CN102070670A - Purine derivatives for treating hepatitis B and preparation method and application thereof - Google Patents
Purine derivatives for treating hepatitis B and preparation method and application thereof Download PDFInfo
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- CN102070670A CN102070670A CN2009101028766A CN200910102876A CN102070670A CN 102070670 A CN102070670 A CN 102070670A CN 2009101028766 A CN2009101028766 A CN 2009101028766A CN 200910102876 A CN200910102876 A CN 200910102876A CN 102070670 A CN102070670 A CN 102070670A
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- 0 *C(C(OCCCOP(COCC[n]1c2ncnc(*)c2nc1)(OCCOC(*)=O)=O)=O)N Chemical compound *C(C(OCCCOP(COCC[n]1c2ncnc(*)c2nc1)(OCCOC(*)=O)=O)=O)N 0.000 description 1
Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to purine compounds capable of treating hepatitis B and having a structure shown in a structural general formula I, and pharmacologically acceptable inorganic or organic acid salts thereof, and a preparation method and application thereof. Pharmacological tests prove that: the compounds have obvious activity of resisting hepatitis B virus and can be applied to preparing anti-virus medicines.
Description
Technical field
The present invention relates to the synthetic and area of pharmacology of medicine.Particularly, relate to the non-cyclic nucleoside phosphonate compound and the preparation of compositions method thereof that contain L-amino acid and nonsteroidal anti-inflammatory agent group, and the purposes of this compounds in the preparation antiviral.
Background technology
(Hepatitis B Virus HBV), is one of virus of the easy infection mankind to hepatitis B virus.WHO report thinks that the whole world has 2,000,000,000 people of surpassing once infected, still has 3.5-4 hundred million to be the chronic HBV infection person at present approximately.Statistics shows has 80% liver cancer case in the world all owing to hepatitis B virus infection causes, hepatitis B virus infection also is the major cause that causes liver failure in addition, and the whole world has a million people to die from and hepatitis b virus infected relevant hepatopathy every year approximately.Current, treat hepatitis b virus infected two approach that mainly contain: the one, immunotherapy is as interferon-alpha; The 2nd, carry out antiviral therapy at viral target spot, as nucleoside compound (comprising nucleoside analog and acyclonucleosides phosphonic acid ester).Existing at present three non-cyclic nucleoside phosphonate medicines listing, adefovir ester (Adefovir Dipivoxil wherein, ADV) be to ratify the small molecules acyclonucleosides phosphonic acids prodrug that first is used for the treatment of chronic viral hepatitis B through FDA in 2002, this medicine can obviously improve hepatitis B patient liver histological character, reduce serum HBV-DNA and transaminase level, increase e antigen (HBeAg) transformation efficiency (Yuen, M.-F.Expert Opin Pharmacother 2004,5, (11): 2361).Although adefovir ester has above advantage, it is to produce dosage according to the patience renal toxicity that but its deficiency is found in clinical study, discharge and have Cytotoxic trimethylacetic acid and formaldehyde, while compound less stable in gastrointestinal fluid, (Roula B.Clinical Therapeutics 2003,25 (12): 3084 can not effectively to increase the drug level of action target spot; Nozomu T.Human Pathology 2001,32 (7) 734; Douglash, H.S.Am J Physiol RenalPhysiol.2001,281, F 197).Studies show that in the Adefovir Dipivoxil design be that ectogenic fragment is connected by ester bond with the acyclonucleosides phosphonic acids, thereby in the process that discharges former medicine Adefovir, may produce cytotoxic carrier segments; Do not consider how to reduce the dose-dependently renal toxicity that the phosphonic acids pairs of anion that forms after the carrier cracking is produced in addition in the design of this prodrug, thereby may limit the clinical application of these prodrugs to a certain extent.
We are according to the principle of design (Isabel of small intestinal mucosa peptide transporter (PEPT1) to the active transport mechanism of oligopeptides and the antiviral prodrug of nucleosides L-amino acid esters reported in early-stage Study, Rubio-A.TrendsPharmacol Sci 2003,23, (9): 434), design, synthesized the two L-amino acid ester prodrugs of the novel Adefovir that does not appear in the newspapers.Anti-HBV activity research finds that this compounds has the anti-HBV activity stronger than adefovir ester, lower cytotoxicity and the plasma stability of Geng Gao (Xiaozhong Fu.Bioorg MedChem Lett.2007,17 (2): 465-470).
Find by the nosetiology Mechanism Study that adefovir ester is produced the dose-dependently renal toxicity, medicine enters cracking forms after the blood circulation Adefovir phosphonic acids pairs of anion and can be present in organic anion transporter 1 (hOAT1) transmembrane transport on the renal tubular basement membrane and be deposited in the renal proximal tubules, the latter by suppressing proximal tubular epithelial cells plastosome DN (mtDNA) thus duplicate and make mtDNA consumption tone tablet, and final cytochrome C oxidase (COX) level that reduces by the mtDNA coding, destroying epithelial cell oxidation respiratory is the basic reason (Edmund that medicine produces renal toxicity, S.H.J Am Soc Nephrol.2000,11,383; Roula B.Clinical Therapeutics 2003,25 (12): 3084).Pharmaceutical research is found under the treatment concentration of Adefovir, NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) is as Ibuprofen BP/EP (Ibuprofen), Ketoprofen (Ketoprofen), flurbiprofen (Flurbiprofen), Naproxen Base (Naproxen) etc. can effectively suppress the Adefovir of hOAT1 mediation and stride the renal tubular basement membrane transport process and reduce the nephrocyte toxicity that the latter produces, NSAID (non-steroidal anti-inflammatory drug) is identical with probenecid to the transhipment inhibition mechanism of Adefovir, and its half-inhibition concentration is lower than probenecid, and research finds also that simultaneously NSAIDs does not influence the antiviral activity of adefovir ester.Above-mentioned in addition NSAIDs is to expressing the Chinese hamster ovary cell (CHO of hOAT1
HOAT) half-inhibition concentration of growth strides half-inhibition concentration (Andrew, S.M.J Pharmacol Exp The.2000,295,10 of renal tubular basement membrane transhipment much larger than its Adefovir to hOAT1 mediation; Tomas Cihlar Nucleosides, Nucleotides and Nucleic Acids, 2001,20 (4-7): 641).Research finds to utilize the NSAID (non-steroidal anti-inflammatory drug) of hOAT1 mediation and the mutual transhipment antagonism between the Adefovir to concern strategy (the Douglas H.S.Toxicology andApplied Pharmacology 2005 that realizes reducing by two class medicine renal toxicitys clinically and do not reduce its result of treatment simultaneously, 204,198).These studies show that NSAIDs can effectively suppress renal cells under the Cytotoxic prerequisite Adefovir is absorbed not producing, and reduces the nephrocyte toxicity of Adefovir.
