* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organometallic Chemistry, 1981, vol. 216, # 2, p. 139 - 147
2
[ 626-60-8 ]
[ 859842-81-2 ]
[ 100-55-0 ]
Yield
Reaction Conditions
Operation in experiment
12%
With potassium phosphate; water In 1,4-dioxane at 20 - 100℃; for 14.25 h;
To a solution of 3-chloropyridine (50 mg, 0.44 mmol) in 1,4-dioxane (2 ml) and water (200 μl) were added sodium [(2,2-dimethyl)propionyloxy]methyl trifluoroborate (181 mg, 0.88 mmol), palladium (II) acetate (9.9 mg, 0.044 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (36mg, 0.088 mmol), and potassium phosphate (405 mg, 1.76 mmol) at room temperature. The reaction mixture was stirred at 100°C for 14 hours and 15 minutes under the nitrogen atmosphere. After the reaction mixture was cooled at room temperature, water was added to the mixture, followed by filtration using Celite. After the filtrate was extracted with ethyl acetate, the organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off from the filtrate under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=2:1) to obtain the title compound (10 mg, 0.052 mmol, 12percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 1.23(9H, s), 5.13(2H, s), 7.28-7.32(1H, m), 7.66-7.69(1H, m), 8.58(1H, dd, J=1.7 Hz, 4.8 Hz), 8.62(1H, d, J=1.7 Hz); As a side product of (Example B-13), the title compound (6.8 mg, 0.062 mmol, 14percent) was obtained. 1H-NMR Spectrum (CDCl3) δ (ppm) : 4. 73 (2H, s), 7.28-7.31(1H, m), 7.72-7.75(1H, m), 8.49(1H, dd, J=1.7 Hz, 4. 9 Hz), 8.55(1H, d, J=2.0 Hz).
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 41, p. 13552 - 13554
[2] Journal of Molecular Structure, 1994, vol. 322, p. 223 - 232
5
[ 626-60-8 ]
[ 18364-47-1 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 1313
6
[ 626-60-8 ]
[ 22353-34-0 ]
Reference：
[1] Roczniki Chemii, 1938, vol. 18, p. 210[2] Chem. Zentralbl., 1939, vol. 110, # II, p. 2779
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 59, p. 14733 - 14737
10
[ 626-60-8 ]
[ 40138-16-7 ]
[ 176690-44-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259,12
[2] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259
11
[ 626-60-8 ]
[ 108-95-2 ]
[ 2176-45-6 ]
Yield
Reaction Conditions
Operation in experiment
75%
With sodium dodecyl-sulfate; potassium carbonate In water at 80℃; for 10 h; Green chemistry
General procedure: To a stirred suspension of appropriate aryl halide(2.0 mmol) and phenol (2.0 mmol) in 6 ml water, Ni-alumina (0.125g, 6 mol percent ofnickel metal) was added followed by K2CO3 (0.28 g, 2mmol) and SDS (0.04 g, 8 molpercent). The reaction mixture was stirred for therequired period of time at 80°C till the reaction was complete (monitored withTLC). Then the reaction mixture was cooled to room temperature, ethyl acetate(20 mL) was added to dissolve the product and the catalyst was separated simplyby filtration. The residue (recovered catalyst) was thoroughly washed withEtOAc (4×5 mL) followed by water (2×10 mL). The aqueous reaction mixture was repeatedly extracted with ethyl acetate (3×5 mL). The combined organic extractswere washed with water (3× 10 mL) and dried over anhydrous Na2SO4.The crude product was obtained by removal of the solvent under reduced pressure which was furtherpurified by filtration chromatography on a short column of silica gel using1-4percent ethyl acetate-hexane as eluent.
