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1-Hydroxybenzotriazole → 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropan]-2-yl)amino]-3-methoxy-N-(1-methyl-4-piperidinyl)benzamide

HRID 2111386
Notes
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Reaction equation

HRID 2111386 reaction equation
[CH:1]1([N:6]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:14][C:11]3([CH2:12][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27375314-Amino-1-methylpiperidineHCID 576350144-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropan]-2-yl)amino]-3-methoxybenzoic acidHCID 178484289HCID 178484289, compound

Product 1

HCID 25015540
4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropan]-2-yl)amino]-3-methoxy-N-(1-methyl-4-piperidinyl)benzamide
Yield 55.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a suspension of 0.2463 g (0.000563 mole) of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methoxybenzoic acid (I-53) in 15 mL of dimethylformamide was added 0.1222 g (0.00091 mole) of 1-hydroxybenzotriazole, 0.3307 g (0.00087 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.59 mL (0.00339 mole) of ethyldiisopropylamine. The mixture was stirred for 20 minutes and then 0.0980 g (0.00086 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2-80:20) to give 0.166 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methoxy-N-(1-methyl-4-piperidinyl)benzamide (I-54).

Workup

  1. stirringThe mixture was stirred for an additional 2.5 hours
  2. concentrationconcentrated under reduced pressure
  3. dissolutionThe residue was dissolved in ethyl acetate
  4. washwashed successively with 1 M sodium hydroxide, brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel chromatography
  9. washeluting with dichloromethane-methanol (98:2-80:20)

Sources & evidence

ORD record
ord-6471008d9d864883997f255ea6b7f6a8
Source dataset
uspto-grants-2009_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07517873B2

Reaction notes

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