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CAS No. : | 61798-24-1 | MDL No. : | MFCD05664382 |
Formula : | C8H18N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JRHPOFJADXHYBR-UHFFFAOYSA-N |
M.W : | 142.24 | Pubchem ID : | 551074 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 44.06 |
TPSA : | 24.06 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) : | -6.67 cm/s |
Log Po/w (iLOGP) : | 2.3 |
Log Po/w (XLOGP3) : | 0.7 |
Log Po/w (WLOGP) : | 0.74 |
Log Po/w (MLOGP) : | 0.9 |
Log Po/w (SILICOS-IT) : | 0.87 |
Consensus Log Po/w : | 1.1 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.03 |
Solubility : | 13.2 mg/ml ; 0.0931 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.78 |
Solubility : | 23.5 mg/ml ; 0.165 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.94 |
Solubility : | 1.64 mg/ml ; 0.0115 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.0 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3259 |
Hazard Statements: | H302-H314 | Packing Group: | Ⅲ |
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 |
---|---|---|
With potassium phosphate; CuI; In toluene; | Preparation of 1-(2-aminophenyl)indole at 80 C. Using the general procedure, indole (0.117 g, 1.00 mmol) was coupled at 80 C. with 2-iodoaniline (0.263 g, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (32 muL, 0.20 mmol, 20 mol %) and toluene (1.0 mL) to give the crude product. The above product was identified by comparison (GC) to a previously prepared sample and the GC yield was determined to be 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45-50% | With potassium phosphate; CuI; In toluene; | 1-(2-Methylpropenyl)indole Using the general procedure described above, indole (0.117 g, 1.00 mmol) was coupled with 1-bromo-2-methylpropene (123 muL, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (16 muL, 0.10 mmol, 10 mol %) and toluene (1.0 mL) at 80 C. to give 45-50% conversion of indole (GC); the structure of the product was assigned using GC/MS analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium phosphate; CuI; In toluene; | Preparation of 1-(2-pyridyl)indole from 2-chloropyridine Using the general procedure, indole (0.117 g, 1.00 mmol) was coupled with 2-chloropyridine (113 muL, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (32 muL, 0.20 mmol, 20 mol %) and toluene (1.0 mL) to give the crude product. Column chromatography (2*15 cm, hexane:ethyl acetate 9:1) provided 0.194 g (100% yield) of the product as a yellow oil. 1H NMR (400 MHz, CDCl3): delta9.24 (s, 1H), 9.05 (s, 1H), 8.41 (s, 1H), 7.75 (m, 2H), 7.60 (m, 2H), 7.48 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium phosphate; CuI; In dodecane; ethyl acetate; toluene; | Example 153 Preparation of 1-phenylindole in Air To a flame-dried resealable test tube was added CuI (0.002 g, 0.01 mmol), indole (0.117 g, 1.00 mmol) and K3PO4 (0.446 g, 2.1 mmol). A rubber septum was fitted and dodecane (45 muL, 0.20 mmol), iodobenzene (134 muL, 1.20 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (16 muL, 0.10 mmol) and toluene (1 mL) were added successively in air. The reaction tube was sealed and the contents were stirred with heating via an oil bath at 110 C. for 24 hours. The reaction mixture was cooled to ambient temperature, diluted with 2-3 mL ethyl acetate, and filtered through a plug of silica gel eluding with 10-20 mL of ethyl acetate. Comparison to authentic material showed that the product was formed in an 82% GC yield. |
With potassium phosphate; In dodecane; ethyl acetate; toluene; | Example 154 Preparation of 1-phenylindole using Various Copper Sources To a flame-dried resealable test tube was added the copper source (0.050 mmol), indole (0.117 g, 1.00 mmol) and K3PO4 (0.446 g, 2.1 mmol) under an atmosphere of argon. A rubber septum was fitted and dodecane (45 muL, 0.20 mmol), iodobenzene (134 muL, 1.20 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (16 muL, 0.10 mmol) and toluene (1 mL) were added successively under a stream of argon. The reaction tube was sealed and the contents were stirred with heating via an oil bath at 110 C. for 24 hours. The reaction mixture was cooled to ambient temperature, diluted with 2-3 mL ethyl acetate, and filtered through a plug of silica gel eluding with 10-20 mL of ethyl acetate. The GC yields of the desired product are tabulated below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; CuI; In toluene; | Preparation of 1-(4-ethoxycarbonylphenyl)indole at 80 C. Using the general procedure, indole (0.117 g, 1.00 mmol) was coupled at 80 C. with ethyl-4-iodobenzoate (0.331 g, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (32 muL, 0.20 mmol, 20 mol %) and toluene (1.0 mL) to give the crude product. The above product was identified by comparison (GC) to a previously prepared sample and the GC yield was determined to be 96%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium phosphate; CuI; In toluene; | 1-(1-Hexenyl)indole Using the general procedure described above, indole (0.117 g, 1.00 mmol) was coupled with 1-iodo-1-hexene (171 muL, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (16 muL, 0.10 mmol, 10 mol %) and toluene (1.0 mL) at ambient temperature to give 42% conversion of indole (GC); the structure of the product was assigned by GC/MS analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium phosphate; CuI; In toluene; | 1-(2-Aminophenyl)indole Using the general procedure, indole (0.117 g, 1.00 mmol) was coupled with 2-bromoaniline (0.206 g, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (16 muL, 0.10 mmol, 10 mol %) and toluene (1.0 mL) to give the crude product. Column chromatography (2*15 cm, hexane: ethyl acetate 5:1) provided 0.148 g (71% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): delta 7.64 (m, 1H), 7.18 (m, 6H), 6.82 (m, 2H), 6.64 (m,, 1H), 3.52 (bs, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium phosphate; CuI; In N-methyl-acetamide; | 1 -Phenylbenzotriazole Using the general procedure, benzotriazole (0.119 g, 1.00 mmol) was coupled with iodobenzene (134 muL, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (16 muL, 0.10 mmol, 10 mol %) and dimethylformamide (1.0 mL) to give the crude product. Column