Straightforward synthesis of pyrimido[4,5-e][1,4]diazepines via 6-aminopyrimidin-5-carbaldehydes

Jose M. de la Torre; Manuel Nogueras; Justo Cobo

doi:10.1016/j.arabjc.2016.07.012

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Original article

12 (

); 4579-4595

doi:

10.1016/j.arabjc.2016.07.012

Straightforward synthesis of pyrimido[4,5-e][1,4]diazepines via 6-aminopyrimidin-5-carbaldehydes

Jose M. de la Torre, Manuel Nogueras, Justo Cobo^⁎

Departamento de Química Inorgánica y Orgánica, Facultad de Ciencias Experimentales, Campus las Lagunillas, Universidad de Jaén, E-23071 Jaén, Spain

⁎Corresponding author. Fax: +34 953211876. jcobo@ujaen.es (Justo Cobo)

Received: 2016-5-24, Accepted: 2016-7-23, Published: 2016-12-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

A high-throughput method to obtain several pyrimido[4,5-e][1,4]diazepines is described by a two-step acylation/cyclization sequence from key intermediates 6-amino-5-(amino)methylpyrimidines, which were prepared from the precursor 6-aminopyrimidin-5-carbaldehydes. The acylation is accomplished with haloacyl halides to render ((4-aminopyrimidin-5-yl)-methyl)-2-haloamide intermediates. The cyclization step worked successfully, but depending on the substituents, competitive reactions versus the cyclization to pyrimido[4,5-e][1,4]diazepines were found to afford indolinones or acrylamides which were formed via alternative cyclization or elimination respectively. The pyrimido[4,5-e][1,4]diazepines were derivatized by alkylation at N(9), and a two-step one-pot procedure, cyclization/alkylation, from the ((pyrimidin-5-yl)-methyl)-2-haloamide intermediates was optimized to the formation of these N(9)-substituted derivatives.

Keywords

4(6)-Aminopyrimidines

Diazepines

Fused heterocycles

Acylation

Cyclization

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1 Introduction

The benzodiazepine system has been described as a privileged structure due to the ability of compounds with such frame to link to multiple biological receptors (Costantino and Barlocco, 2006; Horton et al., 2003). On the other hand, pyrimidine-fused compounds are of interest in medicinal chemistry and chemical biology due to their wide range of biological activities (Sagar et al., 2015; Dinakaran et al., 2012; Wang et al., 2004; McGuigan et al., 2004; Gangjee et al., 2004 ). The fusion of pyrimidine and diazepine rings will result in purine/pteridine mimicking bicyclic scaffold, which has attracted the chemists’ attention for many years (Freidinger et al., 1992; Di Braccio et al., 2001; Schaefer et al., 1981; Kobayashi, 1974, 1975 ). Pyrimidodiazepines have been reported for a wide range of biological applications (see Fig. 1) such as in the treatment of different disorders via inhibition of phenylalanine hydroxylase (Pike et al., 1986), Aurora A kinase (Kanhed et al., 2015), tyrosine kinase (A) (Gracias et al., 2008) or EGFR (Xu et al., 2012), having immunosuppressive activity (B) (Dlugosz, 1998) with properties such as anticonvulsant (Kim and Santilli, 1969; Murthy and Knaus, 1999) antipyretics, (Juby and Hudyma, 1974) or gastric secretion inhibitors (C) (Dlugosz, 1990), or prepared as second generation of ß-secretase modulators (AZ1136) (Borgegard et al., 2012).

Examples of bioactive pyrimidodiazepines.

The most common pyrimidodiazepine system described in the literature is the pyrimido[4,5-b][1,4]diazepine such as A (see Fig. 1). Regarding these derivatives, we have already reported the synthesis of diverse compounds and tested their biological applications. Most of them have been prepared from 4,5-diaminopyrimidines by reaction with biselectrophilic reagents such as chalcones (Insuasty et al., 2008, 2010, 2014 ) or from 6-methoxy-5-nitrosopyrimidines in a three step sequential methodology: aromatic nucleophilic substitution/reduction/cyclocondensation (Marchal et al., 2002, 2010; Cobo et al., 2008 ).

As we are interested in exploring the non-common pyrimido[4,5-e][1,4]diazepine system as an interesting biological target scaffold like those shown in Fig. 1, we describe the synthesis of a novel series of those derivatives focused on the 6-aminopyrimidine-5-carbaldehydes as key precursors in a high-throughput methodology, as an alternative to the preparation of pyrimido[4,5-e][1,4]diazepin-7-ones reported by a sequence of five steps starting from 4,6-dichloropyrimidin-5-carbaldehyde using α-aminoesters and primary amines (Xiang et al., 2010). Our approach consists of four-step process initially starting from the corresponding 6-aminopyrimidines, that includes a formylation reaction followed by condensation with amines rendering the intermediates 6-amino-5-(amino)methylpyrimidines and finally an acylation/cyclization sequence in reaction with haloacyl derivatives. This is an extension of the previous work reporting the synthesis of 6-amino-5-(amino)methyl pyrimidines by reductive amination from their corresponding pyrimidin-5-carbaldehyde derivatives that were used as key intermediates to pyrimidopyrimidine derivatives (de la Torre et al., 2014).

2 Results and discussion

Our first approach, to reach the target pyrimidodiazepines, was by the reaction of the precursor 6-aminopyrimidin-5-carbaldehydes 1a,b with aminoesters. Likewise to the building of the diazepine ring from 2-aminobenzaldehydes, we tried different conditions and/or reduction agents in order to perform condensation or reductive amination reactions in compounds 1. A failure of those reactions could be explained in regard to the lesser reactivity of both 6-amino and aldehyde in the pyrimidine system than in benzene. Next, we carried out the reaction of the 6-amino-(5-aminomethyl)pyrimidines 2a–f (de la Torre et al., 2014) with α- and β-bromoesters in a polar solvent (DMF) and using a base (potassium carbonate) as promoter. It afforded the desired intermediates 3 which were isolated nearly quantitative yields (see Scheme 1). Unfortunately, all the attempts of cyclization of intermediates 3 to pyrimidodiazepines did not work. Hence we tried acid (HOAc, PTSA, TFA) and base (NaOH, NaOEt, K₂CO₃) catalysis, microwave irradiation and fusion which led to the decomposition of the starting material observed in most of these reactions.

Synthesis of the (4-aminopyrimidin-5-yl)methylamino ester intermediates 3.

Thereafter, we decided to increase the nucleophilicity of the 6-amino group by formation of the corresponding silyl or phosphorane intermediates, but the desired cyclized derivatives were not formed. The absence of the corresponding ester (or amide if cyclized) moiety in the spectroscopic data was not observed. Instead of that, the analysis of the NMR and MS spectra indicated the formation of the methylene bispyrimidin-5-yl derivatives 4 (see Scheme 2 and experimental for interpretation). It seems that secondary amino linked to 5-methylenepyrimidine is also attacked by the silyl or phosphine reagents, leading to the formation of cationic intermediates that caused the cleavage of a bond around methylene residue, via α or β cleavage with respect to the amino group resembling elimination/addition found in the equilibria of asymmetric aminals as compounds 3 can be considered like phenylogous aminals. In the case of 4a, in addition to the formation of the methylene bispyrimidin-5-yl derivative, a demethylation and cyclization take place in the formation of this compound.

Results arisen from attempts of cyclization via compounds 3 to yield 5,5′-methylenebispyrimidines (4).

Because of the above unfruitful results, we used the classical haloacyl halides as biselectrophilic reagent to accomplish our target, which reacted with diaminopyrimidine intermediates 2 to afford the corresponding amide intermediates 5 in yields >99%, in only 5 min at 0 °C using THF as solvent in the presence of triethylamine (see Scheme 3 and Fig. S1 in supporting information). When the reaction was carried out at room temperature or with some excess of the 2-haloacyl halide the corresponding bisamide derivatives 6 were obtained. In addition to the usual spectroscopic characterization of compounds 5, where the new signals corresponding to the haloacyl moiety are observed (see Tables S3 and S4 in supporting information for a complete assignation of NMR spectra), the structure of derivative 5i was solved by single crystal X-ray diffraction (see Fig. 2), in which the intramolecular hydrogen bond between 4-amino group and the oxygen of amide residue is shown.

Synthesis of the halo-amide derivatives 5 used as intermediates.

ORTEP drawing of the structure 5i with 50% probability ellipsoids.

It has to be noted that in the case of the reaction of 2a (R¹ = phenyl) with 2-chloro-2,2-diphenylacetyl chloride, we have found that instead of the expected chloroacetamide 5a′, an intramolecular Friedel-Craft cyclization took place to afford hybrid compound 7 (Scheme 4). This is explained by means of the formation of the carbocation at α position of carbonyl group, species I, which is stabilized by the two attached phenyl groups, which is then attacked by the activated phenyl ring linked to nitrogen.

Synthesis of the indoline derivative (7).

This compound 7 is characterized by the observation in its ¹H NMR spectrum of the typical coupling system found in ortho disubstituted benzene moieties (see experimental for signal interpretation), and in its ¹³C NMR spectrum the downshielded displacement of the signal C⚌O in the five member ring in this new indolinone residue, at 179. 8 ppm, in respect of the open related compounds 5g and 5t (in this R¹ = benzyl) at 171.5 ppm can be observed. A similar effect is found in the corresponding IR signal for the C⚌O group, with an increase of 15–20 cm⁻¹ with respect to the related compounds 5g and 5t, in agreement to the formation of the new five member ring.

In order to build the diazepinic nucleus, compounds 5 were heated at 80-90 °C in DMF with potassium carbonate as promoter, to afford the desired pyrimidodiazepines 8 in good to excellent yields (see table in Scheme 5). When sodium hydride was used as a promoter at room temperature the reaction is 5–60 times quicker with simpler work-up and without need of chromatographic purification.

Cyclization of intermediates 5 to pyrimidin[4,5-e][1,4]diazepines (8). Yields under conditions i: K2CO3, DMF, 90 °C; ii: NaH, DMF, room temperature.

Compounds 8 were fully characterized by the standard spectroscopic methods (see Tables S5 and S6 in supporting information for full assignation of NMR spectra). The cyclization was confirmed by ¹H NMR due to the coupling of hydrogen at N(9) with H-8 and if R² ≠ H the two hydrogens at C(5) became diastereotopic and also because in some cases HMBC correlation between hydrogen at N(9) and C(8) was observed. In addition, the structure of compound 8u was unambiguously confirmed by single crystal X-ray diffraction, which is displayed in Fig. 3.

ORTEP drawing of the structure 8u with 50% probability ellipsoids.

We have to note that in some derivatives where R² = Ph; R³ = H (5c, 5p, 5s, 5y) or R² = R³ = Ph (5g, 5m, 5t) the cyclization merges with decomposition which could explain the problems with reproducibility observed for those reactions. As depicted in Scheme 4, a stabilized carbocation can be formed favorably in polar solvent (DMF) such as the one used in the reaction can evolve in many different ways, such as the one leading to 7 because of the low nucleophilicity of 6-amino group.

In the case of steric hindered derivative 5j, the treatment with the base gave rise to elimination rather than intramolecular nucleophilic substitution and therefore affording acrylamide derivative 9a (see Scheme 6). The acrylamide residue is observed in the ¹H NMR spectra appearing the two geminal alkenyl H as broad singlets in the ¹H NMR at 5.07 and 5.12 ppm, and the two new signal for the alkenyl in the ¹³C NMR at 115.4 (CH₂) and 137.5 (see Tables S7 and S8 in supporting information for a full interpretation of NMR spectra). However this compound 9a, in turn, could be a good precursor to pyrimidodiazocine system. Unfortunately the attempts to perform such cyclization were unsuccessful. A similar behaviour was observed for R² alkyl substituents that could explain the low yield for 8h (R² = Et), or the lack of reproducibility of some reactions when running with NaH.

Elimination reaction in the steric hindered derivative 5j.

Considering the good results afforded for the preparation of pyrimidodiazepines 8, we have also postulated the preparation of pyrimidodiazocine system in a similar fashion. Some diaminopyrimidine compounds type 2 were treated with β-haloacyl halides, as shown in Scheme 7, resulting in the corresponding amides 10a–c. In addition to the spectroscopic characterization, we have also performed a single crystal X-ray diffraction analysis on compound 10a, structure of which is shown in Fig. 4. Accordingly, these amides 10a–c were treated with base for the corresponding cyclization, but instead they accomplished formation again of acrylamide derivatives type 9b,c, showing similar spectroscopic characteristics as previously described for 9a. This elimination reaction is favored by the acid character of hydrogen at β position with respect to the halogen in the basic media.

Reaction pathway to the acrylamide derivatives from compounds 10.

ORTEP drawing of the structure 10a with 50% probability ellipsoids.

Further transformations of these pyrimido[4,5-e]diazepine 8 can be done in order to increase the diversity, such as N₍₉₎ alkylation, aminolysis through methylthio group after oxidation, debenzylation. Here we present the methylation of N₍₉₎ carried out using methyl iodide as alkylating agent in DMF and in the presence of NaH as base. A total of six pyrimido[4,5-e]diazepines 11 have been prepared (see Scheme 8) and completely characterized (Tables S9 and S10 in supporting information for a full interpretation of NMR spectra), including solution of crystalline structure of 11f by single crystal X-ray diffraction (Fig. 5).

Methylation at N(9) of some pyrimido[4,5-e][1,4]diazepines.

ORTEP drawing of the structure 11f with 50% probability ellipsoids.

Because both the solvent and the base used for both cyclization and methylation processes are the same, the corresponding one-pot tandem two-step reaction from the amide intermediates 5 towards the final methylated derivatives 11a–f was tried and resulted successfully in similar global yield to slightly higher than doing the two reactions.

Due to the attractive biological potential of intermediates 5 and pyrimidodiazepine 8 preliminary biological assays have been carried out, including antimicrobial with pathogenic fungi and bacteria, antiviral or antitumoral activities, but up to this moment we have not obtained any positive results.

3 Conclusions

We have developed a simple and straight-forward three-step procedure to obtain several pyrimido[4,5-e][1,4]diazepines starting from 6-aminopyrimidin-5-carbaldehydes, consisting of a reductive amination to intermediates 6-amino-5-(amino)methylpyrimidines and an acylation/cyclization sequence in reaction with haloacyl derivatives. In the reaction to reach cyclized derivatives we have also found the hybrid indolinone or acrylamide derivatives formed by competitive routes, that is, an alternative cyclization or elimination respectively, opening a synthetic way to obtain those interesting hybrids. Derivatization of these pyrimido[4,5-e][1,4]diazepines is easily accomplished through the N(9) position without need of isolation from cyclization step.

4 Experimental

Melting points were determined on a Barstead Electrothermal 9100 melting point apparatus and are uncorrected. IR spectra were recorded in KBr discs on Bruker TENSOR 27 spectrophotometer from “Centro de Instrumentación Científico-Técnica (CICT) at Universidad de Jaén”. ¹H and ¹³C NMR spectra were recorded on a Bruker Avance 400 spectrometer (CICT) operating at 400 MHz and 100 MHz respectively, using CDCl₃ and [D₆]DMSO as solvents and tetramethylsilane as internal standard; the carbon type described p (primary), s (secondary), t (tertiary) and q (quaternary) at ¹³C NMR was deduced from DEPT-135 and 2D-NMR experiments. Mass spectra were run on a SHIMADZU-GCMS 2010-DI-2010 spectrometer (equipped with a direct inlet probe) operating at 70 eV. High resolution Mass spectra were run on a Waters Micromass AutoSpec-Ultima spectrometer (equipped with a direct inlet probe) operating at 70 eV. Silicagel aluminium plates (Merck 60 F₂₅₄) were used for analytical TLC. Silicagel 60 (35–70 μm) purchased from Merck was used for flash column chromatography. The microwave assisted reactions were carried out in a focused mono-mode microwave oven apparatus (“Discover” by CEM Corporation) using 10 ml glass sealed tubes and working at standard mode by controlling the target temperature. The starting amines and haloacyl derivatives were purchased from Aldrich, Fluka and Acros (analytical reagent grades) and were used without further purification.

4.1

4.1 Preparation of intermediates (4-aminopyrimidin-5-yl)methylamino esters

To a solution of 6-amino-5-((substituted-amino)methyl)pyrimidin-4(3H)-one 2 (1 mmol) in DMF (2 mL), a suspension of potassium carbonate (0.2 g, 1.5 mmol) in water (2 mL) is added and stirred for 10 min and then the corresponding haloester (2 mmol) is added drop-wise to the above white paste. The reaction mixture was stirred for the appropriate time until the compound 2 was not detected by TLC (eluent DCM/MeOH, 9:1). When reaction finished 10 ml of water was poured into the solution and a colourless solid was formed, which was filtered and washed with water.

4.1.1

4.1.1 Ethyl-2-{[(4-amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl](benzyl)amino}acetate (3a)

From 0.274 g of 6-amino-5-((benzylamino)methyl)-2-methoxy-3-methylpyrimidin-4(3H)-one 2b and 0.3 ml of ethyl bromoacetate. Reaction time: 3 h. Yield: 89%. M.p. 108 – 9 °C. ¹H NMR (DMSO-d₆). δ_ppm: 1.15 (t, 7.0 Hz, 3H); 3.13 (s, 2H); 3.16 (s, 3H); 3.43 (s, 2H); 3.46 (s, 2H); 3.88 (s, 3H); 4.06 (q, 7.0 Hz, 2H); 6.74 (bs, 2H); 7.20–7.29 (m, 5H). ¹³C NMR (DMSO-d₆) δ_ppm: 13.9 p; 27.0 p; 48.8 s; 54.0 s; 55.0 p; 56.1 s; 60.3 s; 85.9 q; 126.85 t; 128.1 t; 128.6 t; 138.9 q; 155.4 q; 160.4 q; 162.1 q; 171.8 q. IR (KBr) ν (cm⁻¹): 3398 (s); 3331 (m); 3228 (m); 3060 (w); 3028 (w); 2954 (w); 2845 (w); 1739 (s); 1634 (s, b); 1544 (s, b); 1487 (m). MS (70 eV) m/z (%): 360 (M⁺, 0.3), 269 (53); 192 (48); 168 (100); 120 (28); 106 (14); 91 (85). HR MS: calc for C₁₈H₂₄N₄O₄ 360.1798; found 360.1802.

