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Showing posts with label Ljubljana. Show all posts
Showing posts with label Ljubljana. Show all posts

Sunday 24 July 2016

Esomeprazole Magnesium Trihydrate



Nexium.png

Esomeprazole Magnesium Trihydrate


Nexium; KS-1054; Esomeprazole magnesium; AC1L2XMA; 217087-09-7; AC-402;  
Molecular Formula:C34H42MgN6O9S2
Molecular Weight:767.16708 g/mol

magnesium;5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide;trihydrate


Esomeprazole magnesium dihydrate (CAS 217087-10-0)



A proton pump inhibitor
CAS Number:217087-10-0
Purity:≥98%
Molecular Weight:749.15
Molecular Formula:C34H36MgN6O6S2 2H2O

 (−)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole, i.e. S-omeprazole.


The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, having the generic name omeprazole, and therapeutically acceptable salts thereof, are described in EP 5129. The specific alkaline salts of omeprazole are disclosed in EP 124 495. Omeprazole is a proton pump inhibitor, i.e. effective in inhibiting gastric acid secretion, and is useful as an antiulcer agent. In a more general sense, omeprazole may be used for prevention and treatment of gastric-acid related diseases in mammals and especially in man.
Omeprazole is a sulfoxide and a chiral compound, wherein the sulfur atom being the stereogenic center. Thus, omeprazole is a racemic mixture of its two single enantiomers, the R and S-enantiomer of omeprazole, herein referred to as R-omeprazole and S-omeprazole. The absolute configurations of the enantiomers of omeprazole have been determined by an X-ray study of an N-alkylated derivative of the (+)-enantiomer in non-salt form. The (+)-enantiomer of the non-salt form and the (−)-enantiomer of the non-salt form were found to have R and S configuration, respectively, and the (+)-enantiomer of the magnesium salt and the (−)-enantiomer of the magnesium salt were also found to have R and S configuration, respectively. The conditions for the optical rotation measurement for each of these enantiomers are described in WO 94/27988.
Esomeprazole sold under the brand name Nexium among others,[1] is a proton pump inhibitor which reduces stomach acid. It is used in the treatment of dyspepsiapeptic ulcer diseasegastroesophageal reflux disease, and Zollinger-Ellison syndrome.
It decreases secretion of acid through inhibition of the H+/K+-ATPase in the parietal cells of the stomach. By inhibiting the functioning of this transporter, the drug prevents formation of stomach acid.
Esomeprazole is the (S)-(−)-enantiomer of omeprazole. Esomeprazole is currently sold over the counter in the US and the UK.

IR in KBr pellets




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(1HNMR)




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MASS






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Factors Influencing the Selectivity in Asymmetric Oxidation of Sulfides Attached to Nitrogen Containing Heterocycles Muthu Seenivasaperumal,a Hans-Jürgen Federsel,b Anne Ertanbc and Kálmán J. Szabóa * a Stockholm University, Arrhenius Laboratory, Department of Organic Chemistry SE-106 91 Stockholm, Sweden; b Global Process R&D and c Early Development, Pharmaceutical and Analytical R&D, AstraZeneca, SE-151 85 Södertälje, Sweden E-mail: kalman@organ.su.se. Fax: +46-8-15 49 08
http://www.rsc.org/suppdata/cc/b7/b700860k/b700860k.pdf

Esomeprazole (5a). This product was prepared according to the above general procedure except that it was isolated as a potassium salt (78% yield and 97% ee) by addition of potassium methoxide to the reaction mixture. The 1 H-NMR data obtained for 5a agrees 3 with the literature values.

8 1 H NMR (DMSO-d6): δ 8.25 (s, 1H), 7.37 (d, 8.6 Hz, 1H), 7.02 (d, 2.6 Hz, 1H), 6.60 (dd, 2.5 Hz, 8.4 Hz, 1H), 4.72 and 4.46 (d (AB system, 12.7 Hz, 2H), 3.75 (s, 3H), 3.70 (s, 3H), 2.21(s, 6H);


13C NMR (DMSO-d6): δ 163.4, 161.8, 153.7, 151.9, 149.1, 147.0, 141.6, 126.5, 124.9, 117.5, 109.0, 99.4, 59.7, 55.2, 48.6, 12.9, 11.3. [α]D 20 = +30.1 (c 1.0, H2O); Lit.8 : [α]D 20 = +30.5 (c 1.0, H2O) for (S), 99.5% ee.

The ee was determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH/AcOH 50:50:0.1, flow rate 0.6 mL/min; tR (minor) = 9.9 min; tR (major) = 11.7 min, λ = 300.3 nm).





