CN101870713A - Industrial production process for tenofovir disoproxil fumarate - Google Patents
Industrial production process for tenofovir disoproxil fumarate Download PDFInfo
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- CN101870713A CN101870713A CN 201010185710 CN201010185710A CN101870713A CN 101870713 A CN101870713 A CN 101870713A CN 201010185710 CN201010185710 CN 201010185710 CN 201010185710 A CN201010185710 A CN 201010185710A CN 101870713 A CN101870713 A CN 101870713A
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- vitamin
- tynofovir
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- ester
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- 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 15
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 title abstract description 4
- 238000009776 industrial production Methods 0.000 title abstract 3
- -1 magnesium alkoxide Chemical class 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000004519 manufacturing process Methods 0.000 claims abstract description 22
- 239000011777 magnesium Substances 0.000 claims abstract description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 18
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 16
- 238000009833 condensation Methods 0.000 claims abstract description 14
- 230000005494 condensation Effects 0.000 claims abstract description 14
- 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 13
- 238000006482 condensation reaction Methods 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 88
- 239000011782 vitamin Substances 0.000 claims description 60
- 229940088594 vitamin Drugs 0.000 claims description 60
- 229930003231 vitamin Natural products 0.000 claims description 60
- 235000013343 vitamin Nutrition 0.000 claims description 60
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 55
- 150000002148 esters Chemical class 0.000 claims description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 19
- 239000010410 layer Substances 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 16
- 238000007670 refining Methods 0.000 claims description 15
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 14
- 238000010792 warming Methods 0.000 claims description 14
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 13
- 238000006555 catalytic reaction Methods 0.000 claims description 13
- NLTCPNKKJDMJQD-UHFFFAOYSA-N chloromethyl 2-methylpropyl carbonate Chemical compound CC(C)COC(=O)OCCl NLTCPNKKJDMJQD-UHFFFAOYSA-N 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims description 12
- 230000007062 hydrolysis Effects 0.000 claims description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 239000002798 polar solvent Substances 0.000 claims description 8
- 238000010025 steaming Methods 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- 239000012044 organic layer Substances 0.000 claims description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 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 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 159000000003 magnesium salts Chemical class 0.000 claims description 5
- 235000019260 propionic acid Nutrition 0.000 claims description 5
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 5
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 238000000638 solvent extraction Methods 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 229960004556 tenofovir Drugs 0.000 abstract description 7
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 abstract 3
- 229930024421 Adenine Natural products 0.000 abstract 3
- 229960000643 adenine Drugs 0.000 abstract 3
- 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 2
- 230000003197 catalytic effect Effects 0.000 abstract 2
- JHYNXXBAHWPABC-UHFFFAOYSA-N chloromethyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OCCl JHYNXXBAHWPABC-UHFFFAOYSA-N 0.000 abstract 1
- 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 abstract 1
- 239000000047 product Substances 0.000 description 31
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 28
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 16
- 238000000967 suction filtration Methods 0.000 description 15
- 239000001530 fumaric acid Substances 0.000 description 14
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- 238000009413 insulation Methods 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 5
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 230000006340 racemization Effects 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 208000002672 hepatitis B Diseases 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 description 2
- XNYBQIJQJLOUNI-UHFFFAOYSA-N C(C)(C)OC(C)C.C(=O)=O Chemical compound C(C)(C)OC(C)C.C(=O)=O XNYBQIJQJLOUNI-UHFFFAOYSA-N 0.000 description 2
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 229910001425 magnesium ion Inorganic materials 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical class N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-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
- 241000628997 Flos Species 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- UVNKIYPMUDFRGV-UHFFFAOYSA-N [Mg].C(CC)(=O)O Chemical compound [Mg].C(CC)(=O)O UVNKIYPMUDFRGV-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- XDKQUSKHRIUJEO-UHFFFAOYSA-N magnesium;ethanolate Chemical compound [Mg+2].CC[O-].CC[O-] XDKQUSKHRIUJEO-UHFFFAOYSA-N 0.000 description 1
- TZNULHNPXDZANP-UHFFFAOYSA-N magnesium;methanol Chemical compound [Mg].OC TZNULHNPXDZANP-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- LPEKGGXMPWTOCB-GSVOUGTGSA-N methyl (R)-lactate Chemical compound COC(=O)[C@@H](C)O LPEKGGXMPWTOCB-GSVOUGTGSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960001355 tenofovir disoproxil Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an industrial production process for tenofovir disoproxil fumarate represented by a structural formula (II). The production process comprises the following steps of: (1) preparing R-9-(2-hydroxypropyl)adenine by taking adenine and R-propylene carbonate as initial raw materials; (2) performing a condensation reaction on the obtained R-9-(2-hydroxypropyl)adenine and diethyl(tosyloxy)methylphosphonate under the catalytic action of magnesium alkoxide to prepare R-9[2-(diethyl-phosphonic acid methoxy)propyl]adenine; (3) hydrolyzing R-9[2-(diethyl-phosphonic acid methoxy)propyl]adenine to obtain tenofovir; and (4) performing condensation on the tenofovir and the chloromethyl isopropyl carbonate under the catalytic action of triethylamine to prepare the tenofovir disoproxil fumarate. The process of the invention has the characteristics of low cost, safe process, high product quality and suitability for industrial production.
