CN100569787C - A kind of preparation technology of Adefovir - Google Patents
A kind of preparation technology of Adefovir Download PDFInfo
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- CN100569787C CN100569787C CNB2007100197147A CN200710019714A CN100569787C CN 100569787 C CN100569787 C CN 100569787C CN B2007100197147 A CNB2007100197147 A CN B2007100197147A CN 200710019714 A CN200710019714 A CN 200710019714A CN 100569787 C CN100569787 C CN 100569787C
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- Prior art keywords
- vitamin
- benzoyl
- ethyl
- hydroxyethyl
- adefovir
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- 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 title claims abstract description 36
- 229960001997 adefovir Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000005516 engineering process Methods 0.000 title claims abstract description 15
- 239000011782 vitamin Substances 0.000 claims abstract description 98
- 229940088594 vitamin Drugs 0.000 claims abstract description 98
- 229930003231 vitamin Natural products 0.000 claims abstract description 98
- 235000013343 vitamin Nutrition 0.000 claims abstract description 98
- 150000003722 vitamin derivatives Chemical class 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 47
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 37
- -1 ethylene carbonate ester Chemical class 0.000 claims abstract description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 18
- JJPBKCZJVYSKGV-UHFFFAOYSA-N diethoxyphosphane Chemical compound CCOPOCC JJPBKCZJVYSKGV-UHFFFAOYSA-N 0.000 claims abstract description 17
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims abstract description 17
- SVHLBZGQSUMSNJ-UHFFFAOYSA-N CCC1=NC(N)=C2NC(O[SiH3])=NC2=N1 Chemical compound CCC1=NC(N)=C2NC(O[SiH3])=NC2=N1 SVHLBZGQSUMSNJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 62
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 23
- 239000012467 final product Substances 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 230000006837 decompression Effects 0.000 claims description 21
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 238000004821 distillation Methods 0.000 claims description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 19
- 238000000605 extraction Methods 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 239000012044 organic layer Substances 0.000 claims description 15
- 238000000967 suction filtration Methods 0.000 claims description 15
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 238000004440 column chromatography Methods 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- UVOJYMYZFYIFBX-UHFFFAOYSA-N C(O)CCOP(OCC)(O)=O Chemical compound C(O)CCOP(OCC)(O)=O UVOJYMYZFYIFBX-UHFFFAOYSA-N 0.000 claims description 13
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 13
- 238000001953 recrystallisation Methods 0.000 claims description 12
- 238000010792 warming Methods 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 11
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- 229960000583 acetic acid Drugs 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- 235000009518 sodium iodide Nutrition 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012153 distilled water Substances 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 235000011181 potassium carbonates Nutrition 0.000 claims description 8
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 7
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 7
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 235000017550 sodium carbonate Nutrition 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000008098 formaldehyde solution Substances 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- 235000015320 potassium carbonate Nutrition 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000000284 extract Substances 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 230000000903 blocking effect Effects 0.000 abstract description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 238000001291 vacuum drying Methods 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 230000005311 nuclear magnetism Effects 0.000 description 5
- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical compound OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 description 5
- 150000003222 pyridines Chemical class 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000005654 Michaelis-Arbuzov synthesis reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- KJYDNQGQUQQEBB-UHFFFAOYSA-N C(C)OP(OCC)(O)C.[O].ClC=C Chemical compound C(C)OP(OCC)(O)C.[O].ClC=C KJYDNQGQUQQEBB-UHFFFAOYSA-N 0.000 description 2
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- UAXIBJPHBMEGSP-UHFFFAOYSA-N di(propan-2-yloxy)phosphorylmethanol Chemical compound CC(C)OP(=O)(CO)OC(C)C UAXIBJPHBMEGSP-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- CKSRFHWWBKRUKA-UHFFFAOYSA-N ethyl 2-ethoxyacetate Chemical compound CCOCC(=O)OCC CKSRFHWWBKRUKA-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- QDWLBCPOTMKDHK-UHFFFAOYSA-N 2-[4-(trifluoromethyl)pyridin-3-yl]ethanamine Chemical compound NCCC1=CN=CC=C1C(F)(F)F QDWLBCPOTMKDHK-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DMPREIBRPICGNW-UHFFFAOYSA-N [O].C(=C)Cl Chemical compound [O].C(=C)Cl DMPREIBRPICGNW-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- SULWMEGSVQCTSK-UHFFFAOYSA-N diethyl hydrogen phosphite Chemical class CCOP(O)OCC SULWMEGSVQCTSK-UHFFFAOYSA-N 0.000 description 1
- WOAFDHWYKSOANX-UHFFFAOYSA-N diisopropyl methylphosphonate Chemical compound CC(C)OP(C)(=O)OC(C)C WOAFDHWYKSOANX-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 231100000707 mutagenic chemical Toxicity 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a kind of preparation technology of Adefovir; technical scheme of the present invention comprises N6-benzoyl-9-three silyloxy ethyl adenine synthesis procedures; N6-benzoyl-9-hydroxyethyl VITAMIN B4 synthesis procedure; N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] the VITAMIN B4 synthesis procedure; N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 synthesis procedure; hydrolyzing process; the present invention compared with prior art; with 9-hydroxyethyl VITAMIN B4 is raw material; through protection; remove blocking group; replace; the synthetic Adefovir of reaction such as hydrolysis; reaction is classical reaction; yield calculates with VITAMIN B4 and can reach more than 10%; when 9-hydroxyethyl VITAMIN B4 VITAMIN B4; when the ethylene carbonate ester synthesizes; whole piece route reaction mild condition, scale operation easily.
Description
Technical field:
The invention belongs to this technical field of preparation of medicine, belong to this technical field of preparation technology of Adefovir especially.
