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CAS No. : | 755039-55-5 | MDL No. : | MFCD10698781 |
Formula : | C14H19ClN4O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RDOMCFLYXZACAX-SNVBAGLBSA-N |
M.W : | 294.78 | Pubchem ID : | 24820413 |
Synonyms : |
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.64 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 86.14 |
TPSA : | 49.33 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.98 cm/s |
Log Po/w (iLOGP) : | 3.02 |
Log Po/w (XLOGP3) : | 2.98 |
Log Po/w (WLOGP) : | 1.87 |
Log Po/w (MLOGP) : | 1.91 |
Log Po/w (SILICOS-IT) : | 1.86 |
Consensus Log Po/w : | 2.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.64 |
Solubility : | 0.0683 mg/ml ; 0.000232 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.68 |
Solubility : | 0.0617 mg/ml ; 0.000209 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.48 |
Solubility : | 0.0978 mg/ml ; 0.000332 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.26 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate In 1,4-dioxane at 90℃; for 6 h; Inert atmosphere | Compound IV (260 mg, 0.93 mmol) was dissolved in dioxane (5 ml).Trimethylphosphate (650 mg, 4.6 mmol) and K2CO3 (192 mg, 1.39 mmol) were added, and the reaction mixture was stirred under 2 at 90 °C for 6hr until the starting material was consumed. The reaction mixture was diluted with water and extracted with EtOAc. The solvent was removed, and the residue was purified by silica gel column chromatography (PE: EtOAc=l : l) to give intermediate B as a white solid (270 mg, 86 percent). 3/4 NMR (CDCI3) δ: 7.7 (s, 1H), 4.34 (m, 1H), 4.25 (m, 1H), 3.33 (s, 3H), 2.1-1.6 (m, 10H) and 0.86 ppm (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In acetone for 2 h; Reflux; Inert atmosphere | Step 11 (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one; (7R)-2-Chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one In (3.50 g, 12.50 mmol) was dissolved in 80 mL of acetone followed by the addition of methyl p-toluenesulfonate (3.40 g, 18.70 mmol) and potassium carbonate (3.45 g, 25 mmol). The resulting mixture was heated to reflux for 2 hours with stirring and then cooled down to room temperature. The reaction mxiture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o (3.40 g, yield: 93.0percent) as a white solid. MS m/z (ESI): 295.4 [M+1] |
93% | With potassium carbonate In acetone for 2 h; Reflux | Step 11 (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one (7R)-2-Chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one 1n (3.50 g, 12.50 mmol) was dissolved in 80 mL of acetone followed by the addition of methyl p-toluenesulfonate (3.40 g, 18.70 mmol) and potassium carbonate (3.45 g, 25 mmol). The resulting mixture was heated to reflux for 2 hours with stirring and then cooled down to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o (3.40 g, yield: 93.0percent) as a white solid.MS m/z (ESI): 295.4 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With toluene-4-sulfonic acid; for 5.0h;Heating / reflux; | (7/?)-2-Chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one (WO2004076454; 200 mg,0.68 mmol), methyl 4-amino-3-methoxy-benzoate (123 mg, 0.68 mmol) andp-toluenesulfonic acid (323 mg, 1.70 mmol) were suspended in (2i?/5)-4-methyl-2-pentanol (1 mL) and heated at reflux for 5 h, allowing the MeOH evaporate during the reaction. The reaction mixture was cooled and loaded onto an SCX-2 column and washed with MeOH (40 mL). The crude product was then eluted from the SCX-2 column with NH3(40 mL, 7M in MeOH) and the volatiles removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient 0-100% EtOAc in /s°-hexane) afforded the title compound (185 mg, 53%) as a gum. 1H NMR (400 MHz, DMSO-d6) deltaH 0.77 (t, 3H), 0.91 (dd, 6H), 1.29 (d, 3H), 1.37 - 1.48 (m, IH), 1.55 - 2.08 (m, 12H), 3.30 (s, 3H), 3.95 (s, 3H), 4.25 (dd, IH), 4.37 (quintet, IH), 5.09 - 5.17 (m, IH), 7.49 (d, IH), 7.58 (dd, IH), 7.71 (s, IH), 7.86 (s, IH), 8.51 (dt, IH); MS m/z 510 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With toluene-4-sulfonic acid; In Methyl isobutyl carbinol; for 12.0h;Heating / reflux; | (7lambda)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one (WO2004076454; 281 mg, 0.95 mmol)), 4-amino-2-fluoro-N-(l-methyl-4-piperidyl)benzamide (Intermediate 5; 263 mg, 1.05 mmol) and />-toluenesulfonic acid (452 mg, 2.38 mmol) were suspended in (2R/S)-4- methyl-2-pentanol (10 mL) and heated at reflux for 12 h. The reaction mixture was cooled and loaded onto an SCX-2 column then washed with MeOH (20 mL). The crude compound was eluted from the SCX-2 column with NH3 (40 mL, 7M in MeOH). Purification by column chromatography (SiO2, eluting with MeOH) afforded a gum. The gum was dissolved in DCM and filtered to afford the title compound (319 mg, 66%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) deltaH 0.75 (tr, 3H), 1.60-2.10 (m, 14H), 2.74 (s, 3H), 3.09 (m, 2H), 3.22 (s, 3H), 3.39 (m, 2H), 4.03 (m, IH), 4.20 (m, IH), 4.41 (s, IH), 7.38 (d, IH), 7.53 (tr, IH), 7.78 (s, IH), 7.89 (d, IH); MS m/z 510 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With toluene-4-sulfonic acid; In Methyl isobutyl carbinol; for 24.0h;Heating / reflux; | (7/?)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one (WO2004076454, 250 mg, 0.85 mmol), 3-ethoxy-iV-(l-methyl-4-piperidyl)-4-amino-benzamide (Intermediate 20; 236 mg, 0.85 mmol), and p-toluenesulfonic acid (405 mg, 2.13 mmol) were dissolved in (2R/S)-4- methyl-2-pentanol (4 mL) and stirred at reflux for 24 h. The reaction mixture was then cooled, and poured onto SCX-2 column. The SCX-2 column was washed with MeOH (20 mL) and the crude product was eluted from the SCX-2 column with NH3 (20 mL, 7M in MeOH). Purification by column chromatography (SiO2, gradient eluent: 0-10% NH3 [7M in MeOH] in DCM) afforded the title compound (109 mg, 24%) as a solid. 1H NMR (400 MHz, CDCl3) deltaH 0.88 (t, 3H), 1.50 (t, 3H), 1.60 - 1.76 (m, 6H), 1.81 - 1.91 (m, 4H), 1.98 - 2.19 (m, 6H), 2.30 (s, 3H), 2.82 (d, 2H), 3.33 (s, 3H), 3.95 - 4.02 (m, IH), 4.21 (q, 3H), 4.40 - 4.45 (m, IH), 5.89 (d, IH), 7.21 - 7.24 (m, IH), 7.40 (d, IH), 7.61 (s, IH), 7.68 (s, IH), 8.54 (d, IH); MS m/z 536 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In ISOPROPYLAMIDE; at -10 - 20℃; for 0.833333h; | 25.0 g of the compound Z3d and 6.5 mL (0.1 mol) methyl iodide were placed in 250 mL dimethylacetamide and at -10 C. 3.8 g (0.95 mol) sodium hydride were added as a 60% dispersion in mineral oil. The mixture was stirred for 20 min. at 0 C., then 30 min. at ambient temperature and finally ice was added. The reaction mixture was evaporated down and combined with 300 mL water. The precipitate formed was suction filtered and washed with petroleum ether. Yield: 23.0 g of a compound Z3e (colourless solid) | |
