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CAS No. : | 5470-70-2 | MDL No. : | MFCD00006340 |
Formula : | C8H9NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VYPPZXZHYDSBSJ-UHFFFAOYSA-N |
M.W : | 151.16 | Pubchem ID : | 231548 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 40.48 |
TPSA : | 39.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.6 cm/s |
Log Po/w (iLOGP) : | 1.92 |
Log Po/w (XLOGP3) : | 2.28 |
Log Po/w (WLOGP) : | 1.18 |
Log Po/w (MLOGP) : | 0.66 |
Log Po/w (SILICOS-IT) : | 1.64 |
Consensus Log Po/w : | 1.54 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.49 |
Solubility : | 0.495 mg/ml ; 0.00327 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.74 |
Solubility : | 0.275 mg/ml ; 0.00182 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.47 |
Solubility : | 0.512 mg/ml ; 0.00339 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.43 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: With sodium hydride In ethyl acetate; N,N-dimethyl-formamide; toluene at 80℃; for 10 h; Stage #2: With sulfuric acid In water at 110℃; for 2 h; Stage #3: With potassium carbonate In water |
Example 1 Preparation of 2-methyl-5-acetylpyridine 50g of methyl 6-methylnicotinate was dissolved in 200ml of ethyl acetate; 60percentNaH 26.5g, toluene 400ml and DMF 34ml were added to a three-necked bottle, 10percent methyl 6-methylnicotinate ethyl acetate solution 20ml was added, heated to 80°C, stirred for 0.5h. To the reaction bottle, the residual methyl 6-methylnicotinate ethyl acetate solution was added dropwise slowly within about 1.5h. After addition, the reaction was conducted at 80°C for 8h. The reaction stopped, cooled to room temperature. 300ml of water was added to the reaction bottle, skimmed, the water layer was extracted with ethyl acetate three times, 200ml per time. All ethyl acetate layers were combined, distillated at a reduced pressure to evaporate ethyl acetate, then 10percentH2SO4 aqueous solution 400ml was added, heated to 110°C, refluxed for 2h. The reaction was then stopped, cooled to room temperature. Solid K2CO3 was used to adjust PH to 9, suction filtration was performed, the filter cake was washed with ethyl acetate. The filtrate was extracted with ethyl acetate four times, combined and rotary evaporated to dry, to obtain 35g of 2-methyl-5-acetylpyridine, yield was about 65percent. MS(EI) 135.1 (M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: With sodium hydride In N,N-dimethyl-formamide; toluene at 80℃; for 10 h; Stage #2: With sulfuric acid In water at 110℃; for 2 h; Stage #3: With potassium carbonate In water |
Example 1Preparation of 2-methyl-5-acetylpyridine; 50 g of methyl 6-methylnicotinate was dissolved in 200 ml of ethyl acetate; 60percent NaH 26.5 g, toluene 400 ml and DMF 34 ml were added to a three-necked bottle, 10percent methyl 6-methylnicotinate ethyl acetate solution 20 ml was added, heated to 80° C., stirred for 0.5 h. To the reaction bottle, the residual methyl 6-methylnicotinate ethyl acetate solution was added dropwise slowly within about 1.5 h. After addition, the reaction was conducted at 80° C. for 8 h. The reaction stopped, cooled to room temperature. 300 ml of water was added to the reaction bottle, skimmed, the water layer was extracted with ethyl acetate three times, 200 ml per time. All ethyl acetate layers were combined, distillated at a reduced pressure to evaporate ethyl acetate, then 10percent H2SO4 aqueous solution 400 ml was added, heated to 110° C., refluxed for 2 h. The reaction was then stopped, cooled to room temperature. Solid K2CO3 was used to adjust PH to 9, suction filtration was performed, the filter cake was washed with ethyl acetate. The filtrate was extracted with ethyl acetate four times, combined and rotary evaporated to dry, to obtain 35 g of 2-methyl-5-acetylpyridine, yield was about 65percent.MS(EI) 135.1 (M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With lithium aluminium tetrahydride In tetrahydrofuran at -5 - 23℃; for 2 h; | [0156] To a stirred solution of compound 11(21 g; 140 mmol; 1 eq) in dry THF (150 mL) was added 1M LiA1H4 solution in THF (210 mL; 210 mmol; 1.5 eq) dropwise at -5 °C and after completion of the addition it was stirred at 23 °C for 2 h. The mixture was cooled to -10°C and quenched with sodium sulfate decahydrate and ethyl acetate until effervescence ceased. The mixture was filtered through a Celite® pad and the filtrate was evaporated to dryness to afford the title compound (17 g, 100percent). 1H NMR (DMSO-d6) ö 8.37 (s, 1H), 7.59 (dd, 1H, J = 2, 8 Hz), 7.19 (d, 1H, J = 8 Hz), 5.22 (t, 1H, J = 6 Hz), 4.47 (d, 2H, J = 6 Hz), 2.45 (s, 3H). |
