* 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 the American Chemical Society, 1950, vol. 72, p. 1988
2
[ 39931-77-6 ]
[ 6293-56-7 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1992, vol. 29, # 6, p. 1663 - 1665
[2] Journal of Organic Chemistry, 2003, vol. 68, # 3, p. 718 - 725
[3] Patent: WO2012/75917, 2012, A1, . Location in patent: Page/Page column 36
3
[ 39931-77-6 ]
[ 6443-85-2 ]
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 1988
4
[ 39931-77-6 ]
[ 501-81-5 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 150,153
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1981, vol. <B> 20, # 9, p. 793 - 795
[3] Patent: US6407120, 2002, B1, . Location in patent: Page column 23-24
5
[ 39931-77-6 ]
[ 74-89-5 ]
[ 106271-65-2 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 2573,2577
6
[ 626-55-1 ]
[ 6148-64-7 ]
[ 39931-77-6 ]
Yield
Reaction Conditions
Operation in experiment
87%
With dmap; bis(η3-allyl-μ-chloropalladium(II)); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,3,5-trimethyl-benzene at 140℃; for 20 h; Inert atmosphere
General procedure: after standard cycles of evacuation and back-filling with dry and pure nitrogen, an oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Pd source (see Table 1, Table 2, Table 3 and Table 4), ligand (see Table 1, Table 2, Table 3 and Table 4), N,N-dimethylpyridin-4-amine (DMAP, see Table 1, Table 2, Table 3 and Table 4), and ethyl potassium malonate (see Table 1, Table 2, Table 3 and Table 4). The tube was evacuated and backfilled with argon (this procedure was repeated three times). Under a counter flow of argon, aryl halide (see Table 1, Table 2, Table 3 and Table 4) and solvent (see Table 1, Table 2, Table 3 and Table 4) were added by syringe. The tube was sealed and stirred at room temperature for 10 min. Then the tube was connected to the Schlenk line, which was full of argon, stirred in a preheated oil bath (140-150 °C) for the appointed time (20-25 h). Upon completion of the reaction, the mixture was cooled to room temperature and diluted with diethyl ether, and the yields were determined by gas chromatography using 1,3-dimethoxybenzene as the internal standard.
Reference：
[1] Chemical Communications, 2001, # 24, p. 2704 - 2705
8
[ 64-17-5 ]
[ 6419-36-9 ]
[ 39931-77-6 ]
Yield
Reaction Conditions
Operation in experiment
93%
for 6 h; Reflux
To a solution of 3-pyridylacetic acid hydrochloride (51) (12.00 g, 69.19 mmol) in EtOH (120 mL) was added concentrated H2SO4 (5 mL) and the solution was heated at reflux (6 h). The reaction mixture was concentrated in vacuo and diluted with EtOAc (200 mL). The EtOAc layer was washed with saturated aqueous NaHCO3 (3 x 200 mL) and brine (2 x 200 mL), and dried (Na2SO4). The crude product was purified by flash column chromatography (SiO2; 4:5 EtOAc/hexanes) to give the desired product (10.67 g, 93percent) as a pale yellow oil. Rf 0.37 (4:1 EtOAc/hexanes). 1H NMR (CDCl3) δ 1.26 (t, J = 7.2 Hz, CH2CH3), 3.63 (s, CH2C5H4N), 4.17 (q, J = 7.2 Hz, CH2CH3), 7.25-7.30 (m, C5H), 7.64-7.67 (m, C4H), 8.45-8.59 (m, C2H, C6H). 13C NMR (CDCl3) δ 13.7 (CH2CH3), 38.0 (CH2C5H4N), 60.7 (CH2CH3), 122.9 (C5H), 129.5 (C3H), 136.4 (C4H), 148.0 (C2H or C6H), 149.9 (C6H or C2).
Reference：
[1] Synthetic Communications, 2012, vol. 42, # 8, p. 1137 - 1145
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3551 - 3564
[3] Patent: WO2012/75917, 2012, A1, . Location in patent: Page/Page column 36
9
[ 1120-90-7 ]
[ 6148-64-7 ]
[ 39931-77-6 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 277 - 280
10
[ 626-60-8 ]
[ 6148-64-7 ]
[ 39931-77-6 ]
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 19, p. 4470 - 4474
11
[ 1120-90-7 ]
[ 141-97-9 ]
[ 39931-77-6 ]
Reference：
[1] Chemical Communications, 2013, vol. 49, # 60, p. 6767 - 6769
12
[ 100-55-0 ]
[ 95-92-1 ]
[ 39931-77-6 ]
Reference：
[1] Chemistry - A European Journal, 2013, vol. 19, # 23, p. 7334 - 7337
13
[ 1120-90-7 ]
[ 137344-20-8 ]
[ 39931-77-6 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 277 - 280
14
[ 1120-90-7 ]
[ 5764-82-9 ]
[ 39931-77-6 ]
Reference：
[1] Chemical & Pharmaceutical Bulletin, 1985, vol. 33, # 10, p. 4309 - 4313
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 277 - 280
15
[ 64-17-5 ]
[ 5423-64-3 ]
[ 39931-77-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 12, p. 2343 - 2361
A. A solution of ethyl 3-pyridylacetate (1.65 g, 9.90 mmol) in 32% peracetic acid (10 mL) was stirred at 80-90 C. for 2 h. The reaction was concentrated and the residue coevaporated with methanol (2*) then methylene chloride to afford ethyl 3-pyridylacetate N-oxide (1.80 g, 100%) as a white solid: 1H NMR (CDCl3, 300 MHz, ppm) 8.38 (s, 1H), 8.22 (d, 1H), 7.39 (d, 1H), 4.20 (q, 2H), 3.62 (s, 2H), 1.26 (t, 3H).
100%
In peracetic acid;
A. A solution of ethyl 3-pyridylacetate (1.65 g, 9.90 mmol) in 32% peracetic acid (10 mL) was stirred at 80-90 C. for 2 h. The reaction was concentrated and the residue coevaporated with methanol (2*) then methylene chloride to afford ethyl 3-pyridylacetate Noxide (1.80 g, 100%) as a white solid: 1H NMR (CDCl3, 300 MHz, ppm) 8.38 (s, 1H), 8.22 (d, 1H), 7.39 (d, 1H), 4.20 (q, 2H), 3.62 (s, 2H), 1.26 (t, 3H).
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃;
A solution of ethyl 3-pyridylacetate (10.0 g, 0.061 mol; Aldrich Chemical Company, Inc., Milwaukee, Wl) and m-chloroperoxybenzoic acid (36.87 g, 0.182 mol) in dichloromethane (300 ml_) was stirred at RT overnight. TLC (dichloromethane: methanol = 15:1 ) indicated the reaction was complete. The reaction mixture was quenched with Na2SO3, and then the solvent was removed under reduced pressure to give a crude product. The crude product was purified by chromatography on silica (dichloromethane: methanol = 60:1 ? 30:1 ?20:1 ) to give crude (l-30c) (15.2 g, 40.5% purity by LC-MS) as a solid.
m-Chloro perbenzoic acid (6.2g, 36.06mmol) in CHC13 (30mL) was added drop wise to a solution of ethyl 2-(pyridin-3-yl)acetate (3.5g, 21.21mmol) in CHCI3 (30mL) at room temperature under nitrogen atmosphere and the resulting reaction mass was stirred at room temperature for 5 hours. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mass was basified using aqueous NaHC03 solution to pH 7 and extracted using CHCI3. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford 4.8 g of the crude product. LCMS: 60.09 %, m/z = 182.0 (M+ 1 )
With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 20℃; for 5h;Inert atmosphere;
Preparation of Intermediate 3-(2-ethoxy-2-oxoethyl)pyridine-1-oxide (I-67a) m-Chloro perbenzoic acid (6.2 g, 36.06 mmol) in CHCl3 (30 mL) was added drop wise to a solution of ethyl 2-(pyridin-3-yl)acetate (3.5 g, 21.21 mmol) in CHCl3 (30 mL) at room temperature under nitrogen atmosphere and the resulting reaction mass was stirred at room temperature for 5 hours. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mass was basified using aqueous NaHCO3 solution to pH 7 and extracted using CHCl3. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford 4.8 g of the crude product. LCMS: 60.09%, m/z=182.0 (M+1)
D573-pyridinethanolTo a solution of pyridin-3-yl-acetic acid ethyl ester (33 g, 197.36 mmol) in methanol (400 mL) was added sodium borohydride (74.66 g, 1.9 mole). The reaction mixture was refluxed for 12 h, then cooled to rt, quchenched with water (300 mL), concentrated. The residue was extracted with DCM (500 mL), dried over sodium sulfate, concentrated to afford the title product (20.76 g).
