Tris(hydroxymethyl)aminomethane → 1,1-dimethylethyl (2R,6S)-4-{[4-(2-{4-[(4-fluorophenyl)amino]-1-piperidinyl}-1-methyl-2-oxoethyl)phenyl]methyl}-2,6-dimethyl-1-piperazinecarboxylate

HRID 43361Notes

Reaction equation

HRID 43361 reaction equation
[CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:25])[C:22](O)=[O:23])=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH3:26])=[O:7])([CH3:4])[CH3:3].[CH2:27]1CCC(N=C=NC2CCCCC2)CC1.ON1C2C=CC=CC=2N=N1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][CH:54]=1.C(O)C(N)(CO)CO.[N-]=C=O>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[F:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][CH:60]2[CH2:65][CH2:64][N:63]([C:22](=[O:23])[CH:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[CH2:12][C@H:13]([CH3:27])[N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:1])[CH3:3])=[O:7])[C@H:9]([CH3:26])[CH2:10]4)=[CH:20][CH:19]=3)[CH3:25])[CH2:62][CH2:61]2)=[CH:55][CH:54]=1

Participants

9

Reactant 6

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 105034IsocyanateHCID 4778193N-(4-Fluorophenyl)-4-piperidinamineHCID 671280982-{4-[((3S)-4-{[(1,1-Dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]phenyl}propanoic acid

Product 1

HCID 252241001,1-dimethylethyl (2R,6S)-4-{[4-(2-{4-[(4-fluorophenyl)amino]-1-piperidinyl}-1-methyl-2-oxoethyl)phenyl]methyl}-2,6-dimethyl-1-piperazinecarboxylate

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

A mixture of D46 (100 mg, 0.27 mmol), polymer-supported DCC (310 mg, 1.3 mmol/g, 0.40 mmol) and 1-hydroxybenzotriazole (50 mg, 0.324 mmol) in 2:1 DMF/DCM (3 ml) was treated with D2 (51 mg, 0.26 mmol) and the mixture stirred overnight. Scavenger resins (PS-trisamine, PS-isocyanate and Si-carbonate) together with DCM (˜3 ml) were added. The mixture was stirred for ˜3 h and then filtered and concentrated to give 1,1-dimethylethyl (2R,6S)-4-{[4-(2-{4-[(4-fluorophenyl)amino]-1-piperidinyl}-1-methyl-2-oxoethyl)phenyl]methyl}-2,6-dimethyl-1-piperazinecarboxylate. MS (ES): MH+ 553. This whole was dissolved in DCM (2 ml) and TFA (1 ml) then stirred for 1.5 h. The solvents were removed in vacuo and the residue re-evaporated from toluene and ether. Purification using an Isolute SCX cartridge eluting with MeOH followed by 2M NH3 in MeOH gave the title compound. MS (ES): MH+ 453. This whole was dissolved in DCM and treated with 1.1 eq 1M HCl in ether to give a hydrochloride salt of the title compound (122 mg). MS (ES): MH+ 453.

Workup

  1. stirringThe mixture was stirred for ˜3 h
  2. filtrationfiltered
  3. concentrationconcentrated

Sources & evidence

ORD record
ord-390e555476734643a654101bfa77b3fc
Source dataset
uspto-grants-2013_09
Patent number
US08536182B2

Reaction notes

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