Background technology:
Adefovir (Adefovir ADV) is a kind of Antihepatitis medicament, its English 9-[2-(phosphonomethoxy) ethyl by name] adenine (PMEA). molecular formula is C
8H
12O
4N
5P.
The synthetic route of common Adefovir has following three:
Route one: Zhang Yong, Li Xin (Shenyang Pharmaceutical University's journal 2001,18 (2)) be starting raw material with Virahol and 1-chloro-2-chlorine methyl ethyl ether, with phosphonous acid three isopropyl esters the Arbuzov reaction taking place obtains 2-chloroethene oxygen methyl-phosphorous acid diisopropyl fat, with VITAMIN B4 generation substitution reaction, reduction at last obtains the product Adefovir again.
This route is that the Arbuzov reaction takes place for raw material and 1-chloro-2 chlorine methyl ethyl ethers with phosphonous acid three isopropyl esters successfully, synthesizes to have obtained 2-chloroethene oxygen diisopropylmethylpho-sphonate(DIMP), and this side chain and the used alkaline catalysts of VITAMIN B4 condensation have changed Cs into
2CO
3Synthetic 9-(2-diisopropoxy phosphono methoxyethyl) VITAMIN B4, to its method for hydrolysis with the Morita report, adopt trimethylchlorosilane back flow reaction in the presence of sodium iodide to carry out, this method can directly obtain the solid of Adefovir, react completely, the water recrystallization obtains Adefovir, has saved the column chromatography operation in the former report.But having used 1-chloro-2-chlorine methyl ethyl ether in this route is to bring out mutagens, has stronger toxicity, and has used ethylene chlorhydrin in its preparation process, not only the be heated easy firing blast of this compound, and also decomposes be hypertoxic phosgene.These reagent require highly to experiment condition and equipment, and its danger is higher relatively when being applied to industrial production simultaneously, so this route is not a method that ideal scale operation is used.
Route two: with 1, the 3-dioxolane is a starting raw material, earlier with Acetyl Chloride 98Min. Synthetic 2-chloromethane ethoxyacetic acid ethyl ester (Banijamali, A.R.; Foye, W.O.J.Hetero.Chem 1986,23), again with the reaction of phosphonous acid triethyl, to react with VITAMIN B4 again through obtaining chloroethene oxygen methyl-phosphorous acid diethyl ester behind hydrolysis, the chloro, reduction at last obtains PMEA (Holy, A.; Rosenberg, I.Cllect Czech Chem Commun2002,52).
This route replaces phosphonous acid three isopropyl esters and 2-chloromethane ethoxyacetic acid ethyl ester to carry out the Arbuzov reaction with the phosphonous acid triethyl, and this route is too much in the step of synthetic side chain chloroethene oxygen methyl-phosphorous acid diethyl ester, and the ability of leaving away of chlorine is general, with 9 N generation S of VITAMIN B4
N2 react difficulty carries out.
Route three: with 9-hydroxyethyl VITAMIN B4 is raw material, reduces at last with the hydroxymethyl phosphonic acid diisopropyl ester reaction of p-toluenesulfonyl protection and obtains PMEA (Prous, J.; Graul, A.; Castaner, J.Drugs ofthe Future 1997,22 (8)).
In this route; with oxyethane and the synthetic 9-hydroxyethyl VITAMIN B4 of VITAMIN B4 reaction; the hydroxymethyl phosphonic acid diisopropyl ester reaction that itself and p-toluenesulfonyl are protected; restore after the keyed jointing side chain and obtain product; the solvability extreme difference of 9-hydroxyethyl VITAMIN B4, to cause the contact of two materials be not very abundant, and amino also can react.
Summary of the invention:
Technical problem to be solved by this invention provides a kind of preparation technology of new Adefovir.
The technical scheme of technical solution problem of the present invention is: a kind of preparation technology of Adefovir comprises: N6-benzoyl-9-three silyloxy ethyl adenine synthesis procedures, N6-benzoyl-9-hydroxyethyl VITAMIN B4 synthesis procedure, N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] VITAMIN B4, N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 synthesis procedure, hydrolyzing process:
Described N6-benzoyl-9-three silyloxy ethyl adenine synthesis procedures are:
Under nitrogen protection, the pyridine and the N that 9-hydroxyethyl VITAMIN B4 are added capacity, in the mixed solvent of N dimethyl formamide (DMF), after stirring, under 0-5 ℃ condition, add trimethylchlorosilane, stirred 1-3 hour, be warming up to 25-35 ℃ again, reaction is not less than 24 hours, 9-hydroxyethyl VITAMIN B4, the trimethylchlorosilane mol ratio is: 1: 0.8-1.2, the volume ratio of pyridine and DMF is 1: 0.5-1.5, add an amount of pyridine again, and add Benzoyl chloride down, stir after 1-3 hour at 0-5 ℃, temperature rises to 80-110 ℃, backflow is not less than 10 hours, is cooled to room temperature, and the mol ratio of 9-hydroxyethyl VITAMIN B4 and Benzoyl chloride is 1: 1.2-2.5; Underpressure distillation, extraction, washing, dry, be 1 with volume ratio: the ethyl acetate of 8-12 and normal hexane recrystallization get final product.
