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[ CAS No. 1022931-45-8 ]

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Chemical Structure| 1022931-45-8
Chemical Structure| 1022931-45-8
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Product Details of [ 1022931-45-8 ]

CAS No. :1022931-45-8 MDL No. :MFCD08447340
Formula : C7H7F3N2O Boiling Point : 279.2°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :192.14 g/mol Pubchem ID :-
Synonyms :

Safety of [ 1022931-45-8 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
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Application In Synthesis of [ 1022931-45-8 ]

  • Downstream synthetic route of [ 1022931-45-8 ]

[ 1022931-45-8 ] Synthesis Path-Downstream   1~18

  • 1
  • [ 1062295-93-5 ]
  • [ 1022931-45-8 ]
  • [ 1062294-62-5 ]
YieldReaction ConditionsOperation in experiment
With dimethylaminoacetic acid; potassium carbonate In dimethyl sulfoxide at 190℃; for 0.5h; Microwave irradiation; 35 Example 35: λ/-{(2/?S)-5-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)- yl]-2,3-dihydro-1H-inden-2-yl}acetamide A mixture of /V-(5-bromo-2,3-dihydro-1 H-inden-2-yl)acetamide (53.0mg, 0.17mmol), 3- (trifluoromethyl)-1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole (85.0mg, 0.44mmol), K2CO3 (102mg, 0.74mmol), λ/,λ/-dimethylglycine (44.0mg, 0.34mmol), and copper (I) iodide (48.0mg, 0.25mmol) in anhydrous DMSO (1.3ml) was stirred at 19O0C under microwave heating for 30 minutes. The mixture was partitioned between DCM (2 x 20ml) and water (10ml). The separated organic phases were combined, concentrated in vacuo, and purified by MDAP, giving the title compound (31.7mg, 86.7μmol).LC/MS (ES): Found 366 (ES+), retention time 2.65 mins. Ci8H18F3N3O2 requires 365. 1HNMR (400MHz, CDCI3): 1.96 (3H, s), 2.78-2.93 (4H, m), 3.31-3.39 (2H, m), 3.87-3.99 (2H, m), 4.74-4.86 (3H, m), 5.72 (1 H, d, J=7Hz), 7.25-7.34 (2H, m), 7.38-7.41 (1 H, m).
  • 2
  • [ 158351-87-2 ]
  • [ 1022931-45-8 ]
YieldReaction ConditionsOperation in experiment
68% With hydrazine In ethanol at 60 - 70℃; for 9h; 10 Description 10: 3-(trifluoromethyl)-1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole; A mixture of 3-(trifluoroacetyl)tetrahydro-4H-pyran-4-one (5.42g, 27.7mmol, Description 9), and hydrazine hydrate (1.38g, 1.4ml, 27.6 mmol) in ethanol (120ml) was stirred at 6O0C under argon for 6 hours. A further 0.7ml (14mmol) of hydrazine hydrate was added and the reaction stirred at 7O0C for 3 hours. The reaction mix was allowed to cool and the solvent removed by rotary evaporation. The residue was partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulphate, and solvent removed by rotary evaporation. The aqueous layer was neutralised with 2N HCI and re-extracted with dichloromethane. The organic layer was separated, dried over sodium sulphate, and the solvent removed by rotary evaporation. The 2 extracts were combined to give the title compound as a yellow solid (3.64g, 68%).LC/MS (ES): Found 191 (ES-), retention time 1.92 mins. C7H7F3N2O requires 192. 1 H-NMR (400MHz, CDCI3): δ 2.83 (2H, m), 3.95 (2H, m), 4.76 (2H, s), 1 1.32 (1 H, bs).
