* 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.
Reference：
[1] Helvetica Chimica Acta, 1951, vol. 34, p. 496,499
[2] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 12, p. 4022 - 4036
2
[ 6313-54-8 ]
[ 22282-72-0 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 25, p. 9420 - 9430
[2] Helvetica Chimica Acta, 1951, vol. 34, p. 496,499
3
[ 33252-30-1 ]
[ 6313-54-8 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 60 - 65℃; for 2.4 h; Green chemistry
General procedure: Aromatic or aliphatic nitriles (2 mmol) were dissolved in 5 ml of [bmim]HSO4 and the reaction mixture was heated at 60-65 °C for 1-3 h. The progress of reaction was monitored by TLC. After completion of reaction, as checked by TLC, the reaction mixture was poured into water containing crushed ice. The product was precipitated out, filtered and dried. The yield of the final product was high (>90percent) in all cases. All final products obtained were found sufficiently pure so it didn’t need further purification.The filtrate was concentrated under vacuum, washed with diethylether twice and concentrated under high vacuum. After proper drying under reduced pressure, approximately 95percent ionic liquid was recovered from the reaction and compared with the original ionic liquid to check its authenticity. The efficiency of recovered ionic liquid in conversion of nitriles to acids was found unchanged in comparison to the original one and we reused it up to 5-6 cycles without any significant loss of its activity.
Reference：
[1] Tetrahedron Letters, 2014, vol. 55, # 28, p. 3802 - 3804
[2] Roczniki Chemii, 1955, vol. 29, p. 1019,1025[3] Chem.Abstr., 1956, p. 12045
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 12, p. 4022 - 4036
15
[ 6313-54-8 ]
[ 74-88-4 ]
[ 58481-11-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 25℃; for 0.5 h; Inert atmosphere Stage #2: at 50℃; for 2 h;
To a solution of 2-chloroisonicotinic acid (2.0 g, 0.0 12 mole) in DMF (5 mL)under N2 at 25 °C, was added sodium hydride (0.73 g, 0.0 15 mole) and stirred for 0.5hour. Methyl iodide (1.5 mL, 0.025 mole) was added at RT and the reaction mixturewas warmed to 50 °C for 2 hours. The reaction mixture was dissolved in ice water (50mL) and extracted with ethyl acetate (50 mL x 3). Organic layer was washed with brine solution (50 mL) and dried over Na2SO4. The organic phase was concentrated under vacuum to obtain methyl 2-chloroisonicotinate. Yield: 2.1 g (100 percent); Mass (mlz): 172.0 (M+H) , 174.0 (M+H) .
87%
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 20 h;
Step 1: A mixture of 2-chloro-isonicotinic acid (4.0 g, 25.4 mmol), sodium bicarbonate (5.33 g, 63.48 mmol) and iodomethane (9.7 mL, 156.0 mmol) in N,N dimethyl formamide (60 mL) is stirred at room temperature for 20 hours. The mixture is poured into water and extracted with ether. The organic layer is washed with brine, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate provides an oil which solidifies on standing to yield 3.8 g (87percent) of 2-chloro-isonicotinic acid methyl ester as a white solid. MS 172.0 [M+H].
2-Chloro-isonicotinic acid (5.10 g, 32.38 mmol) was dissolved in methanol (150 mL). Thionyl chloride (12 mL) was added. This suspension was stirred 5 h at 70 0C and concentrated in vacuo. The residue was dissolved in dichloromethane (250 mL) washed with a solution of 10 percent aqueous K2CO3 (2 x 150 mL) dried with MgSO4, filtered and evaporated. Methyl 2-chloropyridine-4-carboxylate SLA 07150 was obtained as a yellow solid (5.06 g, 91 percent).SLA 07150 MW: 171.58; Yield: 91 percent; Yellow Solid; Mp (0C): 33.0. Rf\\ 0.80 (MeOH:CH2CI2 = 10:90).1H-NMR (CDCI3, δ): 3.98 (s, 3H, CH3), 7.78 (dd, 1 H, J = 5.1 Hz, J = 1.3 Hz, ArH), 7.89 (d, 1 H, J = 0.6 Hz ArH), 8.55 (dd, 1 H, J = 5.1 Hz, J = 0.6 Hz, ArH).
81%
at 0 - 20℃; for 16 h;
To a solution of 2-chloroisonicotinic acid 19-1 A (5 g, 31.8 mmol) in MeOH (50 mL) was added SOCl2 (2.7 mL, 38.2 mmol) portion-wise at 0 °C, and the mixture was stirred at RT for 16 hr. Solvent was evaporated under reduced pressure. The reaction was quenched with saturated sodium carbonate and diluted with EtOAc (50 mL) washed with water (50 mL), brine (20 mL) and dried over Na2S04, and the organic phase was concentrated under reduced pressure. Obtained crude compound was purified using silica gel chromatography (15percent EtOAc in hexanes) to afford 19- 2A (4.4 g, 25.7 mmol, 81percent yield) as an off-white solid. MS (ESI): m/z 172.1 (M+l)+.
75%
for 3 h; Heating / reflux
Preparation 1; SYNTHESIS OF 2-[4-(5-FLUORO-2-TRIFLUOROMETHYLBENZOYL)PIPERAZIN-1-YL]ISONICOTINIC ACID METHYL ESTER; A. A mixture of 2-chloroisonicotinic acid (1.000 g, 6.340 mmol) and 5 drops of concentrated sulfuric acid in anhydrous methanol (50 mL) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo, diluted with 20 mL of water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried and concentrated. The compound obtained was used for next step reaction without further purification. Yield 0.816 g, 75percent.
Reference：
[1] Patent: WO2008/11478, 2008, A2, . Location in patent: Page/Page column 76
[2] Patent: WO2016/154241, 2016, A1, . Location in patent: Paragraph 578; 579
[3] Patent: US2008/167321, 2008, A1, . Location in patent: Page/Page column 14
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2785 - 2790
[5] Patent: EP1754706, 2007, A1, . Location in patent: Page/Page column 76
[6] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3615 - 3621
17
[ 6313-54-8 ]
[ 58481-11-1 ]
Yield
Reaction Conditions
Operation in experiment
73%
With thionyl chloride In methanol; toluene
Step 1 Preparation of Methyl-2-chloroisonicotinate To a solution of thionyl chloride (13.85 mL, 190.38 mmol) in toluene (50 mL) was added 2-chloropyridine-4-carboxylic acid (15 g, 95 mmol). The solution was heated to reflux for 3 hours. The resulting brown color solution was cooled to room temperature, and methanol (11.56 mL, 285.6 mmol) was added slowly dropwise. The mixture was brought to reflux for 15 minutes and became clear. The solution was then cooled to room temperature and poured into water (150 mL), basified with 50 percent sodium hydroxide and extracted with ethyl acetate (2*200 ml). The organic layer was separated and washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the titled compound (11.93 g, 73percent) as a brown color solid. This was used in the next step without further purification.
83%
With thionyl chloride In methanol; water; toluene
Step 2 Preparation of Methyl 2-Chloroisonicotinate: To a solution of thionyl chloride (15.0 g, 0.127 mol) in 20 mL of toluene was added 2-chloroisonicotinic acid (10.0 g, 0.063 mol) and the reaction was heated at reflux until gas evolution ceased. Then a solution of methanol (7.7 mL, 0.19 mol) in 10 mL of toluene was added at room temperature over 15 min. The reaction mixture was then refluxed for 1 h and then cooled to room temperature. The clear solution was poured into 100 mL of water, basified with 40percent NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate filtered. The filtrate was concentrated in vacuo to give 8.2 g (83percent) of product as a brown oil which solidified upon standing, mp: 36-37 C.
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2785 - 2790
23
[ 6313-54-8 ]
[ 6813-38-3 ]
Yield
Reaction Conditions
Operation in experiment
85%
With hydrogenchloride; sodium hydroxide In methanol; water
Example 5 5.00 g of 2-chloroisonicotinic acid and 2.80 g of sodium hydroxide are dissolved in a mixture of 20 ml of water and 16 ml of methanol. Following the addition of 1.02 g of palladium (10percent by weight on activated carbon) as catalyst, the mixture is stirred for 6 h at 80-85° C. at 0.1 MPa. The catalyst is then filtered off. Following acidification to pH 1 using hydrochloric acid, the product, 2,2'-bipyridyl-4,4'-dicarboxylic acid, precipitates out as a white solid. This gives 3.3 g (85percent yield).
Reference：
[1] Patent: US6500956, 2002, B1,
24
[ 6313-54-8 ]
[ 64-17-5 ]
[ 54453-93-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 6, p. 1667 - 1675
[2] Patent: WO2005/70934, 2005, A1, . Location in patent: Page/Page column 39-40; 81-82
[3] Patent: WO2003/99787, 2003, A1, . Location in patent: Page 21
[4] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 8, p. 2286 - 2297
25
[ 6313-54-8 ]
[ 54453-93-9 ]
Reference：
[1] Patent: US6362336, 2002, B1, . Location in patent: Example 58
[2] Patent: US2004/248884, 2004, A1, . Location in patent: Page 120
26
[ 6313-54-8 ]
[ 79-37-8 ]
[ 54453-93-9 ]
Reference：
[1] Patent: US5962458, 1999, A,
27
[ 6313-54-8 ]
[ 66572-56-3 ]
Reference：
[1] Journal of Porphyrins and Phthalocyanines, 2015, vol. 19, # 1-3, p. 344 - 351
28
[ 6313-54-8 ]
[ 89937-77-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 12, p. 4022 - 4036
29
[ 6313-54-8 ]
[ 100704-10-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 0℃; for 0.166667 h; Stage #3: With hydrogenchloride In tetrahydrofuran; water
Carbonyldiimidazole (CDI, 7.88 g, 46.2 mmol, 1.5 equiv) is added at room temperature to a solution of 2-chloroisonicotinic acid (5.0 g, 30.8 mmol) in THF (70 ml). The reaction mixture is stirred at rt overnight, and then added dropwise to a cold (0 0C) solution of NaBH4 (6.07 g, 154 mmol, 5.0 eq) in water (175 ml). After stirring for 10 minutes at 0 0C, HCI (2 M aqueous solution) is carefully added. Volatiles are removed via rotary evaporation, and the residue is dissolved in an aqueous 10percent solution of NaHCO3. After five extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. 1H-NMR analysis of the residue indicated adequate purity for direct use of the product (4.40 g, 99percent) in the next step. 1H NMR (400 MHz, CDCI3): δ = 8.37 (d, J = 5.1 Hz, 1 H), 7.39 (s, 1 H), 7.23 (d, J = 5.1 Hz, 1H), 4.78 (s, 2H). MS (ES+): 144 (M+H)+.
93%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0 - 50℃; for 61 h; Stage #2: With water; ammonium chloride In tetrahydrofuran; ethyl acetate at 20℃;
Borane-dimethyl sulfide complex (14.30 mL, 14.30 mmols) was added to tetrahydrofuran solution of 2-chloroisonicotinic acid (17.56 g, 11.5 mmols) under cooling with ice, and stirred at room temperature for 2.5 days, followed by further an hour's stirring at 50°C. Cooling the reaction liquid to room temperature, ethyl acetate was added, followed by washing with saturated aqueous ammonium chloride solution and saturated brine and drying over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the title compound (15.0 g, 93percent) was obtained.
85.8%
Stage #1: With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at -10 - 20℃; Stage #2: With water In tetrahydrofuran
Preparation B-11; A. 2-Chloro-4-(chloromethyl)pyridine; Boron trifluoride diethyl etherate (71 g, 0.5 mol) was added dropwise to a suspension of 2-chloroisonicotinic acid (20 g, 0.125 mol) and sodium borohydride (14.3 g, 0.376 mol) in THF (200 ml.) with stirring at -10-5 0C, then the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (100 ml_), and extracted with ethyl acetate (3 *200 ml_). The organic layers were combined, washed with brine (200 ml_), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1 IA) and afforded 2-chloro-4- (hydroxymethyl)pyridine (15.4 g, 85.8 percent yield) as an oil.
60%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 49 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0℃; for 0.5 h; Stage #3: With sodium hydroxide In tetrahydrofuran; water
(2-Chloro-pyridin-4-yl)-methanol:; To a stirred solution of 2-chloroisonicotinic acid (3.15 g, 20 mmol) in anhydrous THF (40 ml) cooled in an ice bath, was added borane-methyl sulfide complex (6 mL, 60 mmol). After 1 hr, the mixture was stirred for 48 hr at room temperature. The mixture was cooled in an ice bath and conc. HCl (30 ml) was added and stirred for 30 min. The mixture was then basified by addition of 50percent aqueous NaOH (30 ml). The product was extracted with dichloromethane, dried with anhydrous potassium carbonate, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (5:1)) to afford 172 g (60percent) of 2-chloro-4-pyridinemethanol as a white solid. m.p. 77-79° C.; 1H NMR (200 MHz, CDCl3) δ 2.97(1H, br. s), 4.74 (2H, s), 7.20 (1H, d, J=5.7 Hz), 7.36 (1H, s), 8.28 (1H, d, J=5.7 Hz).
