Sodium Carbonate → (3R,4S)-3-amino-4-(3-boronopropyl)-1-(piperidin-2-ylmethyl)pyrrolidine-3-carboxylic acid

HRID 590711Notes

Reaction equation

HRID 590711 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.S([O-])([O-])(=O)=O.[Na+].[Na+].C([N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[CH:52]=O)(OCC1C=CC=CC=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:56])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH2:4][C@:5]1([C:22]([OH:23])=[O:56])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:52][CH:47]2[CH2:48][CH2:49][CH2:50][CH2:51][NH:46]2)[CH2:6]1

Participants

8

Reactant 5

HCID 10340Sodium CarbonateHCID 24436Sodium SulfateHCID 5049666Sodium triacetoxyborohydrideHCID 18375697Benzyl 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 57331434(3R,4S)-3-amino-4-(3-boronopropyl)-1-(piperidin-2-ylmethyl)pyrrolidine-3-carboxylic acidYield 99.6%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 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) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and cbz-piperidine-2-carboxaldehyde (173 mg, 0.7 mmol), stirred for 3 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) 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 saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and 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-(piperidin-2-ylmethyl)pyrrolidine-3-carboxylic acid (156 mg, 74%) as a pale amber solid. NMR (D2O) 3.85-4.05 (m, 2 H), 3.76 (d, J=12.5 Hz, 1 H), 3.50-3.65 (m, 3 H), 3.39 (m, 2 H), 2.95 (dt, J1=12.5 Hz, J2=3 Hz, 1 H), 2.55-2.70 (m, 1 H), 2.00 (m, 1 H), 1.80 (m, 2 H), 1.45-1.65 (m, 4 H), 1.15-1.35 (m, 3 H), 0.65-0.72 (m, 2 H). MS (m+1): 314.1; MS (m−H2O+1): 296.2.

Workup

  1. stirringstirred for 18 h
  2. stirringthe mixture stirred for a few minutes
  3. extractionextracted with ethyl acetate (30 mL
  4. washThe combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. customisolated

Sources & evidence

ORD record
ord-d5795458a8544cdf821a27bf50b505b7
Source dataset
uspto-grants-2016_01
Patent number
US09233985B2

Reaction notes

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