Diisopropylethylamine → 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1lambda6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicylo[3.1.1]hept-3-yl)amide

HRID 1879469Notes

Reaction equation

HRID 1879469 reaction equation
[CH3:1][C@H:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6]2)[CH2:4][C@@H:3]1[NH2:11].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N[C@@H](CCSSCC[C@H](N)C(O)=O)C(O)=O.[CH3:50][N:51]([CH2:53][C@@H:54]([NH:62][CH2:63][C:64]1[CH:65]=[C:66]([CH:78]=[CH:79][CH:80]=1)[CH2:67][N:68]1[CH:72]([C:73](O)=[O:74])[CH2:71][CH2:70][S:69]1(=[O:77])=[O:76])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:52].C(N(CC)C(C)C)(C)C>CN(C)C=O.C[C@H]1C2C(C)(C)C(C2)C[C@@H]1N.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N[C@@H](CCSSCC[C@H](N)C(O)=O)C(O)=O>[CH3:1][C@@H:2]1[C@@H:3]([NH:11][C:73]([CH:72]2[CH2:71][CH2:70][S:69](=[O:77])(=[O:76])[N:68]2[CH2:67][C:66]2[CH:78]=[CH:79][CH:80]=[C:64]([CH2:63][NH:62][C@H:54]([CH2:53][N:51]([CH3:50])[CH3:52])[CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH:65]=2)=[O:74])[CH2:4][C@H:5]2[CH2:6][C@@H:7]1[C:8]2([CH3:10])[CH3:9]

Participants

10

Reactant 5

HCID 81531DiisopropylethylamineHCID 439579L-HomocystineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 16212502(2S,3S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amineHCID 582804442-{3-[((S)-1-Dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1lambda6-isothiazolidine-3-carboxylic acid2×

Product 1

HCID 671532832-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1lambda6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicylo[3.1.1]hept-3-yl)amideYield 244.9%

Reagents, catalysts & solvents 4

HCID 439579L-HomocystineCatalystHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateCatalystHCID 16212502(2S,3S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amineCatalystHCID 6228DimethylformamideSolvent

Procedure

(+)-Isopinocampheylamine (Aldrich; 29 mg, 0.19 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (available from Aldrich; 58.4 mg, 0.18 mmol), N-hydroxybenzotriazole (available from 3B Scientific Corporation, Libertyville, Ill. 60048, USA; 24.3 mg, 0.18 mmol) were added to a cooled (0° C.) solution of 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (100 mg 80% pure, 0.18 mmol) in dry N,N-dimethylformamide (3 mL) under argon. N,N-Diisopropylethylamine (70 μL, 0.4 mmol) was then added. The solution was then stirred at room temperature. After 30 minutes more (+)-isopinocampheylamine (6 mg, 0.04 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (available from Aldrich; 6 mg, 0.002 mmol) and N-hydroxybenzotriazole (available from 3B Scientific Corporation, Libertyville, Ill. 60048, USA; 3 mg, 0.002 mmol) were added. After 90 minutes all of the starting material had been consumed. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1N NaOH (3×15 mL), and brine (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give the crude product (132 mg). This material was combined with the crude product from an identical experiment using 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (250 mg). The combined lots were chromatographed, eluting with 0-10% methanol/dichloromethane to give 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicylo[3.1.1]hept-3-yl)amide (256 mg, 60%) as a tan foam.

Workup

  1. customAfter 90 minutes all of the starting material had been consumed
  2. additionThe reaction mixture was diluted with ethyl acetate (50 mL)
  3. washwashed with 1N NaOH (3×15 mL), and brine (20 mL)
  4. dry with materialThe organic phase was dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give the crude product (132 mg)
  8. customThe combined lots were chromatographed
  9. washeluting with 0-10% methanol/dichloromethane

Sources & evidence

ORD record
ord-a47de7aae8b643108406111892b425d9
Source dataset
uspto-grants-2012_11
Patent number
US08314250B2

Reaction notes

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