* 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.
Stage #1: at 120℃; for 1.5 h; Stage #2: With ammonia In water for 1 h; Cooling with ice Stage #3: With hydrogenchloride In water
3-Oxo-pentanedioic acid dimethyl ester (100 g, 575 mmol), (EtO)3CH (95 mL, 575 mmol), Ac2O (108 mL) and HOAc (108 mL) were mixed and heated at 120° C. for 1.5 hours, then allowed to cool to 25° C. The volatiles were removed under reduced pressure while maintaining the water bath around 85° C. To the crude liquid was added aqueous NH3 (25percent, 150 mL) in portions with swirling in an ice bath and the stirring was continued for 1 hour. The mixture was acidified by the addition of 6 N HCl. The yellow precipitate was collected by filtration, boiled in toluene, cooled and filtered to give 4,6-dihydroxy-nicotinic acid methyl ester as an orange solid. (Yield 65 g, 67percent). 1H NMR (300 MHz, d6-DMSO): δ 8.06 (s, 1H), 5.65 (s, 1H), 3.83 (s, 3H). LC-MS: [M+H]+ 170.
55%
Stage #1: at 150℃; for 4 h; Stage #2: at 100℃; for 1 h;
A (460.0 g, 2.64 mol) and triethyl orthoformate (586.5 g, 3.96 mol) were dissolved in 690 mL of acetic anhydride,After stirring at 150 ° C for 4 hours,The reaction mixture was volume-concentrated to 600 mL at 100 ° C.Slowly add 920 mL of NH3 · H2O with stirring, and after 1 hour,The reaction mixture was acidified with 2.3 L of 5 mol / L HCl.The precipitate was collected by filtration and dried to give 243.0 g of product B in 55percent yield.
46%
Stage #1: at 130℃; for 2 h; Stage #2: With ammonia In water for 0.5 h; Stage #3: With hydrogenchloride In water
A solution containing dimethyl-1, 3-acetonedicarboxylate (2000 g, 11.5 mol), ethyl orthoformate (1947 mL, 11.5 mol), and acetic anhydride (2168 mL, 23.0 mol) was heated at 130 °C for 2 h. The reaction was allowed to be cooled to room temperature then concentrated in vacuo to 1500 mL. The crude reaction was cooled in ice bath and aqueous ammonia (2 L) was added in portions with stirring. After 30 min, the mixture was acidified with concentrated HC1 (-300 mL) and the suspension was filtered. The crude product was dried under vacuum to give methyl 4,6- dihydroxynicotinate (900 g, 46percent) which was taken on directly into the next step.
Stage #1: at 130℃; for 1.5 h; Stage #2: With ammonia In water at 0℃; for 1 h;
Example 1 Synthesis of 2,4-dichloro-5-nitro-pyridine Dimethyl-1,3-acetonedicarboxylate (50.0 g, 287 mmol), triethylorthoformate (47.8 mL, 287 mmole), and acetic anhydride (54.2 mL, 102 mmol) were combined and heated to 130° C. for 1.5 h then allowed to cool to 25° C. The volatiles were removed in vacuo while maintaining the water bath around 85° C. until the volume of the reaction was reduced to about 25 mL. This crude liquid was poured into a 2000 mL flask and cooled in an ice bath. To this cooled flask was added 75 mL of concentrated aqueous NH3 in portions with swirling. After 1 hour the mixture was acidified by the addition of 6 N HCl (~250 mL). The yellow precipitate was collected by vacuum filtration and allowed to dry under a stream of air. The crude powder was boiled in 200 mL of benzene and allowed to cool and filtered to provide 4,6-dihydroxy-nicotinic acid methyl ester as an orange solid (25.7 g, 53percent).
