ITMI20070435A1 - 2 ', 3'-DI-O-acyl-5-FLUORONUCLEOSIDI - Google Patents
2 ', 3'-DI-O-acyl-5-FLUORONUCLEOSIDI Download PDFInfo
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- ITMI20070435A1 ITMI20070435A1 ITMI20070435A ITMI20070435A1 IT MI20070435 A1 ITMI20070435 A1 IT MI20070435A1 IT MI20070435 A ITMI20070435 A IT MI20070435A IT MI20070435 A1 ITMI20070435 A1 IT MI20070435A1
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- fluorocytidine
- acetyl
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 23
- 108090001060 Lipase Proteins 0.000 claims description 15
- 239000004367 Lipase Substances 0.000 claims description 15
- 102000004882 Lipase Human genes 0.000 claims description 15
- 235000019421 lipase Nutrition 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 239000000872 buffer Substances 0.000 claims description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- 239000008363 phosphate buffer Substances 0.000 claims description 9
- 108090000371 Esterases Proteins 0.000 claims description 8
- -1 n-pentyloxycarbonyl Chemical group 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- YUNXATKIDPLXRX-DNRKLUKYSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-(4-amino-5-fluoro-2-oxopyrimidin-1-yl)-2-(hydroxymethyl)oxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(=O)C)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C(F)=C1 YUNXATKIDPLXRX-DNRKLUKYSA-N 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 229920000936 Agarose Polymers 0.000 claims description 3
- 230000002209 hydrophobic effect Effects 0.000 claims description 3
- 239000006184 cosolvent Substances 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 4
- 241000589516 Pseudomonas Species 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229960004117 capecitabine Drugs 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 3
- 241000222175 Diutina rugosa Species 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- DCHZIYNXLDDRGG-HKUMRIAESA-N [(2r,3r,4r,5r)-3,4-diacetyloxy-5-(4-amino-5-fluoro-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(N)C(F)=C1 DCHZIYNXLDDRGG-HKUMRIAESA-N 0.000 description 3
- 125000003700 epoxy group Chemical group 0.000 description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FHMGDOKTRLXNCF-CZFOOCMKSA-N C(CCCC)OC(=O)[C@@]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)N=C(N)C(=C1)F Chemical compound C(CCCC)OC(=O)[C@@]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)N=C(N)C(=C1)F FHMGDOKTRLXNCF-CZFOOCMKSA-N 0.000 description 2
- 241000589540 Pseudomonas fluorescens Species 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 210000000692 cap cell Anatomy 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940104302 cytosine Drugs 0.000 description 2
- 230000007071 enzymatic hydrolysis Effects 0.000 description 2
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- GUPXYSSGJWIURR-UHFFFAOYSA-N 3-octoxypropane-1,2-diol Chemical compound CCCCCCCCOCC(O)CO GUPXYSSGJWIURR-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 241000589513 Burkholderia cepacia Species 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 108010093096 Immobilized Enzymes Proteins 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001661345 Moesziomyces antarcticus Species 0.000 description 1
- 241000589776 Pseudomonas putida Species 0.000 description 1
- 241000235402 Rhizomucor Species 0.000 description 1
- 229910018540 Si C Inorganic materials 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 241000235015 Yarrowia lipolytica Species 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 108010079522 solysime Proteins 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Description
Descrizione dell'invenzione avente per titolo: 2',3'-Di-O-acil-5-fluoronucleosidi. Description of the invention having as title: 2 ', 3'-Di-O-acyl-5-fluoronucleosides.
OGGETTO DELL'INVENZIONE OBJECT OF THE INVENTION
La presente invenzione concerne nuovi 2',3'-di-o-acil-5-fluoronucleosidì utili come intermedi nella preparazione di 5'-deossi-2',3'-di-o-acil-5-fluoronucleosidi. Per semplice deacetilezione in posizione 2' e 3' forniscono importanti medicamenti come per esempio la capecitabina. The present invention relates to new 2 ', 3'-di-o-acyl-5-fluoronucleosides useful as intermediates in the preparation of 5'-deoxy-2', 3'-di-o-acyl-5-fluoronucleosides. By simple deacetilection in 2 'and 3' positions they provide important medicaments such as capecitabine.
Più particolarmente, l'invenzione si riferisce a derivati della 2',3'-di-O-acetil-5-fluorocitidìna e a un procedimento per la loro preparazione per idrolisi enzimatica del solo gruppo acetilìco in posizione 5' della corrispondente 2',3',5'-tri-O-acetil-5-fluorocitidìna. More particularly, the invention relates to derivatives of 2 ', 3'-di-O-acetyl-5-fluorocytidine and to a process for their preparation by enzymatic hydrolysis of the acetyl group alone in position 5' of the corresponding 2 ', 3 ', 5'-tri-O-acetyl-5-fluorocytidine.
