- Synthesis and characterization of an epimer of tacrolimus, an immunosuppressive drug
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8-Epitacrolimus (2), a new l-pipecolic acid macrolide lactone, was obtained by base-catalyzed epimerization of tacrolimus (FK-506, 1), an important immunosuppressive drug, and its structure determined by a single-crystal X-ray diffraction method. The compound was fully characterized by spectroscopic techniques. The epimer is of importance due to its potential biological effects as well as because of its possible formation during formulation, handling, and use of tacrolimus products.
- Skytte, Dorthe M.,Frydenvang, Karla,Hansen, Liselotte,Nielsen, Peter G.,Jaroszewski, Jerzy W.
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- Some transformations of tacrolimus, an immunosuppressive drug
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Transformations of the macrocyclic lactone tacrolimus (1), an important immunosuppressive drug produced by Streptomyces species, are described. These transformation products are primarily of interest as reference substances for drug impurity analyses. Upon action of acid (p-toluenesulfonic acid in toluene), tacrolimus is dehydrated by loss of water from the b-hydroxyketone moiety with partial inversion of configuration at C-8, resulting in formation of 5-deoxy-D5,6-tacrolimus and 5-deoxy-δ5,β-8-epitacrolimus. The structure of the latter was determined by single-crystal X-ray crystallography. The same products are formed upon action of free radicals (iodine in boiling toluene), along with formation of 8- epitacrolimus. The latter is converted by p-toluenesulfonic acid to 5-deoxy-D5,6-8-epitacrolimus. Treatment of tacrolimus with weak base (1,5-diazabicyclo[4.3.0]nonene) gives, in addition to 8-epitacrolimus, the open-chain acid corresponding to 5-deoxy-Δ5,β-tacrolimus, a rare non-cyclic derivative of tacrolimus. Strong base (t-butoxide) causes pronounced degradation of the molecule. Thermolysis of tacrolimus leads to ring expansion by an apparent [3,3]-sigmatropic rearrangement of the allylic ester moiety with subsequent loss of water from the b-hydroxyketone moiety. 1H and 13C NMR spectra of the obtained compounds, complicated by the presence of amide bond rotamers and ketal moiety tautomers, were assigned by extensive use of 2D NMR techniques.
- Skytte, Dorthe M.,Jaroszewski, Jerzy W.,Johansen, Kenneth T.,Hansen, Steen Honore,Hansen, Liselotte,Nielsen, Peter G.,Frydenvang, Karla
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p. 514 - 522
(2013/05/21)
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- Characterization of FK506 biosynthetic intermediates involved in post-PKS elaboration
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The post-PKS modification steps of FK506 biosynthesis include C9-oxidation and 31-O-methylation, but the sequence of these reactions and the exact route have remained unclear. This study details the post-PKS modification pathways in FK506 biosynthesis thr
- Ban, Yeon Hee,Shinde, Pramod B.,Hwang, Jae-Yeon,Song, Myoung-Chong,Kim, Dong Hwan,Lim, Si-Kyu,Sohng, Jae Kyung,Yoon, Yeo Joon
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p. 1091 - 1098
(2013/07/26)
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- PROCESS FOR PURIFICATION OF MACROLIDES
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The invention is a novel process for purification of macrolides such as Tacrolimus using a new polymer resin and copper salts containing cupric ions. The novel polymer resin contains polyvinyl pyrrolidone, metha acrylate, divinyl benzene based compounds. In the said process manufacturing of new polymer resin and use of cupric salt is very much cost effective. The same metal salts can also be used along with other neutral non-ionic adsorption resins of polyethylene i e HP2O, HP2OSS, Sepabeads SP207 and the like. The concentration of copper ions may be generally 0.20 to 1.5 mol/L, preferably 0.30 to 0.40 mol/L. As an aqueous medium for the copper ion containing aqueous solvent, an aqueous acetone, an aqueous alcohol, an aqueous acetonitrile or the like. The invention covers Tacrolimus having a purity of more than 99.7%.
