Acetic Acid → (3R,4S)-3-amino-4-(3-boronopropyl)-1-(piperidin-3-yl)pyrrolidine-3-carboxylic acid

HRID 590718Notes

Reaction equation

HRID 590718 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][C:38](=O)[CH2:37]1)(OC(C)(C)C)=O.S([O-])([O-])(=O)=[O:44].[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:44])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH:38]2[CH2:39][CH2:40][CH2:41][NH:36][CH2:37]2)[CH2:6]1

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 10340Sodium CarbonateHCID 24436Sodium SulfateHCID 2756825Tert-butyl 3-oxopiperidine-1-carboxylateHCID 5049666Sodium triacetoxyborohydrideHCID 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 57331441(3R,4S)-3-amino-4-(3-boronopropyl)-1-(piperidin-3-yl)pyrrolidine-3-carboxylic acidYield 92.3%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
40 °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 N—BOC-piperidine-3-one (0.199 g, 1.0 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 40° C. for 3 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (276 mg, 1.3 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 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-3-yl)pyrrolidine-3-carboxylic acid (138 mg, 68%) as an amber solid. NMR (D2O) δ 3.80-4.10 (m, 2 H), 3.60-3.80 (m, 2 H), 3.30-3.50 (m, 2 H), 3.00-3.15 (m, 1 H), 2.80-2.95 (m, 1 H), 2.45-2.60 (m, 1 H), 2.30 (m, 1 H), 1.95-2.10 (m, 1 H), 1.50-1.85 (m, 4 H), 1.10-1.40 (m, 3 H), 0.60-0.70 (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 saturated aqueous sodium chloride (20 mL each)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated
  8. customisolated

Sources & evidence

ORD record
ord-6c25cff544d84bda97ccc687f7246a05
Source dataset
uspto-grants-2016_01
Patent number
US09233985B2

Reaction notes

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