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CAS No. : | 5470-70-2 |
Formula : | C8H9NO2 |
M.W : | 151.16 |
SMILES Code : | O=C(OC)C1=CN=C(C)C=C1 |
MDL No. : | MFCD00006340 |
InChI Key : | VYPPZXZHYDSBSJ-UHFFFAOYSA-N |
Pubchem ID : | 231548 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
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 |
---|---|---|
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 |
---|---|---|
100% | With lithium aluminium tetrahydride; In tetrahydrofuran; at -5 - 23℃; for 2h; | [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 -10C 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, 100%). 1H NMR (DMSO-d6) oe 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 3h; | 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, 98%). Its 1H NMR data data matchedthose previously reported.27,28 HPLC > 99%. |
97% | Example 2 Diethyl alpha-(3,5-dimethoxy-4-hydroxyphenyl)-beta-(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, 97%) of 5-(hydroxymethyl)-2-methylpyridine as an orange oil; GC-analysis indicated a purity of 98%. |
87% | With lithium aluminium tetrahydride; In tetrahydrofuran; at -78℃; for 1h; | To a solution of 90 (5.0 g, 3.31 mmol) in THE was cooled to -78C, followed by addition of LAH solution (2M in THE, 4.13 mL, 8.27 mmol) slowly. The resulting mixture was stirred at -78C for 1 h. After completion of reaction (TLC monitoring), water (4.0mL) and 15% 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, 87%) as a light yellowish liquid. 1H-NMR (400 MHz, DMSO-d6): oe 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 10% EtOAc in hexanes to yield 92 (1.3 g, 31%) as a light yellow solid. 1H-NMR (400 MHz,CDCI3): oe 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): oe 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% | 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, 85%). 1H NMR (300MHz, CDCI3) delta: 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). | |
83% | a) 6-methyl-3-pyridylcarbinol Following the procedure of Example 2(b), except substituting methyl 6-methylnicotinate for N-cyclopropylmethyl isobutyramide, the title compound was prepared as a yellow oil (4.32 g, 83%). MS (ESI): 123.8 (M+H)+. | |
82% | 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, 82%) as a yellow oil.1H-NMR(CDCl3)delta(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% | 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, 64% yield) as a light yellow oil. | |
62% | 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 (62%) of the title compound as an off-white solid. HPLC: retention time=0.19 min. | |
62% | 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 (62%) of the title compound as an off-white solid. HPLC: retention time=0.19 min. | |
In tetrahydrofuran; water; | Reference Example 5 A solution of methyl 6-methylnicotinate (45.4 g) in tetrahydrofuran (50 ml) was added dropwise to a suspension of lithium aluminium hydride (LiAlH4, 5.7 g) in tetrahydrofuran (250 ml) at room temperature. The mixture was stirred at room temperature for additional 1 hour and water (30 ml) was added dropwise with ice-cooling. Insoluble materials were filtered off and the filtrate was concentrated. The residue was distilled under reduced pressure to obtain 6-methyl-3-pyridylmethanol (31 g, yield: 84%), b.p. 98-100 C./0.5 mmHg. | |
In tetrahydrofuran; water; | Step B: Preparation of 2-methyl-5-hydroxymethylpyridine Methyl 6-methylnicotinate (0.05 mole) is stirred in dry tetrahydrofuran (50 ml.) at 10 C. while solid lithium aluminum hydride (0.0125 mole) is added over one hour. Water (10 ml.) is added with stirring, and the mixture is concentrated to dryness. The residue is extracted several times with hot isopropanol and the combined extracts are filtered and concentrated to dryness to give 2-methyl-5-hydroxymethylpyridine. | |