With sodium hydride; In ISOPROPYLAMIDE; at -10 - 20℃; for 0.833333h; | 25.0 g of the compound Z3d and 6.5 mL (0.1 mol) methyl iodide are placed in 250 mL dimethylacetamide and at -100C 3.8 g (0.95 mol) sodium hydride as a 60% dispersion in mineral oil is added. It is stirred for 20 min at 00C, then for 30 min at ambient temperature and finally ice is added. The reaction mixture is evaporated down and combined with 300 mL water. The precipitate formed is suction filtered and washed with petroleum ether. Yield: 23.0 g of a compound Z3e (colourless solid) | |
With sodium hydride; In ISOPROPYLAMIDE; at 0 - 20℃; for 0.833333h; | 25.0 g of the compound Z3d and 6.5 mL (0.1 mol) methyl iodide are placed in 250 mL dimethylacetamide and at -10 C. 3.8 g (0.95 mol) sodium hydride are added as a 60% dispersion in mineral oil. The mixture is stirred for 20 min. at 0 C., then 30 min. at ambient temperature and finally ice is added. The reaction mixture is evaporated down and combined with 300 mL water. The precipitate formed is suction filtered and washed with petroleum ether. Yield: 23.0 g of a compound Z3e (colourless solid) |
With sodium hydride; In ISOPROPYLAMIDE; at 4 - 20℃; for 7.0h; | Preparation of Compound 9; 38 g (0.95 mol) sodium hydride (60% dispersion in mineral oil) are added batchwise to a solution of 264 g (0.94 mol) of 8 and 161 g (1.13 mol) methyl iodide in 2 L dimethylacetamide at 4-10 C. within one hour. The cooling bath is removed and the mixture is allowed to come up to 20 C. within 2 hours. It is cooled to 10 C. and a further 0.38 g (9.5 mmol) sodium hydride are added. The mixture is stirred for 4 hours at 10-15 C. 100 mL ethyl acetate and 1 kg ice are added to the reaction solution. The resulting suspension is diluted with 3 L demineralised water. The suspension is stirred for 2 hours, the precipitate is suction filtered and the filter cake is washed with demineralised water. The product is dried at 50 C. in the vacuum drying cupboard. 273 g of product 9 are obtained as colourless crystals. | |
With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 0 - 20℃; for 0.833333h; | 25.0 g of the compound Z3d and 6.5 mL (0.1 mol) methyl iodide were placed in 250 mL dimethylacetamide and at -10 C. 3.8 g (0.95 mol) sodium hydride as a 60% dispersion in mineral oil was added. It was stirred for 20 min at 0 C., then for 30 min at ambient temperature and finally ice was added. The reaction mixture was evaporated down and combined with 300 mL water. The precipitate formed was suction filtered and washed with petroleum ether. Yield: 23.0 g of a compound Z3e (colourless solid) | |
With sodium hydride; In ISOPROPYLAMIDE; at 4 - 20℃; for 7.0h;Product distribution / selectivity; | 38 g (0.95 mol) sodium hydride (60% dispersion in mineral oil) are added batchwise to a solution of 264 g (0.94 mol) of 8 and 161 g (1.13 mol) methyl iodide in 2 L dimethylacetamide at 4-10 C. within one hour. The cooling bath is removed and the mixture is allowed to come up to 20 C. within 2 hours. It is cooled to 10 C. and a further 0.38 g (9.5 mmol) sodium hydride are added. The mixture is stirred for 4 hours at 10-15 C. 100 mL ethyl acetate and 1 kg ice are added to the reaction solution. The resulting suspension is diluted with 3 L demineralised water. The suspension is stirred for 2 hours, the precipitate is suction filtered and the filter cake is washed with demineralised water. The product is dried at 50 C. in the vacuum drying cupboard. 273 g of product 9 are obtained as colourless crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In ethanol; water; for 48.0h;Heating / reflux; | 6.0 g of the compound Z3e and 5.1 g (31 mmol) 4-amino-3-methoxybenzoic acid are suspended in 90 mL ethanol and 350 mL water, combined with 3.5 mL concentrated hydrochloric acid and refluxed for 48 h. The reaction mixture is evaporated down, the residue stirred with methanol/diethyl ether and the precipitate formed is suction filtered. Yield: 6.3 g of a compound Z3 (light beige crystals) | |
With hydrogenchloride; In ethanol; water; for 48.0h;Heating / reflux; | 6.0 g of the compound Z3e and 5.1 g (31 mmol) of 4-amino-3-methoxybenzoic acid are suspended in 90 mL ethanol and 350 mL water, combined with 3.5 mL conc. hydrochloric acid and refluxed for 48 h. The reaction mixture is evaporated down, the residue is stirred with methanol/diethyl ether and the precipitate formed is suction filtered. Yield: 6.3 g of a compound Z3 (light beige crystals) | |
With hydrogenchloride; In ethanol; water; for 48.0h;Heating / reflux; | 6.0 g of the compound Z3e and 5.1 g (31 mmol) 4-amino-3-methoxybenzoic acid were suspended in 90 mL ethanol and 350 mL water, combined with 3.5 mL conc. hydrochloric acid and refluxed for 48 h. The reaction mixture was evaporated down, the residue stirred with methanol/diethyl ether and the precipitate formed was suction filtered. Yield: 6.3 g of a compound Z3 (light beige crystals) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethylcarbonate; at 130℃; for 6.0h;Autoclave;Product distribution / selectivity; | A suspension of 100 g (356 mmol) 8 and 73.8 g (534 mmol) potassium carbonate in 400 mL dimethylcarbonate is heated to 130 C. in an autoclave for 6 hours. The mixture is left to cool and 300 mL demineralised water and 200 mL ethyl acetate are added with stirring. The aqueous phase is separated off together with undissolved salts. 