Diisopropylethylamine → HCID 87122896, compound

HRID 708704Notes

Reaction equation

HRID 708704 reaction equation
[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:33][O:34][C:35](=[O:85])[C@@H:36]([NH:52][C:53]([CH:55]1[CH2:64][C:63]2[CH:62]=[C:61]3[O:65][CH2:66][C@H:67]([C:69]4[CH:74]=[CH:73][C:72]([O:75][CH2:76][C:77]5[CH:82]=[CH:81][C:80]([Cl:83])=[C:79]([Cl:84])[CH:78]=5)=[CH:71][CH:70]=4)[O:68][C:60]3=[CH:59][C:58]=2[CH2:57][NH:56]1)=[O:54])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH3:33][O:34][C:35](=[O:85])[C@@H:36]([NH:52][C:53]([CH:55]1[CH2:64][C:63]2[CH:62]=[C:61]3[O:65][CH2:66][C@H:67]([C:69]4[CH:74]=[CH:73][C:72]([O:75][CH2:76][C:77]5[CH:82]=[CH:81][C:80]([Cl:83])=[C:79]([Cl:84])[CH:78]=5)=[CH:71][CH:70]=4)[O:68][C:60]3=[CH:59][C:58]=2[CH2:57][N:56]1[C:15]([C:11]1[S:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:13][C:12]=1[CH3:14])=[O:17])=[O:54])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[CH:48][CH:49]=2)=[CH:40][CH:39]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2756770N-Boc-amino-4-methylthiazole-5-carboxylic acidHCID 2774761Tetramethylfluoroformamidinium hexafluorophosphateHCID 66719338(S)-3-(4'-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester

Product 1

HCID 87122896HCID 87122896, compound

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

2-tert-Butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid (1 eq) and TFFH (1 eq) were taken in 2 mL anhydrous THF and stirred for 10 min. (S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (50 mg) and DIEA (3 eq) were added to the reaction mixture and stirred for 1 hour. Reaction mixture was diluted with EtOAc (5 mL), washed with water and brine and dried over Na2SO4. The solvent was removed by rotavap and the residue was purified by silicagel column to give (S)-2-({(S)-7-(2-tert-butoxycarbonylamino-4-methyl-thiazole-5-carbonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (42 mg). Treatment with HCl according to General Procedure C followed by NaHCO3 wash gave (S)-2-({(S)-7-(2-Amino-4-methyl-thiazole-5-carbonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (35 mg).

Workup

  1. additionwere added to the reaction mixture
  2. customReaction mixture
  3. washwashed with water and brine
  4. dry with materialdried over Na2SO4
  5. customThe solvent was removed by rotavap
  6. customthe residue was purified by silicagel column

Sources & evidence

ORD record
ord-4779975d45de4aa58e16fa7ad32d3009
Source dataset
uspto-grants-2015_11
Patent number
US09175003B2

Reaction notes

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