* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; hexane at 0℃; for 2 h; Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; water at 20℃; for 1 h; Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; hexane; water
Reference Example 7 2-Chloropyridine-4-methanol (Reference compound No.7-1) A 0.95 M solution of diisobutylaluminum hydride in hexane (200 mL, 190 mmol) was added dropwise to a solution of 2-chloroisonicotinic acid methyl ester (11 g, 62 mmol) in anhydrous tetrahydrofuran (300 mL) under a nitrogen atmosphere under ice-cooling, and then the mixture was stirred under ice-cooling for 2 hours. After that, 1 N hydrochloric acid (200 mL) was added thereto, the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogencarbonate solution (400 mL) was added to the reaction mixture, then the whole was extracted with ethyl acetate (100 mL) three times. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 8.5 g of the title reference compound as a white solid. (Yield 95percent) 1H-NMR(500MHz,DMSO-d6) δ 4.56(d,J = 5.8 Hz,2H),5.54(t,J = 5.8 Hz,1H),7.34(d,J = 4.9 Hz,1H),7.41(s,1H),8.34(d,J = 4.9 Hz,1H)
94%
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; hexanes at -78 - 20℃; for 4.5 h; Stage #2: With ammonium chloride In tetrahydrofuran; hexanes; water
Methyl 2-chloropyridine-4-carboxylate (2.50 g, 14.60 mmol) was dissolved in anhydrous THF (50 mL) and this solution was cooled to -78 0C under N2 atmosphere. Diisobutylaluminium hydride 1.0 M in hexanes (63.3 mL, 63.30 mmol) was added dropwise stabilizing the temperature between - <n="79"/>50 0C and -70 0C. The reaction mixture was stirred 1 .5 h at -78 0C and allowed to stand at room temperature for 3 h. A solution of aqueous 10 percent NH4CI was slowly added and the mixture was extracted with ethyl acetate (3 x 300 ml_). The combined organic layers were washed with water (3 x 20 ml_), brine (2 x 20 ml_), dried over MgSO4, filtered and evaporated. (2- Chloropyridin-4-yl)methanol SLA 07152 was obtained as a yellow oil (1 .97 g, 94 percent yield).SLA 07152MW: 143.71 ; Yield: 94 percent; Yellow Oil. Rf : 0.35 (EtOAc:cyclohexane = 30:70).1H-NMR (CDCI3, δ): 2.95 (s broad, 1 H, OH), 4.75 (s, 2H, CH2O), 7.21 (dd, 1 H, J = 5.1 Hz, J = 1.2 Hz, ArH), 7.37 (d, 1 H, J = 1.2 Hz ArH), 8.29 (d, 1 H, J = 5.1 Hz, ArH).MS-ESI m/z (rel. int.): 144.0 ([MH]+, 100).HP LC: Method A, detection UV 254 nm, SLA 07152 RT = 3.45 min, peak area 99.9 percent.
71%
With lithium borohydride In tetrahydrofuran at 25 - 30℃; for 3 h; Inert atmosphere; Cooling
To a cooled solution of methyl 2-chloroisonicotinate (1.7 g, 0.009 mole) inTHF (30 mL) under N2, was added lithium borohydride (0.43 g, 0.019 mole) inportions. The reaction mixture was warmed to RT and stirred further for 3 hours. Thereaction mixture was concentrated under reduced pressure; residue was dissolved inice cold water (50 mL) 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 the crude compound which was further purified by flash chromatography using ethyl acetate: n-hexane (40: 60) to afford (2-chloropyridin-4-yl)-methanol.Yield: 1.0 g (71 percent); ‘H - NMR (CDC13, 400MHz) ö ppm: 2.29 (bs, 1H), 4.75 (s, 2H),7.20 - 7.21 (d, J = 4.9 Hz, 1H), 7.31 (s, 1H), 8.32 - 8.33 (d, J = 5.0 Hz, 1H); Mass(m/z): 144.0 (M+H), 145.9 (M+H).
70.8%
Stage #1: With lithium borohydride In tetrahydrofuran; methanol at 0 - 20℃; for 4 h; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water at 0℃;
A sample of methyl 2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in 10 niL THF, treated with 10 drops of methanol, and cooled to 0 0C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 0C and quenched with 1 N HCl solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.1H NMR (300 MHz, CD3CN) δ 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
70.8%
Stage #1: With methanol; lithium borohydride In tetrahydrofuran at 0 - 20℃; for 4 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; methanol at 0℃;
Intermediate T : Preparation of 2-chloro-4-(chloromethyl)pyridine; Step 1: Preparation of (2-chloropyridin-4-yl)methanol; A sample of methyl 2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in 10 mL THF, treated with 10 drops of methanol, and cooled to 0 °C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 °C and quenched with 1 N HC1 solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.'H NMR (300 MHz, CD3CN) 5 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
70.8%
With lithium borohydride In tetrahydrofuran; methanol at 20℃; for 4 h;
Preparation of (2-chloropyridin-4-yl)methanolA sample of methyl 2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in 10 mL THF, treated with 10 drops of methanol, and cooled to 0 C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71 mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 C and quenched with 1 N HCl solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.1H NMR (300 MHz, CD3CN) ? 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
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] Patent: US6362336, 2002, B1, . Location in patent: Example 58
[2] Patent: US2009/82329, 2009, A1, . Location in patent: Page/Page column 16
[3] Patent: US2004/248884, 2004, A1, . Location in patent: Page 120
4
[ 925-90-6 ]
[ 101066-61-9 ]
[ 100704-10-7 ]
Yield
Reaction Conditions
Operation in experiment
49%
Stage #1: With lanthanium (III) chloride bis(lithium chloride) complex In tetrahydrofuran at 0 - 20℃; for 0.75 h; Stage #2: at 0℃; for 1.33333 h;
To a solution of 2-chloropyridine-4-carbaldehyde (0.71 g, 5.06 mmol) in anhydrous THF (16 mL) was added a solution of lanthanum(III) chloride bis(lithium chloride) complex (0.6M in THF, 16.7 mL, 10.03 mmol) and the mixture was stirred at room temperature for 0.75 hours, then cooled to 0° C. Ethyl magnesium bromide (3M in diethyl ether, 3.34 mL, 10.03 mmol) was added dropwise over 5-10 minutes. The mixture was stirred at 0° C. for 80 minutes, then quenched with aqueous ammonium chloride, diluted with water and extracted with ethyl acetate (3*). The organic extracts were dried (Na2SO4) and evaporated. The crude product was chromatographed on silica gel (eluted with 0-50percent ethyl acetate/cyclohexane) to give the title compound (423 mg, 49percent yield). LCMS (ESI): RT (min)=2.14, [M+H]+=172, method=K.
Stage #1: With phosphorus tribromide In dichloromethane at 0 - 20℃; for 3 h; Inert atmosphere Stage #2: With potassium carbonate In dichloromethane; water at 0℃;
Step 4b: Synthesis of 4-(bromomethyl)-2-chloropyridine (2-chloropyridin-4-yl)methanol (1.1 g, 7.3 mmol) is dissolved in 20 mL DCM; flushed with argon and cooled to 0 °C. PBr, (0.76 mL; 8.1 mmol) is added drop wise via a syringe (solution turned cloudy) and reaction mixture is stirred at RT for 3 h. Cooled to 0 °C and quenched with 5 mL water. The reaction mixture is ad j usted to pi f 7 by the addition of 2M K2CO3. The aqueous and organic layer are separated and the aqueous layer is extracted 3x with EtOAc. The organic layers are combined, dried over anhydrous sodium sulfate, filtered and deposited on silica. Column chromatography on silica gel (pre-washed with 1percent NEt3), using a solvent gradient from hexanes to EtOAc lead to the isolation of the product as pale pink crystals (700 mg, 50percent yield based on recovered starting material). NMR (300 MHz, CDCI3) δ 8.37 (d, J = 5.1 Hz, 1H), 7.35 (s, 1H), 7.27 - 7.20 (m, 1 H ), 4.35 (s, 21 1).
34.77%
With phosphorus tribromide In dichloromethane at 0 - 20℃; for 3 h;
To a stirred solution of (2-chloropyridin-4-yl)methanol (2g, 13.93 mmol) in dry in dry DCM (40 ml), PBr3 (1.6 ml, 16.71 mmol) was added dropwise at 0°C. The reaction mixture was stirred at ambient temperature for 3h. The progress of the reaction was monitored by TLC (3:7, Ethyl acetate: pet. ether). After completion of the reaction the reaction mixture was cooled o room temperature and quenched with aqueous 10percent NaHCO3 solution (30 ml) and extracted with DCM (3 X 50 ml). The combined organic layer was dried over anhydrous sodium sulfate and removed under reduced pressure. The crude was purified by column chromatography (60-120 mesh silica gel) using 8percentEthyl acetate in pet ether as eluent to yield pure 4-(bromomethyl)-2- chioropyridine (lg, 34.77percent) as a pale yellow oil.