500 mL of solvent are distilled off from the organic phase at a pressure 180 mbar and a heating bath temperature of 70 C. 600 mL demineralised water are added to the residue and 100 mL solvent are distilled off at a pressure of 150 mbar and a heating bath temperature of 80 C. 350 mL ethanol are added to the suspension which is then heated to 65 C. The solution is left to cool and inoculated. It is cooled to 10 C., the precipitate is suction filtered and washed with a mixture of demineralised water and ethanol (2.5:1). The product is dried at 50 C. in the vacuum drying cupboard. 95.5 g product 2 are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; In Methyl isobutyl carbinol; for 5.0h;Heating / reflux; | Preparation of the Compound of Example No. 46 by Reacting 4 with 9; A suspension of 201 g (1.06 mol) para-toluenesulphonic acid-hydrate, 209 g (706 mmol) 9 and 183 g (695 mmol) 4 in 800 mL 2-methyl-4-pentanol is refluxed. 100 mL solvent are distilled off. The mixture is refluxed for 3 hours, 200 mL of 2-methyl-4-pentanol are added and 120 mL of solvent are distilled off. After 2 hours heating at reflux temperature a further 280 mL solvent are distilled off. The mixture is cooled to 100 C. and 1 L demineralised water and then 0.5 L ethyl acetate are added to the reaction solution. The organic phase is separated off and the aqueous phase is again washed with 0.5 L ethyl acetate. 1.5 L dichloromethane and 0.5 L ethyl acetate are added to the acidic aqueous phase. The pH value of the aqueous phase is adjusted to pH 9.2 with 260 mL of 6 normal sodium hydroxide solution. The aqueous phase is separated off and the organic phase is washed three times with in each case 1 L of 1 normal aqueous sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate, filtered and the solvent is evaporated down under reduced pressure. 406 g of crude product are obtained.The crude product is dissolved in 1.5 L ethyl acetate. At a temperature of 50-55 C. 2.5 L of methyl-tert.-butylether are added. The mixture is inoculated at 45 C. and stirred for 16 hours with cooling to ambient temperature. The suspension is stirred for 3.5 hours at 0-5 C. and the precipitate is suction filtered. The filter cake is washed again with methyl-tert.-butylether/ethyl acetate (2:1) and methyl-tert.-butylether. The product is dried at 50 C. in the vacuum drying cupboard. 236 g of crystalline compound of Example no. 46 are obtained as the anhydrate (I). | |
A suspension of 201 g (1.06 mol) para-toluenesulphonic acid-hydrate, 209 g (706 mmol) 9 and 183 g (695 mmol) 4 in 800 mL 2-methyl-4-pentanol is refluxed. 100 mL solvent are distilled off. The mixture is refluxed for 3 hours, 200 mL of 2-methyl-4-pentanol are added and 120 mL of solvent are distilled off. After 2 hours heating at reflux temperature a further 280 mL solvent are distilled off. The mixture is cooled to 100 C. and 1 L demineralised water and then 0.5 L ethyl acetate are added to the reaction solution. The organic phase is separated off and the aqueous phase is again washed with 0.5 L ethyl acetate. 1.5 L dichloromethane and 0.5 L ethyl acetate are added to the acidic aqueous phase. The pH value of the aqueous phase is adjusted to pH 9.2 with 260 mL of 6 normal sodium hydroxide solution. The aqueous phase is separated off and the organic phase is washed three times with in each case 1 L of 1 normal aqueous sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate, filtered and the solvent is evaporated down under reduced pressure. 406 g crude product are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 120℃; for 5.0h; | 1.5 g Z3e and 1.22 g tert-butyl 4-amino-3-methoxy-phenyl-carbamate were melted together at 120 C. for 5 h. After cooling the reaction mixture was dissolved in dichloromethane and extracted 2× with potassium carbonate solution and 2× with water. After drying the org. phase the mixture was separated by silica gel chromatography (eluant 99:1, CH2Cl2:MeOH) and the product fractions were combined. Yield: 0.92 g of a compound Z3f (light brown crystals) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Stage 1 - (7R)-2-[(4-Bromo-2-fluorophenyl)amino]-8-cyclopentyl-7-ethyl-5-methyl-7,8- dihydropteridin-6(5H)-oneTo a suspension of 4-bromo-2-fluoro-phenylamine (388mg, 2.04mmol) in ethanol (2.5ml) and water (10ml) was added concentrated HCI (0.26ml) and intermediate A (300mg, 1.02mmol). The mixture was heated at 800C for 18 hours, cooled and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (10ml) and washed with saturated NaHCO3 (2 x 10 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography (20 - 50% EtOAc in heptane) to afford the title product as a yellow oil (90mg, 20%). ESMS: m/z 448, 449, 450 [Br splitting]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Intermediate 2A:(y/^^delta-Cvclopentyl-T-ethyl^-rf^hvdroxyphenv?aminoi-delta-methyl-y.delta-dihvdropteridin- 6(5H)-one; The title intermediate was prepared from Intermediate 1 according to the general procedure (Scheme 1 ).To a solution of (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5AV)- one [Intermediate 1] (200mg, 0.68mmol) in EtOH (2ml_), water (8ml_) and concentrated HCI (0.2ml_) was added 4-aminophenol (148mg, 1.36mmol). The reaction mixture was refluxed for 18 hours and concentrated under reduced pressure. The residue was partitioned between sat. NaHCO3 (2OmL) and a mixture of MeOH/DCM (1 :3, 2OmL). The aqueous layer was separated and extracted with MeOH/DCM (1 :3, 20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to leave a brown solid. Trituration with Et?O afforded the titled intermediate as a grey solid (125mg, 50% yield). ESMS: m/z 368 [M+H]+ 1H NMR (DMSO-d6, 300 MHz) 8.90 (1 H, s), 8.64 (1 H, s), 7.74 (1H, s), 7.43 (2H, d, J=8.9 Hz), 6.64 (2H, d, J=8.9 Hz), 4.39- 4.29 (1 H, m), 4.16 (1H, dd, J=3.6, 7.8 Hz), 3.22 (3H, s), 1.99-1.54 (10H, m), 0.77 (3H, t, J=7.4 Hz). EPO <DP n="24"/; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | In 2-ethoxy-ethanol; at 150℃; for 4.0h; | Stage 1; - Cyclopentyl lambda/-(terf-butoxycarbonyl)-4-[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-5,6,7.8-tetrahydropteridin-2-yl]amino}-L-phenylalaninateTo a solution of (7f?)