CN110143983A - A kind of preparation method of high stability Aldoforwe ester - Google Patents
A kind of preparation method of high stability Aldoforwe ester Download PDFInfo
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- CN110143983A CN110143983A CN201910558431.2A CN201910558431A CN110143983A CN 110143983 A CN110143983 A CN 110143983A CN 201910558431 A CN201910558431 A CN 201910558431A CN 110143983 A CN110143983 A CN 110143983A
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- 150000002148 esters Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 17
- 229940125782 compound 2 Drugs 0.000 claims abstract description 10
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims abstract description 7
- -1 pivaloyloxymethyl Chemical group 0.000 claims abstract description 6
- 229940126214 compound 3 Drugs 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 229940125904 compound 1 Drugs 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940125898 compound 5 Drugs 0.000 claims abstract description 3
- 150000003009 phosphonic acids Chemical class 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 53
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 36
- 238000002425 crystallisation Methods 0.000 claims description 24
- 230000008025 crystallization Effects 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 239000013078 crystal Substances 0.000 claims description 17
- 239000002585 base Substances 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 12
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 7
- 229910000077 silane Inorganic materials 0.000 claims description 7
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 239000012454 non-polar solvent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 2
- 150000004040 pyrrolidinones Chemical class 0.000 claims 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000006641 stabilisation Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 60
- 239000012065 filter cake Substances 0.000 description 37
- 238000010792 warming Methods 0.000 description 33
- 239000008213 purified water Substances 0.000 description 31
- 239000007788 liquid Substances 0.000 description 27
- 238000000926 separation method Methods 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 16
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 15
- 238000005119 centrifugation Methods 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 238000003825 pressing Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 229960003205 adefovir dipivoxil Drugs 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000010583 slow cooling Methods 0.000 description 8
- 229960001997 adefovir Drugs 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical group C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000009413 insulation Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000007306 turnover Effects 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 208000002672 hepatitis B Diseases 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000004031 devitrification Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000003746 feather Anatomy 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- MERJTCXDDLWWSK-UHFFFAOYSA-N 1-methylpyrrole pyrrolidin-2-one Chemical compound CN1C=CC=C1.N1C(CCC1)=O MERJTCXDDLWWSK-UHFFFAOYSA-N 0.000 description 1
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- OATWCNSODQAOQC-UHFFFAOYSA-N [SiH4].Br Chemical compound [SiH4].Br OATWCNSODQAOQC-UHFFFAOYSA-N 0.000 description 1
- JCHGDLSNQMRKGZ-UHFFFAOYSA-N [SiH4].[I] Chemical compound [SiH4].[I] JCHGDLSNQMRKGZ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical synthesis field, a kind of preparation method of high stability Aldoforwe ester, it is characterised in that the following steps are included: 1) compound 1 replaces through bromotrimethylsilane, then obtain compound 2 through NaOH aqueous hydrolysis；2) compound 2 and compound 3 are catalyzed to obtain compound 4 through triethylamine in N-Methyl pyrrolidone；3) compound 4 obtains compound 5, i.e. [[2- (6- amino -9H- purine -9- base) ethyoxyl] methyl] phosphonic acids two (pivaloyloxymethyl) ester by purification.A kind of preparation method of high stability Aldoforwe ester of the present invention, this method have the advantages that raw material drug stabilisation is good, simple production process, are suitble to large-scale commercial production.
Description
Technical field
The present invention relates to one kind to have hepatitis type B virus active replication evidence for treating, and with serum amino transferase
The adult chronic hepatitis B patient that (ALT or AST) is persistently increased or the liver function of liver histological activity lesion is compensatory
Preparation method, and in particular to the preparation method of Aldoforwe ester belongs to pharmaceutical synthesis field.
Background technique
Aldoforwe ester is the precursor of adefovirdipivoxil, plays antivirus action after being hydrolyzed to adefovirdipivoxil in vivo.A De
Good fortune Wei ester is a kind of thermal instability drug, susceptible to hydrolysis.It is used for long-term treatment, the nucleotide analog of chronic hepatitis B
Antiviral drugs.In addition, Aldoforwe ester has, drug resistance incidence is low, drug resistant evening time, long-term administration safety occurs
Well, the features such as clinical efficiency is high.Therefore, Aldoforwe ester still has preferable market prospects.Original grinds patent CN1216062 guarantor
Anhydrous crystal forms (form 1), dihydrate crystal form (form 2), methanol solvate crystal form (form 3), fumarate crystal form (shape are protected
State 4), wherein anhydrous crystal forms are medicinal crystal-form, and DSC nearby has an endothermic peak at 102 DEG C, powder diffraction 2 angles θ 6.9,11.8,
15.7,17.2,20.7 nearby there are XRD spectrum peaks.
