistent challenges”. AIDS 23 (2): 147–60. doi:10.1097/QAD.0b013e3283217f9f. PMID 19098484.
- Biswas P, Tambussi G, Lazzarin A (May 2007). “Access denied? The status of co-receptor inhibition to counter HIV entry”. Expert Opinion on Pharmacotherapy 8 (7): 923–33.doi:10.1517/14656566.8.7.923. PMID 17472538.
- Gay News From 365Gay.com
- Krauskopf, Lewis (August 6, 2007). “Pfizer wins U.S. approval for new HIV drug”. Reuters. Retrieved 2007-08-06.
- Reuters, Europe gives final approval to Pfizer HIV drug
- ^ Jump up to:a b Stephenson J (April 2007). “Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus”. JAMA 297 (14): 1535–6. doi:10.1001/jama.297.14.1535.PMID 17426263.
- Emmelkamp JM, Rockstroh JK (October 2007). “CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions–review of the literature”. European Journal of Medical Research 12 (9): 409–17. PMID 17933722.
- “Maraviroc reduces viral load in naive patients at 48 weeks”. AIDS Patient Care and STDs 21 (9): 703–4. September 2007. PMID 17941136.
- BBC News story: Drug ‘stops HIV’s entry to cells’
- Maraviroc data at aidsmap
- Maraviroc early access program
- New HIV Drug Recommended for Approval
- maraviroc at the US National Library of Medicine Medical Subject Headings (MeSH)
…………………
Maraviroc and its pharmaceutically acceptable salt or solvate thereof were disclosed in U.S. Patent No. 6,667,314 (herein after refer to ‘314 patent). Maraviroc is chemically, N- {(lS)-3-[3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-exo-8-azabicyclo- [3.2.1]oct-8-yl]-l- phenylpropyl}-4,4-difluorocyclohexanecarboxamide and has the structural formula:
Maraviroc as modulators of the chemokine receptor CCR5 and thus useful in the treatment of retroviral diseases caused by viruses that utilize CCR5 to enter cells. In particular maraviroc has been disclosed as being a useful therapeutic in the treatment of HIV, a retroviral infection genetically related to HIV, AIDS, or an inflammatory disease.
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other
Maraviroc or its salts can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
According to the ‘314 patent, maraviroc can be prepared by reacting a solution of (l S)-3-[3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1]oct-8-yl]-l- phenyl- 1 -propanamine in methylene chloride and saturated sodium carbonate with a solution of 4,4-difluorocyclohexanecarbonyl chloride in toluene, and isolating to obtain maraviroc.
Crystalline polymorph form A and form B of maraviroc were disclosed in U.S. patent no. 7,576,097.
An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals
, Ian R. Baxendale, Steven V. Ley and Nikzad Nikbin Corresponding author emailA novel and very promising HIV treatment is Pfizer’s maraviroc (286, Celsentri). HIV uses a member of the G-protein coupled receptor family called CCR-5 as an anchor to attach itself to white blood cells such as T-cells and macrophages followed by viral fusion and entry into white blood cells. Maraviroc blocks this pathway by acting as an antagonist for the CCR-5 receptor hence disrupting HIV life cycle. The structural features of this molecule are a geminal difluorocyclohexyl carboxamide which is linked to a β-aminoacid, and a tropinone-type unit bound to a 1,2,4-triazole ring. Relatively simple and straightforward chemical transformations are used to assemble the main fragments of maraviroc such as amide bond formation and reductive amination (Scheme 57) [86]. The triazole ring incorporation is achieved at an early stage by N-acylation of the tropinone fragment 287 with 2-methylpropanoyl chloride (288). The resulting amide 289 is then converted to the corresponding imidoyl chloride 290 using phosphorous pentachloride in dichloromethane (which proved to be superior to phosphoryl chloride) followed by condensation with acetic hydrazide (291). It was found that the dryness of the acetic hydrazide was crucial in order to minimise the hydrolysis of the starting amide 289.
