Amino-thienopyrimidine Series

 

The first round of suggestions of modifications to OSM-S-106.  This is also being disscussed here on G+.  This post will be updated and modified as the synthesis and disscussion contiunes.

Number	InchI	Progress
1	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)	waiting on SM
2	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)	waiting on SM
3	InChI=1S/C12H8ClN3O2S2/c13-20(17,18)8-3-1-2-7(4-8)10-5-9-11(19-10)12(14)16-6-15-9/h1-6H,(H2,14,15,16)	waiting on SM
4	InChI=1S/C13H10N4OS/c14-12-11-9(16-6-17-12)5-10(19-11)7-2-1-3-8(4-7)13(15)18/h1-6H,(H2,15,18)(H2,14,16,17)	waiting on SM
5	InChI=1S/C15H14N4OS/c1-19(2)15(20)10-5-3-4-9(6-10)12-7-11-13(21-12)14(16)18-8-17-11/h3-8H,1-2H3,(H2,16,17,18)	waiting on SM
6	InChI=1S/C18H19N5OS/c1-22-5-7-23(8-6-22)18(24)13-4-2-3-12(9-13)15-10-14-16(25-15)17(19)21-11-20-14/h2-4,9-11H,5-8H2,1H3,(H2,19,20,21)	waiting on SM
7	InChI=1S/C13H11N3S/c14-13-12-11(15-8-16-13)7-10(17-12)6-9-4-2-1-3-5-9/h1-5,7-8H,6H2,(H2,14,15,16)	waiting on SM
8	InChI=1S/C12H10N4O2S2/c13-12-11-9(15-6-16-12)5-10(19-11)7-1-3-8(4-2-7)20(14,17)18/h1-6H,(H2,13,15,16)(H2,14,17,18)	waiting on SM
9	InChI=1S/C13H10N4OS/c14-12-11-9(16-6-17-12)5-10(19-11)7-1-3-8(4-2-7)13(15)18/h1-6H,(H2,15,18)(H2,14,16,17)	waiting on SM
10	InChI=1S/C15H14N4OS/c1-19(2)15(20)10-5-3-9(4-6-10)12-7-11-13(21-12)14(16)18-8-17-11/h3-8H,1-2H3,(H2,16,17,18)	waiting on SM
11	InChI=1S/C17H16N4O2S/c18-16-15-13(19-10-20-16)9-14(24-15)11-1-3-12(4-2-11)17(22)21-5-7-23-8-6-21/h1-4,9-10H,5-8H2,(H2,18,19,20)	waiting on SM
12	InChI=1S/C18H19N5OS/c1-22-6-8-23(9-7-22)18(24)13-4-2-12(3-5-13)15-10-14-16(25-15)17(19)21-11-20-14/h2-5,10-11H,6-9H2,1H3,(H2,19,20,21)	waiting on SM
13	InChI=1S/C12H9N3S/c13-12-11-9(14-7-15-12)6-10(16-11)8-4-2-1-3-5-8/h1-7H,(H2,13,14,15)	AB10-1
14	InChI=1S/C12H15N3S/c13-12-11-9(14-7-15-12)6-10(16-11)8-4-2-1-3-5-8/h6-8H,1-5H2,(H2,13,14,15)	waiting on SM

These compounds were missed off the G+ post by mistake.

	InChI
16	InChI=1S/C12H8ClN3O2S2/c13-20(17,18)8-3-1-7(2-4-8)10-5-9-11(19-10)12(14)16-6-15-9/h1-6H,(H2,14,15,16)
17	InChI=1S/C13H12N4O2S2/c1-15-21(18,19)9-4-2-8(3-5-9)11-6-10-12(20-11)13(14)17-7-16-10/h2-7,15H,1H3,(H2,14,16,17)
18	InChI=1S/C14H14N4O2S2/c1-18(2)22(19,20)10-5-3-9(4-6-10)12-7-11-13(21-12)14(15)17-8-16-11/h3-8H,1-2H3,(H2,15,16,17)

 

