CN106699814A - Preparation method of adefovir dipivoxil crystals - Google Patents
Preparation method of adefovir dipivoxil crystals Download PDFInfo
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- CN106699814A CN106699814A CN201710064530.6A CN201710064530A CN106699814A CN 106699814 A CN106699814 A CN 106699814A CN 201710064530 A CN201710064530 A CN 201710064530A CN 106699814 A CN106699814 A CN 106699814A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 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 23
- 229960003205 adefovir dipivoxil Drugs 0.000 title claims abstract description 20
- 239000013078 crystal Substances 0.000 title claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims abstract description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 63
- 238000006243 chemical reaction Methods 0.000 claims description 50
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- 238000001914 filtration Methods 0.000 claims description 31
- 238000003756 stirring Methods 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
- 229930024421 Adenine Natural products 0.000 claims description 19
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 19
- 229960000643 adenine Drugs 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 16
- -1 diethyl phosphono methoxyl Chemical group 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 239000012467 final product Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- 230000006837 decompression Effects 0.000 claims description 7
- 239000007789 gas Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- RWIGWWBLTJLKMK-UHFFFAOYSA-N diethoxyphosphorylmethanol Chemical compound CCOP(=O)(CO)OCC RWIGWWBLTJLKMK-UHFFFAOYSA-N 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000004519 grease Substances 0.000 claims description 5
- 229920002866 paraformaldehyde Polymers 0.000 claims description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 230000004224 protection Effects 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- GIACZVMHUIVRAY-UHFFFAOYSA-N C(C)OP(OCC)(=O)C.S(=O)(=O)=O.C1=CC=CC=C1 Chemical compound C(C)OP(OCC)(=O)C.S(=O)(=O)=O.C1=CC=CC=C1 GIACZVMHUIVRAY-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 1
- UFLFSNVZQRNKOX-UHFFFAOYSA-N carbonic acid;ethenyl acetate Chemical compound OC(O)=O.CC(=O)OC=C UFLFSNVZQRNKOX-UHFFFAOYSA-N 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 229920006324 polyoxymethylene Polymers 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
- 229960002668 sodium chloride Drugs 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 229960001997 adefovir Drugs 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 abstract description 2
- 229940011051 isopropyl acetate Drugs 0.000 abstract description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 6
- VAQOTZQDXZDBJK-UHFFFAOYSA-N 2-(6-aminopurin-9-yl)ethanol Chemical compound NC1=NC=NC2=C1N=CN2CCO VAQOTZQDXZDBJK-UHFFFAOYSA-N 0.000 abstract 1
- SACBMARVYGBCAK-UHFFFAOYSA-N 9-[2-(diethoxyphosphorylmethoxy)ethyl]purin-6-amine Chemical compound N1=CN=C2N(CCOCP(=O)(OCC)OCC)C=NC2=C1N SACBMARVYGBCAK-UHFFFAOYSA-N 0.000 abstract 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- YACKEPLHDIMKIO-UHFFFAOYSA-L methylphosphonate(2-) Chemical compound CP([O-])([O-])=O YACKEPLHDIMKIO-UHFFFAOYSA-L 0.000 abstract 1
- 239000000047 product Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 235000015170 shellfish Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- DSQSVZNUCMMULT-UHFFFAOYSA-N C1(CCCCC1)C1(N(CCOC1)C(=N)N)C1CCCCC1.C(C(C)(C)C)(=O)OCCl Chemical compound C1(CCCCC1)C1(N(CCOC1)C(=N)N)C1CCCCC1.C(C(C)(C)C)(=O)OCCl DSQSVZNUCMMULT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 241000175212 Herpesvirales Species 0.000 description 1
- 238000005654 Michaelis-Arbuzov synthesis reaction Methods 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FIMJSWFMQJGVAM-UHFFFAOYSA-N chloroform;hydrate Chemical compound O.ClC(Cl)Cl FIMJSWFMQJGVAM-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical class CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 229940097709 hepsera Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical class [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- FZGRPBJBMUNMQH-UHFFFAOYSA-N trimethyl-$l^{3}-chlorane Chemical compound CCl(C)C FZGRPBJBMUNMQH-UHFFFAOYSA-N 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
The invention belongs to the technical field of drug preparation and in particular relates to a preparation method of adefovir dipivoxil crystals. The preparation method comprises the following steps: synthesizing diethyl phosphite; synthesizing diethyl (p-phenylsulfonyloxy)methylphosphonate; synthesizing 9-(2-hydroxyethyl) adenine; synthesizing 4,9-[2-(diethylphosphonomethoxy)ethyl]adenine; synthesizing adefovir; synthesizing adefovir dipivoxil. Compared with the prior art, the preparation method of the adefovir dipivoxil crystals, provided by the invention, takes acetonitrile as a water-soluble organic medium, and the difficulty that DMF (Dimethyl Formamide) is difficult to remove is overcome; ethyl acetate is used for replacing isopropyl acetate in a previous process, isopropyl ether is used for replacing ethyl ether and ethanol is used for replacing acetone; the preparation method is simple to operate; the obtained product has good purity and high yield; the industrialized production is easy to realize and the production cost is reduced.
