* 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.
c) 6-Bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one To a solution of methyl (+-)-6-bromo-2-oxo-1,2,3,4-tetrahydro-1H-1,8-naphthyridine-3-carboxylate (2.00 g, 7.0 mmole) in CH3OH (75 mL) was added 1.0 M NaOH (30 mL). The reaction was heated to reflux for 4 hrs and then cooled to RT. The reaction was neutralized with 1.0 M HCl (30 mL) then was heated at reflux overnight. The reaction slurry was concentrated to dryness and the residues was suspended in 95:5 CHCl3/CH3OH. The solids were removed by filtration and the filtrate was concentrated to afford the title compound (1.40 g, 88percent) as an off-white solid: MS (ES) m/e 228 (M + H)+.
58%
Stage #1: With sodium hydroxide In methanol at 20℃; for 4 h; Reflux Stage #2: With hydrogenchloride In methanol; water at 20℃; Reflux
Step 5: 6-Bromo-3,4-dihydro-lW-l,8-naphthyridin-2-oneA solution of sodium hydroxide (IN, 248 ml_) was added to a suspension of 6- bromo-2-oxo-l,2,3,4-tetrahydro-lH-l,8-naphthyridine-3-methylcarboxylate (16.6 g, 58.24 mmol; which may be prepared as described in Dl, Step 4) in methanol (620 ml_) at room temperature. The reaction mixture was then refluxed for 4 hours and cooled down to room temperature. A solution of hydrochloric acid (IN, 248 ml_) was then added and the mixture was refluxed overnight. The methanol was removed and the residue filtered. The resulting precipitate was washed with water and dried under high vacuum to afford the title product as a white solid (7.7 g, 58percent).LCMS (ESI-APCI) m/z 227.0-229.0 (M + H)+
46%
Stage #1: With water; sodium hydroxide In methanol for 4 h; Reflux Stage #2: With hydrogenchloride In methanolReflux
To a solution of methyl 6-bromo-2-oxo-l,2,3,4-tetrahydro-l,8-naphthyridine-3- carboxylate (6.8 g, 23.9 mmol) in MeOH (250 mL) was added NaOH aqueous solution (105 mL, 1 M). The reaction was heated to reflux and stirred further for 4 hours, then cooled to rt, and neutralized with HCl aqueous solution (100 mL, 1 M). The resulted mixture was re fluxed overnight, and concentrated in vacuo. The residue was suspended in CHCI3/CH3OH (95/5, 25 mL), then filtered, and the filtrate was concentrated in vacuo to give the title compound as an off-white solid (2.5 g, 46percent). MS (ESI, pos. ion) m/z: 227.0 (M+l); 1H NMR (400 MHz, DMSO-de): δ 2.46-2.55 (m, 2H), 2.90 (t, J = 7.6 Hz, 2H), 7.85 (d, J = 1.5 Hz, 1H), 8.20 (d, J= 2.3 Hz, 1H), 10.62 (s, 1H).
46%
With sodium hydroxide In methanol; water for 4 h; Reflux
The compound 6 - bromo -2 - oxo - 1, 2, 3, 4 - tetrahydro - 1, 8 - naphthyridine -3 - carboxylic acid methyl ester (6.8 g, 23.9 mmol) dissolved in MeOH (250 ml) in, then added to the reaction solution in the NaOH aqueous solution (105 ml, 1 M), heating to reflux, the reaction stirred 4 hours, cooling to room temperature, then adding HCl aqueous solution (100 ml, 1 M) the reaction obtain recipe to neutral, once again heating to reflux, stirring overnight, then concentrated under reduced pressure, the residue suspended in CHCl3 /CH3 OH (95/5, 25 ml) in, then filtered, the filtrate is concentrated under reduced pressure, to obtain the title compound as a yellowish solid (2.5 g, 46percent).
c) 6-Bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one To a solution of methyl (+-)-6-bromo-2-oxo-1,2,3,4-tetrahydro-1H-1,8-naphthyridine-3-carboxylate (2.00 g, 7.0 mmole) in CH3OH (75 mL) was added 1.0 M NaOH (30 mL). The reaction was heated to reflux for 4 hrs and then cooled to RT. The reaction was neutralized with 1.0 M HCl (30 mL) then was heated at reflux overnight. The reaction slurry was concentrated to dryness and the residues was suspended in 95:5 CHCl3/CH3OH. The solids were removed by filtration and the filtrate was concentrated to afford the title compound (1.40 g, 88%) as an off-white solid: MS (ES) m/e 228 (M + H)+.