Original grinds the preparation route that patent CN1216062 describes Aldoforwe ester.The route utilizes the ([[2- (6- of compound 1
Amino -9H- purine -9- base) ethyoxyl] methyl] diethyl phosphonate) replace through bromotrimethylsilane, then hydrolyze to obtain through NaOH
Compound 2 (adefovirdipivoxil), compound 2 and compound 3 (chloromethyl pivalate) are in N-Methyl pyrrolidone, triethylamine catalysis
Under obtain compound 4 (Aldoforwe ester):
The synthetic route step is short, and raw material and reagent, solvent are easily obtained, easy to operate, no special installation demand, in a word
The technique is more mature.But patent CN1216062 technological parameter is ground according to original, obtained bulk pharmaceutical chemicals (anhydrous crystal forms) heat is unstable
It is fixed, it is susceptible to hydrolysis；Stability is poor, and the shelf-life is shorter；Partial size is smaller, and mobility is poor, is unfavorable for subsequent preparation and uses.
Summary of the invention
The present invention is directed to described problem, and inventor enhances raw material drug stabilisation, extends the bulk pharmaceutical chemicals shelf-life, explores one
The preparation method of kind high stability Aldoforwe ester, this method is easy to operate, bulk pharmaceutical chemicals high income, and bulk pharmaceutical chemicals quality and technique are steady
It is fixed, it is suitble to commercially produce.
The technical solution adopted by the invention is as follows:
A kind of preparation method of high stability Aldoforwe ester, characterized by comprising:
(1) compound 1 replaces in reaction reagent a through silane reagent, then obtains compound 2 through NaOH aqueous hydrolysis；
(2) compound 2 and compound 3 are catalyzed to obtain compound 4 through organic weak base in reaction dissolvent b；
(3) compound 4 passes through crystal refining, obtains compound 5, i.e. [[2- (6- amino -9H- purine -9- base) ethyoxyl] first
Base] phosphonic acids two (pivaloyloxymethyl) ester.
Reaction temperature described in the step (1) is 50~80 DEG C；The reaction dissolvent a be polar non-solute or
Nonpolar solvent；1 dosage of compound is 1 molar equivalent；The silane reagent dosage is 2~5 molar equivalents.
Reaction dissolvent a described in the step (1) is DMF, acetonitrile or tetrahydrofuran；The silane reagent is trimethyl
Chlorosilane, bromotrimethylsilane or Iodotrimethylsilane.
Reaction temperature described in the step (2) is 40~70 DEG C；The reaction dissolvent b be polar non-solute or
Nonpolar solvent；The reaction is organic weak base with alkali；The base amount is 2~6 molar equivalents；The compound 3
Dosage is 4~8 molar equivalents.
Reaction dissolvent b described in the step (2) is DMF, N-Methyl pyrrolidone；The organic weak base is triethylamine
Or pyridine.
Reaction temperature described in the step (3) is 40~60 DEG C；The crystallization solvent be ethyl acetate, isopropyl ether,
Acetone, methyl tertiary butyl ether(MTBE), acetone and isopropyl ether is a kind of or any two or more combinations.
The proportion of crystallization solvent described in the step (3) is compound 4: ethyl acetate or acetone: isopropyl ether or methyl- tert
Butyl ether is 1:2:2, wherein the solvent water content is less than 0.1%.
Crystallization mode described in the step (3) is 35~40 DEG C of 0.1~1% crystal seeds of addition, is cooled to 25~35 DEG C of guarantors
Warm crystallization, then it is cooled to 0~10 DEG C of crystallization.
It further illustrates: preferably 50~80 DEG C of reaction temperature described in the step (1), more preferable 60~70 DEG C,
Reaction time 1~2 hour.
The preferred DMF of reaction dissolvent, acetonitrile, tetrahydrofuran described in the step (1), more preferable acetonitrile.
The preferred trim,ethylchlorosilane of silane reagent described in the step (1), bromotrimethylsilane, trimethyl iodine silicon
Alkane, more preferable bromotrimethylsilane.
Bromotrimethylsilane dosage preferably 2~5 molar equivalents described in the step (1), more preferable 3.5 moles are worked as
Amount.
Preferably 40~70 DEG C of reaction temperature described in the step (2), more preferable 50~55 DEG C, the reaction time 5~7
Hour.
Reaction dissolvent described in the step (2) is preferably DMF, N-Methyl pyrrolidone, more preferable N- methyl pyrrole
Pyrrolidone.
The preferred triethylamine of reaction alkali, pyridine described in the step (2), more preferable triethylamine.
Base amount preferably 2~6 molar equivalents, more preferable 4 molar equivalent described in the step (2).
3 dosage of compound preferably 4~8 molar equivalents, more preferable 6 molar equivalent described in the step (2).
Preferably 40~60 DEG C of reaction temperature described in the step (3), more preferable 40~45 DEG C.