Description
Technical field
The invention belongs to field of medicine preparing technology, it particularly relates to arrive a kind of preparation of adefovir dipivoxil crystal thing
Method.
Background technology
Aldoforwe ester (Adefovir aipivoxil), chemical entitled 9- [double [(isoamyl acyloxy) methoxyl group] phosphine oxides
Base]-methoxy ethyl acyl adenine is the ucleosides viral inhibitors of Gilead Sciences companies of U.S. research and development, 2002
Listed in the U.S. first, trade name Hepsera.This product is the esters precursor medicine of adefovirdipivoxil, with spectrum antiviral activity, energy
Effectively suppress Hepadna Virus, retrovirus and herpesviral.The listing of Aldoforwe ester changes chronic hepatitis B patient and lacks
The present situation of active drug treatment, with good Social benefit and economic benefit.
At this stage, the preparation technology on Aldoforwe ester, predominantly two kinds：1) Holy improved methods：By the chloro- 2- chloromethanes of 1-
Epoxide ethane is with triethyl phosphite through Arbuzov reaction generation side chain 2- chloroethene oxygen methyl acid phosphate diethylesters, this side chain and gland
It is solvent condensation generation 9- [2- (diethyl phosphono methoxyl group) with DMF (DMF) under purine morning NaH effects
Ethyl] adenine, hydrolysis obtains crude product after the latter reacts with bromotrimethylsilane, and crude product is obtained after being separated through ion exchange column chromatography
Sterling, it is also possible to crude product is recrystallized in acetonitrile or acetone, with chloromethyl pivalate dicyclohexyl-morpholine amidine for catalysis
Agent, DMF be solvent under carry out being condensed to yield target product.This route is cumbersome, whard to control, and total recovery is too low.2)Kelly
Deng the synthetic route of proposition：Adenine and ethylene carbonate ester condensation generate 9- (2- ethoxys) adenine, with diethyl phosphite,
Paraformaldehyde first synthesizes methine diethyl phosphite for raw material, then generates p-methyl benzenesulfonic acid diethyl with to the effect of toluene semi-annular jade pendant acyl chlorides
Epoxide phosphono methyl esters, generates 9- [2- (diethyl phosphono methoxyl group) ethyl] adenine in the presence of sodium tert-butoxide；Again with
Chloromethyl pivalate is condensed to yield Aldoforwe ester in 1-METHYLPYRROLIDONE solvent under the conditions of triethylamine.Although this route
Reaction condition is gentle, but post processing trouble, product purity be not high.
The content of the invention
The invention provides a kind of preparation method of adefovir dipivoxil crystal thing, the preparation method is simple to operate, and gained is produced
Product purity is good, yield is high.