![[1860-5397-7-57-i57]](https://i0.wp.com/beilstein-journals.org/bjoc/content/inline/1860-5397-7-57-i57.png)
TET LETT 46, 2005, PG5005
FDA Breakthrough Therapy Designation: 28 And Counting
On December 20, GlaxoSmithKline (GSK) and Medicines for Malaria Venture (MMV), announce that the FDA grants a Breakthrough Therapy Designation (BTD) for Tafenoquine, an investigational medicine for the treatment and relapse prevention of Plasmodium vivax malaria. This is the 28th BTD that is announced by a sponsor company – GSK and MMV. This is the 3rd FDA BTD that GSK receives in 2013:
Row Num | Drug Name | Sponsor Company | Indication |
1 | Drisapersen | GlaxoSmithKline | Duchenne Muscular
Dystrophy |
2 | Ofatumumab | Genmab/GSK | Chronic Lymphocytic
Leukemia (CLL) |
3 | Tafenoquine | GSK/Medicines for Malaria Venture | Plasmodium Vivax Malaria |
Plasmodium vivax malaria is a “neglected” tropical disease and a major cause of uncomplicated malaria. It is prevalent in Latin America, Southeast Asia, and the horn of Africa, where the majority of the approximately 70-390 million annual clinical cases exist. Plasmodium vivax malaria of all the…
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Ondansetron
ondansetron
Ondansetron hydrochloride dihydrate, cas 99614-01-4, GG-032, SN-307, GR-C505/75,
Ondansetron hydrochloride dihydrate is a serotonin-3 (5-HT3) receptor antagonist. J Org Chem1980, 45, (15): 2938 Heterocycles1997, 45, (10): 2041 EP 0595111 WO 0172716, Ondansetron (INN) (/ɒnˈdænsɛtrɒn/; developed and first marketed by GlaxoSmithKline as Zofran) is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic (to treat nausea and vomiting), often following chemotherapy. It affects both peripheral and central nerves. Ondansetron reduces the activity of the vagus nerve, which deactivates the vomiting center in the medulla oblongata, and also blocks serotonin receptors in thechemoreceptor trigger zone. It has little effect on vomiting caused by motion sickness, and does not have any effect on dopamine receptors ormuscarinic receptors. Although an effective anti-emetic agent, the high cost of brand-name ondansetron initially limited its use to controlling postoperative nausea and vomiting (PONV) and chemotherapy-induced nausea and vomiting (CINV). The active ingredient in ZOFRAN Tablets and ZOFRAN Oral Solution is ondansetron hydrochloride (HC1) as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula:
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The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9. Ondansetron HC1 dihydrate is a white to off-white powder that is soluble in water and normal saline. The active ingredient in ZOFRAN ODT Orally Disintegrating Tablets is ondansetron base, the racemic form of ondansetron, and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (+) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-yl)methyl]-4H-carbazol-4-one. It has the following structural formula:
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The empirical formula is C18H19N3O representing a molecular weight of 293.4. The 5-HT3 receptor antagonists are the primary drugs used to treat and prevent chemotherapy-induced nausea and vomiting (CINV). A common use case is to give them intravenously about 30 minutes before commencement of a chemotherapy treatment.
Ondansetron is used off-label to treat morning sickness and hyperemesis gravidarum of pregnancy. A cohort study of over 600,000 pregnancies in Denmark found that ondansetron administration during pregnancy is not associated with a significantly increased risk of spontaneous abortion,stillbirth, major birth defect, preterm birth, low birth weight, or small for gestational age. However, in practice, ondansetron is typically used after trials of other drugs have failed.
Ondansetron is one of several anti-emetic agents used during the vomiting phase of cyclic vomiting syndrome. Trials in emergency department (ED) settings support the use of ondansetron to reduce vomiting associated with gastroenteritis and dehydration.A retrospective review found that it was used commonly for this purpose, being administered in over 58% of cases. Its use reduced hospital admissions, but was also associated with higher rates of return visits to the ED. Furthermore, patients who had initially received ondansetron were more likely to be admitted on the return visit than patients who had not received the drug. However, this effect may simply be due to the agent being used more frequently in patients who present with more severe illness. Its use was not found to mask serious diagnoses.
