CN109384813A - A kind of preparation method of tenofovir disoproxil fumarate analog - Google Patents
A kind of preparation method of tenofovir disoproxil fumarate analog Download PDFInfo
- Publication number
- CN109384813A CN109384813A CN201710649577.9A CN201710649577A CN109384813A CN 109384813 A CN109384813 A CN 109384813A CN 201710649577 A CN201710649577 A CN 201710649577A CN 109384813 A CN109384813 A CN 109384813A
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- Prior art keywords
- base
- oxygen
- methyl
- propyl
- purine
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical class 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 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims description 33
- -1 (diethoxy phosphono) methyl Chemical group 0.000 claims abstract description 71
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims abstract description 59
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 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 claims abstract description 22
- 229930024421 Adenine Natural products 0.000 claims abstract description 13
- 229960000643 adenine Drugs 0.000 claims abstract description 13
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 9
- YFLBCDPISIYMHR-UHFFFAOYSA-N C(OCCl)(OC(C)(C)OOCCCC)=O Chemical compound C(OCCl)(OC(C)(C)OOCCCC)=O YFLBCDPISIYMHR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 7
- 230000008025 crystallization Effects 0.000 claims abstract description 7
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000001953 recrystallisation Methods 0.000 claims abstract description 3
- 239000002585 base Substances 0.000 claims description 107
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 73
- 229910052760 oxygen Inorganic materials 0.000 claims description 73
- 239000001301 oxygen Substances 0.000 claims description 73
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 32
- 150000002148 esters Chemical class 0.000 claims description 32
- 239000003960 organic solvent Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 19
- 150000007530 organic bases Chemical class 0.000 claims description 16
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 13
- 239000000047 product Substances 0.000 claims description 13
- 229910019142 PO4 Inorganic materials 0.000 claims description 10
- 239000003444 phase transfer catalyst Substances 0.000 claims description 10
- 239000010452 phosphate Substances 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 239000003495 polar organic solvent Substances 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 6
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 150000003242 quaternary ammonium salts Chemical group 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical group [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 150000002736 metal compounds Chemical class 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 150000004982 aromatic amines Chemical class 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- LQOBMKYCRQDMTN-UHFFFAOYSA-N 3-(2-ethylphenyl)pentan-3-amine;hydrochloride Chemical compound Cl.CCC1=CC=CC=C1C(N)(CC)CC LQOBMKYCRQDMTN-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- JWLJBISFJGEYMT-UHFFFAOYSA-M benzyl(triethyl)azanium;iodide Chemical compound [I-].CC[N+](CC)(CC)CC1=CC=CC=C1 JWLJBISFJGEYMT-UHFFFAOYSA-M 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000012546 transfer Methods 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 2
- 238000003408 phase transfer catalysis Methods 0.000 claims 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims 1
- 150000004040 pyrrolidinones Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 25
- 229960004556 tenofovir Drugs 0.000 abstract description 13
- 230000008569 process Effects 0.000 abstract description 6
- 238000011084 recovery Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- LLDBOMNUMJVCBX-UHFFFAOYSA-N 2-butylperoxypropan-2-yl hydrogen carbonate Chemical compound CCCCOOC(C)(C)OC(O)=O LLDBOMNUMJVCBX-UHFFFAOYSA-N 0.000 description 12
- 239000012535 impurity Substances 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 239000012071 phase Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 5
- 238000007039 two-step reaction Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 description 3
- 238000004679 31P NMR spectroscopy Methods 0.000 description 3
- GOOHAUXETOMSMM-GSVOUGTGSA-N R-propylene oxide Chemical compound C[C@@H]1CO1 GOOHAUXETOMSMM-GSVOUGTGSA-N 0.000 description 3
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000003301 hydrolyzing effect Effects 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- MTEVPAXEFVFOLE-UHFFFAOYSA-N ClC[C]C(C)C Chemical compound ClC[C]C(C)C MTEVPAXEFVFOLE-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- ADLSFYJDHWUKFP-UHFFFAOYSA-N 5-methoxy-11,12-dihydroindolo[2,3-a]carbazole-6-carbonitrile Chemical compound N1C2=C3NC4=CC=C[CH]C4=C3C(OC)=C(C#N)C2=C2[C]1C=CC=C2 ADLSFYJDHWUKFP-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- DLYAOBADVUJCDM-UHFFFAOYSA-N C[C]C(C)C Chemical compound C[C]C(C)C DLYAOBADVUJCDM-UHFFFAOYSA-N 0.000 description 1
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- UERFYFDULXZCSY-UHFFFAOYSA-N [NH4+].[Br-].C(C1=CC=CC=C1)[PH3+].[Br-] Chemical compound [NH4+].[Br-].C(C1=CC=CC=C1)[PH3+].[Br-] UERFYFDULXZCSY-UHFFFAOYSA-N 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- SXGBREZGMJVYRL-UHFFFAOYSA-N butan-1-amine;hydrobromide Chemical compound [Br-].CCCC[NH3+] SXGBREZGMJVYRL-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- FOWDZVNRQHPXDO-UHFFFAOYSA-N propyl hydrogen carbonate Chemical compound CCCOC(O)=O FOWDZVNRQHPXDO-UHFFFAOYSA-N 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of methods for preparing tenofovir disoproxil fumarate analog.The present invention using adenine as raw material, in the presence of a base with (RSubstitution reaction occurs for)-propene carbonate, substitution reaction occurs with (diethoxy phosphono) methyl -4- oluene sulfonic acides ester again, it is hydrolyzed again with concentrated hydrochloric acid solution, crystallization obtains anhydrous tenofovir, and products therefrom reacts to obtain again Tenofovir with chloromethyl butylperoxyisopropyl carbonate, with 2- bromopropane reaction obtains the target compound again.Starting material selected by the present invention is cheap and easy to get, and simple process improves material utilization and total recovery.The method that the intermediate of this method selects recrystallization is purified, and yield is high, purity is high.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of antiviral drugs tenofovir disoproxil fumarate class
Like object ((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen) methyl) (isopropyl oxygen) phosphine) oxygen) methyl isopropyl
The preparation method of base carbonic ester.
Background technique
The present invention relates to a kind of antiviral drugs tenofovir disoproxil fumarate analog ((((((R) -1- (6- ammonia
Base -9HPurine -9- base) propyl -2- base) oxygen) methyl) (isopropyl oxygen) phosphine) oxygen) isopropyl methyl carbonic ester (formula VI) preparation side
Method.