The synthesis procedure of described N6-benzoyl-9-hydroxyethyl VITAMIN B4 is:
N6-benzoyl-9-three silyloxy ethyl adenines and phosphofluoric acid are closed in the Glacial acetic acid and tetrahydrofuran (THF) mixed solvent that tetra-n-butyl amine joins capacity, at 20-30 ℃ of following stirring reaction 15-30 hour, the mol ratio that N6-benzoyl-9-three silyloxy ethyl adenines and phosphofluoric acid close tetra-n-butyl amine is 1: 0.15-0.25, the volume ratio of Glacial acetic acid and tetrahydrofuran (THF) is 1: 100-200, underpressure distillation, extraction, washing, dry, get final product;
Described N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] the VITAMIN B4 synthesis procedure is:
Under nitrogen protection, with N6-benzoyl-9-hydroxyethyl VITAMIN B4, Anhydrous potassium carbonate, sodium iodide, add in the organic solvent that contains pyridine of capacity, after stirring, add tolysulfonyl oxygen ylmethyl diethyl phosphonate, reaction is not less than 24 hours under being warming up to 35-45 ℃, is cooled to room temperature, and underpressure distillation removes and desolvates, extraction, drying, column chromatography gets final product; The mol ratio of N6-benzoyl-9-hydroxyethyl VITAMIN B4, Anhydrous potassium carbonate or yellow soda ash, sodium iodide, tolysulfonyl oxygen ylmethyl diethyl phosphonate is 1: 1-1.2: 0.1-0.5: 1.5-2.5, and the volume ratio of organic solvent and pyridine is 1: 1-3;
Described organic solvent is DMF, dimethyl sulfoxide (DMSO).
Described extraction agent is methylene dichloride, ether, ethyl acetate.
The filler of described column chromatography is a silica gel, and applied sample amount and silica gel are than 1: 100-200.
The developping agent that described column chromatography is used is ethyl acetate and methyl alcohol, and the ratio of ethyl acetate and methyl alcohol is 1: 0.015-0.02.
Described N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 synthesis procedure is:
Under nitrogen protection, with acetonitrile dissolving N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] after the VITAMIN B4, under 0-5 ℃ condition, add bromotrimethylsilane, react and be warming up to 35-45 ℃ after 1-3 hour, reaction is not less than 24 hours, and decompression steams solvent, dissolving, washing, dry, suction filtration, the PH that adjusts filtrate is 12-14, leaves standstill to cotton-shaped solid to separate out suction filtration fully, washing leaching cake, with the filter cake dissolved in distilled water, the pH value of regulator solution extracts to neutral, drying, concentrated getting final product; N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] mol ratio of VITAMIN B4, bromotrimethylsilane is 1: 3-6;
Described hydrolyzing process is:
With DMF dissolving N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4, add strong base solution again, under 95-105 ℃ of condition, reflux and be not less than 24 hours, decompression steams solvent, and it is neutral adjusting the pH value, extraction, dry getting final product.
Described highly basic is NaOH or KOH, and the mol ratio of highly basic and N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 is 1: 1-3.
The synthesis technique of described 9-hydroxyethyl VITAMIN B4 is:
After the DMF dissolving of VITAMIN B4, ethylene carbonate ester, salt of wormwood with capacity, 135 ℃-145 ℃ backflow 15-25 hour, be cooled to room temperature, underpressure distillation, recrystallization gets final product; The mol ratio of VITAMIN B4, ethylene carbonate ester, salt of wormwood is 1: 1-1.5: 0.1-0.5.
The solvent of the used recrystallization of described 9-hydroxyethyl VITAMIN B4 is that volume ratio is 1: the dimethyl sulfoxide (DMSO) of 6-10 and dehydrated alcohol.
Use the ethylene carbonate ester can avoid in the route 3, can form the harm of explosive mixture, help industrialized big production with air because oxyethane is gas (10.73 ℃ of b.p) at normal temperatures.
The synthesis technique of described tolysulfonyl oxygen ylmethyl diethyl phosphonate is:
Under 0-5 ℃ condition, the mixing solutions of methylol diethyl phosphoric acid and triethylamine is added in the methylene dichloride dissolved Tosyl chloride (TsCl), reaction is not less than 2 hours, suction filtration, wash filtrate merges organic layer, drying, underpressure distillation gets final product, and the mol ratio of methylol diethyl phosphoric acid, triethylamine, Tosyl chloride is 1: 3-5: 0.5-1.
The synthesis technique of described methylol diethyl phosphoric acid is:
Under 0-5 ℃ condition, be that the formaldehyde solution of 20-40% joins in diethyl phosphite, the triethylamine with weight concentration, reaction is not less than 1 hour, and 120 ℃ cut is collected in underpressure distillation, gets final product; The volume ratio of formaldehyde solution, diethyl phosphite, triethylamine is 1: 1-2: 1-4.
The synthesis material of methylol diethyl phosphoric acid commonly used is a Paraformaldehyde 96, but emits the formaldehyde gas that is insoluble to organic solvent because of its decomposes, make gas-liquid two-phase react not competent and fully carry out, and reaction needed is reacted in pressurized vessel.
Adefovir synthetic route of the present invention is as follows:
Described TMS represents TMS, and Bz represents benzoyl.
The synthetic route of tolysulfonyl oxygen ylmethyl diethyl phosphonate is as follows:
The present invention compared with prior art; with 9-hydroxyethyl VITAMIN B4 is raw material; through protecting, go the synthetic Adefovir of reactions such as blocking group, replacement, hydrolysis; reaction is classical reaction; yield calculates with VITAMIN B4 can reach 10%; when 9-hydroxyethyl VITAMIN B4 VITAMIN B4, when the ethylene carbonate ester is synthetic, whole piece route reaction mild condition, scale operation easily.
Embodiment:
Used phosphofluoric acid closes tetra-n-butyl amine among the embodiment 1-10, tolysulfonyl oxygen ylmethyl diethyl phosphonate (can buy) all can be bought from the market.
The used 9-hydroxyethyl VITAMIN B4 of embodiment 1-10 is according to the method preparation of route 3.
