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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; |
36.a 6-(Trifluoromethyl)nicotinoyl chloride
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinic acid (45 g, 235.5 mmol), dichloromethane (540 mL) and DMF (0.910 mL, 11.77 mmol) via syringe. To this solution was added oxalyl chloride (24.51 mL, 282.56 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was condensed in vacuo to afford the title compound as a brownish semisolid. |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
15.a 6-(Trifluoromethyl)nicotinoyl chloride
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinic acid (45 g, 235.5 mmol), dichloromethane (540 mL) and DMF (0.910 mL, 11.77 mmol) via syringe. To this solution was added oxalyl chloride (24.51 mL, 282.56 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was concentrated in vacuo to afford the title compound as a brownish semisolid |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; |
2.a 6-(Trifluoromethyl)nicotinoyl chloride
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinic acid (45 g, 235.5 mmol), dichloromethane (540 mL) and DMF (0.910 mL, 11.77 mmol) via syringe. To this solution was added oxalyl chloride (24.51 mL, 282.56 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was concentrated in vacuo to afford the title compound as a brownish semisolid. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere; |
4.a intermediate 4: step a 6-(Trifluoromethyl)nicotiiio\ chloride
intermediate 4: step a 6-(Trifluoromethyl)nicotiiio chloride To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)mcotinie acid (45.0 g, 236 mmol), dichlorornethane (540 mL) and DMF (0.910 mL, 1 1 .8 mmol) via swinge. To this solution was added oxalyl chloride (24.5 mL, 283 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was concentrated in vacuo to afford the title compound as a brown semisolid. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere; |
4.a Intermediate 4: Step a6-(Trifluoromethyl)nicotinoyl chloride
[0192] To a 1 L 3-neck flask equipped with an overheadstirrer, Claisen adaptor, nitrogen bubbler, 60 mE addition funnel, and thermocouple was added 6-(trifluoromethyl) nicotinic acid (45.0 g, 236 mmol), dichloromethane (540 mE) and DMF (0.910 mE, 11.8 mmol) via syringe. To this solution was added oxalyl chloride (24.5 mE, 283 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was concentrated in vacuo to afford the title compound as a brown semisolid. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere; |
2.a 6-(trifluoromethyl)nicotinoyl chloride
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinic acid (45 g, 235.5 mmol), dichloromethane (540 mL) and DMF (0.910 mL, 11.77 mmol) via syringe. To this solution was added oxalyl chloride (24.51 mL, 282.56 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was condensed in vacuo to afford the title compound as a brownish semisolid. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere; |
2.a Intermediate 2:
step a
6-(Trifluoromethyl)nicotinoyl chloride
Intermediate 2: step a 6-(Trifluoromethyl)nicotinoyl chloride To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 niL addition funnel, and thermocouple was added 6-(trifluoromethyr)nicotinic acid (45 g, 235.5 nimol), dichloromethane (540 mL) and DMF (0.910 mL, 11.77 mmol) via syringe. To this solution was added oxaiyl chloride (24.51 mL, 282.56 mmol) and the reaction was allowed to stir at ambient temperature overnight,'The reaction was then filtered and the clear filtrate was condensed in vacuo to afford the title compound as a brownish semisolid. |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; |
2.a intermediate 2: step a
6-(trifluoromethyl)nicotinoyl chloride
intermediate 2: step a6-(trifluoromethyl)nicotinoyl chlorideTo a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple was added 6-itrifluorometh i)nicotimc acid (45 g, 235.5 mmol), dichloromethane (540 mL) and DMF (0.910 mL, 1 1.77 mmol) via syringe. To this solution was added oxaiyl chloride (24.51 mL, 282.56 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was concentrated in vacuo to afford the title compound as a brownish semisolid. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; |
10.a 6-(Trifluoromethyl)nicotinoyl chloride
