Diisopropylamine → 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester

HRID 546149Notes

Reaction equation

HRID 546149 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([C@@H:24]([CH2:38][CH:39]2[CH2:43][CH2:42][CH2:41]C2)[C:25](NC2C=CN(CCC(O)=O)N=2)=[O:26])[CH:17]=[CH:18][C:19]=1[S:20]([CH3:23])(=O)=O.IC[C@H]1CC[CH2:48][O:47]1.[O:51]1CCCC1>CN1CCCN(C)C1=O>[CH3:48][O:47][C:25](=[O:26])[CH:24]([C:16]1[CH:17]=[CH:18][C:19]([S:20][CH3:23])=[C:14]([Cl:13])[CH:15]=1)[CH2:38][C@H:39]1[CH2:43][CH2:42][CH2:41][O:51]1

Participants

7

Reactant 5

HCID 7912DiisopropylamineHCID 8028Tetrahydrofuran2×HCID 40548299(2R)-2-(iodomethyl)oxolaneHCID 671905033-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acidHCID 178418339Butyllithium

Product 1

HCID 671878922-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl esterYield 34%

Reagents, catalysts & solvents 1

HCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-Solvent2×

Conditions

Temperature
-78 °C

Procedure

In a round bottom flask under argon was placed tetrahydrofuran (15 mL) and diisopropyl amine (357 μL, 2.55 mmol) and it was cooled to −78° C. in a dry ice/acetone bath. To this cooled solution was then added n-butyl lithium (2.5 M solution in hexanes, 970 μL, 2.43 mmol) and it was stirred for 15 min at −78° C. To this cooled solution was then added a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in PCT WO 2003/095438 A1, Example 4, 511 mg, 2.21 mmol) in tetrahydrofuran (5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL) dropwise. This was then stirred for one hour at −78° C. After such time, 2(R)-iodomethyl-tetrahydro-furan (657 mg, 3.1 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was added dropwise at −78° C. The reaction was then allowed to slowly warm to 25° C. and it was stirred for 16 h. After such time, the reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL) and then extracted with ethyl acetate (3×20 mL). The organics were dried over magnesium sulfate, filtered and then concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 5% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (237 mg, 34%) as a reaction of two diastereomers which was a light yellow oil: ES-HRMS m/e calcd for C15H19O3SCl (M+Na)+ 337.0635, observed 337.0635.

Workup

  1. customIn a round bottom flask under argon was placed
  2. temperatureto slowly warm to 25° C.
  3. stirringit was stirred for 16 h
  4. customAfter such time, the reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL)
  5. extractionextracted with ethyl acetate (3×20 mL)
  6. dry with materialThe organics were dried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification on an AnaLogix Intelliflash system (40 g column, 5% ethyl acetate/hexanes to 20% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-bdbbb091631849f287a2cee682e5a0f3
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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