CN102649788B - Beta-L-2'-desoxy-thymin-nucleoside derivative, preparation method and purposes thereof - Google Patents

Beta-L-2'-desoxy-thymin-nucleoside derivative, preparation method and purposes thereof Download PDF

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CN102649788B
CN102649788B CN201110046505.8A CN201110046505A CN102649788B CN 102649788 B CN102649788 B CN 102649788B CN 201110046505 A CN201110046505 A CN 201110046505A CN 102649788 B CN102649788 B CN 102649788B
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compound
independently
derivative
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alkyl
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CN102649788A (en
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谢永美
魏于全
李炯
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Sichuan University
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Sichuan University
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Abstract

The invention belongs to the technical field of chemical medicines, and particularly relates to a Beta-L-2'-desoxy-thymine nucleoside derivative, a preparation method and purposes thereof. The Beta-L-2'-desoxy-thymine nucleoside derivative has a structure as showed in a format I, wherein R1 and R2 are independent O, S or Se; when one of the R1 and the R2 is O, R3 is halogen, -OH, -NH2, C1-C8 alkyl, (CH2)nF, (CH2)n-1CHF or CF3; R4 is halogen, H, or CF3; and n is 1-8. The invention provides the derivative which has activity of resisting hepatitis virus, and offers a new choice for preparing medicines capable of treating the hepatitis.

Description

β-L-2 '-deoxidation-thymidine derivative and its production and use
Technical field
The invention belongs to technical field of chemical medicine, particularly β-L-2 '-deoxidation-thymidine derivative and its production and use.
Background technology
Chronic hepatitis B (Chronic Hepatitis B, CHB) is a kind of transmissible disease of global wide-scale distribution, and it is great challenge that hepatitis B virus (Hepatitis B virus, HBV) infects the publilc health in the whole world.According to the statistics of the World Health Organization (WHO), infected in the people of hepatitis B virus (HBV) in the whole world about 2,000,000,000, more than 400000000, people suffers from chronic HBV infection, 1,000,000 patients are about had to die from hepatitis b virus infected relevant liver cirrhosis or liver cancer (Kim KH every year, Kim ND, Seong BL.Molecules, 2010,15 (9): 5878-5908).More seriously, in global Hepatitis B Virus Infection, 75% Asia is distributed in.About there is the Hepatitis B Virus Infection of 1.2 hundred million in China, and the new case of annual generation HBV is more than 3,000,000, and annual treatment expenditure is up to 30,000,000,000 ~ 50,000,000,000 yuan of (Wang GF, Shi LP, Zuo JP.Virologica Sinica, 2008,23 (2): 137-145).Thus, research has the Anti-HBV drugs of independent intellectual property right is an instant social concern.
CHB often causes liver function incompensation, liver cirrhosis and hepatocellular carcinoma (Kremsdorf D, Soussan P, Paterlini-Brechot P, et al.Oncogene, 2006,25:3823-3833; Brechot C.Gastroenterology, 2004,127:S56-S61), the target of antiviral therapy suppresses to greatest extent or eliminates HBV, improves patients ' life quality and extend its survival time.Antiviral therapy used at present, mainly by intervening virus replication or the different links for host anti-virus, reaches the effect of opposing virus, protection body.The treatment of CHB comprises pharmacological agent and non-drug therapy two kinds, and its drug treatment is occupied an leading position.Pharmacological agent comprises Interferon, rabbit, Zadaxin, nucleoside medicine, non-nucleoside like thing, polypeptide drug, therapeutic vaccine and herbal medicine and effective constituent.Wherein, nucleoside medicine, as the first-selected curative of the virus diseases such as current clinical treatment acquired immune deficiency syndrome (AIDS), hepatitis, bleb, not only suppresses the enzyme of virus replication, and can participate in the competition in the DNA of infiltration virus replication as substrate analogue, the prolongation of blocking dna chain, thus suppress virus replication.
Telbivudine as the nucleoside analog of the Treatment chronic Hepatitis B virus of the 4th granted listing, have specificity good, act on strong feature, provide new selection for clinical.But Telbivudine has following shortcoming: have that potential renal toxicity, virus easily produce resistance, body produces dependency to medicine, drug withdrawal easily rebounds, begin treatment, some patients must could have rhabdomyolysis tendency etc. when liver falls ill.According to bioisosterism, fluorine atom is introduced in 2 ' position of Telbivudine sugar ring, obtain Clevudine, its curative effect is better than Telbivudine, toxicity is lower than Telbivudine, and more than continuing to suppress HBV DNA half a year after drug withdrawal (Jules L.Dienstag.Hepatology, 2009,49 (5): S112-S121).Show that the medicine designed by bioisosterism is the effective means reducing drug toxicity, improve curative effect.