This patent is the key breakthrough mouth to reduce the dosage that produces in the adefovir ester clinical application according to the patience renal toxicity, to have higher anti-HBV Adefovir pair L-amino acid esters active and than low cytotoxicity is lead compound, the structure principle of hybridization of utilization in the medicinal design introduced L-amino acid and nonsteroidal anti-inflammatory drug structure fragment simultaneously on the phosphonyl group of Adefovir and designed, synthetic Adefovir list L-amino acid ester, single nonsteroidal anti-inflammatory drug carboxylicesters prodrug, be intended to utilize the L-amino acid ester fragment in the prodrug structure to improve the active and effect selectivity of its anti-HBV, utilize the nonsteroidal anti-inflammatory drug fragment to reduce its renal toxicity, have than high antiviral active in the hope of finding, the anti-HBV Adefovir prodrug of low renal toxicity.Thereby realize reducing the active purpose of anti-HBV that the dose-dependently renal toxicity that occurs in the adefovir ester clinical application improves medicine simultaneously.
Summary of the invention
The purpose of this invention is to provide a class and have on the purine compound of anti-hepatitis B virus activities and the pharmacology thereof the inorganic or organic salt crystalline hydrate of acceptable, solvate.
Another object of the present invention provides the preparation method of above-claimed cpd
A further object of the present invention provides the pharmaceutical composition that comprises above-claimed cpd
A further object of the present invention provides the medicinal use of above-claimed cpd
A further object of the present invention provides the medicinal use of above-mentioned composition
The invention provides a class and have on the purine compound of structure shown in the following structural formula I and the pharmacology thereof the inorganic or organic salt crystalline hydrate of acceptable, solvate.
Wherein,
R1 is amino;
R2 is that nonsteroidal anti-inflammatory agent acetylsalicylic acid acyl group, Ibuprofen BP/EP acyl group, fluorine are than Luo Fen acyl group;
R3 is alkyl or hydrogen atom.
Preferably, representative compounds of the present invention can be following compound:
1) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester, single acetylsalicylic acid propyl diester
2) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-leucine propyl diester, single acetylsalicylic acid propyl diester
3) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, single acetylsalicylic acid propyl diester
4) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, single acetylsalicylic acid propyl diester
5) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base glycine propyl diester, single Ibuprofen BP/EP propyl diester
6) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-L-Ala propyl diester, single Ibuprofen BP/EP propyl diester
7) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester, single Ibuprofen BP/EP propyl diester
8) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-leucine propyl diester, single Ibuprofen BP/EP propyl diester
9) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, single Ibuprofen BP/EP propyl diester
10) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, single Ibuprofen BP/EP propyl diester
11) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base glycine propyl diester, single flurbiprofen propyl diester
12) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-L-Ala propyl diester, single flurbiprofen propyl diester
13) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester, single flurbiprofen propyl diester
14) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-leucine propyl diester, single flurbiprofen propyl diester synthetic
15) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, single flurbiprofen propyl diester
16) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, single flurbiprofen propyl diester
17) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Xie Ansuan of VITAMIN B4 propyl diester, single acetylsalicylic acid propyl group
18) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-leucine of VITAMIN B4 propyl diester, single acetylsalicylic acid propyl diester
19) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Isoleucine of VITAMIN B4 propyl diester, single acetylsalicylic acid propyl diester
20) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-phenylalanine of VITAMIN B4 propyl diester, single acetylsalicylic acid propyl diester
21) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single glycine propyl diester of VITAMIN B4, single Ibuprofen BP/EP propyl diester
22) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-L-Ala of VITAMIN B4 propyl diester, single Ibuprofen BP/EP propyl diester
23) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Xie Ansuan of VITAMIN B4 propyl diester, single Ibuprofen BP/EP propyl diester
24) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-leucine of VITAMIN B4 propyl diester, single Ibuprofen BP/EP propyl diester
25) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Isoleucine of VITAMIN B4 propyl diester, single Ibuprofen BP/EP propyl diester
26) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-phenylalanine of VITAMIN B4 propyl diester, single Ibuprofen BP/EP propyl diester
27) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single glycine propyl diester of VITAMIN B4, single flurbiprofen propyl diester
28) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-L-Ala of VITAMIN B4 propyl diester, single flurbiprofen propyl diester
29) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Xie Ansuan of VITAMIN B4 propyl diester, single flurbiprofen propyl diester
30) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-leucine of VITAMIN B4 propyl diester, single flurbiprofen propyl diester synthetic
31) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Isoleucine of VITAMIN B4 propyl diester, single flurbiprofen propyl diester
32) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-phenylalanine of VITAMIN B4 propyl diester, single flurbiprofen propyl diester
The structural formula of representation compound of the present invention sees Table 1
Table 1 representation compound 17-32 of the present invention structural formula
The present invention also provides the method for preparing above-claimed cpd
The method for preparing above-claimed cpd may further comprise the steps:
(1) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 (PMEA) and N-tertbutyloxycarbonyl-L-amino acid 3-bromopropyl ester be in polar aprotic solvent; with N; N '-dicyclohexyl-4-morpholinyl-amidine (DCMC) or 1; 8-diazabicyclo [5,4,0] undecane-7 alkene is alkali, and reaction obtains compound:
(2) above-mentioned steps 1) behind the compound that obtains without separation; the acetylsalicylic acid 3-bromopropyl ester, Ibuprofen BP/EP 3-bromopropyl ester or the flurbiprofen 3-bromopropyl ester that promptly add suitable proportion; the rising temperature of reaction makes the compound and the ester condensation of nonsteroidal anti-inflammatory drug 3-bromopropyl that obtain in the step 1) generate 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-amino acid propyl ester, single NSAID (non-steroidal anti-inflammatory drug) propyl diester:
(3) above-mentioned steps 2) compound that obtains sloughs tertbutyloxycarbonyl with an amount of 85% phosphoric acid solution or Acetyl Chloride 98Min./methanol system and obtains target compound in polarity or non-polar solvent:
The preparation method of target compound is shown in flow process (I) particularly:
Wherein, a:N, N '-dicyclohexyl-4-morpholinyl-amidine (DCMC), N, dinethylformamide, 30～60 ℃; B:N, N '-dicyclohexyl-4-morpholinyl-amidine (DCMC), N, dinethylformamide, 60～120 ℃; C:85% phosphoric acid solution/chloroform or Acetyl Chloride 98Min./methyl alcohol ,-5 ℃～25 ℃.
