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

HRID 77585

Reaction equation

HRID 77585 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([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][CH: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:7]=1.[F:34][C:35]1[CH: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][CH: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:6]2[CH:7]=[C:2]([NH:1][C:41]([C:38]3[CH:37]=[CH:36][C:35]([F:34])=[CH:40][N:39]=3)=[O:42])[CH:3]=[CH:4][C:5]=2[F:33])[N:9]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1

Participants

9

Reactant 5

HCID 14798Sodium HydroxideHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27628765-fluoropyridine-2-carboxylic AcidHCID 86762771N-[7a-(5-Amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762773N-[3-[2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-fluoro-pyridine-2-carboxamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

N-[7a-(5-Amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (302 mg, 647 μmol) and 5-fluoropyridine-2-carboxylic acid (110 mg, 777 μmol) are combined in dichloromethane (3 mL) and dimethylformamide (0.5 mL). 1-Hydroxybenzotriazole (116 mg, 842 μmol) and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (164 mg, 842 μmol) are added and the mixture is stirred overnight at room temperature under nitrogen. The reaction mixture is diluted with water and the pH adjusted with 1 N NaOH to ˜12 and then extracted with ethyl acetate (3×). The organic layers are combined and filtered to collect the insoluble material. The solids are washed with water and ethyl acetate and dried under vacuum to give the title compound. The organic layer from the filtrate is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue is purified over silica gel with a 20 minute 5% to 100% ethyl acetate in hexanes gradient to give additional title compound with a combined yield (275 mg, 72%). ES/MS (m/e): 590 (M+H).

Workup

  1. extractionextracted with ethyl acetate (3×)
  2. filtrationfiltered
  3. customto collect the insoluble material
  4. washThe solids are washed with water and ethyl acetate
  5. customdried under vacuum

Sources & evidence

ORD record
ord-258d603614084f209c8cfc42264afd78
Source dataset
uspto-grants-2014_09
Patent number
US08841293B1

Linked notes

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