4.1.2

4.1.2 Ethyl-3-{[(4-amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl](benzyl)amino}propanoate (3b)

From 0.274 g of 2b and 0.3 ml of ethyl bromopropionate. Reaction time: 16 h. Yield: 78%. M.p. 125 – 7 °C. ¹H NMR (DMSO-d₆). δ_ppm: 1.10 (t, 7.0 Hz, 3H); 2.45 (t, 6.8 Hz, 2H); 2.59 (t, 6.8 Hz, 2H); 3.16 (s, 3H); 3.37 (s, 2H); 3.43 (s, 2H); 3.87 (s, 3H); 3.96 (q, 7.0 Hz, 2H); 6.27 (bs, 2H); 7.21–7.30 (m, 5H). ¹H NMR (CDCl₃). δ_ppm: 1.16 (t, 7.0 Hz, 3H); 2.49 (t, 6.8 Hz, 2H); 2.78 (t, 6.8 Hz, 2H); 3.31 (s, 3H); 3.52 (s, 2H); 3.56 (s, 2H); 3.92 (s, 3H); 4.02 (q, 7.0 Hz, 2H); 5.51 (bs, 2H); 7.21–7.30 (m, 5H). ¹³C NMR (DMSO-d₆) δ_ppm: 13.9 p; 27.0 p; 31.6 s; 48.2 s; 48.8 s; 55.0 p; 56.9 s; 59.8 s; 86.1 q; 126.7 t; 128.0 t; 128.8 t; 139.2 q; 155.3 q; 160.2 q; 162.0 q; 172.2 q. ¹³C NMR (CDCl₃) δ_ppm: 14.0 p; 27.5 p; 32.6 s; 48.8 s; 49.6 s; 55.1 p; 57.9 s; 60.35 s; 88.3 q; 126.9 t; 128.2 t; 129.1 t; 139.4 q; 155.7 q; 160.3 q; 163.25 q; 172.9 q. IR (KBr) ν (cm⁻¹): 3448 (m); 3311 (m); 3199 (w); 3027 (w); 2977 (w); 2835 (w); 1727 (s); 1640 (s); 1621 (s); 1548 (s). MS (70 eV) m/z (%): 283 (57); 206 (100); 168 (72); 120 (25); 106 (41); 91 (95). HR MS: calc for C₁₉H₂₆N₄O₄ 374.1954; found 374.1955.

4.1.3

4.1.3 Ethyl-2-{[(4-amino-1-methyl-2-methylthio-6-oxo-1,6-dihydropyrimidin-5-yl)methyl](benzyl)amino}acetate (3c)

From 0.290 g of 6-amino-5-((benzylamino)methyl)-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (2e) and 0.3 ml of ethyl bromoacetate. Reaction time: 4 h. Yield: 99%. M.p. 109 – 10 °C. ¹H NMR (DMSO-d₆). δ_ppm: 1.17 (t, 7.0 Hz, 3H); 2.52 (s, 3H); 3.15 (s, 2H); 3.30 (s, 3H); 3.47 (s, 2H); 3.49 (s, 2H); 4.08 (q, 7.0 Hz, 2H); 6.81 (bs, 2H); 7.22–7.34 (m, 5H). ¹³C NMR (DMSO-d₆). δ_ppm: 13.9 p; 14.1 p; 29.4 p; 48.6 s; 54.0 s; 56.2 s; 60.3 s; 87.9 q; 126.9 t; 128.2 t; 128.6 t; 138.8 q; 159.7 q; 160.3 q; 161.6 q; 171.8 q. IR (KBr) ν (cm⁻¹): 3440 (m); 3331 (m); 2983 (w); 2928 (w); 1734 (m); 1607 (s); 1530 (s); 1454 (m). MS (70 eV) m/z (%): 285 (63); 192 (68); 184 (100); 120 (21); 106 (11); 91 (78). HR MS: calc for C₁₈H₂₄N₄O₃S 376.1569; found 376.1564.

4.2

4.2 Cyclization attempts of derivatives 3. Synthesis of methylene bis-pyrimidines (4)

4.2.1

4.2.1 1,9-Dimethyl-4,6-bis((triphenyl-λ⁵-phosphanylidene)amino)-5,9-dihydro-2H-pyrano[2,3-d:6,5-d’]dipyrimidine-2,8(1H)dione (4a)

CCl₄ (0.3 mL), NEt₃ (2 mmol) and PPh₃ (2 mmol) were added in such order to a suspension of 3a (1 mmol) in 20 ml of CH₃CN. The resulting mixture was heated to reflux for 19 h and after that filtered hot. The product obtained is a colourless solid. Yield: 47%. ¹H NMR (CDCl₃). δ_ppm: 3.39 (s, 6H, 2 N-CH₃); 3.88 (s, 2H, C(5)H₂); 7.44–7.52 (m, 12H, H_o of six Ph); 7.52–7.60 (m, 6H, H_m of six Ph); 7.90–7.95 (m, 12H, H_p of six Ph). ¹³C NMR (CDCl₃) δ_ppm: 20.1 s (C5); 28.7 p (N(1,9)-CH₃); 89.9 q (d, 25.5 Hz, C4a, C5a); 128.4 q (d, 99.8 Hz, C_i of six Ph); 128.5 t (d, 11.7 Hz, C_o of six Ph); 132.1 t (C_p of six Ph); 133.4 t (d, 2.9 Hz, C_m of six Ph); 151.9 q (C2, C8); 155.1 q (C9a, C10a); 169.9 q (d, 6.6 Hz, C4, C6). MS (70 eV) m/z (%): 796 (M⁺, 3); 534 (10); 477 (6); 400 (11); 301 (21); 277 (100); 262 (42); 199 (7); 152 (20); 108 (22); 77 (29). HR MS: calc for C₄₇H₃₈N₆O₃P₂ 796.2481; found 796.2493.

4.2.2

4.2.2 5,5′-Methylenebis[2-methoxy-3-methyl-6-(trimethylsilylamino)pyrimidin-4(3H)-one] (4b)

Hexamethyldisilazane (HDMS) (4.5 mmol) and anhydrous (NH₄)₂SO₄ (0.15 mmol) were added to a suspension of 3b (1 mmol) in 1 ml of THF. The resulting mixture is irradiated with MW and continuous stirring during 25 min at 150 °C (max. power 300 W). Then, 10 ml of MeOH is poured over the reaction mixture and the solid (3b) is filtered. The solution is dried and the product is isolated by column chromatography (silicagel, Hexane/AcOEt, 7:3). Yield: 43%. M.p. 228 – 9 °C. ¹H NMR (CDCl₃). δ_ppm: 0.27 (s, 18H, 2 Si(CH₃)₃); 3.32 (s, 6H, 2 N-CH₃); 3.51 (s, 2H, CH₂); 3.91 (s, 6H, OCH₃); 7.19 (bs, 2H, two 6-NHSi). ¹³C NMR (CDCl₃) δ_ppm: 0.4 p (Si-CH₃); 19.2 s (CH₂); 27.7 p (N-CH₃); 55.15 p (OCH₃); 93.9 q (C5); 154.1 q (C2); 162.1 q (C6); 164.3 q (C4). MS (70 eV) m/z (%): 466 (M⁺, 9); 451 (8); 394 (11); 305 (8); 240 (11); 168 (10); 73 (100). HR MS: calc for C₁₉H₃₄N₆O₄Si₂ 466.2180; found 466.2179.

4.2.3

4.2.3 5,5′-Methylenebis[6-amino-3-methyl-2-(methylthio)pyrimidin-4(3H)-one] (4c)

From 0.390 g of 3c (1 mmol), 1.0 ml de hexamethyldisilazane (HMDS) (4.5 mmol) and 0.02 g of (NH₄)₂SO₄ (0.15 mmol) in 1 ml of THF. The mixture is irradiated with microwaves during 25 min. at 150 °C (power max. 300 W). Then, 10 ml of MeOH is added and stirred during 10 h. The product is filtered and the solid is washed with MeOH. Yield: 68%. M.p. > 300 °C. ¹H NMR (CDCl₃). δ_ppm: 2.51 (s, 6H, 2 SCH₃); 3.36 (s, 6H, 2 N-CH₃); 3.36 (s, 2H, CH₂); 6.72 (bs, 4H, two 6-NH₂). ¹³C NMR (CDCl₃) δ_ppm: 13.5 p (S-CH₃); 18.1 s (CH₂); 29.3 p (N—CH₃); 91.2 q (C5); 158.6 q (C2);159.0 q (C6); 162.7 q (C4). IR (KBr) ν (cm⁻¹): 3328 (m, b); 3176 (m, b); 2924 (w, b); 1722 (w); 1633 (s, b); 1511 (s); 1412 (s, b); 1101 (s, b). MS (70 eV) m/z (%): 354 (M⁺, 50); 339 (13); 290 (13); 249 (28); 184 (28); 88 (100). HR MS: calc for C₁₃H₁₈N₆O₂S₂ 354.0933; found 354.0935.

4.3

4.3 Preparation of intermediates (6-aminopyrimidin-5-yl)methyl(substituted)amino acyl halides (5, 6 & 7)

Anhydrous triethylamine (0.14 ml) was added to a solution of 6-amino-5-((substituted-amino)methyl)pyrimidin-4(3H)-one 2 (1 mmol) in 10 ml of THF anhydrous and the mixture was cooled down to 0 °C. Then the corresponding haloacyl halide was added drop-wise with continuous stirring for 5 min. The white solid in suspension (NEt₃·HCl) was removed by filtration and washed with cold THF. The solvent was removed under reduced pressure and the solid residue was recrystallized from a mixture ethanol – hexane (1:1), to give yields > 99% for derivatives 5 and 6.

4.3.1

4.3.1 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimdin-5-yl)methyl]-2-chloro-N-phenylacetamide (5a)

From 0.260 g of 6-amino-2-methoxy-3-methyl-5-((phenylamino)methyl)pyrimidin-4(3H)-one (2a) and 0.08 ml of chloroacetyl chloride. The white solid filtered contains a small amount of the product, so the solid is digested in hot THF and the solid in suspension filtered hot. M.p. 214 – 6 °C. ¹H NMR (CDCl₃). δ_ppm: 3.15 (s, 3H); 3.83 (s, 2H); 3.93 (s, 3H); 4.85 (s, 2H); 5.40–6.25 (bs, 2H); 7.15–7.17 (m, 2H); 7.36–7.39 (m, 3H). ¹³C NMR (CDCl₃) δ_ppm: 27.5 p; 42.0 s; 44.6 s; 55.2 p; 87.3 q; 127.8 t; 128.9 t; 129.7 t; 140.4 q; 156.0 q; 160.1 q; 163.2 q; 167.7 q. IR (KBr) ν (cm⁻¹): 3391 (m); 3322 (m); 3211 (m); 2950 (w); 1658 (s); 1630 (s); 1534 (s); 1408 (m). MS (70 eV) m/z (%): 336 (M⁺, 1); 259 (12); 168 (100); 111 (18); 77 (4). HR MS: calc for C₁₅H₁₇N₄O₃Cl 336.0989; found 336.0992.

4.3.2

4.3.2 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimdin-5-yl)methyl]-2-chloro-N-phenylpropanamide (5b)

From 0.260 g of 2a and 0.100 ml of 2-chloropropionyl chloride. M.p. 178 – 9 °C. ¹H NMR (CDCl₃). δ_ppm: 1.56 (d, 6.6 Hz, 3H); 3.14 (s, 3H); 3.94 (s, 3H); 4.24 (q, 6.6 Hz, 1H); 4.80 (d, 14.5 Hz, 1H); 4.91 (d, 14.5 Hz, 1H); 5.40–6.20 (bs, 2H); 7.17 (bs, 2H); 7.36–4.40 (m, 3H). ¹³C NMR (CDCl₃) δ_ppm: 21.4 p; 27.5 p; 44.3 s; 50.4 t; 55.2 p; 87.1 q; 127.9 t; 128.7 t; 129.6 t; 140.4 q; 156.0q; 160.1 q; 163.1 q; 171.0 q. IR (KBr) ν (cm⁻¹): 3385 (m, b); 3327 (m); 3214 (m); 2941 (w); 1652 (s, b); 1597 (m); 1510 (s); 1411(s); 1225 (m). MS (70 eV) m/z (%): 350 (M⁺, 1%); 259 (14); 168 (100); 111 (14). HR MS: calc for C₁₆H₁₉N₄O₃Cl 350.1146; found 350.1148.

4.3.3

4.3.3 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimdin-5-yl)methyl]-2-chloro-N,2-diphenylacetamide (5c)

From 0.260 g of 2a and 0.161 ml of 2-chloro-2-phenylacetyl chloride. M.p. 156 – 8 °C. ¹H NMR (CDCl₃). δ_ppm: 3.12 (s, 3H); 3.92 (s, 3H); 4.79 (d, 14.6 Hz, 1H); 4.90 (d, 14.6 Hz, 1H); 5.28 (s, 1H); 5.40–6.25 (bs, 2H); 6.83 (bs, 1H); 7.26–7.31 (m, 7H); 7.37–7.45 (m, 2H). ¹³C NMR (CDCl₃) δ_ppm: 27.5 p; 44.7 s; 55.1 p; 57.1 t; 87.0 q; 127.9 t; 128.1 t; 128.6 t; 129.0 t; 129.5 t; 129.6 t; 136.3 q; 140.3 q; 156.0 q; 160.1 q; 163.1 q; 169.1 q. IR (KBr) ν (cm⁻¹): 3445 (m); 3325 (m); 3222 (m); 3062 (w); 3031 (w); 2964 (w); 1655 (s); 1629 (s, b); 1595 (m); 1551 (s); 1494 (m); 1485 (m). MS (70 eV) m/z (%): 412 (M⁺, 0.4); 259 (15); 168 (100); 111 (11); 89 (2); 72 (3). HR MS: calc for C₂₁H₂₁N₄O₃Cl 412.1302; found 412.1309.

4.3.4

4.3.4 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-chloroacetamide (5d)

From 0.274 g of 6-amino-5-((benzylamino)methyl)-2-methoxy-3-methylpyrimidin-4(3H)-one (2b) and 0.080 ml of chloroacetyl chloride. M.p. 134 – 6 °C. ¹H NMR (CDCl₃). δ_ppm: 3.29 (s, 3H); 3.94 (s, 3H); 4.05 (s, 2H); 4.53 (s, 2H); 4.81 (s, 2H); 5.55–6.36 (bs, 2H); 7.23–7.29 (m, 3H); 7.35 (pt, 7.4 Hz, 2H). ¹³C NMR (CDCl₃) δ_ppm: 27.6 p; 41.6 s; 42.0 s; 51.6 s; 55.3 p; 88.5 q; 126.2 t; 127.6 t; 128.9 t; 136.5 q; 156.0 q; 160.8 q; 164.3 q; 168.6 q. IR (KBr) ν (cm⁻¹): 3329 (m, b); 3189 (m); 2949 (w); 1639 (s, b); 1588 (m); 1556 (s, b); 1482 (m). MS (70 eV) m/z (%): 350 (M⁺, 2); 273 (15); 259 (31); 183 (24); 168 (100); 111 (23); 91 (41). HR MS: calc for C₁₆H₁₉N₄O₃Cl 350.1146; found 350.1148.

4.3.5

4.3.5 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-chloropropanamide (5e)

From 0.274 g of 2b and 0.100 ml of 2-chloropropionyl chloride. M.p. 117 – 20 °C. ¹H NMR (CDCl₃). δ_ppm: 1.58 (d, 6.6 Hz, 3H); 3.29 (s, 3H); 3.94 (s, 3H); 4.43 (d, 14.6 Hz, 1H); 4.51 (q, 6.6 Hz, 1H); 4.65 (d, 14.6 Hz, 1H); 4.81 (d, 17.3 Hz, 1H); 4.88 (d, 17.3 Hz, 1H); 5.57–6.30 (bs, 2H); 7.21–7.37 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 21.1 p; 27.6 p; 41.6 s; 49.6 t; 51.1 s; 55.3 p; 88.3 q; 126.0 t; 127.5 t; 128.9 t; 136.9 q; 156.0 q; 160.9 q; 164.3 q; 171.5 q. IR (KBr) ν (cm⁻¹): 3329 (m, b); 3183 (m); 2958 (w); 1640 (s, b); 1586 (m); 1557 (s); 1541 (s); 1452 (m). MS (70 eV) m/z (%): 364 (M⁺, 3); 273 (62); 183 (21); 168 (100); 154 (4); 111 (14); 91 (16); 57 (8). HR MS: calc for C₁₇H₂₁N₄O₃Cl 364.1302; found 364.1294.

4.3.6

4.3.6 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-chloro-2-phenylacetamide (5f)

From 0.274 g of 2b and 0.161 ml of 2-chloro-2-phenylacetyl chloride. M.p. 147 – 8 °C. ¹H NMR (CDCl₃). δ_ppm: 3.26 (s, 3H); 3.93 (s, 3H); 4.55 (d, 14.7 Hz, 1H); 4.59 (d, 14.7 Hz, 1H); 4.76 (d, 17.4 Hz, 1H); 4.85 (d, 17.4 Hz, 1H); 5.53 (s, 1H); 5.60–6.40 (bs, 2H); 7.21–7.37 (m, 10H). ¹³C NMR (CDCl₃) δ_ppm: 27.6 p; 42.4 s; 51.4 s; 55.3 p; 57.2 t; 88.2 q; 126.0 t; 127.6 t; 128.2 t; 128.8 t; 129.0 t; 129.1 t; 135.9 q; 136.7 q; 156.0 q; 160.8 q; 164.3 q; 169.8 q. IR (KBr) ν (cm⁻¹): 3385 (m, b); 3213 (m); 3030 (w); 2959 (w); 1649 (s, b); 1590 (m); 1542 (s, b); 1488 (m); 1457 (m); 1216 (m). MS (70 eV) m/z (%): 426 (M⁺, 1); 335 (13); 272 (31); 168 (100); 111 (12); 91 (24). HR MS: calc for C₂₂H₂₃N₄O₃Cl 426.1459; found 426.1456.

