Tetrahydrofuran → (3R,4R)-1-Benzyl-4-fluoropyrrolidin-3-amine bis(4-methylbenzenesulfonate)

HRID 928179Notes

Reaction equation

HRID 928179 reaction equation
[F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(OC([N:31]1[C@H:38]2[C@H:34]([CH2:35][N:36]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:37]2)OS1(=O)=O)=O)(C)(C)C.O.[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55]([OH:58])(=[O:57])=[O:56])=[CH:51][CH:50]=1>CCOC(C)=O>[S:55]([C:52]1[CH:53]=[CH:54][C:49]([CH3:59])=[CH:50][CH:51]=1)([OH:58])(=[O:57])=[O:56].[S:55]([C:52]1[CH:53]=[CH:54][C:49]([CH3:59])=[CH:50][CH:51]=1)([OH:58])(=[O:57])=[O:56].[CH2:39]([N:36]1[CH2:35][C@@H:34]([F:1])[C@H:38]([NH2:31])[CH2:37]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 521998p-Toluenesulfonic acid monohydrateHCID 2724141Tetrabutylammonium FluorideHCID 118081949Tert-butyl (3AR,6AS)-5-benzyltetrahydropyrrolo[3,4-D][1,2,3]oxathiazole-3(3AH)-carboxylate 2,2-dioxide

Product 1

HCID 131735055(3R,4R)-1-Benzyl-4-fluoropyrrolidin-3-amine bis(4-methylbenzenesulfonate)Yield 83%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 1M tetrabutylammonium fluoride in THF (1.27 L, 1.27 mol, 2.5 eq) and (3aR,6aS)-5-benzyl-2,2-dioxo-tetrahydro-1-oxa-2λ6-thia-3-5-diaza-pentalene-3-carboxylic acid t-butyl ester (180 g, 0.508 mol, 1.0 eq) were heated at 60° C. (jacket temperature) for 2 hr. Upon reaction completion, the mixture was partially distilled under vacuum to remove the THF. After concentration to a low stir volume, THF was displaced with EtOAc (2×500 mL). After again reducing to a low stir volume, EtOAc (3.6 L) and p-toluenesulfonic acid monohydrate (396 g, 2.10 mol, 4.1 eq) were charged and heated at 80° C. for 2 hr. The mixture was cooled to 10° C. over 1.5 hr and then granulated at 10° C. for 2 hr. The solid product was filtered and washed with EtOAc (2×900 mL) and dried at 50° C. in a vacuum oven for 12 hr. The title compound was isolated as an air stable crystalline solid in 83% yield (231 g, 419 mmol). 1H NMR (400 MHz, D2O) δ ppm 7.69-7.61 (m, 4 H) 7.56-7.42 (m, 5 H) 7.36-7.29 (m, 4 H) 5.65-5.49 (m, 1 H) 4.47 (br. s., 2H) 4.37-4.23 (m, H) 4.15 (ddd, J=12.8, 8.2, 1.4 Hz, 1 H) 3.88 (dd, J=19.1, 1.2 Hz, 1 H), 3.74 (ddd, J=33.2, 14.0, 5.5 Hz, 1 H) 3.44 (dd, J=12.8, 8.2 Hz, 1 H) 2.34 (s, 6 H). m/z (EI+) for C11H15FN2 194.8 (M+H)+.

Workup

  1. customUpon reaction completion
  2. distillationthe mixture was partially distilled under vacuum
  3. customto remove the THF
  4. concentrationAfter concentration to a low stir volume, THF
  5. additionwere charged
  6. temperatureThe mixture was cooled to 10° C. over 1.5 hr
  7. filtrationThe solid product was filtered
  8. washwashed with EtOAc (2×900 mL)
  9. customdried at 50° C. in a vacuum oven for 12 hr

Sources & evidence

ORD record
ord-3e9a28fb07bd47078208a26b7bbc4d5a
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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