Trifluoroacetic acid → N1-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(cyclohexylmethyl)-2-hydroxypropyl]-5-methyl-N3,N3-dipropylisophthalamide hydrochloride

HRID 14277

反応式

HRID 14277 の反応式
[CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])OC(C)(C)C)[C@H:9]2[CH2:11][O:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25].C(O)(C(F)(F)F)=O.CN1CCOCC1.[CH2:43]([N:46]([CH2:59][CH2:60][CH3:61])[C:47]([C:49]1[CH:50]=[C:51]([CH:55]=[C:56]([CH3:58])[CH:57]=1)C(O)=O)=[O:48])[CH2:44][CH3:45].[ClH:62].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>C(O)(C)C.CN(C)C=O>[ClH:62].[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][CH2:11][C@@H:9]([OH:10])[C@@H:8]([NH:12][C:13](=[O:19])[C:51]1[CH:55]=[C:56]([CH3:58])[CH:57]=[C:49]([C:47]([N:46]([CH2:43][CH2:44][CH3:45])[CH2:59][CH2:60][CH3:61])=[O:48])[CH:50]=1)[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

参加物

10

反応物 7

HCID 6422Trifluoroacetic acidHCID 79724-MethylmorpholineHCID 457587Benzenemethanamine, 3-bromo-HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 9816868erythro-N-Boc-L-cyclohexylalanine epoxideHCID 113913935-methyl-N,N-dipropylisophthalamic acid

生成物 1

HCID 68609227N1-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(cyclohexylmethyl)-2-hydroxypropyl]-5-methyl-N3,N3-dipropylisophthalamide hydrochloride収率 38.9%

試薬・触媒・溶媒 2

HCID 3776Isopropanol溶媒HCID 6228Dimethylformamide溶媒2 回

実験手順

tert-Butyl (1S)-2-(cyclohexyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (225 mg, 0.84 mmol) was refluxed with m-bromobenzylamine (380 mg, 2.0 mmol) in 7 mL of isopropanol under nitrogen for 2 h, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. It was washed three times with small portions of 10% HCl, and the aqueous phases were back-extracted with ethyl acetate. The combined organic phases were washed with 1 N NaHCO3 and brine, dried over Na2SO4, and concentrated. The resulting oil (356 mg) was dissolved in 3 mL of dichloromethane and 2 mL of TFA and stirred for 1.5 h. It was concentrated, and by weight determined to contain 3 eq. of TFA. To this was added 2 mL of dry dimethylformamide (DMF) and 0.35 mL (3.2 mmol) of 4-methyl morpholine. To this was added a pre-mixed solution of 3-[(dipropylamino)carbonyl]-5-methylbenzoic acid (240 mg, 0.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 190 mg, 1 mmol), and 1-hydroxybenzotriazole hydrate (HOBT, 135 mg, 1 mmol) in 3 mL of dry DMF, which had been stirring together for 1.5 h. After 3 days the reaction was quenched with 1 N KH2PO4 and dissolved in ethyl acetate. The organic phase was washed with 1 N KH2PO4, 1 N NaHCO3 (2×) and brine, dried over Na2SO4, and concentrated. Chromatography over silica gel, eluting with 5% methanol (containing 1% NH4OH) in dichloromethane afforded 208 mg (0.32 mmnol) of N1-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(cyclohexylmethyl)-2-hydroxypropyl]-5-methyl-N3,N3-dipropylisophthalamide hydrochloride (EXAMPLE SP-257) after formation of the salt with ethereal HCl: CI MS m/z 600 [M+H]+.

後処理

  1. customthe solvent was removed in vacuo
  2. dissolutionthe residue was dissolved in ethyl acetate
  3. washIt was washed three times with small portions of 10% HCl
  4. extractionthe aqueous phases were back-extracted with ethyl acetate
  5. washThe combined organic phases were washed with 1 N NaHCO3 and brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. dissolutionThe resulting oil (356 mg) was dissolved in 3 mL of dichloromethane
  9. concentrationIt was concentrated
  10. stirringhad been stirring together for 1.5 h
  11. customAfter 3 days the reaction was quenched with 1 N KH2PO4
  12. dissolutiondissolved in ethyl acetate
  13. washThe organic phase was washed with 1 N KH2PO4, 1 N NaHCO3 (2×) and brine
  14. dry with materialdried over Na2SO4
  15. concentrationconcentrated
  16. washChromatography over silica gel, eluting with 5% methanol (containing 1% NH4OH) in dichloromethane

出典と根拠

ORDレコード
ord-5839283babe54f5bbaa5631fe2ee7dc9
出典データセット
uspto-grants-2010_06
特許番号
US07727997B2

関連ノート

読み込み中…