chromatography (2*15 cm, hexane:ethyl acetate 9:1) provided 0.186 g (95% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): delta8.17 (m, 1H), 7.78 (m, 3H), 7.62 (m, 2H), 7.55 (m, 2H), 7.42 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium phosphate; CuI; In toluene; | 1-Phenyltryptamine Using the general procedure, tryptamine (0.160 g, 1.00 mmol) was coupled with iodobenzene (134 muL, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (32 muL, 0.20 mmol, 20 mol %) and toluene (1.0 mL) to give the crude product. Column chromatography (2*5 cm, methylene chloride (saturated with ammonia):methanol 50:1) provided 0.206 g (87% yield) of the product as a yellow oil. 1H NMR (400 MHz, CDCl3): delta 7.65 (m, 1H), 7.55 (m, 1H), 7.47 (m, 4H), 7.31 (m, 1H), 7.18 (m, 3H), 3.06 (t, J=7 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 1.40 (bs, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With thionyl chloride; In diethyl ether; dichloromethane; | EXAMPLE 20 Trans-(+-)-2-(2,6-dichlorophenoxy)-N-methyl-N-[2-(methylamino)cyclohexyl]acetamide monohydrochloride 2,6-dichlorophenoxyacetic acid (0.50 g, 2.3 mmol) was treated with thionyl chloride (6 ml) at room temperature for 60 hours. The solution was concentrated in vacuo to give an oil which was dissolved in dichloromethane (2.5 ml) and added dropwise over three minutes to a stirred solution of trans-(+-)-N,N'-dimethylcyclohexane-1,2-diamine (0.35 g, 3.1 mmol) in dichloromethane (2.5 ml). After 1.5 hours at room temperature the mixture was filtered and the filtrate treated with diethyl ether until precipitation occurred. The resulting white solid was recrystallized (dichloromethane-diethyl ether) to give trans-(+-)-2-(2,6-dichlorophenoxy)-N-methyl-N-[2-(methylamino)cyclohexyl]acetamide monohydrochloride (171 mg, 19%); VmaxC=0 (liquid file) 1655 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | EXAMPLE 8 Trans-(+-)-N,N'-dimethylcyclohexane-1,2-diamine A vigorously stirred mixture of N-methylazabicyclo-[4.1.0]-heptane (36.1 g), monomethylamine (162 ml of a 23-30% aqueous solution) and ammonium chloride (0.50 g) was heated in an oil bath at 94-99 C. for 21.5 hours. After cooling to 0 C. the mixture was treated with sodium hydroxide (10 g) and extracted with diethyl ether (4*100 ml). The combined ethereal fractions furnished a residue which was distilled to give pure trans-(+-)-N-N'-dimethylcyclo-hexane-1,2-diamine (18 g, 39%); b.p. 78 C. (14 mm) which solidified after standing at 17 C.; found: C, 67.5; H, 13.1; N, 19.65. Calc. for C8 H18 N2; C, 67.55, H, 12.75; N, 19.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; 1,1'-carbonyldiimidazole; In tetrahydrofuran; diethyl ether; dichloromethane; | EXAMPLE 9 Trans-(+-)-N-methyl-N-[2-(methylamino)cyclohexyl]benzo[b]thiophene-4-acetamide monohydrochloride A solution of benzo[b]thiophene-4-acetic acid (4.65 g, 24 mmol) and carbonyldiimidazole (3.95 g, 24 mmol) in tetrahydrofuran (20 ml) was heated to reflux for 0.5 hours, then cooled to 0 C. and added dropwise over 25 minutes to a stirred solution of trans-(+-)-N,N'-dimethylcyclohexane-1,2-diamine (3.0 g, 21 mmol) in tetrahydrofuran (10 ml) at -13 C. The mixture was stirred for a further two hours and allowed to warm to room temperature. The solvent was removed in vacuo to give residue which was dissolved in dichloromethane (100 ml) and washed with aqueous potassium carbonate (100 ml) then water (100 ml). The organic fraction furnished an oily residue which after high pressure liquid chromatography (Waters 500 Prep HPLC silica gel, 80:20:1 ethyl acetatemethanol-triethylamine) gave a light yellow oil (3.3 g); Vmax (liquid file) 3320, 1635 cm-1. Formation of hydrochloride salt: Method L: The oil (3.3 g) was dissolved in diethyl ether (100 ml), filtered through a plug of cotton wool and treated with a solution of hydrogen chloride in diethyl ether until the solution became acidic. The resulting white precipitate was isolated by filtration and washed with diethyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18 g (39%) | With ammonium chloride; methylamine; | EXAMPLE 2 trans-N,N'-Dimethylcyclohexane-1,2-diamine 7-Methyl-7-azabicyclo[4.1.0]heptane (36.1 g prepared by the method detailed in Example 1), methylamine (162 ml of a 23-30% aqueous solution) and 0.5 g of ammonium chloride were heated in an oil bath at 9414 99 C. for 21.5 hours. After cooling to 0 C. the mixture was treated with 10 g of solid sodium hydroxide and extracted four times with 100 ml portions of ether. The combined ether extracts were dried over anhydrous magnesium sulfate, the ether evaporated, and the residue distilled to yield 18 g (39%) of trans-N,N'-dimethylcyclohexane-1,2-diamine, bp 78 C. (at a pressure of 1866 Pascal) which solidified upon standing to a solid which melted at 17 C. Analysis--found: C, 67.5%; H, 13.1%; N, 19.65%. Calc. for C8 H18 N2: C, 67.55%; H, 12.75%; N, 19.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With CuI; caesium carbonate; In 1,4-dioxane; | d) 1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-phenethylpiperazin-2-one dihydrochloride (Enantiomer A) (-)-tert-Butyl 3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate (enantiomer A) (70.0 mg, 0.180 mmol), 4-phenethylpiperazin-2-one (40.0 mg, 0.200 mmol), CuI (69.0 mg, 0.360 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (5.60 muL, 0.0400 mmol) and Cs2CO3 (117 mg, 0.360 mmol) in dioxane (5 mL) were reacted following the procedure for Example 2 (step c) to give tert-butyl 5-methyl-3-(2-oxo-4-phenethylpiperazin-1-yl)-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate (580 mg) as a yellow solid. The yellow solid was deprotected and converted to the hydrochloride salt according to the procedure for Example 2 (step d) to provide the title compound (12.8 mg, 15%) as a yellow solid. Free Base: 1H NMR (500 MHz, CDCl3) delta 7.47 (d, J=8.5 Hz, 1H), 7.33-7.30 (m, 2H), 7.26-7.23 (m, 3H), 7.19 (d, J=1.5 Hz, 1H), 6.96 (dd, J=8.0, 1.5 Hz, 1H), 4.70-4.69 (m, 1H), 4.21-4.40 (m, 1H), 3.76-3.73 (m, 2H), 3.44 (s, 2H), 3.43 (s, 3H), 3.42 (dd, J=16.0, 4.0 Hz, 1H), 2.92-2.86 (m, 4H), 2.77-2.74 (m, 2H), 2.56 (d, J=16.0 Hz, 1H), 2.40-2.20 (m, 2H), 2.08-2.04 (m, 1H), 1.63-1.60 (m, 1H); HPLC (Method A) 