60%
Stage #1: With borane-THF In tetrahydrofuran at 50℃; Stage #2: With methanol In tetrahydrofuran at 20℃;
Example 4: Synthesis of (2-(2-(l H-indazol-4-yl)pyridin-4-yl)-l -fluoroethane-1 ,1 - diyl)diphosphonic acidStep 4a: Synthesis of (2-chloropyridin-4-yl)methanol2-Chl oroi son icot inic acid (2.0 g; 12.7 mmol) is dissolved in 25 mL THF under anhydrous conditions and borane (1.0 M in THF; 25.4 ml; 25.4 mmol) is added drop wise via a syringe. The solution is stirred overnight at 50 °C. The mixture is cooled to R Γ and quenched with 5 mL MeOH, concentrated under reduced pressure and purified by column chromatography on silica gel using a solvent gradient of hexanes to EtOAc. The final product is isolated as a white powder (1.1 g, 60percent yield). NMR (300 MHz, CDC3/4): δ 8.34 (d, J = 5.1 Hz, 1H), 7.36 (dq, J = 1.6, 0.8 Hz, 1H), 7.22 - 7.19 (m, lH). 4.75 (s, 2H).
Reference：
[1] Polish Journal of Chemistry, 1981, vol. 55, # 7/8, p. 1667 - 1672
37
[ 6313-54-8 ]
[ 101066-61-9 ]
Reference：
[1] Patent: WO2008/11478, 2008, A2,
38
[ 6313-54-8 ]
[ 639091-78-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 12, p. 4022 - 4036
39
[ 6313-54-8 ]
[ 36805-97-7 ]
[ 295349-62-1 ]
Yield
Reaction Conditions
Operation in experiment
56%
for 2 h; Heating / reflux
A solution of 10.0 g (63.4 mmol) 2-chloro-isonicotinic acid in 100 ml chloroform is heated to reflux temperature. In total 91.2 ml (380 mmol, 6 eq) N,N-dimethylformamide di-tert-butylacetal is added in 3 portions of each 30.4 ml at the start, after 1 h and after 2 h. After cooling to rt the mixture is diluted with EtOAc, washed with aq. bicarbonate and brine, and dried over sodium sulfate. The residue is purified by chromatography on silica (flashmaster, hexane to hexane/EtOAc 95/5) to give 7.6 g (35.6 mmol, 56percent) of the product as white solid.MS (LC/MS): 158=[M+H-tBu]+1H-NMR (300 MHz, CDCl3): 8.55 (d, 1H), 7.85 (s, 1H), 7.76 (d, 1H), 1.64 (s, 9H).
33%
at 90℃; for 20 h;
a) To a solution of 2-chloroisonicotinic acid (5.00 g, 31.7 mmol) in toluene is added N,Ndimethylformamide di-tert. butylacetal (17.9 g, 79.3 mmol). The mixture is stirred at 90°C for 20 h. The mixture is concentrated, filtered and the filtrate is diluted with EA and washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting heptane:EA 5:1 to give tert. butyl 2-chloroisonicotinate (2.23 g, 33percent) as a colourless oil; LC-MS: tR = 0.98 mm, [M+1+CH3CN] = 255.31.
Reference：
[1] Patent: US2008/132477, 2008, A1, . Location in patent: Page/Page column 28
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 1, p. 110 - 130
[3] Patent: WO2014/141171, 2014, A1, . Location in patent: Page/Page column 17; 18
40
[ 6313-54-8 ]
[ 24424-99-5 ]
[ 295349-62-1 ]
Reference：
[1] Patent: WO2008/11499, 2008, A1, . Location in patent: Page/Page column 37
[2] Organic Process Research and Development, 2009, vol. 13, # 6, p. 1145 - 1155
41
[ 6313-54-8 ]
[ 67098-46-8 ]
[ 295349-62-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4233 - 4249
With 1-butyl-3-methylimidazolium hydrogen sulfate; water; at 60 - 65℃; for 2.4h;Green chemistry;
General procedure: Aromatic or aliphatic nitriles (2 mmol) were dissolved in 5 ml of [bmim]HSO4 and the reaction mixture was heated at 60-65 C for 1-3 h. The progress of reaction was monitored by TLC. After completion of reaction, as checked by TLC, the reaction mixture was poured into water containing crushed ice. The product was precipitated out, filtered and dried. The yield of the final product was high (>90%) in all cases. All final products obtained were found sufficiently pure so it didn?t need further purification.The filtrate was concentrated under vacuum, washed with diethylether twice and concentrated under high vacuum. After proper drying under reduced pressure, approximately 95% ionic liquid was recovered from the reaction and compared with the original ionic liquid to check its authenticity. The efficiency of recovered ionic liquid in conversion of nitriles to acids was found unchanged in comparison to the original one and we reused it up to 5-6 cycles without any significant loss of its activity.
Step 1 Preparation of Methyl-2-chloroisonicotinate To a solution of thionyl chloride (13.85 mL, 190.38 mmol) in toluene (50 mL) was added 2-chloropyridine-4-carboxylic acid (15 g, 95 mmol). The solution was heated to reflux for 3 hours. The resulting brown color solution was cooled to room temperature, and methanol (11.56 mL, 285.6 mmol) was added slowly dropwise. The mixture was brought to reflux for 15 minutes and became clear. The solution was then cooled to room temperature and poured into water (150 mL), basified with 50 percent sodium hydroxide and extracted with ethyl acetate (2*200 ml). The organic layer was separated and washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the titled compound (11.93 g, 73%) as a brown color solid. This was used in the next step without further purification.
8.2 g (83%)
With thionyl chloride; In methanol; water; toluene;
Step 2 Preparation of Methyl 2-Chloroisonicotinate: To a solution of thionyl chloride (15.0 g, 0.127 mol) in 20 mL of toluene was added 2-chloroisonicotinic acid (10.0 g, 0.063 mol) and the reaction was heated at reflux until gas evolution ceased. Then a solution of methanol (7.7 mL, 0.19 mol) in 10 mL of toluene was added at room temperature over 15 min. The reaction mixture was then refluxed for 1 h and then cooled to room temperature. The clear solution was poured into 100 mL of water, basified with 40% NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate filtered. The filtrate was concentrated in vacuo to give 8.2 g (83%) of product as a brown oil which solidified upon standing, mp: 36-37 C.
With hydrogenchloride; sodium hydrogencarbonate; In methanol;
Step 1 2-Chloropyridine-4-carboxylic acid (15.5 g, 98 mmol) was suspended in methanol (175 ml) and anhydrous hydrogen chloride gas was slowly bubbled through the reaction mixture while cooling in a methanol/water (20/80) dry ice bath. Bubbling was continued for 40 min. during which time the suspension cleared to a partial solution. Ice bath was removed and the reaction mixture was heated to reflux under anhydrous conditions for 30 min. to give a clear yellow solution. The solution was cooled in an ice bath and saturated sodium bicarbonate was slowly added with stirring till the pH was neutral. The organics were removed in vacuo and the product was extracted into ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 2-chloropyridine-4-carboxylic acid methyl ester as a brown liquid.
2-Chloro-isonicotinic acid (5.10 g, 32.38 mmol) was dissolved in methanol (150 mL). Thionyl chloride (12 mL) was added. This suspension was stirred 5 h at 70 0C and concentrated in vacuo. The residue was dissolved in dichloromethane (250 mL) washed with a solution of 10 % aqueous K2CO3 (2 x 150 mL) dried with MgSO4, filtered and evaporated. Methyl 2-chloropyridine-4-carboxylate SLA 07150 was obtained as a yellow solid (5.06 g, 91 %).SLA 07150 MW: 171.58; Yield: 91 %; Yellow Solid; Mp (0C): 33.0. Rf 0.80 (MeOH:CH2CI2 = 10:90).1H-NMR (CDCI3, delta): 3.98 (s, 3H, CH3), 7.78 (dd, 1 H, J = 5.1 Hz, J = 1.3 Hz, ArH), 7.89 (d, 1 H, J = 0.6 Hz ArH), 8.55 (dd, 1 H, J = 5.1 Hz, J = 0.6 Hz, ArH).
81%
With thionyl chloride; at 0 - 20℃; for 16h;
To a solution of 2-chloroisonicotinic acid 19-1 A (5 g, 31.8 mmol) in MeOH (50 mL) was added SOCl2 (2.7 mL, 38.2 mmol) portion-wise at 0 C, and the mixture was stirred at RT for 16 hr. Solvent was evaporated under reduced pressure. The reaction was quenched with saturated sodium carbonate and diluted with EtOAc (50 mL) washed with water (50 mL), brine (20 mL) and dried over Na2S04, and the organic phase was concentrated under reduced pressure. Obtained crude compound was purified using silica gel chromatography (15% EtOAc in hexanes) to afford 19- 2A (4.4 g, 25.7 mmol, 81% yield) as an off-white solid. MS (ESI): m/z 172.1 (M+l)+.
75%
sulfuric acid; for 3h;Heating / reflux;
Preparation 1; SYNTHESIS OF 2-[4-(5-FLUORO-2-TRIFLUOROMETHYLBENZOYL)PIPERAZIN-1-YL]ISONICOTINIC ACID METHYL ESTER; A. A mixture of 2-chloroisonicotinic acid (1.000 g, 6.340 mmol) and 5 drops of concentrated sulfuric acid in anhydrous methanol (50 mL) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo, diluted with 20 mL of water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried and concentrated. The compound obtained was used for next step reaction without further purification. Yield 0.816 g, 75%.
(1) 2-chloro-4-pyridinecarboxylic acid was dissolved in methanol, then thionyl chloride was added to the solution, and the mixture was stirred overnight at 80C. The obtained reaction solution was concentrated and then poured onto water, and the reaction solution was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate, and the solvent was removed to obtain a methyl ester product [122-2]. [Show Image] The spectral data of the compound represented by the above Formula [122-2] is presented below. 1H-NMR (CDCl3) delta: 8.55 (1H, dd, J=0.8, 4.8 Hz), 7.90 - 7.80 (1H, m), 7.78 (1H, dd, J=1.2, 4.8 Hz), 3.98 (3H, s).
Example 1; Step A; 2-Chloro-isonicotinic acid ethyl ester (1); The mixture of 2-chloro-isonicotinic acid (16.8 g, 0.107 mol), 100 mL absolute ethanol and concentrate H2S04 (3.28 mL, 0.118 mol) was refluxed under nitrogen for 15 h. After all starting material converted, the mixture was cool down to rt, and vacuumed down all ethanol. The resulted mixture was diluted with 250 mL ethyl acetate, washed with sat. NaHCO3, dried over anhydrous Na2SO4. Purified by a short column, the title compound was obtained as a pale yellow liquid.
Reference Example 21 In 400 ml of tetrahydrofuran was dissolved 31.5 g of 2- chloroisonicotinic acid, and 32.5 g of 1, [1'-] carbonyldiimidazole was added thereto. The mixture was stirred under ice-cooling for an hour. To the solution was added 50 ml of ethanol, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated, and extracted by adding ethyl acetate and water. The organic layer was dried over magnesium sulfate, and the residue was vacuum dried, to give 35.6 g of ethyl 2-chloroisonicotinate as shown in Table 132 below.
2-chloropyridine-4-carbonyl chloride hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride;N,N-dimethyl-formamide; In chloroform; at 0℃; for 2h;Heating / reflux;
To a solution of 2-chloroisonicotinic acid (6.00 g) in DMF (0.29 mL) and CHCl3 (60 mL) cooled on an ice-bath was added thionyl chloride (3.2 mL) and the mixture was stirred at reflux for 1 h. To the mixture was added thionyl chloride (1.6 mL) and the mixture was stirred at reflux for 30 min. To the mixture was added thionyl chloride (3.2 mL) and the mixture was stirred at reflux for 30 min and concentrated under reduced pressure. The residue was diluted with CHCl3 (20 mL) and the solution was poured into a mixture of MeOH (1.85 mL), CHCl3 (19 mL), and Et3N (6.4 mL) cooled on an ice-bath. The mixture was stirred at 0 0C for 5 min and at ambient temperature for 60.5 h and quenched with aqueous saturated NaHCO3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, filtrated, concentrated under reduced pressure, EPO <DP n="96"/>and purified by medium-pressure liquid chromatography (silica gel, 9% to 20% EtOAc in hexane) to give methyl 2-chloroisonicotinate (6.05 g) as a colorless oil.1HNMR (SOO MHz, CDCl3, delta): 3.95-4.01 (m, 3H), 7.76-7.81 (m, IH), 7.88-7.93 (m, IH), 8.53-8.59 (m, IH); CI MS m/z 172 (M++., 100%).
With thionyl chloride; for 2h;Heating / reflux;
<strong>[6313-54-8]2-Chloroisonicotinic acid</strong> (5.00 g, 31.7 mmol) was added to thionyl chloride (40 mL), followed by stirring under heating and reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (1 mL). The resulting solution was added to a pyridine (16 mL) solution of 2-amino-4-(2-furyl)-5-morpholinothiazole (880 mg, 5.00 mmol) obtained in Step 1 of Example 29, and then N,N-dimethylaminopyridine (48.8 mmol, 0.400 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate = 1:3 to ethyl acetate) to afford the entitled Compound 39 (1.05 g, 66 %) 1H NMR (CDCl3, delta ppm): 3.03 (t, J = 4.6 Hz, 4H), 3.60 (t, J = 4.6 Hz, 4H), 6.52 (dd, J = 1.6, 3.5 Hz, 1H), 6.88 (dd, J = 0.8, 3.5 Hz, 1H), 6.95 (dd, J = 1.4, 5.1 Hz, 1H), 7.10-7.12 (m, 1H), 7.46 (dd, J = 0.8, 1.6 Hz, 1H), 8.35 (dd, J = 0.8, 5.1 Hz, 1H), 9.33 (br s, 1H).