98% | With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 3 h; | To a solution of LiAlH4 (80.0 g, 2.11 mol) in anhydrous THF (1 L) at 0C, a solution ofmethyl 6-methylnicotinate (1, 200 g, 1.32 mol) in THF (1 L) was added dropwise. Afterstirring at 0C for 3 h, the reaction mixture was quenched with saturated aqueous Na2SO4(ca. 150 mL, 0.43 mol) at 0C. The mixture was filtered, and the solid washed with ethylacetate. The organic layer of filtrate was separated and dried over anhydous MgSO4. Solventwas removed to give 2 as a yellow oil (160 g, 98percent). Its 1H NMR data data matchedthose previously reported.27,28 HPLC > 99percent. |
97% | Stage #1: With lithium aluminium tetrahydride In diethyl ether at 55℃; for 1.5 h; Heating / reflux Stage #2: With water In diethyl ether at 0℃; for 1 h; |
Example 2 Diethyl α-(3,5-dimethoxy-4-hydroxyphenyl)-β-(5-(2-methylpyridyl)) ethylphosphonate A solution of methyl 6-methylnicotinate (25.0 g, 165 mmol) in 50 ml dry ether was added dropwise to a vigorously stirred suspension of LiAlH4 (9.41 g, 248 mmol) in 325 ml dry ether. The reaction mixture was heated to reflux with the oil bath of 55° for 1.5 h and was then cooled to 0°. Water (45 ml) was added dropwise and, 1 h later, the upper layer was decanted off. The remaining suspension was extracted with ether (9 portions of 250 ml). The combined organic phases were dried with MgSO4 and evaporated to yield 19.7 g (160 mmol, 97percent) of 5-(hydroxymethyl)-2-methylpyridine as an orange oil; GC-analysis indicated a purity of 98percent. |
87% | With lithium aluminium tetrahydride In tetrahydrofuran at -78℃; for 1 h; | To a solution of 90 (5.0 g, 3.31 mmol) in THE was cooled to -78°C, followed by addition of LAH solution (2M in THE, 4.13 mL, 8.27 mmol) slowly. The resulting mixture was stirred at -78°C for 1 h. After completion of reaction (TLC monitoring), water (4.0mL) and 15percent NaOH solution (4 mL) were added slowly. The resulting reaction mixture was filtered through Celite and washed with EtOAc (2 times). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure to yield 91(3.5 g, 87percent) as a light yellowish liquid. 1H-NMR (400 MHz, DMSO-d6): ö 8.36 (s,1H), 7.58 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 5.21 (t, J= 5.6 Hz, 1H), 4.46 (d,J=5.6 Hz, 2H) and 2.45 (s, 3H). LC-MS: 124.06 (M-H). To an ice-cold solution of 43(1.0 eq) and 91 (1.5 eq) in DCM was added DIAD (3.0 eq) and TPP (3.0 eq). Themixture was stirred at RT for 16h. After completion of reaction, the mixture was dilutedwith water and extracted with DCM (3 times). The combined organics was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified over silica gel column chromatography, eluting with 10percent EtOAc in hexanes to yield 92 (1.3 g, 31percent) as a light yellow solid. 1H-NMR (400 MHz,CDCI3): ö 8.59 (5, 1H), 7.64-7.68 (m, 2H), 7.46-7.47 (m, 1H), 7.14-7.18 (m, 2H), 5.10 (5, 2H), 3.85 (5, 3H), 2.58 (5, 3H) and 2.34 (5, 3H). MS: 272.16 (M+H). This material was then converted to 93 using the same conditions as described for 89. Analtyical data for 93: 1H-NMR (400 MHz, DMSO-d6): ö 12.90 (br s, 1H), 8.88 (5, 1H), 8.55 (5, 1H), 7.76-7.77 (m, 1H), 7.54 (5, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H),5.17 (5, 2H), 2.47 (5, 3H) and 2.22 (5, 3H). LC-MS: 258.14 (M+H). |
85% | Stage #1: With lithium aluminium tetrahydride In diethyl ether at -78℃; for 4 h; Stage #2: With water; ammonium chloride In diethyl ether |
Intermediate G:; Methyl (2E)-3-r6-(Hvdroxyrnethyl)pyridin-3-yllacrylic acid <n="28"/>The title compound was prepared by the following methodology:LiAIH4, Et2O MnO2, DCM Stage 1 Stage 2 MeO OMe Stage 3K2CO3, H2OTFAA, THF mCPBA, DCM Stage 5 Stage 4 Intermediate G; Stage 1 - Preparation of (6-methylpyridin-3-yl)methanol; To a suspension of lithium aluminium hydride (7.24g, 191mmol) in Et2O (400ml) at -780C was added via cannula over a period of one hour a solution of methyl 6-methylnicotinate (19.62g, 130mmol) in Et2O (20OmL). Once addition was completed, the mixture was stirred for a further 3h. Excess lithium aluminium hydride was quenched by dropwise addition of EtOAc (40 ml). The mixture was then warmed using a water-ice bath, and further quenched with sat NH4CI (50OmL). The ethereal layer was decanted, and EtOAc was added (50OmL). The mixture was stirred vigorously, and the organic layer was again decanted. The extraction procedure was repeated twice (50OmL EtOAc). The combined organic extracts were dried (MgSO4) and concentrated to yield the desired product (13.6g, 85percent). 1H NMR (300MHz, CDCI3) δ: 8.39 (1 H, s), 7.62 (1 H, dd, J=2.1 , 8.1 Hz), 7.14 (1 H, d, J=7.8Hz), 4.68 (2H, s), 2.54 (3H, s). |
82% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1.83333 h; Stage #2: With water In tetrahydrofuran at 0 - 20℃; for 1 h; |
A solution of methyl 6-methylnicotinate (50 g, 0.33 mol) in anhydrous tetrahydrofuran (100 ml) was slowly added dropwise to a suspension of LAH (12.6 g, 0.33 mol) in anhydrous tetrahydrofuran (500 ml) over a period of 30 minutes while cooling on ice, and the mixture was stirred at the same temperature for 1 hour and 20 minutes. After confirming completion of the reaction by thin layer chromatography, H2O (25 ml) was slowly added dropwise over a period of 30 minutes while cooling on ice, and the stirring was continued at room temperature for 30 minutes. Magnesium sulfate was added for drying, and the precipitate was filtered through celite and washed three times with ethyl acetate. The solvent was distilled off under reduced pressure to yield the title compound (33.6 g, 82percent) as a yellow oil.1H-NMR(CDCl3)δ(ppm) 2.55(3H.s), 4.69(2H.brs), 7.16(1H.d.J=8.4Hz), 7.61(1H.dd.J=8.4and2.4Hz), 8.46(1H.d.J=2.4Hz). |
64% | Stage #1: With sodium tetrahydroborate In methanol at 20℃; Stage #2: With water In methanol |
Step A: Preparation of (6-methylpyridin-3-yl)methanol: A solution of methyl6-methylnicotinate (16.3 g, 108 mmol) in MeOH (150 mL) was treated with sodium borohydride (12.2 g, 323 mmol) at ambient temperature in portions. The mixture was quenched with water (100 mL) and concentrated. This mixture was diluted with water (300 mL) and extracted with EtOAc. The combined organic extracts were dried (phase separator silicone treated filter paper) and concentrated to give (6-methylpyridin-3-yl)methanol (8.5 g, 64percent yield) as a light yellow oil. |
62% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at -78℃; for 20 h; Stage #2: With water In tetrahydrofuran; diethyl ether; ethyl acetate at 0℃; for 0.666667 h; |
Preparation of Reagent 3-(6-(chloromethyl)pyridin-3-yl)isoxazole; A. Preparation of (6-methylpyridin-3-yl)methanol; To a solution of lithium aluminum hydride (1 M in diethyl ether, 80 mL, 80 mmol) in 20 mL THF at -78° C. under argon, a solution of methyl 6-methylnicotinate (6.05 g, 40 mmol) in 60 mL diethyl ether was added over 1 h. The resulting reaction mixture was stirred at -78° C. for 1 h before 12 mL EtOAc was added over 10 min. The reaction mixture was allowed to warm up to 0° C. and 12 mL water was added drop-wise over 10 min. The resulting mixture was stirred for 30 min, then filtered through Celite. The filtrate was dried (Na2SO4), filtered and concentrated to obtain 3.07 g (62percent) of the title compound as an off-white solid. HPLC: retention time=0.19 min. |
62% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at -78℃; for 2 h; Stage #2: With water In tetrahydrofuran; diethyl ether; ethyl acetate at 0℃; for 0.166667 h; |
A. Preparation of (6-methylpyridin-3-yl)methanol To a solution of lithium aluminum hydride (1 M in diethyl ether, 80 mL, 80 mmol) in 20 mL THF at -78° C. under argon, a solution of methyl 6-methylnicotinate (6.05 g, 40 mmol) in 60 mL diethyl ether was added over 1 h. The resulting reaction mixture was stirred at -78° C. for 1 h before 12 mL EtOAc was added over 10 min. The reaction mixture was allowed to warm up to 0° C. and 12 mL water was added drop-wise over 10 min. The resulting mixture was stirred for 30 min, then filtered through Celite. The filtrate was dried (Na2SO4), filtered and concentrated to obtain 3.07 g (62percent) of the title compound as an off-white solid. HPLC: retention time=0.19 min. |
