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USD 80+
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Structure of 3099-29-4 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Yakugaku Zasshi, 1955, vol. 75, p. 1233[2] Chem.Abstr., 1956, p. 8664
2
[ 1122-71-0 ]
[ 3099-29-4 ]
Yield
Reaction Conditions
Operation in experiment
85.8%
With thionyl chloride In dichloromethane for 0.666667 h; Heating / reflux
Manufacturing Example 10-1-1 2-Chloromethyl-6-methyl-pyridine; A solution of (6-methyl-pyridin-2-yl)-methanol (1.44 g, 11.7 mmol), thionyl chloride (1.45 mL, 19.9 mmol) and methylene chloride (20 mL) was stirred under reflux for 40 minutes. The reaction solution was cooled to room temperature and then concentrated under a reduced pressure. The residue was partitioned into sodium bicarbonate solution and diethyl ether. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (1.42 g, 85.8percent).1H-NMR Spectrum (DMSO-d6) δ (ppm): 2.47 (3H, s), 4.72 (2H, s), 7.22 (1 H, d, J=7.6 Hz), 7.33 (1H, d, J=7.6 Hz), 7.72 (1H, dd, J=7.6, 7.6 Hz).
85.8%
Stage #1: With thionyl chloride In dichloromethane for 0.666667 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In diethyl ether; water
A solution of (6-methyl-pyridin-2-yl)-methanol (1.44 g, 11.7 mmol), thionyl chloride (1.45 mL, 19.9 mmol) and methylene chloride (20 mL) was stirred under reflux for 40 minutes. The reaction solution was cooled to room temperature and then concentrated under a reduced pressure. The residue was partitioned into sodium bicarbonate solution and diethyl ether. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (1.42 g, 85.8percent). 1H-NMR Spectrum (DMSO-d6) δ (ppm): 2.47 (3H, s), 4.72 (2H, s), 7.22 (1H, d, J=7.6 Hz), 7.33 (1H, d, J=7.6 Hz), 7.72 (1H, dd, J=7.6, 7.6 Hz).
Reference：
[1] Journal of the American Chemical Society, 2005, vol. 127, # 29, p. 10197 - 10204
[2] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 64
[3] Patent: US2007/105904, 2007, A1, . Location in patent: Page/Page column 61
[4] Chinese Chemical Letters, 2018, vol. 29, # 11, p. 1637 - 1640
[5] Chemistry Letters, 1998, # 9, p. 915 - 916
[6] Yakugaku Zasshi, 1954, vol. 74, p. 790[7] Chem.Abstr., 1955, p. 11646
[8] Journal of the Chemical Society, 1958, p. 3594,3601
[9] Yakugaku Zasshi, 1955, vol. 75, p. 1233[10] Chem.Abstr., 1956, p. 8664
[11] Journal of Medicinal Chemistry, 1992, vol. 35, # 3, p. 438 - 450
3
[ 108-48-5 ]
[ 3099-29-4 ]
Reference：
[1] Chemische Berichte, 1987, vol. 120, p. 649 - 652
[2] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1980, vol. 16, # 1, p. 89 - 93[3] Khimiya Geterotsiklicheskikh Soedinenii, 1980, vol. 16, # 1, p. 105 - 110
4
[ 1073-23-0 ]
[ 3099-29-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 3, p. 438 - 450
[2] Yakugaku Zasshi, 1954, vol. 74, p. 790[3] Chem.Abstr., 1955, p. 11646
5
[ 13287-64-4 ]
[ 3099-29-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 3, p. 438 - 450
[2] Yakugaku Zasshi, 1954, vol. 74, p. 790[3] Chem.Abstr., 1955, p. 11646
6
[ 108-48-5 ]
[ 3099-29-4 ]
[ 3099-28-3 ]
[ 56533-58-5 ]
[ 56533-57-4 ]
Reference：
[1] Synthesis, 1984, # 8, p. 676 - 679
7
[ 13602-11-4 ]
[ 3099-29-4 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 3594,3601
8
[ 1073-23-0 ]
[ 74405-07-5 ]
[ 3099-29-4 ]
[ 30914-88-6 ]
[ 76809-18-2 ]
[ 76809-28-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 10, p. 3020 - 3028
9
[ 6890-58-0 ]
[ 10025-87-3 ]
[ 3512-75-2 ]
[ 3099-29-4 ]
Reference：
[1] Yakugaku Zasshi, 1955, vol. 75, p. 1233[2] Chem.Abstr., 1956, p. 8664
With thionyl chloride; In dichloromethane; for 0.666667h;Heating / reflux;
Manufacturing Example 10-1-1 2-Chloromethyl-6-methyl-pyridine; A solution of (6-methyl-pyridin-2-yl)-methanol (1.44 g, 11.7 mmol), thionyl chloride (1.45 mL, 19.9 mmol) and methylene chloride (20 mL) was stirred under reflux for 40 minutes. The reaction solution was cooled to room temperature and then concentrated under a reduced pressure. The residue was partitioned into sodium bicarbonate solution and diethyl ether. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (1.42 g, 85.8%).1H-NMR Spectrum (DMSO-d6) delta (ppm): 2.47 (3H, s), 4.72 (2H, s), 7.22 (1 H, d, J=7.6 Hz), 7.33 (1H, d, J=7.6 Hz), 7.72 (1H, dd, J=7.6, 7.6 Hz).
