Diisopropylethylamine → Complement factor D-IN-1

HRID 1527603Notes

Reaction equation

HRID 1527603 reaction equation
[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=O)[N:5]=1)(=[O:3])[NH2:2].[Br:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([C@@H:27]2[CH2:32][C@@H:31]3[C@@H:29]([CH2:30]3)[NH:28]2)=[O:26])[CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([C@@H:27]2[CH2:32][C@@H:31]3[C@@H:29]([CH2:30]3)[N:28]2[C:14](=[O:16])[CH2:13][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([C:1]([NH2:2])=[O:3])=[N:5]2)=[O:26])[CH:21]=[CH:20][CH:19]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 682833421386457-64-2HCID 86673882(1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (6-bromo-pyridin-2-yl)-amide

Product 1

HCID 86673884Complement factor D-IN-1

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

(3-Carbamoyl-indazol-1-yl)-acetic acid (130 mg, 0.59 mmol, prepared as described in Scheme A25), (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (6-bromo-pyridin-2-yl)-amide (2 TFA salt, 303 mg, 0.59 mmol) and HBTU (337 mg, 0.89 mmol) were dissolved in DMF (3 mL). DIPEA (406 μL, 2.37 mmol) was added and the reaction mixture was stirred at 25° C. for 1 h. The crude reaction mixture was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% TFA). The pure fractions were combined, neutralized with an aqueous saturated solution of NaHCO3 and extracted with CH2Cl2 to give the desired compound. TLC, Rf (CH2Cl2/MeOH 9:1)=0.55; MS: 483.1/485.1 [M+H]+, 965.4/967.4 [2M+H]+, 982.4/984.3 [2M+NH4]+, 481.1/483.2 [M−H]−, 527.2/529.1 [M+HCOO]−; tR (HPLC conditions a): 2.79 min. Alternatively, for final compounds containing a basic residue: the pure HPLC fractions were combined, CH3CN was evaporated under reduced pressure, the resulting aqueous solution was adjusted to pH 8-9 by addition of an aqueous saturated solution of NaHCO3, extracted with CH2Cl2 (×3), the combined organic extracts were dried (Na2SO4) and concentrated under vacuum.

Workup

  1. customThe crude reaction mixture
  2. customwas purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% TFA)
  3. extractionextracted with CH2Cl2

Sources & evidence

ORD record
ord-7ed0dc9907e342818e68e2a4709708dc
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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