Hydrochloric Acid → 1-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)cyclopropanamine

HRID 1177461Notes

Reaction equation

HRID 1177461 reaction equation
[CH2:1]([Mg]Br)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]1)[N:17]=2)[C:9]#[N:10].B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>C(OCC)C.C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(Cl)Cl>[F:5][C:6]1[CH:7]=[C:8]([C:9]2([NH2:10])[CH2:2][CH2:1]2)[CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]1)[N:17]=2

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 8000Boron trifluoride etherateHCID 14798Sodium HydroxideHCID 671117463-Fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)benzonitrileHCID 178418443HCID 178418443, compound

Product 1

HCID 446011061-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)cyclopropanamine

Reagents, catalysts & solvents 4

HCID 11026Titanium isopropoxideCatalystHCID 1140TolueneSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

Ethylmagnesium bromide (1 M solution in t-butyl methyl ether) (0.764 mL, 0.764 mmol) was added at −78° C. to a solution of 3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)benzonitrile (0.113 g, 0.306 mmol) and titanium (iv) isopropoxide (0.098 mL, 0.336 mmol) in ethyl ether (3 mL) and toluene (3 mL) under argon. After stirring at −78° C. for 10 min, the yellow solution was allowed to warm to room temperature (1 h), during which boron trifluoride diethyl etherate (0.023 mL, 0.187 mmol) was added. After the reaction mixture was stirred for 1 h, 1 N HCl (ca. 0.5 mL) and CH2Cl2 were added. NaOH (10% aq, ca. 1 mL) was added to the resulting two clear phases and the mixture was extracted with CH2Cl2. The combined CH2Cl2 layers were dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 10% MeOH/CH2Cl2 failed to give a pure batch of 1-(3-fluoro-4-(5-(1-phenyl-cyclopropyl)thiazolo-[5,4-b]pyridine-2-yl)phenyl)cyclopropanamine. Further purification on the reverse phase prep. HPLC provided the title compound as an off-white solid. MS (ESI) m/z: Calculated: 401.1; Observed: 402.1 (M++1).

Workup

  1. temperatureto warm to room temperature (1 h)
  2. stirringAfter the reaction mixture was stirred for 1 h
  3. extractionthe mixture was extracted with CH2Cl2
  4. dry with materialThe combined CH2Cl2 layers were dried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customISCO purification with 10% MeOH/CH2Cl2

Sources & evidence

ORD record
ord-1c5f4d48cd824c1283036ec479795249
Source dataset
uspto-grants-2010_11
Patent number
US07842685B2

Reaction notes

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