* 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.
In ethyl acetate (1 ml) and acetic acid (1 ml), a mixture of2-cyano-3- (trifluoromethyl) -5-nitropyridine A10 (0.095 g, 0.44 mmol) and ironpowder (0.112 g, 2 mmol) was heated for 15 hours. The solid particles werefiltered through Celite, the filtrate was concentrated and subjected tochromatography (EtOAc: pentane, 1: 1) to give compound A11 (0.075g, 0.4mmol,91percent).
91%
With iron; acetic acid In ethyl acetate for 15 h; Heating
Synthesis of 2-cyano-3-(trifluoromethyl)-5-aminopyridine, A11 (0058) A mixture of 2-cyano-3-(trifluoromethyl)-5-nitropyridine A10 (0.095 g, 0.44 mmol) and iron powder (0.112 g, 2 mmol) in ethyl acetate (1 ml) and acetic acid (1 ml) was heated for 15 hours. The solid particle was filtered through Celite and the filtrate was concentrated and chromatographed (EtOAc:pentane, 1:1) to yield compound A11 (0.075 g, 0.4 mmol, 91percent). 1H NMR (400 MHz, CDCl3) δ 6.36 (bs, 2H), 7.38 (d, J=2.4 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H). (0059) Alternatively, 2-cyano-3-(trifluoromethyl)-5-nitropyridine A10 can be reacted with hydrogen over Raney-Ni to obtain 2-cyano-3-(trifluoromethyl)-5-aminopyridine, A11.
67%
With iron; acetic acid In ethyl acetate at 65℃; for 2 h;
5-amino-2-cyano-3-trifluoromethylpyridine [0068] 2-cyano-5-nitro-3-trifluoromethylpyridine (7 mg, 0.032 mmol) is dissolved in1 :1 EtOAc/AcOH (1 mL) and heated to 65 0C. Iron powder (9 mg, 0.161 μmol, 5 eq, 325 mesh) is added and the mixture strirred for 2 hours. The mixture is filtered through celite, <n="50"/>and the filtrate is concentrated under vacuo. The crude residue is purified by flash chromatography on silica gel (hexane /EtOAc) to afford 4 mg (67percent) of the desired product. [0069] 1H NMR (400 MHz CDC13) δ 7.20 (d, J = 2.4 Hz, IH), 8.22 (d, J = 2.4 Hz,IH).
54.5%
With iron; acetic acid In ethyl acetateReflux
Synthesis of 5-amino-3-trifluoromethyl-2-cyanopyridine (Intermediate 5) To a mixture of compound 4 (1.15 g, 4.9 mmol) in EtOAc (20 mL) and CH3CO2H (4 mL), iron powder (890 mg) was added. The mixture was refluxed for 16 h before cooling to room temperature. Then solids were filtered off, followed by washed with ethyl acetate for three times, and the combined organic phases were dried over anhydrous sodium sulfate, the solvent was removed to afford the residue, which was purified by column chromatography to give compound 5 as light brown solid (540 mg, 54.5percent yield). 1H NMR (CDCl3, 400 MHz): δ 8.23 (1H, d, J=2.8 Hz), 7.20 (1H, d, J=2.8 Hz), 4.51 (2H, br) ppm.
54%
With iron; acetic acid In ethyl acetate for 16 h; Inert atmosphere; Reflux
To a solution of compound 4 (1.15g, 4.9mmoles) in EA (20ml) and AcOH (4ml) was added Fe (890mg) portion-wise under N2 at room temperature. The reaction mixture was refluxed for 16h. After cooling to room temperature, the reaction mixture was filter, then, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silics gel (DCM/MeOH=50/1) to afford 5-amino-3-(trifluoromethyl)picolinonitrile (5) (540mg, 54percent). 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J=2.8Hz, 1H)7.30 (d, J=2.8Hz, 1H)7.02 (br, 2H). 13C NMR (101 MHz, DMSO-d6) δ 147.97 , 139.37, 129.9 (q, J =30.3 Hz), 122.2 (q, J = 274.7 Hz), 116.0 (d, J = 1.8 Hz), 115.0 (q, J = 4.0 Hz), 112.9.
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80percent yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55percent). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40percent). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis(diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92percent). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95percent). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74percent to 95percent).
85%
With trifluoroacetic acid In dichloromethane at 20℃; for 2 h;
5-amino-2-cyano-3-trifluoromethylpyridine H: TFA (1 niL) is added dropwise to a solution of pyridine L (83 mg, 0.27 mmol) in dry DCM (0.5 mL) under argon. The solution is stirred overnight at room temperature. After completion of the reaction, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (Hexane/EtOac) to afford the desired product quantitatively. 1H NMR (500 MHz CDC13) δ 7.20 (d, J = 2.4 Hz, IH), 8.22 (d, J = 2.4 Hz,IH).; Scale up and purification of H For the larger scales, an improved process calls for dissolving pyridine L (53 g, 0.172 mol) in TFA/DCM (170 mL, 4:1) at room temperature. Upon reaction completion (approximately 2 hours at room temperature), the volatiles were removed under reduced pressure. The residue is then diluted with EtOAc (800 mL), and washed with saturated aqueous NaHCO3. Vacuum concentration and precipitation from DCM-Hexane (1-2, v-v) gave a relatively clean product. Further washing with DCM gave pure intermediate H as a white solid (27.43 g, 85percent).
With iron; acetic acid; In ethyl acetate; for 15h;
In ethyl acetate (1 ml) and acetic acid (1 ml), a mixture of2-cyano-3- (trifluoromethyl) -5-nitropyridine A10 (0.095 g, 0.44 mmol) and ironpowder (0.112 g, 2 mmol) was heated for 15 hours. The solid particles werefiltered through Celite, the filtrate was concentrated and subjected tochromatography (EtOAc: pentane, 1: 1) to give compound A11 (0.075g, 0.4mmol,91%).