With sodium sulfate; In tetrahydrofuran; | Reference example 2. 6-methylpyridine-3-carboaldehyde 1.00g (6.62mmol) of methyl 6-methyl nicotinate (Lancaster) was dissolved in 20ml of tetrahydrofuran anhydrous, and then 0.25g (6.59mmol) of lithium aluminum hydride was added thereto under ice bath cooling, followed by stirring for 30 minutes. Sodium sulfate 10 hydrate was added to the reaction mixture until no foam appeared, and after stirring for 2 hours, filtration with Celite was performed. The filtrate was subjected to vacuum concentration, and the residue was purified with silica gel column chromatography (ethyl acetate) to obtain 0.80g of 6-methylpyridine-3-methyl alcohol. | |
In a 500 ml round-bottomed flask at room temperature under nitrogen, methyl 6-methyl-3- pyridinecarboxylate (10 g, 66.2 mmol) was dissolved in dry tetrahydrofuran (100 ml) to give a orange solution. The mixture was then cooled down to 00C and lithium aluminum hydride (36.4 ml, 72.8 mmol) was added dropwise, keeping internal temperature below 00C. At the end of addition the ice-bath was removed and the resulting solution was stirred at room temperature for 3 hours. The mixture was slowly additioned with 2.73 ml of water, 2.73 ml of NaOH 1 M and 8.2 ml of water. The resulting yellow suspension was stirred at room temperature for -30 minutes and then filtered over a Gooch funnel. The solid was washed with Et2O (3 x 100 ml). The combined organics were dried over Na2SO4, filtered and concentrated to give the title product (7.48 g) as orange oil. | ||
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1.5h; | To a slurry of lithium aluminum hydride (500 mg, 13.2 mmol) in anhydrous tetrahydrofuran (45 mL) at 0 C. under nitrogen was added dropwise a solution of methyl 4-methylnicotinate (15, 1.0 g, 6.6 mmol) in anhydrous tetrahydrofuran (5 mL). After 1.5 h the suspension was diluted with water (1 mL) and 6 N NaOH solution (5 mL). The precipitate was removed by vacuum filtration and the filtrate was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to provide the title compound as a light yellow oil: 1H NMR (300 MHz) 8.34 (s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 4.65 (s, 2H), 4.18-4.10 (bs, 1H), 2.51 (s, 3H) ppm. | |
To aluminum lithium hydride (2.0 g) in THF (156 ml) was added dropwise methyl 6-methylnicotinate (7.8 g) in THF (78 ml) at 0C. The mixture was stirred for 2 hours at room temperature at 0C, and water (7.8 ml), 15% aqueous solution of sodium hydroxide (7.8 ml), and water (23.4 ml) were sequentially added to the mixture. The mixture was filtered with Celite, and washed with methanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give (6-methyl-3-pyridinyl)methanol (6.3 g)· 1H-NMR (200 MHz, CDCl3) delta 2.50 (3H, s), 4.64 (2H, s), 7.13 (1H, d, J = 8.0 Hz), 7.58 to 7.64 (1H, m), 8.34 (1H, s) | ||
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 2h; | Reference Example 18 Production of (6-methylpyridin-3-yl)methanol To a solution of methyl 6-methylnicotinate (2.45 g) in tetrahydrofuran (30 ml) was added slowly lithium aluminum hydride (0.62 g) at 0 C. After the temperature of the reaction mixture was elevated to room temperature, the reaction mixture was stirred at the same temperature for 2 hours.. The reaction mixture was poured into saturated brine, and extracted with ethyl acetate.. The ethyl acetate layer was dried over magnesium sulfate and concentrated.. The residue was purified by column chromatography (carrier: silicagel, eluant: hexane-ethyl acetate) to obtain the titled compound (1.49 g) as a yellow oily substance.1H-NMR (CDCl3) delta 2.51 (3H, s), 3.86 (1H, brs), 4.66 (2H, s), 7.13 (1H, d, J=8.0 Hz), 7.61 (1H, dd, J=2.2, 8.0 Hz), 7.63 (1H, d, J=2.2 Hz). | |
A solution of methyl 6-methylnicotinate (0.5 g, 3.3 mmol) in THF (16 mL) at 0 C. was treated dropwise with lithium aluminum hydride in THF (6.6 mL, 1 M), stirred at 0 C. for 1.5 hours, treated with ethyl acetate (3 mL), stirred at 25 C. The reaction was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the residue (0.395 g) in dichloromethane (16 mL) was treated with MnO2 (2 g), stirred at 25 C. for 68 hours, filtered through celite to give the title compound (0.326 g, 80% yield), which was used without further purification. | ||