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinic acid (45 g, 235.5 mmol), dichloromethane (540 mL) and DMF (0.910 mL, 11.77 mmol) via syringe. To this solution was added oxalyl chloride (24.51 mL, 282.56 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was condensed in vacuo to afford the title compound as a brownish semisolid. |
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With thionyl chloride for 2.5h; Reflux; |
General Procedure for Synthesis of Intermediate Compounds 8
General procedure: General Procedure for Synthesis of Intermediate Compounds 8 Intermediate carboxylic acids 7 (1.2 mmol) were heated atreflux in SOCl2 for 2.5 h. Then, excess thionyl chloride wasremoved under vacuum, and crude carbonyl chloride wasobtained as yellow oil (100 % yield), which was used directly inthe next step without further purification. To a mixture of2-iodoaniline 5 (1 mmol) and N,N-diisopropylethylamine(1.2 mmol) in dichloromethane (DCM; 15 mL) was added thesolution of pyrazole carbonyl chloride in dichloromethane(1.0 mL) at 0-58C dropwise. The reaction mixture was thenstirred at room temperature for 3-4 h and washed with watersuccessively. The organic layer was dried over anhydrous sodium sulfate. Then, the solvent was removed under vacuum,and the residue was subjected to column chromatography onsilica gel with petroleum ether and ethyl acetate as solvents togive products 8. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; |
6-(trifluoromethyl)nicotinoyl chloride
6- (Trifluoromethyl) nicotinic acid (45.0 g, 236 mmol) was added via syringe to a 1 L three-necked flask equipped with an overhead stirrer, Claisen adapter, nitrogen bubbler, 60 mL addition funnel and thermocouple, Dichloromethane (540 mL) and DMF (0.910 mL, 11.8 mmol) were added. To this solution was added oxalyl chloride (24.5 mL, 283 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was then filtered and the clear filtrate was concentrated in vacuo to give the title compound as a brown solid. |
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With oxalyl dichloride In dichloromethane at 20℃; for 1.5h; |
1.5
Step 5. (at)(6R,9aS)-6-(4-Methoxy-2,3-dirnethylpherayl)-octahydYO pyrido(at)l,2-aJpyrazira-2 ylJ-(6- trifluoromethyl-pyridin-3-yl)-iiiethanone. [0145] A magnetically stirred suspension of 6-trifluoromethyl nicotinic acid (1.54 g, 8.07 mmol) in 50 mL of anhydrous CH2Cl2 (0.16M), under nitrogen, is treated with oxalyl chloride (2M in CH2C12, 10.0 mL, 20.0 mmol, 2.5 eq) followed by the careful dropwise addition of 250 µL of DMF. Vigorous gas evolution ensues and the mixture becomes homogeneous. The solution is stirred at ambient temperature for 1.5 h, and then concentrated in vacuo to produce the acid chloride as a white solid. This was suspended in toluene and concentrated again and used with no further purification. |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 40℃; for 3h; |
17.1
To a solution of 77 (0.73 g, 3.82 mmol) in CH2Cl2 (10 mL) was added (COCl)2 (0.41 mL, 4.58 mmol) followed by DMF (0.1 mL) and the reaction was maintained at 40°C for 3 h. The reaction was then concentrated to provide a brown solid which was dissolved in CH2Cl2 (10 mL). N,O-dimethyl-OHamine hydrochloride (0.56 g, 5.73 mmol) and DIPEA (1.33 mL) were added and the reaction was stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue purified by chromatography to provide 78 (3.2 g, 84%). |
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With oxalyl dichloride In dichloromethane at 20℃; for 2h; Inert atmosphere; |
1
6-(Trifluoromethyl)nicotinic acid (Sigma-Aldrich; 178 mg, 0.934 mmol) was stirred in DCM (10 ml_). Oxalyl chloride (0.131 ml_, 1.494 mmol) then DMF (2.89 μl, 0.037 mmol) were added and the reaction mixture was left to stir at room temperature for 2hrs under Argon. The reaction mixture was evaporated to dryness and the resulting residue was dissolved in DCM (10 ml_). A solution of [(2-trifluoromethyl-1 H-indol-5-yl)methyl]amine (Intermediate 4, 160 mg, 0.747 mmol) in DCM (1OmL) was added followed by triethylamine (0.208 ml_, 1.494 mmol). The reaction mixture was left to stir at room temperature for 1 h. The reaction mixture was evaporated to dryness and the resulting residues where purified by MDAP to give the title compound (176 mg); m/z (ES+) 388 (M+1 );1 H NMR (400MHz, d4MeOD): δ 9.35 (1 H, d), 8.43 (1 H, dd), 8.12 (1 H, d), 7.67 (1 H, s), 7.43 (1 H, d), 7.33 (1 H, dd), 6.86 (1 H, s), 4.69 (2H, s) |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; |
(1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone
To a 1 L 3-neck flask equipped with an overheadstirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, andthermocouple was added 6-(trifluoromethyl)nicotinic acid (45 g, 235.5 mmol),dichloromethane (540 mL) and DMF (0.910mL, 11.77 mmol) via syringe. To this solution was added oxalyl chloride (24.51mL, 282.56 mmol) and the reaction was allowed to stir at ambient temperatureovernight. The reaction was then filtered and the clear filtrate was condensed in vacuo to afford 6-(trifluoromethyl)nicotinoylchloride as a brownish semisolid. |
| 786 g |
With thionyl chloride; N,N-dimethyl-formamide In toluene at 80℃; for 3.5h; |
1-F; 2-E Step 1 -F : Preparation of 6-(trifluoromethyl)nicotinoyl chloride
A 5L, four-necked, round-bottomed flask equipped with an internal thermometer, a mechanical stirrer, a dropping funnel, and a reflux condenser was charged with 6- (trifluoromethyl)nicotinic acid (782 g, 4.09 mol), N,N-dimethylformamide (10.6 g) and toluene (2340 g). After heating the mixture to 80 °C, thionylchloride (878 g, 7.38 mol) was added dropwisely over 1.5 hr. After stirring at 80 °C for 2 hr, the mixture was cooled to 40°C and concentrated under reduced pressure at 50 °C, to give 6-(trifluoromethyl)nicotinoyl chloride (786 g) as yellow oil. The 6-(trifluoromethyl)nicotinoyl chloride obtained was used for the next step without further purification. |
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With thionyl chloride Reflux; |
15.1 Step 1
To 238 (5.0 g, 26.2 mmol) was added SOCl 2 (10 mL) , the mixture was refluxed for overnight. After cooling, SOCl 2 was removed under reduced pressure and the residual SOCl 2 was removed by azeotropic distillation with toluene. The crude product obtained was used directly in the next step. |
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With oxalyl dichloride In dichloromethane at 20℃; for 1.5h; |
1.5
A magnetically stirred suspension of 6-trifluoromethylnicotinic acid (1.54 g, 8.07 mmol) in 50 mL of anhydrous DCM (0.16M), under nitrogen, is treated with oxalyl chloride (2M in DCM, 10.0 mL, 20.0 mmol, 2.5 eq) followed by the careful dropwise addition of 250 μL of DMF. Vigorous gas evolution ensues and the mixture becomes homogeneous. The solution is stirred at ambient temperature for 1.5 h, and then concentrated in vacuo to produce the acid chloride as a white solid. This solid is suspended in toluene and concentrated again and used with no further purification. A solution of (6R,9aS)-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazine (1.77 g, 6.45 mmol) in anhydrous DCM (50 mL) is treated with NEt3 (1.4 mL, 10.08 mmol) and DMAP (78.8 mg, 0.65 mmol). This mixture is stirred under nitrogen and treated with a solution of the previously prepared acid chloride in 10 mL DCM (an additional 5 mL is used as a rinse). The mixture is stirred at ambient temperature for 18 h and quenched by the addition of 80 mL 50% saturated NaHCO3. The phases are separated and the aqueous phase is extracted twice with DCM. The combined extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified using flash chromatography on silica gel eluting with 70%-60% hexanes/EtOAc to give [(6R,9aS)-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-methanone as a white foam. LC/MS: 448 (M+1). 1H NMR (mixture of rotamers, 400 MHz, CDCl3): 8.74 (1H, d), 7.90 (1H, dd), 7.76 (1H, dd), 7.34 (1H, dd), 6.74 (1H, dd), 4.50 (1H, dd), 3.79 (3H, d), 3.42-3.32 (2H, bm), 3.23-3.00 (1H, m), 2.91-2.53 (3H, bm), 2.21-2.14 (6H, m), 1.90-1.74 (4H, bm), 1.52-1.30 (3H, bm). |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere; |
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| 189 mg |
With oxalyl dichloride |
14.1; 41.1 Preparation of N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-6-(trifluoromethyl)nicotinamide
Step 1: 6-(Trifluoromethyl)nicotinic acid (200 mg, 1.046 mmol) was reacted with oxalyl chloride (0.26 ml, 3.139mmol), and the obtained 6-(trifluoromethyl)nicotinoyl chloride (189 mg, 0.769 mmol) and 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (200 mg, 0.816 mmol) were reactedin a similar manner as described in Example 27 to afford the product(202 mg) as a yellow solid.LC-MS (ESI, m/z) = 563.1 (M+H+) |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5h; |
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With thionyl chloride In N,N-dimethyl-formamide at 80℃; for 3h; |
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