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1939, vol. 58, p. 709,721
[2] Roczniki Chemii, 1938, vol. 18, p. 39,41[3] Chem. Zentralbl., 1939, vol. 110, # I, p. 1366
14
[ 626-60-8 ]
[ 22353-33-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2005, vol. 3, # 3, p. 538 - 541
[2] Acta Chemica Scandinavica, 1999, vol. 53, # 2, p. 141 - 144
[3] Roczniki Chemii, 1938, vol. 18, p. 210[4] Chem. Zentralbl., 1939, vol. 110, # II, p. 2779
15
[ 626-60-8 ]
[ 108-42-9 ]
[ 57976-57-5 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 4, p. 616 - 622
16
[ 626-60-8 ]
[ 98273-79-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 27 - 32
17
[ 626-60-8 ]
[ 6148-64-7 ]
[ 39931-77-6 ]
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 19, p. 4470 - 4474
18
[ 626-60-8 ]
[ 201230-82-2 ]
[ 71-36-3 ]
[ 6938-06-3 ]
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 18, p. 7096 - 7101
[2] Angewandte Chemie - International Edition, 2001, vol. 40, # 15, p. 2856 - 2859
[3] Journal of Organometallic Chemistry, 2002, vol. 641, # 1-2, p. 30 - 40
[4] Synthesis, 2001, # 7, p. 1098 - 1109
19
[ 626-60-8 ]
[ 592-84-7 ]
[ 6938-06-3 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2010, vol. 352, # 7, p. 1205 - 1209
20
[ 626-60-8 ]
[ 88912-27-0 ]
Yield
Reaction Conditions
Operation in experiment
12%
With hydrogenchloride; n-butyllithium; carbon dioxide; diisopropylamine; lithium diisopropyl amide In tetrahydrofuran
A. 3-Chloro-N-(4-chlorophenyl)pyridine-4-carboxamide. A solution of 3-chloropyridine (1.00 mL, 10.5 mmol) in THF at -78° C. was treated dropwise with a solution of lithium diisopropylamide in THF [freshly prepared by addition of butyllithium (7.21 mL, 11.5 mmol) to diisopropylamine (11.5 mmol)]. After 0.25 h, the mixture was treated with carbon dioxide(g) and slowly warmed to ambient temperature. The mixture was concentrated, partitioned between EtOAc and water, and the aqueous layer was washed with EtOAc (2*). The pH of the aqueous layer was adjusted (~3) by addition of 1 N HCl and then washed with EtOAc (3*). The combined extracts were dried with magnesium sulfate and concentrated. The residue was recrystallized from EtOAc yielding 200 mg (12percent) of 3-chloroisonicotinic acid.
Reference：
[1] Patent: US6610704, 2003, B1,
21
[ 626-60-8 ]
[ 124-38-9 ]
[ 88912-27-0 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 27 - 32
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1846 - 1852
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -75℃; for 4 h; Stage #2: With iodine In tetrahydrofuran at -75℃; for 1 h;
To a cold solution of 3-chloro pyridine (1.0 g, 8.88 mmol) in THF (30.0 mL) was added LDA (5.9 mL, 8.88 mmol) at -75°C. The reaction mixture was stirred at -75°C for 4 h. Iodine (2.2 g, 8.88 mmol) was added and continued stirring at -75°C for 1 h. The reaction mixture was quenched in water at -70°C, extracted with ethyl acetate and concentrated to afford 0.500 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 8.01 (d, J = 5.1 Hz, 1H), 8.14 (d, / = 4.8 Hz, 1H), 8.63 (s, 1H).
