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CAS No. : | 21573-10-4 | MDL No. : | MFCD00511094 |
Formula : | C7H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KLCGMDWRXACELA-UHFFFAOYSA-N |
M.W : | 126.15 | Pubchem ID : | 11018869 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.71 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 34.05 |
TPSA : | 34.14 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.88 cm/s |
Log Po/w (iLOGP) : | 1.21 |
Log Po/w (XLOGP3) : | 0.26 |
Log Po/w (WLOGP) : | 0.88 |
Log Po/w (MLOGP) : | 0.31 |
Log Po/w (SILICOS-IT) : | 1.56 |
Consensus Log Po/w : | 0.85 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.59 |
Solubility : | 32.6 mg/ml ; 0.258 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.54 |
Solubility : | 36.6 mg/ml ; 0.29 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.13 |
Solubility : | 9.42 mg/ml ; 0.0746 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.34 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
47% | Stage #1: With ethanol; sodium hydride In tetrahydrofuran at 20℃; Inert atmosphere; Cooling with ice Stage #2: at 40℃; for 4 h; |
PREPARATION 176 1 -Cyclopropylbutane-1 ,3-dione Sodium hydride (60percent dispersion in oil, 0.95 g, 23.8 mmol) was washed several times with pentane and then suspended in 18 ml tetrahydrofuran under nitrogen. Ethyl acetate (2.3 ml, 23.5 mmol) and 2 drops of ethanol were added. A solution of cyclopropyl methyl ketone (1 .0 g, 1 1 .9 mmol) dissolved in 5 ml tetrahydrofuran was added drop-wise with stirring, maintaining the reaction temperature below 20 °C with an ice-bath. 18-Crown-6 (63 mg, 0.25 mmol) was added and the mixture was stirred at 40 °C for 4 h. The mixture was evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous phase was washed with ether. The aqueous was then acidified to pH 2 with 2N hydrochloric acid. The aqueous was extracted three times with ether and the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 0.7 g (5.5 mmol, 47percent) of the title compound. Purity 100percent. 1 H NMR (400 MHz, CHLOROFORM-c/) mixture of keto and enol tautomers Keto form δ ppm 0.83 - 0.99 (m, 2 H), 1 .07 - 1 .17 (m, 2 H), 1 .55 - 1 .71 (m, 1 H), 2.25 (s, 3 H), 3.69 (s, 2 H). Enol form δ ppm 0.83 - 0.99 (m, 2 H), 1 .07 - 1 .17 (m, 2 H), 1 .55 - 1 .71 (m, 1 H), 2.02 (s, 3 H), 5.61 (s, 1 H). UPLC/MS (3 min) retention time 0.69, 1 .33 min. LRMS: m/z 127 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | PREPARATION 176 1 -Cyclopropylbutane-1 ,3-dione Sodium hydride (60percent dispersion in oil, 0.95 g, 23.8 mmol) was washed several times with pentane and then suspended in 18 ml tetrahydrofuran under nitrogen. Ethyl acetate (2.3 ml, 23.5 mmol) and 2 drops of ethanol were added. A solution of cyclopropyl methyl ketone (1 .0 g, 1 1 .9 mmol) dissolved in 5 ml tetrahydrofuran was added drop-wise with stirring, maintaining the reaction temperature below 20 °C with an ice-bath. 18-Crown-6 (63 mg, 0.25 mmol) was added and the mixture was stirred at 40 °C for 4 h. The mixture was evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous phase was washed with ether. The aqueous was then acidified to pH 2 with 2N hydrochloric acid. The aqueous was extracted three times with ether and the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 0.7 g (5.5 mmol, 47percent) of the title compound. Purity 100percent. 1 H NMR (400 MHz, CHLOROFORM-c/) mixture of keto and enol tautomers Keto form delta ppm 0.83 - 0.99 (m, 2 H), 1 .07 - 1 .17 (m, 2 H), 1 .55 - 1 .71 (m, 1 H), 2.25 (s, 3 H), 3.69 (s, 2 H). Enol form delta ppm 0.83 - 0.99 (m, 2 H), 1 .07 - 1 .17 (m, 2 H), 1 .55 - 1 .71 (m, 1 H), 2.02 (s, 3 H), 5.61 (s, 1 H). UPLC/MS (3 min) retention time 0.69, 1 .33 min. LRMS: m/z 127 (M+1 ). | |
Sodium hydride (60percent dispersion in oil, 1.9 g, 47.5 mmol) was washed several times with pentane and then suspended in 35 ml tetrahydrofuran under nitrogen. Ethyl acetate (4.7 ml, 48 mmol) and 2 drops of ethanol were added. A solution of cyclopropyl methyl ketone (2.0 g, 23.8 mmol) dissolved in 10 ml tetrahydrofuran was added drop-wise with stirring, maintaining the reaction temperature below 20 ºC with an ice-bath. 18-Crown-6 (130 mg, 0.49 mmol) was added and the mixture was stirred at 40 ºC for 3 h. The mixture was evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous phase was extracted with ether. The aqueous was then acidified to pH 2 with 5N hydrochloric acid. The aqueous was further extracted three times with ether and the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 3.1 g of the crude title compound.1H NMR (400 MHz, CHLOROFORM-d) ) delta ppm 0.88 - 0.95 (m, 2 H), 1.07 - 1.14 (m, 2 H), 1.56 - 1.68 (m, 1 H), 2.02 (s, 3 H), 3.70 (s, 2 H).UPLC/MS (3 min) retention time 1.33 min.LRMS: m/z 127 (M+1). | ||
With 18-crown-6 ether; ethanol; sodium hydride; In tetrahydrofuran; at 20 - 40℃; for 3h;Inert atmosphere; | Sodium hydride (60percent dispersion in oil, 1 .9 g, 47.5 mmol) was washed several times with pentane and then suspended in 35 ml tetrahydrofuran under nitrogen. Ethyl acetate (4.7 ml, 48 mmol) and 2 drops of ethanol were added. A solution of cyclopropyl methyl ketone (2.0 g, 23.8 mmol) dissolved in 10 ml tetrahydrofuran was added drop- wise with stirring, maintaining the reaction temperature below 20 °C with an ice-bath. 18-Crown-6 (130 mg, 0.49 mmol) was added and the mixture was stirred at 40 °C for 3 h. The mixture was evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous phase was extracted with ether. The aqueous was then acidified to pH 2 with 5N hydrochloric acid. The aqueous was further extracted three times with ether and the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 3.1 g of the crude title compound. 1 H NMR (400 MHz, CHLOROFORM-d) ) delta ppm 0.88 - 0.95 (m, 2 H), 1 .07 - 1 .14 (m, 2 H), 1 .56 - 1 .68 (m, 1 H), 2.02 (s, 3 H), 3.70 (s, 2 H). UPLC/MS (3 min) retention time 1 .33 min. LRMS: m/z 127 (M+1 ). |
With potassium tert-butylate; In tetrahydrofuran; at 35 - 60℃; for 3h; | ntermediate 163-(Aminomethyl)-6-c lopropyl-4-methyl-2(lH)-pyridinoneStep 1l-Cyclopropyl-l,3-butanedioneTo a a stirring solution of THF (100 mL) was suspended potassium tert-butoxide (5.60 g, 49.5 mmol), followed by a mixture of cyclopropyl methyl ketone (3.27mL, 33 mmol) and ethyl acetate (9.69 mL, 99 mmol) in 30 mL THF at 35 °C, via addition funnel over a 25 min period. The contents were heated and stirred at 60 °C. After 3 h, the contents were removed from heating, and allowed to stir with cooling to roomtemperature. The reaction mixture was carefully diluted with 30 mL 2N HCl and stirred for 10 min. The mixture was extracted with diethyl ether (3 x 50 mL), and the combined organic layers washed with brine (1 x 50 mL). The organic layer was dried over MgSC^, filtered, and concentrated in vacuo. The crude oil was chromatographed on silica gel (eluent: 0 to 15percent EtOAc in hexanes) with good separation to afford the desired product as a light yellow colored oil, 3.9 g in -75percent purity (residual solvent), for an overall yield of 70percent. 1H NMR (400 MHz, CHLOROFORM- ) ? ppm 0.89 - 0.96 (m, 2 H), 1.09-1.15 (m, 2 H), 1.59-1.69 (m, 1H), 2.04 (s, 3H), 5.63 (s, 1 H), 15.5 - 16.0 (br s, 1H). | |
