CN1142171C - 9-[2-[[[di (trimethylacetoxyl) methyl phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application - Google Patents
9-[2-[[[di (trimethylacetoxyl) methyl phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application Download PDFInfo
- Publication number
- CN1142171C CN1142171C CNB021510326A CN02151032A CN1142171C CN 1142171 C CN1142171 C CN 1142171C CN B021510326 A CNB021510326 A CN B021510326A CN 02151032 A CN02151032 A CN 02151032A CN 1142171 C CN1142171 C CN 1142171C
- Authority
- CN
- China
- Prior art keywords
- ethyl
- methyl
- phosphoroso
- vitamin
- crystal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- -1 trimethylacetoxyl Chemical group 0.000 title claims abstract description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims abstract description 46
- 239000013078 crystal Substances 0.000 title claims abstract description 37
- 229930024421 Adenine Natural products 0.000 title abstract description 6
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 title abstract description 6
- 229960000643 adenine Drugs 0.000 title abstract description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 title abstract 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims abstract description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 9
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 5
- 239000011782 vitamin Substances 0.000 claims description 52
- 235000013343 vitamin Nutrition 0.000 claims description 52
- 229940088594 vitamin Drugs 0.000 claims description 52
- 229930003231 vitamin Natural products 0.000 claims description 52
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 52
- 229910052760 oxygen Inorganic materials 0.000 claims description 42
- 239000001301 oxygen Substances 0.000 claims description 42
- 239000002904 solvent Substances 0.000 claims description 21
- 238000002425 crystallisation Methods 0.000 claims description 20
- 230000008025 crystallization Effects 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 7
- 241000701027 Human herpesvirus 6 Species 0.000 claims description 6
- 230000008030 elimination Effects 0.000 claims description 6
- 238000003379 elimination reaction Methods 0.000 claims description 6
- 229960004756 ethanol Drugs 0.000 claims description 6
- 125000006850 spacer group Chemical group 0.000 claims description 4
- 241000700588 Human alphaherpesvirus 1 Species 0.000 claims description 3
- 241000701074 Human alphaherpesvirus 2 Species 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 241000700605 Viruses Species 0.000 claims 1
- 229960001997 adefovir Drugs 0.000 abstract description 12
- 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 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 229960003205 adefovir dipivoxil Drugs 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 229960003328 benzoyl peroxide Drugs 0.000 abstract 2
- 210000002858 crystal cell Anatomy 0.000 abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 13
- 239000011259 mixed solution Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 230000037396 body weight Effects 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 6
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 6
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 241000272525 Anas platyrhynchos Species 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 2
- 241000725618 Duck hepatitis B virus Species 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 238000002105 Southern blotting Methods 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical group [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000009834 vaporization Methods 0.000 description 2
- 230000008016 vaporization Effects 0.000 description 2
- UXTFKIJKRJJXNV-UHFFFAOYSA-N 1-$l^{1}-oxidanylethanone Chemical compound CC([O])=O UXTFKIJKRJJXNV-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 1
- 101000807541 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 24 Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229910003691 SiBr Inorganic materials 0.000 description 1
- 206010041660 Splenomegaly Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 102100037176 Ubiquitin carboxyl-terminal hydrolase 24 Human genes 0.000 description 1
- AZVBFIXINWVFEA-UHFFFAOYSA-N [O].C(C)OS(=O)(=O)CC Chemical compound [O].C(C)OS(=O)(=O)CC AZVBFIXINWVFEA-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 229940107816 ammonium iodide Drugs 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 238000011951 anti-virus test Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940083599 sodium iodide Drugs 0.000 description 1
- 150000003527 tetrahydropyrans Chemical class 0.000 description 1
Images
Abstract
The present invention relates to a 9-[2-[[[double(trimethyl acetoxyl)methyl]phosphoroso]methoxy]-ethyl]adenine(Adefovir ester) crystal with the space group of P-1, the crystal cell volume of 1345.5(9)<3> and the following crystal cell parameters: a is equal to 6.020(2), b is equal to 11.155(4), c is equal to 20.833(8), alpha is equal to 93.798(6)degrees, beta is equal to 97.458(6)degrees and gamma is equal to 102.897(6)degrees. The present invention also relates to a method for using anhydrous alcohol to crystallize 9-[2-[[[bi(trimethyl acetoxyl) methyl]phosphoroso] methoxyl]-ethyl]adenine for obtaining the 9-[2-[[[bi(trimethyl acetoxyl)methyl]phosphoroso]methoxy]-ethyl]adenine(adefovir dipivoxil) crystal, and the application of the crystal for preparing antiviral medicines.
Description
Technical field
The present invention relates to two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] a kind of novel crystal of VITAMIN B4 (adefovir ester), the present invention also relates to described crystalline preparation method, the present invention further also relates to this crystalline and uses.