Embodiment 1:
(a) N6-benzoyl-9-three silyloxy ethyl adenines are synthetic:
Under nitrogen protection; with 6.5 moles of 9-hydroxyethyl VITAMIN B4, add in 50 liters the pyridine and DMF mixed solvent, the volume ratio of pyridine and DMF is 1: 1 in the mixed solvent; after stirring; under 0-5 ℃ condition, add 7 moles of trimethylchlorosilanes, stirred 1 hour; be warming up to 25-30 ℃ again; reacted 24 hours, and added 20 liters of pyridines again, and add Benzoyl chloride 9mol down at 0-5 ℃; stir after 1 hour; temperature rises to 100 ℃, refluxes the cooling room temperature 10 hours; add the 30L methylene dichloride; with weight concentration 10% sodium hydrogen carbonate solution 20L washed twice, merge organic layer, anhydrous sodium sulfate drying 3 hours.Filter, the filtrate decompression distillation is separated out pink solid except that desolvating and adding excessive normal hexane, after having distilled normal hexane, solid 11L ethyl acetate: normal hexane is that 1: 10 mixed solvent is done recrystallization, heat filtering obtains white solid, and 40 ℃ of vacuum-dryings are spent the night, and gets the 1.65kg product, productive rate 74%, fusing point 195-196 ℃.
The data of the nuclear-magnetism figure of product are:
1HNMR (CDCl
3, 300MHz) δ: 8.30 (s, 1H, Ade-H), 8.10 (s, 1H, Ade-H), 7.90-7.20 (m, 5H, ArH), 5.97 (s, 1H, NH), 4.66 (t, J=5.13,2H, OCH
2), 4.36 (t, J=5.18,2H, CH
2), 0.07 (s, 9H, Si (CH
3)
3) ppm.
(b) synthesizing of N6-benzoyl-9-hydroxyethyl VITAMIN B4:
Get N6-benzoyl-9-three silyloxy ethyl adenine 3.5mol, phosphofluoric acid closes tetra-n-butyl amine 0.6mol, adds the 0.2L Glacial acetic acid, the 25L tetrahydrofuran (THF), and 25-27 ℃ of following stirring reaction 20 hours, decompression steams solvent, obtains white solid.With 30L methylene dichloride dissolving, and be that 40% sodium carbonate solution is regulated PH=9, extraction, organic layer usefulness anhydrous sodium sulfate drying 3 hours with weight concentration.Filter, decompression steams solvent, and vacuum-drying gets white powder solid 0.7kg, productive rate 75%, fusing point 183-185 ℃.
The aftertreatment of this reaction uses the sodium carbonate solution titration to weakly alkaline, rather than with before the washing of rare sodium hydrogen carbonate solution, be that to be a kind of phase-transfer catalyst with portioned product transferred in the water because the reactant phosphofluoric acid closes tetra-n-butyl amine and caused waste.
The data of the nuclear-magnetism figure of product are: 1HNMR (CDCl3,300MHz) δ: 8.37 (s, 1H, Ade-H), 7.90 (s, 1H, Ade-H), 7.97-7.27 (m, 5H, ArH), 5.85 (s, 1H, NH), 4.70 (t, J=5.37,2H, OCH2), 4.63 (t, J=5.16,2H, CH2), 3.17 (t, J=8.28,1H, OH) ppm.
(c) ethyl N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group)] VITAMIN B4 is synthetic:
Under nitrogen protection; get N6-benzoyl-9-hydroxyethyl VITAMIN B4 1mol; Anhydrous potassium carbonate 1.5mol; sodium iodide 0.2mol is in retort; add 25LDMF and 25L pyridine; after stirring, be added dropwise to 1.8mol tolysulfonyl oxygen ylmethyl diethyl phosphonate, reacted 24 hours down in 40-42 ℃.Be cooled to room temperature, decompression is steamed solvent and is obtained yellow solid, with the dissolving of 30L methylene dichloride, and is 20% sodium hydrogen carbonate solution 30L washing washed twice with weight concentration, merges organic layer, uses anhydrous sodium sulfate drying 3 hours.Filter, column chromatography for separation, ethyl acetate that column chromatography is used and methyl alcohol, the ratio of ethyl acetate and methyl alcohol is 1: 0.017, gets product 0.3kg, productive rate 57%, fusing point 215-216 ℃.
This reaction in the selection of reaction conditions, particularly has innovation in the use of alkali for complete synthesis committed step.Before this, used alkali such as sodium hydroxide, sodium hydride, triethylamine, trimethyl carbinol lithium, potassium tert.-butoxide, pyridine, cesium carbonate respectively according to bibliographical information, but reaction does not have successfully all.After protection amino, under the condition of the mixed base of Anhydrous potassium carbonate, pyridine, add the sodium iodide of catalytic amount, carried out eventually with the reaction of tolysulfonyl oxygen ylmethyl diethyl phosphonate.
The data of the nuclear-magnetism figure of product are
1HNMR (CDCl
3, 300MHz) δ: 8.12 (s, 1H, Ade-H), 8.00 (s, 1H, Ade-H), 7.96-7.78 (m, 5H, ArH), 4.73 (s, 1H, NH), 4.10-4.20 (m, 10H, 5CH
2) 1.35-1.40 (t, J=7.15,6H, CH
3) ppm.
(d) N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 synthesis procedure
Under nitrogen protection; get N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] VITAMIN B4 1mol is in reaction vessel, and the acetonitrile that adds capacity dissolves, and drips bromotrimethylsilane 4mol down at 0-5 ℃; stir and be warming up to 40-42 ℃ after 1 hour, reacted 24 hours.Decompression steams solvent, get white solid, white solid dissolves with the 20L methylene dichloride, and with distilled water 40L washing for several times, use anhydrous sodium sulfate drying, suction filtration, the adding weight concentration is 50% sodium hydroxide solution in the dichloromethane solution, regulating pH value is 13, leave standstill to cotton-shaped solid and separate out fully, suction filtration with methylene dichloride, washing with acetone, obtains the phosphonic acids sodium salt of white.Yield is 62%; with phosphonic acids sodium salt dissolved in distilled water; and be neutralized to PH=7 with the acetimetry of weight concentration 20%; with solution dichloromethane extraction, anhydrous sodium sulfate drying, suction filtration; concentrate; obtain N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4, productive rate 84%, fusing point 273-275 ℃.Productive rate from the fast quinoline of gland is 13%.
