The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study

ARKIVOC Volume 2006
Part (v): Commemorative Issue in Honor of 
Facilitator: Luba Ignatovich
Scientific Editor: Mikael Begtrup 

2. The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study (EL-1719AP)
Rosa M. Claramunt, Concepción López and José Elguero 
Full Text: PDF (193K)
pp. 5 - 11 

The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study

Rosa M. Claramunt,a Concepción López,a and José Elguero b *

a Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain

b Instituto de Química Médica, CSIC, Juan de la Cierva, 3. E-28006 Madrid, Spain E-mail: iqmbe17@iqm.csic.es

To our friend Professor Edmunds Lukevics on his 70th anniversary

 Edmunds Lukevics 

Abstract

The 13C and 15N CPMAS spectra of a solid sample of Omeprazole have been recorded and all the signals assigned. The sample consists uniquely of the 6-methoxy tautomer. For analytical purposes, the signals of the other tautomer, the 5-methoxy one, were estimated from the data in solution (Magn. Reson. Chem. 2004, 42, 712).

Keywords: Omeprazole, NMR, 13C, 15N, CPMAS, tautomerism, benzimidazole

see at

http://www.arkat-usa.org/arkivoc-journal/browse-arkivoc/2006/5/graphical-abstracts/

http://www.arkat-usa.org/get-file/22955/

Edmunds LUKEVICS

(14.12.1936 - 21.11.2009)

Professor Edmunds LUKEVICS Latvian Institute of Organic Synthesis, Head of the Laboratory of Organometallic Chemistry Aizkraukles iela 21, Riga, LV-1006 Latvia

Born: December 14, 1936, Liepaja, Latvia
Departed: November 21, 2009, Riga, Latvia

Interests:

• Organometallic Compounds
• Heterocyclic Compounds
• Biological Activity of Organic Compounds

Main Research:

Development of methods for the synthesis of organosilicon and -germanium derivatives of furan, thiophene and nitrogen-containing heterocycles ; study of the influence of organosilicon ,-germanium and -tin substituents on the direction of substitution and addition reactions of furan and thiophene derivatives ; study of hydrosilylation and hydrogermylation reactions, synthesis and investigation of properties of penta- and hexacoordinated organosilicon and -germanium derivatives; application of alkenyl silanes and germanes in the synthesis of nitrogen-containing heterocycles; application of phase-transfer catalysis and ultrasonic irradiation in organometallic synthesis; synthesis of biologically active organosilicon and organogermanium compounds and studies of their properties.

Education:

• University of Latvia (Faculty of Chemistry), 1958
• Dr.chem. (Candidate of Science in former USSR, Ph.D. in Western countries), Latvian Academy of Sciences, Riga, 1966
• Dr.habil.chem. (Doctor of Science in former USSR), Latvian Academy of Sciences, Riga, 1973

Experience:

Latvian Institute of Organic Synthesis -

• Junior Researcher, 1958-1967
• Senior Researcher, 1968-1970
• Head, Laboratory of Organometallic Chemistry, 1970 - 2009
• Vice-director, 1980-1982
• Director, 1982 - 2003

Honours and Awards:

• Corresponding Member, Latvian Academy of Sciences , 1982
• Full Member, Latvian Academy of Sciences , 1987
• Member, New York Academy of Sciences, 1993
• The Latvian Academy of Sciences Gustavs Vanags Prize (in Chemistry), 1986
• Latvian SSR State Prize, 1974, 1989
• S.Hiller Medal (Latvian Institute of Organic Synthesis), 1990
• G.Vanags Medal (Riga Technical University), 1991
• D.H.Grindel Medal (company ‘Grindex’, Latvia), 1995
• L.Liepina Medal (Institute of Inorganic Chemistry, Riga), 1996
• The Latvian Academy of Sciences Grand Medal, 1996
• Silver Medal of Milan University, 1996
• Schmiedebergs Medal (Latvian Pharmacological Society), 1998
• The Latvian Academy of Sciences and Company "GRINDEX" Prize, 1999
• Paul Walden's Medal (Riga Technical University), 2000
• Latvian Academy of Sciences Presidium Award, 1971, 1973, 1977, 1981, 1982, 1985,1987, 1989, 1992
• International Man of the Year (The International Biographic Centre of Cambridge, England), 1992-1993, 1994-1995
• Man of the Year (The American Biographical Institute), 1994, 2005
• The first-level Badge of Honour of the Order of Three Stars, 1997
• Company “Grindex” gold badge of honour, 2001
• The Cabinet of Ministers of the Republic of Latvia Prize , 2004
• American Medal of Honor (ABI), 2005
• Gold Medal for Latvia (ABI), 2006
• The Plato Award (IBC), 2006
• Man of Achievement (ABI), 2007

Professional Activities:

• Member of Presidium and Senate, Latvian Academy of Sciences, 1987-1991
• Member of Board, Division of Chemical and Biological Sciences, Latvian Academy of Sciences, 1983-1993
• Member, Latvian Academy of Sciences Commission on Terminology, 1987- 1999
• Chairman, Habilitation and Promotion Council (Chemistry and Pharmacy), Latvian Institute of Organic Synthesis, 1994 -1999
• Member (Chairman,1991-1993, 1997-2002), Latvian Council of Science Expert Committee for Chemistry, 1991 - 2006
• Vice-chairman, Habilitation and Promotion Council (Chemistry), University of Latvia, 1998- 2009
• Member of Editorial Board for:

Khimiya Geterotsikicheskikh. Soedinenii (Chemistry of Heterocyclic Compounds, Springer), 1980-1985; Editor-in-chief, 1985 - 2009
Proceedings of Latvian Academy of Sciences, 1982-1990
Latvian Journal of Chemistry, 1991 - 2009
Bioorganicheskaya Khimiya, 1989 - 1993
Applied Organometallic Chemistry, 1990 - 2009
Main Group Metal Chemistry, 1992 - 2009
Metal-Based Drugs, 1993 - 2003
Mendeleev Communications, 1994 - 2009
Advances in Heterocyclic Chemistry, 1994 - 2009
Silicon Chemistry, 2001-2007
Arkivoc, 2001 -  2009
Bioinorganic Chemistry and Applications, 2003 - 2006
Heterocyclic Communications, 2005 -  2009
Molecules, 2008 -  2009
Journal of Organic and Pharmaceutical Chemistry (Ukraine), 2009 - 2009

• Chairman, Scientific Council “Chemistry and Technology of Sulfur Organic Compounds”, USSR State Committee of Science and Technics, 1982-1987
• Chairman, Council “Application of Organometallic Compounds in National Economy”, USSR (Russian) Academy of Sciences, 1984-1992
• Member, United Libraries Informative Council, USSR Academy of Sciences, 1985-1990
• Member, Scientific Council “Physiologically Active Compounds”, USSR Academy of Sciences, 1986-1992
• Member, Scientific and Technical Council, USSR Ministry of Medical and Microbiological Industry, 1987-1990
• Member, Soviet National Committee on collecting and estimating information in science and technics “CODATA”, 1987-1990
• Member of Council for Coordination of scientific work, Department of Biochemistry, Biophysics and Physiologically Active Compounds, USSR Academy of Sciences, 1988-1991
• Member of International Organizing Committees
      - International Conference on the Coordination and Organometallic Chemistry of Germanium, Tin and Lead, 1992, 1995, 1998, 2001
      -  International Symposium on Organosilicon Chemistry, 1993, 1996, 1999, 2002, 2005, 2008.

