* 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 lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.666667 h; Stage #2: With water In tetrahydrofuran
General Procedure for the Synthesis of Intermediate Benzylbromo bromides; [0116] Typical romides[0117] Step 1. Methyl 5-methylnicotinate (10 mmol, 1.52g) was dissolved in 50 Ml dried THF, then cooled to 0 deg with ice-bath. LiAlH4 (16 mmol, 0.61g) was added in small portions during about 20 minutes. The mixture stirred for another 20 minutes until the reaction was completed, which monitored by TLC. 1.5 mL water was dropwised into the mixture to quench the reaction, then filtered, solution was concentrated to get the (5-methylpyridin-3-yl)methanol, Yield was high to 85percent
84%
With sodium tetrahydroborate; sodium methylate In methanol
Example-2 Synthesis of 5-methylpyridine-3-methanol (Formula-9) from 5-Methyl-nicotinic acid methyl ester (Formula-8) 5-methyl nicotinic acid methyl ester (Formula-8) (100.0 gm, 0.66 moles) in methanol (400 ml) and stir the reaction mass. Then add Sodium borohydride (36.72gm, 0.96 moles) and Sodium methoxide (10.68 gm, 0.2 moles) are added under continuously stirring. On completion of reaction, methanol is distilled the methanol and then MDC and water to the reaction mixture. pH of reaction mixture is adjusted to <2.5 by using HCl aqueous layer is separated and pH is adjusted to 9-10 using NaOH and then product is extracts using MDC. Saturated brine solution is added with stirring followed by separating MDC layer. MDC is distilled completely to obtained title intermediate compound. (64-68.0 g; Yield=79-84percent).
84.9%
With potassium borohydride; magnesium chloride In tetrahydrofuran at 40 - 67℃; for 2.3 h;
S2, Preparation of 5-methyl-3-pyridinemethanol:According to the molar portion of 2 parts of magnesium chloride,2 parts of potassium borohydride,Tetrahydrofuran mixture,The temperature was raised to 67 ° C,Reflux 2h,Cooled to room temperature to obtain a solution B;Methyl 5-methyl nicotinate obtained in S1 was added to tetrahydrofuran for dissolution,Adjust the temperature to 40 ,Solution B was added dropwise,Solution B was added dropwise within 1.3h,Insulation 1h,Dropping and insulation kept stirring process,Cooled to room temperature to obtain a solution C;The reaction was quenched by adding methanol,Warmed to 40 ° C,Rotary evaporation to remove tetrahydrofuran and methanol to give a concentrate D;After adding water to concentrate D,Add ethyl acetate extract,Co-extraction three times,The combined ethyl acetate phase,Add anhydrous sodium sulfate until the moisture content of 0.3wtpercentFiltering, taking ethyl acetate phase rotary evaporation 5-methyl-3-pyridine methanol;
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6299 - 6310
[2] Synthetic Communications, 2008, vol. 38, # 1, p. 122 - 127
[3] Patent: WO2012/97196, 2012, A1, . Location in patent: Page/Page column 34
[4] Patent: EP2824103, 2015, A1, . Location in patent: Paragraph 0040
[5] Patent: CN106560471, 2017, A, . Location in patent: Paragraph 0055; 0061; 0067; 0073; 0079; 0085; 0091; 0096
[6] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521
[7] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 2206 - 2210
[8] Heterocyclic Communications, 2015, vol. 21, # 4, p. 203 - 205
[9] Patent: WO2016/185423, 2016, A1, . Location in patent: Page/Page column 74
2
[ 92444-99-0 ]
[ 102074-19-1 ]
Yield
Reaction Conditions
Operation in experiment
76%
With hydrogen; sodium acetate; palladium dichloride In methanol at 35℃; for 2 h;
Typical procedures: 6-bromonicotinaldehyde (930 mg, 5.0 mmol), NaOAc (820 mg, 10.0 mmol), MeOH (30 mL), and PdCl2 (45 mg) were mixed in a glass bottle capped with a balloon filled with hydrogen. After stirred at 35 °C for 4 h, the mixture was filtered and washed with MeOH. The solvent was removed and the residue was dissolved in water, neutralized with solid NaHCO3, and extracted with ethyl acetate. The organic phase was dried over anhyd Na2SO4, and then filtered. The solvent was removed and the residue was subjected to chromatography to yield pyridin-3-ylmethanol (428 mg, 78percent).