The data of the nuclear-magnetism figure of product are
1HNMR (CDCl
3, 300MHz) δ: 8.12 (s, 1H, Ade-H), 8.00 (s, 1H, Ade-H), 7.96-7.78 (m, 5H, ArH), 4.73 (s, 1H, NH), 4.10-4.20 (m, 10H, 5CH
2) 1.35-1.40 (t, J=7.15,6H, CH
3) ppm.
(e) hydrolyzing process:
With DMF 10L dissolving N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 1mol; add 20 liters of 0.1M sodium hydroxide solutions again; refluxed 24 hours at 95-105 ℃; decompression steams solvent; it is neutral adjusting the pH value with the 0.1M hydrochloric acid soln, uses dichloromethane extraction, anhydrous sodium sulfate drying; concentrate, get final product.
The data of the nuclear-magnetism figure of product are
1HNMR (D
2O, 300MHz) δ: 8.22 (s, 1H), 7.93 (s, 1H), 4.39 (s, 2H), 4.38 (t, J=4.86,2H, OCH
2), 4.18 (t, J=4.67,2H, CH
2), 3.67 (s, 2H, OCH
2).
The Adefovir yield is calculated as 10.63% with VITAMIN B4.
Embodiment 2:
Except that (a) N6-benzoyl-9-three silyloxy ethyl adenines were synthetic, all the other were identical with embodiment 1.
Under nitrogen protection; with 6.5 moles of 9-hydroxyethyl VITAMIN B4, add in 70 liters the pyridine and DMF mixed solvent, the volume ratio of pyridine and DMF is 1: 0.5 in the mixed solvent; after stirring; under 0-5 ℃ condition, add 5.2 moles of trimethylchlorosilanes, stirred 2 hours; be warming up to 28-32 ℃ again; reacted 36 hours, and added 20 liters of pyridines again, and add Benzoyl chloride 8mol down at 0-5 ℃; stir after 2 hours; temperature rises to 80 ℃, refluxes 15 hours, is cooled to room temperature; add the 30L methylene dichloride; with weight concentration 20% sodium hydrogen carbonate solution 20L washed twice, merge organic layer, anhydrous sodium sulfate drying 5 hours.Filter, the filtrate decompression distillation is removed to desolvate and add excessive normal hexane separate out pink solid, distillation, with the 9L volume ratio is 1: 8 ethyl acetate and normal hexane recrystallization, and 40 ℃ of vacuum-dryings are spent the night, the 1.69kg product, productive rate 76%, fusing point 195-196 ℃.
The Adefovir yield is calculated as 10.52% with VITAMIN B4.
Embodiment 3:
Except that (a) N6-benzoyl-9-three silyloxy ethyl adenines were synthetic, all the other were identical with embodiment 1.
Under nitrogen protection; with 6.5 moles of 9-hydroxyethyl VITAMIN B4, add in 80 liters the pyridine and DMF mixed solvent, the volume ratio of pyridine and DMF is 1: 1.5 in the mixed solvent; after stirring; under 0-5 ℃ condition, add 7.8 moles of trimethylchlorosilanes, stirred 3 hours; be warming up to 30-35 ℃ again; reacted 48 hours, and added 30 liters of pyridines again, and add Benzoyl chloride 16mol down at 0-5 ℃; stir after 3 hours; temperature rises to 110 ℃, refluxes 24 hours, is cooled to room temperature; add the 30L methylene dichloride; with weight concentration 30% sodium hydrogen carbonate solution 20L washed twice, merge organic layer, anhydrous sodium sulfate drying; filter; the filtrate decompression distillation being separated out pink solid except that desolvating and adding excessive normal hexane, distill, is 1: 12 ethyl acetate and normal hexane recrystallization with the 13L volume ratio; 40 ℃ of vacuum-dryings are spent the night; get the 1.71kg product, productive rate 76.6%, fusing point 195-196 ℃.
The Adefovir yield is calculated as 10.71% with VITAMIN B4.
Embodiment 4:
Except that (b) N6-benzoyl-9-hydroxyethyl VITAMIN B4 synthetic, all the other are identical with embodiment 2.
Get N6-benzoyl-9-three silyloxy ethyl adenine 3.5mol; phosphofluoric acid closes tetra-n-butyl amine 0.52mol; add the 0.2L Glacial acetic acid; the 20L tetrahydrofuran (THF); 15-20 ℃ of following stirring reaction 30 hours, decompression steams solvent, obtains white solid; dissolve with the 30L methylene dichloride; and regulate PH=9 with the sodium carbonate solution of weight concentration 30%, and extraction, organic layer was with anhydrous sodium sulfate drying 5 hours; filter; decompression steams solvent, and vacuum-drying gets white powder solid 0.71kg; productive rate 75%, fusing point 183-185 ℃.
The Adefovir yield is calculated as 10.34% with VITAMIN B4.
Embodiment 5:
Except that (b) N6-benzoyl-9-hydroxyethyl VITAMIN B4 synthetic, all the other are identical with embodiment 2.