The step of a kind of preparation method of adefovir dipivoxil crystal thing of the present invention, preparation method, is specific such as
Under：
1) preparation of diethyl phosphite：In reaction bulb, absolute ethyl alcohol 122g, chloroform 133mL, ice salt bath condition are added
Lower stirring, starts that phosphorus trichloride 91.6g is added dropwise at 5 DEG C, its reaction temperature is controlled between 5~10 DEG C, 40min completion of dropping
Continue to stir 30min afterwards, reaction notes the absorption of hydrogen chloride gas, removes ice salt bath, continue to stir 2h at room temperature, after 50 DEG C
Lower decompression pumps hydrogen chloride gas；Cool at room temperature, be slowly added dropwise the sodium bicarbonate aqueous solution of saturation, be subsequently adding bicarbonate
Sodium solid regulation reaction solution pH value is 7~8；The salt that filtering removal is separated out, point liquid, water is extracted 1 time with chloroform, is then combined with chlorine
Imitative phase, chloroform phase is respectively washed 1 time with the sodium bicarbonate aqueous solution and water of saturation, and chloroform is reclaimed in vacuum distillation, is obtained final product；
2) to the preparation of benzene sulfonyl oxygen methylphosphonic acid diethylester：In reaction bulb, diethyl phosphite 76.6kg is added, taken
Paraformaldehyde 20g and K2CO3244g, first adds 15% amount, adds 277mL toluene, when being warming up to 60 DEG C or so, waits number
After minute, it was observed that after obvious exothermic phenomenon, starting to continue to be dividedly in some parts remaining paraformaldehyde, about 15min is added；Then
Continue to be incubated 2h at 60 DEG C, remaining K is constantly added in insulating process2CO3, after terminating PH=7.5~8, reaction, filtering subtracts
Receipts toluene is pushed back, hydroxymethyl phosphonic acid diethylester crude product 92.1g is obtained；In 1L reaction bulbs, hydroxymethyl phosphonic acid diethylester is added
78.8g, toluene 278mL and triethylamine 90g, are no more than at 30 DEG C in temperature, and the 166mL toluene of paratoluensulfonyl chloride 90g is added dropwise
Solution, after 1h is dripped off, is warming up to after the completion of 60 DEG C of insulation 5h, HPLC display reactions, washes toluene organic layer, 277mL × 2 with water
It is secondary, toluene is recovered under reduced pressure, light yellow liquid is obtained, cooling is obtained final product；
3) preparation of 9- (2- ethoxys) adenine：In reaction bulb, adenine 37g is suspended in acetonitrile 93mL, is added
Ethylene carbonate 29.4g, triethylamine 14.8g are in N214h is reacted in 125 DEG C under protection, it is slightly cold, acetonitrile is recovered under reduced pressure and obtains solid
Particle, it is slightly cold, plus absolute ethyl alcohol 74mL, the 1.5h that flows back and be incubated is heated to, ice bath is filtered after 2h is stirred at being cooled to 0 DEG C, obtained
Filter cake is dried, and is obtained final product；
4) preparation of 9- [2- (diethyl phosphono methoxyl group) ethyl] adenine：In reaction bulb, DMF is separately added into
182mL, 9- (2- ethoxys) adenine 45.6g, tert-butyl alcohol magnesium 21.4g, is slowly heated to 80 DEG C, tolysulfonyl oxygen methoxyl group
Diethyl phosphonate 120.8g is slowly added in reaction solution, and completion of dropping continues to react 12h, and glacial acetic acid is neutralized to neutrality, depressurizes
DMF is reclaimed to dry, water 114mL, dichloromethane continuous extraction 8h is added, organic phase solvent is recovered under reduced pressure, residue adds toluene
Freeze overnight, filtering, filtration cakes torrefaction is obtained final product；
5) preparation of adefovirdipivoxil：In reaction bulb, 9- [2- (diethyl phosphono methoxyl group) ethyl] gland is put into respectively fast
Purine 57.6g, trim,ethylchlorosilane 94g, are added dropwise chlorobenzene 184mL, are heated to 120 DEG C and react 10h, slightly cold, remove solvent under reduced pressure, remain
Excess adds 92mL water, is warming up to 70 DEG C of reaction 2h, is cooled to room temperature, and the NaOH aqueous solution to pH about 3.2 is added dropwise, and filtering, filter cake is used
A small amount of water washing, drying；
6) preparation of Aldoforwe ester：In reaction bulb, adefovirdipivoxil 40.2g, 1-METHYLPYRROLIDONE 80g are put into respectively
With triethylamine 35mL, chloromethyl pivalate 110.2g, stirring reaction 12h at 30~40 DEG C is added dropwise, then heats up 50~60 DEG C and stir
Mix 4h；Room temperature is cooled to, ethyl acetate 608mL is added, 1~2h is stirred at room temperature；Filtering, filter cake is washed with ethyl acetate, filtrate
Washed with saturated sodium-chloride water solution, the organic layer anhydrous sodium sulfate drying for obtaining, stand a night；Filtering, filtrate decompression is dense
Contracting obtains grease, adds ethanol 173mL, stirs 10min, after stirring, adds isopropyl ether, crystallization, now solution
Become cloudy, continue to stir 7~8h；Filtering, absolute ethanol washing is obtained final product.