0.61 g | With lithium triethylborohydride In tetrahydrofuran at -78 - 0℃; | b) (6-methylpyridin-3-yl)methanol 1 M Lithium triethylborohydride (super hydride) in THF (12.0 mL, 0.01 moles) was added to a stirred solution of methyl 6-methylnicotinate (0.9 g, 0.06 moles) as obtained in step a) in dry THF (10 mL) at -78°C. The reaction mixture was slowly allowed to rise to 0 °C and stirred for 1 .5 h. Once the starting material was consumed (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with water, dried over anhydrous Na2S04 and concentrated under reduced pressure. Purification by column chromatography (silica gel, 3percent MeOH in dichloromethane) provided the title compound as pale yellow solid (0.61 g, 84percent). 1 H NMR (400 MHz, DMSO): δ 8.37 (s, 1 H), 7.57 (dd, J = 2.0 Hz & J2 = 7.9 Hz; 1 H), 7.19 (d, J = 7.8 Hz; 1 H), 5.21 (t, J = 5.9 Hz; 1 H), 4.47 (d, J = 5.4 Hz; 2H), 2.43 (s, 3H); MS (ES-MS): m/z 124.0 (M + 1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | at 20℃; for 4 h; | Reference Example 184 6-methylnicotinamide; A mixture of methyl 6-methylnicotinate (13.9 g) and 28percent aqueous ammonia (140 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 8.98 g, 72percent). 1H-NMR (CDCl3) δ: 2.63 (3H, s), 5.60-6.20 (2H, brm), 7.25-7.28 (1H, m), 8.04-8.07 (1H, m), 8.90 (1H, d, J=2.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | for 17 h; Reflux | [0154] To a stirred solution of compound I (40 g; 290 mmol; 1 eq) in methanol (0.75 L) was added sulfuric acid (40 mL) and the resulting mixture was heated at reflux for 17 h. The mixture was then evaporated to dryness and the pH was adjusted to 7 using saturated ice-cold aqueous NaHCO3 solution and solid NaHCO3. The organic components were extracted from the aqueous layer with ethyl acetate (3 x 500 mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to afford the title compound (33 g, 75percent) as an off-white solid. 1H NMR (CDC13) ö 9.06 (s, 1H), 8.13 (dd, 1H, J = 2, 8 Hz), 7.20 (d, 1H, J = 8 Hz), 3.89 (s, 3H), 2.58 (s, 3H). LCMS: m/z = 152.4 [M+Hj , RT = 2.36 minutes, (Program P1, Column W). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With iodine; trifluoroacetic acid In dimethyl sulfoxide at 160℃; for 2 h; | A mixture of methyl 6-methylnicotinate (5.0 g, 33.0 mmol), 12 (8.4 g, 33.2 mmol) andTFA (7.5 mL, 11.5 g, 0.1 mol) in DMSO (100 mL) was heated to 160°C for 2 h. Themixture was allowed to cool to RT and poured into a 1 N solution ofNa2S2O3 (aq.) (0.5L) solution, made alkaline using NaOH (2 N) and extracted with EtOAc (3 x 0.2 L).The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in DCM and applied on a short pad of silica. The product was eluted with EtOAc to afford the product as a yellowish solid (3.8 g, 23 mmol, 70percent). |
46% | Stage #1: With iodine; tert-Butyl iodide; trifluoroacetic acid In dimethyl sulfoxide at 160℃; for 3 h; Stage #2: With sodium thiosulfate In water; dimethyl sulfoxide Stage #3: With sodium hydrogencarbonate In water; dimethyl sulfoxide |
A solution of 6-methyl nicotinic acid methyl ester (1.00 g, 6.62 mmol), iodine (1.68 g, 6.62 mmol), 2-iodo-2-methylpropane (0.478.g, 2.60 mmol) and trifluoroacetic acid (2.26 g, 19.8 mmol) in anhydrous DMSO was heated for 3 h at 160° C. The reaction mixture was cooled to room temperature (rt) and treated with 1 N aq. Na2S2O3 (50 mL). The reaction mixture was adjusted to pH 10 with 1 N aq. NaHCO3. The reaction mixture was extracted with ethyl acetate (3*100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. Chromatography of the residue (SiO2; 0-3percent EtOH:DCM) gave the title compound as a solid (0.506 g, 46percent). |
37% | With iodine; trifluoroacetic acid In dimethyl sulfoxide at 0 - 140℃; for 3.5 h; | Iodine (33.5g, 0.13mmol) and trifluoroacetic acid (35.3ml, 0.4mmol) were added to a solution of methyl 6-carboxylate-1-picoline (20g, 0.13mol) in N,N-dimethylsulfoxide (200ml) at 0°C and the mixture was stirred for 1 hourand then heated to 140°C and stirred for 2.5 hours. After being cooled to 0°C, the reaction was quenched with saturatedsodium thiosulfate solution (30ml) and stirred for 30 minutes. The aqueous layer was extracted with ethyl acetate (150ml3 3) and the organic layers were combined and washed with brine (50ml 3 2), dried over anhydrous sodium sulfate,filtered, concentrated in vacuo and the residue was purified by flash silica gel column chromatography to give the titlecompound (8g, yield 37percent). 1H NMR (400MHz, CHLOROFORM-d) ppm :10.14 (s, 1H), 9.36 (s, 1H), 8.47 (dd, J=1.3, 8.0Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 4.05 - 3.94 (s, 3H). |