With potassium tert-butylate; In tetrahydrofuran; at 35 - 60℃; for 3h; | To a stirring solution ofTHF (100 mL) was added potassium tert-butoxide (5.60 g, 49.5 mmol), followed by a mixture of cyclopropyl methyl ketone (3 .27 mL, 33 mmol) andethyl acetate (9.69 mL, 99 mmol) in 30 mL THF at 35 °C, via addition funnel over a 25min period. The contents were heated and stirred at 60 °C. After 3 h, the contents wereremoved from heating, and allowed to cool to room temperature. The reaction mixture wascarefully diluted with 30 mL 2 N HCl and stirred for 10 min The mixture was extracted with diethyl ether (3 x 50 mL), and the combined organic layers washed with brine (1 x 50mL). The organic layer was dried over MgS04, filtered, and concentrated in vacuo.Purification by chromatography on silica gel (eluent: 0 to 15percent EtOAc in hexanes) withgood separation afforded 1-cyclopropyl-1,3-butanedione as a light yellow colored oil, 3.9gin ~75percent purity (residual solvent), for an overall yield of70percent. 1H NMR (400 MHz, CDCb) 8 ppm 0.89-0.96 (m, 2 H), 1.09-1.15 (m, 2 H), 1.59-1.69 (m, 1H), 2.04 (s, 3H),5.63 (s, 1 H), 15.5- 16.0 (br s, 1H). | |
With sodium methylate; In tetrahydrofuran; methanol; at 0 - 20℃; | General procedure: To a freshly prepared sodium methylate solution in methanol and THF ethyl trifluoroacetate (1.2 equiv) was added under stirring at 0° followed by addition of ketone 2 (1.0 equiv). The reaction mixture was allowed to stir for additional 3-24 h until the starting materials were consumed, as determined by thin-layer chromatography (TLC). Then the solvent was removed under reduced pressure and the residue was acidified with hydrochloric acid (1 N), followed by extracted with acetic ether. The combined organic layers were dried (MgSO4), Fitered and the filtrate was concentrated under reduced pressure. The crude product was puried by column chromatography. Yield: 40-90percent. For some cases, the crude products can be straight used for step c without the column chromatography procedure. | |
To a stirring solution of THF (100 mL) was added potassium tert-butoxide (5.60 g, 49.5 mmol), followed by a mixture of cyclopropyl methyl ketone (3.27 mL, 33 mmol) and ethyl acetate (9.69 mL, 99 mmol) in 30 mL THF at 35° C., via addition funnel over a 25 min period. The contents were heated and stirred at 60° C. After 3 h, the contents were removed from heating, and allowed to cool to room temperature. The reaction mixture was carefully diluted with 30 mL 2 N HCl and stirred for 10 min. The mixture was extracted with diethyl ether (3×50 mL), and the combined organic layers washed with brine (1×50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (eluent: 0 to 15percent EtOAc in hexanes) with good separation afforded 1-cyclopropyl-1,3-butanedione as a light yellow colored oil, 3.9 g in 75percent purity (residual solvent), for an overall yield of 70percent. 1H NMR (400 MHz, CDCl3) delta ppm 0.89-0.96 (m, 2H), 1.09-1.15 (m, 2H), 1.59-1.69 (m, 1H), 2.04 (s, 3H), 5.63 (s, 1H), 15.5-16.0 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1 Preparation of 1-cyclopropylbutane-1,3-dione 14.2 g (0.2 mol) of potassium methoxide were suspended in 75 ml of methyl tert-butyl ether, 8.4 g (0.1 mol) of CPMK were added, and 17.6 g (0.2 mol) of ethyl acetate were metered in within the space of 45 minutes. After 3 h at 30° C., the reaction mixture was worked up with aqueous hydrochloric acid and the low-boiling point constituents were distilled off after extraction. Yield of crude product: 12.18 g, corresponding to 97.4percent of theory, purity: 98.5percent by weight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Magnesium turnings (3.04 g, 125 mmol), suspended in methanol (145 ml), were heated to reflux under nitrogen for 1 hour, then cooled to room temperature and the P-keto acid described in Preparation 7 (25.5 g, 250 mmol), dissolved in methanol (25 ml), was added dropwise, with ice-cooling. The reaction mixture was stirred for 1 hour, at room temperature, and then the solvent was removed under reduced pressure to give the magnesium salt of the acid. Meanwhile, cyclopropane-carboxylic acid (9.91 ml, 125 mmol) was dissolved in dimethylformamide (200 ml). Carbonyldiimidazole (22.4 g, 138 mmol) was then added portionwise, under nitrogen, at 0° C. This reaction mixture was stirred for 1.5 hours, and then the magnesium salt from above was added as a solution in N,N-dimethylformamide (100 ml) at 0° C. The reaction mixture was allowed to stir at room temperature for 92 hours, and then it was poured into 2M aqueous hydrochloric acid (85 ml), followed by dilution with water (170 ml). The mixture was extracted with diethyl ether (6.x.200 ml), and the combined organic extracts were then washed with brine (3.x.200 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual orange oil was purified by flash chromatography on silica gel eluting with pentane:diethyl ether (100:0 then 90:10 then 80:20, by volume) to provide the title compound (7.39 g, 24percent) as a yellow oil. 1H NMR (400 MHz, CDCl3): delta=0.83-0.95 (m, 2H), 1.06-1.10 (m, 2H), 1.54-1.63 (m, 1H), 2.00 (s, 3H); LRMS (electrospray): m/z 149 [MNa+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; tetrabutylammomium bromide; dimethyl sulfoxide; In acetonitrile; at 0 - 20℃; for 1.5h; | [CHLOROTRIMETHYLSILANE] (18. [9ML, 174MMOL) ] was added to a solution of tert- butylammonium bromide (932mg, 2. [89MMOL) IN DRY ACETONITRILE (50ML) ] under nitrogen at room temperature and the mixture was cooled to [0C.] The diketone from Preparation 5 (7.3g, 57. [9MMOL)] in acetonitrile [(36ML)] was then added followed by dropwise addition of dry dimethylsulfoxide (12. [3MOI,] [174MMOL).] The reaction was stirred at [0C] for 1.5 hours and the mixture was diluted with water [(500ML),] extracted with [DIETHYLETHER (2X200ML ] and [100ML)] and the combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with pentane: diethylether (100: 0 changing to 95: 5 then 90: 10, by volume) to provide the title compound (5.76g) as a colourless oil. 'H NMR [(400MHZ,] CDCl3) : [8] = 1.04 (m, 2H), 1.18 (m, 2H), 2.27 (s, 3H), 2.42 (m, [1H),] 15.78 (s, [1H).] LRMS [(ELECTROSPRAY)] : m/z [M-H+] 159. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 60 mg (0.26 mmol) (2-amino-5,6-dihydro-4H-cyclopenta [b]thiophen-3-yl)-furan-2-yl-methanone (the preparation of which is described in example 18) in 2 ml acetic acid was added 43 mg (0.34 mmol) of 1-cyclopropyl-butane- 1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30percent CH3CN/H20) afforded 17 mg (21 percent) cyclopropyl-(4-furan-2-yl-2-methyl-6>7-dihydro- 5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-methanone as a light brown solid. ES-MS m/e (percent): 324 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 60 mg (0.24 mmol) (2-amino-5,6-dihydro-4H- cyclopenta[b]tHophen-3-yl)-thiophen-2-yl-methanone) (the preparation of which is described in example 2) in 2 ml acetic acid was added 40 mg (0.32 mmol) of 1- cyclopropyl-butane-l,3-dione and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30percent CH3CN/H20) afforded 15 mg (19 percent) cyclopropyl-(2-methyl-4-thiophen-2- yl-6,7-dihydro-5H-cyclopenta[4>5]thieno[2>3-b]pyridin-3-yl)-methanone as a light brown oil. ES-MS m/e (percent): 340 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 60 mg (0.29 mmol) (2-amino-tHophen-3-yl)-phenyl-methanone (the preparation of which is described in example 20) in 2 ml acetic acid was added 50 mg (0.39 mmol) of l-cyclopropyl-butane-l,3-dione and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane / ethyl acetate 6:1) afforded 7 mg (8 percent) cyclopropyl-(6-methyl-4-phenyl-thieno[2,3-b]pyridin-5-yl)-methanone as a colorless oil. ES-MS m/e (percent): 294 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 36 mg (0.11 mmol) (2-amino-5,6,7,8-tetrahydro-4H- cyclohepta[b]thiophen-3-yl)-(3,4-dichloro-phenyl)-methanone in 2 ml acetic acid was added 18 mg (0.11 mmol) of l-cyclopropyl-butane-l,3-dione and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30percent CH3CN/H20) afforded 10 mg (19 percent) cyclopropyl-[4-(3,4-dichloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-10-thia-l-aza- benzo[a]azulen-3-yl)-methanone as a light yellow oil. ES-MS m/e (percent): 430 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With acetic acid;sulfuric acid; at 70℃; for 2h;microwave irradiation; | To a stirred solution of 100 mg (0.38 mmol) (2-ammo-4,7-dihydro-5H-thieno[2,3- c]pyran-3-yl)-phengammal-methanone in 5 ml acetic acid was added 73 mg (0.57 mmol) of 1- cyclopropyl~butane-l,3-dione (prep, described in the patent DE 94-4404059) and one drop of sulfuric acid. The mixture was then stirred at 70 0C for 2 hours and then concentrated in vacuo. Plash chromatography (heptane / ethyl acetate 3:1) afforded 50 mg (37 percent) cyclopropyl-(2-methyl-4-phenyl-5,8-dihydro-6H-7-oxa-9-thia-l-aza-fluoren-3- yl)-methanone_as a yellow solid. ES-MS m/e (percent): 350 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With acetic acid;sulfuric acid; at 110℃; for 0.333333h;microwave irradiation; | To a stirred solution of 0.130 g (0.465 mmol) (2-amino-5-phenyl-thiophen-3-yl)~phenyl- methanone in 7 ml acetic acid was added 62 mg (0.491 mmol) of 1-cyclopropyl-butane- 1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 110 0C for 20 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30percent CH3CN/H2O) afforded 29 mg (17 percent) cyclopropyl-(6-methyl-2,4-diphenyl-thieno [2,3- b]pyridin-5-yl)-methanone as a light yellow powder. ES-MS m/e (percent): 370 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 60 mg (0.24 mmol) (2-amino-5,6-dihydro-4H- cyclopenta[b]thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 3) in 2 ml acetic acid was added 41 mg (0.32 mmol) of 1-cyclopropyl-butane- 1,3-dione (prep, described in the patent DE 94-4404059) and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30percent CH3CN/H20) afforded 27 mg (33 percent) cyclopropyl-(2-methyl-4-phenyl-6>7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3- yl)-methanone as a light brown oil. ES-MS m/e (percent): 334 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 60 mg (0.21 mmol) (2-amino-4,5,6,7-tetrahydro- benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (the preparation of which is described in example 8) in 2 ml acetic acid was added 35 mg (0.28 mmol) of 1- cyclopropyl-butane-l,3-dione and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. PreparativeHPLC (30percent CH3CN/H20) afforded 25 mg (32 percent) cyclopropyl-[4-(4-methoxy-rhohenyl)-2- methyl-5)6,7,8-tetrahydro-benzo[4,5]thieno[2)3-b]pyridin-3-vl)-methanone as a light brown oil. ES-MS m/e (percent): 378 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 60 mg (0.22 mmol) (2-amino-5,6-dihydro-4H- cyclopenta[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (the preparation of which is described in example 10) in 2 ml acetic acid was added 37 mg (0.29 mmol) of 1- cyclopropyl-butane-l,3-dione and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. PreparativeHPLC (30percent CH3CN/H20) afforded 17 mg (22 percent) cyclopropyl-[4-(4-methoxy-phenyl)-2- EPO <DP n="39"/>methyl-6,7-dihydro-5H-cyclopenta[455]thieno [2,3-b]pyridin-3-yl)-methanone as a light brown solid. ES-MS m/e (percent): 364 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With acetic acid;sulfuric acid; at 100℃; for 0.5h; | To a stirred solution of 1.0 g (2.79 mmol) 2-amino-3-benzoyl-4,7-dihydro-5H- thieno[2,3-c]pyridine-beta-carboxylic acid tert-butyl ester (the preparation of which is described in example 23) in 15 ml acetic acid was added 0.70 g (5.55 mmol) of 1- cyclopropyl-butane-l,3-dione and three drops of sulfuric acid. The mixture was then stirred at 1000C for 30 minutes and then concentrated in vacuo. Flash chromatography (dichloromethane / methanol 95:5) afforded 0.47 g (48 percent) cyclopropyl-(2-methyl-4- phenyl-5,6>7,8-tetrahydro-9-tma-l)7-diaza-fluoren-3-yl)-methanone_as a brown oil. ES- MS m/e (percent): 349 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 60 mg (0.18 mmol) (2-amino-4,5,6,7-tetrahydro-benzo[b] thiophen-3-yl)-(3,4-dichloro-phenyl)-methanone in 2 ml acetic acid was added 31 mg (0.24 mmol) of l-cyclopropyl-butane-l,3-dione and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30percent CH3CN/H20) afforded 18 mg (23 percent) cydopropyl-[(4- (3,4-dichloro-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno [2,3-b]pyridin-3- yl)] -methanone as a light brown solid. ES-MS m/e (percent): 416 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 60 mg (0.20 mmol) 4-(2-amino-5,6-dihydro-4H- cyclopenta[b]thiophene-3-carbonyl)-benzoic acid methyl ester in 2 ml acetic acid was added 33 mg (0.26 mmol) of l-cydopropyl-butane-l,3-dione and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30percent CH3CN/H20) afforded 22 mg (28 percent) 4- (3-cyclopropanecarbonyl-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3- b]pyridin-4-yl) -benzoic acid methyl ester as a light brown oil. ES-MS m/e (percent): 392 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 60 mg (0.19 mmol) 4-(2-Amino-4,5,6,7-tetrahydro-benzo[b] thiophene-3-carbonyl)-benzoic acid methyl ester in 2 ml acetic acid was added 32 mg (0.25 mmol) of l-cyclopropyl-butane-lbeta-dione and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30percent CH3CNyH2O) afforded 28 mg (37 percent) 4-(3- cyclopropanecarbonyl-2-methyl-5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-b] pyridin-4- yl) -benzoic acid methyl ester as a light pink solid. ES-MS m/e (percent): 406 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 20 mg (0.06 mmol) 4-(2-Amino-5,6,7,8-tetrahydro-4H- cyclohepta[b]thiophene-3-carbonyl)-benzoic