WO2015051900A1 - Procédé de préparation d'entécavir au moyen de nouveaux intermédiaires - Google Patents
Procédé de préparation d'entécavir au moyen de nouveaux intermédiaires Download PDFInfo
- Publication number
- WO2015051900A1 WO2015051900A1 PCT/EP2014/002704 EP2014002704W WO2015051900A1 WO 2015051900 A1 WO2015051900 A1 WO 2015051900A1 EP 2014002704 W EP2014002704 W EP 2014002704W WO 2015051900 A1 WO2015051900 A1 WO 2015051900A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- entecavir
- preparation
- hydroxyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 69
- 229960000980 entecavir Drugs 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 title claims abstract 16
- 239000000543 intermediate Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 139
- -1 trimethylsilylmethylmagnesium halide Chemical class 0.000 claims description 53
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 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 description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical group 0.000 claims description 24
- 238000010511 deprotection reaction Methods 0.000 claims description 21
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 19
- 125000004122 cyclic group Chemical group 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 238000003379 elimination reaction Methods 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 150000002148 esters Chemical group 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 238000005859 coupling reaction Methods 0.000 claims description 11
- KVWLUDFGXDFFON-UHFFFAOYSA-N lithium;methanidyl(trimethyl)silane Chemical compound [Li+].C[Si](C)(C)[CH2-] KVWLUDFGXDFFON-UHFFFAOYSA-N 0.000 claims description 11
- 238000001953 recrystallisation Methods 0.000 claims description 11
- 125000006242 amine protecting group Chemical group 0.000 claims description 10
- 150000008378 aryl ethers Chemical group 0.000 claims description 10
- 150000004649 carbonic acid derivatives Chemical group 0.000 claims description 10
- 230000008878 coupling Effects 0.000 claims description 10
- 238000010168 coupling process Methods 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002955 isolation Methods 0.000 claims description 8
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000005103 alkyl silyl group Chemical group 0.000 claims 1
- 239000003443 antiviral agent Substances 0.000 abstract description 3
- QDGZDCVAUDNJFG-FXQIFTODSA-N entecavir (anhydrous) Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)C1=C QDGZDCVAUDNJFG-FXQIFTODSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 125000006239 protecting group Chemical group 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 0 *C[C@@]1[C@@]2OCO[C@@]2C[C@]1* Chemical compound *C[C@@]1[C@@]2OCO[C@@]2C[C@]1* 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 6
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 6
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- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
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- 238000006751 Mitsunobu reaction Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 238000006772 olefination reaction Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 3
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 3
- WJSVJNDMOQTICG-UHFFFAOYSA-N 2-amino-1-[(2-methyl-4-methylidene-5-oxooxolan-2-yl)methyl]-7h-purin-6-one Chemical compound NC1=NC=2N=CNC=2C(=O)N1CC1(C)CC(=C)C(=O)O1 WJSVJNDMOQTICG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- 238000004440 column chromatography Methods 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 3
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- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 3
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
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- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 2
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- 125000002619 bicyclic group Chemical group 0.000 description 1
- MPQAQJSAYDDROO-VMAIWCPRSA-N bis[(1r,3r,4s,5r)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]boron Chemical compound C([C@H]([C@@H]1C)[B][C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@H]2C)[C@H]2C(C)(C)[C@@H]1C2 MPQAQJSAYDDROO-VMAIWCPRSA-N 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 150000002118 epoxides Chemical group 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- BXBLTKZWYAHPKM-UHFFFAOYSA-M magnesium;methanidyl(trimethyl)silane;chloride Chemical compound [Mg+2].[Cl-].C[Si](C)(C)[CH2-] BXBLTKZWYAHPKM-UHFFFAOYSA-M 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- CCTHTLJWXPUNGT-UHFFFAOYSA-L nysted reagent Chemical compound C1CCOC1.Br[Zn]C[Zn]C[Zn]Br CCTHTLJWXPUNGT-UHFFFAOYSA-L 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- WIWVNQBYNTWQOW-UHFFFAOYSA-L oxovanadium(2+);diacetate Chemical compound [V+2]=O.CC([O-])=O.CC([O-])=O WIWVNQBYNTWQOW-UHFFFAOYSA-L 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QWLSHZKQRSNZKL-UHFFFAOYSA-N phenyl(pyridin-2-yl)diazene Chemical compound C1=CC=CC=C1N=NC1=CC=CC=N1 QWLSHZKQRSNZKL-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical class [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- JQUZTGJSSQCTPV-UHFFFAOYSA-N sodium;cyclopenta-1,3-diene Chemical compound [Na+].C1C=CC=[C-]1 JQUZTGJSSQCTPV-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 230000007484 viral process Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Definitions
- the present invention relates to a novel process for the antiviral drug compound Entecavir.