91%
With iron; acetic acid; In ethyl acetate; for 15h;Heating;
Synthesis of 2-cyano-3-(trifluoromethyl)-5-aminopyridine, A11 (0058) A mixture of 2-cyano-3-(trifluoromethyl)-5-nitropyridine A10 (0.095 g, 0.44 mmol) and iron powder (0.112 g, 2 mmol) in ethyl acetate (1 ml) and acetic acid (1 ml) was heated for 15 hours. The solid particle was filtered through Celite and the filtrate was concentrated and chromatographed (EtOAc:pentane, 1:1) to yield compound A11 (0.075 g, 0.4 mmol, 91%). 1H NMR (400 MHz, CDCl3) delta 6.36 (bs, 2H), 7.38 (d, J=2.4 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H). (0059) Alternatively, 2-cyano-3-(trifluoromethyl)-5-nitropyridine A10 can be reacted with hydrogen over Raney-Ni to obtain 2-cyano-3-(trifluoromethyl)-5-aminopyridine, A11.
90%
With hydrogen; In ethanol; under 1520.1 Torr;Autoclave;
Step 2: Add 200 g of intermediate 1 to the autoclave, add Raney nickel, 650 mL of ethanol, and introduce hydrogen to 2 atm. After the reaction is completed, cool, replace with nitrogen, filter, wash, and concentrate the filtrate to obtain 155 g of intermediate 2. Yield: 90%.
67%
With iron; acetic acid; In ethyl acetate; at 65℃; for 2h;Product distribution / selectivity;
5-amino-2-cyano-3-trifluoromethylpyridine [0068] 2-cyano-5-nitro-3-trifluoromethylpyridine (7 mg, 0.032 mmol) is dissolved in1 :1 EtOAc/AcOH (1 mL) and heated to 65 0C. Iron powder (9 mg, 0.161 mumol, 5 eq, 325 mesh) is added and the mixture strirred for 2 hours. The mixture is filtered through celite, <n="50"/>and the filtrate is concentrated under vacuo. The crude residue is purified by flash chromatography on silica gel (hexane /EtOAc) to afford 4 mg (67%) of the desired product. [0069] 1H NMR (400 MHz CDC13) delta 7.20 (d, J = 2.4 Hz, IH), 8.22 (d, J = 2.4 Hz,IH).
54.5%
With iron; acetic acid; In ethyl acetate;Reflux;
Synthesis of 5-amino-3-trifluoromethyl-2-cyanopyridine (Intermediate 5) To a mixture of compound 4 (1.15 g, 4.9 mmol) in EtOAc (20 mL) and CH3CO2H (4 mL), iron powder (890 mg) was added. The mixture was refluxed for 16 h before cooling to room temperature. Then solids were filtered off, followed by washed with ethyl acetate for three times, and the combined organic phases were dried over anhydrous sodium sulfate, the solvent was removed to afford the residue, which was purified by column chromatography to give compound 5 as light brown solid (540 mg, 54.5% yield). 1H NMR (CDCl3, 400 MHz): delta 8.23 (1H, d, J=2.8 Hz), 7.20 (1H, d, J=2.8 Hz), 4.51 (2H, br) ppm.
54%
With iron; acetic acid; In ethyl acetate; for 16h;Inert atmosphere; Reflux;
To a solution of compound 4 (1.15g, 4.9mmoles) in EA (20ml) and AcOH (4ml) was added Fe (890mg) portion-wise under N2 at room temperature. The reaction mixture was refluxed for 16h. After cooling to room temperature, the reaction mixture was filter, then, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silics gel (DCM/MeOH=50/1) to afford 5-amino-3-(trifluoromethyl)picolinonitrile (5) (540mg, 54%). 1H NMR (400 MHz, DMSO-d6) delta 8.21 (d, J=2.8Hz, 1H)7.30 (d, J=2.8Hz, 1H)7.02 (br, 2H). 13C NMR (101 MHz, DMSO-d6) delta 147.97 , 139.37, 129.9 (q, J =30.3 Hz), 122.2 (q, J = 274.7 Hz), 116.0 (d, J = 1.8 Hz), 115.0 (q, J = 4.0 Hz), 112.9.
E. 5-Amino-2-cyano-3-trifluoromethylpyridine (763E) 2-Cyano-5-nitro-3-trifluoromethylpyridine (0.065 g, 0.3 mmol) was reacted in the same manner as described in example 762D to give the desired compound 763E (0.046 g, 82%) as a gold colored solid after trituration with ether. HPLC: 100% at 2.07 min(YMC S5 ODS column) eluding with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 187.82 [M+H]+.