CONTESTO DELL'INVENZIONE BACKGROUND OF THE INVENTION
La capecitabina, Denominazione Comune Internazionale della 5'-deossi-N<4>-pentìlossicarbonil-5-fluorocitidìna o pentil 1-{5-deossi-β-D-rìbofuranosil)-5-fluoro-1,2-diidro-2-oxo-4-pirimidincarbamato di formula A Capecitabine, International Common Name of 5'-deoxy-N <4> -pentylloxycarbonyl-5-fluorocytidine or pentyl 1- {5-deoxy-β-D-rìbofuranosyl) -5-fluoro-1,2-dihydro-2- oxo-4-pyrimidincarbamate of formula A
tosilazione dell'ossidrile primario,· (iv) riduzione con LiAlH4,e (v) acetilazione a dare il 5-deossi-tri-oacetilribosio. tosylation of the primary hydroxy, (iv) reduction with LiAlH4, and (v) acetylation to give 5-deoxy-tri-oacetylribose.
SOMMARIO DELL'INVENZIONE SUMMARY OF THE INVENTION
La presente invenzione concerne nuovi 2',3'-dì-0-acil-5-fluoronucleosidi, in particolare la 2',3'-di-o-acetil-5-fluorocitidina e i suoi N<4>-derivati (globalmente designati "2',3'-di-O-acetil-5-fluorocitidina-derivati", utili come intermedi nella preparazione della capecitabina. The present invention relates to new 2 ', 3'-di-0-acyl-5-fluoronucleosides, in particular 2', 3'-di-o-acetyl-5-fluorocytidine and its N <4>-derivatives (globally designated "2 ', 3'-di-O-acetyl-5-fluorocytidine-derivatives", useful as intermediates in the preparation of capecitabine.
E' stato infatti trovato che, trattando un 2',3',5'-trio-acetil-5-fluorocitidina-derivato in ambiente acquoso tamponato a un pH da 4,0 a 9,0 con una lipasi immobilizzata avviene un'idrolisi selettiva del gruppo acetossi in posizione 5' che trasforma il derivato della 2',3',5'-tri-O-acetil-5-fluorocitidina nel corrispondente 2',3'-di-oacetil-5-fluorocitidina-derivato con una resa dell'75-95%, che può essere facilmente trasformato nel corrispondente 5'-deossi-2',3'-di-o-acetil-5-fluorocitidina-derivato e in capecitabina. In fact, it has been found that by treating a 2 ', 3', 5'-trio-acetyl-5-fluorocytidine-derivative in an aqueous environment buffered at a pH from 4.0 to 9.0 with an immobilized lipase, a hydrolysis occurs selective acetoxy group in the 5 'position which transforms the 2', 3 ', 5'-tri-O-acetyl-5-fluorocytidine derivative into the corresponding 2', 3'-di-oacetyl-5-fluorocytidine-derivative with a yield of 75-95%, which can be easily transformed into the corresponding 5'-deoxy-2 ', 3'-di-o-acetyl-5-fluorocytidine-derivative and into capecitabine.
DESCRIZIONE DETTAGLIATA DETAILED DESCRIPTION
Così, secondo uno dei suoi aspetti, la presente invenzione fornisce un 2',3'-di-O-acil-5-fluorocitidinaderivato di formula I Thus, according to one of its aspects, the present invention provides a 2 ', 3'-di-O-acyl-5-fluorocytidine derivative of formula I
in cui Ac rappresenta un gruppo acile, X rappresenta idrogeno o un gruppo n-pentilossiearbonile e Y rappresenta un gruppo ossidrile. where Ac represents an acyl group, X represents hydrogen or an n-pentyloxyearbonyl group and Y represents a hydroxyl group.
Il termine "acile", nel presente contesto, designa un acile contenente da 2 a 9 atomi di carbonio, come acetile, proponile, butirroile, pivaloile, benzoile, p-toluoile fenilacetile, p-toluoilacetìle, il gruppo acetile essendo preferito. The term "acyl" herein designates an acyl containing from 2 to 9 carbon atoms, such as acetyl, proponyl, butyroyl, pivaloyl, benzoyl, p-toluoyl phenylacetyl, p-toluoyl acetyl, the acetyl group being preferred.