Tenofovir disoproxil fumarate (formula VII) is that Ji Leadd B.V, the U.S. (Gilead sciences) is developed
Nucleotide reverse transcriptase inhibitors (nucleotide reverse transcriptase inhibitors, NtRTIs), beauty
State FDA ratified its listing in 2001, for treating AIDS (HIV infection), ratifies it again within 2008 and is used to treat chronic
Type hepatitis (HBV infection).Tenofovir disoproxil fumarate has tolerance is good, resistant rate is low, drug withdrawal rebound rate is low, renal toxicity is small etc.
Feature, especially merging HBV infection patient to HIV has preferable potential applicability in clinical practice.Tenofovir disoproxil fumarate
It is the prodrug of tenofovir, since tenofovir is almost absorbed without gastrointestinal tract, so to be esterified, be replaced at salt for fumaric acid
Nuo Fuwei dipivoxil, the latter have water solubility, can be rapidly absorbed and metabolic degradation plays disease-resistant at tenofovir in vivo
Toxic action.
It, can be a small amount of along with generating one during producing tenofovir disoproxil fumarate (VII) bulk pharmaceutical chemicals
Process impurity tenofovir disoproxil fumarate analog (VI), chemical name are as follows: ((((((R)- 1- (6- amino -9HIt is fast
Purine -9- base) propyl -2- base) oxygen) methyl) (isopropyl oxygen) phosphine) oxygen) isopropyl methyl carbonic ester is (referred to asiPr-POC PMPA).It is miscellaneous
Matter research is one of critical project in drug quality research, and content is the direct indicator for reflecting drug purity.And fixed
Property and when quantitative analysis impurity, essentially need a certain amount of impurity as object of reference, and object of reference needs
Higher purity.Therefore, the higher impurity of purity is obtained by synthetic method to have great importance.
Currently, about tenofovir disoproxil fumarate impurity (VI) Study of synthesis method it has been reported that but these
It there are still some drawbacks in synthetic method and shortcoming, such as:
(1) Cai Zhi is by force equal (Chinese Journal of Pharmaceuticals, 2014,45(9): 818-821) report using adenine as starting material,
By with (RThe reaction of)-propylene oxide, reacts at ether, and the hydrolysis that TMSBr is participated in obtains tenofovir.Tenofovir and chlorine
Isopropyl methyl carbonate reaction obtains related substance B (Tenofovir), yield only 42.2%；Related substance B (replaces promise good fortune
Wei monoesters) related substance E(abbreviation is obtained with isopropanol reaction in the presence of DEAD and triphenyl phosphorus:iPr-POC PMPA),
Exactly the present invention synthesize target compound ((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen) methyl)
(isopropyl oxygen) phosphine) oxygen) isopropyl methyl carbonic ester, yield only 67.9%.The last two steps overall yield of reaction is 28.7%.In the route
Purifying in relation to substance B and the purifying in relation to substance E are required to silica gel chromatograph column purification, need a large amount of organic solvents, and yield is low,
Pollution is big, is not suitable for largely preparing the impurity reference substance.
(2) beam southern exposure etc. (chemical management, 2013,7:68-70) report ((((((R) -1- (6- amino -9HPurine -9-
Base) propyl -2- base) oxygen) methyl) (isopropyl oxygen) phosphine) oxygen) synthetic strategy of isopropyl methyl carbonic ester is first to synthesize tenofovir
Single isopropyl ester, that is, be exactly the mono- isopropyl ester of T3- named in document, yield only 60.5%；Then tenofovir list isopropyl ester and chlorine
Isopropyl methyl carbonate reaction obtain impurity ((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen) first
Base) (isopropyl oxygen) phosphine) oxygen) isopropyl methyl carbonic ester is exactly the T-D named in document, while this step reaction product needs
Silica gel chromatograph column purification is wanted, a large amount of organic solvents are needed, yield is low, and pollution is big, yield only 40%, and two-step reaction total recovery is
24.2%.It is also not suitable for largely preparing the impurity reference substance.
(3) strategy that Chen Guohua etc. (CN201410502508.1) take is former for starting with tenofovir diisopropyl ester
Material, then hydrolysis obtains tenofovir list isopropyl ester in NaOH aqueous solution, which needs with ethanol/methylene
System is that eluant, eluent carries out silica gel chromatograph column purification, yield 82.8%.Tenofovir list isopropyl ester again with chloromethyl isopropyl carbon
Acid esters react to obtain impurity ((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen) methyl) (isopropyl oxygen) phosphine)
Oxygen) isopropyl methyl carbonic ester, the step reaction product be also required to using ethanol/methylene system as eluant, eluent carry out silica gel chromatograph
Column purification, yield only 38.4%.Two-step reaction total recovery is 31.8%.Simultaneously because to be required to silica gel chromatographic column pure for two-step reaction
Change, need a large amount of organic solvents, pollution is big, and yield is low, is not suitable for largely preparing the impurity reference substance.
In the reaction process of above 3 kinds of methods, there is intermediate and final product is needed using silica gel chromatograph column purification
Problem, chromatography process generally require a large amount of organic solvent, and pollution is big, and yield is low, are not suitable for largely preparing such
Like object, be not suitable for the application in industrial amplification production.
Summary of the invention
The object of the present invention is to provide a kind of tenofovir disoproxil fumarate analog (VI), chemical name is
((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen) methyl) (isopropyl oxygen) phosphine) oxygen) isopropyl methyl carbon
The preparation method of acid esters.The synthesis technology of the method for the present invention is simple, does not have to silica gel chromatograph column purification intermediate and target product, fits
Close the needs of industrialized production.