Description
One, technical field
The present invention relates to the industrialized manufacturing technique of the intermediate tynofovir ester of a kind of antiviral fumaric acid tynofovir ester ((R)-[[2-(6-amino-9H-purine-9-yl)-1-methyl ethoxy] methyl] phosphonic acids diisopropyl oxygen carbonyl oxygen base methyl esters fumarate).
Two, background technology
Fumaric acid tynofovir ester (tenofovir disoproxil fumarate, TDF), chemistry (R)-[[2-(6-amino-9H-purine-9-yl)-1-methyl ethoxy] methyl] phosphonic acids diisopropyl oxygen carbonyl oxygen base methyl esters fumarate by name, its structure is suc as formula shown in (I), be to research and develop by U.S. Glead Sciences company, October calendar year 2001 is first in U.S.'s listing, now in the listing of countries and regions such as Europe, Australia and Canada.In-11 the 58th U.S.'s hepatopathy research association annual meetings in 2007 and the 43rd European hepatopathy annual meeting of 2008-04, the report for the treatment of chronic hepatitis B CHB about the tynofovir ester has caused concern widely.
Fumaric acid tynofovir ester is novel nucleoside (acid) analogue, is infected by the approval treatment HIV of FDA Food and Drug Administration (FDA) in calendar year 2001.It obtains medicinal ingredients tynofovir (structure is suc as formula shown in (III)) after the hydrolysis in vivo.Therefore it get a good chance of becoming HIV/HBV concurrent infection HAART therapy a member in the external activity that can significantly suppress hbv replication.TDF is the prodrug of tynofovir (tenofovir), is a novel acyclic nucleotide (acid) analogue, in the external activity that anti-HIV-1 and HIV-2 are arranged.
TDF has been one of nucleosides (acid) class Revertase inhibitor of widely used treatment HIV at present.The effect that it is outstanding, favorable applicability and proper dosage all make him become the most popular medicine of a line, and are recommended as better nucleosides (acid) the class Revertase inhibitor use of a line antiviral therapy at present by a lot of guides.Viread (fumaric acid tenofovir two pyrrole furan esters) has obtained China's listing at present, is used for the treatment of chronic viral hepatitis B.The curative effect that studies confirm that tenofovir treatment chronic viral hepatitis B is apparently higher than Adefovir.
Chinese patent CN200910157993.2 has announced a kind of new synthetic process of tynofovir ester; with (R)-methyl lactate is chiral raw material; with the ester condensation of diisopropyl ester tolysulfonyl aminomethylphosphonic acid; obtain 2-O-(20,000 and amino-phosphono-methyl)-(R)-methyl lactate (formula 3); obtain 2-O-(dialkyl group oxygen base-phosphoryl-methyl)-(R)-propyl alcohol (formula 4) with sodium borohydride reduction; formula 4 compounds and Tosyl chloride reaction; obtain 2-O-(dialkyl group oxygen base-phosphoryl-methyl)-(R)-propyl group tosic acid branch (formula 5); formula 5 compounds and VITAMIN B4 condensation; obtain (R)-9-[2-(dialkyl group-phosphono) methoxy-propyl] VITAMIN B4 (formula 6); the hydrolysis under the bromotrimethylsilane effect of formula 6 compounds; obtain (R)-9-[2-phosphono-methoxy-propyl] VITAMIN B4 (formula III), formula III obtains the finished product tynofovir ester (formula II) with the reaction of chloromethyl isobutyl carbonate propyl ester again.Synthetic route is as follows:
Above-mentioned operational path operation more complicated, sodium borohydride of using and sodium hydrogen all belong to highly dangerous product, especially sodium hydrogen, with the water electrode explosive, bromotrimethylsilane price comparison costliness, in addition, in the whole technology, because a large amount of uses of sodium hydrogen can cause the product racemization, finally cause the finished product chiral purity defective.
Chinese patent CN200810083233.7 (the lucky Reed science of the U.S.) has also reported a kind of synthesis technique of fumaric acid tynofovir ester, it is a raw material with basic material S-N.F,USP MANNITOL, cyclization obtains the R-propylene carbonate through palladium carbon catalytic hydrogenation, and then with the VITAMIN B4 condensation, the product that obtains under the catalysis of trimethyl carbinol lithium with the condensation of tolysulfonyl oxygen base diethyl phosphonate, hydrolysis under the product bromotrimethylsilane that obtains, obtain the key intermediate tynofovir, and then with chloromethyl isobutyl carbonate propyl ester condensation salify after obtain the finished product fumaric acid tynofovir ester.Synthetic route is as follows:
The route of this process using is relatively more classical at present synthetic method, but, in the processing of details, expose many problems, the one, the use of n-Butyl Lithium, as everyone knows, n-Butyl Lithium needs low-temperature storage, and cost an arm and a leg, a large amount of aborning uses can cause safety and accident potential, and in addition, bromotrimethylsilane is as main hydrolysing agent, the price of organosilicon product is mainly grasped in the hand of national manufacturers such as Germany, Britain at present, and a large amount of uses also can cause the raising on the cost.Analyze theoretically, this technology does not propose particular requirement in treatment of details, shows according to our experiment, tends to cause exceeding standard of the finished product foreign matter content.
In addition, patents such as CN01813161.8CN97197460.8CN98807435.4CN200480002190.5CN20 0510099916.8CN200610056926.8CN200710014625.3 have also proposed the viewpoint of oneself respectively to the synthesis technique of fumaric acid tynofovir ester, but catalyzer all is to have adopted sodium hydrogen, n-Butyl Lithium, trimethyl carbinol lithium or other noble metal catalysts basically, nearly all is to have adopted bromotrimethylsilane as hydrolysing agent at hydrolysis reaction.We tend to cause the finished product cost value high by these technologies that experiment showed, of oneself, and bring other a series of uncertain factors on environmental protection of producing and safety.