To a solution of 54 (5.00 g, 30.30 mmol) in dry EtOH (20 mL) was added NaOEt (21 wt%) in EtOH (11.3 mL, 30.30 mmol), followed by t-BuONO9 (5.39 mL, 45.45 mmol) and the reaction stirred (20 h). CH3CO2H (5.0 mL) was added to the reaction and stirred 1 h before the reaction was diluted with H2O (300 mL). The precipitate was filtered and washed with a saturated aqueous NaHCO3 (100 mL) and H2O (200 mL) and dried in a P2O5 desicator to give the desired product (3.08 g, 52%) as an off-white solid. Mp 178-179 C (lit.8 mp 166-171 C). Rf 0.40 (2:50 MeOH/CHCl3). 1H NMR (DMSO-d6) delta 1.25 (t, J = 7.2 Hz, CH2CH3), 4.25 (q, J = 7.2 Hz, CH2CH3), 7.45-7.49 (m, C5H), 7.82-7.86 (m, C4H), 8.57-8.59 (m, C2H, C6H), 12.78 (s, NOH). 13C NMR (DMSO-d6) delta 14.0 (CH2CH3), 61.3 (CH2CH3), 123.1 (C5H), 126.1 (C3H), 136.9 (C4H), 146.0, 149.5, 149.7 (C2H, C6H, C(NOH)), 163.2 (C(O)OCH2CH3). HRMS (ESI) [M+H+] 195.0768 (calcd for C9H10N2O3H+ 195.0770); 217.0590 [M+Na+] (calcd for C9H10N2O3Na+ 217.0589).
The ethyl 2-methyl-2-pyridin-3-yl-propanoate used as starting material was prepared as described below To a solution of ethyl 3-pyridyl acetate (3.30 g, 20.0 mmol) in DMF (30.0 mL) was added a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (80.0 mL, 40 mmol). The reaction mixture was stirred at room temperature for 30 minutes before adding MeI (3.99 mL, 64.0 mmol) in one portion. The reaction mixture was then stirred at room temperature for 18 hours.The reaction mixture was evaporated to dryness and dissolved in DCM (150 mL), and washed sequentially with saturated NH4Cl (25 mL), water (50 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 2-methyl-2-pyridin-3-yl-propanoate (1.80 g, 9.3 mmol, 47%) as an orange oil.1H NMR (400.13 MHz, DMSO-d6) delta1.14 (3H, t), 1.55 (6H, s), 4.08 (2H, q), 7.35-7.39 (1H, m), 7.70-7.75 (1H, m), 8.46-8.48 (1H, m), 8.56 (1H, d)m/z (ESI+) (M+H)+=194; HPLC tR=0.71 min.
Chiral Preparation Racemic piperidin-3-yl-acetic acid ethyl ester Following the procedure described in WO 00/71519, which is incorporated herein by reference, page 19, Example 24. Into a Parr hydrogenation flask (2.25 L) was placed ethyl-3- pyridylacetate (61.12 g, 370 mmol), L-tartaric acid (56.97 g, 380 mmol), platinum oxide (IV) (Pt20) (2.179 g, 9.60 mmol) and anhydrous ethyl alcohol (absolute ethanol 200 proof) (550 mL). The resulting mixture was hydrogenated (H2) at -50 psi (-3.4 bar) with shaking at room temperature until no more hydrogen consumption was observed (-4 to 5 hours). After removal of hydrogen gas the mixture was then filtered through a Celite bed to remove the catalyst and rinsed with methanol (MeOH) (400 -mL). The filtrate was evaporated under vacuum to yield a colorless viscous oil. The viscous oil was neutralized with NaHCOs (saturated solution) (gas evolution was observed). The mixture was basified with 10 N NaOH (pH -1 1-12) and extracted with EtOAc (4x200 mL). The combined organics were washed with brine, dried over Na2S04, filtered and concentrated under reduced vacuum to yield a pale yellow oil (55.85 g, 88%).
With L-Tartaric acid; hydrogen;platinum(IV) oxide; In ethanol; under 2585.81 Torr; for 24h;
EXAMPLE 24 Preparation of ethyl 3-Piperidinylacetate Commercially available ethyl-3-pyridylacetate (4.04 g; 24.5 mmol) was dissolved in absolute ethanol (100 ml). L(+) tartaric acid (3.67 g; 24.5 mmol) and platinum oxide (546.1 mg; 2.4 mmol) were added, and the partial suspension was placed under hydrogen gas at 50 psi with shaking for 24 hours.. The hydrogen was removed, and the mixture was then filtered through celite to remove the catalyst.. The filtrate was evaporated at ambient temperature under reduced pressure to a small volume.. This residue was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate.. The aqueous solution was then basified with 1 N sodium hydroxide and extracted with fresh ethyl acetate.. The ethyl acetate extracts were combined, dried with anhydrous potassium carbonate, and evaporated at ambient temperature under reduced pressure, giving ethyl 3-piperidinylacetate (2.96 g) as a very pale yellow oil without further purification. MS m/z (positive ion) 172 (MH+; 100).
With hydrogen;Rh/Al2O3; In ethanol; at 60℃; under 3102.97 Torr; for 16h;
Bx;»?i|>le_2:S;S^JlXbl..Ii£.theta?k.3dd <n="25"/>Slop 1 ; A mixture of pyrid-3-yJaeetic add ethyl exter (12,6 g) axt rhodium on aksnna ( 12.6 r } is? eth^nos (200 mL) i-s put on Parr shaker At OiTC and 60 PSI for 16 hours. The suspension is uttered through 8 Ceiite pad. The pad is washed wiih ethanoi and the filtrate is concentrated ta a volume of approximate.:; y 50 mL and water (600 mL) is added. The solution is extracted with EtOAc (3 X 100 ml.,), 'The combined organic layer is washed with brine, dried (Na^SO4 }, filtered and evaporated m vacuo. The residue, is dissolved hi JIlP ( 150 mL) and iribetathyla?iine (10.7 mL} is added. The sokson is cooled n> VfC am bcnzylcKloroforotste ( 1 1 ?iL) is added dropwiseiy. The soSution is stirred ar (TC for swo hours. The stmio? ss concentred in u volume of approximately 50 mL and water (6(X) mi.,) is added. The poiuon h extracted with BiOAc (2 X 150 mL). The combined organic Saver k< washed wuii brine, dried (NthSOJ, filtered and evaporated in vacuo to afford 3^phi>>?warhMlambdanvimeyi]^ij?eridine ester (21.5 g). which is used for next step without further purification. MS: 306 /M-HH); .H NM R (3(X) MHz, DMSO-45 5 7.3 On, 5H); 5.05 . 2H); 3.S-4. 1 (mf 4H}; 2.5-2.6 6«, I H); L5- L? ( m. 4B); 1 - 1.4 On, 4H).
