Diisopropylethylamine → HCID 9808736, compound

HRID 2185544Notes

Reaction equation

HRID 2185544 reaction equation
CC[N:3](C(C)C)C(C)C.FC(F)(F)[C:12](O)=[O:13].[F:17][C:18]1[CH:19]=[C:20]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:21][NH:22][C:23]([N:25]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH2:26][CH3:27])=[O:24].[CH:38]([C@@H:40]1[C@@H:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:43][N:42]([C@H:51]([CH:64]2[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]2)[C:52]([O:54]CC2C=CC(OC)=CC=2)=[O:53])[CH2:41]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH3:3].[CH3:12][OH:13].[F:17][C:18]1[CH:19]=[C:20]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:21][NH:22][C:23]([N:25]([CH:28]1[CH2:33][CH2:32][N:31]([CH2:38][C@@H:40]2[C@@H:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:43][N:42]([C@H:51]([CH:64]3[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]3)[C:52]([OH:54])=[O:53])[CH2:41]2)[CH2:30][CH2:29]1)[CH2:26][CH3:27])=[O:24]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 22458234HCID 22458234, compoundHCID 53654320alpha-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid 4-methoxybenzyl ester

Product 2

HCID 9808736HCID 9808736, compoundYield 53.6%HCID 21705897Ammonia methanol

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent2×

Procedure

To a solution of DIEA (0.019 mL, 0.11 mmol) in 0.5 mL of 1,2-dichloroethane was added 4-(N-(N-(3,4-difluorobenzyl)carbamoyl)-N-ethylamino)piperidine trifluoroacetate (41 mg, 0.1 mmol, from Step B). To this solution, a solution of 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (26 mg, 0.05 mmol, Aldehyde 5) was added. After mixing well, a slurry of sodium triacetoxyborohydride (35 mg, 0.17 mmol) in 0.5 mL of 1,2-dichloroethane was added. The reaction mixture was stirred well and allowed to stand at rt for 16 h. The solvent was removed and the product was purified by preparative HPLC (column: YMC Combiprep ODS-A 20×50 mm, gradient: 10% acetonitrile/water w/0.1% TFA for 1.5 min then ramp to 90% acetonitrile/water w/0.1% TFA over 7.5 min, flow: 20 mL/min). The isolated material was stirred in 3 mL formic acid for 16 h. After removal of solvent, the residue was purified by ion exchange chromatography (0.5 grams Varian SCX resin, eluting with 100% MeOH, then with 2.0 M NH3/MeOH) to give 16 mg (53%) of the title compound. 1H-NMR (400 MHz, CD3OD) δ1.06-1.14 (m, 6H), 1.33 (m, 2H), 1.54 (m, 1H), 1.67-2.05 (m, 10H), 2.57 (m, 1H), 2.87 (br d, J=13, 1H), 2.98 (br t, J=12, 1H), 3.11 (m, 1H), 3.18 (m, 2H), 3.25 (m, 1H), 3.48 (br t, J=11, 2H), 3.65 (m, 2H), 3.71 (d, J=3.1, 1H), 3.79 (dd, J=6.8, 11, 1H), 3.87 (m, 1H), 4.16 (brt, J=12, 1H), 4.29 (s, 2H), 7.04 (m, 1H), 7.10-7.19 (m, 2H), 7.35-7.46 (m, 5H); ESI-MS: 597.4 (M+H); HPLC A: 2.27 min.

Workup

  1. additionAfter mixing well
  2. customThe solvent was removed
  3. customthe product was purified by preparative HPLC (column
  4. customfor 1.5 min
  5. customover 7.5 min
  6. stirringThe isolated material was stirred in 3 mL formic acid for 16 h
  7. customAfter removal of solvent
  8. customthe residue was purified by ion exchange chromatography (0.5 grams Varian SCX resin
  9. washeluting with 100% MeOH

Sources & evidence

ORD record
ord-953a9a62f47e4b2eba037be6307581ac
Source dataset
uspto-grants-2002_06
Patent number
US06399619B1

Reaction notes

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