With ammonium vanadate; platinum on carbon; hydrogen; hypophosphorous acid; In 5,5-dimethyl-1,3-cyclohexadiene; water; at 70℃; under 3750.38 Torr; for 1.5h;Autoclave;
Preparation of modified catalyst slurry. (0137) In a 20 mL beaker glass 0.156 g (0.129 mL, 50 % w/w) of H3PO2 was added to a slurry of 1.00 g 5 % Pt/C catalyst F101 R/W (from Evonik AG, contains ~60 % water) and 4.0 mL of deionized water. After 15 minutes while stirring with a magnetic stirring bar, 58 mg of NH4VO3 was added and the slurry was again stirred for 15 minutes. Hydrogenation. A 100 mL autoclave was charged with a solution of 10.0 g of compound (III) (46.1 mmol) in 26.7 mL of xylenes and 13.3 mL of butyronitrile. To this solution, the modified catalyst slurry was added with the aid of 2 mL of deionized water. The autoclave was closed, then inertized by pressurizing 3 times with nitrogen to 10 bar and 3 times hydrogen to 10 bar. The reactor pressure was set to 5.0 bar hydrogen, stirring was started (hollow shaft turbine stirrer, 1200 rpm) and the mixture heated up to 70 C within 50 min. As soon as 70 C was reached, the hydrogen uptake ceased. After stirring for another 40 min, the heating was stopped and the autoclave was allowed to cooling. The slurry was filtered through a fiberglass filter and washed in portions using 40 mL of xylenes at 20-23 C. Compound (IV) was crystallized from the solution upon distillation of the butyronitrile solvent. 1H NMR (300 MHz, DMSO-d6) G 8.20 (d, J=2.4Hz, 1H), 7.31 (d, J=2.6Hz, 1H), 7.04 (s, NH). Step D. Preparation of Compound (VII).
0.8 g
With iron; acetic acid; In ethyl acetate; for 15h;Reflux;
5 ml of ethyl acetate and 5 ml of acetic acid were mixed, and 1 g of 2-cyano-3-trifluoromethyl-5-nitropyridine and 1.12 g of iron powder were added with stirring, and the mixture was heated under reflux for 15 hours with stirring. The solid was filtered off and the filtrate was evaporated to dryness vacuo. The residue was subjected to silica gel column chromatography eluting with ethyl acetate: petroleum ether (1:1) solvent.There was obtained 0.8 g of 2-cyano-3-trifluoromethyl-5-aminopyridine.
Alternative syntheis of A52hr 2 hr [0090] Thiophosgene (1.23 niL, 16.0 mmol) is added dropwise to a solution of 5- amino-2-cyano-3-trifluoromethylpyridine (3.0 g, 16.0 mmol) and N-methyl-4-(l- cyanocyclobutylamino)-2-fluorobenzamide (3.96 g, 16.0 mmol) in dry DMA (35 mL) under Argon. The solution is stirred overnight at 6O0C. To this mixture were added MeOH (60 mL) and aq. 2M HCl (30 mL), then it was brought to reflux temperature for 2 h. After cooling down to the ambiant, the mixture was poured into ice water (100 mL) and extracted with EtOAc (3 x 60 mL). The organic layer was dried over Mg2SO4, filtered over celite, and concentrated under reduced pressure. Silica gel chromatography using DCM/-acetone 19-1 (v-v) yielded the desired product (5.78 g, 76percent).Scale up.[0091] Thiophosgene (5.48 mL, 1.05 eq, 70.9 mmol) is added dropwise to a solution of 5-amino-2-cyano-3-trifluoromethylpyridine (13.27 g, 1.05 eq, 70.9 mmol) and N-methyl- 4-(l-cyanocyclobutylamino)-2-fluorobenzamide (16.7 g, 67.5 mmol) in dry DMA (110 mL) under Argon at 0 0C. After 10 min, the solution was heated up to 60 0C and allowed to stir at that temperature for an overnight period. This was then diluted with MeOH (200 mL) and treated with aq. 2M HCl (140 mL), then the mixture was refluxed for 2 h. After cooling down to RT, the mixture was poured into ice water (500 mL), and filtered over buchner. The solid was recrystallized from DCM/EtOH to get desired product (20.6g, 64percent).
41%
To a solution of compound 5 (50mg, 0.26mmol) and compound 11 (66mg, 0.26mmol) in DMA (0.5ml) was added thiophosgene (32mg, 0.26mmol) under N2. The reaction mixture was stirred for 16h at 60°C. To this mixture were added MeOH (2ml) and 2M HCl (2ml), then the reaction mixture was reflux for 2h. After cooling to room temperature, the reaction mixture was poured into ice water (10ml) and extracted with EtOAc (10ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silics gel (EA/PE=1/1) to afford 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide (18) (51.3mg, 41percent). 1H NMR (400 MHz, Methanol-d4) delta 9.17 (d, J = 2.1 Hz, 1H), 8.65 (d, J = 2.3 Hz, 1H), 7.95 (t, J = 8.2 Hz, 1H), 7.52 ? 7.32 (m, 2H), 2.98 (s, 3H), 2.75-2.70 (m, 2H), 2.65-2.48 (m, 2H), 2.29-2.09 (m, 1H), 1.72-1.62 (m, 1H). MS (ESI): m/z 478.1 (M+H+, positive mode).
41%
Synthesis of N-methyl-4- [7-(6-cyano-5-trifluoromethylpyridin-2-yl)-8-oxo-6-thioxo-5,7- diazaspiro [3.4] octan-5-yl] -2-fluorobenzamide (A52)One Pot Small Scale (2.8 gr) Thiohydantoin Formation in DMF[0089] Thiophosgene (1.2 mL, 1.16 eq, 15.6 mmol) is added dropwise to a solution of 5-amino-2-cyano-3-trifluoromethylpyridine (2.8 g, 1.1 eq, 15.0 mmol) and N-methyl-4- (l-cyanocyclobutylamino)-2-fluorobenzamide (3.35 g, 13.5 mmol) in dry DMF (25 mL) under Argon. The solution is stirred overnight at 60 0C. To this mixture were added MeOH (60 mL) and aq. 2M HCl (30 mL), then the mixture was reflux for 2 h. After cooling to rt, the mixture was poured into ice water (100 mL) and extracted with EtOAc (3 x 60 mL). The organic layer was dried over Mg2SO4, concentrated and chromatographed on silica gel using 5percent acetone in DCM to yield the desired product (2.65 g, 41percent).
