Tetrahydro- and dihydroquinazolinones
a technology of tetrahydroquinazoline and dihydroquinazoline, which is applied in the direction of plant growth regulators, enzymes, biocide, etc., can solve the problems of inseparable mixtures, and achieve the effects of not diminishing the mitotic rate, reducing the expression of vegf, and contributing to tumour growth
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example 2
[0274]When a mixture of methyl 2-chloro-2-cyclopropylidineacetate (see formula 1) and two equivalents of benzamidine hydrochloride (see formula 2a) is stirred in dioxane in the presence of 4 equivalents of triethylamine for 48 h at room temperature, 3-phenyl-2,4-diazabicyclo[4.2.0]octa-1(6),2-diene-5-one (see formula 3a) is isolated in 83% yield. Similarly, under the same conditions the corresponding pyrimidinones are obtained in good yields (68-0.82%). Less reactive S-methylisothiourea hemisulphate (see formula 2g) produces the corresponding pyrimidinone (see formula 3g) at 50° C. in 74% yield (Scheme 2).
Scheme 2: Michael addition of amidines to compounds of formula 1 for synthesis of cyclobuteneannelated pyrimidinones (see formula 3).AmidinesR (= R1 according to the invention)ProductYield (%)2aPh3a83 2bp-ClC6H43b78 2co-BrC6H43c76 2do-FC6H43d82 2ep-(C6H5CH2O)C6H43e68 2fo-PhC6H43f80 2gSMe3g74**Reaction was carried out at 50°C.,
[0275]These cyclobutene-annelated pyrimidinones (see for...
example 3
[0278]Since the tetrahydroquinazoline ring has been formed, the next issue is to remove the sulfonyl group. Although there are several methods known for this purpose, the method involving Na / Hg amalgam in the presence of Na2HPO4 (B. M. Trost, H. C. Arndt, P. E. Strege, T. R. Verhoeven, Tett. Lett. 1976, 39, 3477-3478) has been most widely used. However, when the compound of formula 5a as well as its O-TMS protected or N-Boc protected equivalent is reacted with Na / Hg and Na2HPO4 (4 equiv. each) in MeOH, only (deprotected) starting material is isolated without any reductive elimination. By changing the reagents to Na-sand / EtOH (Y. Masaki, Y. Serizawa, K. Nagata, K. Kaji, Chemistry Lett. 1984, 2105-2108; D. F. Taber, Q. Jiang, B. Chen, W, Zhang, C. L. Campbell, J. Org. Chem., 2002, 67, 4821-4827) only substantial amount of benzaldehyde is isolated. This problem is solved by using a two-step procedure: basic elimination of the PhSO2-group followed by Pd-catalysed hydrogenation of C═C bo...
example 4
[0279]The presence of a strong electron acceptor at C-6—phenyl sulfonyl group—makes possible further derivatization at this centre, namely alkylation of the corresponding anion generated from an O- or N-protected precursor. Surprisingly, when a THF solution of N-Boc protected compound (the compound of formula 5a-Boc) is subjected to nBuLi followed by treatment with MeI, no alkylation at C-6 is observed, and only N-Boc-2-phenyl-8-methyl-6-phenylsulfonyltetrahydroquinazolin-one (see formula 8) is isolated instead. Changing the base from nBuLi to either LDA or NaHMDS gives the same product in lower yield (Scheme 6).
Scheme 6: Alkylation at C-8 of N-Boc-protected compound of formula 5a.Compound 8EntryReaction conditionsYield (%)1nBuLi, −78° C. → 25° C., THF, 2 h282LDA, −78° C. → 25° C., THF, 2 h193NaHMDS, −78° C. → 25° C., THF, 3 h14
[0280]However, substitution at C-6 position can be achieved by changing the protecting group. Thus, when O-TMS protected compound (see formula 5a-TMS) is sub...
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