Reaction-crystallization solvent ethyl acetate described in the step (3) and isopropyl ether, acetone and methyl- tert fourth
Base ether, acetone and isopropyl ether, more preferable acetone and methyl tertiary butyl ether(MTBE).
Preferably 35~40 DEG C 0.1~1% crystal seeds of addition of crystallization mode described in the step (3), more preferable 37~
39 DEG C of 0.3% crystal seeds of addition.
Crystallization mode described in the step (3) is preferably cooled to 25~35 DEG C of heat preservation crystallizations, and more preferable 30~35
DEG C crystallization.
Beneficial effect
Innovation of the present invention:
The raw material drug stabilisation that the prior art obtains is poor, and the shelf-life is shorter；Partial size is smaller, and mobility is poor, is unfavorable for
Subsequent preparation uses.Improvement is optimized such as to existing technique in the problem of for technique, the present invention:
1. being refined using acetone and methyl tertiary butyl ether(MTBE) to the compound 4 of preparation, dropped by the way that crystal seed and gradient is added
Warm crystallization obtains big partial size Aldoforwe ester, reduces its surface area contacted with the external world, reaches preparation high stability adefovirdipivoxil
The purpose of ester.
2. a pair original grinds patent CN1216062 and respectively walks all materials proportion, re-starts and investigate and be optimized.
By improving above, reduces side reaction, improve bulk pharmaceutical chemicals quality, enhance the stability of bulk pharmaceutical chemicals, be suitable for
In commercially producing.
For present invention process without especial equipment requirements, no special reaction parameter is easy to operate, and 1 feather weight work is completed at present
Skill verifying, meets business mass production demand, route total recovery reaches 30%~40%, and 99.9% or more purity meets internal control mark
It is quasi-.
Detailed description of the invention
Fig. 1 is 2 nuclear magnetic resonance spectroscopy of compound；
Fig. 2 is 2 carbon-13 nmr spectra of compound；
Fig. 3 is 5 nuclear magnetic resonance spectroscopy of compound；
Fig. 4 is 5 carbon-13 nmr spectra of compound；
Fig. 5 is 1 compound of embodiment, 5 differential calorimetric (DSC)；
Fig. 6 is 1 compound of embodiment, 5 powder diffraction；
Fig. 7 is 1 compound of embodiment, 5 infrared spectrum.
Fig. 8 is 1 compound of comparative example, 5 differential calorimetric (DSC)；
Fig. 9 is 1 compound of comparative example, 5 powder diffraction
Specific embodiment
Below with reference to embodiment and specific embodiment, the present invention is described in further detail.But this should not be understood
It is only limitted to embodiment below to invent the range of the theme, it is all that this hair is belonged to based on the technology that the content of present invention is realized
Bright range.
Embodiment 1:
Acetonitrile 5.20kg (2w/w) is added into 50L reaction kettle, is added with stirring 1 2.60kg of compound (1eq), front three
Bromide silane 4.24kg (3.5eq) is warming up to 65 ± 5 DEG C, insulation reaction 2 hours.45 ± 5 DEG C of organic phases are concentrated under reduced pressure into aneroid
Body distillates, organic to be added to purified water 7.80kg (3w/w) dissolution, is warming up to 55 ± 5 DEG C and stirs 0.5 hour；To 50L reaction kettle
Middle dropwise addition 30%NaOH aqueous solution tune pH to 2.5~3.5, is warming up to 75 ± 5 DEG C of insulated and stirreds 2 hours；It is cooled to 3 ± 3 DEG C of guarantors
Temperature stirring 3 hours；Centrifugation, filter cake are successively washed with purified water 2.60kg (1w/w), ethyl alcohol 1.30kg (0.5w/w)；It is anti-to 50L
It answers in kettle and adds purified water 10.40kg (4w/w), be added with stirring filter cake, be warming up to 75 ± 5 DEG C, be beaten 2 hours；It is cooled to 3 ± 3
DEG C heat preservation 3 hours；Centrifugation, filter cake are washed with purified water 2.60kg (1w/w)；Filter cake obtains compound 2 in 65 ± 5 DEG C of vacuum dryings
White powder 1.86kg, yield 86.2%.1HNMR(400MHz,dDMSO) δ: 3.3898~3.4108 (d, 2H, O-CH2-P),
3.7974~3.8104 (m, 2H, O-CH2-CH2), 4.1678~4.1939 (m, 2H ,-CH2CH2-N),7.8276(s,1H,N-
CH-N),8.0001(s,1H,N-CH-N-CH2)。13CNMR(400Hz,DMSO)δ:43.3421,68.2786,69.9573,
117.7349,142.6915,148.2684,151.9032,154.8810 seeing attached drawing 1~2.
Saline solution is prepared: 39.00kg purified water being added into 50L kettle, is added with stirring 14.62kgNaCl.