Reference：
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, p. 785 - 791
[2] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 5, p. 989 - 992
37
[ 626-60-8 ]
[ 68-12-2 ]
[ 72990-37-5 ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; Stage #2: at 20℃; for 1 h;
Preparatio example 411·' 3-chloroi son i cot inaldehyde To a 250 ml round-bottomed flask, LDA (11ml, 22.02mmol) was added to 3- chloropyr icli edg, 8.80mmol) in THF(20 ml) dropwise at -78 °C and stirred at same temperature for l~2hr. Then DMF(822//.P, , 10.56mmol )was added and stirred at room temperature for Ihr. EA (Ethyl acetate) and water were added to the reaction mixture, and after the separation of the layers, the aqueous phase was further extracted with the organic solvent. The combined organic extracts were dried over anhydrous Sodium sulfate (Na2S04), filtered and concentrated under vacuum. The crude compound was purified by. a silica gel column, to produce the title compound (0.33g, 30~65percent) NMR (400MHz, CDC 13 ) δ 7.73 (d, J = 8.0, 1H) 8.71 (cl, J = 4.0, 1H) 8.81 (s, 1H) 10.52 (s, 1H)
Stage #1: With boron trifluoride diethyl etherate In diethyl ether at 0℃; Inert atmosphere Stage #2: With lithium diisopropyl amide In diethyl ether at -78 - 20℃; Inert atmosphere Stage #3: With iodine In diethyl ether at -78℃; Inert atmosphere
General procedure: A solution of 1a (1.70 g, 1.40 mL, 15.0 mmol) or 1b (2.37 g,1.44 mL, 15.0 mmol) in dry diethyl ether (60 mL) was cooled to 0 C and boron trifluoride etherate (BF3Et2O) in diethyl ether (2.34 g,2.07 mL, 16.5 mmol) was added to it. The resulting white suspension of 3-chloro-/3-bromopyridine-BF3 adduct (2a/2b) was cooled to 78 C and LDA/LTMP (16.5 mmol) was added to it. The reddish brown solution, indicating the formation of carbanion 3a/3b, was stirred for 5-10 min at 78 C. Benzaldehyde (1.75 g, 1.67 mL, 16.5 mmol) was added drop wise to a solution of 3a (15.0 mmol) at -78 °C. The reaction mixture was slowly brought to room temperature and hydrolyzed with cold water. The organic layer was extracted with diethyl ether, washed with water, brine solution, and then again with water. The combined organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give the crude product. The crude product was purified by column chromatography (60-120 mesh silica gel and 20percent EtOAc/hexane) to give the title compound.
Reference：
[1] Journal of Fluorine Chemistry, 1994, vol. 68, # 2, p. 131 - 134
54
[ 626-60-8 ]
[ 68-12-2 ]
[ 206181-90-0 ]
Reference：
[1] Angewandte Chemie - International Edition, 2014, vol. 53, # 30, p. 7933 - 7937[2] Angew. Chem., 2014, vol. 126, # 30, p. 8067 - 8071,5
[3] Patent: JP2017/25014, 2017, A, . Location in patent: Page/Page column 0046
55
[ 626-60-8 ]
[ 24721-92-4 ]
[ 96042-30-7 ]
[ 7757-82-6 ]
[ 206181-90-0 ]
Reference：
[1] Patent: US2008/269271, 2008, A1,
56
[ 626-60-8 ]
[ 73183-34-3 ]
[ 329214-79-1 ]
Yield
Reaction Conditions
Operation in experiment
49%
With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; potassium acetate In 1,4-dioxane at 60℃; for 10 h; Inert atmosphere; Sealed tube
General procedure: In a nitrogen-filled glove box, Silica-3p-TPP ([P] 0.11 mmol/g, 45.5 mg, 0.005 mmol P, 1 mol percent P), anhydrous, degassed benzene (0.8 mL), and a solution of [PdCl(η3-cinnamyl)]2 (0.65 mg, 0.00125 mmol, 0.5 mol percent Pd) in benzene (0.2 mL) were placed in an oven-dried, 10-mL glass tube containing a magnetic stirring bar. After stirring of the mixture for 5 min, KOAc (147 mg, 1.5 mmol), bis(pinacolato)diboron (2, 140 mg, 0.55 mmol), and p-chlorotoluene (1a, 63.3 mg, 0.50 mmol) were added. The tube was sealed with a screw cap and was removed from the glove box. The mixture was stirred at 25 °C for 10 h, and was filtered through a Celite pad (eluting with Et2O). Solvent was removed under reduced pressure. An internal standard (1,1,2,2-tetrachloroethane) was added to a residue to determine the yield of the product by 1H NMR (95percent). The crude material was then purified by silica gel chromatography to give arylboronate 3a (87.0 mg, 0.40 mmol, 80percent yield).
41%
With N-ethyl-N,N-diisopropylamine; triphenylphosphine In methanol at 20 - 50℃; Inert atmosphere
Under a nitrogen atmosphere, a reaction vessel of 20 ml in volume was charged with bis(pinacolate)diboron (1.34 g (5.3 mmol)), degassed methanol (7.2 g) and diisopropylethylamine (1.36 g (10.6 mmol)) and stirred at room temperature. The reaction vessel was charged with bis(l,5-cyclooctadiene)nickel (39 mg (0.14 mmol)), triphenylphosphine (74 mg (0.28 mmol)), and 3-chloropyridine (0.40 g (3.52 mmol)) and stirred at 300C for 21 hours, and thereafter stirred at500C for 3 hours. The reaction solution was analyzed by gas chromatography. As a result, 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine was contained in an amount of 0.29 g (1.42 mmol, yield: 41percent).
