Diisopropylethylamine → 2-{4-(2-({(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(propylamino)pyridin-4-yl)phenoxy}ethyl N2,N6-bis(tert-butoxycarbonyl)-L-lysyl-L-alaninate

HRID 1968304Notes

Reaction equation

HRID 1968304 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:64][C@H:65]([C:67]([O:69][CH2:70][CH2:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([C:79]2[C:84]([C:85]#[N:86])=[C:83]([NH:87][CH2:88][CH2:89][CH3:90])[N:82]=[C:81]([S:91][CH2:92][C:93]3[N:94]=[C:95]([C:98]4[CH:103]=[CH:102][C:101]([Cl:104])=[CH:100][CH:99]=4)[S:96][CH:97]=3)[C:80]=2[C:105]#[N:106])=[CH:75][CH:74]=1)=[O:68])[CH3:66]>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:64][C@H:65]([C:67]([O:69][CH2:70][CH2:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([C:79]2[C:84]([C:85]#[N:86])=[C:83]([NH:87][CH2:88][CH2:89][CH3:90])[N:82]=[C:81]([S:91][CH2:92][C:93]3[N:94]=[C:95]([C:98]4[CH:103]=[CH:102][C:101]([Cl:104])=[CH:100][CH:99]=4)[S:96][CH:97]=3)[C:80]=2[C:105]#[N:106])=[CH:75][CH:74]=1)=[O:68])[CH3:66])=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 7349648(2S)-2,6-bis((((tert-butoxy)carbonyl)amino))hexanoic acidHCID 468509402-{4-(2-({(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(propyl-amino)pyridin-4-yl)phenoxy}ethyl L-alaninate trifluoroacetate

Product 1

HCID 866438492-{4-(2-({(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(propylamino)pyridin-4-yl)phenoxy}ethyl N2,N6-bis(tert-butoxycarbonyl)-L-lysyl-L-alaninate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

445 mg (1.284 mmol) of N2,N6-bis(tert-butoxycarbonyl)-L-lysine were initially charged in 12.3 ml of DMF. 268 mg (1.400 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 237 mg (1.750 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.51 ml (2.917 mmol) of N,N-diisopropylethylamine were added, and 872 mg (1.167 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(propylamino)pyridin-4-yl)phenoxy}ethyl L-alaninate trifluoroacetate (Example 38) were then added and the mixture was stirred at RT overnight. Water was added, and the reaction solution was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated by evaporation. The residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). For further purification, the product obtained was subjected to column chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 1/1). This gave 698 mg (62% of theory) of the target compound.

Workup

  1. extractionthe reaction solution was extracted three times with ethyl acetate
  2. dry with materialThe combined organic phases were dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated by evaporation
  5. customThe residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA)
  6. customFor further purification
  7. customthe product obtained

Sources & evidence

ORD record
ord-2dc9837ab6ba4c8882d241061784ae79
Source dataset
uspto-grants-2013_04
Patent number
US08420825B2

Reaction notes

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