- Entecavir (Formula I) is an antiviral drug used for the treatment of chronic hepatitis B.
- the chemical name of Entecavir is 2-amino-9-[(lS, 3R, 4S)-4-hydroxy-3- (hydroxymethyl)-2-methylidenecyclopentyl]-6,9-dihydro-3H-purin-6-one.
- the trade name is Baraclude ® and it is marketed as monohydrate by Bristol-Myers Squibb.
- Entecavir being a nucleoside analog, acts as an inhibitor of reverse transcription, DNA replication and transcription in the viral process.
- Entecavir begins with the cyclopentadienyl anion.
- the carbocyclic core is built up to the point where all the oxygen substituents are protected and then, the coupling with the guanine base is accomplished via epoxide ring opening.
- the exocyclic methylene moiety may be formed under standard olefination conditions. The synthesis is completed with two deprotection steps.
- This process lines up a number of well-known synthetic transformations in an efficient way to reach the suitably protected cyclopentanone, as a key intermediate.
- What follows is an olefination reaction, coupling with a guanine derivative under Mitsunobu conditions and a two-step deprotection sequence.
- the process suffers from low yields at these crucial steps.
- the olefination reaction performed with the use of Nysted reagent, affords, according to the experimental data provided in said application, the exomethylene product in 35% w/w yield.
- the Mitsunobu reaction proceeds also with a yield particularly low for a coupling reaction, namely 82% w/w.
- the present invention encompasses a process for the preparation of compound of formula II and its use for the preparation of Entecavir (formula I).
- the illustrated process holds a number of features suitable for industrial purposes, including high yields, efficient purification methods and reagents and conditions that are easy to use in an industrial process.
- R ⁇ and R 2 are independently selected from hydrogen or a hydroxyl-protecting group or R ⁇ and R 2 may together form a cyclic hydroxyl- protecting group and R 3 is selected from hydrogen or a hydroxyl-protecting group.
- the invention also provides a process for the preparation of Entecavir (Formula I) from compounds of formula II, said process comprising:
- Entecavir is prepared according to the above process, from compound of formula II, wherein R ⁇ and R 2 are t- butyldimethylsilyl.
- the invention also provides a process for the preparation of compound of formula
- Rj and R 2 are independently selected from hydrogen or a hydroxyl-protecting group or Ri and R 2 may together form a cyclic hydroxyl- protecting group and R3 is selected from hydrogen or a hydroxyl-protecting group.
- the invention further provides a process for the preparation of Entecavir (Formula I) from compounds of formula III, said process comprising: a) subjecting compound of formula III to reaction with trimethylsilylmethylmagnesium halide (TMSCH 2 MgX, wherein X is halogen) or trimethylsilylmethyl lithium, to form compound of formula IV;
- TMSCH 2 MgX trimethylsilylmethylmagnesium halide
- hydroxyl protecting group refers to protecting groups known in the art and exemplified such as in Greene's Protective Groups on Organic Synthesis 4 th Edition, John Wiley & Son, Peter G. M. Wuts, Theodora W. Greene, Print ISBN: 9780471697541.