Intermediate 1 Ethyl (2£)-3-(5-formylpyridin-2-yl)acrylateStage 1; Lithium aluminium hydride (23g, 1.2eq) in THF (50OmL) was cooled to -78C. Methyl-6- methylnicotinate was dissolved in THF (20OmL) and charged to the reaction at below - 700C. The reaction was allowed to warm to 00C over 1h and aged at ~0C for 1 h. On completion the reaction was quenched with sat. NaHCO3 (25OmL) below 10C.The reaction mixture was filtered to remove inorganics, the filter cake was washed with THF and the filtrate concentrated in vacuo to remove most of the THF. The residue was separated between ethyl acetate and water, the aqueous layer being extracted three times with EtOAc. Combined organics washed with K2CO3(aq), dried (MgSO4) then concentrated to dryness to afford the product (40.5g). 1H NMR (CDCI3): (8.35 ,1 H,s), 7.61 (1 H,dd), 7.13 (1 H,d), 4.65 (2H,d), 2.51 (3H,d). A second extraction of the aqueous layer provided additional product (5.5g) which was combined with the product from the first extraction. | ||
With hydrogenchloride; diisobutylaluminium hydride; In methanol; ethyl acetate; toluene; | Preparation of 5-hydroxymethyl-2-methyl-pyridine 5-Methoxycarbonyl-2-methyl-pyridine (3.0 g, 19.8 mmole) was dissolved in toluene (60 ml) and cooled to -78 C. To this solution, a 39.7 ml of a solution of 1M diisobutylaluminum hydride in toluene was added dropwise. The reaction mixture was stirred for 1 hour at -78 C., allowed to warm to room temperature and stirred for an additional 18 hours. Methanol (8 ml) was then added dropwise at room temperature to the reaction mixture. The mixture was stirred until a thick gel was formed. 1N HCl (10 ml) was added to dissolve the gel. The resulting phases were separated, the organic phase was extracted in ethyl acetate and dried over MgSO4. The solvents were removed yielding crude 5-hydroxymethyl-2-methylpyridine (540 mg) as an oil, which was used without further purification. | |
A solution of methyl 6-methylnicotinate (30 g, 198 mmol) in dry THF (150 mL) was added dropwise into a suspension of LiAlH4 (11 g, 289 mmol) in THF (200 mL) at 0 to - 5 C. The grey suspension was stirred at RT for lh. The reaction mixture was cooled to -5 to 0 C and water (11 mL) was added dropwise under nitrogen followed by slow addition of 15% NaOH (11 mL) and water (33 mL). The reaction was warmed to RT and stirred for 30 min. at RT. The resulting suspension was filtered and the filtrate was concentrated under vacuum to give (6-methylpyridin-3-yl)methanol as a yellow oil (23 g). | ||
With lithium aluminium tetrahydride; In tetrahydrofuran; at -5 - 5℃; for 2h; | (6-Methylpyridin-3-yl)methanolThe (6-Methylpyridin-3-yl)methanol used in the above process was prepared as follows:THF (4 L) was added to a flask containing LiAIH4 (150.4 g, 3.96 mol) and the resulting suspension cooled to < 0 C. Methyl 6-methylnicotinate (500 g, 3.31 mol) in THF (1 L) was added dropwise to the reaction over 2.5 h, maintaining a temperature < 5 C. Stirring was continued at 0+/- 5 C for 2 h and then the reaction was quenched slowly over 1 h 25 min with satd. NaHC03 (1 L) at < 10 C. The reaction was then stirred overnight at ambient temperature. The reaction was then filtered, and the filter cake washed with EtOAc (2.5 L) and the filtrate concentrated to dryness. The residue was partitioned between NaHC03 (500 ml_) and EtOAc (1 .5 L). The layers were separated and the aqueous layer extracted with EtOAc (3 x 1 L). The combined organic layers were concentrated to dryness. The residue was dissolved in EtOAc (1 L), dried (Na2S04) and concentrated to dryness to give the title compound (366 g). 1H NMR (CDCI3): 8.31 (1H, d, J=2.1 ), 7.59 (1 H, dd, J=7.8, 2.1 ), 7.10 (1 H, d, J=7.8), 4.69 (2H, s), 2.48 (3H, s). | |