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5/-/)- one [Intermediate 1] (100mg, 0.34mmol) in 2-ethoxyethanol (2mL) was added cyclopentyl 4-amino-lambda/-(terf-butoxycarbonyl)-L-phenylalaninate [Intermediate 6A] (170mg, 0.51 mmol). The reaction mixture was heated at 150C for 4 hours, cooled and concentrated under reduced pressure to give a brown residue. The residue was purified by column chromatography (5% methanol / 1% NH4OH in EtOAc) to afford the product as a yellow solid (89mg, 43% yield). ESMS: m/z 607 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | To a suspension of (R)-2-Chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydro-5H- pteridin-6-one (0.60 g, 2 mmol), prepared as described in WO 2004/076454, in a 2/1 mixture E^O/Ethanol (60 mL), were added 37%HC1 (0.6 mL) and 2-trifluoromethoxy-5-(4-Methyl-piperazin-l-yl)-phenylamine (0.55 g, 2 mmol), prepared as described inPreparation 1. The reaction was refluxed for 72 hours, concentrated to small volume(20 mL) diluted with water (30 mL) and extracted with DCM (2 X 50 mL). The aqueous phase was neutralized by addition of NaHCCh then extracted with DCM (2 X 50 mL).The organic fractions were combined, dried over sodium sulfate and solvent was evaporated to drieness. Purification of crude solid by flash chromatography on silica gel <n="22"/>(eluant: DCM/EtOH 90/10) yield the title compound as an light brown solid (0.23 g ,22% yield).1H NMR (400 MHz, DMSO-J6) delta ppm 0.76 (t, J=7.50 Hz, 3 H) 1.44 (m, 2H) 1.60 (m,2H) 1.73 (m, 2H) 1.82 (m, 4H) 2.27 (s, 3 H) 2.49 - 2.53 (m, 4 H) 3.09 - 3.18 (m, 4 H) 3.23 (s, 3 H) 4.18 (dd, J=7.56, 3.66 Hz, 1 H) 4.20 - 4.28 (m, 1 H) 6.67 (dd, J=9.15, 3.05Hz, 1 H) 7.12 - 7.21 (m, 1 H) 7.54 (d, J=3.05 Hz, 1 H) 7.77 (s, 1 H) 7.93 (s, 1 H); MS(ESI): 534 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; tert-butyl alcohol;1,3-bis-(diphenylphosphino)propane; palladium diacetate; In dimethyl sulfoxide; at 80℃; under 7600.51 Torr; for 10.0h; | Intermediate B (10.0 g, 34.01 mmol) was dissolved in 15 mL of DMSO and 185 mL of tBuOH and Pd(OAc)2 (1.14 g, 5.1 mmol), DPPP (2.2 g, 5.1 mmol) and TEA (7.7 g, 76.5 mmol) were added. The solution was stirred at 80 C for 10 h under CO (10 atm). The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with water and brine, dried with Na2S04, purified by silica gel column (DCM:MeOH = 20: 1) to give (R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridine-2-carboxylic acid (compound 1-245, 2.2 g) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In 1,4-dioxane; isopropyl alcohol; at 160℃; for 1.0h;microwave irradiation; | To a solution of the Intermediate B (400 mg, 1.36 mmol) in 5 mL of isopropanol in a microwave vial, 4N HCI in dioxane (0.43 mL) and 4-aminopyridine (320 mg, 2 eq) were added and the vial was heated in a microwave oven at 160 C for 1 hour. Solvent was removed under reduced pressure and the resulting yellow solid was purified by reversed phase HPLC to give the title compound. XH NMR (CDCI3) delta: 9.62 (bs, IH), 8.91 (d, J = 7.7 Hz, 2H), 7.81 (s, IH), 7.37 (d, J = 7.8 Hz, 2H), 4.44- 4.36 (m, 2H), 3.41 (s, 3H), 2.08-1.71 (m, 10H), 0.89 (t, J = 7.5 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ISOPROPYLAMIDE; at 150℃; for 2.0h; | To a stirring mixture of Intermediate B (600 mg, 1 eq) in 2.1 mL of DMA, sodium methanethiolate (286 mg, 2.0 eq) was added. The reaction mixture was placed in a 150 C preheated oil bath and stirred for 2 hr. The reaction mixture was cooled to rt and slowly diluted with ethyl ether and brine. The layers were separated. The aqueous layer was extracted with ethyl ether (2 x 30 mL). The combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure. To a stirring mixture of the crude methyl sulfide pteridine in 5 mL of HOAc at 0 C, a solution of KMn04 (643 mg, 2 eq) in 5 mL of water was added slowly over 10 min. The reaction mixture was reacted for 1 h before additional KMn04 (320 mg, 0.5 eq) in water was added. Cold water and a 10% a2S203 solution were added. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure. The resulting material was purified by MPLC to give compound 1-306. LCMS: 339.1 m/z (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; In 1,2-dimethoxyethane; at 200℃; for 2.0h;microwave irradiation; | A mixture of intermediate B (50 mg, 0.17 mmol), 2-phenyl-lH-imidazole (3.4 mmol, 20 equivalents, 490 mg), Cul (0.05 equivalents, 0.009 mmol, 1.7 mg), trans- l,2-bis(methylamino)cyclohexane (14.2 mg, 0.003 mL) and K2CO3 (1.7 mmol, 233 mg) in 2 mL of DME were heated in a microwave at 200 C for 2h. The reaction was diluted with DME, filtered through Celite and evaporated. The residue was purified by reverse phase HPLC using a gradient of 30-50% CH3CN (0.1% TFA) over 30 min with a flow rate of 20 mL/min eluting from a PCRP-5 column (2.5 x 30 cm). Following lyophylization, 22.8 mg of the title compound was obtained with a purity > 99%. ¾ NMR (CDCI3) delta: 7.9-7.3 (m, 8H), 4.2 (m, 1H), 3.55 (m, 1H), 3.3 (s, 3H), 2.0-1.1 (m, 10H) and 0.85 ppm (t, 3H); LCMS: 403.2 m/z (M+H)+; ret. Time: 3.77 min (Analytical Method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; In N,N-dimethyl-formamide; at 110℃; for 18.0h;Inert atmosphere; sealed vial; | A mixture of intermediate B (150 mg, 0.509 mmol), 2-(lH-imidazol-4- yl)acetonitrile (1.01 mmol, 2 equivalents, 108 mg), Cul (0.1 equivalents, 0.0509 mmol, 10 mg), trans-1,2 bis(methylamino)cyclohexane (14 mg, 0.102 mmol) and CS2CO3 (1.01 mmol, 331 mg) in DMF (1 mL) was purged with nitrogen and was subsequently heated in a sealed vial at 110 C for 18 h. The reaction was diluted with ethyl acetate, filtered through Celite and evaporated. The residue was purified by reverse phase preparative HPLC and lyophilized to give the title compound (185 mg). ^ MR CDCls) delta: 8.66 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 4.31-4.37 (m, 2H), 3.91 (s, 2H), 3.38 (s, 3H), 1.70-2.13 (m, 10H), and 0.93 ppm (t, J= 7.4 Hz, 3H); LCMS: 366.1 m/z (M+H)+; ret. Time: 3.444 min (Analytical Method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; for 18.0h;Inert atmosphere; Reflux; | To a solution of Intermediate B (1.0 eq) in DMF, ethynylbenzene (compound III-139, 3.0 eq), Pd(PPh3)2Cl2 (0.2 eq), Cul (0.25 eq) and Et3N (5.0 eq) were added. The mixture was refluxed for 18 h under argon, extracted with EtOAc and purified by silica gel column to give (R)-8-cyclopentyl-7-ethyl-5-methyl-2- (phenylethynyl)-7,8-dihydropteridin-6(5H)-one (compound IV- 139). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In water; toluene; at 120℃; for 60.0h;Inert atmosphere; | 5.0 g of Intermediate B, 2.5 eq of acetophenone, 0.05 eq of Pd2(dba)3, 0.1 eq of BINAP and 2.0 eq of CS2CO3 were suspended in a mixture of 50 mL toluene and 10 mL of water, then heated to 120 C under 2 for 60 hours. After cooling to rt, added 100 mL of water and washed the organic phase, dried with anhydrous a2S04, concentrated and purified by silica gel column (PE:EA=3: 1) to give the pureIntermediate B-l (1.2 g, 19 %) as yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 120℃; for 0.666667h;microwave irradiation; | To a solution of 150 mg of intermediate B in DME (5 mL) and water (4: 1) Pd(dppf)Ci2 (75 mg), a2C03 (162 mg), and pyridin-4-ylboronic acid (90 mg) were added. The reaction mixture was heated in a microwave at 120 C for 40 min. The mixture was concentrated and extracted with EtOAc and dried with a2S04. The solvent was removed and the residue was purified by silica column to give the title compound (107 mg, yield 64%). LCMS (0.05%TFA): 338.0 m/z (M+H)+; XH-NMR (CDCI3, 400MHz): delta: 8.72 (d, 2H, J=3.6 Hz), 8.17 (d, 2H, J=3.6Hz), 7.80 (s, 1H), 4.46 (m, 1H), 4.32 (m, 1H), 3.40 (s, 3H), 2.17 (m, 1H), 2.06 (m, 1H), 1.99(m, 1H), 1.92 (m, 4H), 1.70-1.76 (m, 3H), 0.88 (t, 3H, J=6Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 140℃; for 0.666667h;microwave irradiation; | To a solution of intermediate B (300 mg, 1.2 mmol) in 6 mL of DME and 2 mL of water, 2-(fluoro)pyridin-4-ylboronic acid (719 mg, 5.1 mmol), Pd(dppf)Ci2 (160 mg, 0.13 mmol), and 2M a2C03 (324 mg, 3.06 mL) were added. The mixture was microwave heated at 140 C for about 40 min. The mixture was concentrated under reduced pressure and extracted with EtOAc. The combined organic phase was 8576.98-304 dried with Na2S04 and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (PE: EA=75%) to give the title compound as a white solid (200 mg, 65% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In 1,4-dioxane; at 90℃; for 6.0h;Inert atmosphere; | Compound IV (260 mg, 0.93 mmol) was dissolved in dioxane (5 ml).Trimethylphosphate (650 mg, 4.6 mmol) and K2CO3 (192 mg, 1.39 mmol) were added, and the reaction mixture was stirred under 2 at 90 C for 6hr until the starting material was consumed. The reaction mixture was diluted with water and extracted with EtOAc. The solvent was removed, and the residue was purified by silica gel column chromatography (PE: EtOAc=l : l) to give intermediate B as a white solid (270 mg, 86 %). ¾ NMR (CDCI3) delta: 7.7 (s, 1H), 4.34 (m, 1H), 4.25 (m, 1H), 3.33 (s, 3H), 2.1-1.6 (m, 10H) and 0.86 ppm (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine; In ethanol; at 120℃; for 1.0h;microwave irradiation; | Intermediate B and hydrazine (6 equivalents) in ethanol was heated in a microwave for 1 h at 120 C. The solvent was removed to give Intermediate B-2. This material was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In acetone; for 2.0h;Reflux; Inert atmosphere; | Step 11 (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one; (7R)-2-Chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one In (3.50 g, 12.50 mmol) was dissolved in 80 mL of acetone followed by the addition of methyl p-toluenesulfonate (3.40 g, 18.70 mmol) and potassium carbonate (3.45 g, 25 mmol). The resulting mixture was heated to reflux for 2 hours with stirring and then cooled down to room temperature. The reaction mxiture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o (3.40 g, yield: 93.0%) as a white solid. MS m/z (ESI): 295.4 [M+1] |
93% | With potassium carbonate; In acetone; for 2.0h;Reflux; | Step 11 (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one (7R)-2-Chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one 1n (3.50 g, 12.50 mmol) was dissolved in 80 mL of acetone followed by the addition of methyl p-toluenesulfonate (3.40 g, 18.70 mmol) and potassium carbonate (3.45 g, 25 mmol). The resulting mixture was heated to reflux for 2 hours with stirring and then cooled down to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o (3.40 g, yield: 93.0%) as a white solid.MS m/z (ESI): 295.4 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Step 12 methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylate; (7R)-2-Chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o(670 mg, 2.30 mmol), methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate 1g (440 mg, 2.30 mmol) and p-toluenesulfonic acid (700 mg, 3.68 mmol) were dissolved in 25 mL 4-methyl-2-pentanol. The resulting solution was heated to reflux for 6 hours with stirring. The reaction solution was added with 25 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (50 mL×3) and saturated sodium chloride solution (50 mL×3) successively, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylate 1p (0.77 g, yield: 74.0%) as a light yellow solid. MS m/z (ESI): 452.3 [M+1] | |
74% | Step 12 methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylate (7R)-2-Chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o (670 mg, 2.30 mmol), methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate 1g (440 mg, 2.30 mmol) and p-toluenesulfonic acid (700 mg, 3.68 mmol) were dissolved in 25 mL 4-methyl-2-pentanol. The resulting solution was heated to reflux for 6 hours with stirring. The reaction solution was added with 25 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with water (50 mL*3) and saturated sodium chloride solution (50 mL*3) successively, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylate 1p (0.77 g, yield: 74.0%) as a light yellow solid.MS m/z (ESI): 452.3 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Step 5 Methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylate; Methyl 7-amino-2,2-dimethyl-3H-benzofuran-4-carboxylate 4d (770 mg, 3.48 mmol) was dissolved in 20 mL of 1,3-dimethyl-butanol followed by the addition of <strong>[755039-55-5](7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one</strong> 1o (1.23 g, 4.18 mmol) and p-toluenesulfonic acid (1.06 g, 5.57 mmol) successively. The reaction solution was heated to reflux for 2 hours with stirring. The resulting solution was added with 50 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (30 mL), saturated sodium chloride solution (20 mL) successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylate 4e (1.78 g, yield: 100%) as a light yellow solid. MS m/z (ESI): 480.4 [M+1] | |
