Acetic Acid → (3R,4S)-3-amino-4-(3-boronopropyl)-1-(pyrrolidin-2-ylmethyl)pyrrolidine-3-carboxylic acid

HRID 590726Notes

Reaction equation

HRID 590726 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.C([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1C=O)(OC(C)(C)C)=O.S([O-])([O-])(=O)=[O:45].[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:45])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:40][CH:41]2[CH2:39][CH2:38][CH2:37][NH:36]2)[CH2:6]1

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 10340Sodium CarbonateHCID 24436Sodium SulfateHCID 5049666Sodium triacetoxyborohydrideHCID 10656219tert-Butyl 2-formylpiperidine-1-carboxylateHCID 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 57331517(3R,4S)-3-amino-4-(3-boronopropyl)-1-(pyrrolidin-2-ylmethyl)pyrrolidine-3-carboxylic acidYield 96.3%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

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 N—BOC-piperidine-2-carboxaldehyde (0.15 g, 0.75 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at room temperature for 3 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and brine (20 mL each), dried (MgSO4), and concentrated in vacuo. 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-(pyrrolidin-2-ylmethyl)pyrrolidine-3-carboxylic acid (144 mg, 70%) as a white foam. NMR (D2O) δ 3.85-4.05 (m, 3 H), 3.60-3.80 (m, 3 H), 3.40 (m, 1 H), 3.30 (m, 2 H), 2.55-2.70 (m, 1 H), 2.20-2.35 (m, 1 H), 1.85-2.10 (m, 2 H), 1.75 (m, 1 H), 1.60 (m, 1 H), 1.15-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 300.1; MS (m−H2O+1): 282.1.

Workup

  1. temperaturecooled to room temperature
  2. stirringstirred for 18 h
  3. stirringthe mixture stirred for a few minutes
  4. extractionextracted with ethyl acetate (30 mL
  5. washThe combined organic solution was washed with water and brine (20 mL each)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. customisolated

Sources & evidence

ORD record
ord-87aefc83ca7f492aadc23b85f05b3b5d
Source dataset
uspto-grants-2016_01
Patent number
US09233985B2

Reaction notes

Loading…