In order to achieve the above object, the technical scheme adopted by the invention is that:
Using adenine as starting material, under base catalysis, with (R)-propene carbonate reaction, it is crystallized obtain (R) -1- (6- ammonia
Base -9H- purine -9- base) propyl -2- alcohol (II)；(II) in the presence of a base, with (diethoxy phosphono) methyl -4- toluenesulfonic acid
Ester react to obtain (R)-diethyl (((1- (6- amino -9H- purine -9- base) propyl -2- alcohol) oxygen) methyl) phosphate (III)；
(III) it is reacted with concentrated hydrochloric acid solution, it is crystallized to obtain anhydrous tenofovir (IV)；(IV) with organic base and chloromethyl isopropyl carbon
Acid esters reaction to (R)-(((((1- (6- amino -9H- purine -9- base) propyl -2- base) oxygen) methyl) phosphine) oxygen) methyl isopropyl
Base carbonic ester (V) (referred to as: Tenofovir)；(V) in the presence of a phase transfer catalyst, anti-with organic base and 2- N-Propyl Bromide
It answers, obtains ((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen) methyl) (isopropyl oxygen) phosphine) oxygen) methyl is different
Propyl carbonate (VI) (referred to as:iPr-POC PMPA), synthetic route reaction equation is as follows:
In order to realize that said synthesis route, specific embodiment of the invention are as follows:
Step 1: (R) -1- (6- amino -9H- purine -9- base) propyl -2- alcohol (II) preparation
Under 120~140 DEG C of reaction temperatures, adenine (I) is molten in organic solvent, in the presence of a base with (R)-propene carbonate
Reaction, it is crystallized obtain (R) -1- (6- amino -9H- purine -9- base) propyl -2- alcohol (II)；
Step 2: (R)-diethyl (((1- (6- amino -9H- purine -9- base) propyl -2- alcohol) oxygen) methyl) phosphate (III)
Preparation
Under -10~40 DEG C of reaction temperatures, by the first step react products therefrom (R) -1- (6- amino -9H- purine -9- base) third
Base -2- alcohol (II) is dissolved in organic solvent system, in the presence of an inorganic base, with (diethoxy phosphono) methyl -4- toluenesulfonic acid
Ester react to obtain (R)-diethyl (((1- (6- amino -9H- purine -9- base) propyl -2- alcohol) oxygen) methyl) phosphate (III)；
Step 3: the preparation of anhydrous tenofovir (IV)
Under 30~100 DEG C of reaction temperatures, by second step react products therefrom (R((((6- amino -9H- is fast by 1- for)-diethyl
Purine -9- base) propyl -2- alcohol) oxygen) methyl) phosphate (III) reacts with 36% ~ 38% concentrated hydrochloric acid solution, it is crystallized obtain it is anhydrous
Tenofovir (IV)；
Step 4: (R)-(((((1- (6- amino -9H- purine -9- base) propyl -2- base) oxygen) methyl) phosphine) oxygen) isopropyl methyl
The preparation of carbonic ester (V)
Under 30~60 DEG C of reaction temperatures, by third step reaction products therefrom be dissolved in organic solvent, in the presence of an organic base and
Chloromethyl butylperoxyisopropyl carbonate reaction to (R)-(((((1- (6- amino -9H- purine -9- base) propyl -2- base) oxygen) methyl)
Phosphine) oxygen) isopropyl methyl carbonic ester (V)
Step 5: ((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen) methyl) (isopropyl oxygen) phosphine) oxygen) first
The preparation of base butylperoxyisopropyl carbonate (VI)
Under 60~90 DEG C of reaction temperatures, the 4th step products therefrom (V) is dissolved in organic solvent, in phase transfer catalyst and
With 2- bromopropane reaction in the presence of organic base, tenofovir disoproxil fumarate analog (VI) is obtained.
In order to obtain higher yield and product purity, above-mentioned technical process is optimized in the present invention.Above-mentioned technique
In the process, organic solvent used is aprotic polar organic solvent；Alkali used in the first step is the hydrogen of alkali metal
Oxide；Inorganic base used in the second step is the metal compound of the tert-butyl alcohol；It is used in 4th or the 5th step
Organic base be selected from the fatty amine containing 1-15 carbon atom or the aromatic amine containing 4-15 carbon atom；In 5th step
Phase transfer catalyst used is quaternary ammonium salt phase transfer catalyst.
Further, the preferred n,N-Dimethylformamide of aprotic polar organic solvent, n,N-dimethylacetamide, diformazan
Base sulfoxide, one of N-Methyl pyrrolidone or more than one combination；The preferred NaOH, KOH of the hydroxide of alkali metal,
One or more kinds of combinations of CsOH；The metal compound of the tert-butyl alcohol is selected from tert-butyl alcohol lithium, sodium tert-butoxide, the tert-butyl alcohol
Potassium, one of tert-butyl alcohol magnesium or more than one combination；The fatty amine containing 1-15 carbon atom is selected from triethylamine
Or diisopropyl ethyl amine；The aromatic amine containing 4-15 carbon atom is selected from pyridine or imidazoles；Quaternary ammonium salt phase transfer is urged
The preferred tetrabutylammonium chloride of agent, tetra-n-butyl ammonium bromide, tetrabutylammonium iodide, triethyl benzyl ammonia chloride, triethyl group
One or more kinds of combinations of Benzylphosphonium Bromide ammonium or triethylbenzyl ammonium iodide.
Specific embodiment after optimization is as follows:
It is above-mentioned step 1: (R) preparation of -1- (6- amino -9H- purine -9- base) propyl -2- alcohol (II) is to be with adenine (I)
Starting material, it is molten in organic solvent, in the presence of a base with (R)-propene carbonate react to obtain (R) (6- amino -9H- is fast by -1-
Purine -9- base) propyl -2- alcohol (II).Alkali used is the hydroxide of alkali metal, one kind selected from NaOH, KOH, CsOH or one
Kind or more combination, preferably NaOH；Organic solvent used be aprotic polar organic solvent, be selected from DMF, DMAC, NMP or
One or more kinds of combinations of DMSO, preferably DMF；(RThe dosage of)-propene carbonate be adenine (I) molal quantity 1~
4 times, preferably 1.3~2 times；Reaction temperature is 120 DEG C~140 DEG C；It with isopropanol volume ratio is 1 that recrystallisation solvent used, which is methanol,
: 2~2: 1 premix bonding solvent and the mixing with reaction dissolvent used in former reaction system premix bonding solvent preferred volume ratio
For 1: 1 methanol and the mixed solution of isopropanol；Crystallization temperature is -10~20 DEG C, preferably 0~20 DEG C.
It is above-mentioned step 2: (R)-diethyl (((1- (6- amino -9H- purine -9- base) propyl -2- alcohol) oxygen) methyl) phosphorus
The preparation of acid esters (III) be by the first step reaction products therefrom (II) be dissolved in organic solvent system, in the presence of an inorganic base with
(diethoxy phosphono) methyl -4- oluene sulfonic acides ester (referred to as: DESMP) reaction obtain (R)-diethyl (((1- (6- amino-
9H- purine -9- base) propyl -2- alcohol) oxygen) methyl) phosphate (III).The metal compound of the tert-butyl alcohol used in it is selected from tertiary fourth
Lithium alkoxide, sodium tert-butoxide, potassium tert-butoxide or tert-butyl alcohol magnesium, preferably tert-butyl alcohol magnesium；Organic solvent used is that aprotonic polar is organic
Solvent is selected from DMF, DMAC, one or more kinds of combinations of NMP or DMSO, preferably DMF；Reaction temperature is -10~40oC,
It is preferred that 0~25 DEG C；Post-treated products therefrom direct plunges into react in next step.