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521
5
[ 102074-19-1 ]
[ 100910-66-5 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 20℃;
Step 2. 5-methyl-3-pyridinecarboxaldehyde. A mixture of 5-methyl-3-pyridinemethanol (106 mg, 0.86 mmol) and activated MnO2 (376 mg) in methylenechloride (10 mL) was stirred at room temperature overnight. The black solid of MnO2 was removed by filtration. The filtrate was concentrated in vacuo to yield the title compound as an oil (100 mg, 85percent). 1H NMR (CDCl3): 10.10 (s, 1H), 8.89 (s, 1H), 8.68 (s, 1H), 7.98 (s, 1H), 2.45 (s, 3H)
Reference：
[1] Patent: EP1230232, 2004, B1, . Location in patent: Page 40
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6299 - 6310
[3] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521
[4] Patent: WO2016/185423, 2016, A1, . Location in patent: Page/Page column 74
6
[ 102074-19-1 ]
[ 1235342-53-6 ]
Yield
Reaction Conditions
Operation in experiment
80%
With hydrogen bromide In water for 5 h; Reflux
Step 2.; Alcohol (10 mmol) were refluxed in 10ml HBr (40percent aq) for more than 5 hours, and monitored through TLC or LC-MS. After completed, mixture were heated in order to evaporator solvents (water and excess HBr) until the mixture became sticky. Cool the mixture, add acetone to the mixture, precipitated solid and filtered followed by drying. Yield was high to80percent.
Step 2. 5-methyl-3-pyridinecarboxaldehyde. A mixture of 5-methyl-3-pyridinemethanol (106 mg, 0.86 mmol) and activated MnO2 (376 mg) in methylenechloride (10 mL) was stirred at room temperature overnight. The black solid of MnO2 was removed by filtration. The filtrate was concentrated in vacuo to yield the title compound as an oil (100 mg, 85%). 1H NMR (CDCl3): 10.10 (s, 1H), 8.89 (s, 1H), 8.68 (s, 1H), 7.98 (s, 1H), 2.45 (s, 3H)
With manganese(IV) oxide; In dichloromethane; at 20℃; for 4h;
Step 2: Mn02 (46.2 g, 531 mmol) was added to a stirred solution of (5-methylpyridin- 3-yl)methanol in dry DCM (75 mL). The suspension was stirred at rt for 4 h. The mixturewas filtered and the solvent was removed under reduced pressure to give 1.91 g (60%) of 5- methylpyridine-3-carbaldehyde. Crude product was used without further purification. MS (m/z) 122 (M+H).
General Procedure for the Synthesis of Intermediate Benzylbromo bromides; [0116] Typical romides[0117] Step 1. Methyl <strong>[29681-45-6]5-methylnicotinate</strong> (10 mmol, 1.52g) was dissolved in 50 Ml dried THF, then cooled to 0 deg with ice-bath. LiAlH4 (16 mmol, 0.61g) was added in small portions during about 20 minutes. The mixture stirred for another 20 minutes until the reaction was completed, which monitored by TLC. 1.5 mL water was dropwised into the mixture to quench the reaction, then filtered, solution was concentrated to get the (5-methylpyridin-3-yl)methanol, Yield was high to 85%
84%
With sodium tetrahydroborate; sodium methylate; In methanol;
Example-2Synthesis of 5-methylpyridine-3-methanol (Formula-9) from 5-Methyl-nicotinic acid methyl ester (Formula-8)<strong>[29681-45-6]5-methyl nicotinic acid methyl ester</strong> (Formula-8) (100.0 gm, 0.66 moles) in methanol (400 ml) and stir the reaction mass. Then add Sodium borohydride (36.72gm, 0.96 moles) and Sodium methoxide (10.68 gm, 0.2 moles) are added under continuously stirring. On completion of reaction, methanol is distilled the methanol and then MDC and water to the reaction mixture. pH of reaction mixture is adjusted to <2.5 by using HCl aqueous layer is separated and pH is adjusted to 9-10 using NaOH and then product is extracts using MDC. Saturated brine solution is added with stirring followed by separating MDC layer. MDC is distilled completely to obtained title intermediate compound. (64-68.0 g; Yield=79-84%).
