KR101703258B1 - Preparation method for (r)-9-[2-(phosphonomethoxy)propyl]adenine with high purity - Google Patents
Preparation method for (r)-9-[2-(phosphonomethoxy)propyl]adenine with high purity Download PDFInfo
- Publication number
- KR101703258B1 KR101703258B1 KR1020140194296A KR20140194296A KR101703258B1 KR 101703258 B1 KR101703258 B1 KR 101703258B1 KR 1020140194296 A KR1020140194296 A KR 1020140194296A KR 20140194296 A KR20140194296 A KR 20140194296A KR 101703258 B1 KR101703258 B1 KR 101703258B1
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- compound
- propyl
- adenine
- phosphonomethoxy
- Prior art date
Links
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims description 13
- 238000000034 method Methods 0.000 claims abstract description 33
- YOEPLZNPYRBUPF-UHFFFAOYSA-N CC1=C(C2=CC=CC=C2C=C1)S(=O)(=O)OP(=O)(OCC)OCC Chemical compound CC1=C(C2=CC=CC=C2C=C1)S(=O)(=O)OP(=O)(OCC)OCC YOEPLZNPYRBUPF-UHFFFAOYSA-N 0.000 claims abstract description 22
- -1 Diethoxyphosphoryl Chemical group 0.000 claims abstract description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 37
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 239000003960 organic solvent Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000011777 magnesium Substances 0.000 claims description 14
- 229910052749 magnesium Inorganic materials 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 8
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000006900 dealkylation reaction Methods 0.000 claims description 6
- 230000020335 dealkylation Effects 0.000 claims description 5
- RTKCPZYOLXPARI-UHFFFAOYSA-N magnesium;2-methylpropan-2-olate Chemical group [Mg+2].CC(C)(C)[O-].CC(C)(C)[O-] RTKCPZYOLXPARI-UHFFFAOYSA-N 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- RVDLHGSZWAELAU-UHFFFAOYSA-N 5-tert-butylthiophene-2-carbonyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)S1 RVDLHGSZWAELAU-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- HFTSQAKJLBPKBD-UHFFFAOYSA-N magnesium;butan-1-olate Chemical compound [Mg+2].CCCC[O-].CCCC[O-] HFTSQAKJLBPKBD-UHFFFAOYSA-N 0.000 claims description 2
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical group [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 claims description 2
- WNJYXPXGUGOGBO-UHFFFAOYSA-N magnesium;propan-1-olate Chemical compound CCCO[Mg]OCCC WNJYXPXGUGOGBO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims 1
- 229960005305 adenosine Drugs 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 abstract description 49
- 238000004519 manufacturing process Methods 0.000 abstract description 19
- 239000002253 acid Substances 0.000 abstract description 8
- 150000003839 salts Chemical class 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- QUFIXTQDTDCCLJ-UHFFFAOYSA-N methyl naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)OC)=CC=CC2=C1 QUFIXTQDTDCCLJ-UHFFFAOYSA-N 0.000 abstract description 2
- 239000011343 solid material Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 11
- 229960004556 tenofovir Drugs 0.000 description 11
- 239000013078 crystal Substances 0.000 description 10
- MJZYTEBKXLVLMY-RXMQYKEDSA-N (2r)-1-(6-aminopurin-9-yl)propan-2-ol Chemical compound N1=CN=C2N(C[C@H](O)C)C=NC2=C1N MJZYTEBKXLVLMY-RXMQYKEDSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 229930024421 Adenine Natural products 0.000 description 8
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 8
- 229960000643 adenine Drugs 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 7
- UOEFFQWLRUBDME-UHFFFAOYSA-N diethoxyphosphorylmethyl 4-methylbenzenesulfonate Chemical compound CCOP(=O)(OCC)COS(=O)(=O)C1=CC=C(C)C=C1 UOEFFQWLRUBDME-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- DASJFYAPNPUBGG-UHFFFAOYSA-N naphthalene-1-sulfonyl chloride Chemical compound C1=CC=C2C(S(=O)(=O)Cl)=CC=CC2=C1 DASJFYAPNPUBGG-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- RWIGWWBLTJLKMK-UHFFFAOYSA-N diethoxyphosphorylmethanol Chemical compound CCOP(=O)(CO)OCC RWIGWWBLTJLKMK-UHFFFAOYSA-N 0.000 description 5
- GTTBQSNGUYHPNK-UHFFFAOYSA-N hydroxymethylphosphonic acid Chemical compound OCP(O)(O)=O GTTBQSNGUYHPNK-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- GCOFRXOOFANVPB-SNVBAGLBSA-N 9-[(2r)-2-(diethoxyphosphorylmethoxy)propyl]purin-6-amine Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCC)OCC)C=NC2=C1N GCOFRXOOFANVPB-SNVBAGLBSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229960001355 tenofovir disoproxil Drugs 0.000 description 2
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- KTVKQTNGWVJHFL-UHFFFAOYSA-N 2-ethylchromen-4-one Chemical compound C1=CC=C2OC(CC)=CC(=O)C2=C1 KTVKQTNGWVJHFL-UHFFFAOYSA-N 0.000 description 1
- DQEFVRYFVZNIMK-FEDPJRJMSA-N 4-amino-5-fluoro-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one;[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate;(e)-but-2-enedioic acid;4-[[4-[4-[(e)-2-cyanoe Chemical compound OC(=O)\C=C\C(O)=O.C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1.CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N DQEFVRYFVZNIMK-FEDPJRJMSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 235000019750 Crude protein Nutrition 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- 208000027219 Deficiency disease Diseases 0.000 description 1
- 102100021202 Desmocollin-1 Human genes 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229940068561 atripla Drugs 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- JHYNXXBAHWPABC-UHFFFAOYSA-N chloromethyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OCCl JHYNXXBAHWPABC-UHFFFAOYSA-N 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229940029487 complera Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RDYMFSUJUZBWLH-UHFFFAOYSA-N endosulfan Chemical compound C12COS(=O)OCC2C2(Cl)C(Cl)=C(Cl)C1(Cl)C2(Cl)Cl RDYMFSUJUZBWLH-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229940071203 oleanolate Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003904 phospholipids Chemical group 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940070590 stribild Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
- 229940008349 truvada Drugs 0.000 description 1
Images
Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
본 발명은 고순도의 (R)-9-[2-(포스포노메톡시)프로필]아데닌(PMPA)의 제조방법에 관한 것으로서, 반응 공정이 용이하고 반응 중 불순물 생성이 적어 순도가 높은 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트를 중간체로 사용하므로, 순도가 높은 PMPA를 제조할 수 있다. 특히, (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트는 고체상의 물질로 PMPA 제조에 사용시 취급이 용이하여 대량 생산에 적합하고 균질하고 일정한 품질로 생산이 가능하여 반응시 정확한 당량의 투입이 가능한 장점을 가지고 있다. 뿐만 아니라, 수분 및 공기접촉에 민감한 시약을 사용하지 않으므로 안전하고, 재현성 있으며 대량생산에 적합한 장점을 가지고 있다. 또한, 본 발명의 방법으로 제조된 PMPA는 순도가 매우 높으므로 이를 사용하면 테노포비어 디소프록실 및 이의 산 부가염을 고순도로 제조할 수 있어 고품질의 원료의약품을 생산하는데 매우 유리하다.The present invention relates to a process for producing (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA) of high purity, which is easy to carry out, Diethoxyphosphoryl) methylnaphthalene-1-sulfonate is used as an intermediate, PMPA having high purity can be produced. Particularly, (diethoxyphosphoryl) methylnaphthalene-1-sulfonate is a solid material, which is easy to handle when used in the production of PMPA, and is suitable for mass production and can be produced in homogeneous and constant quality, It has advantages. In addition, it does not use reagents sensitive to moisture and air contact, so it is safe, reproducible and suitable for mass production. Also, since PMPA prepared by the method of the present invention has a very high purity, it can be advantageously used to produce a high-quality raw material medicine because it can produce telopoxil and its acid addition salt in high purity.
Description
본 발명은 고순도의 (R)-9-[2-(포스포노메톡시)프로필]아데닌(PMPA)의 제조방법 및 이에 사용되는 결정형의 중간체 화합물에 관한 것이다. The present invention relates to a process for producing high purity (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA) and to crystalline intermediates used therefor.
테노포비어 디소프록실 푸마레이트(TDF, tenofovir disoproxil fumarate, 화학명: 9-[(R)-2-[[비스[[(이소프로폭시카보닐)옥시]메톡시]포스피닐]메톡시]프로필]아데닌 푸마레이트)는 B형 간염 질환이나 후천성면역결핍증 질환의 치료에 의약 원료물질로 유용하게 사용되고 있는 일종의 프로드럭(prodrug)으로서, 경구 투여하면 디소프록실기가 가수분해된 포스폰산 형태의 테노포비어(화학명: (R)-9-[2-(포스포노메톡시)프로필]아데닌, PMPA)로 대사되면서 활성을 나타내게 된다.(TDF, tenofovir disoproxil fumarate, chemical name: 9 - [ (R) -2 - [[Bis [[(isopropoxycarbonyl) oxy] methoxy] phosphinyl] methoxy] propyl ] Adenine fumarate) is a kind of prodrug which is usefully used as a raw material for medicines in the treatment of hepatitis B disease or acquired immune deficiency diseases. When administered orally, the phospholipid form (R) -9- [2- (phosphonomethoxy) propyl] adenine, PMPA).
TDF는 현재 전세계적으로 다양한 상품명으로 판매되고 있으며, 예를 들면 후천성면역결핍증 질환 치료제로서 트루바다(Truvada®), 아트리플라(Atripla®), 콤플레라(Complera®) 및 스트리빌드(Stribild®)가 판매되고 있고, 또한 B형 간염 질환의 치료제로서 비리어드(Viread®)가 판매되고 있다.TDF has been sold in a variety of trade names currently in the world, for example, AIDS true ocean as a deficiency disease treatment (Truvada ®), art ripple LA (Atripla ®), comb player called (Complera ®) and registry building (Stribild ® ), And Viread ( R ) is being marketed as a treatment for hepatitis B disease.