(2-Methoxy-pyridin-4-yl)-methanol:; (2-Chloro-pyridin-4-yl)-methanol (2.82 g, 19.67 mmol) was refluxed with 25 wt. percent sodium methoxide (25 ml) solution for 24 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexane (1:1)) to afford 1.8 g (60percent) of (2-Methoxy-pyridin-4-yl)-methanol as a pale brown oil. 1H NMR (200 MHz, CDCl3) δ 2.16(3H, s), 2.21 (3H, s), 5.13 (2H, s), 6.99 (1H, d, J=5.6 Hz), 8.11 (1H, br. s), 8.12 (1H, s), 8.23 (1H, d, J=5.6 Hz).
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78 - -45℃; for 2.08333 h; Stage #2: With triethylamine In dichloromethane at 0℃; for 0.333333 h;
In a 250 mL tricol equipped with a low temperature thermometer and two equalizing dropping funnels was charged oxalyl dichloride (1.24 g, 9.81 mmol) in dichloromethane (15 mL) and this solution was stirred under N2 at - 78 0C. The first equalizing dropping funnel was connected to a nitrogen flow line and was charged with a solution of (2-chloropyridin-4-yl)methanol SLA 07152 (0.94 g, 6.54 mmol) with dichloromethane (15 mL). The other was charged with a solution of dimethyl sulfoxide anhydrous (1 .7 mL, 19.63 mmol) in dichloromethane (2 mL) and this solution was added dropwise (25 min) in <n="80"/>order to stabilize the temperature between -60 0C and -70 0C. At the end of the addition the reaction solution was warmed to -60 0C over a period of 20 min then the solution of (2-chloropyhdin-4-yl)methanol SLA 07152 was added dropwise (50 min) keeping the temperature between -50 0C and -60 0C in the reactor then the mixture reaction was warmed to -45 0C over a period of 30 min. The dropping funnel was washed with dichloromethane (2 x 5 mL) and charged with a solution of thethylamine (480 μl_, 6.51 mmol) in dichloromethane (4 mL) which was added (10 min) to the reaction mixture and finally the reaction flask was allowed to warm to 0 0C over 10 min. The reaction solution was transferred to a 500 mL separatory funnel charged with 130 mL of a 5 percent aqueous NH4CI solution. The two phases were separated the aqueous phase was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were washed with 1 M aqueous phosphate buffer (pH = 7; 4x10OmL), then dried over MgSO4, filtered and evaporated. 2- Chloropyridine-4-carbaldehyde SLA 07156 was obtained as an orange solid (0.740 g, 76 percent yield).SLA 07156MW: 141.57; Yield: 76 percent; Orange Solid. Rf: 0.35 (EtOAc:cyclohexane = 30:70).1H-NMR (CDCI3, δ): 7.65 (dd, 1 H, J = 5.0 Hz, J = 1 .3 Hz, ArH), 7.75 (d, 1 H, J = 1.3 Hz, ArH) 8.66 (d, 1 H, J = 5.0 Hz, ArH), 10.05 (s, 1 H, CHO).
67%
With N-Bromosuccinimide; sodium carbonate; potassium carbonate In ethyl acetate
b) 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-pyridinemethanol (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2CO3 (11.75 g, 97.1 mmol) in EtOAc was refluxed for 3 h. A second portion of NBS (14.9 g, 83.9 mmol) and Na2CO3 (12.0 g, 114 mmol) were added and the reaction was heated to reflux for an additional 3.5 h, cooled and filtered through a pad of celite. The filtrate, after concentrattion to a small volume, was subjected to flash chromatography eluding with 0.5-4percent CH3OH/CH2Cl2. The fractions containing product were combined, washed successively with sat aq NaHCO3 10percent Na2S2O3, and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a light yellow solid; yield 5.3 g (67percent). 1H NMR (CDCl3) δ10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
b 2-Chloro4-pyridinecarboxaldehyde A suspension of 2-chloro-4-hydroxymethylpyridine (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in ethyl acetate was refluxed for 3 h. Another portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) was added and heating was continued another 3.5 h. The reaction mixture was cooled, filtered through a pad of celite, concentrated under reduced and chromatographed with 0.5-4percent CH3 OH/CH2 Cl2. The combined fractions were washed with NaHCO3 (sat.), 10percent Na2 S2 O3, and NaCl (sat.), dried, filtered and evaporated to give the title compound as a light yellow solid (5.3 g, 67percent yield). 1 H NMR (CDCl3): δ10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
67%
With N-Bromosuccinimide In ethyl acetate
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-hydroxymethylpyridine (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in ethyl acetate was refluxed for 3 h. Another portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) was added and heating was continued another 3.5 h. The reaction mixture was cooled, filtered through a pad of celite, concentrated under reduced and chromatographed with 0.5-4percent CH3 OH/CH2 Cl2. The combined fractions were washed with NaHCO3 (sat.), 10percent Na2 S2 O3, and NaCl (sat.), dried, filtered and evaporated to give the title compound as a light yellow solid (5.3 g, 67percent yield). 1 H NMR (CDCl3): δ10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H,J=5.0 Hz).
Reference：
[1] Patent: US5977103, 1999, A,
[2] Patent: US5756499, 1998, A,
13
[ 100704-10-7 ]
[ 497-19-8 ]
[ 584-08-7 ]
[ 101066-61-9 ]
Yield
Reaction Conditions
Operation in experiment
67%
With N-Bromosuccinimide In ethyl acetate
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-pyridinemethanol (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in EtOAc was refluxed for 3 h. A Second portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) were added and the reaction was heated to reflux for an additional 3.5 h, cooled and filtered through a pad of celite. The filtrate, after concentrattion to a small volume, was subjected to flash chromatography eluding with 0.5-4percent CH3 OH/CH2 Cl2. The fractions containing product were combined, washed successively with sat aq NaHCO3 10percent Na2 S2 O3, and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a light yellow solid; yield 5.3 g (67percent). 1 H NMR (CDCl3) δ 10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
67%
With N-Bromosuccinimide In ethyl acetate
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-pyridinemethanol (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in EtOAc was refluxed for 3 h. A second portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) were added and the reaction was heated to reflux for an additional 3.5 h, cooled and filtered through a pad of celite. The filtrate, after concentration to a small volume, was subjected to flash chromatography eluding with 0.5-4percent CH3 OH/CH2 Cl2. The fractions containing product were combined, washed successively with sat aq NaHCO3 10percent Na2 S2 O3, and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a light yellow solid; yield 5.3 g (67percent). 1 H NMR,,(CDCl3) δ 10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
Reference：
[1] Patent: US5658903, 1997, A,
[2] Patent: US5739143, 1998, A,
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 3 h;
Stage b) 2-chloro-4-(chloromethyl)pyridine To a solution of 11.3 g of (2-chloropyridin-4-yl)methanol obtained in stage a) below in 200 mL of dichloromethane are added 6.896 mL of thionyl chloride and then 2.1 mL of dimethylformamide, the reaction mixture is stirred for 3 hours and 50 mL of water are then added dropwise. The solution is dried over magnesium sulfate, filtered and concentrated under vacuum to give 12.8 g (100percent) of product in the form of an amber-coloured liquid, which is used without further purification. RfTLC silica=0.44 (eluent: dichloromethane).
100%
With thionyl chloride In dichloromethane at -5 - 20℃;
SOCI2 (4.2 g, 35.5 mol) was added dropwise to a suspension of the alcohol (5 g, 34.8 mmol) in CH2CI2 (50 mL) at -5 0C with stirring, The mixture was stirred at room temperature overnight, then quenched with water (100 mL), and extracted with CH2CI2 (3 x 100 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 /5) and afforded the title compound (5.5 g, near quantitative yield) as an oil.
97%
With thionyl chloride In dichloromethane at 20℃;
1.00 g (6.97 mmol) of (2-chloropyridin-4-yl)methanol was dissolved in 40 ml of methylene chloride, 10 ml of thionyl chloride were slowly added at RT and the mixture was stirred at RT overnight. The mixture was then concentrated on a rotary evaporator and the residue was stirred in a mixture of methylene chloride and aqueous sodium bicarbonate solution. The phases were separated and the methylene chloride phase was dried over anhydrous magnesium sulphate, filtered and concentrated on a rotary evaporator. 1.10 g (97percent of th.) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, δ/ppm): 8.49 (d, 1H), 7.38 (s, 1H), 7.27-7.22 (m, 1H), 4.52 (s, 2H).LC/MS (method E, ESIpos): Rt=1.43 min, m/z=162 [M+H]+.