4.3.7

4.3.7 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-chloro-2,2-diphenylacetamide (5g)

From 0.274 g of 2b and 0.273 ml of 2-chloro-2,2-diphenylacetyl chloride. M.p. 131 – 5 °C. ¹H NMR (CDCl₃). δ_ppm: 3.23 (s, 3H); 3.94 (s, 3H); 4.45 (s, 2H); 4.60 (s, 2H); 5.60-6.30 (bs, 2H); 7.22–7.34 (m, 15H). ¹³C NMR (CDCl₃) δ_ppm: 27.6 p; 41.9 s; 53.2 s; 55.2 p; 75.5 q; 88.6 q; 127.2 t; 127.6 t; 128.0 t; 128.2 t; 128.4 t; 128.6 t; 129.0 t; 129.9 t; 130.6 t; 136.8 q; 141.4 q; 155.9 q; 160.9 q; 164.1 q; 171.5 q. IR (KBr) ν (cm⁻¹): 3386 (m, b); 3312 (m); 3203 (m, b); 3064 (w); 3032 (w); 2954 (w, b); 1719 (m); 1655 (s); 1621 (s, b); 1583 (m); 1540 (f); 1485 (m); 1447 (m); 1411 (m). MS (70 eV) m/z (%): 466 (M-HCl, 10); 453 (8); 347 (56); 333 (40); 272 (27); 194 (100); 165 (76); 91 (60).

4.3.8

4.3.8 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-bromobutanamide (5h)

From 0.274 g of 2b and 0.135 ml of 2-bromobutyryl bromide. M.p. 141 – 3 °C. ¹H NMR (CDCl₃). δ_ppm: 0.83 (t, 7.3 Hz, 3H); 1.90–2.00 (m, 1H); 2.05–2.16 (m, 1H); 3.29 (s, 3H); 3.94 (s, 3H); 4.21 (t, 7.2 Hz, 1H); 4.46 (d, 14.5 Hz, 1H); 4.68–4.73 (m, 2H); 4.89 (d, 17.4 Hz, 1H); 5.60–6.31 (bs, 2H); 7.20–7.28 (m, 3H); 7.34 (pt, 7.4 Hz, 2H). ¹³C NMR (CDCl₃) δ_ppm: 12.1 p; 27.6 p; 28.4 s; 41.7 s; 45.4 t; 51.3 s; 55.3 p; 88.1 q; 126.0 t; 127.4 t; 128.8 t; 137.1 q; 156.0 q; 160.9 q; 164.3 q; 171.3 q. IR (KBr) ν (cm⁻¹): 3336 (s, b); 3179 (s); 2959 (m); 1640 (s, b); 1581 (s); 1557 (s, b); 1483 (s); 1450 (s, b); 1416 (s); 1213 (m). MS (70 eV) m/z (%): 422/424 (M/M + 2, 1/1); 348 (3); 331 (10); 273 (25); 210 (17); 183 (13); 168 (100); 111 (8); 91 (11). HR MS: calc for C₁₈H₂₃N₄O₃Br 422.0954; found 422.0958.

4.3.9

4.3.9 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-bromohexanamide (5i)

From 0.274 g of 2b and 0.167 ml of 2-bromohexanoyl bromide. M.p. 132 – 3 °C. ¹H NMR (CDCl₃). δ_ppm: 0.81 (t, 7.0 Hz, 3H); 1.08–1.25 (m, 4H); 1.89–1.97 (m, 1H); 2.02–2.11 (m, 1H); 3.29 (s, 3H); 3.94 (s, 3H); 4.27 (t, 7.2 Hz, 1H); 4.46 (d, 14.5 Hz, 1H); 4.68–4.73 (m, 2H); 4.89 (d, 17.1 Hz,1H); 5.62–6.42 (sa, 2H); 7.21–7.28 (m, 3H); 7.34 (pt, 7.4 Hz, 2H). ¹³C NMR (CDCl₃) δ_ppm: 13.7 p; 22.0 s; 27.6 p; 29.4 s; 34.6 s; 41.8 s; 43.9 t; 51.3 s; 55.3 p; 88.0 q; 126.0 t; 127.4 t; 128.8 t; 137.2 q; 156.0 q; 160.9 q; 164.3 q; 171.5 q. IR (KBr) ν (cm⁻¹): 3409 (m); 3334 (m); 3218 (m); 2955 (m); 2870 (m); 1657 (s, b); 1624 (s, b); 1592 (s); 1543 (s, b); 1484 (s); 1215 (m). MS (70 eV) m/z (%): 450/452 (M/M + 2, 1/1); 371 (3); 361 (10); 359 (10); 273 (28); 238 (18); 183 (13); 168 (100); 111 (11); 91 (14). HR MS: calc for C₂₀H₂₇N₄O₃Br 450.1267; found 450.1265.

Crystal data for 5i were deposited at CCDC with reference CCDC 1,037,317: Chemical formula C₂₀H₂₇BrN₄O₃, M_r 450.13, triclinic, P-1, 120 K, cell dimensions a, b, c (Å) 8.6720 (8), 8.9471 (6), 13.9607 (17); α, β, γ (°) 78.450 (8), 89.372 (7), 74.219 (8). V (Å³) 1020.18 (17), Z = 2, F(000) = 468, D_x (Mg m⁻³) = 1.469, Mo Kα, μ (mm⁻¹) = 2.043, Crystal size (mm) = 0.37 × 0.28 × 0.27. Data collection: KappaCCD Diffractometer, Monochromator graphite, CCD rotation images, thick slices φ & θ scans, absorption correction SADABS 2.10, Tmin, Tmax 0.5185, 0.6084 No. of measured, independent and observed [I > 2σ(I)] reflections 35,442, 4676, 3855, Rint = 0.044, θ values (°): θmax = 27.5, θmin = 2.92; Range h = −11 → 11, k = −11 → 11, l = −18 → 18, Refinement on F2:R[F2 > 2σ(F2)]=0.036, wR(F2)=0.072, S = 1.06. No. of reflections 4676, No. of parameters 256, No. of restraints 0. Weighting scheme: w = 1/σ²(F_o²) + (0.0263P)² + 1.0085P where P = (F_o² + 2F_c²)/3. (Δ/σ) < 0.001, Δρ_max, Δρ_min (e Å⁻³) 0.39, −0.44.

4.3.10

4.3.10 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-bromo-2-methylpropanamide (5j)

From 0.274 g of 2b and 0.126 ml of 2-bromoisobutyryl bromide. M.p. 159 °C. ¹H NMR (CDCl₃). δ_ppm: 1.94 (s, 6H); 3.25 (s, 3H); 3.92 (s, 3H); 4.41 (s, 2H); 5.23 (s, 2H); 5.53–6.33 (bs, 2H); 7.21–7.27 (m, 3H); 7.33 (pt, 7.4 Hz, 2H). ¹³C NMR (CDCl₃) δ_ppm: 27.6 p; 33.1 p; 42.4 s; 52.9 s; 55.2 p; 57.1 q; 89.1 q; 126.5 t; 126.9 t; 128.5 t; 137.2 q; 155.8 q; 160.9 q; 164.3 q; 172.3 q. IR (KBr) ν (cm⁻¹): 3353 (m); 3319 (m); 3182 (m); 3007 (w); 2933 (w); 1643 (s, b); 1616 (s); 1552 (s, b); 1452 (m); 1416 (m); 1219 (m); 1169 (m). MS (70 eV) m/z (%): 422/424 (M/M + 2, 1/1); 333 (14); 331 (14); 210 (17); 168 (100); 111 (10); 91 (11). HR MS: calc for C₁₈H₂₃N₄O₃Br 422.0954; found 422.0950.

4.3.11

4.3.11 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-2-chloro-N-cyclohexylacetamide (5k)

From 0.266 g of 6-amino-5-((cyclohexylamino)methyl)-2-methoxy-3-methylpyrimidin-4(3H)-one (2c) and 0.08 ml of chloroacetyl chloride. M.p. 193 – 5 °C. ¹H NMR (CDCl₃). δ_ppm: 1.18–1.32 (m, 3H); 1.60–1.67 (m, 3H); 1.75–1.85 (m, 2H); 1.92–2.01 (m, 2H); 3.34 (s, 3H); 3.55 (tt, 3.5 Hz and 12.0 Hz, 1H); 3.93 (s, 3H); 4.18 (s, 2H); 4.58 (s, 2H); 5.55–6.35 (bs, 2H). ¹³C NMR (CDCl₃) δ_ppm: 24.9 s; 26.3 s; 27.7 p; 30.9 s; 42.3 s; 55.1 p; 59.6 t; 89.1 q; 155.7 q; 160.2 q; 163.2 q; 168.2 q. IR (KBr) ν (cm⁻¹): 3369 (m, b); 3201 (m); 2936 (m); 2860 (w); 1643 (s, b); 1595 (m); 1538 (s, b); 1488 (m); 1453 (m); 1222 (m). MS (70 eV) m/z (%): 342 (M⁺, 2); 265 (100); 259 (35); 183 (31); 168 (54); 111 (12). HR MS: calc for C₁₅H₂₃N₄O₃Cl 342.1459; found 342.1457.

4.3.12

4.3.12 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-2-chloro-N-cyclohexylpropanamide (5l)

From 0.266 g of 2c and 0.100 ml of 2-chloropropyl chloride. M.p. 160 – 1 °C. ¹H NMR (CDCl₃). δ_ppm: 1.17–1.34 (m, 3H); 1.55–1.63 (m, 2H); 1.69 (d, 6.4 Hz, 3H); 1.74–1.84 (m, 3H); 1.89–1.98 (m, 2H); 3.33 (s, 3H); 3.68–3.74 (m, 1H); 3.93 (s, 3H); 4.60 (s, 2H); 4.70 (q, 6.4 Hz, 1H); 5.55–6.35 (bs, 2H). ¹³C NMR (CDCl₃) δ_ppm: 21.7 p; 25.0 s; 26.4 s; 27.7 p; 31.6 s; 37.0 s; 50.6 t; 55.1 p; 59.0 t; 89.2 q; 155.6 q; 160.2 q; 163.25 q; 171.05 q. IR (KBr) ν (cm⁻¹): 3380 (s, b); 3172 (m, b); 2934 (m); 2858 (m); 1635 (s, b); 1591 (s); 1538 (s, b); 1451 (s); 1222 (m). MS (70 eV) m/z (%): 356 (M⁺, 1); 273 (29); 265 (100); 259 (35); 183 (27); 168 (57); 111 (10). HR MS: calc for C₁₆H₂₅N₄O₃Cl 356.1615; found 356.1618.

4.3.13

4.3.13 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-2-chloro-N-cyclohexyl-2,2-diphenylacetamide (5m)

From 0.266 g of 2c and 0.273 ml of 2-chloro-2,2-diphenyl chloride. The product is isolated by column chromatography (DCM/MeOH, 95:5). M.p. 178 – 80 °C. ¹H NMR (CDCl₃). δ_ppm: 0.64 (qt, 3.3 and 13.0 Hz, 2H); 1.03 (qt, 3.9 and 13.2 Hz, 1H); 1.27–1.39 (m, 3H); 1.48 (pd, 13.0 Hz, 2H); 1,6-1.7 (bs, 1.3 Hz); 1.73 (qd, 3.3 and 11.8 HZ, 2H); 3.31 (s, 3H); 3.80 (tt, 2.7 and 11.5 Hz, 1H); 3.95 (s, 3H); 4.69 (s, 2H); 7.26–7.37 (m, 10H). ¹³C NMR (CDCl₃) δ_ppm: 25.0 s; 26.2 s; 27.7 p; 30.0 s; 37.3 s; 55.1 p; 59.4 t; 76.9 q; 89.7 q; 127.8 t; 128.1 t; 128.5 t; 141.5 q; 155.6 q; 160.0 q; 163.3 q; 171.5 q. IR (KBr) ν (cm⁻¹): 3418 (m); 3191 (m); 3077 (w); 3008 (w); 2932 (m); 2853 (m); 1650 (s, b); 1619 (s); 1587 (m); 1538 (s); 1488 (m); 1448 (m); 1208 (m). MS (70 eV) m/z (%): 458 (M-HCl, 6); 444 (14); 333 (61); 304 (20); 194 (100); 166 (48); 55 (15). HR MS: calc for C₂₇H₃₀N₄O₃ (M-HCl) 458.2318; found 458.2308.

4.3.14

4.3.14 N-{[4-Amino-1-methyl-2-methylthio-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-2-chloro-N-phenylacetamide (5n)

From 0.276 g of 6-amino-3-methyl-2-methylthio-5-((phenylamino)methyl)pyrimidin-4(3H)-one (2d) and 0.08 ml of chloroacetyl chloride. The white solid filtered contains a small amount of the product, so the solid is digested in hot THF and the solid in suspension filtered hot. M.p. 192 – 4 °C. ¹H NMR (CDCl₃). δ_ppm: 2.51 (s, 3H); 3.26 (s, 3H); 3.83 (s, 2H); 4.87 (s, 2H); 5.43–6.20 (bs, 2H); 7.13–7.20 (m, 2H); 7.35–7.42 (m, 3H). ¹³C NMR (CDCl₃) δ_ppm: 14.7 p; 30.0 p; 41.9 s; 44.5 s; 88.95 q; 127.7 t; 128.9 t; 129.75 t; 140.4 q; 159.3 q; 161.8 q; 162.5 q; 167.8 q. IR (KBr) ν (cm⁻¹): 3424 (m); 3324 (m); 3237 (w); 2942 (w); 1655 (s); 1616 (s); 1576 (m); 1530 (s); 1493 (m); 1454 (m). MS (70 eV) m/z (%): 352 (M⁺, 1); 275 (16); 184 (100); 93 (5); 88 (9); 77 (5). HR MS: calc for C₁₅H₁₇N₄O₂SCl 352.0761; found 352.0760.

4.3.15

4.3.15 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-2-chloro-N-phenylpropanamide (5o)

From 0.276 g of 2d and 0.100 ml of 2-chloropropionyl chloride. M.p. 162 – 4 °C. ¹H NMR (CDCl₃). δ_ppm: 1.57 (d, 6.6 Hz, 3H); 2.51 (s, 3H); 3.25 (s, 3H); 4.24 (q, 6.6 Hz, 1H); 4.82 (d, 14.7 Hz, 1H); 4.92 (d, 14.7 Hz, 1H); 5.45–6.25 (bs, 2H); 7.18 (bs, 2H); 7.35–7.42 (m, 3H). ¹³C NMR (CDCl₃) δ_ppm: 14.6 p; 21.4 p; 29.9 p; 44.2 s; 50.3 t; 88.8 q; 127.9 t; 128.8 t; 129.6 t; 140.4 q; 159.3 q; 161.7 q; 162.5 q; 171.1 q. IR (KBr) ν (cm⁻¹): 3396 (m); 3327 (m); 3226 (w); 3209 (w); 2932 (w); 1650 (s); 1616 (s); 1571 (m); 1529 (m); 1409 (m). MS (70 eV) m/z (%): 366 (M⁺, 1); 275 (19); 183 (100); 88 (2). HR MS: calc for C₁₆H₁₉N₄O₂SCl 366.0917; found 366.0926.

4.3.16

4.3.16 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-2-chloro-N,2-diphenylpropanamide (5p)

From 0.276 g of 2d and 0.161 ml of 2-phenyl-2-chloroacetyl chloride. M.p. 156 °C. ¹H NMR (CDCl₃). δ_ppm: 2.50 (s, 3H); 3.23 (s, 3H); 4.81 (d, 14.6 Hz, 1H); 4.91 (d, 14.6 Hz, 1H); 5.28 (s, 1H); 5.50–6.30 (bs, 2H); 6.83 (bs, 1H); 7.25–7.35 (m, 7H); 7.35–7.45 (m, 2H). ¹³C NMR (CDCl₃) δ_ppm: 14.6 p; 29.9 p; 44.65 s; 57.1 t; 88.7 q; 127. 9 t; 128.1 t; 128.6 t; 128.9 t; 129.6 t; 129.7 t; 136.2 q; 140.3 q; 159.3 q; 161.8 q; 162.45 q; 169.2 q. IR (KBr) ν (cm⁻¹): 3324 (m); 3231 (w); 2927 (w); 1662 (m); 1613 (s); 1575 (m); 1529 (m). MS (70 eV) m/z (%): 428 (M⁺, 0.4); 275 (21); 258 (2); 184 (100); 125 (4); 88 (4). HR MS: calc for C₂₁H₂₁N₄O₂SCl 428.1074; found 428.1078.

4.3.17

4.3.17 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-chloroacetamide (5q)

From 0.290 g of 6-amino-5-((benzylamino)methyl)-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (2e) and 0.080 ml of chloroacetyl chloride. M.p. 157 – 8 °C. ¹H NMR (CDCl₃). δ_ppm: 2.51 (s, 3H); 3.39 (s, 3H); 4.05 (s, 2H); 4.54 (s, 2H); 4.81 (s, 2H); 5.44–6.48 (bs, 2H); 7.21–7.30 (m, 3H); 7.32–7.38 (m, 2H). ¹³C NMR (CDCl₃) δ_ppm: 14.7 p; 30.0 p; 41.5 s; 41.9 s; 51.7 s; 90.2 q; 126.2 t; 127.6 t; 128.9 t; 136.4 q; 159.9 q; 161.9 q; 163.6 q; 168.6 q. IR (KBr) ν (cm⁻¹): 3345 (m, b); 3195 (m); 2933 (w); 1634 (s); 1610 (s); 1572 (m); 1533 (s); 1511 (m), 1453 (m); 1415 (m). MS (70 eV) m/z (%): 366 (M⁺, 2); 289 (15); 275 (34); 199 (26); 184 (100); 91 (34); 88 (17). HR MS: calc for C₁₆H₁₉N₄O₂SCl 366.0917; found 366.0922.

4.3.18

4.3.18 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-chloropropanamide (5r)

From 0.290 g of 2e and 0.100 ml of 2-chloropropionyl chloride. M.p. 176 – 9 °C. ¹H NMR (CDCl₃). δ_ppm: 1.59 (d, 6.6 Hz, 3H); 2.51 (s, 3H); 3.40 (s, 3H); 4.45 (d, 14.5 Hz, 1H); 4.52 (q, 6.6 Hz, 1H); 4,65 (d, 14.5 Hz, 1H); 4.82 (d, 17.2 Hz, 1H); 4.88 (d, 17.2 Hz, 1H); 5.64–6.38 (bs, 2H); 7.20–7.24 (m, 2H); 7.25–7.30 (m, 1H); 7.32–7.38 (m, 2H). ¹³C NMR (CDCl₃) δ_ppm: 14.7 p; 21.1 p; 30.1 p; 41.6 s; 49.6 t; 51.2 s; 90.0 q; 126.0 t; 127.5 t; 128.9 t; 136.8 q; 160.0 q; 161.8 q; 163.6 q; 171.6 q. IR (KBr) ν (cm⁻¹): 3341 (m, b); 3195 (m); 2934 (w); 1635 (s); 1614 (s); 1534 (m); 1511 (m); 1450 (m); 1415 (m). MS (70 eV) m/z (%): 380 (M⁺, 2); 289 (56); 199 (24); 183 (100); 91 (25); 88 (12). HR MS: calc for C₁₇H₂₁N₄O₂SCl 380.1074; found 380.1073.

