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With bromine; mercury(II) oxide; In tetrachloromethane; at 80℃; for 2h;
The synthesis of 2-(4-amino-l-(3-mophiholinocyclobutyl)-lH-pyrazolo [3, 4-d]pyrimidin-3- yl)-lH-indol-5-ol (Compound 12-6) is described in Scheme 12. Bromocyclobutanone is produced from compound 12-1 by reaction with mercuric oxide and bromine, which is coupled with pyrazolopyrimidine iodide, compound 2-2, to yield compound 12-3. Reductive amination with morpholine affords compound 12-4. Compound 12-4 is then coupled with a boronic acid derivative to produce compound 12-6.
With bromine; mercury(II) oxide; In tetrachloromethane; at 70℃;
A solution of bromine (0.51 ml_, 10 mmol) in CCI4 (20 ml.) was heated to 70 0C, then a mixture of 3-oxocyclobutanecarboxylic acid (1.14 g, 10 mmol) and red mercuric oxide (1.56 g, 7.9 mmol) was added over 30 min. After 1 h, the reaction mixture became colorless. The solids were filtered off and solvent was removed at 30 0C using rotary evaporator (product is volatile, 22 °C/0.5 mmHg). The residue was dissolved in hexanes and filtered through a silica gel pad and concentrated to give 3-bromocyclobutane, which contains CCI4. 1H NMR (CDCI3, 300 MHz): delta = 3.44-3.50 (m, 2 H), 3.72-3.80 (m, 2 H), 4.51-4.55 (m, 1 H).
With bromine; mercury(II) oxide; In tetrachloromethane; at 70℃; for 1.5h;
3-BromocyclobutanoneA solution of bromine (0.51 mL, 10 mmol) in CCl4 (20 mL) was heated to 70° C. and a mixture of 3-oxocyclobutanecarboxylic acid (1.14 g, 10 mmol) and red mercuric oxide (1.56 g, 7.9 mmol) was added over 30 min.After 1 h, the reaction mixture became colorless.The solids were filtered off and solvent was removed at 30° C. using rotary evaporator (product is volatile, 22° C./0.5 mm).The residue was dissolved in hexanes and filtered through silica and concentrated to give the title compound containing CCl4.It was used directly in the next step. 1H NMR (300 MHz, CDCl3): delta=3.44-3.50 (m, 2H), 3.72-3.80 (m, 2H), 4.51-4.55 (m, 1H).
With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 0.333333h;
The synthesis of 2-(4-amino-l-(3-mophiholinocyclobutyl)-lH-pyrazolo [3, 4-d]pyrimidin-3- yl)-lH-indol-5-ol (Compound 12-6) is described in Scheme 12. Bromocyclobutanone is produced from compound 12-1 by reaction with mercuric oxide and bromine, which is coupled with pyrazolopyrimidine iodide, compound 2-2, to yield compound 12-3. Reductive amination with morpholine affords compound 12-4. Compound 12-4 is then coupled with a boronic acid derivative to produce compound 12-6.
With pyridinium p-toluenesulfonate; In benzene; for 12h;Reflux;
A mixture of <strong>[23761-24-2]3-bromocyclobutanone</strong> (Compound 100F, 5.9 g, 39.6 mmol), 1 ,2-ethanediol (8.6 mL, 158.4 mmol) and PPTS (1.9 g, 7.92 mmol) in benzene (40 mL) was heated to reflux in a Dean-Stark apparatus. After 12 h, the reaction mixture was allowed to cool and washed with water (2 x 30 ml_). The organic phase was dried (Na2SO4) and concentrated and the residue was purified by column chromatography (ethyl acetate/ hexanes: 1 :5) to give 984 mg of 2- bromo-5,8-dioxa-spiro[3.4]octane. 1H NMR (CDCI3, 300 MHz): delta = 2.77-2.82 (m, 2 H), 2.95- 3.00 (m, 2 H), 4.19-4.23 (m, 1 H).
