Diisopropylethylamine → (S)-4-amino-1-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide

HRID 422998Notes

Reaction equation

HRID 422998 reaction equation
CCN(C(C)C)C(C)C.[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Br:31][C:32]1[C:40]2[C:39](Cl)=[N:38][CH:37]=[N:36][C:35]=2[NH:34][CH:33]=1>C(O)CCC.CCOC(C)=O>[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][N:14]([C:39]2[C:40]3[C:32]([Br:31])=[CH:33][NH:34][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:13][CH2:12]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 53807105-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine2×HCID 57750388(S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide2×

Product 1

HCID 42602262(S)-4-amino-1-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamideYield 10.8%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

DIPEA (0.670 mL, 3.85 mmol) was added to (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (400 mg, 1.28 mmol) and 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 50) (298 mg, 1.28 mmol) in butan-1-ol (6 mL). The resulting solution was stirred at 60° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% MeOH with ammonia in DCM. The product was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and triturated with diethyl ether to afford (S)-4-amino-1-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (70.0 mg, 10.8%) as a white solid.

Workup

  1. washwashed sequentially with water (25 mL) and saturated brine (25 mL)
  2. dry with materialThe organic layer was dried over MgSO4
  3. filtrationfiltered
  4. customevaporated
  5. customto afford crude product
  6. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 6% MeOH with ammonia in DCM
  7. customThe product was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length)
  8. additionFractions containing the desired compound
  9. customwere evaporated to dryness
  10. customtriturated with diethyl ether

Sources & evidence

ORD record
ord-d867d0e9ec284ef4bc2698bd2637b6cd
Source dataset
uspto-grants-2012_01
Patent number
US08101623B2

Reaction notes

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