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Acetic Acid → (S)-2-amino-6-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methylamino)hexanoic acid

HRID 1026810
Notes
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Reaction equation

HRID 1026810 reaction equation
[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C([NH:40][C@H:41]([C:47]([OH:49])=[O:48])[CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])(OC(C)(C)C)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[NH2:40][C@@H:41]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][CH2:30][C:27]1[CH:26]=[N:25][C:24]([C:22]2[S:23][C:16]3[C:17](=[N:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:6])=[CH:9][C:10]=3[F:32])[CH:21]=2)=[CH:29][CH:28]=1)[C:47]([OH:49])=[O:48]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 2733284epsilon-tert-Butyloxycarbonyl-lysineHCID 5049666Sodium triacetoxyborohydrideHCID 582365791-Cyclopropyl-3-(3-fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea

Product 1

HCID 58236641(S)-2-amino-6-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methylamino)hexanoic acid
Yield 69%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 6422Trifluoroacetic acidSolvent

Procedure

To a suspension of 321 (0.26 g, 0.58 mmol) and N-Boc-lysine (1.1 g, 4.6 mmol) in dichloromethane (75 mL) and was added acetic acid (0.066 mL, 1.2 mmol). The reaction mixture was stirred for 1 h, then sodium triacetoxyborohydride (0.37 g, 1.7 mmol) was added and the resulting mixture stirred for 18 h. The mixture was then partitioned between water and dichloromethane, and the solid precipitate removed by suction filtration through celite. The product was mostly in the solid filter cake, so this was solubilized by washing with 1:1 dichloromethane/methanol. This solution was concentrated and the residue was purified by Gilson reverse phase HPLC (35-75% MeOH/H2O, Aquasil C18, 30 min) and lyophilized to yield BOC-protected product. This was dissolved in dichloromethane (75 mL) and trifluoroacetic acid (3 mL), and stirred at r.t. for 3 h. The mixture was concentrated and the residue was purified by Gilson reverse phase HPLC (35-75% MeOH/H2O, Aquasil C18, 30 min) and lyophilized to yield title compound 324 (44 mg, 69% yield). 1H NMR (DMSO-d6) δ (ppm) 1H: 9.02 (s, 1H); 8.66 (s, 1H); 8.53 (d, J=5.3, 1H); 8.35 (s, 1H); 8.28 (d, j=8.4, 1H); 7.98 (d, J=6.3, 1H); 7.72 (dd, J=13.5, 2.3, 1H); 7.37 (t, J=9.0, 1H); 7.21 (d, J=10.0, 1H); 6.89 (s, 1H); 6.68 (d, J=5.3, 1H); 4.00 (s, 2H); 2.75-2.70 (m, 2H); 2.55-2.52 (m, 1H); 2.45 (m, 1H); 1.70-1.30 (m, 6H); 0.67-0.62 (m, 2H); 0.44-0.40 (m, 2H). LRMS: 579.5 (M+H).

Workup

  1. stirringthe resulting mixture stirred for 18 h
  2. customThe mixture was then partitioned between water and dichloromethane
  3. customthe solid precipitate removed by suction filtration through celite
  4. filtrationfilter cake
  5. washby washing with 1:1 dichloromethane/methanol
  6. concentrationThis solution was concentrated
  7. customthe residue was purified by Gilson reverse phase HPLC (35-75% MeOH/H2O, Aquasil C18, 30 min)
  8. customto yield BOC-protected product
  9. concentrationThe mixture was concentrated
  10. customthe residue was purified by Gilson reverse phase HPLC (35-75% MeOH/H2O, Aquasil C18, 30 min)

Sources & evidence

ORD record
ord-9e67ec07bede4293a5a5f351fbd740bc
Source dataset
uspto-grants-2014_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08729268B2

Reaction notes

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