Background technology
Adefovir ester (Adefovir Dipivoxil, abbreviation AD) chemical structural formula is two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4, it all has stronger extracorporeal antivirus effect activity to HIV, HBV, people CMV, HSV-1 and HSV-2, and can suppress duplicating of human herpes virus 6 (HHV-6) in the HSB-2 cell, therefore can suppress cytopathic effect and HHV-6-specific antigen that HHV-6-causes and express.Behind the vivo medicine-feeding, this compound can also delay tumour formation and death of mouse and the splenomegaly that the obvious FLV-of inhibition causes that MSV-brings out significantly.
Clinical study finds that adefovir ester can be treated the patient that HIV infects effectively, and its toxicity is lower.In addition, adefovir ester also can be used as the preliminary treatment of chronic hepatitis B (HBV) or combines medication with other anti-HBV medicine.
Based on the above-mentioned widespread use of adefovir ester, people are sought after low cost, the adefovir ester that use properties is good.
United States Patent (USP) 4,724,233 and 4,808,716, EP 481,214 grades have disclosed adefovir ester and preparation method thereof, and what it was prepared all is amorphous form, and its physicals is unfavorable for follow-up use.
WO 99/04774 (PCT/US98/15304) has disclosed and has contained AD crystalline composition and application thereof, and it has also related to the method for synthetic AD.Be initiator with the VITAMIN B4 in this documents, by using NSC 11801, the bromo trimethyl silane, chloro methyl pivalate, reaction reagents such as second cyanogen and toluene, the synthetic mixed solution that obtains containing AD, and then with being selected from acetone, the mixed solution of di-n-butyl ether, the mixed solution of ethyl acetate and di ether, the mixed solution of the trimethyl carbinol and di-n-butyl ether, the mixed solution of methylene dichloride and di-n-butyl ether, the mixed solution of ether and di ether, the mixed solution of tetrahydrofuran (THF) and di-n-butyl ether, the mixed solution of ethyl acetate and di-n-butyl ether, the mixed solution of tetrahydropyrans and di-n-butyl ether, the mixed solution of ethyl acetate and ether, t-butyl methyl ether, ether, di-n-butyl ether, the trimethyl carbinol, toluene, the solvent of isopropyl acetate or ethyl acetate carries out crystallization, obtains the AD crystal, and crystallization yield is lower than 50%.Total recovery is lower than 10%.
Above-mentioned part reagent and recrystallisation solvent or depend on external import, or its cost costliness, thus adefovir ester crystalline production cost improved greatly; be unfavorable for the use of adefovir ester, yield is low, and solvent-oil ratio is big; partial solvent toxicity height is unfavorable for environment protection.
The present technique field is devoted to develop two (pivalyl oxygen) methyl of 9-[2-[[[of the novelty that production cost is low, result of use is good for a long time always] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystal.
Summary of the invention
An object of the present invention is to provide two (pivalyl oxygen) methyl of 9-[2-[[[of a kind of novelty] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystal.
A further object of the present invention provides two (pivalyl oxygen) methyl of described 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 crystalline preparation method.
A further object of the present invention provides the medicine of antiviral particularly anti-HBV, HIV, people CMV, HSV-1, HSV-2 and the human herpes virus 6 (HHV-6) of highly effective and safe.
Another object of the present invention provides and contains described crystalline pharmaceutical composition.
Design of the present invention is implemented by following technical proposal:
Two (pivalyl oxygen) methyl of a kind of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystal, the colourless profile of crystal is needle-like, be of a size of 0.40 * 0.04 * 0.04mm, crystal belongs to triclinic(crystalline)system, spacer is P-1, unit cell parameters a=6.020 (2) , b=11.155 (4) , c=20.833 (8) , α=93.798 (6) °. β=97.458 (6) °. γ=102.897 (6) °. unit cell volume 1345.5 (9)
3
Described crystal can be used for preparing the composition of antiviral, particularly antiviral.According to the routine techniques of pharmaceutical field, two (pivalyl oxygen) methyl of 9-[2-[[[of the present invention] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystal can be mixed with various formulations, as tablet, capsule etc.The those of ordinary skill of pharmaceutical field can select suitable pharmaceutically acceptable vehicle to prepare required pharmaceutical composition according to routine techniques.
Two (pivalyl oxygen) methyl of the amorphous 9-[2-[[[of the present invention] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 makes by following reaction process:
a.Et
3N，b.TsCl，c.KOH/NaOH，d.DMF，e.CH
3ONa/DMF/CH
2Cl
2
F.Me
3SiCl/CH
2Cl
2/ H
2O/ catalyst A and/or B, g.NMP/ catalyst A and/or B
Described catalyst A is bromated mineral compound or bromated organic compound, preferably is selected from Sodium Bromide, Potassium Bromide, brometo de amonio, (R
1R
2R
3) NBr, wherein R
1, R
2And R
3Can be identical or different, be selected from C independently of one another
1-16The straight or branched alkyl.Described catalyst B is the organic compound that contains the mineral compound of iodine or contain iodine, preferably is selected from sodium iodide, potassiumiodide, ammonium iodide or (R
1R
2R
3) NI, wherein R
1, R
2And R
3Definition the same.