N-Methyl pyrrolidone is added into 50L reaction kettle, is added with stirring 2 1.70kg of compound, triethylamine 2.52kg
(4eq), 3 5.62kg of compound (6eq), nitrogen charging gas shielded are warming up to 50~55 DEG C, keep the temperature 5~7 hours, and HPLC monitors chemical combination
4 > 74% of object；Reaction solution is cooled to 25 ± 5 DEG C；Reaction solution is transferred in 100L turnover barrel and adds 34kg (20w/w) acetic acid second
Ester, 25 ± 5 DEG C of stirring 0.5h；Filters pressing, filter cake are washed with 8.50kg ethyl acetate (5w/w), merge organic phase to 200L kettle；Have
Machine is added 17.00kg purified water (10w/w), stirs 0.5h, liquid separation；Water phase is transferred in 200L kettle, adds 17.00kg ethyl acetate
(10w/w) stirs 0.5h, liquid separation；Merge organic phase, add 17.00kg purified water (10w/w), stirs 0.5h, liquid separation；Organic phase
Middle addition 17.00kg purified water (10w/w) stirs 0.5h, liquid separation；Organic addition 17.00kg saline solution (10w/w), stirring
0.5h, liquid separation；Organic addition 17.00kg saline solution (10w/w) stirs 0.5h, liquid separation；Organic addition 17.00kg saline solution
(10w/w) stirs 0.5h, liquid separation；Organic addition 3.40kg (2w/w) anhydrous sodium sulfate, 170g (0.1w/w) active carbon, in 25
± 5 DEG C of stirring 1h；Filters pressing, filter cake are washed with 3.40kg (2w/w) ethyl acetate；Filtrate is transferred in 200L kettle, and 40 ± 5 DEG C subtract
Pressure is concentrated into about 8.5L (5v/w)；It is added 15.30kg methyl tertiary butyl ether(MTBE) (9w/w), is warming up to 43 ± 3 DEG C, stir 0.5h；It is cold
But to 5 ± 5 DEG C, crystallization 12h；Centrifugation, filter cake are washed with 1.70kg methyl tertiary butyl ether(MTBE) (1w/w)；Filter cake is in 40 ± 5 DEG C of vacuum
It is dry, obtain 4 white 1.66kg of compound, yield 53.2%.
Acetone 2.50kg (2w/w) is added into 10L four-hole bottle, is added with stirring 4 1.25kg of compound, it is warming up to 40~
45℃；It is slowly added to methyl tertiary butyl ether(MTBE) 2.50kg (2w/w), is warming up to 40~45 DEG C, insulated and stirred 0.5h；Keep the temperature filters pressing extremely
In 20L devitrification of glass kettle, 40~45 DEG C are warming up to, keeps the temperature 0.5h；Slow cooling；38 ± 1 DEG C of 0.3% crystal seeds of addition；Slowly drop
Temperature keeps the temperature growing the grain 6h to 30~35 DEG C；Slow cooling keeps the temperature crystallization 12h to 5 ± 5 DEG C；Centrifugation, filter cake methyl tertiary butyl ether(MTBE)
1.25kg (1w/w) washing；Filter cake is dried in vacuo in 40 ± 5 DEG C, obtains 5 white crystalline powder 1.00kg of compound, yield
78.1%.1HNMR(400MHz,dDMSO)δ:1.1452(s,18H,-CH3), 3.9021~3.9914 (m, 4H, N-CH2-CH2-O),
4.3267~4.3529 (s, 2H, O-CH2- P), 5.5453~5.6049 (m, 4H, O-CH2-CO),7.1958(s,2H,NH2),
8.0760~8.1465 (m, 2H, N-CH-N)13CNMR(400Hz,DMSO)δ:175.9465,155.8738,152.2783,
149.4673,140.8699,118.5507,81.4563,70.4544,64.9420,63.3296,42.2869,26.3393.See
Attached drawing 3~4.
It is operated according to embodiment 1, total recovery 35.8%.
Embodiment 2
DMF5.20kg (2w/w) is added into 50L reaction kettle, is added with stirring 1 2.60kg of compound (1eq), trimethyl
Chlorosilane 1.72kg (2eq) is warming up to 55 ± 5 DEG C, insulation reaction 2 hours.45 ± 5 DEG C of organic phases are concentrated under reduced pressure into no liquid and evaporate
Out, organic to be added to purified water 7.80kg (3w/w) dissolution, it is warming up to 55 ± 5 DEG C and stirs 0.5 hour；It is dripped into 50L reaction kettle
Add 30%NaOH aqueous solution tune pH to 2.5~3.5, is warming up to 75 ± 5 DEG C of insulated and stirreds 2 hours；3 ± 3 DEG C of heat preservations are cooled to stir
It mixes 3 hours；Centrifugation, filter cake are successively washed with purified water 2.60kg (1w/w), ethyl alcohol 1.30kg (0.5w/w)；To 50L reaction kettle
In plus purified water 10.40kg (4w/w), be added with stirring filter cake, be warming up to 75 ± 5 DEG C, be beaten 2 hours；It is cooled to 3 ± 3 DEG C of guarantors
Temperature 3 hours；Centrifugation, filter cake are washed with purified water 2.60kg (1w/w)；Filter cake obtains 2 white of compound in 65 ± 5 DEG C of vacuum dryings
Powder 1.71kg, yield 79.2%.