With dmap; In 1-methyl-pyrrolidin-2-one; at 25℃; for 17.0h;
Example 5 to~/-butyl 2-chloroisonicotinate; A 1-L jacketed 3-neck round bottom flask equipped with overhead stirrer, N2-InIeI vented to the atmosphere and thermocouple was charged with 2-chloroisonicotinic acid (78,0 g, 495 mrnol), di-foer/-butyl dicarbonate (230.1 g, 1054 mmol), and l-methyl-2-pyitauolidinone (179 3 g) A solution of 4-dimethyJamino pyridine (1 1.61 g, 95 mrnol) dissolved in l -methyl-2- pyriolidinone (60 0 g) was charged to the mixture and the temperature was adjusted to 25 +/-10°C The reaction was quenched after stirring for about 17 hours by the addition of an ice-cold solution of sodium chloride (30 0 g) and monobasic potassium phosphate (30 2 g) in water (320~7 g). Methyl tert-buty. ethei (278 g) was added, and the mixture was stirred and allowed to settle. The layers were separated The organic phase was washed three times with water1 (-230-240 g each) then diluted with toluene (239 g) and distilled under vacuum to a red oil (150 8 g,KP 29 9 ppm H2O), 1H NMR (400 MHz, CDCl3) delta ppm 1.60 (s, 9 H) 7 69 - 7 72 (m, 1 H) 7.79 -7.81 (m, 1 H) 8 49 (dd, 7=5.08, 0..69 Hz, 1 H)
HOBt (823 mg, 6.09 mmol), and EDCI (1.2 g, 6.09 mmol) were added to a suspension of 2-chloro-isonicotinic acid (800 mg, 5.08 mmol) in acetonitrile (10.3 ml) at room temperature. After two h a solution of hydrazine monohydrate (0.493 ml, 10.2 mmol) in acetonitrile (5.0 ml) was added drop-wise at [0C.] After 30 min, the solvent was removed using a roto-evaporator and the residue was diluted with ethyl acetate, quenched with water, dried over sodium sulfate, filtered and concentrated to afford 2-chloro-isonicotinic acid hydrazide (493 mg, 57%, yellow solid). 1H NMR (DMSO) d (ppm): 10.21 (bs, [1H),] 8.55 (d, 1H), 7.82 (s, 1H), 7.75 (d, 1H), 4.69 (bs, 2H).
4-Amino-N-[4-([(2-chloro-4-pyridinyl)carbonyl]amino}methyl)phenyl]-2-methyl-6-quinolinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With triethylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 24h;
To a solution of 27mg (0.05mmol) 4-Amino-N-[4-(aminomethyl)phenyl]-2-methyl-6-quinolinecarboxamide, 9mg (0.1mmol) 2-chloropyridine-4-carboxylic acid, and 0.07ml (0.5mmol) triethylamine in 2ml dichloromethane was added 90mg (2.0mmol) PyBrop and stirred at room temparature for 1d. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 17mg (74%) of the title compound. MS 446.3 (M+1)+, 1H-NMR (DMSO-d6) delta:2.60 (s, 3H), 4.47 (d, 2H), 6.64 (s, 1H), 7.34 (d, 2H), 7.73 (d, 2H), 7.81 (dd, 1H), 7.87 (d, 1H), 7.91 (s, 1H), 8.35 (dd, 1H), 8.57 (d, 1H), 8.95 (s, 1H), 9.00 (br. 2H), 9.41 (t, 1H), 10.47 (s, 1H).
In tetrahydrofuran; diethyl ether; water; at -70 - 0℃; for 3.0h;
(1) In 440 ml of THF was suspended 22 g of 2-chloroisonicotinic acid, and under nitrogen flow, the mixture was cooled to -70°C or lower, 245 ml of methyl lithium (1.14 M solution in diethyl ether) was added dropwise to the mixture.. After stirring at the same temperature for an hour, a temperature of the mixture was raised to 0°C over an hour, and stirred at the same temperature for further an hour.. To the reaction mixture was added 500 ml of water, and the reaction mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate.. Activated charcoal was added to the mixture, and after filtration, the filtrate was concentrated under reduced pressure to give 19.5 g of 4-acetyl-2-chloropyridine as colorless crystals.. Melting point: 36°C.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 20℃; for 24h;
31.A Step A
Step A A solution of 315 mg of 2-chloroisonicotinic acid and 209 mg of morpholine in EtOAc (4.0 ML) was stirred as 1.27 g of a 50% solution of 1-propanephosphonic acid cyclic anhydride was added.This mixture was stirred at room temperature for six hrs. and another 1.27 g of the anhydride was added followed by stirring for another 18 hrs.The reaction was poured into saturated sodium bicarbonate solution and extracted with EtOAc (3*).The organic layers were dried over sodium sulfate, filtered, and concentrated to provide the morpholine amide.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 20℃; for 24h;
31.A
Preparation 31 N1-(4-Morsholin-4-vimethvl-pvridin-2-yl)-ethane- 1, 2-diamine Step A; A solution of 315 mg of 2-chloroisonicotinic acid and 209 mg of morpholine in EtOAc (4.0 mL) was stirred as 1.27 g of a 50% solution of 1-propanephosphonic acid cyclic anhydride was added. This mixture was stirred at room temperature for six h. and another 1.27 g of the anhydride was added followed by stirring for another 18 h. The reaction was poured into saturated sodium bicarbonate solution and extracted with EtOAc (3 x). The organic layers were dried over sodium sulfate, filtered, and concentrated to provide the morpholine amide.
With 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetratetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 16h;Heating / reflux;
2-Chloroisonicotinic acid (3.3g, 21mmol), HATU (8.75g, 23mmol), diisopropylethyl amine (10. 9ml, 63mmol) and <strong>[35944-64-0]3-iodo-4-methylaniline</strong> (5. 00g, 21mmol) in dimethylformamide (50ml) were heated under nitrogen for 16 hours. The reaction was cooled, solvent removed in vacuo and the residue taken up in dichloromethane (150ml). The organic solution was washed with water (3xlOOml) and brine (100ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (40: 60 ethyl acetate: cyclohexane) to give 2-chloro-N- (3-iodo-4- methylphenyl) -isonicotinamide as a white solid (7. 00g, 18. 8mmol). LCMS: retention time 3.59 min Mu373. NMR: 8H [2H6]-DMSO 10.52 (1H, s), 8.62 (1H, d), 8.29 (1H, d), 7.99 (1H, b), 7.87 (1H, dd), 7.70 (1H, dd), 7.34 (1H, d), 2.36 (3H, s).
With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); for 16h;
2-Chloroisonicotinic acid (3.3g) HATU (8.75g) DIPEA (10. 9ml) and 3-iodo-4- methylaniline (5. 00g) in DMF (50ml) were heated under nitrogen for 16h. The reaction was cooled, the solvent was removed under vacuum and the residue was dissolved in dichloromethane (150ml). The solution was washed with water (3xlOOml) and brine (100ml) dried (magnesium sulphate) and the solvent was removed under vacuum. The residue was purified by column chromatography on silica eluting with ethyl acetate/cyclohexane (40: 60) to give the title compound as a white solid (7. 00g). NMR: oH [d6-DMSO] 10.52 (1H, s), 8.62 (1H, d), 8.29 (1H, d), 7.99 (1H, b), 7.87 (1H, dd), 7.70 (1H, dd), 7.34 (1H, d), 2.36 (3H, s). LCMS: Rt 3.59 min MH'373.
With hydrogen iodide; sodium iodide; In butanone; for 6.0h;Heating / reflux;
Reference Example 98 2-Iodo-4-pyridinecarboxylic acid Hydroiodic acid (4.0 ml) was added to a 2-butanone solution (150 ml) of 2-chloroisonicotinic acid (5.0 g) and sodium iodide (17.0 g), followed by heating under reflux for 6 hours. After cooling, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in water. The mixture was alkalified with 1 N NaOH, and then the insoluble substance was removed by filtration, and an aqueous sodium sulfite solution was added to the filtrate. The reaction solution was acidified by adding 1 N HCl and concentrated hydrochloric acid, and then the resulting precipitate was collected by filtration. The product was washed with isopropyl alcohol and diisopropyl ether and then dried to obtain the title compound (4.8 g) as a crystalline solid. 1H-NMR (400 MHz, DMSO-d6) δ: 7.82 (1H, dd, J=5.1 Hz, 1.2 Hz), 8.15 (1H, d, J=0.5 Hz), 8.55 (1H, d, J=4.9 Hz), 13.91 (1H, br s). FAB-MS m/z: 250 (N4+H)+.
With methylamine In tetrahydrofuran; ethanol; N,N-dimethyl-formamide
2-Chloro-N-methyl-isonicotinamide (8-2)
2-Chloro-N-methyl-isonicotinamide (8-2) 2-Chloro-isonicotinic acid (12-1, 5.15 g, 32.7 mmol) was stirred in 65 mL anhydrous THF under N2. The reaction (not homogeneous) was cooled to 0° C. and oxalyl chloride (2.85 mL, 32.7 mmol) was added, followed by addition of 1 drop anhydrous DMF. Slight bubbling occurred. The reaction was allowed to warm to room temperature. After 4 hours reaction is homogeneous and after a total of 5 hours the reaction was quickly added by pipette to a solution of methylamine (7.11 g, 228 mmol) in EtOH (20 mL). The resulting solution was concentrated in vacuo and diluted with saturated NaHCO3 (aq). The solution was extracted 3* with EtOAc and the organic extracts were dried over Na2SO4, filtered ands concentrated to provide the titled compound. 1H NMR (CDCl3) δ 8.50 (d, 1H, J=5.1 Hz), 7.66 (s, 1H), 7.53 (d, 1H, J=5.1 Hz), 6.36 (bs, 1H), 3.04 (d, 2H, J=5.0 Hz).
With methylamine In tetrahydrofuran; ethanol
2-Chloro-N-methyl-isonicotinamide (12-2)
2-Chloro-N-methyl-isonicotinamide (12-2) 2-Chloro-isonicotinic acid (12-1, 5.15 g, 32.7 mmol) was stirred in 65 mL anhydrous THF under N2. The reaction (not homogeneous) was cooled to 0° C. and oxalyl chloride (2.85 mL, 32.7 mmol) was added, followed by addition of 1 drop anh DMF. Slight bubbling occurs. The reaction was allowed to warm to RT. After 4 h reaction is homogeneous and after a total of 5 h the reaction was quickly added by pipet to a solution of methylamine (7.11 g, 228 mmol) in EtOH (20 mL). The resulting solution was concentrated in vacuo and diluted with sat NaHCO3 (aq). The solution was extracted 3* with EtOAc and the organic extracts were dried over Na2SO4, filtered ands concentrated to provide the titled compound. 1H NMR (CDCl3) δ 8.50 (d, 1H, J=5.1 Hz), 7.66 (s, 1H), 7.53 (d, 1H, J=5.1 Hz), 6.36 (bs, 1H), 3.04 (d, 2H, J=5.0 Hz).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
In a round bottom flask containing 4-pyridinecarboxylic acid (11: 200 mg, 1.0 equivalent), EDC · HCl (1.2 equivalent), DMAP (1.0 equivalent), Me (MeO) NH · HCl (1.05 equivalent), Et3N (2.8 equivalent) Eq.) And CH2Cl2 (0.2 M) were added.After stirring the mixture at room temperature for several hours while checking the progress of the reaction by TLC, the reaction was quenched with saturated aqueous NaHCO and extracted three times with CH Cl,Washed with saturated saline.The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography to give amide 12.
With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; In N,N-dimethyl-formamide;
2-Chloro-N-methoxy-N-methylisonicotinamide (16-1) <strong>[6313-54-8]2-Chloroisonicotinic acid</strong> (12-2, 2.0 g, 12.7 mmole), N,O-dimethylhydroxylamine hydrochloride (3.71 g, 38.1 mmole), EDC (2.92 g, 15.2 mmole), and HOBt (2.06 g, 15.2 mmole) were combined in dry DMF (40 mL). To this was added Et3N (8.9 mL, 63.47 mmole) at RT. After 60 hr the mixture was diluted with H2O and extracted with EtOAc (4*). The combined organic layers were washed with H2O, brine; then dried (MgSO4), filtered, and concentrated to give the titled compound as an amber oil which solidified on standing. The material was sufficiently pure for use in the next step. 1H-NMR (500 MHz, CDCl3) delta 8.47 (d, 1 H, J=5.13 Hz), 7.57 (s, 1 H), 7.45 (m, 1 H), 3.56 (s, 3 H), 3.38 (s, 3 H).
With 4-methyl-morpholine; hydrogenchloride; dmap; In dichloromethane;
Step 1: 2-Chloro-N-methoxy-N-methyl-isonicotinamide To a suspension of 2-chloroisonicotinic acid (20 g, 0.127 mol), N,O-dimethyl-hydroxylamine HCl (19.8 g, 0.203 mol), 4-methylmorpholine (20.5 g, 0.203 mol) and DMAP (1.55 g, 0.013 mol) in dichloromethane (300 ml) at 0 C. was added EDCI HCl (29.2 g, 0.152 mol). The mixture was stirred at 0 C. for 10 min and at room temperature for 17 h. The mixture was poured into water/1M aqueous HCl and extracted with dichloromethane. The combined organic phases were washed with water, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (24.9 g) as a white solid. MS(m/e)=201.2 [M+H+].
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane;
To a solution of 2-chloroisonicotinic acid (3.08 g) in dichloromethane (60 mL) were added WSC/HCl (5.62 g), HOBt (4.5 g), N,O-dimethylhydroxyamine hydrochloride (2.9 g) and triethylamine (8.3 mL), and the mixture was stirred overnight. The reaction mixture was diluted with aqueous ammonium chloride solution, extracted with dichloromethane, dehydrated with sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to give Compound II (3.51 g).
