Sodium triacetoxyborohydride → 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester

HRID 1946067Notes

Reaction equation

HRID 1946067 reaction equation
[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1([CH3:44])[CH3:43])=[O:36])([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:18][C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)[CH2:39][C:38]1([CH3:44])[CH3:43])=[O:36])([CH3:33])([CH3:31])[CH3:32]

Participants

5

Reactant 3

HCID 5049666Sodium triacetoxyborohydrideHCID 299224001,1-Dimethylethyl 2,2-dimethyl-1-piperazinecarboxylateHCID 596059872-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde

Product 1

HCID 674922904-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (530 mg, 1.35 mmol), 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (350 mg, 1.63 mmol) and molecular sieves (4 Å, powdered, 2.5 g) in DCE (30 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (427 mg, 2.02 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; 100:0 to 95:5 to 90:10) to give 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH before the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 98:2 to 95:5 to 90:10 to 80:20) to afford 552 as a cream solid (144 mg, 22%). LCMS (Method I): RT=2.56 min, M+H+=490. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H); 7.75 (m, 1 H); 7.29 (m, 2 H); 4.35 (m, 4 H); 3.92-3.83 (m, 7 H); 3.70 (s, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 2.97 (m, 2 H); 2.47 (m, 2 H); 2.28 (s, 2 H); 1.49-1.42 (m, 3 H) and 1.19 (s, 6 H)

Workup

  1. stirringthe mixture stirred for 17 h
  2. washThe cartridge was then washed with methanol
  3. washthe desired product was subsequently eluted
  4. customThe product was collected
  5. concentrationconcentrated in vacuo
  6. customThe resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; 100:0 to 95:5 to 90:10)

Sources & evidence

ORD record
ord-69dc901550884926b04c23edf4cc67a1
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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