100% | Step 5 Methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylate Methyl 7-amino-2,2-dimethyl-3H-benzofuran-4-carboxylate 4d (770 mg, 3.48 mmol) was dissolved in 20 mL of 1,3-dimethyl-butanol followed by the addition of <strong>[755039-55-5](7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one</strong> 1o (1.23 g, 4.18 mmol) and p-toluenesulfonic acid (1.06 g, 5.57 mmol) successively. The reaction solution was heated to reflux for 2 hours with stirring. The resulting solution was added with 50 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with water (30 mL), saturated sodium chloride solution (20 mL) successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylate 4e (1.78 g, yield: 100%) as a light yellow solid.MS m/z (ESI): 480.4 [M+1] | |
With toluene-4-sulfonic acid; In Methyl isobutyl carbinol; | Step 5 Methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylate Methyl 7-amino-2,2-dimethyl-3H-benzofuran-4-carboxylate 4d (770 mg, 3.48 mmol) was dissolved in 20 mL of 1,3-dimethyl-butanol followed by the addition of <strong>[755039-55-5](7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one</strong> 1o (1.23 g, 4.18 mmol) and p-toluenesulfonic acid (1.06 g, 5.57 mmol) successively. The reaction solution was heated to reflux for 2 hours with stirring. The resulting solution was added with 50 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with water (30 mL), saturated sodium chloride solution (20 mL) successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylate 4e (1.78 g, yield: 100%) as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.2% | Step 8 benzyl 7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate; Benzyl 7-amino-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate 29g (212 mg, 0.65 mmol) was dissolved in 20 mL of 4-methyl-2-pentanol followed by the addition of <strong>[755039-55-5](7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one</strong> 1o (230 mg, 0.78 mmol) and p-toluenesulfonic acid monohydrate (198 mg, 1.04 mmol). The reaction solution was heated to reflux for 3 hours with stirring and concentrated under reduced pressure. The resulting residue was added with 30 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 ml×3). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate 29h (0.13 g, yield: 34.2%) as a white solid. MS m/z (ESI): 585.5 [M+1] | |
34.2% | Step 8 benzyl 7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate Benzyl 7-amino-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate 29g (212 mg, 0.65 mmol) was dissolved in 20 mL of 4-methyl-2-pentanol followed by the addition of <strong>[755039-55-5](7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one</strong> 1o (230 mg, 0.78 mmol) and p-toluenesulfonic acid monohydrate (198 mg, 1.04 mmol). The reaction solution was heated to reflux for 3 hours with stirring and concentrated under reduced pressure. The resulting residue was added with 30 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 ml*3). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate 29h (0.13 g, yield: 34.2%) as a white solid.MS m/z (ESI): 585.5 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With hydrogenchloride; In ethanol; water; for 16.0h;Reflux; Inert atmosphere; | Step 5 7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid; 7-Amino-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 40d (160 mg, 0.70 mmol) and (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydro-5H-pteridin-6-one 1o (232 mg, 0.80 mmol) were dissolved in 34 mL of the mixture solvent of ethanol and water (V:V = 1:2.4) followed by the addition of 0.4 mL of concentrated hydrochloric acid. The reaction solution was heated to reflux for 16 hours with stirring, then cooled down resulting in the formation of precipitate. The precipitate was filtered to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 40e (0.15 g, yield: 43.0%) as a yellow solid. MS m/z (ESI): 480.3 [M-1] |
43% | With hydrogenchloride; In ethanol; water; for 16.0h;Reflux; | Step 5 7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 7-Amino-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 40d (160 mg, 0.70 mmol) and (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydro-5H-pteridin-6-one 1o (232 mg, 0.80 mmol) were dissolved in 34 mL of the mixture solvent of ethanol and water (V:V=1:2.4) followed by the addition of 0.4 mL of concentrated hydrochloric acid. The reaction solution was heated to reflux for 16 hours with stirring, then cooled down resulting in the formation of precipitate. The precipitate was filtered to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 40e (0.15 g, yield: 43.0%) as a yellow solid.MS m/z (ESI): 480.3 [M-1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Step 3 7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-methyl-2,3-dihydrobenzofuran-4-carboxylate; Methyl 7-amino-2-methyl-2,3-dihydrobenzofuran-4-carboxylate 30b (80 mg, 0.38 mmol), <strong>[755039-55-5](7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one</strong> 1o (113 mg, 0.38 mmol) and p-toluenesulfonic acid monohydrate (115 mg, 0.60 mmol) were dissolved in 20 mL of 4-methyl-2-pentanol. The reaction solution was heated to reflux for 2.5 hours with stirring. The resulting solution was concentrated under reduced pressure followed by the addition of 30 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (50 ml×3). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by the preparation plate to obtain the title compound 77-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-methyl-2,3-dihydrobenzofuran-4-carboxylate 30c (0.10 g, yield: 56.0%) as a white solid. | |