Memberships:

• Member of Organometallic Chemistry Division, Federation of European Chemical Societies, 1995-2005
• Member of Organometallic Chemistry Division, European Association for Chemical & Molecular Sciences, 2006
• Member, Latvian Chemical Society, 1995
• Member, American Chemical Society, 1997
• Member, National Geographic Society, 1997
• Honorary Member,  Pharmacological Society of Latvia, 1998

Lectures

Invited Lectures at Universities

• Indian Institute of Science, Bangalore (India), 1989
• Indian Institute of Technology, Bombay (India), 1989
• University of Dresden (Germany), 1989
• Universities of Bordeaux, Tolouse, Montpellier, Marseilles (France), 1990, 1994
• University of Lund (Sweden), 1992
• University of Alcala de Henares ( Spain), 1993
• Tohoku University (Sendai, Japan), 1991, 1992
• Tokyo University of Science (Japan), 1997
• Kyoto University (Japan), 1997
• Universities of Kyoto and Kanagawa, Japan, 2002.

Invited Lectures and Symposium’s Plenary Lectures:

• 40th Nobel Symposium (Lidingö, Sweden), 1977
• VI Symposium on Chemistry of Heterocyclic Compounds (Brno, Czechoslovakia), 1978
• 7th International Symposium on Organosilicon Chemistry (Kyoto, Japan), 1984
• VI FECHEM Conference on Organometallic Chemistry (riga, Latvia), 1985
• II Soviet-Indian Symposium on Organometallic Chemistry( Irkutsk, Russia), 1989
• 17th DDR-Poland Colloquy on Organometallic Chemistry (Holzhau, Germany), 1989
• 6th International Conference on Organometallic and Coordination Chemistry of Germanium, Tin and Lead (Brussels, Belgium), 1989
• Huang Minlon Symposium on Organic Chemistry (Shanghai, China), 1989
• International Chemical Conference on Silicon and Tin ( Kuala Lumpur, Malaisia), 1989
• 9th International Symposium on Organosilicon Chemistry (Edinburgh, UK), 1990
• 1st Meeting of the European Society of Sonochemistry, Autrans (Grenoble, France), 1990
• 11th International Symposium on Medicinal Chemistry (Jerusalem, Israel), 1990
• S.Hiller Memorial Lectures (Riga, Latvia), 1990
• 1st Meeting of Japanese Germanium Discussion Group (Tokyo, Japan), 1991
• International Conference on Environmental and Biological Aspects of Maingroups Organometals (Padua, Italy), 1991
• 3rd Swedish-German workshop: Nucleic Acid Synthesis, Structure and Function (Uppsala, Sweden), 1992
• 2nd ANAIC Conference on Materials Science and Environmental Chemistry of Main Group Elements (Kual Lumpur, Malaysia), 1993
• Todai Symposium “Ge-Sn-Pb Tokyo’93”: International Symposium on Organic, Bioorganic and Bioinorganic Chemistry of Compounds of higher row Group 14-elements (Tokyo, Japan), 1993
• 10th International Symposium on Organosilicon Chemistry (Poznan, Poland), 1993
• 3rd Meeting of the European Society of Sonochemistry (Figueira da Foz, Portugal), 1993
• 14th Nordic Meeting of Structural Chemists (Helsinki, Finland), 1993
• 8th International Conference on the Organometallic Chemistry of Germanium, Tin and Lead (Sendai, Japan), 1995
• 8th IUPAC Symposium on Organometallic Chemistry Directed Towards Organic Synthesis (Santa Barbara, USA), 1995
• 8th Symposium Heterocycles in Bioorganic Chemistry (Como, Italy), 1996
• 9th International Conference on the Coordination and Organometallic Chemistry of Germanium, Tin, and Lead (Melbourne, Australia), 1998
• 12th International Conference on Organosilicon Chemistry (Sendai, Japan), 1999
• International Conference on Organic Synthesis "Balticum Organicum Sinteticum-2000"(Vilnius, Lithuania), 2000
• X International Symposium "Jubilee Krka Prizes" (Novo Mesto, Slovenia), 2000

Recent/Representative Publications:

• E.Ya. Lukevits, M.G.Voronkov. Organic Insertion Reactions of Group IV Elements, 1966, New York: Consultants Bureau, 413 pp.
• S.N.Borisov, M.G.Voronkov, E.Ya.Lukevits. Organosilicon Heteropolymers and Heterocompounds, 1970, NewYork: Plenum Press, 633 pp.
• S.N.Borisov, M.G.Voronkov, E.Ya.Lukevits. Organosilicon Derivatives of Phosphorus and Sulfur, 1971, NewYork; London: Plenum Press, 343 pp.
• M.G.Voronkov, G.I..Zelchan, E.Ya.Lukevits. Silizium und Leben, 1975, Berlin: Akademie-Verlag, 370 pp.
• E.Lukevics, O.Pudova, R.Sturkovich. Molecular Structure of Organosilicon Compounds, 1989, Chichester: Ellis Horwood Ltd., 359 pp.
• E.Lukevics, T.Gar, L.Ignatovich, V.Mironov. Biological Activity of Germanium Compounds, 1990, Riga: Zinatne, 191 pp. (in Russian).
• E.Lukevics, A.Zablocka. Nucleoside Synthesis: Organosilicon Methods, 1991, Chichester: Ellis Horwood, 496 pp.
• E.Lukevics,  L.Ignatovich. Biological activity of organogermanium compounds. - In: The Chemistry of Organic Germanium, Tin and Lead Compounds/Ed. Z.Rappoport/, Wiley, Chichester, 2002, vol. 2, pt. 2, pp. 1653-1683.
• E.Lukevics,  O.Pudova. Biological activity of organogermanium compounds. - In: The Chemistry of Organic Germanium, Tin and Lead Compounds/Ed. Z.Rappoport/, Wiley, Chichester, 2002, vol. 2, pt. 2, pp. 1685-1714.