The embodiment of flow process (I) is described in detail as follows:
1, with N-tertbutyloxycarbonyl-L-amino acid, nonsteroidal anti-inflammatory drug (acetylsalicylic acid, Ibuprofen BP/EP, flurbiprofen) is that reaction raw materials is according to the synthetic N-tertbutyloxycarbonyl of bibliographical information method-L-amino acid 3-bromopropyl ester and nonsteroidal anti-inflammatory drug 3-bromopropyl ester (Tetrahedron Lett.1979 with 3-bromo-1 propyl alcohol, 20, (40), 3811-381.4.J.Chem.Res.1991，10，292-302)；
2, N-tertbutyloxycarbonyl-L-amino acid 3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] ratio of VITAMIN B4 is 1.0～5.5: 1mol, in polar aprotic solvent, with N, N '-dicyclohexyl-4-morpholinyl-amidine (DCMC) or 1,8-diazabicyclo [5,4,0] undecane-7 alkene (DBU) is alkali, reacted 4～48 hours down at 30-90 ℃, optimum reaction condition is N-tertbutyloxycarbonyl-L-amino acid 3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] ratio of VITAMIN B4 is 1.0～2.0: 1mol, with N, N '-dicyclohexyl-4-morpholinyl-amidine (DCMC) is an alkali, at N, dinethylformamide is under the solvent condition, reacted 4～10 hours down at 30～60 ℃, obtain 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-amino acid propyl ester intermediate;
3, the 9-[2-that produces in the system (phosphonium mesitoyl methoxy) ethyl] after VITAMIN B4 mono-N-tert-butoxycarbonyl base L-amino acid propyl ester intermediate transformation efficiency reaches maximum, system is without separation, promptly adding and 9-[2-(phosphonium mesitoyl methoxy) ethyl] the VITAMIN B4 ratio is 1-0～5.5: 1mol NSAID (non-steroidal anti-inflammatory drug) 3-bromopropyl ester, system was reacted 10～48 hours down at 60～120 ℃, optimum reaction condition is NSAID (non-steroidal anti-inflammatory drug) 3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] the VITAMIN B4 ratio is 1.0～2.0: 1mol, system obtains compound 1-16 60～100 ℃ of reactions 10～18 hours;
4, compound 1-16 in polarity or non-polar solvent with an amount of 85% phosphoric acid solution or Acetyl Chloride 98Min./methanol system, under-10～25 ℃, reacted 0.2～16 hour, optimum reaction condition is for being under the solvent condition at chloroform, system was reacted under-5 ℃～room temperature 8～12 hours with 85% phosphoric acid, or in Acetyl Chloride 98Min./methanol system 0 ℃～25 ℃ the reaction 5-12 hour, obtain target compound 17-32.
The present invention also provides the pharmaceutical composition that comprises above-mentioned purine compound, and described composition comprises the compound of the present invention as active ingredient for the treatment of effective dose, and assistant agent.
The present invention also provides above-mentioned purine compound to be used for the treatment of application in the hepatitis B in preparation.
The present invention also provide said medicine be combined in the treatment hepatitis B medicine in application.
Unless dated especially, term used herein has to give a definition:
Straight chain, the branched alkane hydrocarbon chain of " alkyl " saturated or undersaturated, replacement of expression or non-replacement, concrete enumerates as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, 1-methyl butyl, 2-methyl butyl, 2-methyl-propyl, hexyl, isohexyl, 1-methyl amyl, 2-methyl amyl, 3-methyl amyl, 2-methyl butyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl etc.In these groups, being that the individual alkyl of 1-4 is good with carbonatomss such as methyl, ethyl, propyl group, sec.-propyl, butyl, is the best with methyl, ethyl, propyl group.
" pharmacy acceptable salt " can enumerate the salt with mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphonic acids particularly, with organic acid and the acid salt of acidic amino acids such as aspartic acid, L-glutamic acid or the salt that form with basic aminoacidss such as Methionin, arginine, ornithines such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acids.
Embodiment
Make each embodiment 1:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester, the preparation of single acetylsalicylic acid propyl diester
Under drying, the nitrogen protection condition, with 9-[2-(phosphonium mesitoyl methoxy) ethyl] and VITAMIN B4 (0.4g, 1.47mmol); N, and N '-dicyclohexyl-4-morpholinyl-amidine (DCMC) (0.84g, 2.88mmol); place the dry N of 40mL, in the dinethylformamide, 80 ℃ are heated 1 hour to clear; be cooled to 60 ℃; contain N-tertbutyloxycarbonyl-L-Xie Ansuan-3-bromopropyl ester (0.7g, 2.16mmol) 10mLN, dinethylformamide solution in the gradation dropping; finish, continue insulation 12h.After TLC monitors and transforms fully to monoesters, add acetylsalicylic acid-3-bromopropyl ester (0.43g, 1.44mmol), 70 ℃ were reacted 12 hours, TLC removes reaction solvent under reduced pressure after monitoring and transforming fully to dibasic acid esters, and resistates is dissolved among the EtOAc of 50mL, left standstill 1-2 hour in low temperature (10 ℃), filter, filtrate is respectively with 0.5% hydrochloric acid soln, and water and saturated nacl aqueous solution washing are to neutral, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and resistates is with ethyl acetate: methyl alcohol=20: 1 is eluent, silica gel column chromatography separate colorless oil target product 157mg, productive rate 14.3%.
1H-NMR(400MHz，DMSO-d6)δ：8.11(s，1H)，8.06(s，1H)，7.79(d，J＝8.0Hz，1H)，7.52(t，J＝8.0Hz，1H)，7.20(brs，3H)，6.97(d，J＝8.4Hz，1H)，6.92(t，J＝7.6Hz，1H)，4.33-3.80(m，15H)，2.25(m，1H)，1.96(brs，5H)，1.80(t，J＝5.6Hz，2H)，1.34(s，9H)，0.83(d，J＝6.0Hz，6H)。
Preparation embodiment 2:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base-L-leucine propyl diester, the preparation of single acetylsalicylic acid propyl diester
With compound N-tertbutyloxycarbonyl-L-leucine-3-bromopropyl ester, acetylsalicylic acid-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 1 method.Get the colorless oil target product, productive rate 10.4%.
1H-NMR(400MHz，DMSO-d6)δ：8.10(s，1H)，8.05(s，1H)，7.95(d，J＝7.6Hz，1H)，7.79(m，1H)，7.26(m，1H)，6.97(m，1H)，4.25(m，7H)，4.04(m，4H)，3.87(m，4H)，2.25(s，1H)，1.97(m，4H)，1.80(m，2H)，1.58(s，9H)，0.84(m，6H)。
Make each embodiment 3:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, the preparation of single acetylsalicylic acid propyl diester
With N-tert-butoxy-oxo-L-isoleucine-3-bromopropyl ester, acetylsalicylic acid-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 1 method.Get the colorless oil target product, productive rate 19.6%.
1H-NMR(400MHz，DMSO-d6)δ：8.10(s，1H)，8.06(s，1H)，7.79(d，J＝7.6Hz，1H)，7.50(m，1H)，7.21(m，1H)，6.97-6.92(m，1H)，4.33(t，J＝6.0Hz，4H)，4.07-3.89(m，7H)，3.89(m，2H)，3.87(d，J＝7.2Hz，2H)，1.97(s，3H)，1.81-1.78(m，5H)，1.65-1.55(m，2H)，1.34(s，9H)，0.78(m，6H)。
Preparation embodiment 4:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, the preparation of single acetylsalicylic acid propyl diester
With N-tertbutyloxycarbonyl-L-4-quinone-bromopropyl ester, acetylsalicylic acid-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 1 method.Get the colorless oil target product, productive rate 9.6%.