Summary of the invention
First technical problem to be solved by this invention is to provide the derivative of β-L-2 '-deoxidation-thymidine, and structure is such as formula shown in I:
Wherein, R 1, R 2be independently O, S or Se, and R 1and R 2be asynchronously O;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; N=1 ~ 8.
Preferably, R 1, R 2be independently O, S or Se, and R 1and R 2be asynchronously O;
R 3for F, Cl, Br ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; N=1 ~ 8.
Preferably, R 1, R 2be independently O, S or Se, and R 1and R 2be asynchronously O;
R 3for C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; N=1 ~ 8.
Preferably, R 1, R 2be independently O, S or Se, and R 1and R 2be asynchronously O;
R 3for C 1~ C 8alkyl;
R 4for F, Cl, Br, H or CF 3.
Preferably, R 1, R 2be independently O, S or Se, and R 1and R 2be asynchronously O;
R 3for C 1~ C 8alkyl;
R 4for H.
Most preferred, R 1, R 2be independently O, S or Se, and R 1and R 2be asynchronously O;
R 3for methyl; R 4for H.
Preferred further, the derivative of β-L-2 '-deoxidation-thymidine, structure is such as formula shown in II:
Wherein, R 2be independently S or Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; N=1 ~ 8.
Preferably, R 2be independently S or Se;
R 3for F, Cl, Br ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; N=1 ~ 8.
Preferably, R 2be independently S or Se; R 3for C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; N=1 ~ 8.
Preferably, R 2be independently S or Se; R 3for C 1~ C 8alkyl; R 4for F, Cl, Br, H or CF 3.
Preferably, R 2be independently S or Se; R 3for C 1~ C 8alkyl; R 4for H.
Preferably, R 2be independently S or Se; R 3for methyl; R 4for H.
Preferred further, the derivative of β-L-2 '-deoxidation-thymidine, structure is as shown in formula III:
Wherein, R 2be independently O, S or Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; N=1 ~ 8.
Preferably, R 2be independently O, S or Se;
R 3for F, Cl, Br ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; N=1 ~ 8.
Preferably, R 2be independently O, S or Se; R 3for C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; N=1 ~ 8.
Preferably, R 2be independently O, S or Se; R 3for C 1~ C 8alkyl; R 4for F, Cl, Br, H or CF 3.
Preferably, R 2be independently O, S or Se; R 3for C 1~ C 8alkyl; R 4for H.
Preferably, R 2be independently O, S or Se; R 3for methyl; R 4for H.
Preferred further, the derivative of β-L-2 '-deoxidation-thymidine, structure is such as formula shown in IV:
Wherein, R 2be independently O, S or Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; N=1 ~ 8.
Preferably, R 2be independently O, S or Se;
R 3for F, Cl, Br ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; N=1 ~ 8.
Preferably, R 2be independently O, S or Se; R 3for C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; N=1 ~ 8.
Preferably, R 2be independently O, S or Se; R 3for C 1~ C 8alkyl; R 4for F, Cl, Br, H or CF 3.
Preferably, R 2be independently O, S or Se; R 3for C 1~ C 8alkyl; R 4for H.
Preferably, R 2be independently O, S or Se; R 3for methyl; R 4for H.
The intermediate used time prepared by the derivative that second technical problem to be solved by this invention is to provide the-L-2 ' of β shown in formula I-deoxidation-thymidine, structure is such as formula shown in V:
Wherein, R 1, R 2be independently O, S or Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H;
n＝1～8。
Preferably, R 1, R 2be independently O, S or Se;
R 3for F, Cl, Br ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H; N=1 ~ 8.
Preferably, R 1, R 2be independently O, S or Se;
R 3for C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently H, C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H;
n＝1～8。
Preferably, R 1, R 2be independently O, S or Se;
R 3for C 1~ C 8alkyl;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently H, C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H.
Preferably, R 1, R 2be independently O, S or Se, and R 1and R 2be asynchronously O;
R 3for C 1~ C 8alkyl;
R 4for H; R 5, R 6be independently H, C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H.
Most preferred, R 1, R 2be independently O, S or Se, and R 1and R 2be asynchronously O;
R 3for methyl; R 4for H; R 5, R 6be independently H, ethanoyl, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H.
Or the intermediate used time prepared by the derivative of β-L-2 '-deoxidation-thymidine, structure is such as formula shown in VI:
Wherein, R 1for O, S or Se, R 2for Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H;
n＝1～8。
Preferably, R 1for O, S or Se, R 2for Se;
R 3for F, Cl, Br ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz; N=1 ~ 8.