Three, summary of the invention
The technical problem to be solved in the present invention is to provide that a kind of cost is low, process safety, good product quality, be suitable for the production technique of the tynofovir ester of industrialization.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
A kind of structure comprises the following steps: suc as formula the production technique of the tynofovir ester shown in (II)
(1) is starting raw material suc as formula VITAMIN B4 shown in (VII) and structure suc as formula the R-propylene carbonate shown in (VIII) with structure, makes structure suc as formula the R-9-shown in (VI) (2-hydroxypropyl) VITAMIN B4;
(2) gained R-9-(2-hydroxypropyl) VITAMIN B4 and the structure tolysulfonyl oxygen base diethyl phosphonate shown in formula V carries out condensation reaction under the catalysis of magnesium alkoxide, makes structure suc as formula the R-9-[2-shown in (IV) (diethyl phosphono methoxyl group) propyl group] VITAMIN B4;
(3) gained R-9-[2-(diethyl phosphono methoxyl group) propyl group] the VITAMIN B4 hydrolysis obtains the tynofovir shown in the formula (III);
(4) the gained tynofovir under the catalysis of weakly alkaline material with the condensation of chloromethyl isobutyl carbonate propyl ester, make structure suc as formula the tynofovir ester shown in (II);
Below technique scheme is specifically described.
The present invention recommends described step (1) specifically to comprise: VITAMIN B4 and the condensation reaction under basic catalyst of R-propylene carbonate, and fully the separation of reaction back obtains crude product, and crude product is through refining R-9-(2-hydroxypropyl) VITAMIN B4 that obtains.The described condensation reaction of step (1) is carried out under the N2 protection.
Further, in the described step (1), be reaction solvent preferably with dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) (DMSO).
Further, in the described step (1), described basic catalyst is preferably sodium hydroxide or potassium hydroxide.
Further, in the described step (1), the temperature of reaction of preferred preparation VITAMIN B4 and R-propylene carbonate is controlled at 100～130 ℃.In the step (1), the carrying out of available HPLC monitoring reaction determined reaction end by the variation of material content.
Further, in the described step (1), the molar ratio of described R-propylene carbonate and VITAMIN B4 is preferably 1.2～1.5: 1.
Further, we find through a large amount of experiment: the usage quantity of basic catalyst directly influences the chiral purity of product, the amount of catalyzer conference cause a large amount of racemizations of product, catalyst levels reduces, and can influence the efficient of reaction again; So the molar ratio of the preferred VITAMIN B4 of the present invention and basic catalyst is 7.5～15: 1, more preferably 9～12: 1.In addition, we also find, racemization is inevitable in the reaction process of step (1), how much all can causing of catalyzer usage quantity, so we have taked further refining to remove chiral isomer, the refining refining solvent that adopts is the mixture of lower aliphatic alcohols or the pure and mild toluene of lower aliphatic, and wherein the volume content of toluene in mixture is no more than 30%; Described lower aliphatic alcohols particular methanol or ethanol.
Step of the present invention (2) specifically comprises: under the anhydrous and oxygen-free condition, R-9-(2-hydroxypropyl) VITAMIN B4 under the catalysis of magnesium alkoxide with the condensation of tolysulfonyl oxygen base diethyl phosphonate, fully the reaction back neutralizes with organic acid, steaming desolventizes, add methylene dichloride and water, separate out magnesium salts after the stirring, filter and divide water, concentrated R-9-[2-(the diethyl phosphono methoxyl group) propyl group that obtains of organic layer] VITAMIN B4.
Further, in the described step (2), described pure Mg catalyst is selected from the magnesium salt compound of the alcohol of C1～C4, particular methanol magnesium, magnesium ethylate or trimethyl carbinol alcohol, more preferably tert-butyl alcohol magnesium.
Further, in the described step (2), the condensation reaction of R-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate is preferably carried out in reaction solvent dimethyl formamide (DMF).
Further, in the described step (2), because reaction is a catalyzer with the magnesium alkoxide, a large amount of magnesium ions can be brought in the subsequent reactions, causes product impurity to improve greatly, also influences yield, so need to adopt purification step in the step (2).Consider that the organic acid magnesium salts is water-soluble bigger, thus we adopt organic acid directly in and magnesium ion, in aftertreatment, remove magnesium salts.The used organic acid that neutralizes is preferably formic acid, acetate or propionic acid, more preferably formic acid.
Further, in the described step (2), the molar ratio of R-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate is 1: 1.2～2.0; The molar ratio of R-9-(2-hydroxypropyl) VITAMIN B4 and magnesium alkoxide is 1: 0.5～1.5, be preferably 1: 0.8～and 1.2.
Further, in the described step (2), preferred 60～90 ℃ of the setting-up point of R-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate.In the step (2), the carrying out of available HPLC monitoring reaction determined reaction end by the variation of material content.
The described hydrolysis of step of the present invention (3) is preferably carried out under the hydrobromic effect of hydrolysing agent, and reaction is quick, and raw material is cheap and easy to get.
Further, described step (3) specifically comprises: with step (2) gained R-9-[2-(diethyl phosphono methoxyl group) propyl group] VITAMIN B4 adds in the hydrobromic acid aqueous solution, the intensification hydrolysis, fully the reaction postcooling adds organic solvent extraction, and it is 2.5～3.5 that water layer is regulated the pH value with alkali lye, cooling crystallization, filter, crystal's system obtains tynofovir after the drying.