15% | With selenium(IV) oxide In 1,4-dioxane at 85℃; Inert atmosphere | 250mL single-neck flask was added methyl 6-methylpyridine-3-carboxylate (10g, 66.15mmol) and 1,4-dioxane (100mL), was added under stirring selenium dioxide (14.7g, 132mmol), nitrogen heated to 85 under the protection of the reaction overnight. Cooling to room temperature, filtered, and the solvent was removed by rotary evaporation, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1/1), give a pale yellow solid 1.6g, Yield: 15percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.04 g | With dmap; triethylamine In dichloromethane at 20℃; for 1 h; | Method 23 Synthesis of (5-bromo-2-pyridyl)-(1-methylindol-3-yl)methanone (Intermediate 33) To a solution of R-8 (5.00 g, 34.45 mmol), DMAP (0.42 g, 3.44 mmol) and triethylamine (9.6 mL, 68.89 mmol) in DCM (300 mL) is added di-tert-butyl dicarbonate (8.27 g, 37.89 mmol) and the resultant solution stirred at room temperature for 1 h. The solution is washed with saturated aqueous NH4Cl and brine then dried over anhydrous Na2SO4. The solvent is removed in vacuo to give I-29 (8.04 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 6 h; Heating / reflux | 0.471 g (1.0 equivalent) of N-bromosuccinimide and 64 mg (0.1 equivalent) of benzoyl peroxide are added to a solution of 0.4 g of the product obtained in the preceding Stage 1 in 15 ml of carbon tetrachloride. The solution is brought to reflux for 6 hours, then filtered and evaporated under reduced pressure. The residue is purified by chromatography on silica gel (dichloromethane/ethyl acetate: 95/5) to produce 0.262 g of the expected product. [ Yield: 43percent MS: MH+ 231 |
37% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 75℃; for 18 h; | [01 10j To a solution of methyl 6-methylnicotinate (0.5 g, 3.31 mmol) in carbon tetrachloride (15 mL) was added N-bromosuccinimide (0.647 g, 3.63 mmol) followed by azobisisobutyronitrile (0.054 g, 0.33 mmol). The reaction mixture was heated at 75 °C for 18 h. The reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by silica gel column chromatography, using 50percent ethyl acetate in hexane to afford methyl 6- (bromomethyl)nicotinate (0.28 g, 37percent yield) as a brownish solid. Calculated M+H: 229.97; Found M+H: 230.01. |
35% | With N-Bromosuccinimide In tetrachloromethane | [Step 1] Synthesis of methyl 6-bromomethylnicotinate methyl 6-methylnicotinate (1 g) was dissolved in carbon tetrachloride (100 ml), and N-bromosuccinimide (1.3 g) was added. The mixture was heated under reflux in an argon atmosphere for 8 hours, and allowed to cool. The precipitated crystals were removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/methylene chloride=1:3) to obtain the title compound (540 mg, 35percent). m.p.: 75.2-76.3° C. IR spectrum (KBr tab.) νcm-1: 1728, 1713, 1595, 1435, 1286, 1124, 1103. NMR spectrum (*DMSO-d6) δ ppm: 9.05 (1H, s), 8.34-8.30 (1H, m), 7.71 (1H, d, J=7.9 Hz), 4.77 (2H, s), 3.89 (3H, s). |
34% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 75℃; for 12 h; | Step A: At room temperature, to a solution of methyl 6-methylnicotinate (10 g, 0.0662 mol) in CCl4 (100 mL) was added NBS (13.0 g, 0.0728 mol) and BPO (1.6 g, 0.0066 mol). The reaction mixture was heated to 75°C and stirred for 12 h. After cooling, water was added (80 mL) and the mixture was extracted with ethyl acetate (200 mL*2). The organic layer was washed with saturated sodium thiosulfate aqueous solution (80 mL), dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1) to give methyl 6-(bromomethyl)nicotinate (5.2 g, yield 34percent) as brown solid. 1HNMR(CDCl3,400MHz):δ9.18(d,J=1.6Hz,1H),8.32(dd,J1=8.0Hz,J2=2.0Hz,1H),7.55(d,J=8.0Hz,1H),4.60 (s,2H),3.97(s,3H). MS(ESI)m/z:230,232[M+H+]. |
34% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 75℃; for 12 h; | NBS (13.0 g, 0.0728 mol) and BPO (1.6 g, 0.0066 mol) were added to a solution of methyl 6-methylnicotinate (10 g, 0.0662 moles) in CCl4 (100 ml) at room temperature TheThe reaction mixture was heated to 75 & lt; 0 & gt; C and stirred for 12 hours. After cooling, water (80 ml) was added,And extracted with ethyl acetate (200 ml x 2). The organic layer was sequentially saturated with sodium thiosulfate (80 ml)Aqueous solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (eluent: petroleum ether / ethyl acetate = 20/1) to give methyl 6- (bromomethyl) nicotinate (5.2 g, yield 34percent) as a brown solid. |
28% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In ethyl acetate at 80℃; for 3 h; | Methyl 6-methyl nicotinate (1.05 g, 10 mmol) was dissolved in ethyl acetate (50 ml), followed by addition of NBS (3.56 g, 20 mmol) and AIBN (329 mg, 2 mmol). After stirring at 80C for 3 hours, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane; 4/1) to give the title compound (682 mg, 28percent) as orange amorphous product.1H-NMR(CDCl3) ?: 3.96 (3H, s), 4.58 (2H, s), 7.53 (1H, d, J = 8.2 Hz), 8.30 (2H, dd, J = 1.8, 8.2 Hz), 9.17 (1H, d, J = 1.8 Hz) |
28% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); sodium hydrogencarbonate In ethyl acetate at 80℃; for 3 h; | Reference Example 4 Production of methyl 6-(bromomethyl)nicotinate Methyl 6-methylnicotinate (1.05 g, 10 mmol) was dissolved in ethyl acetate (50 ml), and NBS (3.56 g, 20 mmol) and AIBN (329 mg, 2 mmol) were added thereto. The reaction mixture was stirred at 80 °C for 3 hours, combined with an aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane = 1/4) to give the title compound (682 mg, 28 percent) as an orange amorphous compound. 1H-NMR(CDCl3) δ: 3.96 (3H, s), 4.58 (2H, s), 7.53 (1H, d, J = 8.2 Hz), 8.30 (2H, dd, J = 1.8, 8.2 Hz), 9.17 (1H, d, J = 1.8 Hz). |
26% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 95℃; Inert atmosphere | A mixture of methyl 6-methylnicotinate (2 g, 13.2 mmol, 1.0 eq), NBS (2.4 g, 13.2 mmol, 1.0 eq) and BPO (319 mg, 1.32 mmol, 0.1 eq) in CCI4 (40 mL) was stirred at 95 °C under N2 overnight. Then the reaction was quenched with water (10 mL), extracted with DCM (50 mLx3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated. The residue was purified on silica gel column (PE/EtOAc = 20/1) to afford a yellow solid (780 mg, 26percent). |
22.2% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; | To a solution of methyl 6-methylnicotinate (30 g, 197 mmol) and NBS (52.7 g, 296 mmol) in CC14 (300 mL) was added AIBN (3 g). Then the reaction mixture was heated to 80 °C and stirred overnight. Then the reaction mixture was cooled and filtered, and the filtrate was concentrated under vacuum to give a crude residue. The crude residue was purified by silica gel column chromatography (PE/EA = 5/1) to give methyl 6-(bromomethyl)nicotinate (10 g, yield 22.2 percent). 1H NMR (400MHz, CDC13) 5 = 9.17 (d, J=1.5 Hz, 1H), 8.30 (dd, J=2.0, 8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 4.58 (s, 2H), 3.96 (s, 3H). |
22.2% | With N-Bromosuccinimide; azobisisobutyronitrile In tetrachloromethane at 80℃; | (a) methyl 6-(bromomethyl)nicotinate To a solution of methyl 6-methylnicotinate (30 g, 197 mmol) and NBS (52.7 g, 296 mmol) in CCl4 (300 mL) was added AIBN (3 g). Then the reaction mixture was heated to 80° C. and stirred overnight. Then the reaction mixture was cooled and filtered, and the filtrate was concentrated under vacuum to give a crude residue. The crude residue was purified by silica gel column chromatography (PE/EA=5/1) to give methyl 6-(bromomethyl)nicotinate (10 g, yield 22.2percent). 1H NMR (400 MHz, CDCl3) δ=9.17 (d, J=1.5 Hz, 1H), 8.30 (dd, J=2.0, 8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 4.58 (s, 2H), 3.96 (s, 3H). |
22.2% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; | To a solution of methyl 6-methylnicotinate (30 g, 197 mmol) and NBS (52.7 g, 296 mmol) in CC14 (300 mL) was added AIBN (3 g). Then the reaction mixture was heated to 80 °C and stirred overnight. Then the reaction mixture was cooled and filtered, and the filtrate was concentrated under vacuum to give a crude residue. The crude residue was purified by silica gel column chromatography (PE/EA = 5/1) to give methyl 6-(bromomethyl)nicotinate (10 g, yield 22.2 percent). 1H NMR (400MHz, CDC13) 5 = 9.17 (d, J=1.5 Hz, 1H), 8.30 (dd, J=2.0, 8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 4.58 (s, 2H), 3.96 (s, 3H). |
21% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 20 - 80℃; for 12 h; Inert atmosphere | Azobisisobutyronitrile (1.08g, 7mmol) was added to a solution of 6-methyl-nicotinic acid methyl ester (5g,30mmol) and bromosuccinimide (6.48g, 30mmol) in carbon tetrachloride (40mL) at room temperature under nitrogen.The reaction solution was heated to 80°C, stirred for 12 hours, and filtered while hot. The filtrate was evaporated todryness and the residue was purified by flash silica gel column chromatography to give the title compound (1.6g, yield21percent). 1H NMR (400 MHz, CHLOROFORM-d) ppm 9.16 (d, J=1.00 Hz, 1H), 8.29 (dd, J=1.76, 8.03 Hz, 1H), 7.53 (d,J=8.03 Hz, 1H), 4.58 (s, 2H), 3.95 (s, 3H). |