Compared with prior art, the preparation method of adefovir dipivoxil crystal thing of the present invention utilizes water miscible organic Jie
Matter is acetonitrile, solves the difficulty that DMF is difficult to remove；The isopropyl acetate in former technique is substituted with ethyl acetate, isopropyl ether is replaced
For ether, ethanol substitutes the method for acetone, and simple to operate, products obtained therefrom purity is good, yield is high, it is easy to industrialized production, saves
Production cost.
Specific embodiment
The preparation method of adefovir dipivoxil crystal thing of the present invention is described further with reference to specific embodiment,
But protection scope of the present invention is not limited to this.
Embodiment 1
1) synthesis of diethyl phosphite：
In 500mL reaction bulbs, absolute ethyl alcohol 122g (2.650mol), chloroform 133mL are added, stirred under the conditions of ice salt bath
Mix, start that phosphorus trichloride 91.6g (0.667mol) is added dropwise at 5 DEG C, its reaction temperature is controlled between 5~10 DEG C, 40min drops
To add continue after finishing and stir 30min, reaction notes the absorption of hydrogen chloride gas, removes ice salt bath, continue to stir 2h at room temperature, after
Hydrogen chloride gas are pumped in decompression at 50 DEG C；Cool at room temperature, be slowly added dropwise the sodium bicarbonate aqueous solution of saturation, be subsequently adding
Sodium bicarbonate solid regulation reaction solution pH value is 7~8；The salt that filtering removal is separated out, point liquid, water chloroform extraction 1 time, then
Merge chloroform phase, chloroform phase is respectively washed 1 time with the sodium bicarbonate aqueous solution and water of saturation, chloroform is reclaimed in vacuum distillation, obtains target
Product diethyl phosphite 77.7g, yield is 84.5%.
2) synthetic method of benzene sulfonyl oxygen methylphosphonic acid diethylester：
In 500mL reaction bulbs, diethyl phosphite 76.6kg (0.554mol), paraformaldehyde 20g are added
(0.667mol first adds 15% amount), K2CO3 244g (1.765mol first adds 15% amount) and 277mL toluene, heat up
During to 60 DEG C or so, after waiting several minutes, it was observed that after obvious exothermic phenomenon, starting to continue to be dividedly in some parts remaining poly first
Aldehyde, about 15min are added.Then continue at 60 DEG C to be incubated 2h.Remaining K2CO3 is constantly added in insulating process, make PH=7.5~
8.After reaction terminates, filtering is recovered under reduced pressure toluene, hydroxymethyl phosphonic acid diethylester crude product 92.1g is obtained, through gas chromatographic detection content
More than 96%, yield is up to 95%.It is directly used in next step reaction.
In 1L reaction bulbs, hydroxymethyl phosphonic acid diethylester 78.8g (0.472mol), toluene 278mL and triethylamine 90g are added
(0.889mol).It is no more than at 30 DEG C in temperature, the 166mL toluene solutions of paratoluensulfonyl chloride 90g (0.472mol), 1h is added dropwise
After dripping off, 60 DEG C of insulation 5h are warming up to.HPLC display reactions complete (paratoluensulfonyl chloride residual quantity<0.5%) after, wash with water
(277mL × 2 time) toluene organic layer, is recovered under reduced pressure most of solvent toluene, obtains light yellow liquid, cool down solid to toluene sulphur
Acyl-oxygen methoxyl group diethyl phosphonate 130.5g, yield 87%.