58%
Step 5: 6-Bromo-3,4-dihydro-lW-l,8-naphthyridin-2-oneA solution of sodium hydroxide (IN, 248 ml_) was added to a suspension of 6- bromo-2-oxo-l,2,3,4-tetrahydro-lH-l,8-naphthyridine-3-methylcarboxylate (16.6 g, 58.24 mmol; which may be prepared as described in Dl, Step 4) in methanol (620 ml_) at room temperature. The reaction mixture was then refluxed for 4 hours and cooled down to room temperature. A solution of hydrochloric acid (IN, 248 ml_) was then added and the mixture was refluxed overnight. The methanol was removed and the residue filtered. The resulting precipitate was washed with water and dried under high vacuum to afford the title product as a white solid (7.7 g, 58%).LCMS (ESI-APCI) m/z 227.0-229.0 (M + H)+
46%
To a solution of methyl 6-bromo-2-oxo-l,2,3,4-tetrahydro-l,8-naphthyridine-3- carboxylate (6.8 g, 23.9 mmol) in MeOH (250 mL) was added NaOH aqueous solution (105 mL, 1 M). The reaction was heated to reflux and stirred further for 4 hours, then cooled to rt, and neutralized with HCl aqueous solution (100 mL, 1 M). The resulted mixture was re fluxed overnight, and concentrated in vacuo. The residue was suspended in CHCI3/CH3OH (95/5, 25 mL), then filtered, and the filtrate was concentrated in vacuo to give the title compound as an off-white solid (2.5 g, 46%). MS (ESI, pos. ion) m/z: 227.0 (M+l); 1H NMR (400 MHz, DMSO-de): delta 2.46-2.55 (m, 2H), 2.90 (t, J = 7.6 Hz, 2H), 7.85 (d, J = 1.5 Hz, 1H), 8.20 (d, J= 2.3 Hz, 1H), 10.62 (s, 1H).
46%
With sodium hydroxide; In methanol; water; for 4h;Reflux;
The compound 6 - bromo -2 - oxo - 1, 2, 3, 4 - tetrahydro - 1, 8 - naphthyridine -3 - carboxylic acid methyl ester (6.8 g, 23.9 mmol) dissolved in MeOH (250 ml) in, then added to the reaction solution in the NaOH aqueous solution (105 ml, 1 M), heating to reflux, the reaction stirred 4 hours, cooling to room temperature, then adding HCl aqueous solution (100 ml, 1 M) the reaction obtain recipe to neutral, once again heating to reflux, stirring overnight, then concentrated under reduced pressure, the residue suspended in CHCl3 /CH3 OH (95/5, 25 ml) in, then filtered, the filtrate is concentrated under reduced pressure, to obtain the title compound as a yellowish solid (2.5 g, 46%).
(i) LAH, Dry THF, reflux, 16h; (ii) Br2, HOAc, 20-35C, 3h: (iii) 48% HBr.refhix, dimethyl malonate, CH3OH, 20-35C, 16h; (v) NaOH, CH3OH, reflux, 4h, then HC1, reflux, 16h; (vi) tert-butyl acrylate, Pd(OAc)2, P(o- tolyl)3, DIEA, DMF.Propionitrile, 90C, 16h; (vii) TFA, CH2C12 , 20-35T, 4h, then 4% dioxane. HC1, 20-35C, 2h. (Reference for Step-(i): WO 2005095391 and Step-(ii-vii): J. Med. Chem. 2003, 46, 1627-1635)
6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 18h;
6-r4-(Trifluoromethv?phenyll-3.4-dihvdro-1.8-naphthyridin-2(1 H)-oneTo a stirred solution of 6-bromo-3,4-dihydro-1 ,8-naphthyridin-2(1 H)-one (0.5 EPO <DP n="51"/>g, 2.2 mmol) (J. Med. Chem., 2003, 46(9), 1627-1635.) and [4- (trifluoromethyl)phenyl]boronic acid (0.42 g, 2.2 mmol) in a solution of dimethylformamide (25 ml_) and 2M aq. potassium carbonate was added tetrakis(triphenylphosphine)palladium (0) (0.100 g, 0.09 mmol). The reaction was purged with nitrogen then heated to 100 0C and stirred for 18 h. After cooling to room temperature, the reaction was concentrated to dryness under vacuum. Purification by flash chromatography on silica gel (3% methanol/dichloromethane), trituration with (1 :1) ether/petroleum ether, filtration and drying under vacuum gave the title compound (470 mg, 73%) as a white solid: 1H NMR (400 MHz, DMSO-Qf6) delta ppm 10.67 (s, 1 H), 8.52 (d, J = 2.3 Hz, 1 H)1 8.03 (d, J = 2.0 Hz, 1 H) 7.93 (d, J = 8.3 Hz, 2 H), 7.82 (d, J = 8.3 Hz, 2 H), 2.98 (t, 2 H), 2.56 (t, 2 H); MS (ES) m/e 293.2 (M + H)+.