<strong>[6313-54-8]2-Chloroisonicotinic acid</strong> (26, 21.0 g, 133.3 mmol) was suspended in SOCl2 (60 mL) and the mixture was stirred at reflux temperature for 5 h. After removingthe excess of solvent, the residue was taken up in dry DCM and added dropwise to an ice-cooled previously prepared suspension of N,O-dimethylhydroxylamine hydrochloride (15.6 g, 160 mmol) and NEt3 (45.0 mL, 320 mmol) in dry DCM (50 mL). After completion of the addition the mixture was letheating at rt and stirred overnight. After evaporating the solvent at reduced pressure H2O was addedand the aqueous phase was extracted with DCM. The combined organic layers were then washed with NaCl saturated solution, dried over anhydrous Na2SO4, and concentrated at reduced pressure giving 26.0 g of product as a light brown solid, which was directly used for the following step without furtherpurification (97% yield); 1H-NMR (300 MHz, CDCl3) delta 3.35 (s, 3H), 3.53 (s, 3H), 7.43 (dd, J = 5.0, 1.2 Hz,1H), 7.54 (s, 1H), 8.45 (d, J = 5.1 Hz, 1H); 13C-NMR (75 MHz, CDCl3) delta 32.9, 61.5, 120.7, 122.8, 144.5,149.8, 151.6, 166.0; ESI-MS: (m/z) 201.1 [M + H]+; HPLC: tr = 2.051 min.
2-Iodo-isonicotinic Acid Methyl Ester A solution of 2-chloro-pyridine-4-carboxylic acid (5g, 31.7 mmol) in butan-2-one (150 ml) was heated under reflux with sodium iodide for 6 h to afford the 2-iodo-isonicotinic acid (7.3 g, 92.4% yield) following extractive aqueous workup. This material was dissolved in THF (50 ml) and esterified with fresh etheral diazomethane solution (44 ml, 0.55 mol/l). After evaporation of the solvent and filtration through a pad of silica gel, [elution with CH2Cl2/(2M NH3 MeOH)=19:1] the title compound (2.3 g, 44%) was obtained as a dark yellow oil. MS: m/e=263.0 (M4).
With hydrogenchloride; sodium hydroxide;palladium; In methanol; water;
Example 5 5.00 g of 2-chloroisonicotinic acid and 2.80 g of sodium hydroxide are dissolved in a mixture of 20 ml of water and 16 ml of methanol. Following the addition of 1.02 g of palladium (10% by weight on activated carbon) as catalyst, the mixture is stirred for 6 h at 80-85 C. at 0.1 MPa. The catalyst is then filtered off. Following acidification to pH 1 using hydrochloric acid, the product, 2,2'-bipyridyl-4,4'-dicarboxylic acid, precipitates out as a white solid. This gives 3.3 g (85% yield).
With hydrogenchloride; sodium hydroxide; In 1,4-dioxane; ammonium hydroxide; ethanol;
Step A. Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-(2-acetamido)-pyridyl))-propionate A solution of 2-chloroisonicotinic acid (25.0 g, 0.16 mol) in 65 mL of concentrated ammonium hydroxide was warmed to 205 Celsius in a steel bomb for 72 h. After cooling to 23 C, the solution was acidified to a pH of 1 using 6N HCl and subsequently filtered to remove unreacted starting material. The solution was concentrated to one fourth the original volume (approx 200 mL) in vacuo, and carefully adjusted to a pH of 6 using 1 N NaOH. After storing the cloudy solution at 0 C for 20 h, the desired 2-aminoisonicotinic acid was filtered off. To a suspension of 2-aminoisonicotinic acid in ethanol (600 mL) was added 47.1 mL of 4 N anhydrous HCl in dioxane. After warming to achieve reflux for 20 h, an additional 47.1 mL of 4 N anhydrous HCl in dioxane was added and the reaction was warmed to -reflux for an additional 20 h. Concentration with a stream of nitrogen in the hood was followed by further concentration in vacuo, the remaining solid was diluted with saturated bicarbonate (200 mL), extracted with ethyl acetate (2*200 mL), dried (Na2SO4). After concentration in vacuo, the desired ethyl 2-aminoisonicotinate was obtained.
Carbonyldiimidazole (CDI, 7.88 g, 46.2 mmol, 1.5 equiv) is added at room temperature to a solution of 2-chloroisonicotinic acid (5.0 g, 30.8 mmol) in THF (70 ml). The reaction mixture is stirred at rt overnight, and then added dropwise to a cold (0 0C) solution of NaBH4 (6.07 g, 154 mmol, 5.0 eq) in water (175 ml). After stirring for 10 minutes at 0 0C, HCI (2 M aqueous solution) is carefully added. Volatiles are removed via rotary evaporation, and the residue is dissolved in an aqueous 10% solution of NaHCO3. After five extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. 1H-NMR analysis of the residue indicated adequate purity for direct use of the product (4.40 g, 99%) in the next step. 1H NMR (400 MHz, CDCI3): delta = 8.37 (d, J = 5.1 Hz, 1 H), 7.39 (s, 1 H), 7.23 (d, J = 5.1 Hz, 1H), 4.78 (s, 2H). MS (ES+): 144 (M+H)+.
93%
Borane-dimethyl sulfide complex (14.30 mL, 14.30 mmols) was added to tetrahydrofuran solution of 2-chloroisonicotinic acid (17.56 g, 11.5 mmols) under cooling with ice, and stirred at room temperature for 2.5 days, followed by further an hour's stirring at 50C. Cooling the reaction liquid to room temperature, ethyl acetate was added, followed by washing with saturated aqueous ammonium chloride solution and saturated brine and drying over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the title compound (15.0 g, 93%) was obtained.
85.8%
Preparation B-11; A. 2-Chloro-4-(chloromethyl)pyridine; Boron trifluoride diethyl etherate (71 g, 0.5 mol) was added dropwise to a suspension of 2-chloroisonicotinic acid (20 g, 0.125 mol) and sodium borohydride (14.3 g, 0.376 mol) in THF (200 ml.) with stirring at -10-5 0C, then the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (100 ml_), and extracted with ethyl acetate (3 *200 ml_). The organic layers were combined, washed with brine (200 ml_), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1 IA) and afforded 2-chloro-4- (hydroxymethyl)pyridine (15.4 g, 85.8 % yield) as an oil.
60%
(2-Chloro-pyridin-4-yl)-methanol:; To a stirred solution of 2-chloroisonicotinic acid (3.15 g, 20 mmol) in anhydrous THF (40 ml) cooled in an ice bath, was added borane-methyl sulfide complex (6 mL, 60 mmol). After 1 hr, the mixture was stirred for 48 hr at room temperature. The mixture was cooled in an ice bath and conc. HCl (30 ml) was added and stirred for 30 min. The mixture was then basified by addition of 50% aqueous NaOH (30 ml). The product was extracted with dichloromethane, dried with anhydrous potassium carbonate, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (5:1)) to afford 172 g (60%) of 2-chloro-4-pyridinemethanol as a white solid. m.p. 77-79 C.; 1H NMR (200 MHz, CDCl3) delta 2.97(1H, br. s), 4.74 (2H, s), 7.20 (1H, d, J=5.7 Hz), 7.36 (1H, s), 8.28 (1H, d, J=5.7 Hz).
60%
Example 4: Synthesis of (2-(2-(l H-indazol-4-yl)pyridin-4-yl)-l -fluoroethane-1 ,1 - diyl)diphosphonic acidStep 4a: Synthesis of (2-chloropyridin-4-yl)methanol2-Chl oroi son icot inic acid (2.0 g; 12.7 mmol) is dissolved in 25 mL THF under anhydrous conditions and borane (1.0 M in THF; 25.4 ml; 25.4 mmol) is added drop wise via a syringe. The solution is stirred overnight at 50 C. The mixture is cooled to R Gamma and quenched with 5 mL MeOH, concentrated under reduced pressure and purified by column chromatography on silica gel using a solvent gradient of hexanes to EtOAc. The final product is isolated as a white powder (1.1 g, 60% yield). NMR (300 MHz, CDC¾): delta 8.34 (d, J = 5.1 Hz, 1H), 7.36 (dq, J = 1.6, 0.8 Hz, 1H), 7.22 - 7.19 (m, lH). 4.75 (s, 2H).
With hydrogenchloride; sodium borohydrid; In tetrahydrofuran;
Reference Example 71 4-Carboxy-2-chloropyridine (78.7 g) is added slowly to a suspension of sodium borohydride (28.4 g) in tetrahydrofuran (750 ml) under nitrogen atmosphere, and thereto is added dropwise boron trifluoride-ether complex (123 ml). The mixture is reacted at room temperature for six hours. To the mixture is added a 6 M hydrochloric acid (960 ml), and the mixture is concentrated under reduced pressure to remove the solvent. The resultant is basified with sodium hydroxide, and extracted with chloroform. The chloroform layer is washed with a saturated aqueous sodium hydrogen carbonate solution, dried and concentrated under reduced pressure to remove the solvent to give 2-chloro-4-hydroxymethylpyridine (62.2 g). M.p. 63-65 C.
With dimethylsulfide borane complex; In tetrahydrofuran; at 20℃; for 17h;
Stage a): 2-Chloro-4-hydroxymethylpyridine 78.78 g of 2-chloroisonicotinic acid are added, under argon, portionwise, to 300 mL of a 2M solution of dimethyl sulphide-borane in tetrahydrofuran. The reaction mixture is stirred for 17 hours at room temperature and then treated successively with 20 mL of water dropwise and 20 mL of 5N hydrochloric acid. 300 mL of ethyl acetate are then added, the phases are separated and the organic phase is washed with three times 100 mL of saturated sodium chloride solution, dried over magnesium sulphate and filtered. The filtrate is then concentrated under reduced pressure to give 68.6 g of 2-chloro-4-hydroxymethylpyridine in the form of a pale yellow solid. Rf: silica TLC=0.38 (eluent: dichloromethane/methanol 90/10 by volume).
With dimethylsulfide borane complex; In tetrahydrofuran; at 20℃;Cooling with ice;
To an ice-cold solution of 2-chloroisonicotinic acid (1.1 g) in tetrahydrofuran (10 mL) was added borane-dimethyl sulfide complex (1.0 mL), and the mixture was stirred at room temperature overnight. The reaction solution was cooled with ice, and thereto was added methanol, and the mixture was concentrated under reduced pressure. The residue was diluted with brine, extracted with ethyl acetate, dehydrated with sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to give Compound II (4.18 g).
With borane-THF; In tetrahydrofuran; at 20℃; for 12h;
[01122] BH3.THF (190 mL, 2.21 mol, 2.99 equiv) was added dropwise into a solution of 2- chloropyridine-4-carboxylic acid (10 g, 63.47 mmol, 1.00 equiv) in tetrahydrofuran (200 mL) at 0C. After being stirred for 12 h at room temperature the reaction was quenched by methanol and concentrated under vacuum. The residue was purified by a silica gel colunm eluting with dichloromethane/ethyl acetate (50/1) to afford the title compound (11.9 g, crude) as brown oil. LCMS [M+H] 144.
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 12h;
BH3 THF solution (190 mL, 2.21 mol, 2.99 equiv) was added dropwise into a solution of 2- chloropyridine-4-carboxylic acid (10 g, 63.47 mmol, 1.00 equiv) in tetrahydrofuran (200 mL) at 0 C. After stirring for 12 h at room temperature, the reaction was quenched by methanol and concentrated under vacuum. The residue was purified by a silica gel column eluting with dichloromethane/ethyl acetate (50/1) to afford the title compound (11.9 g, crude) as brown oil. LCMS [M+H+] 144.
II 2-Chloropyridine-4-carbonyl chloride
EXAMPLE II 2-Chloropyridine-4-carbonyl chloride A mixture of pyridine-4-carboxylic acid-N-oxide (28 g) and phosphorous oxychloride (120 g) was heated at reflux for 7 hours. The reaction mixture was cooled and poured into ice-water (500 mL). The precipitate was collected and crystallized from a large volume of ethyl acetate and gave 23.1 grams of 2-chloropyridine-4-carboxylic acid as a white granular solid having a melting point of 225°-227° C. A solution of 2-chloropyridine-4-carboxylic acid (10 g) in thionyl chloride (90 mL) was heated under reflux for 20 hours. The excess thionyl chloride was removed by distillation at atmospheric pressure and the oily residue was distilled to give 9.26 grams of 2-chloropyridine-4-carbonyl chloride having a boiling point of 144°-148° C.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In water; N,N-dimethyl-formamide at 20℃; for 17h;
47.A
To a solution of 2-chloroisonicotinic acid (2.00 g) in DMF (20 mL) were added aqueous 50 % Me2NH (1.37 mL), Et3N (4.42 mL), EDC-HCl (2.92 g), and HOBt-H2O (2.92 g). The mixture was stirred at ambient temperature for 17 h and added to H2O (100 mL). The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, filtrated, and concentrated under reduced pressure. The residue was diluted with EtOAc and the solution was washed with H2O and brine two times. The aqueous layer was extracted with mixture of EtOAc and CHC I3 five times. The combined organic layer was dried over MgSO4, filtrated, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (silica gel, 20% to 99% EtOAc in hexane) to give 2-chloro-N,N-dimethylisonicotinamide (2.04 g) as a pale yellow oil. 1HNMR (300 MHz, CDCl3, δ): 2.96 (s, 3H), 3.12 (s, 3H), 7.23 (dd, J= 5.1, 1.3 Hz, IH), 7.34-7.35 (m, IH), 8.47 (dd, J= 5.0, 0.8 Hz, IH); ESI MS m/z 185 (M++l, 45%), 207 (M++23, 100%).
