* 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 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] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[2] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[3] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[4] Bulletin of the Chemical Society of Japan, 2000, vol. 73, # 5, p. 1227 - 1231
3
[ 105827-78-9 ]
[ 616-45-5 ]
[ 5326-23-8 ]
[ 6271-78-9 ]
[ 23100-12-1 ]
[ 463-04-7 ]
[ 625-74-1 ]
[ 120868-66-8 ]
Reference：
[1] Chinese Journal of Chemistry, 2012, vol. 30, # 1, p. 127 - 132
4
[ 21543-49-7 ]
[ 23100-12-1 ]
Yield
Reaction Conditions
Operation in experiment
96%
With oxalyl dichloride; triethylamine In dimethyl sulfoxide at -78 - 20℃; for 2.5 h;
According to a procedure of Lee et al. [22] oxalylchloride (3.81 g, 30.0 mmol, 3.0 eq) was dissolved in CH2Cl2 (35 mL) at -78C (dry ice/acetone). Then DMSO (46.9 g, 0.60 mol, 60.0 eq.)was added dropwise under stirring and the reaction mixture was stirred for additional 30 min at -78C. Then 2-chloro-5-(hydroxymethyl)pyridine (1.44 g, 10.0 mmol, 1.00 eq) was dissolved in CH2Cl2(10 mL) and added dropwise with a syringe to the cold reaction mixture. Afterwards, the reaction mixture was stirred for 40 min at -78C and NEt3 (91.9 g, 0.90 mol, 90.0 eq) was added to the reaction mixture at a rate of 2.0 mL/min. The reaction mixture was stirred for 1 h at -78C, followed by another 1.5 h stirring at r.t. The reaction mixture was then diluted with Et2O (60 mL) and the organic phase was washed successively withNaHCO3(sat., aq., 2 × 30 mL), KHSO4(1 M, aq., 60 mL) and NaHCO3(sat., aq., 30 mL). After phase separation the organic phase was dried over Na2SO4, the solid removed by filtration and the solvent was removed in vacuum. Further cleaning with liquid chromatography(LC) (SiO2, n-pentane/EtOAc/NEt3= 200/100/6) gave the desired product as yellowish solid (1.35 g, 96percent).
94%
at 20℃; for 6 h;
General procedure: To a mixture of alcohol in dry DMSO (10 volume) was added 1 equiv of polymer bromide and the reaction mixture was stirred at room temperature for a given period of time (Table 1). After the completion of the reaction, the reaction mixture was filtered and the polymer bed washed with DMSO. Combined DMSO layers were quenched with ice-water mixture and extracted with ether. The ether layer was given water wash, brine wash, dried over anhydrous sodium sulphate, and concentrated to get the pure carbonyl compounds. All the products were characterized by NMR and MS analysis.
87%
With manganese(IV) oxide In chloroform at 60℃;
To a solution of the alcohol from above (481 mg, 3.35 mmol) in CHCl3 (25 mL) was added MnO2 (85percent, 3.14 g, 30.7 mmol) and the suspension stirred at 60 0C overnight. The reaction was cooled, filtered through Celite.(R)., washing the cake with CH2Cl2 and MeOH and the resultant filtrate concentrated to afford the desired aldehyde (0.41 g, 87percent) as a yellow solid. To a solution of 6-chloro-3-pyridinecarboxaldehyde (210 mg, 1.48 mmol) and ρyrimidine-5-boronic acid (207 mg, 1.67 mmol) in THF/DME/2 M Na2CO3 (1:2:1, 4 mL) was added Pd(PPh3)4 (154 mg, 0.13 mmol) and the reaction stirred under argon at 90 0C overnight. Standard work-up and purification by column chromatography on silica gel (CH2Cl2ZMeOH, 95:5) afforded -pyrimidm-S-yl-pyridme-S-carbaldehyde (80 mg, 29percent) as a yellow solid. 1H NMR (CDCl3) δ 7.96 (d, IH, J= 8.1 Hz), 8.32 (dd, IH, J= 8.1, 1.5 Hz), 9.20 (d, IH, J = 1.5 Hz), 9.32 (s, IH), 9.42 (s, 2H), 10.18 (s, IH).
89 %Chromat.
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In dichloromethane at 25℃; for 0.5 h;
General procedure: DBDMH (1 mmol) was added to a mixture of 1b (1 mmol) and dichloromethane (20ml). The reaction was kept at room temperature. After the mixture was stirred for0.5h, the mixture was washed with water (330 ml),dried with anhydrous MgSO4,filtered, and vacuum evaporated. The residue was purified by column chromatography (silica gel: petroleum ether/ethyl acetate, 30:1) to afford the product as light yellowsolid (93percent yield).
15 g
With pyridinium chlorochromate In dichloromethane at 0 - 20℃; for 2 h;
To a solution of PCC (58 g, 0.27 mol) in DCM (1500 ml) was added the product of the proceeding step (26 g, 0.184mol) as a solution in DCM drop wise at 0°C. The mixture was then stirred for 2h at 20°C. It was filtered through diatomaceous earth and the filter contents were washed with DCM. The organic phase was concentrated to give the crude product, which was purified by column chromatography to give the product (15 g, yield: 60.1 percent). 1H NMR (400 MHz, CDCI3): δ 10.067 (s, 1 H), 8.874 (s, 1 H, J=3Hz), 8.158-8.138 (d, 1 H, J=8Hz), 7.534-7.513 (d, 1 H, J=8Hz)
Reference：
[1] Chemical Communications, 1999, # 18, p. 1907 - 1908
[2] Organic Letters, 2005, vol. 7, # 14, p. 2965 - 2967
[3] Electrochimica Acta, 2014, vol. 140, p. 101 - 107
[4] Chemistry - A European Journal, 2016, vol. 22, # 15, p. 5319 - 5326
[5] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 10, p. 1253 - 1255
[6] Tetrahedron Letters, 2011, vol. 52, # 51, p. 6971 - 6973
[7] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 5, p. 694 - 707
[8] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 1079 - 1089
[9] Journal of Organic Chemistry, 1993, vol. 58, # 21, p. 5600 - 5602
[10] Synthesis, 1998, # 9, p. 1335 - 1338
[11] Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1274 - 1286
[12] Patent: WO2007/22371, 2007, A2, . Location in patent: Page/Page column 72
[13] Organic Letters, 2001, vol. 3, # 19, p. 3009 - 3012
[14] Journal of Organic Chemistry, 1998, vol. 63, # 3, p. 760 - 768
[15] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 9, p. 1571 - 1574
[16] Journal of Physical Organic Chemistry, 2017, vol. 30, # 2,
[17] Synthesis, 1994, # 1, p. 87 - 92
[18] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 2013 - 2016
[19] Synthetic Communications, 2014, vol. 44, # 8, p. 1155 - 1164
[20] Patent: WO2014/167084, 2014, A1, . Location in patent: Page/Page column 80
[21] Synthetic Communications, 2016, vol. 46, # 7, p. 636 - 644
5
[ 2591-86-8 ]
[ 53939-30-3 ]
[ 23100-12-1 ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: With n-butyllithium In diethyl ether; hexane at -50 - -45℃; Inert atmosphere Stage #2: at -70 - 20℃;
5-Bromo-2-chloropyridine (T-9) (15.0 g) and diethyl ether (450 ml) were put in a reaction vessel and cooled to -50 °C under an atmosphere of nitrogen. n-Butyllithium (1.57 M in n-hexane; 54.6 ml) was added dropwise in the temperature range of -50 °C to -45 °C, and the stirring was continued for another 90 minutes. After the reaction vessel had been cooled to -70 °C, formylpiperidine (9.70 g) was added dropwise in the temperature range of -70 °C to -65 °C, and the stirring was continued for another 60 minutes while the mixture was allowed to return to room temperature. The resulting reaction mixture was poured into ice-water (500 ml) and mixed with it. Diethyl ether (200 ml) was added to the solution to separate organic and aqueous phases, and extraction was carried out. The combined organic phase was washed with water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified with a fractional operation by means of column chromatography (silica gel; toluene). The product was further purified by recrystallization from heptane. The solvent was distilled off and the product was dried, giving 2-chloro-5-formylpyridine (T-10) (7.01 g). The yield based on the compound (T-9) was 68percent.