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PATENT

Reference Example A S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole Magnesium Salt
(The method used is in accordance with the method described in Example A in WO 96/01623)
Magnesium (0.1 μg, 4.5 mmol) was dissolved and reacted with methanol (50 ml) at 40° C. with a catalytic amount of methylene chloride. The reaction was run under nitrogen and was finished after five hours. At room temperature a mixture of the two enantiomers [90%(−)-isomer and 10%(+)-isomer] of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (2.84 g, 8.2 mmol) was added to the magnesium methoxide solution. The mixture was stirred for 12 hours whereupon a small amount of water (0.1 ml) was added in order to precipitate inorganic magnesium salts. After 30 minutes stirring, these inorganic salts were filtered off and the solution was concentrated on a rotavapor. The residue was now a concentrated methanolic solution of the enantiomeric mixture (i.e. the title compound contaminated with the (+)-isomer), with an optical purity (enantiomeric excess, e.e.) of 80%. This mixture was diluted with acetone (100 ml) and after stirring at room temperature for 15 minutes, a white precipitate was obtained. Additional stirring for 15 minutes and thereafter filtration afforded 1.3 g (50%) of the title compound as white crystals. Chiral analyses of the crystals and mother liquor were performed by chromatography on an analytical chiral column. The optical purity of the crystals and mother liquor was found to be 98.4 e.e. and 64.4% e.e., respectively. Thus, the optical purity (e.e.) has been enhanced from 80% to 98.4% simply by crystallizing the Mg-salt from a mixture of acetone and methanol. The product was crystalline as shown by powder X-ray diffraction and the magnesium content was 3.44% as shown by atomic absorption spectroscopy. [α]D 20=−131.5° (c=0.5%, methanol).




PATENT

Figure US08394963-20130312-C00002


WO1998054171A1 *May 25, 1998Dec 3, 1998Astra AktiebolagNovel form of s-omeprazole
WO2008092939A2 *Jan 31, 2008Aug 7, 2008Krka, Tovarna Zdravil, D.D., Novo MestoProcess for the preparation of optically pure omeprazole via salt formation with a chiral amine or treatment with an entiomer converting enzyme and chromatographic separation
WO2009060064A2 *Nov 7, 2008May 14, 2009Valpharma S.A.Pharmaceutical formulations for the oral administration of ppi
WO2011144994A1 *May 20, 2011Nov 24, 2011Lupin LimitedPharmaceutical compositions of nsaid and acid inhibitor
EP2147918A1 *Jul 21, 2008Jan 27, 2010LEK Pharmaceuticals D.D.Process for the preparation of S-omeprazole magnesium in a stable form
US7411070Sep 25, 2003Aug 12, 2008Astrazeneca AbForm of S-omeprazole
US4255431Apr 5, 1979Mar 10, 1981Aktiebolaget HassleGastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion
US4738974 *Apr 21, 1986Apr 19, 1988Aktiebolaget HassleBase addition salts of omeprazole
US4786505Apr 20, 1987Nov 22, 1988Aktiebolaget HasslePharmaceutical preparation for oral use
US5530160Apr 17, 1995Jun 25, 1996Rhone-Poulenc ChimieProcess for the preparation of L-aspartic acid from ammonium aspartate
US5676884Nov 20, 1996Oct 14, 1997Minnesota Mining And Manufacturing CompanyNonlinear optical materials containing polar disulfone-functionalized molecules
US5690960 *Jul 8, 1994Nov 25, 1997Astra AktiebolagPharmaceutical formulation of omeprazole
US5693818 *May 27, 1994Dec 2, 1997Astra AktiebolagProcess for preparing pure salts of pyridinylmethyl-sulfinyl-1H-benzimidazole
US5714504 *Jan 23, 1995Feb 3, 1998Astra AktiebolagCompositions
US5817338Jun 7, 1995Oct 6, 1998Astra AktiebolagMultiple unit tableted dosage form of omeprazole
US5877192Apr 11, 1997Mar 2, 1999Astra AktiebolagMethod for the treatment of gastric acid-related diseases and production of medication using (-) enantiomer of omeprazole
US5900424Jul 8, 1994May 4, 1999Astra AktiebolagOmeprazole magnesium salt form
US6369085May 5, 1998Apr 9, 2002Astrazeneca AbForm of S-omeprazole
US6677455Feb 14, 2002Jan 13, 2004Astrazeneca AbPotassium salt of S-omeprazole
US6747155Apr 1, 2002Jun 8, 2004Astrazeneca AbProcess
CN1136564AMay 25, 1995Nov 27, 1996常州市第四制药厂Aomeilazole salt hydrate for gastric acid inhibitor and its preparing method
DE4035455A1Nov 8, 1990May 14, 1992Byk Gulden Lomberg Chem FabEnantiomerentrennung
EP0005129A1Apr 3, 1979Oct 31, 1979Aktiebolaget HässleSubstituted pyridylsulfinylbenzimidazoles having gastric acid secretion properties, pharmaceutical preparations containing same, and intermediates for their preparation
EP0124495A2Feb 28, 1984Nov 7, 1984Aktiebolaget HässleOmeprazole salts
EP0247983A2Apr 16, 1987Dec 2, 1987Aktiebolaget HässleNew pharmaceutical preparation for oral use
WO1994027988A1May 27, 1994Dec 8, 1994Astra AktiebolagOptically pure salts of pyridinylmethyl sulfinyl-ih-benzimidazole compounds
WO1995001977A1Jul 8, 1994Jan 19, 1995Astra AktiebolagMagnesium omeprazole
WO1996001623A1Jun 7, 1995Jan 25, 1996Astra AktiebolagMultiple unit tableted dosage form i
WO1996002535A1Jul 3, 1995Feb 1, 1996Astra AktiebolagProcess for synthesis of substituted sulphoxides