40.4%
Synthesis of 4-[7-(6-cyano-5-trifluoromethyl-3-pyridyl)-8-oxo-6-thio-5,7-diazaspiro[3,4]-5-octyl]-2-fluoro-N-methyl-benzamide (Compound 10) To the mixture of compound 9 (68 mg, 0.26 mmol) and compound 5 (50 mg, 0.26 mmol) in DMA (10 ml), thiophosgene (32 mg, 0.26 mmol) was added in dropwise. The mixture was heated to 60° C. for 16 h, and then methanol (10 mL), water (10 mL) and concentrated hydrochloric acid (2 mL) were added in and the mixture was heated at reflux for 1 h. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (PE:EA/1:1) to give a brown solid as crude product, which was purified by preparative chromatography to give compound 10 as a white solid (51.3 mg, 40.4percent yield). 1H NMR (CD3OD, 400 MHz): delta 9.17 (1H, d, J=2.0 Hz), 8.65 (1H, d, J=2.0 Hz), 7.95 (1H, m), 7.41 (2H, m), 2.98 (3H, s), 2.73 (2H, m), 2.60 (2H, m), 2.16 (1H, m), 1.67 (1H, m) ppm. MS: 481.2 (M+H+).
In N,N-dimethyl acetamide; at 60 - 65℃; for 5h;Inert atmosphere;
Charged 60.0 gm of 4-[(l-Cyano cyclobutyl)amino]-2-fluoro-N- methylbenzamide, Dimethylacetamide and 69.5gm of 5-Amino-3-(trifluoromethyl)-2- pyridinecarbonitrile at below 35°C under N2 atmosphere. The obtained slurry was cooled to 0- 5°C then 42.7g of thiophosgene was added slowly to the slurry at 0-5°C and maintained for 5- lOmin at same temperature (0-5°C), gently raise the reaction mass temperature to room temperature then heat the reaction mixture to 60-65°C and maintained for 5hr (to ensure the unreacted 1st component should be<20.0percent by HPLC), once its complies then cooled the reaction mixture to below 25°C, then charged 900ml of methanol and 6.0gm of Norit charcoal, stirred for 30min at 20-30°C.The obtained reaction mass was filtered through hyflo then 480ml (2M)Hydro chloride was charged to the filtrate at 20-30°C, heated the reaction mass to 60-65°C and maintained for 2hr, then cooled to 20-25°C. Slowly quenched the reaction mass to the 1500ml prechilled (0-5°C) DM Water and maintained for 30-45min at same temperature. The slurry was filtered and washed with prechilled DM Water kept the solid under vacuum suction for lhr to obtain the crude. Dissolved the crude in 600ml of IP A and heat the slurry to reflux in order to obtained the clear solution and maintain for 30min then slowly cool the solution to 0- 5°C and slurry was stirred for lhr at 0-5°C. The obtained slurry was filtered and washed with 60ml of chilled IP A and kept for vacuum suction for lhr to obtain 90gm of wet material.
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80 C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130 C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2?-bis(diphenylphosphino)-1,1?-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1?-bis(diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25 C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
85 - 100%
With trifluoroacetic acid; In dichloromethane; at 20℃; for 2h;Product distribution / selectivity;
5-amino-2-cyano-3-trifluoromethylpyridine H: TFA (1 niL) is added dropwise to a solution of pyridine L (83 mg, 0.27 mmol) in dry DCM (0.5 mL) under argon. The solution is stirred overnight at room temperature. After completion of the reaction, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (Hexane/EtOac) to afford the desired product quantitatively. 1H NMR (500 MHz CDC13) delta 7.20 (d, J = 2.4 Hz, IH), 8.22 (d, J = 2.4 Hz,IH).; Scale up and purification of H For the larger scales, an improved process calls for dissolving pyridine L (53 g, 0.172 mol) in TFA/DCM (170 mL, 4:1) at room temperature. Upon reaction completion (approximately 2 hours at room temperature), the volatiles were removed under reduced pressure. The residue is then diluted with EtOAc (800 mL), and washed with saturated aqueous NaHCO3. Vacuum concentration and precipitation from DCM-Hexane (1-2, v-v) gave a relatively clean product. Further washing with DCM gave pure intermediate H as a white solid (27.43 g, 85%).
With trifluoroacetic acid; In dichloromethane; at 20℃; for 3h;
5-Amino-3-(trifluoromethyl)picolinonitrile [00380] 5-((4-Methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile (15 g, 49.02 mmol) was taken up in DCM (30 mL) and TFA (50 mL) was added. The resulting reaction mixture was stirred at room temperature for 3h (until done by LC-MS). The solvent and TFA were removed in vacuo and MeOH was added to the residue. The beige solid that was not soluble in MeOH was filtered and washed with MeOH. The filtrate was evaporated to dryness and the residue was partitioned between EtOAc and a saturated solution of sodium bicarbonate. The organic layer was washed two more times with a saturated aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness. The residue was dissolved in DCM and hexanes with swirling until a yellow solid precipitated. This solid was filtered and washed with hexanes to afford 7.2 g of 5-amino-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. lK NMR (300 MHz, DMSO-d6) delta 8.17 (d, 1H), 7.28 (d, 1H), 6.99 (bs, 2H).