acid methyl ester in 1 ml acetic acid was added 10 mg (0.06 mmol) of l-cyclopropyl-butane-l,3-dione and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30percent CH3CN/H20) afforded 11 mg (44 percent) 4- (3-cyclopropanecarbonyl-2-methyl-6,7,8,9-tetrahydro-5H-10-thia-l-aza- benzo[a]azulen-4-yl)-benzoic acid methyl ester as a light yellow solid. ES-MS m/e (percent): 420 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With acetic acid;sulfuric acid; at 100℃; for 0.166667h;microwave irradiation; | To a stirred solution of 60 mg (0.19 mmol) (2-amino-5,6-dihydro-4H- cyclopenta[b]thiophen-3-yl)-(3)4-dichloro-phenyl)-methanone (the preparation of EPO <DP n="38"/>which is described in example 1) in 2 ml acetic acid was added 32 mg (0.25 mmol) of 1- cydopropyl-butane-l)3-dione and one drop of sulfuric acid. The mixture was then stirred at 1000C for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30percent CH3CN/H20) afforded 24 mg (31 percent) cyclopropyl-[(4-(3,4-dichloro-phenyl)- 2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin~3-yl)-methanone as a light brown solid. ES-MS m/e (percent): 402 (M+ H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 85 2-Chloro-1-cyclopropyl-1,3-butanedione Trimethylsilyl chloride (18.9 ml, 174 mmol) was added to a solution of tert-butylammonium bromide (932 mg, 2.89 mmol) in dry acetonitrile (50 ml) under nitrogen at room temperature and the mixture was cooled to 0° C. The diketone from Preparation 84 (7.3 g, 57.9 mmol) in acetonitrile (36 ml) was then added followed by dropwise addition of dry dimethylsulfoxide (12.3 ml, 174 mmol). The reaction was stirred at 0° C. for 1.5 hours and the mixture was diluted with water (500 ml), extracted with diethylether (2*200 ml and 100 ml) and the combined organic extracts were dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluding with pentane:diethylether (100:0 changing to 95:5 then 90:10, by volume) to provide the title compound (5.76 g) as a colourless oil. 1H NMR (400 MHz, CDCl3): delta 0.99-1.08 (m, 2H), 1.15-1.20 (m, 2H), 2.27 (s, 3H), 2.38-2.46 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-carbonyldiimidazole; In N-methyl-acetamide; | The reaction was stirred for 1 hour at room temperature and the solvent was removed under reduced pressure to give the magnesium salt of the acid. Meanwhile, cyclopropane-carboxylic acid (9.91 ml, 125 mmol) was dissolved in dimethylformamide (200 ml) and carbonyldiimidazole (22.4 g, 138 mmol) was added portionwise under nitrogen at 0° C. This was stirred for 1.5 hour and the magnesium salt from above was added as a solution in dimethylformamide (100 ml) at 0° C. The reaction was allowed to stir at room temperature for 92 hours and the mixture was poured into 2M aqueous hydrochloric acid (85 ml) then diluted with water (170 ml). The mixture was extracted with diethylether (6*200 ml) and the combined organic extracts were washed with brine (3*200 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual orange oil was purified by flash chromatography on silica gel eluding with pentane:diethylether (100:0 changing to 90:10 then 80:20, by volume) to provide the title compound (7.39 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): delta=0.83-0.95 (m, 2H), 1.06-1.10 (m, 2H), 1.54-1.63 (m, 1H), 2.00 (s, 3H). | |
With sodium hydroxide; In water; acetone; | EXAMPLE 11 Production of 1-cyclopropylbutane-1,3-dione (intermediate) Boron trifluoride gas is introduced for one hour at 40° C. into a mixture of 191 g of cyclopropanecarboxylic acid and 45 g of acetone. There is formed a black oily product, which is diluted with 800 ml of ether. The ether phase is then washed 4 times with 300 ml of water each time, and, with ice cooling, 30percent sodium hydroxide solution is finally added until the pH value is ~9. The ether layer is separated, and the aqueous phase is extracted three times with 300 ml of ether each time. The ether phases are collected, dried over sodium sulfate, purified with active charcoal, filtered, and concentrated by evaporation. The oil which remains is purified by chromatography through a silica gel column with ether/hexane (1:3) as the eluant. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 23 3-[(4-Cyanophenyl)methylene]-4-cyclopropyl-2,4-butanedione The procedure described in Example 19 was repeated by using 2.6 g 4-cyanobenzaldehyde and 2.5 g 4-cyclopropyl-2,4-butanedione. The product was purified by column chromatography. Yield 0.37 g, mp 83°-85° C. | ||
Example 23 3-[(4-Cyanophenyl)methylene]-4-cyclopropyl-2,4-butanedione The procedure described in Example 19 was repeated by using 2.6 g 4-cyanobenzaldehyde and 2.5 g 4-cyclopropyl-2,4-butanedione. The product was purified by column chromatography. Yield 0.37 g, mp 83-85°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxylamine hydrochloride; In ethanol; at 130℃; for 0.1h;sealed vessel in the microwave; | l-Cyclopropyl-butane-l,3-dione (prepared according to DE 4404059, EP 569760)(3.5 g, 25.4 mmol), hydroxylaraine hydrochloride (2.12 g, 30.5 mmol) and ethanol (1 ml)were mixed and the mixture heated in a sealed vessel in the microwave at 130°C twicefor 3 minutes. The mixture was diluted with water (50 ml) and extracted with diethylether (3x 25 ml). The combined organic phases were dried over magnesium sulfate andconcentrated. The brown oil was filtered through a plug of silica gel. The silica gel waswashed with diethyl ether and the filtrate was concentrated. The mixture of crudeproducts (5.6 g) was used without further purification. | |
With hydroxylamine hydrochloride; potassium carbonate; In ethanol; for 12h;Reflux; | [00338] Step B1: Synthesis of the mixture of 5-cyclopropyl-3-methylisoxazole and 3- cyclopropyl-5-methylisoxazole. A mixture of <strong>[21573-10-4]1-<strong>[21573-10-4]cyclopropylbutane-1,3-dione</strong></strong> (or any other suitable 1,3-dione, 15.9 mmol), NH2OH-HCl (2.2 g, 31.75 mmol) and K2CO3(6.6 g, 47.62 mmol). in EtOH (12 mL) was stirred under reflux for 12 h., cooled to room temperature filtered and concentrated to render a mixture of 5-cyclopropyl-3-methylisoxazole and 3- cyclopropyl-5-methylisoxazole (ratio = 4/1, determined by HNMR) as a yellow oil. Assumed quantitative yield. ESI-LCMS (m/z): 124 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5% | In diethyl ether; water; | Example 1.1 Preparation of 2-phenylamino-4-methyl-6-cyclopropylpyrimidine STR36 10 g (51 mmol) of phenylguanidine hydrogen carbonate and 9.7 g (77 mmol) of <strong>[21573-10-4]1-cyclopropyl-1,3-butanedione</strong> are heated at 110° C. for 6 hours with stirring, the evolution of carbon dioxide which occurs subsiding as the reaction progresses. After the dark brown emulsion has been cooled to room temperature, 50 ml of diethyl ether are added and the mixture is washed twice with 20 ml of water each time, dried over sodium sulfate and filtered, and the solvent is evaporated. The dark brown oil which remains (=13.1 g) is purified by