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Structure of 3430-18-0 * 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.
With sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; palladium diacetate; triphenylphosphine In tetrahydrofuran at 25℃; for 0.5 h; Inert atmosphere
General procedure: Pd(OAc)2-PPh3, Pd2(dba)3-tbpf, Pd2(dba)3-DavePhos Pd2(dba)3-P(t-Bu)3 Pd2(dba)3-XantPhos and Pd(OAc)2-XPhos. Anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes, then Pd(OAc)2 (7.2 mg, 0.033 mmol, 5 molpercent) and PPh3 (17.7 mg, 1.132 mmol, 20 molpercent) were added and the resulting mixture stirred at room temperature for 30 min. The halogenated heterocycle (0.66 mmol), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature or heated at 65 °C under argon for the proper time. The residue was taken up in brine and extracted with ethyl acetate. The organic phase was separated, dried, the solvent was evaporated and the residue was purified by flash chromatography (mixtures of petroleum ether and ethyl acetate) to give pure hydrodehalogenated heterocycles
Reference：
[1] Journal of Molecular Catalysis A: Chemical, 2014, vol. 393, p. 191 - 209
2
[ 3430-21-5 ]
[ 3430-18-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
With hydrogen bromide; bromine; sodium nitrite In water at -15 - 23℃; for 3 h;
2,5-Dibromo-3-methylpyridine (49) [0175] (J. Med. Chem. 2007, 50, 3730-3742.) 5-Bromo-3-methylpyridin-2-amine (48, 69 g, 0.37 mol) was suspended in hydrobromic acid (200 mL, 48percent in water), and the mixture was cooled to −15° C. Bromine (95 g, 0.59 mol) was added dropwise to the mixture, followed by addition of sodium nitrite (69 g, 1 mol) in water (100 mL). Temperature of the reaction mixture was kept below −15° C. during addition. After addition, the cooling bath was removed and the reaction mixture was stirred for 3 h. The reaction mixture was cooled to −15° C. and quenched with potassium hydroxide (112 g, 2 mol) in water (500 mL). The cooling bath was removed, and the mixture was stirred for 1.5 h. The products were extracted with ethyl acetate (3×300 mL). The combined extracts were washed with water (2×200 mL), saturated aqueous sodium bicarbonate (200 mL), dried with sodium sulfate, and evaporated to dryness. The oily residue was redissolved in chloroform (100 mL), and the solution was filtered through a pad of silica gel, washing with chloroform. The combined filtrates were evaporated to provide 49 as light-yellow solid (87 g, 94percent): mp 38-40° C. (lit. (Recl. Tray. Chim. Pays-Bas 1965, 84, 951-964) mp 41-42° C.). 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J=2.4 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 2.33 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 148.29, 143.05, 141.15, 137.15, 119.68, 22.06.
67%
at 0℃; for 3.25 h;
Example 2 In a 250ml three-necked flask equipped with a stirrer and thermometer was added 50mL 48percent hydrobromic acid and 7.5g (0.052mol) cuprous bromide dissolved in hydrobromic acid solution. At 0°C maintained by ice water bath, 7.6g (0.04mol) 2-amino-3-methyl-5-bromopyridine was slowly added. Maintaining the temperature for 15min, 4.8mL saturated sodium nitrite solution was slowly added dropwise and stirred for 3h. 40percent sodium hydroxide solution was added to adjust pH=7-8. The solution was distilled under reduced pressure to obtain the product in a yield of 67percent.
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1682 - 1697
[2] Patent: US2014/18360, 2014, A1, . Location in patent: Paragraph 0175
[3] Patent: CN105348177, 2016, A, . Location in patent: Paragraph 0012; 0017
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 11, p. 1129 - 1131
[5] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3730 - 3742
[6] Patent: WO2004/814, 2003, A1, . Location in patent: Page 71; 72
3
[ 1603-40-3 ]
[ 3430-18-0 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1989, vol. 24, # 3, p. 249 - 258
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1682 - 1697
[3] Patent: US2014/18360, 2014, A1,
4
[ 3430-18-0 ]
[ 65550-78-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 23, p. 7631 - 7639
5
[ 3430-18-0 ]
[ 156072-86-5 ]
Yield
Reaction Conditions
Operation in experiment
74%
for 2 h; Reflux
5-Bromo-3-methylpicolinonitrile (50) [0176] Copper(I) cyanide (21 g, 0.24 mol) was added to a solution of 2,5-dibromo-3-methylpyridine (49, 60 g, 0.24 mol) in dry DMF (200 mL), and the mixture was heated at reflux for 2 h. After cooling to room temperature, water (1500 mL) was added to the mixture and the products were extracted with ethyl acetate (3×300 mL). The combined extracts were washed with water (3×300 mL), brine (300 mL), dried with sodium sulfate and evaporated to dryness. The brown oily residue was subjected to flash column chromatography (silica gel), eluting with chloroform, to yield 50 as a white solid (35 g, 74percent): mp 86-88° C. 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=1.8 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 149.75, 140.68, 139.95, 132.25, 124.61, 115.90, 18.59; EIMS m/z 196/198 (Mt); CIMS 197/199 (MH+). The 1H NMR spectrum is consistent with previously published data (Bioorg. Med. Chem. 1999, 7, 1845-1855).
61.3%
at 120℃; for 12 h;
1. Preparation of 5-bromo-3-methyl-2-cyanopyridine To a solution of 2,5-dibromo-3-methylpyridine (5.0g, 19.9mmol) in N,N-dimethyl formamide (20mL) was added cuprous cyanide (1.8g, 20.0mmol). The resulting mixture was reacted at 120°C under stirring for 12hrs. The reaction mixture was cooled, to which water was added. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified with a silica-gel column chromatography (petroleum ether:ethyl acetate=5:1) to produce 2.4 g of the title compound as a white solid in a yield of 61.3percent.