Thiophosgene (0.36 mL, 4.67 mmol) was added dropwise to a solution of 5-amino-3- (trifluoromethyl)picolinonitrile (Intermediate 1, 795 mg, 4.25 mmol) and l-((4-bromo-3- fluorophenyl)amino)cyclobutanecarbonitrile (Intermediate 90, 1.14g, 4.25 mmol) in DMA (30 mL). The resulting mixture was heated to 60C overnight. MeOH (8 mL) and HC1 (2M, 8 mL) were added and the mixture was refluxed for 2h then cooled to room temperature. Water was slowly added until a light brown solid precipitated. The solid was filtered, washed with water, dried, dissolved in MeOH, and absorbed on silica gel. Purification by column chromatography on silica gel eluting with 10% EtOAc/hexanes afforded 616 mg of 5-(5-(4-bromo-3- fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a white solid. ¾ NMR (300 MHz, DMSO-d6) delta 9.21 (d, 1H), 8.74 (d, 1H), 8.00 (t, 1H), 7.55 (dd, 1H), 7.28 (dd, 1H), 2.67-2.59 (m, 2H), 2.55-2.45 (m, 2H), 1.99-1.95 (m, 1H), 1.61-1.56 (m, 1H).
Thiophosgene (1.3 mL, 16.04 mmol) was added to a mixture of 5-amino-3- (trifluoromethyl) picolinonitrile (Intermediate 1 , 3 g, 16.0 mmol) and l-((3-fluoro-4- hydroxyphenyl)amino)cyclobutane-carbonitrile (Intermediate 19, 3.3 g, 16.0 mmol) in DMA (40 mL) and the mixture was heated to 60C for 18h. MeOH (60 mL) and HC1 (2M, 40 mL) were added and the mixture was refluxed for 2h. The mixture was cooled to room temperature and slowly poured into an ice/water bath. The brown solid was filtered, washed with water, dried, and purified by column chromatography on silica gel eluting with 0 to 50%EtOAc/hexanes to afford 3 g of 5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a beige solid. NMR (300 MHz, DMSO-d6) delta 10.44 (s, 1H), 9.21 (d, 1H), 8.74 (d, 1H), 7.27-7.05 (m, 3H), 2.64-2.42 (m, 4H), 2.01-1.91 (m, 1H), 1.61-1.54 (m, 1H).
A mixture of thiophosgene (0.55 mL, 5.35 mmol), 5-amino-3- (trifluoromethyl)picolinonitrile (Intermediate 1, lg, 5.35 mmol), and ethyl 4-((l- cyanocyclobutyl)amino)-2-fluorobenzoate (Intermediate 20, 1.4g, 5.35 mmol) in DMA (25 mL) was heated to 70C overnight. MeOH (20 mL) and HC1 (2M, 20 mL) were added and the mixture was refluxed for 2h then cooled to room temperature. Water/ice was added and the aqueous layer was extracted with DCM (4x). The organics were combined, dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0 to 50% EtOAc/hexanes to afford lg of ethyl 4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoate as a yellow foam. ¾ NMR (300 MHz, DMSO-d6) delta 9.21 (s, 1H), 8.74 (s, 1H), 8.13 (m, 1H), 7.53 (d, 1H), 7.45 (d, 1H), 4.37 (q, 2H), 2.65-2.62 (m, 2H), 2.56-2.45 (m, 2H), 2.05-1.91 (m, 1H), 1.61-1.57 (m, 1H), 1.34 (t, 3H).
4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(3-(pyrrolidin-1-yl)propyl)benzamide 2,2,2-trifluoroacetate[ No CAS ]
To a reactor containing compound (VI) (25 g) and compound (IV) (14 g) was added 1-(2-oxopyridine-1-carbothioyl)pyridin-2-one (18 g) and toluene (316 mL). The reaction mixture was stirred and heated to 100C for 20 h. A solvent switch from toluene to DMA (8 L/kg final composition) was performed, then EtOH (400 mL) was added. The mixture was then heated to 70C before addition of HCl (2 M, 160 mL). After stirring for 2 h, the reaction was cooled down to 0 C. The precipitate was collected by filtration, rinsed with EtOH/H2O (100 mL, 1:1), and dried to give compound (VII) (24 g, 63%). 1H NMR (300 MHz, CDCl3) G 9.09 (d, J=2.1Hz, 1H), 8.35 (d, J=2.1Hz, 1H), 8.01 (dd, J=8.3, 6.8Hz, 1H), 7.07 (dd, J=7.9, 2.3Hz, 1H), 6.94 (dd, JJ=8.0, 2.0Hz, 1H), 2.72 (m, 2H), 2.58 (m, 2H), 2.30 (m, 1H), 1.74 (m, 1H).
4-[(2-cyanopropan-2,2-bitrideuteratedmethyl)amino]-2-fluoro-N-methylbenzamide[ No CAS ]
4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-bitrideuteratedmethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
Compound 28 (68 mg, 0.26 mmol) and compoundS (50 mg, 0.26 mmol) were dissolved in DMA (10 ml) followed by the addition of thiophosgene (32 mg, 0.26 mmol). The mixture was stirred at 60 C. for 16 h, and methanol (10 ml), water (10 ml) and concentrated HC1 (2 ml) were added to the reaction mixture the resulting mixture was heated at reflux for 1 h. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (PE:EA1:1) to give a brown solid which was further purified by preparative chromatography to give compound 29 as a white solid (48 mg, 40% yield). ?H NMR (CD3OD, 400 MHz): oe 9.19 (1H, d, J=1.2 Hz), 8.70 (1H, d=1.2 Hz), 7.91 (1H, m), 7.39 (2H, m), 2.97 (3H, s) ppm. MS: 472.2 (M+Hj.