Described catalyst A and catalyst B can be used separately or composition uses, and its blending ratio is not particularly limited.
Crystal of the present invention makes through the following steps:
With two (pivalyl oxygen) methyl of gained 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 crude product (V) heating is dissolved in the dehydrated alcohol, elimination insolubles while hot; It is abundant to crystallization to add the second crystallization stirring solvent in the ethanol solution of gained, filtration final vacuum drying, obtain two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystal, the described second crystallization solvent is selected from a) by formula R
1-O-R
2Expression alkyl oxide, wherein R
1, R
2Be identical or different, representative is C separately
1-6Alkyl; B) C
5-7Alkane; C) CH
3COOR, wherein R is C
1-5Alkyl.
Description of drawings
Fig. 1 is two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 crystalline structure and atom numbering figure.
Fig. 2 is two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] accumulation graph of VITAMIN B4 crystallization unit cell.
Embodiment
Two (pivalyl oxygen) methyl of 9-[2-[[[of the present invention] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 crystal (C
2OH
32N
5O
8P) be with dehydrated alcohol and being selected from a) by formula R
1-O-R
2Expression alkyl oxide, wherein R
1, R
2Be identical or different, representative is C separately
1-6Alkyl; B) .C
5-7Alkane; C) .CH
3COOR, wherein R is C
1-5The crystal that the second crystallization solvent crystallization of alkyl obtains, molecular weight is 501.48, density is 1.266g/cm
3, F (000)=1064, asymmetric cell contains a molecule.This crystalline profile is needle-like, be of a size of 0.40 * 0.04 * 0.04mm, crystal belongs to triclinic(crystalline)system, its spacer is P-1, unit cell parameters a=6.020 (2) , b=11.155 (4) , c=20.833 (8) , α=93.798 (6) °. β=97.458 (6) °. γ=102.897 (6) °. unit cell volume 1345.5 (9)
3, the condition determination of described unit cell parameters is: temperature 295 (2) K, wavelength 0.71073 .
Two (pivalyl oxygen) methyl of table-1 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 crystalline atomic coordinate (* 10
4) and equivalent isotropy alternate parameter
(equivalent?isotropic?displacement?parameters)(
2×10
3)
x y z U(eq)
O(1) 9035(2) 6971(1) 1948(1) 72(1)
O(2) 7181(1) 5192(1) 3361(1) 56(1)
O(3) 4799(1) 5567(1) 4099(1) 58(1)
O(4) 4143(2) 7018(1) 3472(1) 75(1)
O(5) 9517(1) 4623(1) 2587(1) 57(1)
O(6) 8159(1) 2507(1) 2338(1) 54(1)
O(7) 11143(2) 2466(1) 3076(1) 91(1)
O(8) 5396(1) 4736(1) 2171(1) 59(1)
N(1) 11099(2) 12057(1) 984(1) 51(1)
N(2) 12673(2) 10343(1) 1292(1) 59(1)
N(3) 10042(2) 8396(1) 918(1) 45(1)
N(4) 7050(2) 9054(1) 441(1) 48(1)
N(5) 7466(2) 11827(1) 416(1) 48(1)
C(1) 9117(2) 11321(1) 692(1) 39(1)
C(2) 12719(2) 11528(1) 1260(1) 59(1)
C(3) 10705(2) 9657(1) 989(1) 38(1)
C(4) 8833(2) 10046(1) 690(1) 41(1)
C(5) 7867(2) 8106(1) 586(1) 50(1)
C(6) 11418(2) 7563(1) 1155(1) 60(1)
C(7) 11347(2) 7429(1) 1869(1) 59(1)
C(8) 8695(2) 6829(1) 2590(1) 61(1)
C(9) 4934(2) 4811(1) 3551(1) 61(1)
C(10) 4253(2) 6662(1) 3993(1) 53(1)
C(11) 3909(2) 7307(1) 4608(1) 54(1)
C(12) 3000(3) 8437(1) 4450(1) 107(1)
C(13) 6167(2) 7673(1) 5061(1) 87(1)
C(14) 2146(2) 6452(1) 4928(1) 82(1)
C(15) 9424(2) 3608(1) 2134(1) 58(1)
C(16) 9224(2) 1990(1) 2816(1) 54(1)
C(17) 7795(2) 795(1) 2948(1) 49(1)
C(18) 7490(2) -109(1) 2351(1) 73(1)
C(19) 5449(2) 953(1) 3067(1) 83(1)
C(20) 8980(2) 316(1) 3531(1) 81(1)
O(9) 3483(2) 4541(1) 876(1) 84(1)
O(10) 2450(2) 5546(1) -323(1) 97(1)
H(5A) 7690 12617 428 57
H(5B) 6179 11362 226 57
H(2) 14076 12073 1459 70
H(5) 7030 7295 472 60
H(6A) 13001 7875 1088 72