Get N6-benzoyl-9-three silyloxy ethyl adenine 3.5mol; phosphofluoric acid closes tetra-n-butyl amine 0.87mol; add the 0.2L Glacial acetic acid; the 40L tetrahydrofuran (THF); 20-30 ℃ of following stirring reaction 15 hours, decompression steams solvent, obtains white solid; dissolve with the 30L methylene dichloride; and regulate PH=9 with the sodium carbonate solution of weight concentration 20%, and extraction, organic layer was with anhydrous sodium sulfate drying 8 hours; filter; decompression steams solvent, and vacuum-drying gets white powder solid 0.72kg; productive rate 75%, fusing point 183-185 ℃.
The Adefovir yield is calculated as 10.66% with VITAMIN B4.
Embodiment 6:
Except that (c) N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] VITAMIN B4 was synthetic, all the other were identical with embodiment 4.
Under nitrogen protection; get N6-benzoyl-9-hydroxyethyl VITAMIN B4 1mol; Anhydrous potassium carbonate 1mol; sodium iodide 0.1mol adds 25 liters of dimethyl sulfoxide (DMSO) and 50 liters of pyridines, after stirring in retort; be added dropwise to 1.5mol tolysulfonyl oxygen ylmethyl diethyl phosphonate; reacted 48 hours down in 35-40 ℃, be cooled to room temperature, decompression is steamed solvent and is obtained yellow solid; use the 40L ether dissolution; and be 15% sodium hydrogen carbonate solution 30L washed twice with weight concentration, merge organic layer, use anhydrous sodium sulfate drying; filter; column chromatography for separation, the filler of column chromatography are silica gel, the weight ratio of applied sample amount and silica gel 1: 100; the ethyl acetate that column chromatography is used and the volume ratio of methyl alcohol are 1: 0.015; get product 0.31kg, productive rate 57%, fusing point 215-216 ℃.
The Adefovir yield is calculated as 10.57% with VITAMIN B4.
Embodiment 7:
Except that (c) N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] VITAMIN B4 was synthetic, all the other were identical with embodiment 4.
Under nitrogen protection; get N6-benzoyl-9-hydroxyethyl VITAMIN B4 1mol; Anhydrous potassium carbonate 1.2mol; sodium iodide 0.5mol adds 25 liters of DMF and 75 liters of pyridines, after stirring in retort; be added dropwise to 2.5mol tolysulfonyl oxygen ylmethyl diethyl phosphonate; reacted 60 hours down in 40-45 ℃, be cooled to room temperature, decompression is steamed solvent and is obtained yellow solid; use the 30L acetic acid ethyl dissolution; and be 18% sodium hydrogen carbonate solution 30L washed twice with weight concentration, merge organic layer, use anhydrous sodium sulfate drying; filter; column chromatography for separation, the filler of column chromatography are silica gel, the weight ratio of applied sample amount and silica gel 1: 200; the ethyl acetate that column chromatography is used and the volume ratio of methyl alcohol are 1: 0.02; get product 0.32kg, productive rate 58%, fusing point 215-216 ℃.
The Adefovir yield is calculated as 10.49% with VITAMIN B4.
Embodiment 8:
Except that (d) N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 was synthetic, all the other were identical with embodiment 7.
Under nitrogen protection; get N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] VITAMIN B4 1mol is in reaction vessel, and the acetonitrile that adds 50 liters dissolves, and drips bromotrimethylsilane 3mol down at 0-5 ℃; stir and be warming up to 35-39 ℃ after 1 hour, reacted 48 hours.Decompression steams solvent; get white solid; white solid dissolves with the 30L methylene dichloride; and with distilled water 30L washing for several times, organic layer anhydrous sodium sulfate drying, suction filtration; add the 0.1M sodium hydroxide solution in the dichloromethane solution; regulating PH is 12, leaves standstill to cotton-shaped solid to separate out suction filtration fully; use methylene dichloride; washing with acetone; obtain the phosphonic acids sodium salt of white, vacuum-drying, yield 62%; behind dissolved in distilled water phosphonic acids sodium salt; acetic acid with weight concentration 20% is neutralized to solution PH=6.5, with solution dichloromethane extraction, anhydrous sodium sulfate drying; concentrate; obtain N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4, productive rate 84.5%, fusing point 273-275 ℃.
The Adefovir yield is calculated as 10.72% with VITAMIN B4.
Embodiment 9:
Except that (d) N6-benzoyl 9-(2-phosphono methoxyethyl) VITAMIN B4 was synthetic, all the other were identical with embodiment 7.
Under nitrogen protection; get N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] VITAMIN B4 1mol is in reaction vessel, and the acetonitrile that adds 60 liters dissolves, and drips bromotrimethylsilane 6mol down at 0-5 ℃; stir and be warming up to 42-45 ℃ after 3 hours, reacted 72 hours.Decompression steams solvent; get white solid; white solid dissolves with the 40L methylene dichloride, and with distilled water 30L washing for several times, the organic layer anhydrous sodium sulfate drying; suction filtration; add the 0.5M sodium hydroxide solution in the dichloromethane solution, regulating PH is 14, leaves standstill to cotton-shaped solid to separate out fully; suction filtration; use methylene dichloride; washing with acetone obtains white phosphonic acids sodium salt, vacuum-drying; yield 61.5%; behind dissolved in distilled water phosphonic acids sodium salt, be neutralized to solution PH=7 with the acetic acid of weight concentration 20%, with the solution dichloromethane extraction; anhydrous sodium sulfate drying; concentrate, obtain N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4, productive rate 84.2%; fusing point 273-275 ℃, the Adefovir yield is calculated as 10.62% with VITAMIN B4.
Embodiment 10:
Except that (e) hydrolyzing process, all the other are identical with embodiment 8.
With DMF20L dissolving N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 1mol; add 30 liters of 0.1M potassium hydroxide solutions again; refluxed 36 hours at 95-100 ℃; decompression steams solvent; it is neutral adjusting the pH value with the 0.1M hydrochloric acid soln, uses dichloromethane extraction, anhydrous sodium sulfate drying; concentrate, get final product.