To a solution of 2-chloroisonicotinic acid (2.0 g, 0.0 12 mole) in DMF (5 mL)under N2 at 25 C, was added sodium hydride (0.73 g, 0.0 15 mole) and stirred for 0.5hour. Methyl iodide (1.5 mL, 0.025 mole) was added at RT and the reaction mixturewas warmed to 50 C for 2 hours. The reaction mixture was dissolved in ice water (50mL) and extracted with ethyl acetate (50 mL x 3). Organic layer was washed with brine solution (50 mL) and dried over Na2SO4. The organic phase was concentrated under vacuum to obtain methyl 2-chloroisonicotinate. Yield: 2.1 g (100 %); Mass (mlz): 172.0 (M+H) , 174.0 (M+H) .
87%
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 20h;
Step 1: A mixture of 2-chloro-isonicotinic acid (4.0 g, 25.4 mmol), sodium bicarbonate (5.33 g, 63.48 mmol) and iodomethane (9.7 mL, 156.0 mmol) in N,N dimethyl formamide (60 mL) is stirred at room temperature for 20 hours. The mixture is poured into water and extracted with ether. The organic layer is washed with brine, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate provides an oil which solidifies on standing to yield 3.8 g (87%) of 2-chloro-isonicotinic acid methyl ester as a white solid. MS 172.0 [M+H].
A solution of 10.0 g (63.4 mmol) 2-chloro-isonicotinic acid in 100 ml chloroform is heated to reflux temperature. In total 91.2 ml (380 mmol, 6 eq) N,N-dimethylformamide di-tert-butylacetal is added in 3 portions of each 30.4 ml at the start, after 1 h and after 2 h. After cooling to rt the mixture is diluted with EtOAc, washed with aq. bicarbonate and brine, and dried over sodium sulfate. The residue is purified by chromatography on silica (flashmaster, hexane to hexane/EtOAc 95/5) to give 7.6 g (35.6 mmol, 56percent) of the product as white solid.MS (LC/MS): 158=[M+H-tBu]+ 1H-NMR (300 MHz, CDCl3): 8.55 (d, 1H), 7.85 (s, 1H), 7.76 (d, 1H), 1.64 (s, 9H).
33%
In toluene; at 90℃; for 20.0h;
a) To a solution of 2-chloroisonicotinic acid (5.00 g, 31.7 mmol) in toluene is added N,Ndimethylformamide di-tert. butylacetal (17.9 g, 79.3 mmol). The mixture is stirred at 90°C for 20 h. The mixture is concentrated, filtered and the filtrate is diluted with EA and washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting heptane:EA 5:1 to give tert. butyl 2-chloroisonicotinate (2.23 g, 33percent) as a colourless oil; LC-MS: tR = 0.98 mm, [M+1+CH3CN] = 255.31.
24. 1 -(2-Chloroisonicotinoyl)-3,3-dimethylpiperidin-4-one; To a solution of 3,3-dimethylpiperidin-4-one HCl salt (7.3g, 45 mmol) in DMA (100 mL) is added TEA (24.9 mL, 180 mmol). After 5 min of stirring, 2-chloro- <n="65"/>isonicotinic acid (7.80 g, 49.5 mmol) and BOP (29.8 g, 67.5 mmol) are added. The mixture is stirred at 4O0C overnight. The reaction is cooled to rt, diluted with EtOAc, washed with 50% saturated Na2CO3, water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (hexane : EtOAc = 1:1) to afford the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) delta: 8.51 (d, IH), 7.38 (s, IH), 7.25 (d, IH), 4.03 (t, IH), 3.77 (s, IH), 3.64 (t, IH), 3.36 (s, IH), 2.65 (t, IH), 2.51 (t, IH), 1.23 (s, 3H), 1.05 (s, 3H). MS: 267.08 (M+H).
1-(2-chloropyridin-4-yl)carbonylspiro[indoline-3,4'-piperidine]-1'-caroxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
Thionyl chloride (20 ml) was added to 2-chloroisonicotinic acid (1.2 g) at room temperature. DMF (2 drops) was added and the mixture was heated to reflux for 1 hour. The excess thionyl chloride was evaporated and the residue was dissolved in dichloromethane (50 ml). Triethylamine (2 ml) was added followed by dropwise addition of a solution of spiro [indoline- 3, [4'-PIPERIDINE]-1'-CARBOXYLIC] acid tert-butyl ester (1.7 g) dissolved in dichloromethane (20 ml). The mixture was stirred for 48 hours. The reaction mixture was washed with pH 9.4 buffer (100 ml) and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate), filtered and evaporated. The crude product was purified by chromatography [[SI02] ; ethyl acetate-hexane-triethylamine (50: 50: 1), increasing polarity to (100: 0: 1) ] to give 2.4 g (94%) of the desired amide. M. p. [212 C ;'H] NMR (400 MHz, d6- DMSO) 1.50 (s, 9H), 1.6-1. 8 [(M,] 4H), 2.8 (br s, 2H), 3.9 (br s, 2H), 4.08 (d, 2H), 7.0-7. 2 (m, 3H), 7.30 (d, J = 6Hz, [1H),] 8.43 (d, J = 6Hz, [1H),] 7.40 (s, [1H),] 8.0-8. 2 (br [M, 1H)] ; MS (ES+) 428/430 [(M+H+),] 372/374 (M+H+-isobutene).
To a solution of 2-chloro-pyridine-4-carboxylic acid (2.55 g, 16.2 mmol) in dioxane (50 mL), Pd(dppf) (132 mg, 0.162 mmol) is added. The mixture is stirred under argon at rt and isobutyl zinbromide (6.55 g, 32.4 mmol, 65 mL of a 0.5 M solution in <n="37"/>THF) is added dropwise. The mixture is stirred at rt for 1 h, then at 100C for 16 h. The mixture is cooled to rt and diluted with EA (250 ml_) and cold water (0C). The mixture is acidified by adding aq. 25% HCI. The org. phase is separated and the aq. phase is extracted with EA (4x50 ml_) followed by DCM (6x50 ml_). The combined org. extracts are concentrated and dried. The crude product is purified by MPLC on silica gel to give the title compound (2.0 g) in form of a pale yellow oil. LC-MS: tR = 0.47 min, [M+1]+ = 180.09. 1H NMR (CD3OD): £1.03 (d, J = 6.8 Hz, 6 H), 2.12-2.24 (m, 1 H), 3.00 (d, J = 7.3 Hz, 2 H), 8.29 (dd, J = 5.8, 1.5 Hz, 1 H), 8.34 (s, 1 H), 8.88 (d, J = 5.8 Hz, 1 H).
Pd(dppf); In tetrahydrofuran; 1,4-dioxane; at 20 - 100℃; for 17h;Inert atmosphere;
2-Isobutyl-isonicotinic acid To a solution of 2-chloro-pyridine-4-carboxylic acid (2.55 g, 16.2 mmol) in dioxane (50 mL), Pd(dppf) (132 mg, 0.162 mmol) is added. The mixture is stirred under argon at rt and isobutyl zinbromide (6.55 g, 32.4 mmol, 65 mL of a 0.5 M solution in THF) is added dropwise. The mixture is stirred at rt for 1 h, then at 100 C. for 16 h. The mixture is cooled to rt and diluted with EA (250 mL) and cold water (0 C.). The mixture is acidified by adding aq. 25% HCl. The org. phase is separated and the aq. phase is extracted with EA (4×50 mL) followed by DCM (6×50 mL). The combined org. extracts are concentrated and dried. The crude product is purified by MPLC on silica gel to give the title compound (2.0 g) in form of a pale yellow oil. LC- MS: tR=0.47 min, [M+1]+=180.09. 1H NMR (CD3OD): delta 1.03 (d, J=6.8 Hz, 6H), 2.12-2.24 (m, 1H), 3.00 (d, J=7.3 Hz, 2H), 8.29 (dd, J=5.8, 1.5 Hz, 1H), 8.34 (s, 1H), 8.88 (d, J=5.8 Hz, 1H).
1-(tert-butyloxycarbonyl)-6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine][ No CAS ]
6-chloro-4-aza-1-(2-chloropyridin-4-yl)-carbonyl-1'-carboxylic acid tert-butylester spiro-[indoline-3,4'-piperidine][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
A mixture of 2-chloro-isonicotinic acid (324 mg), thionyl chloride (0.43 ml), DMF (trace) in toluene (6.4 ml) was heated to reflux for 2 hrs. After concentration in vacuo, the residue was dissolved in 2 ml dichloromethane and added dropwise at 0C under nitrogen to a mixture of 6-chloro-4-aza-spiro [indoline-3, 4'-piperidine]-1'-carboxylic acid tert-butylester, (220 mg), triethylamine (0.6 ml) and dichloromethane ((20 mol). The mixture was stirred at room temperature for 1 hr. The mixture was diluted in a saturated sodium carbonate solution. The organic layer was separated and the aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with saturated sodium bicarbonate, dried (magnesium sulfate), filtered and concentrated in vacuo 473 mg (102%) of 6-chloro-4-aza-1- (2-chloropyridin-4-yl-) carbonyl-1'-carboxylic acid tert-butylester spiro [indoline-3, 4'- piperidine] ; MS (ES+) 407 (M-Me2C=CH2+H+).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere;
<strong>[6313-54-8]2-Chloroisonicotinic acid</strong> (200 mg, 1.26 mmol), N,N-diethylethylenediamine (0.2 mL, 30 1.39 mmol), HOBT (257 mg, 1.90 mmol) and EDCI (365 mg, 1.90 mmol) were dissolved in dry DMF (Aldrich anhydrous, 2 mL) under N2. Diisopropylethylamine (0.49 mL, 2.83 mmol) was added to the mixture and the reaction stirred o/n at RT. Following complete consumption of the acid by TLC the reaction was diluted with H2O (2OmL) and extracted with DCM (3 x 2OmL). The organics were combined, washed with water (4 x 20 mL), dried over MgSO4, filtered and evaporated to a crude oil, from which the title compound was purified by silica gel column chromatography using EtOAc-MeOH-NH3 (5-1 -trace) as the mobile phase as a clear oil (210 mg, 65 %). 1H NMR (CDCl3, 400 MHz) delta: 8.48 (d, J = 5.2 Hz, IH, Ar-H-6), 7.64 (s, IH, Ar-H-3), 7.49 (dd, J = 5.2, 1.6 Hz, IH, Ar-H-5), s 7.07 (bs, IH, NH), 3.40 (q, J = 5.6 Hz, 2H, CONH-CH2-CH2), 2.64 (t, J = 5.6 Hz, 2H, CONH-CH2-CH2), 2.58 (q, J = 6.8 Hz, 4H,N-(CH2-CH3)2), 1.03 (t, J = 6.8 Hz, 6H, N- (CH2-CH3)2). 13C NMR (CDCl3, 100 MHz) delta: 163.8 (CONH), 152.4 (Ar-CH-Cl), 150.3 (Ar-CH-6), 144.8 (Ar-CH-CONH), 122.1 (Ar-CH-3), 119.5 (Ar-CH-5), 50.5 (CONH- CH2-CH2), 46.7 (N-(CH2-CH3)2), 37.2 (CONH-CH2-CH2), 11.7 (N-(CH2-CH3)2). o LRMS ES(+) 258.1 (21 %), 256 (64 %, M+H+), 185 (32 %), 183 (100 %).
34
Reference Example 34; 2-(Pyrrolidin-1-yl)isonicotinic acidA solution of 2-chloroisonicotinic acid (0.25 g, 1.58 mmol) in pyrrolidine (1.5 mL) was heated at 80° C. overnight. The solvent was evaporated, water and CHCl3 were added and the phases were separated. The pH of the aqueous phase was adjusted to 5, precipitating a solid that was filtered and washed with water and CHCl3. After drying the product under vacuum, 95 mg of the title compound were obtained (yield: 31%).LC-MS (method 1): tR=1.14 min; m/z=193.1 [M+H]+.
Preparation 29 4-Chloro-3H-furo[3,4-c]pyridine-1-one A solution of 2,2,6,6-tetramethyl-piperidine (4.05 ml, 24 mmol) in a 100 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 20 ml of dry THF is added. The reaction mixture is cooled to -50 C. by adding a controlled amount of dry ice to an acetone bath. The cooled reaction mixture is treated dropwise with nBuLi solution (8.8 mL of a 2.5 M solution in hexanes, 22 mmol) and the reaction is let stir at -50 C. for 0.5 h. Solid 2-chloro-isonicotinic acid, (1.58 g, 10 mmol) is added as a solid to the reaction mixture at -50 C. The reaction is stirred at -50 C. for 0.5 h. The reaction mixture is treated with paraformaldehyde (7 equivalents) dropwise at -50 C. The reaction is stirred at -50 C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated to remove solvent and water and ether are added. The aqueous layer is extracted with ether (6*50 ml). The aqueous phase is treated with aqueous 1N HCl solution, until, the pH of aqueous layer is ~5 and is then extracted with ether (2*40 mL) The aqueous solution is treated with aqueous 1N HCl solution until the pH ~2. An oily residue separated which from solution is collected to give the title compound as a yellow oil (0.62 g, 36%).