TDF를 제조하기 위하여 다음과 같은 다양한 방법들이 공지되어 있다.Various methods for manufacturing TDF are known as follows.
대한민국 공개특허공보 제2000-29705호는, 하기 반응식 1과 같이, (R)-9-[2-(히드록시)프로필]아데닌(HPA)을 디메틸포름아미드 중에서 디에틸 p-톨루엔설포닐옥시메틸포스포네이트(DESMP) 및 리튬 t-부톡사이드와 반응시켜 중간체를 제조한 후, 이를 아세토니트릴 중에서 브로모트리메틸실란을 사용하여 탈알킬화하는 방법을 개시하고 있다.Korean Patent Laid-Open Publication No. 2000-29705 discloses a process for producing (R) -9- [2- (hydroxy) propyl] adenine (HPA) in diethyl p -toluenesulfonyloxymethyl Phosphonate (DESMP) and lithium t -butoxide to produce an intermediate, which is then dealkylated in acetonitrile using bromotrimethylsilane.
[반응식 1][Reaction Scheme 1]
또한, 대한민국 공개특허공보 제2006-105807호는, 하기 반응식 2와 같이, HPA와 DESMP를 디메틸포름아미드 중에서 마그네슘 t-부톡사이드와 반응시켜 중간체를 제조한 후, 브로모트리메틸실란을 사용하여 탈알킬화하는 방법을 개시하고 있다. Korean Patent Laid-Open Publication No. 2006-105807 discloses a process for producing an intermediate by reacting HPA and DESMP with magnesium t -butoxide in dimethylformamide as shown in Reaction Scheme 2 below, dealkylating the intermediate using bromotrimethylsilane A method is disclosed.
[반응식 2][Reaction Scheme 2]
또한, 국제특허공개 제WO 2014/033688호는 HPA와 디알킬 p-톨루엔설포닐옥시메틸포스포네이트 또는 디알킬 메틸설포닐옥시메틸포스포네이트를 알코올을 포함하는 유기용매 중에서 2,2,6,6-테트라메틸피페리디닐마그네슘과 반응시켜 중간체를 제조한 후, 탈알킬화하는 방법을 개시하고 있다.In addition, International Patent Publication No. WO 2014/033688 discloses a process for the preparation of 2,2,6,6-trichloro- p -toluenesulfonyloxymethylphosphonate or dialkylmethylsulfonyloxymethylphosphonate in an organic solvent containing an alcohol, , 6-tetramethylpiperidinyl magnesium to produce an intermediate, followed by dealkylation.
상기의 방법들은 모두 테노포비어 디소프록실 및 이의 산 부가염을 제조하기 위하여 사용하는 중요 중간체인 (R)-9-[2-(포스포노메톡시)프로필]아데닌(PMPA)을 제조하는 공정에 관한 것으로, 반응에 사용하는 원료의 이탈기가 p-톨루엔설포닐기를 포함하는 구조를 가지고 있다. 이 원료의 경우 액상으로 존재하기 때문에 정제 및 취급이 어려워 고순도로 제조하는 것이 매우 어렵다. 그렇기 때문에, 이 중간체 제조 단계에서 불순물 생성을 최소화하여 고순도의 PMPA를 제조하는 것이 제약 산업 분야의 요구에 부합하는 고순도의 테노포비어 디소프록실 및 이의 산 부가염을 제조하는데 핵심이라고 할 수 있다. The above methods all involve the production of (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA) which is a key intermediate used for the preparation of tenofovir disoproxyl and its acid addition salts , Wherein the leaving group of the starting material used in the reaction has a structure containing a p -toluenesulfonyl group. Since this raw material is present in a liquid phase, purification and handling are difficult, and it is very difficult to produce the raw material with high purity. Therefore, the production of PMPA of high purity by minimizing the generation of impurities in the intermediate production step is essential for producing high purity cannabisidicloxyl and its acid addition salt meeting the needs of the pharmaceutical industry.
이에 본 발명자들은 고순도의 PMPA를 제조하기 위하여 일련의 연구를 수행하던 중 HPA를 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트 및 마그네슘 알콕사이드와 반응시킬 경우 고순도의 PMPA를 제조할 수 있다는 결과를 얻어 본 발명을 완성하게 되었다.Accordingly, the present inventors have conducted a series of studies to produce high purity PMPA It has been found that when HPA is reacted with crystalline (diethoxyphosphoryl) methylnaphthalene-1-sulfonate and magnesium alkoxide, PMPA of high purity can be produced.
따라서, 본 발명의 목적은 고순도의 (R)-9-[2-(포스포노메톡시)프로필]아데닌을 제조하는 방법 및 이에 사용되는 결정형의 중간체 화합물을 제공하는 것이다. Accordingly, it is an object of the present invention to provide a process for preparing high purity (R) -9- [2- (phosphonomethoxy) propyl] adenine and a crystalline form of the intermediate compound used therein.
상기 목적에 따라, 본 발명은 In accordance with the above object,
(1) 하기 화학식 1의 화합물을 하기 화학식 2의 화합물과 반응시켜 하기 화학식 4의 화합물을 제조하는 단계; (1) reacting a compound of formula (1) with a compound of formula (2) to produce a compound of formula (4);
(2) 상기 단계 (1)에서 얻은 화학식 4의 화합물을 물, 유기용매, 또는 이들의 혼합 용매 중에서 결정화하여 결정형의 화학식 4의 화합물을 제조하는 단계; (2) crystallizing the compound of formula (4) obtained in step (1) in water, an organic solvent, or a mixed solvent thereof to prepare a compound of formula (4) in crystalline form;
(3) 상기 단계 (2)에서 얻은 결정형의 화학식 4의 화합물을 하기 화학식 3의 화합물 및 마그네슘 알콕사이드와 반응시켜 하기 화학식 5의 화합물을 제조하는 단계; 및(3) reacting the compound of the formula (4) obtained in the above step (2) with a compound of the following formula (3) and a magnesium alkoxide to prepare a compound of the formula (5) And
(4) 상기 단계 (3)에서 얻은 화학식 5의 화합물을 탈알킬화하여 하기 화학식 6의 화합물을 제조하는 단계를 포함하는, (R)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법을 제공한다:(4) The compound of formula (5) obtained in the above step (3) The compound is dealkylated to give a compound of formula (R) -9- [2- (phosphonomethoxy) propyl] adenine, comprising the step of:
[화학식 1][Chemical Formula 1]
[화학식 2](2)
[화학식 3] (3)
[화학식 4][Chemical Formula 4]
[화학식 5][Chemical Formula 5]
[화학식 6][Chemical Formula 6]
상기 화학식 1, 4 및 5에서, R1은 C1-6알킬이다.In the above general formulas (1), (4) and (5), R 1 is C 1-6 alkyl.
본 발명은 또한 X-선 회절 스펙트럼상에서 6.44±0.2°, 12.20±0.2°, 12.70±0.2°, 14.42±0.2°, 16.01±0.2°, 16.38±0.2°, 16.90±0.2°, 18.39±0.2°, 18.98±0.2°, 19.65±0.2°, 20.57±0.2°, 21.75±0.2°, 21.99±0.2°, 22.85±0.2°, 23.46±0.2°, 24.86±0.2°, 25.35±0.2°, 25.98±0.2°, 31.72±0.2° 및 33.10±0.2°의 회절 각도(2θ)에서의 피크를 포함하는, 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트를 제공한다.The present invention also relates to the use of the compounds according to the invention in the form of 6.44 + - 0.2 [deg.], 12.20 + - 0.2 [deg.], 12.70 ± 0.2 °, 14.42 ± 0.2 °, 16.01 ± 0.2 °, 16.38 ± 0.2 °, 16.90 ± 0.2 °, 18.39 ± 0.2 °, 18.98 ± 0.2 °, 19.65 ± 0.2 °, 20.57 ± 0.2 °, 21.75 ± 0.2 °, The peak at a diffraction angle (2?) Of 21.99 ± 0.2 °, 22.85 ± 0.2 °, 23.46 ± 0.2 °, 24.86 ± 0.2 °, 25.35 ± 0.2 °, 25.98 ± 0.2 °, 31.72 ± 0.2 ° and 33.10 ± 0.2 ° (Diethoxyphosphoryl) methylnaphthalene-1-sulphonate, which is a compound of formula (I).
본 발명에 따른 (R)-9-[2-(포스포노메톡시)프로필]아데닌(PMPA)의 제조방법은, 반응 공정이 용이하고 반응 중 불순물 생성이 적어 순도가 높은 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트를 중간체로 사용하므로, 순도가 높은 PMPA를 제조할 수 있다. The process for producing (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA) according to the present invention is advantageous in that the reaction process is easy, Phenyl) methylnaphthalene-1-sulfonate is used as an intermediate, PMPA having high purity can be produced.
특히 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트는 고체상의 물질로서, 이미 알려진 오일상의 디에틸 p-톨루엔설포닐옥시메틸포스포네이트보다 PMPA 제조에 사용시 취급이 용이하여 대량 생산에 적합하며 고체상의 물질이기에 오일상의 물질보다 균질하고 일정한 품질로 생산이 가능하여 반응시 정확한 당량의 투입이 가능한 장점을 가지고 있다. Particularly, crystalline (diethoxyphosphoryl) methylnaphthalene-1-sulfonate is a solid substance, which is easier to handle in the case of using PMPA than diethyl p-toluenesulfonyloxymethylphosphonate, It is a solid material and it is more homogeneous than the oil phase and can be produced with a constant quality.
뿐만 아니라, 그리냐르(Grignard) 시약과 같이 수분 및 공기접촉에 민감한 시약을 사용하지 않으므로 안전하고, 재현성 있는 생산이 가능하며, 반응에 사용하는 마그네슘 알콕사이드의 취급이 용이하기 때문에 대량생산에 적합한 장점을 가지고 있다. In addition, since it does not use water and air-sensitive reagents like Grignard reagent, it is safe, reproducible production, easy handling of magnesium alkoxide used in reaction, Have.