97%
Stage #1: With thionyl chloride In dichloromethane at 20℃; Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Example 29A; 2-Chloro-4-(chloromethyl)pyridine 1.00 g (6.97 mmol) of (2-chloropyridin-4-yl)methanol was dissolved in 40 ml of dichloromethane, 10 ml of thionyl chloride were slowly added at RT and the mixture was stirred at RT overnight. The mixture was then concentrated on a rotary evaporator and the residue was stirred in a mixture of dichloromethane and aqueous sodium bicarbonate solution. The phases were separated and the dichloromethane phase was dried over anhydrous magnesium sulphate, filtered and concentrated on a rotary evaporator. 1.10 g (97percent of theory) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, δ/ppm): 8.49 (d, 1H), 7.38 (s, 1H), 7.27-7.22 (m, 1H), 4.52 (s, 2H).LC/MS (method E, ESIpos): Rt=1.43 min, m/z=162 [M+H]+.
97%
With thionyl chloride In dichloromethane at 20℃;
Example 43A 2-Chloro-4-(chloromethyl)pyridine 1.00 g (6.97 mmol) of (2-chloropyridin-4-yl)methanol was dissolved in 40 ml of methylene chloride, 10 ml of thionyl chloride were slowly added at RT and the mixture was stirred at RT overnight. The mixture was then concentrated on a rotary evaporator and the residue was stirred in a mixture of methylene chloride and aqueous sodium bicarbonate solution. The phases were separated and the methylene chloride phase was dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator. 1.10 g (97percent of th.) of the title compound were obtained. 1H-NMR (400 MHz, CDCl3, δ/ppm): 8.49 (d, 1H), 7.38 (s, 1H), 7.27-7.22 (m, 1H), 4.52 (s, 2H). LC/MS (method E, ESIpos): Rt=1.43 min, m/z=162 [M+H]+.
88.6%
With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 20℃;
A sample of (2-chloropyridin-4-yl)methanol (110.0 mg, 0.77 mmol) was dissolved in anhydrous THF (1.5 mL), treated with /Y,iV-diisopropylethylamine (0.29 mL, 1.69 mmol) and cooled to -78 0C. Methanesulfonyl chloride was added (0.07 mL, 0.84 mmol), and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo yielding the title compound (110.0 mg, 88.6percent).1H NMR (300 MHz, CD3CN) δ 8.40 (d, 1 H), 7.49 (s, 1 H), 7.39 (d, 1 H) and 4.63 ppm (s, 2 H); ES-MS m/z 183.2 [M+Na]+, HPLC RT (min) 2.30.
88.6%
With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 20℃;
Step 2: Preparation of 2-chloro-4-(chloromethyl)pyridine; A sample of (2-chloropyridin-4-yl)methanol (110.0 nig, 0.77 mmol) was dissolved in anhydrous THF (1.5 mL), treated with ^V.A'-diisopropylethylamine (0.29 mL, 1.69 mmol) and cooled to -78 °C. Methanesulfonyl chloride was added (0.07 mL, 0.84 mmol), and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layerwas dried over Na2SO4 and concentrated in vacuo yielding the title compound (110.0 mg,88.6percent).1H NMR (300 MHz, CD3CN) 8 8.40 (d, 1 H), 7.49 (s, 1 H), 7.39 (d, 1 H) and 4.63ppm (s, 2 H); ES-MS m/z 183.2 [M+Na]+, HPLC RT (min) 2.30.
88.6%
With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 20℃;
Preparation of 2-chloro-4-(chloromethyl)pyridineA sample of (2-chloropyridin-4-yl)methanol (110.0 mg, 0.77 mmol) was dissolved in anhydrous THF (1.5 mL), treated with N,iV-diisopropylethylamine (0.29 niL, 1.69 mmol) and cooled to -78 C. Methanesulfonyl chloride was added (0.07 mL, 0.84 mmol), and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo yielding the title compound (110.0 mg, 88.6percent).1H NMR (300 MHz, CD3CN) ? 8.40 (d, 1 H), 7.49 (s, 1 H), 7.39 (d, 1 H) and 4.63 ppm (s, 2 H); ES-MS m/z 183.2 [M+Na]+, HPLC RT (min) 2.30.
(2-Methoxy-pyridin-4-yl)-methanol:; (2-Chloro-pyridin-4-yl)-methanol (2.82 g, 19.67 mmol) was refluxed with 25 wt. % sodium methoxide (25 ml) solution for 24 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexane (1:1)) to afford 1.8 g (60%) of (2-Methoxy-pyridin-4-yl)-methanol as a pale brown oil. 1H NMR (200 MHz, CDCl3) delta 2.16(3H, s), 2.21 (3H, s), 5.13 (2H, s), 6.99 (1H, d, J=5.6 Hz), 8.11 (1H, br. s), 8.12 (1H, s), 8.23 (1H, d, J=5.6 Hz).
In tetrahydrofuran; at 200℃; for 48h;Autoclave; Inert atmosphere;
To a solution of 330 <strong>[100704-10-7](2-chloro-4-pyridyl)methanol</strong> (1.0 g, 7.0 mmol) in 20 tetrahydrofuran (5 mL) wasadded 2 mol/L 620 dimethylamine-tetrahydrofuran solution (20 mL, 40 mmol), and the mixture wasstirred with heating in an autoclave under a nitrogen atmosphere at 200 C. for 2 days. The reaction mixturewas concentrated under reduced pressure and the obtained residue was purified by high performance liquidchromatography (water-acetonitrile) to give the 621 title compound ( 0.27 g , 1.7 mmol, 25%). MS (ESI) m/z 153 (M+H)+ 1H NMR (400 MHz, CD3OD): delta 7.98 (d, J=5.2 Hz, 1H), 6.69 (s, 1H), 6.59 (d, J=5.2 Hz, 1H), 4.58 (s, 2H),3.09 (s, 6H) .
In water; at 150℃; for 0.25h;Microwave irradiation;
[00246] To a solution of <strong>[100704-10-7](2-chloropyridin-4-yl)methanol</strong> (500 mg, 3.48 mmol) in water (3 mL) was added methylamine (0.54 g, 17.4 mmol). The reaction was stirred at 150C under MW condition for 15 min. The mixture was concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of Hex (20%) and EtOAc (80%) to EtOAc (100%) to provide (2-(methylamino)pyridin-4-yl)methanol (400 mg, 2.9 mmol) as a yellow oil . LC/MS [M+H]+ = 139.3.
Stage a) (2-Chloropyridin-4-yl)methanol To a solution of 14.85 g of ethyl 2-chloroisonicotinate in 300 mL of ethanol are added, under argon, 9.08 g of sodium borohydride portionwise at 40 C. for 45 minutes. After addition, the reaction mixture is stirred for 15 minutes and the temperature is then gradually raised to reflux, which is maintained for 4 hours. After cooling to room temperature, 50 mL of saturated ammonium chloride solution are added and the solvents are evaporated off under reduced pressure. The residue is taken up in 200 mL of water and extracted with 3*100 mL of ethyl acetate, and the organic phase is washed with 2*100 mL of saturated sodium chloride solution, dried over sodium sulfate and filtered. After evaporation under reduced pressure, the product is obtained in the form of a white solid: 11.4 g. Rf TLC silica=0.38 (eluent: dichloromethane/methanol 90/10).
With sodium tetrahydroborate; In ethanol; at 0℃; for 3h;Heating / reflux;
2.04 g of sodium borohydride are added portionwise to a solution of 1.7 g of ethyl 2-chloropyridine-4-carboxylate in 20 ml of ethanol, under an inert atmosphere of argon at a temperature in the region of 0 C. The reaction mixture is refluxed with stirring for 3 hours and then concentrated to dryness under reduced pressure. The residue thus obtained is taken up in dichloromethane and then washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. 1 g of 2-chloro-4-(hydroxymethyl)pyridine is thus obtained.
4-(chloromethyl)-2-chloropyridine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; In toluene;
A mixture of <strong>[100704-10-7]2-chloro-4-hydroxymethylpyridine</strong> (180 mg, 1.25 mmol), thionyl chloride (0.2 ml) in toluene (10 ml) was stirred at ambient temperature for 1 hour. The volatiles were removed by evaporation to give 2-chloro-4-chloromethylpyridine hydrochloride (180 mg, 0.9 mmol).
With triethylamine; In water; ethyl acetate; pentane;
Step 1 To a 0 C. solution of <strong>[100704-10-7](2-chloro-pyridin-4-yl)-methanol</strong> (2.00 g, 13 mmol) (prepared from the corresponding carboxylic acid according to the procedure in U.S. Pat. No. 6,218,537), ethyl acetate (30 mL) and triethylamine (2.9 mL, 21 mmol) was added drop wise methansulfonyl chloride (1.4 mL, 18 mmol). The solution was stirred for 10 minutes and then water (5 mL) was added. The reaction mixture was extracted with three 30 mL portions of ethyl acetate, the organics combined and washed with water (30 mL) and brine (30 mL), dried on sodium sulfate, and concentrated to a crude oil. Pentane was added to the residue and stirred at 0 C. The precipitate was collected and dried in vacuo to give methanesulfonic acid 2-chloro-pyridin-4-ylmethyl ester (3.09 g, 100%).
