1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide

HRID 1051205Notes

Reaction equation

HRID 1051205 reaction equation
[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=4[Cl:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:31]2)[CH2:26][O:25]1

Participants

6

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 57346986(S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-4-methylpentanoic acidHCID 59344941(R)-1-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-3-amine

Product 1

HCID 57920139(S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amideYield 88.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
4 °C

Procedure

To a 200-L glass-lined reactor was charged with 46.3 kg of dichloromethane (DCM). To the reactor was added additional 112.0 kg of dichloromethane followed by 11.9 kg (36.8 mol) of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methylpentanoic acid and 8.0 kg (40.6 mol) of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine. With agitation, to the mixture was added 0.44 kg of 1-hydroxybenzotriazole. After cooling to 4° C., 14.0 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added in 4 portions (5.0 kg+3.1 kg+3.8 kg+2.1 kg) over 3 h while maintaining the batch temperature at 4-10° C. The mixture was agitated at 4-12° C. for additional 5 h. HPLC analysis at 2.5 h indicated the completion of the reaction. The mixture was transferred into a 500 L glass-line reactor. After adjusting the batch temperature to below 10° C., the reaction was quenched by adding 119.0 kg of water. The aqueous phase was separated and the organic solvent was removed by distillation in vacuo to a final volume of ca. 30 L. To the residue was added 106.0 kg of ethyl acetate. The mixture was stirred for 30 min, cooled to 0-10° C., and washed with 5 wt % citric acid solution, 10 wt % sodium carbonate solution and 2.5 wt % sodium chloride solution. The solvent was removed by distillation in vacuo at 18-30° C. to a final volume of ca. 30 L. To the residue solution was added 64.7 kg of n-heptane over 2.5 h. After adjusting the batch temperature to 0-5° C. the mixture was agitated for 4.5 h. The solids were collected in a Nutsche filter, rinsed with 16.2 kg of n-heptane, dried with nitrogen flow at 40-45° C. for 20 h to afford 17.2 kg (88.1% yield) of ((S)-2-[4-(2-Chlorophenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide. 1H NMR (300 MHz, DMSO-d6, ethanol removed) δ ppm 0.90 (d, J=6.4 Hz, 3 H), 0.94 (d, J=6.4 Hz, 3 H), 1.05 (br. s., 3 H), 1.06 (br. s., 3 H), 1.36-1.64 (m, 2 H), 1.68-1.84 (m, 1 H), 3.89 (s, 2 H), 4.20 (d, J=18.4 Hz, 1 H), 4.62 (d, J=18.4 Hz, 1 H), 4.68 (s, 1 H), 4.78 (s, 1 H), 4.90 (dd, J=10.7, 4.7 Hz, 1 H), 6.44 (d, J=2.1 Hz, 1 H), 7.37 (td, J=7.8, 1.8 Hz, 1 H), 7.46 (td, J=7.8, 1.2 Hz, 1 H), 7.50-7.56 (m, 2 H), 7.66 (dd, J=7.8, 1.2 Hz, 1 H), 10.81 (s, 1 H).

Workup

  1. temperaturewhile maintaining the batch temperature at 4-10° C
  2. waitHPLC analysis at 2.5 h indicated
  3. customthe completion of the reaction
  4. customThe mixture was transferred into a 500 L glass-line reactor
  5. customto below 10° C.
  6. customthe reaction was quenched
  7. additionby adding 119.0 kg of water
  8. customThe aqueous phase was separated
  9. customthe organic solvent was removed by distillation in vacuo to a final volume of ca. 30 L
  10. additionTo the residue was added 106.0 kg of ethyl acetate
  11. stirringThe mixture was stirred for 30 min
  12. temperaturecooled to 0-10° C.
  13. washwashed with 5 wt % citric acid solution, 10 wt % sodium carbonate solution and 2.5 wt % sodium chloride solution
  14. customThe solvent was removed by distillation in vacuo at 18-30° C. to a final volume of ca. 30 L
  15. additionTo the residue solution was added 64.7 kg of n-heptane over 2.5 h
  16. customto 0-5° C.
  17. stirringwas agitated for 4.5 h
  18. customThe solids were collected in a Nutsche
  19. filtrationfilter
  20. washrinsed with 16.2 kg of n-heptane
  21. customdried with nitrogen flow at 40-45° C. for 20 h

Sources & evidence

ORD record
ord-d092be08ed8047f3aada2da001f932a5
Source dataset
uspto-grants-2016_07
Patent number
US09388168B2

Reaction notes

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