4-((2-cyanopropan-2,2-bitrideuterated-methyl)amino)-2-fluoro-N-trideuteratedmethylbenzamide[ No CAS ]
4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-bitrideuteratedmethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-trideuteratedmethyl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
10139] Compound 30(68mg, 0.26 mmol) and compoundS (50 mg, 0.26 mmol) were dissolved in DMA (10 ml), followed by the addition ofthiophosgene (32 mg, 0.26 mmol) it was stirred at 60 C. for 16 h, and methanol (10 ml), water (10 ml) and concentrated HC1 (2 ml) was added in. The resulting mixture was heated at reflux for 1 h. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (PE:EA1 :1) to give a brown solid which was further purified by preparative chromatography to give compound 31 as a white solid (48 mg, 40% yield). ?H NMR (CD3OD, 400 MHz): oe 9.19 (1H, d, J=1 .6Hz), 8.70 (1H, d, J=1.6 Hz), 7.91 (1H,m), 7.39 (2H,m)ppm. MS: 475.1 (M+Hj.
4-((1-cyanocyclobutyl)amino)-2-fluoro-N-trideuteriomethylbenzamide[ No CAS ]
4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-trideuteriomethylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43.6%
Synthesis of 4-[7-(6-cyano-5-trifluoromethyl-3-pyridyl)-8-oxo-6-thio-5,7-diazaspiro[3,4]-5-octyl]-2-fluoro-N-trideuteromethyl-benzamide (Compound 14) To the mixture of compound 13 (68 mg, 0.26 mmol) and compound 5 (50 mg, 0.26 mmol) in DMA (10 ml), thiophosgene (32 mg, 0.26 mmol) was added in dropwise. The mixture was heated to 60 C. for 16 h, and then methanol (10 mL), water (10 mL) and concentrated hydrochloric acid (2 mL) were added in and the mixture was heated at reflux for 1 h. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (PE:EA/1:1) to give a brown solid as crude product, which was purified by preparative chromatography to give compound 14 as a white solid (52.3 mg, 43.6% yield). 1H NMR (CD3OD, 400 MHz): delta (ppm) 9.17 (1H, d, J=2.0 Hz), 8.65 (1H, d, J=2.0 Hz), 7.95 (1H, m), 7.41 (2H, m), 2.73 (2H, m), 2.60 (2H, m), 2.16 (1H, m), 1.67 (1H, m), MS: 481.2 (M+H+).
General procedure: To a solution of compound 5 (50mg, 0.26mmol) and compound 11 (66mg, 0.26mmol) in DMA (0.5ml) was added thiophosgene (32mg, 0.26mmol) under N2. The reaction mixture was stirred for 16h at 60C. To this mixture were added MeOH (2ml) and 2M HCl (2ml), then the reaction mixture was reflux for 2h. After cooling to room temperature, the reaction mixture was poured into ice water (10ml) and extracted with EtOAc (10ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silics gel (EA/PE=1/1) to afford 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide (18) (51.3mg, 41%).
4-(1-cyano-cyclobutylamino)-3,5-bideuterium-2-fluoro-N-methyl-benzamide[ No CAS ]
3,5-dideuterio-4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-trideuteriomethylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
To a mixture of compound 16 (68 mg, 0.26 mmol) and compound 5 (50 mg, 0.26 mmol) in DMA (10 ml), thiophosgene (32 mg, 0.26 mmol) was added in dropwise. The mixture was heated to 60 C. for 16 h. Methanol (10 mL), water (10 mL) and concentrated hydrochloric acid (2 mL) were added in, and the resulting mixture was heated at reflux for 1 h. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. A brown solid was obtained by column chromatography (PE:EA/1:1), which was further purified by preparative chromatography to give compound 17 as a white solid (38.4 mg, yield 32%). 1H NMR (CD3OD, 400 MHz): delta 9.17 (1H, d, J=2.0 Hz), 8.65 (1H, d, J=2.0 Hz), 7.96 (1H, d, J=8.0 Hz), 2.98 (3H, s), 2.73 (2H, m), 2.60 (2H, m), 2.16 (1H, m), 1.67 (1H, m) ppm. MS: 480.1 (M+H+).
General procedure: To a solution of compound 5 (50mg, 0.26mmol) and compound 11 (66mg, 0.26mmol) in DMA (0.5ml) was added thiophosgene (32mg, 0.26mmol) under N2. The reaction mixture was stirred for 16h at 60C. To this mixture were added MeOH (2ml) and 2M HCl (2ml), then the reaction mixture was reflux for 2h. After cooling to room temperature, the reaction mixture was poured into ice water (10ml) and extracted with EtOAc (10ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silics gel (EA/PE=1/1) to afford 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide (18) (51.3mg, 41%).
4-((1-cyanocyclobutyl)amino)-3,5-bideuterium-2-fluoro-N-trideuteromethylbenzamide[ No CAS ]
4-(1,1,3,3-tetradeuterio-7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
Compound 19 (68 mg, 0.26 mmol) and compoundS (50 mg, 0.26 mmol) were dissolved in DMA (10 ml), followed by the addition of thiophosgene (32 mg, 0.26 mmol). The mixture was stirred at 60 C. for 16 h, and methanol (10 ml), water (10 ml) and concentrated HC1 (2 ml) was added in. The resulting mixture was heated at refluxing for 1 h. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (PE:EA1 :1) to give a brown solid which was further purified by preparative chromatography to give compound 20 as a white solid (48 mg, 40% yield). HNMR(CD3OD, 400MHz): oe 9.17 (1H, d, J=2.OHz), 8.65 (1, d, J=2.OHz), 7.95 (1H, d, J=8.OHz), 2.73 (2H, m), 2.60 (2H, m), 2.16 (1H, m), 1.67 (1H, m)ppm. MS:483.3 (M+Hj.20
General procedure: To a solution of compound 5 (50mg, 0.26mmol) and compound 11 (66mg, 0.26mmol) in DMA (0.5ml) was added thiophosgene (32mg, 0.26mmol) under N2. The reaction mixture was stirred for 16h at 60C. To this mixture were added MeOH (2ml) and 2M HCl (2ml), then the reaction mixture was reflux for 2h. After cooling to room temperature, the reaction mixture was poured into ice water (10ml) and extracted with EtOAc (10ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silics gel (EA/PE=1/1) to afford 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide (18) (51.3mg, 41%).
