Amino-thienopyrimidine Series

Summary

This is the third synthesis in a series of three amino-thienoyprimidine compounds with a modification to the sulfonamide group on the right-hand portion of the molecule. The sulfonamide in this target is substituted with the dimethylamine group.

Hazard and Risk Assessment:

Reaction Scheme:

Procedure:

The procedure used is analogous to Patrick's synthesis, PT-22, and my previous syntheses: TF3-1, TF4-1, TF7-1 and TF8-1.

Two equivalents of the sulfonamide from the previous step, TF14-1, were used in order to adjust for the ~50% purity.

N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [TF14-1] (47.0 mg, 0.139 mmol, 2 equiv), 6-bromothieno[3,2-d]pyrimidin-4-amine [TF15-1] (17.5 mg, 0.0761 mol, 1 equiv) and Pd₂Cl₂(dppf) (12.2 mg, 20 mol%) were dissolved in isopropanol (1.5 mL), and potassium carbonate solution (1M, 0.15 mL) was added.

The reaction was heated to 90°C for 30 minutes under microwave irradiation in a sealed vessel.

The product was then purified using column chromatography (0-10% methanol in chloroform for 20 tubes) and evaporated to dryness to give a yield of 27.3 mg (0.0816 mmol, 58.7 %) of pale brown solid.

Data:

InChi:

InChI=1S/C14H14N4O2S2/c1-18(2)22(19,20)10-5-3-4-9(6-10)12-7-11-13(21-12)14(15)17-8-16-11/h3-8H,1-2H3,(H2,15,16,17)

Summary

This is the second synthesis in a series of three amino-thienoyprimidine compounds with a modification to the sulfonamide group on the right-hand portion of the molecule. The sulfonamide in this target is substituted with the methylamine group.

Hazard and Risk Assessment:

Reaction Scheme:

Procedure:

The procedure used is analogous to Patrick's synthesis, PT-22, and my previous syntheses: TF3-1, TF4-1, TF7-1 and TF8-1.

Two equivalents of the sulfonamide from the previous step, TF13-1, were used in order to adjust for the ~50% purity.

N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [TF13-1] (118.9 mg, 0.40 mmol, 2 equiv), 6-bromothieno[3,2-d]pyrimidin-4-amine [TF15-1] (46.02 mg, 0.2 mmol, 1 equiv) and Pd₂Cl₂(dppf) (32 mg, 20 mol%) were dissolved in isopropanol (4 mL), and potassium carbonate solution (1M, 0.4 mL) was added.

The reaction was heated to 90°C for 30 minutes under microwave irradiation in a sealed vessel.

The product was then purified using column chromatography (0-10% methanol in chloroform for 20 tubes) and evaporated to dryness to give a yield of 85.9 mg (0.268 mmol, 67.0 %) of pale brown solid.

Data:

InChi:

InChI=1S/C13H12N4O2S2/c1-15-21(18,19)9-4-2-3-8(5-9)11-6-10-12(20-11)13(14)17-7-16-10/h2-7,15H,1H3,(H2,14,16,17)

Summary

This is the first synthesis in a series of three amino-thienoyprimidine compounds with a modification to the sulfonamide group on the right-hand portion of the molecule. The sulfonamide in this target is substituted with the pyrollidine group.

Hazard and Risk Assessment:

Reaction Scheme:

Procedure:

The procedure used is analogous to Patrick's synthesis, PT-22, and my previous syntheses: TF3-1, TF4-1, TF7-1 and TF8-1.

Two equivalents of the sulfonamide from the previous step, TF12-1, were used in order to adjust for the ~50% purity.

1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidine [TF12-1] (90.0 mg, 0.269 mmol, 2 equiv), 6-bromothieno[3,2-d]pyrimidin-4-amine [TF15-1] (30.8 mg, 0.134 mmol, 1 equiv) and Pd₂Cl₂(dppf) (21.4 mg, 20 mol%) were dissolved in isopropanol (3 mL), and potassium carbonate solution (1M, 0.3 mL) was added.

The reaction was heated to 90°C for 30 minutes under microwave irradiation in a sealed vessel.

The product was then purified using column chromatography (0-10% methanol in chloroform for 20 tubes) and evaporated to dryness to give a yield of 43.5 mg (0.120 mmol, 44.6 %) of pale brown solid.

Data:

InChi:

InChI=1S/C16H16N4O2S2/c17-16-15-13(18-10-19-16)9-14(23-15)11-4-3-5-12(8-11)24(21,22)20-6-1-2-7-20/h3-5,8-10H,1-2,6-7H2,(H2,17,18,19)

Summary

AT-6-1 was repeated using 400mg of substrate.

Hazard and Risk Assessment:

Reaction Scheme:

Procedure:

0.400 g of bromochlorothienopyrimidine (0.8 mmol, 1 equiv) was added to 4 mL isopropanol and 8 mL ammonia, and stirred at 120^oC in a sealed vessel for 3 hours. The solvents were removed under vacuum to give a yield of yellow-orange solid (222.5 mg, 0.967 mmol, 60.4 %) which was sufficiently pure to use as-is.

Data:

InChi:

InChI=1S/C6H2BrClN2S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H

Summary:

Follow-up to TF11-2. Substitution of Br for PinB at the 3-position by reaction with B₂Pin₂. Analogous to the synthesis performed by Patrick, PT-1-20.

Hazard and Risk Assessment:

Reaction Scheme:

Procedure:

284 mg B₂Pin₂ (1.118 mmol, 4.5 equiv), 294 mg KOAc (3 mmol, 12 equiv), 30 mg Pd(dppf)₂CH₂Cl₂ (17 μmol, 15 mol %) and 98.26 mg amide [TF11-2] (0.372 mmol, 1 equiv) were dissolved in 1,4-dioxane (4 mL) and heated to 100°C in a sealed tube for 19 hours. 

The reaction mixture was evaporated to dryness and purified by dry flash column chromatography to give an impure yield of brown oil / gooey solid (237.0 mg, >99% yield, ~50% purity). Impurities are speculated to be residual pinocol and water. This product will be used as-is in the next stage of the synthesis (TF18-1), with masses adjusted to accomodate for the impure yield.

Data:

InChi:

InChI=1S/C14H22BNO4S/c1-13(2)14(3,4)20-15(19-13)11-8-7-9-12(10-11)21(17,18)16(5)6/h7-10H,1-6H3