68% With hydrazine hydrate In ethanol at 60 - 70℃; for 9h; Inert atmosphere; 4 A mixture of 3-(trifluoroacetyl)tetrahydro-4H-pyran-4-one (D4, 5.42 g, 27.7 mmol), and hydrazine hydrate (1.38 g, 1.4 ml, 27.6 mmol) in ethanol (120 ml) was stirred at 60° C. under argon for 6 hours. A further 0.7 ml (14 mmol) of hydrazine hydrate was added and the reaction stirred at 70° C. for 3 hours. The reaction mix was allowed to cool and the solvent removed by rotary evaporation. The residue was partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulphate, and solvent removed by rotary evaporation. The aqueous layer was neutralised with 2N HCl and re-extracted with dichloromethane. The organic layer was separated, dried over sodium sulphate, and the solvent removed by rotary evaporation. The 2 extracts were combined to give the title compound as a yellow solid (3.64 g, 68%).1H-NMR (400 MHz, CDCl3) δ: 11.32 (1H, br s), 4.76 (2H, s), 3.95 (2H, m), 2.83 (2H, m); LC/MS Retention time 1.92 mins/(ES-) 191 (M-H, C7H7F3N2O requires 192).
68% With hydrazine hydrate In ethanol at 60 - 70℃; for 9h; Inert atmosphere;
68% With hydrazine In ethanol at 60 - 70℃; for 9h; 13 Description 13: 3-(trifluoromethyl)-1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazoleA mixture of 3-(trifluoroacetyl)tetrahydro-4H-pyran-4-one (5.42g, 27.7mmol), and hydrazine hydrate (1.38g, 1.4ml, 27.6 mmol) in ethanol (120ml) was stirred at 6O0C under argon for 6 hours. A further 0.7ml (14mmol) of hydrazine hydrate was added and the reaction stirred at 7O0C for 3 hours. The reaction mix was allowed to cool and the solvent removed by rotary evaporation. The residue was partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulphate, and solvent removed by rotary evaporation. The aqueous layer was neutralised with 2N HCI and re- extracted with dichloromethane. The organic layer was separated, dried over sodium sulphate, and the solvent removed by rotary evaporation. The 2 extracts were combined to give the title compound as a yellow solid (3.64g, 68%).LC/MS (ES): Found 191 (ES-), retention time 1.92 mins. C7H7F3N2O requires 192.1 H-NMR (400MHz, CDCI3): 2.83 (2H, m), 3.95 (2H, m), 4.76 (2H, s), 1 1.32 (1 H, br s).

  • 3
  • [ 1022931-45-8 ]
  • [ 1062295-88-8 ]
  • [ 1062294-67-0 ]
YieldReaction ConditionsOperation in experiment
With dimethylaminoacetic acid; caesium carbonate In dimethyl sulfoxide at 190℃; for 0.5h; Microwave irradiation; 38 Example 38 and 39:The following compounds were synthesised each from 2-[(2/?)-5-bromo-2,3-dihydro-1 H- inden-2-yl]isothiazolidine 1 ,1-dioxide (148 mg; 0.47 mmol) and either 3-(trifluoromethyl)- 1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole 92.4 mg; 0.48 mmol) or 3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indazole (92.8 mg; 0.49 mmol) in a similar manner (with Cs2CO3 replacing K2CO3) and using the same stoichiometry as for Example 35. The reactions were quenched with aqueous hydrochloric acid (2N, 2ml), prior to work up and purified in a similar fashion to Example 35.Table 4
  • 4
  • [ 1022931-45-8 ]
  • [ 1062295-72-0 ]
  • [ 1062294-82-9 ]
YieldReaction ConditionsOperation in experiment
With dimethylaminoacetic acid; caesium carbonate In dimethyl sulfoxide at 190℃; for 0.5h; Microwave irradiation; 45 Example 45: 1-[(2S)-2-(1,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1H-inden-5-yl]-3- hydropyrano[4,3-c]pyrazoleUnder an inert atmosphere of argon, a mixture of 3-(trifluoromethyl)-1 , 4,6,7- tetrahydropyrano[4,3-c]pyrazole (Description 13, 94.4 mg, 0.49 mmol), 2-[(2S)-5-bromo- 2,3-dihydro-1 H-inden-2-yl]isothiazolidine 1 ,1-dioxide (Description 17, 150.4 mg, 0.48 mmol), λ/,λ/-dimethylglycine (59.7 mg, 0.58 mmol), cesium carbonate (305.5 mg, 0.94 mmol) and copper(l) oxide (74.2 mg, 0.52 mmol) in DMSO (2 ml.) was stirred under microwave heating at 190 0C for 30 minutes. The reaction was quenched with aqueous HCI (2N, 1 ml_), diluted with DCM (1 ml_), and stirred for a further 30 minutes. This mixture was partitioned between DCM (35 ml.) and water (15 ml_). The separated aqueous phase was further extracted with DCM (2x30 ml_). The combined organic phase was concentrated in vacuo. Purification by column chromatography gave the desired product (26.8 mg).LC/MS (ES): Found 428 (ES+), retention time 1.11 mins. (2 minute method) C19H20F3N3O3S requires 427.