With potassium tert-butylate; In tetrahydrofuran; at 90℃;
To a mixture of intermediate d (1.00 mmol, 0.281g) in L S (10 ml), was added potassium tert-butoxide (1.10 equiv. , 1.10 mmol, 0.123 g) and ethyl 3-pyridylacetate (1. 00 equiv. , 1.00 mmol, 0.165 g). The mixture was stirred and heated at 90 C overnight. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with water. The organic phase was dried with magnesium sulphate, filtered and evaporated to dryness. The residue was purified with preparative HPLC, affording compound 64 (0. 008G, yield = 2 %, purity (LC) >50%).
2%
With potassium tert-butylate; In tetrahydrofuran; at 90℃;
To a mixture of intermediate d (1.00 mmol, 0.281 g) in THF (10 ml), was added potassium tert-butoxide (1.10 equiv. , 1.10 mmol, 0.123 g) and ethyl 3-pyridylacetate (1.00 equiv., 1.00 mmol, 0.165 g). The mixture was stirred and heated at 90 C overnight. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with water. The organic phase was dried with magnesium sulphate, filtered and evaporated to dryness. The residue was purified with preparative HPLC, affording compound 64 (0.008g, yield = 2 %, purity (LC) >50%).
With N,N,N,N,N,N-hexamethylphosphoric triamide; potassium hexamethylsilazane; In tetrahydrofuran; at 0 - 20℃; for 0.75h;
STEP 5 : 3-{carbethoxy-2-(3-cyclopropyloxy-4-difluoromethoxyphen-2-[2-(2-((2-trimethylsilylethoxy)methoxy)-propan-2-yl) 5-pyridyl]ethyl}pyridine; HMPA (3eq. ) was added to a 0C solution of ethyl-3-pyridyl acetate (3eq. ) in tetrahydrofuran (0.3m), followed by addition of KHMDS (3eq. ). the mixture was stirred at 0C for 45min, then a solution of (3-cyclopropyloxy-4- difluoromethoxyphenyl)-{2-[2-((2-trimethylsilylethoxy) methoxy) propane-2-yl] 5- pyridyl} chloromethane (example 6, step 4) in tetrahydrofuran (0.4m) was added. the reaction mixture was warmed to rt, stirred overnight, then quenched with saturated NH4C1. the aqueous phase was extracted with ethyl acetate, the organic layer washed once with brine, dried over Na2SO4, filtered and concentrated. the crude material was purified by flash chromatography on silica gel (50-70% ethyl acetate in hexanes) to afford the ester as a yellow oil.
With lithium diisopropyl amide; In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; at -78℃; for 0.5h;
Step 1: LDA (5. 1mL of a 1. 5mmol mL-l solution in C-C6H12, 7. 6MMOL) was added to a stirred solution of ethyl 3-pyridylacetate (1. 15G, 6. 9MMOL) in anhydrous THF-HMPA (3: 1,260mL) AT-78 C. After 30min, iodomethylcyclopentane (1.46g, 6. 9MMOL) was added, then stirring was continued AT-78 C for 4. 5H. The mixture was allowed to warm to 20 C, before being stirred for 16h. The reaction mixture was carefully quenched with saturated aqueous NH4C1 (20ML), then H20 (lOOmL) was added. The mixture was extracted with EtOAc (3 x 50ML), then the extracts were dried (NA2SO4). Filtration, solvent evaporation, and column chromatography (N-C6HL4-ETOAC) furnished ethyl 3-cyclopentyl-2-pyridin-3-ylpropionate: m/z (ES) = 248.3 [M+ H] +. Step 2: A stirred solution of this compound (0.73g, 3. 0MMOL) in THF (3mL) was treated with 2M NAOH (3mL, 6. 0MMOL). After 16h at 20 C, the organic solvent was removed under reduced pressure, then the pH of the remaining solution was adjusted to 6.5, before being extracted with EtOAc. The EtOAc extracts were dried (NA2S04), filtered, and concentrated to give the title compound: M/Z (ES+) = 220.2 [M+ H] +.
With sodium hydride; In tetrahydrofuran; at 0 - 20℃;
Pyridin- 3-yl-acetic acid ethyl ester (22.5g, 0.136 mol) in tetrahydrofuran (50 ML) was slowly added to a suspension of sodium hydride (60% in mineral oil, 6 G, 0.4 mol) in tetrahydrofuran (50 mL) at 0 C. A solution of ethyl iodide (23.4g, 0.150 mol) in tetrahydrofuran (50 mL) was added to and the reaction mixture was allowed to stir overnight at room temperature. The mixture was poured into ice and the aqueous layer was extracted three times with ethyl acetate. The organic layer washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude residue was purified by preparative reverse phase liquid chromatography (13.5g, 0.0699 mol, 51.3 %). ESI-MS M/Z calc. 193.1, found 194.2 (M+1)+ 1H NMR (CDC13) B : 9.42-9. 39 (m, 2 H), 8.58-8. 55 (m, 1 H), 8.17-8. 13 (m, 1 H), 5.09- 4.97 (m, 2 H), 4.35 (t, 1 H, J = 7.6 Hz), 3.04-2. 95 (m, 1 H), 2.74-2. 65 (M, 1 H), 2.10 (t, 3 H, J=7.2 HZ), 1.79 (t, 3 H, J = 7.6 Hz).
With n-butyllithium; diisopropylamine; In tetrahydrofuran;
tert-butylamino-<strong>[39931-77-6]pyridin-3-yl-acetic acid ethyl ester</strong> A typical synthesis of bromo-<strong>[39931-77-6]pyridin-3-yl-acetic acid ethyl ester</strong> is described: A solution of fresh lithium diisopropylamide (IDA) was prepared at -10 C. from diisopropylamine (8.54 mL; 60.5 mmol) and n-butyllithium (nBuLi) (37.8 mL of a 1.6 M hexanes solution; 12.1 mmol) and stirred for 10 min. After chilling the fresh LDA to -78 C., ethyl 3-pyridylacetate (9.21 mL; 60.5 mmol) was added and the solution was stirred another 10 min. TMSCl (7.68 mL; 60.5 mmol) was added to the resulting opaque yellow slurry and the solution was stirred 5 min. Finally a solution of 4-(dimethylamino) pyridinium tribromide (22.0 g; 60.5 mmol) in tetrahydrofuran was added and the reaction solution was stirred 10 min. After warming to rt. the reaction solution was quenched with saturated NH4CL (aq) and extracted twice with ethyl acetate. The combined organic layer was washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo.
With n-butyllithium; chloro-trimethyl-silane; diisopropylamine; In tetrahydrofuran;
Pyridin-3-yl-(pyridin-2-yloxy)-acetic acid ethyl ester A typical synthesis of bromopyridin-3-ylacetic acid ethyl ester is described: A solution of fresh lithium diisopropylamide (LDA) was prepared at -10 C. from diisopropylamine (8.54 mL; 60.5 mmol) and n-butyllithium (37.8 mL of a 1.6 M hexanes solution; 12.1 mmol) and stirred for 10 min. After chilling the fresh LDA to -78 C., ethyl 3-pyridylacetate (9.21 mL; 60.5 mmol) was added and the solution was stirred another 10 min. Chlorotrimethylsilane (7.68 mL; 60.5 mmol) was added to the resulting opaque yellow slurry and the solution was stirred 5 min. Finally a solution of 4-(dimethylamino)pyridinium tribromide (22.0 g; 60.5 mmol) in tetrahydrofuran was added and the reaction solution was stirred 10 min. After warming to room temperature the reaction solution was quenched with saturated NH4Cl(aq) and extracted twice with ethyl acetate. The combined organic layer was washed once with saturated NaCl(aq), dried with Na2SO4(S), filtered, and concentrated in vacuo.