96.0% (AUC), tR=10.1 min. HCl salt: 1H NMR (500 MHz, CD3OD) delta 7.64 (d, J=8.5 Hz, 1H), 7.44 (d, J=1.5 Hz, 1H), 7.40-7.35 (m, 4H), 7.32-7.28 (m, 1H), 7.08 (dd, J=8.0, 1.5 Hz, 1H), 5.22 (d, J=5.5 Hz, 1H), 4.55-4.52 (m, 1H), 4.30-3.80 (m, 6H), 3.70 (s, 3H), 3.62-3.58 (m, 2H), 3.50 (dd, J=17.5, 4.5 Hz, 1H), 3.21-3.16 (m, 2H), 3.06 (d, J=17.0 Hz, 1H), 2.49-2.34 (m, 2H), 2.29-2.24 (m, 1H), 2.00-1.97 (m, 1H); ESI MS m/z 415 [M+H]+; HPLC (Method A) 97.8% (AUC), tR=10.0 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With CuI; caesium carbonate; In 1,4-dioxane; | b) 4-(4-Chlorophenethyl)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridin-2-yl)-piperazin-2-one dihydrochloride tert-Butyl 2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxylate (214 mg, 0.550 mmol), 4-(4-chlorophenethyl)piperazin-2-one (131 mg, 0.550 mmol), CuI (157 mg, 0.530 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (17.0 muL, 0.110 mmol) and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (5 mL) were reacted following the procedure for Example 2 (step c) to give tert-butyl 2-(4-(4-chlorophenethyl)-2-oxopiperazin-1-yl)-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxylate (83.3 mg) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide; In ethanol; hexane; water; ethyl acetate; | k) [5-(3-Azido-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester [5-(3-Bromo-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (2.25, 5.55 mmol), sodium azide (2.89 g, 44.4 mmol), sodium ascorbate (0.440 g, 2.22 mmol), copper iodide (0.423 g, 2.22 mmol) and rac-trans-N,N'-dimethyl-cyclohexane-1,2-diamine (0.790 g, 5.55 mmol) were dissolved in ethanol (76.6 ml) and water (33.0 ml). The mixture was stirred under N2 at 70 C. for 30 minutes. After completion hexane/ethyl acetate 1/1 were added and the reaction mixture was filtered over silica gel. The filtrate was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/TBME 9/1 to obtain azide, later hexane/ethyl acetate 2/1 to 1/1 to obtain aniline as side product) to yield the title compound. 1H-NMR (360 MHz, CDCl3): 7.42 (m, 1H), 7.25 (m, 2H), 7.07 (m, 1H), 5.97 (t, 1H, CHF2), 4.80 (d, 1H), 4.65 (d, 1H), 4.25 (d, 1H), 3.80 (d, 1H), 1.55 (s, 9H); MS: 368 [(M+H)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide; CuI; In ethanol; water; | i) [5-(5-Azido-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester To a solution of 7.27 g (17.18 mmol) [5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester and 2.443 g (17.18 mmol) trans-N,N'-dimethylcyclohexane-1,2-diamine in 237 ml EtOH was added a solution of 8.93 g (137 mmol) sodium azide and 1.361 g (6.87 mmol) sodium-ascorbate in 102 ml water. The mixture was degassed and brought under nitrogen atmosphere. CuI (1.309 g, 6.87 mmol) was added and the mixture was heated at 70 C. The initially formed suspension turned into a homogeneous blue solution. The mixture was cooled to rt, diluted with water and TBME. The organic phase was washed with brine and dried with MgSO4.H2O. The crude product was purified by chromatography on silica gel (hexane/5-8% TBME) to give the desired product as a colorless solid. HPLC: RtH1=3.173 min; ESIMS [M+H]+=386; 1H-NMR (CDCl3, 360 MHz, signals broadened due to rotamers): 7.39-7.44 (m, 1H), 7.15-7.06 (m, 1H), 7.05-6.98 (m, 1H), 6.14 (t, 1H, CHF2), 4.80 (d, 1H), 4.60 (d, 1H), 4.39 (d, 1H), 3.97 (d, 1H), 1.52 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide; dimethyl sulfoxide; In water; ethyl acetate; | a) (1R,2S,7R,8S)-5-(7-Azido-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (1R,2S,7R,8S)-3-(4-Fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 1a, 0.513 g, 0.864 mmol), sodium azide (1.12 g, 17.2 mmol), sodium ascorbate (0.086 g, 0.43 mmol), copper (I) iodide (0.16 g, 0.84 mmol), and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.20 mL, 1.27 mmol) were dissolved in a 5:1 mixture of dimethyl sulfoxide and water (10 mL) at 25 C. The reaction flask was degassed and backfilled with nitrogen (5*). After stirring at 25 C. for 14 h, the reaction mixture was partitioned between water (150 mL) and ethyl acetate (2*150 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 60% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-5-(7-azido-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.348 g, 0.684 mmol, 79%), as a dark brown foam, which was used in the next step without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; | Step 2: tert-butyl ((5R,6S)-5-(5-azido-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate A flask was charged with copper(I) iodide (0.158 g, 0.831 mmol), sodium azide (1.080 g, 16.62 mmol), (+)-sodium 1-ascorbate (0.165 g, 0.831 mmol) and tert-butyl ((5R,6S)-5-(5-bromo-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (1 g, 2.077 mmol). Trans-N,N'-dimethylcyclohexane-1,2-diamine (0.262 ml, 1.662 mmol), ethanol (7 ml) and water (3 ml) were added, the flask was flushed with nitrogen, capped, and heated at 50 C. for 45 minutes. The reaction mixture was diluted with water and ethyl acetate. The organic layer was collected, dried over sodium sulfate and concentrated to yield tert-butyl ((5R,6S)-5-(5-azido-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.921 g, 2.077 mmol) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In 1,4-dioxane; | Step 8. (R)-N-(5-(8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6-yl)-6-fluoropyridin-3-yl)-5-chloro-3-methylpicolinamide To a solution of (R)-8-amino-6-(5-bromo-2-fluoropyridin-3-yl)-6-methyl-4-thia-7-azaspiro[2.5]oct-7-ene 4,4-dioxide (200 mg, 0.552 mmol) in 1,4-dioxane (1.3 mL) was added potassium carbonate (305 mg, 2.209 mmol), copper(I) iodide (15.77 mg, 0.083 mmol), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (0.013 mL, 0.083 mmol). The resulting mixture was then stirred at RT for 15 min. Then, 5-chloro-3-methylpicolinamide (188 mg, 1.104 mmol) was added and the mixture was then stirred at 105 C. for 14 h. Copper(i) iodide (15.77 mg, 0.083 mmol) and trans-N,N'-dimethyl-1,2-cyclohexanediamine (0.013 mL, 0.083 mmol) were added and the mixture was then heated at 105 C. for 14 h. The mixture was then cooled to RT, saturated NaHCO3 (5 mL) was added and the mixture was extracted with DCM (2*20 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography, eluent 0%-25% MeOH/DCM to give 145 mg of the title compound as yellow solid. MS (ESI, positive ion) m/z: 452.1 (M+H). 