Detto 2',3'-di-o-acil-5-fluorocitidina-derivato di formula I viene preparato mediante un procedimento caratterizzato dal fatto che si sottopone il corrispondente 2 ' ,3’,5'-tri-O-acil-5-fluorocitidina-derivato di formula II Said 2 ', 3'-di-o-acyl-5-fluorocytidine-derivative of formula I is prepared by a process characterized in that the corresponding 2', 3 ', 5'-tri-O-acyl-5 is subjected -fluorocytidine-derivative of formula II
in cui Ac e X hanno il significato sopra definito, a idrolisi selettiva del gruppo acilossi in posizione 5' in un tampone a un pH da 4,0 a 9,0 in presenza di una lipasi o un'esterasi immobilizzata, wherein Ac and X have the meaning defined above, a selective hydrolysis of the acyloxy group at the 5 'position in a buffer at a pH of 4.0 to 9.0 in the presence of an immobilized lipase or esterase,
I 2',3',5'- tri-O-acil-5-fluoronucleosidi di partenza di formula II sono prodotti noti o possono essere facilmente preparati mediante reazione del corrispondente tetra-O-acilribosìo con citosina. In particolare, la2',3',5'-tri-oacetil-5-fluorocitidina {formula II, X = H) è facilmente preparabile mediante reazione del tetra-O-acetilribosìo con citosina. Anche la 2',3',5'-tri-O-acetil-N<4>-npentìlossicarbonileitidina (formula II, X = npentilossicarbonile) è nota in letteratura (Biorg. Med. Chem. Lett., EN, 12, 3, 2002, 483-486). The starting 2 ', 3', 5'-tri-O-acyl-5-fluoronucleosides of formula II are known products or can be easily prepared by reaction of the corresponding tetra-O-acylribosium with cytosine. In particular, 2 ', 3', 5'-tri-oacetyl-5-fluorocytidine (formula II, X = H) is easily prepared by reaction of tetra-O-acetylribose with cytosine. 2 ', 3', 5'-tri-O-acetyl-N <4> -npentìloxycarbonylitidine (formula II, X = npentyloxycarbonyl) is also known in the literature (Biorg. Med. Chem. Lett., EN, 12, 3 , 2002, 483-486).
L'idrolisi selettiva è condotta in ambiente acquoso, tamponato per esempio con tampone TRIS o, preferibilmente, tampone fosfato (con "tampone fosfato" si intende un tampone KH2PO4la cui concentrazione può variare tra 10 e 100 mM e che sarà preferibilmente dì circa 25 mM), a un valore di pH da 4,0 a 9, vantaggiosamente da 6,5 a 7,5, eventualmente in presenza di un co-solvente organico a una concentrazione fino al 50%, preferibilmente al 10 - 30% di acetonitrile o acetone, a una temperatura da 0°C a 25°C. Come catalizzatori possono essere utilizzate idrolasi quali lipasi o esterasi, eventualmente immobilizzate. The selective hydrolysis is carried out in an aqueous environment, buffered for example with TRIS buffer or, preferably, phosphate buffer (with "phosphate buffer" we mean a KH2PO4 buffer whose concentration can vary between 10 and 100 mM and which will preferably be about 25 mM ), at a pH value from 4.0 to 9, advantageously from 6.5 to 7.5, possibly in the presence of an organic co-solvent at a concentration of up to 50%, preferably 10 - 30% acetonitrile or acetone, at a temperature from 0 ° C to 25 ° C. Hydrolases such as lipases or esterases, possibly immobilized, can be used as catalysts.
La lipasi utilizzata come catalizzatore per l'idrolisi selettiva è in generale ottenibile da un microrganismo, per esempio del genere Rhizomucor, Candida o Pseudomonas . Vantaggiose lipasi microbiche sono quelle ottenibili da microrganismi dei generi Candida e Pseudomonas. The lipase used as a catalyst for selective hydrolysis is generally obtainable from a microorganism, for example of the genus Rhizomucor, Candida or Pseudomonas. Advantageous microbial lipases are those obtainable from microorganisms of the genera Candida and Pseudomonas.
La lipasi da Candida può essere ottenuta da Candida rugosa, Candida antarctica, Candida lipolytica , quella da Candida rugosa, preferibilmente immobilizzata come descritto in WG 03/057894, essendo preferita. Lipase from Candida can be obtained from Candida rugosa, Candida antarctica, Candida lipolytica, that from Candida rugosa, preferably immobilized as described in WG 03/057894, being preferred.
La lipasi da Pseudomonas può essere ottenuta da Pseudomonas putida, Pseudomonas cepacia o, vantaggiosamente, da Pseudomonas fluorescens , preferbilmente immobilizzata come descritto in WC 03/057894. Pseudomonas lipase can be obtained from Pseudomonas putida, Pseudomonas cepacia or, advantageously, from Pseudomonas fluorescens, preferably immobilized as described in WC 03/057894.