Preferably, R 1for O, S or Se, R 2for Se;
R 3for C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz;
n＝1～8。
Preferably, R 1for O, S or Se, R 2for Se;
R 3for C 1~ C 8alkyl;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz.
Preferably, R 1for O, S or Se, R 2for Se;
R 3for C 1~ C 8alkyl;
R 4for H; R 5and R 6be independently C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz.
Preferably, R 1for O, S or Se; R 2for Se;
R 3for methyl; R 4for H; R 5and R 6be independently ethanoyl, I, TBDMS, DMTr or Bz.
Most preferred, R 1for O, S or Se; R 2for Se; R 3for methyl; R 4for H; R 5and R 6for Bz.
Or the intermediate used time prepared by the derivative of β-L-2 '-deoxidation-thymidine, structure is such as formula shown in VII:
Wherein, R 1for O, S or Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H;
n＝1～8。
Preferably, R 1for O, S or Se;
R 3for F, Cl, Br ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H; N=1 ~ 8.
Preferably, R 1for O, S or Se;
R 3for C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz;
n＝1～8。
Preferably, R 1for O, S or Se;
R 3for C 1~ C 8alkyl;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz.
Preferably, R 1for O, S or Se;
R 3for C 1~ C 8alkyl;
R 4for H; R 5and R 6be independently C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz.
Preferably, R 1for O, S or Se;
R 3for methyl; R 4for H; R 5and R 6be independently ethanoyl, I, TBDMS, DMTr or Bz.
Most preferred, R 1for O, S or Se; R 3for methyl; R 4for H; R 5and R 6for Bz.
Or the intermediate used time prepared by the derivative of β-L-2 '-deoxidation-thymidine, structure is such as formula shown in VIII:
Wherein, R 1for S, R 2for O, S or Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H; N=1 ~ 8.
Preferably, R 1for S, R 2for O, S or Se;
R 3for F, Cl, Br ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H; N=1 ~ 8.
Preferably, R 1for S, R 2for O, S or Se;
R 3for C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently H, C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H; N=1 ~ 8.
Preferably, R 1for S, R 2for O, S or Se; R 3for C 1~ C 8alkyl;
R 4for F, Cl, Br, H or CF 3; R 5, R 6be independently H, C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H.
Preferably, R 1for S; R 2for O, S or Se; R 3for C 1~ C 8alkyl;
R 4for H; R 5, R 6be independently H, ethanoyl, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H.
Preferably, R 1for S; R 2for O, S or Se; R 3for methyl; R 4for H; R 5for DMTr, R 6for H.
Most preferred, R 1for S; R 2for O; R 3for methyl; R 4for H; R 5for DMTr, R 6for H.
Or the intermediate used time prepared by the derivative of β-L-2 '-deoxidation-thymidine, structure is such as formula shown in IX:
Wherein, R 2be independently O, S or Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz.
Preferably, R 2be independently O, S or Se;
R 3for F, Cl, Br ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz.
Preferably, R 2be independently O, S or Se; R 3for C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for F, Cl, Br, H or CF 3; R 6be independently C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz.
Preferably, R 2for O, S or Se; R 3for C 1~ C 8alkyl;
R 4for F, Cl, Br, H or CF 3; R 6be independently C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz.
Preferably, R 2for O, S or Se; R 3for C 1~ C 8alkyl;
R 4for H; R 6for C1 ~ C8 alkyloyl, TBDMS, DMTr or Bz.
Preferably, R 2for O; R 3for methyl; R 4for H; R 6for C 1~ C 8alkyloyl.
Most preferred, R 2for O; R 3for methyl; R 4for H; R 6for ethanoyl.
3rd technical problem to be solved by this invention is to provide the preparation method of the derivative of-L-2 ' of β shown in formula I-deoxidation-thymidine, comprises following several:
One,
Wherein, R 1for O, S or Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H; N=1 ~ 8.
Preferably, R 5, R 6for Bz.
Compound a is obtained by reacting compound b by hydroxyl protection, and compound b is obtained by reacting compound c under lawesson reagent (Lawesson ' s Reagent) catalysis, and compound c takes off hydroxy-protective group and get final product.
Two,
Wherein, R 1for O, S or Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H; N=1 ~ 8.
Preferably, R 5, R 6for Bz.
Compound b is at POCl 3, 1,2,4-triazole, Et 3compound d is obtained by reacting, compound d NaBH under N catalysis 4, (NCCH 2cH 2se) 2be obtained by reacting Verbindung under catalysis, the ethanolic soln of Verbindung and NaOH reacts and get final product.
Three,
Wherein, R 2for O, S or Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; R 5for methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz, R 6for H, methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, I, TBDMS, DMTr or Bz; N=1 ~ 8.