84.9%
With potassium borohydride; magnesium chloride; In tetrahydrofuran; at 40 - 67℃; for 2.3h;
S2, Preparation of 5-methyl-3-pyridinemethanol:According to the molar portion of 2 parts of magnesium chloride,2 parts of potassium borohydride,Tetrahydrofuran mixture,The temperature was raised to 67 C,Reflux 2h,Cooled to room temperature to obtain a solution B;Methyl 5-methyl nicotinate obtained in S1 was added to tetrahydrofuran for dissolution,Adjust the temperature to 40 ,Solution B was added dropwise,Solution B was added dropwise within 1.3h,Insulation 1h,Dropping and insulation kept stirring process,Cooled to room temperature to obtain a solution C;The reaction was quenched by adding methanol,Warmed to 40 C,Rotary evaporation to remove tetrahydrofuran and methanol to give a concentrate D;After adding water to concentrate D,Add ethyl acetate extract,Co-extraction three times,The combined ethyl acetate phase,Add anhydrous sodium sulfate until the moisture content of 0.3wt%Filtering, taking ethyl acetate phase rotary evaporation 5-methyl-3-pyridine methanol;
With methanol; sodium tetrahydroborate; at 20℃; for 6h;Reflux;
Step 1: NaBH4 (3.31 g, 87.5 mmol) was added at rt to a solution of methyl <strong>[29681-45-6]5-methylnicotinate</strong> (2.37 g, 15.7 mmol) in MeOH (50 mL). The mixture was stirred at rt for 6 h then heated overnight at reflux. The reaction was allowed to cool to rt then it was quenched by cautious addition of Na2504 10H20. The suspension was stirred for 2 h at rt, thenvolatiles were removed under reduced pressure. The residue was taken up in CH2C12, filtered and concentrated under reduced pressure to yield 1.85 g (97%) of crude (5-methylpyridin-3- yl)methanol which was used in next step without further purification. MS (m/z) 124 (M+H).
4.2 g
With sodium tetrahydroborate; In methanol; at 55℃; for 1h;
In a 100mL three-neck bottle,Add the above product (3) methyl <strong>[29681-45-6]5-methylnicotinate</strong> (5.0 g, 0.033 mol)And 50mL of methanol,Heated to 55 C,Sodium borohydride (4,4 g, 0.12 mol) was added in small portions, and the solution changed from colorless to yellow.And a lot of bubbles are generated.Reaction at 55 C for 1 h, TLC showed the reaction was complete.An appropriate amount of water was added, and methanol was evaporated under reduced pressure. The residue was purified with ethyl acetate.The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated.A yellow liquid (4.2 g) was obtained without further purification.Used directly in the next step of the reaction.
3-(chloromethyl)-5-methylpyridine hydrogen chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.1%
With thionyl chloride; In 1,4-dioxane; at 25 - 70℃; for 4h;
S3,Preparation of 3-methyl-5-chloromethylpyridine hydrochloride:One mole portion of <strong>[102074-19-1]5-methyl-3-pyridinemethanol</strong> obtained in S2 was dissolved in dioxane,Dropping 2 parts of thionyl chloride,During the dropwise addition, the temperature of the liquid was kept at 25 C,Warmed to 70 , heat 4h,Dropping and insulation kept stirring process,Cool to 25 ,After removing the thionyl chloride by evaporation under reduced pressure,The temperature was raised to 70 C,Dioxane was evaporated under reduced pressure to give 3-methyl-5-chloromethylpyridine hydrochloride;
94%
With thionyl chloride; In dichloromethane; at 20℃; for 4h;Inert atmosphere;
The 3-(chloromethyl)-5-methylpyridine hydrochloride used as starting material was prepared as follows:Thionyl chloride (5.18 mL, 71.05 mmol) was added portion- wise to (5-methylpyridin-3- yl)methanol (0.5 g, 4.06 mmol), under argon in DCM (22 mL). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated to give 3- (chloromethyl)-5-methylpyridine hydrochloride (0.680 g, 94 %).1H NMR (400.13 MHz, MeOH-d4) delta 4.79 - 4.82 (4H, m), 8.50 (1H, d), 8.63 (1H, s), 8.73 (1H, d); m/z (ES) (M+H)+ = 141.