H(6B) 10846 6759 909 72
H(7A) 12269 6863 2018 71
H(7B) 11963 8224 2122 71
H(8A) 7681 7335 2720 73
H(8B) 10154 7081 2878 73
H(9A) 3760 4873 3197 73
H(9B) 4668 3957 3648 73
H(12A) 4093 8983 4242 161
H(12B) 2774 8859 4844 161
H(12C) 1559 8183 4164 161
H(13A) 6722 6948 5148 131
H(13B) 5945 8074 5461 131
H(13C) 7274 8228 4862 131
H(14A) 744 6170 4627 122
H(14B) 1843 6889 5307 122
H(14C) 2734 5755 5052 122
H(15A) 10975 3531 2094 69
H(15B) 8695 3745 1710 69
H(18A) 6770 209 1982 109
H(18B) 6538 -888 2421 109
H(18C) 8969 -221 2270 109
H(19A) 5623 1556 3432 124
H(19B) 4536 178 3158 124
H(19C) 4697 1225 2688 124
H(20A) 10524 300 3466 122
H(20B) 8142 -505 3579 122
H(20C) 9024 849 3916 122
H(91) 2660(10) 3876(4) 933(3) 50(3)H(92) 3460(2)
5110(5) 1140(3) 345(13)
H(101) 2559(16) 5308(6) 42(2) 66(3)
H(102) 3680(7) 5743(15) -464(3) 236(9)
Two (pivalyl oxygen) methyl of above-mentioned 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystal is preparation like this:
(1) in reaction vessel, add diethyl phosphite, Paraformaldehyde 96, add SULPHURYL CHLORIDE below 0 ℃, triethylamine, reaction is finished, and obtains reaction product (I);
(2) in reaction vessel, add by diethyl carbonate, ethylene glycol and N, after the mixed solution reaction that dinethylformamide (DMF) is formed, add sodium hydroxide and VITAMIN B4 again, until VITAMIN B4 content≤0.3%.Add Iso Butyl Acetate, obtain reaction product (II);
(3) add reaction product (II), DMF, the CH that step (2) obtains successively
3ONa stirs the back and adds the mixed solution that the reaction product (I) that obtained by step (1) and DMF form, stirs the back and adds methylene dichloride, refluxes, and stirring at normal temperature gets light brown solid (III), i.e. 9-[2-(diethyl phosphate methoxy) ethyl again] VITAMIN B4;
(4) in reaction vessel, add (III) successively, methylene dichloride, the chloro trimethyl silane adds described catalyst A and/or B, is stirred to react completely, and transfers pH3.0～3.5, gets 9-[2-(phosphate methoxy) ethyl] the VITAMIN B4 product (IV, PMEA);
(5) in (IV), add Chloro methyl pivalate, NMP and triethylamine, add described catalyst A and/or catalyst B, be stirred to and react completely, add Iso Butyl Acetate again and stir back filtering solid, boil off solvent, add acetone and n-butyl ether, stir two (pivalyl oxygen) methyl of crude product 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 (V).
(6) with two (pivalyl oxygen) methyl of the unbodied 9-[2-[[[of gained] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 crude product (V) heating is dissolved in the dehydrated alcohol, elimination insolubles while hot; It is abundant to crystallization to add the second crystallization stirring solvent in the ethanol solution of gained, filtration final vacuum drying, obtain two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystal, the described second crystallization solvent is selected from a) by formula R
1-O-R
2Expression alkyl oxide, wherein R
1, R
2Be identical or different, representative is C separately
1-6Alkyl; B) C
5-7Alkane; C) CH
3COOR, wherein R is C
1-5Alkyl.
Two (pivalyl oxygen) methyl of wherein unbodied 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] weight ratio of VITAMIN B4 crude product and dehydrated alcohol is 1: 1-5, preferably 1: 2.Two (pivalyl oxygen) methyl of described 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] ethanol solution of VITAMIN B4 and the volume ratio of the described second crystallization solvent be 1: 6-8.
Set forth two (pivalyl oxygen) methyl of 9-[2-[[[of the present invention below in conjunction with specific embodiment] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystal and preparation method thereof.