(26-1) 3-Pyridylethanol Ethyl 3-pyridylacetate (2.0 ml) was dissolved in tetrahydrofuran (66 ml). Under ice cooling, lithium aluminum hydride (0.5 g) was added thereto followed by stirring for 30 min. After adding water (0.5 ml), a 5 N aqueous solution of sodium hydroxide (0.5 ml) and further water (1.5 ml), the resulting precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (1.636 g) as a pale yellow oil (1.636 g) (yield: quantitative). 1H-NMR (400 MHz, CDCl3): delta(ppm) 2.84(2H, t, J=6.4Hz), 3.85(2H, t, J=6.4Hz), 7.20(1H, m), 7.57 (1H, m), 8.36 (2H, m).
EXAMPLE 11 4-[(R,S)-2-(3-Pyridyl)propyl]-1-{(R,S)-2-fluoro-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperazine Ethyl 3-pyridylacetate (12.2 g, 73.9 mmol) in THF (30 ml) was added to LDA (81 mmol) in THF (150 ml) over 10 min at -78 C. After 1 h Mel (5.1 ml, 81 mmol) was added to the yellow suspension and the mixture brought to room temperature. H2 O (300 ml) and ether (300 ml) was added, the mixture separated, and the organic layer washed with H2 O and brine, dried and evaporated to give ethyl 2-(3-pyridyl)propanoate (8.3 g) as a yellow oil.
Step A Ethyl 2-methyl-2-(pyridin-3-yl)propanoate A solution of ethyl-3-pyridylacetate (10.0 g, 60.5 mmol) in THF (50 mL) was added over approximately 0.5 h via pressure equalizing addition funnel to a stirred mixture of potassium hexamethyldisilazane (48.3 g, 0.242 mmol) in THF (250 mL) at -20 C. After 0.5 h, MeI was added dropwise so as to maintain the internal temperature between -15 C. to -20 C. After warming to approximately 0 C. over 12 h, the reaction was quenched with saturated aqueous NH4 Cl and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic phase separated and the aqueous phase re-extracted with ethyl acetate (*3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexanes as eluent) to give the title compound as a pale yellow oil (10.1 g, 86%).
86%
With methyl iodide; In tetrahydrofuran;
Step A Ethyl 2-methyl-2-(pyridin-3-yl)propanoate A solution of ethyl-3-pyridylacetate (10.0 g, 60.5 mmol) in THF (50 mL) was added over approximately 0.5 h via pressure equalizing addition funnel to a stirred mixture of potassium hexamethyldisilazane (48.3 g, 0.242 mmol) in THF (250 mL) at-20 C. After 0.5 h, MeI was added dropwise so as to maintain the internal temperature between -15 C. to -20 C. After warming to approximately 0 C. over 12h, the reaction was quenched with saturated aqueous NH4 Cl and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic phase separated and the aqueous phase re-extracted with ethyl acetate (*3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexanes as eluent) to give the title compound as a pale yellow oil (10.1 g, 86%).
In tetrahydrofuran;
Step A Ethyl 2-methyl-2-(pyridin-3-yl)propanoate A solution of ethyl-3-pyridylacetate (10.0 g, 60.5 mmol) in THF (50 mL) was added over approximately 0.5 h via pressure equalizing addition funnel to a stirred mixture of potassium hexamethyldisilazane (48.3 g, 0.242 mmol) in THF (250 mL) at -20 C. After 0.5 h, MeI was added dropwise so as to maintain the internal temperature between -15 C. to -20 C. After warming to approximately 0 C. over 12 h, the reaction was quenched with saturated aqueous NH4 Cl and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic phase separated and the aqueous phase re-extracted with ethyl acetate (*3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexanes as eluent) to give the title compound as an oil (10.1 g).
With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium; diisopropylamine; In tetrahydrofuran;
B. Synthesis of Ethyl alpha-(3-Butynyl)-3-pyridylacetate To a stirred solution of anhydrous diisopropylamine (8.91 mL, 6.43 g, 63.5 mmol) in anhydrous THF (100 mL) was added 2.5M n-butyllithium in hexanes (25.4 mL, 63.5 mmol) at -20 C. under a dry argon atmosphere in an oven-dried apparatus. The resulting solution was stirred for 30 min at -20 C. A solution of ethyl 3-pyridylacetate (9.21 mL, 10.0 g, 60.5 mmol) in anhydrous THF (70 mL) was added to the LDA solution at -20 C. Hexamethylphosphoramide (20 mL) was added to dissolve the dark yellow precipitate The solution was stirred for 30 min at -20 C. and then 30 min at -78 C. A solution of the 3-butynyl triflate of Part A (12.9 g, 63.5 mmol) in anhydrous THF (30 mL) was added dropwise at -78 C. The resultant dark red solution was allowed to warm to room temperature and was stirred for 18 h. The reaction mixture was quenched by pouring it onto saturated NH4 Cl (500 mL). The mixture was extracted with ether (3*500 mL). The combined extracts were washed with H2 O, saturated NaCl and dried (MgSO4). The solvent was removed in vacuo to give a brown oil (24.8 g). Purification by silica gel (Aldrich catalog #22,719-6, 230-400 mesh) Chromatography using CHCl3 /MeOH (99/1, v/v) afforded 10.6 g (81% yield) of product as a yellow oil (Rf =0.62, 95:5 (v/v) CHCl3 /MeOH, Bakerflex IBF-2 silica TLC plates): 300 mHz 1 H NMR (CDCl3) delta1.22 (t, J=7.1 Hz, 3H), 2.15 (m, 4H), 3.82 (t, J=7.6 Hz, 1H), 4.15 (m, 2H), 7.27 (dd, J=8.2, 5.1 Hz, 1H), 7.67 (dt, J=8.0, 2.0 Hz, 1H), 8.54 (dd, J=4.8, 1.6 Hz, 1H), 8.57 (d, J=1.7 Hz, 1H); 75 mHz 13 C NMR (CDCl3) delta173.13, 150.18, 149.34, 135.58, 134.40, 124.00, 82.92, 70.19, 61.60, 47.98, 32.09, 16.73, 14.47; chemical ionization mass spectrum (CH4) m/z 218 (M+H)+.
1-cyclopentyl-3-ethyl-6-[3-pyridinylmethyl]pyrazolo[3,4-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium; acetic acid; In ethanol; water;
EXAMPLE 13 Sodium (0.11 g) was dissolved in ethanol and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.49 g, 2.21 mmol) was added, followed 10 minutes later by ethyl 3-pyridinylacetate (0.73 g) in ethanol (2 mL). The reaction mixture was refluxed overnight, additional 3-pyridinylacetate (0.35 g) was added and the reaction mixture was again refluxed overnight. The reaction mixture was cooled to room temperature, the solvent was stripped and the residue was dissolved in water and treated with acetic acid (to pH of 7). The mixture was extracted with CHCl3 (3*50 mL), the organic layers were combined, dried over MgSO4 and stripped to a pale yellow oil. The oil was crystallized by the addition of ether and the product was collected by filtration and washed with ether to afford 0.4 g of 1-cyclopentyl-3-ethyl-6-[3-pyridinylmethyl]pyrazolo[3,4-d]pyrimidin-4-one.