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Page/Page column 2; 3
(2008/12/05)
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- A PROCESS FOR PURIFICATION OF MACROLIDES
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The present invention relates to a process for separating a macrolide from a mixture comprising homologs, analogs or isomers thereof by using silver-impregnated silica gel chromatography.
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Page/Page column 5-6
(2008/06/13)
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- METHOD OF PURIFYING MACROLIDES
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A method for purifying macrolide is provided in which a loading charge of macrolide is placed in juxtaposition with a bed of wet sorption resin, the loading charge and bed are eluted at a temperature greater than 30°C with an eluent of an organic solvent selected from the group consisting of THF, acetonitrile, n-propyl alcohol, iso-propyl alcohol, ethyl alcohol, and acetone, the heart cut of the eluent is collected, and purified macrolide is collected.
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Page/Page column 10-15
(2008/06/13)
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- METHOD OF PURIFYING MACROLIDES
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Provided is a method of purifying a macrolide, especially tacrolimus, that includes loading macrolide onto a bed of sorption resin and elting with a suitable eluent such as a combination of water and tetrahydrofuran.
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- A PROCESS FOR THE RECOVERY OF SUBSTANTIALLY PURE TRICYCLIC MACROLIDE
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Process for the recovery of a macrolide in substantially pure form comprising: a) treating the macrolide with water immiscible solvent followed by concentration, b) mixing with water, water miscible solvent or mixture thereof, c) performing hydrophobic interaction chromatography and collecting the fractions, d)extracting the fraction containing macrolide with water immiscible solvent followed by concentration, e) adding water miscible solvent to effect separation of impurities from the macrolide compound, f) performing silica gel chromatography and collecting the fractions, g) isolating the macrolide compound in substantially pure form. The macrolide is preferably rapamycin, tacrolimus or immunomycin.
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Page/Page column 8-9
(2008/06/13)
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- CRYSTALLIZATION AND PURIFICATION OF MACROLIDES
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Provided is a method for crystallization and purification of a macrolide such as tacrolimus, sirolimus, pimecrolimus, or everolimus that includes the step of providing a combination of a macrolide, and a polar solvent, dopolar aprotic solvent, or hydrocarbon solvent at pH of 7 or above.
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- Rapid synthesis of 11C-labeled FK506 for positron emission tomography
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The present study describes a rapid synthesis method for labeled [11C]FK506 for positron emission tomography (PET). A one-pot reaction from [11C]CH3I, involving a Wittig reaction as the key carbon-carbon bond formation was developed. The chemical process was accomplished using a designed, fully automated synthetic apparatus, and an injectable solution of [11C]FK506 was obtained in only 34 min from [11C]CH3I. The decay-corrected radiochemical yield based on [11C]CH3I was 11.9%, and the specific activity was 39.8 GBq/μmol.
- Murakami, Yoshihiro,Kuroda, Akio,Osoda, Kazuhiko,Nishimura, Shintaro
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p. 641 - 644
(2007/10/03)
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- Pharmaceutical compositions and methods for treating immune-response associated diseases of the surface and the anterior segment of the eye
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A pharmaceutical composition for the treatment of immune-related diseases of ocular surface and the anterior segment of the eye. More specifically, the invention relates to a composition comprising tacrolimus in a pharmaceutically acceptable formulation, particularly a suitable local treatment formulation, such as eye drops and ointments. Also disclosed is a method for the treatment of immune-response related ocular diseases of the anterior segment of the eye and the eye surface, wherein the method comprises administering to a patient in need thereof the pharmaceutical composition of the present invention. The method of the present invention preferably further comprises administering to the patient an immunosuppressant in addition to tacrolimus.