With sodium dihydrogenphosphate; potassium bromide In dimethyl sulfoxide; toluene at 90 - 100℃; Inert atmosphere
Take 50g of raw material 2-chloro-5-chloromethyl pyridine,Soluble in 100g DMSO and 200g tolueneAdd 48g of sodium dihydrogen phosphate,3g of potassium bromide. Stirring,Nitrogen was bubbled under the liquid surface.Warm up to 90100°C reaction.After the reaction was completed, it was briefly distilled under reduced pressure and purified by distillation. The distillate was added with 50 g of water and 100 g of methyl tert-butyl ether (MTBE). The mixture was washed and separated, and the MTBE was recovered from the organic phase to obtain 2-chloro-5-aldehyde pyridine, which was weighed 35.6 g and the molar yield was about 81percent.
Reference：
[1] Patent: CN107698497, 2018, A, . Location in patent: Paragraph 0072; 0073; 0074; 0077; 0080; 0083
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 10, p. 1253 - 1255
20
[ 105827-78-9 ]
[ 616-45-5 ]
[ 5326-23-8 ]
[ 6271-78-9 ]
[ 23100-12-1 ]
[ 463-04-7 ]
[ 625-74-1 ]
[ 120868-66-8 ]
Reference：
[1] Chinese Journal of Chemistry, 2012, vol. 30, # 1, p. 127 - 132
21
[ 23100-12-1 ]
[ 101990-45-8 ]
Reference：
[1] Patent: CN107698497, 2018, A, . Location in patent: Paragraph 0090; 0091
22
[ 23100-12-1 ]
[ 90196-32-0 ]
Reference：
[1] Patent: CN104529881, 2017, B,
23
[ 23100-12-1 ]
[ 1121-55-7 ]
[ 536-78-7 ]
[ 90196-32-0 ]
Reference：
[1] Patent: CN104529881, 2017, B,
24
[ 23100-12-1 ]
[ 149806-06-4 ]
Yield
Reaction Conditions
Operation in experiment
28.7 g
at 80 - 90℃; Autoclave
Take 30g of 2-chloro-5-aldehyde pyridine in a Hastelloy autoclave,Add 40percent hydrobromic acid/acetic acid solution 240g,The reaction vessel was sealed and heated to 80-90°C with stirring.After the reaction is completed, the acetic acid is recovered by desolvation.The residue is added to 100g DCM,Adjust to neutral with saturated sodium bicarbonate.After separation and separation of the organic phase, 34.4 g of 2-bromo-5-aldehyde pyridine was obtained, with a yield of about 87percent.After desolvation, 100ml n-hexane was added to reflux for 30min. After cooling down to 0-10°C, it was filtered and dried to obtain 28.7g of a brown-yellow solid. The GC detection content was 99.2percent, and 2-chloro-5-aldehyde pyridine was 0.5percent in the product.
Reference：
[1] Patent: CN107698497, 2018, A, . Location in patent: Paragraph 0086; 0087; 0088; 0089
25
[ 33252-28-7 ]
[ 3731-52-0 ]
[ 23100-12-1 ]
[ 97004-04-1 ]
Reference：
[1] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[2] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[3] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[4] Bulletin of the Chemical Society of Japan, 2000, vol. 73, # 5, p. 1227 - 1231
Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: 6-chloronicotinylaldehyde In tetrahydrofuran at 0 - 20℃; for 2.5h;
2 preparation of 2-chloro-5-vinylpyridine
under 0 ° C, potassium tert-butoxide (28 g, 250mmol) is added portion-wise into a methyltriphenylphosphonium bromide (107 g, 300mmol) suspension of anhydrous tetrahydrofuran (500 ml). After stirring for 0.5 hours, drops of 2-chloro-5-formylpyridine (35.4 g, 250mmol) of anhydrous tetrahydrofuran (200 ml) solution slowly added into the reaction system. After finished the drops, the reaction mixture is stirred at 0 ° C for 1 hour. Subsequently, remove from the ice bath, the reaction mixture is stirred at room temperature for 1.5 hours. Add the saturated ammonium chloride solution (750 ml) and ethyl acetate (400 ml). After separation of the two phases, the aqueous phase is extracted with 100 ml of ethyl acetate; the combined organic phases are dried over anhydrous magnesium sulfate, filtered, and concentrated to about 100 ml by steaming, after column chromatography obtained 2-chloro-5-vinylpyridine 31.9g, a colorless liquid, yield 92%.
30%
With anhydrous ammonium chloride In tetrahydrofuran; n-butyllithium; tetrahydric furan
9 EXAMPLE 9
EXAMPLE 9 To the previously dried triphenyl methyl phosphonium bromide in tetrahydro furan at -78° C., in which the n-butyl lithium (1.1 mole) was added dropwise to form the ylide. The reaction mixture was stirred for 1 hour at -78° C. the 6-chloro-3 pyridine carboxyaldehyde of the formula (2) of the drawings in dry tetrahydric furan was introduced to the reaction mixture. After stirring for 1 hour, the reaction mixture temperature was slowly raised to 0° C. Reaction was quenched with 10% ammonium chloride solution. The aqueous layer extracted with ether. The ether solvent was removed and the residue column chormatographed to give 6- chloro-3-vinyl pyridine of formula (4) where X represents H in 30% yield.
With sodium hydride 1.) room temp.; Yield given. Multistep reaction;
With potassium-t-butoxide In tetrahydrofuran; diethyl ether at 20℃; Inert atmosphere;
With sodium methylate; In methanol; for 1h;Heating / reflux;
Sodium methoxide (1 M in methanol, 5.0 ml) was added slowly into a solution of diethyl-(4-nitro-benzyl)-phosphonate (546 mg, 2.0 mmol) and 2- chloro-5-rhoyridyl aldehyde (283 mg, 2.0 mmol) in methanol (5.0 ml). The <n="44"/>reaction mixture was then refluxed for 1 h. After cooled down to 0 0C, yellow precipitate was filtered and washed with cold methanol to obtain product 3 (458 mg, Yield: 88%), which was used directly for next step without further purification. 3: 1H NMR (200 MHz, CDCl3): delta.8.53 (IH, d, J= 2.4 Hz), 8.25 (2H, d, J= 8.8 Hz), 7.85 (IH, d, d, J1 = 8.4 Hz, J2 = 2.4 Hz), 7.65 (2H, d, J= 8.8 Hz), 7.36 (IH, d, J = 8.4 Hz), 7.19 (2H, s), HRMS (EI) mlz calcd. for [C13H9ClN2theta2]+ 260.0353.
75%
With sodium methylate; In methanol; at 0℃; for 2h;Reflux;
Sodium methoxide (IM in methanol, 10.0 ml) was added slowly into a solution of <strong>[2609-49-6]diethyl 4-nitrobenzylphosphonate</strong> (1.092 g, 4.0 mmol) and 6- chloropyridine-3-carboxaidehyde (566 mg, 4.0 mmoi) in methanol (10.0 mL), The reaction mixture was refluxed for 2 h, then cooled down to 0 0C. Yellow precipitate was collected by filtration and washed with cold methanol and dried over vacuum to give (E)-2-chioro-5-(4- nitrosty1yI)p7ridine, 782 mg, yield 75%. Orbitrap ESI-MS caicd. for C13H9C1N2O2 260.04 Found 261.08.
With dimethylaminosulphur trifluoride In dichloromethane at -78 - 20℃;
With dimethylaminosulphur trifluoride In dichloromethane at -78 - 20℃;
20.B
To a solution of 4-chloro-3-pyridinecarboxaldehyde (3.7 g, 26 mmol) in 15 mL of dichloromethane at-78° was added (dimethylamino) sulfur trifluoride (15 ML, 0.15 mol), and the reaction was allowed to warm up to room temperature overnight. The reaction was quenched by carefully transferring into a mixture of ice (100 g) and sodium sulfite (10 g). The product was extracted with ether (100 ML x 2), and the combined extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 0 to 10% ether in hexane to give the title compound. 1H NMR (500 MHz, CD30D) : 8 8.59 (s, 1H), 7.84 (d, 1H), 7.48 (d, 1H), 6.74 (t, 1H).