EXAMPLE VII 3-(Aminocarbonylmethyl)piperidine 16.8 g of ethyl-3-pyridylacetate and 1 l of methanolic ammonia solution are shaken in a pressure vessel at 100 C. for 40 hours. After cooling and concentration, the precipitate is triturated with ether and filtered off with suction. 12.7 g of the 3-(aminocarbonylmethyl)pyridine obtained in this way are hydrogenated with 250 ml of ethanol and 3 g of rhodium/platinum catalyst at 50 C. under a pressure of 3 bar of hydrogen for 2 hours. After cooling, filtration and concentration, the precipitate is triturated with ether and filtered off with suction. Yield 13.3 g (96% of theory),; Rf: 0.15 (silica gel; methylene chloride/methanol/concentrated ammonia=16:4:1)
PREPARATION 1 Preparation of (3'R) ethyl 2-(piperidin-3-yl)acetate STR6 Ethyl-3-pyridylacetate (100 g, 0.606 mol) was dissolved in ethanol (1.8 liters), treated with 5% rhodium on alumina (100 g) and hydrogenated at 60 C. and 60 psi hydrogen gas overnight. The catalyst was removed by filtration and the solvent evaporated to give a brown liquid (101.4 g, 98%). The brown liquid was dissolved in ethyl acetate (600 ml) and treated with L-(+)-mandelic acid in warm ethyl acetate (600 ml). After cooling in the refrigerator for four hours, the solid was collected and the crystallization fluid reserved for processing to the other enantiomer, infra. The solid was again recrystallized from ethyl acetate (1.55-1.6 liters, overnight at ambient temperature) to give the desired title product as white needles. Yield: 81.6 grams, 41%.
With magnesium; In tetrahydrofuran; dichloromethane; water; Petroleum ether;
PREPARATION 142 [alpha,alpha-Bis(4-fluorophenyl)]-3-pyridineethanol A Grignard solution was prepared from 19.4 g (0.8 mole) of magnesium chips and 148.8 g (0.85 mole) of 1-bromo-3-fluorobenzene in 1.25 liters of dry tetrahydrofuran (THF). To this solution was added in a stream a solution of 41.3 g (0.25 mole) of ethyl-3-pyridylacetate (Aldrich) in 250 ml of THF. The mixture was stirred at ambient temperature overnight and then poured into 2.5 liters of saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted once with 500 ml of methylene chloride and twice with 250 ml of methylene chloride. The combined organic layers were washed successively with 250 ml water, 250 ml of a 4% sodium hydroxide solution, 250 ml of water and 250 ml of brine. The organic layer was dried (over sodium sulfate) and concentrated to give a gum which crystallized when triturated with a mixture of 100 ml of petroleum ether (30-60 C.) and 100 ml of 2-propyl ether. The solid was collected by filtration, air dried and slurried with 500 ml of water. The solid was collected by filtration, washed with petroleum ether and dried to yield 32.5 g of tan solid. Mass spec shows m/e=312. The solid was slurried with 500 ml of water, collected by filtration and dried. The solid was next heated to reflux in ~300 ml of 2-propanol and filtered to remove insolubles. The filtrate was concentrated to give a solid residue. The solid was recrystallized from cyclohexane-benzene to yield 24.3 g(31%) of off-white solid, mp 137-141 C. Analysis: Calculated for C19 H15 F2 NO: C,73.30;H,4.86;N,4.50. Found: C73.42;H,4.77;N,4.51.
Example 4 The 2',4'-dichloro-2-(3-pyridyl)-acetophenone required as the starting material in Example 1 can be prepared as follows: A mixture of 27.6 g of <strong>[56882-52-1]ethyl 2,4-dichlorobenzoate</strong> and 20.81 g of ethyl 3-pyridylacetate at 20-25 is treated portionwise with 10.59 g of sodium methoxide. The mixture is subsequently heated at 65-70 and resulting readily volatile products are blown off with dry nitrogen. After 20 hours, the mixture is treated with 40 ml of concentrated hydrochloric acid and heated at reflux temperature for 18 hours. The mixture is washed with diethyl ether and the aqueous phase is made basic by adding concentrated ammonia and extracted with methylene chloride. The organic phase is concentrated and the crude product is chromatographed on silica gel with methylene chloride/methanol (98:2) to yield 2',4'-dichloro-2-(3-pyridyl)-acetophenone, which can be crystallized from diethyl ether/n-pentane and melts at 55-56.
With dimethyl sulfoxide; In water; benzyl bromide;
EXAMPLE 2 Preparation of cis+trans ethyl 3-allylthio-3-benzyl thio-2-(3-pyridyl)acrylate (Compound No. 8) In a 250-ml three-necked flask equipped with magnetic stirrer, thermometer, and reflux condenser with drying tube were placed 2.15 grams (13.0 mmoles) ethyl 3-pyridylacetate, 28 ml HPLC-grade dimethyl sulfoxide, 1.68 grams (30.0 mmoles) powdered reagent potassium hydroxide and 0.99 grams (13.0 mmoles) reagent carbon disulfide. The mixture was stirred overnight at room temperature. A red color developed and most of the potassium hydroxide dissolved. In single portions were added 2.22 grams (13.0 mmoles) of benzyl bromide and eighty minutes later 1.57 grams (13.0 mmoles) of allyl bromide. In the first alkylation there was an exotherm from 22.3 C. to 33.0 C.; in the second alkylation an exotherm from 22.8 C. to 26.4 C. The reaction mixture was stirred seventy hours at room temperature and then worked up by quenching in water (1800 ml) and extracting with chloroform (4*30 ml). The combined extracts were washed with water (2*1500 ml) and evaporated down to give 2.9 grams of crude product. Chromatography on Brockmann grade 1 alumina eluted with chloroform gave 1.5 grams of pure product (31% yield). Thin-layer chromatography on silica eluted with 5% methanol in methylene chloride gave a single spot, but the NMR spectrum, consistent with the structure above, shows two triplets for the methyl group. Hence there are cis and trans isomers with some methyl near a benzyl and other methyl near an allyl. The complete NMR spectrum was as follows: NMR (CDCl3)?: t,t(3)1.0-1.4; m(4)3.3-4.0; m(2)4.0-4.2; m(2)4.8-5.4; m(1)5.5-6.0; m(6)7.0-7.4; m(1)7.4-7.9; m(2)8.3-8.8.
37.4 g (226 mmol) of ethyl pyridin-3-ylacetate in 100 g (679 mmol) of dimethylformamide diethyl acetal are heated at 100 C. overnight. After cooling, the mixture is concentrated and the residue is prepurified by flash chromatography on silica gel (mobile phase: gradient cyclohexane/ethyl acetate 1:1?ethyl acetate/ethanol 9:1). The resulting product is subjected to fine purification by vacuum distillation (1 mbar, 200 C. bath temperature).Yield: 35.0 g (70% of theory)1H-NMR (400 MHz, DMSO-d6): delta=8.37 (dd, 1H), 8.31 (dd, 1H), 7.59 (s, 1H), 7.51 (dt, 1H), 7.29 (ddd, 1H), 4.00 (q, 2H), 2.67 (s, 6H), 1.11 (t, 3H).LC-MS (Method 1): Rt=2.38 min; MS (ESIpos): m/z=221 [M+H]+.
70%
at 100℃;
37.4 g (226 mmol) of ethyl pyridin-3-ylacetate in 100 g (679 mmol) of dimethylformamide diethyl acetal are heated at 100 C. overnight. After cooling, the mixture is concentrated and the residue is initially pre-purified by flash chromatography on silica gel (mobile phase: gradient cyclo-hexane/ethyl acetate 1:1 ethyl acetate/ethanol 9:1). The product obtained in this manner is then subjected to fine purification by distillation under reduced pressure (1 mbar, bath temperature 200 C.).Yield: 35.0 g (70% of theory)1H-NMR (400 MHz, DMSO-d6): delta=8.37 (dd, 1H), 8.31 (dd, 1H), 7.59 (s, 1H), 7.51 (dt, 1H), 7.29 (ddd, 1H), 4.00 (q, 2H), 2.67 (s, 6H), 1.11 (t, 3H).LC-MS (Method 1): Rt=2.38 min; MS (ESIpos): m/z=221 [M+H]+.