  • 6
  • [ 952402-39-0 ]
  • [ 1022931-45-8 ]
  • [ 1138449-96-3 ]
YieldReaction ConditionsOperation in experiment
With copper(l) iodide; dimethylaminoacetic acid; potassium carbonate In dimethyl sulfoxide at 150℃; for 18h; 22 5-iodo-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)- 2,4(1 H,3H)-pyrimidinedione (Prepi O, 150 mg, 0.282 mmol), copper (1 +) iodide (59.1 mg, 0.310 mmol), N,N-dimethylglycine (32.0 mg, 0.310 mmol) and K2CO3 (86 mg, 0.620 mmol) were dissolved in Dimethyl Sulfoxide (DMSO) (2 ml) to give a light blue solution with a white precipitate. To this mixture, 3-(trifluoromethyl)-1 ,4,6,7-tetrahydropyrano[4,3- c]pyrazole (starting material prepared according to a similar procedure to that described in Prep38 followed by Prep39, 179 mg, 0.931 mmol) was added. After 18h shaking at 150 0C, the reaction mixture was diluted with EtOAc (5ml) and the organic phase was washed with water (4x1 OmI), then brine (5ml), dried over Na2SO4, then filtered and the solvent evaporated. The obtained crude was passed through an SCX cartridge and eluted with 2M solution of ammonia in MeOH. The resulting mixture was further purified by preparative LC-MS to obtain 9.6 mg of the title compound as a free base. [Preparative LC-MS conditions: Column: Gemini C18 AXIA, 50 x 21 mm, 5 μm; Mobile phase: A: NH4HCO3 sol. 10 mM, pH 10; B: CH3CN; Gradient: 20% (B) for 1 min, 20% to 60% (B) in 9 min, 60% (B) for 1 min, 60% to 100% (B) in 0.1 min, 100% (B) for 1.9 min; Flow rate: 17 ml/min; UV range: 210-350 nm; Ionization: ES+; Mass range: 100-900 amu]. MS (ES) (m/z): 570.16 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.65 (1 H, br. s.) 7.84 (1 H, s) 7.53 - 7.57 (2 H, m) 7.20 - 7.25 (2 H, m) 4.77 (2 H, s) 3.91 - 3.98 (4 H, m) 3.42 (1 H, d) 3.19 (1 H, d) 2.79 (2 H, t) 2.56 - 2.67 (3 H, m) 2.51 (1 H, dd) 1.90 - 1.99 (2 H, m) 1.79 - 1.85 (1 H, m) 1.35 (1 H, t) 0.86 (1 H, dd).