Saline solution is prepared: 39.00kg purified water being added into 50L kettle, is added with stirring 14.62kgNaCl.
DMF is added into 50L reaction kettle, is added with stirring 2 1.70kg of compound, triethylamine 1.26kg (2eq), chemical combination
3 3.75kg of object (4eq), nitrogen charging gas shielded are warming up to 40~50 DEG C, keep the temperature 5~7 hours, and HPLC monitors 4 > 74% of compound；
Reaction solution is cooled to 25 ± 5 DEG C；Reaction solution is transferred in 100L turnover barrel and adds 34kg (20w/w) ethyl acetate, 25 ± 5 DEG C are stirred
Mix 0.5h；Filters pressing, filter cake are washed with 8.50kg ethyl acetate (5w/w), merge organic phase to 200L kettle；Organic addition 17.00kg
Purified water (10w/w) stirs 0.5h, liquid separation；Water phase is transferred in 200L kettle, is added 17.00kg ethyl acetate (10w/w), stirring
0.5h, liquid separation；Merge organic phase, add 17.00kg purified water (10w/w), stirs 0.5h, liquid separation；17.00kg is added in organic phase
Purified water (10w/w) stirs 0.5h, liquid separation；Organic addition 17.00kg saline solution (10w/w) stirs 0.5h, liquid separation；Organic phase
Add 17.00kg saline solution (10w/w), stirs 0.5h, liquid separation；Organic addition 17.00kg saline solution (10w/w) stirs 0.5h, point
Liquid；Organic addition 3.40kg (2w/w) anhydrous sodium sulfate, 170g (0.1w/w) active carbon, in 25 ± 5 DEG C of stirring 1h；Filters pressing, filter
Cake is washed with 3.40kg (2w/w) ethyl acetate；Filtrate is transferred in 200L kettle, and 40 ± 5 DEG C are concentrated under reduced pressure into about 8.5L (5v/
w)；It is added 15.30kg methyl tertiary butyl ether(MTBE) (9w/w), is warming up to 43 ± 3 DEG C, stir 0.5h；5 ± 5 DEG C are cooled to, crystallization 12h；
Centrifugation, filter cake are washed with 1.70kg methyl tertiary butyl ether(MTBE) (1w/w)；Filter cake is dried in vacuo in 40 ± 5 DEG C, obtains 4 white of compound
1.42kg, yield 45.5%.
Ethyl acetate 2.50kg (2w/w) is added into 10L four-hole bottle, is added with stirring 4 1.25kg of compound, is warming up to
40~45 DEG C；It is slowly added to isopropyl ether 2.50kg (2w/w), is warming up to 40~45 DEG C, insulated and stirred 0.5h；Filters pressing is kept the temperature to 20L
In devitrification of glass kettle, 40~45 DEG C are warming up to, keeps the temperature 0.5h；Slow cooling；36 ± 1 DEG C of 0.1% crystal seeds of addition；Slow cooling is extremely
25~30 DEG C, keep the temperature growing the grain 6h；Slow cooling keeps the temperature crystallization 12h to 5 ± 5 DEG C；Centrifugation, filter cake methyl tertiary butyl ether(MTBE)
1.25kg (1w/w) washing；Filter cake is dried in vacuo in 40 ± 5 DEG C, obtains 5 white crystalline powder 0.86kg of compound, yield
68.8%.
It is operated according to embodiment 2, total recovery 24.8%.
Embodiment 3
Into 50L reaction kettle be added tetrahydrofuran 5.20kg (2w/w), be added with stirring 1 2.60kg of compound (1eq),
Iodotrimethylsilane 7.92kg (5eq) is warming up to 75 ± 5 DEG C, insulation reaction 2 hours.45 ± 5 DEG C of organic phases are concentrated under reduced pressure into nothing
Liquid distillates, organic to be added to purified water 7.80kg (3w/w) dissolution, is warming up to 55 ± 5 DEG C and stirs 0.5 hour；It is reacted to 50L
30%NaOH aqueous solution tune pH to 2.5~3.5 is added dropwise in kettle, is warming up to 75 ± 5 DEG C of insulated and stirreds 2 hours；It is cooled to 3 ± 3 DEG C
Insulated and stirred 3 hours；Centrifugation, filter cake are successively washed with purified water 2.60kg (1w/w), ethyl alcohol 1.30kg (0.5w/w)；To 50L
Add purified water 10.40kg (4w/w) in reaction kettle, be added with stirring filter cake, be warming up to 75 ± 5 DEG C, is beaten 2 hours；It is cooled to 3
± 3 DEG C keep the temperature 3 hours；Centrifugation, filter cake are washed with purified water 2.60kg (1w/w)；Filter cake obtains chemical combination in 65 ± 5 DEG C of vacuum dryings
2 yellow powder 1.76kg of object, yield 81.5%.