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;
Reference Production Example 14 To a mixture of 0.71 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 0.63 g of 2-chloroisonicotinic acid and 7 ml of pyridine, 1.05 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.77 g of 2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide. [Show Image] 1H-NMR (DMSO-d6) delta: 10.12 (br s, 1H), 8.62 (d, J=5.1 Hz, 1H), 8.03-7.97 (m, 2H), 7.87 (dd, J=5.2, 1.3 Hz, 1H), 7.46-7.43 (m, 1H), 7.10 (d, J=8.2 Hz, 1H)
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;
Reference Production Example 14To a mixture of 0.71 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 0.63 g of 2-chloroisonicotinic acid and 7 ml of pyridine, 1.05 g of WSC was added and stirred while heating at 60 C. for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.77 g of 2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 10.12 (br s, 1H), 8.62 (d, J=5.1 Hz, 1H), 8.03-7.97 (m, 2H), 7.87 (dd, J=5.2, 1.3 Hz, 1H), 7.46-7.43 (m, 1H), 7.10 (d, J=8.2 Hz, 1H)
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In pyridine; at 60℃; for 4h;
Reference Production Example 14To a mixture of 0.71 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 0.63 g of 2- chloroisonicotinic acid and 7 ml of pyridine, 1.05 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.77 g of 2-chloro-N-[2-hydroxy-5- (trifluoromethyl)phenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 10.12 (br s, IH), 8.62 (d, J=5.1 Hz, IH), 8.03-7.97 (m, 2H), 7.87 (dd, 5=5.2, 1.3 Hz, IH), 7.46-7.43 (m, IH), 7.10 (d, J=8.2 Hz, IH)
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;
To a mixture of 0.71 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 0.63 g of 2- chloroisonicotinic acid and 7 ml of pyridine, 1.05 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.77 g of 2-chloro-N-[2-hydroxy-5- (trifluoromethyl)phenyl]isonicotinamide.1 H-NMR (DMSO-d6) delta: 10.12 (br s, IH), 8.62 (d, J=5.1 Hz, IH), 8.03-7.97 (m, 2H), 7.87 (dd, J=5.2, 1.3 Hz, IH), 7.46-7.43 (m, IH), 7.10 (d, J=8.2 Hz, IH)
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;
To a mixture of 0.71 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 0.63 g of 2- chloroisonicotinic acid and 7 ml of pyridine, 1.05 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.77 g of 2-chloro-N-[2-hydroxy-5- (trifluoromethyl)phenyl]isonicotinamide.-NMR (DMSO-d6) delta: 10.12 (br s, IH), 8.62 (d, J=5.1 Hz, IH), 8.03-7.97 (m, 2H), 7.87 (dd, J=5.2, 1.3 Hz, IH), 7.46-7.43 (m, IH), 7.10 (d, J=8.2 Hz, IH)
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;
Reference Production Example 14To a mixture of 0.71 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 0.63 g of 2- chloroisonicotinic acid and 7 ml of pyridine, 1.05 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.77 g of 2-chloro-N-[2-hydroxy-5- (trifluoromethyl)phenyl]isonicotinamide.1 H-NMR (DMSO-d6) delta: 10.12 (br s, IH), 8.62 (d, J=5.1 Hz, IH), 8.03-7.97 (m, 2H), 7.87 (dd, J=5.2, 1.3 Hz, IH), 7.46-7.43 (m, IH), 7.10 (d, J=8.2 Hz, IH)
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;
Reference Production Example 14To a mixture of 0.71 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 0.63 g of 2- chloroisonicotinic acid and 7 ml of pyridine, 1.05 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.77 g of 2-chloro-N-[2-hydroxy-5- (trifluoromethyl)phenyl] isonicotinamide .-NMR (DMSO-d6) delta: 10.12 (br s, IH), 8.62 (d, J=5.1 Hz, IH), 8.03-7.97 (m, 2H), 7.87 (dd, J=5.2, 1.3 Hz, IH), 7.46-7.43 (m, IH), 7.10 (d, J=8.2 Hz, IH)
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃;
(2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone 0.50 g (3.2 mmol) <strong>[6313-54-8]2-chloroisonicotinic acid,</strong> 0.63 mg (3.3 mmol) 4,5-difluoroindoline-hydrochloride, 0.91 mL (6.5 mmol) TEA and 1.1 g (3.4 mmol) TBTU in 10 mL DMF were stirred overnight at RT. Then the reaction mixture was poured onto 200 mL of 15% potassium carbonate solution, the precipitate formed was suction filtered, washed with water and dried. Yield: 0.90 g (96% of theory) ESI-MS: m/z=295 (M+H)+ Rt (HPLC-MS): 3.80 min (method E)
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;
To a solution of 2-isonicotinic acid (1.0 g, 6.3 mmol) in DMF (20 mL) was added diisopropylethylamine (5.0 mL, 25 mmol), HATU (2.6 g, 6.9 mmol) followed by the above aniline (1.3 g, 5.8 mmol). The reaction was stirred at room temperature for 18 h then diluted with ethyl acetate. The organic layer was washed with aqueous 1% LiCI solution, dried over sodium sulfate, filtered and concentrated to dryness without any further purification to afford te/t-butyl (3-[(2-chloropyridin-4yl)carbonyl]amino}benzyl)carbamate.
Preparation 13. <strong>[6313-54-8]2-Chloroisonicotinic acid</strong>, 2,2-dimethyl-propyl ester. <strong>[6313-54-8]2-Chloroisonicotinic acid</strong> (2.0 g, 13 mmol) was suspended in 50 mL dry CH2Cl2 and treated with oxalyl chloride (3.5 mL, 5.0 g, 39 mmol) plus 3 drops DMF. The mixture was stirred for 4 h, the volatiles removed in vacuo and the residue taken up in 50 mL CH2Cl2. After cooling to 0 C. and treating with neopentyl alcohol (1.7 ml, 1.4 g, 16 mmol), Et3N (2.5 mL, 1.8 g, 18 mmol) was added in portions. The mixture was warmed to 25 C., stirred for 15 h, washed sequentially with 15 mL H2O, 15 mL saturated aqueous NaHCO3, and 15 mL brine, then dried (Na2SO4), filtered, and concentrated in vacuo to give 2.4 g (80%) of <strong>[6313-54-8]2-chloroisonicotinic acid,</strong> 2,2-dimethyl-propyl ester as an oil, used without additional purification: 1H NMR (300 MHz, CDCl3) delta 8.56 (d, J=5.6 Hz, 1H), 7.88 (s, 1H), 7.78 (d J=5.0 Hz, 1H), 4.06 (s, 2H), 1.05 (s, 9H).
Step 1: 6-(2-chloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one 2.80 mL (38.1 mmol) thionyl chloride and 0.50 mL DMF were added to 2.10 g (12.9 mmol) 2-chloroisonicotinic acid in 30.0 mL DCM and the mixture was refluxed for 2 h. The reaction mixture was evaporated to dryness and coevaporated twice with toluene. The residue was combined with 8.00 g (60.0 mmol) aluminium trichloride and 1.79 g (12.0 mmol) 4-methyl-3H-benzoxazol-2-one and stirred overnight at 130 C. The mixture was decomposed with ice water and extracted twice with EtOAc. The organic phases were combined, dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was triturated with DIPE and isopropanol, suction filtered and dried. Yield: 1.70 g (46% of theoretical) ESI-MS: m/z=287/289 (Cl) (M-H)-
Step C: To a suspension of 2-chloro-isonicotinic acid (56 g) in toluene (1500 ml) and Lambda/,Lambda/-dimethylformamide (0.5 ml) under a nitrogen atmosphere at ambient temperature, was added dropwise thionyl chloride (81 ml) and the mixture was stirred at 600C until the all the solids dissolved (3 hours). The solution was concentrated in vacuo and the residue was dissolved in tetrahydrofuran (300 ml). This solution was added dropwise into a solution of the product obtained in Step B (103 g) in tetrahydrofuran (3000 ml) and vV,jV-diisopropyl- ethylamine (155 ml) at ambient temperature. The reaction mixture was stirred for 3 hours at ambient temperature, quenched by addition of aqueous sodium hydrogen carbonate(saturated) (1000 ml) and extracted with ethyl acetate (3x 500 ml). The combined organic extracts were washed with water (3x 500 ml) then brine (200 ml), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether, the solid isolated by filtration and dried under high vacuum to afford 4-{2-[(2-chloro-pyridine-4-carbonyl)-amino]- 5-trifluoromethyl-phenyl}-piperidine-l-carboxylic acid tert-bvLambday ester (143 g) as a white powder. MS (ES+) 384 / 386 (MH+-BOC), 428 / 430 (MH+-isobutene), 484 / 486 (MH+); IH NMR (400 MHz, CDCl3) 1.5 (s, 9H), 1.7 (m, 2H), 1.85 (m, 2H), 2.8 (m, 3H), 4.3 (m, 2H), 7.6 (m, 2H), 7.65 (d, IH), 7.70 (d, IH), 7.80 (s, IH), 8.0 (s, IH), 8.6 (d, IH).
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃;
(2-chloropyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanone 174 mg (1.27 mmol) 5-fluoro-2,3-dihydro-1H-indole were added to 198 mg (1.26 mmol) <strong>[6313-54-8]2-chloroisonicotinic acid,</strong> 351 muL (2.50 mmol) triethylamine and 434 mg (1.35 mmol) TBTU in 3 mL DMF. The reaction mixture was stirred overnight at RT. Purification was carried out by preparative HPLC. The product fractions were combined and evaporated down i. vac. Yield: 230 mg (66% of theory) ESI-MS: 277/279 (M+H)+
General procedure: A mixture of 11 (100 mg, 0.24 mmol), an acid (0.72 mmol), EDCI (125 mg, 0.78 mmol), HOBt (88 mg, 0.78 mmol), TEA (0.167 mL, 1.2 mmol) and DMF (4 mL) was stirred at ambient temperature under N2 protection for 24 h, the reaction was monitored by TLC (CH2Cl2:MeOH = 5:1), upon the completion of the coupling reaction, MeOH (5 mL), and K2CO3 (199 mg, 1.44 mmol) were added to the mixture and stirred at ambient temperature overnight. The mixture was then filtered through celite. The filtrate was concentrated to remove DMF and methanol. The residue was partitioned between CH2Cl2 (50 mL) and H2O (50 mL). The organic layer was separated and washed with H2O (50 mL x 3), dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was then purified by column chromatography (Silica Gel 15 g), eluented with CH2Cl2 (150 mL), CH2Cl2/MeOH (80:1, 160 mL), CH2Cl2/MeOH (60:1, 180 mL), CH2Cl2/MeOH (40:1, 160 mL),CH2Cl2/MeOH (20:1, 160 mL), CH2Cl2/MeOH (10:1, 200 mL) successively to afford the corresponding target compound as free base. Upon confirmation by 1H NMR and 13C NMR, the free base was then transformed into hydrochloride salt by soluting in MeOH (0.1 mL), adding HCl methanol solution (1.25 M, 0.3 mL) and stirred at ambient temperature for 30 min. Diethyl ether (10 mL) was then added and the precipitate formed was collected by filtration, dried in vacuum to give the target compound as hydrochloride salt.
Example A18a) Preparation of Intermediate 33; 2-Chloro-4-pyridinecarboxylic acid (0.0635 mol) was dissolved in THF (25 ml) and CH3CN (25 ml). 1,1'-Carbonylbis-1H-Imidazole (0.0698 mol) was added to the solution and stirred for 2.5 hours at room temperature to result in reaction mixture (A). Magnesium chloride (0.095 mol) and Et3N (0.1905 mol) were added to a solution of monoethyl ester propanedioic acid, potassium salt (0.0667 mol) in CH3CN (50 ml) while ice-cooling. The reaction mixture was stirred for 5 hours at room temperature. Then reaction mixture (A) was added to the reaction mixture and stirred for 15 hours at room temperature. The mixture was poured in ice-water. This mixture was acidified with HCl (concentrated) to pH=5 to pH=6. This mixture was extracted with EtOAc. The separated organic layer was dried (Na2SO4), filtered and the solvent was evaporated. The residue was purified by column chromatography. The product fractions were collected and the solvent was evaporated, yielding 10 g (69%) of intermediate 33.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; lithium hydroxide; In 1,4-dioxane; water; at 80℃; for 0.5h;Inert atmosphere;
General procedure: To a solution of 2-chloroheteroaryl compound 1 (0.50 mmol) in 1,4-dioxane (4.0 mL) were added pinacol boronate 3, 5, or 7 (0.60 mmol), Pd(OAc)2 (1.1 mg, 5.0 mumol), S-Phos (4.1 mg, 10.0 mumol), and 2 M LiOH solution (1.0 mL, 2.0 mmol) at room temperature, and the mixture was stirred for 30 min at 80 C under N2 atmosphere. The reaction was quenched by adding water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by silica-gel column chromatography. The solvent was removed in vacuo, and the residue was triturated with Et2O to give biaryl compounds.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
General procedure: Compound 3 (1 mmol) and amine compounds (1.2 mmol) and HATU (1.2 mmol) or EDCI (1.2 mmol) and HOBt (1.2 mmol) were added to DCM (10 mL) containing Et3N (0.5 mmol); the mixture was then stirred at room temperature for 6-12 h. After the reaction was completed, the mixture was poured onto 100 mL of distilled water and partitioned with ethyl acetate (3 × 50 mL). The target compounds were purified on a flash column with chloroform/methanol (20:1, v/v) to yield compounds 4a-4w. The structures were confirmed by IR, ESI-MS, 1H NMR and 13C NMR (see Supporting information).