49%
at 120℃; for 12 h;
Step A 5-bromo-3-methylpyridine-2-carbonitrile To a solution of 2,5-dibromo-3-methylpyridine (5.0 g, 20. mmol) in N,N-dimethylformamide (20.0 mL, 259 mmol) was added copper cyanide (1.8 g, 20. mmol) and the reaction was stirred at 120° C. for 12 h. The reaction was partitioned between EtOAc and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and purified by combi-flash chromatography to afford 1.94 g (49percent yield) of the desired product as a white solid.
600 mg
at 120℃;
To a solution of 2 5-dibromo-3-methylpyridine (5 g) in DMF (20 mL) was added cyanocopper (1.785 g) . The mixture was stirred at 120 overnight and then cooled to RT. The mixture was partitioned between EA (50 mL) and water (50 mL) . The organic layer was washed with brine (50 mL) dried over Na2SO4and concentrated in vacuo. The resulting residue was purified by column chromatography (eluting with EAPE20) to afford the title compound (600 mg) as a white solid. MS (ESI) C7H5BrN2requires 195 found 196 [M+H]+.
600 mg
at 120℃;
Description 1325-Bromo-3-methylpicolinonitrile (D132)N;1To a solution of 2,5-dibromo-3-methylpyridine (5 g) in DMF (20 mL) was added cyanocopper (1.785 g). The mixture was stirred at 120°C overnight and then cooled to RT. The mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine(50 mL), dried over Na2SO4 and concentrated under vacuum to leave the crude, which was purifiedby column chromatography (silica gel, petroleum ether/EtOAc = 4:1) to afford the title compound(600 mg, 13.14 percent yield) as white solid. MS (ESI): C7H5BrN2 requires 195; found 196 [M+H].
0.83 g
at 170℃; for 2 h; Inert atmosphere
A mixture of 2,5-dibromo-3-methyl-pyridine (2.58 mL), copper(I) cyanide (2.14 g) and N,N-dimethylformamide (20 mL) was stirred under a nitrogen stream at 170°C for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Insoluble material was removed by filtration, and the filtrate was washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.75 g). MS: [M+H]+ 197.0.
600 mg
at 120℃;
In a solution containing 2,5-dibromo-3-methylpyridine (5 g)Of DMF (20 mL)The solution was added with copper cyanide (1.785 g). The mixture was stirred overnight at 120 ° C, Cool to RT. The mixture was dissolved in ΕΑ (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dehydrated by Na2S04 and concentrated in vacuo. The resulting residue was purified by column chromatography (using ΕΑ: PE = 20percent> to give the title compound (600 mg) as a white solid
Example 9.1: 5-bromo-3-methylpyridine-2-carbonitrile; "TX N CN To a solution of 2}5-dibromo-3-methyIpyridine (2.5 g, 9.96 mmol) in dimethylformamide (10 mL) was added copper cyanide (892 mg, 9.96 mmol) and the reaction was stirred at 120 0C for 12 h. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered, concentrated and purified by column chromatography to afford the product a white solid (970 mg, 57.6 percent). 1H NMR (300 MHz, CDCl3): δ 8.55 (s, IH), 7.64 (t, IH), 2.54 (s, 3H).
With sodium iodide In acetyl chloride; acetonitrile for 24 h; Reflux
To a solution of 2,5-dibromo-3-methylpyridine (M-12) (5.02 g, 20.0 mmol) in acetonitrile (50 mL) were addedsodium iodide (12.0 g, 80.0 mmol) and acetyl chloride (2.85 mL, 40.0 mmol), and the mixture was stirred with heatingunder reflux for 24 hr. The reaction mixture was cooled, water was added, and neutralized (pH 8) with saturated aqueoussodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (n-hexane:ethyl acetate = 98:2 →70:30) to give compound (M-13) (yield5.76 g, 97percent) as a red oiL
97%
With acetyl chloride; sodium iodide In acetonitrile for 24 h; Reflux
Sodium iodide (12.0 g, 80.0 mmol) and acetyl chloride (2.85 mL, 40.0 mmol) were added to a solution of 2,5-dibromo-3-methylpyridine (M-12) (5.02 g, 20.0 mmol) in acetonitrile (50 mL) Is added,And the mixture was stirred under heating reflux for 24 hours.The reaction solution was cooled, water was added,And neutralized with saturated aqueous sodium hydrogen carbonate solution(pH 8). Extraction with ethyl acetate,After drying the organic layer with anhydrous sodium sulfate,It was filtered. After distilling off the solvent under reduced pressure,The residue was purified by silica gel column chromatography(n-hexane: ethyl acetate = 98: 2 → 70: 30)Compound (M-13)(Yield 5.76 g, Yield 97percent)As a red oil.
94.78%
With acetyl chloride; sodium iodide In acetonitrile for 16 h; Reflux
To a stirred solution of 2,5-dibromo-3-methyl-pyridine (20. Og, 79.7mmol, 1 eq) in acetonitrile (120ml_) was added acetyl chloride (8.5ml_, 1 19.5mmol, 1 .5eq) followed by addition of Nal (47.8gm, 319mmol, 4eq) at room temperature. Resulting reaction mixture was refluxed for 16 hours. After complete consumption of starting material, reaction mixture was quenched with water (200ml_) and extracted with ethyl acetate (3 x 200ml_). Organic layer was washed with aqueous sodium bicarbonate (2 x 300ml_), brine (300ml_) and dried over sodium sulfate. Organic layer was concentrated under reduced pressure to afford brown oil (35.5g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 5percent EtOAc in hexane to get title compound as brown oil (22.5g, 94.78percent). H NMR (400 MHz, CDCI3)8: 2.36 (s, 3H), 7.56 (d, J = 2.4 Hz, 1 H), 8.24 (d, J = 2.28 Hz, 1 H). LC- MS (m/z): 297.9 (M+H).