• E.Lukevics, O.Pudova. Silyl imidic esters. - In: Science of Synthesis, Thieme, 2002, vol. 4, pp. 305-315.
• E. Lukevics, P. Arsenyan, S. Belyakov, O. Pudova. Synthesis, structure and chemical transformations of ethynylgermatranes – Eur. J. Inorg. Chem., 2003, Iss.17, pp.3139-3143.
• R. Abele, E. Abele, M. Fleisher, S. Grinberga, E. Lukevics. Novel fluoride ion mediated synthesis of unsymmetrical siloxanes under phase transfer catalysis conditions. – J. Organomet. Chem., 2003, vol.686, N 1/2, pp.52-57.
• E. Lukevics, L. Ignatovich, I.Shestakova. Synthesis, psychotropic and anticancer activity of 2,2-dimethyl-5-[5-trialkylgermyl(silyl)-2’-hetarylidene]-1,3-dioxane-4,6-diones and their analogues. - Appl.Organomet. Chem., 2003, vol. 17, N 12, pp.898-905.
• P. Arsenyan, K. Rubina, I. Shestakova, E. Abele, R. Abele, I. Domracheva, A. Nesterova, J. Popelis, E. Lukevics. Synthesis and cytotoxicity of silylalkylthio-substituted N-heterocycles and their hydroselenites. – Appl. Organomet. Chem., 2003, vol. 17, N 11, pp.825-830.
• E. Lukevics, L. Ignatovich, T. Shul’ga, S. Belyakov. The crystal structure of 2-benzo[b]thienylgermatrane. – Appl. Organomet. Chem., 2003, vol. 17, N 9, pp.745-746.
• K. Rubina, E. Abele, P. Arsenyan, M. Fleisher, J. Popelis, A. Gaukhman, E. Lukevics. The role of palladium catalyst and base in stereoselective tranformations of (E)-2-chlorovinylsulfides. –Tetrahedron, 2003, vol.59, N 38, pp.7603-7607.
• I. Iovel, L. Golomba, J. Popelis, S. Grinberga, E. Lukevics Catalytic hydrosilylation of furan, thiophene, and pyridine aldimines. – Chem. Heterocycl. Comp., 2003, vol.39, N 1, pp.49-55.
• G. Veinberg, M. Vorona, I. Shestakova, I. Kanepe, E. Lukevics. Design of ß-lactams with mechanism based nonbacterial activities. – Current Medicinal Chemistry, 2003, vol.10, N 17, pp.1741-1757.
• E. Lukevics, P. Arsenyan, O. Pudova. Methods for the synthesis of oligothiophenes. – Heterocycles, 2003, vol.60, N 3, pp.663-687.
• V.Dirnens, V.Klusa, J.Skuyins, S.Svirskis, S.Germane, A.Kemme, E.Lukevics. Synthesis and pharmacological activity of silyl isoxazolines-2. - Silicon Chemistry, 2003 (publ. 2004), vol. 2, N 1/2, pp. 11-25.
• I.Iovel, L.Golomba, M.Fleischer, J.Popelis, S.Grinberga, E.Lukevics. Hydrosilylation of (hetero)aromatic aldimines in the presence of Pd(I) complex. - Chem.Heterocycl. Comp., 2004, vol. 40, N 6, pp. 701-714.
• P.Arsenyan, O.Pudova, J.Popelis, E.Lukevics. Novel radial oligothienylsilanes. - Tetrahedron Lett., 2004, vol. 45, N 15, pp. 3109-3111.
• E.Lukevics, L.Ignatovich, S.Belyakov. Crystallographic report: 2-furfurylgermatrane. - Appl. Organomet. Chem., 2004, vol. 18, N 4, p. 203.
• G. Veinberg, I. Shestakova, M. Vorona, I. Kanepe, E. Lukevics.  Synthesis of antitumor 6-alkylidenepenicillanate sulfones and related 3-alkylidene-2-azetidinones. -   Bioorg. Med. Chem. Letters, 2004, vol. 14, No 1, 147-150.
• E.Lukevics, L.Ignatovich, T.Shulga, S.Belyakov. 1-[4-(2-Thienyl)phenyl]germatrane. -   Appl. Organomet. Chem., 2005, vol. 19, N 1, pp. 167-168.
• E.Lukevics, L.Ignatovich. Biological activity of organosilicon compounds. - In:  Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. The Use of Metals in Medicine / Eds. M.Gielen, E.R.T.Tiekink/, 2005, J.Wiley & Sons, Ltd. Chichester, pp. 83-107.
• E.Lukevics, L.Ignatovich. Biological activity of organogermanium compounds. - In:  Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. The Use of Metals in Medicine / Eds. M.Gielen, E.R.T.Tiekink/, 2005, J.Wiley & Sons, Ltd. Chichester, pp. 279-295.
• Yu.Melnik, M.Vorona, G.Veinberg, J.Popelis, L.Ignatovich, E.Lukevics. Synthesis and stereoisomerization of 2-(1-alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans. -   Chem. Heterocycl. Comp., 2005, vol. 41, N 6, pp. 718-721.
• L.Ignatovich, J.Popelis, E.Lukevics. Synthesis and NMR spectra of diaryl-  and dihetarylsilacycloalkanes. - In: Organosilicon Chemistry VI / Eds. N.Auner and J.Weis/, Wiley-VCH Weinheim, 2005, vol. 1, pp. 559-562.
• L.Ignatovich, D.Zarina, I.Shestakova, S.Germane, E.Lukevics. Synthesis and bological activity of silicon derivatives of 2-trifluoroacetylfuran and their oximes. - In: Organosilicon Chemistry VI / Eds. N.Auner and J.Weis/, Wiley-VCH Weinheim, 2005, vol. 1, pp. 563-568.
• E.Lukevics, L.Ignatovich, I.Sleiksha, I.Shestakova, I.Domrachova, J.Popelis. Synthesis and cytotoxic activity of silacycloalkylsubstituted heterocyclic aldehydes. -  Appl. Organomet. Chem., 2005, vol. 19, N 10, pp. 1109-1113.
• S.Belyakov, E.Alksnis, V.Muravenko, I.Turovskis, J.Popelis, E.Lukevics. Crystal structure and conformation of 8-(2-hydroxyethylamino)-  and 8-(pyrrolidin-1-yl)adenosines. - Nucleosides, Nucleotides & Nucleic Acid, 2005, vol. 24, N 8, pp. 1199-1208.
• A. Zablotskaya, I.Segal, S.Belyakov, E.Lukevics. Silyl modification of biologically active compounds. 11. Synthesis, physico-chemical and biological evaluation of N-(trialkoxysilylalkyl)tetrahydro(iso,silaiso)quinoline derivatives. Appl. Organomet. Chem. 2006, vol.20, N 2, 149-159.  
• A.Zablotskaya, I.Segal, J.Popelis, E.Lukevics, S.Baluja, I.Shestakova, I.Domracheva. Silyl modification of biologically active compounds. 12. Silyl group as true incentive to antitumour and antibacterial action of choline and colamine analogues. - Appl. Organomet. Chem. 2006, vol. 20, N 11, 721-728.
• E.Lukevics, L.Ignatovich, I.Sleiksha, V.Muravenko, I.Shestakova, S.Belyakov, J.Popelis. Synthesis, structure and cytotoxic activity of 2-acetyl-5-trimethylsilylthiophene(furan) and their oximes. - Appl. Organomet. Chem. 2006, vol 20, N 7, 454-458.   
• L.Ignatovich, V.Muravenko, S.Grinberga, E.Lukevics. Novel reactions to form an Si-O-Ge group. - Chem.Heterocycl. Comp., 2006, vol. 42, N 2, 268-271.  