  • 7
  • [ 1022931-45-8 ]
  • [ 112704-79-7 ]
  • [ 1022931-90-3 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole With copper(l) iodide; potassium carbonate In dimethyl sulfoxide for 0.0833333h; Stage #2: 2-fluoro-4-bromobenzoic acid With dimethylaminoacetic acid In dimethyl sulfoxide at 130℃; for 10h; Inert atmosphere; Stage #3: With hydrogenchloride In water 28 A mixture of 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (D4, 500 mg, 2.60 mmol), copper (I) iodide (500 mg, 2.60 mmol), potassium carbonate (720 mg, 5.20 mmol) and dimethylsulfoxide (8 ml) was stirred for 5 minutes, 4-bromo-2-fluorobenzoic acid (570 mg, 2.60 mmol) and N,N-dimethylglycine (267 mg, 2.60 mmol) were then successively added. The reaction mixture was heated with stirring at 130° C. under argon for 10 hours, then the reaction mixture was diluted with ethyl acetate and water, filtered through kieselguhr to remove the catalyst, aqueous layer was retained and acidified to pH 2 using 5 N aqueous hydrochloric acid. Aqueous fraction was then extracted with ethyl acetate (×3). Organic layers were combined and dried over sodium sulphate, filtered and the solvent was removed by rotary evaporation to give the title compound as a crude dark brown solid >75% pure (850 mg, 74%).1H-NMR (400 MHz, DMSO-d6) δ: 8.04 (1H, m), 7.68 (2H, m), 4.73 (2H, s), 3.86 (2H, m), 3.03 (2H, m), 13.47 (1H, br s); LC/MS Retention time 2.73 mins/(ES+) 331 (M+H, C14H10F4N2O3 requires 330).
  • 8
  • [ 1022931-45-8 ]
  • [ 619-58-9 ]
  • [ 1022931-76-5 ]
YieldReaction ConditionsOperation in experiment
20% With potassium carbonate In dimethyl sulfoxide at 130℃; for 3.25h; 20 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (D4, 1.08 g, 5.6 mmol), 4-iodobenzoic acid (1.39 g, 5.6 mmol), copper (I) iodide (10 mol %, 107 mg, 0.56 mmol), N,N-dimethylglycine (20 mol %, 116 mg, 1.12 mmol), potassium carbonate (1.62 g, 11.7 mmol) and dimethylsulfoxide (15 ml) were added sequentially to a 20 ml microwave vial. Reaction mixture was heated in an oil bath at 130° C. for 3.25 hours. The reaction mixture was then filtered under vacuum and the filtrate separated between ethyl acetate and water. The aqueous layer was retained and acidified to pH2 using 5M hydrochloric acid (aq). Aqueous fraction was then washed with ethyl acetate (×3). Organic layers were combined and dried over sodium sulphate and the solvent removed by rotary evaporation to give the title compound as a yellow solid (346 mg, 20%).1H-NMR (400 MHz, CDCl3) δ: 8.24 (2H, m), 7.69 (2H, d, J=9Hz), 4.82 (2H, m), 3.96 (2H, t, J=6 Hz), 2.97 (2H, m); LC/MS Retention time 2.75 mins/(ES+) 313 (M+H, C14H11F3N2O3 requires 312).
  • 9
  • [ 168317-99-5 ]
  • [ 1022931-45-8 ]
  • [ 1022930-30-8 ]
YieldReaction ConditionsOperation in experiment
60% With caesium carbonate In dimethyl sulfoxide at 130℃; for 16h; 1 1-[4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole A mixture of 1-[(4-iodophenyl)carbonyl]pyrrolidine (D2, 843 mg, 2.80 mmol), 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (D4, 563 mg, 2.93 mmol), copper (I) oxide (10 mol %, 0.3 mmol, 43 mg), N,N-dimethylglycine (20 mol %, 0.6 mmol, 62 mg) and cesium carbonate (5.8 mmol, 1.89 g) in dimethylsulfoxide (8 ml) was stirred at 130° C. (oilbath temperature) for 16 h. The reaction mix was cooled and then partitioned between water (30 ml) and dichloromethane (2*20 ml). The organic layers were dried over sodium sulphate and the solvent removed under reduced pressure. The crude product was added to a 20 g isolute pre-packed silica gel sep-pak column and eluted from 0-75% ethyl acetate in petroleum ether. The solvent was removed under reduced pressure to give the title compound as a yellow solid (616 mg, 60%). 1H-NMR (400 MHz, CDCl3) δ: 7.66 (2H, m), 7.58 (2H, m), 4.81 (2H, s), 3.94 (2H, t, J=6 Hz), 3.67 (2H, t, J=7 Hz), 3.44 (2H, t, J=7 Hz), 2.90 (2H, t, J=6 Hz), 2.03-1.88 (4H, m); LC/MS Retention time 2.85 mins/(ES+) 366 (M+H, C18H18F3N3O2requires 365).