4-[(1-cyano-2,2,4,4-tetradeuteratedcyclobutyl)amino]-2-fluoro-N-methylbenzamide[ No CAS ]
4-[1,1,3,3-tetradeuterated-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)]-2-fluoro-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39.3%
10119] Compound 22 (54 mg, 0.21 mmol) and compound 5 (37 mg, 0.21 mmol) were dissolved in DMA (10 ml) followed by the addition of thiophosgene (25.6 mg, 0.21 mmol). The mixture was stirred at 60 C. for 16 h, and methanol (10 ml), water (10 ml) and concentrated HC1 (2 ml) were added to the reaction mixture. The resulting mixture was heated at refluxing for 1 h. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (PE:EA1:1) to give a brown solid, which wasther purified by preparative chromatography to give compound 20 as a white solid (23 mg, 39.6% yield). ?H NMR (CD3OD, 400 MHz): oe 9.17 (1H, d, J=1.6 Hz), 8.65 (1H, d, J=1.6 Hz), 7.95 (1H, m), 7.41 (2H, m), 2.98 (3H, s), 2.13 (1H, m), 1.64 (1H, m) ppm. MS: 482.2 (M+H).
4-((2-cyanopropan-2-yl)amino)-2-fluoro-N-trideuteratedmethyl-benzamide[ No CAS ]
[ 951753-38-1 ]
Yield
Reaction Conditions
Operation in experiment
40%
j0129] Compound 26 (68 mg, 0.26 mmol) and compound 5 (50 mg, 0.26 mmol) were dissolved in DMA (10 ml) followed by the addition of thiophosgene (32 mg, 0.26 mmol). Themixture was stirred at 60 C. for 16 h, and methanol (10 ml), water (10 ml) and concentrated HC1 (2 ml) were added to the reaction mixture the resulting mixture was heated at reflux for 1 h. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (PE:EA1 :1) to give a brown solid, which was thrther purified by preparative chromatography to give compound 27 as a white solid (48 mg, 40% yield). ?H NMR (CD3OD, 400 MHz): oe 9.19 (1H, d, J=1.6 Hz), 8.70 (1H, d=1.6 Hz) 7.91 (1H, m), 7.39 (2H, m), 1.63 (6H, s) ppm. MS: 469.2 (M+H).
4-{7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl}-2-fluoro-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93.44%
Compound 24 (68 mg, 0.26 mmol) and compound 5 (50 mg, 0.26 mmol) were dissolved in DMA (10 ml), followedby the addition ofthiophosgene (25.6 mg, 0.21 mmol). The mixture was stirred at 60 C. for 16 h, and methanol (10 ml), water (10 ml) and concentrated HC1 (2 ml) were added in. The resulting mixture was heated at refluxing for 1 h. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (PE:EA1 :1) to give a brown solid, which was thrther purified by preparative chromatography to give compound 25 as a white solid (48 mg, 40% yield). ?H NMR (CD3OD, 400 MHz): oe 9.19 (1H, d, J=1.6 Hz), 8.70 (1H, d, J=1.6 Hz), 7.91 (1H,m), 7.40 (2H,m), 2.97 (3H, s), 1.63 (6H, s) ppm. MS: 465.1 (M+Hj.
In chloroform; N,N-dimethyl acetamide; water; at 20℃; for 0.333333h;
To a solution of <strong>[573762-62-6]5-amino-3-(trifluoromethyl)picolinonitrile</strong> (14.97 g, 80 mmol) inchloroform (150 mL) was added water (90 mL) and the mixture was stirred vigorously.DMA (10 mL) and thiophosgene (12.2 mL, 160 mmol) were then added dropwise. After20 mm, the layers were separated, the organic layer was dried over MgSO4, filtered andconcentrated to give 5-i sothiocyanato-3 -(trifluoromethyl)picolinonitrile (18.335 g, 100%) used directly into the next step.
100%
In acetonitrile; at 20 - 30℃;Inert atmosphere;
SM3 (20 g) and MeCN (300 mL) were added into a four-necked round bottom flask equipped with a mechanical stirrer and a thermometer at 20-30 C. under nitrogen followed by cooling to 0-10 C. Thiophosgene (13.7 mL) was added and the mixture was warmed to 20-30 C. After the reaction was completed, the reaction mixture was cooled to 0-10 C. and added saturated NaHCO3 to adjust the pH value to 6-7. The organic layer was separated and concentrated to dryness. The compound of Formula III was obtained (24.93 g) in 100% yield as the brown oil.
97%
In dichloromethane; water; at 20℃; for 16h;
A biphasic mixture of the compound of Formula (8) (2.52 g, 13.47 mmol) in water (63 mL) and methylene chloride (25 mL) was treated with thiophosgene (2 mL, 26.09 mmol) dropwise at room temperature. The resulting mixture was allowed to stir at room temperature for 16 hours. After this time, additional methylene chloride (50 mL) was added to the clear, biphasic system, and the phases were separated. The aqueous layer was extracted with methylene chloride (50 mL), and the combined organic layers were washed with saturated sodium bicarbonate solution. Following separation, the organic layer was dried over sodium sulfate, filtered, concentrated and dried in vacuo at room temperature to afford the compound of Formula (7) (3.0 g, 97% yield) as an orange solid. (0108) 1H-NMR of the compound of Formula (8): (CDCl3, 300 MHz) delta: 7.86 (1H, d, J=2.2 Hz), 8.74 (1H, d, J=2.2 Hz).