Example 2.11: (5-methylpyridin-3-yl)metlianol; [0242] To stirring solution of 233 mg (1.70 mmol) of 5-methylnicotinic acid (synthesized following the general procedure for 5-fluoro-isophthalic acid) in 30 mL of THF at 0 C was added 181 mg (4.76 mmol) OfLiAlH4. After 25 min., the reaction was quenched by adding successively 180 muL OfH2O, 180 muL of 15% aqueous NaOH, and 540 muL of brine. The mixture was filtered through Celite and concentrated to give 87 mg of crude alcohol which was used for the next reaction without further purification.
Example 2.23: (5-methylpyridin-3-yI)methanol; [0261] To stirring solution of 233 mg (1.70 mmol) of 5-methylnicotinic acid (synthesized following the general procedure for 5-fluoro-isophthalic acid) in 30 mL of THF at 0 C was added 181 mg (4.76 mmol) OfLiAlH4. After 25 min., the reaction was quenched by adding successively 180 muL OfH2O, 180 muL of 15% aqueous NaOH, and 540 muL of brine. The mixture was filtered through Celite and concentrated to give 87 mg of crude (5- methylpyridin-3-yl)methanol which was used for the next reaction without further purification.
With lithium aluminium hydride; In tetrahydrofuran; at 20℃; for 2h;
Step 1. 5-Methyl-3-pyridinemethanol. To a solution of methyl 5-methyl-3-pyridinecarboxylate (0.95 g, 6.3 mmol) in THF (10 mL) was added LiAlH4 (300 mg, 7.9 mmol) at 0C. The mixture was stirred at room temperature for 2 h, quenched with water, and extracted with 1:1 hexane/EtOAc (80 mL). The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as an oil (400 mg, 3.2 mmol, 51%). 1H NMR (CDCl3): 8.40 (s, 1H), 8.37 (s, 1H), 7.31 (s, 1H), 4.71 (s, 2H), 2.35 (s, 3H).
Example 1.1.41: (5-methylpyridin-3-yl)methanamine; To stirring solution of 233 mg (1.70 mmol) of 5-methylnicotinic acid (synthesized following the general procedure for 5-fluoro-isophthalic acid) in 30 mL of THF at 0 0C was added 181 mg (4.76 mmol) of LiAlH4. After 25 min., the reaction was quenched by adding successively 180 muL of H2O, 180 muL of 15% aqueous NaOH, and 540 muL of brine. The mixture was filtered through Celite and concentrated to give 87 mg of (5-methylpyridin-3- yl)methanol which was used for the next reaction without further purification.
Step 2.; Alcohol (10 mmol) were refluxed in 10ml HBr (40% aq) for more than 5 hours, and monitored through TLC or LC-MS. After completed, mixture were heated in order to evaporator solvents (water and excess HBr) until the mixture became sticky. Cool the mixture, add acetone to the mixture, precipitated solid and filtered followed by drying. Yield was high to80%.