60% With copper(I) oxide; dimethylaminoacetic acid; caesium carbonate In dimethyl sulfoxide at 130℃; for 16h;
  • 10
  • [ 326885-27-2 ]
  • [ 1022931-45-8 ]
  • [ 1022931-04-9 ]
YieldReaction ConditionsOperation in experiment
26% Stage #1: 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole With potassium carbonate In dimethyl sulfoxide for 0.0166667h; Stage #2: 4-iodo-N-(tetrahydro-2-furanylmethyl)benzenesulfonamide With dimethylaminoacetic acid In dimethyl sulfoxide at 180℃; for 0.666667h; Microwave irradiation; 30 N-(tetrahydro-2-furanylmethyl)-4-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)-yl]benzenesulfonamide A mixture of copper (I) iodide (10 mol %, 0.09 mmol, 18 mg), 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (D4, 100 mg, 0.52 mmol), potassium carbonate (144 mg, 1.03 mmol) and dimethylsulfoxide (3 ml) was stirred for 1 minute, 4-iodo-N-(tetrahydro-2-furanylmethyl)benzenesulfonamide (D27, 191 mg, 0.52 mmol) and N,N-dimethylglycine (20 mol %, 0.10 mmol, 10 mg) were then successively added. The reaction tube was quickly sealed and the contents were heated in a microwave reactor at 180° C. for 40 minutes. Then the reaction mixture was cooled and partitioned between ethyl acetate and water, organic layer separated, dried with sodium sulphate and evaporated. The residue was purified by mass directed auto-preparation (MDAP) to give the title compound as a pale yellow solid (59 mg, 26%). 1H-NMR (400 MHz, CDCl3) δ: 8.0 (2H, m), 7.72 (2H, m), 4.92 (1H, m), 4.81 (2H, s), 3.96 (3H, m), 3.79 (1H, m), 3.71 (1H, m), 3.18 (1H, m), 2.95 (3H, m), 1.90 (3H, m), 1.60 (1H, m); LC/MS Retention time 2.82 mins/(ES+) 432 (M+H, C18H20F3N3O4S requires 431).
  • 11
  • [ 950785-27-0 ]
  • [ 1022931-45-8 ]
  • [ 1022930-33-1 ]
YieldReaction ConditionsOperation in experiment
67% With potassium carbonate In dimethyl sulfoxide at 190℃; for 0.5h; Microwave irradiation; 2 1-({4-(3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)-yl]phenyl}methyl)-2-pyrrolidinone A mixture of 1-[(4-iodophenyl)methyl]-2-pyrrolidinone (D1, 150 mg, 0.5 mmol), 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (D4, 96 mg, 0.5 mmol), copper (I) iodide (10 mol %, 0.05 mmol, 10 mg), N,N-dimethylglycine (20 mol %, 0.1 mmol, 10 mg) and potassium carbonate (1 mmol, 138 mg) in dimethylsulfoxide (2 ml) was stirred at 190° C. in a microwave reactor for 30 mins. The reaction mix was cooled and then partitioned between water (5 ml) and dichloromethane (5 ml). The organic layer was added to a 5 g isolute pre-packed silica gel sep-pak column and washed through with ethyl acetate. The solvent was removed under reduced pressure and the residue purified via mass-directed auto-preparation to give the title compound as a yellow oil (122 mg, 67%). 1H-NMR (400 MHz, CDCl3) δ: 7.48 (2H, m), 7.37 (2H, d, J=8 Hz), 4.80 (2H, s), 4.51 (2H, s), 3.93 (2H, t, J=6 Hz), 3.29 (2H, m), 2.87 (2H, t, J=6 Hz), 2.46 (2H, m), 2.03 (2H, m); LC/MS Retention time 2.72 mins/(ES+) 366 (M+H, C18H18F3N3O2 requires 365).