With diethylamino-sulfur trifluoride In chloroform at 0 - 20℃;
A9.1
A solution of β-chloro-pyridine-S-carbaldehyde (3.2 mmol) in dry chloroform (6 mL) is cooled to 00C and N,Λ/-diethylaminosulfur trifluoride (6.4 mmol) is slowly added under vigorous stirring. The reaction mixture is reacted 2 hours at 00C and is then allowed to reach room temperature and is further stirred at this temperature overnight. The reaction is diluted by the addition of chloroform (18 mL), an aqueous saturated sodium carbonate solution (15 mL) is added drop wise and the resulting mixture is stirred for 10 minutes. The organic phase is collected and washed with water (10 mL), brine (10 mL), is dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product which is used in the next step without further purification
With sulfuric acid; diisobutylaluminium hydride In methanol; toluene
1 2-Chloro-5-formylpyridine
EXAMPLE 1 2-Chloro-5-formylpyridine To a cooled 5° C., stirred solution of 2-chloro-5-cyanopyridine (25.0 grams) in anhydrous toluene (540 mL) was added a 1M solution of diisobutylaluminum hydride (189 mL) over a 30 minute period. The resulting red-colored solution was treated with methanol (50 mL) and 2M sulfuric acid (150 mL), sequentially. The resulting biphasic solution was allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous brine. The organic phase was stirred over activated charcoal for 20 minutes, dried over anhydrous sulfate and concentrated in vacuo to afford the title compound as a light-yellow colored solid, 23.5 grams 1H NMR (400 MHz, CDCl3) δ=10.08 (s, 1H); 8.85 (s, 1H); 8.12 (d, 1H); 7.50 (d, 1H).
With sulfuric acid; diisobutylaluminium hydride In methanol; toluene
Preparation of 2-Chloro-5-formylpyridine (I-2a):
Preparation of 2-Chloro-5-formylpyridine (I-2a): To a cooled (5° C.), stirred solution of 2-chloro-5-cyanopyridine (25.0 g) in anhydrous toluene (540 mL) was added a 1 M solution of diisobutylaluminum hydride (189 mL) over a 30-min period. The resulting red-colored solution was treated with methanol (50 mL) and 2M sulfuric acid (150 mL), sequentially. The resulting biphasic solution was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous brine. The organic phase was stirred over activated charcoal for 20 min, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 23.5 g of the title compound (I-2a) as a light-yellow colored solid. 1H NMR (CDCI3): δ=10.08 (s, 1H); 8.85 (s, 1H); 8.12 (d, 1H); 7.50 (d, 1H).
In formic acid; water
21.a (a)
(a) Preparation of 2-chloro-5-formyl pyridine 2-Chloro-5-cyanopyridine (15 g) in 90% formic acid (60 ml) and water (15 ml) was stirred at 55° and treated with Raney nickel/aluminum alloy (15 g). The mixture was stirred at 55° for 91/2 hours and the warm solution filtered. The residue was washed with warm ethanol (ca. 25 ml) and the filtrates combined and diluted to 600 ml with water. The solution was extracted with ether (3*250 ml). The ether extract was washed with aqueous sodium carbonate and water, dried, and evaporated to give a pale yellow solid identified as 2-chloro-5-formylpyridine.
With sulfuric acid; diisobutylaluminium hydride In methanol; toluene
1 2-Chloro-5-formylpyridine
Example 1 2-Chloro-5-formylpyridine To a cooled 5°C, stirred solution of 2-chloro-5-cyanopyridine (25.0 grams) in anhydrous toluene (540mL) was added a 1M solution of diisobutylaluminum hydride (189mL) over a 30 minute period. The resulting red-colored solution was treated with methanol (50mL) and 2M sulfuric acid (150mL), sequentially. The resulting biphasic solution was allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous brine. The organic phase was stirred over activated charcoal for 20 minutes, dried over anhydrous sulfate and concentrated in vacuo to afford the title compound as a light-yellow colored solid, 23.5grams 1H NMR (400 MHz, CDCl3) δ = 10.08 (s, 1H); 8.85 (s, 1H); 8.12(d, 1H); 7.50 (d, 1H).
Stage #1: 6-chloronicotinonitrile With diisobutylaluminium hydride In toluene at 5℃; for 0.333333h;
Stage #2: With sulfuric acid In methanol; water; toluene at 20℃; for 48h;
25
2-Chloro-5-cyanopyridine (5g, 36mmol) was dissolved in anhydrous toluene (100ml) and cooled to 50C. 1.5M DIBAL-H in toluene (25.2ml, 38mmol) was added dropwise over 20 min. The resulting solution was treated with MeOH (10ml) and then 2M H2SO4 (30ml) and stirred at room temp, for 48h. The mixture was concentrated and the residue partitioned between EtOAc and water. The organic layer was separated, washed with brine and saturated NaHCO3 solution, then dried (Na2SO4) and concentrated to give the title compound as a pale yellow solid (5.41 g). δH (CDCI3) 7.51 (1 H, d), 8.14 (1 H, m), 8.87 (1 H, d), 10.10 (1 H1 s).
With diisobutylaluminium hydride In toluene at 5℃; for 0.5h;
2-[(E)-2-(6-CHLORO-PYRIDIN-3-YL)-VINYL]-7-METHOXY-2, 3-DIMETHYL-6-OXAZOL-5-YL-2, 3, 4A, 8A-TETRAHYDRO-1H-QUINAZOLIN-4-ONE[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: 6-chloronicotinylaldehyde; 1-triphenylphosphoranylidene-2-propanone With piperidine; 2-(1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate In tetrahydrofuran at 20℃; for 18h; Stirred;
Stage #2: With 2-AMINO-4-METHOXY-N-METHYL-5-OXAZOL-5-YL-benzamide; p-toluenesulfonic acid monohydrate In DMF (N,N-dimethyl-formamide); toluene at 150℃; for 1.5h;
75 2-[(E)-2- (6-CHLORO-PYRIDIN-3-YL)-VINYL]- 7-METHOXY-2, 3- DIMETHYL-6-OXAZOL-5- YL-2, 3, 4A, 8A-TETRAHYDRO- 1H- QUINAZOLIN-4-ONE
A solution of 2-chloropyridine-5-carboxaldehyde (CAS 23100-12-1) (0. [2G)] and 1-triphenylphosphoranylidene-2-propanone (0. 45g) in THF (15ml) were stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue purified by column chromatography on silica eluting with 25-100% EtOAc/heptane to yield the desired product as an off-white solid. This was dissolved in [DMF/TOLUENE (10ML/10ML)] and treated with Intermediate 2 (0. [31G)] and PTSA (2mg). The reaction mixture was heated at [150C] under Dean- Stark conditions for 90 mins. The solvent was removed in vacuo and the residue purified by column chromatography on silica eluting with 2-10% MeOH/DCM to afford the title compound as a yellow solid (0.42g, 75%). A sample of this was further purified by preparative HPLC (Method C) to afford the title compound. TLC Rf 0.20 (10% MeOH/DCM). LCMS 411 [[M+H] +,] RT 2.97 [MINS.'H] NMR 300MHz (CDCI3) 8.34 (1H, s), 8.33-8. 32 (1H, d), 7.85 (1H, s), 7.74-7. 70 (1 H, dd), 7.36 (1 H, s), 7.28-7. 25 (1 H, d), 7.39 (1 H, s), 6.53- 6.47 (1H, d), 6.33-6. 27 (1H, d), 6.17 (1H, s), 4.50 (1H, s), 3.94 (3H, s), 3.11 (3H, s), 1.83 (3H, s).
In tetrahydrofuran; diethyl ether; ethyl acetate; Petroleum ether
2 2-Chloro-5-vinylpyridine
EXAMPLE 2 2-Chloro-5-vinylpyridine To a cooled 5° C., stirred slurry of methyltriphenylphosphonium bromide (75.7 grams) in tetrahydrofuran (530 mL) was added potassium t-butoxide (23.8 grams) portionwise over a 5 minute period to produce a yellow slurry. After 30 minutes, 2-chloro-5-formylpyridine (25.0 grams) was added in one portion to produce a purple colored slurry. After an additional 30 minutes, the reaction mixture was treated with saturated aqueous ammonium chloride (200 mL) and a majority of the tetrahydrofuran was removed in vacuo. The resulting mixture was washed with ethyl acetate, the combined organic layers washed with saturated aqueous brine, stirred over activated charcoal for 20 minutes, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting semi-solid was stirred for 30 minutes with a solution of 2:1 diethyl ether/petroleum ether (375 mL), filtered and the solids washed with an additional portion of 2:1 diethyl ether/petroleum ether (300 mL). The combined filtrates were concentrated in vacuo, pre-loaded on 60 grams of silica gel and chromatographed over 700 grams of silica gel eluding with a gradient of ethyl acetate(0-8%)/hexanes to afford the title compound as a colorless oil, 15.2 grams 1H NMR (400MHz, CDCl3): δ=8.35 (s, 1H); 7.69 (d,1H); 6.65 (dd, 1H); 5.79 (d, 1H); 5.40 (d, 1H).