A mixture of 3-fluorobenzene-l,2-diamine (0.50 g, 3.96 mmol), 2- chloroisonicotinic acid (0.63 g, 4.00 mmol) and PPA (5 mL) was heated to 160 C and allowed to stir at this temperature for 3 hours. The reaction mixture was added to water and basified with NaOH until pH ~7. The solution was extracted with EtOAc, the organic extract was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with PE : EtOAc = 1 : 1) to provide 2-(2-chloropyridin-4- yl)-7-fluoro-lH- benzo[d]imidazole (600 mg, yield: 61%). 1H-NMR (CDC13, 400 MHz) delta 8.56 (d, / = 5.2 Hz, 1H), 8.01 (s, 1H), 7.86-7.88 (m, 1H), 7.42-7.46 (br s, 1H), 7.27-7.32 (m, 1H), 7.04-7.09 (m, 1H), 6.52-6.65 (m, 1H).
61%
With PPA; at 160℃; for 3h;
A mixture of 3-fluorobenzene-l,2-diamine (0.50 g, 3.96 mmol), 2- chloroisonicotinic acid (0.63 g, 4.00 mmol) and PPA (5 mL) was heated to 160 C and allowed to stir at this temperature for 3 hours. The reaction mixture was added to water and basified with NaOH until pH ~7. The solution was extracted with EtOAc, the organic extract was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with PE : EtOAc = 1 : 1) to provide 2-(2-chloropyridin-4- yl)-7-fluoro-lH- benzo[d]imidazole (600 mg, yield: 61%). 1H-NMR (CDC13, 400 MHz) delta 8.56 (d, / = 5.2 Hz, 1H), 8.01 (s, 1H), 7.86-7.88 (m, 1H), 7.42-7.46 (br s, 1H), 7.27-7.32 (m, 1H), 7.04-7.09 (m, 1H), 6.52-6.65 (m, 1H).
61%
With PPA; at 160℃; for 3h;
Step 1-Synthesis of 2-(2-chloropyridin-4-yl)-7-fluoro-1H-benzo[d]imidazole A mixture of 3-fluorobenzene-1,2-diamine (0.50 g, 3.96 mmol), 2-chloroisonicotinic acid (0.63 g, 4.00 mmol) and PPA (5 mL) was heated to 160 C. and allowed to stir at this temperature for 3 hours. The reaction mixture was added to water and basified with NaOH until pH?7. The solution was extracted with EtOAc, the organic extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with PE:EtOAc=1:1) to provide 2-(2-chloropyridin-4-yl)-7-fluoro-1H-benzo[d]imidazole (600 mg, yield: 61%). 1H-NMR (CDCl3, 400 MHz) delta 8.56 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.86?7.88 (m, 1H), 7.42?7.46 (br s, 1H), 7.27?7.32 (m, 1H), 7.04?7.09 (m, 1H), 6.52?6.65 (m, 1H).
General procedure: To 6-chloronicotinic acid 19a (10 g) in methylene chloride(100 ml) solution, N,N?-diisopropyl-O-tert-butylisourea (50 g) wasadded and the mixture was stirred under heating and reflux for16 h. The insoluble compound was filtered out, and the filtratewas concentrated. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate = 6/1) to obtain the compound 20a (11.66 g). To the compound 20a (6.0 g) in dimethylacetoamide (30 ml) solution, tris(dibenzylideneacetone)dipalladium (0.51 g), zinc cyanide (0.22 g), diphenylphosphinoferrocene (0.62 g), and zinc powder (1.98 g) were added and the mixture was stirred under argon atmosphere at 120 °C for 3 h. The reaction solution was filtered by sellite, which was then washed with ethyl acetate. Then, the filtrate was washed with distilled water and saturated saline, then the organic layer was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate= 5/1) to obtain the compound 21a (3.59 g). To copper(I) iodide(0.93 g) in tetrahydrofuran (50 ml) suspension, ethylmagnesium bromide (0.86 M tetrahydrofuran solution)(12.5 ml) was added dropwise under cooling at 0 °C, the mixture was stirred at 0 °C for 30 min, then the compound 21a (1.0 g) obtained above in tetrahydrofuran (10 ml) solution was added atthe 20 °C. After stirring for 30 min at that temperature, 28percent ammonia solution in water and ethyl acetate were added to the mixture and the solution separated. The aqueous layer was extracted with ethyl acetate, while the combined organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate= 8/1) to obtained the compound 22a (0.47 g). To the compound 22a (200 mg) in tetrahydrofuran (1 ml) solution, (-)-B-chlorodiisopinocampheylborane (65percent hexane solution) (0.92 ml) was added dropwise under cooling at 20 °C, then the mixture was stirred at that temperature for 18 h. Then, ether and distilled water were added to the reaction mixture, and the solution was separated. The organic layer was extracted with distilled water and 1 M hydrogen chloride. Then, the combined aqueous layer was neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. Organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated to obtained the title compound (150 mg, 84percent ee). The optical purity was determined using CHIRALCEL AD-H(Daicel Chemical Industries) (movement phase: hexane/ethanol= 98/2, 1.0 ml/min).
With water; potassium hydroxide; at 0℃; for 36h;Reflux;
To a stirred solution of 2-chloroisonicotinic acid (15 g, 1.0 eq) in 200 mL water at 0 C was added KOH (40 g, 7.5 eq). Then the reaction mixture was heated to reflux for 36 h., cooled, and 3 N HCl (aq) was added to pH = 1~3. The precipitate was collected by filtration and washed with water to give the product as a white solid (13.1 g, 99% yield). :H NMR (400 MHz, DMSO-c ) delta 12.80 (brs, 2H), 7.47 (d, J= 6.4 Hz, 1H), 6.79 (s, 1H), 6.50 (dd, J= 6.8 Hz, 1.6 Hz, 1H).
With sodium hydroxide; In dichloromethane; water; at 0 - 20℃; for 18h;Cooling with ice; Inert atmosphere;
2-chloro-isonicotinic acid (2.0 g, 12.7 mmoles, 1 eq.) was placed in acetonitrile (25.4 mL) under an inert atmosphere of argon. Thionyl chloride (1.2 mL, 16.5 mmoles, 1.3 eq.) and DMF (100 muL, 1.27 mmole, 0.1 eq.) were slowly added. The reaction mixture was heated at reflux and stirred for 1 hour. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. N,N-Diethylpropylenediamine (2.5 mL, 15.7 mmoles, 1.2 eq.) was placed in a 3N NaOH aqueous solution (20 mL) and dichloromethane (10 mL) was added to the solution. The reaction mixture was cooled down to 0C with an ice bath and a solution of the 2-chloro-isonicotinoyl chloride residue (12.7 mmoles, 1 eq.) in dichloromethane (13 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an inert atmosphere of argon. Upon decantation, the organic phase was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-chloro-N-(3-diethylaminopropyl)isonicotinamide (1.8 g, 47%). 1H NMR (300 MHz, CDCl3) delta 9.62 (s, 1H), 8.49 (d, J= 5.0 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 5.1 Hz, 1H), 3.59 (dd, J = 10.4, 5.0 Hz, 2H), 2.70 - 2.55 (m, 6H), 1.81 - 1.72 (m, 2H), 1.06 (t, J= 7.1 Hz, 6H).
PREPARATION 1 : 2-Hydrazin lpyridine-4-carboxylic acid [00163] To a solution of 2-chloropyridine-4-carboxylic acid (1.57 g, 100 mmol) in 1,4- dioxane (30 mL) was added hydrazine hydrate (1.0 g, 200 mmol) dropwise at rt. The reaction mixture was heated at 100 C overnight. The mixture was concentrated, and the residue was purified by flash column chromatography (CH2Cl2/MeOH = 20/1) to afford the title compound (650 mg, 42%) as a white solid. [M+H] Calc'd for C6H7N3O2, 154; Found, 154.
General procedure: <strong>[6313-54-8]2-Chloroisonicotinic acid</strong> (0.157g, 1mmol) and sodium ethoxide (0.068g, 1mmol) were added to a solution of methanol (30ml) in a Schlenk flask and stirred for 30min. Then dimethyltin dichloride (0.219g, 1mmol) was added and the reaction mixture was stirred for 12h at 40C. The solution was filtered and the solvent of the filtrate was gradually removed by evaporation under vacuum until a solid product was obtained. The solid was recrystallized from methanol and a transparent colorless crystal was formed. Yield: 0.235g (75%, based on Me2SnCl2). M.P. >250C. Anal. Calc. for C32H36Cl4N4O10Sn4: C, 30.67; H, 2.90; N, 4.47%. Found: C, 30.31; H, 3.27; N, 4.26%. IR (KBr, cm-1): vas(COO) 1647; vs(COO) 1455; nu(Sn-O-Sn) 634; nu(Sn-C) 568; nu(Sn-O) 476. 1H NMR (CDCl3, ppm) delta: 8.54, 7.80, 7.72 (12H, 4C5H3N), 0.94 (24H, 8CH3, 2JSn-H=8.8Hz). 13C NMR (CDCl3, ppm) delta: 170.1 (COO); 152.5, 150.6, 143.6, 124.5, 122.2 (C5H3N); 6.96 (Sn-CH3, 1JSn-C=398Hz). 119Sn NMR (CDCl3, ppm) delta: -166.3 (2J(119Sn-O-117/119Sn) 118Hz), -188.5 (2J(119Sn-O-117/119Sn) 118Hz).
65%
The procedure used was similar to that for complex 1, 2-chloroisonicotinic acid (0.157g, 1mmol), sodium ethoxide (0.068g, 1mmol) and diphenyltin dichloride (0.343g, 1mmol) were reacted for 12h at 40C. On recrystallization from diethyl ether, a transparent colorless crystal was formed. Yield: 0.239g (65%, based on Ph2SnCl2). M.P. >250C. Anal. Calc. for C60H48Cl2N2O8Sn4: C, 49.00; H, 3.29; N, 1.90%. Found: C, 48.67; H, 3.55; N, 1.71%. IR (KBr, cm-1): nuas(COO) 1648; nus(COO) 1399; nu(Sn-O-Sn) 639; nu(Sn-C) 559; nu(Sn-O) 463. 1H NMR (CDCl3, ppm) delta: 7.89, 7.65 7.54 (6H, 2C5H3N), 7.27-7.58 (m, 40H, 8C6H5). 13C NMR (CDCl3, ppm) delta: 172.1 (COO); 153.2, 150.1, 145.4, 127.9, 123.1 (C5H3N); 130.4-137.4 (C6H5). 119Sn NMR (CDCl3, ppm) delta: -92.8 (2J(119Sn-O-117/119Sn) 98Hz), -97.1 (2J(119Sn-O-117/119Sn) 98Hz).
General procedure: <strong>[6313-54-8]2-Chloroisonicotinic acid</strong> (0.157g, 1mmol) and sodium ethoxide (0.068g, 1mmol) were added to a solution of methanol (30ml) in a Schlenk flask and stirred for 30min. Then dimethyltin dichloride (0.219g, 1mmol) was added and the reaction mixture was stirred for 12h at 40C. The solution was filtered and the solvent of the filtrate was gradually removed by evaporation under vacuum until a solid product was obtained. The solid was recrystallized from methanol and a transparent colorless crystal was formed. Yield: 0.235g (75%, based on Me2SnCl2). M.P. >250C. Anal. Calc. for C32H36Cl4N4O10Sn4: C, 30.67; H, 2.90; N, 4.47%. Found: C, 30.31; H, 3.27; N, 4.26%. IR (KBr, cm-1): vas(COO) 1647; vs(COO) 1455; nu(Sn-O-Sn) 634; nu(Sn-C) 568; nu(Sn-O) 476. 1H NMR (CDCl3, ppm) delta: 8.54, 7.80, 7.72 (12H, 4C5H3N), 0.94 (24H, 8CH3, 2JSn-H=8.8Hz). 13C NMR (CDCl3, ppm) delta: 170.1 (COO); 152.5, 150.6, 143.6, 124.5, 122.2 (C5H3N); 6.96 (Sn-CH3, 1JSn-C=398Hz). 119Sn NMR (CDCl3, ppm) delta: -166.3 (2J(119Sn-O-117/119Sn) 118Hz), -188.5 (2J(119Sn-O-117/119Sn) 118Hz).
A) methyl 2-methoxyisonicotinate Under a nitrogen atmosphere, to a solution of 2-chloroisonicotinic acid (10.0 g) in DMF (150 mL) was added a 28% solution of sodium methoxide in methanol (38.6 mL), and the mixture was stirred at 130C for 14 hr. Iodomethane (15.9 mL) was added to the reaction mixture at 80C, and the mixture was stirred at 80C for 5 min. Water was added at 0C, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (8.57 g) as a pale-yellow oil.
(4-(but-3-en-1-yl)-2-methoxy-6-methylpyridin-3-yl)methanamine[ No CAS ]
N-((4-(but-3-en-1-yl)-2-methoxy-6-methylpyridin-3-yl)methyl)-2-chloroisonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;
a) N-((4-(but-3-en-l-yl)-2-methoxy-6-methylpyridin-3-yl)methyl)-2- chloroisonicotinamide To a mixture of 2-chloroisonicotinic acid (0.62 g, 3.94 mmol), (4-(but-3-en-l-yl)- 2-methoxy-6-methylpyridin-3-yl)methanamine (0.834 mL, 4.13 mmol), HO At (0.643 g, 4.72 mmol), and EDC (0.905 g, 4.72 mmol) in DMF (20 mL) was added N- methylmorpholine (1.731 mL, 15.74 mmol) and all solids slowly dissolved. The reaction was allowed to stir at room temperature overnight. The reaction was diluted into water (100 mL) with stirring and then partitioned with 20% EtOAc in Et20 (50 mL, 2x). The organics were combined and washed with brine, dried over MgS04, filtered and concentrated in vacuo to a residue which was purified via flash column chromatography (Isco, Rf, 40gram Gold silica, 5-60% EtOAc in heptane), to afford N-((4-(but-3-en-l-yl)- 2-methoxy-6-methylpyridin-3-yl)methyl)-2-chloroisonicotinamide (1.24 g, 3.51 mmol, 89 % yield) as a residue that solidified on standing. LC-MS(ES) m/z = 346.1 [M+H]+.