1H NMR (DMSO-d6) d: 10.87 (s, 1H), 8.52-8.61 (m, 2H), 8.34 (dd, J=9.3, 2.6 Hz, 1H), 7.99-8.06 (m, 1H), 5.92 (s, 2H), 3.58-3.84 (m, 2H), 2.57 (s, 3H), 1.79 (dd, J=8.0, 4.7 Hz, 1H), 1.67 (s, 3H), 1.55-1.63 (m, 1H), 1.43-1.53 (m, 1H), 1.31-1.42 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.5% | With potassium carbonate; | Step 2: R-N-(5-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-methoxypyridin-3-yl)-5-chloropicolinamide A microwave vial was charged with (R)-5-amino-3-(5-bromo-2-methoxypyridin-3-yl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (0.200 g, 0.532 mmol), 5-chloropicolinamide (0.125 g, 0.797 mmol), copper(i) iodide (0.020 g, 0.106 mmol) and potassium carbonate, powder, particle size -325 mesh (0.220 g, 1.595 mmol). The vial was purged with N2 followed by the addition of 1,4-dioxane (2.0 mL) and trans-n,n'-dimethyl-1,2-cyclohexanediamine (0.084 mL, 0.532 mmol). The vial was sealed and heated at 120 C. for 16 hrs. LCMS indicated reaction went to completion. The reaction mixture was allowed to cool to room temperature and then partitioned between EtOAc and water. The aqueous layer was back extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by Shimadzu HPLC to afford the title compound (0.078 g, 0.173 mmol, 32.5% yield) as off-white solid (free base), LC/MS (ESI+) m/z=452 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (101 mg, 0.421 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (128 mg, 0.349 mmol) and Cs2CO3 (148 mg, 0.454 mmol) in toluene (5 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (75 mg, 0.53 mmol) and CuI (100 mg, 0.53 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (62 mg, 34%) as an off-white solid: ESI MS m/z 526 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | b) tert-Butyl 7-(2'-oxo-5-(trifluoromethyl)-[2,4'-bipyridin]-1'(2'H)-yl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate A mixture of 4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (164 mg, 0.683 mmol), tert-butyl 7-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (200 mg, 0.57 mmol) and Cs2CO3 (240 mg, 0.74 mmol) in toluene (7 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (121 mg, 0.851 mmol) and CuI (162 mg, 0.851 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, (CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 75:25) afforded the title compound (218 mg, 75%) as white solid: 1H NMR (300 MHz, DMSO-d6) delta 9.16-9.14 (m, 1H), 8.42-8.34 (m, 2H), 7.87 (d, J=7.2 Hz, 1H), 7.75-7.69 (m, 2H), 7.35-7.30 (m, 2H), 7.08 (dd, J=7.2, 1.8 Hz, 1H), 4.56 (s, 2H), 3.78 (t, J=5.7 Hz, 2H), 2.90-2.86 (m, 2H), 1.46 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(2-oxo-4-((6-(trifluoromethyl)pyridin-2-yl)methoxy)pyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-((6-(trifluoromethyl)pyridin-2-yl)methoxy)pyridin-2(1H)-one (170 mg, 0.63 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (192 mg, 0.524 mmol) and Cs2CO3 (222 mg, 0.681 mmol) in toluene (6 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (149 mg, 1.05 mmol) and CuI (200 mg, 1.05 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (229 mg, 79%) as a white solid: ESI MS m/z 556 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With ammonium hydroxide; caesium carbonate; In dichloromethane; toluene; | c) tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydrobenzofuro[2,3-c]pyridine-2(1H)-carboxylate tert-Butyl 7-bromo-3,4-dihydrobenzofuro[2,3-c]pyridine-2(1H)-carboxylate (0.15 g, 0.43 mmol), 4-benzyloxy pyridinone (0.10 g, 0.51 mmol), and Cs2CO3 (0.18 g, 0.55 mmol) were suspended in toluene (6 mL), and N2 was bubbled through the suspension for 30 min. The suspension was treated with (1S,2S)N,N'-bismethyl-1,2-cyclohexane-diamine (0.10 mL, 0.63 mmol) and bubbled with N2 for 5 min. Copper iodide (0.12 g, 0.63 mmol) was added, and the resulting suspension was heated at reflux under N2 for 18 h. The mixture was cooled to ambient temperature, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (10 mL) and stirred for 20 min. A solution of 2:1 brine/NH4OH (20 mL) was added followed by CH2Cl2 (30 mL), and the resulting layers were separated. The aqueous phase was extracted with CH2Cl2 (2*30 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (4*30 mL) and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 for 3 min, increased to 0:100 over 30 min and held for 3 min) gave the title compound (0.18 g, 88%) as a light pink solid: 1H NMR (500 MHz, DMSO-d6) delta 7.62-7.58 (m, 3H), 7.48-7.40 (m, 4H), 7.39-7.34 (m, 1H), 7.22 (d, J=8.5 Hz, 1H), 6.11 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.14 (s, 2H), 4.58 (s, 2H), 3.68 (t, J=5.5 Hz, 2H) 2.76-2.69 (m, 2H), 1.44 (s, 9H); ESI MS m/z 473 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With ammonium hydroxide; caesium carbonate; In toluene; | b) tert-Butyl 7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydrobenzofuro[2,3-c]pyridine-2(1H)-carboxylate tert-Butyl 7-bromo-3,4-dihydrobenzofuro[2,3-c]pyridine-2(1H)-carboxylate (0.15 g, 0.43 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (0.11 g, 0.51 mmol), and Cs2CO3 (0.18 g, 0.55 mmol) were suspended in toluene (6 mL), and N2 was bubbled through the suspension for 15 min. The suspension was treated with (1S,2S)N,N'-bismethyl-1,2-cyclohexane-diamine (0.10 mL, 0.63 mmol) and bubbled with N2 for 5 min. Copper iodide (0.12 g, 0.63 mmol) was added, and the resulting suspension was heated at reflux under N2 for 18 h. The mixture was cooled to ambient temperature and diluted with a solution of 2:1 brine/NH4OH (30 mL), and the resulting suspension was stirred for 30 min. The suspension was diluted with CH2Cl2 (30 mL), and the resulting biphasic solution was stirred for 15 min. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2*30 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (4*25 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 for 3 min, increased to 0:100 over 30 min and held for 3 min) gave the title compound (0.16 g, 78%) as an off-white foam: 1H NMR (500 MHz, DMSO-d6) delta 8.61 (d, J=3.