With pyridinium p-toluenesulfonate; In benzene; for 12h;Reflux; Dean-Stark apparatus;
2-Bromo-5,8-dioxaspiro[3.4]octane; A mixture of <strong>[23761-24-2]3-bromocyclobutanone</strong> (5.90 g, 39.6 mmol), 1,2-ethanediol (8.6 mL, 158 mmol, 4 eq.) and PPTS (1.90 g, 7.92 mmol) in benzene (40 mL) was heated to reflux using Dean-Stark assembly. After 12 h, the reaction mixture was allowed to cool and washed with water (2.x.30 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (ethyl acetate/hexanes 1:5) to give the title compound (51percent yield starting from 3-oxocyclobutanecarboxylic acid). 1H NMR (300 MHz, CDCl3): delta=2.77-2.82 (m, 4H), 2.95-3.00 (m, 4H), 4.19-4.23 (m, 1H).
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 10h;
To a solution of 3-iodo-5-(tetrahydrofuran-3-yl)-1H-pyrazole (2 g, 7.5 mmol) inN,N-dimethylformamide (20 mL) was added <strong>[23761-24-2]3-bromocyclobutanone</strong> (2.24 g, 15.1 mmol) andpotassium carbonate (2 g, 15.1 mmol). The mixture was stirred at 25 °C for 10 h. Ethyl acetate (50 mL) was added to the reaction mixture, and the resulting suspension was filtered. The filtrate was concentrated in vacuo. Purification by flash column chromatography afforded product (800 mg, 32percent yield, Rf= 0.3 in 30percent ethyl acetate in hexanes) LCMS (El): [MH] = 332.8.
3-(4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium carbonate; In tetrahydrofuran; at 20℃;
Compound 120 (1.2356 g, 6.82 mmol) was dried in the tared reaction flask and weighed. This was taken up in 22 mL tetrahydrofuran, and a magnetic stir bar was added. 3-Bromocyclobutan-1-one (1.3837 g, 9.29 mmol) was weighed into a tared vial and added to the reaction in 11 mL tetrahydrofuran solution. Potassium carbonate (1.417 g, 10.25 mmol) was weighed out and added, and the reaction was stirred overnight at room temperature. The reaction was next recharged with <strong>[23761-24-2]3-bromocyclobutan-1-one</strong> (1.232 g, 8.27 mmol) in 5 mL tetrahydrofuran and stirred overnight at room temperature. The mixture was then concentrated to remove THF, and partitioned between ethyl acetate and water. The aqueous was extracted three times more with ethyl acetate and the combined organic layer was washed with brine and dried over sodium sulfate. This was filtered and concentrated and it spontaneously crystallized. The solid was collected, washed with a minimal volume of dichloromethane and dried on high vacuum to give 677.2 mg of the title compound 122. A second crop isolated after crystallizing from the filtrate gave 432.2 mg more product 122 (65percent yield). A 1D NOE experiment confirmed the N1 assignment of the pyrazole alkylation. 1H NMR (300 MHz, DMSO-d6) delta 9.44 (s, 1H), 5.34 (p, J = 6.9 Hz, 1H), 3.67 (d, J = 6.7 Hz, 4H). Parent ion not observed.
2,5-dichloro-N-(3-((5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)pyrimidin-4-amine[ No CAS ]
3-(3-(3-((2,5-dichloropyrimidin-4-yl)amino)propoxy)-5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
To a solution of D33 (1 .5 g, 4.32 mmol) in anhydrous DMF (20 mL) was added NaH (207 mg, 5.17 mmol) at 0 °C under argon. The reaction was stirred at room temprature for 0.5 hour. <strong>[23761-24-2]3-bromocyclobutanone</strong> (1 .3 g, 8.73 mmol) was added and the reaction was stirred at room temperature for 2.5 hrs. Water was added and the resultant was extracted with EtOAc (3x20 mL). The combined organics were washed with water (4x30 mL) and brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated. The crude was purified by column chromatography on silica gel (CH2CI2: MeOH= 100: 1 ) to give the title compound as a white solid (690 mg, yield 38percent). LC-MS: 415.3 [M+H]+.
(R)-2,5-dichloro-N-(4-((3-methyl-4-nitro-1H-pyrazol-5-yl)oxy)butan-2-yl)pyrimidin-4-amine[ No CAS ]
(R)-3-(3-(3-((2,5-dichloropyrimidin-4-yl)amino)butoxy)-5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
To a solution of D79 (1 g, 2.8 mmol) in DMF (50 mL) was added NaH (124 mg, 3.1 mmol) at 0 °C. After stirred for 30 min, 3-bromocyclobutan-1 -one (834.3 mg, 5.6 mmol) was added and the mixture was stirred at room temperature for 4 hrs. Then the mixture was poured into ice water and extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04and concentrated in vacuo. The crude was purified by column chromatography on silica gel (PE: EtOAc= 2:1 ) to give the title compound as a off-white solid (850 mg, yield 71 percent). LC-MS: 429.2 [M+H]+.
