Sodium Hydroxide → N-[3-[(4aR,7aS)-2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-methoxy-pyrazine-2-carboxamide

HRID 876735Notes

Reaction equation

HRID 876735 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[CH3:33][O:34][C:35]1[N:36]=[CH:37][C:38]([C:41](O)=[O:42])=[N:39][CH:40]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>ClCCl.CN(C)C=O.O>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:4]2[CH:3]=[C:2]([NH:1][C:41]([C:38]3[CH:37]=[N:36][C:35]([O:34][CH3:33])=[CH:40][N:39]=3)=[O:42])[CH:7]=[CH:6][CH:5]=2)[N:9]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1

Participants

9

Reactant 5

HCID 14798Sodium HydroxideHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 457898115-Methoxy-2-pyrazinecarboxylic acidHCID 86762768N-[(4aR,7aS)-7a-(3-Aminophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762772N-[3-[(4aR,7aS)-2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-methoxy-pyrazine-2-carboxamideYield 92.4%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

N-[(4aR,7aS)-7a-(3-Aminophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (400 mg, 891.81 μmole) and 5-methoxypyrazine-2-carboxylic acid (165 mg, 1.07 mmol) are combined in dichloromethane (4 mL) and dimethylformamide (0.5 mL). 1-Hydroxybenzotriazole (160 mg, 1.16 mmol) and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (226 mg, 1.16 mmol) are added and the resulting mixture is stirred for 5 hours at room temperature under nitrogen. The reaction mixture is diluted with water and the pH is adjusted to ˜12 with 1 N NaOH. The mixture is extracted with ethyl acetate (3×). The combined organic extracts are dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is purified over silica gel with a 20 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (482 mg, 92%). ES/MS (m/e): 585 (M+H).

Workup

  1. extractionThe mixture is extracted with ethyl acetate (3×)
  2. dry with materialThe combined organic extracts are dried over sodium sulfate
  3. filtrationfiltered
  4. customthe solvent removed in vacuo
  5. customThe crude product is purified over silica gel with a 20 minute 5% to 100% ethyl acetate in hexanes gradient

Sources & evidence

ORD record
ord-0a2d6edb2cdc4dd793a8cc35be42442a
Source dataset
uspto-grants-2015_03
Patent number
US08987254B2

Reaction notes

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