phenyl 3-(1-methyl-1H-tetraazol-5-yl)phenylcarbamate → (3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-4-{3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid t-butyl ester

HRID 497457Notes

Reaction equation

HRID 497457 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([O:37][C:38](=O)[NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]3[N:50]([CH3:51])[N:49]=[N:48][N:47]=3)[CH:41]=2)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:38]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]3[N:50]([CH3:51])[N:49]=[N:48][N:47]=3)[CH:41]=2)=[O:37])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 2

HCID 22252681phenyl 3-(1-methyl-1H-tetraazol-5-yl)phenylcarbamateHCID 69748878HCID 69748878, compound

Product 1

HCID 69747686(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-4-{3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid t-butyl esterYield 75%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a dry flask (3R,4R)-4-amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (350 mg, 0.834 mmol) was dissolved in dimethylformamide (5 mL) and [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (285 mg, 0.965 mmol) was added. The reaction mixture was stirred for 19 hours. The reaction mixture was diluted with ethyl acetate and extracted three times with water. The combined aqueous extracts were extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with 70-100% ethyl acetate/hexanes to give a solid (387 mg, 75%). A small amount was further purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (33 mg, 62%). 1H NMR (300 MHz, CDCl3), δ: 7.88 (m, 1H), 7.49 (m, 2H), 7.40 (m, 1H), 7.19 (m, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 6.86 (m, 1H), 4.31 (m, 1H), 4.17 (s, 3H), 4.03 (m, 4H), 3.16 (m, 1H), 3.05 (m, 1H), 2.88 (m, 3H), 2.67 (m, 1H), 2.50 (m, 2H), 2.37 (m, 1H), 1.95 (m, 1H), 1.65 (m, 5H), 1.47 (s, 9H), 1.23 (m, 1H). HRMS (ESI), C32H42FN8O4 m+/z: calc.=621.3313, found=621.3337.

Workup

  1. extractionextracted three times with water
  2. extractionThe combined aqueous extracts were extracted with ethyl acetate
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried with sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe resulting oil was purified by flash column chromatography with 70-100% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-4ecc34464eb741cd8e752921feccee76
Source dataset
uspto-grants-2005_09
Patent number
US06949546B2

Reaction notes

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