Trimethyl orthoformate → 9-[2-chloro-4-ethoxycarbonylmethoxy-5-(2,3-difluoro-6-methoxybenzyloxy)phenyl]-6-methoxy-2-(1,1-dimethoxyethyl)-7,9-dihydro-8H-purin-8-one

HRID 1513072Notes

Reaction equation

HRID 1513072 reaction equation
[C:1]([C:4]1[N:12]=[C:11]2[C:7]([NH:8][C:9](=[O:39])[N:10]2[C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]3[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[C:23]([F:29])[C:22]=3[F:30])[C:16]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:15][C:14]=2[Cl:38])=[C:6]([O:40][CH3:41])[N:5]=1)(=[O:3])[CH3:2].O.[C:43]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:54](OC)(OC)[O:55]C>CO>[Cl:38][C:14]1[CH:15]=[C:16]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:17]([O:19][CH2:20][C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[C:23]([F:29])[C:22]=2[F:30])=[CH:18][C:13]=1[N:10]1[C:9](=[O:39])[NH:8][C:7]2[C:11]1=[N:12][C:4]([C:1]([O:55][CH3:54])([O:3][CH3:43])[CH3:2])=[N:5][C:6]=2[O:40][CH3:41]

Participants

5

Reactant 3

HCID 9005Trimethyl orthoformateHCID 521998p-Toluenesulfonic acid monohydrateHCID 593101042-acetyl-9-[2-chloro-4-ethoxycarbonylmethoxy-5-(2,3-difluoro-6-methoxybenzyloxy)phenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one

Product 1

HCID 685094559-[2-chloro-4-ethoxycarbonylmethoxy-5-(2,3-difluoro-6-methoxybenzyloxy)phenyl]-6-methoxy-2-(1,1-dimethoxyethyl)-7,9-dihydro-8H-purin-8-one

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A mixture of 2-acetyl-9-[2-chloro-4-ethoxycarbonylmethoxy-5-(2,3-difluoro-6-methoxybenzyloxy)phenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (0.18 g), p-toluene-sulfonic acid monohydrate (12 mg), trimethyl orthoformate (1 mL) and methanol (1 mL) was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give 9-[2-chloro-4-ethoxycarbonylmethoxy-5-(2,3-difluoro-6-methoxybenzyloxy)phenyl]-6-methoxy-2-(1,1-dimethoxyethyl)-7,9-dihydro-8H-purin-8-one (74 mg). This material was dissolved in ethanol (1 mL)-tetrahydrofuran (1 mL). To the solution was added sodium borohydride (45 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). To the solution were added concentrated hydrochloric acid (0.1 mL) and water (0.1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give the title compound (25 mg).

Workup

  1. temperaturewas heated
  2. temperatureat reflux overnight
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. customthe residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate)

Sources & evidence

ORD record
ord-94e550920ab44e9b8f7286c6e6b41fe4
Source dataset
uspto-grants-2012_07
Patent number
US08217069B2

Reaction notes

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