Further, in the described step (3), described R-9-[2-(diethyl phosphono methoxyl group) propyl group] VITAMIN B4 and hydrobromic molar ratio be preferably 1: 4～and 8.
Further, in the described step (3), preferred 80～100 ℃ of hydrolysising reacting temperature.In the step (3), the carrying out of available HPLC monitoring reaction determined reaction end by the variation of mono ethyl ester content.
Further, in the described step (3),, add the mono ethyl ester (promptly only slough the byproduct of an ethyl) of organic solvent extraction to remove unreacted raw material and generation for improving product purity.Extraction is preferred one of following with organic solvent: methylene dichloride, ethyl acetate, normal hexane, chloroform, more preferably methylene dichloride or ethyl acetate.
Further, the pH value of preferably regulating water layer with alkali lye is 3.0～3.3.
Step of the present invention (4) specifically comprises: tynofovir and the condensation under the catalysis of weakly alkaline material of chloromethyl isobutyl carbonate propyl ester, fully react postcooling, add entry and dichloromethane extraction, alkaline aqueous solution washing dichloromethane layer, dry, steaming removes methylene dichloride and obtains crude product, add low polar solvent in the crude product, cooling crystallization obtains the tynofovir ester.
Further, in the described step (4), described weakly alkaline material is preferably triethylamine, sodium bicarbonate or yellow soda ash.
Further, in the described step (4), the condensation reaction of tynofovir and chloromethyl isobutyl carbonate propyl ester preferably is reaction solvent with the 1-Methyl-2-Pyrrolidone.
Further, in the described step (4), the temperature of reaction of tynofovir and chloromethyl isobutyl carbonate propyl ester preferably is controlled at 45～80 ℃, preferred 50～60 ℃.In this step, the carrying out of available HPLC monitoring reaction is when list (POC) ester content is for best below 20%.
Further, in the described step (4), the molar ratio of described tynofovir and chloromethyl isobutyl carbonate propyl ester is preferably 1: 3.5～and 5.5; The molar ratio of described weakly alkaline material and tynofovir is 2.5～4.5: 1.
Further, in the described step (4), we find in the finished product, the impurity of single (POC) ester is very easy to exceed standard, and be difficult to directly remove by the purified method, so we adopt alkaline aqueous solution washing organic layer to remove the monoesters in the product, the pH of preferred alkaline aqueous solution is 7.5～10.0, if alkalescence causes product to decompose and racemization too by force easily.Described alkaline aqueous solution can select for use pH at aqueous solution such as 7.5～10.0 triethylamine, sodium bicarbonate, yellow soda ash, and more preferably pH is at 7.5～10.0 triethylamine aqueous solution or sodium bicarbonate aqueous solution.
Further, in the described step (4), one of described low polar solvent is preferred following: ethyl acetate, hexanaphthene, sherwood oil, normal hexane.
The present invention is concrete to recommend described production technique to carry out according to following steps:
(1) N
2Under the protection, in reaction solvent dimethyl formamide or dimethyl sulfoxide (DMSO), VITAMIN B4 and R-propylene carbonate carry out condensation reaction in 100～130 ℃ under basic catalyst; Fully the separation of reaction back obtains crude product, and crude product obtains R-9-(2-hydroxypropyl) VITAMIN B4 through refining; Described basic catalyst is sodium hydroxide or potassium hydroxide, and the molar ratio example of described VITAMIN B4 and basic catalyst is 7.5～15: 1; The refining refining solvent that adopts is the mixture of lower aliphatic alcohols or the pure and mild toluene of lower aliphatic, and wherein the volume content of toluene in mixture is no more than 30%;
(2) under the anhydrous and oxygen-free condition, in dimethyl formamide, R-9-(2-hydroxypropyl) VITAMIN B4 under the catalysis of magnesium alkoxide with the condensation under 60～90 ℃ temperature condition of tolysulfonyl oxygen base diethyl phosphonate, fully the reaction back neutralizes with organic acid, steaming desolventizes, and adds methylene dichloride and water, separates out magnesium salts after the stirring, filter and divide water, concentrated organic layer obtains R-9-[2-(diethyl phosphono methoxyl group) propyl group] VITAMIN B4; Described pure Mg catalyst is selected from the magnesium salt compound of the alcohol of C1～C4; The used organic acid that neutralizes is formic acid, acetate or propionic acid; The molar ratio of described R-9-(2-hydroxypropyl) VITAMIN B4 and magnesium alkoxide is 1: 0.5～1.5;
(3) with step (2) gained R-9-[2-(diethyl phosphono methoxyl group) propyl group] VITAMIN B4 adds in the hydrobromic acid aqueous solution, be warming up to 80～100 ℃ of hydrolysis, fully react postcooling, add organic solvent extraction, it is 2.5～3.5 that water layer is regulated the pH value with alkali lye, and cooling crystallization filters, crystal's system obtains tynofovir after the drying; Described R-9-[2-(diethyl phosphono methoxyl group) propyl group] VITAMIN B4 and hydrobromic molar ratio be 1: 4～8; Extraction is selected from one of following with organic solvent: methylene dichloride, ethyl acetate, normal hexane, chloroform;
(4) step (3) gained tynofovir and chloromethyl isobutyl carbonate propyl ester carry out condensation reaction in 45～80 ℃ under the catalysis of triethylamine in 1-Methyl-2-Pyrrolidone, fully react postcooling, add entry and dichloromethane extraction, with pH at 7.5～10.0 alkaline aqueous solution washing dichloromethane layer, dry, steaming obtains crude product after removing methylene dichloride, crude product adds low polar solvent, and cooling crystallization obtains the tynofovir ester; It is one of following that described low polar solvent is selected from: ethyl acetate, hexanaphthene, sherwood oil, normal hexane.