또한, 본 발명의 방법으로 제조된 PMPA는 순도가 매우 높으므로, 이를 사용하면 테노포비어 디소프록실(TD) 및 테노포비어 디소프록실(TD)의 산 부가염을 고순도로 제조할 수 있어 고품질의 원료 의약품을 생산하는데 매우 유리하다.
In addition, since the PMPA prepared by the method of the present invention has a very high purity, the acid addition salt of terfenoviride sofferoxyl (TD) and terfenoviride sofferoxyl (TD) can be produced with high purity It is very advantageous to produce high quality raw medicine.
도 1 및 2는 각각 제조예 1-1 및 1-2에서 얻은 1-DENMP 결정의 DSC 분석결과이다.
도 3 및 4는 각각 제조예 1-1 및 1-2에서 얻은 1-DENMP 결정의 XRD 분석결과이다.
1 and 2 are DSC analysis results of the 1-DENMP crystals obtained in Production Examples 1-1 and 1-2, respectively.
3 and 4 are XRD analysis results of the 1-DENMP crystals obtained in Production Examples 1-1 and 1-2, respectively.
이하 본 발명을 보다 구체적으로 설명한다.
Hereinafter, the present invention will be described more specifically.
본 발명의 (R)-9-[2-(포스포노메톡시)프로필]아데닌(PMPA)의 제조방법은, The process for producing (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA)
하기 반응식 3 및 4에 나타낸 바와 같이, As shown in the following Reaction Schemes 3 and 4,
(1) 하기 화학식 1의 화합물을 하기 화학식 2의 화합물과 반응시켜 하기 화학식 4의 화합물을 제조하는 단계; (1) reacting a compound of formula (1) with a compound of formula (2) to produce a compound of formula (4);
(2) 상기 단계 (1)에서 얻은 화학식 4의 화합물을 물, 유기용매, 또는 이들의 혼합 용매 중에서 결정화하여 결정형의 화학식 4의 화합물을 제조하는 단계; (2) crystallizing the compound of formula (4) obtained in step (1) in water, an organic solvent, or a mixed solvent thereof to prepare a compound of formula (4) in crystalline form;
(3) (R)-9-[2-(히드록시)프로필]아데닌(화학식 3)을 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트(화학식 4) 및 마그네슘 알콕사이드와 반응시켜 (R)-9-[2-(디알킬포스포노메톡시)프로필]아데닌(화학식 5)을 제조하는 단계; 및 (3) Reaction of (R) -9- [2- (hydroxy) propyl] adenine (Formula 3) with (diethoxyphosphoryl) methylnaphthalene-1-sulfonate 4 and magnesium alkoxide , -9- [2- (dialkylphosphonomethoxy) propyl] adenine (Formula 5); And
(4) (R)-9-[2-(디알킬포스포노메톡시)프로필]아데닌(화학식 5)을 탈알킬화하여 (R)-9-[2-(포스포노메톡시)프로필]아데닌(화학식 6)을 제조하는 단계를 포함한다.(4) Dealkylation of (R) -9- [2- (dialkylphosphonomethoxy) propyl] adenine 5 to give (R) -9- [2- (phosphonomethoxy) (6). ≪ / RTI >
[반응식 3][Reaction Scheme 3]
상기 반응식 3에서, R1은 C1-6알킬이다.In the above Reaction Scheme 3, R 1 is C 1-6 alkyl.
[반응식 4][Reaction Scheme 4]
상기 반응식 4에서, R1은 C1-6알킬이다.
In the above Reaction Scheme 4, R 1 is C 1-6 alkyl.
본 발명의 제조방법의 각 단계를 보다 구체적으로 설명하면 다음과 같다.
Each step of the manufacturing method of the present invention will be described in more detail as follows.
단계 (1)의 절차The procedure of step (1)
먼저, 상기 반응식 3에서와 같이, 디알킬 히드록시메틸포스포네이트(화학식 1)와 1-나프탈렌설포닐 클로라이드(화학식 2)를 반응시켜, 상기 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트(화학식 4)를 제조할 수 있다.(Diethoxyphosphoryl) methylnaphthalene-1-sulfonate (formula 1) is obtained by reacting dialkyl hydroxymethylphosphonate (Formula 1) with 1-naphthalene sulfonyl chloride (Formula 2) (Formula 4).
보다 구체적으로, 디알킬 히드록시메틸포스포네이트(화학식 1)를 유기용매에 가하고 염기를 첨가한 후 냉각한 다음, 1-나프탈렌설포닐 클로라이드(화학식 2)를 가하고 교반하여 고체를 석출시킨 후, 반응물을 여과하여 여액을 분리하고 추출 및 농축하여 고체상의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트(화학식 4)를 제조할 수 있다.More specifically, a dialkyl hydroxymethylphosphonate (Formula 1) is added to an organic solvent, a base is added thereto, followed by cooling, followed by addition of 1-naphthalenesulfonyl chloride (Formula 2) and stirring to precipitate a solid. The reaction product is filtered to separate the filtrate, which is then extracted and concentrated to obtain solid (diethoxyphosphoryl) methylnaphthalene-1-sulfonate (Chemical Formula 4).
여기서, 상기 유기용매로는 디클로로메탄, 클로로포름, 메틸아세테이트, 에틸아세테이트, 아세토니트릴, 테트라히드로퓨란, 아세톤, 메틸에틸케톤, 톨루엔 등을 단독으로 또는 혼합하여 사용할 수 있다.Here, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, toluene, etc. may be used alone or in combination as the organic solvent.
또한, 상기 염기로는 트리메틸아민, 트리에틸아민, 트리부틸아민, 수산화나트륨, 수산화칼륨, 탄산나트륨, 탄산칼륨 등의 유기염기 및 무기염기를 단독으로 또는 혼합하여 사용할 수 있다. 상기 염기는 디알킬 히드록시메틸포스포네이트 1 당량에 대하여 0.5 내지 5 당량의 양으로 사용할 수 있으며, 바람직하게는 1 내지 2 당량의 양으로 사용할 수 있다.As the base, organic bases such as trimethylamine, triethylamine, tributylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, and inorganic bases may be used alone or in combination. The base may be used in an amount of 0.5 to 5 equivalents based on 1 equivalent of dialkyl hydroxymethylphosphonate, preferably 1 to 2 equivalents.
또한, 1-나프탈렌설포닐 클로라이드는 디알킬 히드록시메틸포스포네이트 1 당량에 대하여 0.5 내지 3.0 당량의 양으로 사용할 수 있으며, 바람직하게는 0.5 내지 1.5 당량의 양으로 사용할 수 있다.Also, 1-naphthalenesulfonyl chloride can be used in an amount of 0.5 to 3.0 equivalents, preferably 0.5 to 1.5 equivalents, based on 1 equivalent of dialkyl hydroxymethylphosphonate.
상기 반응의 반응 온도는 0℃ 내지 80℃로 진행할 수 있으며, 바람직하게는 20℃ 내지 40℃로 진행할 수 있다. 또한, 반응 시간은 2 내지 48 시간 동안 진행할 수 있으며, 바람직하게는 2 내지 24 시간 동안 진행할 수 있다.
The reaction may be carried out at a temperature ranging from 0 ° C to 80 ° C, preferably from 20 ° C to 40 ° C. In addition, the reaction time can be from 2 to 48 hours, preferably from 2 to 24 hours.
단계 (2)의 절차The procedure of step (2)
다음으로, 상기 단계 (1)에서 얻은 화학식 4의 화합물을 물, 유기용매, 또는 이들의 혼합 용매 중에서 결정화하여 결정형의 화학식 4의 화합물을 제조하는 단계이다.Next, the compound of Chemical Formula 4 obtained in the above step (1) is crystallized in water, an organic solvent, or a mixed solvent thereof to prepare a crystalline compound of Chemical Formula 4.
이때 상기 유기용매로는 디메틸설폭사이드, 디메틸포름아미드, 디메틸아세트아미드, 아세톤, 에탄올, 아이소프로판올, 메탄올 및 이들의 혼합용매로 이루어진 군에서 선택되는 유기용매를 사용할 수 있다.The organic solvent may be an organic solvent selected from the group consisting of dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetone, ethanol, isopropanol, methanol, and a mixed solvent thereof.
상기 결정화시에는 상기 물과 유기용매를 번갈아가며 1회 이상 사용할 수도 있다.
In the crystallization, the water and the organic solvent may be used one or more times alternately.
상기 결정화 반응에서 물 또는 유기용매의 사용량은 디알킬 히드록시메틸포스포네이트 1g을 기준으로 1 내지 40 ㎖일 수 있고, 보다 구체적으로는 1 내지 8 ㎖일 수 있다.The amount of water or organic solvent used in the crystallization reaction may be 1 to 40 ml, more specifically 1 to 8 ml, based on 1 g of dialkyl hydroxymethylphosphonate.
상기 결정화 반응의 온도 조건은, 예를 들어 0~60℃일 수 있고, 보다 구체적으로는 0~35℃일 수 있다.The temperature condition of the crystallization reaction may be, for example, 0 to 60 ° C, more specifically 0 to 35 ° C.
상기 결정화 반응의 시간은, 예를 들어 1~24 시간일 수 있고, 보다 구체적으로는 1~6 시간일 수 있다.
The time of the crystallization reaction may be, for example, 1 to 24 hours, and more specifically, 1 to 6 hours.
그 결과, 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트를 얻을 수 있다.As a result, crystalline (diethoxyphosphoryl) methylnaphthalene-1-sulfonate can be obtained.
