1,2-Dichloroethane → Indoline

HRID 2175929Notes

Reaction equation

HRID 2175929 reaction equation
C(Cl)CCl.N1([C:10]2[N:11]=[CH:12][C:13]3[CH:18]([C:19](O)=O)[CH2:17][CH2:16][C:14]=3N=2)C=NN=N1.FC1C(C#N)=C(C)C([C@@H]2OC[C@H]3CNCCN3C2)=CC=1>ClCCl>[NH:11]1[C:10]2[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12]1

Participants

5

Reactant 3

HCID 111,2-DichloroethaneHCID 712736236-fluoro-2-methyl-3-((3S,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrileHCID 712737752-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid

Product 1

HCID 10328Indoline

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

EDC (2.24 g, 11.68 mmol) was added to a suspension of 2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid [I-67] (2.51 g, 9.73 mmol) and 6-fluoro-2-methyl-3-[(3S,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile [I-40C-1] (2.81 g, 10.21 mmol) in dichloromethane (25 mL). The reaction mixture was stirred at RT for 1.5 hours. Most of the solvent was evaporated. The residue was dissolved in EtOAc and washed with water, NaHCO3 solution and brine, dried (Na2SO4), filtered, and the solvent evaporated to afford a crude mixture of the two diastereomers. The crude product was purified on silica (220 g cartridge) with gradient elution from CH2Cl2 (solvent A) to 50% CH2Cl2:MeOH 90:10 (solvent B) to afford a mixture of the title diastereomers which were separated by chiral preparative SFC HPLC (SFC on Chiralpak IC column, Diacel Chemical Industries, LTD., 30×250 mm, 60% 2:1 MeOH:MeCN/CO2, 70 mL/min., 100 bar, sample in DCM/MeCN, 35C, 254 nm) to afford the separated aza-indane diastereomers: Isomer 2A, faster eluting, and Isomer 2B, slower eluting. Stereochemical assignment at the aza-indane chiral center was made by X-ray crystallography of the slower eluting isomer. Isomer A was dissolved in 1 mL acetonitrile and 1 eq. 1 M HCl in ether was added, and. the solid was filtered to yield the hydrochloride salt. Isomer 2A HCl salt: NMR 500 MHz (CD3OD+D2O) (mixture amide rotamers) 10.04 (s, 1H); 8.72 (s, 0.4H); 8.68 (s, 0.6H); 7.81-7.88 (m, 1H); 7.25-7.31 (m, 1H); 5.12 (t, 1H); 4.63-4.75 (m, 1.5H); 4.40-4.46 (m, 1H); 4.33-4.38 (dd, 0.5H); 4.23-4.28 (dd, 0.5H); 3.72-3.90 (m, 2H); 3.42-3.52 (m, 3H); 3.14-3.28 (m, 3H); 2.84-3.1 (m, 2H); 2.86-2.97 (m, 1H); 2.73-2.82 (m, 1H); 2.60 (s, 3H); 2.50-2.35 (m, 1H); LC/MS 512 (M+Na), 490 (M+H), 462 (M+H−N2): The HCl salt of Isomer 2B was made in a similar fashion. Isomer 2B HCl salt: NMR 500 MHz (CD3OD+D2O) (mixture amide rotamers) 10.0 (s, 1H); 8.7 (s, 1H); 7.82-7.86 (dd, 1H); 7.29 (t, 1H); 5.26 d, 1H); 4.66-4.76 (m, 1H); 4.49-4.54 (m, 1H); 4.45-4.59 (m, 1H); 4.35 (d, 0.5H); 3.90-4.03 (m, 1H); 3.76-3.88 (m, 0.5H); 3.11-3.43 (m, 5.5H); 2.88-3.00 (m, 0.5H); 2.70-2.82 (m, 1H); 2.63 (s, 3H); 2.21-2.40 (m, 1H); LC/MS 512 (M+Na), 490 (M+H), 42 (M+H−N2).

Workup

  1. customMost of the solvent was evaporated
  2. dissolutionThe residue was dissolved in EtOAc
  3. washwashed with water, NaHCO3 solution and brine
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. customthe solvent evaporated
  7. customto afford a crude
  8. additionmixture of the two diastereomers
  9. customThe crude product was purified on silica (220 g cartridge) with gradient elution from CH2Cl2 (solvent A) to 50% CH2Cl2:MeOH 90:10 (solvent B)
  10. customto afford
  11. additiona mixture of the title diastereomers which
  12. customwere separated by chiral preparative SFC HPLC (SFC on Chiralpak IC column, Diacel Chemical Industries, LTD., 30×250 mm, 60% 2:1 MeOH:MeCN/CO2, 70 mL/min., 100 bar, sample in DCM/MeCN, 35C, 254 nm)

Sources & evidence

ORD record
ord-f92c0a44d798422da7762dfc8d8e7d24
Source dataset
uspto-grants-2015_06
Patent number
US09062070B2

Reaction notes

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