85.8%
A solution of (6-methyl-pyridin-2-yl)-methanol (1.44 g, 11.7 mmol), thionyl chloride (1.45 mL, 19.9 mmol) and methylene chloride (20 mL) was stirred under reflux for 40 minutes. The reaction solution was cooled to room temperature and then concentrated under a reduced pressure. The residue was partitioned into sodium bicarbonate solution and diethyl ether. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (1.42 g, 85.8%). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 2.47 (3H, s), 4.72 (2H, s), 7.22 (1H, d, J=7.6 Hz), 7.33 (1H, d, J=7.6 Hz), 7.72 (1H, dd, J=7.6, 7.6 Hz).
(ii) 2-Chloromethyl-6-methylpyridine The above product 3.32 g (0.27 mmole) in 20 ml methylene chloride was treated with 1.94 ml (27 mmole) thionyl chloride at room temperature for one hour. The mixture was neutralized (NaHCO3) and extracted with chloroform. Evaporation of solvent gave 3.22 g of product as an oil which was used in the next step.
(ii) 2-Chloromethyl-6-methylpyridine The above product 3.32 g (0.27 mmole) in 20 ml methylene chloride was treated with 1.94 ml (27 mmole) thionyl chloride at room temperature for one hour. The mixture was neutralized (NaHCO3) and extracted with chloroform. Evaporation of solvent gave 3.22 g of product as an oil which was used in the next step.
2-methyl-6-{4-[1-(4-chlorophenyl)-1-hydroxypropyl]-phenoxymethyl}-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In hexane; water; ethyl acetate;
EXAMPLE 3 2-Methyl-6-{4-[1-(4-chlorophenyl)-1-hydroxypropyl]-phenoxymethyl}-pyridine 13.1 g. of alpha-ethyl-alpha-(4-chlorophenyl)-4-hydroxybenzyl-alcohol, 14 g. of anhydrous potassium carbonate, 0.85 g. of tetrabutylammonium hydrogensulfate and 7.8 g. of <strong>[3099-29-4]2-methyl-6-chloromethyl-pyridine</strong> in 140 ml. of ethyl acetate are boiled for 18 hours. The solvent is distilled off under reduced pressure, to the residue water is added, and it is extracted with ether. The ethereal solution is washed to neutral with a 5% aqueous potassium hydroxide solution and subsequently water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Crystallization of the residue from a mixture of hexane and ethyl acetate yields 13.6 g. of the title compound, melting at 100 to 101 C. Analysis for C22 H22 ClNO2: Calculated: C: 71.83%, H: 6.03%, Cl: 9.64%, N: 3.81%; Found: C: 71.75%, H: 6.25%, Cl: 9.80%, N: 3.66%.
