Binap, (A+-)- → (3R,4S)-3-amino-4-(3-boronopropyl)-1-(4-methylpyridin-3-yl)pyrrolidine-3-carboxylic acid

HRID 61378

Reaktionsgleichung

Reaktionsgleichung von HRID 61378
C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.Br[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][C:35]=1[CH3:36].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-:86])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:4][C@:5]1([C:22]([OH:23])=[O:86])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:35]=2[CH3:36])[CH2:6]1

Komponenten

8

Edukt 4

HCID 634876Binap, (A+-)-HCID 8176303-Bromo-4-methylpyridineHCID 23676156Sodium t-butoxideHCID 67516451(3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide

Produkt 1

HCID 57331480(3R,4S)-3-amino-4-(3-boronopropyl)-1-(4-methylpyridin-3-yl)pyrrolidine-3-carboxylic acidAusbeute 14,3 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 1140TolueneLösungsmittelHCID 6344DichloromethaneLösungsmittel

Reaktionsbedingungen

Temperatur
70 °C

Versuchsvorschrift

A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and 3-bromo-4-methylpyridine (0.258 g, 1.5 mmol) in anhydrous toluene (5 mL) was degassed under nitrogen for 15 min, then treated with Pd2dba3 (46 mg, 0.05 mmol), rac-binap (50 mg, 0.075 mmol), and sodium t-butoxide (0.18 g, 1.87 mmol). The mixture was heated to 70° C. for 18 h, cooled to room temperature, diluted with methylene chloride (20 mL), filtered through Celite® and the filtrate concentrated. the crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(4-methylpyridin-3-yl)pyrrolidine-3-carboxylic acid (22 mg, 12%) as a pale amber solid. NMR (D2O) δ 7.99 (d, J=6 Hz, 1 H), 7.95 (s, 1 H), 7.57 (d, J=6 Hz, 1 H), 3.80 (d, J=5 Hz, 2 H), 3.72 (t, J=9.5 Hz, 1 H), 3.25 (t, J=9.5 Hz, 1 H), 2.49 (s, 3 H), 2.40-2.60 (m, 1 H), 1.50-1.60 (m, 1 H), 1.20-1.45 (m, 3 H), 0.65-0.75 (m, 2 H). MS (m−H2O+1): 290.0; MS (m−2 H2O+1): 271.9.

Aufarbeitung

  1. temperaturecooled to room temperature
  2. filtrationfiltered through Celite®
  3. concentrationthe filtrate concentrated
  4. customisolated

Quellen und Nachweise

ORD-Eintrag
ord-b0243ec901af458b9fbe83332d3514f9
Quelldatensatz
uspto-grants-2016_09
Patentnummer
US09440995B2

Verknüpfte Notizen

Wird geladen…