In tetrahydrofuran; diethyl ether; ethyl acetate; Petroleum ether
Preparation of 2-Chloro-5-vinylpyridine (I-2b):
Preparation of 2-Chloro-5-vinylpyridine (I-2b): To a cooled (5° C.), stirred slurry of methyltriphenylphosphonium bromide (75.7 g) in tetrahydrofuran (530 mL) was added potassium t-butoxide (23.8 g) portionwise over a 5-min period to produce a yellow slurry. After 30 min, 2-chloro-5-formylpyridine (25.0 g) was added in one portion to produce a purple colored slurry. After an additional 30 min, the reaction mixture was treated with saturated aqueous ammonium chloride (200 mL) and a majority of the tetrahydrofuran was removed in vacuo. The resulting mixture was washed with ethyl acetate, the combined organic layers washed with saturated aqueous brine, stirred over activated charcoal for 20 min, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting semi-solid was stirred for 30 min with a solution of 2:1 diethyl ether/petroleum ether (375 mL), filtered and the solids washed with an additional portion of 2:1 diethyl ether/petroleum ether (300 mL). The combined filtrates were concentrated in vacuo, pre-loaded on 60 g of silica gel and chromatographed over 700 g of silica gel eluding with a gradient of ethyl acetate (0-8%)/hexanes to afford 15.2 g of the title compound (I-2b) as a colorless oil. 1H NMR (CDCI3): δ=8.35 (s,1H); 7.69 (d,1H); 7.27 (d,1H); 6.65 (dd, 1H); 5.79 (d,1H); 5.40 (d,1H).
In tetrahydrofuran; diethyl ether; ethyl acetate; Petroleum ether
2 2-Chloro-5-vinylpyridine
Example 2 2-Chloro-5-vinylpyridine To a cooled 5°C, stirred slurry of methyltriphenylphosphonium bromide (75.7grams) in tetrahydrofuran (530mL) was added potassium t-butoxide (23.8 grams) portionwise over a 5 minute period to produce a yellow slurry. After 30 minutes, 2-chloro-5-formylpyridine (25.0 grams) was added in one portion to produce a purple colored slurry. After an additional 30 minutes, the reaction mixture was treated with saturated aqueous ammonium chloride (200mL) and a majority of the tetrahydrofuran was removed in vacuo. The resulting mixture was washed with ethylacetate, the combined organic layers washed with saturated aqueous brine, stirred over activated charcoal for 20 minutes, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting semi-solid was stirred for 30 minutes with a solution of 2:1 diethyl ether/petroleum ether (375mL), filtered and the solids washed with an additional portion of 2:1 diethyl ether/petroleum ether (300mL). The combined filtrates were concentrated in vacuo, pre-loaded on 60 grams of silica gel and chromatographed over 700 grams of silica gel eluding with a gradient of ethyl acetate(0-8%)/hexanes to afford the title compound as a colorless oil, 15.2 grams 1H NMR (400MHz, CDCl3): δ = 8.35 (s, 1H); 7.69(d,1H); 6.65 (dd, 1H); 5.79 (d, 1H);5.40 (d, 1H).
In tetrahydrofuran; argon; isopropyl alcohol; pentane
R.153 1-tert-Butoxycarbonyl-4-[[(2RS)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl]sulfonyl]piperazine
Referential Example 153 1-tert-Butoxycarbonyl-4-[[(2RS)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl]sulfonyl]piperazine In tetrahydrofuran (8 ml), 1-tert-butoxycarbonyl-4-methanesulfonylpiperazine (838 mg) was dissolved, followed by the addition of tert-butyl lithium (a 1.7M pentane solution, 1.72 ml) at -78° C. in an argon gas atmosphere. The resulting mixture was stirred for 2 hours. After the dropwise addition of a solution of 6-chloronicotinaldehyde (346 mg) in tetrahydrofuran (tetrahydrofuran: 4 ml) and stirring at -78° C. for 3 hours, the reaction mixture was added with isopropanol (1 ml). The resulting mixture was heated to room temperature and diluted with ethyl acetate. The diluted solution was washed with water and saturated saline and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was recrystallized from ethyl acetate, whereby the title compound (532 mg, 54%) was obtained. 1H-NMR (CDCl3) δ: 1.46(9H,s), 3.11(1H,dd,J=14.1,2.2 Hz), 3.21(1H,dd,J=14.1,9.8 Hz), 3.23-3.33(4H,m), 3.52-3.57(4H,m), 3.70(1H,br s), 5.37(1H,br), 7.36(1H,d,J=8.3 Hz), 7.72(1H,dd,J=8.3,2.4 Hz), 8.41(1H,d,J=2.4 Hz). MS (FAB) m/z: 405 (M+H)+.
54%
In tetrahydrofuran; argon; isopropyl alcohol; pentane
[Referential Example 104] 1-tert-Butoxycarbonyl-4-[[(2RS)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl]sulfonyl]piperazine
[Referential Example 104] 1-tert-Butoxycarbonyl-4-[[(2RS)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl]sulfonyl]piperazine In tetrahydrofuran (8 ml), 1-tert-butoxycarbonyl-4-methanesulfonylpiperazine(838 mg) was dissolved, followed by the addition of tert-butyl lithium (a 1.7M pentane solution, 1.72 ml) at -78°C in an argon gas atmosphere. The resulting mixture was stirred for 2 hours. After the dropwise addition of a solution of 6-chloronicotinaldehyde (346 mg) in tetrahydrofuran (tetrahydrofuran: 4 ml) and stirring at -78°C for 3 hours, the reaction mixture was added with isopropanol (1 ml). The resulting mixture was heated to room temperature and diluted with ethyl acetate. The diluted solution was washed with water and saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was recrystallized from ethyl acetate, whereby the title compound (532 mg, 54%) was obtained. 1H-NMR (CDCl3) δ: 1.46(9H,s), 3.11(1H,dd,J=14.1,2.2Hz), 3.21(1H,dd,J=14.1,9.8Hz), 3.23-3.33(4H,m), 3.52-3.57(4H,m), 3.70(1H,br s), 5.37(1H,br), 7.36(1H,d,J=8.3Hz), 7.72(1H,dd,J=8.3,2.4Hz), 8.41(1H,d,J=2.4Hz). MS (FAB) m/z: 405 (M+H)+.
diethyl phenyl sulfono methyl phosphonate[ No CAS ]
[ 23100-12-1 ]
[ 157670-28-5 ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium; ammonium chloride
10 EXAMPLE 10
EXAMPLE 10 To a solution of diethyl phenyl sulfono methyl phosphonate (10 gms) in ether at -78° C. was added 1M n-BuLi (22 ml) and the reaction mixture stirred for 3 hours at -78° C. The 6-chloro-3-pyridine carboxyaldehyde (5 gms) was introduced to the reaction mixture, the temperature was allows to come to room temperature and stirred for 12 hours. The reaction was quenched with 10% ammonium chloride solution. The aqueous layer extracted with ether. The solvent removed and the residue being column chromatographed to give 6-chloro-3-vinyl pyridine of the formula (4) where X represents -SO2 Ph (sulfono phenyl).
(S)-4-(6-Chloro-pyridin-3-ylmethyl)-2-phenyl-morpholine; ChiralChiral1 Og of (S)-2-Phenyl-morpholine was dissolved in 61 OmL of dichloroethane. 10.407g of 6- Chloropyridine-3-carboxaldehyde was added and the reaction stirred at room temperature for 30 minutes followed by addition of 23.4g of sodium triacetoxyborohydride. After stirring overnight at room temperature, the solution was poured into an aqueous saturated sodium bicarbonate solution and the layers separated. The organic layer was washed several times with aqueous saturated sodium bicarbonate solution followed by brine. It was then dried over sodium sulfate, filtered and concentrated in vacuo. Purification was accomplished by flash chromatography to afford 11.23g of product. 63.5percent yield. EI m/z289=MH+
Stage #1: methyl triphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 5℃; for 0.583333h;
Stage #2: 6-chloronicotinylaldehyde for 0.5h;
To a mixture of 2,6-difluoro-4-methoxybenzenamine (0.98 g, 6.9 mmol) in toluene(2O mL) was added 6-chloro-3-pyridinecarboxaldehyde (1.0 g, 6.3 mmol). The reaction mixture was heated at reflux with the use of a Dean-Stark trap for azeotropic removal of water. After 16 h the reaction mixture was cooled to room temperature and concentrated <n="76"/>under reduced pressure. The resulting material was dried in a vacuum oven at 55 0C overnight to provide the title compound as a light brown solid (1.66 g).1H NMR (CDCl3): delta 8.74 (s, IH), 8.73 (d, J = 2.44 Hz, IH), 8.32 (dd, J = 2.20 Hz, J =8.29 Hz, IH), 7.44 (d, J= 8.29 Hz, IH), 6.59-6.52 (m, 2H), 3.82 (s, 3H). 1F NMR (CDCl3): delta-121.48 to 121.40 (m, 2F).