L'immobilizzazione della lipasi viene comunemente effettuata su supporti solidi. Vantaggiosamente, l'immobilizzazione della lipasi può essere effettuata su una matrice silicea formata da un composto organosilicico, vale a dire da un composto contenente almeno un legame Si-C (US 6,080,402). Più vantaggiosamente l'immobilizzazione delle lipasi può essere condotta su un gel ottil agaroso come Octyl Sepharose CL-4B o resine a base polimetacrilica e carattere butilico come Sepabeads FP-BU o decaottilico come Sepabeads FP-RPOD che sono già totalmente derivatizzate con gruppi idrofobici, rispettivamente catene butiliche e decaottìlìche. Preferibilmente, il supporto idrofobico di immobilizazzione è ottil-agarosio o decaottil-Sepabeads. Immobilization of lipase is commonly performed on solid supports. Advantageously, the immobilization of the lipase can be carried out on a silica matrix formed by an organosilic compound, that is to say by a compound containing at least one Si-C bond (US 6,080,402). More advantageously, the immobilization of the lipases can be carried out on an octyl agarose gel such as Octyl Sepharose CL-4B or resins with a polymethacrylic base and butyl character such as Sepabeads FP-BU or decaoctyl such as Sepabeads FP-RPOD which are already totally derivatized with hydrophobic groups, butyl and decaoctyl chains respectively. Preferably, the hydrophobic immobilization support is octyl agarose or decaoctyl-Sepabeads.
Alternativamente, l'immobilizzazione può avvenire su una matrice macroporosa di silice o silicati (EP 444 092), su una matrice formata da resine adsorbenti di tipo acrilico, eventualmente reticolate, come Ambelite XAD-8 o Lewatit E 2001/85 (EP 529424), da un supporto anfifìlo contenente catene lipofile (US 5,182,201), su una matrice di stirene e divinilbenzene eventualmente contenente gruppi epossidici come Lewatit R 259 K o R 260 K oppure Diaion HP-40, su una resina poliacrilica contenente gruppi epossidici come FP 4000, su una resina polimetacrilica contenente gruppi epossidici come Sepabeads FP-EP o Eupergit C opportunamente derivatizzate con gruppi idrofobici. Alternatively, the immobilization can take place on a macroporous matrix of silica or silicates (EP 444 092), on a matrix formed by adsorbent resins of the acrylic type, possibly cross-linked, such as Ambelite XAD-8 or Lewatit E 2001/85 (EP 529424) , from an amphiphilic support containing lipophilic chains (US 5,182,201), on a styrene and divinylbenzene matrix possibly containing epoxy groups such as Lewatit R 259 K or R 260 K or Diaion HP-40, on a polyacrylic resin containing epoxy groups such as FP 4000, on a polymethacrylic resin containing epoxy groups such as Sepabeads FP-EP or Eupergit C suitably derivatized with hydrophobic groups.
Come esterasi possono essere utilizzati enzimi di origine animale quali le esterasi da pancreas di maiale o di origine fungina, quale la esterasi da Aspergillus Nìger, immobilizzate su Eupergit* C. As esterases it is possible to use enzymes of animal origin such as esterases from pig pancreas or of fungal origin, such as esterase from Aspergillus Nìger, immobilized on Eupergit * C.
Vantaggiosamente, la soluzione contenente 2',3',5'-tri-oacetil-5-fluoronucleoside di formula II (Ac = acetile) e l'enzima immobilizzato viene portata a un pH da 4,0 a 9,0, vantaggiosamente da 6,5 a 7,5 e mantenuta al pH prescelto e a una temperatura da 0°C a 25°C per 12-120 ore. Advantageously, the solution containing 2 ', 3', 5'-tri-oacetyl-5-fluoronucleoside of formula II (Ac = acetyl) and the immobilized enzyme is brought to a pH from 4.0 to 9.0, advantageously by 6.5 to 7.5 and maintained at the chosen pH and at a temperature from 0 ° C to 25 ° C for 12-120 hours.