- Preferred hydroxyl protecting groups are alkyl and aryl ethers, silyl ethers, esters, carbonates, sulfonates.
- More preferred hydroxyl protecting groups are allyl (All), methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), benzyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl (THP), 2,4-dinitrobenzyl, diphenylmethyl (DPM), trityl (Tr), p-methoxyphenyldiphenylmethyl (MMTr), benzyl (Bn), naphthyl (NAP), p- methoxybenzyl (PMB), p-nitrobenzyl, formyl, acyl (Ac), chloroacyl, methoxyacyl, pivaloyl (Piv), benzoyl (Bz), p-nitrobenzoyl, p-methoxybenzoyl, p-bromobenzoyl, p- phenylbenzoyl, trimethylsily
- cyclic hydroxyl-protecting group refers, also to hydroxyl protecting groups exemplified in the textbook mentioned above.
- Preferred cyclic hydroxyl protecting groups are cyclic acetals, cyclic ketals, cyclic ortho esters, cyclic carbonate, silyl derivatives.
- More preferred cyclic hydroxyl-protecting group are isopropylidene, pentylidene, hexylidene, benzylidene, p-methoxybenzylidene, naphthylidene, 4- phenylbenzylidene, methoxymethylene, ethoxymethylene, cyclic carbonate, 1,3- (1,1 ,3,3-tetraisopropyl)disiloxanediyl (TIPDS).
- TIPDS 1,3- (1,1 ,3,3-tetraisopropyl)disiloxanediyl
- amine protecting group refers, also to protecting groups exemplified in the textbook mentioned above. Preferred amine protecting groups are carbamates, amides, N-alkyl, N-aryl, N-silyl amino and N-sulfonyl derivatives.
- More preferred amine protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc), 2,2,2-trichloroethyl carbonate (Troc), formyl, acetyl, trifluoroacetyl, benzyl (Bn), allyl (All), trityl (Tr), trimethoxyphenylmethylene, trimethylsilyl (TMS), tert-butyldimethylsilyl, (TBS), p- methoxybenzyl (PMB), p-halo-benzyl, diphenylmethyl, naphthylmethyl, benzenesulfonate, tosylate.
- Boc tert-butoxycarbonyl
- allyloxycarbonyl (Alloc)
- amine base may refer to compounds of formula NR 4 R 5 R ⁇ 5, wherein R4, R 5 and 3 ⁇ 4 are selected from hydrogen, alkyl or substituted alkyl groups, aminoacids, heterocyclic bases, such as monocyclic, bicyclic or tricyclic amine bases, protected or unprotected DNA bases and their derivatives;
- a process for the preparation of entecavir from compound of formula III characterized by an elimination reaction of compound of formula II or compound of formula IV.
- the present invention provides a process for the preparation of compounds of formula II comprising: a) subjecting compound of formula III to reaction with trimethylsilyl methyl magnesium halide (TMSCH 2 MgX, wherein X is a halogen) or trimethylsilyl methyl lithium (TMSCH 2 Li) to form compound of formula IV;
- TMSCH 2 MgX trimethylsilyl methyl magnesium halide
- X is a halogen
- TMSCH 2 Li trimethylsilyl methyl lithium
- R l 5 R 2 and R 3 are defined as above and
- Step a) may be performed in a polar aprotic solvent or a non-polar solvent.
- Preferred solvents are halogenated hydrocarbons, ethers, ketones and aromatic hydrocarbons.
- the reaction may be performed at temperatures that range from -20 °C to the boiling point of the solvent used in the reaction. Preferred temperature range is from
- Step b) is a typical deprotection reaction. The step may be performed according to methods described in Greene's Protective Groups on Organic Synthesis 4 th Edition mentioned above.
- Step c) is a recrystallization procedure that may be performed in an organic solvent.