With potassium carbonate; In (methyl)isobutyl ketone; benzene;
EXAMPLE 6 2-Methyl-6-{4-[1-(2-methoxyphenyl)-1-hydroxypropyl]-phenoxymethyl}-pyridine 7.8 g of alpha-ethyl-alpha-(2-methoxyphenyl)-4-hydroxybenzyl-alcohol are dissolved in 65 ml. of methylisobutyl ketone, 9.1 g. of anhydrous potassium carbonate are added, and the reaction mixture is brought up to a boil. Thereafter, a solution of 4.7 g. of <strong>[3099-29-4]2-methyl-6-chloromethyl-pyridine</strong> in 20 ml. of methylisobutyl ketone is added dropwise, and the reaction mixture is slightly boiled for 4 additional hours. After cooling, the reaction mixture is filtered off, and the filtrate is evaporated under reduced pressure. The residue is dissolved in benzene, the solution is washed with a 5% aqueous potassium hydroxide solution and then with water, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The crude product is crystallized from a mixture of ethyl acetate and cyclohexane. Melting point: 110 to 111 C. Analysis for C23 H25 NO3: Calculated: C: 76.00%, H: 6.93%, N: 3.85%; Found: C: 76.18%, H: 6.77%, N: 3.92%.
4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenol[ No CAS ]
[ 76-05-1 ]
3-(3-(4-(6-Methyl-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.7%
Reference Example 10 3-(3-(4-(6-Methyl-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine; Methanol (3 mL) and 1 N aqueous sodium hydroxide solution (0.18 mL) were added to 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (50 mg, 0.19 mmol) described in Manufacturing Example 5-1-1, which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue were added <strong>[3099-29-4]2-chloromethyl-6-methyl-pyridine</strong> (31.8 mg, 0.22 mmol) described in Manufacturing Example 10-1-1 and N,N-dimethylformamide (2 mL), which was stirred for 20 minutes at 60 C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (36 mg, 51.7%).1H-NMR Spectrum (DMSO-d6) delta (ppm): 2.48 (3H, s), 3.96 (2H, s), 5.10 (2H, s), 6.25 (2H, brs), 6.69 (1H, dd, J=4.8, 8.0 Hz), 6.79 (1H, s), 6.97 (2H, d, J=8.0 Hz), 7.18 (1H, d, J=7.6 Hz), 7.25 (2H, d, J=8.0 Hz), 7.27 (1H, d, J=7.6 Hz), 7.70 (1H, dd ,J=7.6, 7.6 Hz), 7.86 (1H, d, J=8.0 Hz), 8.08 (1H, d, J=4.8 Hz).
4-((5-(2,6-diaminopyridin-3-yl)isoxazol-3-yl)methyl)phenol[ No CAS ]
[ 76-05-1 ]
3-(3-(4-(6-Methyl-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2,6-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.5%
Reference Example 23 3-(3-(4-(6-Methyl-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2,6-diamine; To 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (150 mg, 0.53 mmol) described in Manufacturing Example 18-1-1 were added methanol (3 mL) and 1 N aqueous sodium hydroxide solution (0.53 mL), which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue was added <strong>[3099-29-4]2-chloromethyl-6-methyl-pyridine</strong> (90.2 mg, 0.64 moL) described in manufacturing Example 10-1-1 and N,N-dimethylformamide (2 mL), which was stirred for 2 hours and 50 minutes at 60 C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2, then ethyl acetate) to obtain the title compound (106 mg, 51.5%).1H-NMR Spectrum (DMSO-d6) delta (ppm): 2.48 (3H, s), 3.88 (2H, s), 5.10 (2H, s), 5.78 (2H, brs), 5.82 (1H, d, J=8.4 Hz), 6.10(2H, brs), 6.34 (1H, s), 6.96 (2H, d, J=8.0 Hz), 7.18 (1H, d, J=8.0 Hz), 7.22 (2H, d, J=8.0 Hz), 7.27 (1H, d, J=8.0 hz), 7.50 (1H, d, J=8.4 Hz), 7.70 (1H, dd, J=8.0, 8.0 Hz).