Preferibilmente, secondo il procedimento della presente invenzione, il 2',3',5'-tri-O-acetìl-5-fluoronucleoside viene disciolto in un tampone al pH prescelto, per esempio in un tampone fosfato 25 mM contenente 20-30% di acetonitrile o acetone mantenuto al valore di pH desiderato. La soluzione così ottenuta viene trattata con urta lipasi da Candida rugosa o da Pseudomonas fluorescens oppure con un'esterasi da pancreas di maiale o da Aspergillus Niger , preferibilmente immobilizzata, e lasciata in incubazione per un periodo di tempo da 12 a 120 ore, controllando la reazione di idrolisi mediante HPLC, L'immobilizzazione, per esempio su ottil-agarosio, può avvenire come descritto in WO 03/57894. Preferably, according to the process of the present invention, the 2 ', 3', 5'-tri-O-acetyl-5-fluoronucleoside is dissolved in a buffer at the selected pH, for example in a 25 mM phosphate buffer containing 20-30% of acetonitrile or acetone maintained at the desired pH value. The solution thus obtained is treated with urta lipase from Candida rugosa or Pseudomonas fluorescens or with an esterase from pig pancreas or Aspergillus Niger, preferably immobilized, and left to incubate for a period of time from 12 to 120 hours, checking the hydrolysis reaction by HPLC. Immobilization, for example on octyl agarose, can take place as described in WO 03/57894.
Il 2',3'-di-O-acetil-5-fluorocitidina-derivato di formula I (Ac = acetile}così ottenuto viene isolato secondo ì metodi convenzionali, eventualmente eliminando il solvente organico, estraendo il prodotto finale dalla soluzione acquosa, per esempio con acetato d'etile e isolando il 2',3'-di-o-acetil-5-fluorocitidina-derivato di formula I (Ac = acetile) per esempio mediante cromatografia su colonna. The 2 ', 3'-di-O-acetyl-5-fluorocytidine-derivative of formula I (Ac = acetyl} thus obtained is isolated according to conventional methods, optionally eliminating the organic solvent, extracting the final product from the aqueous solution, to for example with ethyl acetate and isolating the 2 ', 3'-di-o-acetyl-5-fluorocytidine-derivative of formula I (Ac = acetyl) for example by column chromatography.
L'idrolisi enzimatica selettiva del gruppo acìlossi in posizione 5', secondo la presente invenzione, si è mostrata essere un metodo semplice, caratterizzato da condizioni sperimentali blande, ridotta percentuale di solvente organico nella soluzione acquosa e bassa temperatura, per l'ottenimento di elevate rese in 2',3'-di-O-acil-5-fluorocitidina-derivati dì formula I caratterizzati da un ossidrile libero in posizione 5'. The selective enzymatic hydrolysis of the acyloxy group in the 5 'position, according to the present invention, has been shown to be a simple method, characterized by mild experimental conditions, reduced percentage of organic solvent in the aqueous solution and low temperature, for obtaining high yields in 2 ', 3'-di-O-acyl-5-fluorocytidine-derivatives of formula I characterized by a free hydroxyl in the 5' position.
L'ossidrile libero in posizione 5' permette la trasformazione dei 2',3'-di-o-acetil-5-fluorocitidinaderivatì di formula X nei corrispondenti 5'-deossi-2',3'-Di-O-acetil-5-fluorocitidina-derivati, per esempio attraverso i corrispondenti esteri solfonici e lodo- o bromoderìvatì e successiva sostituzione dell'alogeno con un atomo di idrogeno con conseguente ottenimento dei corrispondenti 5'-deossi-2',3'-dì-O-acetil-5-fluorocitidina-derivati. The free hydroxyl in the 5 'position allows the transformation of the 2', 3'-di-o-acetyl-5-fluorocytidin-derivatives of formula X into the corresponding 5'-deoxy-2 ', 3'-Di-O-acetyl-5 -fluorocytidine-derivatives, for example through the corresponding sulphonic esters and lodo- or bromoderivatì and subsequent replacement of the halogen with a hydrogen atom with consequent obtaining of the corresponding 5'-deoxy-2 ', 3'-di-O-acetyl- 5-fluorocytidine-derivatives.
I seguenti esempi illustrano l'invenzione. Il controllo del pH durante l'idrolisi è stato effettuato tramite un pH-Stat automatico 718 Stat Tritino della Metrohm (Herìsau, Svìzzera). Le analisi HPLC sono state condotte utilizzando un HPLC Merck Hitachi L-7100, (E.Merck, Darmstadt, Germania) dotato di detector UV L-7400 e di una valvola di iniezione con loop da 20 μL . È stata utilizzata una colonna Shiseìdo Capcell Pak RP C18(250 x 4.6 mm; 5μm). Le analisi sono state effettuate a temperatura ambiente ad una lunghezza d'onda di 260 nm. Per il monitoraggio delle reazioni dì idrolisi le fasi mobili sono state di 10% di acetonìtrile in tampone K3⁄4PO410mM a pH spontaneo e di 10% di 3⁄40 in acetonìtrile,- le fasi mobìli sono state filtrate e sgasate prima dell'uso,· il flusso è stato di lmL/min. The following examples illustrate the invention. The pH control during hydrolysis was carried out by means of an automatic pH-Stat 718 Stat Tritino from Metrohm (Herìsau, Svìzzera). HPLC analyzes were conducted using a Merck Hitachi L-7100 HPLC, (E.Merck, Darmstadt, Germany) equipped with a L-7400 UV detector and a 20 μL loop injection valve. A Shiseìdo Capcell Pak RP C18 column (250 x 4.6 mm; 5μm) was used. The analyzes were carried out at room temperature at a wavelength of 260 nm. To monitor the hydrolysis reactions, the mobile phases were 10% acetonitrile in K3⁄4PO410mM buffer at spontaneous pH and 10% 3⁄40 in acetonitrile, - the mobile phases were filtered and degassed before use, · The flow was lmL / min.