상기 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트는 X-선 회절 스펙트럼상에서 6.44±0.2°, 12.20±0.2°, 12.70±0.2°, 14.42±0.2°, 16.01±0.2°, 16.38±0.2°, 16.90±0.2°, 18.39±0.2°, 18.98±0.2°, 19.65±0.2°, 20.57±0.2°, 21.75±0.2°, 21.99±0.2°, 22.85±0.2°, 23.46±0.2°, 24.86±0.2°, 25.35±0.2°, 25.98±0.2°, 31.72±0.2° 및 33.10±0.2°의 회절 각도(2θ)에서의 피크를 포함한다. 상기 피크들은 상대강도(relative intensity)가 1.0% 이상이고 2θ 값이 35 이하인 피크일 수 있다.The crystalline (diethoxyphosphoryl) methylnaphthalene-1-sulfonate has an X-ray diffraction spectrum of 6.44 0.2, 12.20 0.2, 12.70 0.2, 14.42 0.2, 16.01 0.2, 16.38 0.2, 16.90 0.2, 18.39 0.2, 18.98 0.2, 19.65 0.2, 20.57 0.2, 21.75 0.2, 21.99 0.2, 22.85 0.2, 23.46 0.2, 24.86 0.2 °, 25.35 ± 0.2 °, 25.98 ± 0.2 °, 31.72 ± 0.2 ° and 33.10 ± 0.2 ° at the diffraction angle (2θ). The peaks may be peaks having relative intensities of 1.0% or more and 2 &thetas; values of 35 or less.
또한, 상기 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트는 X-선 회절 스펙트럼상에서 12.99±0.2°, 13.41±0.2°, 15.31±0.2°, 23.74±0.2°, 24.34±0.2°, 29.10±0.2°, 30.62±0.2° 및 32.52±0.2°으로 이루어진 군으로부터 선택되는 회절 각도(2θ)에서의 피크를 추가로 가질 수 있다. 상기 추가되는 피크들은 상대강도(relative intensity)가 0.3% 이상 1.0% 미만이고 2θ 값이 35 이하인 피크일 수 있다.
Also, the crystalline (diethoxyphosphoryl) methylnaphthalene-1-sulfonate has an X-ray diffraction spectrum of 12.99 ± 0.2 °, 13.41 ± 0.2 °, 15.31 ± 0.2 °, 23.74 ± 0.2 °, 24.34 ± 0.2 °, 29.10 占 0.2 占 30.62 占 0.2 占 and 32.52 占 0.2 占 a peak at a diffraction angle (2?) Selected from the group consisting of? The added peaks may be peaks having relative intensities of 0.3% or more and less than 1.0% and 2 &thetas; values of 35 or less.
단계 (3)의 절차The procedure of step (3)
단계 (3)에서는 앞서의 단계에서 얻은 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트를 유기용매 중에서 (R)-9-[2-(히드록시)프로필]아데닌 및 마그네슘 알콕사이드와 반응시켜 (R)-9-[2-(디알킬포스포노메톡시)프로필]아데닌을 제조한다. In step (3), the crystalline (diethoxyphosphoryl) methylnaphthalene-1-sulfonate obtained in the previous step is reacted with (R) -9- [2- (hydroxy) propyl] adenine and magnesium alkoxide in an organic solvent To prepare (R) -9- [2- (dialkylphosphonomethoxy) propyl] adenine.
보다 구체적으로, (R)-9-[2-(히드록시)프로필]아데닌과 마그네슘 알콕사이드를 유기용매에 가하고 교반한 후, 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트를 가하고 교반한다. 반응물을 냉각 후 농축하고 유기용매를 가하여 고체를 석출시킨 다음, 반응물을 여과하고 여액을 다시 농축하여 (R)-9-[2-(디알킬포스포노메톡시)프로필]아데닌을 제조할 수 있다.More specifically, after adding (R) -9- [2- (hydroxy) propyl] adenine and a magnesium alkoxide to an organic solvent and stirring, a crystalline (diethoxyphosphoryl) methylnaphthalene-1-sulfonate is added, do. The reaction product is cooled and concentrated, an organic solvent is added to precipitate a solid, the reaction product is filtered, and the filtrate is concentrated again to obtain (R) -9- [2- (dialkylphosphonomethoxy) propyl] adenine .
상기 마그네슘 알콕사이드로는 마그네슘 메톡사이드, 마그네슘 에톡사이드, 마그네슘 프로폭사이드, 마그네슘 부톡사이드, 또는 마그네슘 t-부톡사이드를 사용할 수 있다.Examples of the magnesium alkoxide include magnesium methoxide, magnesium ethoxide, magnesium propoxide, magnesium butoxide, and magnesium t -butoxide.
또한, 상기 마그네슘 알콕사이드는 (R)-9-[2-(히드록시)프로필]아데닌 1 당량에 대하여 0.9 내지 3 당량의 양으로 사용될 수 있으며, 바람직하게는 1 내지 2 당량의 양으로 사용될 수 있다.The magnesium alkoxide may be used in an amount of 0.9 to 3 equivalents based on 1 equivalent of (R) -9- [2- (hydroxy) propyl] adenine, preferably 1 to 2 equivalents .
상기 반응에 사용하는 유기용매로는 디메틸포름아미드, 디메틸아세트아미드, 디메틸설폭사이드, 디클로로메탄, 클로로포름, 메틸아세테이트, 에틸아세테이트, 아세토니트릴, 테트라히드로퓨란, 아세톤, 메틸에틸케톤 등을 단독으로 또는 혼합하여 사용할 수 있다.Examples of the organic solvent used in the reaction include organic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, Can be used.
또한, 상기 분리(고체석출)를 위해 사용하는 유기용매로는 디클로로메탄, 클로로포름, 메틸아세테이트, 에틸아세테이트, 아세토니트릴, 테트라히드로퓨란, 아세톤, 메틸에틸케톤, 헥산, 헵탄, 시클로헥산 등을 단독으로 또는 혼합하여 사용할 수 있다.Examples of the organic solvent used for separation (solid precipitation) include dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, hexane, heptane, cyclohexane, etc. Or may be used in combination.
상기 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트는 (R)-9-[2-(히드록시)프로필]아데닌 1 당량에 대하여 0.9 내지 3 당량의 양으로 사용할 수 있으며, 바람직하게는 1 내지 2 당량의 양으로 사용할 수 있다. 일 실시예에 따르면, 단계 (3)은 다음과 같이 수행될 수 있다. 먼저, 용기에 (R)-9-[2-(히드록시)프로필]아데닌과 마그네슘 t-부톡사이드를 투입하고, 디메틸포름아미드를 첨가한 후 약 55~65℃까지 승온시키고 30~60분 동안 교반한다. 다시 약 70~80℃까지 승온시키고, (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트를 첨가한 후 약 2시간 동안 교반한다. 반응액을 실온으로 냉각시키고 아세트산을 투입하여 실온에서 30~60분 동안 교반한 후 감압 농축시키고, 디클로로메탄을 첨가한다. 반응액을 실온에서 30~60분 동안 교반하고 여과한 후, 여액을 감압 농축시켜 오일상의 (R)-9-[2-(디에틸포스포노메톡시)프로필]아데닌을 얻을 수 있다.
The (diethoxyphosphoryl) methylnaphthalene-1-sulfonate can be used in an amount of 0.9 to 3 equivalents based on 1 equivalent of (R) -9- [2- (hydroxy) propyl] adenine, To 2 equivalents. According to one embodiment, step (3) may be performed as follows. First, (R) -9- [2- (hydroxy) propyl] adenine and magnesium t -butoxide were added to a vessel, dimethylformamide was added, the temperature was raised to about 55-65 ° C, Lt; / RTI > The temperature is raised again to about 70 to 80 ° C, and (diethoxyphosphoryl) methylnaphthalene-1-sulfonate is added, followed by stirring for about 2 hours. The reaction solution is cooled to room temperature, and acetic acid is added thereto. The mixture is stirred at room temperature for 30 to 60 minutes, concentrated under reduced pressure, and dichloromethane is added. The reaction solution is stirred at room temperature for 30 to 60 minutes, filtered, and the filtrate is concentrated under reduced pressure to obtain (R) -9- [2- (diethylphosphonomethoxy) propyl] adenine in oil phase.
단계 (4)의 절차The procedure of step (4)
본 발명의 제조방법의 단계 (4)에서는 (R)-9-[2-(디알킬포스포노메톡시)프로필]아데닌을 탈알킬화하여 (R)-9-[2-(포스포노메톡시)프로필]아데닌을 제조하는데, 상기 탈알킬화 반응은 공지된 임의의 방법, 예를 들어, 대한민국 공개특허공보 제2000-29705호에 개시된 방법을 사용하여 수행할 수 있다. Dealkylation of (R) -9- [2- (dialkylphosphonomethoxy) propyl] adenine in step (4) of the process of the present invention provides (R) -9- [2- (phosphonomethoxy) Propyl] adenine, which can be carried out using any of the known methods, for example, the method disclosed in Korean Patent Laid-Open Publication No. 2000-29705.
본 발명의 일 실시예에서는 (R)-9-[2-(디알킬포스포노메톡시)프로필]아데닌을 유기용매 중에서 브로모트리메틸실란과 반응시켜 탈알킬화함으로써 (R)-9-[2-(포스포노메톡시)프로필]아데닌을 제조한다.In one embodiment of the present invention, (R) -9- [2- (dialkyl phosphono-methoxy) propyl] adenine by de-alkylation by reacting with bromo-trimethylsilane in an organic solvent, (R) -9- [2- (Phosphonomethoxy) propyl] adenine.
보다 구체적으로, (R)-9-[2-(디알킬포스포노메톡시)프로필]아데닌을 유기용매에 가하고 브로모트리메틸실란을 가한 후 교반한다. 반응액을 농축하고 유기용매 및 물로 결정화한 후 석출된 고체를 여과하여 (R)-9-[2-(포스포노메톡시)프로필]아데닌을 제조할 수 있다.More specifically, (R) -9- [2- (dialkylphosphonomethoxy) propyl] adenine is added to an organic solvent, bromotrimethylsilane is added and stirred. The reaction solution is concentrated, crystallized with an organic solvent and water, and the precipitated solid is filtered to produce (R) -9- [2- (phosphonomethoxy) propyl] adenine.
이때 브로모트리메틸실란은 (R)-9-[2-(디알킬포스포노메톡시)프로필]아데닌 1 당량에 대하여 1 내지 5 당량의 양으로 사용할 수 있으며, 바람직하게는 3 내지 4 당량의 양으로 사용할 수 있다.The bromotrimethylsilane may be used in an amount of 1 to 5 equivalents based on 1 equivalent of (R) -9- [2- (dialkylphosphonomethoxy) propyl] adenine, preferably 3 to 4 equivalents Can be used.
