Methanol tetrahydrofuran water → (+/-)-1-(3-amino-4-cyano-benzyl)-4-(5-chloro-1H-indol-2-ylmethyl)-6-oxo-piperazine-2-carboxylic acid

HRID 1433014Notes

Reaction equation

HRID 1433014 reaction equation
C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][N:19]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([NH2:35])[CH:28]=2)[CH:21]([C:36]([O:38]C)=[O:37])[CH2:20]1)=O)(C)(C)C.C1COCC1.CO.O>CC(O)=O>[NH2:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[C:33]#[N:34])[CH2:26][N:22]1[C:23](=[O:25])[CH2:24][N:19]([CH2:18][C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[CH2:20][CH:21]1[C:36]([OH:38])=[O:37]

Participants

4

Reactant 2

HCID 21892291Methanol tetrahydrofuran waterHCID 54288444(+/-)-2-[4-(3-Amino-4-cyano-benzyl)-3-methoxycarbonyl-5-oxo-piperazin-1-ylmethyl]-5-chloro-indole-1-carboxylic acid tert-butyl ester

Product 1

HCID 53964541(+/-)-1-(3-amino-4-cyano-benzyl)-4-(5-chloro-1H-indol-2-ylmethyl)-6-oxo-piperazine-2-carboxylic acidYield 48%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

LiOH monohydrate (380 mg, 9.06 mmol) is added at ambient temperature to a solution containing (±)-2-[4-(3-amino-4-cyano-benzyl)-3-methoxycarbonyl-5-oxo-piperazin-1-ylmethyl]-5-chloro-indole-1-carboxylic acid tert-butyl ester (1.0 g, 1.81 mmol), EXAMPLE 784, Part E, in 1:1:1 THF/MeOH/water (30 mL). After 16 h, HOAc (0.5 mL) is added and the reaction mixture is concentrated in vacuo. The residue is dissolved in CH3CN/water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 378 mg (48%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.03 (m, 1H), 3.48 (m, 1H), 3.51 (ABq, ΔAB=69.2 Hz, JAB=16.4 Hz, 2H), 3.78 (d, J=15.9 Hz, 1H), 4.05-4.09 (m, 2H), 5.04 (d, J=15.9 Hz, 1H), 6.41 (m, 2H), 6.58 (s, 1H), 7.04 (dd, J=8.6, 2.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.51, d, J=2.0 Hz, 1H) ppm; MS (ISP loop): m/z 438 (M+H).

Workup

  1. concentrationthe reaction mixture is concentrated in vacuo
  2. dissolutionThe residue is dissolved in CH3CN/water
  3. custompurified by reverse-phase HPLC [Buffer A: water

Sources & evidence

ORD record
ord-f86f7c5287464c84bf63e4c5d314e0ce
Source dataset
uspto-grants-2009_11
Patent number
US07612075B2

Reaction notes

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