Diisopropylethylamine → HCID 46199028, compound

HRID 588038Notes

Reaction equation

HRID 588038 reaction equation
Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[NH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.CS(O)(=O)=O.[NH2:38][CH2:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[C:45](=[O:49])[N:44]([CH:50]1[CH2:55][CH2:54][C:53](=[O:56])[NH:52][C:51]1=[O:57])[CH2:43]2>CC#N>[O:57]=[C:51]1[CH:50]([N:44]2[CH2:43][C:42]3[C:46](=[CH:47][CH:48]=[C:40]([CH2:39][NH:38][C:2](=[O:3])[NH:14][CH:15]4[CH2:20][CH2:19][CH:18]([C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]4)[CH:41]=3)[C:45]2=[O:49])[CH2:55][CH2:54][C:53](=[O:56])[NH:52]1

Participants

6

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 821294-Nitrophenyl chloroformateHCID 167917394-AminocyclohexanecarboxamideHCID 866307653-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate

Product 1

HCID 46199028HCID 46199028, compoundYield 30%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

To the solution of para-nitro-phenyl chloroformate (200 mg, 1 mmol) in CH3CN (5 mL), was added the CH3CN solution (5 mL) of 4-Amino-cyclohexanecarboxylic acid amide (210 mg, 1 mmol) and DIPEA (0.3 mL, 2 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 10 min. 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonic acid salt (0.37 g, 1 mmol) was added followed by additional DIPEA (0.15 mL, 1 mmol). The mixture was stirred overnight at ambient temperature. The mixture was then filtered. The filtrate was purified on prep-HPLC to give 4-{3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-ureido}-cyclohexanecarboxylic acid amide as a white solid (130 mg, 30% yield). HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 5% grad 95% in 5 min, CH3CN/0.1% H3PO4: tR=4.78 min (92%); mp: 195-197 0C; 1H NMR (DMSO-d6) δ 1.32-1.73 (m, 8H, CHH+CHH+CHH+CHH), 1.97 (br. S., 1H, CHH), 2.09-2.21 (m, 1H, CHH), 2.40 (d, J=13.4 Hz, 1H, CHH), 2.62 (br. S., 1H, CHH), 2.80-3.03 (m, 1H, CHH), 3.70 (br. S., 1H, CHH), 4.18-4.58 (m, 4H, CH2+CH2), 5.11 (dd, 1H, CHN), 6.15 (d, J=7.9 Hz, 1H, NH), 6.38 (t, J=5.9 Hz, 1H, NH), 6.67 (br. S., 1H, NH), 7.19 (br. S., 1H, NH), 7.38 (d, J=7.7 Hz, 1H, Ar), 7.45 (s, 1H, Ar), 7.67 (d, J=7.9 Hz, 1H, Ar), 10.98 (br. S., 1H, NH); 13C NMR (DMSO-d6) δ 0.03, 22.42, 24.06, 24.19, 29.73, 41.73, 42.79, 44.16, 47.03, 51.49, 121.68, 122.80, 126.71, 130.09, 142.26, 145.37, 157.28, 163.37, 167.89, 170.92, 172.78, 176.83: LC-MS: 442; Anal Calcd for C22H27N5O5+0.5HCOOH+1H2O+0.2CH3CN: C, 56.05; H, 6.21; N, 14.84. Found: C, 55.70: H, 6.46; N, 14.78.

Workup

  1. stirringThe mixture was stirred overnight at ambient temperature
  2. filtrationThe mixture was then filtered
  3. customThe filtrate was purified on prep-HPLC

Sources & evidence

ORD record
ord-0e5744780533498bb889e193d775231f
Source dataset
uspto-grants-2016_01
Patent number
US09227954B2

Reaction notes

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