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A vial of ondansetron for intravenous injection
Ondansetron was developed around 1984 by scientists working at Glaxo’s laboratories in London. It is in both the imidazole and carbazole families of heterocyclic compounds. After several attempts the company successfully filed for U.S. patent protection for the drug in 1986 and was granted in June 1988 while a use patent was granted in June 1988. A divisional use patent was granted on November 26, 1996. Ondansetron was granted FDA approval as Zofran in January 1991. Glaxo did pediatric research on Zofran’s uses, and gained a patent extension as a result, extending U.S. exclusivity until December 24, 2006. The FDA subsequently approved the first generic versions in December 2006, with marketing approval granted to Teva Pharmaceuticals USA and SICOR Pharmaceuticals.
Ondansetron is marketed by GlaxoSmithKline (GSK) under the trade name Zofran. Other manufacturers include Pfizer Injectables (Ondanzetron), Opsonin Pharma Bangladesh (Anset), Strativa Pharmaceuticals (Zuplenz), Indswift Ltd. (Ondisolv), Cipla Ltd. (Emeset), Gedeon Richter Ltd. (Emetron), Korea United Pharmaceuticals (Emodan), Zentiva a.s. (Ondemet), Strides Arcolab (Setronax), Emistat (Unimed and Unihealth Bangladesh Ltd.)Glenmark Generics Ltd. (India) (Ondansetron) and Novell Pharmaceutical Laboratories (Ondavell). On May 29, 2006, Baxter Healthcare received tentative approval to market its own label of Ondansetron Injection, USP, 8 mg/50 mL and 32 mg/50 mL iso-osmotic sodium chloride solution, beginning upon expiration of GSK’s patent later that year.
In 1997, ondansetron was the subject of a meta-analysis case-study published in the British Medical Journal. Researchers examined 84 trials, with 11,980 patients receiving ondansetron, published between 1991 and September 1996. Intravenous ondansetron 4 mg versus placebo was investigated in 16 reports and three further reports which had been duplicated six times. The number needed to treat (NNT) to prevent vomiting within 24 hours was 9.5, with 95% confidence interval 6.9 to 15, in the 16 non-duplicated reports. In the three duplicated reports, the NNT was significantly lower at 3.9 (3.3 to 4.8) with P<0.00001. When all 25 reports were combined the apparent number needed to treat improved to 4.9 (4.4 to 5.6). Inclusion of duplicate reports led to a 23% overestimation of ondansetron’s antiemetic efficacy. In addition, the authors found that the covert duplication of reports on ondansetron was not easy to detect, because of lack of cross-referencing between papers, and that reports containing duplicate findings were cited in eight reviews of the drug. Their analysis was a subject of an editorial in the Journal of the American Medical Association in 1999. ………………………
patents
AU 8538097; BE 0901576; CH 664152; ES 8609309; ES 8708224; ES 8801247; FR 2561244; GB 2153821; JP 1985214784
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(±) l,2,3,9-Tetrahydro-9-methyl-3-[2-methyl-lh-imidazol-l-yl)methyl]-4h- carbazol-4-one having the molecular structure
is a selective 5-HT3 receptor antagonist. It is known by the generic nameondansetron. Ondansetron reduces nausea in patients undergoing chemotherapy. Grunberg, S.M.; Hesketh, P.J. “Control of Chemotherapy-Induced emesis” N. Engl. J. Med. 1993, 329, 1790-96. Ondansetron is indicated for prevention of nausea and vomiting associated with some cancer chemotherapy, radiotherapy and postoperative nausea and/or vomiting.
Several chemical processes are known from the literature for the synthesis ofondansetron. GB-Pat. 2 153 821 and 2 192 885 describe syntheses starting from carbazolone derivative, and EP-Pat. 595 111 as well as a Hungarian patent application ( P 00-01287 ) give detailed information about some different chemical procedures.
Ondansetron is currently available as an anti-emetic agent, particularly in cancer chemotherapy, and in some other uses such as anti-depressive, anti- migraine and anti-psychotic. It is commonly used in the alleviation of cognitive disorders as in Alzheimer disease, in treatment of rhinitis, psychiatric disorders and for increased vigilance and for control of dependence on narcotics.