Embodiment 1
Synthesizing of diethyl sulfonic acid oxygen METHAPHOSPHORIC ACID ester (I)
Toward N
2Add diethyl phosphite (available from the good magnificent chemical industry in Lanxi, Zhejiang company limited) 1.0Kg (7.24 moles), Paraformaldehyde 96 in the reactor of protection successively (available from Shanghai solvent factory; ACS:3525-89-4) 0.28kg (8.77 moles); stirring reaction 2 hours; add SULPHURYL CHLORIDE 1.25kg (6.57 moles) below 0 ℃; triethylamine 1kg (9.88 moles); stirring at room reaction 8～10 hours, the TLC detection reaction is finished.Filter, with solvent 2 * 250ml washing, merging filtrate washing, decolorizing with activated carbon drying, underpressure distillation remove to solvent less than 1% (GC), oily matter, be syrupy shape after the cooling, (I).Yield 75～80%, content: 〉=85% (HPLC).
Embodiment 2
Synthesizing of 9-(2-hydroxyethyl) VITAMIN B4 (II):
Dry reaction still N
2Protection; drop into diethyl carbonate (available from Shanghai reagent head factory) 0.75kg (6.35 moles) successively; ethylene glycol (available from the Shanghai reagent head factory) 0.4Kg (mixed solution that 6.45 moles and DMF 1kg form; insulated and stirred to reaction is finished; drop into (0.125 mole of sodium hydroxide 0.005kg; fine ground); VITAMIN B4 (available from Zhejiang Cheng Yi Pharmaceutical Co., Ltd) 1kg (USP24) (7.40 moles); insulated and stirred HPLC monitoring VITAMIN B4 content≤0.3%, reaction finishes, and adds the 4.0kg Iso Butyl Acetate and stirs 2 hours; leach solid; with the Iso Butyl Acetate washing, vacuum-drying gets pulverulent solids (II); yield 90%～95%, content 〉=90% (HPLC).
Embodiment 3
9-[2-(diethyl phosphate methoxy) ethyl] VITAMIN B4 (III) synthetic
Dry reaction still N
2Protection adds (II) 1.0kg (5.58 moles), DMF 4.8kg successively; CH3ONa1.0kg; (I) 2.25kg (6.98 moles) stirred 8～10 hours, and the HPLC monitoring reaction is finished; adding methylene dichloride 16kg with in the Glacial acetic acid and back stirs; leach solid, with 2 * 1.5kg washed with dichloromethane, merging filtrate; water 2 * 0.8kg washing; methylene dichloride 2 * 1.5kg extracts water, merges organic phase, adds hexanaphthene 3kg behind the recovery methylene dichloride; stir solid; vacuum-drying 2 days gets light brown solid (III), yield 50～65%; content 〉=90% (HPLC), mp136～138 ℃.
Embodiment 4
9-[2-(phosphate methoxy) ethyl] VITAMIN B4 (IV, PMEA) synthetic
Dry reaction still N
2Protection adds (III) 1.0kg (3.03 moles) successively, methylene dichloride 5kg, and chloro trimethyl silane 1.65kg (15.20 moles), stirring reaction 2 days, the product spot is not seen in the thin plate monitoring.
Embodiment 5
9-[2-(phosphate methoxy) ethyl] VITAMIN B4 (IV, PMEA) synthetic
Dry reaction still N
2Protection adds (III) 1.0kg (3.03 moles), methylene dichloride 5kg successively; bromo trimethyl silane 1.65kg (10.78 moles) is stirred to reaction and finishes, and steams to add entry 3kg behind the methylene dichloride and filter; elimination removes insolubles after being dissolved in alkali; the filtrate acidifying gets solid, and vacuum-drying 2 days is pulverized; get white solid (IV); yield 50～55%, content 〉=96% (HPLC), mp 〉=260 ℃ (vaporization).
Embodiment 6
9-[2-(phosphate methoxy) ethyl] VITAMIN B4 (IV, PMEA) synthetic
Dry reaction still N
2Protection adds (III) 1.0kg (3.03 moles), methylene dichloride 5kg, chloro trimethyl silane 1.65kg (15.20 moles) successively; catalyst B (NaI, 2% mole, with respect to III); stirred 3～5 hours, TLC detects (III) and reacts completely, and adds entry 3kg after steaming methylene dichloride; filter, be dissolved in alkali after elimination remove insolubles, the filtrate acidifying gets solid; vacuum-drying 2 days is pulverized, and gets white solid (IV); yield 85～90%, content 〉=98% (HPLC), mp 〉=278 ℃ (vaporization).
Embodiment 7
Two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 (V) synthetic
Dry reaction still N
2Protection adds (IV) 1.0kg (3.66 moles), chloromethyl pivalate 2.5kg (16.60 moles) successively; NMP 4kg, triethylamine 1kg (9.88 moles) stirred 6～10 hours; add Iso Butyl Acetate 12kg; stir filtering solid, organic phase pressure reducing and steaming solvent; add acetone 1kg and normal hexane 6kg in the residual oily matter; stir solid, vacuum-drying, crude product (V).Yield 40～50%, content 〉=97% (HPLC).