86%
at 95℃; for 16 h; Inert atmosphere
Sodium iodide (2 eq., 16 mmol, 2.40 g) and 2,5-dibromo-3-methylpyridine (7.97 mmol, 2 g) were combined in propionitrile (20 mL) and the resulting slurry was stirred under nitrogen for 5 min. Iodotrimethylsilane (0.2 eq., 1.6 mmol, 0.23 mL) was added and the reaction mixture was heated at 95°C with stirring under nitrogen for 16 h. The slurry was cooled to RT, diluted with a 1:1 mixture of ethyl acetate and water. The mixture was stirred for 15 min and the aqueous and organic phases were separated. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution, sodium thiosulfate (5percent aqueous solution) and brine. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the desired product which was purified by flash chromatography over silica gel using an elution of 13percent ethyl acetate in hexane to give 2.03 g (Yield: 86percent) of the title compound 11 as an oil. ESI-MS: m/z 298 [M + H]+
Reference：
[1] Patent: EP3351533, 2018, A1, . Location in patent: Paragraph 0321; 0322
[2] Patent: JP2018/145180, 2018, A, . Location in patent: Paragraph 0315; 0316; 0317
[3] Patent: WO2014/39484, 2014, A1, . Location in patent: Page/Page column 40; 41
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 9, p. 1117 - 1130
[5] Journal of the American Chemical Society, 2017, vol. 139, # 49, p. 18016 - 18023
[6] Organic Letters, 2004, vol. 6, # 26, p. 4905 - 4907
[7] Patent: US2010/222345, 2010, A1, . Location in patent: Page/Page column 97
8
[ 110-91-8 ]
[ 3430-18-0 ]
[ 566158-47-2 ]
Reference：
[1] MedChemComm, 2015, vol. 6, # 2, p. 339 - 346
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3730 - 3742
9
[ 3430-18-0 ]
[ 124-41-4 ]
[ 760207-87-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 120℃; for 0.666667 h;
A) 5-bromo-2-methoxy-3-methyI-pyridine. A suspension of 2,5-dibromo-3-methylpyridine (2.08 g, 8.3 mmol) in a 2 M solution of sodium methoxide in methanol (17 mL) was heated by single node microwave irradiation at 120 ° C for 40 minutes. The reaction mixture was poured onto a mixture of ice and 1 M aqueous hydrochloric acid and extracted with two portions of dichloromethane. The combined organic layers were dried, filtered and concentrated in vacuo to give 1.57 g (89 percent) of the sub-title compound which was used without further purification.1H NMR (400 MHz; chloroform-d as solvent and internal reference) δ(ppm) 8.02 (d, IH, J = 2.3 Hz), 7.45 - 7.47 (m, IH), 3.92 (s, 3H), 2.16 (broad s, 3H).
89%
Stage #1: at 120℃; for 0.666667 h; Stage #2: With hydrogenchloride In methanol; water at 0℃;
A) 5-bromo-2-methoxy-3-methyl-pyridine: A suspension of 235-dibromo-3-methylpyridine (2.08 g, 8.3 mmol) in a 2 M solution of sodium methoxide in methanol (17 mL) was heated by single node microwave irradiation at 120 °C for 40 minutes. The reaction mixture was poured onto a mixture of ice and 1 M aqueous hydrochloric acid and extracted with two portions of dichloro- methane. The combined organic layers were dried, filtered and concentrated in vacuo to give 1.57 g (89 percent) of the sub-title compound which was used without further purification. 1H NMR (400 MHz; chloroform-d as solvent and internal reference) δ(ppm) 8.02 (d, IH, J= 2.3 Hz), 7.45 - 7.47 (m, IH), 3.92 (s, 3H), 2.16 (broad s, 3H).
77.8%
at 100℃; for 2 h; Inert atmosphere
[0231] A solutionof2,5-dibromo-3-methylpyridine (1) 3 g,12.1 mmol) in methanol (20 ml) was added sodium methoxide(2M, 20 mL) and refluxed at 100° C. for 2 h. The reactionmixture was poured on ice water and neutralized with aqueoushydrochloric acid (1M) and extracted with dichloromethane(2x15 ml). The combined organic layer waswashed with water, brine, dried over sodium sulfate, andconcentrated at reduced pressure to give 5-Bromo-2-methoxy-3-methyl-pyridine (35), which was used without furtherpurification (1.9 g, 77.8percent).
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 25℃; for 3 h; Stage #2: at 17 - 25℃; for 1 h;
Method 4; Preparation of 6-bromo-5-methylnicotinaldehyde; 2,5-Dibromo-3-picoline (5.1 g, 20.30 mmol) in tetrahydrofuran (25 ml) was added dropwise to a 2M solution of isopropylmagnesium chloride (10.7 ml, 21.3 mmol) in tetrahydrofuran at 0° C. The solution was stirred for 2 hours at 0° C. and then for 1 hour at ambient temperature. A solution of 4-formylmorpholine (2.1 ml, 20.3 mmol) in tetrahydrofuran (25 ml) was added dropwise and the solution stirred at ambient temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solution concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 10percent ethyl acetate in isohexane, to give the title compound (3.0 g, 74percent); NMR Spectrum: (DMSO-d6) 2.44 (s, 3H), 8.19 (s, 1H), 8.73 (s, 1H), 10.09 (s, 1H).
74%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 3 h; Stage #2: at 20℃; for 1 h;
Method 3; Preparation of 6-bromo-5-methvmicotmaldehvde; 2,5-Dibromo-3-picoline (5.1 g, 20.30 mmol) in tetrahydrofuran (25 ml) was added dropwise to a 2M solution of isopropylmagnesium chloride (10.7 ml, 21.3 mmol) in tetrahydrofuran at 0 0C. The solution was stirred for 2 hours at 0 0C and then for 1 hour at ambient temperature. A solution of 4-formylmorpholine (2.1 ml, 20.3 mmol) in tetrahydrofuran (25 ml) was added dropwise and the solution stirred at ambient temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solution concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 10 percent ethyl acetate in isohexane, to give the title compound (3.0 g, 74 percent); NMR Spectrum: (DMSO-d6) 2.44 (s, 3H), 8.19 (s, IH), 8.73 (s, IH), 10.09 (s, IH).