- Preferred solvents are alcohols, ketones, esters, ethers, aromatic and aliphatic hydrocarbons or mixtures thereof. More preferred solvents are methanol, ethanol, 2- propanol, dichloromethane, chloroform, tetrahydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, acetone, methyl isobutyl ketone.
- Ri, R 2 and R 3 are representing hydroxyl protecting groups, or Ri and R 2 together form a cyclic hydroxyl protecting group and R 3 represents a hydroxyl protecting groups, wherein the hydroxyl protecting groups are preferably selected from alkyl and aryl ethers, silyl ethers, esters and carbonates.
- More preferred hydroxyl protecting groups are allyl (All), methoxymethyl (MOM), 2- methoxyethoxymethyl (MEM), methylthiomethyl (MTM), benzyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl (THP), 2,4-dinitrobenzyl, diphenylmethyl (DPM), trityl (Tr), p-methoxyphenyldiphenylmethyl (MMTr), benzyl (Bn), naphthyl (NAP), p-methoxybenzyl (PMB), p-nitrobenzyl, formyl, acyl (Ac), chloroacyl, methoxyacyl, pivaloyl (Piv), benzoyl (Bz), p-nitrobenzoyl, p- methoxybenzoyl, p-bromobenzoyl, p-phenylbenzoyl, trimethylsilyl
- hydroxyl protecting groups are allyl (All), methoxymethyl (MOM), tetrahydropyranyl (THP), diphenylmethyl (DPM), trityl (Tr), p- methoxyphenyldiphenylmethyl (MMTr), benzyl (Bn), p-methoxybenzyl (PMB), acetyl (Ac) pivaloyl (Piv), benzoyl (Bz), p-nitrobenzoyl, p-phenylbenzoyl, triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert- butyldiphenylsilyl (TBDPS).
- Step a) may be performed in a polar aprotic solvent.
- Preferred solvents are defined as above.
- the reaction may be performed at temperatures that range from -20 °C to the boiling point of the solvent used in the reaction. Preferred temperature range is from
- Step b) is a typical deprotection reaction.
- the cleavage of the benzyl group may be achieved according to procedures described in Greene's Protective Groups on Organic Synthesis 4 th Edition.
- Preferred conditions for this step are catalytic hydrogenation conditions. More preferred conditions are a palladium-based catalyst and a hydrogen source.
- Step c) is a recrystallization procedure that may be performed in an organic solvent or a mixture of organic solvents, as described above.
- Ri and R 2 are defined as above.
- Ri and R 2 are preferably alkyl and aryl ethers, silyl ethers, esters, carbonates, or Ki and R 2 together form a cyclic hydroxyl protecting group. More preferably, Ri and R 2 are silyl ethers, esters, alkyl and aryl esters. Even more preferably, Ri and R 2 are silyl protecting groups.
- R 1 ; R 2 and R 3 are defined as above.
- R ⁇ and R 2 are preferably alkyl and aryl ethers, silyl ethers, esters, carbonates, or R ⁇ and R 2 together form a cyclic hydroxyl protecting group. More preferably, R ⁇ and R 2 are silyl ethers, esters, alkyl and aryl esters.
- R 3 is preferably a hydroxyl protecting group that can be cleaved in the presence of hydroxyl protecting groups R ⁇ and R 2 .
- Rj, R 2 and R 3 represent hydroxyl protecting groups, or Ri and R 2 together form a cyclic hydroxyl protecting group and R 3 represents a hydroxyl protecting group, wherein the hydroxyl protecting groups are selected from alkyl and aryl ethers, silyl ethers, esters, carbonates.
- a process for the preparation of Entecavir from compound of formula II comprising: a) elimination reaction and Mitsunobu coupling with compound of formula VI, to yield compound of formula V, wherein R ⁇ and R 2 are defined as above, X may be a halogen, OH or OBn and, R and R' are independently selected from amine protecting groups or hydrogen, as defined above;
- Step a) comprises of a Mitsunobu reaction and an elimination reaction in one chemical step.
