1-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acid → 4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester

HRID 527489Notes

Reaction equation

HRID 527489 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][C@@H:19]([N:21]([CH2:32][CH3:33])[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:42]1C=CC(OC(=O)N([C@H]2[C@H](C3C=CC(Cl)=CC=3)CN(CC3C=CC=CC=3)C2)C2CC2)=CC=1.C(OC(N1CCC(C(O)=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:16]2[CH2:20][C@@H:19]([N:21]([CH:32]3[CH2:42][CH2:33]3)[C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[O:23])[C@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17]2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

4

Reactant 3

HCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 583126274-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl esterHCID 58312679rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid 4-fluoro-phenyl ester

Product 1

HCID 583126484-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester

Procedure

In analogy to the procedure described for the synthesis of rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester the title compounds were prepared from rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid 4-fluoro-phenyl ester by cleavage of the benzyl group and subsequent coupling with 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. The resulting rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was subjected to separation by chiral HPLC on CHIRALPAK AD eluting with i-propanol/heptane. After evaporation of the product containing fractions 4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was obtained as light brown foam. MS m/e: 586.3 [M+H]+. 4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was obtained as yellow viscous oil. MS m/e: 586.3 [M+H]+.

Workup

  1. customThe resulting rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was subjected to separation by chiral HPLC on CHIRALPAK AD
  2. washeluting with i-propanol/heptane
  3. customAfter evaporation of the product
  4. additioncontaining fractions 4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester
  5. customwas obtained as light brown foam

Sources & evidence

ORD record
ord-bb0c6358d16c459c997be8d66cae7341
Source dataset
uspto-grants-2016_05
Patent number
US09346786B2

Reaction notes

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