41%
With N-ethyl-N,N-diisopropylamine; triphenylphosphine In methanol at 20 - 50℃; for 24 h; Inert atmosphere
Under a nitrogen atmosphere, a reaction vessel of 20 ml in volume was charged with bis(pinacolate)diboron (1.34 g (5.3 mmol)), degassed methanol (7.2 g) and diisopropylethylamine (1.36 g (10.6 mmol)) and stirred at room temperature. The reaction vessel was charged with bis(1,5-cyclooctadiene)nickel (39 mg (0.14 mmol)), triphenylphosphine (74 mg (0.28 mmol)), and 3-chloropyridine (0.40 g (3.52 mmol)) and stirred at 30° C. for 21 hours, and thereafter stirred at 50° C. for 3 hours. The reaction solution was analyzed by gas chromatography. As a result, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was contained in an amount of 0.29 g (1.42 mmol, yield: 41percent).
Preparatio example 411·' 3-chloroi son i cot inaldehyde To a 250 ml round-bottomed flask, LDA (11ml, 22.02mmol) was added to 3- chloropyr icli edg, 8.80mmol) in THF(20 ml) dropwise at -78 C and stirred at same temperature for l~2hr. Then DMF(822//.P, , 10.56mmol )was added and stirred at room temperature for Ihr. EA (Ethyl acetate) and water were added to the reaction mixture, and after the separation of the layers, the aqueous phase was further extracted with the organic solvent. The combined organic extracts were dried over anhydrous Sodium sulfate (Na2S04), filtered and concentrated under vacuum. The crude compound was purified by. a silica gel column, to produce the title compound (0.33g, 30~65%) NMR (400MHz, CDC 13 ) delta 7.73 (d, J = 8.0, 1H) 8.71 (cl, J = 4.0, 1H) 8.81 (s, 1H) 10.52 (s, 1H)
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]thieno[2,3-c]pyridine-2-carboxamide Dihydrochloride[ No CAS ]
[ 72990-37-5 ]
Yield
Reaction Conditions
Operation in experiment
55%
In tetrahydrofuran; diisopropylamine;
EXAMPLE 17 N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]thieno[2,3-c]pyridine-2-carboxamide Dihydrochloride Preparation of the Acid: THF (200 mL) is chilled to -70 C. in a dry flask under N2, and N-butyllithium (24.4 mL, 55.0 mmol) is added drop-wise. The reaction is placed in an ice bath and diisopropyl amine (7.71 mL, 55.0 mmol) in THF (20 mL) is added drop-wise. The solution is again chilled to -70 C., and 3-chloropyridine (4.75 mL, 50.0 mmol) in THF (20 mL) is added drop-wise. The reaction is allowed to stir for 4 h at -70 C. and ethyl formate (4.44 mL, 55.0 mmol) in THF (20 mL) is added. The reaction is stirred for an additional 3 h at -70 C. and quenched with H2O (500 mL). The layers are allowed to separate, and the aqueous layer is extracted with EtOAc (3*250 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated to a dark brown solid. The crude material is chromatographed over 250 g slurry-packed silica, eluding with 50% EtOAc/hexane. The fractions with the desired compound are collected and concentrated to give 3-chloroisonicotinaldehyde (C120) as an off-white solid (55% yield). MS (EI) for C6H4ClNO, m/z: 141 (M)+.