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.67-7.64 (m, 1H), 7.62-7.58 (m, 3H), 7.22 (dd, J=8.5, 1.5 Hz, 1H), 6.14 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=3.0 Hz, 1H), 5.21 (s, 2H), 4.58 (s, 2H), 3.68 (t, J=5.5 Hz, 2H), 2.73-2.69 (m, 2H), 1.44 (s, 9H); ESI MS m/z 492 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With ammonium hydroxide; caesium carbonate; In dichloromethane; toluene; | b) tert-Butyl 7-(2'-oxo-6-(trifluoromethyl)-[3,4'-bipyridin]-1'(2'H)-yl)-3,4-dihydrobenzofuro[2,3-c]pyridine-2(1H)-carboxylate tert-Butyl 7-bromo-3,4-dihydrobenzofuro[2,3-c]pyridine-2(1H)-carboxylate (0.10 g, 0.28 mmol), 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (82 mg, 0.34 mmol), and Cs2CO3 (0.12 g, 0.37 mmol) were suspended in toluene (4 mL), and N2 was bubbled through the suspension for 15 min. The suspension was treated with (1S,2S)N,N'-bismethyl-1,2-cyclohexane-diamine (67 muL, 0.43 mmol) and bubbled with N2 for 5 min. Copper iodide (81 mg, 0.43 mmol) was added, and the resulting suspension was heated at reflux under N2 for 18 h. The mixture was cooled to ambient temperature and diluted with a solution of 1:1 brine/NH4OH (30 mL) followed by CH2Cl2 (75 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3*30 mL). The combined organic extracts were washed with 1:1 brine/NH4OH (3*40 mL) and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO Gold column, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 for 2 min, increased to 50:50 over 30 min and held for 10 min) gave the title compound (0.12 g, 79%) as yellow solid: 1H NMR (500 MHz, DMSO-d6) delta 9.19 (d, J=2.0 Hz, 1H), 8.49 (dd, J=8.0, 2.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.88 (d, J=7.0 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.33 (dd, J=8.0, 1.5 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.81 (dd, J=7.0, 2.0 Hz, 1H), 4.60 (s, 2H), 3.70 (t, J=5.5 Hz, 2H), 2.75-2.72 (m, 2H), 1.45 (s, 9H); ESI MS m/z 512 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With hydrogenchloride; caesium carbonate; In diethyl ether; dichloromethane; water; toluene; | b) (S)-4-(Benzyloxy)-1-(3-methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-7-yl)pyridin-2(1H)-one hydrochloride A mixture of (S)-7-bromo-3-methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (300 mg, 1.13 mmol), 4-(benzyloxy)pyridin-2(1H)-one (227 mg, 1.13 mmol), CuI (421 mg, 2.21 mmol), (1S,2S)-N,N'-dimethylcyclohexane-1,2-diamine (315 mg, 2.21 mmol) and Cs2CO3 (432 mg, 1.32 mmol) in toluene (7 mL) was degassed for 15 min. This mixture was heated at 105 C. for 24 h with stirring. After cooling, the reaction mixture was diluted with a 95:5 (9:1) CH2Cl2/(MeOH/NH4OH) mixture of solvents. The organic layer was washed with NH4OH and brine (200 mL), and the resulting solution was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on an ISCO 40 g gold column using CH2Cl2/CMA [CH2Cl2 (80%)/MeOH (18%)/NH4OH (2%)](0-20% CMA) as the eluent to afford the free base of the title compound with reasonable purity. Further purification through column chromatography using CH2Cl2/MeOH (85:15) as the eluent afforded pure material which was converted to the hydrochloride using 2 N HCl in Et2O (0.050 mL, 0.1 mmol). The resulting suspension was concentrated and lyophilized using water and CH3CN to afford the title compound (24.5 mg, 5%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) delta 9.57 (br s, 1H), 9.39 (br s, 1H), 7.68 (m, 2H), 7.59 (d, J=7.65 Hz, 1H), 7.42 (m, 5H), 7.26 (dd, J=8.2 Hz, 6.6 Hz, 1H), 6.12 (dd, J=7.6 Hz, 5.0 Hz, 1H), 5.98 (s, 1H), 5.15 (s, 2H), 4.42 (m, 2H), 3.79 (br s, 1H), 3.22 (dd, J=17.3 Hz, 13.2 Hz, 1H), 2.90 (dd, J=17.2 Hz, 7.9 Hz, 1H), 1.45 (d, J=6.5 Hz, 3H); ESI MS m/z 387 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With hydrogenchloride; caesium carbonate; In diethyl ether; dichloromethane; water; toluene; | Example 34 Preparation of (S)-1-(3-Methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-one hydrochloride A mixture of (S)-7-bromo-3-methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (300 mg, 1.13 mmol), 4-(pyridin-2-ylmethoxy)pyridin-2(1H)-one (227 mg, 1.13 mmol), CuI (421 mg, 2.21 mmol), (1S,2S)-N,N'-dimethylcyclohexane-1,2-diamine (315 mg, 2.21 mmol) and Cs2CO3 (432 mg, 1.32 mmol) in toluene (7 mL) was degassed for 15 min. This mixture was heated at 105 C. for 24 h with stirring. After cooling, the reaction mixture was diluted with a 95:5 (9:1) CH2Cl2/(MeOH/NH4OH) mixture of solvents. The organic layer was washed with NH4OH and brine (200 mL), and the resulting solution was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on an ISCO 40 g gold column using CH2Cl2/CMA [CH2Cl2 (80%)/MeOH (18%)/NH4OH (2%)](0-45% CMA) as the eluent to afford the free base of the title compound with reasonable purity. Further purification through column chromatography using CH2Cl2(A)/[CH2Cl2/MeOH(14% MeOH)](B) (0-65% of gradient solvent B) as the eluent afforded pure material which was converted to the hydrochloride using 2 N HCl in Et2O (0.050 mL, 0.1 mmol). The resulting suspension was concentrated and lyophilized using water and CH3CN to afford the title compound (29 mg, 6%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) delta 9.62 (br s, 1H), 9.42 (br s, 1H), 8.63 (m, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.69 (m, 2H), 7.62 (m, 2H), 7.43 (t, J=6.7 Hz, 1H), 7.26 (m, 1H), 6.17 (m, 1H), 5.98 (s, 1H), 5.24 (s, 2H), 4.38 (m, 2H), 3.79 (m, 1H), 3.22 (dd, J=17.4 Hz, 12.7 Hz, 1H), 2.90 (dd, J=17.4 Hz, 7.9 Hz, 1H), 1.40 (d, J=6.56 Hz, 3H); ESI MS m/z 388 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 5-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (93 mg, 0.42 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (128 mg, 0.349 mmol) and Cs2CO3 (148 mg, 0.454 mmol) in toluene (5 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (75 mg, 0.53 mmol) and CuI (100 mg, 0.53 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (102 mg, 58%) as an off-white solid: ESI MS m/z 507 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (114 mg, 0.422 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (128 mg, 0.349 mmol) and Cs2CO3 (148 mg, 0.454 mmol) in toluene (5 