Reference：
[1] Patent: US2006/217417, 2006, A1, . Location in patent: Page/Page column 12
[2] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 1363 - 1366
[3] Journal of the Chinese Chemical Society, 2016, vol. 63, # 9, p. 758 - 769
Reference：
[1] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 1363 - 1366
[2] Journal of the Chinese Chemical Society, 2016, vol. 63, # 9, p. 758 - 769
7
[ 79398-27-9 ]
[ 65973-52-6 ]
Yield
Reaction Conditions
Operation in experiment
97.2%
at 0 - 120℃; for 2 h;
4,6-Dihydroxy-nicotinic acid methyl ester (3.9 g, 23 mmol) (from Example 7 supra) was added to POCl3 (20 mL) at 0° C., then Et3N (5 mL) was added to the mixture slowly. After addition, the mixture was heated at 120° C. for 2 hours, then allowed to cool to 0° C. The reaction solution was poured slowly and portion-wise into ice-water (100 mL). Solid K2CO3 was added to adjust pH to 8. The resulting precipitate was collected by filtration. The solid was dissolved in ethyl acetate (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford 4,6-dichloro-nicotinic acid methyl ester. (Yield 4.6 g, 97.2percent). 1H NMR (301 MHz, CDCl3) δ 8.85 (s, 1H), 7.47 (s, 1H), 3.97 (s, 3H). LC-MS: [M+H]+ 205.9.
88%
at 25 - 120℃; for 20 h;
4,6-Dihydroxy-nicotinic acid methyl ester (25.7 g, 152 mmol) was dissolved in POCl3 (218 mL). Diethyl aniline (36.3 mL, 243.2 mmol) was added and the reaction was fitted with an air cooled condenser and heated to 120° C. for 2 h then allowed to cool to 25° C. over 18 h. The reaction solution was poured slowly and portion-wise over the ice. Following the addition of the complete contents, EtOAc was added and the biphasic mixture was poured into a separatory funnel. The aqueous phase was separated and extracted twice with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The resultant orange oil crystallized upon standing to afford 4,6-dichloro-nicotinic acid methyl ester as an orange solid (27.4 g, 88percent).
79%
Stage #1: at 0 - 80℃; for 21.3333 h; Stage #2: at 0℃;
[00215] Step A: Methyl 4.6-dichloronicotinate: <n="62"/>[00216] To a suspension of methyl 4,6-dihydroxynicotinate (19.99 g, 118.3 mmol) in 100 ml POCl3 was added NEt3 (15.2 ml) dropwise at 0°C over a period of 20 min. The thick suspension was warmed to room temperature and then to 80 °C for 3 h with stirring. Then, it was cooled down to room temperature and stirred for an additional 18 h. The mixture was poured into 1.5 l crushed ice, extracted with EtOAc (3 x 150 ml), dried (Na2SO4) and concentrated under reduced pressure. The crude product was filtrated over silica using DCM to obtain the title compound as a yellow oil (19.2g, 79percent). Rf (EtOAc/Hexanes 1 :1) = 0.55. 1H-NMR (500 MHz, CDCl3): δ = 8.82 (s, 1H), 7.45 (s, 1H), 3.90 (s, 3H).
70%
With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline for 4 h; Reflux
After B (199.0 g, 1.18 mol) was dissolved in N, N-dimethylaniline (285.4 g, 2.36 mol)Was added to 1.6 L of phosphorus oxychloride (POCl3) and the mixture was refluxed.After 4 h the reaction mixture was concentrated, the residue was poured into water,use Ethyl acetate (1.0 L x 3). The organic layer was dried and concentrated to 500 mL using a silica gel column (mobile phase petroleum) Ether: ethyl acetate = 60: 1) to give 168.7 g of product C in 70percent yield.
42%
at 120℃; for 2 h;
To a solution of methyl 4, 6-dihydroxynicotinate (900 g, 5.3 mol) in phosphoryl chloride (4000 mL) was added NN-diethyl aniline (1035 mL, 6.4 mol). The reaction was heated to 120 °C for 2 h and then allowed to cool to room temperature. The reaction mixture was reduced in vacuo and poured slowly onto ice portionwise. The mixture was extracted with EtOAc (2x). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified via flash chromatography on silica gel (solvent gradient: 0percent-5percent EtOAc in petroleum ether) to afford methyl 4,6-dichloronicotinate (400 g, yield 42 percent). LCMS (ESI) [M+H] = 206.1 ; 'H NMR (400 MHz, DMSO- d6) δ 8.84 (s, 1H), 7.98 (s, 1H), 3.90 (s, 3H).
37%
for 14 h; Reflux
A mixture of 4,6-dihydroxy-nicotinic acid methyl ester (9.10 g, 53.8 mmol) in POCl3 (46 mL) was heated to reflux for 14 h. The RM was chilled and the volatiles were removed under reduced pressure. The residue was diluted with sat. aqueous Na2CO3 solution and was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (SiO2, Hex/EtOAc) to yield the desired compound (4.1 g, 37percent). [0345] LC-MS (Method 3): m/z [M+H]+=206.1 (MW calc.=206.3); Rt=3.46 min.