1H-NMR(400MHz，DMSO-d6)δ：8.11(s，1H)，8.06(s，1H)，7.79(d，J＝7.6Hz，1H)，7.50(t，J＝7.6Hz，1H)，7.35(d，J＝8.0Hz，1H)，7.26-7.17(m，5H)，6.97-6.90(m，2H)，4.33(t，J＝6.4Hz，4H)，4.14-3.98(m，8H)，3.98-3.85(m，3H)，2.94-2.83(2m，2H)，1.96(brs，5H)，1.73(t，J＝4.8Hz，2H)，1.34(s，9H)。
Preparation embodiment 5:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base-glycine propyl diester, the preparation of single Ibuprofen BP/EP propyl diester
Under drying, the nitrogen protection condition; with 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 (0.4g; 1.47mmol); N; (0.84g 2.88mmol) places the dry N of 40mL, in the dinethylformamide to N '-dicyclohexyl-4-morpholinyl-amidine (DCMC); 80 ℃ be heated to clarification after, be cooled to 60 ℃.(0.44g 1.47mmol), finishes, and continues insulation reaction 18 hours slowly to drip N-tertbutyloxycarbonyl-glycine-3-bromine propyl ester.TLC adds and contains Ibuprofen BP/EP-3-bromine propyl ester (0.48g, 10mL N 1.47mmol) after monitoring and transforming fully to monoesters, dinethylformamide solution, 80 ℃ were reacted 20 hours, and TLC removes solvent under reduced pressure after monitoring and transforming fully to dibasic acid esters, resistates is dissolved in the 50mL ethyl acetate, low temperature (10 ℃) leaves standstill, and filters, and filtrate is respectively with 0.5% hydrochloric acid soln, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying spends the night.Filter, the solvent evaporated under reduced pressure, crude product is with methylene dichloride: methyl alcohol=15: 1 is eluent, silica gel column chromatography separate faint yellow oily target product 248mg, productive rate 24.4%.
1H-NMR(400MHz，CDCl
3)δ：8.33(s，1H)，7.91(s，1H)，7.19(d，J＝8.0Hz，2H)，7.09(d，J＝7.6Hz，2H)，4.38-4.37(m，2H)，4.19-4.10(m，4H)，4.03-3.87(m，8H)，3.74-3.66(m，3H)，2.43(d，J＝7.2Hz，2H)，1.91-1.88(m，4H)，1.85-1.79(m，1H)，1.51-1.44(m，12H)1.88(d，J＝6.4Hz，3H)。
Preparation embodiment 6:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-L-Ala propyl diester, the preparation of single Ibuprofen BP/EP propyl diester
With N-tert-butoxycarbonyl-l-alanine-3-bromopropyl ester, Ibuprofen BP/EP-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 5 methods.Get the colorless oil target product, productive rate 32.4%.
1H-NMR(400MHz，CDCl
3)δ：8.33(s，1H)，7.91(s，1H)，7.18(d，J＝7.6Hz，2H)，7.08(d，J＝7.6Hz，2H)，4.44-4.27(m，2H)，4.18-4.01(m，8H)，3.70-3.61(m，5H)，3.48-3.44(m，1H)，2.43(d，J＝6.4Hz，2H)，1.91-1.78(m，4H)，1.48-1.37(m，15H)，0.88-0.87(d，J＝6.4Hz，3H)。
Preparation embodiment 7:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester, the preparation of single Ibuprofen BP/EP propyl diester
With N-tertbutyloxycarbonyl-L-Xie Ansuan-3-bromopropyl ester, Ibuprofen BP/EP-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 5 methods.Get faint yellow oily target product, productive rate 22.9%.
1H-NMR(400MHz，CDCl
3)δ：8.34(s，1H)，7.91(s，1H)，7.19(d，J＝7.6Hz，2H)，7.09(d，J＝7.6Hz，2H)，4.39(m，2H)，4.38-4.00(m，9H)，3.89-3.88(m，2H)，3.75-3.68(m，3H)，2.43(d，J＝6.8Hz，2H)，1.92-1.81(m，5H)，1.49-1.43(m，12H)，0.96-0.87(m，5H)。
Preparation embodiment 8:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-leucine propyl diester, the preparation of single Ibuprofen BP/EP propyl diester
With N-tertbutyloxycarbonyl-L-leucine-3-bromopropyl ester, Ibuprofen BP/EP-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 5 methods.Get faint yellow oily target product, productive rate 7.3%.
1H-NMR(400MHz，CDCl
3)δ：8.34(s，1H)，7.91(s，1H)，7.26(d，J＝7.2Hz，2H)，7.09(d，J＝7.6Hz，2H)，5.30(m，1H)，4.39-4.33(m，3H)，4.17-4.12(m，4H)，4.02-4.00(m，4H)，3.89(d，J＝7.2Hz，2H)，1.91(m，6H)，1.49-1.43(m，12H)，0.93(d，J＝6.4Hz，12H)。
Preparation embodiment 9:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, the preparation of single Ibuprofen BP/EP propyl diester
With N-tert-butoxy-oxo-L-isoleucine-3-bromopropyl ester, Ibuprofen BP/EP-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 5 methods.Get the colorless oil target product, productive rate 8.9%.
1H-NMR(400MHz，CDCl
3)δ：δ：8.33(s，1H)，7.91(s，1H)，7.19(d，J＝8.4Hz，2H)，7.09(d，J＝8.0Hz，2H)，4.40-4.36(m，2H)，4.20-4.13(m，4H)，4.08-3.99(m，4H)，3.90-3.87(m，1H)，3.75-3.66(m，4H)，3.39-3.37(q，J＝7.6Hz，1H)，2.43(d，J＝6.8Hz，2H)，1.95-1.89(m，4H)，1.84-1.72(m，2H)，1.42(s，9H)1.48(d，J＝7.2Hz，3H)，1.25-1.16(m，2H)，0.94(d，J＝6.8Hz，3H)，0.91-0.87(m，9H)。
Preparation embodiment 10:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, the preparation of single Ibuprofen BP/EP propyl diester
With N-tertbutyloxycarbonyl-L-4-quinone-bromopropyl ester, Ibuprofen BP/EP-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 5 methods.Get the colorless oil target product, productive rate 8.4%.
1H-NMR(400MHz，CDCl
3)δ：8.32(s，1H)，7.89(s，1H)，7.27-7.12m，6H)，7.08-7.07(m，2H)，4.652(s，1H)，4.37-4.36(m，2H)，4.15-3.95(m，8H)，3.88-3.87(m，2H)，3.74-3.66(m，3H)，2.47-2.41(m，2H)，1.91-1.80(m，5H)，1.48-1.46(d，J＝7.2Hz，3H)，1.39(s，9H)，0.88(d，J＝6.4Hz，6H)。
Preparation embodiment 11:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base glycine propyl diester, the preparation of single flurbiprofen propyl diester
With N-tertbutyloxycarbonyl-glycine-3-bromopropyl ester, flurbiprofen-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 5 methods.Get faint yellow oily target product, productive rate 21.3%.
1H-NMR(400MHz，CDCl
3)δ：8.32(s，1H)，7.91(s，1H)，7.53-7.51(m，2H)，7.44-7.33(m，4H)，7.15-7.10(m，2H)，4.37-4.36(m，2H)，4.17-4.16(m，4H)，4.04-4.02(m，4H)，3.93-3.87(m，4H)，3.77-3.72(m，3H)，1.95-1.89(m，4H)，1.54(d，J＝6.8Hz，3H)，1.44(s，9H)。
Preparation embodiment 12:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-L-Ala propyl diester, the preparation of single flurbiprofen propyl diester
With N-tert-butoxycarbonyl-l-alanine-3-bromopropyl ester, flurbiprofen-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 5 methods.Get faint yellow oily target product, productive rate 22.2%.
