A kind of preparation method of (r)-1-(6-amino-9h-purin-9-yl) 2-phenyl ester

A purine and amino technology, applied in the field of chemical synthesis and preparation of -1-2-phenyl ester, can solve the problems of long reaction time, difficult industrialized production, low yield and the like, and achieve easily controllable conditions and easy industrialized production. , the effect of high yield

Inactive Publication Date: 2018-11-02
EAST CHINA NORMAL UNIV
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Problems solved by technology

Using ((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid as a raw material, using DCC as a condensing agent to condense with phenol to obtain the target product phenyl Hydrogen (((S)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid, the synthetic route has lower yield and longer reaction time , it is difficult to produce industrially

Method used

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  • A kind of preparation method of (r)-1-(6-amino-9h-purin-9-yl) 2-phenyl ester
  • A kind of preparation method of (r)-1-(6-amino-9h-purin-9-yl) 2-phenyl ester
  • A kind of preparation method of (r)-1-(6-amino-9h-purin-9-yl) 2-phenyl ester

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] 1.1 Preparation of (iodomethyl) phenyl phosphonate

[0022] Dissolve 10 g of (chloromethyl)phenyl phosphonate in 50 mL of acetonitrile, then add 9.88 g of NaI, react at 80°C for 15 hours, and the reaction is complete. The residual solid was removed by suction filtration, the solvent was evaporated to dryness under reduced pressure, 50 mL of ethyl acetate and 50 mL of water were added, and the organic layer was washed with NaS 2 o 3 The saturated solution was washed once, and the organic layer was dried and evaporated to dryness to obtain 9.76 g of the product with a yield of 73.6%.

[0023] 1 H-NMR (CDCl3, 400M) δ=3.9(d, J=3.2Hz, 2H), 7.21(m, J=8Hz, 6H), 7.36(m, J=8Hz, 4H)

[0024] MS(EI): m / e=374.02

[0025] 1.2 Preparation of phenyl (iodomethyl)phosphonate

[0026] Dissolve 10 g of phenyl (chloromethyl) phosphonate in 50 mL of DMF, then add 9.88 g of NaI, react at 80° C. for 15 hours, and the reaction is complete. The residual solid was removed by suction filtra...

Embodiment 2

[0030] 2.1 Preparation of phenyl hydrogen (iodomethyl) phosphonic acid phenyl ester

[0031] 11.7 g of phenyl (iodomethyl)phosphonate was dissolved in 60 mL of acetonitrile, and then 60 mL of 1M sodium hydroxide solution was slowly added dropwise. After the dropwise addition, the reaction system gradually became clear, and the reaction was complete after 3 hours. Evaporate to dryness under reduced pressure, add 50Ml of clear water, wash with ethyl acetate three times, adjust the pH of the ion exchange resin in the water layer to 1, evaporate the water phase, and pass through petroleum Ether: ethyl acetate = 1:1 beating and purification to obtain 7.65 g of the product with a yield of 82.08%.

[0032] 1 H-NMR (CDCl3, 400M) δ=3.4(d, J=3.2Hz,d), 7.21(m, J=8Hz, 3H), 7.4(m, J=8Hz, 2H)

[0033] MS (EI): m / e = 298.02.

[0034] 2.2 Preparation of phenyl hydrogen (iodomethyl) phosphonate

[0035] Dissolve 8.6 g of phenyl (iodomethyl)phosphonate in 60 mL of chloroform, and then slowl...

Embodiment 3

[0043] 3.1 Preparation of (R)-1-(6-amino-9H-purin-9-yl) 2-phenyl ester

[0044] Dissolve 3g of (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol in 40mL of dry DMF, add 3.4g of magnesium tert-butoxide under ice-cooling, and react under nitrogen protection for 0.5 After 20 hours, 5 g of phenyl hydrogen (iodomethyl) phosphonic acid phenyl was added, and reacted under the protection of nitrogen, and the reaction was complete after 20 hours. The solvent was evaporated to dryness under reduced pressure, and water was added to adjust the pH to 2-3. After suction filtration, it was purified by beating with MeOH:H2O=1:1 to obtain 4.2 g of the product with a yield of 74.46%.

[0045] 1H-NMR (D2O, 400M) δ = 1.31 (d, J = 6.1Hz, 3H), 3.59 (dd, J = 14.0, 9.0Hz, 1H), 3.85 (dd, J = 14.0, 9.0 Hz, 1H), 4.1(m,1H),4.3(dd,J=15.0,9.0Hz,1H),4.5(dd,J=15.0,2Hz,1H),6.75(d,J=7Hz,2H),7.15(t,J =7Hz, 1H), 7.25(t, J=7Hz, 2H), 8.26(s, 1H), 8.35(s, 1H).

[0046] MS (EI): m / e = 363.31.

[0047] 3.2 Preparation of...

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Abstract

The invention discloses a preparation method of preparation method of (R)-1-(6-amino-9H-purine-9-yl)2-phenyl ester, and belongs to the field of chemical synthesis. According to the preparation method, in a solvent, (chloromethyl) phosphonic acid phenyl ester is taken as an initial raw material, substitution reaction with sodium iodide is carried out, basic hydrolysis is carried out, and an obtained product is reacted with (S)-1-(6-amino-9H-purine-9-yl) propan-2-ol so as to obtain the reaction finished product (R)-1-(6-amino-9H-purine-9-yl)2-phenyl ester. The conditions are convenient to control; post-treatment is simple; few side reaction is caused; yield is high; and requirements of industrialized production are satisfied.

Description

technical field [0001] The invention belongs to chemical synthesis in the field of medicinal chemistry, and relates to a preparation method for (R)-1-(6-amino-9H-purin-9-yl) 2-phenyl ester. Background technique [0002] Tenofovir alafenamide fumarate (TAF) is a new type of nucleoside reverse transcriptase inhibitor (NRTI) developed by Gilead. Tenofovir alafenamide fumarate is A prodrug of tenofovir. TAF has stronger cell penetration ability, so it can exert the same drug effect as tenofovir at a smaller dose. In clinical trials, the drug has been proven to have a very high anti-inflammatory effect at a dose lower than one-tenth of Gilead's marketed drug Viread (tenofovir disoproxil fumarate tablets, Viread, TDF). Viral effects, while improving renal and skeletal parameters. (R)-1-(6-amino-9H-purin-9-yl)2-phenyl ester is the key intermediate of tenofovir alafenamide fumarate. Its structural formula is: [0003] [0004] At present, a kind of synthetic method of (R)-1-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 占莉丘佳焜徐运楠王思洋姜能桥姜建桥罗宇
Owner EAST CHINA NORMAL UNIV
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