It is above-mentioned step 3: the preparation of anhydrous tenofovir (IV) is that (mass percent is dense with concentrated hydrochloric acid by intermediate (III)
Degree: 36%~38%) reacting, crystallized, be dried to obtain anhydrous tenofovir (IV).Wherein the dosage of concentrated hydrochloric acid is intermediate (III)
1~8 times of molal quantity, preferably 3~6 times；Reaction temperature is 30~100 DEG C, preferably 70~90 DEG C；Anhydrous tenofovir (IV) knot
The solvent of crystalline substance purifying is water, and crystallization temperature is 0~10 DEG C.
It is above-mentioned step 4: (R)-(((((1- (6- amino -9H- purine -9- base) propyl -2- base) oxygen) methyl) phosphine) oxygen) first
The preparation of base butylperoxyisopropyl carbonate (V) is that the anhydrous tenofovir of intermediate (IV) is dissolved in organic solvent, is acted in organic base
It is lower reacted with chloromethyl butylperoxyisopropyl carbonate arrive (R)-(((((1- (6- amino -9H- purine -9- base) propyl -2- base) oxygen) first
Base) phosphine) oxygen) isopropyl methyl carbonic ester (V).Organic solvent used in it is aprotic polar organic solvent, is selected from DMF,
One of DMAc, NMP or DMSO or more than one combinations；Organic base used be the fatty amine containing 1-15 carbon atom or
Containing 4-15 carbon atom aromatic amine, one kind selected from triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine or imidazoles or
More than one combination；The dosage of organic base is 1~5 times of anhydrous tenofovir (IV) molal quantity；Chloromethyl isopropyl carbonic acid
The dosage of ester is 1~5 times of anhydrous tenofovir (IV) molal quantity；Reaction temperature is 30~60 DEG C, preferably 40~60 DEG C；After
Reason products therefrom direct plunges into react in next step.
It is above-mentioned step 5: ((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen) methyl) (isopropyl oxygen)
Phosphine) oxygen) preparation of isopropyl methyl carbonic ester (VI) is that intermediate (V) is dissolved in organic solvent, in phase transfer catalyst and
In the presence of organic base with 2- bromopropane reaction, obtain ((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen)
Methyl) (isopropyl oxygen) phosphine) oxygen) isopropyl methyl carbonic ester (VI) (referred to as:iPr-POC PMPA).2- N-Propyl Bromide used is
(R)-(((((1- (6- amino -9H- purine -9- base) propyl -2- base) oxygen) methyl) phosphine) oxygen) isopropyl methyl carbonic ester (V)
1~5 times of molal quantity, phase transfer catalyst used are quaternary ammonium salt phase transfer catalyst, just selected from tetrabutylammonium chloride, four
Butylammonium bromide, tetrabutylammonium iodide, triethyl benzyl ammonia chloride, triethylbenzyl ammonium bromide or triethylbenzyl iodate
Ammonium, preferably tetrabutylammonium iodide, triethylbenzyl ammonium iodide；The dosage of phase transfer catalyst be (R)-(((((1- (6- ammonia
Base -9H- purine -9- base) propyl -2- base) oxygen) methyl) phosphine) oxygen) 0.5~2 times of isopropyl methyl carbonic ester (V) molal quantity；
Organic base used is the fatty amine containing 1-15 carbon atom or contains 4-15 carbon atom aromatic amine, selected from triethylamine
(TEA), one or more kinds of combinations of diisopropylethylamine (DIPEA), pyridine or imidazoles；Organic base dosage (R)-
(((((1- (6- amino -9H- purine -9- base) propyl -2- base) oxygen) methyl) phosphine) oxygen) isopropyl methyl carbonic ester (V) mole
Several 1~5 times；Reaction organic solvent used is aprotic polar organic solvent, in DMF, DMAC, NMP or DMSO
One or more combination.Reaction temperature is 60~90 DEG C, preferably 70~80 DEG C.
Chinese and the English abbreviation control of chemical substance involved in the present invention are as follows:
(diethoxy phosphono) methyl -4- oluene sulfonic acides ester abbreviation: DESMP
((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen) methyl) (isopropyl oxygen) phosphine) oxygen) methyl isopropyl
Base carbonic ester (VI) abbreviation:iPr-POC PMPA
Dimethylformamide abbreviation: DMF
Dimethyl acetamide abbreviation: DMAC
N-Methyl pyrrolidone abbreviation: NMP
Dimethyl sulfoxide abbreviation: DMSO
Triethylamine abbreviation: TEA
Chloromethyl butylperoxyisopropyl carbonate abbreviation: CMIC
Diisopropyl ethyl amine abbreviation: DIPEA
Trim,ethylchlorosilane abbreviation: TMSCl
Bromotrimethylsilane abbreviation: TMSBr.
The present invention compared with the conventional method, has synthesis technology simple, does not have to silica gel chromatograph column purification intermediate and target
Product, yield is high, pollutes small, the advantage of gained impurity purity is high, and specific advantage possessed by the present invention and innovative point are as follows:
1. the present invention select it is cheap and easy to get (R)-propene carbonate is that chiral source reacts to obtain with adenine in the presence of a base
(R) -1- (6- amino -9H- purine -9- base) propyl -2- alcohol (II), reagent selected by improved technique is all relatively inexpensive,
This method is relative to Cai Zhiqiang etc. (Chinese Journal of Pharmaceuticals, 2014,45(9): 818-821) report is starting with adenine
Raw material, with (R)-propylene oxide reaction method: advantage is as follows: 1. due to (R)-propylene oxide reactivity height leads to adenine
Primary amine group be also easy to and (RThe reaction of)-propylene oxide generates more by-product, and product yield is low；2. (R)-propylene oxide boiling point
Low, only 35 DEG C, risk is higher in production process, very high to equipment sealing requirements.Therefore present invention use (R)-carbonic acid third
Enester is chiral source reagent, and side reaction is few, and impurity is few, and yield is high, and process safety is high, and the intermediate (II) as obtained by crystallization is pure
Degree is high, and the three wastes that reaction process generates are few, is very suitable to high-volume industrial production.