N-(3-(2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide[ No CAS ]
2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(3-oxocyclobutyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 0℃; for 2h;Inert atmosphere;
To a solution of N-(3 -(2H- 1,2,3 -triazol-4-yl)bicyclo [1.1.1 Ipentan- 1 -yl)-2-(4-chloro-3 - fluorophenoxy)acetamide (600 g, 1.78 mmol) in DMF (5 mL) was added Cs2CO3 (581 mg, 1.78 mmol) and <strong>[23761-24-2]3-bromocyclobutanone</strong> (400 mg, 2.67 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The reaction was poured into ice-water (20 mL), and extracted with EtOAc (3 x 20 mL), the combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(3- oxocyclobutyl)-2H-1,2,3-triazol-4-yl)bicyclo[1 .1. ljpentan-1-yl)acetamide. LC-MS mlz: = 405.1,407.1 [M+Hj.
ethyl 1-(3-oxocyclobutyl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at -10℃; for 1h;Inert atmosphere;
To a solution of ethyl 1H-pyrazole-5-carboxylate (940 mg, 6.7 mmol) in DMF (50 mL) was added Cs2CO3 (2.2 g, 6.71 mmol) and <strong>[23761-24-2]3-bromocyclobutanone</strong> (1.0 g, 6.7 mmol) at -10 °C. The reaction mixture was stirred at -10 °C for 1 h. The reaction mixture was quenched by H20 (90 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Mixture of regioisomers. LC-MS: mlz = 209.1 [M+Hj.
tert-butyl N-[(3R,6S)-6-(2H-triazol-4-yl)tetrahydropyran-3-yl]carbamate[ No CAS ]
tert-butyl N-[(3R,6S)-6-[2-(3-oxocyclobutyl)triazol-4-yl]tetrahydropyran-3-yl]carbamate[ No CAS ]
tert-butyl N-[(3R,6S)-6-[1-(3-oxocyclobutyl)triazol-4-yl]tetrahydropyran-3-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at -20℃; for 2h;Inert atmosphere;
To a mixture of tert-butyl N-[(3R,6S)-6-(2H-triazol-4-yl)tetrahydropyran-3-yl]carbamate (1.5 g, 5.59 mmol) in DMF (10 mL) at -20 °C was added CS2CO3 (1.82 g, 5.59 mmol) and <strong>[23761-24-2]3-bromocyclobutanone</strong> (833 mg, 5.59 mmol) and the resulting mixture was stirred at -20 °C for 2 h. The reaction mixture was poured into ice-water (40 mL) and EtOAc (25 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (2 x 5 mL), dried over anhydrous NaaSO/t, filtered and concentrated under reduced pressure to provide a mixture of tert-butyl N-[(3R,6S)-6-[2-(3-oxocyclobutyl)triazol-4-yl]tetrahydropyran-3-yl]carbamate and tert-butyl N-[(3R,6S)-6-[l-(3-oxocyclobutyl)triazol-4-yl]tetrahydropyran-3-yl]carbamate (2.28 g, crude).