Preferably, R 5for DMTr, R 6for H.
Compound f is obtained by reacting compound g by hydroxyl protection, and compound g and methyl iodide, DBU (1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene) are obtained by reacting compound h, selenium and NaBH 4reaction after and compound h react to obtain compound i, compound i sloughs hydroxyl protecting group and get final product.
Four,
Wherein, R 2for O, S or Se;
R 3for halogen ,-OH ,-NH 2, C 1~ C 8alkyl, (CH 2) nf, (CH 2) n-1cHF 2or CF 3;
R 4for halogen, H or CF 3; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz; N=1 ~ 8.
Preferably, R 5for TBDMS, R 6for C1 ~ C8 alkyloyl.
Compound j is obtained by reacting compound k by selectivity hydroxyl protection, and compound k and methyl triple phenoxyl iodate phosphorus reaction obtain compound L, and compound L and Silver monoacetate are obtained by reacting compound m, compound m in the basic conditions with H 2s reacts to obtain compound n, and compound n sloughs hydroxyl protection and get final product.
4th technical problem to be solved by this invention is to provide the purposes of derivative in the preparation treatment hepatitis medicament of-L-2 ' of β shown in formula I-deoxidation-thymidine.Described hepatitis is chronic hepatitis B or hepatitis C.
Pharmaceutical composition commonly uses auxiliary material by activeconstituents interpolation medicine to be prepared from; At least one in the solvate of the derivative that described activeconstituents is the-L-2 ' of β shown in formula I-deoxidation-thymidine, the pharmaceutical salts of this derivative, the hydrate of this derivative or this derivative.Be preferably the derivative of β-L-2 '-deoxidation-thymidine shown in formula I.
The derivative of β-L-2 ' of the present invention-deoxidation-thymidine has the activity of hepatitis virus resisting, for the medicine of preparation treatment hepatitis provides a kind of selection newly.
Embodiment
Embodiment 14-sulphur-2 '-deoxidation-L-thymidine
A. the synthesis of compound 2
Get 9.68g 2-deoxidation-L-thymidine (1), add anhydrous pyridine 200ml, after stirring and dissolving, add 9.6ml Benzoyl chloride, be heated to 50 DEG C of reactions 10 ~ 20 hours, after TLC detection reaction completes, be concentrated to about 30ml, trash ice is added under stirring, produce precipitation, filter, press dry, with ethyl alcohol recrystallization, obtain 14g white solid.
1H NMR(400MHz，CDCl 3)：δ1.618(s，3H)，2.308～2.382(m，1H)，2.718(dd，1H)，4.544(d，1H)，4.667～4.828(m，2H)，5.662(d，1H)，6.474(q，1H)，7.472～8.082(m，10H)，8.391(s，1H)。
B. the synthesis of compound 3
Get 9g compound 2, add 200ml dioxane, stirring and dissolving, add 15g lawesson reagent (Lawesson ' sReagent), back flow reaction, TLC monitors reaction process, after having reacted, concentrated dry, add water, with chloroform extraction, water layer is concentrated dry, and column chromatography obtains 7.7g faint yellow solid.
1H NMR(400MHz，DMSO)：δ1.609(s，3H)，2.504～2.682(m，2H)，4.564～4.691(m，3H)，5.661(d，1H)，6.272(t，1H)，7.508～7.723(m，7H)，7.991～8.048(m，4H)，12.808(s，1H)。
C. the synthesis of compound 4
Get 4.66g compound 3, add methyl alcohol 200ml, after stirring and dissolving, add 1.62g sodium methylate, stirring at room temperature.TLC monitors reaction process, and after having reacted, regulate pH to neutral with glacial acetic acid, concentrated dry, column chromatography, obtains yellow solid 1.9g.
1H NMR(400MHz，DMSO)：δ1.967(s，3H)，2.127～2.155(q，2H)，3.546～3.641(m，2H)，3.796(q，1H)，4.242(s，1H)，5.101(s，1H)，5.273(d，1H)，6.107(t，1H)，7.896(s，1H)，12.704(s，1H)。
Embodiment 24-selenium-2 '-deoxidation-L-thymidine
A. the synthesis of compound 5
By 33ml POCl 3be added drop-wise to containing 99g1, in the anhydrous acetonitrile suspension (1000ml) of 2,4-triazole, N 2protection, 0 DEG C is stirred 10min; Then by anhydrous for 200ml Et 3n is added drop-wise in above-mentioned mixing solutions, and 0 DEG C is stirred 35min; Finally add the acetonitrile solution (500ml) being dissolved with 10.85g compound 2, stirred at ambient temperature 4h.TLC detects raw material point and disappears, and adds the saturated NaHCO of about 200ml 3, be then extracted with ethyl acetate, washing, dry, concentrated, obtain white solid 5 (11g).