column chromatography over silica gel (diethyl ether/toluene: 5/3). After the eluant mixture has been evaporated off, the brown oil is made to crystallise and recrystallized from diethyl ether/petroleum ether at 30°-50° C. Light-brown crystals are obtained. Melting point: 67°-69° C.; yield: 8.55 g (38 mmol) (=74.5percent of the theoretical yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.5% | With hydrogenchloride; urea; In diethyl ether; ethanol; | Example 1.7 Preparation of 2-hydroxy-4-methyl-6-cyclo-propylpyrimidine STR42 15 ml of concentrated hydrochloric acid are added at room temperature to 6 g (100 mmol) of urea and 12.6 g (100 mmol) of <strong>[21573-10-4]1-cyclopropyl-1,3-butanedione</strong> in 35 ml of ethanol. After the mixture has stood for 10 days at room temperature, it is concentrated in a rotary evaporator at a bath temperature not exceeding 45° C. The residue is dissolved in 20 ml of ethanol, the hydrochloride of the reaction product precipitating after a short time. 20 ml of diethyl ether are added with stirring, and the precipitated white crystals are filtered off, washed with an ethanol/diethyl ether mixture and dried. Concentration of the filtrate and recrystallisation from an ethanol/diethyl ether mixture: 1/2 yield a further quantity of hydrochloride. The white crystals melt >230° C. Yield: hydrochloride 12.6 g (67.5 mmol; 67.5percent of the theoretical yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | EXAMPLE 12 Production of 2-amino-4-cyclopropyl-6-methylpyrimidine (intermediate) 15 g of guanidine carbonate are added to a mixture of 10 g of <strong>[21573-10-4]1-cyclopropyl-butane-1,3-dione</strong> and 150 g of water, and stirring is maintained at 95° C. for 5 hours. The mixture is then concentrated by evaporation to a volume of 50 ml, and the cooled aqueous concentrate is extracted three times with 100 ml of ethylene chloride each time. The organic phase is dried over magnesium sulfate and concentrated by evaporation. The residue crystallises to thus yield 5 g of the title compound, m.p. 113°-115° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxylamine hydrochloride; potassium carbonate; In ethanol; | EXAMPLE 6(a) A mixture of 1-cyclopropylbutan-1,3-dione (65.3g), hydroxylamine hydrochloride (36.6g) and anhydrous potassium carbonate (71.8 g) in ethanol (375 ml) was stirred and heated at reflux for 2 hours. The mixture was cooled and filtered and the filtrate was evaporated to dryness. The residue was distilled under reduced pressure to give 5-cyclopropyl-3-methyl isoxazole containing approximately 20 percent 3-cyclopropyl-5-methylisoxazole (51.85g) as a clear oil, b.p. 74°C / 12 mm.Hg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 4: 1-Cyclopropyl-1,3-butanedione Magnesium turnings (3.04 g, 125 mmol), suspended in methanol (145 mL), were heated to reflux under nitrogen for 1 hour, then cooled to room temperature and the beta-keto acid described in Preparation 3 (25.5 g, 250 mmol), dissolved in methanol (25 mL), was added dropwise, with ice-cooling. The reaction mixture was stirred for 1 hour, at room temperature, and then the solvent was removed under reduced pressure to give the magnesium salt of the acid. Meanwhile, cyclopropane-carboxylic acid (9.91 mL, 125 mmol) was dissolved in dimethylformamide (200 mL). Carbonyldiimidazole (22.4 g, 138 mmol) was then added portionwise, under nitrogen, at 0° C. This reaction mixture was stirred for 1.5 hours, and then the magnesium salt from above was added as a solution in N,N-dimethylformamide (100 mL) at 0° C. The reaction mixture was allowed to stir at room temperature for 92 hours, and then it was poured into 2M aqueous hydrochloric acid (85 mL), followed by dilution with water (170 mL). The mixture was extracted with diethyl ether (6.x.200 mL), and the combined organic extracts were then washed with brine (3.x.200 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residual orange oil was purified by flash chromatography on silica gel eluting with pentane:diethyl ether (100:0 then 90:10 then 80:20, by volume) to provide the title compound (7.39 g, 24percent) as a yellow oil. 1H NMR (400 MHz, CDCl3) delta=0.83-0.95(m, 2H), 1.06-1.10(m, 2H), 1.54-1.63(m, 1H), 2.00(s, 3H); LRMS ES+m/z 149 [MNa+]. | ||
Magnesium turnings (3.04g, [125MMOL)] suspended in [METHANOL (145M1) ] were heated to reflux under nitrogen for 1 hour, cooled to room temperature and the [?-] keto acid from Preparation 4 (25.5g, [250MOL)] dissolved in methanol [(25MOI)] was added dropwise with ice-cooling. The reaction was stirred for 1 hour at room temperature and the solvent was removed under reduced pressure to give the magnesium salt of the acid. Meanwhile, cyclopropane-carboxylic acid [(9. 91MOL, ] [125MOL)] was dissolved in [DIMETHYLFORMAMIDE (200ML) ] and [CARBONYLDIIMIDAZOLE] (22.4g, [138MMOL)] was added portionwise under nitrogen at [0C.] This was stirred for 1.5 hour and the magnesium salt from above was added as a solution in [DIMETHYLFORMAMIDE (100ML) ] at [0C.] The reaction was allowed to stir at room temperature for 92 hours and the mixture was poured into 2M aqueous hydrochloric acid (85ml) then diluted with water (170ml). The mixture was extracted with [DIETHYLETHER (6X200ML) ] and the combined organic extracts were washed with brine [(3#200ML), ] dried over magnesium sulphate and concentrated under reduced pressure. The residual orange oil was purified by flash chromatography on silica gel eluting with pentane: diethylether (100: 0 changing to 90: 10 then 80: 20, by volume) to provide the title compound (7.39g) as a yellow oil. [1H] NMR [(400MHZ,] CDCl3) : [8] = 0.89 (m, 2H), 1.08 (m, 2H), 1.59 (m, 1 H), 2.00 (s, [3H),] 5.61 (s, [1H),] 15.62 (s, [1H).] LRMS (electrospray) : m/z [[MNA+]] 149. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 3 1-Cyclopropyl-1,3-butanedione Magnesium turnings (3.04 g, 125 mmol), suspended in methanol (145 ml), were heated to reflux under nitrogen for 1 hour, then cooled to room temperature and the beta-keto acid from Preparation 2 (25.5 g, 250 mmol) dissolved in methanol (25 ml) was added dropwise, with ice-cooling. The reaction mixture was stirred for 1 hour, at room temperature, and then the solvent was removed under reduced pressure to give the magnesium salt of the acid. Meanwhile, cyclopropane-carboxylic acid (9.91 ml, 125 mmol) was dissolved in dimethylformamide (200 ml). Carbonyldiimidazole (22.4 g, 138 mmol) was then added portionwise, under nitrogen, at 0° C. This reaction mixture was stirred for 1.5 hours, and then the magnesium salt from above was added as a solution in N,N-dimethylformamide (100 ml) at 0° C. The reaction mixture was allowed to stir at room temperature for 92 hours, and then it was poured into 2M aqueous hydrochloric acid (85 ml), followed by dilution with water (170 ml). The mixture was extracted with diethyl ether (6.x.200 ml), and the combined organic extracts were then washed with brine (3.x.200ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual orange oil was purified by flash chromatography on silica gel eluting with pentane:diethyl ether (100:0 then 90:10 then 80:20, by volume) to provide the title compound (7.39 g, 24percent) as a yellow oil. 1H NMR (400 MHz, CDCl3): delta=0.83-0.95 (m, 2H), 1.06-1.10 (m, 2H), 1.54-1.63 (m, 1H), 2.00 (s, 3H); LRMS (electrospray): m/z 149 [MNa+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With acetic acid; at 120℃; for 0.5h; | Intermediate 30. To a solution of the pyrazole intermediate 4 (3.22 g, 12.08 mM) in acetic acid (25 ml) was added l-cyclopropyl-l,3-butanedione (2.28 g, 18.13 mM) and the solution stirred at 120 °C for 30 min. Volatiles were removed under reduced pressure at 40 °C, and the resulting residue was purified by silica gel column (Hexane/EtOAc, gradient from 0percent to 50percent) to afford intermediate 30 (1.72 g, 26percent).1H-NMR (CDC13, 400 MHz): delta 6.44 (s 1H), 6.28 (s 1H), 5.58 (s, 1H), 4.13-4.04 (m, 1H), 2.96- 2.92 (m, 1H), 2.67 (s, 3H), 2.46-2.42 (m, 1H), 2.14-1.85 (m, 4H), 1.47 (s, 9H), 1.13-1.02 (m, 6H).LCMS m/z [M+H]+ C20H28N4O2 requires: 357.46. Found 357.13 |
26% | With acetic acid; at 120℃; for 0.5h; | Example 24 Preparation of Intermediate 25 [0514] [0515] To a solution of the pyrazole intermediate 4 (3.22 g, 12.08 mmol) in acetic acid (25 ml) was added <strong>[21573-10-4]1-cyclopropyl-1,3-butanedione</strong> (2.28 g, 18.13 mmol) and the solution was stirred at 120° C. for 30 min. The volatiles were removed under reduced pressure at 40° C., and the resulting residue was purified by silica gel column (hexane/EtOAc, gradient from 0percent to 50percent) to afford intermediate 25 (1.72 g, 26percent). [0516] 1H-NMR (CDCl3, 400 MHz): delta 6.44 (s 1H), 6.28 (s 1H), 5.58 (s, 1H), 4.13-4.04 (m, 1H), 2.96-2.92 (m, 1H), 2.67 (s, 3H), 2.46-2.42 (m, 1H), 2.14-1.85 (m, 4H), 1.47 (s, 9H), 1.13-1.02 (m, 6H). [0517] LCMS m/z [M+H]+ C20H28N4O2 requires: 357.46. Found 357.13 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine; In ethanol; for 3.5h;Reflux; | (2Z)-2-[2-Bromo-5-(trifluoromethyl)benzylidene]-<strong>[21573-10-4]1-<strong>[21573-10-4]cyclopropylbutane-1,3-dione</strong></strong> 25 (1.0 g) was dissolved in 22 ml ethanol. 2-Bromo-5-(trifluoromethyl)benzaldehyde (2.0 g, 7.9 mmol) was added followed by 0.3 ml piperidine and 0.6 ml acetic acid. The mixture was stirred at reflux for 3.5 h. The mixture was then evaporated under reduced pressure and the residue was purified using the SP1 Purification System (ethyl acetate-hexane gradient, 0:100 rising to 5:95) to give 1.13 g of the crude title compound as a white waxy solid. Purity 88percent.1H NMR (400 MHz, CHLOROFORM-d) ) delta ppm 0.86 - 0.96 (m, 2 H), 1.17 (m, 2 H), 1.83 - 1.93 (m, 1 H), 2.45 (s, 3 H), 7.50 (d, J=8.21 Hz, 1 H), 7.61 (s, 1 H), 7.74 - 7.82 (m, 2 H).UPLC/MS (3 min) retention time 1.87 min. LRMS: m/z 361, 363 (M+1). | |
With piperidine; acetic acid; In ethanol; for 3.5h;Reflux; | The crude title compound of Preparation 25 (1 .0 g) was dissolved in 22 ml ethanol. 2- Bromo-5-(trifluoromethyl)benzaldehyde (2.0 g, 7.9 mmol) was added followed by 0.3 ml piperidine and 0.6 ml acetic acid. The mixture was stirred at reflux for 3.5 h. The mixture was then evaporated under reduced pressure and the residue was purified using the SP1 Purification System (ethyl acetate-hexane gradient, 0: 100 rising to 5:95) to give 1 .13 g of the crude title compound as a white waxy solid. Purity 88percent. 1 H NMR (400 MHz, CHLOROFORM-d) ) delta ppm 0.86 - 0.96 (m, 2 H), 1 .17 (m, 2 H), 1 .83 - 1 .93 (m, 1 H), 2.45 (s, 3 H), 7.50 (d, J=8.21 Hz, 1 H), 7.61 (s, 1 H), 7.74 - 7.82 (m, 2 H). UPLC/MS (3 min) retention time 1 .87 min. LRMS: m/z 361 , 363 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With piperidine; In ethanol; at 75℃; for 0.5h;Reflux; | Step 26-Cyclopropyl-4-methyl-2-o -l,2-dihydro-3-pyridinecarbonitrile To a stirring solution of ethanol (5 mL) were suspended l-cyclopropyl-1,3- butanedione (505 mg, 3.00 mmol) and cyanoacetamide (252 mg, 3.00 mmol), and the heterogenous contents heated until homogenous (ca. 75 °C). Next added piperidine (0.395 mL, 4.00 mmol), and the mixture was stirred with warming at reflux for 30 min. The reaction mixture was allowed to cool to room temperature, wherein precipitation ensued. The solid precipitate was filtered and set aside. The filtrate was concentrated in vacuo, and the oily residue treated with minimal EtOAc and then 10 mL hexanes to afford a 2nd crop of solid. The solid product crops were combined, suspended in water (7 mL), vigorously stirred, and vacuum filtered to afford a nearly white solid as 380 mg (73percent). LCMS E-S (M+H) = 175.1. 1H NMR (400 MHz, CHLOROFORM-;/) ? ppm 1.01 - 1.09 (m, 2 H), 1.28 (dd, J=8.59, 2.27 Hz, 2 H), 1.95-2.01 (m, 1H), 2.43 (s, 3H), 5.82 (s, 1 H). |
73% | With piperidine; In ethanol; for 0.5h;Reflux; | To a stirred solution of ethanol (5 mL) were added <strong>[21573-10-4]1-cyclopropyl-1,3-butanedione</strong>(505 mg, 3.00 mmol) and cyanoacetamide (252 mg, 3.00 mmol), and the heterogenouscontents heated until homogenous (ca. 75 °C). Piperidine was added (0.395 mL, 4.00mmol) and the mixture was heated at reflux for 30 min The reaction mixture was allowedto cool to room temperature, wherein precipitation ensued. The solid precipitate wasfiltered and set aside. The filtrate was concentrated in vacuo and the oily residue treated with minimal EtOAc and then 10 mL hexanes to afford a second crop of solid. The solidproduct crops were combined, suspended in water (7 mL ), vigorously stirred, and vacuumfiltered to afford 6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile as anearly white solid (380 mg, 73percent). LCMS E-S (M+H) = 175.1. 1HNMR (400 MHz,CDCb) 8 ppm 1.01 - 1.09 (m, 2 H), 1.28 (dd, J=8.59, 2.27 Hz, 2 H), 1.95-2.01 (m, 1H), 2.43 (s, 3H), 5.82 (s, 1 H). |
With 1,4-diaza-bicyclo[2.2.2]octane; In ethanol; at 20℃;Reflux; | General procedure: Cyanothioacetamide (for X=S) (1.5 equiv) or cyanoacetamide (for X=O) (1.5 equiv) was added to a solution of the 1, 3-diones (for R4= -CF3 and -CH3) (1.0 equiv) or enaminones (for R4=H) (1.0 equiv) in ethanol in the presence of DABCO (1.0 equiv) at room temperature. The reaction mixture was stirred under reux for 3-6 h until complete conversion of the starting materials, as monitored by TLC. After cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was neutralized with diluted hydrochloric acid (1 N) to precipitate the crude products. After filtrated and dried in vacuo, the product can be straight used for step d. Yield: 70-90percent. |