4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenol[ No CAS ]
3-(3-(4-(6-Methyl-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.7%
Methanol (3 mL) and 1 N aqueous sodium hydroxide solution (0.18 mL) were added to 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (50 mg, 0.19 mmol) described in Manufacturing Example 5-1-1, which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue were added <strong>[3099-29-4]2-chloromethyl-6-methyl-pyridine</strong> (31.8 mg, 0.22 mmol) described in Manufacturing Example 10-1-1 and N,N-dimethylformamide (2 mL), which was stirred for 20 minutes at 60 C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (36 mg, 51.7%). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 2.48 (3H, s), 3.96 (2H, s), 5.10 (2H, s), 6.25 (2H, brs), 6.69 (1H, dd, J=4.8, 8.0 Hz), 6.79 (1H, s), 6.97 (2H, d, J=8.0 Hz), 7.18 (1H, d, J=7.6 Hz), 7.25 (2H, d, J=8.0 Hz), 7.27 (1H, d, J=7.6 Hz), 7.70 (1H, dd, J=7.6, 7.6 Hz), 7.86 (1H, d, J=8.0 Hz), 8.08 (1H, d, J=4.8 Hz).
4-((5-(2,6-diaminopyridin-3-yl)isoxazol-3-yl)methyl)phenol[ No CAS ]
3-(3-(4-(6-Methyl-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2,6-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.5%
To 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (150 mg, 0.53 mmol) described in Manufacturing Example 18-1-1 were added methanol (3 mL) and 1 N aqueous sodium hydroxide solution (0.53 mL), which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue was added <strong>[3099-29-4]2-chloromethyl-6-methyl-pyridine</strong> (90.2 mg, 0.64 moL) described in manufacturing Example 10-1-1 and N,N-dimethylformamide (2 mL), which was stirred for 2 hours and 50 minutes at 60 C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2, then ethyl acetate) to obtain the title compound (106 mg, 51.5%). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 2.48 (3H, s), 3.88 (2H, s), 5.10 (2H, s), 5.78 (2H, brs), 5.82 (1H, d, J=8.4 Hz), 6.10 (2H, brs), 6.34 (1H, s), 6.96 (2H, d, J=8.0 Hz), 7.18 (1H, d, J=8.0 Hz), 7.22 (2H, d, J=8.0 Hz), 7.27 (1H, d, J=8.0 Hz), 7.50 (1H, d, J=8.4 Hz), 7.70 (1H, dd, J=8.0, 8.0 Hz).
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 24h;
A solution of 3-bromo-4-nitro-l H-indole (1.0 g) and 2-(chloromethyl)-6- methylpyridine (0.74 g) in N,N-dimethylformamide (10 mL) was mixed with potassium carbonate (1.15 g) at 25C for 24 hrs by stirring. The reaction mixture was extracted with ethyl acetate (20 mL, three times) and water (20 mL) to separate the organic layer. This layer was dried over anhydrous magnesium sulfate and subjected to vacuum filtration and vacuum distillation. The residue was purified using column chromatography to obtain the desired compound (0.75 g).
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 24h;
3-Bromo-4-nitro-lH-indazole (1.0 g) and <strong>[3099-29-4]2-(chloromethyl)-6-methylpyridine</strong> (0.8 g) obtained in Preparation Example 8 were added to N,N-dimethylformamide (10 mL). Potassium carbonate (1.14 g) was added to the solution, and stirred at 25C for 24 hrs. The reaction mixture was extracted with ethyl acetate (20 mL, three times) and water (20 mL), and the organic layers thus obtained were pooled, dried over anhydrous magnesium sulfate, and subjected to vacuum filtration and vacuum distillation. The residue was purified using column chromatography to afford the desired compound (1.36 g).
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 24h;
General procedure: 3-Bromo-4-nitro-1H-indazole 2 (1.0 g) and R1CH2Cl (0.8 g) were added to N,N-dimethylformamide (10 mL). Potassium carbonate (1.14 g) was added to the solution, and stirred at 25C for 24 hrs. The reaction mixture was extracted with ethyl acetate (20 mL, three times) and water (20 mL), and the organic layers thus obtained were pooled, dried over anhydrous magnesium sulfate, and subjected to vacuum filtration and vacuum distillation. The residue was purified using column chromatography to afford the desired compound (1.36 g).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
The compound (100 mg, 0.39 mmol) obtained in step 3) was stirred, together with <strong>[3099-29-4]2-chloromethyl-6-methyl-pyridine</strong> (77 mg, 0.43mmol) and potassium carbonate (216 mg, 1.56 mmol), in dimethylformamide (1.5 mL) at room temperature for 16 hrs. The reaction mixture was diluted in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, followed by vacuum distillation. The residue was purified using column chromatography (ethyl acetate :hexane = 1 :4) to obtain the desired compound (130 mg, 92%).