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (75 mg, 0.53 mmol) and CuI (100 mg, 0.53 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (186 mg, 96%) as a white solid: ESI MS m/z 556 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-((6-methylpyridin-3-yl)methoxy)-2-oxopyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-one (91 mg, 0.42 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (128 mg, 0.349 mmol) and Cs2CO3 (148 mg, 0.454 mmol) in toluene (5 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (75 mg, 0.53 mmol) and CuI (100 mg, 0.53 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (170 mg, 97%) as a white solid: ESI MS m/z 502 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (100 mg, 0.42 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (128 mg, 0.349 mmol) and Cs2CO3 (148 mg, 0.454 mmol) in toluene (5 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (75 mg, 0.53 mmol) and CuI (100 mg, 0.53 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (159 mg, 87%) as an off-white solid: ESI MS m/z 525 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (92 mg, 0.42 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (128 mg, 0.349 mmol) and Cs2CO3 (148 mg, 0.454 mmol) in toluene (5 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (75 mg, 0.53 mmol) and CuI (100 mg, 0.53 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (77 mg, 44%) as a white solid: ESI MS m/z 506 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-(2-(5-fluoropyridin-2-yl)ethyl)-2-oxopiperazin-1-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-(2-(5-fluoropyridin-2-yl)ethyl)piperazin-2-one (94 mg, 0.42 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (128 mg, 0.349 mmol) and Cs2CO3 (148 mg, 0.454 mmol) in toluene (5 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (75 mg, 0.53 mmol) and CuI (100 mg, 0.53 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (109 mg, 61%) as a colorless solid: ESI MS m/z 509 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-(4-chlorophenethyl)-2-oxopiperazin-1-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-(4-chlorophenethyl)piperazin-2-one (150 mg, 0.63 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (192 mg, 0.524 mmol) and Cs2CO3 (225 mg, 0.691 mmol) in toluene (8 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (112 mg, 0.787 mmol) and CuI (150 mg, 0.79 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (178 mg, 65%) as a colorless solid: ESI MS m/z 524 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-(2-(5-chloropyridin-2-yl)ethyl)-2-oxopiperazin-1-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-(2-(5-chloropyridin-2-yl)ethyl)piperazin-2-one (151 mg, 0.626 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (192 mg, 0.524 mmol) and Cs2CO3 (225 mg, 0.691 mmol) in toluene (8 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (112 mg, 0.787 mmol) and CuI (150 mg, 0.79 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (172 mg, 62%) as a colorless solid: ESI MS m/z 525 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-(2-(5-chloropyridin-2-yl)ethyl)-2-oxopyrimidin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-(2-(5-chloropyridin-2-yl)ethyl)pyrimidin-2(1H)-one (140 mg, 0.59 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (167 mg, 0.456 mmol) and Cs2CO3 (193 mg, 0.592 mmol) in toluene (7 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (97 mg, 0.68 mmol) and CuI (130 mg, 0.68 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (96 mg, 40%) as a tan solid: ESI MS m/z 521 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (99 mg, 0.42 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (128 mg, 0.349 mmol) and Cs2CO3 (148 mg, 0.454 mmol) in toluene (5 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (75 mg, 0.53 mmol) and CuI (100 mg, 0.53 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (58 mg, 32%) as an off-white solid: ESI MS m/z 522 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate A mixture of 4-(benzyloxy)pyridin-2(1H)-one (85 mg, 0.42 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (128 mg, 0.349 mmol) and Cs2CO3 (148 mg, 0.454 mmol) in toluene (6 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (75 mg, 0.53 mmol) and CuI (100 mg, 0.53 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (35 mg, 21%) as a white solid: ESI MS m/z 487 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[2,3-d]azepine-3(2H)-carboxylate A mixture of 4-(benzyloxy)pyridin-2(1H)-one (204 mg, 1.02 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[2,3-d]azepine-3(2H)-carboxylate (310 mg, 0.85 mmol) and Cs2CO3 (358 mg, 1.10 mmol) in toluene (7 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (241 mg, 1.69 mmol) and CuI (322 mg, 1.69 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (139 mg, 34%) as a light yellow solid: ESI MS m/z 487 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With ammonium hydroxide; caesium carbonate; In toluene; | a) tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate tert-Butyl 7-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.15 g, 0.42 mmol), 4-benzyloxy pyridinone (0.10 g, 0.51 mmol), and Cs2CO3 (0.18 g, 0.55 mmol) were suspended in toluene (15 mL), and N2 was bubbled through the suspension for 20 min. The suspension was treated with (1S,2S)N,N'-bismethyl-1,2-cyclohexane-diamine (0.10 mL, 0.63 mmol) and bubbled with N2 for 5 min. Copper iodide (0.12 g, 0.63 mmol) was added, and the resulting suspension was heated at reflux under N2 for 18 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 30 min. A solution of 2:1 brine/NH4OH (30 mL) was added, and the solution was extracted with CH2Cl2 (3*50 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*50 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 for 3 min, increased to 50:50 over 25 min and held for 5 min; increased to 0:100 over 5 min and held for 3 min) gave the title compound (0.14 g, 68%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) delta 7.64 (d, J=8.0 Hz, 1H), 7.61-7.58 (m, 2H), 7.48-7.41 (m, 4H), 7.38-7.37 (m, 1H), 7.20 (dd, J=8.0, 2.0 Hz, 1H), 6.11 (dd, J=7.5, 3.0 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 4.53 (s, 2H), 3.76 (t, J=5.5 Hz, 2H) 2.85 (t, J=5.5 Hz, 