1H NMR(400MHz，CDCl 3)：2.221(s，3H)，2.309-2.382(m，1H)，3.212(dd，1H)，4.124(q，1H)，4.675～4.725(m，2H)，4.932(dd，1H)，5.682(d，1H)，6.376(q，1H)，7.401～7.661(m，5H)，7.969-8.104(m，5H)，8.215(s，1H)，9.255(s，1H)。
B. the synthesis of compound 6
By 1.5gNaBH 4join containing 2.88ml (NCCH 2cH 2se) 2with in the round-bottomed flask of 120ml ethanol, ice bath, N 2tHF (50ml) solution being dissolved with 6g compound 5 is added, TLC detection reaction process under protection.Reacting completely, add the water of about 150ml, is 7 with the pH of the acetic acid regulator solution of 10%, and concentrated dry, column chromatography obtains white solid 6 (5g).
1H NMR(400MHz，CDCl 3)：1.784(s，3H)，2.253-2.327(m，1H)，2.980(t，2H)，3.054-3.109(m，1H)，3.334-3.421(m，2H)，4.657-4.691(m，2H)，4.867(q，1H)，5.651(d，1H)，6.356(q，1H)，7.263～7.497(m，5H)，7.518-7.650(m，2H)，7.966-8.096(m，4H)。
C. the synthesis of compound 7
1g sodium hydroxide is dissolved in 400ml dehydrated alcohol, is then joined by 4.5g compound 6 in NaOH ethanolic soln above, and stirred at ambient temperature reacts, TLC detection reaction process, having reacted rear use 10% acetic acid regulator solution pH is 7, is concentrated into dry, add 50ml water dissolution, use CH 2cl 2extracted several times, aqueous phase is concentrated to dry, silica gel column chromatography, obtains safran solid 7 (1.8g).
1H NMR(400MHz，DMSO)：δ2.087(s，3H)，2.162(t，2H)，3.560-3.650(m，2H)，3.800(q，1H)，4.239(s，1H)，5.123(s，1H)，5.280(d，1H)，6.038(t，1H)，8.048(s，1H)，13.301(s，1H)。
Embodiment 32-sulphur-2 '-deoxidation-L-thymidine
A. the synthesis of compound 8
Get 9.68g compound 1, add 200ml dry DMF, after stirring and dissolving, add 8g imidazoles and 6g TERT-BUTYL DIMETHYL CHLORO SILANE; nitrogen protection is reacted, and after TLC detection reaction completes, adds ethyl acetate 100ml, washes with water; dried over mgso, is concentrated to dry, obtains white solid 13.5g.
1H NMR(400MHz，CDCl 3)：1.118(d，6H)，0.923(s，9H)，1.921(s，3H)，1.997(br，1H)，2.080-2.148(m，1H)，2.325-2.379(m，1H)，3.823-3.914(m，2H)，4.029(q，1H)，4.476(t，1H)，6.362(q，1H)，7.496(d，1H)，8.222(s，1H)。
B. the synthesis of compound 9
Get 11.9g compound 8, add the pyridine of 100ml drying, stirring and dissolving, add diacetyl oxide 5ml, stirring at room temperature is reacted, and after TLC detection reaction completes, is concentrated into dry, column chromatography, obtains white solid 11.2g.
C. the synthesis of compound 10
Be dissolved in 100mlTHF by 11.2g compound 9, add 8.8g tetrabutyl ammonium fluoride, stirring at room temperature reaction disappears to raw material, and be evaporated to dry, column chromatography obtains white solid 6.8g.
1H NMR(400MHz，CDCl 3)：1.935(s，3H)，2.115(s，3H)，2.355-2.436(m，2H)，3.908-3.947(m，2H)，4.102(d，1H)，5.352(t，1H)，6.254(q，1H)，7.501(s，1H)，8.271(s，1H)。
D. the synthesis of compound 11
Get 4.3g compound 10 and 11g methyl triple phenoxyl iodate phosphorus, add 50mlDMF, 25 DEG C of stirring reactions have reacted for 2 hours, add 5ml methyl alcohol, and concentrating under reduced pressure is to dry, and column chromatography obtains 5.5g product.
1H NMR(400MHz，CDCl 3)：1.952(s，3H)，2.105(s，3H)，2.098-2.407(m，2H)，3.405-3.712(m，2H)，4.011(m，1H)，5.097(m，1H)，6.318(q，1H)，7.576(q，1H)，8.510(s，1H)。
E. the synthesis of compound 12
Get 5g compound 11 and 10g Silver monoacetate, add the acetonitrile of 200ml drying, back flow reaction, TLC detection reaction completes, cooling, and suction filtration removing Silver monoacetate, be concentrated into dry, column chromatography obtains 2.8g product.