100%
With triethylamine; In ethyl acetate; at 0℃; for 0.166667h;
Step 1 To a 0 C. solution of <strong>[100704-10-7](2-chloro-pyridin-4-yl)-methanol</strong> (2.00 g, 13 mmol) (prepared from the corresponding carboxylic acid according to the procedure in U.S. Pat. No. 6,218,537), ethyl acetate (30 ML) and triethylamine (2.9 ML, 21 mmol) was added drop wise methansulfonyl chloride (1.4 ML, 18 mmol).The solution was stirred for 10 minutes and then water (5 ML) was added.The reaction mixture was extracted with three 30 ML portions of ethyl acetate, the organics combined and washed with water (30 ML) and brine (30 ML), dried on sodium sulfate, and concentrated to a crude oil.Pentane was added to the residue and stirred at 0 C. The precipitate was collected and dried in vacuo to give methanesulfonic acid 2-chloro-pyridin-4-ylmethyl ester (3.09 g, 100%).
98%
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 0.5h;
At 0 C., 12.9 ml (167 mmol) of methanesulphonyl chloride were added dropwise to a solution of 20 g (139 mmol) of <strong>[100704-10-7](2-chloropyridin-4-yl)methanol</strong> and 25.2 ml (181 mmol) of triethylamine in 400 ml of THF, with the reaction temperature increasing to 20 C. during the addition. After removal of the cooling bath, the mixture was stirred at RT for another 30 min. A little water, saturated sodium bicarbonate solution and ethyl acetate were then added to the reaction mixture, and the phases were separated. The aqueous phase was reextracted once with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was triturated with pentane. The solid formed was filtered off, washed with pentane and dried under high vacuum. This gave 30.60 g (98% of theory) of the title compound. 1H NMR (400 MHz, CDCl3, delta/ppm): 8.44 (d, 1H), 7.37 (s, 1H), 7.25 (d, 1H), 5.22 (s, 2H), 3.10 (s, 3H). LC/MS (Method 3, ESIpos): Rt=0.61 min; m/z=222 [M+H]+.
68%
With triethylamine; In dichloromethane; at 0 - 20℃;
Intermediate-4: (2-chloropyridin-4-yl)methyl methanesulfonate.To a stirred solution of <strong>[100704-10-7](2-chloropyridin-4-yl)methanol</strong> (0.500 g, 3.496 mmol) in dichloromethane (15 mL), triethylamine (0.424 g, 4.195 mmol) and methanesulfonylchloride (0.440g, 3.846 mmol) were added at 0C and stirred at room temperature for 2-3 h. The reaction was quenched with water and extracted with dichloromethane. The organic layer was concentrated in vacuo to give (2-chloropyridin-4-yl)methyl methanesulfonate (0.530 g, 68 %); MS: 221.9 (M+l).
With triethylamine; In chloroform; at 0℃; for 1.1 - 1.5h;Product distribution / selectivity;
Example N; To a stirred solution of <strong>[100704-10-7]2-chloropyridine-4-methanol</strong> (143 mg, 1 mmol) in chloroform (10 ml) cooled in an ice bath under nitrogen atmosphere, was added triethylamine (210 mul, 1.5 mmol) and methanesulfonyl chloride (90 mul, 1.2 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo for ca. 20 min. and mixed with (32) (297 mg, 1 mmol), powdered anhydrous potassium carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol). DMF (5 ml) was then added to the mixture at room temperature and stirred for overnight. After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 120 mg (28%) a white foam. Recrystallization from chloroform/ether/hexane resulted in a white solid. m.p. 206-207 C.; 1H-NMR (200 MHz, CDCl3) delta 1.13(3H, d, J=6.9 Hz), 1.23 (3H, d, J=6.9 Hz), 2.18 (1H, m), 2.43 (3H, s), 4.51 (1H, d, J=16.4 Hz), 5.06 (1H, d, J=16.4 Hz), 6.91-6.96 (2H, m), 7.66 (1H, s), 7.70 (1H, s), 7.88 (1H, s), 8.19 (1H, d, J=0.8 Hz, 5.5 Hz), 8.98 (1H, s); m/z (EI) 422(M+); HRMS (EI) Calcd, 422.114525, Found 422.114568.; Example BL; To a stirred solution of 2-chloro-4-pyridinemethanol (144 mg, 1 mmol) in chloroform (10 ml) at 0 C. (ice bath), was added triethylamine (210 mul, 1.5 mmol) and methanesulfonyl chloride (90 mul, 1.2 mmol). After stirring for 1.5 hr., the mixture was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo and mixed with 3-[3-(5-Isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (323 mg, 1 mmol), anhydrous powdered potassium carbonate (138 mg, 1 mmol), lithium iodide (134 mg, 1 mmol). Anhydrous DMF (5 ml) was then added into the mixture and stirred for overnight at room temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through celite pad, and the filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, methanol:chloroform (2:98)) to afford 174 mg (38%) of a white solid. m.p. 242-244 C.; 1H-NMR (200 MHz, CDCl3/CD3OD) delta 1.12(3H, d, J=6.8 Hz), 1.22 (3H, d, J=6.8 Hz), 2.28 (1H, m), 2.40 (3H, s), 4.55 (1H, d, J=17.0 Hz), 4.97 (1H, d, J=17.0 Hz), 6.03 (1H, d, J=16.6 Hz), 6.97-6.99 (2H, m), 7.39 (1H, d, J=16.6 Hz), 7.55 (2H, s), 7.71 (1H, s), 8.15 (1H, d, J=5.8 Hz); m/z (EI) 448(M+).
Step 4b: Synthesis of 4-(bromomethyl)-2-chloropyridine <strong>[100704-10-7](2-chloropyridin-4-yl)methanol</strong> (1.1 g, 7.3 mmol) is dissolved in 20 mL DCM; flushed with argon and cooled to 0 C. PBr, (0.76 mL; 8.1 mmol) is added drop wise via a syringe (solution turned cloudy) and reaction mixture is stirred at RT for 3 h. Cooled to 0 C and quenched with 5 mL water. The reaction mixture is ad j usted to pi f 7 by the addition of 2M K2CO3. The aqueous and organic layer are separated and the aqueous layer is extracted 3x with EtOAc. The organic layers are combined, dried over anhydrous sodium sulfate, filtered and deposited on silica. Column chromatography on silica gel (pre-washed with 1% NEt3), using a solvent gradient from hexanes to EtOAc lead to the isolation of the product as pale pink crystals (700 mg, 50% yield based on recovered starting material). NMR (300 MHz, CDCI3) delta 8.37 (d, J = 5.1 Hz, 1H), 7.35 (s, 1H), 7.27 - 7.20 (m, 1 H ), 4.35 (s, 21 1).
34.77%
With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 3h;
To a stirred solution of <strong>[100704-10-7](2-chloropyridin-4-yl)methanol</strong> (2g, 13.93 mmol) in dry in dry DCM (40 ml), PBr3 (1.6 ml, 16.71 mmol) was added dropwise at 0C. The reaction mixture was stirred at ambient temperature for 3h. The progress of the reaction was monitored by TLC (3:7, Ethyl acetate: pet. ether). After completion of the reaction the reaction mixture was cooled o room temperature and quenched with aqueous 10% NaHCO3 solution (30 ml) and extracted with DCM (3 X 50 ml). The combined organic layer was dried over anhydrous sodium sulfate and removed under reduced pressure. The crude was purified by column chromatography (60-120 mesh silica gel) using 8%Ethyl acetate in pet ether as eluent to yield pure 4-(bromomethyl)-2- chioropyridine (lg, 34.77%) as a pale yellow oil.
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 1h;
Reference Example 14 2-(2-Chloropyridin-4-ylmethylthio)pyridine-3-carboxylic acid (Reference compound No.14-1) Triphenylphosphine (19 g, 71 mmol) and carbon tetrabromide (29 g, 88 mmol) were added to a solution of <strong>[100704-10-7]2-chloropyridine-4-methanol</strong> (8.5 g, 59 mmol, Reference compound No.7-1) in methylen chloride (250 mL), then the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give 4-bromomethyl-2-chloropyridine.
With dibromotriphenylphosphorane; In dichloromethane; at 20℃; for 1h;
A solution of 0.2 g of <strong>[100704-10-7]2-chloro-4-(hydroxymethyl)pyridine</strong> in 2.5 ml of dichloromethane is added dropwise to a solution of 0.706 g of dibromotriphenylphosphorane in 9.5 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 20 C. Stirring is continued at this temperature for about 1 hour. The reaction medium is taken up in 50 ml of dichloromethane and then washed with 3*50 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 20 mm in diameter packed with 10 g of 20-40 mum conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate) (8/2) (v/v) at a flow rate of 8 ml/minute. The fractions between 8 and 24 ml are concentrated under reduced pressure. 0.1 g of 2-chloro-4-(bromomethyl)pyridine is thus obtained.
