Cyclopropylamine → (R)-3-(1-(5-cyano-6-(cyclopropylamino)pyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea

HRID 1050624Notes

Reaction equation

Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[N:16]([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:25]#[N:26].[CH:27]1([NH2:30])[CH2:29][CH2:28]1>CS(C)=O.CCOC(C)=O>[C:25]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[N:16]([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)=[N:7][C:2]=1[NH:30][CH:27]1[CH2:29][CH2:28]1)#[N:26]

Participants

Conditions

Temperature: 70 °C

Procedure

(R)-3-(1-(6-Chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea (513, 100 mg) was dissolved in 4 mL DMSO in a sealed tube. To it was added cyclopropylamine (210 μL, 3 mmol) and the mixture was stirred in 70° C. bath for 16 hours. It was diluted with 60 mL EtOAc, washed with water ×2, concentrated in vacuo to afford crude (R)-3-(1-(5-cyano-6-(cyclopropylamino)pyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea (514). It was dissolved in 4 mL MeOH and 2 mL DMSO. To it were added one NaOH solid pellet (about 50-100 mg) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 45 min, diluted with 10 mL MeCN, stirred for 5 min, concentrated on rotavap. The residue was treated with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-3-(cyclopropylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide (515) as HCl salt (74 mg, 67% yield). LC-MS (ESI): m/z (M+1) 410.3. UV: λ=283, 317, 369 nm.

Workup

washwashed with water ×2
concentrationconcentrated in vacuo

Sources & evidence

ORD record: ord-eb921db6ef3b43f4abd668079611bc38
Source dataset: uspto-grants-2016_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09382246B2

Reaction notes

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