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 3h; Reflux;
Step 2: 2,5-dibromo-3-(bromomethyl)pyridine
[0096] A mixture of 2,5-dibromo-3-methylpyridine (20.0 g, 80.0 mmol), N- bromosuccinimide (12.8 g, 72 mmol) and benzoyl peroxide (1.03 g, 4 mmol) in CC14 (300 mL) was heated to reflux for 3 h. The mixture was cooled to rt, washed with water (2 x 100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (HQ) to give 2,5-dibromo-3- (bromomethyl)pyridine (11.0 g, 42%) as a white solid. 1H NMR: (CDC13, 400 MHz): δ 8.38- 8.39 (d, J = 2.4 Hz, 1H), 7.91-7.92 (d, J = 2.4 Hz, 1H), 4.51 (s, 2H).
42%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 3h; Reflux;
A3.2 Step 2: 2,5-dibromo-3-(bromomethyl)pyridine
A mixture of 2,5-dibromo-3-methylpyridine (20.0 g, 80.0 mmol), N-bromosuccinimide (12.8 g, 72 mmol) and benzoylperoxide (1.03 g, 4 mmol) in CC14 (300 mE) was heated to reflux for 3 h. The mixture was cooled to rt, washed with water (2x100 mE) and brine (100 mE), dried over anhydroussodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by preparative HPEC (HC1) to give2,5-dibromo-3-(bromomethyl)pyridine (11.0 g, 42%) as a white solid. ‘H NMR: (CDC13, 400 MHz): ö 8.38-8.39 (d,J=2.4 Hz, 1H), 7.91-7.92 (d, J=2.4 Hz, 1H), 4.51 (s, 2H).
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 4h; Heating; irradiation;
4 g
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 0 - 20℃; for 7.25h;
29.1 the preparation of compound 29-2
To a solution of /7-bromosuccinimide (NBS) (2.16 g. 12 mmol) and compound 29-1 (2.51 g. 10 mmol) in CC14 (20.0 mL) was added benzoyl peroxide (0.24 g.1.0 mmol) dropwise at 0°C. At the end of the addition, the mixture was stirred at room temperature for 15 mins and then refluxed for another 7.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL), and then washed with water (50 mL x 3) and brine, dried over anhydrous concentrated in vacuo to give the title compound (4.0 g), which was used for the next step without further purification. The compound was characterized by the follow ing spectroscopic data: MS (ESI, pos.ion) mlz: 330.5 [M+H] '; and '}] NMR (400 MHz, CDCL) d (ppm): 8.18-8.17 (m.1H).7.79 (m.1H).4.66-4.65 (m.2H).
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 0 - 20℃; for 7.25h; Reflux;
18.1 Step 1) Synthesis of compound 18-2
NBS (2.16 g, 12 mmol) and compound 18-1 (2.51 g, 10 mmol) were dissolved in CCl4(20 mL) and dibenzoylperoxide (0.24 g, 1.0 mmol) was slowly dropped at 0 ° C. Afterthe addition was completed, the mixture was stirred at room temperature for 15 minutesand then refluxed for 7.0 hours. After the reaction is complete, CCl is removed 4Theresidue was dissolved in EtOAc (100 mL), washed with water (50 mL x 3) and brine, driedover anhydrous sodium sulfate and concentrated to give 3.2 g of crude product, which wasused directly in the next reaction.
With hydrogen bromide; bromine; sodium nitrite; In water; at -15 - 23℃; for 3h;
2,5-Dibromo-3-methylpyridine (49) [0175] (J. Med. Chem. 2007, 50, 3730-3742.) 5-Bromo-3-methylpyridin-2-amine (48, 69 g, 0.37 mol) was suspended in hydrobromic acid (200 mL, 48% in water), and the mixture was cooled to -15 C. Bromine (95 g, 0.59 mol) was added dropwise to the mixture, followed by addition of sodium nitrite (69 g, 1 mol) in water (100 mL). Temperature of the reaction mixture was kept below -15 C. during addition. After addition, the cooling bath was removed and the reaction mixture was stirred for 3 h. The reaction mixture was cooled to -15 C. and quenched with potassium hydroxide (112 g, 2 mol) in water (500 mL). The cooling bath was removed, and the mixture was stirred for 1.5 h. The products were extracted with ethyl acetate (3×300 mL). The combined extracts were washed with water (2×200 mL), saturated aqueous sodium bicarbonate (200 mL), dried with sodium sulfate, and evaporated to dryness. The oily residue was redissolved in chloroform (100 mL), and the solution was filtered through a pad of silica gel, washing with chloroform. The combined filtrates were evaporated to provide 49 as light-yellow solid (87 g, 94%): mp 38-40 C. (lit. (Recl. Tray. Chim. Pays-Bas 1965, 84, 951-964) mp 41-42 C.). 1H NMR (300 MHz, CDCl3) delta 8.22 (d, J=2.4 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 2.33 (s, 3H); 13C NMR (75 MHz, CDCl3) delta 148.29, 143.05, 141.15, 137.15, 119.68, 22.06.
