Methyl iodide → Simvastatin phenylboronate

HRID 381713

Reaction equation

HRID 381713 reaction equation
N1CCC[CH2:2]1.C([Li])CCC.[CH3:11][CH2:12][C@@H:13]([C:15]([O:17][C@@H:18]1[C@@H:23]2[C@@H:24]([CH2:29][CH2:30][C@H:31]3[O:37][C:35](=[O:36])[CH2:34][C@H:33]([OH:38])[CH2:32]3)[C@@H:25]([CH3:28])[CH:26]=[CH:27][C:22]2=[CH:21][C@H:20]([CH3:39])[CH2:19]1)=[O:16])[CH3:14].[C:40]1([B:46]([O-:48])[O-:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CI>C1COCC1>[CH3:11][CH2:12][C:13]([C:15]([O:17][C@@H:18]1[C@@H:23]2[C@@H:24]([CH2:29][CH2:30][C@H:31]3[O:37][C:35](=[O:36])[CH2:34][C@H:33]([OH:38])[CH2:32]3)[C@@H:25]([CH3:28])[CH:26]=[CH:27][C:22]2=[CH:21][C@H:20]([CH3:39])[CH2:19]1)=[O:16])([CH3:2])[CH3:14].[C:40]1([B:46]([O-:48])[O-:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 31268PyrrolidineHCID 86757523Lovastatin phenylboronateHCID 178418339Butyllithium

Product 1

HCID 86757524Simvastatin phenylboronateYield 98.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-57.5 °C

Procedure

A 2L 3-necked flask was charged with pyrrolidine (56 mL, 0.67 mol) and dry THF (453 g) under a nitrogen atmosphere. n-Butyllithium (419 mL, 1.6 M hexane solution, 0.67 mol) was added dropwise at a temperature between −20 and −25° C. over a period of 1 hour. The solution was maintained at this temperature for 30 minutes and then cooled to −55 to −60° C. A solution of lovastatin phenylboronate (101.7 g, 0.20 mol) in 274.7 g of THF was cooled to a temperature of −50° C. and then added to the cold lithium pyrrolidide solution at a rate such that the internal temperature was between −50 and −55° C. during the addition. The reaction was held at this temperature for 4 hours and then methyl iodide (116.4 g, 0.82 mol) was added at a temperature below −55°C. The reaction was stirred for 13 hours at −15 to −20° C. and then quenched with 500 mL of 2M HCl at a temperature below 0° C. After warming to 20° C., the layers were separated and the aqueuous layer was extracted with ethyl acetate. The combined organic layers were washed with 5% NaHSO3 solution and deionized water. The solution was filtered through a Celite pad and concentrated to yield 102.8 g (98.4%) of crude simvastatin phenylboronate at >95% purity by HPLC. A portion of the above material (50.0 g) was charged into a nitrogen purged flask with acetonitrile (100 mL). The suspension was heated at 110° C. for 3 hours and then cooled to −5 to −10° C. for 1 hour. The product was filtered and washed with 25 mL of −5° C. acetonitrile and dried under vacuum to provide 43.7 g of simvastatin phenylboronate at >99% purity by HPLC.

Workup

  1. temperatureThe solution was maintained at this temperature for 30 minutes
  2. additionwas between −50 and −55° C. during the addition
  3. customquenched with 500 mL of 2M HCl at a temperature below 0° C
  4. temperatureAfter warming to 20° C.
  5. customthe layers were separated
  6. extractionthe aqueuous layer was extracted with ethyl acetate
  7. washThe combined organic layers were washed with 5% NaHSO3 solution
  8. filtrationThe solution was filtered through a Celite pad
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-4c8efffeaea74b76a5321f9b488cce6c
Source dataset
uspto-grants-2001_10
Patent number
US06307066B1

Linked notes

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