STEP 1 : 3-{carbethoxy-2-[3,4-bis (difluoromethoxv)phenyl]-2-(2-bromo-5-pyridvl) ethyl}pyridine: To a 0C THF solution of ethyl 3-pyridylacetate (1. 9eq) was added 1. 9eq of HMPA followed by 1. 9eq of a 0.5M solution of KHMDS in toluene. This solution was stirred at 0C for 30min, the ice bath was removed and leq a 0.5M solution of [3,4-bis (difluoromethoxy) phenyl]- (2-bromo-5-pyridyl) chloromethane in THF was added. The mixture was stirred at rt for 2h, quenched with a saturated aqueous solution of NH4CI and diluted with ethyl acetate. The organic layer was washed with brine, dried over MGS04 and concentrated. The residue was used directly in the next step without any purification.
[3,4-bis (difluoromethoxy)phenyl]-{4-[2-((2-trimetthylsilylethoxy)methoxy)-1, 1,1,3,3,3-hexafluoropropane-2-yl] phenyl} bromomethane[ No CAS ]
3-{carbethoxy-2-[3,4-bis(difluoromethoxy)phenyl]-2-[4-(2-((2-trimethylsilylethoxy)methoxy)-1,1,1,3,3,3-hexafluoropropane-2-yl)phenyl]ethyl}pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
STEP 2: 3-{carbethoxy-2-[3.4-bis(difluoromethoxy)phenyl]-2-[4-(2-trimethylsilylethoxy)methoxy)-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]ethyl}pyridine; To a 0C THF solution of ethyl 3-pyridylacetate (3eq) was added 3eq of HMPA followed by 3eq of a 0.5M solution of KHMDS in toluene. This solution was stirred at 0C for 30min, the ice bath was removed and leq of a 0.3M solution of [3,4-bis (difluoromethoxy) phenyl]-{4-[2-((2-trimethylsilylethoxy) methoxy) - 1, 1, 1, 3,3, 3-hexafluoropropane-2-yl] phenyl} bromomethane (EXAMPLE 1, STEP 1) in THF was added. The mixture was stirred at rt for 2h and diluted with a 25% aqueous solution of NH40Ac and ethyl acetate. The organic layer was washed with brine, dried over MgS04 and concentrated. Flash chromatography of the residue (silica gel; 40% EtOAc/hexane) provided the ester pyridine
3-{carbethoxy-2-[3,4-bis(difluoromethoxy)phenyl]-2-[4-(2-((2-trimethylsilylethoxy)methoxy)-propan-2-yl)phenyl]ethyl}pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
STEP4 : 3-{carbethoxy-2-[3,4-bis(difluoromethoxy)phenyl]-2-[4-(2-((2-trimethylsilylethoxy)methoxy)-propan-2-yl)phenyl] ethyl}pyridine To a 0C THF solution of ethyl 3-pyridylacetate (3eq) was added 3eq of HMPA followed by 3eq of a 0.5M solution of KHMDS in toluene. This solution was stirred at 0C for 30min, the ice bath was removed and leq a 0.3M solution of [3,4-bis (difluoromethoxy)phenyl]-{4-[2-((2-trimethylsilylethoxy)methoxy)propane-2- yl]phenyl} chloromethane (EXAMPLE 3, STEP 3) in THF was added. The mixture was stirred at rt for 24h, quenched with a saturated aqueous solution of NH4C1 and diluted with a 25% aqueous solution of NH4OAc and ethyl acetate. The organic layer was washed with brine, dried over MgS04 and concentrated. The residue was used directly in the next step without any purification.
Example 1.5: Preparation of 4-Hvdroxy-3-pyridin-3-yl- H-l, 81naphthyridin-2-one (Compound No. Dl 1 of Table D); To a solution of 2-amino-nicotinic acid methyl ester (200 mg) (Example 1.1) in N.N-dimethylformamide ("DMF") (2ml) was added sodium ethoxide (21 mul) (21% by weight in ethanol) followed by ethyl-3-pyridyl-acetate (200 mul). The reaction mixture was heated in the microwave at 1500C for 15 minutes. The mixture was quenched by addition of aqueous hydrochloric acid (2M) (0.72ml) and then diluted with water. The precipitate was isolated by filtration and washed with water and finally triturated with diethyl ether to give 4-hydroxy-3-pyridin-3-yl-lH-[l,8]naphthyridin-2-one as a beige solid (109 mg). 1eta-nuMR (400 MHz, d6-DMSO): 11.75 (bs, IH), 8.70 (m, IH), 8.52-8.53 (dd, IH), 8.48-8.49 (dd, IH), 8.35-8.37 (dd, IH), 7.98 (d, IH), 7.45-7.49 (dd, IH), 7.23- 7.26 (dd, IH) ppm.
(ii): A solution of pyridin-3-ylacetic acid ethyl ester (5 g, 30 mmol) in dry N,N-dimethylformamide (20 ml) was added dropwise to a suspension of potassium tertiary butylate (7.54 g, 66.6 mmol) in dry N,N-dimethylformamide (30 ml) at 0 C. under argon. The reaction mixture was stirred at room temperature for 45 min and then cooled again to 0 C., and tert-butyl bis(2-chloroethyl)carbamate (7.23 g, 30 mmol), dissolved in N,N-dimethylformamide (20 ml), was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate (300 ml). The organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Alox neutral) with 5% ethyl acetate in hexane. Yield: 24%.
24%
(ii): A solution of pyridin-3-ylacetic acid ethyl ester (5 g, 30 mmol) in dry N,N-dimethylformamide (20 ml) was added dropwise at 0 C., under argon, to a suspension of potassium tert-butylate (7.54 g, 66.6 mmol) in dry N,N-dimethyl-formamide (30 ml). The reaction mixture was stirred for 45 min at room temperature and then cooled to 0 C. again; tert-butyl bis(2-chloroethyl)carbamate (7.23 g, 30 mmol), dissolved in N,N-dimethylformamide (20 ml), was added dropwise. The ice bath was removed and stirring was carried out for 16 h at room temperature. The reaction mixture was extracted with ethyl acetate (300 ml). The organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (neutral alumina) with 5% ethyl acetate in hexane.Yield: 24%
To a suspension of sodium hydride (1.446 g, 36.15 mmol, 60 %) in DMF (30 mL) was added at 0 C ethyl 3-pyridylacatate and stirred at this temperature for 1 hrs, and another 30 minutes at room temperature. The solution was re-cooled to 0 C and neat 2,2-dimethoxyl-bromoethane (5.05 ML, 47 mmol) was added via syringe. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. It was diluted with diethyl ether (200 mL) and washed with water (2 x 50 mL). The organic phase was dried (anhydrous magnesium sulfate), and the solvent was removed on Rotavap. The remaining oil was purified by vacuum distillation (b. p.: 138-140 C/0. 1 mmHg) to yield 6. 58 g (79%) of the desired PRODUCT. 1H NMR (CDC13) : 8.55 (bd, J = 3.2 Hz, 1H), 7.68, (bd, J = 8.0 Hz, 1H), 7.27 (m, 1H), 4.25 (bt, 5.5 Hz, 1H), 4,12 (m, 2H), 3.74 (t, J = 7.3 Hz, 1H), 3.32 (s, 3H), 3.28 (s, 3H), 2.4 (m, 1H), 1.99 (ddd, J = 14. 0,6. 9, 5.3 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H).