Reference：
[1] Patent: US2012/184562, 2012, A1, . Location in patent: Page/Page column 6; 17
[2] Patent: US2006/217417, 2006, A1, . Location in patent: Page/Page column 12
[3] Patent: WO2008/89459, 2008, A1, . Location in patent: Page/Page column 60-61
[4] Journal of the Chinese Chemical Society, 2016, vol. 63, # 9, p. 758 - 769
[5] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 7, p. 787 - 792
[6] Patent: CN106854177, 2017, A, . Location in patent: Paragraph 0016; 0018; 0019; 0024; 0025; 0030; 0031
[7] Patent: WO2014/210354, 2014, A1, . Location in patent: Page/Page column 40; 41
[8] Patent: US2015/166505, 2015, A1, . Location in patent: Paragraph 0342; 0343; 0344; 0345
[9] Patent: WO2012/110860, 2012, A1, . Location in patent: Page/Page column 98
Example 1 Synthesis of 2,4-dichloro-5-nitro-pyridine Dimethyl-1,3-acetonedicarboxylate (50.0 g, 287 mmol), triethylorthoformate (47.8 mL, 287 mmole), and acetic anhydride (54.2 mL, 102 mmol) were combined and heated to 130 C. for 1.5 h then allowed to cool to 25 C. The volatiles were removed in vacuo while maintaining the water bath around 85 C. until the volume of the reaction was reduced to about 25 mL. This crude liquid was poured into a 2000 mL flask and cooled in an ice bath. To this cooled flask was added 75 mL of concentrated aqueous NH3 in portions with swirling. After 1 hour the mixture was acidified by the addition of 6 N HCl (~250 mL). The yellow precipitate was collected by vacuum filtration and allowed to dry under a stream of air. The crude powder was boiled in 200 mL of benzene and allowed to cool and filtered to provide 4,6-dihydroxy-nicotinic acid methyl ester as an orange solid (25.7 g, 53%).
EXAMPLE 76 A 3-neck 5 L round-bottomed flask equipped with an overhead stirrer, a temperature probe with a chart recorder and a condenser (chilled with syltherin XLT, at a temperature of 2.6 C.) is charged with dimethyl acetonedicarboxylate (696.6 g, 4 mol), trimethylorthoformate (424.5 g, 4 mol) and acetic anhydride (816.72 g, 8 mol) under a stream of nitrogen. The resulting amber homogenous solution is stirred rapidly (400 rpm) and heated to reflux at a temperature of 115 C. in 40 minutes using a heating mantle. A gentle reflux is maintained by adjusting the heating over the next hour. (The boiling point of the mixture gradually decreases to 95 C. as the reaction progresses). The resulting orange, homogenous mixture is then distilled at maximum a temperature of 115 C. under vacuum (20 mm Hg) using a Claisen head. About 1000 mL of distillate (containing AcOH, and MeOAc) is collected. The dark orange residue is cooled with an ice bath at a temperature of 6 C.) and ammonium hydroxide (1 L, 8 mol) is then added dropwise in order to control the exothermic reaction to a temperature of less than 25 C., total time=1.5 hours. The yellow suspension is acidified with HCl (pH 2.0) (750 mL, 9 mol) and the resulting tan solid is filtered, washed with 1 L MeOH and dried by suction until constant weight. Thus, a first crop of methyl 4,6-dihydroxy nicotinate (351 g, 51%) is obtained with 97% purity. A second crop of methyl 4,6-dihydroxy nicotinate (35 g) may be obtained by halving the volume of the methanolic filtrate. Mass Spec., 169 (M+, 97%) 137 (100%).
With triethylamine; trichlorophosphate; at 0 - 120℃; for 2h;
4,6-Dihydroxy-nicotinic acid methyl ester (3.9 g, 23 mmol) (from Example 7 supra) was added to POCl3 (20 mL) at 0 C., then Et3N (5 mL) was added to the mixture slowly. After addition, the mixture was heated at 120 C. for 2 hours, then allowed to cool to 0 C. The reaction solution was poured slowly and portion-wise into ice-water (100 mL). Solid K2CO3 was added to adjust pH to 8. The resulting precipitate was collected by filtration. The solid was dissolved in ethyl acetate (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford 4,6-dichloro-nicotinic acid methyl ester. (Yield 4.6 g, 97.2%). 1H NMR (301 MHz, CDCl3) delta 8.85 (s, 1H), 7.47 (s, 1H), 3.97 (s, 3H). LC-MS: [M+H]+ 205.9.