F. the synthesis of compound 13
2.2g compound 12 is dissolved in 200mlDMF, adds 25ml triethylamine, be cooled to ~ 70 DEG C, pass into H2S reaction, after TLC detection reaction completes, concentrated dry, column chromatography obtains 0.8g product.
1H NMR(400MHz，CDCl 3)：1.997(s，3H)，2.142(s，3H)，2.105-2.406(m，2H)，3.401-3.720(m，2H)，4.052(m，1H)，5.101(m，1H)，6.314(q，1H)，7.918(q，1H)，9.451(s，1H)。
G. the synthesis of compound 14
100mg sodium hydroxide is dissolved in 50ml dehydrated alcohol, is then joined by 600mg compound 13 in NaOH ethanolic soln above, and stirred at ambient temperature reacts, TLC detection reaction process, having reacted rear use 10% acetic acid regulator solution pH is 7, is concentrated into dry, add 50ml water dissolution, use CH 2cl 2extracted several times, aqueous phase is concentrated to dry, silica gel column chromatography, obtains white solid 14 (420mg).
1H NMR(400MHz，DMSO)：δ2.085(s，3H)，2.204(t，2H)，3.552-3.648(m，2H)，3.815(q，1H)，4.240(s，1H)，5.136(s，1H)，5.264(d，1H)，6.103(t，1H)，8.124(s，1H)，13.125(s，1H)。
Embodiment 42-selenium-2 '-deoxidation-L-thymidine
A. the synthesis of compound 15
5.2g compound 14 and 100mgDMAP are dissolved in the pyridine of 100ml drying, 0 DEG C of stirring and dissolving, by 9g 4; 4 ' ~ dimethoxytrityl chlorine adds solution above, nitrogen protection stirring reaction 10 hours, and TLC detection reaction completes; add 5ml methyl alcohol, concentrating under reduced pressure, to dry, adds ethyl acetate 100ml; wash three times with water; each 50ml, organic phase with sodium sulfate is dry, filters; be concentrated into dry, column chromatography obtains colorless solid 9.8g.
1H NMR(400MHz，CDCl 3)δ：1.454(s，3H)，2.316(m，1H)，2.685(ddd，1H)，3.411(dd，1H)，3.568(dd，1H)，3.792(2s，6H)，4.610(m，1H)，6.851-6.853(m，4H)，6.941(t，1H)，7.428-7.536(m，9H)，7.885(d，1H)，8.653(m，2H)，10.418(br，1H)。
B. the synthesis of compound 16
Be dissolved in the DMF of 60ml drying by 9g compound 15 and 10ml methyl iodide, nitrogen protection 0 DEG C stirring, adds in solution above by 4mlDBU, and 0 DEG C of stirring reaction 1 hour, then adds 30ml cold water in reaction mixture, add 300ml ethyl acetate.Wash with water, organic layer dried over sodium sulfate, filter, be concentrated into dry, column chromatography obtains white solid 8.2g.
1H NMR(400MHz，CDCl 3)δ：1.554(s，3H)，2.342(m，1H)，2.523(ddd，1H)，2.581(s，3H)，3.209(br，1H)，3.415(dd，1H)，3.547(dd，1H)，3.785(2s，6H)，4.136(m，1H)，4.648(m，1H)，6.241(dd，1H)，6.752-6.896(m，4H)，7.185-7.526(m，9H)，7.853(s，1H)。
C. the synthesis of compound 17
In absolutely dry ethanol (150ml), add 3.8g selenium and 1.9gNaBH4 at 0 DEG C, stirring reaction 30min, 8g compound 16 is dissolved in 100ml dehydrated alcohol.The sodium hydrogen selenide solution of preparation is added the ethanolic soln of compound 16, room temperature reaction 72 hours, add ethyl acetate 300ml and sodium chloride solution 100ml successively, organic layer uses saturated sodium-chloride, water washing successively, dried over sodium sulfate, filters, concentrated dry, column chromatography, obtains yellow solid 7.1g.
1H NMR(400MHz，CDCl 3)δ：1.390(s，3H)，2.721-2.668(m，2H)，3.407(dd，1H)，3.570(dd，1H)，3.786(2s，6H)，4.141(m，1H)，4.625(m，1H)，6.842(m，4H)，7.018(t，1H)，7.134-7.396(m，9H)，7.947(d，1H)，10.634(br，1H)。
D. the synthesis of compound 18
Get 7g compound 17, add trifluoroacetic acid/dichloromethane (2: 8) solution 50ml, stirring at room temperature is to complete reaction, and concentrated dry, column chromatography obtains 2.4g compound 18.