91.8%
Add 93.5 g (0.5 mol) of <strong>[3430-21-5]5-bromo-2-amino-3-methylpyridine</strong> and 300 g of hydrobromic acid to a 1 L four-necked flask, start stirring, and lower the temperature to below -10 C;Add 103.9g (0.65mol) bromine dropwise, control the drop temperature to -15 -10 , and add the drop time to 1-2h; add dropwise a solution prepared by 103.5g (1.5mol) sodium nitrite and 155.0g water Control the dropping temperature at -15 -10 and the dropping time at 1.5-2h;After the dropwise addition, stir at 15-20 C for 3h; lower the temperature to below 0 C and adjust the pH to 7-8 with liquid alkali;Suction filtration, washing once with 120 ml of methanol, and drying at 40-45 C to obtain 115.2 g of 2,5-dibromo-3-methylpyridine with a yield of 91.8% and an HPLC content of 99.0%.The content of <strong>[3430-21-5]5-bromo-2-amino-3-methylpyridine</strong> is 0.2%, and the content of 2,3-bromo-5-methylpyridine is 0.2%;
67%
With hydrogen bromide; copper(I) bromide; sodium nitrite; at 0℃; for 3.25h;
Example 2 In a 250ml three-necked flask equipped with a stirrer and thermometer was added 50mL 48% hydrobromic acid and 7.5g (0.052mol) cuprous bromide dissolved in hydrobromic acid solution. At 0C maintained by ice water bath, 7.6g (0.04mol) <strong>[3430-21-5]2-amino-3-methyl-5-bromopyridine</strong> was slowly added. Maintaining the temperature for 15min, 4.8mL saturated sodium nitrite solution was slowly added dropwise and stirred for 3h. 40% sodium hydroxide solution was added to adjust pH=7-8. The solution was distilled under reduced pressure to obtain the product in a yield of 67%.
67%
In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 50 ml of a 48% hydrobromic acidsolution was added, and 7.5 g (0.052 mol) of cuprous bromide was dissolved in a hydrobromic acid solution,and the ice water bath was kept at a temperature of 0 C and slowly added to 7.6. g (0.04 mol) <strong>[3430-21-5]2-amino-3-methyl-5-bromopyridine</strong>, maintaining the temperature for 15 min, slowly adding 4.8 ml of saturated sodiumnitrite solution, stirring for 3 h after the addition, neutralizing with 40% sodium hydroxide solution The reactionwas carried out until pH = 7-8, and the product was distilled under reduced pressure to give a yield of 67%.
67%
Add 50ml of 48% hydrobromic acid solution to a 250ml three-necked bottle equipped with a stirrer and thermometer, and dissolve 7.5g (0.052mol) of cuprous bromide in the hydrobromic acid solution.Slowly add 7.6g (0.04mol) <strong>[3430-21-5]2-amino-3-methyl-5-bromopyridine</strong> while maintaining the temperature at 0 C in an ice water bath.Keep the temperature for 15min,Slowly add 4.8ml of saturated sodium nitrite solution,Stir for 3h after the addition, neutralize the reaction with 40% sodium hydroxide solution to pH = 7-8, and distill under reduced pressure to obtain the product in 67% yield.
[5-BROMO-3-METHYL-PYRIDIN-2-YLAMINE] [(L.] [OEQ.)] was added portionwise to aqueous [HBR] (48%; [1.] [OM).] The mixture was stirred lh at rt then cooled [TO-20C.] Bromine (2.8eq.) was added dropwise followed by a aqueous solution [OF NAN02] [(1.] OM; 2.7eq.). The final mixture was warmed to rt and stirred for 2h. The mixture was cooled back to-20C then aqueous [NAOH] [(1.] OM; 3. 0eq.) was added dropwise over [LH.] The final mixture was warmed to rt and extracted with Et20 (2x). The combined organic extracts were washed with brine, dried over [MGS04,] filtered and concentrated to afford the title compound as a yellow solid.
With hydrogen bromide; bromine; sodium nitrite; In water; at -15 - 20℃; for 4h;
To a solution of compound 4 (7.91 g, 42.29 mmol) in 48% HBr(25 mL) was added Br2 (10.81 g, 114.18 mmol) and 12 mL NaNO2aqueous solution (7.88 g, 67.66 mmol) at -15 C, respectively. Themixture was stirred at room temperature for 4 h and then quenchedwith 58 mL KOH aqueous solution (12.8 g, 228 mmol) at -15 C. Then,the mixture was stirred at room temperature for 0.5 h and extractedwith EtOAc (100 mL×3). The combined organic phase was washedwith saturated sodium bicarbonate solution (100 mL×3) and water(100 mL×3), dried over Na2SO4, filtered, and concentrated in vacuo.The crude product 5 was given as a brown liquid (8 g, 75.4%) and couldbe used in the next step without further purification.
48
Preparation 48; [(R)-l-(5-Bromo-3-methyl-pyridin-2-yl)-pyrrolidin-3-yl]-dimethyl-amine; Combine 2,5-dibromo-3-methyl-pyridine (2.00 g, 7.97 mmol) with dimethyl-(R)- pyrrolidin-3-yl-amine (2.40 g, 20.72 mmol) andp-toluenesulfonic acid monohydrate (0.39 g, 2.07 mmol) in a sealed tube and heat at 100 0C overnight. Dilute with EtOAc (100 mL), wash with saturated NaHCO3 (3 x 40 mL), dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography, eluting with 2%NH3 H2O in 1: 1 CH3OHiEtOAc to give 2.09 g (99%) of the title compound. LC-MS/ES m/z (79Br) 284.3 [M+H]+.
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In toluene; acetonitrile; at 80℃; under 4137.29 Torr; for 16h;
To a 400 mL autoclave was charged 1.6 g (6.06 mmol) of 2,5-dibromo-3-methylpyridine, 0.45 g (0.64 mmol) of (PPh3)2PdCl2, 30 mL of toluene/CH3CN (1:1), 0.33 mL (95 mmol) of Et3N and 4 eq. of CH3OH. The autoclave was sealed, evacuated, flushed with nitrogen three times and charged with carbon monoxide to 80 psi. The autoclave was heated to 80C for 16 hrs, cooled to r.t. and the excess carbon monoxide was evacuated under vacuum. The conversion was about 55% as determined by NMR. The contents of the autoclave were transferred into a flask for concentration. The residue was then purified on a silica gel column, eluting with hexane:EtOAc to give the ester as a white solid. M.p. 61-62C. 1H NMR (CDCl3): delta 8.58 (d, J = 1.9 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 3.96 (s, 3H), 2.58 (s, 3H). 13C NMR (CDCl3): delta 165.82, 147.94, 145.17, 142.20, 137.63, 123.56, 52,74, 19.96. IR: 1715 cm-1.