To a solution of <strong>[100704-10-7]2-chloropyridine-4-methanol</strong> (1.02 g, 7.10 mmol) in 15 mL of dichloromethane was added thionyl bromide (1.77 g, 8.53 mmol) dropwise. After 15 min, the reaction was quenched with saturated aqueous ammonium chloride. The organic solution was washed 2x with water, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 4-(bromomethyl)- 2-chloropyridine that gave a mass ion (ES+) of 208.0 for [M+H]+.
Reference Example 7 2-Chloropyridine-4-methanol (Reference compound No.7-1) A 0.95 M solution of diisobutylaluminum hydride in hexane (200 mL, 190 mmol) was added dropwise to a solution of <strong>[58481-11-1]2-chloroisonicotinic acid methyl ester</strong> (11 g, 62 mmol) in anhydrous tetrahydrofuran (300 mL) under a nitrogen atmosphere under ice-cooling, and then the mixture was stirred under ice-cooling for 2 hours. After that, 1 N hydrochloric acid (200 mL) was added thereto, the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogencarbonate solution (400 mL) was added to the reaction mixture, then the whole was extracted with ethyl acetate (100 mL) three times. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 8.5 g of the title reference compound as a white solid. (Yield 95percent) 1H-NMR(500MHz,DMSO-d6) delta 4.56(d,J = 5.8 Hz,2H),5.54(t,J = 5.8 Hz,1H),7.34(d,J = 4.9 Hz,1H),7.41(s,1H),8.34(d,J = 4.9 Hz,1H)
94%
Methyl 2-chloropyridine-4-carboxylate (2.50 g, 14.60 mmol) was dissolved in anhydrous THF (50 mL) and this solution was cooled to -78 0C under N2 atmosphere. Diisobutylaluminium hydride 1.0 M in hexanes (63.3 mL, 63.30 mmol) was added dropwise stabilizing the temperature between - <n="79"/>50 0C and -70 0C. The reaction mixture was stirred 1 .5 h at -78 0C and allowed to stand at room temperature for 3 h. A solution of aqueous 10 percent NH4CI was slowly added and the mixture was extracted with ethyl acetate (3 x 300 ml_). The combined organic layers were washed with water (3 x 20 ml_), brine (2 x 20 ml_), dried over MgSO4, filtered and evaporated. (2- Chloropyridin-4-yl)methanol SLA 07152 was obtained as a yellow oil (1 .97 g, 94 percent yield).SLA 07152MW: 143.71 ; Yield: 94 percent; Yellow Oil. Rf : 0.35 (EtOAc:cyclohexane = 30:70).1H-NMR (CDCI3, delta): 2.95 (s broad, 1 H, OH), 4.75 (s, 2H, CH2O), 7.21 (dd, 1 H, J = 5.1 Hz, J = 1.2 Hz, ArH), 7.37 (d, 1 H, J = 1.2 Hz ArH), 8.29 (d, 1 H, J = 5.1 Hz, ArH).MS-ESI m/z (rel. int.): 144.0 ([MH]+, 100).HP LC: Method A, detection UV 254 nm, SLA 07152 RT = 3.45 min, peak area 99.9 percent.
71%
With lithium borohydride; In tetrahydrofuran; at 25 - 30℃; for 3h;Inert atmosphere; Cooling;
To a cooled solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (1.7 g, 0.009 mole) inTHF (30 mL) under N2, was added lithium borohydride (0.43 g, 0.019 mole) inportions. The reaction mixture was warmed to RT and stirred further for 3 hours. Thereaction mixture was concentrated under reduced pressure; residue was dissolved inice cold water (50 mL) 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 the crude compound which was further purified by flash chromatography using ethyl acetate: n-hexane (40: 60) to afford (2-chloropyridin-4-yl)-methanol.Yield: 1.0 g (71 percent); ?H - NMR (CDC13, 400MHz) oe ppm: 2.29 (bs, 1H), 4.75 (s, 2H),7.20 - 7.21 (d, J = 4.9 Hz, 1H), 7.31 (s, 1H), 8.32 - 8.33 (d, J = 5.0 Hz, 1H); Mass(m/z): 144.0 (M+H), 145.9 (M+H).
70.8%
A sample of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (5.00 g, 29.14 mmol) was dissolved in 10 niL THF, treated with 10 drops of methanol, and cooled to 0 0C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 0C and quenched with 1 N HCl solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.1H NMR (300 MHz, CD3CN) delta 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
70.8%
Intermediate T : Preparation of 2-chloro-4-(chloromethyl)pyridine; Step 1: Preparation of (2-chloropyridin-4-yl)methanol; A sample of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (5.00 g, 29.14 mmol) was dissolved in 10 mL THF, treated with 10 drops of methanol, and cooled to 0 °C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 °C and quenched with 1 N HC1 solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.'H NMR (300 MHz, CD3CN) 5 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
70.8%
With lithium borohydride; In tetrahydrofuran; methanol; at 20℃; for 4h;
Preparation of (2-chloropyridin-4-yl)methanolA sample of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (5.00 g, 29.14 mmol) was dissolved in 10 mL THF, treated with 10 drops of methanol, and cooled to 0 C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71 mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 C and quenched with 1 N HCl solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.1H NMR (300 MHz, CD3CN) ? 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
To a suspension of lithium aluminum hydride (221 mg) in Et2O (10.0 mL) cooled to -40C was added <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (1.00 g) in Et2O (2 mL) dropwise and the mixture was stirred at -4 0C for 30 min and quenched with water. The aqueous layer was extracted with EtOAc three times. The combined organic layer was washed with aqueous saturated NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to give (2-chloropyridin-4-yl)methanol (641 mg) as a pale brown solid.1HNMR (300 MHz, CDCl3, delta): 2.81-2.93 (m, IH), 4.72-4.80 (m, 2H), 7.17-7.26 (m, IH), 7.34-7.41 (m, IH), 8.30 (dd, J= 5.1, 0.6 Hz5 IH); ESI MS m/z 144 (M++., 100percent).
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 3h;
Stage b) 2-chloro-4-(chloromethyl)pyridine To a solution of 11.3 g of (2-chloropyridin-4-yl)methanol obtained in stage a) below in 200 mL of dichloromethane are added 6.896 mL of thionyl chloride and then 2.1 mL of dimethylformamide, the reaction mixture is stirred for 3 hours and 50 mL of water are then added dropwise. The solution is dried over magnesium sulfate, filtered and concentrated under vacuum to give 12.8 g (100%) of product in the form of an amber-coloured liquid, which is used without further purification. RfTLC silica=0.44 (eluent: dichloromethane).
~ 100%
With thionyl chloride; In dichloromethane; at -5 - 20℃;
SOCI2 (4.2 g, 35.5 mol) was added dropwise to a suspension of the alcohol (5 g, 34.8 mmol) in CH2CI2 (50 mL) at -5 0C with stirring, The mixture was stirred at room temperature overnight, then quenched with water (100 mL), and extracted with CH2CI2 (3 x 100 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 /5) and afforded the title compound (5.5 g, near quantitative yield) as an oil.
97%
With thionyl chloride; In dichloromethane; at 20℃;
1.00 g (6.97 mmol) of (2-chloropyridin-4-yl)methanol was dissolved in 40 ml of methylene chloride, 10 ml of thionyl chloride were slowly added at RT and the mixture was stirred at RT overnight. The mixture was then concentrated on a rotary evaporator and the residue was stirred in a mixture of methylene chloride and aqueous sodium bicarbonate solution. The phases were separated and the methylene chloride phase was dried over anhydrous magnesium sulphate, filtered and concentrated on a rotary evaporator. 1.10 g (97% of th.) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, delta/ppm): 8.49 (d, 1H), 7.38 (s, 1H), 7.27-7.22 (m, 1H), 4.52 (s, 2H).LC/MS (method E, ESIpos): Rt=1.43 min, m/z=162 [M+H]+.
97%
Example 29A; 2-Chloro-4-(chloromethyl)pyridine 1.00 g (6.97 mmol) of (2-chloropyridin-4-yl)methanol was dissolved in 40 ml of dichloromethane, 10 ml of thionyl chloride were slowly added at RT and the mixture was stirred at RT overnight. The mixture was then concentrated on a rotary evaporator and the residue was stirred in a mixture of dichloromethane and aqueous sodium bicarbonate solution. The phases were separated and the dichloromethane phase was dried over anhydrous magnesium sulphate, filtered and concentrated on a rotary evaporator. 1.10 g (97% of theory) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, delta/ppm): 8.49 (d, 1H), 7.38 (s, 1H), 7.27-7.22 (m, 1H), 4.52 (s, 2H).LC/MS (method E, ESIpos): Rt=1.43 min, m/z=162 [M+H]+.