1H-NMR(400MHz，CDCl
3)δ：8.33(s，1H)，7.91(s，1H)，7.53-7.51(m，2H)，7.45-7.34(m，4H)，7.15-7.10(m，2H)，4.37(m，3H)，4.17-4.16(m，4H)，4.08-4.03(m，4H)，3.90-3.88(m，1H)，3.79-3.72(m，4H)，1.95-1.92(m，4H)，1.54-1.42(d，J＝7.2Hz，3H)，1.43(s，9H)，1.38-1.36(d，J＝7.2Hz，3H)。
Preparation embodiment 13:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester, the preparation of single flurbiprofen propyl diester
With N-tertbutyloxycarbonyl-L-Xie Ansuan-3-bromopropyl ester, flurbiprofen-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 5 methods.Get faint yellow oily target product, productive rate 17.7%.
1H-NMR(400MHz，CDCl
3)6：8.33(s，1H)，7.91(s，1H)，7.52(d，J＝7.6Hz，2H)，7.45-7.36(m，4H)，7.15-7.10(m，2H)，4.38-4.37(m，2H)，4.18-4.03(m，8H)，3.89-3.72(m，6H)，1.93-1.92(m，5H)，1.54-1.52(d，J＝7.2Hz，3H)，1.43(s，9H)，0.96-0.86(m，6H)。
Make each embodiment 14:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-leucine propyl diester, the preparation of single flurbiprofen propyl diester
With N-tertbutyloxycarbonyl-L-leucine-3-bromopropyl ester, flurbiprofen-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 5 methods.Get faint yellow oily target product, productive rate 11.1%.
1H-NMR(400MHz，CDCl
3)δ：8.31(s，1H)，7.99(s，1H)，7.53-7.52(m，2H)，7.45-7.36(m，4H)，7.15-7.10(m，2H)，4.39-4.38(m，3H)，4.27-4.05(m，8H)，3.88-3.72(m，5H)，1.94(m，4H)，1.54-1.52(m，2H)，1.46-1.42(m，13H)，0.94-0.91(m，6H)。
Preparation embodiment 15:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, the preparation of single flurbiprofen propyl diester
With N-tert-butoxy-oxo-L-isoleucine-3-bromopropyl ester, flurbiprofen-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 5 methods.Get faint yellow oily target product, productive rate 14.2%.
1H-NMR(400MHz，CDCl
3)δ：δ：8.31(s，1H)，7.91(s，1H)，7.53(d，J＝8.0Hz，2H)，7.44-7.32(m，4H)，7.15-7.10(m，2H)，4.38-4.35(m，2H)，4.20-4.09(m，8H)，3.90-3.69(m，5H)，3.37-3.35(m，1H)，1.96-1.91(m，4H)，1.74-1.71(m，1H)，1.53(d，J＝7.2Hz，3H)，1.43(s，9H)，1.26-1.14(m，42H)，0.92-0.86(m，6H)。
Preparation embodiment 16:9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, the preparation of single flurbiprofen propyl diester
With N-tertbutyloxycarbonyl-L-4-quinone-bromopropyl ester, flurbiprofen-3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is that reaction raw materials is according to being similar to the preparation of embodiment 5 methods.Get faint yellow oily target product, productive rate 9.8%
1H-NMR(400MHz，CDCl
3)δ：8.31(s，1H)，7.88(s，1H)，7.53(d，J＝8.4Hz，2H)，7.44-7.30(m，4H)，7.28-7.2δ(m，2H)，7.23-7.10(m，5H)，4.37-4.35(m，2H)，4.34-3.15(m，4H)，4.03-3.94(m，4H)，3.89-3.84(m，2H)，3.80-3.71(m，5H)，2.17-1.84(m，4H)，1.53(d，J＝7.2Hz，3H)，1.44(s，9H)。
Make each embodiment 17:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Xie Ansuan of VITAMIN B4 propyl diester, the preparation of single acetylsalicylic acid propyl diester
Exsiccant 4.2mL ethyl acetate is placed the round-bottomed flask of 25mL, and ice-water bath stirs, add successively methyl alcohol (0.032mL, 0.74mmol), Acetyl Chloride 98Min. (0.054mL, 0.74mmol), insulation reaction 4h.With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester; single acetylsalicylic acid propyl diester (80mg; 0.106mmol) be dissolved in the ethyl acetate of 4.2mL; be added in the above-mentioned reaction system; insulation reaction 2 hours; after rise to room temperature gradually, reacted 8 hours.TLC monitoring reaction process to product transforms fully back (developping agent methylene dichloride: methyl alcohol=15: 1).Stopped reaction, leave standstill, remove solvent under reduced pressure, add the 5mL ether, make and separate out precipitation, shift the solution part to centrifuge tube centrifugation (5000r/m), abandoning supernatant, a small amount of anhydrous alcohol solution also merges precipitation, adds the 5mL ether precipitation is separated out, and repeats above-mentioned washing operation and makes for 3 times solution to closely medium-sized totally.Decompressing and extracting gets colourless colloidal compound, and with chloroform: methyl alcohol=10: 1 is eluent, silica gel column chromatography separate colorless oil target product 11mg, yield 15.9%.
1H-NMR(400MHz，DMSO-d6)δ：8.11(s，1H)，8.06(s，1H)，7.79(d，J＝8.4Hz，1H)，7.50(m，1H)，7.21(m，1H)，6.97(m，1H)，4.38(m，2H)，4.30(m，4H)，4.24(m，2H)，3.95(d，J＝6.4Hz，2H)，3.89(m，5H)，2.25(s，3H)，1.81(m，5H)，0.83(d，J＝6.4Hz，3H)，0.79(d，J＝6.4Hz，3H)；ESI-MS(m/z)：637.6(M+H)
+。
Preparation embodiment 18:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-leucine of VITAMIN B4 propyl diester, the preparation of single acetylsalicylic acid propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-leucine propyl diester, single acetylsalicylic acid propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 17 methods, gets colourless colloidal target product, yield 16.9%.
1H-NMR(400MHz，DMSO-d6)δ：8.11(s，1H)，8.08(s，1H)，7.94(d，J＝7.6Hz，1H)，7.66(m，1H)，7.41(m，1H)，7.23(m，1H)，7.20(brs，4H)，4.30(m，2H)，4.25(m，2H)，4.12(m，2H)，4.03(m，4H)，3.94(m，5H)，2.25(s，3H)，1.84(m，4H)，1.60(m，2H)，1.20(m，1H)，0.84(d，J＝6Hz，6H)；ESI-MS(m/z)：651.5(M+H)
+。
Preparation embodiment 19:9-12-(phosphonium mesitoyl methoxy) ethyl] the single L-Isoleucine of VITAMIN B4 propyl diester, the preparation of single acetylsalicylic acid propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, single acetylsalicylic acid propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 17 methods, gets colourless colloidal target product, yield 13.6%.
1H-NMR(400MHz，DMSO-d6)δ：8.11(s，1H)，8.07(s，1H)，7.95(d，J＝8.4Hz，1H)，7.69(t，J＝7.6Hz，1H)，7.41(t，J＝7.6Hz，1H)，7.23(m，3H)，4.30(m，2H)，4.25(m，2H)，4.12(m，5H)，3.99(m，3H)，3.87(m，4H)，3.77(m，2H)，2.25(s，3H)，1.82(m，4H)，1.41(m，1H)，0.81(m，8H)；ESI-MS(m/z)：651.7(M+H)
+。
Preparation embodiment 20:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-phenylalanine of VITAMIN B4 propyl diester, the preparation of single acetylsalicylic acid propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, single acetylsalicylic acid propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 17 methods, gets colourless colloidal target product, yield 34.3%.
