Formic Acid → benzyl N-[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamate

HRID 2068530Notes

Reaction equation

HRID 2068530 reaction equation
CO[CH:3](OC)[CH2:4][NH:5][C:6]1[CH:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10][C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=2[N:7]=1.C(O)=O>ClCCl>[CH:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=3[CH2:10][CH2:11][C@@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]2=[N:5][CH:4]=1

Participants

4

Reactant 2

HCID 284Formic AcidHCID 178495874HCID 178495874, compound

Product 1

HCID 58304077benzyl N-[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamateYield 73%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Heat a mixture of benzyl N-[2-(2,2-dimethoxyethylamino)-4,5-dihydro-3H-1-benzazepin-3-yl]carbamate (1.80 kg, 4.1 mol) and formic acid (6.4 L) at 95° C. for 80 minutes. Concentrate the mixture under reduced pressure to give a black oil and partition it between dichloromethane (7.0 L) and water (5 L). Add sodium carbonate until the pH of the aqueous layer is 7. Remove the organic layer and wash with water (3×). Extract the aqueous layers with dichloromethane. Combine the organic layers and concentrate under reduced pressure to give a black oil. Divide the 2.297 kg of the black oil into approximately 250 g sections and dissolve each section in dichloromethane (250 mL). Add to 3.5 kg Merck 9385, 60 A, 230-400 mesh silica. Elute target compound with 75:25 ethyl acetate/heptane beginning with six column volumes (faster eluting impurities elute first). Follow with 5:95 methanol/ethyl acetate to remove remaining product (1082 g recovered). Assay product mixture using chiral HPLC conditions as follows: 4.6×150 mm Chiralpak AD-H column, 15:85:0.2 acetonitrile/3A grade ethanol/dimethylethylamine mobile phase, 0.6 mL/min flow rate, 250 nm UV detection. Observe isomer ratio 3:2 desired/undesired under these conditions. Dissolve isomer mixture at 30 mg/mL 20:80 acetonitrile/3A ethanol. Purify isomers using prep chiral HPLC conditions as follows: 8×40.5 cm Chiralpak AD (20 micron) column, 20:80:0.2 acetonitrile/3A ethanol/N,N-dimethylethylamine (DMEA) mobile phase, 490 mL/min flow rate, 250 nm UV detection, 1.5 g (50 mL) injections, 4.6 minute cycle time/injection using Steady State Recycle (SSR) technology (J. H. Kennedy, M. D. Belvo, V. S. Sharp, J. D. Williams, Comparison of separation efficiency of early phase active pharmaceutical intermediates by steady state recycle and batch chromatographic techniques, Journal of Chromatography A, 1046 p 55-60 (2004)). The collection of isomer 1 is from 0.4-0.9 min and collection of isomer 2 is from 2.4-4.2 min. The desired isomer (Isomer 2; R isomer) is the second eluter: benzyl N-[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamate. Concentrate the product containing fractions under reduced pressure to give the title compound (615 g, 73%) as a white solid: MS (m/z): 334 (M+1).

Workup

  1. temperatureHeat
  2. concentrationConcentrate the mixture under reduced pressure
  3. customto give a black oil
  4. custompartition it between dichloromethane (7.0 L) and water (5 L)
  5. customRemove the organic layer
  6. washwash with water (3×)
  7. extractionExtract the aqueous layers with dichloromethane
  8. concentrationconcentrate under reduced pressure
  9. customto give a black oil
  10. additionAdd to 3.5 kg Merck 9385, 60 A, 230-400 mesh silica
  11. washElute target compound with 75:25 ethyl acetate/heptane beginning with six column volumes (
  12. washfaster eluting impurities
  13. washelute first)
  14. customto remove
  15. customproduct (1082 g recovered)
  16. dissolutionDissolve isomer mixture at 30 mg/mL 20:80 acetonitrile/3A ethanol
  17. custom8×40.5 cm Chiralpak AD (20 micron) column, 20:80:0.2 acetonitrile/3A ethanol/N,N-dimethylethylamine (DMEA) mobile phase, 490 mL/min flow rate, 250 nm UV detection, 1.5 g (50 mL) injections, 4.6 minute cycle time/injection
  18. customWilliams, Comparison of separation efficiency of early phase active pharmaceutical intermediates by steady state recycle and batch chromatographic techniques, Journal of Chromatography A, 1046 p 55-60 (2004))
  19. customThe collection of isomer 1
  20. customcollection of isomer 2
  21. waitis from 2.4-4.2 min
  22. concentrationConcentrate the product
  23. additioncontaining fractions under reduced pressure

Sources & evidence

ORD record
ord-36beec25f55f44b1a400a41b772d58a0
Source dataset
uspto-grants-2012_10
Patent number
US08299061B2

Reaction notes

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