A) 5-bromo-2-methoxy-3-methyI-pyridine. A suspension of 2,5-dibromo-3-methylpyridine (2.08 g, 8.3 mmol) in a 2 M solution of sodium methoxide in methanol (17 mL) was heated by single node microwave irradiation at 120 C for 40 minutes. The reaction mixture was poured onto a mixture of ice and 1 M aqueous hydrochloric acid and extracted with two portions of dichloromethane. The combined organic layers were dried, filtered and concentrated in vacuo to give 1.57 g (89 %) of the sub-title compound which was used without further purification.1H NMR (400 MHz; chloroform-d as solvent and internal reference) delta(ppm) 8.02 (d, IH, J = 2.3 Hz), 7.45 - 7.47 (m, IH), 3.92 (s, 3H), 2.16 (broad s, 3H).
89%
A) 5-bromo-2-methoxy-3-methyl-pyridine: A suspension of 235-dibromo-3-methylpyridine (2.08 g, 8.3 mmol) in a 2 M solution of sodium methoxide in methanol (17 mL) was heated by single node microwave irradiation at 120 C for 40 minutes. The reaction mixture was poured onto a mixture of ice and 1 M aqueous hydrochloric acid and extracted with two portions of dichloro- methane. The combined organic layers were dried, filtered and concentrated in vacuo to give 1.57 g (89 %) of the sub-title compound which was used without further purification. 1H NMR (400 MHz; chloroform-d as solvent and internal reference) delta(ppm) 8.02 (d, IH, J= 2.3 Hz), 7.45 - 7.47 (m, IH), 3.92 (s, 3H), 2.16 (broad s, 3H).
77.8%
In methanol; at 100℃; for 2h;Inert atmosphere;
[0231] A solutionof2,5-dibromo-3-methylpyridine (1) 3 g,12.1 mmol) in methanol (20 ml) was added sodium methoxide(2M, 20 mL) and refluxed at 100 C. for 2 h. The reactionmixture was poured on ice water and neutralized with aqueoushydrochloric acid (1M) and extracted with dichloromethane(2x15 ml). The combined organic layer waswashed with water, brine, dried over sodium sulfate, andconcentrated at reduced pressure to give 5-Bromo-2-methoxy-3-methyl-pyridine (35), which was used without furtherpurification (1.9 g, 77.8%).
Method 9; Preparation of 6-bromo-5-methylnicotinic acid; 2,5-Dibromo-3-picoline (5.07 g, 20.21 mmol) in tetrahydrofuran (30 ml) was added dropwise to a 2M solution of isopropylmagnesium chloride (11.11 ml, 22.23 mmol) in tetrahydrofuran at 0 C. The solution was stirred for 1 hour at 0 C. and for 1 hour at ambient temperature, then added to diethyl ether which had been saturated with carbon dioxide pellets. After 18 hours water was added to the mixture and the diethyl ether layer separated and discarded. The aqueous layer was acidified to pH 4 with a 2M aqueous solution of hydrochloric acid and extracted with ethyl acetate (100 ml×2). The combined organics were washed with brine then dried over magnesium sulphate, filtered and concentrated under reduced pressure. The solid obtained was triturated with dichloromethane then filtered, to give the title compound (764 mg, 18%); NMR Spectrum: (DMSO-d6) 2.41 (s, 3H), 8.21 (d, 1H), 8.67 (d, 1H), 13.55 (br s, 1H); Mass Spectrum: M+H+ (81Br) 218.
Method 4; Preparation of 6-bromo-5-methylnicotinaldehyde; 2,5-Dibromo-3-picoline (5.1 g, 20.30 mmol) in tetrahydrofuran (25 ml) was added dropwise to a 2M solution of isopropylmagnesium chloride (10.7 ml, 21.3 mmol) in tetrahydrofuran at 0 C. The solution was stirred for 2 hours at 0 C. and then for 1 hour at ambient temperature. A solution of 4-formylmorpholine (2.1 ml, 20.3 mmol) in tetrahydrofuran (25 ml) was added dropwise and the solution stirred at ambient temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solution concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 10% ethyl acetate in isohexane, to give the title compound (3.0 g, 74%); NMR Spectrum: (DMSO-d6) 2.44 (s, 3H), 8.19 (s, 1H), 8.73 (s, 1H), 10.09 (s, 1H).
74%
Method 3; Preparation of 6-bromo-5-methvmicotmaldehvde; 2,5-Dibromo-3-picoline (5.1 g, 20.30 mmol) in tetrahydrofuran (25 ml) was added dropwise to a 2M solution of isopropylmagnesium chloride (10.7 ml, 21.3 mmol) in tetrahydrofuran at 0 0C. The solution was stirred for 2 hours at 0 0C and then for 1 hour at ambient temperature. A solution of 4-formylmorpholine (2.1 ml, 20.3 mmol) in tetrahydrofuran (25 ml) was added dropwise and the solution stirred at ambient temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solution concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 10 % ethyl acetate in isohexane, to give the title compound (3.0 g, 74 %); NMR Spectrum: (DMSO-d6) 2.44 (s, 3H), 8.19 (s, IH), 8.73 (s, IH), 10.09 (s, IH).