With dihydrogen peroxide; nitric acid; In sulfuric acid; water; acetic anhydride;
1. Preparation of 3-Chloro-4-nitropyridine N-oxide Aqueous hydrogen peroxide (30 mL of 30%) is added dropwise to an ice cold mixture of 3-chloropyridine (6.0 g, 53 mmol) in acetic anhydride (30 mL). The mixture is allowed to stir at ambient temperature for 24 h, water is then added and the mixture concentrated. The residue is taken up in concentrated sulfuric acid (10 mL) and fuming sulfuric acid (5 mL), and then cooled to 0 C. Concentrated nitric acid (24 mL) is added slowly, and the ice bath removed. The reaction is then heated at reflux for 2 h, icooled, and poured into ice water. Ammonium bicarbonate is added carefully until pH 8 is achieved, the solution is then extracted with dichloromethane. The organic layer is washed with water, dried (NaSO4), and concentrated to give 3-Chloro-4-nitropyridine N-oxide as a yellow solid. 1H NMR (CDCl3): delta 8.47 (d, J=4 Hz, H), 8.35 (dd, J=5, 12 Hz, 1H), 7.73 (ddd, J=4, 9, 12 Hz, 1H).
With dihydrogen peroxide; nitric acid; In sulfuric acid; acetic anhydride;
1. Preparation of 3-Chloro-4-nitro-pyridine-1-oxide Aqueous 30% H2O2 (60 mL) is added dropwise to a magnetically stirred solution of 3-chloro-pyridine (12 g, 105 mmol) in acetic anhydride (60 mL) under cold conditions (0 to 10 C.). The resulting mixture is allowed to warm up to room temperature slowly and then stirred overnight at room temperature. The reaction mixture is quenched with water (50 mL), diluted with toluene and concentrated to obtain the crude N-oxide as an oil in near quantitative yield. Fuming H2SO4 (25 mL) is added dropwise to a solution of crude 3-chloro-pyridine-1-oxide in concentrated H2SO4 (25 mL) under cold conditions (0 C.) with stirring. HNO3 (fuming, 90%, 60 mL) is added carefully to the above mixture with caution to keep the offset of any exotherm under control, and then allowed to warm to room temperature slowly. The resulting mixture is then heated at 120 C. for 4 h with stirring, cooled, poured into ice-cold water, and extracted with CHCl3. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 3-Chloro-4-nitro-pyridine-1-oxide as an yellow solid. 1H NMR (300 MHz, CDCl3): delta 8.31 (d, J=1.5 Hz, 1H), 8.13 (dd, J=1.5, 5.4 Hz, 1H), 7.95 (d, J=7.2 Hz, 1H)
With potassium fluoride;palladium diacetate; In tetrahydrofuran;
EXAMPLE 43 Synthesis of 3-(3-acetylphenyl)pyridine An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol percent), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol percent), 3-acetylphenylboronic acid (246 mg, 1.5 mmol), and potassium fluoride (173 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 3-chloropyridine (0.095 mL, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was heated to 50° C. with stirring until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 181 mg (92percent) of the title compound.
181 mg (92%)
With potassium fluoride;palladium diacetate; In tetrahydrofuran;
Example 43 Synthesis of 3-(3-acetylphenyl)pyridine An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol percent), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol percent), 3-acetylphenylboronic acid (246 mg, 1.5 mmol), and potassium fluoride (173 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 3-chloropyridine (0.095 mL, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was heated to 50° C. with stirring until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 181 mg (92percent) of the title compound.
With m-chloroperoxybenzoic acid; potassium carbonate; triethylamine; In dichloromethane; acetonitrile;
EXAMPLE 10 Dimethyl 2-methyl-5-(3-chloro-2-pyridinyl)pyrrole-3,4-dicarboxylate (10) At room temperature, 258.9 g of (85%) m-chloroperoxybenzoic acid was added in portions over 20 minutes to a stirred solution of 150 g of 3-chloropyridine in one liter of methylene chloride, the mixture being cooled to hold its temperature below 35 C. Then the mixture was stirred at room temperature for 2 days, washed with a 25% aqueous solution of potassium carbonate, dried (MgSO4) and stripped of volatiles. The product was triturated with ether at -78 C., then stripped of solvent to give the N-oxide (10A), as a white solid, m.p.: 51.5-55 C. 125 g of trimethylsilyl cyanide was added to a stirred mixture of 54.3 g of 10A, 85 g of triethylamine and 420 ml of acetonitrile at room temperature. The mixture was heated at reflux for 4 hours, cooled and stripped of volatiles under reduced pressure. 3N aqueous sodium carbonate solution was added until the mixture was basic then the mixture was extracted with methylene chloride. The extract was dried (MgSO4), and stripped of solvent. The residue was chromatographed on silica gel with a 1:3 v:v mixture of ethyl acetate and hexane as eluent, to give 3-chloro-2-cyanopyridine (10B), as an off-white solid, m.p.: 80.5-83 C.