1H-NMR(400MHz，DMSO-d6)δ：8.47(s，1H)，8.41(s，1H)，7.94(d，J＝7.6Hz，1H)，7.69(t，J＝8.0Hz，1H)，7.41(t，J＝7.6Hz，1H)，7.31(d，J＝6.8Hz，1H)，7.27-7.21(m，5H)，4.41(brs，2H)，4.26(m，4H)，4.06-4.03(m，5H)，3.88-3.84(m，4H)，3.21-3.18(m，2H)，3.08-3.04(m，2H)，2.25(s，3H)，1.96(m，2H)，1.73(m，2H)；ESI-MS(m/z)：685.6(M+H)
+。
Make each embodiment 21:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single glycine propyl diester of VITAMIN B4, the preparation of single Ibuprofen BP/EP propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base-glycine propyl diester; single Ibuprofen BP/EP propyl diester (150mg; 0.22mmol)) place the dry round-bottomed flask of 25mL; add the stirring of 2.0mL anhydrous tetrahydro furan and make dissolving fully; phosphoric acid solution (the 1.7mL of adding 85%; 24.6mmol); 20～25 ℃ were reacted 4.5 hours, added distilled water 40.0mL in the afterreaction system, used chloroform extraction three times (3 * 15mL); discard chloroform layer; water layer is placed 0 ℃ of ice-water bath, and slowly the sodium hydroxide solution of Dropwise 5 0% adds chloroform extraction three times (3 * 15mL) again to system pH=6～8; the combined chloroform layer; anhydrous magnesium sulfate drying filters the solvent evaporated under reduced pressure; get colorless oil target product 70mg, yield 50.8%.
1H-NMR(400MHz，CDCl
3)δ：8.09(brs，2H)，7.16(d，J＝7.6Hz，2H)，7.07(d，J＝7.6Hz，2H)，4.29(m，2H)，4.07(m，2H)，4.01-3.74(m，8H)，3.66-3.64(m，2H)，2.42d，J＝6.8Hz，2H)，1.83-1.78(m，4H)，1.67(m，3H)，1.48(d，J＝6.8Hz，3H)，1.25(m，2H)；ESI-MS(m/z)：621.5(M+H)
+。
Preparation embodiment 22:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-L-Ala of VITAMIN B4 propyl diester, the preparation of single Ibuprofen BP/EP propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-L-Ala propyl diester, single Ibuprofen BP/EP propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 21 methods, gets faint yellow oily target product, yield 49.4%.
1H-NMR(400MHz，DMSO-d6)δ：8.42(s，1H)，8.35(s，1H)，7.16(d，J＝8.0Hz，2H)，7.09(d，J＝8.0Hz，2H)，4.39-4.38(m，2H)，4.15-3.966(m，8H)，3.87-3.85(m，6H)，2.39-2.37(d，J＝7.2Hz，2H)，1.86-1.77(m，5H)，1.39-1.34(m，6H)，0.83-0.81(d，J＝6.8Hz，6H)；ESI-MS(m/z)：635.6(M+H)
+。
Preparation embodiment 23:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Xie Ansuan of VITAMIN B4 propyl diester, the preparation of single Ibuprofen BP/EP propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester, single Ibuprofen BP/EP propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 21 methods, gets faint yellow oily target product, yield 85.8%.
1H-NMR(400MHz，CDCl
3)δ：8.34(s，1H)，7.91(s，1H)，7.19(d，J＝7.6Hz，2H)，7.09(d，J＝7.6Hz，2H)，6.03(brs，2H)，4.38(m，2H)，4.20-3.99(m，8H)，3.90(m，2H)，3.73-3.66(m，3H)，3.35(brs，1H)，0.83-0.81(d，J＝6.8Hz，6H)，2.43(d，J＝7.2Hz，2H)，4.38(m，2H)，2.05-1.79(m，6H)，1.49(d，J＝7.6Hz，3H)，0.98((d，J＝6.8Hz，3H)，0.92-0.87(m，9H)；ESI-MS(m/z)：663.8(M+H)
+。
Preparation embodiment 24:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-leucine of VITAMIN B4 propyl diester, the preparation of single Ibuprofen BP/EP propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-leucine propyl diester, single Ibuprofen BP/EP propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 21 methods, gets faint yellow target compound, yield 61.8%.
1H-NMR(400MHz，CDCl
3)δ：8.33(s，1H)，7.91(s，1H)，7.19(d，J＝7.6Hz，2H)，7.09(d，J＝7.6Hz，2H)，4.39-4.37(m，2H)，4.17-3.99(m，8H)，3.90-3.87(m，1H)，3.75-3.68(m，4H)，3.50-3.49(m，1H)，2.43-2.41(m，2H)，1.95-1.74(m，6H)，1.54-1.42(m，5H)，0.94-0.87(m，12H)；ESI-MS(m/z)：677.6(M+H)
+。
Preparation embodiment 25:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Isoleucine of VITAMIN B4 propyl diester, the preparation of single Ibuprofen BP/EP propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, single Ibuprofen BP/EP propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 21 methods, gets faint yellow target compound, yield 61.8%.
1H-NMR(400MHz，CDCl
3)δ：8.33(s，1H)，7.91(s，1H)，7.19(d，J＝7.6Hz，2H)，7.09(d，J＝7.6Hz，2H)，4.39-4.37(m，2H)，4.17-3.99(m，8H)，3.90-3.87(m，1H)，3.75-3.68(m，4H)，3.50-3.49(m，1H)，2.43-2.41(m，2H)，1.95-1.74(m，6H)，1.54-1.42(m，5H)，0.94-0.87(m，12H)；ESI-MS(m/z)：677.6(M+H)
+。
Preparation embodiment 26:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-phenylalanine of VITAMIN B4 propyl diester, the preparation of single Ibuprofen BP/EP propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, single Ibuprofen BP/EP propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 21 methods, gets faint yellow target compound 85mg, yield 57.3%.
1H-NMR(400MHz，CDCl
3)δ：8.32(s，1H)，7.89(s，1H)，7.30-7.28m，2H)，7.24-7.17(m，5H)，7.09-7.06(d，J＝8.4Hz，2H)，4.38-4.35(m，2H)，4.17-4.11(m，4H)，4.10-3.95(m，2H)，3.89-3.84(m，1H)，3.79-3.76(m，1H)，3.74-3.66(m，4H)，3.10-3.05(m，1H)，3.19-2.86(m，1H)，2.43(d，J＝6.8Hz，2H)，1.91-1.80(m，5H)，1.48(d，J＝6.8Hz，3H)，0.89(m，6H)；ESI-MS(rn/z)：711.8(M+H)
+。
Preparation embodiment 27:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single glycine propyl diester of VITAMIN B4, the preparation of single flurbiprofen propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base glycine propyl diester, single flurbiprofen propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 21 methods, gets faint yellow target compound, yield 56.7%.