88%
With N,N-diethylaniline; trichlorophosphate; at 25 - 120℃; for 20h;
4,6-Dihydroxy-nicotinic acid methyl ester (25.7 g, 152 mmol) was dissolved in POCl3 (218 mL). Diethyl aniline (36.3 mL, 243.2 mmol) was added and the reaction was fitted with an air cooled condenser and heated to 120 C. for 2 h then allowed to cool to 25 C. over 18 h. The reaction solution was poured slowly and portion-wise over the ice. Following the addition of the complete contents, EtOAc was added and the biphasic mixture was poured into a separatory funnel. The aqueous phase was separated and extracted twice with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The resultant orange oil crystallized upon standing to afford 4,6-dichloro-nicotinic acid methyl ester as an orange solid (27.4 g, 88%).
79%
[00215] Step A: Methyl 4.6-dichloronicotinate: <n="62"/>[00216] To a suspension of <strong>[79398-27-9]methyl 4,6-dihydroxynicotinate</strong> (19.99 g, 118.3 mmol) in 100 ml POCl3 was added NEt3 (15.2 ml) dropwise at 0C over a period of 20 min. The thick suspension was warmed to room temperature and then to 80 C for 3 h with stirring. Then, it was cooled down to room temperature and stirred for an additional 18 h. The mixture was poured into 1.5 l crushed ice, extracted with EtOAc (3 x 150 ml), dried (Na2SO4) and concentrated under reduced pressure. The crude product was filtrated over silica using DCM to obtain the title compound as a yellow oil (19.2g, 79%). Rf (EtOAc/Hexanes 1 :1) = 0.55. 1H-NMR (500 MHz, CDCl3): delta = 8.82 (s, 1H), 7.45 (s, 1H), 3.90 (s, 3H).
70%
With trichlorophosphate; In N,N-dimethyl-aniline; for 4h;Reflux;
After B (199.0 g, 1.18 mol) was dissolved in N, N-dimethylaniline (285.4 g, 2.36 mol)Was added to 1.6 L of phosphorus oxychloride (POCl3) and the mixture was refluxed.After 4 h the reaction mixture was concentrated, the residue was poured into water,use Ethyl acetate (1.0 L x 3). The organic layer was dried and concentrated to 500 mL using a silica gel column (mobile phase petroleum) Ether: ethyl acetate = 60: 1) to give 168.7 g of product C in 70% yield.
42%
With N,N-diethylaniline; trichlorophosphate; at 120℃; for 2h;
To a solution of methyl 4, 6-dihydroxynicotinate (900 g, 5.3 mol) in phosphoryl chloride (4000 mL) was added NN-diethyl aniline (1035 mL, 6.4 mol). The reaction was heated to 120 C for 2 h and then allowed to cool to room temperature. The reaction mixture was reduced in vacuo and poured slowly onto ice portionwise. The mixture was extracted with EtOAc (2x). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified via flash chromatography on silica gel (solvent gradient: 0%-5% EtOAc in petroleum ether) to afford methyl 4,6-dichloronicotinate (400 g, yield 42 %). LCMS (ESI) [M+H] = 206.1 ; 'H NMR (400 MHz, DMSO- d6) delta 8.84 (s, 1H), 7.98 (s, 1H), 3.90 (s, 3H).
37%
With trichlorophosphate; for 14h;Reflux;
A mixture of <strong>[79398-27-9]4,6-dihydroxy-nicotinic acid methyl ester</strong> (9.10 g, 53.8 mmol) in POCl3 (46 mL) was heated to reflux for 14 h. The RM was chilled and the volatiles were removed under reduced pressure. The residue was diluted with sat. aqueous Na2CO3 solution and was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (SiO2, Hex/EtOAc) to yield the desired compound (4.1 g, 37%). [0345] LC-MS (Method 3): m/z [M+H]+=206.1 (MW calc.=206.3); Rt=3.46 min.