With n-butyllithium; In tetrahydrofuran; hexane; water; N,N-dimethyl-formamide;
Synthesis of 3-chloropyridine-2-carbaldehyde (F) A 2.5 M solution of n-butyllithium (96 ml, 240 ml) in n-hexane was added to a solution of N,N dimethylaminoethanol (10.65 g, 120 mmol) in abs. THF (70 ml) at -5 C. under argon within 25 min. The reaction mixture was stirred for 30 min at 0 C. and cooled down to -70 C. At a temperature of -70 to -65 C., a solution of 3-chloropyridine (3.8 ml, 4.5 g, 40 mmol) in abs. THF (60 ml) was added within 10 min and stirred for a further hour at this temperature. Abs. DMF (12.3 ml, 11.7 g, 160 mmol) in THF (100 ml) was then added within 15 min at -65 to -60 C. The dark brown solution was heated within 1 h to 10 C. At a temperature of -20 to -10 C., the reaction mixture was hydrolyzed with sat. ammonium chloride solution (120 ml). The mixture was then stirred for 30 min at 0 C. The phases were not separated. The organic solvents were removed under vacuum. The residue was extracted with DCM (120 ml). The phases were separated. The aqueous phase was extracted with DCM (3*120 ml). The organic phases were combined and concentrated without drying. The residue was a brown oil which was further purified by adding water (4*50 ml) and decanting. After the addition of DCM (250 ml) and sodium sulphate, the mixture was dried overnight and then concentrated. The crude product of the 3-chloropyridine-2-carbaldehyde (F) was obtained as a hydrate (brown oil 8.73 g, theoretical yield 6.3 g). Chromatographic purification of the crude product was not possible.
With sodium t-butanolate;palladium diacetate; (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; In 1,2-dichloro-ethane; at 100℃; for 20h;
Compound 13 Isomers; 3-methyl-N-3-pyridinyl-L-valyl-(4R)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((6-methoxy-1-isoquinolinyl)oxy)-L-prolinamide and3-methyl-N-3-pyridinyl-D-valyl-(4R)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((6-methoxy-1-isoquinolinyl)oxy)-L-prolinamide; Example 13; Preparation of Compounds 13A and 13B; Step 1:; To a mixture of 3-chloropyridine (0.410 g, 3.61 mmol) and sodium tert-butoxide (1.18 g, 12.3 mmol) in dry 1,2-dichloroethane (5 mL) was added a pre-mixed solution of Pd(OAc)2 (0.0405 g, 0.180 mmol) and (R)-(-)-1-[(S)-(dicyclohexylphosphino) ferrocenyl]ethyl di-tert-butyl phosphine (0.100 g, 0.180 mmol, Strem Chemicals catalog No.26-0975, CAS No. [158923-11-6]) in dry 1,2-dimethoxyethane (2 mL). The mixture was shaken briefly, treated quickly with <strong>[119483-45-3]tert-leucine tert-butyl ester hydrochloride</strong> (0.970 g, 4.33 mmol) and shaken again. The mixture was heated to 100 C. for 20 hours, added to a rapidly stirred mixture of pH=7 buffer solution (100 mL) and 1.0M aqueous HCl (12 mL), treated with ethyl acetate, and shaken. The phases were allowed to separate and the organic extract was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to a deep orange residue. The crude product was purified by flash silica gel chromatography (linear gradient 100% hexanes to 1:1 hexanes:ethyl acetate) to give a flesh colored solid (0.583 g, 61.1% yield). LC-MS, MS m/z 265 (M++H).
