Entecavir intermediate and preparation method thereof

Abstract

The present invention relates to important intermediate 2 of entecavir and a method for preparing entecavir intermediate compound 1 through ring-closing reaction of compound 2 under the condition of free radicals with transition metals as the center.

Description

technical field [0001] The invention relates to a hepatitis B drug intermediate and a preparation method thereof, in particular to a methylene cyclopentane compound, a key intermediate of entecavir, and a preparation method thereof. Background technique [0002] Entecavir (Entecavir), an antiviral (HBV) prescription drug, was first listed in the United States by Bristol-Myers Squibb in April 2005. The chemical name is: [1S-(1α, 3α, 4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one; the chemical structure is as follows: [0003] [0004] The report on its use as an antiviral drug first appeared in US526244; the report on entecavir low-dose drug combination used to treat hepatitis B virus infection was found in CN1310999 and CN1658844. JOC1985 (50) 755, CN1061972, WO9809964, CN1747959 etc. have described its preparation method, and the key is by synthesizing key intermediate cyclopentane compound, and this intermediate has the...

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Problems solved by technology

[0005] First, the preparation method uses achiral cyclopentadiene as the starting material, and constructs chiral groups by using expensive chiral ligands or chiral resolution. The efficiency of introducing chiral groups is low and the cost is low. high

[0006] Second, the yield is low in the next reaction with guanine derivatives, wherein JOC1985 (50) 755, the reported yield is only 27%

[0007] Third, the position selection and chiral selectivity of guanine ring opening are poor. After ring opening, there are multiple stereoisomers mixed, and it is difficult to prepare high-purity products even through multiple column chromatography.

[0008] Fourth, the product after ring opening needs to further protect the amino group on guanine in the next reaction, the protection reaction is difficult, the product is unstable, and it is easy to decompose even on a silica gel column, and it is difficult to purify

[0009] Fifth, CN1747959 also reported the use of silane as the precursor of hydroxyl groups. After the basic structure synthesis of the target molecule was completed, very harsh oxidation conditions were used to complete the conversion of silane groups into hydroxyl groups, so the purity and yield were not high, and Requires special resins to separate

[0019] This method uses low temperature of -78°C and expensive and toxic Nysted Reagent reagent in the 5' methylation step of the compound, which is not easy to realize industrial production

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