56% | Step 3 7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-methyl-2,3-dihydrobenzofuran-4-carboxylate Methyl 7-amino-2-methyl-2,3-dihydrobenzofuran-4-carboxylate 30b (80 mg, 0.38 mmol), <strong>[755039-55-5](7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one</strong> 1o (113 mg, 0.38 mmol) and p-toluenesulfonic acid monohydrate (115 mg, 0.60 mmol) were dissolved in 20 mL of 4-methyl-2-pentanol. The reaction solution was heated to reflux for 2.5 hours with stirring. The resulting solution was concentrated under reduced pressure followed by the addition of 30 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (50 ml*3). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by the preparation plate to obtain the title compound 77-[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-methyl-2,3-dihydrobenzofuran-4-carboxylate 30c (0.10 g, yield: 56.0%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In tert-butyl alcohol; at 100℃; for 16.0h; | Example 4. Preparation of (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6, 7,8- tetrahydropteridin-2-yl)amino)-N-(l-methylpiperidin-4-yl)benzamide (i?)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (14.7 mg, 0.050 mmol, 1 eq), 4-amino-N-(l-methylpiperidin-4-yl)benzamide (14.0 mg, 0.060 mmol, 1.2 eq), Pd2dba3 (2.3 mg, 0.0025 mmol, 5 mol%), XPhos (3.6 mg, 0.0075 mmol, 15 mol%) and K2C03 (27.6 mg, 0.20 mmol, 4 eq) were dissolved in tBuOH (0.5 mL, 0.1 M) and heated to 100 C for 16 hours. The mixture was filtered through celite, washed with DCM and condensed. Purification by column chromatography (ISCO, 4 g silica column, 0-15% MeOH/DCM, 15 minute gradient) gave the desired product as a yellow solid (7.37 mg, 0.0150 mmol, 30%). 1H NMR (400 MHz, Methanol-^) delta 7.87 - 7.65 (m, 5H), 4.52 (q, J = 8.6, 8.1 Hz, 1H), 4.25 (dd, J= 7.8, 3.7 Hz, 1H), 3.96 (ddd, J= 15.2, 11.2, 4.1 Hz, 1H), 3.33 (s, 3H), 3.10 (d, J= 12.2 Hz, 2H), 2.48 (d, J= 3.8 Hz, 5H), 2.19 - 2.10 (m, 1H), 2.07 - 1.96 (m, 3H), 1.94 - 1.66 (m, 10H), 0.86 (t, J= 7.5 Hz, 3H). 13C NMR (100 MHz, cd3od) delta 169.54, 165.63, 156.84, 153.75, 145.65, 139.44, 130.02, 129.19, 127.48, 118.76, 117.36, 114.65, 61.28, 60.02, 55.42, 47.44, 45.48, 31.72, 30.47, 30.03, 28.59, 28.02, 24.32, 23.99, 9.37. LCMS 492.45. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In tert-butyl alcohol; at 100℃; for 16.0h; | Example 3. Preparation of (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6, 7,8- tetrahydropteridin-2-yl)amino)-3-(cyclopentyloxy)-N-(l-methylpiperidin-4-yl)benzamide (i?)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (14.7 mg, 0.050 mmol, 1 eq), 4-amino-3-(cyclopentyloxy)-N-(l-methylpiperidin-4-yl)benzamide (19.9 mg, 0.060 mmol, 1.2 eq), Pd2dba3 (2.3 mg, 0.0025 mmol, 5 mol%), XPhos (3.6 mg, 0.0075 mmol, 15 mol%) and K2C03 (27.6 mg, 0.20 mmol, 4 eq) were dissolved in tBuOH (0.5 mL, 0.1 M) and heated to 100 C for 16 hours. The mixture was filtered through celite, washed with DCM and condensed. Purification by column chromatography (ISCO, 4 g silica column, 0-15% MeOH/DCM, 15 minute gradient) gave the desired product as a yellow solid (8.54 mg, 0.0148 mmol, 30%). 1H NMR (400 MHz, Methanol-^) delta 8.49 (d, J= 8.4 Hz, 1H), 7.77 (s, 1H), 7.50 - 7.44 (m, 2H), 5.01 (dq, J= 5.8, 2.9 Hz, 1H), 4.43 (p, J= 8.3 Hz, 1H), 4.28 (dd, J= 7.5, 3.6 Hz, 1H), 3.95 (dq, J= 8.4, 5.6, 4.1 Hz, 1H), 3.33 (s, 3H), 3.07 (d, J = 12.1 Hz, 2H), 2.47 - 2.36 (m, 5H), 2.20 - 1.82 (m, 16H), 1.82 - 1.67 (m, 7H), 0.85 (t, J= 7.5 Hz, 3H). 13C NMR (100 MHz, cd3od) delta 169.40, 165.55, 156.24, 153.59, 146.72, 139.16, 135.09, 127.49, 121.04, 117.49, 117.43, 112.68, 82.06, 62.01, 60.80, 55.55, 47.75, 45.64, 33.81, 31.86, 30.33, 30.03, 28.58, 28.08, 24.94, 24.66, 24.45, 9.22. LCMS 575.63 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); johnphos; In toluene; at 90℃; for 18.0h; | Example 1. Preparation of (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6, 7,8- tetrahydropteridin-2-yl)oxy)-3-methoxy-N- ( I -methylpiperidin-4-yl)benzamide (i?)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (synthesized as previously reported in Budin et al, ACIEE, 2011, 50, 9378) (29.5 mg, 0.10 mmol, 1 eq), 4-hydroxy-3-methoxy-N-(l-methylpiperidin-4-yl)benzamide (52.9 mg, 0.20 mmol, 2 eq), Pd2dba3 (6.4 mg, 0.007 mmol, 7 mol%), JohnPhos (8.4 mg, 0.028 mmol, 28 mol%) and K P04 (106 mg, 0.5 mmol, 5 eq) were dissolved in toluene (1 mL, 0.1 M) and heated to 90 C for 18 hours. The mixture was then diluted with EtOAc and washed three times with aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and condensed. Purification by column chromatography (ISCO, 4 g silica column, 0- 15% MeOH/DCM, 13 minute gradient) gave the desired product as a white solid (5.46 mg, 0.0104 mmol, 10% yield). 1H NMR (400 MHz, Methanol-^) delta 7.64 (s, 1H), 7.49 (d, J= 2.0 Hz, 1H), 7.43 (dd, J= 8.2, 2.0 Hz, 1H), 7.09 (d, J= 8.2 Hz, 1H), 4.15 (dd, J= 6.6, 3.3 Hz, 1H), 3.83 (d, J= 4.3 Hz, 1H), 3.70 (s, 3H), 3.58 - 3.46 (m, 2H), 3.23 (s, 3H), 2.85 (d, J = 12.2 Hz, 2H), 2.23 (s, 3H), 2.11 (t, J= 11.1 Hz, 2H), 1.98 - 1.44 (m, 12H), 1.14 (dd, J= 8.3, 5.6 Hz, 2H), 0.68 (t, J= 7.5 Hz, 3H). 13C NMR (100 MHz, cd3od) delta 168.66, 165.62, 161.32, 153.98, 153.15, 146.60, 138.92, 133.47, 123.65, 121.28, 119.60, 112.84, 64.67, 63.44, 56.39, 55.40, 47.65, 45.39, 31.59, 29.06, 28.60, 28.53, 28.00, 24.60, 24.41, 8.62. LCMS 522.68 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In tert-butyl alcohol; at 100℃; for 20.0h; | (R)-ethyl 4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2- yl)amino)-3-methoxybenzoate (i?)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (88.4 mg, 0.30 mmol, 1 eq), ethyl 4-amino-3-methoxybenzoate (70.3 mg, 0.36 mmol, 1.2 eq), Pd2dba3 (13.7 mg, 0.015 mmol, 5 mol%), XPhos (21.5 mg, 0.045 mmol, 15 mol%) and K2C03 (166 mg, 1.2 mmol, 4 eq) were dissolved in tBuOH (3 mL, 0.1 M) and heated to 100 C for 20 hours. The mixture was filtered through celite, washed with DCM and condensed. Purification by column chromatography (ISCO, 4 g silica column, 0-100% EtOAc/hexanes, 12 minute gradient) gave the desired product as a dark yellow oil (119 mg, 0.262 mmol, 87%). 1H NMR (400 MHz, Chloroform-;/) delta 8.57 (d, J= 8.5 Hz, 1H), 7.68 (tt, J = 4.2, 2.1 Hz, 3H), 7.53 (d, J= 1.4 Hz, 1H), 4.50 (q, J= 7.4 Hz, 1H), 4.36 (qd, J= 7.1, 1.2 Hz, 2H), 4.22 (dd, J= 7.8, 3.6 Hz, 1H), 3.96 (d, J= 1.2 Hz, 3H), 3.32 (d, J= 1.3 Hz, 3H), 2.22 - 2.10 (m, 1H), 2.04 - 1.96 (m, 1H), 1.89 - 1.78 (m, 4H), 1.70 (dq, J= 14.2, 8.2, 7.4 Hz, 4H), 1.39 (td, J= 7.1, 1.2 Hz, 3H), 0.91 - 0.82 (m, 3H). LCMS 453.80 (M+H). |
77% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In tert-butyl alcohol; at 100℃; for 21.0h; | <strong>[755039-55-5](R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one</strong> (44.2 mg, 0.15 mmol, 1 eq), ethyl 4-amino-3-methoxybenzoate (35.1 mg, 0.18 mmol, 1.2 eq), Pd2dba3 (6.9 mg, 0.0075 mmol, 5 mol %), XPhos (10.7 mg, 0.0225 mmol, 15 mol %) and potassium carbonate (82.9 mg, 0.60 mmol, 4 eq) were dissolved in tBuOH (1.5 mL, 0.1 M) and heated to 100 C. After 21 hours, the mixture was cooled to room temperature, filtered through celite, washed with DCM and concentrated under reduced pressure. Purification by column chromatography (ISCO, 4 g silica column, 0-100% EtOAc/hexanes over an 18 minute gradient) gave a yellow oil (52.3 mg, 0.1 15 mmol, 77%). NMR (400 MHz, Chloroform- delta 8.57 (d, J = 8.5 Hz, 1H), 7.69 (td, J = 6.2, 2.9 Hz, 2H), 7.54 (d, J = 1.8 Hz, 1H), 4.52 (t, J = 7.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.23 (dd, J = 7.9, 3.7 Hz, 1H), 3.97 (s, 3H), 3.33 (s, 3H), 2.20 - 2.12 (m, 1H), 2.03 - 1.97 (m, 1H), 1.86 (ddd, J = 13.9, 7.6, 3.6 Hz, 4H), 1.78 - 1.65 (m, 4H), 1.40 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H). LCMS 454.32 (M+H). |
77% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In tert-butyl alcohol; at 100℃; for 21.0h; | <strong>[755039-55-5](R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one</strong> (44.2 mg, 0.15 mmol, 1 eq), ethyl 4-amino-3-methoxybenzoate (35.1 mg, 0.18 mmol, 1.2 eq), Pd2dba3 (6.9 mg, 0.0075 mmol, 5 mol %), XPhos (10.7 mg, 0.0225 mmol, 15 mol %) and potassium carbonate (82.9 mg, 0.60 mmol, 4 eq) were dissolved in tBuOH (1.5 mL, 0.1 M) and heated to 100 C. After 21 hours, the mixture was cooled to room temperature, filtered through celite, washed with DCM and concentrated under reduced pressure. Purification by column chromatography (ISCO, 4 g silica column, 0-100% EtOAc/hexanes over an 18 minute gradient) gave a yellow oil (52.3 mg, 0.115 mmol, 77%). 1H NMR (400 MHz, Chloroform-d) delta 8.57 (d, J=8.5 Hz, 1H), 7.69 (td, J=6.2, 2.9 Hz, 2H), 7.54 (d, J=1.8 Hz, 1H), 4.52 (t, J=7.9 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 4.23 (dd, J=7.9, 3.7 Hz, 1H), 3.97 (s, 3H), 3.33 (s, 3H), 2.20-2.12 (m, 1H), 2.03-1.97 (m, 1H), 1.86 (ddd, J=13.9, 7.6, 3.6 Hz, 4H), 1.78-1.65 (m, 4H), 1.40 (t, J=7.1 Hz, 3H), 0.88 (t, J=7.5 Hz, 3H). LCMS 454.32 (M+H). |
77% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In tert-butyl alcohol; at 100℃; for 21.0h; | (R)-2-chloro-8-cyclopentyl-7-ethyl-5 -methyl-7, 8-dihydropteridin-6(51])-one (44.2 mg, 0.15 mmol, 1 eq), ethyl 4-amino-3-methoxybenzoate (35.1 mg, 0.18 mmol, 1.2 eq), Pd2dba3 (6.9mg, 0.0075 mmol, 5 mol %), XPhos (10.7 mg, 0.0225 mmol, 15 mol %) and potassium carbonate(82.9 mg, 0.60 mmol, 4 eq) were dissolved in tBuOH (1.5 mL, 0.1 M) and heated to 100 C. After21 hours, the mixture was cooled to room temperature, filtered through celite, washed with DCMand concentrated under reduced pressure. Purification by column chromatography (ISCO, 4 gsilica column, 0-100% EtOAc/hexanes over an 18 minute gradient) gave a yellow oil (52.3 mg,0.115 mmol, 77%). ?HNMR (400 MHz, Chloroform-cl) 8.57 (d,J= 8.5 Hz, 1H), 7.69 (td,J=6.2, 2.9 Hz, 2H), 7.54 (d, J= 1.8 Hz, 1H), 4.52 (t, J= 7.9 Hz, 1H), 4.37 (q, J= 7.1 Hz, 2H), 4.23(dd, J= 7.9, 3.7 Hz, 1H), 3.97 (s, 3H), 3.33 (s, 3H), 2.20-2.12 (m, 1H), 2.03- 1.97 (m, 1H), 1.86(ddd, J 13.9, 7.6, 3.6 Hz, 4H), 1.78 - 1.65 (m, 4H), 1.40 (t, J 7.1 Hz, 3H), 0.88 (t, J= 7.5 Hz,3H). LCMS 454.32 (M+H). |
77% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In tert-butyl alcohol; at 100℃; for 21.0h; | <strong>[755039-55-5](R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one</strong> (44.2 mg, 0.15 mmol, 1 eq), ethyl 4-amino-3-methoxybenzoate (35.1 mg, 0.18 mmol, 1.2 eq), Pd2dba3 (6.9 mg, 0.0075 mmol, 5 mol %), XPhos (10.7 mg, 0.0225 mmol, 15 mol %) and potassium carbonate (82.9 mg, 0.60 mmol, 4 eq) were dissolved in tBuOH (1.5 mL, 0.1 M) and heated to 100 C. After 21 hours, the mixture was cooled to room temperature, filtered through celite, washed with DCM and concentrated under reduced pressure. Purification by column chromatography (ISCO, 4 g silica column, 0-100% EtOAc/hexanes over an 18 minute gradient) gave a yellow oil (52.3 mg, 0.115 mmol, 77%). 1H NMR (400 MHz, Chloroform-d) delta 8.57 (d, J = 8.5 Hz, 1H), 7.69 (td, J = 6.2, 2.9 Hz, 2H), 7.54 (d, J = 1.8 Hz, 1H), 4.52 (t, J = 7.9 Hz, 1H), 4.37 (q, J = 7.1Hz, 2H), 4.23 (dd, J = 7.9, 3.7 Hz, 1H), 3.97 (s, 3H), 3.33 (s, 3H), 2.20- 2.12 (m, 1H), 2.03- 1.97 (m, 1H), 1.86 (ddd, J = 13.9, 7.6, 3.6 Hz, 4H), 1.78- 1.65 (m, 4H), 1.40 (t, J = 7.1Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H). LCMS 454.32 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In tert-butyl alcohol; at 100℃; for 21h; | (R)-methyl l-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2- yl)indoline-5-carboxylate (i?)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (44.2 mg, 0.150 mmol, 1 eq), methyl indoline-5-carboxylate (31.9 mg, 0.180 mmol, 1.2 eq), Pd2dba3 (6.9 mg, 0.0075 mmol, 5 mol%), XPhos (10.7 mg, 0.0225 mmol, 15 mol%) and K2C03 (82.9 mg, 0.60 mmol, 4 eq) were dissolved in tBuOH (1.5 mL, 0.1 M) and heated to 100 C for 21 hours. The mixture was filtered through celite, washed with DCM and condensed. Purification by column chromatography (ISCO, 4 g silica column, 0-100% EtOAc/hexanes, 18 minute gradient) gave the desired product as a yellow oil (43.4 mg, 0.0997 mmol, 66%). 1H NMR (400 MHz, Chloroform-;/) delta 8.30 (d, J= 8.6 Hz, 1H), 7.89 (dd, J= 8.6, 1.8 Hz, 1H), 7.82 (d, J= 1.3 Hz, 1H), 7.76 (s, 1H), 4.47 (p, J= 8.5 Hz, 1H), 4.32 - 4.19 (m, 3H), 3.88 (s, 3H), 3.33 (s, 3H), 3.18 (t, J= 8.8 Hz, 2H), 2.21 - 2.11 (m, 1H), 2.04 - 1.98 (m, 1H), 1.86 (ddt, J= 16.3, 8.7, 4.4 Hz, 4H), 1.76 - 1.62 (m, 4H), 0.87 (t, J= 7.5 Hz, 3H). 13C NMR (100 MHz, cdcl3) delta 167.22, 163.83, 154.78, 152.04, 148.37, 137.77, 132.00, 130.05, 125.80, 121.94, 115.94, 113.23, 60.15, 58.76, 51.72, 49.52, 29.62, 29.18, 28.13, 27.07, 26.65, 23.36, 23.02, 9.17. LCMS 436.49. |
Tags: 755039-55-5 synthesis path| 755039-55-5 SDS| 755039-55-5 COA| 755039-55-5 purity| 755039-55-5 application| 755039-55-5 NMR| 755039-55-5 COA| 755039-55-5 structure
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P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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