Acetyl chloride → (R)-6-(7-acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester

HRID 1778469Notes

Reaction equation

HRID 1778469 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[Cl:33])[N:7]=[C:8]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:9][C:10]=1[CH2:11][N:12]1[CH:17]2[CH2:18][NH:19][CH2:20][CH:13]1[CH2:14][O:15][CH2:16]2)=[O:4].C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[Cl:33])[N:7]=[C:8]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:9][C:10]=1[CH2:11][N:12]1[CH:13]2[CH2:20][N:19]([C:41](=[O:43])[CH3:42])[CH2:18][CH:17]1[CH2:16][O:15][CH2:14]2)=[O:4]

Participants

5

Reactant 3

HCID 6367Acetyl chlorideHCID 8471TriethylamineHCID 117700087(R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester

Product 1

HCID 86293080(R)-6-(7-acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl esterYield 84.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound AC) (50 mg, 0.1 mmol) and triethylamine (0.042 mL, 0.3 mmol) in CH2Cl2 (5 mL) was added acetyl chloride (16 mg, 0.2 mmol) dropwise at ice-bath. The mixture was stirred at 0° C. for 2 hours. The mixture was concentrated in vacuo. The residue was extracted with ethyl acetate (20 mL×2) and then washed with saturated aqueous sodium bicarbonate solution (20 mL×2). The organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by prep-HPLC to afford (R)-6-(7-acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Example 15) as a light yellow solid (45 mg).

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. extractionThe residue was extracted with ethyl acetate (20 mL×2)
  3. washwashed with saturated aqueous sodium bicarbonate solution (20 mL×2)
  4. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by prep-HPLC

Sources & evidence

ORD record
ord-61556b95809a4ca8ac0465ee5e8c1ba8
Source dataset
uspto-grants-2016_02
Patent number
US09266904B2

Reaction notes

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