2H), 1.44 (s, 9H); ESI MS m/z 473 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[2,3-d]azepine-3(2H)-carboxylate A mixture of 4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (170 mg, 0.63 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[2,3-d]azepine-3(2H)-carboxylate (192 mg, 0.524 mmol) and Cs2CO3 (222 mg, 0.681 mmol) in toluene (6 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (112 mg, 0.787 mmol) and CuI (150 mg, 0.79 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (141 mg, 48%) as an off-white solid: ESI MS m/z 556 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[2,3-d]azepine-3(2H)-carboxylate A mixture of 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (139 mg, 0.631 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[2,3-d]azepine-3(2H)-carboxylate (192 mg, 0.524 mmol) and Cs2CO3 (222 mg, 0.681 mmol) in toluene (6 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (149 mg, 1.05 mmol) and CuI (200 mg, 1.05 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (60 mg, 23%) as a white solid: ESI MS m/z 506 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | a) tert-Butyl 8-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-4,5-dihydro-1H-benzofuro[2,3-d]azepine-3(2H)-carboxylate A mixture of 4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (240 mg, 1.02 mmol), tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro[2,3-d]azepine-3(2H)-carboxylate (310 mg, 0.85 mmol) and Cs2CO3 (358 mg, 1.10 mmol) in toluene (7 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (241 mg, 1.69 mmol), CuI (322 mg, 1.69 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 25:75) afforded the title compound (123 mg, 28%) as a light yellow oil: ESI MS m/z 522 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With ammonium hydroxide; caesium carbonate; In toluene; | a) tert-Butyl 7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate tert-Butyl 7-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.15 g, 0.42 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (0.11 g, 0.51 mmol), and Cs2CO3 (0.18 g, 0.55 mmol) were suspended in toluene (15 mL), and N2 was bubbled through the suspension for 15 min. The suspension was treated with (1S,2S)N,N'-bismethyl-1,2-cyclohexane-diamine (0.10 mL, 0.63 mmol) and bubbled with N2 for 5 min. Copper iodide (0.12 g, 0.63 mmol) was added, and the resulting suspension was heated at reflux under N2 for 18 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (20 mL) and stirred for 1 h. A solution of 2:1 brine/NH4OH (30 mL) was added, and the solution was stirred for 30 min. The solution was diluted with CH2Cl2 (100 mL), and the resulting layers were separated. The aqueous phase was extracted with CH2Cl2 (3*75 mL), and the combined organic extracts were washed with 2:1 brine/NH4OH (3*100 mL) and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 for 3 min, increased to 0:100 over 30 min and held for 5 min) gave the title compound (0.12 g, 58%) as an off-white foam: 1H NMR (500 MHz, DMSO-d6) delta 8.61 (d, J=3.0 Hz, 1H), 7.84-7.80 (m, 1H), 7.67-7.59 (m, 4H), 7.20 (dd, J=8.5, 2.0 Hz, 1H), 6.14 (dd, J=8.0, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.21 (s, 2H), 4.53 (s, 2H), 3.76 (t, J=5.5 Hz, 2H), 2.88-2.82 (m, 2H), 1.44 (s, 9H); ESI MS m/z 492 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dichloromethane; toluene; | b) (R)-4-((5-Fluoropyridin-2-yl)methoxy)-1-(3-methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-7-yl)pyridin-2(1H)-one A mixture of (R)-tert-butyl 7-bromo-3-methyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (404 mg, 1.10 mmol, mixture of regioisomers), 4-[(5-fluoropyridin-2-yl)methoxy]pyridin-2(1H)-one (243 mg, 1.10 mmol), CuI (478 mg, 2.56 mmol), (1S,2S)-N,N'-dimethylcyclohexane-1,2-diamine (357 mg, 2.56 mmol) and Cs2CO3 (490 mg, 1.50 mmol) in toluene (7 mL) was degassed for 15 min. The mixture was heated at 105 C. for 24 h with stirring. The reaction mixture was allowed to cool and diluted with a 95:5 (9:1) CH2Cl2/(MeOH/NH4OH) mixture of solvents. The organic layer was washed with NH4OH and brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on an ISCO 24 g gold column using CH2Cl2/CMA[CH2Cl2(80%)/MeOH (18%)/NH4OH(2%)](0-20% CMA) as eluent to afford (R)-tert-butyl 7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-3-methyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (316 mg) as a mixture of regiosiomers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With ammonium hydroxide; caesium carbonate; In dichloromethane; toluene; | a) tert-Butyl 7-(2'-oxo-6-(trifluoromethyl)-[3,4'-bipyridin]-1'(2'H)-yl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate tert-Butyl 7-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.10 g, 0.28 mmol, prepared according to Example 10, step b), 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (82 mg, 0.34 mmol), and Cs2CO3 (0.12 g, 0.37 mmol) were suspended in toluene (4.0 mL), and N2 was bubbled through the suspension for 15 min. The suspension was treated with (1S,2S)N,N'-bismethyl-1,2-cyclohexane-diamine (67 muL, 0.43 mmol) and bubbled with N2 for 5 min. Copper iodide (81 mg, 0.43 mmol) was added, and the resulting suspension was heated at reflux under N2 for 18 h. The mixture was cooled to ambient temperature and diluted with a solution of 1:1 brine/NH4OH (30 mL) followed by CH2Cl2 (75 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3*50 mL). The combined organic extracts were washed with 1:1 brine/NH4OH (4*30 mL) and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO Gold column, CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 for 2 min, increased to 50:50 over 30 min and held for 10 min) gave the title compound (84 mg, 57%) as yellow solid: 1H NMR (500 MHz, DMSO-d6) delta 9.19 (d, J=2.0 Hz, 1H), 8.49 (dd, J=8.0, 2.