Chapter I. Synthesis, modification and bioactivity of bicyclic thieno[3,2-D]pyrimidines

1.1.22Synthesis of N3-Substituted Derivatives of the Thienopyrimidinone Core
There are some stage(A,B,C) for the synthesis of N3-substituted of the thienopyrimidinone were described by these stages were we can see below. We can synthesis of derivatives of the thienopyrimidinone and their other derivatives to the purpose we use for the A stage reagents and conditions: (a) benzyl bromide (for 9a), (2-bromoethyl)benzene (for 9b), 1-bromo-3-phenylpropane (for 9c), 4-nitrobenzyl bromide (for 9d), 2-nitrobenzyl bromide (for 9e), 3-nitrobenzyl bromide (for 9f), 4-cyanobenzyl bromide, (for 9g), 4-methoxybenzyl bromide (for 9h.
A.

B.


C.

Reagents and conditions: (a) benzyl bromide (for 9a), (2-bromoethyl)benzene (for 9b), 1-bromo-3-phenylpropane (for 9c), 4-nitrobenzyl bromide (for 9d), 2-nitrobenzyl bromide (for 9e), 3-nitrobenzyl bromide (for 9f), 4-cyanobenzyl bromide, (for 9g), 4-methoxybenzyl bromide (for 9h), ethyl bromoacetate (for 11a), tert-butyl 2-chloroacetate (for 11b), K2CO3, DMF, rt, 8−12 h, 42−60%; (b) HNO3, conc. H2SO4, −40 °C rt, 4 h, 41%; (c) LiOH, THF, H2O, 26 (for 27), 11a (for 11c), rt, 8−10 h, 65−87%; (d) acetic anhydride, reflux, 3 h, 84%; (e) 4-methoxylaniline (for 10a), 3-aminobenzoic acid (for 10b), 4-isopropylaniline (for 10c), 4-aminobiphenyl (for 10d), AcOH, reflux, 6−8 h, 24−35%; (f) aniline (for 11d), morpholine (for 11e), N-methyl piperazine (for 11f), EDC, HBTU, triethylamine, DCM, rt, 6 h, 33−40%
1.1.23 Synthesis of C4-Substituted Analogues of the Thienopyrimidinone Core
As depicted in Scheme , compound 12a was prepared from the reaction of 6a with phosphorus oxychloride. The C4- chloro group was then nucleophilically displaced by aniline or morpholine under microwave conditions to obtain 12b or 12c. Target compound 13a with C2- and N3-disubstitution was prepared from the reaction of 9a and 4-fluorobenzaldehyde. The 2,4-disubstituted compound 13b was obtained by treating 8f with phosphorus oxychloride, which upon nucleophilic substitution by morpholine led to 13c as shown in below.

Reagents and conditions: (a) phosphorus oxychloride, reflux, 18 h, 40%, (b) aniline (for 12b), morpholine (for 12c), DMF, MW, 150 °C, 50−70 min, 35−45%