2. the present invention uses 36% present invention improves over the preparation method of the anhydrous tenofovir of third step reaction product (IV)
~ 38% concentrated hydrochloric acid as hydrolysing agent, relative to the uses such as Cai Zhiqiang Lewis acid-type hydrolysing agent bromotrimethylsilane or
The method of trim,ethylchlorosilane, advantage are as follows: 1. low in cost, about 300 yuan/kg of TMSBr or TMSCl, and 36% ~ 38% it is dense
Hydrochloric acid only 2-3 member/kg；2. low energy consumption, excessive TMSBr or TMSCl are generally needed after the completion of hydrolysis in the methods of Cai Zhiqiang
Removing to be concentrated under reduced pressure at relatively high temperatures, reconciling pH with sodium hydroxide solution later can just precipitate crystal for 2.8~3.2, and
Hydrochloric acid in the present invention as hydrolysing agent after the reaction was completed 5 DEG C can directly with sodium hydroxide solution reconcile pH be 2.8~
3.2 can be precipitated solid, simplify operating procedure, reduce energy consumption, be conducive to high-volume industrial production.
3. the present invention use quaternary ammonium salt for catalyst in the reaction of the 5th step, can be improved reaction yield, it is of the invention in finally
The molar yield of single step reaction is 72% ~ 81%, referring to embodiment 9 and embodiment 10.The method of the present invention (is changed relative to beam southern exposure etc.
Work management, 2013,7:68-70) the first upper isopropyl of report, then the method yield of upper chloromethyl butylperoxyisopropyl carbonate base are higher,
The final step reaction yield only 40% of the methods of beam southern exposure.The method of the present invention products therefrom purity is high simultaneously, high performance liquid chromatography
(HPLC) area normalization method purity >=98% is suitble to high-volume industrial production.
Specific embodiment
The present invention is to be described by the following specific embodiments, can better understand this hair by specific embodiment
It is bright, but the scope of the present invention is not restricted by the embodiments:
Embodiment 1:
Step 1: (R) -1- (6- amino -9H- purine -9- base) propyl -2- alcohol (II) preparation
Adenine 80.00g(0.592mol) is added in three-necked flask, n,N-Dimethylformamide (DMF) 380ml is added,
It is added with stirring sodium hydroxide 9.48g(0.237mol), add (S)-propene carbonate 78.60g(0.770mol), it is warming up to
It 130 DEG C, reacts 18 hours, stops reaction, be cooled to 40 DEG C, the mixed solution of methanol 240ml and isopropanol 240ml, drop is added
To 12 DEG C, constant temperature crystallization 1 hour, filtering, filter cake is washed temperature with the mixed solution (4 DEG C) of methanol 40ml and isopropanol 40ml, is taken out
It is dry, place 45 DEG C of vacuum oven and be dried in vacuo 4.5 hours, obtain white solid 87.70g(0.454mol), molar yield is
76.7%。
1H NMR (400 MHz, DMSO-d 6): δ=8.15 (s, 1H), 8.05 (s, 1H), 7.18 (s,
2H), 5.03 (d, J = 4.0 Hz, 1H), 4.11 (q, J = 7.4 Hz, 1H), 4.07 – 3.98 (m, 2H),
1.07 (d, J = 5.8 Hz, 3H) ppm.
13C NMR (100 MHz, DMSO-d 6): δ=155.9 (C-6 '), 152.2 (C-2 '), 149.7 (C-4 '),
141.4 (C-8′), 118.5 (C-5′), 64.6 (C-2), 50.1 (C-1), 20.8 (C-3) ppm.
MS (ESI, +): m/z [M+H]+ calcd forC8H11N5O: 193.1; found: 194.2.
UV(MeOH): λmax=260nm.
Anal. calcd for C8H11N5O: C 49.73, H 5.74, N 36.25. Found C 49.78, H 5.65,
N 36.20.
Embodiment 2:
Step 1: (R) -1- (6- amino -9H- purine -9- base) propyl -2- alcohol (II) preparation
Adenine 40.00g(0.296mol) is added in three-necked flask, n,N-Dimethylformamide (DMF) 190ml is added,
It is added with stirring sodium hydroxide 0.94g(0.0235mol), add (R)-propene carbonate 39.20g(0.384mol), heating
It to 120 DEG C, reacts 27 hours, stops reaction, be cooled to 70 DEG C, the mixed solution of methanol 120ml and isopropanol 120ml is added,
15 DEG C are cooled to, constant temperature crystallization 12 hours, filtering, filter cake was washed with the mixed solution (4 DEG C) of methanol 20ml and isopropanol 20ml,
Drain, place 60 DEG C of vacuum oven and be dried in vacuo 2 hours, obtain white solid 45.51g(0.215mol), molar yield is
72.6%。
Embodiment 3:
Step 2: (R)-diethyl (((1- (6- amino -9H- purine -9- base) propyl -2- alcohol) oxygen) methyl) phosphate (III)
Preparation
Intermediate (II) 40.00g(0.207mol is added in dry three-necked flask) and N-Methyl pyrrolidone (NMP)
(160ml) stirring and dissolving, 25oTert-butyl alcohol magnesium 70.00g(0.414mol is added in C), it is warming up to 70 lateroC is slow added into
(diethoxy phosphono) methyl -4- oluene sulfonic acides ester 100.00g(0.311mol), 70 DEG C of isothermal reaction 4h are cooled to 20 later
± 5 DEG C, acetic acid 36.75g(0.612mol is slowly added into reaction system) pH to 6~7 is adjusted, maintain the temperature at 15~25
DEG C, ethyl acetate 900ml is added into mixture, stirs 30min, stands, supernatant liquor is poured out.Filter cake is placed in bottle and is added
Ethyl acetate 300ml merges in 15~25 DEG C of stirring 30min, filtering with first time filtrate, and filtrate is filtered again after merging, filter
Liquid is concentrated under reduced pressure to give light yellow oil, and crude yield direct plunges into reaction (embodiment 5) in next step with quantitative calculating.