• E.Lukevics, I.Shestakova, I.Domrachova, A.Nesterova, Y.Ashaks, D.Zaruma. Synthesis of complex compounds of methyl derivatives of 8-quinolineselenol with metals and their cytotoxic activity. - Chem.Heterocycl. Comp., 2006, vol. 42, N 1, 53-59.    
• E.Lukevics, L.Ignatovich, I.Sleiksha, V.Romanov, S.Grinberga, J.Popelis, I.Shestakova. A New method for the synthesis of silicon- and germanium-containing 2-acetylfurans and 2-acetylthiophenes. -Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 143-150. 
• V.Dirnens, I.Skrastina, J.Popelis, E.Lukevics. Synthesis of isoxazolinylxanthines. - Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 193-196.   
• E.Lukevics, L.Ignatovich, S.Belyakov. Disordering in the crystal structure of thienylgermatranes. - Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 243-249.   
• E.Lukevics, I.Shestakova, I.Domrachova, E. Yashchenko, D.Zaruma. Y.Ashaks. Cytotoxic di(8-quinolyl)disulfides. - Chem.Heterocycl. Comp., 2007, vol. 43, N 5, 629-633.
• V.M.Vorona, I.Potorocina, G.Veinberg, I.Shestakova, I.Kanepe, M.Petrova, E. Liepinsh, E.Lukevics. Synthesis and structural modification of tert-butyl ester of 7a-chloro-2-(N,N-dimethylaminomethylene)-3-methyl-1,1-dioxoceph-3-em carboxylic acid.- Chem.Heterocycl. Comp., 2007, vol. 43, N 5, 646-652.
• A.Zablotskaya, I.Segal, E.Lukevics, S.Belyakov, H.Spies. Tetrahydroquinoline and tetrahydroisoquinoline mixed ligand rhenium complexes with the SNS/S donor atom set.- Appl.Organomet.Chem.,2007, vol.21, N 4, 288-293.
• A.Zablotskaya, I.Segal, M. Maiorov, D. Zablotsky, A. Mishnev E.Lukevics, I.Shestakova, I. Domracheva. Synthesis and characterization of nanoparticles with an iron oxide magnetic core and a biologically active trialkylsilylated aliphatic alkanolamine shell. J. Magn. Magn. Mater. 2007, 311, pp. 135-139. 
• Zablotskaya A., Segal I., Lukevics E., Maiorov M., Zablotsky D., Blums E., Shestakova I., Domracheva I.  Synyhesis, physico-chemical and biological study of trialkylsiloxyalkylamine coated iron oxide/oleic acid magnetic nanoparticles for the treatment of cancer. - Appl. Organomet. Chem. 2008, vol. 22, pp. 82-88.
• E.Lukevics, E.Abele. Four-membered rings with three heteroatoms not including oxygen, sulfur or nitrogen atom. - In: Comprehensive Heterocyclic Chemistry III., 2008, 2.   Four-membered heterocycles together with all fused systems containing a four-membered heterocyclic ring (Exec. Ed. A. Katritzky, FRS: Eds Ch.A. Ramsden, E.V.Scriven, R.J.Taylor), pp. 973-989.     
• Soualami S., Ignatovich L., Lukevics E.,Ourari A., Jouikov V. Electrochemical oxidation of benzylgermatranes. - J. Organomet. Chem., 2008, vol.693 (7), pp. 1346-1352.
• Lukevics E.,   Ignatovich L., Shul'ga T., Belyakov S. Synthesis and crystal structure of 1-(4-fluorophenyl)- and 1-(4-dimethylamino)phenylgermatranes. - Chem. Heterocycl.Comp. (Engl.Ed.), 2008, vol. 44 (5), pp. 615-620.
• Abele E., Lukevics E. Synthesis of Heterocycles from Oximes. - In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. (Eds. Z.Rapoport, J.F.Liebmann ), J.Wiley, Chichester, 2009,  Part I, pp. 233-302.
• Erchak N., Belyakov S., Kalvinsh I., Pypowski K., Valbahs E., Lukevics E. Two polymorphic modifications of 1-(N-morpholiniomethyl)spirobi(3-oxo-2,5-dioxa-1-silacyclopentan)ate hydrate. -Chem.Heterocycl. Comp.(Engl. Ed.), 2009, vol. 45, N 9, pp.1137-1143..
• Zablotskaya A.,Segal I., Lukevics E., Maiorov M., Zablotsky D., Blums E., Shestakova I., Domracheva I.  Water-soluble magnetic nanoparticleswith biologically active stabilizers. - J.Magn.Mater.,2009, 321, pp. 1428-1432.
• Ignatovich L., Muravenko V., Shestakova I., Domracheva I, Popelis J., Lukevics E. Synthesis and Cytotoxic activity of new 2-[(3-aminopropyl)- dimethylsilyl]-5-triethylsilylfurans. -  Appl. Organomet. Chem. 2009, DOI 10.1002, aoc, 1538.
• Vorona M., Veinberg G.,Liepinsh E., Kazoka H., Andrejeva G., Lukevics E. Enzymatic synthesis of amoxycilloic acids. - Chem.Heterocycl. Comp.(Engl. Ed.), 2009, vol. 45, N 6, pp.782-754.
• Zablotskaya A.,Segal I., Lukevics E. Iron oxide-based magnetic nanostructures bearing cytotoxic organosilicon molecules for drug delivery and therapy. - Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 150-157.
• Ignatovich L., Muravenko V., Shestakova I., Domracheva I, Popelis J., Lukevics E. Synthesis and Cytotoxic activity of new 2-[(3-aminopropyl)- dimethylsilyl]-5-triethylsilylfurans. -  Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 158-161.
• Segal I., Zablotskaya A.,Lukevics E., Maiorov M., Zablotsky D., Blums E., Mishnew A., Georgieva R., Shestakova I., Gulbe A. Preparation and cytotoxic properties of goethite-based nanoparticles covered with decyldimethyl(dimethylaminoethoxy)silane metoxyde. -  Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 193-197.
• Ignatovich L., Muravenko V., RomanovsV,  Sleiksha I., Shestakova I., Domracheva I, Belyakov S., Popelis J., Lukevics E. Synthesis, structure and cytotoxic activity of new 1-[5-organylsilyl(germyl)-2-furyl(thienyl)]nitroethenes. -  Appl. Organomet. Chem. 2010, vol. 24, N 12, pp. 858-864.
• Lukevics E., Abele E., Ignatovich L. Biologically Active Silacyclanes. - Adv. Heterocycl. Chem., 2010, vol. 99, pp. 107-141.
• Abele E., Lukevics E. Synthesis, structure and reactions of organometallic derivatives of oximes. - In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. Eds. by Zvi Rapoport, J.F.Liebman. 2011, Vol.2, Part 1 (Chapter 4), pp. 145-203.
• Katkevics M., Kukosha T., Lukevics E. Heterocycles from hydroxylamines and hydroxamic acids. -  In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. Eds. by Zvi Rapoport, J.F.Liebman. 2011, Vol.2, Part 1 (Chapter 5), pp. 205-293. 