Il monitoraggio è stato eseguito tramite TLC su gel di silice 60 (0.25 mm, E.Merck, Darmstadt, Germania). Monitoring was performed by TLC on silica gel 60 (0.25 mm, E. Merck, Darmstadt, Germany).
I 2',3'-di-O-acetil-5-fluoronucleosidi sono stati identificati tramite analisi<1>H-NMR e COSY 2D NMR registrate in DMSO-d6 (5=ppm) utilizzando come strumentazione un Bruker AMX 400. The 2 ', 3'-di-O-acetyl-5-fluoronucleosides were identified by <1> H-NMR and COZY 2D NMR analyzes recorded in DMSO-d6 (5 = ppm) using a Bruker AMX 400 as instrumentation.
Esempio 1 Example 1
2',3' -Di-O-acetil-5-fluorocitidina 2 ', 3' -Di-O-acetyl-5-fluorocytidine
A una soluzione 100 mM di 2',3',5'-tri-O-acetil-5-fluorocitidina in tampone fosfato 25 mM contenente 10% di acetonitrile a pH mantenuto costante al valore di 7 furono aggiunti 4 g di lipasi da Candida Rugosa immobilizzata. La soluzione venne lasciata sotto agitazione meccanica a temperatura ambiente controllandone il decorso mediante HPLC e il pH venne mantenuto costante a un valore di 7 mediante titolazione automatica. Dopo 3 giorni di incubazione si osservò 90% di conversione del substrato. L'enzima venne rimosso mediante filtrazione, il 2',3'-dì-0-acetil-5-fluorocitidina così ottenuto fu isolato eliminando l'eventuale solvente organico ed estraendo il prodotto dalla soluzione acquosa con acetato d'etile. Dopo evaporazione a pressione ridotta degli estratti organici riuniti, il residuo fu purificato mediante colonna cromatografica di gel di silice usando come eluente una miscela (CH2C12100-CH2Cl2-MeOH 97:3), si ottenne così il 2',3'-di-O-acetil-S-fluorocitidina. Resa globale 85% 4 g of Candida lipase were added to a 100 mM solution of 2 ', 3', 5'-tri-O-acetyl-5-fluorocytidine in 25 mM phosphate buffer containing 10% acetonitrile at a pH maintained constant at 7. Wrinkled immobilized. The solution was left under mechanical stirring at room temperature, controlling its course by HPLC and the pH was kept constant at a value of 7 by automatic titration. After 3 days of incubation 90% substrate conversion was observed. The enzyme was removed by filtration, the 2 ', 3'-di-0-acetyl-5-fluorocytidine thus obtained was isolated by removing any organic solvent and extracting the product from the aqueous solution with ethyl acetate. After evaporation under reduced pressure of the combined organic extracts, the residue was purified by a silica gel chromatographic column using a mixture (CH2C12100-CH2Cl2-MeOH 97: 3) as eluent, thus obtaining 2 ', 3'-di-O -acetyl-S-fluorocytidine. Overall yield 85%
Il prodotto purificato fu identificato tramite analisi<1>H NMR e COSY 2D NMR registrate in DMSO-d6 (δ=ppm) utilizzando come strumentazione un Bruker AMX 400. The purified product was identified by <1> H NMR and COZY 2D NMR analyzes recorded in DMSO-d6 (δ = ppm) using a Bruker AMX 400 as instrumentation.