E. [4, 6-BIS- (3-CHLORO-PYRIDIN-2-YLMETHOXY)- 1, 3, 5] TRIAZIN-2-YL]- (4-TERT-BUTYL- PHENYL)-AMINE 1. (3-CLLLORO-PYRIDIN-2-YL)-NAETHANOL To a solution of 2-dimethylamino-ethanol (3.6 g, 0.04 mol) in hexanes at-20°C add n-butyl lithium (1.6M in hexanes, 50 mL, 0. 08 mol) dropwise. After stirring for 30 minutes, bring the reaction temperature down to-78°C and add 3-chloropyridine (1.51 g, 0.0133 mol) dropwise to the reaction mixture. After 90 minutes AT-78°C, add DIMETHYLFORMAMIDE dropwise then allow the mixture to slowly warm to room temperature with stirring. Add NaBH4 (556 mg) followed by ethanol (5 mL) to the reaction mixture and stir at room temperature for 16 hours. Concentrate under reduced pressure and partition between ether and brine. Wash the ether layer with brine (2x), dry (NA2S04), and concentrate under reduced pressure to give the desired product as an oil.
With potassium phosphate; 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); at 100℃; for 12h;Schlenk technique; Inert atmosphere;
General procedure: To a 25 mL Schlenk tube equipped with a magnetic stir bar were added NiCl2(dppp) (0.01 mmol), aryl chloride (0.5 mmol), arylboronic acid (1.0 mmol), K3PO4 (2.0 mmol), and PEG-400 (3.0 mL) under Ar. The reaction mixture was stirred at 100-110 C until the aryl chloride had disappeared as monitored by TLC. After being cooled to room temperature, the resulting mixture was extracted three times with petroleum ether (3 × 10 mL). The residue of the extraction was heated to 60 C in vacuum for 20 min to remove the residual petroleum ether, and then subjected to a second run of the Suzuki-Miyaura reaction by charging with the same substrates (aryl chloride, arylboronic acid and K3PO4) under the same conditions without further addition of NiCl2(dppp). The combined ether phase was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using petroleum ether or a mixture of petroleum ether and EtOAc as eluent to give the desired cross-coupled products 3.
With (R)-(-)-di-tert-butyl-{1-(S)-[2-(dicyclohexylphosphanyl)ferrocenyl]ethyl}phosphine; palladium diacetate; sodium t-butanolate; In 1,2-dimethoxyethane; at 100℃; for 4h;
A -[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1 H-indol-5-yl)-A -3- pyridinylbenzamide(a) 1 ,1 -Dimethylethyl (3S)-3-[(3-pyridinylamino)methyl]-1 -pyrrolidinecarboxylateA 20 mL tube-shaped pressure bottle was charged with 3-chloropyridine (0.200 g) and sodium tert-butoxide (0.254 g) in 1 ,2-dimethoxyethane (DME) (5 mL) followed by palladium (II) acetate (9 mg) and (R)-(-)-di-tert-butyl-{1 -(S)-2- (dicyclohexylphosphanyl)ferrocenyl]ethyl}phosphine (9 mg) to give a brown suspension. 1 , 1 - Dimethylethyl (3S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate (0.441 g) was then added and the closed vessel heated with stirring at 100 C for 4 hr. The crude reaction mixture was poured directly onto a 20 g silica gel pad and eluted with 6 x 75 mL 100% EtOAc. The appropriate fractions were pooled and evaporated to dryness to afford 250 mg of the titled compound, which was used without further purification.
General procedure: A solution of 1a (1.70 g, 1.40 mL, 15.0 mmol) or 1b (2.37 g,1.44 mL, 15.0 mmol) in dry diethyl ether (60 mL) was cooled to 0 C and boron trifluoride etherate (BF3Et2O) in diethyl ether (2.34 g,2.07 mL, 16.5 mmol) was added to it.The resulting white suspension of 3-chloro-/3-bromopyridine-BF3 adduct (2a/2b) was cooled to 78 C and LDA/LTMP (16.5 mmol) was added to it. The reddish brown solution, indicating the formation of carbanion 3a/3b, was stirred for 5-10 min at 78 C. Benzaldehyde (1.75 g, 1.67 mL, 16.5 mmol) was added drop wise to a solution of 3a (15.0 mmol) at -78 C. The reaction mixture was slowly brought to room temperature and hydrolyzed with cold water. The organic layer was extracted with diethyl ether, washed with water, brine solution, and then again with water. The combined organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give the crude product. The crude product was purified by column chromatography (60-120 mesh silica gel and 20% EtOAc/hexane) to give the title compound.