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- Regio- and stereoselective preparation of ascomycin-d1 and FK 506-d1
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The immunosuppressive macrolides ascomycin 1 and FK 506 2 were stereoselectively deuteriated at C(32) using Curran's radical translocating method. Both AIBN and Et3B/O2 were tested as radical initiator for the radical translocation/reduction step with Bu3SnD as reducing agent. Despite only minor structural differences, ascomycin and FK 506 showed remarkably different behaviour under the radical translocation/reduction conditions. Higher stereoselectivities were observed with Et3B/O2 as initiator, presumably due to lower reaction temperatures applied in this case. Copyright
- Acemoglu, Murat,Andres, Hendrik,Moenius, Thomas
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p. 361 - 370
(2007/10/03)
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- Water soluble polymer-tacrolimus conjugated compounds and process for preparing the same
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The present invention relates to a tacrolimus conjugated compound represented by formula (I): STR1 in which R1 and R2 independently of one another represent hydrogen or a group of formula --CO--CH2 --X--(CH2 CH2 --O)n--CH3 wherein n denotes an integer of 10 to 460, and X represents O or S, provided that both R1 and R2 cannot be hydrogen; to a process for preparing the same and to its use as an immunosuppressive and antiinflammatory agent.
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- Total synthesis of FK-506. Part 2: Completion of the synthesis
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The C15-C16 bond of FK-506 was formed via sulfone anion coupling followed by chelation controlled reduction of the C15 ketone. Efficient methylation of the C15-OH was accomplished by a combination of Me3OBF4-4A molecular sieves in the presence of Proton Sponge. A procedure was developed to avoid epimerization at the C2 position of the pipecolinate section during alkaline hydrolysis. A reductive fragmentation of the C21-C24 [6,6]-spiroketal iodide using active Zn/Aggraphite delivered the α'-allyl aldol section. The C9-C10 [5,6]-spiroketal acetonide was de-blocked via a novel β-elimination, using a combination of LiHMDS-Mg(HMDS)2 in HMPA-DME (I:]), to afford an enediol acetal, which was oxidized with dimethyl dioxirane to generate the C8-C10 a, P diketoanlide acetal function. Final desilylations completed the total synthesis of FK-506.
- Ireland, Robert E.,Liu, Longbin,Roper, Thomas D.,Gleason, James L.
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p. 13257 - 13284
(2007/10/03)
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- A total synthesis of FK-506
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A total synthesis of FK-506 (1) is presented. The synthesis features a highly convergent approach utilizing a block coupling strategy. Top and bottom half sections of the molecule are coupled by addition of a vinyl cuprate with a spiroenone. The α-allyl aldol functionality is revealed by a reductive opening of the spiroenone system. The labile α,β-diketoamide hemiketal portion of the molecule is prepared by a late stage generation and oxidation of a masked enediol. Top and bottom half segments are themselves derived by coupling of smaller subunits, resulting in a very convergent route.
- Ireland,Gleason,Gegnas,Highsmith
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p. 6856 - 6872
(2007/10/03)
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- Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506
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Asymmetric syntheses of FK506 and (C8,C9-13C2)-FK506 are reported. The latter compound was designed to facilitate an investigation of the interactions between FK506 and its receptor, the recently discovered immunophilin, FKBP. The syntheses involved the preparation of intermediates 7-9 in nonracemic form; the key coupling reactions included a Cram-selective addition of the vinyl Grignard reagent derived from bromide 9 to aldehyde 8 and the addition of the lithioanion of phosphonamide 7 to aldehyde 51, followed by thermal elimination. Dithiane 65 was then hydrolyzed, and glycolic ester 6 (or 6*) was added via an aldol reaction that allowed the introduction of 13C labels at C8 and C9. Elaboration to FK506 proceeded via a Mukaiyama lactamization reaction and a selective deprotection/oxidation sequence, the efficiency of which was critically dependent upon the order of protecting group removal.
- Nakatsuka, Masashi,Ragan, John A.,Sammakia, Tarek,Smith, David B.,Uehling, David E.,Schreiber, Stuart L.
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p. 5583 - 5601
(2007/10/02)
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- Chemistry of tricarbonyl hemiketals and application of Evans' technology to the total synthesis of the immunosuppressant (-)-FK-506
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Details of model studies probing the chemistry of the tricarbonyl region of FK-506 are presented, and their use in designing a successful route to this immunosuppressant is outlined. Application of asymmetric oxazolidinone alkylation/aldol methodology to a convergent, highly flexible synthesis of the C10-C18 fragment and to improvements in the preparation of the C20-C34 segment are also discussed.
- Jones,Reamer,Desmond,Mills
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p. 2998 - 3017
(2007/10/02)
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