<1>H NMR (400 MHz, DMSO-de, 25 °C): δ = 8.20 (d, 1 H,6-H, J 7.8 Hz), 7.90 (s, 2 H, N3⁄4), 5.97 (d, 1 H, 1'-H, J 4.8 Hz), 5.43 (t, 5'-OH, J125.9 Hz, J13$.8 Hz ), 5.30-5.26 (m, 2 H, 2'-H,3'-H), 4.08-4.10 (m, IH, 4'-H), 3.68-3.58 {m, 2H, 5'-H), 2.50 (s, 3 H, OAc), 2.06 (s, 3 H, OAc). <1> H NMR (400 MHz, DMSO-de, 25 ° C): δ = 8.20 (d, 1 H, 6-H, J 7.8 Hz), 7.90 (s, 2 H, N3⁄4), 5.97 ( d, 1 H, 1'-H, J 4.8 Hz), 5.43 (t, 5'-OH, J125.9 Hz, J13 $ .8 Hz), 5.30-5.26 (m, 2 H, 2'-H, 3'-H), 4.08-4.10 (m, 1H, 4'-H), 3.68-3.58 {m, 2H, 5'-H), 2.50 (s, 3 H, OAc), 2.06 (s, 3 H , OAc).
Esempio 2 Example 2
2 ' , 3 ' - Di -O-acetil-N4 - (n -pentilossicarbonil ) -5-fluorocitidina A una soluzione 20 mM di 2',3',5'-tri-0-acetil-N<4>-(npentilossicarbonil)-5-fluorocitidina in tampone fosfato 25 mM contenente 30% dì acetonitrile a pH mantenuto costante al valore di 7 furono aggiunti 0.7 g di lipasi da Pseudomona s fluorescens immobilizzata. La soluzione venne lasciata sotto agitazione meccanica a temperatura ambiente controllandone il decorso mediante HPLC e il pH venne mantenuto costante a un valore di 7 mediante titolazione automatica. Dopo 6 ore di incubazione si osservò 82% dì conversione del substrato. L'enzima venne rimosso mediante filtrazione, la 2',3'-di-O-acetil-N<4>(n-pentilossicarbonil)-5-fluorocitidina così ottenuta fu isolata eliminando l'eventuale solvente organico ed estraendo·il prodotto dalla soluzione acquosa con acetato d'etile. Dopo evaporazione a pressione ridotta degli estratti organici riuniti, si ottenne così la 2',3'-dì-O acetil-N<4>(n-pentilossicarbonil)-5-fluorocitìdina. Il prodotto purificato è stato identificato tramite analisi HPLC e<1>H-NMR e COSY 2D NMR registrate in DMSO-d6 (δ=ppm) utilizzando come strumentazione un Bruker AMX 400. 2 ', 3' - Di -O-acetyl-N4 - (n -pentyloxycarbonyl) -5-fluorocytidine A 20 mM solution of 2 ', 3', 5'-tri-0-acetyl-N <4> - ( npentyloxycarbonyl) -5-fluorocytidine in 25 mM phosphate buffer containing 30% acetonitrile at a pH maintained constant at the value of 7, 0.7 g of lipase from immobilized Pseudomona s fluorescens were added. The solution was left under mechanical stirring at room temperature, controlling its course by HPLC and the pH was kept constant at a value of 7 by automatic titration. After 6 hours of incubation 82% substrate conversion was observed. The enzyme was removed by filtration, the 2 ', 3'-di-O-acetyl-N <4> (n-pentyloxycarbonyl) -5-fluorocytidine thus obtained was isolated by removing any organic solvent and extracting the product from the aqueous solution with ethyl acetate. After evaporation of the combined organic extracts under reduced pressure, 2 ', 3'-di-O acetyl-N <4> (n-pentyloxycarbonyl) -5-fluorocytidine was thus obtained. The purified product was identified by HPLC and <1> H-NMR and COZY 2D NMR analyzes recorded in DMSO-d6 (δ = ppm) using a Bruker AMX 400 as instrumentation.
HPLC: Rt14.90 min (A: 10 mM tampone KH2P0490%/CH3CN 10%, B: CH3CN 90% /H 10%, pH spontaneo; Metodo-, 0-3 min 75% A-25% B, 3-10 min 60% A- 40% B, 10-11 min 60% A- 40% B, 11-12 min 50% A- 50% B, 12-18 min 50% A- 50% B, 18-23 min 75% A-25% B, Flusso: 1 mL/min, λ 240 nm, colonna: RP-18 Shiseido Capcell Pak). HPLC: Rt14.90 min (A: 10 mM buffer KH2P0490% / CH3CN 10%, B: CH3CN 90% / H 10%, spontaneous pH; Method-, 0-3 min 75% A-25% B, 3-10 min 60% A- 40% B, 10-11 min 60% A- 40% B, 11-12 min 50% A- 50% B, 12-18 min 50% A- 50% B, 18-23 min 75 % A-25% B, Flow: 1 mL / min, λ 240 nm, column: RP-18 Shiseido Capcell Pak).