67% With copper(l) iodide; dimethylaminoacetic acid; potassium carbonate In dimethyl sulfoxide at 190℃; for 0.5h; Microwave irradiation;
  • 12
  • [ 1022931-81-2 ]
  • [ 1022931-45-8 ]
  • [ 1022930-95-5 ]
YieldReaction ConditionsOperation in experiment
10% With potassium carbonate In dimethyl sulfoxide at 190℃; for 1h; Microwave irradiation; 26 1-[2-fluoro-4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole A mixture of 1-[(4-bromo-3-fluorophenyl)carbonyl]pyrrolidine (D22, 190 mg, 0.7 mmol), 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (D4, 134 mg, 0.7 mmol), copper (I) iodide (10 mol %, 0.07 mmol, 13 mg), N,N-dimethylglycine (20 mol %, 0.14 mmol, 14 mg) and potassium carbonate (193 mg, 1.4 mmol) in dimethylsulfoxide (3 ml) was stirred at 190° C. in a microwave reactor for 0.5 hours. The reaction mix was treated with further copper (I) iodide (10 mol %, 0.07 mmol, 13 mg) and N,N-dimethylglycine (20 mol %, 0.14 mmol, 14 mg) and heating continued at 190° C. in a microwave reactor for 0.5 hours. Then the reaction mix was partitioned between water (5 ml) and dichloromethane (2*3 ml). The organic fractions were added to a 5 g isolute pre-packed silica column and eluted with ethyl acetate. The solvent was removed by rotary evaporation and the residue purified by mass directed auto-preparation to give the title compound as a brown oil (26 mg, 10%). 1H-NMR (400 MHz, CDCl3) δ: 7.57 (2H, m), 7.45 (1H, m), 4.81 (2H, s), 3.94 (2H, m), 3.66 (2H, t, J=6 Hz), 3.45 (2H, m), 2.90 (1H, m), 2.71 (1H, m), 2.07-1.87 (4H, m); LC/MS Retention time 2.83 mins/(ES+) 384 (M+H, C18H17F4N3O2requires 383).
  • 13
  • [ 1022931-58-3 ]
  • [ 1022931-45-8 ]
  • [ 1022930-47-7 ]
YieldReaction ConditionsOperation in experiment
30% With caesium carbonate In dimethyl sulfoxide at 130℃; for 4h; Inert atmosphere; 7 1-({2,6-difluoro-4-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)-yl]phenyl}methyl)-2-pyrrolidinone ;A mixture of 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (D4, 0.993 g, 5.17 mmol), copper (I) oxide 0.739 g, 5.17 mmol), cesium carbonate (3.37 g, 10.34 mmol), 1-[(4-bromo-2,6-difluorophenyl)methyl]-2-pyrrolidinone (D10, 1.5 g, 5.17 mmol) and N,N-dimethylglycine (0.532 g, 5.17 mmol) in DMSO (15 ml) was heated at 130° C. under argon for 4 h. The reaction mixture was diluted with ethyl acetate. Catalyst was filtered off through kieselguhr. The reaction mixture was partitioned between ethyl acetate and water, separated organic layer, washed with brine, dried over sodium sulphate. The solvent was removed by rotary evaporation and the desired product was isolated by column chromatography on silica using 20 to 70% ethyl acetate in n-pentane. The residual material was recrystallized from ether to give the title compound as a white solid (0.62 g, 30%). 1H-NMR (400 MHz, CDCl3) δ: 7.18 (2H, m), 4.78 (2H, s), 4.60 (2H, s), 3.94 (2H, m), 3.30 (2H, m), 2.96 (2H, m), 2.40 (2H, m), 2.0 (2H, m); LC/MS Retention time 2.90 mins/(ES+) 402 (M+H, C18H16F5N3O2 requires 401).