97%
With thionyl chloride; In dichloromethane; at 20℃;
Example 43A 2-Chloro-4-(chloromethyl)pyridine 1.00 g (6.97 mmol) of (2-chloropyridin-4-yl)methanol was dissolved in 40 ml of methylene chloride, 10 ml of thionyl chloride were slowly added at RT and the mixture was stirred at RT overnight. The mixture was then concentrated on a rotary evaporator and the residue was stirred in a mixture of methylene chloride and aqueous sodium bicarbonate solution. The phases were separated and the methylene chloride phase was dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator. 1.10 g (97% of th.) of the title compound were obtained. 1H-NMR (400 MHz, CDCl3, delta/ppm): 8.49 (d, 1H), 7.38 (s, 1H), 7.27-7.22 (m, 1H), 4.52 (s, 2H). LC/MS (method E, ESIpos): Rt=1.43 min, m/z=162 [M+H]+.
88.6%
With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -78 - 20℃;
A sample of (2-chloropyridin-4-yl)methanol (110.0 mg, 0.77 mmol) was dissolved in anhydrous THF (1.5 mL), treated with /Y,iV-diisopropylethylamine (0.29 mL, 1.69 mmol) and cooled to -78 0C. Methanesulfonyl chloride was added (0.07 mL, 0.84 mmol), and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo yielding the title compound (110.0 mg, 88.6%).1H NMR (300 MHz, CD3CN) delta 8.40 (d, 1 H), 7.49 (s, 1 H), 7.39 (d, 1 H) and 4.63 ppm (s, 2 H); ES-MS m/z 183.2 [M+Na]+, HPLC RT (min) 2.30.
88.6%
With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -78 - 20℃;
Step 2: Preparation of 2-chloro-4-(chloromethyl)pyridine; A sample of (2-chloropyridin-4-yl)methanol (110.0 nig, 0.77 mmol) was dissolved in anhydrous THF (1.5 mL), treated with ^V.A'-diisopropylethylamine (0.29 mL, 1.69 mmol) and cooled to -78 C. Methanesulfonyl chloride was added (0.07 mL, 0.84 mmol), and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layerwas dried over Na2SO4 and concentrated in vacuo yielding the title compound (110.0 mg,88.6%).1H NMR (300 MHz, CD3CN) 8 8.40 (d, 1 H), 7.49 (s, 1 H), 7.39 (d, 1 H) and 4.63ppm (s, 2 H); ES-MS m/z 183.2 [M+Na]+, HPLC RT (min) 2.30.
88.6%
With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -78 - 20℃;
Preparation of 2-chloro-4-(chloromethyl)pyridineA sample of (2-chloropyridin-4-yl)methanol (110.0 mg, 0.77 mmol) was dissolved in anhydrous THF (1.5 mL), treated with N,iV-diisopropylethylamine (0.29 niL, 1.69 mmol) and cooled to -78 C. Methanesulfonyl chloride was added (0.07 mL, 0.84 mmol), and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo yielding the title compound (110.0 mg, 88.6%).1H NMR (300 MHz, CD3CN) ? 8.40 (d, 1 H), 7.49 (s, 1 H), 7.39 (d, 1 H) and 4.63 ppm (s, 2 H); ES-MS m/z 183.2 [M+Na]+, HPLC RT (min) 2.30.
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h;
Stage b): 2-Chloro-4-chloromethylpyridine To a solution of 11.3 g of 2-chloro-4-hydroxymethylpyridine obtained in stage a) below in 200 mL of dichloromethane are added dropwise 6.896 mL of thionyl chloride, followed by 2.1 mL of dimethylformamide, the reaction mixture is stirred for 3 hours at room temperature and 50 mL of water are then added dropwise. The phases are separated and the organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 12.8 g of 2-chloro-4-chloromethylpyridine in the form of an amber-coloured liquid, which is used without further purification. Rf: silica TLC=0.44 (eluent: dichloromethane).
b 2-Chloro4-pyridinecarboxaldehyde A suspension of 2-chloro-4-hydroxymethylpyridine (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in ethyl acetate was refluxed for 3 h. Another portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) was added and heating was continued another 3.5 h. The reaction mixture was cooled, filtered through a pad of celite, concentrated under reduced and chromatographed with 0.5-4% CH3 OH/CH2 Cl2. The combined fractions were washed with NaHCO3 (sat.), 10% Na2 S2 O3, and NaCl (sat.), dried, filtered and evaporated to give the title compound as a light yellow solid (5.3 g, 67% yield). 1 H NMR (CDCl3): delta10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
67%
With N-Bromosuccinimide; In ethyl acetate;
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-hydroxymethylpyridine (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in ethyl acetate was refluxed for 3 h. Another portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) was added and heating was continued another 3.5 h. The reaction mixture was cooled, filtered through a pad of celite, concentrated under reduced and chromatographed with 0.5-4% CH3 OH/CH2 Cl2. The combined fractions were washed with NaHCO3 (sat.), 10% Na2 S2 O3, and NaCl (sat.), dried, filtered and evaporated to give the title compound as a light yellow solid (5.3 g, 67% yield). 1 H NMR (CDCl3): delta10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H,J=5.0 Hz).
With dimethyl sulfoxide; triethylamine; In dichloromethane; water;
(1) To a solution of oxalyl chloride (42.2 ml) in methylene chloride (1100 ml) is added dropwise a solution of dimethyl sulfoxide (68.7 ml) in methylene chloride (220 ml) at -60 C. to -50 C., and thereto is further added dropwise a solution of 2-chloro-4-hydroxymethylpyridine (63.2 g) in methylene chloride (440 ml) at the same temperature. The mixture is stirred for 15 minutes, and thereto is added dropwise triethylamine (306.6 ml) at the same temperature. The mixture is stirred for five minutes, and warmed to room temperature. After the reaction is complete, to the reaction mixture is added water (2.2 liters). The methylene chloride layer is separated, and the aqueous layer is extracted again with methylene chloride (2.2 liters). The methylene chloride layers are combined, and washed with a saturated aqueous sodium hydrogen carbonate solution, dried, and concentrated under reduced pressure to remove the solvent to give 2-chloropyridine-4-carbaldehyde.
The starting material was prepared as follows: A mixture of <strong>[100704-10-7]2-chloro-4-hydroxymethylpyridine</strong> (1.0 g, 7 mmol), (prepared as described for the starting material in Example 58), and methylamine (30 ml of a 30% solution in ethanol) was heated in a Carius tube for 16 hours at 200 C. The mixture was allowed to cool and the mixture partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluding with ethyl acetate to give 4-hydroxymethyl-2-(methylamino)pyridine (440 mg, 46%) as a yellow oil. 1 H NMR Spectrum (DMSOd6) 2.72(d, 3H); 4.35(d, 2H); 5.15(t, 1H); 6.30(br d, 1H); 6.35(d, 1H); 6.38(s, 1H); 7.85(d, 1H)
The starting material was prepared as follows: A mixture of <strong>[100704-10-7]2-chloro-4-hydroxymethylpyridine</strong> (1.0 g, 7 mmol), (prepared as described for the starting material in Example 58), and dimethylamine (30 ml of a 30% solution in ethanol) was heated in a Carius tube for 16 hours at 200 C. The mixture was allowed to cool and the mixture partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluding with ethyl acetate to give 4-hydroxymethyl-2-(dimethylamino)pyridine (1 g, 94%) as a yellow oil. 1 H NMR Spectrum (DMSOd6) 3.00(s, 6H); 4.40(d, 2H); 5.20(t, 1H); 6.45(d, 1H); 6.55(s, 1H); 7.96(d, 1H) MS-ESI: 153 [MH]+
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.
C. Production of 2-chloro-4-pyridinemethanol First, 380 g of 15% NaOH aqueous solution was added to the above-mentioned intermediate product in a reaction vessel. Then, the reaction mixture was stirred for 2 hr at a temperature of 60 C. After the reaction mixture was cooled down, 200 g of water was added thereto. Then, the reaction product was extracted two times from the reaction mixture with methylene chloride. The extract was washed with water and a saturated salt solution and then dried. Then, methylene chloride was distilled off. With this, oil was recovered. This recovered oil was distilled under reduced pressure. With this, 2-chloro-4-methylpyridine which is a non-chlorinated raw material and 2-chloro-4-pyridinemethanol as the objective reaction product were recovered. The recovered 2-chloro-4-methylpyridine had a yield of 79.5 g, a boiling point under 15 mmHg of from 86 to 87 C., and a purity (GC purity) of 98.35%. The recovered 2-chloro-4-pyridinemethanol had a yield of 76.6 g, a boiling point under 1 mmHg of from 108 to 110 C., and a purity (GC purity) of 98.60%.
