Diisopropylamine → 3-Cyclopentyl-2-(2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid methyl ester

HRID 546259Notes

Reaction equation

HRID 546259 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:25]=[CH:24][C:20]2[S:21][CH2:22][CH2:23][C:19]=2[CH:18]=1.C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:49][CH:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=N2)C=1)(C)(C)C>O1CCCC1.[Cl-].[NH4+]>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:25]=[CH:24][C:20]2[S:21][CH2:22][CH2:23][C:19]=2[CH:18]=1)[CH2:49][CH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1

Participants

7

Reactant 4

HCID 7912DiisopropylamineHCID 67190452HCID 67190452, compoundHCID 67190969(2,3-Dihydro-benzo[b]thiophen-5-yl)-acetic acid methyl esterHCID 178418339Butyllithium

Product 1

HCID 671913033-Cyclopentyl-2-(2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid methyl esterYield 69.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
-78 °C

Procedure

A round bottom flask with a stir bar and argon inlet was charged with tetrahydrofuran (10 mL) and cooled to −78° C. Diisopropyl amine (155 μL, 1.10 mmol) was then added followed by the dropwise addition of a solution of n-butyl lithium (2.5M solution in hexanes, 422 μL, 1.06 mmol) and it was stirred at −78° C. for 15 min. After this time, a solution of (2,3-dihydro-benzo[b]thiophen-5-yl)-acetic acid methyl ester (200 mg, 0.96 mmol) in tetrahydrofuran (3 mL) and 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was added dropwise. It was then stirred for 1 h at −78° C. It was then treated with a solution of iodomethylcyclopentane (prepared in PCT WO2004/052869 A1 Example 1, 302 mg, 1.44 mmol) in 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) dropwise. The reaction was then stirred at −78° C. and gradually allowed to warm to 25° C. and stirred at 25° C. for 16 h. The reaction was then diluted with a saturated aqueous ammonium chloride solution (30 mL). The aqueous layer was and extracted with ethyl acetate (3×20 mL). The organics were then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 2% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid methyl ester (193 mg, 69).

Workup

  1. stirringIt was then stirred for 1 h at −78° C
  2. stirringThe reaction was then stirred at −78° C.
  3. temperatureto warm to 25° C.
  4. stirringstirred at 25° C. for 16 h
  5. extractionextracted with ethyl acetate (3×20 mL)
  6. dry with materialThe organics were then dried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification on an AnaLogix Intelliflash system (12 g column, 2% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-58cc12a3c4e241fdb2e5532c1a71efb2
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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