30% With copper(I) oxide; dimethylaminoacetic acid; caesium carbonate In dimethyl sulfoxide at 130℃; for 4h; Inert atmosphere;
  • 14
  • [ 1022931-92-5 ]
  • [ 1022931-45-8 ]
  • [ 1022931-18-5 ]
YieldReaction ConditionsOperation in experiment
22% Stage #1: 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole With potassium carbonate In dimethyl sulfoxide for 0.0166667h; Stage #2: 2-(4-bromo-2-fluorophenyl)-1-(pyrrolidin-1-yl)ethan-1-one With dimethylaminoacetic acid In dimethyl sulfoxide at 180℃; for 0.666667h; Microwave irradiation; 35 1-{3-fluoro-4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole A mixture of copper (I) iodide (49.5 mg, 0.26 mmol), 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (D4, 50 mg, 0.26 mmol), potassium carbonate (72 mg, 0.52 mmol) and dimethylsulfoxide (1.5 ml) was stirred for 1 minute, 1-[(4-bromo-2-fluorophenyl)acetyl]pyrrolidine (D31, 74.5 mg, 0.26 mmol) and N,N-dimethylglycine (20 mol %, 0.05 mmol, 5 mg) were then successively added. The reaction tube was quickly sealed and the contents were heated in a microwave reactor at 180° C. for 40 minutes. Then the reaction mixture was cooled and partitioned between ethyl acetate and water, organic layer separated, dried with sodium sulphate and evaporated. The residue purified by mass directed auto-preparation (MDAP) to give the title compound as a brown gum (23 mg, 22%). 1H-NMR (400 MHz, CDCl3) δ: 7.46 (1H, m), 7.28 (2H, m), 4.79 (2H, s), 3.93 (2H, m), 3.69 (2H, s), 3.51 (4H, m), 2.90 (2H, m), 2.0 (2H, m), 1.88 (2H, m); LC/MS Retention time 2.83 mins/(ES+) 398 (M+H, C19H19F4N3O2 requires 397).
  • 15
  • [ 1022931-60-7 ]
  • [ 1022931-45-8 ]
  • [ 1022931-07-2 ]
YieldReaction ConditionsOperation in experiment
30% Stage #1: 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole With potassium carbonate In dimethyl sulfoxide for 0.0166667h; Stage #2: 1-[(4-bromo-2-fluorophenyl)methyl]-2-pyrrolidinone With dimethylaminoacetic acid In dimethyl sulfoxide at 180℃; for 0.666667h; Microeave irradiation; 31 1-({2-fluoro-4-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)-yl]phenyl}methyl)-2-pyrrolidinone A mixture of copper (I) iodide (49.5 mg, 0.26 mmol), 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (D4, 50 mg, 0.26 mmol), potassium carbonate (72 mg, 0.52 mmol) and dimethylsulfoxide (1.5 ml) was stirred for 1 minute, 1-[(4-bromo-2-fluorophenyl)methyl]-2-pyrrolidinone (D11, 71 mg, 0.26 mmol) and N,N-dimethylglycine (20 mol %, 0.05 mmol, 5 mg) were then successively added. The reaction tube was quickly sealed and the contents were heated in a microwave reactor at 180° C. for 40 minutes. Then the reaction mixture was cooled and partitioned between ethyl acetate and water, organic layer separated, dried with sodium sulphate and evaporated. The residue was purified by mass directed auto-preparation (MDAP) to give the title compound as a solid (30 mg, 30%). 1H-NMR (400 MHz, CDCl3) δ: 7.42 (1H, m), 7.31 (2H, m), 4.80 (2H, m), 4.56 (2H, s), 3.93 (2H, m), 3.35 (2H, m), 2.90 (2H, m), 2.44 (2H, m), 2.03 (2H, m); LC/MS Retention time 2.75 mins/(ES+) 384 (M+H, C18H17F4N3O2 requires 383).