Saline solution is prepared: 39.00kg purified water being added into 50L kettle, is added with stirring 14.62kgNaCl.
N-Methyl pyrrolidone is added into 50L reaction kettle, is added with stirring 2 1.70kg of compound, pyridine 2.95kg
(6eq), 3 5.62kg of compound (6eq), nitrogen charging gas shielded are warming up to 60~70 DEG C, keep the temperature 5~7 hours, and HPLC monitors chemical combination
4 > 74% of object；Reaction solution is cooled to 25 ± 5 DEG C；Reaction solution is transferred in 100L turnover barrel and adds 34kg (20w/w) acetic acid second
Ester, 25 ± 5 DEG C of stirring 0.5h；Filters pressing, filter cake are washed with 8.50kg ethyl acetate (5w/w), merge organic phase to 200L kettle；Have
Machine is added 17.00kg purified water (10w/w), stirs 0.5h, liquid separation；Water phase is transferred in 200L kettle, adds 17.00kg ethyl acetate
(10w/w) stirs 0.5h, liquid separation；Merge organic phase, add 17.00kg purified water (10w/w), stirs 0.5h, liquid separation；Organic phase
Middle addition 17.00kg purified water (10w/w) stirs 0.5h, liquid separation；Organic addition 17.00kg saline solution (10w/w), stirring
0.5h, liquid separation；Organic addition 17.00kg saline solution (10w/w) stirs 0.5h, liquid separation；Organic addition 17.00kg saline solution
(10w/w) stirs 0.5h, liquid separation；Organic addition 3.40kg (2w/w) anhydrous sodium sulfate, 170g (0.1w/w) active carbon, in 25
± 5 DEG C of stirring 1h；Filters pressing, filter cake are washed with 3.40kg (2w/w) ethyl acetate；Filtrate is transferred in 200L kettle, and 40 ± 5 DEG C subtract
Pressure is concentrated into about 8.5L (5v/w)；It is added 15.30kg methyl tertiary butyl ether(MTBE) (9w/w), is warming up to 43 ± 3 DEG C, stir 0.5h；It is cold
But to 5 ± 5 DEG C, crystallization 12h；Centrifugation, filter cake are washed with 1.70kg methyl tertiary butyl ether(MTBE) (1w/w)；Filter cake is in 40 ± 5 DEG C of vacuum
It is dry, obtain 4 white 1.46kg of compound, yield 46.8%.
Acetone 2.50kg (2w/w) is added into 10L four-hole bottle, is added with stirring 4 1.25kg of compound, it is warming up to 40~
45℃；It is slowly added to isopropyl ether 2.50kg (2w/w), is warming up to 40~45 DEG C, insulated and stirred 0.5h；Filters pressing is kept the temperature to 20L glass
In crystallization kettle, 40~45 DEG C are warming up to, keeps the temperature 0.5h；Slow cooling；38 ± 1 DEG C of 0.3% crystal seeds of addition；Slow cooling to 30~
35 DEG C, keep the temperature growing the grain 6h；Slow cooling keeps the temperature crystallization 12h to 5 ± 5 DEG C；Centrifugation, filter cake methyl tertiary butyl ether(MTBE) 1.25kg
(1w/w) washing；Filter cake is dried in vacuo in 40 ± 5 DEG C, obtains 5 white crystalline powder 0.88kg of compound, yield 70.4%.
It is operated according to embodiment 3, total recovery 26.9%.
Comparative example 1 (CN1216062):
Acetonitrile 5.20kg (2w/w) is added into 50L reaction kettle, is added with stirring 1 2.60kg of compound (1eq), front three
Base iodine silane 4.24kg (3.5eq) is warming up to 65 ± 5 DEG C, insulation reaction 2 hours.45 ± 5 DEG C of organic phases are concentrated under reduced pressure into aneroid
Body distillates, organic to be added to purified water 7.80kg (3w/w) dissolution, is warming up to 55 ± 5 DEG C and stirs 0.5 hour；To 50L reaction kettle
Middle dropwise addition 30%NaOH aqueous solution tune pH to 2.5~3.5, is warming up to 75 ± 5 DEG C of insulated and stirreds 2 hours；It is cooled to 3 ± 3 DEG C of guarantors
Temperature stirring 3 hours；Centrifugation, filter cake are successively washed with purified water 2.60kg (1w/w), ethyl alcohol 1.30kg (0.5w/w)；It is anti-to 50L
It answers in kettle and adds purified water 10.40kg (4w/w), be added with stirring filter cake, be warming up to 75 ± 5 DEG C, be beaten 2 hours；It is cooled to 3 ± 3
DEG C heat preservation 3 hours；Centrifugation, filter cake are washed with purified water 2.60kg (1w/w)；Filter cake obtains compound 2 in 65 ± 5 DEG C of vacuum dryings
White powder 1.86kg, yield 86.2%.