With N,N-diethylaniline; trichlorophosphate; at 20℃; for 21h;Reflux;
Step-2: Preparation of methyl 4,6-dichloropyridine-3-carboxylate:-To a solution of <strong>[79398-27-9]methyl 4,6-dihydroxypyridine-3-carboxylate</strong> (25.0 g, 0.147 mol) in N,N- diethyl aniline (37.23 g, 0.248 mol) was added phosphorous oxychloride (200.0 mL). The reaction mass was refluxed for 3 h followed by stirring at RT for 18 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was further purified by column chromatography on silica gel eluting with 4.0 % EA: pet ether to afford 23.0 g of desired product. .HNMR (CDC13): delta 3.97 (s, 3H), 7.48 (s, 1H), 8.64 (s, 1H); MS [M+H]+ :206.27.
3-Oxo-pentanedioic acid dimethyl ester (100 g, 575 mmol), (EtO)3CH (95 mL, 575 mmol), Ac2O (108 mL) and HOAc (108 mL) were mixed and heated at 120 C. for 1.5 hours, then allowed to cool to 25 C. The volatiles were removed under reduced pressure while maintaining the water bath around 85 C. To the crude liquid was added aqueous NH3 (25%, 150 mL) in portions with swirling in an ice bath and the stirring was continued for 1 hour. The mixture was acidified by the addition of 6 N HCl. The yellow precipitate was collected by filtration, boiled in toluene, cooled and filtered to give 4,6-dihydroxy-nicotinic acid methyl ester as an orange solid. (Yield 65 g, 67%). 1H NMR (300 MHz, d6-DMSO): delta 8.06 (s, 1H), 5.65 (s, 1H), 3.83 (s, 3H). LC-MS: [M+H]+ 170.
55%
A (460.0 g, 2.64 mol) and triethyl orthoformate (586.5 g, 3.96 mol) were dissolved in 690 mL of acetic anhydride,After stirring at 150 C for 4 hours,The reaction mixture was volume-concentrated to 600 mL at 100 C.Slowly add 920 mL of NH3 · H2O with stirring, and after 1 hour,The reaction mixture was acidified with 2.3 L of 5 mol / L HCl.The precipitate was collected by filtration and dried to give 243.0 g of product B in 55% yield.
46%
A solution containing dimethyl-1, 3-acetonedicarboxylate (2000 g, 11.5 mol), ethyl orthoformate (1947 mL, 11.5 mol), and acetic anhydride (2168 mL, 23.0 mol) was heated at 130 C for 2 h. The reaction was allowed to be cooled to room temperature then concentrated in vacuo to 1500 mL. The crude reaction was cooled in ice bath and aqueous ammonia (2 L) was added in portions with stirring. After 30 min, the mixture was acidified with concentrated HC1 (-300 mL) and the suspension was filtered. The crude product was dried under vacuum to give methyl 4,6- dihydroxynicotinate (900 g, 46%) which was taken on directly into the next step.
Preparation of methyl 4,6-dihydroxypyridine-3-carboxylateA mixture of dimethyl 3-oxopentanedioate (5.0 g, 28.735 mmol), tri ethyl ortho formate (4.25 g, 28.71 mmol) and acetic anhydride was stirred at 130C for 2 h. The reaction mass was allowed to cool at RT. Excess of solvent was removed under vaccum at 85C. The obtained compound was cooled at 0C and liquid ammonia (10 mL) was added. The reaction mass was stirred at 0C for 1 h. The reaction mass was acidified with 6 N HC1 and again stirred at RT for 20 mins. The obtained crude product was stirred in benzene at 60C. The reaction mass was filtered to afford 2.5 g of desired product. .HNMR (DMSO- d6): delta 1.78 (s, 3H), 5.20 (s, 1H), 5.85 (br hump, 2H), 7.81 (s, 1H); [M+H]+ : 170.14.
(3R,5S)-3-N-cyclopropyl-5-N-((2R)-1-ethoxy-4-methylpentan-2-yl)-3-N-(5-isopropyl-4-(3-methoxypropoxy)pyridin-2-yl)piperidine-3,5-dicarboxamide hydrochloride[ No CAS ]
(±)-3-{6-[2-(cis-3-fluoro-4-hydroxypiperidin-1-yl)pyrimidin-4-ylamino]-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-oxoimidazolidine-1-carboxylic acid tert-butyl ester[ No CAS ]
(±)-[2-(cis-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl]-[1-isopropyl-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amine[ No CAS ]
3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine[ No CAS ]
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