380 mg | With piperidine; In ethanol; for 0.5h;Inert atmosphere; Reflux; | To a stirred solution of ethanol (5 mL) were added <strong>[21573-10-4]1-cyclopropyl-1,3-butanedione</strong> (505 mg, 3.00 mmol) and cyanoacetamide (252 mg, 3.00 mmol), and the heterogenous contents heated until homogenous (ca. 75° C.). Piperidine was added (0.395 mL, 4.00 mmol) and the mixture was heated at reflux for 30 min. The reaction mixture was allowed to cool to room temperature, wherein precipitation ensued. The solid precipitate was filtered and set aside. The filtrate was concentrated in vacuo and the oily residue treated with minimal EtOAc and then 10 mL hexanes to afford a second crop of solid. The solid product crops were combined, suspended in water (7 mL), vigorously stirred, and vacuum filtered to afford 6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile as a nearly white solid (380 mg, 73percent). LCMS E-S (M+H)=175.1. 1H NMR (400 MHz, CDCl3) delta ppm 1.01-1.09 (m, 2H), 1.28 (dd, J=8.59, 2.27 Hz, 2H), 1.95-2.01 (m, 1H), 2.43 (s, 3H), 5.82 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,4-diaza-bicyclo[2.2.2]octane; In ethanol; at 20℃;Reflux; | General procedure: Cyanothioacetamide (for X=S) (1.5 equiv) or cyanoacetamide (for X=O) (1.5 equiv) was added to a solution of the 1, 3-diones (for R4= -CF3 and -CH3) (1.0 equiv) or enaminones (for R4=H) (1.0 equiv) in ethanol in the presence of DABCO (1.0 equiv) at room temperature. The reaction mixture was stirred under reux for 3-6 h until complete conversion of the starting materials, as monitored by TLC. After cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was neutralized with diluted hydrochloric acid (1 N) to precipitate the crude products. After filtrated and dried in vacuo, the product can be straight used for step d. Yield: 70-90percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrazine; In ethanol; for 2h;Reflux; | Intermediate 2_:3-Cyclopropyl- -methyl-lH-pyrazole-4-sulfonyl chlorideHydrazine hydrate (7.93 g, 0.158 mol) was added to a solution of l-cyclopropyl- 1,3-butanedione (10 g, 0.079 mol) in ethanol (100 mL) and the reaction was heated to reflux for two hours then concentrated to afford 5-cyclopropyl-3-methyl- lH-pyrazole (9.59 g, 98percent yield). This was reacted with chlorosulfonic acid as described in the preparation of 3,5-dimethyl-lH-pyrazole-4-sulfonyl chloride (Intermediate 1) to afford 5-cyclopropyl-3-methyl- lH-pyrazole-4-sulfonyl chloride. |
98% | With hydrazine hydrate; In ethanol; for 2h;Reflux; | Hydrazine hydrate (7.93 g, 0.158 mol) was added to a solution of 1-cyclopropyl-1,3- butanedione (10 g, 0.079 mol) in ethanol (100 mL) and the reaction was heated to refluxfor two hours then concentrated to afford 5-cyclopropyl-3-methyl-1H-pyrazole (9.59 g,98percent yield). This was reacted with chlorosulfonic acid as described in the preparation of3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1) to afford 5-cyclopropyl-3- methyl- 1H-pyrazole-4-sulfonyl chloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[21573-10-4]1-<strong>[21573-10-4]cyclopropylbutane-1,3-dione</strong></strong> (or any other suitable 1,3-dione, 15.9 mmol), NH2OH-HCl (2.2 g, 31.75 mmol) and K2CO3(6.6 g, 47.62 mmol). in EtOH (12 mL) was stirred under reflux for 12 h., cooled to room temperature filtered and concentrated to render a mixture of 5-cyclopropyl-3-methylisoxazole and 3- cyclopropyl-5-methylisoxazole (ratio = 4/1, determined by HNMR) as a yellow oil. Assumed quantitative yield. ESI-LCMS (m/z): 124 [M+1]+.[00339] Step B2: Synthesis of the mixture of 4-bromo-5-cyclopropyl-3-methylisoxazole and 4-bromo-3-cyclopropyl-5-methylisoxazole. A solution of 5-cyclopropyl-3- methylisoxazole and 3-cyclo- propyl-5-methylisoxazole (15.9 mmol) in DMF (10 mL) was treated with NBS (3.1 g, 17.4 mmol) and the resulting mixture was stirred at roomtemperature for 12 h., diluted with EtOAc (150 mL) and washed with H2O (100 mL x 3) followed by brine (50 mL). The organic layer was dried over Na2SO4, filtered andconcentrated and the residue was purified by automated chromatographic column on silicagel eluted with 0percent to 8percent EtOAc/petroleum ether to give a mixture of 4-bromo-5-cyclopropyl-3- methyl- isoxazole and 4-bromo-3-cyclopropyl-5-methylisoxazole as a yellow oil (2.5 g, 12.3 mmol, 78percent yield in two steps). ESI-LCMS (m/z): 201.9 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[21573-10-4]1-<strong>[21573-10-4]cyclopropylbutane-1,3-dione</strong></strong> (or any other suitable 1,3-dione, 15.9 mmol), NH2OH-HCl (2.2 g, 31.75 mmol) and K2CO3(6.6 g, 47.62 mmol). in EtOH (12 mL) was stirred under reflux for 12 h., cooled to room temperature filtered and concentrated to render a mixture of 5-cyclopropyl-3-methylisoxazole and 3- cyclopropyl-5-methylisoxazole (ratio = 4/1, determined by HNMR) as a yellow oil. Assumed quantitative yield. ESI-LCMS (m/z): 124 [M+1]+.[00339] Step B2: Synthesis of the mixture of 4-bromo-5-cyclopropyl-3-methylisoxazole and 4-bromo-3-cyclopropyl-5-methylisoxazole. A solution of 5-cyclopropyl-3- methylisoxazole and 3-cyclo- propyl-5-methylisoxazole (15.9 mmol) in DMF (10 mL) was treated with NBS (3.1 g, 17.4 mmol) and the resulting mixture was stirred at roomtemperature for 12 h., diluted with EtOAc (150 mL) and washed with H2O (100 mL x 3) followed by brine (50 mL). The organic layer was dried over Na2SO4, filtered andconcentrated and the residue was purified by automated chromatographic column on silicagel eluted with 0percent to 8percent EtOAc/petroleum ether to give a mixture of 4-bromo-5-cyclopropyl-3- methyl- isoxazole and 4-bromo-3-cyclopropyl-5-methylisoxazole as a yellow oil (2.5 g, 12.3 mmol, 78percent yield in two steps). ESI-LCMS (m/z): 201.9 [M+1]+.[00340] Step B3: Synthesis of a mixture of 5-cyclopropyl-3-methyl-4-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)isoxazole and 3-cyclopropyl-5-methyl-4-(4,4,5,5- tetra-methyl-1,3,2-dioxaborolan-2-yl)isoxazole. To a mixture of 4-bromo-5-cyclopropyl-3- methylisoxazole and 4-bromo-3-cyclopropyl-5-methylisoxazole (500 mg, 2.48 mmol) in dioxane (15 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (943 mg, 3.71 mmol), KOAc (1.17 g, 7.43 mmol) and PdCl2(dppf) (181 mg, 0.25 mmol); the system was purged with N2stream, sealed and heated at 105oC for 12 h. After being cooled down to room temperature, the mixture was filtered through a pad of celite and concentrated to give a mixture of 5-cyclopropyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoxazole and 3-cyclopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoxazole as a yellow solid, which was used directly in next step without further purification. ESI- LCMS (m/z): 250.1 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[21573-10-4]1-<strong>[21573-10-4]cyclopropylbutane-1,3-dione</strong></strong> (or any other suitable 1,3-dione, 15.9 mmol), NH2OH-HCl (2.2 g, 31.75 mmol) and K2CO3(6.6 g, 47.62 mmol). in EtOH (12 mL) was stirred under reflux for 12 h., cooled to room temperature filtered and concentrated to render a mixture of 5-cyclopropyl-3-methylisoxazole and 3- cyclopropyl-5-methylisoxazole (ratio = 4/1, determined by HNMR) as a yellow oil. Assumed quantitative yield. ESI-LCMS (m/z): 124 [M+1]+.