Ethylenediamine → 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropylethyl]-3-fluorobenzamide

HRID 571476Notes

Reaction equation

HRID 571476 reaction equation
[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29](COCC[Si](C)(C)C)[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=2[F:17])[CH2:5]1)#[N:2].F[P-](F)(F)(F)(F)F.[N:47]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:51]2[CH:52]=C[CH:54]=[CH:55][C:50]=2N=N1.C1([C@@H](N)C)CC1.C(N(CC)CC)C.C([O-])(O)=O.[Na+].C(N)CN>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:47][C@H:51]([CH:50]3[CH2:55][CH2:54]3)[CH3:52])=[O:13])=[CH:10][C:9]=2[F:17])[CH2:5]1)#[N:2]

Participants

8

Reactant 6

HCID 3301EthylenediamineHCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 516892Sodium BicarbonateHCID 7363995(S)-1-CyclopropylethylamineHCID 71143553HCID 71143553, compound

Product 1

HCID 711557954-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropylethyl]-3-fluorobenzamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluorobenzoic acid (20.0 mg, 0.0365 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (19 mg, 0.044 mmol) in dichloromethylene (1.0 mL) was added to a mixture of (1S)-1-cyclopropylethanamine (4.7 mg, 0.055 mmol) and triethylamine (15 μL, 0.11 mmol) in methylene chloride (0.6 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with dichloromethylene (2×2 mL). The combined organic layers were washed with water (1 mL), concentrated and dried under reduced pressure. The residue was treated with methylene chloride (1.3 mL) and trifluoroacetic acid (0.6 mL), and stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in methanol (1.3 mL). Ethylenediamine (0.086 mL, 1.3 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and purified by RP-HPLC (pH=10) (the conditions are already mention before the examples) to afford the desired product. LCMS (M+H)+: m/z=485.2.

Workup

  1. extractionextracted with dichloromethylene (2×2 mL)
  2. washThe combined organic layers were washed with water (1 mL)
  3. concentrationconcentrated
  4. customdried under reduced pressure
  5. additionThe residue was treated with methylene chloride (1.3 mL) and trifluoroacetic acid (0.6 mL)
  6. stirringstirred at room temperature for 1.5 hours
  7. concentrationThe mixture was concentrated under reduced pressure
  8. dissolutionThe residue was dissolved in methanol (1.3 mL)
  9. stirringThe reaction mixture was stirred at room temperature for 2 hours
  10. custompurified by RP-HPLC (pH=10) (the conditions

Sources & evidence

ORD record
ord-6405d627547844478540a73a727ad3d6
Source dataset
uspto-grants-2015_05
Patent number
US09023840B2

Reaction notes

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