Tenofovir alafenamide fumarate impurity preparing method

A technology of tenofovir alafenamide fumarate and alafenamide, applied in the field of preparation of tenofovir alafenamide fumarate impurity, can solve the synthesis of tenofovir alafenamide fumarate impurity Issues such as insufficient literature

Inactive Publication Date: 2016-02-17
CHINA PHARM UNIV
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Problems solved by technology

There are very few reports on the synthesis of impurities of tenofovir alafenamide fumarate at home and abroad

Method used

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  • Tenofovir alafenamide fumarate impurity preparing method
  • Tenofovir alafenamide fumarate impurity preparing method
  • Tenofovir alafenamide fumarate impurity preparing method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 19-

[0041] Preparation of Example 19-[(R)-2-[[(S)-[[(S)-1-isopropoxyphenoxyphosphinyl]methoxy]propyl]adenine (IV)

[0042] Put 1g of 9-[(R)-2-[[(phenoxyphosphinyl)methoxy]propyl]]adenine in a 50mL three-necked flask, add 15ml of acetonitrile and 0.64g of chlorinated chlorinated For sulfone, heat up to 70°C and stir for 2-3h. After the reaction is complete, concentrate, cool to -5°C, add 10ml of isopropanol, stir for 1h, concentrate, and the concentrate is separated by column chromatography to obtain 0.89g of light yellow oil, which is collected The rate is 80.1%.

[0043] 0.89 g of the yellow oil obtained above was resolved by preparative liquid phase to obtain 0.44 g of a white solid, with a yield of 49.4%.

[0044] Its structural identification data are as follows:

[0045] 1 H-NMR (400Mz, DMSO-d 6 )δ: 1.07 ~ 1.12 (d, 3H, CH 3 ), 1.14~1.21(m, 6H, 2×CH 3 ), 3.90~3.93(m, 1H, OCH), 3.94~4.03(m, 2H, CH 2 N), 4.14~4.30(m, 2H, OCH), 4.59~4.66(m, 1H, OCH(CH 3 ) 2 ), 6.62 (s, 2...

Embodiment 29-

[0047] Preparation of Example 29-[(R)-2-[[(S)-[two-(phenoxy)phosphinyl]methoxy]propyl]adenine (VI)

[0048] Put 1g of 9-[(R)-2-[[(phenoxyphosphinyl)methoxy]propyl]]adenine in a 50mL three-necked flask, add 15ml of acetonitrile and 0.64g of chlorinated chlorinated For sulfone, heat up to 70°C and stir for 2-3h. After the reaction is complete, concentrate, cool to -5°C, add 15mL of acetonitrile and 0.26g of phenol, stir for 1h, concentrate, and the concentrate is separated by column chromatography to obtain 0.85g of white solid. Yield 70.3%.

[0049] Its structural identification data are as follows:

[0050] 1 H-NMR (400Mz, DMSO-d 6 )δ: 1.26 ~ 1.28 (d, 3H, CH 3 ), 3.86~3.94 (m, 1H, CH 2 CHO), 4.11 ~ 4.20 (m, 2H, OCH 2 P), 4.35 ~ 4.39 (m, 2H, CH 2 N) 5.86 (s, 2H, NH 2 ), 7.06~7.36(m, 10H, 2×C 6 h 5 ), 7.89 (s, 1H, H-2), 8.34 (s, 1H, H-8).

[0051] ESI-MS(m / z): 442.10[M+H] + .

Embodiment 39-

[0052] Example 39-[(R)-2-[[two-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phosphinyl]methoxy]propyl]adenine (VII ) preparation

[0053] Put 1g of 9-[(R)-2-(phosphonomethoxy)propyl]adenine in a 50mL three-neck flask, add 15ml of acetonitrile and 0.64g of thionyl chloride at room temperature, heat and stir at 70°C for 2~ 3h, concentrated, cooled to -5°C, added 15mL of acetonitrile and 1.45g of L-alanine isopropyl ester, stirred for 1h, concentrated, the concentrate was separated by column chromatography to obtain 0.85g of white solid, yield 60.1%.

[0054] Its structural identification data are as follows:

[0055] 1 H-NMR (400Mz, DMSO-d 6 )δ: 1.14 ~ 1.15 (d, 3H, CH 3 ), 1.16~1.26 (d, 6H, 2×CH 3 ), 1.28~1.41 (d, 12H, 4×CH 3 ), 3.09(t, 1H, CH 2 CHO), 3.48~3.53(d, 2H, NH), 3.78~3.85(m, 2H, OCH 2 P), 3.89~3.97(m, 2H, CH 2 N), 4.83~4.87(m, 1H, CH(CH 3 ) 2 ), 5.05~5.09(m, 1H, CH(CH 3 ) 2 ), 6.06(s, 2H, NH 2 ), 8.09 (s, 1H, H-2), 8.32 (s, 1H, H-8).

[0056] ESI-MS(m / z): 51...

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Abstract

The invention relates to a novel synthetic method of three tenofovir alafenamide fumarate impurities. The synthetic method has important significance in synthesis of high-quality tenofovir alafenamide fumarate. The invention mainly aims at studying synthesis of a tenofovir alafenamide isopropyl ester impurity 9-[(R)-2-[[(S)-[[(S)-1-isopropoxy phenoxyl phosphinyl] methoxyl] propyl] adenine (IV), a tenofovir alafenamide diphenyl ester impurity 9-[(R)-2-[[(S)-[bi-(phenoxyl) phosphinyl] methoxyl] propyl] adenine (VI) and a tenofovir alafenamide diamide impurity 9-[(R)-2-[[bi-[[(S)-1-(isopropoxy carbonyl) ethyl] amino] phosphinyl] methoxyl] propyl] adenine (VII), and their specific synthesis routes are shown in the description.

Description

technical field [0001] The invention relates to a preparation method of impurity tenofovir alafenamide fumarate. Background technique [0002] Tenofovir alafenamide fumarate (tenofoviralafenamide fumarate), chemical name 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl ]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate is a novel nucleotide reverse transcriptase inhibitor. The compound was developed by Gilead Sciences of the United States and launched in the United States in 2015 for the treatment of HIV infection in adults. The drug is also used to treat hepatitis B and is currently in Phase III clinical trials. This product is rapidly transformed into tenofovir after oral administration, and is phosphorylated into tenofovir diphosphate under the action of cellular kinases, which inhibits viral polymerase and inserts into the virus by competitively combining with natural deoxyribose substrates NDA causes DNA chain elongation and termination, thereby inhibiting HIV ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 陈国华蔡正贵吴斐华
Owner CHINA PHARM UNIV
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