1,2-Dichloroethane → Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-[2-methoxy-methyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

HRID 720206Notes

Reaction equation

HRID 720206 reaction equation
C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:51])[NH:14][CH:15]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[C:16]([N:18]1C[CH2:22][N:21]([CH:24]([C:36](=[O:39])[NH:37][CH3:38])[CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:20][CH:19]1COC)=[O:17])=O)(C)(C)C.ClCCCl.FC(F)(F)C([O-])=O.O1[CH2:68][CH2:67][O:66][CH2:65]C1>Cl>[F:50][C:47]1[CH:48]=[CH:49][C:44]([CH2:43][CH:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:51])[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH:24]([C:36](=[O:39])[NH:37][CH3:38])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:22][C:67]2([CH3:68])[O:66][CH3:65])=[O:17])=[CH:45][CH:46]=1

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 312751,4-DioxaneHCID 84468TrifluoroacetateHCID 695878592-{1-(4-Fluorobenzyl)-2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 131726051Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-[2-methoxy-methyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amideYield 54%

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Procedure

Crude 2-{1-(4-fluorobenzyl)-2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, 67, is dissolved in 4M hydrogen chloride in dioxane (10 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added. Removal of solvents in vacuo gives the crude hydrogen chloride salt of product which is then purified by preparative HPLC to afford 0.22 g (54% yield) of the desired product as the trifluoroacetate salt. A small amount of product is converted into free base by treating with NaHCO3 to obtain NMR spectra. 1H NMR (CDCl3, δ): 7.80–7.60 (m, 4H), 7.45–7.25 (m, 3H), 7.18–7.00 (m, 2H), 7.00–6.85 (m, 2H), 6.32–6.28 (m, 0.5H), 5.08–4.92 (m, 1H), 4.78–4.69 (,0.5H), 4.10 (d, J=13.0 Hz, 0.5H), 3.70–3.58 (m, 1H), 3.58–3.15 (m, 8H), 2.98–2.46 (m, 11H), 2.28–2.15 (m, 0.5H), 2.15–1.50 (m, 8H). HRFAB(positive) m/e 604.2399 calculated for C34H42FN5O4 (M+H)+, Found 604.3292.

Workup

  1. customRemoval of solvents in vacuo
  2. customgives the crude hydrogen chloride salt of product which
  3. customis then purified by preparative HPLC

Sources & evidence

ORD record
ord-2d6ba40ff5a246af9996c8a634c368cf
Source dataset
uspto-grants-2006_11
Patent number
US07132539B2

Reaction notes

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