With sodium disulfite; In N,N-dimethyl-formamide; at 100℃; for 18.0h;
,3-<strong>[603-81-6]Diaminobenzoic acid</strong> (1; 200 mg, 1.31 mmol), 6-chloronicotinaldehyde (5; 186 mg, 1.31 mmol), and Na2S2O5 (324 mg, 1.7 mmol) were taken up in DMF (10 mL) and stirred at 100 C for 18 h. The reaction mixture was cooled to room temperature and diluted with H2O. The resulting mixture was stirred for Ih at room temperature and filtered. The collected solids were washed with water, MeOH, and dried to afford 2-(6- chloropyridin-3-yl)-lH-benzo[d]imidazole-4-carboxylic acid 6 as a pale solid (340 mg, yield: 95%).
6-[(4-nitrophenyl)thio]-3-pyridinecarbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With caesium carbonate In N,N-dimethyl-formamide at 80℃;
6
Intermediate 28; 6-[(4-nitrophenyl)thio]-3-pyridinecarbaldehyde; To a stirred solution of β-Chloro-S-pyridinecarbaldehyde Intermediate 10 (141 mg, 1 mmoi) in 1OmL of N, N-dimethylformamide were added 4-nitrobenzenethiol (199mg, 1mmol) and cesium carbonate (325mg, 1mmol). The resulting mixture was then heated to 800C overnight. After it was cooled down to the room temperature, the reaction mixture was diluted with ethyl acetate (10OmL) and washed with saturated sodium bicarbonate solution. The organic layer was then dried over anhydrous sodium sulfate before evaporation of solvents. The crude product was purified by column chromatography (siiical gel, 0 to70%, CH2CI2 mixed with10% MeOH/ 2M NH3 in CH2CI2) to afford 200mg (77%) of 6-[(4-nitropheϖyl)thio]-3-pyridinecarbaldehyde Intermediate 28 as solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.01 (s, 1 H), 8.90 (s, 1 H), 8.29 (d, J=8.78 Hz, 2 H), 8.12 (dd, J=8.42, 2.20 Hz, 1 H), 7.86 (d, J=8.97 Hz, 2 H), 7.46 (s, 1 H). LC-MS m/z (M+H)+ calcd: 261, obsd: 261.
With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; for 21h;
Example 38. Preparation of 3-(4-chlorophenyl)-2-(6-chloropyridin-3-yl)quinazolin- 4(3H)-one; [0225] 2-Amino-Lambda/-(4-chlorophenyl)benzamide (0.500 g, 2.03 mmol) and 6- chloronicotinaldehyde (2.23 mmol), NaHSO3 (0.253 g, 2.44 mmol) and p-TsOH (0.039 g, 0.20 mmol) were dissolved in DMA (20 ml_) and heated at 1500C for 21 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (2 x 200 mL), dried (Na2SO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 30% ethyl acetate/heptane to 70% ethyl acetate/heptane, afforded the title compound as a white solid (4%). 1H-NMR (300 MHz, DMSO-d6): delta 8.46 (d, J = 2.1 Hz, 1 H), 8.23 (d, J = 8.1 Hz, 1 H), 7.92-7.97 (m, 1 H), 7.80-7.86 (m, 2H), 7.63-7.68 (m, 1 H), 7.47-7.50 (m, 5H). MS (APCI) m/z: 368 (M+H)+.
Step A: Preparation of N-[(6-chloro-3-pyridinyl)methylene]-<strong>[151414-47-0]2,6-difluoro-4-methoxybenzenamine</strong>To a mixture of <strong>[151414-47-0]2,6-difluoro-4-methoxybenzenamine</strong> (0.98 g, 6.9 mmol) in toluene (20 mL) was added 6-chloro-3-pyridinecarboxaldehyde (1.0 g, 6.3 mmol). The reaction mixture was heated at reflux with the use of a Dean-Stark trap for azeotropic removal of water. After 16 h the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting material was dried in a vacuum oven at 55 C. overnight to provide the title compound as a light brown solid (1.66 g).1H NMR (CDCl3): delta 8.74 (s, 1H), 8.73 (d, J=2.44 Hz, 1H), 8.32 (dd, J=2.20 Hz, J=8.29 Hz, 1H), 7.44 (d, J=8.29 Hz, 1H), 6.59-6.52 (m, 2H), 3.82 (s, 3H).1F NMR (CDCl3): delta-121.48 to 121.40 (m, 2F).
In toluene; for 16h;Reflux; Dean-Stark trap;
To a mixture of <strong>[151414-47-0]2,6-difluoro-4-methoxybenzenamine</strong> (0.98 g, 6.9 mmol) in toluene (20 mL) was added 6-chloro-3-pyridinecarboxaldehyde (1.0 g, 6.3 mmol). The reaction mixture was heated at reflux with the use of a Dean-Stark trap for azeotropic removal of water. After 16 h the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting material was dried in a vacuum oven at 55 C overnight to provide the title compound as a light brown solid (1.66 g).in NMR (CDCI3) delta 8.74 (s, 1H), 8.73 (d, J = 2.44 Hz, 1H), 8.32 (dd, J = 2.20 Hz, J= 8.29 Hz, 1H), 7.44 (d, J= 8.29 Hz, 1H), 6.59-6.52 (m, 2H), 3.82 (s, 3H)..9F NMR (CDCI3) delta -121.48 to -121.40 (m, 2F).
Butyltriphenylphosphonium bromide (21.1g) and THF (90.0 ml) were put in a reaction vessel and cooled to -30 C under an atmosphere of nitrogen. Potassium t-butoxide (5.68 g) was added slowly, and the stirring was continued for another 30 minutes. Then, the compound (T-10) (5.98 g) in a THF (50.0 ml) solution was added dropwise in the temperature range of -30 C to -25 C, and the stirring was continued for another 2 hours while the reaction mixture was allowed to return to room temperature. The resulting reaction mixture was poured into ice-water (200 ml) and mixed with it. Toluene (200 ml) was added to the solution to separate organic and aqueous phases, and extraction was carried out. The combined organic phase was washed successively with water, 1N-hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified with a fractional operation by means of column chromatography (silica gel; heptane/ ethyl acetate= 10:1 by volume) to give 2-chloro-5-(1-pentenyl)pyridine (T-11) (6.96 g). The yield based on the compound (T-11) was 99%.
<strong>[53939-30-3]5-Bromo-2-chloropyridine</strong> (T-9) (15.0 g) and diethyl ether (450 ml) were put in a reaction vessel and cooled to -50 C under an atmosphere of nitrogen. n-Butyllithium (1.57 M in n-hexane; 54.6 ml) was added dropwise in the temperature range of -50 C to -45 C, and the stirring was continued for another 90 minutes. After the reaction vessel had been cooled to -70 C, formylpiperidine (9.70 g) was added dropwise in the temperature range of -70 C to -65 C, and the stirring was continued for another 60 minutes while the mixture was allowed to return to room temperature. The resulting reaction mixture was poured into ice-water (500 ml) and mixed with it. Diethyl ether (200 ml) was added to the solution to separate organic and aqueous phases, and extraction was carried out. The combined organic phase was washed with water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified with a fractional operation by means of column chromatography (silica gel; toluene). The product was further purified by recrystallization from heptane. The solvent was distilled off and the product was dried, giving 2-chloro-5-formylpyridine (T-10) (7.01 g). The yield based on the compound (T-9) was 68%.