Research Projects:

• E.Lukevics (Head of Project). Silylheterocycles in Organic Chemistry. Latvian Council of Science (1993-1995).
• E.Lukevics (Head of Project). Bifunctional Organosilicon Compounds. Latvian Council of Science (1993-1995).
• E.Lukevics (Head of Project). Synthesis of Heterocyclic Organosilicon and Organogermanium Compounds, Investigation of their Physical and Chemical Properties. Latvian Council of Science (1997-2000 ).
• E.Lukevics (Head of Project). Asymmetric and Catalytic Synthesis of Heteroaromatic Compounds. Latvian Council of Science (1997-2000 ).
• E.Lukevics (Head of Program). The Development of Modern Methods of Organic Chemistry Directed towards the Development of Pharmaceutical Industry in Latvia. Latvian Council of Science (1997-2000 ).
• E.Lukevics (Head of Project). Experimental and Theoretical Aspects of the Catalytical Synthesis of Heteroaromatic Compounds. Latvian Council of Science (2001 -2004 ).
• E.Lukevics (Head of Project). Comparative Study of the Structure and Biological Activity of Organosilicon and Organogermanium Compounds. Latvian Council of Science (2001 - 2004).
• E.Lukevics (Head of Project). Heterocyclic Derivatives of Tetra- and Hypercoordinated Germanium and Silicon. Latvian Council of Science (2005 -).
• E.Lukevics ( Programme Director). Development  of Organic Synthesis Methods for  Obtaining of Biologically Active Compounds. Latvian Council of Science (2002 -2005 ).
• E.Lukevics ( Programme Director). Development  of  Heteroatom Chemistry for Preparation of Biologically Active Compounds. Latvian Council of Science (2006 - 2009 ).
• E.Lukevics (Head of Project). Carbofunctional Silylheterocycles. Latvian Council of Science (2009 ).

Hobbies:

Opera, Basketball, Mountains.

Edmunds LUKEVICS

Edmunds LUKEVICS  Head of Laboratory of Organometallic Chemistry Latvian Institute of Organic Synthesis Aizkraukles iela 21, Riga, LV-1006 http://www.lza.lv/scientists/lukevics.htm Born: December 14, 1936, Liepaja, Latvia Departed: November 21, 2009, Riga, Latvia

Interests in inventing: Development of medicament synthesis and technology Development of the synthesis and technology of agricultural chemicals Main invention: In the sphere of medicament synthesis: Acylete derivatives of aminobenzylpenicillin with antimicrobe activity.Co-authors: G.Veinbergs, G.Kvitsors a.o. Authors' certificate of USSR Nr.1829360, 1992 Substituted 3-hydrazinopropionates and their pharmaceutically available salts with antiarythmic activity. Co-authors: G.Bremanis, I. Kalvins, I.Ancena a.o.Authors' certificate of USSR Nr.1247012, 1986. Patent of USA Nr. 4633014 Patent of England Nr. 2144121 Patent of France Nr. 2549050 Patent of Italy Nr.1175577 In the sphere of the synthesis of agricultural chemicals: 2,2 –dimethyl-6-alkyl-1,3-dioxa-6-aza-2-silacyclooctanes with antiinsect activity. Co-authors: V.Markina, N.Smirnova a.o. Authors' certificate of USSR Nr.687855, 1978. Lucerne productivity stimulator. Co-authors: L.Sermans, V.Janisevska, G.Zelcans a.o. Authors' certificate of USSR Nr. 1161056, 1985 Selection of patent documents: Totally: 104 authors' certificates of USSR, 11 patents of Latvia, 3 patents of Germany, 3 patents of Canada, 3 patents of France, 3 patents of Italy, 1 patent of Japan, 1 patent of Switzerland, 4 patents of Great Britain, 5 patents of USA. Patents of Latvia: E.Lukevics, D.Feldmane, H.Kazoka, I.Turovskis. Method for obtaining metoxi-alpha-methylbenzyl alcohol. Patent of Latvia Nr. 11864, C 07 C 29/58, 1997; E.Lukevics, V.Slavinska, Dz.Sile, M.Katkevics, E.Korcagova. Method for obtaining 2-oxo-4-phenylbutane acid ethylester. Patent of Latvia Nr. 11891, C 07 C 69/716, 1998; E.Lukevics, V.Slavinska, Dz.Sile, M.Katkevics, E.Korcagova, V.Belikovs. Method for obtaining 2-oxo-4-phenylbutane acid ethylester. Patent of Latvia Nr. 11892, C 07 C 69/716, 1998; E.Lukevics, I.Kalvins, A.Birmans. Cardioprotector "Mildronate". Patent of Latvia Nr. 5402, A 61 K 31/205, 1994; E.Lukevics, G.Veinbergs, I.Sestakova, I.Kalvins. Cephalosporin derivatives with citostatic activity. Patent of Latvia Nr. 11953, C 07 D 501/02, 1998.

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SOFOSBUVIR VISITED

SOFOSBUVIR

SEE NMR PREDICTIONS BELOW

Propan-2-yl (2s)-2-[[[(2r,3r,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
CAS No.:	1190307-88-0
Synonyms:	(S)-2-{(S)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy)phosphorylamino}propionic acid isopropyl ester; SOFOSBUVIR; GS-7977;
Formula:	C22H29FN3O9P
Exact Mass:	529.16300
Molecular Weight:	529.45300

1H NMR PREDICTED
CAS NO. 1190307-88-0, propan-2-yl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate H-NMR spectral analysis




13C NMR PREDICTED
CAS NO. 1190307-88-0, propan-2-yl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate C-NMR spectral analysis
..............................................................................................
J. Med. Chem. 2010, 53, 7202–7218 DOI: 10.1021/jm100863x
http://www.chem.wisc.edu/deptfiles/chem345-gellman/Sp13/Antiviral_Drug/Sofosbuvir%20discovery%2010.pdf
51 (HPLC purity 99.74%, mp 93.9-104.7 C) in 15.2% yield from 6

.......................................................
NMR
http://file.selleckchem.com/downloads/nmr/S279401-Sofosbuvir-PSI-7977-HNMR-Selleck.pdf

......................................
http://www.google.co.in/patents/WO2013040492A2?cl=en
Example 10: Preparation of Compound 10 (from US2010/0298257)