3) synthetic method of 9- (2- ethoxys) adenine：
In 500mL reaction bulbs, adenine 37g (0.273mol) is suspended in acetonitrile 93mL, adds ethylene carbonate
29.4g (0.334mol), triethylamine 14.8g (0.146mol) react 14h under N2 protections in 125 DEG C, slightly cold, and second is recovered under reduced pressure
Nitrile obtains solid particle, slightly cold, plus absolute ethyl alcohol 74mL, the 1.5h that flows back and be incubated is heated to, after ice bath stirs 2h at being cooled to 0 DEG C
Filtering, obtains filter cake and dries to obtain 47.3g white powdery solids i.e. target product, yield 95%.
4) synthesis of 9- [2- (diethyl phosphono methoxyl group) ethyl] adenine：
In 1L reaction bulbs, DMF 182mL, 9- (2- ethoxys) adenine 45.6g (0.254mol), tertiary fourth are separately added into
Magnesium alkoxide 21.4g (0.125mol), is slowly heated to 80 DEG C, tolysulfonyl oxygen methoxyl group diethyl phosphonate 120.8g
(0.375mol) is slowly added in reaction solution, and completion of dropping continues to react 12h, and glacial acetic acid is neutralized to neutrality, DMF is recovered under reduced pressure
To dry, water 114mL, dichloromethane continuous extraction 8h are added, organic phase solvent is recovered under reduced pressure, residue adds toluene to freeze
Night.Filtering, filtration cakes torrefaction obtains 58g white powder solids i.e. target product, yield 70%.
5) synthesis of adefovirdipivoxil：
In 1L reaction bulbs, 9- [2- (diethyl phosphono methoxyl group) ethyl] adenine 57.6g, trimethyl chlorine is put into respectively
Silane 94g, dropwise addition chlorobenzene 184mL. are heated to 120 DEG C and react 10h, slightly cold, remove solvent under reduced pressure, and residue adds 92mL water,
70 DEG C of reaction 2h are warming up to, are cooled to room temperature.The NaOH aqueous solution to pH about 3.2 is added dropwise, filtering, filter cake is washed with a small amount, and dries
Obtain 41g white solids, as object, yield 85%.
6) synthesis of Aldoforwe ester：
In 2L reaction bulbs, adefovirdipivoxil 40.2g (0.147mol), 1-METHYLPYRROLIDONE 80g are put into respectively
(0.807mol) and triethylamine 35mL, is added dropwise chloromethyl pivalate 110.2g (0.731mol), stirring reaction at 30~40 DEG C
12h, then heat up 50~60 DEG C of stirring 4h；Room temperature is cooled to, ethyl acetate 608mL is added, 1~2h is stirred at room temperature；Filtering, filter
Cake is washed with ethyl acetate, and filtrate is washed with saturated sodium-chloride water solution, the organic layer anhydrous sodium sulfate drying for obtaining, and is stood
One night；Filtering, filtrate decompression is concentrated to give grease, adds ethanol 173mL, stirs 10min, after stirring, adds
Isopropyl ether, crystallization, now solution turned cloudy, continues to stir 7~8h；Filtering, absolute ethanol washing obtains white solid powder,
As target compound Aldoforwe ester, yield 32.6%.
Embodiment 2
6) synthesis of Aldoforwe ester：
In 2L reaction bulbs, adefovirdipivoxil 40.2g (0.147mol), 1-METHYLPYRROLIDONE 80g are put into respectively
(0.807mol), her shellfish new 0.2g and triethylamine 35mL, are added dropwise chloromethyl pivalate 110.2g (0.731mol), at 30~40 DEG C
Stirring reaction 12h, then heat up 50~60 DEG C of stirring 4h；It is cooled to room temperature, adds ethyl acetate 608mL, it is stirred at room temperature 1~
2h；Filtering, filter cake is washed with ethyl acetate, and filtrate is washed with saturated sodium-chloride water solution, the organic layer anhydrous slufuric acid for obtaining
Sodium is dried, and stands a night；Filtering, filtrate decompression is concentrated to give grease, adds ethanol 173mL, stirs 10min, is sufficiently stirred for
After uniform, addition isopropyl ether, crystallization, now solution turned cloudy, continues to stir 7~8h；Filtering, absolute ethanol washing obtains white
Color solid powder, as target compound Aldoforwe ester, yield 51.6%.
