Chloromethyl Methyl Ether → tert-butyl 4-[1-{[2-(methoxymethyl)-2H-tetrazol-5-yl]methyl}-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate

HRID 1476591Notes

Reaction equation

HRID 1476591 reaction equation
[H-].[Na+].[O:3]=[C:4]1[N:9]([CH2:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)[C:8]2[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:7]=2[C:6](=[O:25])[N:5]1[CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.[CH3:39][O:40][CH2:41]Cl>C1COCC1.CN(C=O)C>[CH3:39][O:40][CH2:41][N:13]1[N:14]=[N:15][C:11]([CH2:10][N:9]2[C:8]3[CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:18][C:7]=3[C:6](=[O:25])[N:5]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[C:4]2=[O:3])=[N:12]1

Participants

7

Reactant 4

HCID 7864Chloromethyl Methyl EtherHCID 24758Sodium hydrideHCID 67258221tert-butyl 4-[2,4-dioxo-6-phenyl-1-(1H-tetrazol-5-ylmethyl)-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate2×HCID 178452064HCID 178452064, compound

Product 1

HCID 67258758tert-butyl 4-[1-{[2-(methoxymethyl)-2H-tetrazol-5-yl]methyl}-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

To a stirred suspension of sodium hydride (206 mg, 60% dispersion in mineral oil) in 7 ml absolute THF in a sealed tube is added a solution of a tautomeric mixture of tert-butyl 4-[2,4-dioxo-6-phenyl-1-(1H-tetrazol-5-ylmethyl)-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate and 4-[2,4-dioxo-6-phenyl-1-(2H-tetrazol-5-ylmethyl)-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl-]-piperidine-1-carboxylic acid tert-butyl ester (1.74 g; compound 14b) in absolute THF (7 ml) and absolute DMF (7 ml) at 0° C. After stirring for 40 min at 40° C. chloromethyl methyl ether (452 mg) dissolved in absolute DMF (3.5 ml) is added. The reaction mixture is stirred for 3 h at 50° C. and for 16 h at RT. The reaction is quenched by addition of a saturated aqueous solution of sodium bicarbonate and extracted with diethyl ether (two times). The combined organic phases are dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure. The resulting residue is purified by flash chromatography [silica gel, eluent: cyclohexane/diethyl ether, 1/1 (v/v)] to give the separated title compounds as solids.

Workup

  1. additionis added
  2. additionis added
  3. customThe reaction is quenched by addition of a saturated aqueous solution of sodium bicarbonate
  4. extractionextracted with diethyl ether (two times)
  5. dry with materialThe combined organic phases are dried over magnesium sulfate
  6. filtrationfiltered
  7. customthe solvent is removed under reduced pressure
  8. customThe resulting residue is purified by flash chromatography [silica gel, eluent: cyclohexane/diethyl ether, 1/1 (v/v)]
  9. customto give the
  10. customseparated title compounds as solids

Sources & evidence

ORD record
ord-4fcf4417d6ec44c7b548b077ce1f2720
Source dataset
uspto-grants-2015_04
Patent number
US09018175B2

Reaction notes

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