Direct precipitation of Compound 10 (from US2010/0298257; Example 4): To a stirred solution of L-alanine isopropyl ester hydrochloride (10.5 g, 61.5 mmol, azeotropically dried, two times, with 50 mL of toluene each time) in dichloromethane (100 mL) was added
phenydichlorophosphate (7.5 mL, 50 mmol) at room temperature. The mixture was cooled to - 10° C. and then was added a solution of N-Methylimidazole (30.5 mL, 384.3 mmol) in 30 mL of dichloromethane over a period of 30 min. After completion of the addition, the mixture was stirred between -10 and -15° C. for 1 h. To the above mixture was added 2'-deoxy-2'-fluoro-2'- C-methyluridine (10 g, 38.4 mmol) (see US2010/0298257 Example 1) in one lot and the mixture was stirred below -10° C. for 3 h and then slowly allowed to warm to 20° C. (6 h). The mixture was stirred at this temperature overnight (15 h) and then quenched with 10 mL of methanol. The solvent was evaporated and the residue was re-dissolved in EtOAc (200 mL). The EtOAc layer was washed with water (100 mL), 1 N HCI (3x75 mL), 2% aqueous NaHC0₃ solution (50 mL) and brine (50 mL). The organic layer was dried over Na₂S0₄ filtered and concentrated. The residue was dried under high vacuum for 2 h to give white foam (22 g).
The above foam was dissolved in 33 mL of HCI and then was added 65 mL of isopropyl ether to give a saturated solution. The solution was filtered though a small pad of Celite and the filtrate was stirred with seeds of Compound 10 for 72 h at ambient temperature (about 22° C.-note that cooling the suspension to 0° C. led to oiling out the crude product). The white solid was filtered, washed with isopropyl ether (20 mL) and dried to give 4.58 g (-85:15 mixture of Compound 10: R isomer at P respectively as determined by ³¹ P NMR) of a white powder. The above solid was suspended in 23 mL of HCL and then refluxed for 3 h. The mixture was cooled to room temperature and stirred for 15 h. The white solid was filtered, washed with 4.5 mL of cold HCI and dried under high vacuum at 45° C. to give pure Compound 10, mp 93.9-104.7° C HPLC purity 99.74% (3.11 g, 15.2% from the uridine nucleoside).
Compound 10:
¹H-NMR (CDCI₃) δ 8.63 (br s, ¹H, NH), 7.47 (d, 1 H, C6-H), 7.30 (m, 2H, o- aromatic), 7.26-7.18 (m, 3H, m,p-aromatic), 6.18 (br d, IH, Cl'-H), 5.70 (d, IH, C5-H), 5.02 (sept, CH-(CH₃)₂), 4.53 (m, 2H, C-5'-H₂), 4.11 (d, IH, C3'-H), 3.97 (m, 3H, C3'-OH, C4'-H, ala-CH- CH₃), 3.77 (br s, IH, ala-NH), 1.39 (d, 3H.C2'- CH₃), 1.37 (d, 3H, ala- CH₃) 1.24 (d, 6H, CH- (CH₃)₂).

................................
http://www.google.co.in/patents/US20100298257
Synthetic Aspects
In order to prepare the uridine nucleoside, one could take advantage of an advanced tribenzoylated cytidine intermediate in the synthesis of certain 3′,5′-diacylated analogs of 3 (see below) already produced efficiently on a pilot plant scale (see WO 2006/031725 or US 2006/0122146, both of which are incorporated by reference in their entirety). The following method was found to be scalable and cost-efficient.

3′,5′-O-dibenozyl-2′-deoxy-2′-fluoro-2′-C-methyl-N⁴-benzoylcytidine (1) is obtained by a method disclosed in WO 2006/031725 and WO 2008/045419 both of which are hereby incorporated by reference in its entirety. 1 is treated with 70% aqueous acetic acid to form 3′,5′-O-dibenozyl-2′-deoxy-2′-fluoro-2′-C-methyl-uridine (2). Th benzoyl esters can be hydrolyzed by a number of methods as well, e.g., alkoxides in alcoholic solvent, such as sodium methoxide in methanol, potassium carbonate in methanol, or ethanol analogs, alkylamines such as methylamine in methanol, butylamine etc. Methanolic ammonia was chosen for the larger scale work. The uridine product (3) can be purified by crystallization to afford a 70% yield from the tribenzoylated cytidine (1).
Numerous literature procedures detail different routes and conditions to make phosphoramidates using several fold equivalents of reagents. See, for example, McGuigan et al. J. Med. Chem. 2005, 48, 3504-3515 and McGuigan et al. J. Med. Chem. 2006, 49, 7215. For process scale work, there is only one presently known example, which is disclosed in Lehsten et al., Org. Process Res. Dev. 2002, 6, 819-822 (“Lehsten”). In this reference, the authors introduce the concept of a “one-pot procedure” in which an amino acid hydrochloride salt and phenyl dichlorophosphate are reacted together with N-methylimidazole in dichloromethane. Later the nucleoside is added to form the desired 5′-O-phosphoramidate product, which in the present case would yield a compound represented by formula 4. Unfortunately, the Lehsten procedure suffered from drawbacks. For example, the Lehsten procedure utilized a far larger excess of reagents than was necessary which added to the cost and difficulty of chromatographic purification. Furthermore, Lehsten suggested that one could control the reaction selectivity on the 5′-hydroxyl over the 3′-hydroxyl compared to a literature reference through using lower temperatures and slow addition of the nucleoside.