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 -78C. 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, 3% MeOH in dichloromethane) provided the title compound as pale yellow solid (0.61 g, 84%). 1 H NMR (400 MHz, DMSO): delta 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 ). |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 1h; | Step 1: Intermediate 31-b To a solution of methyl 6-methylnicotinate 31-a (20.10 g, 133 mmol) in THF (90 ml) cooled to 0C was added drop wise a 1.0 M solution of LiAIH4 in THF ( 100 ml, 100 mmol) and the reaction was then stirred at 0C for 1 hour. Water (3.8 ml) was slowly added, followed by 15% NaOH (3.5 ml) and water (11.4 ml) and the mixture was stirred at room temperature for 1 hour. The reaction was filtered over celite and volatiles were removed in vacuo to provide intermediate 31-b as a yellow oil. | |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1h; | Step 1: Intermediate 31-b [0181] To a solution of methyl 6-methylnicotinate 31-a (20.10 g, 133 mmol) in THF (90 ml) cooled to 0 C. was added drop wise a 1.0 M solution of LiAlH4 in THF (100 ml, 100 mmol) and the reaction was then stirred at 0 C. for 1 hour. Water (3.8 ml) was slowly added, followed by 15% NaOH (3.5 ml) and water (11.4 ml) and the mixture was stirred at room temperature for 1 hour. The reaction was filtered over celite and volatiles were removed in vacuo to provide intermediate 31-b as a yellow oil. | |
To a solution of methyl 6-methylnicotinate (25 g, 0.16 mol) in ethyl ether (620 mL) under nitrogen was added dropwise sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al) (65wt.% in toluene, 110 mL, 0.37 mol) at room temperature. The mixture was then heated to reflux for 1.5 hr. After cooling, the reaction mixture was quenched with water (500 mL) at 0 0C and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel column to afford the title compound. | ||
To a solution of methyl 6-methylnicotinate (5.0 g, 33 mmol) in THF (120 mL) under argon at -78 0C was added diisobutylaluminium hydride (IM in hexane, 66 mL, 66 mmol). The reaction mixture was allowed to warm to r.t. and stirred for 4 days. DCM (120 mL) was added. The mixture was added to a saturated aqueous solution of Rochelle salt (150 mL) at 0 0C. The mixture was stirred until two layers had formed. The phases were separated and the aqueous phase was extracted with DCM (2 x 150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give (6-methyl-pyridin-3-yl)-methanol as a yellow oil, which was used without further purification in the next step. Analytical LCMS: purity 83% (System A, Rtau = 0.44 min), ES+: 123.9 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
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70% | With iodine; trifluoroacetic acid; In dimethyl sulfoxide; at 160℃; for 2h; | 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% | 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 3.5h; | 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. |
With iodine; dimethyl sulfoxide; at 160℃; for 0.25h; | 6-Methyl-nicotinic acid methyl ester (5.00 g, 33.1 mmol) was mixed with iodine (8.40 g, 33.1 mmol) and a small amount of DMSO was added to promote mixing. After addition of DMSO (5ml), this solution of added to a heated solution of DMSO (15 ml) at 130°C. The temperature of the mixture is then slowly raised to 160°C and stirred at this temperature for 15 minutes. After cooling down the solution, a small amount of a saturated aqueous solution of Na2CO3 is added. Extraction of the product with diethyl ether. Crude compound used without further purification. 1H NMR (400 MHz, CDCl3, 298K) delta 10.00 (s, 1H, CHO), 9.22 (d, 3J (H, H) = 1.5 Hz, 1 H, ArH), 8.34 (dd, 3J (H, H) = 6.0 Hz ; 2.0 Hz, 1 H, ArH), 7.90 (d, 3J (H, H) = 8.0 Hz, 1 H, ArH), 3.87 (s, 3 H, CH3). |
Yield | Reaction Conditions | Operation in experiment |
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With tert-butylmagnesium chloride; In tetrahydrofuran; at 65 - 70℃; for 1.5h; | In a 4-neck anhydrous flask there are introduced at 20-25C 5.0 g of (4-methylsulfonyl)phenyl acetic acid of formula (IV) (1.0 mol. equiv.), 100 mL of Anhydrous THF and the mixture is heated to 65-70C (up to reflux). Maintaining at T=65-70 C there are simultaneously dosed in the mixture in about 1 hour: a) 62.0 g of t-BuMgCl 1.0 M solution in THF (about 70.0 mL) (3.0 mol. equiv.) andb) a solution of 2.3 g of methyl ester of 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) (0.65 mol. equiv.) in 7.5 mL of Anhydrous THF. After completing addition, maintain at 65-70 C for 30 minutes. The reaction is controlled through HPLC: HPLC purity 72.05% (A%) and Impurity '408' = 0.26% (A%). | |
