Ammonia → HCID 118114820, compound

HRID 1050609Notes

Reaction equation

HRID 1050609 reaction equation
Cl[C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CC[N:37](C(C)C)C(C)C.N>C(#N)C>[C:8]([C:7]1[N:6]=[N:5][C:4]([S:13][CH3:14])=[N:3][C:2]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1)(=[O:10])[NH2:37]

Participants

6

Reactant 4

HCID 222AmmoniaHCID 81531DiisopropylethylamineHCID 11557703Ethyl 5-Chloro-3-(Methylthio)-1,2,4-Triazine-6-CarboxylateHCID 21940085tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylate

Product 1

HCID 118114820HCID 118114820, compoundYield 79.5%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (1) (1.20 g, 5.15 mmol) in acetonitrile (40 mL) was added tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (2.14 g, 7.73 mmol) and then DIEA (1350 μL, 7.73 mmol). The mixture was stirred at RT for 1 hour. To the mixture was then added ammonia (7.0 N solution in methanol, 30 mL). The mixture turned cloudy in 10 min and then into a suspension. The mixture was stirred for 8 hours, and the solid was isolated by filtration. It was washed with cold acetonitrile (10 mL×2) and then washed with hexane (10 mL×3). The solid was dried in a vacuum oven to afford tert-butyl 4-(4-(6-carbamoyl-3-(methylthio)-1,2,4-triazin-5-ylamino)phenyl)piperidine-1-carboxylate (490) (1.82 g, 79% yield) in high purity. Compound 490 (600 mg, 1.35 mmol) was dissolved in 20 mL NMP. To it were added dry mCPBA (77% strength, 840 mg, 3.38 mmol). The mixture was stirred at RT for 1 hour. To the mixture was added DIEA (2.10 mL, 12.1 mmol) and (R)-4-methoxy-N-(piperidin-3-yl)benzamide hydrochloride (489) (550 mg, 2.03 mmol). The mixture was stirred at 70° C. for 30 min. The mixture was cooled to RT, diluted with 200 mL chloroform, washed with 1N NaOH (aq) ×2 and water, dried, concentrated in vacuo to dryness for crude (R)-tert-butyl 4-(4-(6-carbamoyl-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazin-5-ylamino)phenyl)piperidine-1-carboxylate (491) (740 mg, 87%). It was treated with 35 mL commercial 4N HCl in dioxane at RT for 45 min. The mixture was concentrated in vacuo to dryness to afford crude (R)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-5-(4-(piperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide (492). A small amount of crude 492 was purified using reverse phase prep HPLC to isolate as HCl salt. LC-MS (ESI): m/z (M+1) 531.1. UV: λ=255 nm.

Workup

  1. waitThe mixture turned cloudy in 10 min
  2. stirringThe mixture was stirred for 8 hours
  3. customthe solid was isolated by filtration
  4. washIt was washed with cold acetonitrile (10 mL×2)
  5. washwashed with hexane (10 mL×3)
  6. customThe solid was dried in a vacuum oven

Sources & evidence

ORD record
ord-6c3ddd17a46d4c46815b2ea0e1cb41b8
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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