85 ml of 15% BuLi in n-hexane are added to a solution of pyridine (1) (25.0 g; 120 mmol) in 300 ml of diethyl ether under nitrogen at -70 C.After 90 minutes, 13.7 ml (120 mmol) of the formylpiperidine (2) solution at the same temperature is added to the batch. After an additional hour, the batch is warmed to -10 [deg.] C, water is added and the mixture is diluted with MTB ether.The organic phase is dried over sodium sulfate and evaporated. The residue obtained is passed through silica gel (MTB ether / n-heptane 1: 1). The product is then crystallized with n-heptane at -20 deg C.
6-(2-methylmorpholin-4-yl)pyridine-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
In N,N-dimethyl-formamide; at 100℃; for 0.333333h;Microwave irradiation;
INTERMEDIATE 65 6-(2-Methy I morphol i n-4-yl)pyridi ne-3-carbaldeh de 2-Chloro-5-pyridinecarboxaldehyde (500mg, 3.53mmol) and <strong>[27550-90-9]2-methylmorpholine</strong> (750mg, 7.42mmol) were dissolved in DMF (2mL) and the reaction mixture was heated at 100C in a microwave reactor for 20min and concentrated in vacuo. The residue was suspended in dioxane (5mL), filtered and concentrated in vacuo to give the title compound (730mg, 100%) as an orange gum. LCMS (ES+): 207.1 [MH]+.
100%
In 1,4-dioxane; N,N-dimethyl-formamide;
6-(2-Methylmorpholin-4-yl)pyridine-3-carbaldehyde 2-Chloro-5-pyridinecarboxaldehyde (500 mg, 3.53 mmol) and <strong>[27550-90-9]2-methylmorpholine</strong> (750 mg, 7.42 mmol) were dissolved in DMF (2 mL) and the reaction mixture was heated at 100 C. in a microwave reactor for 20 min and concentrated in vacuo. The residue was suspended in dioxane (5 mL), filtered and concentrated in vacuo to give the title compound (730 mg, 100%) as an orange gum. LCMS (ES+): 207.1 [MH]+.
3-(6-chloropyridin-3-yl)-3-hydroxy-2-(naphthalen-2-yl)propanenitrile[ No CAS ]
3-(6-chloropyridin-3-yl)-3-hydroxy-2-(naphthalen-2-yl)propanenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 18.19%
2: 7.71%
Stage #1: 2-naphthaleneacetonitrile With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: 6-chloronicotinylaldehyde In tetrahydrofuran Inert atmosphere;
126 Example 126 - Synthesis of Compound ID No. 126 li?,2R)-l-(6-chloropyridin-3- yl -3-(amino -2-(naphthalen-2-yl)pi pan-l-ol anti-3 -(6-chloropyridin-3 -yl)-3 -hydroxy-2-(naphthalen-2-yl)propanenitrile :
A solution of 2-naphthylacetonitrile (5 g, 29.9 mmol) in 200 mL of dry THF was placed in an oven-dried round bottom flask with stirrer under nitrogen. After cooling to - 78°C, diisopropylamine (5.03 mL, 35.9 mmol) was added followed by drop-wise addition of 2.5M butyllithium (14.35 mL, 35.9 mmol). After 30 minutes of stirring at -78°C, 2-chloropyridine 5-carboxaldehyde (5.08 g, 35.9 mmol) was added drop-wise via syringe. After 10 minutes, the reaction was quenched quickly with rapid addition of 25 mL 2:1 THF/acetic acid. The cold bath was removed, and the reaction was allowed to reach ambient temperature. Water was added, and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with water and brine, dried over MgS04, and were concentrated using a rotary evaporator. The residue was dissolved in DCM, and hexane was slowly added. A turbid solution resulted, which was kept at room temperature for 15 minutes. Off-white crystals were filtered and dried. The nfr'-diastereomer crystallized out as the major isomer as an off white solid (yield 1.679 g, 18.19%). 1H MR (DMSO.d6) δ 8.40 (d, 1 H, J= 1.8 Hz), 7.99-7.92 (m, 5 H), 7.58-7.49 (m, 4 H), 6.42 (d, 1 H, J= 5.0 Hz), 5.18 (t, 1 H, J = 5.1 Hz), 4.79 (d, 1 H, J= 5.3 Hz). The syn-diastereomer was also isolated from the supernatant as a white solid (yield 0.712 g, 7.71%). 1H NMR (CDCl3) δ 8.09 (d, 1 H, J= 1.8 Hz), 7.94-7.85 (m, 3 H), 7.71-7.62 (m, 2 H), 7.55-7.50 (m, 2 H), 7.44 (d, 1 H, J= 7.4 Hz), 7.32 (bd, 1 H, J= 7.4 Hz), 6.47 (d, 1 H, J = 4.3 Hz), 5.25 (dd, 1 H, J= 5.1, 5.1 Hz), 4.83 (d, 1 H, J= 6.0).
With caesium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; at 100℃; for 10h;
To a stirred solution of 6-chloronicotinaldehyde (2.0 g, 14.1 mmol, 1.0 eq.) and phenol (1.32 g, 14.1 mmol, 1.0 eq.) in DMF (20 mL) was added Cs2CO3 (5.5 g, 16.9 mmol, 1.2 eq.) and CuCl (1.61 g, 16.9 mmol, 1.2 eq.). The resulting mixture heated at 100 C. for 10 h. Following this, reaction was allowed to cool to RT and filtered through celite pad, the celite pad washed with ethyl acetate and water. The aqueous layer was separated extracted using ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to get the solid residue. The crude was purified by normal phase silica-gel column provided title compound (2.8 g, 99%). LCMS: 200.0 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (s, 1H) 8.70 (d, J=2.19 Hz, 1H) 8.27 (dd, J=8.55, 2.41 Hz, 1H) 7.43-7.52 (m, 2H) 7.18-7.32 (m, 4H)
92%
With caesium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; for 10h;Reflux;
To a solution of 6-chloronicotinaldehyde (3) (0.28 g, 2 mmol) and phenol (0.19 g, 2 mmol) in DMF (30 mL) was added Cs2CO3 (0.78 g, 2.4 mmol) and CuCl (0.24 g, 2.4 mmol), then the mixture was refluxed for 10 h and then cooled to room temperature. The mixture was extracted with EtOAc, and the extract was washed successively with water and brine, and dried over anhydrous Na2SO4. The crude product was purified by recrystallization using methanol to give compound 4 as a white solid (0.36 g, 92%); mp = 91-93 C; 1H NMR (400 MHz, CDCl3): δ 9.98 (s, 1H, CHO), 8.63 (s, 1H, Py-H), 8.19 (d, J = 8.4 Hz, 1H, Py-H), 7.46 (t, J = 7.6 Hz, 2H, Ar-H), 7.30 (d, J = 7.6 Hz, 1H, Ar-H), 7.17 (d, J = 7.6 Hz, 2H, Ar-H), 7.16 (d, J = 8.4 Hz, 1H, Py-H); 13C NMR (100 MHz, CDCl3) δ 189.4, 167.3, 153.0, 152.8, 138.7, 129.9, 127.7, 125.8, 121.6, 112.1. ESI-HRMS (m/z): Calcd for C12H10NO2 [M+H]+ 200.0706. Found 200.0708.
92%
With caesium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; for 10h;Reflux;
6-chloropyridine-3-carbaldehyde (2) (0.28 g, 2 mmol),Phenol (0.I9 g, 2 mmol) was dissolved in DMF (30 mL).Then Cs2CO3 (0.78 g, 2.4 mmol) and CuCl (0.24 g, 2.4 mmol) were added.It was then heated to reflux for 10 hours. Add ethyl acetate and water,Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and dissolve.Recrystallization from methanol gave 0.36 g of a white solid.Yield 92%.
1.38 g
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 0.5h;Microwave irradiation;
6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and Phenol (1.20 g; 12.7 mmol) were dissolved in DMF (10 ml) in a microwave vial; K2CO3 (2.20 g; 15.9 mmol) was added and the reaction mixture was stirred at 110 C. during 30 minutes. The reaction mixture was diluted with water (50 ml) and the obtained precipitate was filtered off, washed with water and dried in the air. Obtained 1.38 g of the desired compound. (0290) Example 5p: HPLC-MS (Method): Z017_S04 Rt [min]: 0.93 MS: 200 [M+H]+
6-(2-(2-hydroxyethoxy)ethoxy)nicotinaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
Stage #1: diethylene glycol With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 6-chloronicotinylaldehyde In N,N-dimethyl-formamide at 20℃; for 24h;
32%
Stage #1: diethylene glycol With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 6-chloronicotinylaldehyde In N,N-dimethyl-formamide at 20℃; for 24h;
1 Example 1 Synthesis of Intermediate 1
Weigh 4.00 g of diethylene glycol (37.7 mmol) in a 100 mL round bottom flask, dissolve in 20 mL of anhydrous DMF, stir at room temperature, slowly add potassium t-butoxide (3.37 g, 30.0 mmol), stir at room temperature for 30 min. 6. Add 6-chloronicotinaldehyde (30.0 mmol) slowly, react at room temperature for 24 h, add deionized water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, remove the desiccant, concentrate by rotary evaporation, and separate on silica gel column. The product obtained, the structure is as follows, the yield: 32%.
