Hydrochloric Acid → Danegaptide Hydrochloride

HRID 1423859Notes

Reaction equation

HRID 1423859 reaction equation
[C:1]([NH:9][C@H:10]1[CH2:14][N:13]([C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)[C@H:12]([C:26]([OH:28])=[O:27])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29].O>CC(C)=O>[ClH:29].[NH2:17][CH2:16][C:15]([N:13]1[CH2:14][C@H:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][C@H:12]1[C:26]([OH:28])=[O:27])=[O:25]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 962WaterHCID 16738323(2S,4R)-4-benzamido-1-(2-((tert-butoxycarbonyl)amino)acetyl)pyrrolidine-2-carboxylic acid

Product 1

HCID 44563896Danegaptide HydrochlorideYield 97.3%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent3×

Conditions

Temperature
50 °C

Procedure

To a slurry of (2S,4R)-4-benzamido-1-(2-(tert-butoxycarbonyl-amino)acetyl)pyrrolidine-2-carboxylic acid (650.2 g) in acetone (4.1 L) was added conc. hydrochloric acid (322 g). The reaction mixture was heated to 50° C. over 15 min and stirred at 50° C. The reaction was monitored for completion by HPLC. Water (520 g) was added. The mixture was heated to reflux to dissolve the solid coating. The resulting clear solution was cooled to 40° C. Acetone (7.0 L) was added over 15 min while temperature was maintained at 30-40° C. The mixture was cooled to room temperature over 30 min, and stirred until a white slurry was formed. Additional acetone (7.0 L) was added over 10 min. The mixture was stirred overnight at about 22-24° C. The precipitated solids were filtered through a Buchner funnel lined with polypropylene and washed with acetone (2×2 L), was dried on the funnel to give 530 g (93.8%) of product as a monohydrate. LC area purity was 99.7%. 1H NMR (DMSO-d6, δ, ppm, for two conformers): 8.77 (d, J=7 Hz, 0.8H), 8.71 (d, J=7 Hz, 0.2H), 8.68-7.95 (br, 2H), 7.92-7.83 (m, 2H), 7.59-7.43 (m, 3H), 4.87-4.79 (m, 0.2H), 4.68-4.54 (m, 0.8H), 4.54-4.44 (m, 1H), 4.0-3.47 (m, 4H), 2.47-2.12 (m, 2H). HRMS calc. for C14H18N3O4 (M+H): 292.1297. found: 292.1294.

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux
  3. dissolutionto dissolve the solid coating
  4. temperatureThe resulting clear solution was cooled to 40° C
  5. temperaturewas maintained at 30-40° C
  6. temperatureThe mixture was cooled to room temperature over 30 min
  7. stirringstirred until a white slurry
  8. customwas formed
  9. stirringThe mixture was stirred overnight at about 22-24° C
  10. filtrationThe precipitated solids were filtered through a Buchner funnel
  11. washwashed with acetone (2×2 L)
  12. customwas dried on the funnel

Sources & evidence

ORD record
ord-97c5f1b98f1347ea82e2a22508238fdc
Source dataset
uspto-grants-2015_01
Patent number
US08927590B2

Reaction notes

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