2-chloro-4-[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; at 20 - 25℃; for 2h;
A solution of propylphosphonic anhydride (50% in EtOAc) (1.5 mL, 2.56 mmol) was added to a solution of 3-(4-chlorophenyl)piperidine (250 mg, 1.27 mmol) (Intermediate la3), triethylamine (0.36 mL, 2.56 mmol) and 2-chloroisonicotinic acid (242 mg, 1.53 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 2 hours. The crude product was purified by column chromatography on basic silica eluting with ethyl acetate/petrol 0-100% to afford 2-chloro-4-{ [3-(4-chlorophenyl)piperidin-l- yljcarbonyljpyridine (413 mg, 1.23 mmol, 96 %) as a solid. MS ES+: 335
2-chloro-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.4%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Synthesis of intermediate chloride: 2-Chloro-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. To 5-(2- fluorophenyl)pyridin-3 -amine (0.5 g, 2.66 mmol) and 2-chloroisonicotinic acid (0.440 g, 2.79 mmol) in DMF (10 mL) was added DIEA (2.320 mL, 13.28 mmol) followed by T3P, 50% in DMF (4.65 mL, 7.97 mmol). The reaction was stirred at rt overnight. It was diluted with EtOAc and washed with water, brine and dried over sodium sulfate. The crude product was dissolved in a small amount of dichloromethane and charged to a 120 g silica gel cartridge which was eluted with 0- 15% dichloromethane / methanol over a period of 40 mins. The desired fractions were combined and dried under vacuo to give 2-chloro-N-(5-(2-fluorophenyl)pyridin- 3-yl)isonicotinamide (0.5 g, 1.526 mmol, 57.4 % yield). 1H NMR (400 MHz, CHLOROFORM- ) delta ppm 11.77 (s, 1 H) 10.00 (d, J=1.96 Hz, 1 H) 9.85 (s, 1 H) 8.69 (d, J=5.87 Hz, 1 H) 8.62 (s, 1 H) 8.28 (br. s., 1 H) 8.04 (s, 1 H) 7.56 - 7.65 (m, 2 H) 7.31 - 7.46 (m, 2 H). MS (ESI) (m/z): 328.0 (M+H)+. 19F NMR (376 MHz, CHLOROFORM-;/) d ppm -116.96 (s, 1 F).
2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2?,4?, 6?-triisopropyl- 1,1?-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); potassium carbonate; In tert-butyl alcohol; at 110℃; for 10h;Inert atmosphere;
2-((5-(Trifluoromethyl)pyridin-2-yl)amino)isonicotinic acidTo an oven-dried vial containing a stir bar, Brettphos precatalyst (0.101 g, 0.127 mmol), Brettphos (0.068 g, 0.127 mmol), 2-chloroisonicotinic acid (2.0 g, 13 mmol), 5- (trifluoromethyl)pyridin-2-amine (2.68 g, 16.5 mmol) and K2CO3(2.63 g, 19.0 mmol) were added. The solid mixture was purged with N2(degassed and flushed) three times. Then tert-butanol (30 mL) was added. The vial was degassed and flushed with N2three times and the vessel was capped and placed in a preheated oil bath at 110 C for 10 h. The sample was cooled to rt, diluted with ethyl acetate, and washed with water. The aqueous layer was acidified to pH 5-6 and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo to give the desired product (1.35 g, 4.77 mmol, 38% yield). The solid was collected by filtration and dried under vacuo to give more of the desired product (1.9 g, 6.71 mmol, 53% yield). Total yield was 91%: MS (ESI) (m/z): 284.1(M+H)+; 1H NMR (400 MHz, DMSO-d6) delta ppm 13.69 (br. s., 1 H) 10.48 (s, 1 H) 8.58 - 8.67 (m, 1 H) 8.44 (d, J=5.14 Hz, 1 H) 8.25 (s, 1 H) 8.04 (dd, J=9.05, 2.45 Hz, 1 H) 7.94 (d, J=9.05 Hz, 1 H) 7.38 (dd, J=5.14, 1.22 Hz, 1 H);19F NMR (376 MHz, DMSO-de) delta ppm -59.78 (s, 3 F).
2-chloro-N-(4-phenylpyridin-3-yl)isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 20℃;
2-Chloro-N-(4-phenylpyridin-3-yl)isonicotinamide (alternative synthesis). To 4- phenylpyridin-3 -amine (0.5 g, 2.94 mmol) and 2-chloroisonicotinic acid (0.486 g, 3.08 mmol) in EtOAc (10 mL) was added DIEA (2.57 mL, 14.69 mmol) followed by T3P, 50% in EtOAc (2 mL, 3.43 mmol). The reaction was stirred at rt overnight. It was diluted with EtOAc and washed with water, brine and dried over sodium sulfate. The crude product was dissolved in a small amount of dichloromethane and charged to a 120 g silica gel cartridge which was eluted with 0-15% dichloromethane / methanol over a period of 40 mins. The desired fractions were combined and dried under vacuo to give 2-chloro-N-(4-phenylpyridin-3-yl)isonicotinamide (0.75g, 2.421 mmol, 82 % yield). MS (ESI) (m/z): 310.0(M+H)+.
With 1,1'-carbonyldiimidazole; In diethyl ether; dichloromethane; at 20℃;
Step 1: 2-chloro-N-methoxyl-N-methylisonicotinamide To a solution of 2-chloroisonicotinic acid (18.0 g, 0.115 mol) in CH2Cl2 (250 mL), N,N'-carbonyldiimidazole (17.0 g, 0.105 mol) was added in portions under stirring at room termperature. Upon completion of the addition, the resultant was stirred for 0.5 hour, then N,O-dimethylhydroxylamine (10.2 g, 0.167 mol) was added, and the resultant was stirred at room temperature overnight. Diethyl ether (200 mL) was added, and the resultant was washed with water, dried, and concentrated to give 2-chloro-N-methoxyl-N-methylisonicotinamide (18.0 g, 78% yield). MS m/z [ESI]: 201.0 [M+1].
[00459] To the solution of 2-chloroisonicotinic acid (5 g, 31.7 mmol) in ACN (30 mL) was added CDI (11.6 g, 71.4 mmol) and the mixture was stirred at 25C for lh. potassium 3-methoxy-3- oxopropanoate (5.4 g, 31.7 mmol) and MgCl2 (2.9 g, 31.7 mmol) were added then the mixture was stirred at 25 C for 12hrs. After removal of the solvent, the residue was extracted with EtOAc (20 mLX3). The organic layer was dried over Na2SO4, concentrated and purified by column chromatography to give compound I. (4.2 g, yield: 58.3%). 1H NMR (400 MHz, DMSO- : delta 12.32 (s, 1H), 8.63 (d, J= 4.8 Hz, 2H), 8.52 (d, J= 5.2 Hz, 1H), 7.93 (s, 2H), 7.87 (s, 1H), 7.79- 7.84 (m, 1H), 6.22 (s, 1H), 4.22-4.28 (m, 4H), 4.10-4.15 (m, 4H), 4.01-4.08 (m, 2H), 1.98 (s, 3H), 1.25-1.29 (m, 3H), 1.20-1.23 (m, 6H).
N-(3-(trifluoromethyl)benzyl)-2-chloroisonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 3h;
Into a 500-mL round bottom flask, was placed a solution of 2-chloroisonicotinic acid (18 g, 113.92 mmol, 2.00 equiv) in dichloromethane (200 mL), 3-(trifluoromethyl)benzylamine (10 g, 57.14 mmol, 1.00 equiv), EDC.HCl (22 g, 115.18 mmol, 2.00 equiv), and 4-dimethylaminopyridine (14 g, 114.75 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25 C. The resulting solution was diluted with 500 mL of dichloromethane. The resulting mixture was washed with 2*50 mL of aqueous NH4Cl, 1*50 mL of 10% sodium bicarbonate, and 1*50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (5:1). The product was obtained as 11.8 g (63%) of a white solid.
(4aR,5S,6S,6aR,9S,11aS,11bR,14R)-5,6,14-trihydroxy-4,4-dimethyl-8-methylene-4,4a,5,6,9,10,11,11a-octahydro-3H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-7(8H)-one[ No CAS ]
ent-6β,7β-dihydroxy-(14β-O-3-chloro-4-pyridoyl)-15-oxo-7,20-epoxykauran-1,16-diene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
The compound of Example 1 (50 mg, 0.14 mmol),Was dissolved in 15 mL of dichloromethane,<strong>[6313-54-8]2-Chloroisonicotinic acid</strong> (27.3 mg, 0.17 mmol) was added,EDCI (1.5 eq),DMAP (catalytic amount),Stirred at room temperature for 12 hours,After completion of the reaction, dichloromethane was added to 50 mL,Washed twice, saturated with salt water once, each 10mL, anhydrous sodium sulfate drying, concentration,Column chromatography (methanol: dichloromethane = 1: 100) gave 43 mg of a white solid (yield 80%).
1-(2-chloropyridin-4-yl)-2-(4-fluorophenyl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
General procedure: Under argon atmosphere Mg turnings (6.94 g, 285.6 mmol) were suspended in dry THF(35 mL). After that 4-fluorobenzyl chloride (13.6 g, 92.5 mmol) was added in portions: after adding 1 mL and starting the reaction, the mixture was cooled at 0 C with an ice bath and the addition continued by 0.5 mL/min at the same temperature. After the addition was competed the mixture was let stirring until warming up to rt. After letting the Mg decanting the supernatant was addedslowly dropwise to a suspension of 2-chloroisonicotinic acid (26, 6.0 g, 38.1 mmol) in dry THF (24 mL), previously cooled at 30 C. During the addition the temperature was maintained between 25 and30 C. After complete addition the mixture was let heating to rt and stirred overnight. The mixturewas poured on NH4Cl saturated solution (100 mL). The aqueous phase was extracted twice with EtOAc and the combined organic layers were dried over anhydrous Na2SO4, and concentrated at reduced pressure. Finally, the residue was purified by flash column chromatography (SiO2, petroleum ether 40/60:EtOAc gradient elution from 3:1 to 1:1) giving 3.37 g of pure compound as a yellow oil, which solidifies after cooling (35% yield).
2-chloro-N-ethyl-N-methylisonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;
To a solution of 2-chloroisonicotinic acid (0.29 g, 1.85 mmol) in DMF (15 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (1.06 g, 2.78 mmol), N-ethylmethylamine (0.24 mL, 2.78 mmol), and N,N-diisopropylethylamine (1.25 mL, 7.4 mmol). The mixture was stirred at room temperature for 18 hours, then diluted with water and extracted with ethyl acetate four times. The extracts were washed with water and brine, dried (Na2SO4) and evaporated. The crude product was chromatographed on silica eluted with 0-50% ethyl acetate/cyclohexane to give the title compound (273 mg, 75% yield). LCMS (ESI): RT (min)=1.99, [M+H]+=199, method=K.
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;
General procedure: Compound 8 (5.0 mg, 0.01 mmol) and various organic acid (1.5 eq.) were dissolved indry dichloromethane (2.0 mL). Then the mixture was combined with DCC (1.5 eq.) and DMAP(1.0 eq.), and then stirred at room temperature for 3-5 h [16]. TLC was used to monitor theproducts. After the reaction was completed, the reaction solvent was evaporated. The resultingresidue was dissolved in acetone or acetonitrile; whereas the insoluble matter was precipitated bycentrifugation. The supernatant was purified by RP18 HPLC to afford the pure corresponding esterifiedproducts (8a-8i).
With zinc(II) oxide; In methanol; at 140℃; for 72h;High pressure;
General procedure: A mixture of HL (78.7mg, 0.50mmol), Ln(Ac)3·4H2O (0.10mmol) (Ln=Sm (1), Eu (2), Dy (3), Tb (4)), and ZnO (8.2mg, 0.10mmol), H2O (5mL) and CH3OH (5mL) were placed in a 25mL Teflon-lined steel vessel and heated to 140C for 3days, then cooled to room temperature at a rate of 5C/h. The resulting rod-shaped crystals were collected after washing with H2O (5mL) and CH3OH (5mL).
With zinc(II) oxide; In methanol; at 140℃; for 72h;High pressure;
General procedure: A mixture of HL (78.7mg, 0.50mmol), Ln(Ac)3·4H2O (0.10mmol) (Ln=Sm (1), Eu (2), Dy (3), Tb (4)), and ZnO (8.2mg, 0.10mmol), H2O (5mL) and CH3OH (5mL) were placed in a 25mL Teflon-lined steel vessel and heated to 140C for 3days, then cooled to room temperature at a rate of 5C/h. The resulting rod-shaped crystals were collected after washing with H2O (5mL) and CH3OH (5mL).
(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)(2-chloropyridin-4-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;
General Procedure for ML210 analog synthesis (25-29)
General procedure: The following ML210 analogs were prepared by stirring overnight a rt solution of 1-(bis(4-chlorophenyl)methyl)piperazine (30 mg, 0.09 mmol, 1 eq.), TBTU (45 mg, 0.14 mmol, 1.5 eq.),DIPEA (20 μL, 0.14 mmol, 1.5 eq.), and the indicated carboxylic acid (0.11 mmol, 1.2 eq.) in dryDCM (1 mL). The reaction was partitioned between DCM and water and the organic layer wasseparated and concentrated under reduced pressure. Purification by flash columnchromatography (0-100% EtOAc/hexanes gradient) afforded the desired compounds.
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