Embodiment 3
6) synthesis of Aldoforwe ester：
In 2L reaction bulbs, adefovirdipivoxil 40.2g (0.147mol), 1-METHYLPYRROLIDONE 80g are put into respectively
(0.807mol), her shellfish piperazine 0.2g and triethylamine 35mL, is added dropwise chloromethyl pivalate 110.2g (0.731mol), at 30~40 DEG C
Stirring reaction 12h, then heat up 50~60 DEG C of stirring 4h；It is cooled to room temperature, adds ethyl acetate 608mL, it is stirred at room temperature 1~
2h；Filtering, filter cake is washed with ethyl acetate, and filtrate is washed with saturated sodium-chloride water solution, the organic layer anhydrous slufuric acid for obtaining
Sodium is dried, and stands a night；Filtering, filtrate decompression is concentrated to give grease, adds ethanol 173mL, stirs 10min, is sufficiently stirred for
After uniform, addition isopropyl ether, crystallization, now solution turned cloudy, continues to stir 7~8h；Filtering, absolute ethanol washing obtains white
Color solid powder, as target compound Aldoforwe ester, yield 33.1%.
Claims (1)
1. a kind of preparation method of adefovir dipivoxil crystal thing, it is characterised in that specific as follows the step of the preparation method：
1) preparation of diethyl phosphite：In reaction bulb, absolute ethyl alcohol 122g, chloroform 133mL are added, stirred under the conditions of ice salt bath
Mix, start that phosphorus trichloride 91.6g is added dropwise at 5 DEG C, its reaction temperature is controlled between 5~10 DEG C, 40min completion of dropping is follow-up
Continuous stirring 30min, reaction notes the absorption of hydrogen chloride gas, removes ice salt bath, continue to stir 2h at room temperature, subtracts after at 50 DEG C
Pressure pumps hydrogen chloride gas；Cool at room temperature, be slowly added dropwise the sodium bicarbonate aqueous solution of saturation, be subsequently adding sodium acid carbonate and consolidate
Body regulation reacting liquid pH value is 7~8；The salt that filtering removal is separated out, point liquid, water is extracted 1 time with chloroform, is then combined with chloroform
Phase, chloroform phase is respectively washed 1 time with the sodium bicarbonate aqueous solution and water of saturation, and chloroform is reclaimed in vacuum distillation, is obtained final product；
2) to the preparation of benzene sulfonyl oxygen methylphosphonic acid diethylester：In reaction bulb, diethyl phosphite 76.6kg is added, take poly
Formaldehyde 20g and K2CO3244g, first adds 15% amount, adds 277mL toluene, when being warming up to 60 DEG C or so, waits several minutes
Afterwards, it was observed that after obvious exothermic phenomenon, starting to continue to be dividedly in some parts remaining paraformaldehyde, about 15min is added；Then 60 DEG C
It is lower to continue to be incubated 2h, remaining K is constantly added in insulating process2CO3, after terminating PH=7.5~8, reaction, filtering is depressurized back
Toluene is received, hydroxymethyl phosphonic acid diethylester crude product 92.1g is obtained；In 1L reaction bulbs, hydroxymethyl phosphonic acid diethylester 78.8g, first are added
Benzene 278mL and triethylamine 90g, is no more than at 30 DEG C in temperature, and the 166mL toluene solutions of paratoluensulfonyl chloride 90g, 1h drops is added dropwise
After complete, it is warming up to after the completion of 60 DEG C of insulation 5h, HPLC display reactions, washes toluene organic layer with water, 277mL × 2 time is depressurized back
Toluene is received, light yellow liquid is obtained, cooling is obtained final product；
3) preparation of 9- (2- ethoxys) adenine：In reaction bulb, adenine 37g is suspended in acetonitrile 93mL, adds carbonic acid