- the skilled person can perform this step by following procedures exemplified in prior art.
- Mitsunobu reactions are performed in the presence of a phosphine and an azo-based compound.
- phosphines are trialkyl and triarylphosphines and their polymer-supported analogues. More preferred phosphines are triphenylphosphine, trimethylphosphine, tributylphosphine.
- Preferred azo-based compounds are diethylazodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD), di-t-butylazodicarboxylate, 2- (phenylazo)pyridine, di-/?-chlorobenzylazodicarboxylate (DCAD), 1,1 '- (azodicarboxyl)dipepidine.
- DEAD diethylazodicarboxylate
- DIAD diisopropylazodicarboxylate
- DCAD di-t-butylazodicarboxylate
- DCAD di-/?-chlorobenzylazodicarboxylate
- 1,1 '- (azodicarboxyl)dipepidine 1,1 '- (azodicarboxyl)dipepidine.
- Mitsunobu reactions are also carried out with the employment of phosphorane ylides.
- Preferred phosphorane ylides are (cyanomethylene)trimethylphosphoran
- Base catalyzed conditions may refer to organic or inorganic bases.
- Organic bases may be amine bases, hydrocarbon or alkoxide alkali metal salts or alkali metal amine salts.
- Inorganic bases may be alkali metal hydrides, alkali metal hydroxides, salts thereof or quaternary ammonium salts or non-nucleophilic bases such as silyl amides.
- Acid catalyzed conditions may refer to strong inorganic acids, Lewis acids or organic acids. By combining the conditions required for the performance of these two reactions, step a) may be performed in a single chemical step.
- Step b) is performed with respect to the protecting groups present on intermediate V.
- the person skilled in the art is enabled to perform this step by referring to textbooks such as Greene's Protective Groups on Organic Synthesis 4 th Edition.
- X is halogen
- the conversion to the free guanine moiety involves a hydrolysis reaction under acidic conditions, which also leads to deprotection of acid labile protecting groups. More specific examples can also be found in prior art, such as WO2010074534 or EP0481754.
- Entecavir may be prepared according to the above described process, wherein Ri and R 2 are representing hydroxyl protecting groups, or Ri and R 2 together form a cyclic hydroxyl protecting group, wherein the hydroxyl protecting groups are selected from silyl ethers, esters, alkyl and aryl ethers, carbonates.
- Entecavir may be prepared according to the above described process, wherein R ⁇ and R 2 are t-butyldimethyl silyl, X is halogen, R is t-butoxycarbonyl (Boc) and R' is H.
- Entecavir may be prepared according to the above described process, wherein Ri and R 2 are t-butyldimethylsilyl, X is halogen and R and R' are H.
- step b) should be interpreted as a deprotection step with respect to all the protecting groups. It can be performed as a global deprotection step, or a suitable sequence of deprotection reactions can be selected. The person skilled in the art can perform this step according to procedures described in Greene's Protective Groups on Organic Synthesis 4 th Edition.
- R] and R 2 are independently selected from hydrogen, hydroxyl-protecting group or Ri and R 2 may together form a cyclic hydroxyl-protecting group and R 3 is a hydroxyl protecting group.
- Steps a)-c) may be performed as already described above. According to another aspect of the present invention there is provided a process for the preparation of entecavir, comprising the following steps:
- Steps a)-f) may be performed as already described above.
Landscapes
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Abstract
La présente invention concerne un nouveau procédé de préparation du composé de médicament antiviral entécavir, au moyen de nouveaux intermédiaires.
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EP2013003016 | 2013-10-08 | ||
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105037363A (zh) * | 2015-07-13 | 2015-11-11 | 山东罗欣药业集团股份有限公司 | 一种恩替卡韦化合物的新合成方法 |
CN109293508A (zh) * | 2018-10-30 | 2019-02-01 | 常州博海威医药科技股份有限公司 | 一种恩替卡韦中间体的制备方法 |
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