Embodiment 4:
Step 2: (R)-diethyl (((1- (6- amino -9H- purine -9- base) propyl -2- alcohol) oxygen) methyl) phosphate (III)
Preparation
Intermediate (II) 40.00g(0.207mol is added in dry three-necked flask) and DMF(160ml) stirring and dissolving,
25oTert-butyl alcohol magnesium 70.00g(0.414mol is added in C), it is warming up to 80 lateroC is slow added into (diethoxy phosphono) methyl -4-
Oluene sulfonic acides ester 100.00g(0.311mol), 80 DEG C of isothermal reaction 4h are cooled to 20 ± 5 DEG C later, delay into reaction system
It is slow that acetic acid 36.75g(0.612mol is added) pH to 6~7 is adjusted, 15~25 DEG C are maintained the temperature at, acetic acid is added into mixture
Ethyl ester 1200ml stirs 30min, then heats up in 55 ± 5 DEG C of stirring 30min, is cooled to 20 ± 5 DEG C, stands, it is clear that upper layer is poured out
Liquid, filtering, filtrate decompression are concentrated to get light yellow oil, and it is (real to direct plunge into reaction in next step with quantitative calculating for crude yield
Apply example 6).
Embodiment 5:
Step 3: the preparation of anhydrous tenofovir (IV)
3 gained light yellow oil of embodiment is dissolved in 36% concentrated hydrochloric acid solution 61ml(0.725mol), 75oC reacts 11h, cooling
To 45oC is concentrated, and ethyl acetate (320ml) washing is added in concentrate and water 160ml, liquid separation, water phase use ethyl acetate again
(320ml) washing, water phase is cooled to 5 DEG C later, and reconciling pH with 40% sodium hydroxide solution is 2.8~3.2, equality of temperature stirring analysis
Brilliant 8h, crosses filter solid, the washing of 150ml cold water, and 80 DEG C of vacuum drying 12h obtain anhydrous tenofovir (IV) 36.33g
(0.127mol), two-step reaction (embodiment 3 and 5) mole total recovery 61%.
1H NMR (400 MHz, DMSO-d 6): δ=8.14 (s, 2H), 7.27 (s, 2H), 4.26 (dd,J
= 14.4, 4.0 Hz, 1H), 4.18 (dd, J = 14.4, 5.6 Hz, 1H), 3.97 – 3.86 (m, 1H),
3.59 (qd, J = 13.2, 9.6 Hz, 2H), 3.39 – 2.80 (bs, 2H), 1.03 (d, J = 6.3 Hz,
3H) ppm.
13C NMR (100 MHz, DMSO-d 6): δ=155.7 (C-6 '), 152.1 (C-2 '), 149.7 (C-4 '),
141.6 (C-8′), 118.2 (C-5′), 75.3 (C-2), 75.2 (C-2), 65.1 (C-4), 63.5 (C-4),
46.4 (C-1), 16.9 (C-2a) ppm.
31P NMR (162 MHz, DMSO-d 6): δ=17.33.
MS (ESI, -): m/z[M-H]? calcd for C9H14N5O4P: 287.1; found: 286.2.
HRMS (ESI, -): m/z[M-H]? calcd for C9H14N5O4P: 287.0783; found:
286.0708.
UV(MeOH): λmax=206nm, 260nm.
Anal. calcd for C9H14N5O4P: C 37.64, H 4.91, N 24.38. Found C 37.68, H
4.96, N 24.36.
Embodiment 6: the preparation of anhydrous tenofovir (IV)
4 gained light yellow oil of embodiment is dissolved in 36% concentrated hydrochloric acid solution 120ml(1.45mol), 90 DEG C of reaction 14h are cooling
Ethyl acetate (320ml) and water (160ml) is added to room temperature, water phase is washed with ethyl acetate (320ml) again after liquid separation, is used in combination
It is 2.8~3.2 that 40% sodium hydroxide solution, which reconciles pH, is cooled to 5 DEG C of stirring and crystallizing 6h, crosses filter solid, and 150ml cold water washs,
80 DEG C of vacuum drying 8h obtain anhydrous tenofovir (IV) 35.70g(0.124mol), two-step reaction (embodiment 4 and 6) mole is total
Yield 60%.
Embodiment 7:(R)-(((((1- (6- amino -9H- purine -9- base) propyl -2- base) oxygen) methyl) phosphine) oxygen) methyl
The preparation of butylperoxyisopropyl carbonate (V)
Anhydrous tenofovir (IV) 10.38g(0.036mol is added in dry three-necked flask) and DMF(42ml) stir it is molten
Solution, sequentially adds triethylamine 14.63g(0.145mol in room temperature) and chloromethyl butylperoxyisopropyl carbonate 11.03g(0.072mol),
It is warming up to 55 DEG C later, equality of temperature reacts 15h, is cooled to room temperature, and filters, and water (40ml) and ethyl acetate is added in filtrate concentration
(40ml) is sufficiently mixed rear liquid separation, and water phase is washed twice (40ml × 2) with ethyl acetate, and water phase is concentrated to viscous liquid, adds
Enter isopropanol 90ml, in 0 DEG C of stirring 1h, filtering, filtrate be concentrated to get (R)-(((((1- (6- amino -9H- purine -9- base) third
Base -2- base) oxygen) methyl) phosphine) oxygen) isopropyl methyl carbonic ester (V) 9.01g(0.022mol), molar yield 62%.
1H NMR (400 MHz, DMSO-d 6) : δ = 8.19 (s, 1H), 8.18 (s, 1H), 7.77 (s,
2H), 5.44 (dt, J = 13.6, 5.4 Hz, 2H), 4.78 (dt, J = 12.5, 6.2 Hz, 1H), 4.30
(dd, J = 14.4, 3.8 Hz, 1H), 4.18 (dd, J = 14.4, 6.0 Hz, 1H), 4.13 – 4.02 (bs,
1H), 3.99 – 3.92 (m, 1H), 3.67 (qd, J = 13.5, 9.1 Hz, 2H), 1.21 (d, J = 6.2
Hz, 6H), 1.05 (d, J = 6.2 Hz, 3H) ppm.
13C NMR (100 MHz, DMSO-d 6): δ=154.4 (C-6 '), 152.8 (C-9), 150.0,149.1
(C-2′), 142.2 (C-4′), 118.1 (C-8′), 84.4 (C-5′), 75.1, 75.0 (C-7), 72.1 (C-
2), 64.6 (C-11), 63.0 (C-4), 46.9 (C-1), 21.3 (C-12, C-11a), 16.7 (C-2a) ppm.
31P NMR (162 MHz, DMSO-d 6): δ=17.83.
MS (ESI): m/z[M-H]? calcd for C14H22N5O7P: 403.1; found: 402.1.
HRMS (ESI): m/z[M-H]? calcd for C14H22N5O7P: 403.1257; found: 402.1246.