1H NMR(400MHz，DMSO)：δ2.182(s，3H)，2.195(t，2H)，3.543-3.658(m，2H)，3.826(q，1H)，4.237(s，1H)，5.145(s，1H)，5.270(d，1H)，6.109(t，1H)，8.140(s，1H)，13.146(s，1H)。
Embodiment 52,4-bis-sulphur-2 '-deoxidation-L-thymidine
A. the synthesis of compound 19
Get 7.8g compound 14, add anhydrous pyridine 200ml, after stirring and dissolving, add 7.5ml Benzoyl chloride, be heated to 50 DEG C of reactions 10 ~ 20 hours, after TLC detection reaction completes, be concentrated to about 30ml, trash ice is added under stirring, produce precipitation, filter, press dry, with ethyl alcohol recrystallization, obtain 12.5g compound 19.
B. the synthesis of compound 20
Get 9.4g compound 19, add 200ml dioxane, stirring and dissolving, add 14g lawesson reagent, back flow reaction, TLC monitors reaction process, after having reacted, concentrated dry, adds water, and with chloroform extraction, water layer is concentrated dry, and column chromatography obtains 8.5g compound 20.
C. the synthesis of compound 21
Get 7g compound 20, add methyl alcohol 200ml, after stirring and dissolving, add 1.8g sodium methylate, stirring at room temperature.TLC monitors reaction process, and after having reacted, regulate pH to neutral with glacial acetic acid, concentrated dry, column chromatography, obtains 5.4g compound 21.
Embodiment 62-selenium-4-sulphur-2 '-deoxidation-L-thymidine
A. the synthesis of compound 22
Get 9.2g compound 18, add anhydrous pyridine 200ml, after stirring and dissolving, add 7.2ml Benzoyl chloride, be heated to 50 DEG C of reactions 10 ~ 20 hours, after TLC detection reaction completes, be concentrated to about 30ml, trash ice is added under stirring, produce precipitation, filter, press dry, with ethyl alcohol recrystallization, obtain 13.8g compound 22.
B. the synthesis of compound 23
Get 10.3g compound 22, add 200ml dioxane, stirring and dissolving, add 12g lawesson reagent, back flow reaction, TLC monitors reaction process, after having reacted, concentrated dry, adds water, and with chloroform extraction, water layer is concentrated dry, and column chromatography obtains 8.2g compound 23.
C. the synthesis of compound 24
Get 8g compound 23, add methyl alcohol 200ml, after stirring and dissolving, add 2g sodium methylate, stirring at room temperature.TLC monitors reaction process, and after having reacted, regulate pH to neutral with glacial acetic acid, concentrated dry, column chromatography, obtains 3.6g compound 24.
Embodiment 72,4-bis-selenium-2 '-deoxidation-L-thymidine
A. the synthesis of compound 25
By 35ml POCl 3be added drop-wise to containing 100g1, in the anhydrous acetonitrile suspension (1000ml) of 2,4-triazole, N 2protection, 0 DEG C is stirred 10min; Then by anhydrous for 200ml Et 3n is added drop-wise in above-mentioned mixing solutions, and 0 DEG C is stirred 35min; Finally add the acetonitrile solution (500ml) being dissolved with 11g compound 22, stirred at ambient temperature reacts, and TLC detects raw material point and disappears, and adds the saturated NaHCO of about 200ml 3, be then extracted with ethyl acetate, washing, dry, concentrated, obtain 10.6g compound 25.
B. the synthesis of compound 26
By 3gNaBH 4join containing 6ml (NCCH 2cH 2se) 2with in the round-bottomed flask of 200ml ethanol, ice bath, N 2tHF (100ml) solution being dissolved with 10g compound 25 is added, TLC detection reaction process under protection.Reacting completely, add the water of about 200ml, is 7 with the pH of the acetic acid regulator solution of 10%, and concentrated dry, column chromatography obtains 9.5g compound 26.
C. the synthesis of compound 27
2g sodium hydroxide is dissolved in 800ml dehydrated alcohol, is then joined by 9.2g compound 26 in NaOH ethanolic soln above, and stirred at ambient temperature reacts, TLC detection reaction process, having reacted rear use 10% acetic acid regulator solution pH is 7, is concentrated into dry, add 100ml water dissolution, use CH 2cl 2extracted several times, aqueous phase is concentrated to dry, silica gel column chromatography, obtains 3.7g compound 27.