The Adefovir yield is calculated as 10.81% with VITAMIN B4.
Embodiment 11:
(f) synthesis technique of 9-hydroxyethyl VITAMIN B4 is:
Get among VITAMIN B4 1mol, 30 liters of DMF of ethylene carbonate ester 1.2mol, salt of wormwood 0.2mol adding, 135-140 ℃ was refluxed 15 hours, be cooled to room temperature, steam solvent, 3.6L volume ratio is 1: 6 dimethyl sulfoxide (DMSO) and dehydrated alcohol recrystallization, get product 1.6kg, productive rate 83%, fusing point 243-244 ℃.
Embodiment 12:
(f) synthesis technique of 9-hydroxyethyl VITAMIN B4 is:
Get among VITAMIN B4 1mol, 40 liters of DMF of ethylene carbonate ester 1.5mol, salt of wormwood 0.5mol adding, 140-145 ℃ was refluxed 25 hours, be cooled to room temperature, steam solvent, 3.6L volume ratio is 1: 10 dimethyl sulfoxide (DMSO) and dehydrated alcohol recrystallization, get product 1.65kg, productive rate 84.1%, fusing point 243-244 ℃.
Embodiment 13:
(g) synthesis technique of methylol diethyl phosphoric acid is:
Under 0-5 ℃ condition, be that 1 liter of 20% formaldehyde solution joins in 1 liter of 1 liter of the diethyl phosphite, triethylamine with weight concentration, to react 1 hour, 120 ℃ cut is collected in underpressure distillation, gets final product.The yield 50% of methylol diethyl phosphoric acid
Embodiment 14:
(g) synthesis technique of methylol diethyl phosphoric acid is:
Under 0-5 ℃ condition, be that 1 liter of 40% formaldehyde solution joins in 4 liters of 2 liters of the diethyl phosphites, triethylamine with weight concentration, to react 3 hours, 120 ℃ cut is collected in underpressure distillation, gets final product.The yield 51% of methylol diethyl phosphoric acid.
Embodiment 15:
(h) synthesis technique of tolysulfonyl oxygen ylmethyl diethyl phosphonate is:
Under 0-5 ℃ condition, the mixing solutions of methylol diethyl phosphoric acid 7.5mol and triethylamine 25mol is added to in 50 liters of methylene dichloride dissolved 5mol Tosyl chlorides (TsCl), reacted 2 hours, suction filtration, wash filtrate merges organic layer, drying, underpressure distillation gets final product, and the yield of tolysulfonyl oxygen ylmethyl diethyl phosphonate is 80%.
Embodiment 16:
(h) synthesis technique of tolysulfonyl oxygen ylmethyl diethyl phosphonate is:
Under 0-5 ℃ condition, the mixing solutions of methylol diethyl phosphoric acid 7.5mol and triethylamine 37.5mol is added to in 60 liters of methylene dichloride dissolved 7.5mol Tosyl chlorides (TsCl), reacted 4 hours, suction filtration, wash filtrate merges organic layer, drying, underpressure distillation gets final product, and the yield of tolysulfonyl oxygen ylmethyl diethyl phosphonate is 81.4%.
Claims (8)
1, a kind of preparation technology of Adefovir comprises: N6-benzoyl-9-three silyloxy ethyl adenine synthesis procedures, N6-benzoyl-9-hydroxyethyl VITAMIN B4 synthesis procedure, N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] VITAMIN B4 synthesis procedure, N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 synthesis procedure, hydrolyzing process:
Described N6-benzoyl-9-three silyloxy ethyl adenine synthesis procedures are:
Under nitrogen protection, the pyridine and the N that 9-hydroxyethyl VITAMIN B4 are added capacity, in the mixed solvent of dinethylformamide (DMF), after stirring, under 0-5 ℃ condition, add trimethylchlorosilane, stirred 1-3 hour, be warming up to 25-35 ℃ again, reaction is not less than 24 hours, 9-hydroxyethyl VITAMIN B4, the trimethylchlorosilane mol ratio is: 1: 0.8-1.2, the volume ratio of pyridine and DMF is 1: 0.5-1.5, add an amount of pyridine again, and add Benzoyl chloride down, stir after 1-3 hour at 0-5 ℃, temperature rises to 80-110 ℃, backflow is not less than 10 hours, is cooled to room temperature, and the mol ratio of 9-hydroxyethyl VITAMIN B4 and Benzoyl chloride is 1: 1.2-2.5; Underpressure distillation, extraction, washing, dry, be 1 with volume ratio: the ethyl acetate of 8-12 and normal hexane recrystallization get final product;
The synthesis procedure of described N6-benzoyl-9-hydroxyethyl VITAMIN B4 is:
N6-benzoyl-9-three silyloxy ethyl adenines and phosphofluoric acid are closed in the Glacial acetic acid and tetrahydrofuran (THF) mixed solvent that tetra-n-butyl amine joins capacity, at 20-30 ℃ of following stirring reaction 15-30 hour, the mol ratio that N6-benzoyl-9-three silyloxy ethyl adenines and phosphofluoric acid close tetra-n-butyl amine is 1: 0.15-0.25, the volume ratio of Glacial acetic acid and tetrahydrofuran (THF) is 1: 100-200, underpressure distillation, extraction, washing, dry, get final product;
Described N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] the VITAMIN B4 synthesis procedure is:
Under nitrogen protection, N6-benzoyl-9-hydroxyethyl VITAMIN B4, Anhydrous potassium carbonate or yellow soda ash, sodium iodide are added in the organic solvent that contains pyridine of capacity, after stirring, add tolysulfonyl oxygen ylmethyl diethyl phosphonate, be warming up to 35-45 ℃ of following reaction and be not less than 24 hours, be cooled to room temperature, underpressure distillation removes and desolvates, extraction, drying, column chromatography gets final product; The mol ratio of N6-benzoyl-9-hydroxyethyl VITAMIN B4, Anhydrous potassium carbonate or yellow soda ash, sodium iodide, tolysulfonyl oxygen ylmethyl diethyl phosphonate is 1: 1-1.5: 0.1-0.5: 1.5-2.5, and the volume ratio of organic solvent and pyridine is 1: 1-3;
Described organic solvent is DMF, dimethyl sulfoxide (DMSO);
Described N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 synthesis procedure is:
Under nitrogen protection, with acetonitrile dissolving N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] after the VITAMIN B4, under 0-5 ℃ condition, add bromotrimethylsilane, react and be warming up to 35-45 ℃ after 1-3 hour, reaction is not less than 24 hours, and decompression steams solvent, dissolving, washing, dry, suction filtration, the PH that adjusts filtrate is 12-14, leaves standstill to cotton-shaped solid to separate out suction filtration fully, washing leaching cake, with the filter cake dissolved in distilled water, the pH value of regulator solution extracts to neutral, drying, concentrated getting final product; N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] mol ratio of VITAMIN B4, bromotrimethylsilane is 1: 3-6;
Described hydrolyzing process is:
DMF dissolving N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 with capacity adds strong base solution again, under 95-105 ℃ of condition, refluxes and is not less than 24 hours, and decompression steams solvent, and it is neutral adjusting the pH value, extraction, dry getting final product.