[00339] Step B2: Synthesis of the mixture of 4-bromo-5-cyclopropyl-3-methylisoxazole and 4-bromo-3-cyclopropyl-5-methylisoxazole. A solution of 5-cyclopropyl-3- methylisoxazole and 3-cyclo- propyl-5-methylisoxazole (15.9 mmol) in DMF (10 mL) was treated with NBS (3.1 g, 17.4 mmol) and the resulting mixture was stirred at roomtemperature for 12 h., diluted with EtOAc (150 mL) and washed with H2O (100 mL x 3) followed by brine (50 mL). The organic layer was dried over Na2SO4, filtered andconcentrated and the residue was purified by automated chromatographic column on silicagel eluted with 0percent to 8percent EtOAc/petroleum ether to give a mixture of 4-bromo-5-cyclopropyl-3- methyl- isoxazole and 4-bromo-3-cyclopropyl-5-methylisoxazole as a yellow oil (2.5 g, 12.3 mmol, 78percent yield in two steps). ESI-LCMS (m/z): 201.9 [M+1]+.[00340] Step B3: Synthesis of a mixture of 5-cyclopropyl-3-methyl-4-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)isoxazole and 3-cyclopropyl-5-methyl-4-(4,4,5,5- tetra-methyl-1,3,2-dioxaborolan-2-yl)isoxazole. To a mixture of 4-bromo-5-cyclopropyl-3- methylisoxazole and 4-bromo-3-cyclopropyl-5-methylisoxazole (500 mg, 2.48 mmol) in dioxane (15 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (943 mg, 3.71 mmol), KOAc (1.17 g, 7.43 mmol) and PdCl2(dppf) (181 mg, 0.25 mmol); the system was purged with N2stream, sealed and heated at 105oC for 12 h. After being cooled down to room temperature, the mixture was filtered through a pad of celite and concentrated to give a mixture of 5-cyclopropyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoxazole and 3-cyclopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoxazole as a yellow solid, which was used directly in next step without further purification. ESI- LCMS (m/z): 250.1 [M+1]+.[00341] Step 1: Synthesis of tert-butyl 2-(tert-butyldimethylsilyloxy)-3-(3-(4-(5-cyclo- propyl-3-methylisoxazol-4-yl)-5-methyl-6-(tetrahydro-2H-pyran-4-ylamino) pyrimidin- 2-yl) phenoxy)propyl(methyl)carbamate. To a solution of tert-butyl 2-(tert- butyldimethylsilyloxy)-3-(3-(4-chloro-5-methyl- 6-(tetrahydro-2H-pyran-4- ylamino)pyrimidin-2-yl)phenoxy)propyl(methyl)carbamate (400 mg, 0.64 mmol) in degassed dioxane and H2O (3/1, 4 mL) was added KF (37 mg, 0.64 mmol), Pd2(dba)3(46 mg, 0.06 mmol), TCP (36 mg, 0.13 mmol) and 5-cyclo-propyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoxazole (containing 30percent of regioisomer: 3-cyclopropyl-5-methyl-4- (4,4,5,5-tetramethyl-1,3,2- dioxa-borolan-2-yl)isoxazole) (319 mg, 1.28 mmol). The system was purged with N2stream, the reaction vessel was sealed, placed in a microwave reactor and irradiated for 1h at external temperature of 130oC. After being cooled down to room temperature, the mixture was diluted with EtOAc (25 mL) and washed with water (20 mL) followed by brine (20 mL). The organic layer was dried over Na2SO4, filtered andconcentrated and the residue was purified by chromatographic column on silicagel(petroleum ether/EtOAc = 10/1 to 1/1) to give a mixture of tert-butyl 2-(tert- butyldimethylsilyloxy)-3-(3-(4-(5-cyclopropyl-3-methylisoxazol-4-yl)-5-methyl-6- (tetrahydro-2H-pyran-4-yl-amino)pyrimidin-2-yl)phenoxy)propyl(methyl)carbamate, along with its regiosiomer tert-butyl 2-(tert butyldimethylsilyloxy)-3-(3-(4-(3-cyclopropyl-5- methyl-isoxazol-4-yl)-5-methyl-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl)phenoxy) propyl(methyl)carbamate (total: 200 mg, 44percent yield). ESI-LCMS (m/z): 708.7 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With acetic acid; at 110℃; for 1h; | [00300] A mixture of l-cyclopropylbutane-l,3-dione (616 mg, 4.0 mmol) in HOAc (10 mL) was heated at 110 °C, followed by the addition of ethyl 2-amino-lH-pyrrole-3-carboxylate (504 mg, 4.0 mmol). The mixture was then stirred at 110 °C for 1 h, and subsequently concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE/EA from 4/1 to 1/1) to afford 450 mg of a brown oil, which was further purified by prep-HP LC (MeCN/10mM NH4HCO3) to afford ethyl 4-cyclopropyl-2-methylpyrrolo[l,2-a]pyrimidine-8- carboxylate (200 mg, 20percent yield) as a grey solid. XH NMR (500 MHz, CDC13): delta 7.41 (d, J = 3.0 Hz, 1H), 7.34 (d, J= 3.0 Hz, 1H), 6.40 (s, 1H), 4.42 (q, J= 7.0 Hz, 2H), 2.62 (s, 3H), 2.10- 2.05 (m, 1H), 1.43 (t, J= 7.0 Hz, 3H), 1.24-1.20 (m, 2H), 0.93-0.90 (m, 2H). LC-MS m/z: 245.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55%; 30% | With acetic acid; at 110℃; for 1h;Microwave irradiation; | General procedure: A mixture of ethyl 5-amino-1H-pyrazole-4-carboxylate (546 mg, 3.52 mmol) and 5,5- dimethylhexane-2,4-dione (1 .03 g, 97 percent purity, 7.03 mmol) in acetic acid (2.7 ml) was heated for 1 h at 11 OC in a microwave reactor (Biotage In itator). Upon cooling to room temperature, the reaction mixture was portioned between water and dichlormethane and the organic phase was washed with water, filtrated through a silicone filter and concentrated undervacuum. The crude product was purified by flash chromatography (25 g Snap Cartrigde, hexanes/ethyl acetate gradient) to yield the title compound (850 mg, 93percent yield). Was preapared in anaolgy to the synthesis of ethyl 7-tert-butyl-5-methylpyrazolo[1 5- a]pyrimidine-3-carboxylate using 1 -cyclopropylbutane-1 ,3-dione (910 p1, 7.9 mmol) as starting material. The crude product was purified by flash chromatography (25 g SnapCartdrige, hexanes/ethyl acetate gradient, 12percent -> 50percent ethyl acetate) to give ethyl 7- cyclopropyl-5-methylpyrazolo[1 ,5-a]pyrimidine-3-carboxylate (549 mg, 55percent yield) and ethyl 5-cyclopropyl-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylate (295 mg, 30percent yield). 7-cycloroyl-5-methylyrazolo[1 ,5-a]yrim idine-3-carboxylate:[C-MS (Method 1): R = 0.97 mm; MS (ESIpos): m/z = 246.1 [M+H]1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.135 (0.40), 1.147 (1.51), 1.153 (1.52), 1.159(1.44), 1.166 (1.47), 1.176 (0.64), 1.285 (4.25), 1.293 (1.60), 1.300 (1.78), 1.303 (10.10),1.314 (1.75), 1.321 (5.49), 1.332 (0.52), 2.523 (0.66), 2.539 (16.00), 2.778 (0.47), 2.786(0.51), 2.799 (0.94), 2.812 (0.48), 2.820 (0.45), 4.245 (1.14), 4.263 (3.75), 4.280 (3.72),4.298 (1.13), 6.845 (4.22), 8.554 (5.58). ethyl 5-cycloroyl-7-m ethylyrazolo[1 ,5-a]yrim idine-3-carboxylate:[C-MS (Method 1): R = 1.04 mm; MS (ESIpos): m/z = 246.1 [M+H]1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.105 (1.33), 1.111 (4.14), 1.116 (3.07), 1.120 (3.11), 1.123 (8.04), 1.129 (2.74), 1.138 (2.08), 1.143 (4.39), 1.150 (1.69), 1.165 (0.50),1.286 (6.99), 1.304 (15.77), 1.322 (7.28), 2.192 (0.44), 2.205 (0.83), 2.211 (0.85), 2.217(0.67), 2.224 (1.81), 2.232 (0.68), 2.237 (0.85), 2.243 (0.78), 2.256 (0.41), 2.523 (1.66),2.536 (0.87), 2.701 (16.00), 2.703 (15.53), 4.219 (2.19), 4.236 (7.14), 4.254 (7.06), 4.272(2.16), 7.134 (4.38), 7.136 (4.35), 8.500 (9.32). |
Tags: 21573-10-4 synthesis path| 21573-10-4 SDS| 21573-10-4 COA| 21573-10-4 purity| 21573-10-4 application| 21573-10-4 NMR| 21573-10-4 COA| 21573-10-4 structure
[ 562-46-9 ]
4,4-Dimethylcyclohexane-1,3-dione
Similarity: 0.84
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