The tynofovir ester that the present invention makes utilizes existing method and fumaric acid salify in Virahol, suction filtration, and drying can obtain highly purified fumaric acid tynofovir ester.
Production technique of the present invention is easy and simple to handle, and all starting material are all inexpensive and be easy to get, and this technology biggest advantage is mainly reflected in following aspect:
1, do not adopt the use of n-Butyl Lithium or these catalyzer of sodium hydrogen, improved the security of producing;
2, this technology provides a kind of production technique of highly purified fumaric acid tynofovir ester, has solved the problem of mono ethyl ester, list (POC) ester and chiral isomer too high levels in product.
3, reaction conditions gentleness has been avoided the reaction conditions of High Temperature High Pressure and very low temperature, is fit to very much industrial method and handles;
4, most of solvent can reclaim in the whole technology, and three wastes generation is few, can be considered as process for cleanly preparing;
In a word, adopt production technique of the present invention, economic benefit and social benefit all very significantly.
Four, specific embodiment
Following Example is to understand content of the present invention for better, but does not limit protection scope of the present invention with this.
Embodiment 1
In the there-necked flask of 2L, add VITAMIN B4 100g (0.74mol), N
2Protection, the DMF that adds 500ml then opens and stirs, and adds, add R-propylene carbonate 95g (0.92mol), add NaOH 3g (0.075mol), stirring at room 10 minutes is after system is even, begin to be warming up to 100～130 ℃, insulation reaction, sampling later in 12 hours detects (reacting as clear as crystal); Content can stopped reaction below 1% in reaction system when VITAMIN B4; Slowly reduce to below 90 ℃, begin to add toluene 600ml, have a large amount of white solids to separate out; After being cooled to room temperature, continue to reduce to 0-5 ℃, insulated and stirred 2 hours; Suction filtration with 200ml ice toluene bubble filter wash cake, obtains the about 180g of wet cake, the about 130-140g of dry product, HPLC purity 85%-90%, fusing point 188-192 ℃;
Refining: as will to go up the ethanol that goes on foot the product 130g adding 600ml that obtains, the toluene of 100ml, be warming up to molten clear, the gac that adds 2g, the suction filtration that refluxes after half an hour is while hot removed gac, and filtrate is reduced to room temperature, further is cooled to 0 ℃, be incubated suction filtration after 1 hour, obtain the product about 105g after the drying, HPLC purity is more than 98%, mol yield about 73%.
Embodiment 2
In the there-necked flask of 2L, add VITAMIN B4 100g (0.74mol), N
2Protection, the DMSO that adds 700ml then opens and stirs, and adds, add R-propylene carbonate 95g (0.92mol), add KOH 4g (0.071mol), stirring at room 10 minutes is after system is even, begin to be warming up to 110～125 ℃, insulation reaction, sampling later in 8 hours detects, and reacts limpid substantially or is with a little floss; Content can stopped reaction below 1% in reaction system when VITAMIN B4; After slowly being cooled to room temperature, continue to reduce to 0-5 ℃, insulated and stirred 2 hours; Suction filtration with 200ml ice toluene bubble filter wash cake, obtains the about 170g of wet cake, the about 125-130g of dry product, HPLC purity 82%-88%, fusing point 182-188 ℃;
Refining: as will to go up the product that the step obtains, 130g adds the methyl alcohol of 500ml, and the toluene of 100ml is warming up to molten clear, the gac that adds 5g, the suction filtration that refluxes after half an hour is while hot removed gac, and filtrate is reduced to room temperature, further is cooled to 0 ℃, be incubated suction filtration after 1 hour, obtain the product about 101g after the drying, HPLC purity is more than 98.5%, mol yield about 70%.
Embodiment 3
In the 1L four-hole boiling flask, add R-9-(2-hydroxypropyl) VITAMIN B4 100g (0.52mol), N
2Protection adds DMF200ml, opens and stirs; Add tert-butyl alcohol magnesium 90g (0.53mol), whole reaction system is the canescence muddiness, (tert-butyl alcohol magnesium is met water decomposition, needs to guarantee whole system anhydrous and oxygen-free);
Slowly be warming up to 50～70 ℃, insulation is 1 hour under this temperature; Be warming up to 60～80 ℃ then, begin to drip 250gDESMP (tolysulfonyl oxygen base diethyl phosphonate) (0.77mol);
Along with the dropping of DESMP, reaction solution meeting heat release, the control drop rate, about 1.5hrs drips off, and when DESMP dripped 75% left and right sides, reaction solution can become limpid gluey transparent orange yellow; Drip after 2 hours and detect HPLC, when raw material among the HPLC is getting final product stopped reaction below 2%; Slowly reduce to room temperature, drip the 75g glacial acetic acid, dropwise about about 15min; After dropwising, stirring at room 30 minutes; Reaction solution is transferred in the there-necked flask of another 2L magnetic agitation, oil bath underpressure distillation; Steam DMF with decompression, the highest in temperature control below 100 ℃, evaporate to dryness about 2 hours; Steam except that after finishing, oil bath is reduced to about 40 ℃, guarantee that a material does not solidify in the bottle; Add the 1000ml methylene dichloride, naturally cool to 25-30 ℃, the tool of changing planes stirred 30 minutes; Add the water of 100ml, have a large amount of white solids to separate out, insulated and stirred 1 hour; Suction filtration is gone out solid, obtains solid 240g (wet product should be magnesium acetate), (available washed with dichloromethane); Behind the standing demix, methylene dichloride is concentrated into dried, obtains the second step product 180g, be faint yellow oily thing, purity is more than 98%, mol yield about 95%.