N-Methyl pyrrolidone is added into 50L reaction kettle, is added with stirring 2 1.70kg of compound, triethylamine 2.52kg
(4eq), 3 5.62kg of compound (6eq), nitrogen charging gas shielded are warming up to 50~55 DEG C, keep the temperature 5~7 hours, and HPLC monitors chemical combination
4 > 74% of object；Reaction solution is cooled to 25 ± 5 DEG C；Reaction solution is transferred in 100L turnover barrel and adds 34kg (20w/w) isopropyl acetate
Ester, 25 ± 5 DEG C of stirring 0.5h；Filters pressing, filter cake are washed with 8.50kg isopropyl acetate (5w/w), merge organic phase to 200L kettle；
Organic addition 17.00kg purified water (10w/w) stirs 0.5h, liquid separation；Water phase is transferred in 200L kettle, adds 17.00kg acetic acid different
Propyl ester (10w/w) stirs 0.5h, liquid separation；Merge organic phase, add 17.00kg purified water (10w/w), stirs 0.5h, liquid separation；Have
17.00kg purified water (10w/w) is added in machine phase, stirs 0.5h, liquid separation；Filtrate is transferred in 200L kettle, and 40 ± 5 DEG C of decompressions are dense
It is reduced to dry；3.40kg acetone (2w/w) dissolution is added, 6.80kg (4w/w) methyl tertiary butyl ether(MTBE) is added and is warming up to 43 ± 3 DEG C, stirs
Mix 0.5h；5 ± 5 DEG C are cooled to, crystallization 12h；Centrifugation, filter cake are washed with 1.70kg methyl tertiary butyl ether(MTBE) (1w/w)；Filter cake is in 40
± 5 DEG C of vacuum drying, obtain 5 white powder 1.25kg of compound, yield 40.1%.
It is operated according to comparative example 1, total recovery 34.6%.
1 sample of embodiment and 1 sample comparison result of comparative example
1 sample of embodiment is compared with 1 sample of comparative example: it is consistent that the two DSC, powder diffraction and original grind patent report,
Show that the two is all five crystal types, other testing results are more consistent in addition to partial size.1 sample D of embodiment50It is 86 μm, and compares
1 sample D of example50It is 35 μm, i.e. 1 sample of embodiment is bigger than 1 sample particle diameter of comparative example；And 1 sample of embodiment is than comparative example 1
Sample flow is good.
1 sample of embodiment and 1 sample comparison result of comparative example
Study on the stability
Sample prepared by embodiment 1 and comparative example 1, carries out acceleration investigation (40 ± 2 DEG C of temperature, humidity 75 ± 5%), and
Data comparison is carried out, as a result as follows:
Embodiment sample accelerates to investigate result
1 sample of embodiment is placed under acceleration conditions, and adefovir (AD) monoester accelerates March, is only risen to by 0.24%
0.34%, increase minimum；Dimer, adefovirdipivoxil are not detected.It is placed under 1 sample acceleration environment of comparative example, adefovirdipivoxil list
Ester accelerates March, only rises to 0.32% by 0.11%, increases larger；Dimer impurity rises to 0.19% by 0, increases larger；
Adefovirdipivoxil is not detected.Therefore 1 sample stability of embodiment, it is much higher than 1 sample of comparative example.
1 sample of embodiment has separately been carried out to the influence factor under the conditions of 40 DEG C of high temperature, high humidity 92.5%, illumination 5000lx to examine
It examines, as a result as follows:
1 sample effects factor of embodiment is investigated
| Test item | Adefovir (AD) monoester/% | Dimer/% | Adefovirdipivoxil/% | Total miscellaneous/% |
| 1 sample of embodiment 0 day | 0.24 | - | - | 0.24 |
| 40 DEG C of 1 high-temperature sample of embodiment 10 days | 0.23 | - | - | 0.23 |
| 1 sample high humidity of embodiment 92.5%10 days | 0.35 | - | - | 0.38 |
| 1 sample illumination 5000lx of embodiment 10 days | 0.22 | - | - | 0.22 |
| 40 DEG C of 1 high-temperature sample of embodiment 30 days | 0.27 | - | - | 0.27 |
| 1 sample high humidity of embodiment 92.5%30 days | 0.40 | - | - | 0.44 |
| 1 sample illumination 5000lx of embodiment 30 days | 0.23 | - | - | 0.23 |
| Chinese Pharmacopoeia limit/% | 1.0 | 0.5 | 0.5 | 2.0 |
1 sample of embodiment is placed under the conditions of influence factor, and only under the conditions of high humidity 92.5%, adefovir (AD) monoester slightly increases
It is long；Dimer, adefovirdipivoxil are not detected.