19.2%
Stage #1: diethylene glycol With potassium <i>tert</i>-butylate In dichloromethane at 20℃; for 0.5h;
Stage #2: 6-chloronicotinylaldehyde In dichloromethane at 20℃; for 3h;
N-((6-chloropyridin-3-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With sodium tetrahydroborate; toluene-4-sulfonic acid; In toluene; at 70℃; for 1h;Molecular sieve; Dean-Stark; Reflux;
To a stirred solution of <strong>[651734-54-2]2,6-difluoro-3,5-dimethoxyaniline</strong> (0.4g, 2.11 mmol) and 6-chloro nicotinaldehyde (0.44g, 3.17 mmol) in toluene (20mL) was added catalytic PTSA and molecular sieves (0.4 g). Heated the reaction mass to reflux in a Dean Stark apparatus for overnight. Concentrated the reaction mass and diluted the residue with methanol, cooled to 0 C and added sodium borohydride (0.3g, 8.4 mmol). Stirred the reaction mass at room temperature for lh and further heated to 70 C for lh. Quenched the reaction mass with ice cold water, warmed to room temperature and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (3x30mL). The organic phase was washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The crude material was purified by silica column chromatography to afford desired title compound (0.2g, 30%) as a solid. LCMS: m/z = 315.1 (M+H)+.
With toluene-4-sulfonic acid; In toluene; for 3h;Reflux;
Add 100 mL of toluene to 13.1 g (111 mmol) of the diol (4), 17.5 g (90%; 111 mmol) of the aldehyde (3) and 1 g of p-toluenesulfonic acid, Heat for 3 hours. Then cooled, the batch is passed through silica gel (toluene). The product obtained is used in the next step without further purification.
6-(2-(pyrrolidin-1-yl)ethoxy)nicotinaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 20℃; for 1.25h;
7 6-(2-(pyrrolidin-1-yl)ethoxy)nicotinaldehyde
To a solution of 2-(pyrrolidin-l-yl)ethanol (750 mg, 6.51 mmol) in DMF (10 mL) at 0 °C was added potassium iert-butoxide (803 mg, 7.15 mmol). The mixture was stirred at 0 °C for 15 min, and 6-chloronicotinaldehyde (1.03 g, 7.28 mmol) in DMF (2 mL) was added. After stirring for 1 h at room temperature, the reaction was quenched at 0 °C with saturated ammonium chloride (1 mL). The reaction was diluted with ethyl acetate (75 mL), washed (2x50 mL H20, 50 mL brine), and dried over Na2S04. The solvent was removed under reduced pressure and the crude material was purified on a silica gel column to give the desired compound (306 mg, 21%). 1H NMR (300 MHz, CDC13): δ 9.97 (s, 1H), 8.86 (s, 1H), 8.07 (d, / = 8.2 Hz, 1H), 6.90 (d, / = 8.2 Hz, 1H), 4.56 (t, / = 5.6 Hz, 2H), 2.94 (t, / = 5.6 Hz, 2H), 2.66 (br s, 4H), 1.84 (br s, 4H).
With toluene-4-sulfonamide; In toluene; at 120℃; for 12h;Inert atmosphere;
A solution of <strong>[1078-28-0]6-methoxy-2-methylquinoline</strong> (200 mg, 1.15 mmol), p-toluenesulfonamide (197 mg, 1.15 mmol) and 6-chloronicotinaldehyde (163 mg, 1.15 mmol) in toluene (5 mL) was refluxed at 120 C. for 12 h in a reaction tube under N2. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure. Then the concentrate was purified by column chromatography with EtOAc/Hexane (1:4, v/v) on silica gel, affording TZ-36-38 as a yellow solid (232 mg, 68%). 1H NMR (400 MHz, CDCl3) delta 8.56 (d, J=1.9 Hz, 1H), 8.04 (dd, J=21.0, 7.7 Hz, 2H), 7.90 (d, J=8.3 Hz, 1H), 7.59 (dd, J=8.7, 6.4 Hz, 2H), 7.49-7.30 (m, 3H), 7.06 (s, 1H), 3.99 (d, J=50.0 Hz, 3H).
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; In dichloromethane; at 80 - 85℃; for 20h;
30 g of 2-chloro-5-aldehyde pyridine and 100 g of dichloromethane were taken and added to a reaction flask, and 100 g of 98% sulfuric acid was added. RiseWarm to 80 ~ 85 C,Dibromohydantoin 80g was added in batches.Reaction for 20 hours.Sampling was adjusted to pH=6-8 with 10% NaOH solution, and the organic phase was subjected to GC detection.2-bromo-5-bromomethylpyridineThe content is only 5.82%, the rest are raw materials and by-products.
6-(3-ethyloxetan-3-ylmethoxy)pyridine-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.86 g
With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 2h;
The 3 - ethyl -3 - oxygen oxetane methanol 4.65 g, 6 - chloro pyridine -3 - formaldehyde 2.83 g, potassium carbonate 5.53 g, dimethyl sulfoxide 13 ml of mixture of 110 °C under microwave irradiation of 2 hours, and then in the 130 °C under microwave irradiation of 2 hours. The reaction [...] the ingress of water, tertiary butyl methyl ether extraction. Filtering to remove the insoluble matter. The distill goes behind the solvent, purification by silica gel column chromatography, to obtain the title compound 0.86 g.
(Z)-2-chloro-5-(3-methylbut-1-en-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.8%
With n-butyllithium; In tetrahydrofuran; at 0℃; for 2.5h;
To a 0 C solution of <strong>[22884-29-3]isobutyltriphenylphosphonium bromide</strong> (705 mg, 1.766 mmol) in THF (10 mL) was added BuLi (0.706 mL, 1.766 mmol) dropwise and allowed to stir at 0 C for 30 minutes. The reaction was then added 6-chloronicotinaldehyde (250 mg, 1.766 mmol) (in 2 mL THF) dropwise at 0 C. The reaction was then allowed towarm up to RT and stir for 2 hrs. The reaction was diluted with sat aq. ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, collected, dried over MgSO4, filtered and volatiles evaporated to afford the crude product. The crude product was purified on silica gel (24 g column, 5-20% EtOAc:Hex) to afford the product (Z)-2-chloro-5-(3-methylbut-1-en-1-yl)pyndine (240 mg, 1.321 mmol, 74.8 %yield). ?H NMR (500 MHz, chloroform-d) 8.30 (d, J=2.4 Hz, 1H), 7.54 (dd, J=8.2, 2.4 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 6.22 (d, J1 1.7 Hz, 1H), 5.66 (dd, J1 1.5, 10.4 Hz, 1H), 2.78 (ddtd, J=13.1, 10.4, 6.6, 0.7 Hz, 1H), 1.07 (d, J=6.6 Hz, 6H).
6-(1-methyl-1H-pyrazol-3-yl)nicotinaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere;
To a mixture of 6-chloronicotinaldehyde (20.0 g) , 1- methyl-3- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -1H- pyrazole (32.32 g) , potassium carbonate (38.99 g) , DME (400 mL) and water (40 mL) was added PdCl2(dppf) dichloromethane adduct (3.45 g) at room temperature. Under an argon atmosphere, the reaction mixture was stirred overnight at 90C, diluted with ethyl acetate at room temperature, and added to water. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate and the solvent was (1299) evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (25.0 g) . (1300) 1H NMR (400 MHz, CDC13) delta 4.01 (3H, s) , 6.97 (1H, d, J = 2.45 Hz), 7.45 (1H, d, J = 2.45 Hz), 8.08 (1H, d, J = 8.4 Hz), 8.19 (1H, dd, J = 8.31, 1.96 Hz), 9.05 (1H, d, J = 1.47 Hz), 10.09 (1H, s).