Embodiment 4
The product that embodiment 3 is obtained adds in the hydrobromic acid solution (45wt%) of 650g, be warming up to 90～95 ℃, react HPLC detection after 6 hours, the content of mono ethyl ester should be below 1%, be cooled to room temperature, add the methylene dichloride of 100ml, stir layering after half an hour, the water intaking layer, about the pH value to 3.2 of sodium hydroxide solution regulator solution, there is a large amount of white solids to separate out, stirring at room half an hour with 40%, continue to be cooled to 0～5 ℃, suction filtration, the white solid that obtains obtains about key intermediate tynofovir 80g with crystal's system of 15 times of amounts, purity is more than 99%, mol yield 55%.
Embodiment 5
In the 1L four-hole boiling flask, add R-9-(2-hydroxypropyl) VITAMIN B4 100g (0.52mol), N
2Protection adds DMF200ml, opens and stirs; Add tert-butyl alcohol magnesium 102g (0.6mol), whole reaction system is the canescence muddiness, and (slowly be warming up to 50～70 ℃, insulation is 1 hour under this temperature; Be warming up to 70～80 ℃ then, begin to drip 200g DESMP (tolysulfonyl oxygen base diethyl phosphonate) (0.77mol);
Along with the dropping of DESMP, reaction solution meeting heat release, the control drop rate, about 1.5hrs drips off, and reaction solution can become limpid gluey transparent orange yellow; Drip after 2 hours and detect HPLC, when raw material among the HPLC is getting final product stopped reaction below 2%; Slowly reduce to room temperature, drip the 95g propionic acid, dropwise about about 15min; After dropwising, stirring at room 30 minutes; Reaction solution is transferred in the there-necked flask of another 2L magnetic agitation, oil bath underpressure distillation; Steam DMF with decompression, the highest in temperature control below 90 ℃, evaporate to dryness about 2 hours; Steam except that after finishing, oil bath is reduced to about 40 ℃, guarantee that a material does not solidify in the bottle; Add the 1000ml methylene dichloride, naturally cool to 25-30 ℃, the tool of changing planes stirred 30 minutes; Add the water of 100ml, have a large amount of white solids to separate out, insulated and stirred 1 hour; Suction filtration is gone out solid, obtains solid 280g (wet product should be propionic acid magnesium), (available washed with dichloromethane); Behind the standing demix, methylene dichloride is concentrated into dried, obtains the second step product 160g, be faint yellow oily thing, purity is more than 97%, mol yield about 88%.
Embodiment 6
The product that embodiment 5 is obtained adds in the hydrobromic acid solution (45wt%) of 600g, be warming up to 90～95 ℃, react HPLC detection after 6 hours, the content of mono ethyl ester should be below 1%, be cooled to room temperature, add the methylene dichloride of 100ml, stir layering after half an hour, the water intaking layer, about the pH value to 3.2 of potassium hydroxide solution regulator solution, there is a large amount of white solids to separate out, stirring at room half an hour with 30%, continue to be cooled to 0～5 ℃, suction filtration, the white solid that obtains obtains about key intermediate tynofovir 75g with crystal's system of 15 times of amounts, purity is more than 99%, mol yield 53%.
Embodiment 7
With 50g (0.174mol) tenofovir, 66g triethylamine (TEA) joins in the remittance of 1L four-hole boiling flask, N
2Protection adds NMPO (N-Methyl pyrrolidone) 150ml, is warming up to 50～60 ℃, slowly drips chloromethyl isobutyl carbonate propyl ester (CMIC) 125g (0.82mol) then, and control dropping temperature and drop rate dropwised in about about 1 hour; After dropwising, 50～60 ℃ of insulation reaction; After 4 hours, HPLC monitors reaction process, when monoester content is lower than 12%, but stopped reaction; Be cooled to room temperature, further be cooled to 10-15 ℃, drip the water of 300ml, further be cooled to 0-5 ℃, insulation reaction 1 hour; The methylene dichloride that adds 150ml continues to stir 30 minutes, layering, and water layer continues with 150ml methylene dichloride (MDC) extraction once; The combined dichloromethane layer, (the about 480ml-500ml of cumulative volume); Dichloromethane layer is with 10% the sodium hydrogen carbonate solution extraction of 100ml 3 times, water with 100ml extracts 3 times more then, the dichloromethane layer drying removes methylene dichloride under reduced pressure, adds the ethyl acetate of 100ml, slowly be cooled to 0～5 ℃, separate out white solid, suction filtration obtains tynofovir ester 45g behind the drying under reduced pressure, purity is more than 99%, mol yield 50%.
The tynofovir ester of 45g is dissolved in the Virahol of 500ml, adds the fumaric acid of 18g, slowly reduce to room temperature after the dissolving, and then be cooled to 0～5 ℃, the insulation half an hour after, suction filtration, obtain fumaric acid tynofovir ester 40g after the drying, purity is more than 99%, mol yield 73%.