  • 16
  • [ 1022931-45-8 ]
  • [ 183128-59-8 ]
  • [ 1022930-85-3 ]
YieldReaction ConditionsOperation in experiment
5% With caesium carbonate In dimethyl sulfoxide at 190℃; for 0.5h; Microwave irradiation; 22 N-({4-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)-yl]phenyl}methyl)methanesulfonamide A mixture of N-[(4-bromophenyl)methyl]methanesulfonamide (D25, 132 mg, 0.5 mmol), 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (D4, 96 mg, 0.5 mmol), copper (I) oxide (10 mol %, 0.05 mmol, 7 mg), N,N-dimethylglycine (20 mol %, 0.1 mmol, 10 mg) and cesium carbonate (1 mmol, 326 mg) in dimethylsulfoxide (2 ml) was stirred at 190° C. in a microwave reactor for 0.5 hours. Then the reaction mix was cooled and partitioned between dichloromethane and water. The organic layer was added directly to a 5 g isolute silica sep-pak column and eluted from ethyl acetate. The solvent was removed under reduced pressure and the residue further purified by mass directed auto-preparation to give the title compound as a pale yellow oil (10 mg, 5%). 1H-NMR (400 MHz, CDCl3) δ: 7.54 (2H, m), 7.49 (2H, d, J=8Hz), 4.81 (2H, s), 4.67 (1H, m), 4.40 (2H, d, J=6 Hz), 3.93 (2H, t, J=6 Hz), 2.94 (3H, s), 2.88 (2H, m); LC/MS Retention time 2.67 mins/(ES+) 376 (M+H, C15H16F3N3O3S requires 375).
  • 17
  • [ 29943-42-8 ]
  • [ 1022931-45-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -70 °C / Inert atmosphere 1.2: -70 - 20 °C / Inert atmosphere 2.1: hydrazine hydrate / ethanol / 9 h / 60 - 70 °C / Inert atmosphere
Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -70 °C 1.2: 16 h / -70 - 20 °C 2.1: hydrazine / ethanol / 9 h / 60 - 70 °C
  • 18
  • [ 1022931-45-8 ]
  • [ 1571820-87-5 ]
  • [ 1571819-19-6 ]
YieldReaction ConditionsOperation in experiment
55% With potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide at 55℃; for 1h; 49 Example 49 Synthesis of 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[3-(trifluoromethyl)-6,7-dihydro-4H-pyrano[4,3-c]pyrazol-1-yl]ethanone Example 49 Synthesis of 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[3-(trifluoromethyl)-6,7-dihydro-4H-pyrano[4,3-c]pyrazol-1-yl]ethanone A mixture of 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (0.050 g, 0.26 mmol), 2-chloro-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-yl]ethanone (0.050 g, 0.17 mmol) and K2CO3 (0.130 g, 0.94 mmol) in THF (0.8 mL) and DMF (0.4 mL) was heated at 55° C. for 1 hr. It was then cooled to rt. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.035 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.44 (dd, J=8.8, 4.6 Hz, 2H), 7.17 (dd, J=8.8, 8.0 Hz, 2H), 5.13 (s, 2H), 4.75 (s, 2H), 3.98 (t, J=5.4 Hz, 2H), 3.87 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 2.10 (m, 2H); MS: (ES) m/z calculated for C21H19F4N5O2 [M+H]+ 450.1, found 450.1.
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