상기 반응에 사용하는 유기용매로는 디메틸포름아미드, 디메틸아세트아미드, 디메틸설폭사이드, 디클로로메탄, 클로로포름, 메틸아세테이트, 에틸아세테이트, 아세토니트릴, 테트라히드로퓨란, 아세톤, 메틸에틸케톤 등을 단독으로 또는 혼합하여 사용할 수 있다.Examples of the organic solvent used in the reaction include organic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, Can be used.
또한, 상기 결정화를 위해 사용하는 유기용매로는 메탄올, 에탄올, 프로판올, 부탄올, t-부탄올, 디클로로메탄, 클로로포름, 메틸아세테이트, 에틸아세테이트, 아세토니트릴, 테트라히드로퓨란, 아세톤, 메틸에틸케톤, 물 등을 단독으로 또는 혼합하여 사용할 수 있다.
Examples of the organic solvent used for the crystallization include methanol, ethanol, propanol, butanol, t -butanol, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, May be used singly or in combination.
발명의 효과Effects of the Invention
본 발명의 (R)-9-[2-(포스포노메톡시)프로필]아데닌(PMPA)의 제조방법은, 반응 공정이 용이하고 반응 중 불순물 생성이 적어 순도가 높은 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트를 중간체로 사용하므로, 순도가 높은 PMPA를 제조할 수 있다. The process for producing (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA) of the present invention is advantageous in that the reaction process is easy and the purity is high (diethoxyphosphoryl) methyl Since naphthalene-1-sulfonate is used as an intermediate, PMPA having high purity can be produced.
특히, (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트는 고체상의 물질로 이미 알려진 오일상의 디에틸 p-톨루엔설포닐옥시메틸포스포네이트보다 PMPA 제조에 사용 시 취급이 용이하여 대량 생산에 적합하며 고체상의 물질이기에 오일상의 물질보다 균질하고 일정한 품질로 생산이 가능하여 반응 시 정확한 당량의 투입이 가능한 장점을 가지고 있다. Particularly, (diethoxyphosphoryl) methylnaphthalene-1-sulfonate is easier to handle when used in the production of PMPA than diethyl p-toluenesulfonyloxymethylphosphonate, which is already known as a solid phase material, and is suitable for mass production Since it is a solid substance, it is more homogeneous than the oil phase and can be produced with a constant quality.
뿐만 아니라, 그리냐르(Grignard) 시약과 같이 수분 및 공기접촉에 민감한 시약을 사용하지 않으므로 안전하고, 재현성 있는 생산이 가능하며, 반응에 사용하는 마그네슘 알콕사이드의 취급이 용이하기 때문에 대량생산에 적합한 장점을 가지고 있다. In addition, since it does not use water and air-sensitive reagents like Grignard reagent, it is safe, reproducible production, easy handling of magnesium alkoxide used in reaction, Have.
또한, 본 발명의 방법으로 제조된 PMPA는 순도가 매우 높으므로 이를 사용하면 테노포비어 디소프록실 및 이의 산 부가염을 고순도로 제조할 수 있어 고품질의 원료의약품을 생산하는데 매우 유리하다.
Also, since PMPA prepared by the method of the present invention has a very high purity, it can be advantageously used to produce a high-quality raw material medicine because it can produce telopoxil and its acid addition salt in high purity.
테노포비어 디소프록실 및 이의 산 부가염의 제조Preparation of terfenoviridisoproxyl and its acid addition salts
본 발명의 방법으로 제조한 고순도의 (R)-9-[2-(포스포노메톡시)프로필]아데닌을 사용하여 하기 반응식 5와 같이 고순도의 테노포비어 디소프록실 및 테노포비어 디소프록실의 산 부가염을 제조할 수 있다.Using high purity (R) -9- [2- (phosphonomethoxy) propyl] adenine prepared by the process of the present invention, high-purity cannabisisopropyl and tenofovir disoproxil Can be prepared.
[반응식 5][Reaction Scheme 5]
상기의 산 부가염으로는 푸마레이트(fumarate), 석시네이트(succinate), 옥살레이트(oxalate), 사카레이트(saccharate), 타르트레이트(tartrate), 시트레이트(citrate), 살리실레이트(salicylate), 옥살레이트(oxalate), 올레아놀레이트(oleanolate), 쿠말레이트(coumalate), 오로테이트(orotate) 등이 부가됨 염을 예시할 수 있다. Such acid addition salts include, but are not limited to, fumarate, succinate, oxalate, saccharate, tartrate, citrate, salicylate, Oxalate, oleanolate, coumalate, orotate, and the like may be exemplified.
상기 제조 공정에 있어서, 구체적인 반응은 공지된 선행기술, 예를 들어 국제특허공개 제WO 1999/005150호, 제WO 2009/074351호, 제WO 2010/142761호 등에 기재된 것을 참조하여 수행할 수 있다. In the above production process, the specific reaction can be carried out with reference to known prior arts, for example, those described in International Patent Publications WO 1999/005150, WO 2009/074351, WO 2010/142761, and the like.
본 발명에서 제조된 PMPA와 테노포비어 디소프록실 산 부가염은 필요한 경우 정제를 통하여 원하는 수준까지 순도를 향상시킬 수 있다.
The PMPA and tenofovir disoproxylic acid addition salts prepared in the present invention can be purified to a desired level through purification if necessary.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.
Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.
사용기기 및 측정조건Equipment used and measurement conditions
테노포비어 디소프록실 푸마레이트의 분석법은 미국약전에 등록 진행 중인 모노그래프(monograph)에 고성능 액상 크로마토그래피(HPLC) 분석법 및 불순물의 관리 기준이 자세히 등재되어 있다(2011년, Authorized USP pending Monograph Ver. 1).
Methods for the determination of tenofovir disoproxil fumarate include a high performance liquid chromatography (HPLC) assay and a control standard for impurities in a monograph registered in the US Pharmacopoeia (2011, Authorized USP pending Monograph Ver. . One).
하기 실시예에 있어서, 화합물의 순도는 고성능 액상 크로마토그래피(HPLC)로 측정하였으며, 이때 정지상(Capcell pak MGII 컬럼, 250 x 4.6mm), 이동상 A(메탄올:t-부틸 알코올:완충액 = 11:1:28(v/v/v)) 및 이동상 B(메탄올:t-부틸 알코올:완충액 = 27:1:12(v/v/v))를 사용하였고, 유속 1.0㎖/분, 오븐온도 35℃, 파장 260㎚에서 측정하였다. 또한, 화합물의 광학적 순도는 키랄 고성능 액상 크로마토그래피(Chiral HPLC)로 측정하였으며, 이때 정지상(Chromtech Chiral AGP 컬럼, 150 x 4.0mm) 및 이동상(메탄올:완충액 = 15:85(v/v))을 사용하였고, 유속 0.8㎖/분, 오븐온도 15℃, 파장 260㎚에서 측정하였다. 상기 완충액(buffer)은 0.01M의 인산수소이나트륨 수용액에 인산을 첨가하여 pH 5.5로 조절하여 조제하였다.In the following examples, the purity of the compounds was determined by high performance liquid chromatography (HPLC) using a stationary phase (Capcell pak MGII column, 250 x 4.6 mm), mobile phase A (methanol: t- butyl alcohol: And the mobile phase B (methanol: t-butyl alcohol: buffer = 27: 1: 12 (v / v / v)) at a flow rate of 1.0 ml / , And a wavelength of 260 nm. Optical purity of the compound was also measured by chiral high performance liquid chromatography (Chromtech Chiral AGP column, 150 x 4.0 mm) and mobile phase (methanol: buffer = 15:85 (v / v)) And measured at a flow rate of 0.8 ml / min, an oven temperature of 15 캜, and a wavelength of 260 nm. The buffer was prepared by adding phosphoric acid to 0.01 M aqueous solution of disodium hydrogen phosphate to adjust the pH to 5.5.
또한, 핵자기공명스펙트럼(NMR)은 300MHz FT-NMR 스펙트로미터(Bruker, Germany)를 사용하여 측정하였다. 또한, X-선 회절분광 스펙트럼(Thin Film X-ray Diffraction Spectrum)은 D2 Phaser X-ray powder diffraction spectrometer (Bruker, Germany)를 사용하여 측정하였고, 시차열량주사(DSC)는 DSC1(Mettler Toledo, Swiss)를 사용하였다.The nuclear magnetic resonance spectrum (NMR) was also measured using a 300 MHz FT-NMR spectrometer (Bruker, Germany). X-ray diffraction spectra were measured using a D2 Phaser X-ray powder diffraction spectrometer (Bruker, Germany) and differential thermal calorimetry (DSC) was performed using DSC1 (Mettler Toledo, Swiss ) Was used.
반응에 사용한 (R)-9-[2-(히드록시)프로필]아데닌(Jingmen ShuaiBang Chem. Sci. & Tech. Co. Ltd., 중국), 디에틸 (히드록시메틸)포스포네이트(LEAPChem, 중국), 1-나프탈렌설포닐 클로라이드(TCI, 일본)는 상업적으로 구입하였다.
(R) -9- [2- (hydroxy) propyl] adenine (Jingmen ShuaiBang Chem Sci. & Tech. Co., Ltd., China), diethyl (hydroxymethyl) phosphonate (LEAPChem, China) and 1-naphthalene sulfonyl chloride (TCI, Japan) were purchased commercially.
제조예 1: (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트(1-DENMP)의 제조Production Example 1: Preparation of (diethoxyphosphoryl) methylnaphthalene-1-sulfonate (1-DENMP)
하기 제조예 1-1 또는 1-2의 절차에 따라 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트(1-DENMP)를 제조하였다.
(Diethoxyphosphoryl) methylnaphthalene-1-sulfonate (1-DENMP) was prepared following the procedure of Preparation 1-1 or 1-2 below.