493 mg | With N-Bromosuccinimide; azobisisobutyronitrile In benzene at 90℃; for 4 h; | Method 9 Synthesis of methyl 6-[[3-[1,2-dimethyl-1-[4-(2-pyridylmethoxy)phenyl]propyl]indol-1-yl]methyl]pyridine-3-carboxylate (Intermediate 13) To a solution of methyl-6-methyl nicotinate R-8 (1 g, 6.63 mmol) in anhydrous benzene (75 mL) is added N-bromosuccinimide (1.77 g, 9.95 mmol) and azobis(isobutyronitrile) (0.217 g, 1.32 mmol). The mixture is stirred at 90° C. for 4 h, then saturated aqueous NaHCO3 is added and the organic layer separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, 50percent DCM in heptane) to give I-12 (493 mg). A mixture of I-12 (75 mg, 0.33 mmol), I-11.40 (0.27 mmol) and KOH (30 mg, 0.54 mmol) in DMSO (1 mL) is stirred at room temperature for 18 h. The mixture is purified by preparative HPLC (Low pH method) to give I-13 (5 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.7% | With tert-butylmagnesium chloride In tetrahydrofuran at 65 - 70℃; for 1 h; | To the reaction flask was added llg (4-methylthio) phenylacetate, 200 mL of anhydrous THF, and the mixture was heated to 65-70The (: Maintaining T = 65-70 ° C while adding 88 ml of a solution of 1.0 M t-BuMgCl in THF and 5.7 g of 6-methylpyridine-3-carboxylic acid methylEster in 50 ml of THF. Dropping to complete the incubation reaction for 1 hour. Cooled to room temperature, dropping 50 ml of 4 M hydrochloric acid, layered, organic layerAnd then 50ml of 4M hydrochloric acid extraction, the water layer, the water layer by adding 50g sodium hydroxide, heated to 40-50 ° C stirring 3 hours, cooling toAt room temperature and filtered to give 8.3 g of a pale yellow solid, 87.7percent yield, 98.6percent pure |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.5% | With tert-butylmagnesium chloride In tetrahydrofuran at 65 - 70℃; for 1 h; | To the reaction flask was added llg (4-methylthio) phenylacetate, 200 mL of anhydrous THF, and the mixture was heated to 65-70 The (: Maintaining T = 65-70 ° C while adding 88 ml of a solution of 1.0 M t-BuMgCl in THF and 5.7 g of 6-methylpyridine-3-carboxylic acid methyl Ester in 50 ml of THF. Dropping to complete the incubation reaction for 1 hour. Cooled to room temperature, dropping 50 ml of 4 M hydrochloric acid, layered, organic layer And then 50ml of 4M hydrochloric acid extraction, the water layer, the water layer by adding 50g sodium hydroxide, heated to 40-50 ° C stirring 3 hours, cooling to At room temperature and filtered to give 7.4 g of a pale yellow solid, yield 78.5percent, purity 98.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tert-butylmagnesium chloride In tetrahydrofuran at 65 - 70℃; for 1 h; | To the reaction flask was added llg (4-methylthio) phenylacetic acid,200 mL of anhydrous THF, and the mixture was heated to 65-70 ° C.Maintain T = 65-70 ° C while dropping175 Mll. 0 M t-BuMgCl in THF and5.7g6-methylpyridine-3-carboxylate50 ml of THF solution. Dropping to complete the incubation reaction for 1 hour.Cooling to room temperature, dropping 50ml4M hydrochloric acid quenching reaction, stratification, organic layer and then 50ml4M hydrochloric acid extraction,The aqueous layer was added and the aqueous layer was added with 50 g of sodium hydroxide,Heated to 40-50 ° C for 3 hours, cooled to room temperature,Filtration gave 6.9 g of a pale yellow solid, 72.0percent yield, 97.3percent pure |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tert-butylmagnesium chloride In tetrahydrofuran at 65 - 70℃; for 1.5 h; | In a 4-neck anhydrous flask there are introduced at 20-25°C, 10.2 g of Lithium (4-methylsulfonyl)phenyl acetate of formula (II- M=Li) (1.0 mol. equiv), 200 mL of Anhydrous THF and the mixture is heated to 65-70°C (up to reflux). Maintaining at T=65-70 °C there are simultaneously dosed in the mixture in about 1 hour: a) 66.0 g of t-BuMgCl 1.0 M solution in THF (about 74.2 mL) (1.6 mol. equiv.) andb) a solution of 4.64 g of the methyl ester of the 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) (0.65 mol. equiv.) in 15 mL of Anhydrous THF. After completing the addition, the mixture is stirred at 65-70 °C for 30 minutes. The reaction is controlled through HPLC then it is cooled to 20-25°C and the reaction mixture is diluted under vigorous stirring with 100 mL of water. Maintaining the temperature comprised in the range between 20°C and 25°C the mixture is brought to pH comprised between 1 and 0 by adding about 15 mL of 32percent hydrochloric acid. Stirring is carried out at 20-25°C for 30 minutes controlling the pH. The phases are separated by putting aside the organic phase useful for recovering the lithium (4-methylsulfonyl)phenyl acetate. The aqueous phase is washed using 2x50 mL of MTBE and the organic phases are recombined