4-(pyrimidin-5-yl)-5,6,7,8-tetrahydroquinolin-2-ol[ No CAS ]
2-[(6-methylpyridin-2-yl)methoxy]-4-(pyrimidin-5-yl)-5,6,7,8-tetrahydroquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7 mg
With silver carbonate; In toluene; at 160℃; for 0.833333h;Microwave irradiation;
[Step 2] Production of 2-[(6-methylpyridin-2-yl)methoxy]-4-(pyrimidin-5-yl )-5,6,7,8-tetrahydroquinoline To 4-(pyrimidin-5-yl)-5,6,7,8-tetrahydroquinolin-2-ol (20 mg), 2- (chloromethyl) -6-methylpyridine (25 mg) and silver carbonate (24 mg) was added toluene (1 mL), and the mixture was reacted under microwave irradiation at 160C for 50 minutes. The reaction mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (7 mg) as a white powder. [MS (ESI) m/z 333.3 (M+H)+]
1-((6-methylpyridin-2-yl)methyl)-1H-indole-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With caesium carbonate; In acetonitrile; at 80℃; for 3h;
To a stirred solution of lH-indole-3-carboxaldehyde (145.2mg, immol) and 2- (chloromethyl)-6-methylpyridine (155.2mg, 1. immol) in 5.0 mL of MeCN was added Cs2CO3(980mg, 3mmol) at room temperature. The mixture was then heated to 80C and kept stirring for 3h. When 1 H-indole-3 -carboxaldehyde was consumed monitored by TLC, MeCN was evaporated. The residue was partitioned in 15 mL of water and 15 mL of ethyl acetate. The aqueous layer was extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried, and concentrated. The crude product was purified by silica gel column chromatography to give 1-((6-methylpyridin-2- yl)methyl)-1H-indole-3-carbaldehyde(200mg, 80% yield).ESI-MS mlz 251.1 [M+H].
(3S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one[ No CAS ]
(3S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl-2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1 (2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
Sodium hydride (12.56 mg, 0.31 mmol) was added to (S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (79 mg, 0.29 mmol) in DMF(3 mL) at 22 C under nitrogen. The resulting suspension was stirred at RT for 30 minutes, then <strong>[3099-29-4]2-(chloromethyl)-6-methylpyridine</strong> (0.03 8 mL, 0.31 mmol) was added. The resulting solution was stirred at 22 C for 3 hours. The reaction mixture was quenched with saturated NH4C1 (20 mL) and then the mixture extracted with DCM (2 x 20 mL) andevaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0.5 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford (3 S)-7-(2-chloro-5 -methylpyrimidin-4-yl)-3 -methyl-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [1 ,2-a]pyrazin- 1 (2H)-one (91 mg, 83 %) as a white solid. ?H NMR (400 MHz, DMSO, 30 C) 1.15 (3H, d), 2.43 (3H, s), 2.46 (3H, s),3.96 - 4.00 (1H, m), 4.23 (1H, dd), 4.30 (1H, d), 4.38 (1H, dd), 5.13 (1H, d), 7.12 - 7.18 (2H, m), 7.28 (1H, d), 7.65 (1H, t), 7.86 (1H, d), 8.50 (1H, s). mlz: ES+ [M+H]+ 382.