Example 10a 3-(2,4-Dichloro-pyrimidin-5-yl)-2-pyridin-3-yl-propionic acid ethyl ester To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 ML) was added n-butyllithium (2.5 M in hexanes, 4.0 ML, 10.0 mmol) (Aldrich) at -78° C. under argon.After 10 minutes, a solution of 2-pyridin-3-yl-acetic acid ethyl ester (1.65 g, 10.0 mmol) (Acros) in tetrahydrofuran (5 ML) was added by injection via a syringe and the reaction mixture was stirred at -78° C. for another 10 minutes.To the reaction mixture was added a solution of <strong>[7627-44-3]2,4-dichloro-5-iodomethyl-pyrimidine</strong> (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 ML) at -78° C. and the reaction mixture was stirred at the same temperature for 2 hours then slowly allowed to warm up to -20° C. and stirred for 10 minutes.The reaction mixture was diluted with ethyl acetate (100 ML) and successively washed with saturated aqueous ammonium chloride solution (100 ML), water (50 ML) and brine (50 ML), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-pyridin-3-yl-propionic acid ethyl ester as a brown oil. (Yield 1.10 g, 68.0percent).
With carbon tetrabromide; 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at -78 - 0℃; for 2.5h;
Example 13; A. Phenylamino-<strong>[39931-77-6]pyridin-3-yl-acetic acid ethyl ester</strong>. To a solution of ethyl 3-pyridylacetate (1.83 g, 11.1 mmol), in THF (100 mL) at -78 C. was added DBU (1.66 mL, 11.1 mmol), and carbon tetrabromide (3.69 g, 11.1 mmol). The reaction mixture was stirred at -78 C. for 1.5 h and at 0 C. for 1 h, partitioned between EtOAc and saturated aqueous NH4Cl, the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. To this crude reaction mixture in THF (20 mL) was added aniline (1.51 mL, 16.7 mmol), and Et3N (3.1 mL, 22.2 mL) and the reaction mixture was stirred at 60 C. overnight. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by MPLC (SiO2, 0-50% gradient eluting with EtOAc/hexanes) gave Compound 13a (1.24 g, 29%). MS 257.1 (M+1)+.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Reflux; Irradiation;
To a solution of ethyl pyridin-3-ylacetate (0.5 g, 3.0 mmol) in CCl4 (20 mL) was added N- bromosuccinimide (0.67 g, 3.8 mmol) and benzoyl peroxide (22 mg, 0.1 mmol). The mixture was stirred next to a 150 W spot lamp which brought the reaction to mild reflux. After 45 min, the reaction was cooled and filtered through a pad of celite. The solution was evaporated and the residue was dissolved in 10 mL Of CH3CN for subsequent displacements
To a cooled solution (-78 0C) of ethyl 2-(pyridin-3-yl)acetate (1.842 mL, 12.11 mmol) in THF (12.2 mL) was added LiHMDS (12.11 mL, 12.11 mmol) and the mixture was stirred 15 min. A solution of benzoyl chloride (1.474 mL, 12.71 mmol) in THF (24.4 mL) was added slowly and the mixture was warmed to room temperature and stirred for 12 h. The reaction was quenched withAcOH (1.386 mL, 24.21 mmol), diluted with H2O (50 mL), and extracted with EtOAc (3 x 75 mL). The combined extracts were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a clear oil (1.82 g). LCMS mlz = 270.2 [M+H]+.
With dmap; bis(eta3-allyl-mu-chloropalladium(II)); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,3,5-trimethyl-benzene; at 140℃; for 20h;Inert atmosphere;
General procedure: after standard cycles of evacuation and back-filling with dry and pure nitrogen, an oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Pd source (see Table 1, Table 2, Table 3 and Table 4), ligand (see Table 1, Table 2, Table 3 and Table 4), N,N-dimethylpyridin-4-amine (DMAP, see Table 1, Table 2, Table 3 and Table 4), and ethyl potassium malonate (see Table 1, Table 2, Table 3 and Table 4). The tube was evacuated and backfilled with argon (this procedure was repeated three times). Under a counter flow of argon, aryl halide (see Table 1, Table 2, Table 3 and Table 4) and solvent (see Table 1, Table 2, Table 3 and Table 4) were added by syringe. The tube was sealed and stirred at room temperature for 10 min. Then the tube was connected to the Schlenk line, which was full of argon, stirred in a preheated oil bath (140-150 C) for the appointed time (20-25 h). Upon completion of the reaction, the mixture was cooled to room temperature and diluted with diethyl ether, and the yields were determined by gas chromatography using 1,3-dimethoxybenzene as the internal standard.
General procedure: To a stirred solution of phenyl acetic acid ethyl ester 1a (1 g, 6.09 mmol) in THF (10 mL) was added LiHMDS (9.1 ml, 1 M sol. in THF, 7.31 mmol) at -78 C and the reaction mixture was stirred at this temperature for 30 min. Ethyl-1-imidazole carboxylate 2 (1.2 g, 9.146 mmol) in dry THF (3 ml) was added drop wise to the reaction mixture at -78 C and stirred at rt for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with water, saturated brine solution, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was chromatographed on a silica gel column. Elution with 4% ethyl acetate/pet ether gave the pure compound 3a (1.1 g, 81% yield) as a colorless liquid.
To a solution of 3-pyridylacetic acid hydrochloride (51) (12.00 g, 69.19 mmol) in EtOH (120 mL) was added concentrated H2SO4 (5 mL) and the solution was heated at reflux (6 h). The reaction mixture was concentrated in vacuo and diluted with EtOAc (200 mL). The EtOAc layer was washed with saturated aqueous NaHCO3 (3 x 200 mL) and brine (2 x 200 mL), and dried (Na2SO4). The crude product was purified by flash column chromatography (SiO2; 4:5 EtOAc/hexanes) to give the desired product (10.67 g, 93%) as a pale yellow oil. Rf 0.37 (4:1 EtOAc/hexanes). 1H NMR (CDCl3) delta 1.26 (t, J = 7.2 Hz, CH2CH3), 3.63 (s, CH2C5H4N), 4.17 (q, J = 7.2 Hz, CH2CH3), 7.25-7.30 (m, C5H), 7.64-7.67 (m, C4H), 8.45-8.59 (m, C2H, C6H). 13C NMR (CDCl3) delta 13.7 (CH2CH3), 38.0 (CH2C5H4N), 60.7 (CH2CH3), 122.9 (C5H), 129.5 (C3H), 136.4 (C4H), 148.0 (C2H or C6H), 149.9 (C6H or C2).
D56Pyridin-3-yI-acetic acid ethyl esterTo a solution of 3-pyridylacetic acid hydrochloride (40g, 230.41mmol) in ethanol (90 mL) was added sulfuric acid(73 g, 744.3 mmole, 98%) under N2. The reaction mixture was refluxed for 4 h, then cooled to rt. Ammonium hydroxide (250 mL, 25%) was added and extracted with DCM (500 mL) twice, dried over sodium sulfate, concentrated to afford the title product (33 g).
With sodium ethanolate; acetic acid; In N,N-dimethyl-formamide; for 19h;
Preparation Example 179 To a solution of 2 g of ethylpyridin-3-yl acetate in 40 ml of DMF were added 1.09 g of paraformaldehyde and 165 mg of sodium ethoxide, followed by stirring for 19 hours. Acetic acid was added thereto under ice-cooling and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.29 g of ethyl 3-hydroxy-2-(hydroxymethyl)-2-(pyridin-3-yl)propanoate.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 48h;Inert atmosphere;
A mixture of 6-chloro-4-(ethyl amino) nicotinaldehyde (Scheme 1 compound 6) (1.0 g, 5.45 mmol), ethyl 2-(pyridin-3-yl) acetate (600 mg, 3.63 mmol) and K2C03 (1.5 g, 10.9 mmol) in dry DMF (6 mL) was heated to 100 C under nitrogen atmosphere for 48 h. After TLC showed the starting material was completely consumed, the reaction mixture was cooled to RT, diluted with EtOAc (3 x 30 mL), washed with water (2 x 10 mL) and brine (10 mL) then dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 80/20) to give 7-chloro-l-ethyl-3-(pyridin-3-yl)-l,6-naphthyridin-2(lH)-one (600 mg, 63%) as a light yellow solid. 1H NMR (400 MHz, CDC13): delta 8.86 (d, J= 2.4 Hz, 1H), 8.71- 8.54 (m, 2H), 8.12 (dt, J= 7.8, 2.1 Hz, 1H), 7.88 (s, 1H), 7.40 (dd, J= 7.9, 4.8 Hz, 1H), 7.27 (s, 1H), 4.34 (m, 2H), 1.42 (t, J= 7.1 Hz, 3H). MS [ESI, MH+] = 286.0.