and used for recovering the (4-methylsulfonyl)phenyl acetate lithium. The aqueous phase is distilled at low pressure for removing the residue organic solvent. The product is precipitated under heat (40-45°C) by adding 7.5 mL of 30percent aqueous NaOH followed by cooling to room temperature. The product is filtered and dried in an oven under vacuum at 50°C for 8 hours. There are obtained 6.9 g of product as a white solid corresponding to a 78percent molar yield. HPLC purity 96.9percent (Apercent). Impurity '408' = 0.21percent (HPLC percent) (Figure 3). The organic phases obtained as described above are recombined to bring to a pH comprised between 11 and 12 by adding about 1 g of LiOH monohydrate solid. The mixture is concentrated to residue at low pressure at a maximum temperature of 40°C. The residue is suspended at room temperature in 2 volumes of Methanol. Stirring is carried out at room temperature for at least 3 hours. The suspension is filtered and the solid is washed using cold methanol then dried at low pressure at 90°C for 8 hours, to obtain 2.5 g of (4-methylsulfonyl)phenyl acetate lithium. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.8 kg | With tert-butylmagnesium chloride In tetrahydrofuran at 70 - 80℃; Large scale | 4-methanesulfonylphenylacetic acid (3.0 kg) was added tetrahydrofuran (6 L),A solution of 1 M t-butylmagnesium chloride in tetrahydrofuran (40 L) was added dropwise,Heating 70 ~ 80 ,A solution of methyl 6-methylnicotinate (1.7 kg) in tetrahydrofuran (5 L) was slowly added dropwise,About 2 to 3 hours dripping.After refluxing for 1 hour.Cooling to 20 ~ 25 ,add water,The pH of the sodium hydroxide aqueous solution (the mass concentration refers to the mass of sodium hydroxide as a percentage of the total mass of the aqueous sodium hydroxide solution) is adjusted to pH = 7 to 8,Precipitate a lot of solid.Centrifugal,The filter cake was rinsed with water and dried in vacuo at 50 ° C for 16 hours,About 3.6 kg of a yellow solid was obtained.Recrystallization from dichloromethane (20 L) gave 1.8 kg of etoposide intermediate II. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride; hydrogen In methanol; water at 80℃; for 21 h; Inert atmosphere | Collection A: Preparation of 6-Me-102A 400-mL Fisher-Porter reactor was charged with methanol (300 mL), concentrated hydrochloric acid (13.0 g), 10percent Pd/C (4.0 g) and methyl-6-methylnicotinate (20.0 g, 132 mmol). The mixture was heated to 80° C. and placed under 60 psi hydrogen pressure. The mixture was then stirred for 21 h under these conditions. The mixture was cooled and filtered. The filtrate was evaporated under reduced pressure to give 6-Me-102 (27.0 g, quantitative). The 1H NMR spectrum was consistent with the assigned structure. |
96.15% | With hydrogenchloride; platinum(IV) oxide; hydrogen In methanol; water at 50℃; for 15 h; | Step 1: PtO2 (3.00 g) was added to a methanol solution (200 mL) of methyl 6-methylpyridine-3-carboxylate(18.00g, 119.08 mmol), and then added with water (10mL) and hydrochloric acid (20mL); under H2 (50psi), the reaction solutionwas heated to 50°C and stirred for 15 h. TLC showed that the reactants were completely consumed; then solid werefiltered, and the filtrate was concentrated under reduced pressure, residues were dissolved in toluol (100 mL), then thesolvent toluol was spin-dried to obtain methyl 6-methylpiperidyl-3-carboxylatewhich was yellow oily matter (18.00 g, yieldwas 96.15percent). The value of C8H15NO2[M+H]+157 was calculated using MS ESI, was 157. |
3.9 g | With palladium on activated charcoal; hydrogen In methanol; acetic acid at 20℃; for 20 h; | To a methanol/acetic acid solution (40 mL/50 mL) of methyl 2-methylnicotinate (5.00 g), palladium/carbon (2.50 g) was added, and the reaction mixture was stirred for 20 hours at room temperature under a medium pressure-hydrogen atmosphere (0.35 MPa). The reaction solution was filtered with Celite, the filtrate was concentrated under reduced pressure. To the obtained residue, a saturated sodium hydrogen carbonate aqueous solution (150 mL) and a 0.2 mol/L sodium hydroxide aqueous solution (50 mL) were added. The product was extracted with dichloromethane (150 mL), and chloroform/methanol (90 mL/10 mL). The organic layer was dried with anhydrous sodium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure to give methyl 6-methylpiperidine-3-carboxylate (3.90 g). |
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