1H-NMR(400MHz，DMSO-d.6)δ：8.11(s，1H)，8.04(s，1H)，7.52-7.43(m，4H)，7.39-7.36(m，1H)，7.24-7.19(m，3H)，4.29-4.28(m，4H)，4.05-4.00(m，4H)，3.96-3.82(m，9H)，1.81-1.77(m，2H)，1.63-1.60(m，2H)，1.42-1.40(d，J＝6.8Hz，3H)；ESI-MS(m/z)：659.7(M+H)
+。
Preparation embodiment 28:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-L-Ala of VITAMIN B4 propyl diester, the preparation of single flurbiprofen propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-L-Ala propyl diester, single flurbiprofen propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 21 methods, gets faint yellow target compound, yield 48.7%.
1H-NMR(400MHz，CDCl
3)δ：8.33(s，1H)，7.95(s，1H)，7.53-7.51(m，2H)，7.45-7.34(m，4H)，7.13-7.10(m，2H)，4.38-4.37(m，2H)，4.17-3.86(m，8H)，3.78-3.66(m，5H)，3.50-3.45(m，1H)，1.95-1.92(m，2H)，1.81-1.79(m，2H)，1.53-1.52(d，J＝6.8Hz，3H)，1.22-1.19(m，4H)；ESI-MS(m/z)：673.6(M+H)
+。
Preparation embodiment 29:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Xie Ansuan of VITAMIN B4 propyl diester, the preparation of single flurbiprofen propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester, single flurbiprofen propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 21 methods, gets faint yellow target compound, yield 57.5%.
1H-NMR(400MHz，CDCl
3)δ：8.32(s，1H)，7.90(s，1H)，7.53-7.51(m，2H)，7.44-7.33(m，4H)，7.15-7.10(m，2H)，4.37-4.36(m，2H)，4.17-4.16(m，4H)，4.06-4.01(m，4H)，3.90-3.86(m，1H)，3.78-3.72(m，4H)，3.31-3.30(m，1H)，2.03-1.93(m，5H)，1.54(d，J＝7.2Hz，3H)，0.97-0.88(m，6H)；ESI-MS(m/z)：701.8(M+H)
+。
Make each embodiment 30:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-leucine of VITAMIN B4 propyl diester, the preparation of single flurbiprofen propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-leucine propyl diester, single flurbiprofen propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 21 methods, gets faint yellow target compound, yield 94.8%.
1H-NMR(400MHz，CDCl
3)δ：8.32(s，1H)，7.90(s，1H)，7.53-7.51(m，2H)，7.45-7.34(m，4H)，7.15-7.10(m，2H)，4.39-4.35(m，2H)，4.20-4.01(m，8H)，3.90-3.86(m，1H)，3.79-3.72(m，4H)，3.51-3.46(m，1H)，2.19-1.91(m，4H)，1.76-1.54(m，2H)，1.54(d，J＝7.2Hz，3H)，1.46-1.40(m，1H)，0.93-0.90(m，6H)；ESI-MS(m/z)：715.6(M+H)
+
Preparation embodiment 31:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Isoleucine of VITAMIN B4 propyl diester, the preparation of single flurbiprofen propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, single flurbiprofen propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 21 methods, gets faint yellow oily target product, yield 75.8%.
1H-NMR(400MHz，CDCl
3)δ：8.31(s，1H)，7.91(s，1H)，7.53(d，J＝8.0Hz，2H)，7.44-7.32(m，4H)，7.15-7.10(m，2H)，4.38-4.35(m，2H)，4.20-4.14(m，4H)，4.09-4.02(m，4H)，3.90-3.69(m，5H)，3.37-3.35(m，1H)，1.96-1.91(m，4H)，1.74-1.71(m，1H)，1.53(d，J＝7.2Hz，3H)，1.26-1.14(m，42H)，0.92-0.86(m，6H)；ESI-MS(m/z)：715.4(M+H)
+。
Make each embodiment 32:9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-phenylalanine of VITAMIN B4 propyl diester, the preparation of single flurbiprofen propyl diester
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, single flurbiprofen propyl diester is a reaction raw materials, according to being similar to the preparation of embodiment 21 methods, gets faint yellow oily target product, yield 34.5%.
1H-NMR(400MHz，CDCl
3)δ：8.31(s，1H)，7.88(s，1H)，7.53(d，J＝8.4Hz，2H)，7.44-7.30(m，4H)，7.28-7.26(m，2H)，7.23-7.10(m，5H)，4.37-4.35(m，2H)，4.34-3.15(m，4H)，4.03-3.94(m，4H)，3.89-3.84(m，2H)，3.80-3.71(m，5H)，2.17-1.84(m，4H)，1.53(d，J＝7.2Hz，3H)；ESI-MS(m/z)：749.7(M+H)
+。
EXPERIMENTAL EXAMPLE
1, test materials
The HepG2.2.15 cell strain is by being provided by Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences; Test compounds is provided by Guiyang Medical College pharmaceutical college; Adefovir ester (the accurate word H20050803 of traditional Chinese medicines, Tianjin Medicine Research Academy Pharmaceutical Co., Ltd); DMEM high glucose medium, G418 are available from Gibco company; Foetal calf serum is available from HyClone company; MTT is available from Sigma company; The HBV PCR kit for fluorescence quantitative is available from ShenZhen PiJi Biology Engineering Co., Ltd; μ Quant enzyme mark detector is available from BIO-TEK company; The automatic fluorescent quantitation detector of ABI GeneAmp7000 is available from U.S. Applied Biosystem company.
2, test method
(1) cell toxicity test
Adopt the tetrazole reduction method, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide, MTT) detection of drugs is to the restraining effect of HepG2.2.15 cell growth.With the HepG2.2.15 cell dissociation is the individual cells suspension, and adjusting cell density is 5 * 10
4Individual/ml, be inoculated in 96 orifice plates (100 μ l/ hole), 37 ℃, 5%CO
2The incubator overnight incubation.Supernatant is removed in suction after treating cell attachment, adds the nutrient solution that contains concentration gradient dilution medicine (1000 μ M, 500 μ M, 250 μ M, 125 μ M, 25 μ M, 5 μ M), puts and continues in the incubator to cultivate.After dosing the 4th day, inhale and remove supernatant, add and contain MTT (0.5mg/ml) serum free medium, cultivated 4 hours, inhale and remove nutrient solution, add 150 μ l DMSO vibration and make Formazan crystallization dissolving, 490nm measures each hole light absorption value, with cell survival rate calculating medicine CC
50Value.
(2) to the inhibition test of hepatitis B virus-DNA
Adopt HepG2 2.2.15 clone as screening model, with the medium effective concentration (EC of compound to the HBV-DNA inhibition
50) be index, in the inhibition effect of all compounds of external preliminary assessment to HBV.With the HepG2.2.15 cell dissociation is the individual cells suspension, and adjusting cell density is 2 * 10
4Individual/ml, be inoculated in 96 orifice plates (100 μ l/ hole), 37 ℃, 5%CO
2The incubator overnight incubation.Supernatant is removed in suction after treating cell attachment, adds the nutrient solution that contains the different concns medicine, puts and continues in the incubator to cultivate.After dosing the 3rd, 6 day, inhale and remove supernatant, add and contain same concentrations medicine fresh medium, and collected each hole supernatant liquor ,-20 ℃ of preservations in the 9th day.Get testing sample 100 μ l, measure its HBV dna content with the HBV PCR kit for fluorescence quantitative.
