1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (2S,4R)-tert-butyl 4-fluoro-2-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylate

HRID 238783

Reaktionsgleichung

Reaktionsgleichung von HRID 238783
[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[C:31]([O:35][C:36]([N:38]1[CH2:42][C@H:41]([F:43])[CH2:40][C@H:39]1[C:44](O)=[O:45])=[O:37])([CH3:34])([CH3:33])[CH3:32].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:43][C@H:41]1[CH2:42][N:38]([C:36]([O:35][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:37])[C@H:39]([C:44](=[O:45])[NH:23][C@@:15]([C:4]2[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=2)([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:40]1

Komponenten

6

Edukt 3

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 12043048(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acidHCID 59458485(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine

Produkt 1

HCID 59459143(2S,4R)-tert-butyl 4-fluoro-2-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylateAusbeute 64 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 142844-(Dimethylamino)pyridineKatalysatorHCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

To a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (42 mg, 0.1 mmol), prepared as described in Procedure 3, 4, 5 and 6, and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (23 mg, 0.1 mmol) in CH2Cl2 (1 mL) was added EDCI (25 mg, 0.1 mmol) and DMAP (16 mg, 0.1 mmol). The reaction mixture was stirred overnight and concentrated to dryness under a stream of argon. The resulting residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with 10-90% MeCN/H2O containing 0.1% TFA, monitoring at 220 nm) to provide (2S,4R)-tert-butyl 4-fluoro-2-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylate (40 mg, 64% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.30 (s, 1H), 7.13-7.03 (m, 5H), 6.95-6.90 (m, 2H), 6.80-6.78 (m, 2H), 6.70 (bs, 1H), 6.51-6.47 (m, 2H), 5.88-5.67 (m, 1H, —CF2H), 5.10 (app d, J=50 Hz, 1H, —CFH), 4.48-4.45 (m, 1H), 3.89-3.78 (m, 2H), 3.70 (d, J=10 Hz, 1H0, 3.29-3.18 (m, 1H), 2.79-2.55 (m, 2H), 2.25-2.11 (m, 1H), 1.32 (s, 9H); LC/MS: RT=3.746 min [M+H] 641.2 Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm.

Aufarbeitung

  1. concentrationconcentrated to dryness under a stream of argon
  2. dissolutionThe resulting residue was dissolved in MeOH
  3. custompurified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with 10-90% MeCN/H2O containing 0.1% TFA, monitoring at 220 nm)

Quellen und Nachweise

ORD-Eintrag
ord-5883903f55c94f1f9aab8ee41d92ac8b
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08642576B2

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