With hydrogen; sodium acetate; palladium dichloride; In methanol; at 35℃; under 760.051 Torr; for 2h;
Typical procedures: 6-bromonicotinaldehyde (930 mg, 5.0 mmol), NaOAc (820 mg, 10.0 mmol), MeOH (30 mL), and PdCl2 (45 mg) were mixed in a glass bottle capped with a balloon filled with hydrogen. After stirred at 35 C for 4 h, the mixture was filtered and washed with MeOH. The solvent was removed and the residue was dissolved in water, neutralized with solid NaHCO3, and extracted with ethyl acetate. The organic phase was dried over anhyd Na2SO4, and then filtered. The solvent was removed and the residue was subjected to chromatography to yield pyridin-3-ylmethanol (428 mg, 78%).
Example-3Synthesis of Rupatadine base (Formula-4) from <strong>[102074-19-1]5-methylpyridine-3-methanol</strong> (Formula-9)Take <strong>[102074-19-1]5-methylpyridine-3-methanol</strong> (Formula-9, 51 gm) in toluene (255 ml) and add slowly thionyl chloride (36.5 ml) between 20-40C. On completion of thionyl chloride addition, reflux the reaction mixture at 60C for 2 hrs. On the completion of reaction toluene is distilled toluene under vacuum. Toluene (250 ml) and water (25 ml) added to the reaction mixture. Stir it between below 20C temperature. Adjust the pH by using 35% NaOH solution and again stir the reaction to separate the layers. Desloratadine (95g) is added to the in the separated organic layers at 25-30C. Then add Potassium carbonate (100g), TBAB (5g) and water (200 ml) is added to the reaction mass followed by reflux at 65-70C for 2 hrs. On the completion of reaction, separate lower aq. Layer and impurity layer using toluene. 10% solution of potassium dihydrogen phosphate (100 ml) is added with stirring for 1 hr. The layers are allowed to separate followed by addition of charcoal in the reaction mass and heat the reaction mass at 40-45C for 2 hrs. Then filter through hyflow bed and evaporate solvent under reduce pressure. Followed by dissolving the oily mass in SDS (300 ml).
(5-methylpyridin-3-yl)methanol hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.7 g
With hydrogen bromide;Cooling with ice;
In a 100mL single-mouth bottle,Add the last step product,Hydrobromide (5 mL, 40%, 0.036 mol) was added dropwise under ice bath conditions.After the addition is completed, the solvent is removed by rotary evaporation.Obtaining a brown solid and adding an appropriate amount of tetrahydrofuran solution (the purpose of adding the tetrahydrofuran solution is to prevent the product from adhering to the container wall),Stir for half an hour, filter,Obtained a white solid (5.7g, 84.4%, above step yield)
With triethylamine; In dichloromethane; at 0 - 20℃;
The mesylate of <strong>[102074-19-1](5-methylpyridin-3-yl)methanol</strong> (100 mg) was prepared by reaction with methanesulfonyl chloride (1 .1 eq) and triethylamine (2 eq) in DCM at 0 C, with warming to ambient temperature. N-[1 -(Fluoromethyl)cyclopropyl]-3-[(1 -methylpyrazol-4- yl)methyl]-2,4-dioxo-1 1H-quinazoline-6-sulfonamide (100 mg, 0.260 mmol), the crude mesylate (58 mg, 0.286 mmol) and potassium carbonate (43 mg, 0.312 mmol) in DMF was conventionally heated to 70 C for 4 h. Usual work-up afforded the desired product (1 1 mg, 0.021 mmol, 8.3%) as a white powder
(5-methylpyridin-3-yl)methylchloroformate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane; at 0 - 20℃; for 8h;Inert atmosphere;
Under nitrogen, the trichloromethyl chloroformate (1.98g, 10.00mmol) was dissolved in dry dichloromethane (10 mL), cooled to 0 deg C After stirring for 5 minutes, a solution of <strong>[102074-19-1]5-methyl-3-pyridinemethanol</strong> (616mg, 5.00mmol) in dry dichloromethane (10 mL) solutionUpon completion, stirring in an ice bath for 2 hours, allowed to warm to room temperature and stirring was continued for 6 hours. The reaction was stopped, concentrated under reduced pressure, and dried to give yellowThe solid (1.2g, 100%), the crude product without further purification was used directly in the next reaction.
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