2-Chloromethyl 2-(trimethylsilyl)ethyl ether → (s)-(4-(1-(2-Cyano-1-cyclopentylethyl)-1h-pyrazol-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

HRID 928504Notes

Reaction equation

HRID 928504 reaction equation
[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C[Si](CCOCCl)(C)C.ClC1C2C=CNC=2N=CN=1>C(O)C>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3].[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]

Participants

6

Reactant 3

HCID 27242712-Chloromethyl 2-(trimethylsilyl)ethyl etherHCID 53566827H-Pyrrolo(2,3-d)pyrimidine, 4-chloro-HCID 59420158(4-(1-(2-Cyano-1-cyclopentylethyl)-1h-pyrazol-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

Product 2

HCID 59420145(R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalateYield 90.8%HCID 68475630(s)-(4-(1-(2-Cyano-1-cyclopentylethyl)-1h-pyrazol-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalateYield 92.3%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A solution of racemic (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 5.2 g, 12.36 mmol) in a mixture of ethanol and hexanes (1:9 by volume) was injected into preparative HPLC system equipped with the chiral column (30×250 mm) packed with a silicagel based packing coated with cellulose tris(3,5-dimethylphenyl)carbamate (available from Daicel Chemical Industries, Ltd. (Daicel) as “Chiralcel® OD-H” (5 μm)). The chiral column was eluted with mobile phase made by a mixture of ethanol (EtOH) and hexanes in a 1 to 9 volume ratio at a flow rate of 32 mL/min at room temperature. The column elution was monitored by UV at wavelength 220 nm. Under these conditions, baseline separation of the two enantiomers was achieved and the retention times were 16.4 minutes (Peak 1, the undesired (S)-enantiomer (S)-21) and 21.0 minutes (Peak 2, the desired (R)-enantiomer (R)-21), respectively. Each injection was 1.4 mL of feed solution at a concentration of 50 mg/mL and each run cycle was 14 minutes by using stack injections. Total 75 injections were taken for this separation process. Fractions for Peak 1 (the undesired (S)-enantiomer, (S)-21) and Peak 2 (the desired (R)-enantiomer, (R)-21) were collected separately from each injection, and fractions collected for each peak were concentrated under reduced pressure. The residue from each evaporator was further dried under high vacuum to constant weight to afford (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-21, 2.36 g, 2.6 g theoretical, 90.8% yield) from Peak 2 as off-white solids and (S)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((S)-21, 2.4 g, 2.6 g theoretical, 92.3% yield) from Peak 1 as off-white solids.

Workup

  1. customequipped with the chiral column (30×250 mm)
  2. washThe chiral column was eluted with mobile phase
  3. additionmade by a mixture of ethanol (EtOH) and hexanes in a 1 to 9 volume ratio at a flow rate of 32 mL/min at room temperature
  4. washThe column elution
  5. customUnder these conditions, baseline separation of the two enantiomers
  6. custom21.0 minutes
  7. waiteach run cycle was 14 minutes
  8. customFractions for Peak 1 (the undesired (S)-enantiomer, (S)-21) and Peak 2 (the desired (R)-enantiomer, (R)-21) were collected separately from each injection, and fractions
  9. customcollected for each peak
  10. concentrationwere concentrated under reduced pressure
  11. customThe residue from each evaporator
  12. customwas further dried under high vacuum to constant weight

Sources & evidence

ORD record
ord-cdc61cf092074a9f8940ec19cd7559cc
Source dataset
uspto-grants-2016_03
Patent number
US09290506B2

Reaction notes

Loading…