tert-butyl N-[(3R,6S)-6-(2H-triazol-4-yl)tetrahydropyran-3-yl]carbamate[ No CAS ]
tert-butyl N-[(3R,6S)-6-[2-(3-cis-hydroxycyclobutyl)triazol-4-yl]tetrahydropyran-3-yl]carbamate[ No CAS ]
tert-butyl N-[(3R,6S)-6-[1-(3-cis-hydroxycyclobutyl)triazol-4-yl]tetrahydropyran-3-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a mixture of tert-butyl N-[(3R,6S)-6-(2H-triazol-4-yl)tetrahydropyran-3-yl]carbamate (1.5 g, 5.59 mmol) in DMF (10 mL) at -20 °C was added CS2CO3 (1.82 g, 5.59 mmol) and <strong>[23761-24-2]3-bromocyclobutanone</strong> (833 mg, 5.59 mmol) and the resulting mixture was stirred at -20 °C for 2 h. The reaction mixture was poured into ice-water (40 mL) and EtOAc (25 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (2 x 5 mL), dried over anhydrous NaaSO/t, filtered and concentrated under reduced pressure to provide a mixture of tert-butyl N-[(3R,6S)-6-[2-(3-oxocyclobutyl)triazol-4-yl]tetrahydropyran-3-yl]carbamate and tert-butyl N-[(3R,6S)-6-[l-(3-oxocyclobutyl)triazol-4-yl]tetrahydropyran-3-yl]carbamate (2.28 g, crude)._tert-butyl N- [(3R,6S)-6- [2-(3-c/s-hydroxycyclobutyl)triazol-4-yl]tetrahydropyran-3- yl] carbamate and tert-butyl 7V-[(3R,6S)-6-[l-(3-c s-hydroxycyclobutyl)triazol-4- yl]tetrahydropyran-3-yl]carbamate: To a mixture of tert-butyl N-[(3R,6S)-6-[2-(3- oxocyclobutyl)triazol-4-yl]tetrahydropyran-3-yl]carbamate and tert-butyl N-[(3R,6S)-6-[l-(3- oxocyclobutyl)triazol-4-yl]tetrahydropyran-3-yl]carbamate (2.28 g, 6.78 mmol) in MeOH (30 mL) at -20 °C was added NaBLL (513 mg, 13.6 mmol) and the mixture was stirred at -20 °C for 2 h. The reaction mixture was diluted with water (30 mL), stirred for 10 min and the volatile organics removed under reduced pressure. The aqueous phase was extracted with EtOAc (3 x 10 mL), the combined organic phases were washed with brine (5 mL), dried over anhydrous NaaSO/i, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10: 1 to 0: 1) to provide tert-butyl N-[(3R,6S)-6-[2-(3-c/5-hydroxycyclobutyl)triazol-4- yl]tetrahydropyran-3-yl] carbamate and tert-butyl N-[(3R,6S)-6-[l-(3-c/5-hydroxycyclobutyl)triazol-4- yl]tetrahydropyran-3 -yl]carbamate .
benzyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-hydroxy-L-serinate[ No CAS ]
6-((9H-fluoren-9-yl)methyl) 7-benzyl (S)-2-bromo-5,9-dioxa-6-azaspiro[3.5]nonane-6,7-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With indium(III) triflate; In dichloromethane; at 0 - 20℃;Inert atmosphere;
In(OTf)3 (77.8 mg, 0.14 mmol, 0.30 equiv) was added to a solution of benzyl-5 (200 mg, 0.46 mmol, 1.00 equiv) and <strong>[23761-24-2]3-bromocyclobutan-1-one</strong> 6 (206 mg, 1.38 mmol, 3.00 equiv) in CH2Cl2 (6 mL) at 0°C. The reaction was allowed to warm to room temperature and was stirred overnight. The solution was diluted with CH2Cl2 and 10percent citric acid solution was added. The phases were separated and the aqueous layer was extracted twice with CH2Cl2 . The combined organic layers were washed with brine and dried over Na2SO4. The drying agent was removed by filtration and the solvent was evaporated. The residue was purified by flash chromatography (hexanes/EtOAc 6:1) to give 20 (140 mg, 0.25 mmol, 54percent).
(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-thiol[ No CAS ]
3-(((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)thio)cyclobutanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;Inert atmosphere;
To a solution of (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-thiol (650 mg, 2.8 mmol) and <strong>[23761-24-2]3-bromocyclobutanone</strong> (535 mg, 3.6 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (60percent, 165 mg, 4.1 mmol) at 0° C. under nitrogen atmosphere. The solution was stirred at 20° C. for 2 h and quenched by addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (3*30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by purified by column chromatography (silica gel, 100-200 mesh, 0 to 30percent ethyl acetate in petroleum ether) to afford 3-[[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]sulfanyl]cyclobutanone (800 mg, 96percent) as yellow oil.
With caesium carbonate; In N,N-dimethyl-formamide; at -10℃; for 1h;
To a solution of 4-iodo-1H-pyrazole (1.00 g, 5.16 mmol) in DMF (40 mL) was added Cs2CO3 (1.68 g, 5.16 mmol), <strong>[23761-24-2]3-bromocyclobutanone</strong> (768 mg, 5.16 mmol) at -10 C, and the mixture was stirred at -10 C for 1 h. The reaction mixture was diluted with H20 (90 mL) and was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography to give the desired product. LCMS: m/z = 263.0 [M+Hj. ?H-NMR (400 MHz, CDC13): oe 7.58 (d, J= 5.51 Hz, 2H), 5.02 (tt, J= 8.02, 5.98 Hz, 1H), 3.83-3.71 (m, 2H), 3.62-3.52 (m, 2H).
