Preparation process of an antiviral drug (entecavir) and intermediates thereof

A technology for entecavir and medicine, which is applied in the preparation of antiviral medicine (entecavir) and the field of intermediates thereof, and can solve the problems such as difficulty in utilizing known methods

Inactive Publication Date: 2013-08-28
ESTEVE QUIMICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0034] Despite the teachings of all these prior art documents, research on new methods of preparation of entecavir is still an active field because known methods are difficult to exploit industrially

Method used

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  • Preparation process of an antiviral drug (entecavir) and intermediates thereof
  • Preparation process of an antiviral drug (entecavir) and intermediates thereof
  • Preparation process of an antiviral drug (entecavir) and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] Example 1: (3S,5R)-7-(Trimethylsilyl)hept-1-en-6-yne-3,5-diol (XI) preparation of

[0123] at 0°C, N 2 To a solution of (+)-DIPCl (90-105%) (25 g, 77.94 mmol) in anhydrous tetrahydrofuran (THF) (40 mL) was added triethylamine (NEt 3 ) (85.02 mmol, 11.6 mL). Then, 98% 4-trimethylsilyl-3-butyn-2-one (70.85 mmol, 9.78 g) was added dropwise, and the reaction mixture was stirred at -5°C-0°C for 2 h. The solution was then cooled to –78°C. A solution of acrolein (90% purity) (102.6 mmol, 7.62 mL) in anhydrous THF (20 mL) was added slowly, and the reaction mixture was stirred at -78 °C for 1 h. Slowly add lithium borohydride (LiBH 4 ) 2M solution in hexane (106.28 mmol, 53 mL). The reaction mixture was stirred for an additional 1 h at −78 °C, then carefully washed with NH 4 A saturated solution of Cl (40 mL) was quenched for 0.5 h. (temperature increased from –78°C to room temperature). H 2 O (40 mL) and tert-butyl methyl ether (TBME) (90 mL) were partitioned. The...

Embodiment 2

[0126] Example 2: (3S,5R)-5-(tert-butyldimethylsilyloxy)-7-(trimethylsilyl) Preparation of Hept-1-en-6-yn-3-ol (X)

[0127] at 0°C, N 2 To a solution of diol (XI) (5.0 g, 25.2 mmol) and imidazole (2.1 g, 30.3 mmol) in anhydrous THF (60 mL) was added dropwise anhydrous THF (20 mL) with TBSCl (4.23 g, 27.7 mmol) under atmosphere. ) solution, and the reaction mixture was warmed to room temperature. The reaction mixture was stirred for 5h. Then, slowly add 22% NH 4 Cl solution (25 mL), and the reaction mixture was stirred for 10 min. The mixture was partitioned and the organic phase was dried (MgSO 4 ), and the volatiles were removed in vacuo. The resulting oily material was then purified by silica gel flash chromatography (hexane-ethyl acetate 90:10 to 80:20) to yield 4.84 g (61%) of the title compound. Pale yellow oil. Rf (Hexane:AcOEt 80:20)=0.55. [α] D =+39.9(c1.0, CHCl 3 ). IR (film) (cm -1 ): 3424, 3081, 2958, 2172.

Embodiment 3

[0128] Example 3: (3S,5R)-5-(tert-butyldimethylsilyloxy)hept-1-en-6-yn-3-ol Preparation of (IXa)

[0129] at room temperature, N 2 K 2 CO 3 (0.101 g, 0.73 mmol) was added in one portion to a stirred solution of (X) (0.455 g, 1.46 mmol) in dry methanol (MeOH) (4.5 mL). The reaction mixture was stirred for 1 h. After the reaction was complete, the volatiles were removed, and CH was added to the residue 2 Cl 2 (10 mL). The mixture was filtered, dried (MgSO 4 ), and removal of volatiles yielded 0.366 g (yield: 100%) of the title compound. Pale yellow oil. Rf (Hexane:AcOEt 80:20)=0.43. [α] D =+32.7(c1.0, CHCl 3 ). IR (film) (cm -1 ): 3417, 3079, 2956, 2109.

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PUM

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Abstract

It comprises a preparation process of entecavir comprising: submitting a (1S, 3R)-3-(tert-butyldimethylsilyloxy)-1 -(oxiran-2-yl)pent-4-yn-1-ol (VIII) to a double esterification and to a radicalary cyclization, yielding a compound of formula (V), where either a compound of formula (VIII) is submitted to a first esterification reaction, then to a catalytic radicalary cyclization using titanocene dichloride as catalyst in the presence of Mn / 2,4,6-collidine HCI or Zn / 2,4,6-collidine / trimethylsilyl chloride, and finally to a second esterification reaction or, alternatively, the compound of formula (VIII) is submitted first to a catalytic radicalary cyclization, and then to an esterification reaction. Entecavir can be obtained by submitting compound (V) to a desilylation reaction to remove the TBS group and then to a Mitsunobu coupling with 2- amino-6-chloroguanine, followed by hydrolysis. It also relates to some new intermediates of the process.

Description

[0001] The present invention relates to the preparation method of the antiviral drug called entecavir and some new intermediates used in the preparation method. Background technique [0002] Entecavir is 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6,9-dihydro-3H-purine- The International Nonproprietary Name (INN) of 6-keto has a CAS number of 142217-69-4. Entecavir is marketed as a monohydrate by Bristol-Myers Squibb under the trade name Baraclude. Entecavir is administered orally in tablet form or as an oral solution containing 0.05 mg / ml. It is a nucleoside analog, more specifically a guanine analog, that inhibits reverse transcription, DNA replication and transcription during viral replication. Entecavir is used to treat chronic hepatitis B. It also helps prevent the hepatitis B virus from multiplying and infecting new liver cells. Entecavir is also indicated for the treatment of chronic hepatitis B in adults with HIV / AIDS infection. [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18C07D303/14C07D303/16C07C13/11C07F7/08
CPCC07D303/14C07D303/16C07D473/18C07F7/081C07F7/1804A61P31/12
Inventor 马蒂·巴特拉桑马蒂拉蒙·贝伦格尔迈莫贾维尔·维拉斯克图尔宝贾维尔·阿里扎皮科尔杰米·法拉斯索勒乔治·加西亚郭迈兹
Owner ESTEVE QUIMICA
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