<제조예 1-1>≪ Production Example 1-1 >
용기에 디에틸 (히드록시메틸)포스포네이트(DEHP) 20g과 에틸아세테이트 100㎖를 투입하고, 트리에틸아민 18.3㎖을 첨가하였다. 25℃에서 1-나프탈렌설포닐 클로라이드 24.3g을 천천히 투입 후 20시간 동안 교반하였다. 상기 반응액의 생성된 결정을 여과하고, 에틸아세테이트 40㎖로 세척한 후 여액에 물 100㎖를 첨가하여 추출하였다. 층분리 후, 수용액층을 에틸아세테이트 100㎖로 한번 더 추출하였다. 유기층을 물 100㎖로 두번 세척한 후 황산마그네슘으로 건조시키고 여과하여 남은 여액을 감압 농축시켰다. 농축액에 물 60㎖를 넣고 실온에서 3시간 교반하였다. 결정을 여과하고 물 40㎖로 세척한 후 약 40℃에서 훈풍 건조하여 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트(1-DENMP) 22.2g(수율: 57.8%)을 얻었다. To the vessel was added 20 g of diethyl (hydroxymethyl) phosphonate (DEHP) and 100 ml of ethyl acetate, and 18.3 ml of triethylamine was added. 24.3 g of 1-naphthalenesulfonyl chloride was added slowly at 25 DEG C, and the mixture was stirred for 20 hours. The resulting crystals of the reaction solution were filtered, washed with 40 ml of ethyl acetate, and then extracted with 100 ml of water to the filtrate. After layer separation, the aqueous layer was extracted once more with 100 mL of ethyl acetate. The organic layer was washed twice with 100 ml of water, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. 60 ml of water was added to the concentrate and the mixture was stirred at room temperature for 3 hours. The crystals were filtered, washed with 40 ml of water and dried under a humid atmosphere at about 40 ° C to obtain 22.2 g (yield: 57.8%) of crystalline (diethoxyphosphoryl) methylnaphthalene-1-sulfonate (1-DENMP).
Purity : 98.3% by HPLCPurity: 98.3% by HPLC
1H-NMR(CDCl3, 400 MHz) δ 8.57(d, 1H, J= 8.6 Hz), 8.23(dd, 1H, J= 1.2 Hz), 8.10(d, 1H, J= 8.4 Hz), 7.91(d, 1H, J= 8.4 Hz), 7.66(t, 1H, J= 7.8 Hz), 7.58(t, 1H, J= 8.2 Hz), 7.52(t, 1H, J= 7.8 Hz), 4.11(d, 2H, J= 10.0 Hz), 3.89-4.06(m, 4H), 1.15(t, 6H, J= 7.1 Hz). 1 H-NMR (CDCl 3, 400 MHz) δ 8.57 (d, 1H, J = 8.6 Hz), 8.23 (dd, 1H, J = 1.2 Hz), 8.10 (d, 1H, J = 8.4 Hz), 7.91 ( d, 1H, J = 8.4 Hz ), 7.66 (t, 1H, J = 7.8 Hz), 7.58 (t, 1H, J = 8.2 Hz), 7.52 (t, 1H, J = 7.8 Hz), 4.11 (d, 2H, J = 10.0 Hz), 3.89-4.06 (m, 4H), 1.15 (t, 6H, J = 7.1 Hz).
DSC 분석결과는 도 1에 나타내었고, XRD 데이터는 도 3 및 하기 표 1에 나타내었다(하기 표 1에는 상대강도(relative intensity) 0.3% 이상, 2θ 값 35 이하인 피크만 기재하였다).The results of the DSC analysis are shown in Fig. 1, and the XRD data are shown in Fig. 3 and the following Table 1 (only the peaks having a relative intensity of 0.3% or more and a 2? Value of 35 or less are shown in Table 1 below).
<제조예 1-2>≪ Production example 1-2 >
용기에 디에틸 (히드록시메틸)포스포네이트(DEHP) 20g과 에틸아세테이트 100㎖를 투입하고, 트리에틸아민 18.3㎖을 첨가하였다. 25℃에서 1-나프탈렌설포닐 클로라이드 24.3g을 천천히 투입 후 20시간 동안 교반하였다. 상기 반응액의 생성된 결정을 여과하고, 에틸아세테이트 40㎖로 세척한 후 여액에 물 100㎖를 첨가하여 추출하였다. 층분리 후, 수용액층을 에틸아세테이트 100㎖로 한번 더 추출하였다. 유기층을 물 100㎖로 두번 세척한 후 황산마그네슘으로 건조시키고 여과하여 남은 여액을 감압 농축시켰다. 농축액에 디메틸설폭사이드 20㎖를 넣고 완전히 용해시킨 후, 물 80㎖를 천천히 첨가하여 실온에서 3시간 교반하였다. 결정을 여과하고 물 40㎖로 세척한 후 약 40℃에서 훈풍 건조하여 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트(1-DENMP) 30.0g(수율: 78.1%)을 얻었다. To the vessel was added 20 g of diethyl (hydroxymethyl) phosphonate (DEHP) and 100 ml of ethyl acetate, and 18.3 ml of triethylamine was added. 24.3 g of 1-naphthalenesulfonyl chloride was added slowly at 25 DEG C, and the mixture was stirred for 20 hours. The resulting crystals of the reaction solution were filtered, washed with 40 ml of ethyl acetate, and then extracted with 100 ml of water to the filtrate. After layer separation, the aqueous layer was extracted once more with 100 mL of ethyl acetate. The organic layer was washed twice with 100 ml of water, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. 20 ml of dimethyl sulfoxide was added to the concentrate and completely dissolved. Then, 80 ml of water was added slowly, and the mixture was stirred at room temperature for 3 hours. The crystals were filtered, washed with 40 ml of water and dried under a humid atmosphere at about 40 ° C to obtain 30.0 g (yield: 78.1%) of crystalline (diethoxyphosphoryl) methylnaphthalene-1-sulfonate (1-DENMP).
Purity : 99.2% by HPLCPurity: 99.2% by HPLC
1H-NMR(CDCl3, 400 MHz) δ 8.57(d, 1H, J= 8.6 Hz), 8.23(dd, 1H, J= 1.2 Hz), 8.10(d, 1H, J= 8.4 Hz), 7.91(d, 1H, J= 8.4 Hz), 7.66(t, 1H, J= 7.8 Hz), 7.58(t, 1H, J= 8.2 Hz), 7.52(t, 1H, J= 7.8 Hz), 4.11(d, 2H, J= 10.0 Hz), 3.89-4.06(m, 4H), 1.15(t, 6H, J= 7.1 Hz). 1 H-NMR (CDCl 3, 400 MHz) δ 8.57 (d, 1H, J = 8.6 Hz), 8.23 (dd, 1H, J = 1.2 Hz), 8.10 (d, 1H, J = 8.4 Hz), 7.91 ( d, 1H, J = 8.4 Hz ), 7.66 (t, 1H, J = 7.8 Hz), 7.58 (t, 1H, J = 8.2 Hz), 7.52 (t, 1H, J = 7.8 Hz), 4.11 (d, 2H, J = 10.0 Hz), 3.89-4.06 (m, 4H), 1.15 (t, 6H, J = 7.1 Hz).
DSC 분석결과는 도 2에 나타내었고, XRD 데이터는 도 4 및 하기 표 2에 나타내었다(하기 표 2에는 상대강도(relative intensity) 0.3% 이상, 2θ 값 35 이하인 피크만 기재하였다).The results of the DSC analysis are shown in Fig. 2, and the XRD data are shown in Fig. 4 and Table 2 (only the peaks having a relative intensity of 0.3% or more and a 2? Value of 35 or less are shown in Table 2 below).
실시예 1: 테노포비어(PMPA)의 제조Example 1: Preparation of Tenofovir (PMPA)
용기에 (R)-9-[2-(히드록시)프로필]아데닌(HPA) 10.0g 및 마그네슘 t-부톡사이드 9.0g을 투입하고, 디메틸포름아미드 20㎖를 첨가한 후 약 60℃까지 승온시키고 60분 동안 교반하였다. 반응액을 약 78℃까지 승온시키고, 상기 제조예 1에서 제조된 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트(1-DENMP) 24.1g을 투입한 후 2시간 동안 교반하였다. 반응액을 실온으로 냉각시키고 아세트산 7.3㎖를 투입하여 상기 온도에서 60분 동안 교반한 후, 감압 농축시켜 디메틸포름아미드를 제거하였다. 상기 농축액에 물 10㎖와 디클로로메탄 200㎖를 투입하고 실온에서 약 60분 동안 교반하였다. 상기 반응액을 여과한 후 남은 여액을 감압 농축시켜 중간체인 오일상의 (R)-9-[2-(디에틸포스포노메톡시)프로필]아데닌(DPPA)을 얻었다. 10.0 g of (R) -9- [2- (hydroxy) propyl] adenine (HPA) and 9.0 g of magnesium t -butoxide were charged in a vessel, 20 ml of dimethylformamide was added, Stir for 60 min. The reaction solution was heated to about 78 캜, and 24.1 g of the crystalline (diethoxyphosphoryl) methylnaphthalene-1-sulfonate (1-DENMP) prepared in Preparation Example 1 was added thereto, followed by stirring for 2 hours. The reaction solution was cooled to room temperature, and 7.3 ml of acetic acid was added thereto. The mixture was stirred at the above temperature for 60 minutes and then concentrated under reduced pressure to remove dimethylformamide. 10 ml of water and 200 ml of dichloromethane were added to the concentrate, and the mixture was stirred at room temperature for about 60 minutes. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain (R) -9- [2- (diethylphosphonomethoxy) propyl] adenine (DPPA) as an intermediate oil.
오일상의 (R)-9-[2-(디에틸포스포노메톡시)프로필]아데닌(DPPA)에 아세토니트릴 10㎖ 및 브로모트리메틸실란 26.8㎖를 넣고 약 65℃에서 1시간 동안 교반하였다. 반응액을 실온으로 냉각한 후 감압농축시키고 물 10㎖와 메탄올 100㎖를 투입하여 완전히 용해시켰다. 20% 소듐하이드록사이드 수용액을 사용하여 pH 3.0으로 조절하고 실온에서 2시간 교반하였다. 상기 결정을 여과하고 물 50㎖와 아세톤 20㎖ 순으로 세척한 후 실온에서 질소 건조하여 조 테노포비어(PMPA) 12.0g(수율: 81%)을 얻었다.10 ml of acetonitrile and 26.8 ml of bromotrimethylsilane were added to (R) -9- [2- (diethylphosphonomethoxy) propyl] adenine (DPPA) on an oil phase and stirred at 65 ° C for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and completely dissolved by adding 10 ml of water and 100 ml of methanol. The mixture was adjusted to pH 3.0 using a 20% sodium hydroxide aqueous solution and stirred at room temperature for 2 hours. The crystals were filtered, washed with 50 ml of water and 20 ml of acetone, and dried under nitrogen at room temperature to obtain 12.0 g of crude tenovourier (PMPA) (yield: 81%).