	InChI	Progress
19	InChI=1S/C17H18N4O3S2/c1-18-26(22,23)13-4-2-3-12(9-13)15-10-14-16(25-15)17(20-11-19-14)21-5-7-24-8-6-21/h2-4,9-11,18H,5-8H2,1H3
20	InChI=1S/C18H20N4O3S2/c1-21(2)27(23,24)14-5-3-4-13(10-14)16-11-15-17(26-16)18(20-12-19-15)22-6-8-25-9-7-22/h3-5,10-12H,6-9H2,1-2H3
21	InChI=1S/C16H14ClN3O3S2/c17-25(21,22)12-3-1-2-11(8-12)14-9-13-15(24-14)16(19-10-18-13)20-4-6-23-7-5-20/h1-3,8-10H,4-7H2
22	InChI=1S/C17H16N4O2S/c18-16(22)12-3-1-2-11(8-12)14-9-13-15(24-14)17(20-10-19-13)21-4-6-23-7-5-21/h1-3,8-10H,4-7H2,(H2,18,22)
23	InChI=1S/C19H20N4O2S/c1-22(2)19(24)14-5-3-4-13(10-14)16-11-15-17(26-16)18(21-12-20-15)23-6-8-25-9-7-23/h3-5,10-12H,6-9H2,1-2H3
24	InChI=1S/C22H25N5O2S/c1-25-5-7-27(8-6-25)22(28)17-4-2-3-16(13-17)19-14-18-20(30-19)21(24-15-23-18)26-9-11-29-12-10-26/h2-4,13-15H,5-12H2,1H3
25	InChI=1S/C17H17N3OS/c1-2-4-13(5-3-1)10-14-11-15-16(22-14)17(19-12-18-15)20-6-8-21-9-7-20/h1-5,11-12H,6-10H2
26	InChI=1S/C16H16N4O3S2/c17-25(21,22)12-3-1-11(2-4-12)14-9-13-15(24-14)16(19-10-18-13)20-5-7-23-8-6-20/h1-4,9-10H,5-8H2,(H2,17,21,22)
27	InChI=1S/C17H16N4O2S/c18-16(22)12-3-1-11(2-4-12)14-9-13-15(24-14)17(20-10-19-13)21-5-7-23-8-6-21/h1-4,9-10H,5-8H2,(H2,18,22)
28	InChI=1S/C19H20N4O2S/c1-22(2)19(24)14-5-3-13(4-6-14)16-11-15-17(26-16)18(21-12-20-15)23-7-9-25-10-8-23/h3-6,11-12H,7-10H2,1-2H3
29	InChI=1S/C21H22N4O3S/c26-21(25-7-11-28-12-8-25)16-3-1-15(2-4-16)18-13-17-19(29-18)20(23-14-22-17)24-5-9-27-10-6-24/h1-4,13-14H,5-12H2
30	InChI=1S/C22H25N5O2S/c1-25-6-8-27(9-7-25)22(28)17-4-2-16(3-5-17)19-14-18-20(30-19)21(24-15-23-18)26-10-12-29-13-11-26/h2-5,14-15H,6-13H2,1H3
31	InChI=1S/C16H15N3OS/c1-2-4-12(5-3-1)14-10-13-15(21-14)16(18-11-17-13)19-6-8-20-9-7-19/h1-5,10-11H,6-9H2
32	InChI=1S/C16H21N3OS/c1-2-4-12(5-3-1)14-10-13-15(21-14)16(18-11-17-13)19-6-8-20-9-7-19/h10-12H,1-9H2
33	InChI=1S/C16H14ClN3O3S2/c17-25(21,22)12-3-1-11(2-4-12)14-9-13-15(24-14)16(19-10-18-13)20-5-7-23-8-6-20/h1-4,9-10H,5-8H2
34	InChI=1S/C17H18N4O3S2/c1-18-26(22,23)13-4-2-12(3-5-13)15-10-14-16(25-15)17(20-11-19-14)21-6-8-24-9-7-21/h2-5,10-11,18H,6-9H2,1H3
35	InChI=1S/C18H20N4O3S2/c1-21(2)27(23,24)14-5-3-13(4-6-14)16-11-15-17(26-16)18(20-12-19-15)22-7-9-25-10-8-22/h3-6,11-12H,7-10H2,1-2H3

Bromination of chlorothienopyrimidine (AT-1). Calculations for this procedure were generated using the "Analyze Stoichiometry" function in ChemDraw. 

