Tenofovir alafenamide compound, preparation method and purpose thereof

A technology of tenofovir alafenamide and compound, which is applied in the field of organic chemistry and can solve the problems of unpublished preparation method, cumbersome preparation process of hemi-fumarate, difficult to obtain and the like

Inactive Publication Date: 2015-11-25
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such as patent document CN1443189A, CN1706855A etc. disclose the fumarate of tenofovir alafenamide, although tenofovir alafenamide fumarate has bigger difference than free base in terms of water solubility and physical properties, etc. Improvement, but its chemical stability and thermodynamic stability are not good
Patent document CN103732594A discloses the hemifumarate of tenofovir alafenamide, wherein it shows that tenofovir alafenamide hemifumarate is compared with tenofovir alafenamide fumarate , has advantages in removing non-enantiomer impurities, chemical stability, and thermodynamic stability, and is a better salt of tenofovir alafenamide; but tenofovir alafenamide semi-fumar The preparation process of the acid salt is cumbersome. For example, it is necessary to add tenofovir alafenamide hemifumarate seed crystals in the preparation process, and the preparation method of the seed crystals is not disclosed in this patent and is not easy to obtain.

Method used

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  • Tenofovir alafenamide compound, preparation method and purpose thereof
  • Tenofovir alafenamide compound, preparation method and purpose thereof
  • Tenofovir alafenamide compound, preparation method and purpose thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0196] Preparation of tenofovir alafenamide (I)

[0197] At 20-25°C, 500.0 g (1.38 mol, 1.0 eq) of tenofovir monophenyl (prepared according to the method disclosed in CN1443189A) was added to 3.0 L of toluene, and the solid was completely dissolved under stirring, and then two Thionyl chloride was 150ml (2.05mol, 1.5eq), and the resulting mixture was heated to about 70°C and stirred for 96 hours. Concentrate to dryness under reduced pressure at 40-45°C, add 2.5L of toluene to the concentrate, add L-alanine isopropyl ester (commercially available) 813.5g (6.21mol, 4.5eq) dropwise at -10°C-10°C ) dissolved in 4.0L of dichloromethane, then stirred at -10°C-10°C for 30 minutes and then raised to room temperature, washed with 10% aqueous sodium dihydrogen phosphate solution 2.5L×2, separated the organic phase, and washed with 15% Potassium bicarbonate aqueous solution was washed with 1.0 L × 2, and then washed with 2.5 L of purified water. The obtained organic phase was dried over...

Embodiment 2

[0200] Preparation of L-tenofovir alafenamide tartrate (1:2)

[0201] At 70-75°C, dissolve 4.76g (10.0mmol) of tenofovir alafenamide and 0.75g (5.0mmol) of L-tartaric acid in 100ml of acetonitrile, stir and cool down to 15-20°C after complete dissolution, and then Continue to stir and crystallize; filter with suction, wash the filter cake with an appropriate amount of acetonitrile, and dry under reduced pressure at 40-45°C to obtain tenofovir alafenamide tartrate (1:2).

[0202] 1 HNMR (400MHz, DMSO-d 6 )δ: 8.14(s, 1H), 8.10(s, 1H), 7.31-7.27(t, 2H), 7.19(s, 2H), 7.15-7.11(m, 1H), 7.07-7.04(m, 2H) , 5.64-5.58(m, 1H), 4.90-4.80(m, 1H), 4.30-4.25(m, 2H), 4.18-4.12(m, 1H), 3.98-3.91(m, 1H), 3.89-3.81( m, 2H), 3.80-3.74 (m, 1H), 1.16-1.13 (t, 9H), 1.08-1.06 (d, 3H).

[0203] Melting range: 158-161°C.

[0204] the above 1In the HNMR results, the signal peaks with chemical shifts at δ8.14 (s, 1H) and 8.10 (s, 1H) were assigned to the two Hs on the adenine ring of tenofovir ala...

Embodiment 3

[0206] Preparation of Tenofovir Alafenamide D-Tartrate (1:1)

[0207] At 70-75°C, dissolve 4.76g (10.0mmol) of tenofovir alafenamide and 1.50g (10.0mmol) of D-tartaric acid in 100ml of acetonitrile, stir and cool down to 15-20°C after dissolution, continue Stir and crystallize; filter with suction, wash the filter cake with an appropriate amount of acetonitrile, and dry under reduced pressure at 40-45°C to obtain D-tenofovir alafenamide tartrate (1:1).

[0208] 1 HNMR (400MHz, DMSO-d 6 )δ: 8.15(s, 1H), 8.11(s, 1H), 7.31-7.28(t, 2H), 7.22(s, 2H), 7.15-7.12(m, 1H), 7.07-7.05(m, 2H) , 5.63-5.58(m, 1H), 4.90-4.81(m, 1H), 4.32-4.26(m, 3H), 4.18-4.13(m, 1H), 4.00-3.92(m, 1H), 3.90-3.81( m, 2H), 3.80-3.74 (m, 1H), 1.16-1.13 (t, 9H), 1.09-1.07 (d, 3H).

[0209] Melting range: 135-138°C.

[0210] the above 1 In the HNMR results, the signal peaks with chemical shifts at δ8.15 (s, 1H) and 8.11 (s, 1H) were assigned to the two Hs on tenofovir alafenamide adenine, δ4.32-4.26 (m, the...

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Abstract

The present invention relates to tenofovir alafenamide complex represented by formula II. The present invention also relates to a preparation method for said tenofovir alafenamide complex, pharmaceutical compositions containing the tenofovir alafenamide complex, and uses of the tenofovir alafenamide complex in preparing medicines for preventing and/or treating virus infection, especially Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.

Description

technical field [0001] The present invention relates to the fields of organic chemistry and pharmacy, in particular to a compound of tenofovir alafenamide, a drug for preventing or / and treating viral infection, a preparation method thereof and the use of the compound in the preparation of preventing and / or treating viral infection, especially Use in medicine for hepatitis B virus (HBV) and / or human immunodeficiency virus (HIV) infection, and a pharmaceutical composition containing the complex. Background technique [0002] Tenofovir alafenamide, chemical name: N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl Oxy]methyl]phenoxyphosphono]-L-alanine-1-methylethyl ester; CAS accession number: 379270-37-8; molecular structure as shown in Formula I: [0003] [0004] Tenofovir alafenamide is an ester prodrug of tenofovir, an acyclic nucleotide reverse transcriptase inhibitor, which has broad-spectrum antiviral effects and can inhibit HIV-1, HIV- 2 reverse transcriptase a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/12A61P31/20A61P31/18
CPCA61K31/675C07F9/6561
Inventor 赵雄袁道义程睿罗杰向志祥
Owner SICHUAN HAISCO PHARMA CO LTD
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