7-(2-chloro-5-methyl-pyrimidin-4-yl)spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-3,1’-cyclopropane]-1-one[ No CAS ]
7-(2-chloro-5-methylpyrimidin-4-yl)-2-[(6-methyl-2-pyridyl)methyl]spiro[4H-pyrrolo[1,2-a]pyrazine-3,1‘-cyclopropane]-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
Sodium hydride (60% dispersion in mineral oil) (11.73 mg, 0.29 mmol) was added to 7?-(2- chloro-5 -methylpyrimidin-4-yl)-2?,4?-dihydro- 1 ?H-spiro [cyclopropane- 1,3 ?-pyrrolo [1,2-a]pyrazin]-1?-one (77 mg, 0.27 mmol) in DMF (5 mL) under nitrogen. The resulting solution was stirred at 20 C for 30 minutes. 2-(Chloromethyl)-6-methylpyridine (41.5 mg, 0.29 mmol) was added and the resulting solution stirred at 20 C for 18 hours. It was diluted with ethyl acetate (50 mL) and washed with brine (15 mL), dried (sodium sulfate),concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 7?-(2-chloro-5 -methylpyrimidin-4-yl)-2?-((6-methylpyridin- 2-yl)methyl)-2?,4?-dihydro- 1 ?H-spiro [cyclopropane- 1,3 ?-pyrrolo [1 ,2-a]pyrazin] -1 ?-one (83 mg, 79 %) as a white solid. ?H NMR (400 MHz, DMSO, 30 C) 0.8 - 0.9 (2H, m), 1.01 -1.11 (2H, m), 2.44 (6H, s), 4.22 (2H, s), 4.61 (2H, s), 7.14 (2H, dd), 7.34 (1H, d), 7.64 (1H, t), 7.79 (1H, d), 8.49 - 8.53 (1H, m). m/z: ES+ [M+H]+ 394.
7-(2-chloro-5-methylpyrimidin-4-yl)-3,3-dimethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one[ No CAS ]
7-(2-chloro-5-methylpyrimidin-4-yl)-3,3-dimethyl-2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
Sodium hydride (60% dispersion in mineral oil) (12.11 mg, 0.30 mmol) was added to 7-(2- chloro-5 -methylpyrimidin-4-yl)-3 ,3 -dimethyl-3 ,4-dihydropyrrolo [1 ,2-a]pyrazin- 1 (2H)-one(80 mg, 0.28 mmol) in DMF (5 mL) under nitrogen. The resulting solution was stirred at20 C for 30 minutes. <strong>[3099-29-4]2-(chloromethyl)-6-methylpyridine</strong> (42.9 mg, 0.30 mmol) was addedand the resulting solution stirred at 20 C for 18 hours. It was diluted with ethyl acetate(50 mL) and washed with brine (15 mL), dried (Na2504), filtered and concentrated invacuo. The crude product was purified by flash silica chromatography, elution gradient 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 7-(2-chloro-5- methylpyrimidin-4-yl)-3 ,3 -dimethyl-2-((6-methylpyridin-2-yl)methyl)-3 ,4- dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (109 mg, 100 %) as a white solid. ?H NMR (400 MHz, DMSO, 30 C) 1.25 (6H, s), 2.45 (6H, d), 4.25 (2H, s), 4.74 (2H, s), 7.10 (1H,d), 7.15 (1H, d), 7.29 (1H, d), 7.61 (1H, t), 7.84 (1H, d), 8.51 (1H, s). m/z: ES+ [M+H]+396.
(3S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one[ No CAS ]
(3S)-3-methyl-7-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo [1,2-a]pyrazin-1(2H)-one[ No CAS ]
With potassium carbonate; In chloroform; at 40 - 60℃; for 48h;
In a thick-walled glass bottle equipped with a magnetic particle, 0.2 g of the above-obtained 2b, 0.13 g of <strong>[3099-29-4]2-chloromethyl-6-methylpyridine</strong> and 2 g of potassium carbonate were added at room temperature, and dissolved in 20 ml of chloroform at 40-60. The mixture was reacted for two days at C, filtered, and the organic solvent was evaporated. The title compound 4b (0.16 g, 54%)
1-methyl-4-((6-methylpyridin-2-yl)methyl)piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With potassium carbonate; In acetonitrile; at 80℃; for 17h;
2-(Chloromethyl)-6-methylpyridine 22b (1 g, 7.06 mmol) and potassium carbonate (1.46 g, 10.59 mmol) were dissolved in 40 mL of acetonitrile. The reaction solution was added with 1-methylpiperazine 22a (848.57 mg, 8.47 mmol, 939.72 uL), and stirred at 80C for 17 hours. The reaction solution was purified by silica gel column chromatography with eluent system A to obtain the title compound 22c (1 g, yield: 69%).
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