1-methyl-4-(pyridin-3-yl)-1H-pyrazol-3-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
5.1.1 1-Methyl-4-(pyridin-3-yl)-1H-pyrazol-3-ol (3a) A mixture of ethyl pyridin-3-ylacetate (2a, 2.00 g, 12.1 mmol) and N,N-dimethylformamide dimethyl acetal (3.61 g, 30.3 mmol) in DMF (10 mL) was stirred at 110 C for 2 h. After cooling at room temperature, the mixture was concentrated in vacuo to give a reddish brown oil. To this reddish brown oil in EtOH (20 mL) were added acetic acid (5.0 mL) and methylhydrazine (1.12 g, 24.2 mmol), and the mixture was stirred at room temperature for 16 h before the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% MeOH in CHCl3) to give 3a (620 mg, 29%) as a beige solid. 1H NMR (DMSO-d6) delta 3.67 (s, 3H), 7.29-7.34 (m, 1H), 7.94-7.99 (m, 2H), 8.30 (dd, 1H, J = 4.7, 1.6 Hz), 8.83 (d, 1H, J = 1.6 Hz), 10.43 (br s, 1H); MS (ESI) m/z 176 [M+H]+.
(R)-t-butyl 4-((5’-chloro-2’-fluoro-[1,1‘-biphenyl]-4-yl)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide[ No CAS ]
C29H32ClFN2O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9.7 mg
[0737] A 1M solution of lithium bis(trimethylsilyl)amideinhexanes (87 f.LL, 87 f.tmol) in THF (110 f.LL) was cooled to ooC. and ethyl 2-(pyridin-3-yl)acetate (13 f.LL, 87 f.tmol) wasadded. After stirring at this temperature for 30 minutes, asolution of (R)-t-butyl 4-((5'-chloro-2'-fluoro-[1 ,1 '-biphenyl]-4-yl)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (46 mg, 104 flillOI) in THF (0.5 mL) was added. Theresulting mixture was stirred at this temperature for 1 hourand then slowly warmed up to room temperature overnight.IN HCI (0.5 mL) was added and the solution was stirred atroom temperature for lOminutes. DCM (1.5 mL)was added,the layers were separated and the aqueous layer was extractedwith DCM (2x1.5 mL). The combined organic layers weredried over Na2S04 , filtered and concentrated. The crudeproduct was purified by colunm chromatography (0-30%EtOAc in hexanes over 20 minutes) to yield Compound 1 (9. 7mg) as a clear oil.
9.7 mg
A 1M solution of lithium bis(trimethylsilyl)amide in hexanes (87 mu^, 87 muiotaetaomicron) in THF (1 10 mu) was cooled to 0C and ethyl 2-(pyridin-3-yl)acetate (13 mu, 87 muiotaetaomicron) was added. After stirring at this temperature for 30 minutes, a solution of(R -?-butyl 4-((5'- chloro-2'-fluoro-[l,r-biphenyl]-4-yl)methyl)-l,2,3-oxathiazolidine-3-carboxylate 2,2- dioxide (46 mg, 104 muiotaetaomicron) in THF (0.5 mL) was added. The resulting mixture was stirred at this temperature for 1 hour and then slowly warmed up to room temperature overnight. IN HC1 (0.5 niL) was added and the solution was stirred at room temperature for 10 minutes. DCM (1.5 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (2x1.5 mL). The combined organic layers were dried over a2S04, filtered and concentrated. The crude product was purified by column chromatography (0- 30% EtOAc in hexanes ov 9.7 mg) as a clear oil.
With potassium tert-butylate; In ethanol; water; at 60℃;
Intermediate 12: Potassium 2-(3-pyridyl)acetate [00297] Ethyl-3-pyridylacetate (0.82mL, 5.41 mmol) was dissolved in EtCH (l5mL) and distilled water (ll5jJL, 6.42mmol) and heated to 60 C. A solution of potassium tert-butoxide (637mg, 5.68mmol) in EtCH (5mL) was then added dropwise and the reaction was stirred at 60 C overnight.The ethanol was removed in vacuo and the resulting residue triturated with ether and dried in the vacuum oven to yield potassium 2-(3-pyridyl)acetate (41 0mg, 2.34mmol, 43% yield) as a colourless solid, which was carried through directly to the next stage without further purification. [00298] 1H NMR (DMSC-d6, 400MHz) O/ppm: 8.35 (1H, d, J= 1.6Hz), 8.28 (1H, m), 7.58 (1H, t, J = 6.0Hz), 7.21 (1H, dd, J 8.0Hz, 4.8Hz), 3.41 (1H, 5), 3.16 (2H, 5).
1-pyridin-3-yl-cyclopropanecarboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a cooled (-78C) solution of LDA (2.0 M, 272 mL) in 500 mL anhydrous THFand 200 mL HIVIPA (dried with molecular sieves) was added gradually a solution of ethyl 3-pyridylacetate 2-1 (75.0 g, 454 mmol) in 50 mL THF. The mixture was stirred for 50 mm at -78C and treated with neat 1,2-dibromoethane (117 mL, 1363 mmol) in one portion. Thereaction mixture was stirred overnight while being allowed to warm to room temperature. The reaction mixture was quenched with saturated NH4C1 and extracted three times with EtOAc. The combined organic layers were washed three times with H20 and then brine. After solvent removal, the residue was purified using silica gel chromatography (100% hexanes to EtOAc/hexane=7/3) to obtain the desired product as an oil.1HNMR(400MHz, CDC13): oe 8.60 (m, 1H), 8.50 (m, 1H), 7.64 (m, 1H), 7.28 (m, 1H), 4.05 (q,2H), 1.66 (q, 2H), 1.22 (q, 2H), 1.16 (t, 3H).
To a stirred solution of ethyl 2- (pyridin-3-yl) acetate (13.7 g, 85 mmol) in 150 mL of THF was added LDA (47 mL, 2.0 M) at -78 under N 2. The resulted mixture was stirred for 30 min. MeI (32.0 g, 225 mmol) was added in drops. The reaction mixture was allowed warm to rt and stirred for 20 hrs. The mixture was quenched with 150 mL of H 2O, extracted with EtOAc (150 mL x 3) . The organic extracts were combined, washed with brine (150 mL x 2) , dried over Na 2SO 4 and concentrated. The residue was purified by column chromatography eluted with PE/EtOAc (5: 1 3: 1) to give the title product (8.1 g, 53%) as a light-yellow oil. MS: M/e 180 (M+1) +.
ethyl 2-(pyridin-3-yl)-2-(quinolin-6-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With palladium diacetate; caesium carbonate; XPhos; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; Schlenk technique;
General procedure: An oven-dried Schlenk tube was charged with Pd(OAc)2 (0.015 mmol, 3.4 mg), X-Phos (0.015 mmol, 7.2 mg), Cs2CO3 (0.9 mmol, 293 mg), substrate 1 (0.3 mmol) and 2 (0.4 mmol). The reaction vessel was evacuated and backfilled again with nitrogen gas, and 1,4-dioxane (1 mL) was added via syringe under nitrogen. The reaction mixture was stirred at 100 C for 12 hours. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The crude was nextfiltered through a plug of celite, which was washed with ethyl acetate. The solution was concentrated and further purifiedby flash column chromatography to afford the corresponding product.
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