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 |
---|---|---|
In a 4-neck anhydrous flask there are introduced at 20-25C 11 g of (4-methylsulfonyl)phenyl acetate sodium of formula (II- M=Na), 200 mL of Anhydrous THF and the mixture is heated to 65-70C. Maintaining at T=65-70C there are rapidly added 21 g (0.5 equiv.) of t-BuMgCl 1.0 M solution in THF (about 23 mL). The mixture is left under stirring for 1 hr at 65-70 C then there is rapidly added, still at 65-70C, a solution of 3.6 g of methyl ester of the 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) (0.5 equiv.) in 10 mL of Anhydrous THF. After completing addition the mixture is maintained at 65-70 C for 1 hr. Maintaining at T=65-70 C there are rapidly added 21 g (0.5 equiv.) of t-BuMgCl 1.0 M solution in THF (about 23 mL). It is left under stirring for 1 hr at 65-70C then there is rapidly added, still at 65-70C, a solution of 520 mg of methyl ester of the 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) (0.075 equiv.) in 2 mL of anhydrous THF. After completing addition, the mixture is maintained at 65-70C for 1 hr. Maintaining at T=65-70 C, there are rapidly added 33.6 g (0.8 equiv.) of t-BuMgCl 1.0 M solution in THF (about 37 mL). The mixture is left under stirring for 1 hr at 65-70C then there is rapidly added, still at 65-70C, a solution of 520 mg of methyl ester of the 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) (0.075 equiv.) in 2 mL of Anhydrous THF. The mixture is left under stirring for 1 hr at 65-70C then it is cooled to 20-25C. The molar yield in solution is equivalent to 90%. After completing the reaction cooling is carried out at 20-25C and the reaction mixture is diluted under vigorous stirring using 100 mL of Water. Maintaining at T= 20-25 C the mixture is brought to pH=1-0 by adding about 25 mL of 32% Hydrochloric acid. Stirring is carried out at 20-25C for 0.5 hrs controlling the pH. The organic phase is put aside (recovery of the sodium salt of the acidic sulfone). The aqueous phase is washed using 2x50 mL of MTBE. The organic phases are combined to the previous ones and they are put aside (recovery of the sodium salt of the acidic sulfon). The process continues with the aqueous phase containing the product. The aqueous phase is distilled to remove the residual organic solvent. The pH of the aqueous phase is corrected up to about pH=6.5-7.5 using 25 mL of 30% NaOH. There is observed the precipitation of the product. Stirring is carried out for at least one hour at 20-25C. Filtration is carried out by washing the solid using 20 mL of purified water and 20 mL of THF. The raw product is dried in an oven at 50C for 8 hrs to obtain 7.7 g of product for a molar yield equivalent to 87%. HPLC purity 85.9% (A%) and Impurity '408'= 3.85% (A%). The (4-methylsulfonyl)phenyl acetate of formula (II-M=Na) used in excess is recovered as follows. The organic phase obtained as described above is brought to pH=11-12 by dosing a solution of 1.25 g of NaOH in form of pearls or scales in 10 mL of Methanol. The mixture is concentrated to residue at low pressure at Tmax=40C. The residue is suspended at room temperature using 10 mL of methanol. Stirring is carried out for at least 3 hrs at room temperature. Filtration is carried out by washing using 5 mL of methanol. The raw product is dried in an oven at 50C for 8 hrs to afford 3.5 g of recovered product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In an anhydrified 4-neck flask there were introduced at 20-25C 5.0 g of (4-methylsulfonyl)phenyl acetic acid of formula (IV) and 100 mL of anhydrous THF and stirring is carried out at 20-25C. 1.0 g of sodium hydride dispersion in mineral oil (60% w/w, MW: 24.00; 1.1 