상기 얻은 조 테노포비어(PMPA) 10.0g에 물 185㎖를 투입하고 약 95℃로 승온하여 30분 동안 완전히 용해시켰다. 용해시킨 반응액을 약 25℃까지 서서히 냉각시키고 다시 3℃로 냉각시킨 후 상기 온도로 유지하여 3시간 동안 교반시켰다. 결정을 여과하고 물 50㎖와 아세톤 20㎖ 순으로 세척한 후 실온에서 질소 건조하여 테노포비어(PMPA) 9.0g(수율: 90%)을 얻었다.185.0 ml of water was added to 10.0 g of the obtained crude protein (PMPA), and the mixture was heated to about 95 ° C and completely dissolved for 30 minutes. The dissolved reaction solution was slowly cooled to about 25 캜, cooled again to 3 캜, and maintained at the above temperature for 3 hours. The crystals were filtered, washed with 50 ml of water and 20 ml of acetone, and then dried under nitrogen at room temperature to obtain 9.0 g (yield: 90%) of terpovapor (PMPA).
순도측정 : 99.3% by HPLCPurity measurement: 99.3% by HPLC
1H-NMR(D2O, 300 MHz) δ 8.25(s, 1H), 8.09(s, 1H), 4.35(dd, 1H), 4.22(dd, 1H), 3.97(m, 1H), 3.57(dd, 1H), 3.46(dd, 1H), 1.11(d, 3H).
1 H-NMR (D 2 O, 300 MHz) ? 8.25 (s, IH), 8.09 (s, IH), 4.35 (dd, IH), 4.22 dd, 1 H), 3.46 (dd, 1 H), 1.11 (d, 3 H).
아울러, 상기 실시예 1에서의 테노포비어 제조시의 반응액의 순도를, 대한민국 공개특허공보 제2000-29705호에 따른 테노포비어 제조시와 비교하여 하기 표 3에 정리하였다.The purity of the reaction solution in the preparation of the Tenofovir in Example 1 is summarized in Table 3 as compared with that in the preparation of Tenofovir in accordance with Korean Patent Publication No. 2000-29705.
참조예 1: 테노포비어 디소프록실 푸마레이트(TDF)의 제조 REFERENCE EXAMPLE 1 Preparation of Tenofovir Dysorofoxyl Fumarate (TDF)
용기에 상기 실시예 1에서 제조한 테노포비어(PMPA) 4.0g을 투입하고 N-메틸피롤리돈 15㎖와 트리에틸아민 5.8㎖를 첨가하였다. 반응액을 약 63℃로 승온하여 30분 동안 교반하고 클로로메틸 아이소프로필 카보네이트 10g을 투입한 후 상기 온도에서 4시간 동안 교반하였다. 반응액을 실온으로 냉각 후 다시 5℃로 냉각시키고, 15℃ 이하 유지하에 차가운 물 25㎖를 투입하였다. 15℃에서 1시간 교반하고, 메틸렌클로라이드 15㎖로 두번 추출하였다. 층분리 후 유기층을 물 10㎖로 두번 세척하고 유기층을 황산마그네슘으로 건조시킨 후 여과하고 남은 여액을 감압 농축시켜 오일상의 테노포비어 디소프록실(TD)을 얻었다. To the container was added 4.0 g of the tenofovir (PMPA) prepared in Example 1, and 15 ml of N-methylpyrrolidone and 5.8 ml of triethylamine were added. The reaction solution was heated to about 63 캜, stirred for 30 minutes, added with 10 g of chloromethyl isopropyl carbonate, and stirred at that temperature for 4 hours. The reaction solution was cooled to room temperature, cooled again to 5 deg. C and kept at 15 deg. C or lower, and 25 ml of cold water was added thereto. The mixture was stirred at 15 DEG C for 1 hour and extracted twice with 15 mL of methylene chloride. After the layer separation, the organic layer was washed twice with 10 ml of water, and the organic layer was dried with magnesium sulfate and filtered. The remaining filtrate was concentrated under reduced pressure to give terpovavir disoproxyl (TD) in oil.
오일상의 테노포비어 디소프록실(TD)에 이소프로필알코올 35㎖와 푸마르산 1.6g을 투입하고 약 50℃로 승온하여 30분 동아 완전히 용해시켰다. 용해시킨 반응액을 약 25℃까지 서서히 냉각시키고 다시 3℃로 냉각시킨 후 상기 온도로 유지하여 4시간 동안 교반하였다. 결정을 여과하고 이소프로필알코올 10㎖로 세척한 후 약 40℃에서 진공 건조하여 목적화합물인 테노포비어 디소프록실 푸마레이트(TDF) 4.7g(수율: 53%)을 얻었다. 35 ml of isopropyl alcohol and 1.6 g of fumaric acid were added to terpovapor discosyl (TD) on an oil phase, and the temperature was raised to about 50 캜 and completely dissolved for 30 minutes. The dissolved reaction solution was gradually cooled to about 25 캜, cooled again to 3 캜, and maintained at the above temperature and stirred for 4 hours. The crystals were filtered, washed with 10 ml of isopropyl alcohol, and then vacuum-dried at about 40 ° C to obtain 4.7 g (yield: 53%) of the desired compound, tenofovir dysoproxyl fumarate (TDF).
상기 얻은 테노포비어 디소프록실 푸마레이트(TDF) 4.7g에 이소프로필알코올 40㎖를 투입하고 약 50℃로 승온하여 30분 동안 완전히 용해시켰다. 용해시킨 반응액을 약 25℃까지 서서히 냉각시키고 다시 3℃로 냉각시킨 후 상기 온도로 유지하여 4시간 동안 교반시켰다. 결정을 여과하고 이소프로필알코올 100㎖로 세척한 후 약 40℃에서 진공 건조하여 결정형의 테노포비어 디소프록실 푸마레이트(TDF) 4.3g(수율: 90%)을 얻었다.40 ml of isopropyl alcohol was added to 4.7 g of the above-obtained tepofibaredisopropyl fumarate (TDF), and the temperature was raised to about 50 캜 and completely dissolved for 30 minutes. The dissolved reaction solution was slowly cooled to about 25 캜, cooled again to 3 캜, and maintained at the above temperature for 4 hours. The crystals were filtered, washed with 100 ml of isopropyl alcohol, and vacuum-dried at about 40 ° C to obtain 4.3 g (yield: 90%) of crystalline type terfenoviridisopropyl fumarate (TDF).
Claims (11)
(2) 상기 단계 (1)에서 얻은 화학식 4의 화합물을 물, 유기용매, 또는 이들의 혼합 용매 중에서 결정화하여 결정형의 화학식 4의 화합물을 제조하는 단계;
(3) 상기 단계 (2)에서 얻은 결정형의 화학식 4의 화합물을 하기 화학식 3의 화합물 및 마그네슘 알콕사이드와 반응시켜 하기 화학식 5의 화합물을 제조하는 단계; 및
(4) 상기 단계 (3)에서 얻은 화학식 5의 화합물을 탈알킬화하여 하기 화학식 6의 화합물을 제조하는 단계를 포함하고,
상기 단계 (2)에서 사용되는 유기용매는 디메틸설폭사이드, 디메틸포름아미드, 디메틸아세트아미드, 아세톤, 에탄올, 아이소프로판올, 메탄올 및 이들의 혼합용매로 이루어진 군에서 선택되며,
상기 결정형의 화학식 4의 화합물은 R1이 에틸인 경우, X-선 회절 스펙트럼상에서 6.44±0.2°, 12.20±0.2°, 12.70±0.2°, 14.42±0.2°, 16.01±0.2°, 16.38±0.2°, 16.90±0.2°, 18.39±0.2°, 18.98±0.2°, 19.65±0.2°, 20.57±0.2°, 21.75±0.2°, 21.99±0.2°, 22.85±0.2°, 23.46±0.2°, 24.86±0.2°, 25.35±0.2°, 25.98±0.2°, 31.72±0.2° 및 33.10±0.2°의 회절 각도(2θ)에서의 피크를 포함하는 결정형의 (디에톡시포스포릴)메틸 나프탈렌-1-설포네이트인 것을 특징으로 하는, (R)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법:
[화학식 1]
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
[화학식 6]
상기 화학식 1, 4 및 5에서, R1은 C1-6알킬이다.
(1) reacting a compound of formula (1) with a compound of formula (2) to produce a compound of formula (4);
(2) crystallizing the compound of formula (4) obtained in step (1) in water, an organic solvent, or a mixed solvent thereof to prepare a compound of formula (4) in crystalline form;
(3) reacting the compound of the formula (4) obtained in the above step (2) with a compound of the following formula (3) and a magnesium alkoxide to prepare a compound of the formula (5) And
(4) The compound of formula (5) obtained in the above step (3) The compound is dealkylated to give a compound of formula Comprising the steps of:
The organic solvent used in step (2) is selected from the group consisting of dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetone, ethanol, isopropanol, methanol,
The crystalline form of the compound of formula (4) is characterized in that when R < 1 > is ethyl, 6.44 0.2, 12.20 0.2, 12.70 0.2, 14.42 0.2, 16.01 0.2, 16.38 0.2 , 16.90 ± 0.2 °, 18.39 ± 0.2 °, 18.98 ± 0.2 °, 19.65 ± 0.2 °, 20.57 ± 0.2 °, 21.75 ± 0.2 °, 21.99 ± 0.2 °, 22.85 ± 0.2 °, 23.46 ± 0.2 °, 24.86 ± 0.2 ° (Diethoxyphosphoryl) methylnaphthalene-1-sulfonate including peaks at diffraction angles (2?) Of 25.35 ± 0.2 °, 25.98 ± 0.2 °, 31.72 ± 0.2 ° and 33.10 ± 0.2 ° (R) -9- [2- (phosphonomethoxy) propyl] adenine,
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
[Chemical Formula 6]
In the above general formulas (1), (4) and (5), R 1 is C 1-6 alkyl.
상기 마그네슘 알콕사이드가 마그네슘 메톡사이드, 마그네슘 에톡사이드, 마그네슘 프로폭사이드, 마그네슘 부톡사이드, 또는 마그네슘 t-부톡사이드인 것을 특징으로 하는, (R)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법.
The method according to claim 1,
(R) -9- [2- (phosphonomethoxy) propyl] -propyl] -methanol, which is characterized in that the magnesium alkoxide is magnesium methoxide, magnesium ethoxide, magnesium propoxide, magnesium butoxide or magnesium t- ≪ / RTI >
상기 마그네슘 알콕사이드가 마그네슘 t-부톡사이드인 것을 특징으로 하는, (R)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법.
The method of claim 3,
A process for producing (R) -9- [2- (phosphonomethoxy) propyl] adenine, wherein the magnesium alkoxide is magnesium t -butoxide.
상기 단계 (3)의 반응이 디메틸포름아미드, 디메틸아세트아미드, 디메틸설폭사이드, 디클로로메탄, 클로로포름, 메틸아세테이트, 에틸아세테이트, 아세토니트릴, 테트라히드로퓨란, 아세톤, 메틸에틸케톤 및 이들의 혼합 용매로 이루어진 군에서 선택되는 유기용매 중에서 수행되는 것을 특징으로 하는, (R)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법.
The method according to claim 1,
Wherein the reaction of step (3) is carried out in a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, (R) -9- [2- (phosphonomethoxy) propyl] adenine, which is characterized in that it is carried out in an organic solvent selected from the group consisting of:
상기 탈알킬화가 화학식 5의 화합물을 유기용매 중에서 브로모트리메틸실란과 반응시켜 수행되는 것을 특징으로 하는, (R)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법.
The method according to claim 1,
9. A process for the preparation of (R) -9- [2- (phosphonomethoxy) propyl] adenine wherein the dealkylation is carried out by reacting the compound of formula (5) with bromotrimethylsilane in an organic solvent.
상기 탈알킬화에 사용되는 유기용매가 디메틸포름아미드, 디메틸아세트아미드, 디메틸설폭사이드, 디클로로메탄, 클로로포름, 메틸아세테이트, 에틸아세테이트, 아세토니트릴, 테트라히드로퓨란, 아세톤, 메틸에틸케톤 및 이들의 혼합 용매로 이루어진 군에서 선택되는 것을 특징으로 하는, (R)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법.
The method according to claim 6,
The organic solvent used for the dealkylation is selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, (R) -9- [2- (phosphonomethoxy) propyl] adenine. ≪ / RTI >
상기 단계 (1)의 반응이 디클로로메탄, 클로로포름, 메틸아세테이트, 에틸아세테이트, 아세토니트릴, 테트라히드로퓨란, 아세톤, 메틸에틸케톤, 톨루엔 및 이들의 혼합 용매로 이루어진 군에서 선택되는 유기용매 중에서 염기의 존재 하에 수행되는 것을 특징으로 하는, (R)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법.
The method according to claim 1,
Wherein the reaction of step (1) is carried out in the presence of a base in an organic solvent selected from the group consisting of dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, toluene, (R) -9- [2- (phosphonomethoxy) propyl] adenine.
상기 염기가 트리메틸아민, 트리에틸아민, 트리부틸아민, 수산화나트륨, 수산화칼륨, 탄산나트륨, 탄산칼륨 및 이들의 혼합물로 이루어진 군에서 선택되는 것을 특징으로 하는, (R)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법.
9. The method of claim 8,
It said base is trimethylamine, triethylamine, tributylamine, sodium hydroxide, characterized in that selected from potassium hydroxide, sodium carbonate, potassium carbonate and mixtures thereof, (R) -9- [2- (Force ≪ / RTI >< RTI ID = 0.0 > adenosine < / RTI >
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020140194296A KR101703258B1 (en) | 2014-12-30 | 2014-12-30 | Preparation method for (r)-9-[2-(phosphonomethoxy)propyl]adenine with high purity |
| JP2017516154A JP2017535520A (en) | 2014-09-30 | 2015-09-24 | Method for producing high purity (R) -9- [2- (phosphonomethoxy) propyl] adenine |
| CN201580047014.1A CN106687467A (en) | 2014-09-30 | 2015-09-24 | Method for preparing high-purity (r)-9-[2-(phosphonomethoxy)propyl]adenine |
| PCT/KR2015/010114 WO2016052930A1 (en) | 2014-09-30 | 2015-09-24 | Method for preparing high-purity (r)-9-[2-(phosphonomethoxy)propyl]adenine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020140194296A KR101703258B1 (en) | 2014-12-30 | 2014-12-30 | Preparation method for (r)-9-[2-(phosphonomethoxy)propyl]adenine with high purity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20160081089A KR20160081089A (en) | 2016-07-08 |
| KR101703258B1 true KR101703258B1 (en) | 2017-02-06 |
Family
ID=56503385
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020140194296A KR101703258B1 (en) | 2014-09-30 | 2014-12-30 | Preparation method for (r)-9-[2-(phosphonomethoxy)propyl]adenine with high purity |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR101703258B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20170033862A (en) * | 2014-07-21 | 2017-03-27 | 장쑤 한서 파마슈티칼 그룹 캄파니 리미티드 | New polycrystalline form of tenofovir prodrug, and preparation method and application therefor |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101909570B1 (en) * | 2016-12-05 | 2018-10-19 | (주) 성운파마코피아 | Preparation method for highly pure tenofovir disoproxil |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014033688A1 (en) * | 2012-09-03 | 2014-03-06 | Ithemba Pharmaceuticals (Proprietary) Limited | A process for the preparation of (r)-9-[2-(phosphonometh-oxy)propyl]adenine (pmpa) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2198003T3 (en) | 1996-07-26 | 2004-01-16 | Gilead Sciences, Inc. | NUCLEOTID ANALOGS |
| AU2001282941C1 (en) | 2000-07-21 | 2016-12-22 | Gilead Sciences, Inc. | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| KR101832238B1 (en) * | 2010-06-07 | 2018-02-26 | 주식회사 엘지화학 | Novel sulfonyloxymethylphosphonate derivatives and process for preparing diisopropyl ((1-(trityloxymethyl)-cyclopropyl)oxy)methylphosphonate using the same |
-
2014
- 2014-12-30 KR KR1020140194296A patent/KR101703258B1/en active IP Right Grant
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014033688A1 (en) * | 2012-09-03 | 2014-03-06 | Ithemba Pharmaceuticals (Proprietary) Limited | A process for the preparation of (r)-9-[2-(phosphonometh-oxy)propyl]adenine (pmpa) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20170033862A (en) * | 2014-07-21 | 2017-03-27 | 장쑤 한서 파마슈티칼 그룹 캄파니 리미티드 | New polycrystalline form of tenofovir prodrug, and preparation method and application therefor |
| KR102476361B1 (en) | 2014-07-21 | 2022-12-09 | 장쑤 한서 파마슈티칼 그룹 캄파니 리미티드 | New polycrystalline form of tenofovir prodrug, and preparation method and application therefor |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20160081089A (en) | 2016-07-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2046792B1 (en) | Process for the preparation of tenofovir | |
| EP1713489B1 (en) | Crystalline form of ibandronate sodium and processes for preparation thereof | |
| KR100919656B1 (en) | Novel polymorphs and pseudopolymorphs of risedronate sodium | |
| ES2712644T3 (en) | Medical use of polymorph A of Ibandronate | |
| RU2644160C2 (en) | Chemical method | |
| KR102162208B1 (en) | 7-((3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl)-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal | |
| WO2006081962A1 (en) | Ibandronate polymorph b | |
| US20080306028A1 (en) | Erianin Salts, Their Preparation Methods and Pharmaceutical Compositions Containing the Same | |
| CZ201629A3 (en) | Crystalline modifications of the (3R)-3-cyclopentyl-3- [4-(7H-pyrrolo [2,3-d] pyrimidin-4yl) pyrazol-1yl] propanenitrile salts and the method of their preparation | |
| KR101703258B1 (en) | Preparation method for (r)-9-[2-(phosphonomethoxy)propyl]adenine with high purity | |
| EP2860185A1 (en) | An improved process for the preparation of Tenofovir disoproxil and pharmaceutically acceptable salts thereof | |
| TW201829420A (en) | New solid forms of [(1s)-1-[(2s,4r,5r)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate | |
| CN106146548B (en) | Preparation and application of aryloxy phosphate monosodium salt | |
| KR101703257B1 (en) | Preparation method for (r)-9-[2-(phosphonomethoxy)propyl]adenine with high purity | |
| JP2017535520A (en) | Method for producing high purity (R) -9- [2- (phosphonomethoxy) propyl] adenine | |
| US20070173484A1 (en) | Process for the preparation of risedronate sodium hemi-pentahydrate | |
| KR20150137899A (en) | Improved Method for Preparing (R)-9-[2-(phosphonomethoxy)propyl]adenine | |
| US20090149427A1 (en) | Pharmaceutically acceptable salts and hydrates of risedronic acid | |
| JP3637019B2 (en) | Novel crystalline pamidronate disodium hydrate and process for producing the same | |
| JPH04316590A (en) | Heterocyclic compound | |
| KR20180064213A (en) | Preparation method for highly pure tenofovir disoproxil | |
| KR102379965B1 (en) | Efficient preparation method of Tenofovir | |
| TWI324931B (en) | Process for preparation of cyclic prodrugs of pmea and pmpa | |
| UA120385C2 (en) | Pyrazolo[3,4-d]pyrimidin derivative and its use for the treatment of leishmaniasis | |
| EP1923052A1 (en) | Novel polymorphs and pseudopolymorphs of risedronate sodium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right |