 

To AT-1 (0.100 g, 0.58 mmol, 1.0 equiv.) in THF (10 mL) at -78 C was added n-BuLi (0.256 mL, 2.5 M in hexanes, 0.64 mmol, 1.1 equiv.) dropwise. The reaction mixture was stirred for 30 minutes and bromine (0.060 mL, 1.17 mmol, 2.0 equiv.) added dropwise. The reaction mixture was warmed to rt with stirring and monitored by TLC. 

Reaction mixture turned dark brown after the addition of n-BuLi. Addition of bromine gave a bright orange reaction mixture. 

The reacton mixture was diluted with an aqueous solution of sodium thiosulfate (20 mL) and extracted into ethyl acetate (3 x 20 mL). The combined organic extracts were dried (MgSO₄), concentrated under reduced pressure and the residue purified by flash column chromatography (7:1 hexanes:ethyl acetate) to give the product as an off-white solid (0.080 g, 55%).

 

HIRAC

 

NMR

Isolated product AT-5 
Comparison of starting material AT-1 and product AT-5 

Bromination of arylthienopyrimidine (AT-2), according to standard bromination conditions. 

 

To AT-2 (0.100 g, 0.47 mmol, 1.0 equiv.) in THF (10 mL) at -78 C was added n-BuLi (2.5 M in hexanes, 0.208 mL, 0.52 mmol, 1.1. equiv.) dropwise with stirring. The reaction mixture was stirred at -78 C for 30 minutes, after which bromine (0.302 g, 0.097 mL, 1.89 mmol, 4.0 equiv.) was added dropwise. The reaction was warmed to rt, stirred, with monitoring by TLC.  

Accidental addition of excess (approx. 2 equiv.) n-BuLi. As a result, the reaction mixture was only stirred for 5 minutes before the addition of bromine. 

The reaction was judged to be complete (complete disappearance of starting material) after 15 minutes; the reaction mixture was quenced with an aqueous solution of sodium thiosulfate (10 mL) and diluted with ethyl acetate (10 mL). The aqueous phase was extracted into ethyl acetate (2 x 10 mL). The combined organic phases were washed with water (20 mL), brine (20mL), dried (MgSO₄) and concentrated under reduced pressure. 

Analysis of the crude reaction mixture by TLC showed the presence of four new compounds. Purification by flash column chromatography (7:1 hexanes:ethyl acetate) gave (in order of increasing polarity):

Fraction 1: 0.057 g, insoluble (after evaporation of eluting solvent) yellow solid
Fraction 2: 0.011 g, unidentified yellow oil, 1H NMR showed the presence of butyl groups
Fraction 3: 0.030 g, dibrominated substrate AT-4b (17%)
Fraction 4: 0.078 g, monobrominated substrate AT-4a (57%) 

 

HIRAC

 

NMR

 1H NMR spectrum of AT-4b

13C NMR spectrum of AT-4b

 1H NMR spectrum of AT-4a

 13C NMR spectrum of AT-4a

 Stacked 1H NMR spectra of AT-2 (bottom), AT-4b (middle) and AT-4a (top)

Scale up of AT-2-4 for more product.

 

Arylation of thienopyrimidine AT-1 was performed on a larger scale, with the use of 0.200 g substrate (AT-1), under the same conditions as those reported for AT-2-4.

The arylated product (AT-2-5) was isolated in 93% yield (0.232 g) as a white solid.

 

NMR

1H NMR

13C{1H} NMR

 

 

HIRAC

Mnr: MNR91-100

Starting material - JRC13-6

As for compound 10a here and MNR100-1

Hazard Assessment

Procedure

A suspension of JRC13-6 (0.70 g, 4.10 mmol) in morpholine (3.5 mL, 041.0 mmol) was gently heated under reflux for 3 hours and then allowed to cool to room temperature.  EtOAC was then added to the mixture to rinse the magnetic stirrer and on doing so a white precipitate formed.  More EtOAc (10 mL) was added and the mixture was filtered and the solid washed with hexane.  

 

Col 80% EtOAc/Hex

 

Frac 7-19 - 0.805 g, 3.63 mmol, 89% as pale yellow, fluffy solid

 

NMR

Starting Material

Product

 

Conclusion

 Good clean high yielding reaction

Strings

 Starting material

InChI=1S/C6H3ClN2S/c7-6-5-4(1-2-10-5)8-3-9-6/h1-3H

Product

InChI=1S/C10H11N3OS/c1-6-15-9-8(1)11-7-12-10(9)13-2-4-14-5-3-13/h1,6-7H,2-5H2