m-Chloroperbenzoic acid → HCID 118114730, compound

HRID 1050610Notes

Reaction equation

HRID 1050610 reaction equation
[C:1]([C:4]1[N:9]=[N:8][C:7](SC)=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)(=[O:3])[NH2:2].C1C=C(Cl)C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.Cl.[CH3:53][O:54][C:55]1[CH:69]=[CH:68][C:58]([C:59]([NH:61][C@@H:62]2[CH2:67][CH2:66][CH2:65][NH:64][CH2:63]2)=[O:60])=[CH:57][CH:56]=1>CN1C(=O)CCC1.C(Cl)(Cl)Cl>[CH3:53][O:54][C:55]1[CH:56]=[CH:57][C:58]([C:59]([NH:61][C@@H:62]2[CH2:67][CH2:66][CH2:65][N:64]([C:7]3[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([CH:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[CH:15][CH:14]=4)[N:6]=3)[CH2:63]2)=[O:60])=[CH:68][CH:69]=1

Participants

7

Reactant 4

HCID 70297m-Chloroperbenzoic acidHCID 81531DiisopropylethylamineHCID 118114820HCID 118114820, compoundHCID 118115143HCID 118115143, compound

Product 1

HCID 118114730HCID 118114730, compound

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

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. stirringThe mixture was stirred at 70° C. for 30 min
  2. temperatureThe mixture was cooled to RT
  3. washwashed with 1N NaOH (aq) ×2 and water
  4. customdried
  5. concentrationconcentrated 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%)
  6. additionIt was treated with 35 mL commercial 4N HCl in dioxane at RT for 45 min
  7. concentrationThe mixture was concentrated in vacuo to dryness

Sources & evidence

ORD record
ord-a7e9daaf4e1f437194190c442c8c9e65
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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