Vinyl acetate 29.4g, triethylamine 14.8g are in N214h is reacted in 125 DEG C under protection, it is slightly cold, acetonitrile is recovered under reduced pressure and obtains solid
Grain, it is slightly cold, plus absolute ethyl alcohol 74mL, the 1.5h that flows back and be incubated is heated to, ice bath is filtered after 2h is stirred at being cooled to 0 DEG C, filtered
Cake is dried, and is obtained final product；
4) preparation of 9- [2- (diethyl phosphono methoxyl group) ethyl] adenine：In reaction bulb, DMF 182mL are separately added into,
9- (2- ethoxys) adenine 45.6g, tert-butyl alcohol magnesium 21.4g, is slowly heated to 80 DEG C, tolysulfonyl oxygen methoxyl group phosphonic acids two
Ethyl ester 120.8g is slowly added in reaction solution, and completion of dropping continues to react 12h, and glacial acetic acid is neutralized to neutrality, DMF is recovered under reduced pressure
To dry, water 114mL, dichloromethane continuous extraction 8h are added, organic phase solvent is recovered under reduced pressure, residue adds toluene to freeze
Night, filtering, filtration cakes torrefaction is obtained final product；
5) preparation of adefovirdipivoxil：In reaction bulb, 9- [2- (diethyl phosphono methoxyl group) ethyl] adenine is put into respectively
57.6g, trim,ethylchlorosilane 94g, are added dropwise chlorobenzene 184mL, are heated to 120 DEG C and react 10h, slightly cold, remove solvent under reduced pressure, remaining
Thing adds 92mL water, is warming up to 70 DEG C of reaction 2h, is cooled to room temperature, and the NaOH aqueous solution to pH about 3.2 is added dropwise, and filtering, filter cake is used few
Amount water washing, drying；
6) preparation of Aldoforwe ester：In reaction bulb, adefovirdipivoxil 40.2g, 1-METHYLPYRROLIDONE 80g and three are put into respectively
Ethamine 35mL, is added dropwise chloromethyl pivalate 110.2g, stirring reaction 12h at 30~40 DEG C, and then heat up 50~60 DEG C of stirring 4h；
Room temperature is cooled to, ethyl acetate 608mL is added, 1~2h is stirred at room temperature；Filtering, filter cake is washed with ethyl acetate, filtrate saturation
Sodium-chloride water solution is washed, the organic layer anhydrous sodium sulfate drying for obtaining, and stands a night；Filtering, filtrate decompression is concentrated to give
Grease, adds ethanol 173mL, stirs 10min, after stirring, adds isopropyl ether, crystallization, now solution turned cloudy,
Continue to stir 7~8h；Filtering, absolute ethanol washing is obtained final product.
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| 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 |
| CN109053799A (en) * | 2018-08-31 | 2018-12-21 | 乐平市赛复乐医药化工有限公司 | A kind of synthetic method of tolysulfonyl oxygen methylphosphonic acid diethylester |
| CN109096328A (en) * | 2018-07-17 | 2018-12-28 | 常州大学 | A kind of method of the continuous synthesizing phosphorous acid diethylester of micro passage reaction |
| CN110172074A (en) * | 2019-01-16 | 2019-08-27 | 湖北益泰药业股份有限公司 | A kind of synthetic method of Aldoforwe ester |
| CN113121596A (en) * | 2021-04-22 | 2021-07-16 | 济南立德医药技术有限公司 | Preparation method of diethyl p-toluenesulfonyloxymethylphosphonate |
| CN114106038A (en) * | 2021-12-09 | 2022-03-01 | 浙江万盛股份有限公司 | Preparation method of hydroxyl phosphonate |
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| 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 |
| CN110172074A (en) * | 2019-01-16 | 2019-08-27 | 湖北益泰药业股份有限公司 | A kind of synthetic method of Aldoforwe ester |
| CN113121596A (en) * | 2021-04-22 | 2021-07-16 | 济南立德医药技术有限公司 | Preparation method of diethyl p-toluenesulfonyloxymethylphosphonate |
| CN114106038A (en) * | 2021-12-09 | 2022-03-01 | 浙江万盛股份有限公司 | Preparation method of hydroxyl phosphonate |
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