Methanesulfonic Acid → Saquinavir Mesylate

HRID 1290022Notes

Reaction equation

HRID 1290022 reaction equation
[NH2:1][C@@H:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:3]([OH:22])[CH2:4][N:5]1[C@H:14]([C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40]([NH:42][C@H:43]([C:48](O)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41].ON1C=CC=CC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:74][S:75]([OH:78])(=[O:77])=[O:76]>C(OCC)(=O)C.O.O1CCCC1>[CH3:74][S:75]([OH:78])(=[O:77])=[O:76].[C:18]([NH:17][C:15]([C@@H:14]1[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6][N:5]1[CH2:4][C@@H:3]([OH:22])[C@@H:2]([NH:1][C:48](=[O:49])[C@H:43]([CH2:44][C:45](=[O:47])[NH2:46])[NH:42][C:40]([C:31]1[CH:32]=[CH:33][C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=1)=[O:41])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]

Participants

9

Reactant 5

HCID 6395Methanesulfonic AcidHCID 10868DicyclohexylcarbodiimideHCID 69975HydroxypyridinoneHCID 9865804(3S,4aS,8aS)-2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-tert-butyldecahydroisoquinoline-3-carboxamideHCID 11044384(S)-4-Amino-4-oxo-2-(((quinolin-2-yl)carbonyl)amino)butanoic acid

Product 1

HCID 60934Saquinavir MesylateYield 95.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent3×

Procedure

125.9 g (312 mmol) of 2-(3(S)-amino-2(R)-hydroxy-4-phenylbutyl)-N-t-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, 94.6 g (328 mmol) of N-(2-quinolylcarbonyl)-L-asparagine and 3.5 g (31 mmol) of 1-hydroxy-2(1H)-pyridone were treated with a mixture of 75 ml of tetrahydrofuran and 1925 ml of ethyl acetate. A solution of 70.9 g (344 mmol) of dicyclohexylcarbodiimide in 500 ml of ethyl acetate was subsequently added dropwise at 25° within 30 minutes while stirring. The reaction mixture was stirred for 10 hours. Then, 50 ml of water of low ion contents were added and the suspension was cooled to 2°-3° and stirred at this temperature for 1 hour. The dicyclohexylurea was then filtered off and washed on the filter with 2 500 ml portions of ethyl acetate. The filtrates were combined and treated slowly at 50° with a solution of 32.5 g (338 mmol) of methanesulphonic acid and 250 ml of ethyl acetate. The suspension was subsequently stirred at 20° for 14 hours. The crystals were then filtered off under suction, washed with a total of 600 ml of ethyl acetate and subsequently dried at 45°/2000 Pa for 24 hours. 229.5 g (95%) of N-t-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide methanesulphonate having a HPLC content of 97.1% were obtained.

Workup

  1. stirringThe reaction mixture was stirred for 10 hours
  2. temperaturethe suspension was cooled to 2°-3°
  3. stirringstirred at this temperature for 1 hour
  4. filtrationThe dicyclohexylurea was then filtered off
  5. washwashed on the
  6. filtrationfilter with 2 500 ml portions of ethyl acetate
  7. stirringThe suspension was subsequently stirred at 20° for 14 hours
  8. filtrationThe crystals were then filtered off under suction
  9. washwashed with a total of 600 ml of ethyl acetate
  10. customsubsequently dried at 45°/2000 Pa for 24 hours

Sources & evidence

ORD record
ord-d340aed2839c476ca95a7c5bfd7a3a9e
Source dataset
uspto-grants-1998_05
Patent number
US05750649

Reaction notes

Loading…