U.S. Patent No. 4,695,578, assigned to the Glaxo Group Limited, describes a process of preparing ondansetron and uses thereof. However, ondansetronprepared according to said process contains impurities and by-products such as l,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one.
The hydrochloride salt of ondansetron is generally safe for oral administration to a patient without causing irritation or other adverse effect. The hydrochloride salt is marketed in tablet form and in oral solution form under the brand name Zofran®. The tablet’s active ingredient is a dihydrate of ondansetronhydrochloride containing two molecules of bound water in ondansetronhydrochloride’ s crystal lattice. The present invention relates to the solid state physical properties of ondansetron hydrochloride. These properties can be influenced by controlling the conditions under which the hydrochloride salt is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
These important physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. Llacer and coworkers have postulated that different spectroscopic characteristics of samples of ondansetron free base prepared differently could be attributable to two different configurations about the methylene bridge between the 1, 2, 3, 9-tetrahydrocarbazol-4-one ring and the imidazole ring. Llacer, J.M.; Gallardo, V.; Parera, A. Ruiz, M.A. InternJ.Pharm., 177, 1999, 221-229.
(±)1,2,3,9-Tetrahydro-9-methyl-3-[2-methyl-1h-imidazol-1-yl)methyl]-4h-carbazol-4-one having the molecular structure
is a selective 5-HT3 receptor antagonist. It is known by the generic nameondansetron. Ondansetron reduces nausea in patients undergoing chemotherapy. Grunberg, S. M.; Hesketh, P. J. “Control of Chemotherapy-Induced emesis” N. Engl. J. Med. 1993, 329, 1790-96. Ondansetron is indicated for prevention of nausea and vomiting associated with some cancer chemotherapy, radiotherapy and postoperative nausea and/or vomiting.
The hydrochloride salt of ondansetron is generally safe for oral administration to a patient without causing irritation or other adverse effect. The hydrochloride salt is marketed in tablet form and in oral solution form under the brand name Zofran®. The tablet’s active ingredient is a dihydrate of ondansetronhydrochloride containing two molecules of bound water in ondansetronhydrochloride’s crystal lattice.
The present invention relates to the solid state physical properties ofondansetron hydrochloride. These properties can be influenced by controlling the conditions under which the hydrochloride salt is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient’s stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient’s bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These important physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. Llacer and coworkers have postulated that different spectroscopic characteristics of samples ofondansetron free base prepared differently could be attributable to two different configurations about the methylene bridge between the 1,2,3,9-tetrahydrocarbazol-4-one ring and the imidazole ring. Llacer, J. M.; Gallardo, V.; Parera, A. Ruiz, M. A. Intern.J.Pharm., 177, 1999, 221-229.
A crystalline polymorphic form of a compound may exhibit different thermal behavior from amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13C NMR spectrometry and infrared spectrometry. There is a wide variety of techniques that have the potential of producing different crystalline forms of a compound. Examples include crystallization, crystal digestion, sublimation and thermal treatment.
U.S. Pat. No. 4,695,578, Example 1a, discloses a preparation ofondansetron by alkylation of 2-methylimidazole with 2,3,4,9 tetrahydro-N,N,N,9-tetramethyl-4-oxo-1H-carbazole-3-methanaminium iodide. In this example,ondansetron was isolated as its hydrochloride salt by suspending the reaction product in a mixture of absolute ethanol and ethanolic HCl, warming the suspension, filtering to remove impurities and precipitating the hydrochloride salt with dry ether.
In Example 10 of the ‘578 patent, ondansetron free base was converted into a hydrochloride salt dihydrate by dissolving the free base in a mixture of isopropanol and water and treating it with concentrated hydrochloric acid. After filtration at elevated temperature, ondansetron was driven out of solution by adding additional isopropanol and cooling. The dihydrate was obtained as a white crystalline solid by recrystallizing it from a 6:10 mixture of water and isopropanol. Ondansetron hydrochloride dihydrate obtained by following Example 10 of the ‘578 patent is denominated Form A in this disclosure. Powdered samples of Form A produce a powder X-ray diffraction pattern essentially the same as the pattern shown in FIG. 1.