41
[ 584-08-7 ]
[ 151477-57-5 ]
[ 100704-10-7 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 2-chloro-4-acetoxymethylpyridine; dichloromethane; water;
C. Production of 2-chloro-4-pyridinemethanol First, 92.75 g of 2-chloro-4-acetoxymethylpyridine recovered in Step B was mixed with 104.3 g of water and 104.3 g of concentrated hydrochloric acid. This 2-chloro-4-acetoxymethylpyridine having a purity of 91.34% contained 7.09% of 2-chloro-4-dichloromethylpyridine. The reaction mixture was stirred for 3 hr at a temperature of 50 C. After the reaction mixture was cooled down, the reaction mixture was washed two times with 25 ml of methylene chloride. With this, impurities such as 2-chloro-4-dichloromethylpyridine were removed. Then, the reaction mixture was made basic by adding thereto 276 g of 50% K2 CO3 aqueous solution. Then, the reaction product was extracted two times from the reaction mixture with 250 ml of methylene chloride. Then, the extract was washed with water and a saturated salt solution and then dried. Then, extraction solvent was distilled off. With this, 2-chloro-4-pyridinemethanol in the form of colorless solid was obtained. This 2-chloro-4-pyridinemethanol had a yield of 62.0 g, a melting point of from 66.1 to 66.5 C., and a purity (GC purity) of 99.34%.
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-pyridinemethanol (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in EtOAc was refluxed for 3 h. A Second portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) were added and the reaction was heated to reflux for an additional 3.5 h, cooled and filtered through a pad of celite. The filtrate, after concentrattion to a small volume, was subjected to flash chromatography eluding with 0.5-4% CH3 OH/CH2 Cl2. The fractions containing product were combined, washed successively with sat aq NaHCO3 10% Na2 S2 O3, and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a light yellow solid; yield 5.3 g (67%). 1 H NMR (CDCl3) delta 10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
5.3 g (67%)
With N-Bromosuccinimide; In ethyl acetate;
b 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-pyridinemethanol (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2 CO3 (11.75 g, 97.1 mmol) in EtOAc was refluxed for 3 h. A second portion of NBS (14.9 g, 83.9 mmol) and Na2 CO3 (12.0 g, 114 mmol) were added and the reaction was heated to reflux for an additional 3.5 h, cooled and filtered through a pad of celite. The filtrate, after concentration to a small volume, was subjected to flash chromatography eluding with 0.5-4% CH3 OH/CH2 Cl2. The fractions containing product were combined, washed successively with sat aq NaHCO3 10% Na2 S2 O3, and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a light yellow solid; yield 5.3 g (67%). 1 H NMR,,(CDCl3) delta 10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
A solution of (2-chloropyridine-4-yl)methanol (from the preparation of Intermediate P, Step 1) and methylamine hydrochloride in pyridine is heated at 200 C in a sealed tube for about 16 h. The solvent is removed by evaporation in vacuo and the crude product residue is purified by chromatography on silica gel using a gradient from dichloromefhane to about 10 % methanol in dichloromethane.
In pyridine; at 200℃; for 16h;Sealed tube;
Preparation of r2-(methylamino)pyridin-4-yllmethanolA solution of (2-chloropyridine-4-yl)methanol (from the preparation of Intermediate P, Step 1) and methylamine hydrochloride in pyridine is heated at 200 C in a sealed tube for about 16 h. The solvent is removed by evaporation in vacuo and the crude product residue is purified by chromatography on silica gel using a gradient from dichloromethane to about 10 % methanol in dichloromethane.
3-chloro-4-fluoro-N-{cis-4-[(4-hydroxymethylpyridin-2-yl)amino]cyclohexyl}benzamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A mixture of (2-chloropyridin-4-yl)rnethanol (250 mg), N-(comega-4-aminocyclohexyl)-3-chloro -4-fluorobenzamide obtained in step A of example 1 (566 mg), and BuOH (1 mL) was heated in a microwave synthesizer at 220 0C for 20 min and 240 0C for 20 min. The mixture was diluted with CHCl3 and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, filtrated, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 33% to 100% EtOAc in hexane). To a solution of the above purified material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at ambient temperature for 1 h and concentrated under reduced pressure. A suspension of the residue in Et2O (10 mL) was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 8O0C under reduced pressure to give 3-chloro-4-fluoro-N-(c-4-[4-(hydroxymethyl)pyridin- 2-yl]amino}cyclohexyl)benzamide hydrochloride (68.0 mg) as a white solid. 1HNMR (300 MHz, DMSO-^6, delta): 1.61-1.98 (m, 8H), 3.80-3.98 (m, 2H), 4.53 (s, 2H), 6.74 (d, J= 7.0 Hz, IH), 7.12 (s, IH), 7.53 (t, J= 8.9 Hz, IH), 7.81-7.95 (m, 2H), 8.11 (dd, J= 7.4, 1.9 Hz, IH), 8.41 (d, J= 6.4 Hz, IH), 8.64-8.76 (m, IH); ESI MS m/z 378 [M (free)++l, 100%].
In a 250 mL tricol equipped with a low temperature thermometer and two equalizing dropping funnels was charged oxalyl dichloride (1.24 g, 9.81 mmol) in dichloromethane (15 mL) and this solution was stirred under N2 at - 78 0C. The first equalizing dropping funnel was connected to a nitrogen flow line and was charged with a solution of (2-chloropyridin-4-yl)methanol SLA 07152 (0.94 g, 6.54 mmol) with dichloromethane (15 mL). The other was charged with a solution of dimethyl sulfoxide anhydrous (1 .7 mL, 19.63 mmol) in dichloromethane (2 mL) and this solution was added dropwise (25 min) in <n="80"/>order to stabilize the temperature between -60 0C and -70 0C. At the end of the addition the reaction solution was warmed to -60 0C over a period of 20 min then the solution of (2-chloropyhdin-4-yl)methanol SLA 07152 was added dropwise (50 min) keeping the temperature between -50 0C and -60 0C in the reactor then the mixture reaction was warmed to -45 0C over a period of 30 min. The dropping funnel was washed with dichloromethane (2 x 5 mL) and charged with a solution of thethylamine (480 mul_, 6.51 mmol) in dichloromethane (4 mL) which was added (10 min) to the reaction mixture and finally the reaction flask was allowed to warm to 0 0C over 10 min. The reaction solution was transferred to a 500 mL separatory funnel charged with 130 mL of a 5 % aqueous NH4CI solution. The two phases were separated the aqueous phase was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were washed with 1 M aqueous phosphate buffer (pH = 7; 4x10OmL), then dried over MgSO4, filtered and evaporated. 2- Chloropyridine-4-carbaldehyde SLA 07156 was obtained as an orange solid (0.740 g, 76 % yield).SLA 07156MW: 141.57; Yield: 76 %; Orange Solid. Rf: 0.35 (EtOAc:cyclohexane = 30:70).1H-NMR (CDCI3, delta): 7.65 (dd, 1 H, J = 5.0 Hz, J = 1 .3 Hz, ArH), 7.75 (d, 1 H, J = 1.3 Hz, ArH) 8.66 (d, 1 H, J = 5.0 Hz, ArH), 10.05 (s, 1 H, CHO).
5.3 g (67%)
With N-Bromosuccinimide; sodium carbonate; potassium carbonate; In ethyl acetate;
b) 2-Chloro-4-pyridinecarboxaldehyde A suspension of 2-chloro-4-pyridinemethanol (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2CO3 (11.75 g, 97.1 mmol) in EtOAc was refluxed for 3 h. A second portion of NBS (14.9 g, 83.9 mmol) and Na2CO3 (12.0 g, 114 mmol) were added and the reaction was heated to reflux for an additional 3.5 h, cooled and filtered through a pad of celite. The filtrate, after concentrattion to a small volume, was subjected to flash chromatography eluding with 0.5-4% CH3OH/CH2Cl2. The fractions containing product were combined, washed successively with sat aq NaHCO3 10% Na2S2O3, and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a light yellow solid; yield 5.3 g (67%). 1H NMR (CDCl3) delta10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 1h;
Imidazole (2.32 g, 33.7 mmol, 1.1 equiv) and tert-butyl-diphenylsilyichioride (8.0 ml, 33.7 mmol, 1.1 equiv) are added sequentially at room temperature to a solution of (2-chloro- pyridin-4-yl)-methanol (4.4 g, 30.6 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture is stirred at room temperature for 1 hour. TLC analysis indicated complete consumption of starting material. The solvent is removed in vacuo, and the residue is purified via flash chromatography (hexane / EtOAc 90 : 10) to yield the title compound (10.7 g, 91 %). 1H NMR (400 MHz, CDCI3): delta = 8.35 (d, J =5.0 Hz, 1 H), 7.69 - 7.67 (m, 4H), 7.48 - 7.35 (m, 11H), 7.20 (d, J = 5.0 Hz, 1H), 4.75 (s, 2H), 1.14 (s, 9H). MS (ES+): 383 (M+H)+.