Embodiment 8
Two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 (V) synthetic
Dry reaction still N
2Protection adds (IV) 1.0kg (3.66 moles), chloromethyl pivalate 2.5kg (16.60 moles), NMP 4kg, triethylamine 1kg (9.88 moles), catalyst A (NH successively
4Br is 2% mole, with respect to IV), stirred 2～3 hours, add Iso Butyl Acetate 12kg, stir the filtering solid, organic phase pressure reducing and steaming solvent adds acetone 1kg and normal hexane 6kg in the residual oily matter, stir filter solid, vacuum-drying, crude product (V).Yield 70～75%, content 〉=97% (HPLC).
Embodiment 9
Two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] preparation of VITAMIN B4 crystalline
Dry reaction still N
2Protection; gained crude product (V) heating is dissolved in the ethanol; elimination insolubles while hot; add normal hexane to muddy, it is abundant to be stirred to crystallization then, filters final vacuum dry 24 hours; get two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystallization; yield 85～90%, content 〉=99.0% (HPLC), mp99～101 ℃.
Two (pivalyl oxygen) methyl of the 9-[2-[[[that embodiment 9 obtains] phosphoroso-] methoxyl group]-ethyl] the colourless needle-like that is of VITAMIN B4 crystalline profile, be of a size of 0.40 * 0.04 * 0.04mm, crystal belongs to triclinic(crystalline)system, and spacer is P-1, and unit cell parameters is as follows:
a＝6.020(2)，
b＝11.155(4)，
c＝20.833(8)，
α＝93.798(6)°。
β＝97.458(6)°。
γ＝102.897(6)°。
Z＝2
Unit cell volume 1345.5 (9)
3,
Density is 1.327g/cm
3,
F(000)＝572。
Asymmetric cell contains a molecule and two water moleculess,
Two (pivalyl oxygen) methyl of the 9-[2-[[[that embodiment 9 obtains] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 X powder diffraction data are as follows:
Sequence number 2 θ angles value interplanar distances (d) value intensity (%)
1 7.120 12.4051 48
2 7.680 11.5018 19
3 12.140 7.2844 19
4 12.700 6.9645 19
5 12.900 6.8569 23
6 13.660 6.4771 13
7 14.260 6.2059 9
8 15.240 5.8090 3
9 15.820 5.5973 38
10 17.480 5.0693 100
11 17.920 4.9458 11
12 19.220 4.6141 4
13 19.880 4.6424 5
14 20.260 4.3795 6
15 20.920 4.2428 74
16 21.380 4.1526 32
17 21.620 4.1070 27
18 22.2820 3.9868 4
19 22.720 3.9106 18
20 23.300 3.8145 20
21 24.120 3.6867 8
22 24.500 3.6304 7
23 25.300 3.5173 9
24 25.620 3.4741 4
25 26.060 3.4165 8
26 27.600 3.2292 10
27 28.100 3.1729 12
28 28.620 3.1164 10
29 28.820 3.0953 10
30 30.740 2.9062 5
31 31.280 2.8572 6
32 32.760 2.7314 6
33 34.620 2.5888 7
Experimental example 1
The antivirus test result:
An age in days Beijing duck intravenous injection duck hepatitis B virus is adopted in experiment, begin after 7 days to the oral Adefovir crystalline esters of the present invention of duck, 3 dosage groups 7.5,15 and 30mg/kg, administration 10 days (Bid * 10), before administration (T0) respectively, after the administration after the 5th day (T5) and 10 days (T10) and the drug withdrawal 3 days (P3) get blood, separation of serum is got liver ,-70 ℃ of preservations.Observe medicine to toxicity of duck and the influence of duck serum duck hepatitis B virus DNA (DHBV-DNA).Experiment shows, after the adefovir ester crystal 3 0mg/kg group of the present invention oral medicine 10 days, nontoxicity had the restraining effect (P＜0.01) of highly significant to duck serum DHBV-DNA.The 15mg/kg group has significant inhibitory effect (P＜0.05).
Two (pivalyl oxygen) methyl of 9-[2-[[[of the present invention] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystal in the 2.2.15 cell cultures to the HBV-DNA restraining effect:
Dot hybridization IC50 40.70 ± 9.60 μ g/ml, SI=12.28; Southern Blot.IC50 16.87 ± 1.79 μ g/ml, SI=29.86.
It is interior to the HBV-DNA restraining effect that the rummy good fortune fixes on the 2.2.15 cell cultures:
Dot hybridization IC50 156.99 ± 7.16 μ g/ml, SI=7.77; Southern Blot.IC50 156.98 ± 8.58 μ g/ml, SI=7.77.