A) 6-(1-methyl-1H-pyrazol-3-yl)nicotinaldehyde The title compound was obtained from 6-chloronicotinaldehyde and <strong>[1020174-04-2]1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> by a method similar to that in step F of Example 1. 1H NMR (400 MHz, CDCl3) delta 4.01 (3H, s), 6.97 (1H, d, J = 2.45 Hz), 7.45 (1H, d, J = 2.45 Hz), 8.08 (1H, d, J = 8.4 Hz), 8.19 (1H, dd, J = 8.31, 1.96 Hz), 9.05 (1H, d, J = 1.47 Hz), 10.09 (1H, s).
6-(1,3-dimethyl-1H-pyrazol-4-yl)nicotinaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 110℃; for 16h;Inert atmosphere;
To a mixture of 6-chloronicotinaldehyde (7.0 g) , 1,4- dioxane (400 mL) and water (10 mL) were added PdCl2(dppf) (0.5 g) , potassium carbonate (13.8 g) and 1, 3-dimethyl-4- (4, 4, 5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl) -lH-pyrazole (16.5 g) , and the mixture was stirred under a nitrogen atmosphere at 110C for 16 hr. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column (1395) chromatography (ethyl acetate/hexane) to give the title compound (8.0 g) . (1396) MS: [M+H]+ 202.1.
8 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 16h;Inert atmosphere;
To a mixture of 6-chloronicotinaldehyde (7 g) and dioxane (400 mL)/water (10 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (500 mg), potassium carbonate (13.8 g), and <strong>[1046832-21-6]1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (16.5 g). The mixture was stirred under a nitrogen atmosphere at 110C for 16 hr. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (8.0 g). MS: [M+H]+ 202.1
Step 1: Preparation of tert-butyl 4-((6-chloropyridin-3-yl)methyl)piperazine-1-carboxylate To a solution of 6-chloronicotinaldehyde (0.5 g, 2.68 mmol) and tert-butyl piperazine-1-carboxylate (0.6 g. 3.22 mmol) in DCE was added acetic acid (0.1 mL) and the reaction was stirred for 2 h at RT. Then NaBH(OAc)3 (1.7 g, 8.1 mmol) was added to the reaction portion-wise at RT. The reaction was stirred at RT for 16 hours. The reaction mixture was then concentrated. The crude material was dissolved in water and basified to pH 8-9 using saturated aqueous NaHCO3 solution. The mixture was extracted with EtOAc (2*25 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to afford tert-butyl 4-((6-chloropyridin-3-yl)methyl)piperazine-1-carboxylate (300 mg, 31% yield).
Stage #1: N,N-dimethyl-formamide With potassium hydroxide for 0.0833333h; Reflux;
Stage #2: 6-chloronicotinylaldehyde at 95℃;
41 Procedure 41. Preparation of 6-(dimethylamino)pyridine-3-carbaldehyde
A mixture of DMF (10 mL) and 10M KOH (4 mL) was heated at reflux for 5 min. 6-chloropyridine- 3-carbaldehyde (1 g, 7.06 mmol, 1 eq) was added and the resulting mixture was heated for 1.5 h at 95°C. 10 M KOH (1 mL) was added every hour for 3 following hours. The mixture was diluted with water (20 mL) and extracted three times with DCM (20 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified was purified by FCC (SiHP, hexane:AcOEt 100:0 to 0:100) to afford the titled compound (0.534 g, 3.55 mmol, yield 50%) as a yellow solid. ESI-MS: 151.3 [M+H]+ 1H NMR (300 MHz, DMSO-ok) d 9.73 (d, J= 0.6 Hz, 1H), 8.58 (dd, J= 2.4, 0.7 Hz, 1H), 7.86 (dd, J= 9.0, 2.4 Hz, 1H), 6.76 (dd, J= 9.1, 0.7 Hz, 1H), 3.16 (s, 6H).
1,3,5-tris-(6-chloropyridin-3-yl)pentane-1,5-dione[ No CAS ]
1,3-bis-(6-chloropyridin-3-yl)propenone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.1%; 44.7%
With lithium hydroxide; In ethanol; water; at 29 - 30℃; for 0.00277778h;Sonication;
To a mixture of <strong>[55676-22-7]1-(6-chloro-pyridin-3-yl)-ethanone</strong> (0.50 g, 3.2 mmol), 6-chloro-pyridine-3-carbaldehyde (0.45 g, 3.2 mmol), and lithium hydroxide (0.08 g, 3.2 mmol), in a 10 mL solution of water and ethanol (1/1), at room temperature, was applied an ultrasonic agitation for 10 seconds (amplitude = 0.3; ti = 29C, tf = 30C; E = 359 J). Immediately after, the precipitate formed was filtered to afford 1d as a white solid. The filtrate was purified by flash chromatography (silica column, CH2Cl2:MeOH = 1:0 to 9:1) to give additional 1d in a first fraction, which was gathered with previously obtained and recrystallized from ethyl ether to obtain pure 1d as a white solid (0.40 g, 1.4 mmol, 44.7% yield), with the same physicochemical properties as described in the literature,4 and 4d in a second fraction as a white solid (2 mg, 4.6 mumol, 0.1% yield). 1d: mp 235-236 C (H2O:EtOH) (Litt: 227-228 C); Rf (CH2Cl2:MeOH = 99:1) = 0.2; 1H NMR (DMSO[d6], 400 MHz) delta ppm 7.67 (d, J = 8.4 Hz, 1H, ArH), 7.77 (d, J = 8.6 Hz, 1H, ArH), 7.83 (d, J = 15.9 Hz, 1H, CHCHCO), 8.11 (d, J = 15.9 Hz, 1H, CHCHCO), 8.47 (dd, J = 8.6, 2.5 Hz, 1H, ArH), 8.52 (dd, J = 8.4, 2.5 Hz, 1H, ArH), 8.90 (d, J = 2.5 Hz, 1H, ArH), 9.20 (d, J = 2.5 Hz, 1H, ArH); 13C NMR (DMSO[d6], 100 MHz) delta ppm 122.5 (CH), 122.9 (CH), 123.0 (CH), 128.2 (C), 130.2 (C), 137.0 (CH), 137.9 (CH), 138.4 (CH), 148.9 (CH), 149.2 (CH), 150.1 (C), 152.6 (C), 185.4 (C); IR nu (cm-1): 1660, 1607, 1458, 825.
tert-butyl (3-((5-formylpyridin-2-yl)oxy)propyl)(methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With caesium carbonate; bis(dibenzylideneacetone)-palladium(0); ruphos In 1,4-dioxane at 100℃; for 4h;
A Step A: tert-butyl (3- ( (5-formylpyridin-2-yl) oxy) propyl) (methyl) carbamate
A mixture of 6-chloronicotinaldehyde (400 mg, 2.84 mmol) , tert-butyl (3-hydroxypropyl) (methyl) carbamate (600 mg, 3.17 mmol) , Pd2(dba)3(180 mg, 0.20 mmol) , RuPhos (187 mmol, 0.40 mmol) and Cs2CO3(2.3 g, 7.0 mmol) in Dioxane (5 mL) was stirred at 100 for 4 hrs. The mixture was treated with 20 mL of EA and 20 mL of H2O. The mixture was filtered through a celite pad. The aqueous layer was extracted with EA (20 mL x 2) . The combined organics was washed with brine (30 mL x 3) , dried over Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA= 2: 1) to obtain the title compound (490 mg, yield: 59%) . MS: M/e 295 (M+1)+.
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h;
Intermediate: Synthesis of 6-(4-chlorophenoxy)nicotinic aldehyde
Dissolve p-chlorophenol (327mg, 2.54mmol) in N,N-dimethylformamide (5mL), add potassium carbonate (438mg, 3.18mmol), stir at room temperature for 30 minutes, then slowly add under nitrogen protection 2-chloronicotin-5-aldehyde (300mg, 2.12mmol), heated to 80°C for 12 hours. After cooling to room temperature, water (35 mL) was slowly added with vigorous stirring, a large amount of solids precipitated out, filtered, and the filter cake was dried to obtain 350 mg of brown solid with a yield of 71%.
In tetrahydrofuran; N,N-dimethyl-formamide at 80℃;
Preparation of compound 1-1
Add 6-chloronicotinaldehyde (20g, 142mmol) and dimethylamine (10% in THF) (10g, 213mmol), 95g of N,N-dimethylformamide (N,N-dimethylformamide) 100mL and heated to 80°C .After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, washed with water three times, and the combined organic layer was treated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure.14.5 g (68% yield) of Compound 1-1 was obtained by separation through silica gel column chromatography.
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