Embodiment 7
With 50g (0.174mol) tenofovir, 70gTEA joins in the remittance of 1L four-hole boiling flask, N
2Protection adds NMPO (N-Methyl pyrrolidone) 150ml, is warming up to 51-53 ℃, slowly drips CMIC 130g (0.85mol) then, and control dropping temperature and drop rate dropwised in about about 1 hour; After dropwising, 50～60 ℃ of insulation reaction; After 4 hours, HPLC monitors reaction process, when monoester content is lower than 15%, but stopped reaction; Be cooled to room temperature, further be cooled to 10-15 ℃, drip the water of 300ml, further be cooled to 0-5 ℃, insulation reaction 1 hour; The ethyl acetate that adds 200ml continues to stir 30 minutes, layering, and water layer continues with the 200ml ethyl acetate extraction once; Merge layer by layer organic, (the about 580ml-600ml of cumulative volume); Organic layer extracts 3 times with the triethylamine aqueous solution about the pH=8 of 100ml, water with 100ml extracts 3 times more then, the organic layer drying removes solvent under reduced pressure, adds the hexanaphthene of 100ml, slowly be cooled to 0～5 ℃, separate out white solid, suction filtration obtains tynofovir ester 50g behind the drying under reduced pressure, purity is more than 99%, mol yield 55%.
The tynofovir ester of 50g is dissolved in the Virahol of 500ml, adds the fumaric acid of 20g, slowly reduce to room temperature after the dissolving, and then be cooled to 0～5 ℃, the insulation half an hour after, suction filtration, obtain fumaric acid tynofovir ester 43g after the drying, purity is more than 99%, mol yield 75%.
Claims (10)
1. a structure is suc as formula the production technique of the tynofovir ester shown in (II), and described production technique comprises the following steps:
(1) is starting raw material suc as formula VITAMIN B4 shown in (VII) and structure suc as formula the R-propylene carbonate shown in (VIII) with structure, makes structure suc as formula the R-9-shown in (VI) (2-hydroxypropyl) VITAMIN B4;
(2) gained R-9-(2-hydroxypropyl) VITAMIN B4 and the structure tolysulfonyl oxygen base diethyl phosphonate shown in formula V carries out condensation reaction under the catalysis of magnesium alkoxide, makes structure suc as formula the R-9-[2-shown in (IV) (diethyl phosphono methoxyl group) propyl group] VITAMIN B4;
(3) gained R-9-[2-(diethyl phosphono methoxyl group) propyl group] the VITAMIN B4 hydrolysis obtains the tynofovir shown in the formula (III);
(4) the gained tynofovir under the catalysis of weakly alkaline material with the condensation of chloromethyl isobutyl carbonate propyl ester, make structure suc as formula the tynofovir ester shown in (II);
2. the production technique of tynofovir ester as claimed in claim 1, it is characterized in that described step (1) specifically comprises: VITAMIN B4 and the condensation reaction under basic catalyst of R-propylene carbonate, fully the separation of reaction back obtains crude product, and crude product is through refining R-9-(2-hydroxypropyl) VITAMIN B4 that obtains.
3. the production technique of tynofovir ester as claimed in claim 2, it is characterized in that in the described step (1): the reaction of VITAMIN B4 and R-propylene carbonate is a reaction solvent with dimethyl formamide or dimethyl sulfoxide (DMSO), and described basic catalyst is sodium hydroxide or potassium hydroxide; The molar ratio of VITAMIN B4 and basic catalyst is 7.5～15: 1; Temperature of reaction is controlled at 100～130 ℃; The refining solvent that crude product refining adopts is the mixture of lower aliphatic alcohols or the pure and mild toluene of lower aliphatic, and wherein the volume content of toluene in mixture is no more than 30%.
4. the production technique of tynofovir ester as claimed in claim 1 is characterized in that described step (2) specifically comprises: under the anhydrous and oxygen-free condition, R-9-(2-hydroxypropyl) VITAMIN B4 under the catalysis of magnesium alkoxide with the condensation of tolysulfonyl oxygen base diethyl phosphonate; Fully neutralize with organic acid after the reaction, steaming desolventizes, and adds methylene dichloride and water, separates out magnesium salts after the stirring, filters and divides water, concentrated R-9-[2-(the diethyl phosphono methoxyl group) propyl group that obtains of organic layer] VITAMIN B4.
5. the production technique of tynofovir ester as claimed in claim 4 is characterized in that in the described step (2): the condensation reaction of R-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate is reaction solvent with the dimethyl formamide; Described pure Mg catalyst is selected from the magnesium salt compound of the alcohol of C1～C4; The molar ratio of described R-9-(2-hydroxypropyl) VITAMIN B4 and magnesium alkoxide is 1: 0.5～1.5; The setting-up point of R-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate is 50～90 ℃; The used organic acid that neutralizes is formic acid, acetate or propionic acid.
6. the production technique of tynofovir ester as claimed in claim 1 is characterized in that the described hydrolysis of step (3) carries out under the hydrobromic effect of hydrolysing agent; Described step (3) specifically comprises: with step (2) gained R-9-[2-(diethyl phosphono methoxyl group) propyl group] VITAMIN B4 adds in the hydrobromic acid aqueous solution, the intensification hydrolysis, fully react postcooling, add organic solvent extraction, it is 2.5～3.5 that water layer is regulated the pH value with alkali lye, and cooling crystallization filters, crystal's system obtains tynofovir after the drying.
