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

HRID 876738Notes

Reaction equation

HRID 876738 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][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:7]=1.[CH3:34][O:35][C:36]1[N:37]=[CH:38][C:39]([C:42](O)=[O:43])=[N:40][CH:41]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[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:6]2[CH:7]=[C:2]([NH:1][C:42]([C:39]3[CH:38]=[N:37][C:36]([O:35][CH3:34])=[CH:41][N:40]=3)=[O:43])[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

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 457898115-Methoxy-2-pyrazinecarboxylic acidHCID 86762775N-[(4aR,7aS)-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 86762774N-[3-[(4aR,7aS)-2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carboxamideYield 75.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

N-[(4aR,7aS)-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 (0.361 g, 0.77 mmol, isomer 1) is dissolved in a mixture of dichloromethane (4 mL) and DMF (0.5 mL). 5-Methoxypyrazine-2-carboxylic acid (240 mg, 1.55 mmol), 1-hydroxybenzotriazole (210 mg, 1.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (300 mg, 1.55 mmol) are added to the mixture and the mixture is stirred overnight at room temperature. The reaction solution is added directly onto a 12 g silica gel loading column and purified using a 40 g silica gel column and eluting with a 0-100% ethyl acetate/hexanes gradient. The product is dissolved in ethyl acetate (200 mL), washed with 1 N NaOH (2×50 mL), and with brine (1×50 mL). The silica gel purification is repeated as described above to give the title compound (350 mg, 74%). ES/MS (m/e): 603 (M+H).

Workup

  1. additionThe reaction solution is added directly onto a 12 g silica gel loading column
  2. custompurified
  3. washeluting with a 0-100% ethyl acetate/hexanes gradient
  4. dissolutionThe product is dissolved in ethyl acetate (200 mL)
  5. washwashed with 1 N NaOH (2×50 mL)
  6. customThe silica gel purification

Sources & evidence

ORD record
ord-002427be918a4b3da3e2af41db739b47
Source dataset
uspto-grants-2015_03
Patent number
US08987254B2

Reaction notes

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