Using the Lehsten procedure for the compounds disclosed herein provided for about 1-5% of mono-substituted 3′-O-phosphoramidate diastereomers (5) and about 10-30% of the bis-substituted product (6). As the polarity of the 3′-diastereomers was very similar to the desired 5′-diastereomers (4), chromatographic separation was very challenging. Scaling up the process was nearly impossible without discarding a substantial portion of the less polar 5′-diastereomers (4) or accepting a higher level of contamination of the 3′-diastereomers (5). In an initial 50 g scale-up, the resultant product contained a 3′-diastereomer (5) contamination of about 3%, which co-eluted with the less polar of the 5′-diastereromer (4).
Disclosed herein are reaction conditions which use lesser amounts of reagents and a method to selectively remove the impurity 3′-O-phosphoramidate diastereomers (5) with an easier chromatographic separation thereby affording the desired 5′-O-phosphoramidate diastereomers in much higher purity (4).
For the reagent stoichiometry, a study was made in which the stoichiometry of the reagents was systematically changed and the results were monitored by phosphorus NMR of the crude reaction as Lehsten had reported. In the more successful runs, the isolated yield and purity of the desired product were compared. It was observed that the primary 5′-hydroxyl reacts at a faster rate than the secondary 3′-hydroxyl. This creates a competing situation between the reaction progress of consuming all the starting nucleoside and converting 5′- and 3′-monosubstituted products (4 and 5) to the 5′,3′-bis substituted products (6). The 3′-monosubstituted product converts to the bis product at a faster rate than the 5′-monosubstituted product, so it is possible to reduce the 3′-diastereomer contamination level by pushing the reaction more to the bis-substituted products. However, with an effective way to remove the 3′-diastereomers, the reaction can be optimized to produce more of the desired 5′-diastereomer without having to sacrifice as much of the 5′-diastereomer being converted to the bis-substituted (6). It was also observed that the amino acid hydrochloride is very hygroscopic. As any water present would consume an equivalent amount of the phenyl dichlorophosphate reagent, care must be taken to keep the amino acid substantially anhydrous or it should be made substantially anhydrous prior to use. In short, Lehsten had reported that the optimum ratio of amino acid to phenyl dichlorophosphate to nucleoside was 3.5:2.5:1 respectively. It was found that the optimum ratio of amino acid to phenyl dichlorophosphate to nucleoside of about 1.6 to about 1.3 to about 1 is optimal under conditions in which the 3′-diastereomer can be efficiently removed and when the amino acid hydrochloride is substantially anhydrous. By using a smaller amount of the reagents, a cost savings is realized coupled with a simplification of the chromatographic separation of the desired product from reagent by-products and from the reduced level of bis diastereomers.
In one alternative procedure, a 3′-hydroxy-blocked derivative of 3 was prepared using a t-butyldimethylsilyl blocking group in two steps. This was then converted to its 5′-phosphoramidate derivative. The desire being that the silyl group could then be removed and there would be no 3′ isomers (5) or 3′,5′-bis phosphoramidates (6). A similar approach was demonstrated by Borch and Fries (U.S. Pat. No. 5,233,031) in a low overall yield on an alkyl phosphoramidate.
Another alternative approach was to use the direct synthesis and then use chemistry to help differentiate the 3′-diastereomer impurities 5 from the desired 5′-diastereomers 4 to help the separation. A group was desired that would selectively react with the free primary hydroxyl of the 3′-O-phosphoramidate impurity 5 over the free secondary hydroxyl of the desired 5′-O-phosphoramidate 4. It was also desired that the blocking group significantly change the polarity of the resulting 5′-O-blocked 3′-O-phoshoramidate product from the desired 5′-O-phosphoramidate 4. There would be no extra step needed to remove the blocking group as the desired 5′-diastereomers 4 would not be changed. The chemically altered 3′-diastereomers would then allow easier chromatographic separation or separation by special scavenging supports or by extractions.
Specifically, the blocking group tert-butyldimethylsilyl (tBDMS) met these criteria and was the first one to be demonstrated and subsequently used on a multi-kilogram scale. Under certain conditions such as in pyridine as solvent and base, the tBDMS group reacts with high selectively at the primary hydroxyl position over the 3′ secondary hydroxyl position. The phosphoramidate reaction uses N-methylimidazole (NMI) as a base. In the presence of NMI, the silylation is less selective. Preferably, the amount of NMI should be reduced. This can be accomplished easily after the phosphoramidate reaction by washing the reaction solution with 1 N hydrochloric acid. The NMI and the remaining starting nucleoside are removed, leaving a crude mixture of mono and bis substituted products and reagent by-products. This is then dissolved in pyridine and treated with tert-butyldimethylsilyl chloride. The 3′-monosubstituted product 5 is converted in a few hours or less to the 5′-O-tBDMS-3′-O-phosphoramidate 7. The reaction progress can be monitored by HPLC. The polarity of this silylated product 7 is less than the bis-phosphoramidate 6 and is readily removed by chromatography. Using this method, it was possible to reduce the level of 3′-monophosphoramidate 5 to less than 0.1% of the 5′-product 4 compared to 1-3% without the silyl treatment. Similarly, treatment with dimethoxytriphenylmethyl chloride (DMT-Cl) under the same conditions worked just as well. It was also easier to identify the DMT reaction product by TLC as DMT containing molecules stain bright orange on heating or exposure to acid. One can also envision many other blocking groups, as noted above.
Both the reaction conditions and the scavenging of the 3′-impurity are general methods and could be applied to most nucleoside phosphoramidates with a free 3′ hydroxyl. The phosphoramidate moiety could be any combination of amino acid ester and aromatic alcohol. The nucleoside moiety could be any nucleoside in which a 5′ phosphoramidate would lead to a 5′-monophosphate and could be further metabolized to the 5′-triphosphate form.
The following scheme is the main reaction scheme illustrated for making isopropyl L-alanate phenyl phosphoramidate of 2′-deoxy-2′-fluoro-2′-C-methyluridine with the major product as the desired 5′-O-phosphoramidate (4, two diastereomers) and the minor product as the 3′-O-phosphoramidate (5, two diastereomers) and the 3′,5′ -bis-O-phosphoramidate (6, four diastereomers). The reagents are added in the stoichiometric ratios as described in the method of preparation section. The reaction is allowed to proceed until about 5% of the starting material remains as judged by UV visualization on thin layer chromatography (TLC). Also UPLC/MS showed approximately 10% of the 3′,5′ bis-phosphoramidate 6 had formed compared to the desired 5′-product. After quenching and an acidic aqueous workup, the crude residue from the organic layer was prepared for the silylation. Under the described reaction conditions, the silyl group preferentially reacted with the free 5′-hydroxyl of the 3′-O-phosphoramidate to form 7. The reaction was continued until the 3′-O-phosphoramidate was no longer detectable by UPLC/MS.

After working up the silylation reaction, the desired product is subjected to chromatography on silica gel and is eluted with a gradient of methanol in dichloromethane (1-4%). The desired 5′-monophosphoramidate 4 elutes last.
Example 4 Preparation and Crystallization of S_P-4
Method 1: Direct precipitation from crude 4: To a stirred solution of L-alanine isopropyl ester hydrochloride (10.5 g, 61.5 mmol, azeotropically dried, two times, with 50 mL of toluene each time) in dichloromethane (100 mL) was added phenydichlorophosphate (7.5 mL, 50 mmol) at room temperature. The mixture was cooled to −10° C. and then was added a solution of NMI (30.5 mL, 384.3 mmol) in 30 mL of dichloromethane over a period of 30 min. After completion of the addition, the mixture was stirred between −10 and −15° C. for 1 h. To the above mixture was added 2′-deoxy-2′-fluoro-2′-C-methyluridine (3) (10 g, 38.4 mmol) in one lot and the mixture was stirred below −10° C. for 3 h and then slowly allowed to warm to 20° C. (6 h). The mixture was stirred at this temperature over night (15 h) and then quenched with 10 mL of methanol. The solvent was evaporated and the residue was re-dissolved in EtOAc (200 mL). The EtOAc layer was washed with water (100 mL), 1N HCl (3×75 mL), 2% aqueous NaHCO₃ solution (50 mL) and brine (50 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was dried under high vacuum for 2 h to give white foam (22 g).
The above foam was dissolved in 33 mL of DCM and then was added 65 mL of IPE (isopropyl ether) to give a saturated solution. The solution was filtered though a small pad of Celite and the filtrate was stirred with S_P-4 seeds for 72 h at ambient temperature (about 22° C.—note that cooling the suspension to 0° C. led to oiling out the crude product). The white solid was filtered, washed with IPE (20 mL) and dried to give 4.58 g (˜85:15 mixture of S_P-4:R_P-4 respectively as determined by ³¹P NMR) of a white powder. The above solid was suspended in 23 mL of DCM and then refluxed for 3 h. The mixture was cooled to room temperature and stirred for 15 h. The white solid was filtered, washed with 4.5 mL of cold DCM and dried under high vacuum at 45° C. to give pure S_P-4, mp 93.9-104.7° C., HPLC purity 99.74% (3.11 g, 15.2% from the uridine nucleoside).
S_P-4 ¹H-NMR (CDCl₃) δ 8.63 (br s, 1H, NH), 7.47 (d, 1H, C6-H), 7.30 (m, 2H, o-aromatic), 7.26-7.18 (m, 3H, m,p-aromatic), 6.18 (br d, 1H, C1′-H), 5.70 (d, 1H, C5-H), 5.02 (sept, CH—(CH₃)₂), 4.53 (m, 2H, C-5′-H₂), 4.11 (d, 1H, C3′-H), 3.97 (m, 3H, C3′-OH, C4′-H, ala-CH—CH₃), 3.77 (br s, 1H, ala-NH), 1.39 (d, 3H,C2′-CH₃), 1.37 (d, 3H, ala-CH₃), 1.24 (d, 6H, CH—(CH₃)₂).



updated

J. Med. Chem. 2005, 48, 5504.
WO2008045419A1
CN201180017181





UPDATE DEC 2015...........