Experimental example 2
The acute toxicity tests:
Two (pivalyl oxygen) methyl of 9-[2-[[[of the present invention] phosphoroso-] methoxyl group] ethyl] VITAMIN B4 crystal single irritates the LD50＞5g/kg body weight of stomach to mouse, is equivalent to 10000 times of referrer's maximum clinical dosage 0.5mg/kg body weight/day; Single intraperitoneal injection is the 792.273mg/kg body weight to the LD50 of mouse, is equivalent to 1584 times of referrer's maximum clinical dosage 0.5mg/kg body weight/day; Single filling stomach is the 135mg/kg body weight to the MTD of Beagle dog, is equivalent to 270 times of referrer's maximum clinical dosage 0.5mg/kg body weight/day, and ALD is the 200mg/kg body weight, is equivalent to 400 times of referrer's maximum clinical dosage 0.5mg/kg body weight/day.Irritating stomach for Beagle dog single gives 9-[2-[[[of the present invention two (pivalyl oxygen) methyl] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 crystal 135mg/kg body weight (be equivalent to referrer's maximum clinical dosage 0.5mg/kg body weight/day 270 times), give 9-[2-[[[of the present invention two (pivalyl oxygen) methyl for the mouse single intraperitoneal injection] phosphoroso-] methoxyl group]-ethyl] during VITAMIN B4 crystal 4 08mg/kg body weight (be equivalent to referrer's maximum clinical dosage 0.5mg/kg body weight/day 816 times), all do not cause animal dead.Therefore, can think be subjected to two (pivalyl oxygen) methyl of reagent 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 crystal toxicity is little.
The present invention is owing to adopted cheaply Me3SiCl reagent substitutes import reagent Me of the prior art3SiBr, and add catalyst A and/or catalyst B, so two (pivaloyl oxygen) methyl of 9-[2-[[[] oxygen The phosphorus base] methoxyl group]-ethyl] the synthetic cost of adenine greatly descends. In addition, the present invention adopts lower-cost Crystallization solvent absolute ethyl alcohol and being selected from a) by formula R1-O-R
2Expression alkyl ether, wherein R1、R
2Be identical or different, representative is C separately1-6Alkyl; B) .C5-7Alkane; C) CH3COOR, wherein R is C1-5Second of alkyl The crystallization solvent substitutes crystallization solvent of the prior art, has obtained a kind of two (front threes of 9-[2-[[[of novelty Base acetyl oxygen) methyl] phosphoroso-] methoxyl group]-ethyl] the adenine crystal, it is low that this crystal has possessed synthetic cost, Advantage easy to use.
Claims (10)
1. two (pivalyl oxygen) methyl of a 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystal, its spacer is P-1, unit cell parameters a=6.020 (2) , b=11.155 (4) , c=20.833 (8) , α=93.798 (6) °. β=97.458 (6) °. γ=102.897 (6) °. unit cell volume 1345.5 (9)
3
2. crystal according to claim 1, it is a triclinic(crystalline)system.
3. crystal according to claim 2, profile is needle-like, is of a size of 0.40 * 0.04 * 0.04mm,
4. one kind prepares the described crystalline method of claim 1, comprise two (pivalyl oxygen) methyl with unbodied 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crude product is dissolved in the dehydrated alcohol, elimination insolubles while hot, in the ethanol solution of gained, add the second crystallization solvent again, stir, filter after drying.Obtain two (pivalyl oxygen) methyl of described 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] the VITAMIN B4 crystal, the described second crystallization solvent is selected from a) by formula R
1-O-R
2Expression alkyl oxide, wherein R
1, R
2Be identical or different, representative is C separately
1-6Alkyl; B) C
5-7Alkane; C) CH
3COOR, wherein R is C
1-5Alkyl.
5. method according to claim 4, two (pivalyl oxygen) methyl of wherein unbodied 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] weight ratio of VITAMIN B4 crude product and dehydrated alcohol is 1: 1-5.
6. method according to claim 5, two (pivalyl oxygen) methyl of wherein unbodied 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] weight ratio of VITAMIN B4 crude product and dehydrated alcohol is 1: 2.
7. method according to claim 6, two (pivalyl oxygen) methyl of wherein said 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] ethanol solution of VITAMIN B4 and the volume ratio of the described second crystallization solvent be 1: 6-8.
8. the application of crystal as claimed in claim 1 in the preparation antiviral.
9. application according to claim 8, wherein said virus are selected from HBV, HIV, people CMV, HSV-1, HSV-2 and human herpes virus 6.