2, the preparation technology of a kind of Adefovir according to claim 1 is characterized in that: at N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] in the VITAMIN B4 synthesis procedure, described extraction agent is methylene dichloride, ether, ethyl acetate.
3, the preparation technology of a kind of Adefovir according to claim 1; it is characterized in that: at N6-benzoyl-9-[(diethoxy phosphonium mesitoyl methoxyl group) ethyl] in the VITAMIN B4 synthesis procedure; the filler of described column chromatography is a silica gel; applied sample amount and silica gel weight ratio are 1: 100-200; developping agent is ethyl acetate and methyl alcohol, and its volume ratio is 1: 0.015-0.02.
4, the preparation technology of a kind of Adefovir according to claim 1 is characterized in that: in hydrolyzing process, described highly basic is NaOH or KOH, and the mol ratio of highly basic and N6-benzoyl-9-(2-phosphono methoxyethyl) VITAMIN B4 is 1: 1-3.
5, the preparation technology of a kind of Adefovir according to claim 1, it is characterized in that: the synthesis technique of described tolysulfonyl oxygen ylmethyl diethyl phosphonate is: under 0-5 ℃ condition, the mixing solutions of methylol diethyl phosphoric acid and triethylamine is added in the methylene dichloride dissolved Tosyl chloride, reaction is not less than 2 hours, suction filtration, wash filtrate, merge organic layer, dry, underpressure distillation gets final product, and the mol ratio of methylol diethyl phosphoric acid, triethylamine, Tosyl chloride is 1: 3-5: 0.5-1.
6, the preparation technology of a kind of Adefovir according to claim 5, it is characterized in that: the synthesis technique of described methylol diethyl phosphoric acid is: under 0-5 ℃ condition, with weight concentration is that the formaldehyde solution of 20-40% joins in diethyl phosphite, the triethylamine, reaction is not less than 1 hour, underpressure distillation, collect 120 ℃ cut, get final product; The volume ratio of formaldehyde solution, diethyl phosphite, triethylamine is 1: 1-2: 1-4.
7, the preparation technology of a kind of Adefovir according to claim 1 is characterized in that: the synthesis technique of described 9-hydroxyethyl VITAMIN B4 is:
After the DMF dissolving of VITAMIN B4, ethylene carbonate ester, salt of wormwood with capacity, 135 ℃-145 ℃ backflow 15-25 hour, be cooled to room temperature, underpressure distillation, recrystallization gets final product; The mol ratio of VITAMIN B4, ethylene carbonate ester, salt of wormwood is 1: 1-1.5: 0.1-0.5.
8, the preparation technology of a kind of Adefovir according to claim 7 is characterized in that: the solvent of used recrystallization is that volume ratio is 1 in the synthesis technique of described 9-hydroxyethyl VITAMIN B4: the dimethyl sulfoxide (DMSO) of 6-10 and dehydrated alcohol.
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| CN102153588B (en) * | 2011-03-01 | 2013-03-06 | 吉林大学 | Adefovir pharmaceutical co-crystal and preparation method thereof |
| CN103848866A (en) * | 2012-12-04 | 2014-06-11 | 上海医药工业研究院 | Method for preparing sulfonyl oxymethyl diethyl phosphate compounds |
| CN105541910A (en) * | 2015-12-21 | 2016-05-04 | 山东金城医药化工股份有限公司 | Diethyl p-toluenesulfonyloxy methylphosphonate synthesis method |
| CN109021011A (en) * | 2018-08-14 | 2018-12-18 | 山东沾化永浩医药科技有限公司 | A method of synthesis tolysulfonyl oxygen methylphosphonic acid diethylester |
| CN109053799B (en) * | 2018-08-31 | 2021-01-08 | 乐平市赛复乐医药化工有限公司 | Synthesis method of diethyl p-toluenesulfonyloxymethylphosphonate |
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| Synthesis of 9-(2-phosphonylmethoxyethyl)adenine andrelated compounds. Holy, A., Rosenberg, I.Collect. Czech. Chem. Commun.,Vol.Vol. 52 . 1987 |
| Synthesis of 9-(2-phosphonylmethoxyethyl)adenine andrelated compounds. Holy, A., Rosenberg, I.Collect. Czech. Chem. Commun.,Vol.Vol. 52 . 1987 * |
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