Under an argon atmosphere, a solution of 2 M isopropylmagnesium chloride in THF (5.5 ml) was cooled to -78 C., and a solution of 2,5-dibromo-3-methylpyridine (2.5 g) in THF (10 ml) was added dropwise. After stirring at the same temperature for 30 minutes, a solution of morpholine-4-carboaldehyde (1.26 g) in THF (5 ml) was added dropwise thereto, followed by elevating the temperature to 0 C. over 30 minutes, followed by stirring at 0 C. for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 6-bromo-5-methyl nicotine aldehyde (1.42 g).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 73℃; for 28.5h;Inert atmosphere;
25.0 g (99.6 mmol) of 2,5-dibromo-3-picoline, 24.0 g (101.6 mmol) of 3,5-dichlorophenylboric acid, 288 ml of toluene, 144 ml of ethanol, 102 ml of 2M sodium carbonate aqueous solution, and 4.0 g (3.46 mmol) of Pd(PPh3)4 were prepared and reacted in a nitrogen atmosphere for 28.5 hours at 73 °C. Chloroform and water were poured into a reactor vessel, and a chloroform layer was fractioned. The chloroform layer was washed with water twice. A crude material obtained by collecting chloroform was purified with a silica gel column using a developing solvent of chloroform / n-hexane mixture solvent. Structure identification was performed by way of MS and 1H-NMR, and it was confirmed that it was a target. Its yield was 17.9 g (56.5percent yields).
Stage #1: 2-methoxy-ethanol With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 0.5h;
Stage #2: 2,5-dibromo-3-methylpyridine In dimethyl sulfoxide; mineral oil at 60℃; for 1h;
A45
Example A45Preparation of intermediate 45: 5-Bromo-2-(2-methoxy-ethoxy)-3-methyl-pyridine2-Methoxy-ethanol (1.18 ml, 14.95 mmol) was added dropwise to a stirred suspension of a 60% dispersion of sodium hydride in mineral oils (0.558 g, 13.95 mmol) in dimethylsulfoxide (30 ml). The mixture was stirred at room temperature for 30 min. and then 2,5-dibromo-3-methylpyridine (2.5 g, 9.96 mmol) was added. The mixture was stirred at 60 °C for 1 h. and then diluted with heptane and washed with water. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; dichloromethane in heptanes 70/30). The desired fractions were collected and concentrated in vacuo to yield intermediate 45 (2.23 g, 91%).
91%
Stage #1: 2-methoxy-ethanol With sodium hydride In dimethyl sulfoxide; mineral oils at 20℃; for 0.5h;
Stage #2: 2,5-dibromo-3-methylpyridine In dimethyl sulfoxide; mineral oils at 60℃; for 1h;
A45
Example A45 Preparation of intermediate 45: 5-Bromo-2-(2-methoxy-ethoxy)-3-methyl-pyridine 2-Methoxy-ethanol (1.18 ml, 14.95 mmol) was added dropwise to a stirred suspension of a 60% dispersion of sodium hydride in mineral oils (0.558 g, 13.95 mmol) in dimethylsulfoxide (30 ml). The mixture was stirred at room temperature for 30 min. and then 2,5-dibromo-3-methylpyridine (2.5 g, 9.96 mmol) was added. The mixture was stirred at 60° C. for 1 h. and then diluted with heptane and washed with water. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; dichloromethane in heptanes 70/30). The desired fractions were collected and concentrated in vacuo to yield intermediate 45 (2.23 g, 91%).
Stage #1: 2,5-dibromo-3-methylpyridine With n-butyllithium In hexane at -78℃; for 0.5h; Inert atmosphere;
Stage #2: With Trimethyl borate In hexane at -78 - 0℃; for 1.5h;
Stage #3: (S)-2-t-butoxycarbonylaminopropan-1-ol
4.A
Under an argon atmosphere, to a solution of 2,5-dibromo- 3-methylpyridine (12.4 g) in THF (100 mL) was added dropwise a hexane solution (1.6 M, 30.9 mL) of n-butyllithium at -78°C, and the obtained mixture was stirred at -78°C for 30 min. To the reaction mixture was added trimethoxyborane (5.52 mL) , and the obtained mixture was stirred at -78°C for 30 min, then at 0°C for 1 hr. To the reaction mixture were added 8 aqueous sodium hydroxide solution (6.18 mL) and aqueous 30% hydrogen peroxide (100 mL) , and the obtained mixture was stirred at 0°C for 30 min, then at room temperature for 30 min. The reaction mixture was acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium thiosulfate solution and thensaturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate) , and the obtained residue was mixed with tert-butyl [ (IS) -2-hydroxy-l-methylethyl] carbamate (4.43 g) , triphenylphosphine (6.63 g) and THF (40 mL) . A toluene solution (1.9 M, 13.3 mL) of diisopropyl azodicarboxylate was added dropwise thereto, and the obtained mixture was stirred at room temperature for 1 hr, then at 70°C overnight. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and HPLC (C18, mobile phase: water/acetonitrile (containing 5 mM ammonium acetate)) to give the title compound (0.739 g) .XH NMR (300 MHz, DMSO-d6) δ 1.11 (3H, d, J = 6.8 Hz), 1.37 (9H, s) , 2.30 (3H, s) , 3.72-4.00 (3H, m) , 6.91 (1H, d, J = 7.2 Hz) , 7.36-7.52 (1H, m) , 7.94 (1H, d, J = 3.0 Hz).
With sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; palladium diacetate; triphenylphosphine; In tetrahydrofuran; at 25℃; for 0.5h;Inert atmosphere;
General procedure: Pd(OAc)2-PPh3, Pd2(dba)3-tbpf, Pd2(dba)3-DavePhos Pd2(dba)3-P(t-Bu)3 Pd2(dba)3-XantPhos and Pd(OAc)2-XPhos. Anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes, then Pd(OAc)2 (7.2 mg, 0.033 mmol, 5 mol%) and PPh3 (17.7 mg, 1.132 mmol, 20 mol%) were added and the resulting mixture stirred at room temperature for 30 min. The halogenated heterocycle (0.66 mmol), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature or heated at 65 C under argon for the proper time. The residue was taken up in brine and extracted with ethyl acetate. The organic phase was separated, dried, the solvent was evaporated and the residue was purified by flash chromatography (mixtures of petroleum ether and ethyl acetate) to give pure hydrodehalogenated heterocycles
5-bromo-2-(2,3-dichlorophenyl)-3-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With palladium diacetate; potassium carbonate; triphenylphosphine; In methanol; acetonitrile; at 50℃; for 24h;Inert atmosphere;
A mixture of 2,5-dibromo-3-methylpyridine (5.0 g, 19.93 mmol), (2,3- dichlorophenyl)boronic acid (4.2 g, 21.92 mmol), Pd(OAc)2 (447 mg, 1.99 mmol), PPh3 (1.1 g, 3.99 mmol), and K2C03 (5.5 g, 39.86 mmol) in CH3CN (150 mL) and MeOH (75 mL) was stirred at 50 C under nitrogen atmosphere for 24 hrs. The reaction mixture was poured into 50 mL of H20 and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 5-bromo-2-(2,3-dichlorophenyl)-3-methylpyridine (5.1 g, 81 % yield) as a light yellow oil. ‘H NIVIR (400 MHz, Chloroform-cl) ppm 8.57 (d, J=9.21 Hz, 1 H) 7.76 (d, J=8.77 Hz, 1 H) 7.52 (t, J=8.33 Hz, 1 H) 7.35 -7.25 (m, 1 H) 7.23 - 7.15 (m, 1 H) 2.13 (d, J9.21 Hz, 3H).
With sodium hydride In N,N-dimethyl-formamide at 100℃; for 3h;
1.3; 2.3; 3.3; 4.3 (3) Preparation of (5-bromo-3-methyl-pyridin-2-yl) -methylamine
Add 125 g of DMF to a 1 L four-necked flask, lower the temperature to 10 ° C, add 5.1 g (0.21 mol) of sodium hydride, stir to dissolve,Add 12.4 g (0.21 mol) of N-methylformamide and 50.2 g (0.2 mol) of 2,5-dibromo-3-methylpyridine, raise the temperature to 100 ° C, and hold the reaction for 3 hours.Reduce the temperature to 20-40 , add 250g of water, adjust the pH to 1,130g with 30% hydrochloric acid to extract impurities, separate the lower aqueous layer, and adjust the pH of the aqueous layer to 9.5-10.5 with 30% liquid alkali.Extract with 200 g of isopropyl acetate, wash the upper organic layer with 0.5% dilute hydrochloric acid to pH 7-8, remove the lower aqueous layer, and distill the isopropyl acetate to dryness under reduced pressure.Distill isopropyl acetate under reduced pressure at a temperature of 45-50 ° C and a degree of vacuum of -0.1 to -0.09 MPa; add 120 g of n-hexane to reduce the temperature to 0-10 ° C and crystallize to obtain flaky crystals.After drying at 80 ° C, 33.8 g of (5-bromo-3-methyl-pyridin-2-yl) -methylamine was obtained with a yield of 84.2% and an HPLC content of 99.7%.The benzoic acid content was not detected, and the N- (3-bromo-5-methylpyridin-2yl) -N-methylbenzamide was 0.05%, and the remaining single impurities were less than 0.2%.
70.4%
Stage #1: N-Methylformamide With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20 - 80℃; for 1.5h;
Stage #2: 2,5-dibromo-3-methylpyridine In N,N-dimethyl-formamide for 2h;
1.1
step one:At room temperature,Potassium tert-butoxide (80.5 g, 0.66 mol) and N-methylformamide (42.4 g, 0.72 mol) were sequentially added to 300 ml of N,N-dimethylformamide, and the mixture was heated to 80 ° C for 1.5 h.2,6-Dibromo-3-methylpyridine (100 g, 0.40 mol) was added and the reaction was continued for 2 h.The system was cooled to room temperature, then poured into 1.5 L of ice water, adjusted to pH = 2 with concentrated hydrochloric acid, and extracted three times with ethyl acetate (250 ml × 3), the aqueous phase was separated, and the aqueous solution was adjusted to pH 10-11.The organic phase was extracted three times with ethyl acetate (3 ml) (3 ml).The crystal was allowed to stand still, and after filtration and drying, 56.3 g of needle crystals were obtained, yield: 70.4%.
5-bromo-3-methyl-2-{9H-pyrido[2,3-b]indol-9-yl}pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With 1-methyl-1H-imidazole; potassium carbonate In toluene at 120℃; for 48h; Sealed tube; Inert atmosphere;
1.1 Step 1: Synthesis of 9-(3-methyl-5-bromopyridin-2-yl)-9H-pyridine [2,3-b]indole-9-(3-methyl-5-bromopyridin-2-yl )-9H-pyridine [2,3-b]indole is synthesized by the following reaction formula 1:
2,5-Dibromo-3-methylpyridine (2.51 g, 10.0 mmol), porphyrin (1.82 g, 11.0 mmol), CuI (381 mg,2.0 mmol), 1-methylimidazole (246 mg, 3.0 mmol), potassium carbonate (2.76 g, 20.0 mmol), toluene (25 mL) was placed in a 38 mL sealed tube. After bubbling nitrogen for 5 min, the temperature was raised to 120 ° C, and the reaction was refluxed for 48 h. . After the reaction is completed, filter,The filter cake was rinsed with ethyl acetate.The obtained filtrate was subjected to distillation under reduced pressure to remove the solvent, and then the obtained product was passed through a silica gel column ( petroleum ether: ethyl acetate = 10:1)→5:1) Purification afforded 9-(3-methyl-5-bromopyridin-2-yl)-9H-pyridine[2,3-b]indole (1.75 g,Yield 52%).
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