Cesium carbonate → 5-[(3R,4S)-3-amino-4-(3-boronopropyl)-3-carboxypyrrolidin-1-yl]pyridine-3-carboxylic acid

HRID 61371

Reaction equation

HRID 61371 reaction equation
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]=[C:34]([CH:40]=1)[C:35]([O:37]CC)=[O: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.C(=O)([O-])[O-:88].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[NH2:4][C@:5]1([C:22]([OH:23])=[O:88])[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]=[C:34]([CH:40]=2)[C:35]([OH:37])=[O:36])[CH2:6]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 140785Ethyl 5-bromopyridine-3-carboxylateHCID 634876Binap, (A+-)-HCID 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

Product 1

HCID 573314385-[(3R,4S)-3-amino-4-(3-boronopropyl)-3-carboxypyrrolidin-1-yl]pyridine-3-carboxylic acidYield 48.6%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

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 ethyl 5-bromonicotinate (138 mg, 0.60 mmol) in anhydrous toluene (2.5 mL) was degassed under nitrogen for 15 min, then treated with palladium diacetate (14 mg, 0.06 mmol), rac-binap (75 mg, 0.12 mmol), and cesium carbonate (0.65 g, 2 mmol). The mixture was heated to 80° 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 5-((3R,4S)-3-amino-4-(3-boronopropyl)-3-carboxypyrrolidin-1-yl)nicotinic acid (82 mg, 40%) as a yellow solid. NMR (D2O) δ 8.37 (s, 1 H), 8.00 (s, 2 H), 3.99 (d, J=11 Hz, 1H), 3.88 (t, J=10 Hz, 1 H), 3.68 (d, J=11 Hz, 1 H), 3.26 (t, J=10 Hz, 1 H), 2.60-2.75 (m, 1 H), 1.60 (m, 1 H), 1.20-1.50 (m, 3 H), 0.65-0.75 (m, 2 H). MS (m+1): 338.2; MS (m−H2O+1): 320.1.

Workup

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

Sources & evidence

ORD record
ord-72f1a834eb4445179b120dfa7edc777d
Source dataset
uspto-grants-2016_09
Patent number
US09440995B2

Linked notes

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