<1>H NMR (400 MHz, DMSO-d6, 25 °C): 5 = 8.10 (s, 1 H, N-H), 7.80 (d, 1H, 6-H, J 7.5 Hz), 6.02 (d, 1H, 1'-H, J 4.6 Hz), 5.40 (t, 5'-OH, , J125.8 Hz, J139.6 Hz }, 5.20-5.10 (m, 2 H, 2'-H,3'-H), 4.05-4.10 (m, 1 H, 4'-H), 4.13-4.20 (m, 2H), 3.60-3.50 (m, 2 H, 5'-H), 2.40 (s, 3 H, OAc), 2.10 (s, 3 H, OAc), 1.28-1.60 (m, 6 H), 0.91-1.00 (d, 3H). <1> H NMR (400 MHz, DMSO-d6, 25 ° C): 5 = 8.10 (s, 1 H, N-H), 7.80 (d, 1H, 6-H, J 7.5 Hz), 6.02 (d, 1H , 1'-H, J 4.6 Hz), 5.40 (t, 5'-OH,, J125.8 Hz, J139.6 Hz}, 5.20-5.10 (m, 2 H, 2'-H, 3'-H ), 4.05-4.10 (m, 1 H, 4'-H), 4.13-4.20 (m, 2H), 3.60-3.50 (m, 2 H, 5'-H), 2.40 (s, 3 H, OAc) , 2.10 (s, 3H, OAc), 1.28-1.60 (m, 6H), 0.91-1.00 (d, 3H).
Claims (10)
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| Application Number | Priority Date | Filing Date | Title |
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| ITMI20070435 ITMI20070435A1 (en) | 2007-03-05 | 2007-03-05 | 2 ', 3'-DI-O-acyl-5-FLUORONUCLEOSIDI |
| EP08719215A EP2176278A2 (en) | 2007-03-05 | 2008-03-04 | 2',3'-di-o-acyl-5-fluoronucleosides |
| PCT/IB2008/000482 WO2008107771A2 (en) | 2007-03-05 | 2008-03-04 | 2',3'-di-o-acyl-5-fluoronucleosides |
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| CN102212095B (en) * | 2010-04-08 | 2016-03-30 | 上海医药工业研究院 | The preparation method of capecitabine and intermediate thereof |
| CN102424697B (en) * | 2011-10-27 | 2014-02-12 | 齐鲁天和惠世制药有限公司 | 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound and preparation method thereof |
| CN103897004B (en) * | 2012-12-27 | 2017-05-31 | 鲁南制药集团股份有限公司 | A kind of synthetic method of capecitabine |
| CN112876526A (en) * | 2021-01-15 | 2021-06-01 | 山东铂源药业有限公司 | Preparation method of capecitabine key intermediate |
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| CA1327358C (en) | 1987-11-17 | 1994-03-01 | Morio Fujiu | Fluoro cytidine derivatives |
| DK638688D0 (en) | 1988-11-16 | 1988-11-16 | Novo Industri As | PARTICULAR IMMOBILIZED LIPASE PREPARATION, PROCEDURE FOR PREPARING IT AND USING THEREOF |
| US5182201A (en) | 1990-10-26 | 1993-01-26 | Uop | Lipase immobilization without covalent bonding on an amphiphilic support containing lipophilic alkyl chains |
| AT398310B (en) | 1991-08-30 | 1994-11-25 | Chemie Linz Gmbh | IMMOBILIZED LIPASE, METHOD FOR THE PRODUCTION THEREOF AND METHOD FOR INCREASING THE ENANTIOSELECTIVITY OF A CANDIDA LIPASE IN THE Esterification of CHIRAL ALCOHOLS |
| AU671491B2 (en) | 1992-12-18 | 1996-08-29 | F. Hoffmann-La Roche Ag | N-oxycarbonyl substituted 5'-deoxy-5-fluorcytidines |
| DE4408152A1 (en) | 1994-03-11 | 1995-09-14 | Studiengesellschaft Kohle Mbh | Immobilized lipases in hydrophobic sol-gel materials |
| US5476932A (en) | 1994-08-26 | 1995-12-19 | Hoffmann-La Roche Inc. | Process for producing N4-acyl-5'-deoxy-5-fluorocytidine derivatives |
| ITMI20020052A1 (en) | 2002-01-14 | 2003-07-14 | Innovate Biotechnology Srl | PROCEDURE FOR THE SELECTIVE HYDROLYSIS OF POLYESTER NUCLEOSIDES |
| JP5350591B2 (en) * | 2003-12-22 | 2013-11-27 | エフ．ホフマン−ラ ロシュ アーゲー | Method for fluorocytidine derivatives |
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