molar equivalents) is added in portions in about 5 minutes, ensuring that the temperature does not exceed 45-50C. After completing the addition the mixture is heated to 65-70C for 1 hr. Maintaining at T=65-70C there are rapidly added 21 g (1.0 equiv.) of t-BuMgCl 1.0 M solution in THF (PM116.87) (23 mL). The mixture is left under stirring for 1 hr at 65-70C then is rapidly added, still at 65-70C, a solution of 1.78 g (0.5 equiv.) of methyl ester of the 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) in 5 ml of Anhydrous THF. After completing the addition the mixture is maintained at 65-70C for 1 hr. Maintaining at T=65-70C there are rapidly added 10.5 g (0.5 equiv.) of t-BuMgCl 1.0 M solution in THF (PM 116.87) (11.5 mL). The mixture is left under stirring for 1 hr at 65-70C then there is rapidly added, still at 65-70C, a solution of 260 mg (0.075 equiv.) of methyl ester of 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) in 1 mL of anhydrous THF. After completing addition the mixture is maintained at 65-70 C for 1 hr. Maintaining at T=65-70 C there are rapidly added 10.5 g (0.5 equiv.) of t-BuMgCl 1.0 M solution in THF (PM 116.87) (11.5 mL). The mixture is left under stirring for 1 hr at 65-70 C then there is rapidly added, still at 65-70 C, a solution of 260 mg (0.075 equiv.) of methyl ester of the 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) in 1 mL of Anhydrous THF. After completing addition the mixture is maintained at 65-70 C for 1 hr. Cooling is carried out to 20-25C. The yield is calculated in solution through titration: 80%. The product is isolated according to the preceding example. It is obtained a molar yield equivalent to 73% and with 94.4% HPLC purity (A%) and amount of impurity '408' = 2.02% (A%) (see figure 4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tert-butylmagnesium chloride; In tetrahydrofuran; at 65 - 70℃; for 1.5h; | In a 4-neck anhydrous flask there are introduced at 20-25C, 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 65-70C (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 20-25C and the reaction mixture is diluted under vigorous stirring with 100 mL of water. Maintaining the temperature comprised in the range between 20C and 25C the mixture is brought to pH comprised between 1 and 0 by adding about 15 mL of 32% hydrochloric acid. Stirring is carried out at 20-25C 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 (40-45C) by adding 7.5 mL of 30% aqueous NaOH followed by cooling to room temperature. The product is filtered and dried in an oven under vacuum at 50C for 8 hours. There are obtained 6.9 g of product as a white solid corresponding to a 78% molar yield. HPLC purity 96.9% (A%). Impurity '408' = 0.21% (HPLC %) (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 40C. 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 90C for 8 hours, to obtain 2.5 g of (4-methylsulfonyl)phenyl acetate lithium. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.8% | With potassium tert-butylate; In tetrahydrofuran; for 3h;Reflux; | 1.74 g (6·0 mmol) of compound C, 1.36 g (9·0 mmol) of methyl 6-methylnicotinate, 1.01 g (9.0 mmol) of potassium t-butoxide were mixed with 21 mL of tetrahydrofuran, and heated to reflux. After the reaction was completed by 3h. TLC, 30 mL of water, 40 mL of dichloromethane was slowly added, and the liquid phase was separated, and the aqueous phase was extracted with dichloromethane (40 mL of X 2 ), dichloromethane was combined, washed twice with saturated brine, and the organic phase was separated. Drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by column chromatography to yield 1.56 g of pale yellow solid, Compound D, yield 63.8% |
Tags: Methyl 6-methylnicotinate | Pyridines | Esters | Organic Building Blocks | Heterocyclic Building Blocks | 5470-70-2
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H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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The concentration of the dissolution solution you need to prepare is mg/mL