4.3.19

4.3.19 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-chloro-2-phenylacetamide (5s)

From 0.290 g of 2e and 0.161 ml of 2-chloro-2-phenylacetyl chloride. M.p. 153 – 6 °C. ¹H NMR (CDCl₃). δ_ppm: 2.50 (s, 3H); 3.37 (s, 3H); 4.58 (s, 2H); 4.77 (d, 17.3 Hz, 1H); 4.85 (d, 17.3 Hz, 1H); 5.54 (s, 1H); 5.58–6.53 (bs, 2H); 7.20–7.39 (m, 10H). ¹³C NMR (CDCl₃) δ_ppm: 14.7 p; 30.0 p; 42.3 s; 51.5 s; 57.15 t; 89.9 q; 126.0 t; 127.6; 128.2 t; 128.8 t; 129.0 t; 129.1 t; 135.9 q; 136.6 q; 160.0 q; 161.9 q; 163.6 q; 169.9 q. IR (KBr) ν (cm⁻¹): 3354 (m); 3317 (m); 3179 (m); 2932 (w); 1645 (s); 1614 (s); 1534 (m); 1515 (m); 1454 (m); 1419 (m). MS (70 eV) m/z (%): 442 (M⁺, 0.3); 351 (M⁺ −91, 12); 288 (67); 273 (16); 258 (15); 197 (43); 184 (100); 91 (45). HR MS: calc for C₂₂H₂₃N₄O₂SCl 442.1230; found 442.1226.

4.3.20

4.3.20 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-chloro-2,2-diphenylacetamide (5t)

From 0.290 g of 2e and 0.273 ml of 2-chloro-2,2-diphenylacetyl chloride. M.p. 144 – 5 °C. ¹H NMR (CDCl₃). δ_ppm: 2.51 (s, 3H); 3.33 (s, 3H); 4.46 (s, 2H); 4.61 (s, 2H); 5.50–6.50 (bs, 2H) 7.15–7.40 (m, 15H). ¹³C NMR (CDCl₃) δ_ppm: 14.7 p; 30.1 p; 42.0 s; 53.4 s; 60.1 q; 90.3 q; 127.6 t; 127.7 t; 128.05 t; 128.6 t; 128.6 t; 128.7 t; 128.9 t; 129.8 t; 130.5 t; 134.9 q; 136.7 q; 141.3 q; 160.0 q; 161.6 q; 163.3, q; 171.6 q. IR (KBr) ν (cm⁻¹): 3418 (m); 3325 (m); 3061 (w); 3025 (w); 2941 (w); 1612 (s, b); 1523 (s); 1446 (m); 1411 (m). MS (70 eV) m/z (%): 482 (M⁺-HCl, 8); 363 (74), 334 (47); 194 (62); 165 (100); 91 (40); 88 (16). HR MS: calc for C₂₈H₂₆N₄O₂S (M-HCl) 482.1776; found 482.1782.

4.3.21

4.3.21 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-bromobutanamide (5u)

From 0.290 g of 2e and 0.135 ml of 2-bromobutyryl bromide. M.p. 124 – 6 °C. ¹H NMR (CDCl₃). δ_ppm: 0.84 (t, 7.3 Hz, 3H); 1.91–2.02 (m, 1H); 2.06–2.16 (m, 1H); 2.51 (s, 3H); 3.39 (s, 3H); 4.22 (t, 7.3 Hz, 1H); 4.48 (d; 14.7 Hz, 1H); 4.66–4.76 (m, 2H); 4.88 (d, 17.3 Hz, 1H); 5.62–6.42 (bs, 2H); 7.20–7.29 (m, 3H); 7.31–7.37 (m, 2H). ¹³C NMR (CDCl₃) δ_ppm: 12.1 p; 14.7 p; 28.4 s; 30.05 p; 41.6 s; 45.3 t; 51.35 s; 89.7 q; 126.0 t; 127.5 t; 128.8 t; 137.0 q; 160.0 q; 161.8 q; 163.6 q; 171.4 q. IR (KBr) ν (cm⁻¹): 3349 (m, b); 3184 (m); 2973 (w); 2932 (w); 2873 (w); 1625 (s, b); 1611 (s, b); 1568 (m); 1531 (s, b); 1448 (m); 1413 (m). MS (70 eV) m/z (%): 438/440 (M⁺ 2/M + 2, 1:1); 349 (10); 347 (10); 289 (24); 199 (17); 183 (100); 91 (8); 88 (3). HR MS: calc for C₁₈H₂₃N₄O₂SBr 438.0725; found 438.0735.

4.3.22

4.3.22 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-bromohexanamide (5v)

From 0.290 g of 2e and 0.167 ml of 2-bromohexanoyl bromide. M.p. 105 – 8 °C. ¹H NMR (CDCl₃). δ_ppm: 0.81 (t, 7.0 Hz, 3H); 1.08–1.25 (m, 4H); 1.88–1.98 (m, 1H); 2.02–2.12 (m, 1H); 2.51 (s, 3H); 3.40 (s, 3H); 4.28 (t, 7.2 Hz, 1H); 4.48 (d, 14.5 Hz, 1H); 4.69–4.74 (m, 2H); 4.89 (d, 17.3 Hz, 1H); 5.54–6.58 (bs, 2H); 7.19–7.29 (m, 3H); 7.31–7.37 (m, 2H). ¹³C NMR (CDCl₃) δ_ppm: 13.7 p; 14.7 p; 22.0 s; 29.4 s; 30.1 p; 34.6 s; 41.7 s; 43.8 t; 51.35 s; 89.7 q; 126.0 t; 127.5 t; 128.8 t; 137.05 q; 160.0 q; 161.8 q; 163.6 q; 171.6 q. IR (KBr) ν (cm⁻¹): 3357 (m, b); 3317 (m, b); 3192 (m); 2957 (m); 2931 (m); 1636 (s, b); 1596 (s, b); 1571 (m); 1533 (s); 1517 (s); 1453 (m); 1417 (m). MS (70 eV) m/z (%): 466/468 (M⁺ 2/M + 2, 0.1:0.1) 375 (3); 289 (7); 204 (61); 184 (34); 91 (100). HR MS: calc for C₂₀H₂₇N₄O₂SBr 466.1038; found 466.1050.

4.3.23

4.3.23 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-2-chloro-N-cyclohexylacetamide (5w)

From 0.282 g of 6-amino-5-((cyclohexylamino)methyl)-3-methyl-2-methylthiopyrimidin-4(3H)-one (2f) and 0.08 ml de chloroacetyl chloride. M.P. 148 – 51 °C. ¹H NMR (CDCl₃). δ_ppm: 1.21–1.30 (m, 3H); 1.59–1.67 (m, 3H); 1.81–1.84 (m, 2H); 1.90–2.00 (m, 2H); 2.49 (s, 3H); 3.44 (s, 3H); 3.55 (tt, 3.3 Hz & 11.8 Hz, 1H); 4.18 (s, 2H); 4.60 (s, 2H); 4.90–6.90 (bs, 2H). ¹³C NMR (CDCl₃) δ_ppm: 14.6 p; 24.9 s; 26.3 s; 30.2 p; 30.9 s; 36.5 s; 42.2 s; 59.6 t; 90.8 q; 159.4 q; 161.2 q; 162.6 q; 168.3 q. IR (KBr) ν (cm⁻¹): 3380 (s); 3200 (m); 2933 (m); 2858 (m); 1640 (s); 1610 (s, b); 1569 (s); 1524 (s); 1452 (s); 1409 (s); 1102 (m). MS (70 eV) m/z (%): 358 (M⁺, 2); 281 (100); 274 (38); 199 (43); 183 (61); 88 (12). HR MS: calc for C₁₅H₂₃N₄O₂SCl 358.1230; found 358.1225.

4.3.24

4.3.24 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-2-chloro-N-cyclohexylpropanamide (5x)

From 0.282 g of 2f and 0.100 ml of 2-chloropropionyl chloride. M.p. 143 – 6 °C. ¹H NMR (CDCl₃). δ_ppm: 1.18–1.34 (m, 3H); 1.56–1.68 (m, 2H); 1.69 (d, 6.4 Hz, 3H); 1.74–1.84 (m, 3H); 1.89–1.98 (m, 2H); 2.49 (s, 3H); 3.44 (s, 3H); 3.72 (tt, 3.3 Hz and 12.0 Hz, 1H); 4.61 (s, 2H); 4.70 (q, 6.4 Hz,1H); 5.00–7.00 (bs, 2H). ¹³C NMR (CDCl₃) δ_ppm: 14.6 p; 21.7 p; 25.0 s; 26.3 s; 26.4 s; 30.2 p; 30.7 s; 31.6 s; 36.7 s; 50.5 t; 59.0 t; 91.0 q; 159.4 q; 161.1 q; 162.65 q; 171.1 q. IR (KBr) ν (cm⁻¹): 3389 (m); 3189 (m, b); 2932 (m); 2857 (m); 1635 (s); 1612 (s); 1568 (m); 1523 (s); 1452 (m); 1423 (m). MS (70 eV) m/z (%): 372 (M⁺, 1); 289 (34); 281 (100); 199 (21); 183 (47); 88 (10). HR MS: calc for C₁₆H₂₅N₄O₄SCl 372.1387; found 372.1390.

4.3.25

4.3.25 N-((4-amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-2-chloro-N-cyclohexyl-2-phenylacetamide (5y)

From 0.282 g of 2f and 0.161 ml of 2-chloro-2-phenylacetyl chloride. M.p. 264 – 7 °C. ¹H NMR (CDCl₃). δ_ppm: 1.09–1.17 (m, 3H); 1.51–1.58 (m, 2H); 1.61–1.68 (m, 1H); 1.74–1.84 (m, 2H); 1.89–1.98 (m, 2H); 2.49 (s, 3H); 3.42 (s, 3H); 3.56-3.66 (m, 1H); 4,60 (d, 15.3 Hz, 1H); 4,65 (d, 15.3 Hz, 1H); 5.00–7.00 (bs, 2H); 5,83 (s, 1H); 7.35–7.42 (m, 3H); 7.45–7.50 (m, 2H). ¹³C NMR (CDCl₃) δ_ppm: 14.6 p; 24.9 s; 26.2, s; 26.4 s; 30.2 p; 44.8 s; 59.1 t; 59.9 t; 90.9 q; 127.6 t; 129.0 t; 129.6 t; 136.6 q; 159.4 q; 161.2 q; 162.6 q; 169.3 q. IR (KBr) ν (cm⁻¹): 3408 (m); 3324 (m); 3148 (m, b); 3052 (m); 2934 (m); 2855 (m); 1719 (m); 1682 (s); 1639 (s); 1613 (s); 1520 (s, b); 1451 (s); 1415 (s); 1423 (m). MS (70 eV) m/z (%): 399 (M⁺-Cl,2); 282 (100); 266 (10); 261 (7); 131 (9); 115 (23); 97 (5); 83 (12).

4.3.26

4.3.26 N-Benzyl-2-chloro-N-{[4-(2-chloroacetamido)-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}acetamide (6a)

From 0.274 g of 2b and 0.160 ml of chloroacetyl chloride at room temperature. M.p. 140 – 2 °C. ¹H NMR (CDCl₃). δ_ppm: 3.39 (s, 3H, N—CH₃); 4.06 (s, 3H, O—CH₃); 4.07 (s, 2H, NBn—CO—CH₂Cl); 4.32 (s, 4H, C5—CH₂—N and 4-N—CO—CH₂—Cl); 5.01 (s, 2H, Bn); 7.23–7.27 (m, 2H, two H_o Ph); 7.29–7.34 (m, 1H, H_m Ph); 7.35–7.42 (m, 2H, two H_o Ph); 11.00 (bs, 1H, 4—NHCO). ¹³C NMR (CDCl₃) δ_ppm: 28.2 p (N—CH₃); 40.9 s (NBn—CO—CH₂Cl); 42.9 s (C5—CH₂—N); 43.8 s (4-N—CO—CH₂—Cl); 53. 2 s (Bn); 58.2 p (O—CH₃); 101.2 q (C5); 126.4 t (C_o Ph); 127.9 t (C_m Ph); 129.1 t (C_p Ph); 136.0 q (C_i Ph); 153.9 q (C2); 155.9 q (C4); 164.6 q (C6); 165.4 q (4-N—CO—CH₂—Cl); 169.0 q (NBn—CO—CH₂Cl). IR (KBr) ν (cm⁻¹): 3231 (w); 3201 (w); 3145 (w); 3021 (w); 2951 (w); 1698 (m); 1649 (s, b); 1613 (s); 1558 (s, b); 1494 (s). MS (70 eV) m/z (%): 426 (M⁺, 1); 335 (41); 244 (70); 180 (29); 168 (43); 111 (24); 106 (31); 91 (100). HR MS: calc for C₁₈H₂₀N₄O₄Cl₂ 426.0862; found 426.0858.

4.3.27

4.3.27 N-Benzyl-2-chloro-N-{[4-(2-chloroacetamido)-(2-methylthio)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}acetamide (6b)

From 0.290 g of 2e and 0.160 ml of chloroacetyl chloride at room temperature. M.p. 134 – 5 °C. ¹H NMR (CDCl₃). δ_ppm: 2.51 (s, 3H, S—CH₃); 3.40 (s, 3H, N—CH₃); 4.08 (s, 2H, NBn—CO—CH₂Cl); 4.29 (s, 2H, C5—CH₂—N) 4.34 (s, 2H, 4-N—CO—CH₂—Cl); 5.00 (s, 2H, Bn); 7.23–7.27 (m, 2H, two H_o Ph); 7.29–7.34 (m, 1H, H_p Ph); 7.36–7.42 (m, 2H, two H_m Ph); 11.00 (s, 1H, 4-NHCO). ¹³C NMR (CDCl₃) δ_ppm: 15.0 p (S—CH₃); 28.2 p (N—CH₃); 40.9 s (NBn—CO—CH₂Cl); 42.9 s (C5—CH₂—N); 43.8 s (4-N—CO—CH₂—Cl); 53.2 s (Bn); 102.6 q (C5); 126.4 t (C_o Ph); 127.9 t (C_m Ph); 129.1 t (C_p Ph); 135.9 q (C_i Ph); 153.1 q (C2); 162.9 q (C4); 164.0 q (C6); 165.1 q (4-N—CO—CH₂—Cl); 169.0 q (NBn—CO—CH₂Cl). IR (KBr) ν (cm⁻¹): 3006 (w); 2929 (w); 1724 (m); 1658 (s); 1621 (s, b); 1525 (s); 1494 (m); 1481 (m); 1414 (m); 1395 (m). MS (70 eV) m/z (%): 351 (M⁺ −91, 20); 261 (22); 184 (22); 91 (100). HR MS: calc for C₁₈H₂₀N₄O₃SCl₂ 442.0633; found 442.0637.

4.3.28

4.3.28 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-3-chloropropanamide (10a)

From 0.274 g of 2b and 0.090 ml of 3-chloropropionyl chloride. M.p. 156 – 7 °C. ¹H NMR (CDCl₃). δ_ppm: 2.77 (t, 6.7 Hz, 2H, CO—CH₂—CH₂Cl); 3.28 (s, 3H, N—CH₃); 3.79 (t, 6.7 Hz, 2H, CO—CH₂—CH₂Cl); 3.93 (s, 3H, O—CH₃); 4.52 (s, 2H, C5—CH₂—N); 4.74 (s, 2H, Bn); 5.42–6.48 (bs, 2H, 4-NH₂); 7.23–7.28 (m, 3H, two H_o and H_p Ph); 7.31–7.37 (m, 2H, two H_m Ph). ¹³C NMR (CDCl₃) δ_ppm: 27.6 p (N—CH₃); 36.0 s (CO—CH₂); 39.8 s (CH₂Cl); 41.0 s (C5—CH₂—N); 51.3 s (Bn); 55.25 p (O—CH₃); 88.8 q (C5); 126.3 t (C_o Ph); 127.3 t (C_m Ph); 128.7 t (C_p Ph); 136. 8 q (C_i Ph); 155. 9 q (C2); 160.7 q (C4); 164.2 q (C6); 171.6 q (N—CO). IR (KBr) ν (cm⁻¹): 3426 (m); 3337 (m); 3227 (w); 2949 (w); 1667 (s); 1641 (s); 1610 (s); 1592 (s); 1542 (s); 1475 (s); 1215 (m). MS (70 eV) m/z (%): 364 (M⁺, 2); 273 (60); 183 (48); 168 (100); 91 (56). HR MS: calc for C₁₇H₂₁N₄O₃Cl 364.1302; found 364.1303.

Crystal data for 10a were deposited at CCDC with reference CCDC 1,037,316: Chemical formula C₁₇H₂₁ClN₄O₃, M_r 364.13, Triclinic, P-1, 120 K, cell dimensions a, b, c (Å) 8.1086 (8), 8.7520 (9), 13.5072 (11); α, β, γ (°) 102.742 (7), 95.910 (9) × 114.045 (8), V (Å³) 833.57 (47), Z = 2, F(000) = 384, D_x (Mg m⁻³) = 1.454, Mo Kα, μ (mm⁻¹) = 0.255, Crystal size (mm) = 0.31 × 0.19 × 0.17. Data collection: KappaCCD Diffractometer, Monochromator graphite, CCD rotation images, thick slices φ & θ scans, absorption correction SADABS 2.10, Tmin, Tmax 0.534, 0.756 No. of measured, independent and observed [I > 2σ(I)] reflections 21,260, 3825, 2721, Rint = 0.044, θ values (°): θmax = 27.5, θmin = 3.2; Range h = −10 → 10, k = −11 → 11, l = −17 → 17, Refinement on F2:R[F2 > 2σ(F2)] = 0.047, wR(F2) = 0.109, S = 1.05. No. of reflections 3825, No. of parameters 228, No. of restraints 0. Weighting scheme: w = 1/σ²(F_o²) + (0.0534P)² + 0.6588P where P = (F_o² + 2F_c²)/3. (Δ/σ) < 0.001, Δρ_max, Δρ_min (e Å⁻³) 0.28, −0.56.

4.3.29

4.3.29 N-[(4-amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-3-bromopropanamide (10b)

From 0.274 g of 2b and 0.100 ml of 3-bromopropionyl bromide. M.p. 168 – 9 °C. ¹H NMR (CDCl₃). δ_ppm: 2.89 (t, 6.7 Hz, 2H, CO—CH₂—CH₂Cl); 3.28 (s, 3H, N—CH₃); 3.62 (t, 6.7 Hz, 2H, CO—CH₂—CH₂Cl); 3.93 (s, 3H, O—CH₃); 4.52 (s, 2H, C5—CH₂—N); 4.74 (s, 2H, Bn); 5.69–6.36 (bs, 2H, 4-NH₂); 7.23–7.29 (m, 3H, two H_o and H_p Ph); 7.30–7.36 (m, 2H, two H_m Ph). ¹³C NMR (CDCl₃) δ_ppm: 27.1 s (CO—CH₂); 27.6 p (N—CH₃); 36.2 s (CH₂Cl); 41.0 s (C5—CH₂—N); 51.3 s (Bn); 55.3 p (O—CH₃); 88.7 q (C5); 126.3 t (C_o Ph); 127.3 t (C_m Ph); 128.7 t (C_p Ph); 136. 8 q (C_i Ph); 155. 9 q (C2); 160.7 q (C4); 164.3 q (C6); 171.9 q (N—CO). IR (KBr) ν (cm⁻¹): 3395 (m); 3321 (m); 3203 (m); 3024 (w); 2953 (w); 2897 (w); 1656 (s, b); 1614 (s, b); 1542 (s, b); 1475 (s); 1211 (s). MS (70 eV) m/z (%): 408/410 (M/M + 2, 2/2); 319 (21); 273 (58); 182 (49); 168 (100); 111 (15); 90 (20). HR MS: calc for C₁₇H₂₁N₄O₃Br 408.0797; found 408.0796.

4.3.30

4.3.30 N-{[4-amino-(2-methylthio)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-3-chloropropanamide (10c)

From 0.290 g of 2e and 0.090 ml of 3-chloropropionyl chloride. M.p. 158 – 60 °C. ¹H NMR (CDCl₃). δ_ppm: 2.50 (s, 3H, S—CH₃); 2.78 (t, 6.6 Hz, 2H, CO—CH₂—CH₂Cl); 3.39 (s, 3H, N—CH₃); 3.79 (t, 6.6 Hz, 2H, CO—CH₂—CH₂Cl); 4.53 (s, 2H, C5—CH₂—N); 4.75 (s, 2H, Bn); 5.72–6.35 (bs, 2H, 4-NH₂); 7.22–7.29 (m, 2H, two H_o Ph); 7.29–7.37 (m, 3H, two H_m and H_p Ph). ¹³C NMR (CDCl₃) δ_ppm: 14.7 p (S—CH₃); 30.0 p (N—CH₃); 36.0 s (CO—CH₂); 39.7 s (CH₂Cl); 41.0 s (C5—CH₂—N); 51.4 s (Bn); 90.4 q (C5); 126.3 t (C_o Ph); 127.5 t (C_m Ph); 128.7 t (C_p Ph); 136. 7 q (C_i Ph); 159.9 q (C2); 161.6 q (C4); 163.6 q (C6); 171.6 q (N—CO). IR (KBr) ν (cm⁻¹): 3346 (m, b); 3195 (m); 2932 (w); 1614 (s, b); 1536 (m); 1513 (m); 1452 (m); 1414 (m). MS (70 eV) m/z (%): 380 (M⁺, 2); 289 (56); 253 (14); 199 (49); 184 (97); 91 (100). HR MS: calc for C₁₇H₂₁N₄O₂SCl 380.1074; found 380.1076.

4.4

4.4 Indoline-pyrimidine hybrid by the reaction of [(6-aminopyrimidin-5-yl)methyl](phenyl)amino with haloacyl halides

1-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3,3-diphenylindolin-2-one (7). From 0.260 g of 2a and 0.273 ml of 2-chloro-2,2-diphenylacetyl chloride according to 4.1.2. general procedure. The product is isolated by flash chromatography (silicagel, DCM/MeOH, 95:5). Yield: 57%. M.p. 228 – 9 °C. ¹H NMR (CDCl3). δppm: 3.37 (s, 3H, N-CH₃); 3.92 (s, 3H, O-CH₃); 4.86 (s, 2H, C5—CH₂—N); 5.50–6.70. (bs, 2H, 4-NH₂); 7.06 (td, 1.0 Hz and 7.4 Hz, 1H, H_5’ in indolinone ring); 7.18 (dd, 1.2 and 7.4 Hz, 1H, H_7′ in indolinone ring); 7.20–7.30 (m, 10H, all Hs in two Ph rings); 7.33 (td, 1.4 and 7.8 Hz, 1H, H_6′ in indolinone ring); 7.83 (pd, 8 Hz, 1H, H_4′ in indolinone ring). ¹³C NMR (CDCl3) δppm: 27.8 p (N—CH₃); 35.6 s (C5—CH₂—N); 55.3 p (O—CH₃); 63.0 q (C3′ in indolinone); 86.9 q (C5); 111.8 t (C5′ indolinone); 123.2 t (C7′ in indolinone); 125.5 t (C6′ in indolinone); 127.3 t (C_p in two Ph); 128.4 t (C_o in two Ph); 128.4 t(C_m in two Ph); 128.8 t (C4′ in indolinone); 132.8 q (C3a′ in indolinone); 141.6 q (C_i in two Ph); 142.1 q (C7a′ in indolinone); 156.1 q (C2); 160.5 q (C4); 163.4 q (C6); 179.75 q (C(2′)⚌O). IR (KBr) ν (cm⁻¹): 3348 (s); 3029 (w); 2928 (w); 1671 (s); 1624 (m); 1601 (m); 1524 (s); 1445 (s). MS (70 eV) m/z (%): 452 (M+, 7); 424 (5); 285 (4); 168 (100); 111 (8). HR MS: calc for C₂₇H₂₄N₄O₃ 452.1848; found 452.1851.

4.5

4.5 Cyclization of intermediates (6-aminopyrimidin-5-yl)methylamino acyl halides to pyrimido[4,5-e][1,4]diazepines (8)

Method A: To a solution of acylated pyrimidine 5 (1 mmol) in dry DMF (4 mL) anhydrous potassium carbonate (1 mmol) was added, and the mixture was heated to 80–90 °C until the starting pyrimidine is not observed by TLC (AcOEt/hexane 8:2). The product was purified by column chromatography (AcOEt/hexane 1:1) if needed and recrystallized from hexane-EtOH (1:1).

Method B: 1 mmol of the starting pyrimidine (3) is solved in 4 ml of DMF anhydrous and placed in an ice bath. 0.05 g (1 mmol) of sodium hydride (60%) with continuous stirring until the starting pyrimidine disappears. The reaction is monitored by TLC (AcOEt/hexane 8:2). Then 10–15 ml of water is added to the reaction mixture and the solid in suspension is filtered and washed with cold water. The solid is recrystallized from hexane - EtOH.

4.5.1

4.5.1 2-Methoxy-3-methyl-6-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8a)

Method A: From 0.336 g of 5a; reaction time: 4 h 30 min; colourless solid (85%). Method B: From 0.336 g of 5a; reaction time: 20 min; colourless solid (98%). M.p. 261 – 5 °C. ¹H NMR (CDCl₃). δ_ppm: 3.35 (s, 3H); 3.93 (s, 3H); 4.33 (d, 2H, 5.8 Hz); 4.98 (s, 2H); 5.11 (t, 5.8 Hz, 1H); 7.18–7.21 (m, 1H); 7.32–7.37 (m, 4H); ¹³C NMR (CDCl₃) δ_ppm: 27.8 p; 45.7 s; 48.4, s; 55.4 p; 89.1 q; 125.2 t; 126.3 t; 128.9 t; 142.4 q; 155.7 q; 158.4 q; 162.0 q; 167.8 q. IR (KBr) ν (cm⁻¹): 3426 (m); 3337 (m); 3227 (w); 2949 (w); 1667 (s); 1641 (s); 1610 (s); 1592 (s); 1542 (s); 1475 (s); 1215 (m). MS (70 eV) m/z (%): 300 (M⁺, 45); 196 (4); 180 (100); 152 (20); 108 (11); 80 (7); 72 (12). HR MS: calc for C₁₅H₁₆N₄O₃ 300.1222; found 300.1227.

4.5.2

4.5.2 2-Methoxy-3,8-dimethyl-6-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8b)

Method A: From 0.350 g of 5b; reaction time: 13 h; colourless solid (85%). Method B: From 0.350 g of 5b; reaction time: 15 min; colourless solid (58%). M.p. 158 °C. ¹H NMR (CDCl₃). δ_ppm: 1.49 (d, 6.6 Hz, 3H); 3.34 (s, 3H); 3.93 (s, 3H); 4.56 (d, 3.7 Hz, 1H); 4.93 (d, 16.8 Hz, 1H); 4.92–5.01 (m, 1H); 5.03 (d, 16.8 Hz, 1H); 7.15–7.20 (m, 1H); 7.25–7.35 (m, 4H). ¹³C NMR (CDCl₃) δ_ppm: 16.6 p; 27.8 p; 45.3 s; 49.3 t; 55.3 p; 89.1 q; 125.4 t; 126.2 t; 128.8 t; 142.9 q; 155.6 q; 158.1 q; 162.0 q; 169.3 q. IR (KBr) ν (cm⁻¹): 3336 (m, b); 2983 (w); 2936 (w); 1651 (s); 1611 (m); 1571 (s); 1517 (s); 1410 (m); 1197 (m). MS (70 eV) m/z (%): 314 (M⁺, 33); 194 (68); 180 (100); 152 (10); 123 (12); 108 (6); 80 (11); 72 (23). HR MS: calc for C₁₆H₁₈N₄O₃ 314.1373; found 314.1371.

4.5.3

4.5.3 6-Benzyl-2-methoxy-3-methyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8d)

Method A: From 0.350 g of 5d; reaction time: 3 h 45 min; colourless solid (70%). Method B: From 0.350 g of 5d; reaction time: 50 min; colourless solid (84%). M.p. 217 – 9 °C. ¹H NMR (CDCl₃). δ_ppm: 3.28 (s, 3H); 3.89 (s, 3H); 4.20 (d, 5.6 Hz, 2H); 4.46 (s, 2H); 4.63 (s, 2H); 5.06 (t, 5.6 Hz, 1H); 7.25–7.33 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 27.7 p; 41.9 s; 47.55 s; 50.4 s; 55.3 p; 88.7 q; 127.4 t; 128.3 t; 128.5 t; 137.1 q; 155.4 q; 158.1 q; 162.2 q; 168.7 q. IR (KBr) ν (cm⁻¹): 3310 (m); 2942 (w, b); 1645 (s); 1612 (m); 1561 (s); 1518 (s); 1228 (m). MS (70 eV) m/z (%): 314 (M⁺, 30); 223 (100); 195 (16); 180 (70); 152 (10); 123 (18); 91 (49); 80 (12); 72 (25). HR MS: calc for C₁₆H₁₈N₄O₃ 314.1379; found 314.1380.

4.5.4

4.5.4 6-Benzyl-2-methoxy-3,8-dimethyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8e)

Method A: From 0.364 g of 5e; reaction time: 20 h; colourless solid (64%). Method B: From 0.364 g of 5e; reaction time: 40 min; colourless solid (88%). M.p. 176 – 84 °C. ¹H NMR (CDCl₃). δ_ppm: 1.46 (d, 6.6 Hz, 3H); 3.27 (s, 3H); 3.90 (s, 3H); 4.26 (d, 14.5 Hz, 1H), 4.44–4.53 (m, 3H); 4.80 (dq, 3.9 Hz and 13.0 Hz, 1H); 5.02 (d, 14.7 Hz, 1H); 7.21–7.32 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 16.52 p; 27.64 p; 41.70 s; 48.72 t; 50.68 s; 55.25 p; 88.8 q; 127.3 t; 128.4 t; 128.4 t; 137.4 q; 155.3 q; 157.8 q; 162.2 q; 170.1 q. IR (KBr) ν (cm⁻¹): 3305 (m); 2995 (w); 2929 (w); 1671 (s); 1642 (s); 1605 (m); 1553 (s); 1520 (s, b); 1447 (m); 1414 (m); 1225 (m); 1193 (m). MS (70 eV) m/z (%): 328 (M⁺, 52); 223 (85); 194 (67); 180 (100); 123 (10); 123 (18); 91 (25); 80 (7); 72 (18). HR MS: calc for C₁₇H₂₀N₄O₃ 328.1535; found 328.1537.

4.5.5

4.5.5 6-Benzyl-2-methoxy-3-methyl-8-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8f)

Method A: From 0.427 g of 5f; reaction time: 3 h; colourless solid (64%). Method B: From 0.427 g of 5f; reaction time: 15 min; colourless solid (82%). M.p. 232 – 4 °C. ¹H NMR (CDCl₃). δ_ppm: 3.29 (s, 3H); 3.75 (d, 16.7 Hz, 1H); 3.95 (s, 3H); 4.27 (d, 16.7 Hz, 1H); 4.42 (d, 14.6 Hz, 1H); 4.87 (d, 14.6 Hz, 1H); 5.40 (d, 6.7 Hz, 1H); 5.49 (d, 6.7 Hz, 1H), 7.22–7.41 (m, 10H). ¹³C NMR (CDCl₃) δ_ppm: 27.7 p; 40.4 s; 51.2 s; 55.3 p; 62.1 t; 89.2 q; 125.3 t; 127.3 t; 128.1 t; 128.2 t; 128.4 t; 129.0 t; 137.1 q; 137.9 q; 155.4 q; 157.5 q; 162.1 q; 169.05 q. IR (KBr) ν (cm⁻¹): 3299 (m); 2954 (w, b); 1687 (m); 1642 (s); 1613 (m); 1569 (s); 1519 (s); 1450 (m); 1236 (m); 1195 (m). MS (70 eV) m/z (%): 390 (M⁺, 7); 257 (100); 242 (21); 180 (9); 91 (16); 80 (3). HR MS: calc for C₂₂H₂₂N₄O₃ 390.1692; found 390.1685.

4.5.6

4.5.6 6-Benzyl-8-ethyl-2-methoxy-3-methyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8h)

Method A: From 0.424 g of 5h; reaction time: 3 h 30 min; colourless solid (38%). M.p. 161 °C. ¹H NMR (CDCl₃). δ_ppm: 1.10 (t, 7.4 Hz, 3H); 1.62–1.71 (m, 1H); 2.07–2.17 (m, 1H); 3.27 (s, 3H); 3.90 (s, 3H); 4.28 (d, 14.6 Hz, 1H); 4.44 (d, 16.8 Hz, 1H); 4.46–4.53 (m, 2H); 4.52 (d, 16.8 Hz, 1H); 5.00 (d, 14.6 Hz, 1H); 7.21–7.32 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 10.8 p; 24.1 s; 27.6 p; 41.7 s; 50.5 s; 54.8 t; 55.3 p; 88.8 q; 127.3 t; 128.35 t; 128.4 t; 137.4 q; 155.3 q; 157.9 q; 162.2 q; 169.6 q. IR (KBr) ν (cm⁻¹): 3262 (m); 2972 (d, a); 2879 (d); 1665 (f); 1640 (f, a); 1567 (f); 1513 (f); 1443 (m); 1224 (m). MS (70 eV) m/z (%): 342 (M⁺, 42); 251 (51); 194 (20); 180 (100); 123 (6); 91 (19); 72 (12). HR MS: calc for C₁₈H₂₂N₄O₃ 342.1692; found 342.1690.

4.5.7

4.5.7 6-Benzyl-8-butyl-2-methoxy-3-methyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8i)

Method A: From 0.452 g of 5i; reaction time: 3 h; colourless solid (55%). Method B: From 0.452 g of 5i; reaction time: 30 min; colourless solid (95%). M.p. 153 – 5 °C. ¹H NMR (CDCl₃). δ_ppm: 0.95 (t, 7.0 Hz, 3H); 1.39–1.46 (m, 4H); 1.62–1.69 (m, 1H); 2.05–2.14 (m, 1H); 3.27 (s, 3H); 3.90 (s, 3H); 4.29 (d, 14.5 Hz, 1H); 4.44 (d, 16.8 Hz, 1H); 4.47–4.59 (m, 1H); 4.52 (d, 16.8 Hz, 1H); 4.47–4.59 (m, 1H); 4.98 (d, 14.5 Hz, 1H); 7.22–7.32 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 13.9 p; 22.6 s; 27.6 p; 28.2 s; 30.6 s; 41.8 s; 50.6 s; 53.3 p; 55.3 p; 88.8 q; 127.3 t; 128.4 t; 128.4 t; 137.4 q; 155.3 q; 157.9 q; 162.2 q; 169.8 q. IR (KBr) ν (cm⁻¹): 3252 (m, b); 2957 (w); 2930 (w); 2873 (w); 1665 (m); 1643 (s); 1607 (m); 1564 (m, b); 1515 (s). MS (70 eV) m/z (%): 370 (M⁺, 41); 279 (59); 237 (43); 208 (31); 194 (24); 180 (100); 168 (46); 91 (39); 72 (22). HR MS: calc for C₂₀H₂₆N₄O₃ 370.2005; found 370.1996.

4.5.8

4.5.8 6-Cyclohexyl-2-methoxy-3-methyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8k)

Method A: From 0.343 g of 5k; reaction time: 3 h; colourless solid (75%). Method B: From 0.343 g of 5k; reaction time: 30 min; colourless solid (57%). M.p. 258 – 60 °C. ¹H NMR (CDCl₃). δ_ppm: 1.16 (qt, 3.3 Hz and 12.8 Hz, 1H); 1.35 (qt, 3.3 Hz and 12.8 Hz, 2H); 1.48 (qd, 3.3 Hz and 12.4 Hz, 2H); 1.57–1.66 (m, 3H); 1.73–1.80 (m, 2H); 3.32 (s, 3H); 3.90 (s, 3H); 4.16 (d, 5.5 Hz, 2H); 4.39 (tt, 3.7 Hz and 11.8 Hz, 1H); 4.45 (s, 2H); 4.99 (t, 5.5 Hz, 1H). ¹³C NMR (CDCl₃) δ_ppm: 25.2 s; 25.6 s; 27.7 p; 30.2 s; 36.4 s; 47.9 s; 52.8 t; 55.2 p; 89.5 q; 155.4 q; 158.3 q; 161.7 q; 168.2 q. IR (KBr) ν (cm⁻¹): 3295 (s); 2942 (m); 2862 (w); 2847 (w); 1635 (w, b); 1562 (w); 1524 (w); 1482 (w); 1416 (m); 1227 (m). MS (70 eV) m/z (%): 306 (M⁺, 51); 224 (44); 180 (100); 152 (14); 123 (14); 98 (8); 72 (11). HR MS: calc for C₁₅H₂₂N₄O₃ 306.1692; found 306.1698.

4.5.9

4.5.9 6-Cyclohexyl-2-methoxy-3,8-dimethyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8l)

Method A: From 0.357 g of 5l; reaction time: 5 h 30 min; colourless solid (62%). Method B: From 0.357 g of 5l; reaction time: 30 min; after the addition of water (15 ml) the solution is extracted with AcOEt (30 ml ×3) dried with Na₂SO₄ and after filtration of the solid the solvent is evaporated. Colourless foam (90%). M.p. 127 – 33 °C. ¹H NMR (CDCl₃). δ_ppm: 1.16 (qt, 3.30 Hz and 12.9 Hz, 1H); 1.25–1.36 (m, 3H); 1.42 (d, 6.6 Hz, 3H); 1.46–1.85 (m, 6H); 3.32 (s, 3H); 3.89 (s, 3H); 4.36 (d, 16.8 Hz, 1H); 4.42–4.48 (m, 1H); 4.57 (d, 16.8 Hz, 1H); 4.78 (dq, 3.9 Hz and 12.9 Hz, 1H). ¹³C NMR (CDCl₃) δ_ppm: 16.6 p; 25.2 s; 25.6 s; 27.7 p; 30.2 s; 30.4 s; 36.1 s; 48.9 t; 53.0 t; 55.2 p; 89.7 q; 155.3 q; 157.9 q; 161.7 q; 169.4 q. IR (KBr) ν (cm⁻¹): 3263 (m, b); 2926 (m); 2854 (m); 1669 (s); 1640 (s, b); 1611 (s); 1564 (s); 1521 (s); 1415 (m); 1226 (m); 1174 (m). MS (70 eV) m/z (%): 320 (M⁺, 35); 238 (7); 195 (87); 180 (100); 152 (9); 98 (6); 80 (6); 72 (16). HR MS: calc for C₁₆H₂₄N₄O₃ 320.1848; found 320.1837.

4.5.10

4.5.10 3-methyl-2-(methylthio)-6-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8n)

Method A: From 0.353 g of 5n; reaction time: 6 h; colourless solid (70%). Method B: From 0.353 g of 5n; reaction time: 20 min; colourless solid (64%). M.p. 214 – 6 °C. ¹H NMR (CDCl₃). δ_ppm: 2.47 (s, 3H); 3.45 (s, 3H); 4.33 (d, 5.6 Hz, 2H); 4.99 (s, 2H); 5.21 (t, 5.6 Hz, 1H); 7.17–7.22 (m, 1H); 7.30–7.37 (m, 4H). ¹³C NMR (CDCl₃) δ_ppm: 14.6 p; 30.2 p; 45.5 s; 48.3 s; 90.7 q; 125.2 t; 126.4 t; 128.9 t; 142.3 q; 157.7 q; 161.2 q; 161.7 q; 167.7 q. IR (KBr) ν (cm⁻¹): 3318 (m); 2914 (w); 1667 (s); 1618 (s, b); 1580 (s); 1547 (m); 1508 (m); 1411 (m). MS (70 eV) m/z (%): 316 (M⁺, 71); 197 (99); 182 (37); 164 (15); 150 (100); 122 (48); 88 (54); 80 (20); 77 (20). HR MS: calc for C₁₅H₁₆N₄O₂S 316.0994; found 316.1001.

4.5.11

4.5.11 3,8-dimethyl-2-(methylthio)-6-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8o)

Method A: From 0.366 g of 5o; reaction time: 4 h; colourless solid (90%). Method B: From 0.366 g of 5o; reaction time: 15 min; colourless solid (94%). M.p. 140 – 50 °C. ¹H NMR (CDCl₃). δ_ppm: 1.50 (d, 6.6 Hz, 3H); 2,49 (s, 3H); 3.45 (s, 3H); 4.66 (d, 3.7 Hz, 1H); 4.94 (d, 16.9 Hz, 1H); 4.93–5.00 (m, 1H); 5.05 (d, 16.9 Hz, 1H); 7.19 (pt, 7.2 Hz, 1H); 7.26–7.36 (m, 4H). ¹³C NMR (CDCl₃) δ_ppm: 14.6 p; 16.5 p; 30.2 p; 45.2 s; 49.2 t; 90.7 q; 125.4 t; 126.3 t; 128.8 t; 142.8 q; 157.4 q; 161.2 q; 161.5 q; 169.2 q. IR (KBr) ν (cm⁻¹): 3420 (m, b); 3357 (m); 3277 (m, b); 2988 (w); 2928 (w); 1676 (m); 1627 (s); 1586 (s); 1531 (s, b); 1496 (s); 1412 (m). MS (70 eV) m/z (%): 330 (M⁺, 48); 210 (71); 196 (100); 184 (12); 164 (38); 136 (22); 88 (54); 77 (14). HR MS: calc for C₁₆H₁₈N₄O₂S 330.1150; found 330.1144.

4.5.12

4.5.12 6-Benzyl-3-methyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8q)

Method A: From 0.367 g of 5q; reaction time: 1 h 30 min; colourless solid (80%). Method B: From 0.367 g of 5q; reaction time: 30 min; colourless solid (77%). M.p. 221 – 3 °C. ¹H NMR (CDCl₃). δ_ppm: 2.45 (s, 3H); 3.38 (s, 3H); 4.21 (d, 5.5 Hz, 2H); 4.48 (s, 2H); 4.63 (s, 2H); 5.14 (t, 5.5 Hz, 1H); 7.24–7.33 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 14.6 p; 30.1 p; 41.7 s; 47.5 s; 50.4 s; 90.4 q; 127.4 t; 128.3 t; 128.5 t; 137.0 q; 157.5 q; 161.2 q; 161.4 q; 168.7 q. IR (KBr) ν (cm⁻¹): 3319 (m); 3059 (w); 3031 (w); 2929 (w); 1664 (s); 1627 (s); 1587 (s); 1541 (s); 1506 (s); 1428 (m); 1225 (m). MS (70 eV) m/z (%): 330 (M⁺, 42); 239 (100); 196 (44); 182 (12); 150 (43); 139 (22); 122 (14); 91 (61); 88 (42); 80 (12). HR MS: calc for C₁₆H₁₈N₄O₂S 330.1150; found 330.1146.

4.5.13

4.5.13 6-Benzyl-3,8-dimethyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8r)

Method A: From 0.380 g of 5r; reaction time: 14 h; colourless solid (84%). Method B: From 0.380 g of 5r; reaction time: 30 min; colourless solid (86%). M.p. 189 – 90 °C. ¹H NMR (CDCl₃). δ_ppm: 1.47 (d, 6.6 Hz, 3H); 2.46 (s, 3H); 3.38 (s, 3H); 4.28 (d, 14.5 Hz, 1H); 4.50–4.55 (m, 3H), 4.77–4.82 (m, 1H); 5.01 (d, 14.5 Hz, 1H); 7.23–7.32 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 14.6 p; 16.5 p; 30.1 p; 41.6 s; 48.7 t; 50.7 s; 90.5 q; 127.3 t; 128.4 t; 128.4 t; 137.3 q; 157.2 q; 161.1 q; 161.4 q; 170.0 q. IR (KBr) ν (cm⁻¹): 3246 (m, b); 3001 (w); 2924 (w); 1656 (s); 1627 (s, b); 1582 (s); 1537 (s, b); 1509 (s, b); 1420 (m). MS (70 eV) m/z (%): 344 (M⁺, 73); 253 (95); 239 (18); 210 (64); 196 (100); 164 (33); 91 (38); 88 (50). HR MS: calc for C₁₇H₂₀N₄O₂S 344.1307; found 344.1311.

4.5.14

4.5.14 6-Benzyl-3-methyl-2-(methylthio)-8-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8s)

Method A: From 0.442 g of 5s; reaction time: 1 h; colourless solid (87%). M.p. 239 °C. ¹H NMR (CDCl₃). δ_ppm: 2.51 (s, 3H); 3.40 (s, 3H); 3.76 (d, 16.7 Hz, 1H); 4.28 (d, 16.7 Hz, 1H); 4.41 (d, 14.7 Hz, 1H); 4.88 (d, 14.7 Hz, 1H); 5.50 (sa, 2H); 7.20–7.30 (m, 5H); 7.30–7.42 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 14.7 p; 30.1 p; 40.3 s; 51.2 s; 62.0 t; 90.9 q; 125.3 t; 127.3 t; 128.1 t; 128.2 t; 128.4 t; 129.0 t; 137.0 q; 137.8 q; 156.9 q; 161.2 q; 161.3 q; 169.0 q. IR (KBr) ν (cm⁻¹): 3314 (m); 3029 (w); 2927 (w); 1645 (s); 1628 (s) 1591 (s); 1540 (s); 1507 (s); 1414 (m). MS (70 eV) m/z (%): 406 (M⁺, 6); 290 (47); 273 (100); 258 (25); 198 (15); 170 (17); 91 (11). HR MS: calc for C₂₂H₂₂N₄O₂S 406.1463; found 406.1468.

4.5.15

4.5.15 6-Benzyl-8-ethyl-3-methyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8u)

Method A: From 0.439 g of 5u; reaction time: 1 h & 20 min; colourless solid (91%). M.p. 172 – 3 °C. ¹H NMR (CDCl₃). δ_ppm: 1.10 (t, 7.4 Hz, 3H); 1.65–1.72 (m, 1H); 2.10–2.17 (m, 1H); 2.47 (s, 3H); 3.37 (s, 3H), 4.31 (d, 14.7 Hz, 1H); 4.46 (d, 17.1 Hz, 1H); 4.45–4.55 (m, 2H); 4.54 (d, 17.1 Hz, 1H); 4.97 (d, 14.7 Hz, 1H); 7.21–7.32 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 10.8 p; 14.6 p; 24.1 s; 30.1 p; 41.6 s; 50.6 s; 54.7 t; 90.5 q; 127.3 t; 128.3 t; 128.4 t; 137.4 q; 157.3 q; 161.0 q; 161.5 q; 169.5 q. IR (KBr) ν (cm⁻¹): 3340 (m); 2979 (w); 2928 (w); 1658 (s); 1632 (s); 1580 (s); 1537 (s); 1501 (s); 1431 (m). MS (70 eV) m/z (%): 358 (M⁺, 20); 267 (37); 225 (29); 196 (100); 184 (12); 170 (61); 124 (20); 91 (15). HR MS: calc for C₁₈H₂₂N₄O₂S 358.1463; found 358.1469.

Crystal data for 8u were deposited at CCDC with reference CCDC 1,037,315: Chemical formula C₁₈H₂₂N₄O₂S, M_r 358.15, Monoclinic, P21/c, 120 K, cell dimensions a, b, c (Å) 7.7280 (8), 26.421 (2), 8.3554 (10); α, β, γ (°) 90, 102.392 (10), 90. V (Å³) 1666.2 (3), Z = 4, F(000) = 760, D_x (Mg m⁻³) = 1.429, Mo Kα, μ (mm⁻¹) = 0.215, Crystal size (mm) = 0.47 × 0.32 × 0.18. Data collection: Diffractometer KappaCCD, Monochromator graphite, CCD rotation images, thick slices φ & θ scans, absorption correction SADABS 2.10, Tmin, Tmax 0.503, 0.756. No. of measured, independent and observed [I > 2σ(I)] reflections 20,117, 3792, 2201, Rint = 0.061, θ values (°): θmax = 27.5, θmin = 2.8; Range h = −10 → 9, k = −34 → 32, l = −10 → 10, Refinement on F2:R[F2 > 2σ(F2)] = 0.055, wR(F2) = 0.118, S = 1.05. No. of reflections 3792, No. of parameters 229, No. of restraints 0. Weighting scheme: w = 1/[σ²(F_o²) + (0.0589P)² + 1.596P] where P = (F_o² + 2F_c²)/3. (Δ/σ) < 0.001, Δρ_max, Δρ_min (e Å⁻³) 0.47, −0.41.

4.5.16

4.5.16 6-Benzyl-8-butyl-3-methyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8v)

Method A: From 0.467 g of 5v; reaction time: 1 h; colourless solid (93%). M.p. 172 – 3 °C. ¹H NMR (CDCl₃). δ_ppm: 0.95 (t, 7.0 Hz, 3H); 1.35–1.48 (m, 4H); 1.60–1.67 (m, 1H); 2.05–2.17 (m, 1H); 2.47 (s, 3H); 3.37 (s, 3H); 4.31 (d, 14.5 Hz, 1H); 4.46 (d, 17.4 Hz, 1H); 4.50–4.60 (m, 3H); 4.97 (d, 14.5 Hz, 1H); 7.20–7.33 (m, 5.0 Hz). ¹³C NMR (CDCl₃) δ_ppm: 13.9 p; 14.6 p; 22.6 s; 28.3 s; 30.3 p; 30.6 s; 41.7 s; 50.6 s; 53.2 t; 90.5 q; 127.3 t; 128.3 t; 128.4 t; 137.4 q; 157.3 q; 161.0 q; 161.4 q; 169.9 q. IR (KBr) ν (cm⁻¹): 3271 (m); 2955 (w); 2928 (w); 2856 (w); 1632 (s, b); 1584 (m); 1529 (s); 1513 (s, b); 1410 (m); 1351 (w). MS (70 eV) m/z (%): 386 (M⁺, 34); 295 (42); 253 (36); 224 (29); 196 (100); 91 (15); 88 (71). HR MS: calc for C₂₀H₂₆N₄O₂S 386.1776; found 386.1768.

4.5.17

4.5.17 6-Cyclohexyl-3-methyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8w)

Method A: From 0.359 g of 5w; reaction time: 1 h & 30 min; colourless solid (56%). Method B: From 0.359 g of 5w; reaction time: 15 min; colourless solid (57%). M.p. 242 – 5 °C. ¹H NMR (CDCl₃). δ_ppm: 1.15 (qt, 3.3 Hz and 12.8 Hz, 1H); 1.34 (qt, 3.3 Hz and 12.8 Hz, 2H); 1.45 (qd, 3.3 Hz and 12.4 Hz, 2H); 1.57–1.67 (m, 3H); 1.77 (pd, 13.0 Hz, 2H); 2.46 (s, 3H); 3.43 (s, 3H); 4.17 (d, 5.5 Hz, 2H); 4.39 (tt, 3.7 Hz and 11.8 Hz, 1H); 4.47 (s, 2H); 5.09 (t, 5.5 Hz, 1H). ¹³C NMR (CDCl₃) δ_ppm: 14.6 p; 25.2 s; 25.6 s; 30.1 p; 30.2 s; 36.3 s; 47.8 s; 52.8 t; 91.2 q; 157.6 q; 161.0 q; 161.1 q; 168.1 q. IR (KBr) ν (cm⁻¹): 3323 (f); 2940 (f); 2857 (m); 1652 (f); 1622 (f); 1582 (f); 1538 (f, a); 1481 (f); 1454 (f). MS (70 eV) m/z (%): 322 (M⁺, 73); 240 (61); 196 (100); 182 (31); 150 (84); 122 (36); 98 (30); 88 (16); 80 (18). HR MS: calc for C₁₅H₂₂N₄O₂S 322.1463; found 322.1457.

4.5.18

4.5.18 6-Cyclohexyl-3,8-dimethyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8x)

Method A: From 0.373 g of 5x; reaction time: 2 h & 15 min; colourless solid (90%). Method B: From 0.373 g of 5x; reaction time: 30 min; colourless solid (88%). M.p. 184 – 5 °C. ¹H NMR (CDCl₃). δ_ppm: 1.25–1.40 (m, 3H); 1.43 (d, 6.6 Hz, 3H); 1.52–1.82 (m, 7H); 2.46 (s, 3H); 3.43 (s, 3H); 4.38 (d, 16.8 Hz, 1H); 4.45 (tt, 3.9 Hz and 11.8 Hz, 1H); 4.49 (d, 3.9 Hz, 1H); 4.59 (d, 16.8 Hz, 1H); 4.75–4.81 (m, 1H). ¹³C NMR (CDCl₃) δ_ppm: 14.6 p; 16.6 p; 25.2 s; 25.6 s; 25.7 s; 30.2 p; 30.2 s; 30.5 s; 36.0 s; 48.9, t; 53.1 t; 91.4 q; 157.4 q; 161.0 q; 169.3 q. IR (KBr) ν (cm⁻¹): 3339 (m); 2941 (m); 2926 (m); 2853 (w); 1657 (s); 1625 (s); 1586 (s); 1534 (s); 1500 (s); 1414 (m). MS (70 eV) m/z (%): 336 (M⁺, 60); 225 (12), 211 (100); 196 (88); 164 (28); 88 (16); 80 (8). HR MS: calc for C₁₆H₂₄N₄O₂S 336.1620; found 336.1620.

4.5.19

4.5.19 6-Cyclohexyl-3-methyl-2-(methylthio)-8-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8y)

Method B: From 0.435 g of 5y; reaction time: 20 min; colourless solid (90%). M.p. 237 – 41 °C. ¹H NMR (CDCl₃). δ_ppm: 1.00–1.20 (m, 1H); 1.25–1.50 (m, 4H); 1.65–1.80 (m, 5H); 2.52 (s, 3H); 3.44 (s, 3H); 3.61 (d, 16.9 Hz, 1H); 4.32 (d, 16.9 Hz, 1H); 4.41–4.47 (m, 1H); 5.41–5.46 (m, 2H); 7.30–7.38 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 14.7 p; 25.2 s; 25.5 s; 25.6 s; 29.9 s; 30.1 s; 30.1 p; 34.5 s; 53.4 t; 62.5 t; 91.6 t; 125.1 t; 128.0 t; 129.0 t; 138.4 q; 157.1 q; 160.9 q; 161.1 q; 168.4 q. IR (KBr) ν (cm⁻¹): 3293 (m, b); 2927 (m); 2854 (m); 1629 (s, b); 1602 (s); 1593 (s); 1525 (s, b); 1449 (m); 1413 (m). MS (70 eV) m/z (%): 398 (M⁺, 3); 273 (100), 253 (23); 198 (12); 170 (17); 88 (16). HR MS: calc for C₂₁H₂₆N₄O₂S 398.1776; found 398.1777.

4.6

4.6 Acylamide-pyrimidine hybrid by the elimination reaction from (6-aminopyrimidin-5-yl)methylamino acyl halides

4.6.1

4.6.1 N-[(4-amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzylmethacrylamide (9a)

Method A: From 0.423 g of 5j; reaction time: 6 h & 30 min; colourless solid (58%). M.p. 146 – 8 °C. ¹H NMR (CDCl₃). δ_ppm: 1.90 (s, 3H); 3.28 (s, 3H); 3.93 (s, 3H); 4.47 (s, 2H); 4.77 (s, 2H); 5.07 (s, 1H); 5.12 (s, 1H); 6.04 (bs, 2H); 7.22–7.34 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 20.7 p; 27.6 p; 39.5 s; 52.5 s; 55.2 p; 89.0 q; 115.4 s; 127.1 t; 127.2 t; 128.4 t; 137.6 q; 140.2 q; 155.9 q; 160.8 q; 164.2 q; 174 .3 q. IR (KBr) ν (cm⁻¹): 3325 (m, b); 3185 (m); 2951 (w); 1643 (s, b); 1611 (s); 1583 (s); 1558 (s); 1474 (s); 1454 (s). MS (70 eV) m/z (%): 342 (M⁺, 3); 273 (46); 251 (48); 168 (100); 111 (8); 91 (17). HR MS: calc for C₁₈H₂₂N₄O₃ 342.1692; found 342.1695.

4.6.2

4.6.2 N-[(4-amino-1-methyl-2-methoxy-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzylacrylamide (9b)

Method A: From 0.365 g of 10a; reaction time: 1 h & 30 min; colourless solid (90%). Method B: From 0.365 g of 10a; reaction time: 2 h; colourless solid (62%). Method B: From 0.409 g of 10b; reaction time: 50 min; colourless solid (73%). M.p. 167 – 8 °C. ¹H NMR (CDCl₃). δ_ppm: 3.29 (s, 3H); 3.93 (s, 3H); 4.54 (s, 2H); 4.80 (s, 2H); 5.67 (dd, 2.1 and 10.0 Hz, 1H); 5.7–6.5 (bs); 6.39 (dd, 2.1 and 16.2 Hz, 1H); 6.55 (dd, 10.0 and 16.2 Hz, 1H); 7.25–7.34 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 27.6 p; 40.8 s; 51.1 s; 55.2 p; 88.7 q; 126.6 t; 127.3 t; 127.6 t; 128.6 t; 128.8 s; 137.3 q; 155.9 q; 160.9 q; 164.3 q; 167.9 q. IR (KBr) ν (cm⁻¹): 3326 (m, b); 3182 (m); 2954 (w); 1642 (s, b); 1604 (m); 1578 (s); 1559 (s); 1538 (m); 1483 (m). MS (70 eV) m/z (%): 328 (M⁺, 9); 273 (60); 237 (78); 183 (57); 168 (100); 111 (24); 91 (29). HR MS: calc for C₁₇H₂₀N₄O₃ 328.1535; found 328.1539.

4.6.3

4.6.3 N-{[4-amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzylacrylamide (9c)

Method A: From 0.380 g of 10c; reaction time: 2 h; colourless solid (80%). M.p. 175 – 7 °C. ¹H NMR (CDCl₃). δ_ppm: 2.49 (s, 3H); 3.40 (s, 3H); 4.55 (s, 2H); 4.80 (s, 2H); 5.68 (dd, 2.1 and 10.0 Hz, 1H); 5.7-6.5 (bs); 6.39 (dd, 2.1 and 16.2 Hz, 1H); 6.55 (dd, 10.0 and 16.2 Hz, 1H); 7.25–7.34 (m, 5H). ¹³C NMR (CDCl₃) δ_ppm: 14.7 p; 30.0 p; 40.8 s; 51.2 s; 90.4 q; 126.5 t; 127.3 t; 127.5 t; 128.6 t; 128.9 s; 137.2 q; 160.0 q; 161.6 q; 163.6 q; 168.0 q. IR (KBr) ν (cm⁻¹): 3340 (m, b); 3191 (m); 2933 (w); 1639 (s); 1615 (s, b); 1536 (m); 1511 (m); 1453 (m); 1414 (m). MS (70 eV) m/z (%): 344 (M⁺, 12); 289 (46); 253 (73); 199 (55); 184 (100); 91 (42). HR MS: calc for C₁₇H₂₀N₄O₂S 344.1307; found 344.1308.

4.7

4.7 Derivatization (N-Methylation) of pyrimido[4,5-e][1,4]diazepines (8)

A equimolar amount of sodium hydride was added to a solution of pyrimido[4,5-e][1,4]diazepine (8) (1 mmol) (or its precursor haloacyl intermediate 5) in DMF (2 mL) at 0 °C and stirred vigorously for 15 min, afterwards methyl iodide was added dropwise (1.6 mmol), and then stirred at 0 °C until no starting product was observed, by TLC monitoring (AcOEt/hexane 8:2). Then, water (10 mL) is poured into the solution and the mixture is stirred. The solid under suspension is filtered and recrystallized from EtOH – Hexane. If no solid is formed the product is extracted with AcOEt (10 ml x 3). The combined organic phases are dried under anhydrous sodium sulphate and the solvent removed under reduced pressure. The remaining solid was then recrystallized from EtOH – hexane.

4.7.1

4.7.1 2-Methoxy-3,8,9-trimethyl-6-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (11a)

From 0.350 g of 5b. Reaction time 35 min. Yellow solid (73%). M.p. 162 – 3 °C. ¹H NMR (CDCl₃). δ_ppm: 1.56 (d, 7.0 Hz, 3H); 3.13 (s, 3H); 3.35 (s, 3H); 3.98 (s, 3H); 4.92 (q, 7.0 Hz, 1H); 4.94 (d, 14.5 Hz, 1H); 4.98 (d, 14.5 Hz, 1H); 7.17 (pt, 7.2 Hz, 1H); 7.23–7.35 (m, 4H). ¹³C NMR (CDCl₃). δ_ppm: 14.1 p; 27.7 p; 31.2 p; 47.6 s; 54.1 t; 55.1 p; 91.6 q; 125.5 t; 126.1 t; 128.8 t; 142.7 q; 154.5 q; 159.9 q; 162.6 q; 168.8 q. IR (KBr) ν (cm⁻¹): 2988 (w); 2944 (w); 2921 (w); 2870 (w); 1680 (s); 1633 (s, b); 1594 (m); 1572 (s); 1530 (s); 1493 (m); 1412 (m). MS (70 eV) m/z (%): 328 (M⁺, 22); 285 (14), 223 (22); 208 (30); 194 (100); 104 (12); 72 (13). HR MS: calc for C₁₇H₂₀N₄O₃ 328.1535; found 328.1535.

4.7.2

4.7.2 6-Benzyl-2-methoxy-3,9-dimethyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (11b)

From 0.350 g of 5e. Reaction time: 35 min. Yellow solid (70%). M.p. 143 – 6 °C. ¹H NMR (CDCl₃). δ_ppm: 3.20 (s, 3H); 3.22 (s, 3H); 3.88 (s, 3H); 4.17 (s, 2H); 4.40 (s, 2H); 4.54 (s, 2H); 7.18–7.24 (m, 5H). ¹³C NMR (CDCl₃). δ_ppm: 27.7 p; 39.0 p; 43.4 s; 50.2 s; 55.1 p; 55.5 s; 89.7 q; 127.4 t; 128.3 t; 128.5 t; 137.1 q; 154.5 q; 158.5 q; 162.4 q; 168.2 q. IR (KBr) ν (cm⁻¹): 3006 (w); 2929 (w, b); 2859 (w); 1670 (s); 1647 (s, b); 1598 (s); 1546 (s); 1500 (m); 1477 (m); 1400 (m). MS (70 eV) m/z (%): 328 (M⁺, 46); 237 (100); 209 (18); 194 (72); 182 (10); 122 (11); 91 (21); 72 (12). HR MS: calc for C₁₇H₂₀N₄O₃ 328.1535; found 328.1534.

4.7.3

4.7.3 6-Benzyl-2-methoxy-3,8,9-trimethyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (11c)

From 0.364 g of 5f. Reaction time: 25 min. Yellow solid (58%). M.p. 131 – 3 °C. ¹H NMR (CDCl₃). δ_ppm: 1.52 (d, 7.0 Hz, 3H); 3.09 (s, 3H); 3.29 (s, 3H); 3.95 (s, 3H); 4.42 (d, 17.3 Hz, 1H); 4.43 (d, 14.4 Hz, 1H); 4.47 (d, 17.0 Hz, 1H); 4.73 (q, 7.0 Hz, 1H); 4.80 (d, 14.4 Hz, 1H); 7.20–7.27 (m, 5H). ¹³C NMR (CDCl₃). δ_ppm: 14.1 p; 27.6 p; 31.5 p; 44.2 s; 50.8 s; 53.9 t; 55.0 p; 91.2 q; 127.2 t; 128.1 t; 128.4 t; 137.4 q; 154.2 q; 159.6 q; 162.7 q; 169.8 q. IR (KBr) ν (cm⁻¹): 3023 (w); 2952 (w, b); 1652 (s, b); 1598 (s); 1548 (s, b); 1481 (m); 1452 (m); 1397 (m). MS (70 eV) m/z (%): 342 (M⁺, 27); 223 (47); 208 (44); 194 (100); 91 (21); 72 (18). HR MS: calc for C₁₈H₂₂N₄O₃ 342.1692; found 342.1688.

4.7.4

4.7.4 6-Cyclohexyl-2-methoxy-3,9-dimethyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (11d)

From 0.306 g of the pyrimido-diazepine 8k. Reaction time: 20 min. Colourless solid (81%). M.p. 151 – 2 °C. ¹H NMR (CDCl₃). δ_ppm: 1.14 (qt, 3.3 & 12.8 Hz, 1H);1.33 (qt, 3.3 & 12.8 Hz, 2H); 1.44 (qd, 3.3 & 11.9 Hz, 2H); 1.56–1.65 (m, 3H); 1.75 (pd, 12.8 Hz, 2H); 3.24 (s, 3H); 3.33 (s, 3H); 3.95 (s, 3H); 4.21 (s, 2H); 4.36 (tt, 3.7 & 11.9 Hz, 1H); 4.46 (s, 2H). ¹³C NMR (CDCl₃). δ_ppm: 25.1 s; 25.5 s; 27.7 p; 30.2 s; 37.8 s; 39.0 p; 52.6 t; 55.0 p; 55.9 s; 90.5 q; 154.5 q; 158.6 q; 162.0 q; 167.6 q. IR (KBr) ν (cm⁻¹): 2923 (m, b); 2854 (m); 1640 (s, b); 1559 (s); 1548 (s, b); 1506 (m); 1406 (m). MS (70 eV) m/z (%): 320 (M⁺, 37); 237 (14); 209 (11); 194 (100); 166 (13); 122 (6); 72 (5). HR MS: calc for C₁₆H₂₄N₄O₃ 320.1848; found 320.1851.

4.7.5

4.7.5 6-Cyclohexyl-2-methoxy-3,8,9-trimethyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (11e)

From 0.356 g of 5l. Reaction time: 30 min. Colourless solid (47%). M.p. 162 – 5 °C. ¹H NMR (CDCl₃). δ_ppm: 1.06–1.19 (m, 1H); 1.26–1.41 (m, 3H); 1.48 (d, 6.9 Hz, 3H); 1.56–1.82 (m, 6H); 3.06 (s, 3H); 3.35 (s, 3H); 3.95 (s, 3H); 4.34 (d, 17.1 Hz, 1H); 4.39 (tt, 3.9 & 11.8 Hz, 1H); 4.53 (d, 17.1 Hz, 1H); 4.72 (q, 6.9 Hz, 1H). ¹³C NMR (CDCl₃). δ_ppm: 14.2 p; 25.2 s; 25.5 s; 27.7 p; 29.7 s; 30.1 s; 30.7 s; 31.4 p; 38.1 s; 52.7 t; 54.1 t; 55.0 p; 92.2 q; 154.3 q; 159.8 q; 162.5 q; 168.9 q. IR (KBr) ν (cm⁻¹): 2998 (w); 2954 (m); 2926 (s); 2854 (m); 1643 (s, b); 1603 (m); 1546 (s, b); 1473 (m); 1450 (m, b). MS (70 eV) m/z (%): 334 (M⁺, 13); 208 (27); 194 (100); 72 (18). HR MS: calc for C₁₇H₂₆N₄O₃ 334.2005; found 334.2002.

4.7.6

4.7.6 3,8,9-trimethyl-2-(methylthio)-6-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (11f)

From 0.350 g of 5o. Reaction time: 50 min. Colourless solid (92%). M.p. 162 – 3 °C. ¹H NMR (CDCl₃). δ_ppm: 1.56 (d, 7.0 Hz, 3H); 2.55 (s, 3H); 3.16 (s, 3H); 3.45 (s, 3H); 4.91 (q, 7.0 Hz, 1H); 4.95 (d, 17.5 Hz, 1H); 5.01 (d, 17.5 Hz, 1H); 7.17 (pt, 7.2 Hz, 1H); 7.23–7.35 (m, 4H). ¹³C NMR (CDCl₃). δ_ppm: 14.0 p; 14.6 p; 30.1 p; 31.2 p; 47.4 s; 54.0 t; 93.2 q; 125.6 t; 126.2 t; 128.8 t; 142.7 q; 159.2 q; 159.9 q; 161.9 q; 168.8 q. IR (KBr) ν (cm⁻¹): 3054 (w); 3007 (w); 2925 (m, b); 2857 (m); 1683 (s); 1652 (s, b); 1597 (s); 1545 (s, b); 1492 (m). MS (70 eV) m/z (%): 344 (M⁺, 29); 301 (18); 239 (22); 223 (30); 209 (100); 178 (10); 88 (25). HR MS: calc for C₁₇H₂₀N₄O₂S 344.1307; found 344.1314.

Crystal data for 11f were deposited at CCDC with reference CCDC 1,422,147: Chemical formula C₁₇H₂₀N₄O₂S, M_r 344.13, Monoclinic, C2/c, 120 K, cell dimensions a, b, c (Å) 19.7765 (14), 12.7797 (17), 13.8467 (14); α, β, γ (°) 90, 110.854 (8), 90. V (Å³) 3270.3 (6), Z = 8, F(000) = 1456, D_x (Mg m⁻³) = 1.399, Mo Kα, μ (mm⁻¹) = 0.216, Crystal size (mm) = 0.25 × 0.20 × 0.18. Data collection: Diffractometer KappaCCD diffractometer, Monochromator graphite, CCD rotation images, thick slices φ & θ scans, absorption correction SADABS 2.10, Tmin, Tmax 0.6446, 0.7456. No. of measured, independent and observed [I > 2σ(I)] reflections 26,146, 3738, 2619, Rint = 0.053, θ values (°): θmax = 27.5, θmin = 3.1; Range h = −25 → 25, k = −16 → 16, l = −17 → 17, Refinement on F2:R[F2 > 2σ(F2)] = 0.043, wR(F2) = 0.092, S = 1.07. No. of reflections 3738, No. of parameters 221, No. of restraints 0. Weighting scheme: w = 1/σ²(F_o²) + (0.0365P)² + 3.3545P where P = (F_o² + 2F_c²)/3. (Δ/σ) < 0.001, Δρ_max, Δρ_min (e Å⁻³) 0.26, −0.27.

Acknowledgements

The authors thank “Centro de Instrumentación Científico-Técnica of Universidad de Jaén” and the staff for data collection, and Universidad de Jaén (project reference UJA_07_16_33), the Consejería de Innovación, Ciencia and Empresa (Junta de Andalucía, Spain) and Ministerio de Ciencia e Innovación (Project reference SAF2008-04685-C02-02) for financial support.

References

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Dinakaran V.S., Bomma B., Srinivasan K.K., . Fused pyrimidines: the heterocycle of diverse biological and pharmacological significance. Der Pharma Chemica. 2012;4(1):255-265.
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Dlugosz A., . A Novel Synthesis of Pyrimidobenzodiazepines. Eine neue Synthese von Pyrimidobenzodiazepinen. Arch. Pharm.. 1990;323:59-60.
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Dlugosz A., . Preparation of novel derivative of pyrimidobenzodiazepine as immunosuppressant. Pol. Pat. Appl.. 1998;129:4665. PL 173147 B1 19980130; Chem .Abstr
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Gracias V., Ji Z., Akritopoulou-Zanze I., Abad-Zapatero C., Huth J.R., Song D., Hajduk P.J., Glaser K.B., Marcotte P.A., Pease L., Soni N.B., Stewart K.D., Davidsen S.K., Michaelides M.R., Djuric S.W., . Scaffold oriented synthesis. Part 2: design, synthesis and biological evaluation of pyrimido-diazepines as receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett.. 2008;18:2691-2695.
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Horton D.A., Bourne G.T., Smythe M.L., . The combinatorial synthesis of bicyclic privileged structures or privileged substructures. Chem. Rev.. 2003;103:893.
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Insuasty B., Orozco F., Lizarazo C., Quiroga J., Abonia R., Hursthouse M., Nogueras M., Cobo J., . Synthesis of new indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones as potential antitumor agents. Bioorg. Med. Chem.. 2008;16(18):8492-8500.
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Insuasty B., Garcia A., Quiroga J., Abonia R., Nogueras M., Cobo J., . Synthesis of novel 6,6a,7,8-tetrahydro-5H-naphtho[1,2-e]pyrimido[4,5-b][1,4]diazepines under microwave irradiation as potential anti-tumor agents. Eur. J. Med. Chem.. 2010;45(7):2841-2846.
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Insuasty B., Orozco F., Quiroga J., Abonia R., Nogueras M., Cobo J., . Synthesis and structure elucidation of new regioisomeric 2-alkylamino-6-aryl-8,9-dihydropyrimido[4,5-b][1,4]diazepin-4(7H)-ones. J. Het. Chem.. 2014;51(1):196-202.
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Juby P.F., Hudyma T.W., . Antihypoxic 11H-pyrimido-[4,5-b][1,4]-benzodiazepines. Ger. Offen. DE 2418285 A1 19741107. Chem. Abstr. 1974;1975(82):73045.
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Kobayashi S., . Pyrimidine-Fused 1,4-Benzodiazepines. Reaction of 1,4-Benzodiazepines with Formamide–POCl₃. Bull. Chem. Soc. Jpn.. 1975;48:302-306.
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Murthy K.S.K., Knaus E.E., . Synthesis of pyrimido[1,4]diazepin-2-one analogs and their evaluation as anticonvulsant agents. Drug Develop. Res.. 1999;46:155.
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Pike D.C., Hora M.T., Bailey S.W., Ayling J.E., . Pyrimidodiazepine, a ring-strained cofactor for phenylalanine hydroxylase. Biochemistry. 1986;25:4762.
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Sagar S.R., Agarwal J.K., Pandya D.H., Dash R.P., Nivsarkar M., Vasu K.K., . Design, synthesis and biological evaluation of novel pyrazolo-pyrimidinones as DPP-IV inhibitors in diabetes. Bioorg. Med. Chem. Lett.. 2015;25(20):4428-4433.
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Xiang J., Wen D., Xie H., Dang Q., Bai X., . Synthesis of novel 8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones. J. Comb. Chem.. 2010;12(4):503-509.
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Xu S., Zhang L., Chang S., Luo J., Lu X., Tu Z., Liu Y., Zhang Z., Xu Y., Ren X., Ding K., . Design, synthesis and biological evaluation of new molecules inhibiting epidermal growth factor receptor threonine⁷⁹⁰ → methionine⁷⁹⁰ mutant. Med. Chem. Commun.. 2012;3(9):1155-1159.
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Appendix A

Supplementary material

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2016.07.012.

Appendix A

Supplementary material

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[1] Borgegard T., Juréus A., Olsson F., Rosqvist S., Sabirsh A., Rotticci D., Paulsen K., Klintenberg R., Yan H., Waldman M., Stromberg K., Nord J., Johansson J., Regner A., Parpal S., Malinowsky D., Radesater A.-C., Li T., Singh R., Eriksson H., Lundkvist J., . First and second generation gamma-secretase modulators (GSMs) modulate Abeta production through different mechanisms. J. Biol. Chem.. 2012;287:11810-11819.
[Google Scholar]

[2] Cobo J., Nogueras M., Low J.N., Rodríguez R., . Bischler-Napieralski cyclocondensation in the synthesis of new 11H-pyrimido[4,5-b][1,4]benzodiazepines. Tetrahedron Lett.. 2008;49(51):7271-7273.
[Google Scholar]

[3] Costantino L., Barlocco D., . Privileged structures as leads in medicinal chemistry. Curr. Med. Chem.. 2006;13(1):65-85.
[Google Scholar]

[4] de la Torre J.M., Nogueras M., Borkowski E.J., Suvire F.D., Enriz R.D., Cobo J., . Easy synthesis of new series of pteridine analogs: di- and tetrahydropyrimido[4,5-d]pyrimidines via 5-pyrimidinecarbaldehydes. ARKIVOC (v) 2014:42-63.
[Google Scholar]

[5] Di Braccio M., Grossi G., Roma G., Vargiu L., Mura M., Marongiu M.E., . 1,5-Benzodiazepines. Part XII. Synthesis and biological evaluation of tricyclic and tetracyclic 1,5-benzodiazepine derivatives as nevirapine analogues. Eur. J. Med. Chem.. 2001;36:935-949.
[Google Scholar]

[6] Dinakaran V.S., Bomma B., Srinivasan K.K., . Fused pyrimidines: the heterocycle of diverse biological and pharmacological significance. Der Pharma Chemica. 2012;4(1):255-265.
[Google Scholar]

[7] Dlugosz A., . A Novel Synthesis of Pyrimidobenzodiazepines. Eine neue Synthese von Pyrimidobenzodiazepinen. Arch. Pharm.. 1990;323:59-60.
[Google Scholar]

[8] Dlugosz A., . Preparation of novel derivative of pyrimidobenzodiazepine as immunosuppressant. Pol. Pat. Appl.. 1998;129:4665. PL 173147 B1 19980130; Chem .Abstr
[Google Scholar]

[9] Freidinger R.M., Evans B.E., Bock M.G., . Preparation of 1,4-benzodiazepines with 6-membered heterocyclic rings as drugs for anxiety treatment. Eur. Pat. Appl.. 1992;1993(118):139861. EP 519678 A2 19921223; Chem. Abstr
[Google Scholar]

[10] Gangjee A., Zeng Y., McGuire J.J., Mehraein F., Kisliuk R.L., . Synthesis of Classical, Three-Carbon-Bridged 5-Substituted Furo[2,3-d]pyrimidine and 6-Substituted Pyrrolo[2,3-d]pyrimidine Analogues as Antifolates. J. Med. Chem.. 2004;47:6893-6901.
[Google Scholar]

[11] Gracias V., Ji Z., Akritopoulou-Zanze I., Abad-Zapatero C., Huth J.R., Song D., Hajduk P.J., Glaser K.B., Marcotte P.A., Pease L., Soni N.B., Stewart K.D., Davidsen S.K., Michaelides M.R., Djuric S.W., . Scaffold oriented synthesis. Part 2: design, synthesis and biological evaluation of pyrimido-diazepines as receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett.. 2008;18:2691-2695.
[Google Scholar]

[12] Horton D.A., Bourne G.T., Smythe M.L., . The combinatorial synthesis of bicyclic privileged structures or privileged substructures. Chem. Rev.. 2003;103:893.
[Google Scholar]

[13] Insuasty B., Orozco F., Lizarazo C., Quiroga J., Abonia R., Hursthouse M., Nogueras M., Cobo J., . Synthesis of new indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones as potential antitumor agents. Bioorg. Med. Chem.. 2008;16(18):8492-8500.
[Google Scholar]

[14] Insuasty B., Garcia A., Quiroga J., Abonia R., Nogueras M., Cobo J., . Synthesis of novel 6,6a,7,8-tetrahydro-5H-naphtho[1,2-e]pyrimido[4,5-b][1,4]diazepines under microwave irradiation as potential anti-tumor agents. Eur. J. Med. Chem.. 2010;45(7):2841-2846.
[Google Scholar]

[15] Insuasty B., Orozco F., Quiroga J., Abonia R., Nogueras M., Cobo J., . Synthesis and structure elucidation of new regioisomeric 2-alkylamino-6-aryl-8,9-dihydropyrimido[4,5-b][1,4]diazepin-4(7H)-ones. J. Het. Chem.. 2014;51(1):196-202.
[Google Scholar]

[16] Juby P.F., Hudyma T.W., . Antihypoxic 11H-pyrimido-[4,5-b][1,4]-benzodiazepines. Ger. Offen. DE 2418285 A1 19741107. Chem. Abstr. 1974;1975(82):73045.
[Google Scholar]

[17] Kanhed A.M., Dash R.C., Parmar N., Das T.K., Giridhar R., Yadav M.R., . Benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one derivatives as Aurora A kinase inhibitors: LQTA-QSAR analysis and detailed systematic validation of the developed model. Mol. Divers.. 2015;19(4):965-974.
[Google Scholar]

[18] Kim D.H., Santilli A.A., . Pyrimido[4,5-e][1,4] diazepin-5-ones and 4,4-ethylenediaminobis(2-phenyl-pyrimidine-5-carboxylic acid) diethyl esters. J. Med. Chem.. 1969;12(5):1121-1122.
[Google Scholar]

[19] Kobayashi S., . Synthesis of pyrimidine-fused 1,4-benzodiazepines. Chem. Lett.. 1974;9:967-970.
[Google Scholar]

[20] Kobayashi S., . Pyrimidine-Fused 1,4-Benzodiazepines. Reaction of 1,4-Benzodiazepines with Formamide–POCl₃. Bull. Chem. Soc. Jpn.. 1975;48:302-306.
[Google Scholar]

[21] Marchal A., Melguizo M., Nogueras M., Sánchez A., Low J.N., . Novel procedure for selective C-nitrosation of aminopyrimidine derivatives under neutral conditions. Scope and synthetic applications. Synlett 2002:255-258.
[Google Scholar]

[22] Marchal A., Nogueras M., Sánchez A., Low J.N., Naesens L., De Clercq E., Melguizo M., . Alkoxy-5-nitrosopyrimidines: useful building block for the generation of biologically active compounds. Eur. J. Org. Chem. 2010:3823-3830.
[Google Scholar]

[23] McGuigan C., Pathirana R.N., Snoeck R., Andrei G., DeClercq E., Balzarini J., . Discovery of a new family of inhibitors of human cytomegalovirus (HCMV) based upon lipophilic alkyl furano pyrimidine dideoxy nucleosides: action via a novel non-nucleosidic mechanism. J. Med. Chem.. 2004;47:1847-1851.
[Google Scholar]

[24] Murthy K.S.K., Knaus E.E., . Synthesis of pyrimido[1,4]diazepin-2-one analogs and their evaluation as anticonvulsant agents. Drug Develop. Res.. 1999;46:155.
[Google Scholar]

[25] Pike D.C., Hora M.T., Bailey S.W., Ayling J.E., . Pyrimidodiazepine, a ring-strained cofactor for phenylalanine hydroxylase. Biochemistry. 1986;25:4762.
[Google Scholar]

[26] Sagar S.R., Agarwal J.K., Pandya D.H., Dash R.P., Nivsarkar M., Vasu K.K., . Design, synthesis and biological evaluation of novel pyrazolo-pyrimidinones as DPP-IV inhibitors in diabetes. Bioorg. Med. Chem. Lett.. 2015;25(20):4428-4433.
[Google Scholar]

[27] Schaefer H., Riedel R., Klemm K., Senn-Bilfinger J., Eltze M., . Benzodiazepinones and pharmaceutical compositions containing them. Eur. Pat. Appl.. 1981;1981(95):132969. EP 24582 A1 19810311; Chem. Abstr
[Google Scholar]

[28] Wang S., Folkes A., Chuckowree I., Cockcroft X., Sohal S., Miller W., Milton J., Wren S.P., Vicker N., Depledge P., Scott J., Smith L., Jones H., Mistry P., Faint R., Thompson D., Cocks S., . Studies on pyrrolopyrimidines as selective inhibitors of multidrug-resistance-associated protein in multidrug resistance. J. Med. Chem.. 2004;47:1329-1338.
[Google Scholar]

[29] Xiang J., Wen D., Xie H., Dang Q., Bai X., . Synthesis of novel 8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones. J. Comb. Chem.. 2010;12(4):503-509.
[Google Scholar]

[30] Xu S., Zhang L., Chang S., Luo J., Lu X., Tu Z., Liu Y., Zhang Z., Xu Y., Ren X., Ding K., . Design, synthesis and biological evaluation of new molecules inhibiting epidermal growth factor receptor threonine⁷⁹⁰ → methionine⁷⁹⁰ mutant. Med. Chem. Commun.. 2012;3(9):1155-1159.
[Google Scholar]

Straightforward synthesis of pyrimido[4,5-e][1,4]diazepines via 6-aminopyrimidin-5-carbaldehydes

Abstract

Keywords

4(6)-Aminopyrimidines

Diazepines

Fused heterocycles

Acylation

Cyclization

1 Introduction

2 Results and discussion

3 Conclusions

4 Experimental

4.1 Preparation of intermediates (4-aminopyrimidin-5-yl)methylamino esters

4.1.1 Ethyl-2-{[(4-amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl](benzyl)amino}acetate (3a)

4.1.2 Ethyl-3-{[(4-amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl](benzyl)amino}propanoate (3b)

4.1.3 Ethyl-2-{[(4-amino-1-methyl-2-methylthio-6-oxo-1,6-dihydropyrimidin-5-yl)methyl](benzyl)amino}acetate (3c)

4.2 Cyclization attempts of derivatives 3. Synthesis of methylene bis-pyrimidines (4)

4.2.1 1,9-Dimethyl-4,6-bis((triphenyl-λ5-phosphanylidene)amino)-5,9-dihydro-2H-pyrano[2,3-d:6,5-d’]dipyrimidine-2,8(1H)dione (4a)

4.2.2 5,5′-Methylenebis[2-methoxy-3-methyl-6-(trimethylsilylamino)pyrimidin-4(3H)-one] (4b)

4.2.3 5,5′-Methylenebis[6-amino-3-methyl-2-(methylthio)pyrimidin-4(3H)-one] (4c)

4.3 Preparation of intermediates (6-aminopyrimidin-5-yl)methyl(substituted)amino acyl halides (5, 6 & 7)

4.3.1 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimdin-5-yl)methyl]-2-chloro-N-phenylacetamide (5a)

4.3.2 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimdin-5-yl)methyl]-2-chloro-N-phenylpropanamide (5b)

4.3.3 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimdin-5-yl)methyl]-2-chloro-N,2-diphenylacetamide (5c)

4.3.4 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-chloroacetamide (5d)

4.3.5 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-chloropropanamide (5e)

4.3.6 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-chloro-2-phenylacetamide (5f)

4.3.7 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-chloro-2,2-diphenylacetamide (5g)

4.3.8 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-bromobutanamide (5h)

4.3.9 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-bromohexanamide (5i)

4.3.10 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-2-bromo-2-methylpropanamide (5j)

4.3.11 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-2-chloro-N-cyclohexylacetamide (5k)

4.3.12 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-2-chloro-N-cyclohexylpropanamide (5l)

4.3.13 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-2-chloro-N-cyclohexyl-2,2-diphenylacetamide (5m)

4.3.14 N-{[4-Amino-1-methyl-2-methylthio-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-2-chloro-N-phenylacetamide (5n)

4.3.15 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-2-chloro-N-phenylpropanamide (5o)

4.3.16 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-2-chloro-N,2-diphenylpropanamide (5p)

4.3.17 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-chloroacetamide (5q)

4.3.18 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-chloropropanamide (5r)

4.3.19 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-chloro-2-phenylacetamide (5s)

4.3.20 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-chloro-2,2-diphenylacetamide (5t)

4.3.21 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-bromobutanamide (5u)

4.3.22 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-2-bromohexanamide (5v)

4.3.23 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-2-chloro-N-cyclohexylacetamide (5w)

4.3.24 N-{[4-Amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-2-chloro-N-cyclohexylpropanamide (5x)

4.3.25 N-((4-amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-2-chloro-N-cyclohexyl-2-phenylacetamide (5y)

4.3.26 N-Benzyl-2-chloro-N-{[4-(2-chloroacetamido)-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}acetamide (6a)

4.3.27 N-Benzyl-2-chloro-N-{[4-(2-chloroacetamido)-(2-methylthio)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}acetamide (6b)

4.3.28 N-[(4-Amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-3-chloropropanamide (10a)

4.3.29 N-[(4-amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzyl-3-bromopropanamide (10b)

4.3.30 N-{[4-amino-(2-methylthio)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzyl-3-chloropropanamide (10c)

4.4 Indoline-pyrimidine hybrid by the reaction of [(6-aminopyrimidin-5-yl)methyl](phenyl)amino with haloacyl halides

4.5 Cyclization of intermediates (6-aminopyrimidin-5-yl)methylamino acyl halides to pyrimido[4,5-e][1,4]diazepines (8)

4.5.1 2-Methoxy-3-methyl-6-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8a)

4.5.2 2-Methoxy-3,8-dimethyl-6-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8b)

4.5.3 6-Benzyl-2-methoxy-3-methyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8d)

4.5.4 6-Benzyl-2-methoxy-3,8-dimethyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8e)

4.5.5 6-Benzyl-2-methoxy-3-methyl-8-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8f)

4.5.6 6-Benzyl-8-ethyl-2-methoxy-3-methyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8h)

4.5.7 6-Benzyl-8-butyl-2-methoxy-3-methyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8i)

4.5.8 6-Cyclohexyl-2-methoxy-3-methyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8k)

4.5.9 6-Cyclohexyl-2-methoxy-3,8-dimethyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8l)

4.5.10 3-methyl-2-(methylthio)-6-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8n)

4.5.11 3,8-dimethyl-2-(methylthio)-6-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8o)

4.5.12 6-Benzyl-3-methyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8q)

4.5.13 6-Benzyl-3,8-dimethyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8r)

4.5.14 6-Benzyl-3-methyl-2-(methylthio)-8-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8s)

4.5.15 6-Benzyl-8-ethyl-3-methyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8u)

4.5.16 6-Benzyl-8-butyl-3-methyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8v)

4.5.17 6-Cyclohexyl-3-methyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8w)

4.5.18 6-Cyclohexyl-3,8-dimethyl-2-(methylthio)-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8x)

4.5.19 6-Cyclohexyl-3-methyl-2-(methylthio)-8-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (8y)

4.6 Acylamide-pyrimidine hybrid by the elimination reaction from (6-aminopyrimidin-5-yl)methylamino acyl halides

4.6.1 N-[(4-amino-2-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzylmethacrylamide (9a)

4.6.2 N-[(4-amino-1-methyl-2-methoxy-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-N-benzylacrylamide (9b)

4.6.3 N-{[4-amino-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-benzylacrylamide (9c)

4.7 Derivatization (N-Methylation) of pyrimido[4,5-e][1,4]diazepines (8)

4.7.1 2-Methoxy-3,8,9-trimethyl-6-phenyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (11a)

4.7.2 6-Benzyl-2-methoxy-3,9-dimethyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (11b)

4.7.3 6-Benzyl-2-methoxy-3,8,9-trimethyl-5,6,8,9-tetrahydro-3H-pyrimido[4,5-e][1,4]diazepine-4,7-dione (11c)

4.2.1 1,9-Dimethyl-4,6-bis((triphenyl-λ⁵-phosphanylidene)amino)-5,9-dihydro-2H-pyrano[2,3-d:6,5-d’]dipyrimidine-2,8(1H)dione (4a)