 

SOFOSBUVIR

NEW PATENT WO2015188782,

(WO2015188782) METHOD FOR PREPARING SOFOSBUVIR

CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD [CN/CN]; No. 8 Julong North Rd., Xinpu District Lianyungang, Jiangsu 222006 (CN)
 




Sofosbuvir synthesis routes currently used include the following two methods:



https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015188782&redirectedID=true

 

Preparation Example 1 sofosbuvir implementation

Step (a):

At 0 ℃, dichloro-phenyl phosphate (6.0g, 28.4mmol) in dry dichloromethane (30ml) and stirred added alanine isopropyl ester hydrochloride (4.8g, 28.4mmol), the mixture After stirring and cooling to -55 ℃, was slowly added dropwise triethylamine (6.5g, 64mmol) and dichloromethane (30ml) mixed solution, keeping the temperature during at -55 ℃, dropping was completed, stirring was continued for 60 minutes, after liters to -5 ℃ stirred for 2 hours, TLC monitored the reaction was complete. To remove triethylamine hydrochloride was filtered and the filtrate evaporated under reduced pressure to give compound 3-1 as a colorless oil (Sp / Rp = 1/1).

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ as internal standard): δ8.25 & 7.94 (1: 1);

¹ HNMR (CDCl ₃ , 300 MHz): δ7.39-7.34 (m, 2H), 7.27-7.18 (m, 3H), 5.10-5.02 (m, 1H), 4.51 (br, 1H), 4.11 (m, 1H ), 1.49 (d, 3H), 1.29-1.24 (m, 6H);

¹³ C NMR (CDCl ₃ , 300 MHz): δ172.1 (Rp), 196.3 (Sp), 129.8,129.6 (d), 125.9,120.5 (d), 69.7 (d), 50.7 (d), 21.6 (d), 20.4 (d).

Step (b):

At 5 ℃, the compound of formula 2 (5.20g, 20.0mmol) in dry THF (30ml) and stirred at t-butyl chloride (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise the compound 3-1 (approximately 28.4mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 4: 1). Toluene was added (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (2.6g, yield 25%, HPLC purity measured 98.8%).

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ as internal standard): δ3.54ppm;

¹³ C NMR (CDCl ₃ , 300 Hz): δ173.1 (d), 162.7 (s), 150.2 (d), 139.3 (d), 129.6 (q);

MS (M + H): 530.1.

Preparation of compounds of formula 2 shown in Example 3-2

(1) a nucleophilic reagent as NaSCN, the phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added dropwise It was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

¹ HNMR (CDCl ₃ , 500Hz): δ7.32-7.13 (m, 3H), 7.08-7.02 (m, 2H), 5.0-4.9 (m, 1H), 3.92 (m, 1H), 1.49 (m, 3H ), 1.23-1.17 (m, 6H);

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ-18.16 / -18.26.

(2) nucleophile NaSCN, phase transfer catalyst is 18-crown-6 ether

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in ethyl acetate (20ml) was added 18-crown -6 (2.8mmol), the NaSCN (35mmol) was added to the above the reaction mixture. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(3) nucleophile NaSCN, phase transfer catalyst is TBAB and 18-crown-6

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol) and 18-crown -6 (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(4) nucleophile as NaN ₃ , phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaN ₃ (35 mmol) in water (2.0ml) solution of was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = N ₃ ).

¹ HNMR (CDCl ₃ , 500Hz): δ7.30-7.33 (m, 2H), 7.27-7.21 (m, 3H), 5.10-5.05 (m, 1H), 4.12-4.00 (m, 1H), 1.43 (d , 3H), 1.28-1.17 (m, 6H);

³¹ PNMR- (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ2.04 / 2.19.

(5) the nucleophilic reagent is KCN, the phase transfer catalyst is TBAB

The compound was dissolved in methylene chloride as in formula 3-1 (20ml), was added TBAB (2.8mmol), the KCN (35mmol) in water (2.0ml) was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give a compound as shown in Formula 3-2 (where X = CN).

¹ HNMR (CDCl ₃ , 300 Hz): δ7.22-7.13 (m, 3H), 7.09-7.02 (m, 2H), 5.01-4.95 (m, 1H), 4.08-3.93 (m, 1H), 1.43-1.35 (m, 3H), 1.20-1.17 (m, 6H);

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ-2.71 / -2.93.

Preparation Example 3 sofosbuvir implementation

(1) X is SCN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 (Preparation Example 2 28.4 mmol, obtained) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. After dropping was completed, the mixture was stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (3.6g, yield 34%, HPLC purity measured 98.7%).

¹ HNMR (CDCl ₃ , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl'-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH ₃ ) ₂ ) , 4.57-4.41 (m, 2H, C5'-H2), 4.12-4.09 (d, 1H, C3'-H), 4.06-3.79 (m, 3H, C3'-OH, C4'-H, Ala-CH -CH ₃ ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2'-H3), 1.36-1.34 (d, 3H, Ala-CH ₃ ), 1.25-1.23 (t, 6H, CH- (CH ₃ ) ₂ );

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

(2) X is N ₃

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. Was added lithium chloride (21.0mmol), was slowly added dropwise after the compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 7: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.2g, yield 40%, HPLC purity measured 98.8%).

¹ HNMR (CDCl ₃ , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl'-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH ₃ ) ₂ ) , 4.57-4.41 (m, 2H, C5'-H2), 4.12-4.09 (d, 1H, C3'-H), 4.06-3.79 (m, 3H, C3'-OH, C4'-H, Ala-CH -CH ₃ ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2'-H3), 1.36-1.34 (d, 3H, Ala-CH ₃ ), 1.25-1.23 (t, 6H, CH- (CH ₃ ) ₂ );

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

(3) X is CN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.02g, yield 40%, HPLC purity measured 98.8%).

¹ HNMR (CDCl ₃ , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl'-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH ₃ ) ₂ ) , 4.57-4.41 (m, 2H, C5'-H2), 4.12-4.09 (d, 1H, C3'-H), 4.06-3.79 (m, 3H, C3'-OH, C4'-H, Ala-CH -CH ₃ ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2'-H3), 1.36-1.34 (d, 3H, Ala-CH ₃ ), 1.25-1.23 (t, 6H, CH- (CH ₃ ) ₂ );

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

 

 
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