Embodiment 82-sulphur-4-selenium-2 '-deoxidation-L-thymidine
A. the synthesis of compound 28
By 35ml POCl 3be added drop-wise to containing 100g1, in the anhydrous acetonitrile suspension (1000ml) of 2,4-triazole, N 2protection, 0 DEG C is stirred 10min; Then by anhydrous for 200ml Et 3n is added drop-wise in above-mentioned mixing solutions, and 0 DEG C is stirred 35min; Finally add the acetonitrile solution (500ml) being dissolved with 10g compound 19, stirred at ambient temperature reacts, and TLC detects raw material point and disappears, and adds the saturated NaHCO of about 200ml 3, be then extracted with ethyl acetate, washing, dry, concentrated, obtain 8.5g compound 28.
B. the synthesis of compound 29
By 3gNaBH 4join containing 6ml (NCCH 2cH 2se) 2with in the round-bottomed flask of 200ml ethanol, ice bath, N 2tHF (100ml) solution being dissolved with 9.5g compound 28 is added, TLC detection reaction process under protection.Reacting completely, add the water of about 200ml, is 7 with the pH of the acetic acid regulator solution of 10%, and concentrated dry, column chromatography obtains 8.2g compound 29.
C. the synthesis of compound 30
2g sodium hydroxide is dissolved in 800ml dehydrated alcohol, is then joined by 8g compound 29 in NaOH ethanolic soln above, and stirred at ambient temperature reacts, TLC detection reaction process, having reacted rear use 10% acetic acid regulator solution pH is 7, is concentrated into dry, add 100ml water dissolution, use CH 2cl 2extracted several times, aqueous phase is concentrated to dry, silica gel column chromatography, obtains 3.6g compound 30.
The external Anti-HBV effect of test example 1
A. to the restraining effect of HBVDNA
The HepG2.2.15 cell of taking the logarithm vegetative period, adjusts cell concn to be 1 × 10 with the DMM nutrient solution containing 10% foetal calf serum 4/ ml, adds 100 μ L single cell suspensions in 96 well culture plates, in 37 DEG C, and 5%CO 2cultivate under condition, cell grows to the compound 100 μ L/ hole that experimental group when converging adds different concns.Positive controls adds the Telbivudine of different concns, continues to cultivate.Take out nutrient solution in 3 days and 6 days, supplement the liquid of equal volume simultaneously, took out nutrient solution in the 9th day, be placed in ~ 20 DEG C stand-by.Supplement the substratum of equal volume, for measuring MTT, under examining or check each experimental concentration, whether medicine is toxic to cell simultaneously.
B. cytotoxicity experiment
Except drug level difference, other operation stepss are identical with a part, for measuring the half toxic concentration (CC of medicine to cell 50).Result is as shown in table 1:
Table 1
Medicine Anti-HBV effect selectivity index (Selectivity Index, SI) is evaluated, and SI calculates according to following formula:
SI＝CC 50/EC 50
As SI > 2, show the effective low toxicity of medicine; When 1≤SI≤2, prompting medicine is effectively poisonous; As SI < 1, then show the toxic effect of medicine.SI value is larger, and show that the restraining effect of compound to HBV is stronger, cytotoxicity is less.
From result in table 1, gained 8 nucleoside analogs have good restraining effect to HBV2.2.15 emiocytosis HBV DNA, selectivity index is all much larger than 2, and the selectivity index of one of them compound 4 (260333) is much larger than the selectivity index (91000) of marketed drug Telbivudine, has good application prospect.

Claims (5)

1. β-L-2 '-deoxidation-thymidine derivative, is characterized in that: structure is such as formula shown in II:
R 2for S; R 3for methyl; R 4for H.
2. the intermediate used when prepared by the derivative of β-L-2 ' shown in formula II-deoxidation-thymidine, structure is such as formula shown in V:
Wherein, R 1for O, R 2for S; R 3for methyl; R 4for H; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H.
3. the preparation method of the derivative of β-L-2 ' shown in claim 1 formula II-deoxidation-thymidine:
Wherein, R 1for O; R 3for methyl; R 4for H; R 5, R 6be independently methyl, the tertiary butyl, 2-THP trtrahydropyranyl, C1 ~ C8 alkyloyl, H, I, TBDMS, DMTr or Bz, and R 5and R 6be asynchronously H;
Compound a is obtained by reacting compound b by hydroxyl protection, and compound b is obtained by reacting compound c under lawesson reagent catalysis, and compound c takes off hydroxy-protective group and get final product.
4. the purposes of derivative in preparation treatment hepatitis medicament of β-L-2 ' described in claim 1-deoxidation-thymidine.
5. pharmaceutical composition commonly uses auxiliary material by activeconstituents interpolation medicine to be prepared from; Described activeconstituents is at least one in β-L-2 ' described in the claim 1-derivative of deoxidation-thymidine or the pharmaceutical salts of this derivative.
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