With GraphPad Prism 5.0 computed in software CC
50, EC
50, calculate therapeutic index SI=CC
50/ EC
50
3, test-results
Each compound suppresses EC to HBV-DNA in the HepG2 2.2.15 cell
50, cytotoxicity CC
50SI sees Table 2 with the effect selectivity index, as shown in Table 2 the restraining effect of duplicating varying strength (SI＞2) of 23,25,29,30,31 couples of HBV DNA of compound in test compound, the wherein strong (EC of compound 31 anti-HBV-DNA activity
503.9 effect selectivity index higher (SI 9.974) μ M).
Table 2.
A:EC
50, half effective inhibition concentration; B:CC
50, half cytotoxicity concentration; C:SI, effect selectivity index (CC
50/ EC
50)
Claims (9)
1. a class has the organic and inorganic salt crystalline hydrate of acceptable, solvate on purine compound shown in the following structural formula (I) and the pharmacology thereof.
Wherein
R1 is amino;
R2 is nonsteroidal anti-inflammatory agent acetylsalicylic acid acyl group, Ibuprofen BP/EP acyl group, flurbiprofen acyl group;
R3 is alkyl or hydrogen atom.
2. purine compound as claimed in claim 1, its feature again in, described compound is:
1) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester, single acetylsalicylic acid propyl diester
2) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-leucine propyl diester, single acetylsalicylic acid propyl diester
3) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, single acetylsalicylic acid propyl diester
4) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, single acetylsalicylic acid propyl diester
5) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base glycine propyl diester, single Ibuprofen BP/EP propyl diester
6) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-L-Ala propyl diester, single Ibuprofen BP/EP propyl diester
7) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester, single Ibuprofen BP/EP propyl diester
8) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-leucine propyl diester, single Ibuprofen BP/EP propyl diester
9) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, single Ibuprofen BP/EP propyl diester
10) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, single Ibuprofen BP/EP propyl diester
11) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base glycine propyl diester, single flurbiprofen propyl diester
12) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-L-Ala propyl diester, single flurbiprofen propyl diester
13) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Xie Ansuan propyl diester, single flurbiprofen propyl diester
14) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-leucine propyl diester, single flurbiprofen propyl diester synthetic
15) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-Isoleucine propyl diester, single flurbiprofen propyl diester
16) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-phenylalanine propyl diester, single flurbiprofen propyl diester
17) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Xie Ansuan of VITAMIN B4 propyl diester, single acetylsalicylic acid propyl diester
18) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-leucine of VITAMIN B4 propyl diester, single acetylsalicylic acid propyl diester
19) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Isoleucine of VITAMIN B4 propyl diester, single acetylsalicylic acid propyl diester
20) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-phenylalanine of VITAMIN B4 propyl diester, single acetylsalicylic acid propyl diester
21) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single glycine propyl diester of VITAMIN B4, single Ibuprofen BP/EP propyl diester
22) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-L-Ala of VITAMIN B4 propyl diester, single Ibuprofen BP/EP propyl diester
23) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Xie Ansuan of VITAMIN B4 propyl diester, single Ibuprofen BP/EP propyl diester
24) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-leucine of VITAMIN B4 propyl diester, single Ibuprofen BP/EP propyl diester
25) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Isoleucine of VITAMIN B4 propyl diester, single Ibuprofen BP/EP propyl diester
26) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-phenylalanine of VITAMIN B4 propyl diester, single Ibuprofen BP/EP propyl diester
27) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single glycine propyl diester of VITAMIN B4, single flurbiprofen propyl diester
28) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-L-Ala of VITAMIN B4 propyl diester, single flurbiprofen propyl diester
29) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Xie Ansuan of VITAMIN B4 propyl diester, single flurbiprofen propyl diester
30) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-leucine of VITAMIN B4 propyl diester, single flurbiprofen propyl diester synthetic
31) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-Isoleucine of VITAMIN B4 propyl diester, single flurbiprofen propyl diester
32) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the single L-phenylalanine of VITAMIN B4 propyl diester, single flurbiprofen propyl diester
3. method that is used to prepare the purine compound of claim 1 is characterized in that said method comprising the steps of:
(1) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 (PMEA) and N-tertbutyloxycarbonyl-L-amino acid 3-bromopropyl ester be in polar aprotic solvent; with N; N '-dicyclohexyl-4-morpholinyl-amidine (DCMC) or 1; 8-diazabicyclo [5,4,0] undecane-7 alkene is alkali, and reaction obtains compound.
(2) above-mentioned steps 1) behind the compound that obtains without separation; the acetylsalicylic acid 3-bromopropyl ester, Ibuprofen BP/EP 3-bromopropyl ester or the flurbiprofen 3-bromopropyl ester that promptly add suitable proportion; the rising temperature of reaction makes the compound and the ester condensation of nonsteroidal anti-inflammatory drug 3-bromopropyl that obtain in the step 1) generate 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 mono-N-tert-butoxycarbonyl base L-amino acid propyl ester, single NSAID (non-steroidal anti-inflammatory drug) propyl diester:
(3) above-mentioned steps 2) compound that obtains sloughs the tertbutyloxycarbonyl protection with an amount of 85% phosphoric acid solution or Acetyl Chloride 98Min./methanol system and obtains target compound in polarity or non-polar solvent.
4. method as claimed in claim 3; it is characterized in that; N-tertbutyloxycarbonyl in step 1)-L-amino acid 3-bromopropyl ester add-on and 9-[2-(phosphonium mesitoyl methoxy) ethyl] ratio of VITAMIN B4 is 1.0～5.5: 1mol; reacted 4～48 hours down at 30-90 ℃; preferred N-tertbutyloxycarbonyl-L-amino acid 3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] ratio of VITAMIN B4 is 1.0～2.0: 1mol is with N; N '-dicyclohexyl-4-morpholinyl-amidine (DCMC) is an alkali; at N; dinethylformamide is under the solvent condition, reacts 4～10 hours down at 30～60 ℃.
5. method as claimed in claim 3; it is characterized in that; in step 2) in NSAID (non-steroidal anti-inflammatory drug) 3-bromopropyl ester add-on and 9-[2-(phosphonium mesitoyl methoxy) ethyl] ratio of VITAMIN B4 is 1.0～5.5: 1mol; reacted 10～48 hours down at 60～120 ℃; preferred NSAID (non-steroidal anti-inflammatory drug) 3-bromopropyl ester and 9-[2-(phosphonium mesitoyl methoxy) ethyl] the VITAMIN B4 ratio is 1.0～2.0: 1mol, system was reacted 10～18 hours at 60～100 ℃.
6. method as claimed in claim 3, it is characterized in that, can select chloroform, methylene dichloride or tetrahydrofuran (THF) for use at the step 3) solvent, perhaps in Acetyl Chloride 98Min./methanol system, reacting 0.2～16 hour down at-10～25 ℃, is under the solvent condition at chloroform preferably, and system was reacted under-5 ℃～room temperature 8～12 hours with 85% phosphoric acid, or Acetyl Chloride 98Min./methanol system reacted 5-12 hour the acquisition target compound for 0 ℃～25 ℃.
7. drug regimen is characterized in that comprising the purine compound and the assistant agent of the claim 1 of dose therapeutically effective.
8. the described purine compound of claim 1 is used for the treatment of application in the medicine of hepatitis B in preparation.
9. the application of the described purine compound of claim 1 in the medicine of treatment hepatitis B.
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