Therefore it is fabulous according to sample stability prepared by embodiment 1, technique is without especial equipment requirements, no special reaction parameter,
It is easy to operate, 1 feather weight process certification is completed at present, meets business mass production demand.
Claims (8)
1. a kind of preparation method of high stability Aldoforwe ester, characterized by comprising:
(1) compound 1 replaces in reaction reagent a through silane reagent, then obtains compound 2 through NaOH aqueous hydrolysis；
(2) compound 2 and compound 3 are catalyzed to obtain compound 4 through organic weak base in reaction dissolvent b；
(3) compound 4 passes through crystal refining, obtains compound 5, i.e. [[2- (6- amino -9H- purine -9- base) ethyoxyl] methyl]
Phosphonic acids two (pivaloyloxymethyl) ester.
2. according to the method described in claim 1, it is characterized by: reaction temperature described in the step (1) is 50 ~ 80 DEG C；
The reaction dissolvent a is polar non-solute or nonpolar solvent；1 dosage of compound is 1 molar equivalent；It is described
Silane reagent dosage be 2 ~ 5 molar equivalents.
3. according to the method described in claim 2, it is characterized by: reaction dissolvent a described in the step (1) is DMF, acetonitrile
Or tetrahydrofuran；The silane reagent is trim,ethylchlorosilane, bromotrimethylsilane or Iodotrimethylsilane.
4. according to the method described in claim 1, it is characterized by: reaction temperature described in the step (2) is 40 ~ 70 DEG C；
The reaction dissolvent b is polar non-solute or nonpolar solvent；The reaction is organic weak base with alkali；The alkali
Dosage is 2 ~ 6 molar equivalents；3 dosage of compound is 4 ~ 8 molar equivalents.
5. according to the method described in claim 4, it is characterized by: reaction dissolvent b described in the step (2) is DMF, N- first
Base pyrrolidones；The organic weak base is triethylamine or pyridine.
6. according to the method described in claim 1, it is characterized by: reaction temperature described in the step (3) is 40 ~ 60 DEG C；
The crystallization solvent is that ethyl acetate, isopropyl ether, acetone, methyl tertiary butyl ether(MTBE), acetone and isopropyl ether are a kind of or two kinds any
Combination of the above.
7. according to the method described in claim 1, it is characterized by: the proportion of crystallization solvent described in the step (3) is chemical combination
Object 4: ethyl acetate or acetone: isopropyl ether or methyl tertiary butyl ether(MTBE) are 1:2:2, wherein the solvent water content is less than 0.1%.
8. according to the method described in claim 1, it is characterized by: crystallization mode described in the step (3) adds for 35 ~ 40 DEG C
Enter 0.1 ~ 1% crystal seed, is cooled to 25 ~ 35 DEG C of heat preservation crystallizations, then be cooled to 0 ~ 10 DEG C of crystallization.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110483575A (en) * | 2019-09-11 | 2019-11-22 | 北京悦康科创医药科技股份有限公司 | A kind of synthetic method of Aldoforwe ester |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1421449A (en) * | 2002-12-04 | 2003-06-04 | 上海瑞广生化科技开发有限公司 | 9-[2-[[[di (trimethylacetoxyl) methyl] phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application |
| CN1763057A (en) * | 1997-07-25 | 2006-04-26 | 吉尔利德科学股份有限公司 | Nucleotide analog compound |
| US20120238753A1 (en) * | 2011-03-14 | 2012-09-20 | Vellenki Siva Rama Prasad | Process for the preparation of adefovir dipivoxil |
| CN104387421A (en) * | 2014-11-27 | 2015-03-04 | 苏州二叶制药有限公司 | Adefovir dipivoxil monohydrate and preparation method thereof |
-
2019
- 2019-06-26 CN CN201910558431.2A patent/CN110143983A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1763057A (en) * | 1997-07-25 | 2006-04-26 | 吉尔利德科学股份有限公司 | Nucleotide analog compound |
| CN1421449A (en) * | 2002-12-04 | 2003-06-04 | 上海瑞广生化科技开发有限公司 | 9-[2-[[[di (trimethylacetoxyl) methyl] phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application |
| US20120238753A1 (en) * | 2011-03-14 | 2012-09-20 | Vellenki Siva Rama Prasad | Process for the preparation of adefovir dipivoxil |
| CN104387421A (en) * | 2014-11-27 | 2015-03-04 | 苏州二叶制药有限公司 | Adefovir dipivoxil monohydrate and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483575A (en) * | 2019-09-11 | 2019-11-22 | 北京悦康科创医药科技股份有限公司 | A kind of synthetic method of Aldoforwe ester |
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