6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate In 1-methyl-pyrrolidin-2-one at 20℃; for 1.5h; Inert atmosphere;
40.W W. Preparation of 6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one
In a 500 mL, single neck, round bottomed flask were placed 6-bromo-3,3- dimethylindolin-2-one (5.0 g, 20.8 mmol) and Cs2CO3 (20.4 g, 62.5 mmol) in NMP (80 mL). To this was dropwise added 3-bromocyclobutan-1-one (4.7 g, 31.2 mmol) under nitrogen. After the mixture was stirred at room temperature for 1.5 h, it was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried (Na2SO4), concentrated, and purified by flash chromatography to give 6-bromo-3,3-dimethyl-1-(3- oxocyclobutyl)indolin-2-one
6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate In acetonitrile at 20℃; for 1h; Inert atmosphere;
40.A A. Preparation of 6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H- pyrrolo[3,2-b]pyridin-2-one
(1631) In a round bottomed flask were placed commercially available 6-bromo-3,3- dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one (15 g, 62 mmol) and K2CO3 (13 g, 93 mmol) in acetonitrile (140 mL) under nitrogen. To this was slowly added 3-bromocyclobutanone (6.8 mL, 75 mmol). After stirring at room temperature for 1 h, the mixture was filtered, and the filtrate was concentrated. To the resulting solid was added acetonitrile. After stirring the mixture for 30 min, the precipitate was filtered to give 6-bromo-3,3-dimethyl-1-(3- oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one
tert-butyl 1-(3-oxocyclobutyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate[ No CAS ]
tert-butyl 2-(3,3-difluoro cyclobutyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate In tetrahydrofuran at 20℃; for 5h; Inert atmosphere;
1 Preparation of Intermediates AF.2 and AF.3, tert-butyl 1-(3-oxocyclobutyl)-6,7-dihydro-1H- pyrazolo[4,3-c]pyridine-5(4H)-carboxylate and tert-butyl 2-(3,3-difluorocyclobutyl)-6,7- dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.
Potassium carbonate (930 mg, 6.72 mmol) was added to a stirred mixture of tert-butyl 6,7- dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (1.0g, 4.48 mmol) and 3- bromocyclobutanone (0.934 g, 6.27 mmol) in THF (10 mL). The resulting mixture was stirred at 20 °C for 5 h. The reaction mixture was then filtered and concentrated, and the resulting crude residue was purified by preparative TLC (silica gel, elution: 50% EtOAc/petroleum ether) to provide tert-butyl 1-(3-oxocyclobutyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)- carboxylate (AF.2) and tert-butyl 2-(3,3-difluoro cyclobutyl)-6,7-dihydro-2H-pyrazolo[4,3- c]pyridine-5(4H)-carboxylate (AF.3). MS (ESI) m/z calc’d for C15H22N3O3 [M+H]+ 292.2, found 292.1.
N-[1-(3-oxocyclobutyl)pyrazol-3-yl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: 3-bromocyclobutan-1-one With triethylamine In chloroform-d1 at 20℃; for 0.166667h;
Stage #2: N-(1H-pyrazol-3-yl)acetamide In chloroform-d1 for 1h;
1 Step 1. Synthesis of N-[1-(3-oxocyclobutyl)pyrazol-3-yl]acetamide (C28)
To a solution of 3-bromocyclobutanone (500 mg, 3.4 mmol) in CDCl3 (10 mL) was added Et3N (375 mg, 3.71 mmol). The mixture was allowed to stir at room temperature for 10 minutes. To the reaction mixture was then added N-(1H-pyrazol-3-yl)acetamide C27 (420 mg, 3.36 mmol). The mixture was allowed to stir for another 1 hour. The mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc in heptane gradient) to afford the product (600 mg, 55%).1H NMR (300 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.79 (d, J = 2.3 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 5.09 (tt, J = 8.0, 5.4 Hz, 1H), 3.67 - 3.28 (m, 5H), 1.98 (s, 3H). LCMS m/z 137.42 [M+H]+.
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