7. the production technique of tynofovir ester as claimed in claim 6 is characterized in that in the described step (3): extraction is selected from one of following with organic solvent: methylene dichloride, ethyl acetate, normal hexane, chloroform; Hydrolysising reacting temperature is controlled at 80～100 ℃; Described R-9-[2-(diethyl phosphono methoxyl group) propyl group] VITAMIN B4 and hydrobromic molar ratio be 1: 4～8.
8. the production technique of tynofovir ester as claimed in claim 1, it is characterized in that described step (4) specifically comprises: tynofovir and the condensation under the catalysis of weakly alkaline material of chloromethyl isobutyl carbonate propyl ester, fully react postcooling, add entry and dichloromethane extraction, alkaline aqueous solution washing dichloromethane layer, dry, steaming removes methylene dichloride and obtains crude product, adds low polar solvent in the crude product, and cooling crystallization obtains the tynofovir ester.
9. the production technique of tynofovir ester as claimed in claim 8, it is characterized in that in the described step (4): described weakly alkaline material is triethylamine, sodium bicarbonate or yellow soda ash, the reaction of described tynofovir and chloromethyl isobutyl carbonate propyl ester is reaction solvent with the 1-Methyl-2-Pyrrolidone, temperature of reaction is controlled at 45～80 ℃, the pH of the washing alkaline aqueous solution that dichloromethane layer adopted is 7.5～10.0, and it is one of following that described low polar solvent is selected from: ethyl acetate, hexanaphthene, sherwood oil, normal hexane.
10. the production technique of tynofovir ester as claimed in claim 1 is characterized in that described production technique carries out according to following steps:
(1) N
2Under the protection, in reaction solvent dimethyl formamide or dimethyl sulfoxide (DMSO), VITAMIN B4 and R-propylene carbonate carry out condensation reaction in 100～130 ℃ under basic catalyst; Fully the separation of reaction back obtains crude product, and crude product obtains R-9-(2-hydroxypropyl) VITAMIN B4 through refining; Described basic catalyst is sodium hydroxide or potassium hydroxide, and the molar ratio example of described VITAMIN B4 and basic catalyst is 7.5～15: 1; The refining refining solvent that adopts is the mixture of lower aliphatic alcohols or the pure and mild toluene of lower aliphatic, and wherein the volume content of toluene in mixture is no more than 30%;
(2) under the anhydrous and oxygen-free condition, in dimethyl formamide, R-9-(2-hydroxypropyl) VITAMIN B4 under the catalysis of magnesium alkoxide with the condensation under 50～90 ℃ temperature condition of tolysulfonyl oxygen base diethyl phosphonate; Fully neutralize with organic acid after the reaction, steaming desolventizes, and adds methylene dichloride and water, separates out magnesium salts after the stirring, filters and divides water, concentrated R-9-[2-(the diethyl phosphono methoxyl group) propyl group that obtains of organic layer] VITAMIN B4; Described pure Mg catalyst is selected from the magnesium salt compound of the alcohol of C1～C4; The used organic acid that neutralizes is formic acid, acetate or propionic acid; The molar ratio of described R-9-(2-hydroxypropyl) VITAMIN B4 and magnesium alkoxide is 1: 0.5～1.5;
(3) with step (2) gained R-9-[2-(diethyl phosphono methoxyl group) propyl group] VITAMIN B4 adds in the hydrobromic acid aqueous solution, be warming up to 80～100 ℃ of hydrolysis, fully react postcooling, add organic solvent extraction, it is 2.5～3.5 that water layer is regulated the pH value with alkali lye, and cooling crystallization filters, crystal's system obtains tynofovir after the drying; Described R-9-[2-(diethyl phosphono methoxyl group) propyl group] VITAMIN B4 and hydrobromic molar ratio be 1: 4～8; Extraction is selected from one of following with organic solvent: methylene dichloride, ethyl acetate, normal hexane, chloroform;
(4) step (3) gained tynofovir and chloromethyl isobutyl carbonate propyl ester carry out condensation reaction in 45～80 ℃ under the catalysis of weakly alkaline material in 1-Methyl-2-Pyrrolidone, fully react postcooling, add entry and dichloromethane extraction, with pH at 7.5～10.0 alkaline aqueous solution washing dichloromethane layer, dry, steaming obtains crude product after removing methylene dichloride, crude product adds low polar solvent, and cooling crystallization obtains the tynofovir ester; Described weakly alkaline material is triethylamine, sodium bicarbonate or yellow soda ash, and it is one of following that described low polar solvent is selected from: ethyl acetate, hexanaphthene, sherwood oil, normal hexane.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101143879A (en) * | 2007-11-08 | 2008-03-19 | 上海交通大学 | Sulfur-containing acyclic nucleoside phosphonic acid analogue and preparation method thereof |
| US20090286981A1 (en) * | 2006-07-12 | 2009-11-19 | Uma Maheswer Rao Vasireddy | Process for the prepartion of tenofovir |
-
2010
- 2010-05-28 CN CN 201010185710 patent/CN101870713A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090286981A1 (en) * | 2006-07-12 | 2009-11-19 | Uma Maheswer Rao Vasireddy | Process for the prepartion of tenofovir |
| CN101143879A (en) * | 2007-11-08 | 2008-03-19 | 上海交通大学 | Sulfur-containing acyclic nucleoside phosphonic acid analogue and preparation method thereof |
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