With hydrazine; In isopropyl alcohol; at 100℃; for 24h;
Example 4; (S)-1-(4-((2-aminopropanamido)methyl)pyridin-2-yl)-N-(2-methoxybenzyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (44); Step 1 (2-hydrazinylpyridin-4-yl)methanol (36); 0216] To a stirred suspension of (2-chloro-4-pyridinyl) methanol (0 885 g, 6 16 mmol) in 2- propanol (9 ml_) was added hydrazine monohydrate (6 0 mL, 124 mmol) The resulting suspension was allowed to stir for 24h at 100 0C Solvent was evaporated The residue was purified by silica gel column chromatography with gradient of MeOH (5-20%) in CH2CI2 to afford 36 (223 mg, 26%) as a white solid LRMS calc 139 1 , found 140 2 (MH) +
With tributylphosphine; di-isopropyl azodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 16.5h;
A. To a solution of tributylphosphine (4.57 g, 22.63 mmol) in anhydrous tetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (4.57 g, 22.63 mmol) at 0 C. The reaction mixture was stirred for 10 minutes at 0 C., then added to a solution of <strong>[100704-10-7](2-chloropyridin-4-yl)methanol</strong> and phenol in anhydrous tetrahydrofuran (50 mL) at 0 C. The reaction mixture was stirred at 0 C. for 20 minutes then at ambient temperature for 16 hours. The reaction was quenched with saturated ammonium chloride solution (10 mL). The solvent was evaporated in vacuo. The residue was diluted with ethyl acetate (350 mL), washed with 1 N sodium hydroxide solution (3*40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/9) to afford 2-chloro-4-(phenoxymethyl)pyridine as a gummy solid in 61% yield (2.34 g): 1H NMR (300 MHz, CDCl3) delta 8.36 (d, J=5.1 Hz, 1H), 7.40 (s, 1H), 7.32-7.24 (m, 3H), 7.01-6.91 (m, 3H), 5.05 (s, 2H); MS (ES+) m/z 220.2 (M+1).
Triethylamine (1.2 mL, 8.4 mmols) was added to a mixture of (2-chloro-4-pyridinyl)methanol (1.0 g, 7.0 mmols), methanesulfonyl chloride (0.6 mL, 7.7 mmols) and ethyl acetate (20 mL) under cooling with ice, and stirred at room temperature for 2 hours. Filtering the reaction liquid, the filtrate was concentrated. To the resulting residue, 4-fluorophenol (0.94 g, 8.4 mmols), potassium carbonate (1.93 g,14.0 mmols) and N,N-dimethylformamide (20 mL) were added and stirred at 80C for 20 hours. Cooling the reaction liquid to room temperature, ethyl acetate was added thereto, followed by washing with saturated aqueous sodium hydrogencarbonate solution and saturated brine and drying over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil, FLASH 40 + M, chloroform) to provide the title compound (845 mg, 51%).
With dibenzyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 2h;
2-Chloro-4-(4-fluoro-phenoxymelhyl)-pyridinc:To a mixture of (2~chIoro-pyridin-4-yI)-mcthaiiol (0.500 g, 3.5 mmol), 4-fluoro-phcnol (0.430 g, 3.83 mmol) and triphenylphosphine (1.00 g, 3.83 mmol) in THF (10 mL) was added DBAD (0.890 g, 3.83 mmol) in a portion. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The crude material was purified over silica gel eluting with 0 to 50% EtOAc/hexanes to give 2-chloro-4-(4- fluoro-phenoxymethyl)-pyridine (1.60 g, di-Boc-hydrizine co-eluted). The material was carried on to the next step without further purification. 1H NMR (300 MHz, CDCl3) ? 8.42 (m, IH), 7.45 (s, IH), 7.29 (m, IH), 7.05 (m, 2H), 6.90 (m, 2H), 5.05 (s, 2H); ESMS m/e: 238.0 (M+H)+.
With sodium hydride; In tetrahydrofuran; mineral oil;Cooling with ice;
To an ice-cold solution of Compound II (850 mg) in tetrahydrofuran (10 mL) were added sodium hydride (517 mg) and methyl iodide (0.74 mL), and the mixture was stirred overnight. The reaction mixture 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=4/1) to give Compound III (674 mg).
3-Methyl-8-(2-chloropyridin-4-ylmethyloxy)pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; water;
General procedure: The reaction was carried out in 10 mL of dichloromethane towhich was added the starting material 9, III,43 V,46 (0.3 mmol),5 mL of 40% sodium hydroxide solution, 0.5 mmol of tetrabutylammoniumbromide (PTC), and the suitable alcohol in large excess(ratio with starting material 1:15) under vigorous stirring. The reaction was monitored by TLC, and when the starting materialdisappeared, the organic layer was separated and the aqueouslayer extracted twice with 10 mL of dichloromethane. The combinedorganic extracts were evaporated and the residue was recoveredwith isopropil ether and then recrystallized by suitablesolvent.
Step 1: [2-(piperazin-1-yl)pyridin-4-yl]methanol Under argon, 120 g (1.39 mol) of piperazine were added to 10.0 g (69.6 mmol) of <strong>[100704-10-7](2-chloropyridin-4-yl)methanol</strong>. With stirring, the mixture was heated at 150 C. overnight. After cooling to RT, the excess piperazine which had formed a deposit in the upper part of the reaction vessel was removed, and the resinous content of the flask was taken up in 700 ml of dichloromethane and stirred at RT for 30 min. The solid formed was filtered off, washed with dichloromethane and discarded, and the filtrate was concentrated. The residue was dried under reduced pressure. This gave 13.3 g (about 99% of theory) of the title compound which, according to 1H NMR, still contained piperazine. 1H NMR (400 MHz, CDCl3, delta/ppm): 8.14 (d, 1H), 6.67 (s, 1H), 6.58 (d, 1H), 4.64 (s, 2H), 3.55-3.45 (m, 4H), 3.01-2.94 (m, 4H). LC/MS (Method 6, ESIpos): Rt=0.19 min, m/z=194 [M+H]+.
99%
In dichloromethane; at 150℃;
Step 1: [2-(piperazin-1-yl)pyridin-4-yl]methanol 120 g (1.39 mol) of piperazine were added to 10.0 g (69.6 mmol) of <strong>[100704-10-7](2-chloropyridin-4-yl)methanol</strong> under argon. The mixture was heated at 150 C. overnight, while stirring. After cooling to RT, part of the excess piperazine which had deposited in the upper part of the reaction vessel was removed, and the resinous contents of the flask were taken up in 700 ml of methylene chloride and the mixture was stirred at RT for 30 min. The solid present was filtered off and rinsed with methylene chloride, the solid was discarded and the filtrate was concentrated. The residue was dried in vacuo. 13.3 g (approx. 99% of th.) of the title compound were obtained, which according to 1H-NMR still contained piperazine. 1H-NMR (400 MHz, CDCl3, delta/ppm): 8.14 (d, 1H), 6.67 (s, 1H), 6.58 (d, 1H), 4.64 (s, 2H), 3.55-3.45 (m, 4H), 3.01-2.94 (m, 4H). LC/MS (method D, ESIpos): Rt=0.19 min, m/z=194 [M+H]+.
In dichloromethane; at 150℃;Inert atmosphere;
Under argon, 120 g (1.39 mol) of piperazine were added to 10.0 g (69.6 mmol) of <strong>[100704-10-7](2-chloropyridin-4-yl)methanol</strong>. The mixture was heated at 150 C. overnight, while stirring. After cooling to RT, part of the excess piperazine which had deposited in the upper part of the reaction vessel was removed. The resinous contents of the flask were taken up in 700 ml of dichloromethane and the mixture was stirred at RT for 30 min. The solid that remained was filtered off, the filter cake was washed with dichloromethane and the solid was then discarded. The collected filtrate was concentrated and the residue was dried under reduced pressure. This gave 13.3 g (about 99% of theory) of the crude title compound which, according to 1H NMR, still contained piperazine. 1H NMR (400 MHz, CDCl3, delta/ppm): 8.14 (d, 1H), 6.67 (s, 1H), 6.58 (d, 1H), 4.64 (s, 2H), 3.55-3.45 (m, 4H), 3.01-2.94 (m, 4H). LC/MS (Method 4, ESIpos): Rt=0.19 min; m/z=194 [M+H]+.
(+/-)-1-(2-chloropyridin-4-yl)propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%; 49%
To a solution of <strong>[101066-61-9]2-chloropyridine-4-carbaldehyde</strong> (0.71 g, 5.06 mmol) in anhydrous THF (16 mL) was added a solution of lanthanum(III) chloride bis(lithium chloride) complex (0.6M in THF, 16.7 mL, 10.03 mmol) and the mixture was stirred at room temperature for 0.75 hours, then cooled to 0 C. Ethyl magnesium bromide (3M in diethyl ether, 3.34 mL, 10.03 mmol) was added dropwise over 5-10 minutes. The mixture was stirred at 0 C. for 80 minutes, then quenched with aqueous ammonium chloride, diluted with water and extracted with ethyl acetate (3*). The organic extracts were dried (Na2SO4) and evaporated. The crude product was chromatographed on silica gel (eluted with 0-50% ethyl acetate/cyclohexane) to give the title compound (423 mg, 49% yield). LCMS (ESI): RT (min)=2.14, [M+H]+=172, method=K.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