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.81 (dd, J=7.0, 2.0 Hz, 1H), 4.56 (s, 2H), 3.77 (t, J=5.5 Hz, 2H), 2.87 (t, J=5.5 Hz, 2H), 1.45 (s, 9H); ESI MS m/z 512 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With ammonium hydroxide; caesium carbonate; In nitrogen; toluene;liquid N2; | c) tert-Butyl 7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate A mixture of 4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (121 mg, 0.512 mmol), tert-butyl 7-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (150 mg, 0.43 mmol) and Cs2CO3 (180 mg, 0.55 mmol) in toluene (6 mL) in a sealed tube was degassed with a nitrogen stream for 10 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (91 mg, 0.64 mmol) and CuI (121 mg, 0.635 mmol) were added, and the mixture was degassed for another 2 min. The tube was sealed, and the mixture was heated at 110 C. for 12 h. The mixture was cooled, diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (15 mL) and stirred for 1 h. Then 2:1 brine/NH4OH (100 mL) was added, and the aqueous phase was extracted with dichloromethane (4*75 mL). The combined organic extracts were washed with 2:1 brine/NH4OH (3*75 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, (CH2Cl2/(90:9:1 CH2Cl2/MeOH/NH4OH), 100:0 to 60:40) afforded the title compound (141 mg, 65%) as white solid: 1H NMR (500 MHz, DMSO-d6) delta 8.68-8.66 (m, 1H), 8.02 (dd, J=8.5, 2.5 Hz, 1H), 7.65-7.60 (m, 4H), 7.21 (dd, J=8.5, 2.0 Hz, 1H), 6.15 (dd, J=7.5, 3.0 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 4.54 (s, 2H), 3.76 (t, J=5.5 Hz, 2H), 2.87-2.85 (m, 2H), 1.45 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With hydrogenchloride; caesium carbonate; In diethyl ether; dichloromethane; water; toluene; | c) (R)-1-(3-Methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-one A mixture of (R)-7-bromo-3-methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (340 mg, 1.28 mmol), 4-(pyridin-2-ylmethoxy)pyridin-2(1H)-one (252 mg, 1.28 mmol), CuI (478 mg, 2.56 mmol), (1S,2S)-N,N'-dimethylcyclohexane-1,2-diamine (357 mg, 2.56 mmol) and Cs2CO3 (490 mg, 1.50 mmol) in toluene (7 mL) was degassed for 15 min. The mixture was heated at 105 C. for 24 h with stirring. The reaction mixture was allowed to cool and diluted with a 95:5 (9:1) CH2Cl2/(MeOH/NH4OH) mixture of solvents. The organic layer was washed with NH4OH and brine (200 mL). The resulting solution was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on an ISCO 24 g gold column using CH2Cl2/CMA[CH2Cl2(80%)/MeOH(18%)/NH4OH(2%)] (0-25% CMA) as eluent. Further purification through column chromatography as well as trituration with ethyl acetate and a 1:1 mixture of CH2Cl2/hexanes afforded the title compound as a free base. The free base was converted to the HCl salt using 2 N HCl in Et2O (0.10 mL, 0.2 mmol). The resulting suspension was concentrated and lyophilized from water and CH3CN to afford the title compound (67 mg, 24%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) delta 9.66 (br s, 1H), 9.47 (br s, 1H), 8.62 (s, 1H), 7.91 (t, J=7.7 Hz, 1H), 7.68 (m, 2H), 7.61 (d, J=7.6 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.42 (m, 1H), 7.27 (d, J=8.25 Hz, 1H), 6.17 (d, J=7.6 Hz, 1H), 5.97 (s, 1H), 5.23 (s, 2H), 4.34 (m, 2H), 3.78 (m, 1H), 3.22 (dd, J=17.3, 12.8 Hz, 1H), 2.90 (dd, J=17.3, 7.9 Hz, 1H), 1.46 (d, J=6.5 Hz, 3H); ESI MS m/z 388 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In ethanol; water; ethyl acetate; | Step 9: tert-Butyl ((4S,6S)-4-(6-amino-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (7k) A sealable vial was charged with (+)-sodium L-ascorbate (0.026 g, 0.13 mmol, Aldrich), sodium azide (0.102 g, 1.56 mmol, Aldrich), copper(I) iodide (0.026 g, 0.13 mmol, Acros), and tert-butyl ((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (7i, 0.238 g, 0.52 mmol). The sealed vial was evacuated and backfilled with Nitrogen. EtOH (2.5 mL) was added followed by water (1 mL) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.021 mL, 0.130 mmol, Aldrich). The reaction mixture was heated to 70 C. for 3 hs. The cooled reaction mixture was partitioned between NH4Cl/NH4OH (9:1) (10 mL) and EtOAc (10 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified via silica gel flash chromatography (gradient 10-50% EtOAc in hexanes) to afford the title compound as a white solid (0.119 g, 0.3 mmol, 58% yield). MS m/z=393.2 [M+H]+. Calculated for C16H20F4N4O3: 392.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; nitrogen; ammonium chloride; In ethanol; water; | Step 9: N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1k) A sealable vial was charged with (+)-sodium L-ascorbate (0.048 g, 0.241 mmol, Arcos Organics), sodium azide (0.470 g, 7.20 mmol, Aldrich), copper(I) iodide (0.138 g, 0.723 mmol, Aldrich), and N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.15 g, 2.41 mmol, step 8). The sealed vial was evacuated and backfilled with nitrogen gas. EtOH (5.62 ml) was added followed by water (2.41 ml) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.069 g, 0.482 mmol). The reaction was stirred in a pre-heated 80 C. oil bath for 16 hours. The reaction mixture was cooled to RT and partitioned between water and EtOAc. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was taken up in MeOH (20 mL) and sodium borohydride (0.091 g, 2.41 mmol, Aldrich) was added. The reaction was stirred at room temperature for 30 minutes. The reaction was quenched with water and further diluted with water and EtOAc. The organic layer was washed three times with a solution of aqueous saturated ammonium hydroxide and aqueous saturated ammonium chloride solution (1:9), and brine. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford the crude title compound as a grey oil, which was used without further purification assuming theoretical yield. MS m/z=413.9 [M+H]+. Calculated for C19H16F5N3O2: 413.341. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With CuI; caesium carbonate; In N-methyl-acetamide; | 1 -Phenylpurine Using the general procedure, purine (0.120 g, 1.00 mmol) was coupled with iodobenzene (225 muL, 2.00 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), Cs2CO3 (2.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (32 muL, 0.20 mmol, 20 mol %) and dimethylformamide (1.0 mL) to give the crude product. Column chromatography (2*15 cm, hexane:ethyl acetate 1:2) provided 0.136 g (69% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): delta8.00 (d, J=0.9 Hz, 1H), 7.52 (m, 3H), 7.42 (m, 5H), 6.73 (dd, J=0.6 Hz and J=3.3 Hz, 1H), 7.60 (m, 2H), 7.48 (m, 1H). |
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