Ethyl Acetate → (R)-1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methylurea

HRID 1050602Notes

Reaction equation

HRID 1050602 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])OC(C)(C)C)[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].[CH2:24]([Cl:26])Cl.[C:27](O)([C:29]([F:32])([F:31])[F:30])=O.C[CH2:35][N:36](C(C)C)[CH:37]([CH3:39])[CH3:38].[CH3:43]COC(C)=O>>[Cl:26][C:24]1[CH:38]=[C:37]([N:36]([CH3:35])[C:15]([NH:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]3[CH:5]=[N:4][C:3]([C:22]#[N:23])=[C:2]([Cl:1])[N:7]=3)[CH2:9]2)=[O:21])[CH:39]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:43]=1

Participants

5

Reactant 4

HCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 21863450Trifluoroacetic acid methylene chlorideHCID 118114972(R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate

Product 1

HCID 118114389(R)-1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methylurea

Procedure

(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 950 mg, 2.8 mmol) was treated with 2:1 DCM/TFA (20 mL/10 mL) at RT for 20 min. The mixture was concentrated in vacuo to dryness as crude (R)-5-(3-aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile (221, TFA salt). It was dissolved in 18 mL DMF. To it were added DIEA (3.9 mL, 22.4 mmol) and then the crude 468 (estimated 5.9 mmol) prepared. The mixture was stirred at RT for 1.5 hour, diluted with 120 mL EtOAc, washed with water and saturated NaHCO3 (aq) solution, dried, concentrated and subjected to silica flash column using 0 to 3.5% MeOH in DCM to isolate (R)-1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methylurea (469) in quantitative yield.

Workup

  1. concentrationThe mixture was concentrated in vacuo to dryness as crude (R)-5-(3-aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile (221, TFA salt)
  2. dissolutionIt was dissolved in 18 mL DMF
  3. customthe crude 468 (estimated 5.9 mmol) prepared
  4. washwashed with water and saturated NaHCO3 (aq) solution
  5. customdried
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-52e22316cfd54bbda87f799211a7746e
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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