Esomeprazole Magnesium Trihydrate

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 dyspepsia, peptic ulcer disease, gastroesophageal 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

https://www.google.com/patents/US7411070

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

WO1998054171A1 *	May 25, 1998	Dec 3, 1998	Astra Aktiebolag	Novel form of s-omeprazole
WO2008092939A2 *	Jan 31, 2008	Aug 7, 2008	Krka, Tovarna Zdravil, D.D., Novo Mesto	Process 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, 2008	May 14, 2009	Valpharma S.A.	Pharmaceutical formulations for the oral administration of ppi
WO2011144994A1 *	May 20, 2011	Nov 24, 2011	Lupin Limited	Pharmaceutical compositions of nsaid and acid inhibitor
EP2147918A1 *	Jul 21, 2008	Jan 27, 2010	LEK Pharmaceuticals D.D.	Process for the preparation of S-omeprazole magnesium in a stable form
US7411070	Sep 25, 2003	Aug 12, 2008	Astrazeneca Ab	Form of S-omeprazole

US4255431	Apr 5, 1979	Mar 10, 1981	Aktiebolaget Hassle	Gastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion
US4738974 *	Apr 21, 1986	Apr 19, 1988	Aktiebolaget Hassle	Base addition salts of omeprazole
US4786505	Apr 20, 1987	Nov 22, 1988	Aktiebolaget Hassle	Pharmaceutical preparation for oral use
US5530160	Apr 17, 1995	Jun 25, 1996	Rhone-Poulenc Chimie	Process for the preparation of L-aspartic acid from ammonium aspartate
US5676884	Nov 20, 1996	Oct 14, 1997	Minnesota Mining And Manufacturing Company	Nonlinear optical materials containing polar disulfone-functionalized molecules
US5690960 *	Jul 8, 1994	Nov 25, 1997	Astra Aktiebolag	Pharmaceutical formulation of omeprazole
US5693818 *	May 27, 1994	Dec 2, 1997	Astra Aktiebolag	Process for preparing pure salts of pyridinylmethyl-sulfinyl-1H-benzimidazole
US5714504 *	Jan 23, 1995	Feb 3, 1998	Astra Aktiebolag	Compositions
US5817338	Jun 7, 1995	Oct 6, 1998	Astra Aktiebolag	Multiple unit tableted dosage form of omeprazole
US5877192	Apr 11, 1997	Mar 2, 1999	Astra Aktiebolag	Method for the treatment of gastric acid-related diseases and production of medication using (-) enantiomer of omeprazole
US5900424	Jul 8, 1994	May 4, 1999	Astra Aktiebolag	Omeprazole magnesium salt form
US6369085	May 5, 1998	Apr 9, 2002	Astrazeneca Ab	Form of S-omeprazole
US6677455	Feb 14, 2002	Jan 13, 2004	Astrazeneca Ab	Potassium salt of S-omeprazole
US6747155	Apr 1, 2002	Jun 8, 2004	Astrazeneca Ab	Process
CN1136564A	May 25, 1995	Nov 27, 1996	常州市第四制药厂	Aomeilazole salt hydrate for gastric acid inhibitor and its preparing method
DE4035455A1	Nov 8, 1990	May 14, 1992	Byk Gulden Lomberg Chem Fab	Enantiomerentrennung
EP0005129A1	Apr 3, 1979	Oct 31, 1979	Aktiebolaget Hässle	Substituted pyridylsulfinylbenzimidazoles having gastric acid secretion properties, pharmaceutical preparations containing same, and intermediates for their preparation
EP0124495A2	Feb 28, 1984	Nov 7, 1984	Aktiebolaget Hässle	Omeprazole salts
EP0247983A2	Apr 16, 1987	Dec 2, 1987	Aktiebolaget Hässle	New pharmaceutical preparation for oral use
WO1994027988A1	May 27, 1994	Dec 8, 1994	Astra Aktiebolag	Optically pure salts of pyridinylmethyl sulfinyl-ih-benzimidazole compounds
WO1995001977A1	Jul 8, 1994	Jan 19, 1995	Astra Aktiebolag	Magnesium omeprazole
WO1996001623A1	Jun 7, 1995	Jan 25, 1996	Astra Aktiebolag	Multiple unit tableted dosage form i
WO1996002535A1	Jul 3, 1995	Feb 1, 1996	Astra Aktiebolag	Process for synthesis of substituted sulphoxides

Esomeprazole

Systematic (IUPAC) name
(S)-(−)-5-Methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzoimidazole
Clinical data
Pronunciation	/ˌɛsoʊˈmɛprəˌzoʊl, -ˈmiː-, -ˌzɒl/[2]
Trade names	Nexium, many others[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a699054
License data	US FDA: Esomeprazole
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	Oral, IV
Legal status
Legal status	UK: General sales list (GSL, OTC) US: Rx only IV OTC oral
Pharmacokinetic data
Bioavailability	50 to 90%
Metabolism	Hepatic (CYP2C19, CYP3A4)
Biological half-life	1–1.5 hours
Excretion	80% Renal 20% Faecal
Identifiers
CAS Number	119141-88-7
ATC code	A02BC05 (WHO)
PubChem	CID 9579578
DrugBank	DB00736
ChemSpider	7843323
UNII	N3PA6559FT
KEGG	D07917
ChEBI	CHEBI:50275
ChEMBL	CHEMBL1201320
Chemical data
Formula	C17H19N3O3S
Molar mass	345.417 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

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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