Sodium Carbonate → 2-[5-Amino-6-(5-phenyl-1,3,4-thiadiazol-2-yl)pyrazin-2-yl]-5-(1,4-diazepane-1-carbonyl)benzonitrile

HRID 2204892Notes

Reaction equation

Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=1[C:12]#[N:13].[C:14]([O-])(=O)[CH3:15].[K+].CC1(C)C(C)(C)OB(B2O[C:30]([CH3:33])(C)[C:29]([CH3:35])([CH3:34])O2)O1.[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC[CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:81]1[N:82]=[C:83]([C:88]2[S:89]C(C3C=CC=CC=3)=[N:91][N:92]=2)[C:84]([NH2:87])=[N:85][CH:86]=1.[NH:99]1[CH2:105]CC[NH:102][CH2:101][CH2:100]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCOCC1.C(OCC)(=O)C.Cl[Pd]Cl.[Fe].[Pd].ClCCl>[NH2:87][C:84]1[N:85]=[CH:86][C:81]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([N:102]3[CH2:15][CH2:14][CH2:105][NH:99][CH2:100][CH2:101]3)=[O:8])=[CH:4][C:3]=2[C:12]#[N:13])=[N:82][C:83]=1[C:88]1[S:89][C:35]([C:29]2[CH:30]=[CH:33][CH:38]=[CH:37][CH:34]=2)=[N:91][N:92]=1

Participants

Conditions

Temperature: 140 °C

Procedure

A mixture of methyl 4-bromo-3-cyano-benzoate (100 mg, 0.4166 mmol), potassium acetate (122.7 mg, 1.250 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (158.7 mg, 0.6249 mmol) and 1-cyclopenta-1,4-dienyl-diphenyl-phosphane; dichloromethane; dichloropalladium; iron (34.02 mg, 0.04166 mmol) was heated in dioxane (10 mL) at 80° C. for 2 h. After this time, the reaction mixture was cooled and palladium; triphenylphosphane (48.14 mg, 0.04166 mmol), sodium carbonate (625.0 μL of 2 M, 1.250 mmol) and 5-bromo-3-(5-phenyl-1,3,4-thiadiazol-2-yl)pyrazin-2-amine (139.2 mg, 0.4166 mmol) were added and heated at 140° C. under microwave conditions for 1 h. After cooling to room temperature, the resulting carboxylic acid was filtered off as brown solid. The solid was dissolved in DMF (3 mL) and 1,4-diazepane (208.3 mg, 2.083 mmol) and TBTU (267.5 mg, 0.8332 mmol) were added. The resulting mixture was stirred at room temperature for 2 h then diluted with ethyl acetate (5 mL), and the organic extract washed with water (1×5 mL) and brine (1×5 mL), dried over MgSO4 and concentrated in vacuo to a solid. This solid was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were collected and lypholised to give the product as a yellow solid (60 mg, 25% yield); 1H NMR (400.0 MHz, DMSO) d 1.9-2.1 (m, 2H), 3.3-3.4 (m, 4H), 3.5-3.55 (m, 2H), 3.65-3.7 (m, 1H), 3.7-3.75 (m, 1H), 3.8-3.9 (m, 2H), 7.5-7.6 (m, 3H), 7.8 (d, 1H), 8.1-8.22 (m, 3H), 8.25 (br s, 1H), 8.75 (br s, 2H) and 8.8 (s, 1H) ppm; MS (ES+) 483.2

Workup

temperatureAfter this time, the reaction mixture was cooled
temperatureAfter cooling to room temperature
filtrationthe resulting carboxylic acid was filtered off as brown solid
dissolutionThe solid was dissolved in DMF (3 mL)
extractionthe organic extract
washwashed with water (1×5 mL) and brine (1×5 mL)
dry with materialdried over MgSO4
concentrationconcentrated in vacuo to a solid
customThis solid was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]
customThe product fractions were collected

Sources & evidence

ORD record: ord-3908ba339a6747a5808615ebeaf9844c
Source dataset: uspto-grants-2016_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09365557B2

Reaction notes

Loading…