10. pharmaceutical composition, it comprises two (pivalyl oxygen) methyl of 9-[2-[[[as claimed in claim 1] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 and pharmaceutically acceptable vehicle.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021510326A CN1142171C (en) | 2002-12-04 | 2002-12-04 | 9-[2-[[[di (trimethylacetoxyl) methyl phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021510326A CN1142171C (en) | 2002-12-04 | 2002-12-04 | 9-[2-[[[di (trimethylacetoxyl) methyl phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1421451A CN1421451A (en) | 2003-06-04 |
| CN1142171C true CN1142171C (en) | 2004-03-17 |
Family
ID=4751892
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021510326A Expired - Fee Related CN1142171C (en) | 2002-12-04 | 2002-12-04 | 9-[2-[[[di (trimethylacetoxyl) methyl phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1142171C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101101962B1 (en) * | 2002-11-12 | 2012-01-02 | 티안진 디실리 인베스트먼트 홀딩 그룹, 리미티드 | A method for preparing a new crystal form of adefovir dipivoxil |
| CN102716136A (en) * | 2012-06-25 | 2012-10-10 | 上海益生源药业有限公司 | High-dose clinorhomboidal adefovir dipivoxil preparation, and preparation method and application thereof |
-
2002
- 2002-12-04 CN CNB021510326A patent/CN1142171C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1421451A (en) | 2003-06-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1052227C (en) | Adhesion receptor antagonists | |
| CN1035829A (en) | (cycloalkyl amido) methylene-bis (phosphonic acids) and with the medicine of this compound as active ingredient | |
| CN1489463A (en) | Novel crystal forms of atorvastatin hemi-calcium and process for their preparation as well as novel process for preparing other forms | |
| CN1045089C (en) | 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative | |
| CN1292785A (en) | Hypolipidemic benzothiazepine compounds | |
| CN101031548A (en) | Salts of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy) phenylmethyl) carbamide and their preparation | |
| CN1898233A (en) | Process for the manufacture of the calcium salt of rosuvatatin (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid and crystallin | |
| CN1259951A (en) | Novel pharmaceutically useful compounds | |
| CN1886383A (en) | Process for the preparation of amorphous rosuvastatin calcium | |
| CN1942437A (en) | Substituted azetidine compounds as cyclooxygenase-1-cyclooxygenase-2 inhibitors, and their preparation and use as medicaments | |
| CN1029968C (en) | Process for preparation of N-heteroaryl-purin-6-amines and their use as medicaments | |
| CN1551880A (en) | Crystalline forms of valacyclovir hydrochloride | |
| CN1039910C (en) | Calanthamine derivatives, a process for their preparation and their use as medicaments | |
| CN1874998A (en) | 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]-methyl piperidine oxalate (donepezil oxalate) and its polymorphs | |
| CN1675193A (en) | Prodrugs of 1-methyl-2-(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carboxylic acid-(n-2-pyridyl-n-2-hydroxycarbonylethyl)-amide | |
| CN1043042C (en) | Cephalosporins derivatives and process for preparing them | |
| CN1142170C (en) | 9-[2-[[[di (trimethylacetoxyl) methyl] phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application | |
| CN1142171C (en) | 9-[2-[[[di (trimethylacetoxyl) methyl phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application | |
| CN1092074A (en) | Azepine derivatives | |
| CN1101259A (en) | Novel aesculetin derivatives and pharmaceutical | |
| CN1849320A (en) | Process for the preparation of renzapride and intermediates thereof | |
| CN1886371A (en) | Processes for the preparation of a polymorph of fluvastatin sodium | |
| CN1170829C (en) | Optically active pyrrolopyridazine compound | |
| CN1194006A (en) | Conversion of indene to (1S)-amino-(2R)-indanol free of any stereoisomer, by combination of dioxygenase bioconversion and chemical steps | |
| CN1050380A (en) | New substituted alkyl piperidines and as the application of cholesterol synthesis inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: SHANGHAI YISHENGYUAN PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: SHANGHAI RUIGUANG BIOCHEMICAL TECHNOLOGY DEVELOPMENT CO., LTD.; LI QISHENG Effective date: 20060609 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20060609 Address after: 201318 Shanghai city Nanhui District Zhoupu town inntech Road No. 98 Patentee after: Shanghai Yishengyuan Pharmaceutical Co., Ltd. Address before: 902 room 1, 200002 Ningbo Road, Shanghai Co-patentee before: Li Qisheng Patentee before: Shanghai Ruiguang Biochemical Sci-Tech Development Co., Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Effective date of registration: 20091015 Pledge (preservation): Pledge |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20100429 Granted publication date: 20040317 Pledgee: Agricultural Bank of China, Limited by Share Ltd, Shanghai, Nanhui branch Pledgor: Shanghai Yishengyuan Pharmaceutical Co., Ltd. Registration number: 2009310000627 |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040317 Termination date: 20201204 |