Esomeprazole
Esomeprazole.svg
Esomeprazole ball-and-stick model.png
Systematic (IUPAC) name
(S)-(−)-5-Methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzoimidazole
Clinical data
Pronunciation/ˌɛsˈmɛprəˌzl-ˈm--ˌzɒl/[2]
Trade namesNexium, many others[1]
AHFS/Drugs.comMonograph
MedlinePlusa699054
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    administration
    Oral, IV
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability50 to 90%
    MetabolismHepatic (CYP2C19CYP3A4)
    Biological half-life1–1.5 hours
    Excretion80% Renal
    20% Faecal
    Identifiers
    CAS Number119141-88-7 
    ATC codeA02BC05 (WHO)
    PubChemCID 9579578
    DrugBankDB00736 Yes
    ChemSpider7843323 
    UNIIN3PA6559FT Yes
    KEGGD07917 Yes
    ChEBICHEBI:50275 Yes
    ChEMBLCHEMBL1201320 
    Chemical data
    FormulaC17H19N3O3S
    Molar mass345.417 g/mol


    The active ingredient in the proton pump inhibitor NEXIUM® (esomeprazole magnesium) Delayed-Release Capsules for oral administration and NEXIUM (esomeprazole magnesium) For Delayed-Release Oral Suspension is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl) magnesium trihydrate. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers. (Initial U.S. approval of esomeprazole magnesium: 2001). Its molecular formula is (C17H18N3O3S)2Mg x 3 H2O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis. The structural formula is:
    Figure 1
    NEXIUM (esomeprazole magnesium) Structural Formula Illustration
    The magnesium salt is a white to slightly colored crystalline powder. It contains 3 moles of water of solvation and is slightly soluble in water. The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the magnesium salt is about 19 hours at 25°C and about 8 hours at 37°C.
    NEXIUM is supplied in delayed-release capsules and in packets for a delayed-release oral suspension. Each delayed-release capsule contains 20 mg, or 40 mg of esomeprazole (present as 22.3 mg, or 44.5 mg esomeprazole magnesium trihydrate) in the form of enteric-coated granules with the following inactive ingredients: glyceryl monostearate 40-55, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, and triethyl citrate. The capsule shells have the following inactive ingredients: gelatin, FD&C Blue #1, FD&C Red #40, D&C Red #28, titanium dioxide, shellac, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, sodium hydroxide, polyvinyl pyrrolidone, and D&C Yellow #10.
    Each packet of NEXIUM For Delayed-Release Oral Suspension contains 2.5 mg, 5 mg, 10 mg, 20 mg, or 40 mg of esomeprazole, in the form of the sameenteric-coated granules used in NEXIUM Delayed-Release Capsules, and also inactive granules. The inactive granules are composed of the following ingredients: dextrose, xanthan gum, crospovidone, citric acid, iron oxide, and hydroxypropyl cellulose. The esomeprazole granules and inactive granules are constituted with water to form a suspension and are given by oral,nasogastric, or gastric administration.
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    CC1=CN=C(C(=C1OC)C)CS(=O)C2=NC3=C([N-]2)C=CC(=C3)OC.CC1=CN=C(C(=C1OC)C)CS(=O)C2=NC3=C([N-]2)C=CC(=C3)OC.O.O.O.[Mg+2]






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