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(2'R)-2'-deoxy-2'-halogenated-2'-methyluridine derivative, preparation method and uses thereof

A phenoxy, branched alkoxycarbonyl technology, applied in the field of preparing sofosbuvir and its analogs, can solve the problems of consumption of tert-butylmagnesium chloride, side reactions, difficulty in purification and the like

Inactive Publication Date: 2016-12-07
SUZHOU VIGONVITA LIFE SCIENCES CO LTD +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In the literature (Journal of Organic Chemistry, 76 (20), 8311-8319; 2011), the compound of formula III is used as a raw material for phosphorylation to obtain sofosbuvir, but the phosphorylation reaction in this method needs to use As a base, tert-butyl magnesium chloride can react with the hydrogen on the N atom of uracil base, consume one equivalent of tert-butyl magnesium chloride, and cause side reactions, generate impurities, and bring difficulties to subsequent purification

Method used

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  • (2'R)-2'-deoxy-2'-halogenated-2'-methyluridine derivative, preparation method and uses thereof
  • (2'R)-2'-deoxy-2'-halogenated-2'-methyluridine derivative, preparation method and uses thereof
  • (2'R)-2'-deoxy-2'-halogenated-2'-methyluridine derivative, preparation method and uses thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087]

[0088] Compound III-2 (0.260g, 1mmol) was dissolved in DMF (2ml), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.30ml, 2mmol) was added , ice bath, after stirring for about 15 minutes, chloromethyl methyl ether (76 μl, 1mmol) was added, and after about 1 hour, TLC showed that the raw materials had basically reacted completely, and about 1ml of methanol was added to quench the reaction, and the compound II- 1 (200 mg).

[0089] 1 HNMR (300MHz, DMSO): 8.05(d, J=8.23Hz, 1H), 6.01(d, J=18.28Hz, 1H), 5.80(d, J=8.21Hz, 1H), 5.67(d, J=6.27 Hz,1H),5.31(t,J=5.72Hz,1H),5.17(s,2H),3.82(dt,J=6.32,13.43Hz,3H),3.63(d,J=10.81Hz,1H), 3.25(s,3H),1.25(d,J=22.45Hz,3H);ESI(M+Cl:339).

Embodiment 2

[0091] Compound II-1 (0.76g, 2mmol) was dissolved in THF (10mL), cooled to -5°C, added tert-butylmagnesium chloride (2.4mL, 2.4mmol), stirred for 30 minutes, raised to room temperature and stirred for 30 minutes, cooled To 5°C, add (S)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphoramido]propionic acid isopropyl ester (1.09 g, 2.4 mmol), after about 4 hours of reaction, TLC showed that the reaction was basically complete, and 917 mg of compound I-1 was obtained by column chromatography.

[0092] 1 HNMR (400M, DMSO): 7.64 (d, J = 8.19Hz, 1H), 7.38 (t, J = 7.89Hz, 2H), 7.21 (m, 3H), 6.06 (dd, J = 9.93, 12.96Hz, 2H ),5.88(d,J=7.03Hz,1H),5.70(d,J=8.15Hz,1H),5.18(s,2H),4.85(p,J=6.27Hz,1H),4.38(m,1H ), 4.25(dt, J=5.67, 12.02Hz, 1H), 4.03(dd, J=4.73, 10.05Hz, 1H), 3.81(m, 2H), 3.27(s, 3H), 1.24(m, 6H) ,1.15(d,J=6.26Hz,6H);ESI(M-1:572).

Embodiment 3

[0094] Compound I-1 (100mg, 0.17mmol) was dissolved in tetrahydrofuran (4ml), 1ml of 10% hydrochloric acid was added, heated for reaction, the reaction was complete after about 4 hours, and sofosbuvir (10mg) was obtained by column chromatography.

[0095] 1 HNMR (400M, DMSO): 11.52(s, 1H), 7.57(d, J=8.17Hz, 1H), 7.37(m, 2H), 7.22(m, 3H), 6.04(m, 2H), 5.86(d ,J=7.08Hz,1H),5.54(d,J=8.06Hz,1H),4.86(p,J=6.25Hz,1H),4.38(dd,J=5.82,11.71Hz),4.24(dt,J =5.77,11.74Hz,1H),4.01(m,1H),3.81(m,2H),1.25(m,6H),1.15(d,J=6.29Hz,6H).

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Abstract

The present invention discloses a compound represented by a formula I, a preparation method and an intermediate thereof, uses of the compound represented by the formula I in preparation of drugs for treatment of viral infection diseases, uses of the compound represented by the formula I in preparation of sofosbuvir and analogs thereof, and a method for preparing the sofosbuvir and the analogs thereof by using the compound represented by the formula I. According to the method of the present invention, the new reaction route is designed, such that the side reaction caused by the use of tert-butyl magnesium chloride in the phosphorylation reaction is avoided, the generated impurity is reduced, and the difficulty of the subsequent purification process is reduced. According to the present invention, the test results prove that the method has characteristics of mild reaction conditions, easy operation, high yield, stable product quality and high product purity, and can be used for industrial scale enlargement production. The formula I is defined in the specification.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, more specifically, to a compound of formula I and its preparation method and intermediates, the use of the compound of formula I in the preparation of drugs for the treatment of viral infection diseases, the compound of formula I in the preparation of sofosbu Uses in Wei and its analogs and methods for preparing sofosbuvir and its analogs using the compound of formula I. Background technique [0002] Sofosbuvir (SFBV) was developed by Pharmasset and continued to be developed by Gilead Science. The results of the published clinical phase III study showed that the combination therapy of sofosbuvir (formerly known as GS-7977) + immune enhancer Ribavirin (Ribavirin) is effective for patients with type 2 or type 3 hepatitis C who have failed previous treatment. The patients were treated for 12 and 16 weeks, and the treatment results were satisfactory. If sofosbuvir is approved as a drug fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H19/073C07H1/00A61K31/7072A61K31/7068A61P31/12
CPCA61P31/12C07H1/00C07H19/10
Inventor 蒋翔锐胡天文田广辉沈敬山
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD