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Example 1; Synthesis of 2-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-N-[5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl]-acetamide (compound (Ia)); Compound (Ia) was synthesised by reacting 2-(7-Amino-9H-thioxanthen-4-yl)-6-morpholin-4-yl-pyran-4-one with chloracetyl chloride followed by cis 2,6-dimethylmorpholine as shown in the scheme below: The synthesis of 2-(7-Amino-9H-thioxanthen-4-yl)-6-morpholin-4-yl-pyran-4-one was performed as described in WO 03/070726 (see Example 9, compound 20 therein), which is incorporated herein by reference. To a solution of 2-(7-Amino-9H-thioxanthen-4-yl)-6-morpholin-4-yl-pyran-4-one (20 mg, 0.051 mmol) in dry DMA (0.55 ml) was added chloroacetyl chloride (4.49 mul, 0.056 mmol) and triethylamine (15.7 mul, 0.11 mmol). The mixture was stirred at room temperature for 90 minutes. To the reaction was then added the Cis 2,6-dimethylmorpholine and the mixture stirred at room temperature overnight. The crude mixture was then submitted for HPLC purification and mass spectrometer analysis as described below. The product was purified on Gilson LC units. Mobile phase A-0.1% aqueous TFA, Mobile phase B-Acetonitrile, Flow rate 6 ml/min., Gradient-typically starting at 90% A/10% B for one minute, rising to 97% B after 15 minutes, holding there for 2 minutes, then back to the starting conditions. Column: Jones Chromatography Genesis 4mu C18 column, 10 mm×250 mm. Peak acquisition based on UV detection at 254 nm. Mass Specs were recorded on a Finnegan LCQ instrument in positive ion mode. Mobile phase A-0.1% aqueous formic acid, Mobile phase B-Acetonitrile, Flow rate 2 ml/min., Gradient-starting at 95% A/5% B for one minute, rising to 98% B after 5 minutes, holding there for 3 minutes, then back to the starting conditions. Column-Phenomenex 5mu Luna C18 column, 4.6 mm×50 mm UV detection at 254 nm, PDA detection scanning from 210 to 600 nm. The results of the analysis were as follows: Purity=85%, retention time (mins)=3.33, M++1=548 |
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Synthesis of (Ia): 2-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-N-[5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl]-acetamide (Compound (Ia)); In a 5 L flask under N2 was charged (VIII) (173.4 g) and chloroform (1673 ml). To the solution was added Na2CO3 (140.6 g) and the reaction stirred for 10 mins. A solution of chloroacetyl chloride (35.2 ml) in CHCl3 (169 ml) was added over 15 mins at <20 C. The reaction was stirred for 1.5 hours at room temperature (HPLC: 1.1% Stage 8, 96.8% Intermediate). Cis 2,6-dimethylmorpholine (108.4 ml) was added over 20 mins at <20 C. and then the reaction heated at 55-60 C. overnight. (HPLC: 91.1% Stage 9, 1.1% Stage 8, 4.2% Intermediate). Cis 2,6-dimethylmorpholine (6 ml) was added and the reaction heated for a further 1 hour (HPLC: 95.2% Stage 9, 1.0% Stage 8, 0.5% Intermediate). The reaction was allowed to cool to room temperature and water (1673 ml) added. After stirring for 20 mins, the organic layer was separated and then washed with water (2×1 L). The organic layer was dried over MgSO4 (50 g), filtered and the solvent removed in vacuo to give a brown oil. This was dissolved in DCM (1.1 L) and TBME (2.2 L) added to give a slurry. The solvents were then removed in vacuo to give a tan solid (441 g). This was slurried in TBME (2.8 L) at 35 C. for 30 mins, before cooling to 10 C. and filtering. The filter cake was washed with TBME (2×450 ml) and pulled dry to give 308 g solid. This was dried at 45 C. in a vacuum oven for 2 days until constant weight. This gave 247 g off-white solid which was subjected to analysis by 1H NMR, mass spec. and HPLC. 1H-NMR spectra were recorded on a Bruker AC3000 Series NMR 300 MHz spectrometer instrument. Chemical shifts were referenced relative to tetramethylsilane in CDCl3. The product was found to contain 12% TBME by 1H NMR. Excluding the TBME, the purity of the final product was >95% by 1H NMR. The 1H NMR spectrum of the product conformed to the structure of compound (Ia). The following chemical shift data were obtained: 9.10 (s, 1H), 7.84 (s, 1H), 7.33 (m, 6H), 6.32 (s, 1H), 5.51 (s, 1H), 3.90 (s, 2H), 3.82 (m, 4H), 3.73 (m, 2H), 3.20 (s, 2H), 3.11 (s, 2H), 2.73 (d, J=10.4 Hz, 2H), 2.03 (t, J=10.4 Hz, 2H), 1.16 (s, 6H) The mass spectrum conformed to the structure of formula (Ia). The purity of the final product was 95.8% by HPLC |