CN103408593A - Preparation method of tenofovir - Google Patents
Preparation method of tenofovir Download PDFInfo
- Publication number
- CN103408593A CN103408593A CN2013102918831A CN201310291883A CN103408593A CN 103408593 A CN103408593 A CN 103408593A CN 2013102918831 A CN2013102918831 A CN 2013102918831A CN 201310291883 A CN201310291883 A CN 201310291883A CN 103408593 A CN103408593 A CN 103408593A
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- CN
- China
- Prior art keywords
- preparation
- tynofovir
- nitro
- reaction
- chloropyrimide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 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 title abstract description 8
- 229960004556 tenofovir Drugs 0.000 title abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 10
- RUOJZAUFBMNUDX-GSVOUGTGSA-N (4r)-4-methyl-1,3-dioxolan-2-one Chemical compound C[C@@H]1COC(=O)O1 RUOJZAUFBMNUDX-GSVOUGTGSA-N 0.000 claims abstract description 9
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 238000006482 condensation reaction Methods 0.000 claims description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- -1 methyl-formiate Chemical compound 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 229910052728 basic metal Inorganic materials 0.000 claims description 4
- 150000003818 basic metals Chemical class 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 2
- 238000004904 shortening Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 13
- 230000005494 condensation Effects 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract description 2
- BWLOHIMQWHFSQF-UHFFFAOYSA-N 6-chloro-5-nitropyrimidin-4-amine Chemical compound NC1=NC=NC(Cl)=C1[N+]([O-])=O BWLOHIMQWHFSQF-UHFFFAOYSA-N 0.000 abstract 2
- CEXCTVLIYVFPCN-SCSAIBSYSA-N (2R)-1-[(6-chloro-5-nitropyrimidin-4-yl)amino]propan-2-ol Chemical compound O[C@@H](CNC1=NC=NC(=C1[N+](=O)[O-])Cl)C CEXCTVLIYVFPCN-SCSAIBSYSA-N 0.000 abstract 1
- 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 abstract 1
- LVNBNKMMTVWRJO-RXMQYKEDSA-N (2r)-1-(6-chloropurin-9-yl)propan-2-ol Chemical compound N1=CN=C2N(C[C@H](O)C)C=NC2=C1Cl LVNBNKMMTVWRJO-RXMQYKEDSA-N 0.000 abstract 1
- 238000006266 etherification reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000007142 ring opening reaction Methods 0.000 abstract 1
- 238000007086 side reaction Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000011782 vitamin Substances 0.000 description 6
- 229940088594 vitamin Drugs 0.000 description 6
- 229930003231 vitamin Natural products 0.000 description 6
- 235000013343 vitamin Nutrition 0.000 description 6
- 150000003722 vitamin derivatives Chemical class 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 229960001355 tenofovir disoproxil Drugs 0.000 description 5
- 230000008569 process Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 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 4
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 208000002672 hepatitis B Diseases 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UWTATZPHSA-M (R)-lactate Chemical compound C[C@@H](O)C([O-])=O JVTAAEKCZFNVCJ-UWTATZPHSA-M 0.000 description 1
- VZIQXGLTRZLBEX-UHFFFAOYSA-N 2-chloro-1-propanol Chemical compound CC(Cl)CO VZIQXGLTRZLBEX-UHFFFAOYSA-N 0.000 description 1
- 0 C[C@](*)C[n]1c2ncnc(N)c2nc1 Chemical compound C[C@](*)C[n]1c2ncnc(N)c2nc1 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- GOOHAUXETOMSMM-GSVOUGTGSA-N R-propylene oxide Chemical compound C[C@@H]1CO1 GOOHAUXETOMSMM-GSVOUGTGSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims (6)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CN201310291883.1A CN103408593B (en) | 2013-07-12 | 2013-07-12 | The preparation method of tynofovir |
Applications Claiming Priority (1)
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CN201310291883.1A CN103408593B (en) | 2013-07-12 | 2013-07-12 | The preparation method of tynofovir |
Publications (2)
Publication Number | Publication Date |
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CN103408593A true CN103408593A (en) | 2013-11-27 |
CN103408593B CN103408593B (en) | 2015-08-26 |
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CN201310291883.1A Expired - Fee Related CN103408593B (en) | 2013-07-12 | 2013-07-12 | The preparation method of tynofovir |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104530050A (en) * | 2014-12-23 | 2015-04-22 | 江西富祥药业股份有限公司 | Synthesis method of tenofovir disoproxil fumarate intermediate impurity 1-amino adenine-2-propyl alcohol |
CN104710424A (en) * | 2013-12-11 | 2015-06-17 | 河南师范大学 | Preparation method of (R)-(+)-9-(2-hydroxypropyl) adenine |
CN105503875A (en) * | 2015-12-23 | 2016-04-20 | 江西富祥药业股份有限公司 | Synthesis method of tenofovir disoproxil fumarate intermediate impurity |
CN108285471A (en) * | 2018-03-16 | 2018-07-17 | 安徽华昌高科药业有限公司 | A kind of preparation method of tenofovir |
CN111961081A (en) * | 2020-10-20 | 2020-11-20 | 北京鑫开元医药科技有限公司 | Preparation method of (R) -2- (2-methoxypropyl phosphate) -adenine |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5935946A (en) * | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
CN101870713A (en) * | 2010-05-28 | 2010-10-27 | 杭州和素化学技术有限公司 | Industrial production process for tenofovir disoproxil fumarate |
-
2013
- 2013-07-12 CN CN201310291883.1A patent/CN103408593B/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5935946A (en) * | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
CN101870713A (en) * | 2010-05-28 | 2010-10-27 | 杭州和素化学技术有限公司 | Industrial production process for tenofovir disoproxil fumarate |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104710424A (en) * | 2013-12-11 | 2015-06-17 | 河南师范大学 | Preparation method of (R)-(+)-9-(2-hydroxypropyl) adenine |
CN104710424B (en) * | 2013-12-11 | 2017-03-01 | 河南师范大学 | (R) (+) preparation method of 9 (2 hydroxypropyl) adenine |
CN104530050A (en) * | 2014-12-23 | 2015-04-22 | 江西富祥药业股份有限公司 | Synthesis method of tenofovir disoproxil fumarate intermediate impurity 1-amino adenine-2-propyl alcohol |
CN105503875A (en) * | 2015-12-23 | 2016-04-20 | 江西富祥药业股份有限公司 | Synthesis method of tenofovir disoproxil fumarate intermediate impurity |
CN105503875B (en) * | 2015-12-23 | 2017-06-20 | 江西富祥药业股份有限公司 | A kind of synthetic method of TDF intermediate impurities |
CN108285471A (en) * | 2018-03-16 | 2018-07-17 | 安徽华昌高科药业有限公司 | A kind of preparation method of tenofovir |
WO2019174101A1 (en) * | 2018-03-16 | 2019-09-19 | 安徽华昌高科药业有限公司 | Method for preparing tenofovir |
CN111961081A (en) * | 2020-10-20 | 2020-11-20 | 北京鑫开元医药科技有限公司 | Preparation method of (R) -2- (2-methoxypropyl phosphate) -adenine |
CN111961081B (en) * | 2020-10-20 | 2021-03-09 | 北京鑫开元医药科技有限公司 | Preparation method of (R) -2- (2-methoxypropyl phosphate) -adenine |
Also Published As
Publication number | Publication date |
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CN103408593B (en) | 2015-08-26 |
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Granted publication date: 20150826 |