95%
In water; for 2h;
To a heterogeneous mixture of 2-cyano-3- (trifluoromethyl)-5-nitropyridine, A 11 (0.075 g, 0.4 mmol) in water (2 ml), thiophosgene (50 mu l) wasadded. This mixture was stirred for 2 hours, then washed with water, andextracted with chloroform. The organic layer was dried over MgSO4,concentrated to give a compound A12 (0.087g, 0.38mmol, 95%).
95%
In water; at 25℃; for 2h;
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80 C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130 C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2?-bis(diphenylphosphino)-1,1?-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1?-bis(diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25 C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
0.7 g
In water; for 2.5h;
0.8 g of <strong>[573762-62-6]2-cyano-3-trifluoromethyl-5-aminopyridine</strong> was added to 20 ml of water.Stir vigorously,0.5 ml of thiophosgene was added dropwise over 30 minutes.After the addition, stirring was continued for 2 hours. The reaction mixture was extracted with chloroform (3×150 mL).The solid was filtered off, and the filtrate was evaporated to dryness under reduced pressure.I got ii-2 0.7 grams.
20 g
In dichloromethane; water; at 20 - 30℃; for 4h;Inert atmosphere;
In a 500 mL four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, (20 g) <strong>[573762-62-6]5-amino-3-(trifluoromethyl)picolinonitrile</strong>, 200 mL water and 100 mL dichloromethane were added at 20-30 C. The reaction mixture was stirred for 15 min and 20 mL thiophosgene was added. The reaction mixture was stirred for 4 hours. After completion of the reaction, the layers were separated. Organic layer washed with 100 mL 8% sodium bicarbonate solution and the organic layer was concentrated completely U/V at 40 C. 140 mL n-hexane was added to the concentrated reaction mass and cooled 0 to 5 C. The compound was filtered, washed with hexane and dried to obtain as solid 20 g titled compound with 96.52% purity by HPLC.
5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile[ No CAS ]
[ 573762-62-6 ]
Yield
Reaction Conditions
Operation in experiment
With trifluoroacetic acid; In dichloromethane; for 3h;
(0084) The crude N-t-butoxycarbonyl nitrile 7 is dissolved in dichloromethane (20 ml) and trifluoroacetic acid (TFA) (4 ml is added. The mixture is stirred for 3 hours and evaporated. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate 2:1) to obtain 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile 8.
4-((3,3,4,4-tetradeuterio-1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide[ No CAS ]
4-[1,1,3,3-tetradeuterated-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)]-2-fluoro-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a solution of compound 5 (50mg, 0.26mmol) and compound 11 (66mg, 0.26mmol) in DMA (0.5ml) was added thiophosgene (32mg, 0.26mmol) under N2. The reaction mixture was stirred for 16h at 60C. To this mixture were added MeOH (2ml) and 2M HCl (2ml), then the reaction mixture was reflux for 2h. After cooling to room temperature, the reaction mixture was poured into ice water (10ml) and extracted with EtOAc (10ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silics gel (EA/PE=1/1) to afford 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide (18) (51.3mg, 41%).
5-[8-[4-[2-(hydroxymethyl)-3,4-dihydro-2H-pyran-6-yl]phenyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-6-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile[ No CAS ]
5-[8-[4-[2-(6-oxa-2-azaspiro[3.3]heptan-2-yl)ethoxy]phenyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-6-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile[ No CAS ]
tert-butyl 3-[4-[6-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-8-yl]phenyl]-8-azabicyclo[3.2.1]octane-8-carboxylate[ No CAS ]
5-[8-[4-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)phenyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-6-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile[ No CAS ]
tert-butyl 6-[6-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-8-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate[ No CAS ]
tert-butyl 3-[[5-[6-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-8-yl]-2-oxo-1-pyridyl]methyl]azetidine-1-carboxylate[ No CAS ]
tert-butyl 3-{5-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]pyridin-2-yloxymethyl}azetidine-1-carboxylate[ No CAS ]
5-[8-[4-[(3R)-1-methylpyrrolidin-3-yl]oxyphenyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-6-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile hydrochloride[ No CAS ]
4-{5-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]pyrimidin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
5-[5-oxo-8-[2-(4-piperidyloxy)pyrimidin-5-yl]-7-thioxo-6,8-diazaspiro[3.4]octan-6-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile hydrochloride[ No CAS ]
5-[8-[4-[[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]oxy]phenyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-6-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile[ No CAS ]
4-{5-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-pyridin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
5-[8-[6-[(1-methyl-4-piperidyl)oxy]-3-pyridyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-6-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile hydrogen chloride[ No CAS ]
5-[5-oxo-7-thioxo-8-[6-[[1-(2,2,2-trifluoroethyl)-4-piperidyl]oxy]-3-pyridyl]-6,8-diazaspiro[3.4]octan-6-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile hydrochloride[ No CAS ]
5-[8-[6-[[1-(cyanomethyl)-4-piperidyl]oxy]-3-pyridyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-6-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile hydrochloride[ No CAS ]
5-[8-[6-[[1-(2-fluoroethyl)-4-piperidyl]oxy]-3-pyridyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-6-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile hydrochloride[ No CAS ]
(1R,3r,5)-tert-butyl 3-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate[ No CAS ]
4-{5-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]indol-1-yl}piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
4-({4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluorobenzoylamino}-methyl)piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
tert-butyl 4-((5-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate[ No CAS ]
N-(3-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3 4]octan-5-yl)phenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide[ No CAS ]
5-(5-(4-(3-aminooxetan-3-yl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile[ No CAS ]
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