In a 200 ml flask purged with nitrogen, 4.3 g of lithium chloride and 20 g of THF were added, and 110 ml of isopropyl magnesium chloride THF solution (concentration 1 M) was added at room temperature while stirring. To this mixed solution, at 20 C. 14.3 g of 2,2,6,6-tetramethylpiperidine was added dropwise over 15 minutes. The mixture was stirred at room temperature for 30 minutes and then cooled to -20 C.,To this mixed solution, 11.4 g of 3-chloropyridine was added dropwise over 15 minutes. After stirring at -20 C. for 30 minutes, To this mixed solution, 8.8 g of N,N-dimethylformamide was added dropwise over 15 minutes. After stirring at -20 to -10 C. for 1 hour, the temperature was raised to room temperature and further stirred for 8 hours. The reaction solution was added to 1 liter of ice water, and the mixture was separated. The THF layer was washed once with 50 ml of a saturated sodium sulfate aqueous solution and then dried over anhydrous magnesium sulfate, and THF and N,N-dimethylformamide were distilled off. 31 g of the obtained concentrated solution was analyzed by GC-MS to confirm formation of 2-formyl-3-chloropyridine. To this concentrated solution was added 20 g of a saturated aqueous sodium bisulfite solution, stirred for 30 minutes, and washed twice with 50 g of toluene. To the obtained aqueous layer, 5 g of sodium carbonate was added and the mixture was extracted twice with 10 g of toluene. The obtained toluene layers were combined, washed with 5% hydrochloric acid, dried over magnesium sulfate, and then toluene was distilled off. As a result,350 mg concentrate was obtained. This concentrate was analyzed by GCMS and it was confirmed to be 2-formyl-3-chloropyridine.
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; hydrogen; triethylamine; In isopropyl alcohol; at 85℃; under 3750.38 Torr; for 3h;
General procedure: Complex (1 .71 mol%) and 3 mL of stock solution (made from 3.333g TCP A in IPA 30 mL) are added to each reactor, followed by NEt3 (446 pL). The reactors are purged with nitrogen (3 times) and hydrogen (3 times) then hydrogenated at 0.5 MPa and 85 C for 180 mm in a Biotage Endeavor. 40 pL aliquot of each reaction mixture is added to 1 mL MeCN and analysed by normal HPLC method.HPLC areas are converted to concentration (pmol/mL) from the gradients equations in the multipoint external standard.
4-((3-chloropyridin-4-yl)(hydroxy)methyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8.1 g
To a -70 C solution of 3-chloropyridine (2.25 g, 17.64 mmol) in THF (50 mL) was added LDA (2 M solution in THF/Hex, 11.00 mL, 22.00 mmol) dropwise. The resulting mixturewas allowed to warm to -60 C and stirred for 1.5 h. A solution of tert-butyl4-formyl-4-methylpiperidine-1-carboxylate (3.95 g, 17.37 mmol) in THF (10 mL) was added dropwise at -70 C. After stirring for 1 h, the mixture was quenched with water (50 mL). The aqueous layer was separated and extracted with EA (60 mL, 30 mL). The combined organic layerswere washed with brine (1 x 80 mL), dried over anhydrous Na2504, filtered and concentratedunder reduced pressure to give tert-butyl 4-((3-chloropyridin-4-yl)(hydroxy)methyl)-4-methylpiperidine- 1 -carboxylate (8.10 g) which was used in next step without any further purification. MS: m/z 341 (M+H) .
8.1 g
at -70 C 3-Chloropyridine (2.25 g, 17.64 mmol) in THF (50 mL)LDA (2M in THF/Hex solution, 11.00 mL, 22.00 mmol) was added dropwise.The system was warmed to -60 C and stirred for 1.5 h.A solution of <strong>[189442-92-0]4-formyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester</strong> (3.95 g, 17.37 mmol) in THF (10 mL). After stirring for 1 h the mixture was quenched with water (50 mL).The organic phase was collected and the aqueous phase separated and extracted with EA (60mL, 30mL).The combined organics were washed with EtOAcq.4-((3-Chloropyridin-4-yl)(hydroxy)methyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (8.10 g),Used in the next step without any purification.
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