UV(MeOH): λmax=260nm.
Anal. calcd for C14H22N5O7P: C 41.69, H 5.50, N 17.36. Found C 41.66, H
5.36, N 17.59.
Embodiment 8:(R)-(((((1- (6- amino -9H- purine -9- base) propyl -2- base) oxygen) methyl) phosphine) oxygen) methyl isopropyl
The preparation of base carbonic ester (V)
Anhydrous tenofovir (IV) 12.64g(0.044mol is added in dry three-necked flask) and DMF(55ml) stir it is molten
Solution, sequentially adds triethylamine 17.81g(0.176mol in room temperature) and chloromethyl butylperoxyisopropyl carbonate 26.86g(0.176mol),
It is warming up to 40 DEG C later, equality of temperature reacts 12h, is cooled to room temperature, and filters, and water (50ml) and ethyl acetate is added in filtrate concentration
(50ml) is sufficiently mixed rear liquid separation, and water phase is washed twice (50ml × 2) with ethyl acetate, and water phase is concentrated to viscous liquid, adds
Enter isopropanol 100ml, in 0 DEG C of stirring 1h, filtering, filtrate be concentrated to get (R)-(((((1- (6- amino -9H- purine -9- base) third
Base -2- base) oxygen) methyl) phosphine) oxygen) isopropyl methyl carbonic ester (V) 13.56g(0.034mol), molar yield 76%.
Embodiment 9:((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen) methyl) (isopropyl oxygen) phosphine)
Oxygen) isopropyl methyl carbonic ester (VI) preparation
Take intermediate (V) 2.00g(5.0mmol) it is dissolved in polar solvent DMF 15ml, triethylamine is sequentially added under stirring
1.01g(10mmol), tetra-n-butyl ammonium bromide 0.81g(2.5mmol) and 2- N-Propyl Bromide 1.23g(10.0 mmol), later 70
DEG C reaction 48h, is cooled to room temperature, water 7ml and ethyl acetate 30ml is added, shake, stand, liquid separation, water phase extracts with ethyl acetate
It takes (30ml × 2) twice, merges organic phase, washed with 4 DEG C of cold water 20ml, then washed with saturated salt solution 20ml, use is anhydrous
Na2SO4Dry, through filtering, filtrate is concentrated to get viscous liquid 1.60g(3.6mmol), molar yield 72%.HPLC area is returned
One changes method purity >=98%.
1H NMR (400 MHz, CDCl3): δ=8.32 (s, 1H), 7.99 (d,J = 2.2 Hz, 1H),
6.00 (s, 2H), 5.68 – 5.53 (m, 2H), 4.91 (dq, J = 12.7, 6.3 Hz, 1H), 4.83 –
4.66 (m, 1H), 4.35 (dt, J = 14.4, 3.4 Hz, 1H), 4.12 (ddd, J = 17.5, 11.9, 7.0
Hz, 1H), 3.98 – 3.79 (m, 2H), 3.62 (ddd, J = 13.7, 9.4, 6.8 Hz, 1H), 1.35 –
1.21 (m, 15H) ppm.
13C NMR (100 MHz, CDCl3): δ=155.4 (C-6 '), 153.2 (C-9), 153.1 (C-9),
152.6 (C-2′), 150.1 (C-4′), 141.9 (C-8′), 128.8 (C-5′), 119.0 (C-7), 84.5 (C-
2), 84.4 (C-2), 73.1 (C-11), 72.3 (C-5b), 72.2 (C-5b), 64.2 (C-4c), 64.1 (C-
4c), 62.5 (C-4c), 62.4(C-4c), 56.7 (C-1), 48.2 (C-5c), 48.1 (C-5c), 29.7 (C-
5c′), 29.3 (C-5c′), 23.9 (C-12), 23.7(C-12), 22.7 (C-12), 21.6 (C-12), 19.1
(C-11a), 16.4 (C-11a), 14.1 (C-2a) ppm.
31P NMR (162 MHz, CDCl3): δ=20.93,20.88.
MS (EI): m/z [M]+ calcd for C17H28N5O7P: 445.2; found: 445.0.
HRMS (EI): m/z [M]+ calcd for C17H28N5O7P: 445.1726; found: 445.1719.
UV(MeOH): λmax=260nm.
Anal. calcd for C17H28N5O7P: C 45.84, H 6.34, N 15.72. Found C 45.88, H
6.36, N 15.79.
Embodiment 10:((((((R) -1- (6- amino -9HPurine -9- base) propyl -2- base) oxygen) methyl) (isopropyl oxygen) phosphine) oxygen)
The preparation of isopropyl methyl carbonic ester (VI)
Take intermediate (V) 2.00g(5.0mmol) it is dissolved in polar solvent DMF 15ml, triethylamine is sequentially added under stirring
1.01g(10mmol), tetrabutylammonium iodide 1.85g(5.0mmol) and 2- N-Propyl Bromide 1.23g(10.0 mmol), later 80
DEG C reaction 48h, is cooled to room temperature, water 7ml and ethyl acetate 30ml is added, shake, stand, liquid separation, water phase extracts with ethyl acetate
It takes (30ml × 2) twice, merges organic phase, washed with 4 DEG C of cold water 20ml, then washed with saturated salt solution 20ml, use is anhydrous
Na2SO4Dry, through filtering, filtrate is concentrated to get viscous liquid 1.80g(4.04mmol), molar yield 81%.HPLC area is returned
One changes method purity >=98%.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications done without departing from the spirit and principles of the present invention,
It should be equivalent replacement mode, be included within the scope of the present invention.