U.S. Pat. No. 5,344,658 describes ondansetron having a particular particle size distribution and the use of such ondansetron in a pharmaceutical composition. The particle size of ondansetron hydrochloride dihydrate obtained by crystallization from a solvent is reduced by desolvating them, e.g. by heating, and then exposing the desolvated crystals to a humid atmosphere. A collection of crystals obtained by this particle size reduction process is said to consist exclusively of crystals of less than 250 micron size and to contain 80% or more crystals of less than 63 microns. Crytals size was determined by air jet seive analysis.
According to the ‘658 patent, ondansetron hydrochloride dehydrate having the same particle size distribution as the rehydrated ondansetron hydrochloride also is provided as part of that invention. Since only one process for dehydratingondansetron hydrochloride is described in the ‘658 patent, a dehydrate is evidently the intermediate compound that is rehydrated in the particle size reduction process.
U.S. Pat. Nos. 4,695,578 and 5,344,658 are incorporated herein by reference.
U.S. Pat. No. 4,695,578 (‘578 patent) discloses a process for preparingondansetron hydrochloride dihydrate having a large particle size (e.g., less than about 60% of the particles are smaller than 250 μm). The ‘578 patent process involves the step of cooling a solution of ondansetron hydrochloride, isopropanol, and water, optionally followed by an additional step of recrystallizing from a mixture of water and isopropanol.
U.S. Pat. No. 5,722,720 (the ‘720 patent) discloses a non-conventional technique for reducing particle size. In particular, the ‘720 patent discloses a multistep process in which ondansetron hydrochloride dihydrate is first dried at elevated temperature and reduced or atmospheric pressure, and is then cooled to ambient temperature. The process requires the heating step to be performed until the ondansetron hydrochloride dihydrate is desolvated, and requires the cooling step to be performed until the ondansetron hydrochloride is rehydrated to form ondansetron hydrochloride dihydrate.
The ‘720 patent process has several disadvantages. First, the ‘720 patent process requires a prolonged time period (i.e., 16-24 hours) for the drying/desolvating step, plus an additional prolonged time period for the cooling/rehydrating step. Second, the ‘720 patent process requires vigorous and carefully controlled drying conditions. For example, when the drying step is performed at 48-52° C., a reduced pressure of 100-200 torr is required. When the drying step is performed at ambient pressure, an elevated temperature of 1 00° C. is required.
An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals
, Ian R. Baxendale, Steven V. Ley and Nikzad Nikbin Corresponding author emailA completely different strategy was used in the synthesis of the serotonin 5-HT3 receptor antagonist ondansetron (119, Zofran). In this synthesis a palladium-catalysed intramolecular Heck-reaction was used to build the tricyclic indole core in a short and concise sequence (Scheme 26) [35,36].
![[1860-5397-7-57-i26]](https://i0.wp.com/beilstein-journals.org/bjoc/content/inline/1860-5397-7-57-i26.png)
Alternatively, a direct Fischer indole synthesis between phenylmethyl hydrazine and a cyclic 1,3-dione derivative could be utilised to prepare the desired fully substituted tricyclic core of ondansetron (Scheme 27) [37].
![[1860-5397-7-57-i27]](https://i0.wp.com/beilstein-journals.org/bjoc/content/inline/1860-5397-7-57-i27.png)
- 35………..Godfrey, N.; Coates, I. H.; Bell, J. A.; Humber, D. C.; Ewan, G. B. Process for Preparing N-Heterocyclic Compounds. U.S. Patent 4,957,609, Sept 18, 1990.
- 36…………Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1980, 45, 2938–2942. doi:10.1021/jo01303a003
- Oxford, A. W.; Eldred, C. D.; Coates, I. H.; Bell, J. A.; Humber, D. C.; Ewan, G. B. Process for Preparing Tetrahydrocarbazolones. U.S. Patent 4,739,072, April 19, 1988.
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
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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).
-
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).
-
-
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.
-
-
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.
-
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.
-
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
-
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
-
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
-
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
-
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
-
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
-
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.
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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] +
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 