Diisopropylethylamine → (R)-benzyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate

HRID 2093451Notes

Reaction equation

HRID 2093451 reaction equation
ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:15]([F:38])=[C:16]([CH:35]=[CH:36][CH:37]=1)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C@H:20]([CH3:34])[CH2:19]1.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=1>C1COCC1.CCOC(C)=O>[F:38][C:15]1[C:14]([NH:13][C:5]([NH:48][C:49]2[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=2)=[O:11])=[CH:37][CH:36]=[CH:35][C:16]=1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C@H:20]([CH3:34])[CH2:19]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 7286704-Amino-2-methylpyridineHCID 58919233(R)-benzyl 4-(3-amino-2-fluorobenzyl)-2-methylpiperazine-1-carboxylate

Product 1

HCID 58919234(R)-benzyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylateYield 27%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a 0° C. solution of triphosgene (150 mg, 0.50 mmol, 0.35 equiv) in THF (15 mL) was slowly added via cannula a solution of (R)-benzyl 4-(3-amino-2-fluorobenzyl)-2-methylpiperazine-1-carboxylate (500 mg, 1.4 mmol, 1.0 equiv) and DIPEA (485 μL, 18.5 mmol, 2.0 equiv) in THF (15 mL) over approximately 15 minutes. The solution was stirred for an additional 20 min at 0° C., and 4-amino-2-methylpyridine was then added. After stirring at room temperature overnight, the reaction was diluted with EtOAc, washed with aq. satd. NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase preparative HPLC provided (R)-benzyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate (180 mg, 27%). LCMS m/z (APCI)=492.3 (M+H).

Workup

  1. stirringAfter stirring at room temperature overnight
  2. washwashed with aq. satd
  3. dry with materialNaHCO3 and brine, dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customPurification by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-af40871e5e664163ac246e330a1b69c2
Source dataset
uspto-grants-2013_05
Patent number
US08445495B2

Reaction notes

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