Claims (7)
1. a kind of preparation method of tenofovir disoproxil fumarate analog (VI),
Characterized by the following steps:
The first step, under 120~140 DEG C of reaction temperatures, adenine (I) is molten in organic solvent, in the presence of a base with (R)-carbon
Acid propylene ester reaction, it is crystallized obtain (R) -1- (6- amino -9H- purine -9- base) propyl -2- alcohol (II)；
Second step, under -10~40 DEG C of reaction temperatures, by the first step react products therefrom (R) -1- (6- amino -9H- purine -9-
Base) propyl -2- alcohol (II) is dissolved in organic solvent system, in the presence of an inorganic base, with (diethoxy phosphono) methyl -4- methylbenzene
Sulphonic acid ester react to obtain (R)-diethyl (((1- (6- amino -9H- purine -9- base) propyl -2- alcohol) oxygen) methyl) phosphate
(III)；
Third step, under 30~100 DEG C of reaction temperatures, by second step react products therefrom (R)-diethyl (((1- (6- amino-
9H- purine -9- base) propyl -2- alcohol) oxygen) methyl) phosphate (III) reacts with concentrated hydrochloric acid solution, it is crystallized obtain it is anhydrous for promise
Fu Wei (IV)；
Third step reaction products therefrom is dissolved in organic solvent, deposits in organic base under 30~60 DEG C of reaction temperatures by the 4th step
Lower and chloromethyl butylperoxyisopropyl carbonate reaction to (R)-(((((1- (6- amino -9H- purine -9- base) propyl -2- base) oxygen)
Methyl) phosphine) oxygen) isopropyl methyl carbonic ester (V)；
4th step products therefrom (V) is dissolved in organic solvent, urges in phase transfer under 60~90 DEG C of reaction temperatures by the 5th step
With 2- bromopropane reaction in the presence of agent and organic base, tenofovir disoproxil fumarate analog (VI) is obtained.
2. the preparation method of tenofovir disoproxil fumarate analog according to claim 1, it is characterised in that institute
The organic solvent stated is aprotic polar organic solvent；Alkali used in the first step is the hydroxide of alkali metal；Institute
Inorganic base used in the second step stated is the metal compound of the tert-butyl alcohol；The choosing of organic base used in 4th or the 5th step
From the fatty amine containing 1-15 carbon atom or the aromatic amine containing 4-15 carbon atom；Phase used in 5th step turns
Shifting catalyst is quaternary ammonium salt phase transfer catalyst.
3. the preparation method of tenofovir disoproxil fumarate analog according to claim 2, it is characterised in that institute
The aprotic polar organic solvent stated is selected from n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide, N- methyl
One of pyrrolidones or more than one combination；The hydroxide of the alkali metal is selected from the one of NaOH, KOH, CsOH
Kind or more than one combination；The metal compound of the tert-butyl alcohol is selected from tert-butyl alcohol lithium, sodium tert-butoxide, potassium tert-butoxide, tertiary fourth
One of magnesium alkoxide or more than one combination；The fatty amine containing 1-15 carbon atom is selected from triethylamine or diisopropyl
Base ethylamine；The aromatic amine containing 4-15 carbon atom is selected from pyridine or imidazoles；The quaternary ammonium salt phase transfer catalysis (PTC)
Agent is selected from tetrabutylammonium chloride, tetra-n-butyl ammonium bromide, tetrabutylammonium iodide, triethyl benzyl ammonia chloride, triethyl group benzyl
One or more kinds of combinations of base ammonium bromide or triethylbenzyl ammonium iodide.
4. the preparation method of tenofovir disoproxil fumarate analog according to any one of claim 1-3,
In the first step described in being characterized in that, used (RThe amount of)-propene carbonate is 1~4 times of adenine (I) molal quantity；Crystallization
Temperature is -10~20 DEG C.
5. the preparation method of tenofovir disoproxil fumarate analog according to any one of claim 1-3,
The concentration for being characterized in that concentrated hydrochloric acid used in the third step is 36%~38%, dosage be (R)-diethyl (((1- (6-
Amino -9H- purine -9- base) propyl -2- alcohol) oxygen) methyl) 1~8 times of phosphate (III) molal quantity；Recrystallisation solvent is water, knot
Brilliant temperature is 0~20 DEG C.
6. the preparation method of tenofovir disoproxil fumarate analog according to any one of claim 1-3,
In the 4th step described in being characterized in that, the dosage of organic base used is 1~5 times of anhydrous tenofovir (IV) molal quantity；Chlorine
The dosage of isopropyl methyl carbonic ester is 1~5 times of anhydrous tenofovir (IV) molal quantity.
7. the preparation method of tenofovir disoproxil fumarate analog according to any one of claim 1-3,
Be characterized in that in the 5th step, 2- N-Propyl Bromide used be (R)-(((((1- (6- amino -9H- purine -9- base) propyl -
2- yl) oxygen) methyl) phosphine) oxygen) 1~5 times of isopropyl methyl carbonic ester (V) molal quantity, the use of phase transfer catalyst used
Amount for (R)-(((((1- (6- amino -9H- purine -9- base) propyl -2- base) oxygen) methyl) phosphine) oxygen) isopropyl methyl carbonic ester
(V) 0.5~2 times of molal quantity；The dosage of organic base used be (R)-(((((1- (6- amino -9H- purine -9- base) third
Base -2- base) oxygen) methyl) phosphine) oxygen) 1~5 times of isopropyl methyl carbonic ester (V) molal quantity.
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| CN110372750A (en) * | 2019-07-12 | 2019-10-25 | 苏利制药科技江阴有限公司 | A kind of synthetic method of tenofovir disoproxil fumarate impurity |
| CN110452269A (en) * | 2019-08-27 | 2019-11-15 | 齐鲁安替（临邑）制药有限公司 | A method of tenofovir is prepared using microreactor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103864846A (en) * | 2012-12-10 | 2014-06-18 | 天津泰普药品科技发展有限公司 | Preparation method of tenofovir isopropyl isoproxil |
| CN104530129A (en) * | 2014-03-26 | 2015-04-22 | 广东东阳光药业有限公司 | Preparation method for (R)-9-[2-(phosphonomethoxy)propyl]adenine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864846A (en) * | 2012-12-10 | 2014-06-18 | 天津泰普药品科技发展有限公司 | Preparation method of tenofovir isopropyl isoproxil |
| CN104530129A (en) * | 2014-03-26 | 2015-04-22 | 广东东阳光药业有限公司 | Preparation method for (R)-9-[2-(phosphonomethoxy)propyl]adenine |
Cited By (4)
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|---|---|---|---|---|
| CN110372750A (en) * | 2019-07-12 | 2019-10-25 | 苏利制药科技江阴有限公司 | A kind of synthetic method of tenofovir disoproxil fumarate impurity |
| CN110372750B (en) * | 2019-07-12 | 2021-12-24 | 苏利制药科技江阴有限公司 | Synthesis method of tenofovir disoproxil fumarate impurity |
| CN110452269A (en) * | 2019-08-27 | 2019-11-15 | 齐鲁安替（临邑）制药有限公司 | A method of tenofovir is prepared using microreactor |
| CN110452269B (en) * | 2019-08-27 | 2021-06-08 | 山东安弘制药有限公司 | Method for preparing tenofovir by using microreactor |
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