(E)-N-(2-isobutoxy-3-methoxybenzyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With N-ethyl-N,N-diisopropylamine;palladium diacetate; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; propiononitrile; for 18h;Heating / reflux;
d) (£)-N-(2-Isobutoxy-3-methoxybenzyl)-N-methyl-3-(7-oxo-5,6,7,8-tetraliydro- [ 1 ,8]naphthyridin-3 -yl)acrylamide; A solution of N-(2-isobutoxy-3-methoxybeiizyl)-N-methyl-acrylamide (0.475 g, 1.71 mmol) in propionitrile (6 mL) and DMF (1.2 niL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.48 mL, 2.77 mmol) and 6- bromo-3,4-dihydro-lH-[l,8]naphthyridin-2-one (0.300 g, 1.32 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.029 g, 0.13 mmol) and P(°-tol)3 (0.080 g, 0.26 mmol) were then added and the mixture was deoxygenated with Ar for 20 min. The mixture was heated to reflux for 18 h. Upon cooling, a precipitate formed. The solids were collected by filtration and washed with water. Purification by column chromatography (silica gel, Ceta2Cl2/Me0eta 9:1) gave an orange solid. The solid was dissolved in CH2Cl2 and the solution was diluted with hexanes. The resulting precipitate was collected by filtration, washed with Et2O (50 mL) and dried to yield the title compound (0.18 g, 32%) as an off-white solid and as a mixture of amide rotamers: 1H nuMR (300 MHz, DMSO-G^) delta 10.66-10.64 (m, IH), 8.36-8.32 (m, IH), 8.09-8.00 (m, IH), 7.53-7.47 (m, IH), 7.27- 7.20 (m, IH), 7.04-7.96 (m, 2H), 6.66-6.60 (m, IH), 4.79-4.64 (m, 2H), 3.79 (s, 3H), 3.72-3.67 (m, 2H), 3.10-2.85 (m, 5H), 2.56-2.49 (m, 2H), 2.03-1.97 (m, IH), 1.00-0.97 (m, 6H); MS (ESI) m/e 424 (M + H)+.
(E)-N-((1,3-dimethyl-1H-indol-1-yl)methyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-napthyridin-3-yl)acrylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With N-ethyl-N,N-diisopropylamine;palladium diacetate; In propiononitrile;
b) (E)-N-(1,3-Dimethyl-1H-indol-2-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-3-yl)acrylamide To a stirred solution of N-(1,3-dimethyl-1H-indol-2-ylmethyl)-N-methylacrylamide (1.7 g, 7 mmole) in propionitrile (50 mL) was added <strong>[129686-16-4]6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one</strong> (1.16 g, 5.1 mmole), DIEA (1.8 mL, 10.3 mmole), palladium(II) acetate (112 mg, 0.5 mmole), and tri-o-tolylphosphine (304 mg, 1.0 mmole). The reaction was purged with argon and heated at reflux for 16 hr, then was cooled to RT and concentrated under vacuum. Purification by flash chromatography on silica gel (5% methanol/CHCl3). trituration with ethyl acetate, filtration, and drying under vacuum gave the title compound (1.17 g, 59%) as an off-white solid: LCMS (ES) m/e 389.2 (M + H)+.
b) (E)-N-Methyl-N-(1-methyl-1H-indol-2-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide According to the procedure of Preparation 2 (a), except substituting N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.90 g, 3.96 mmole) for benzyl acrylate, and substituting <strong>[129686-16-4]6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one</strong> (0.60 g, 2.64 mmole) for 2-amino-5-bromopyridine, the title compound (0.85 g, 86%) was prepared as an off-white solid: MS (ES) m/e 375 (M + H)+.
To a dry three-neck round bottom flask was added NaBH4 (190 mg, 50.00 mmol), followed by a solution of 6-bromo-3,4-dihydro-l,8-naphthyridin- 2(lH)-one (Ref: Seefeld, Mark A., et al. Journal of Medicinal Chemistry 2003, 46, 1627 - 1635) (227 mg, 10.00 mmol) in anhydrous THF (20 mL). Then a 47% solution of BF3 etherate (994 mg, 70 mmol) was added dropwise under nitrogen at 0 C, and the mixture was stirred at rt for 2 h, whereupon analysis by LC-MS indicated the presence of the desired product. The reaction was quenched by saturated aq NH4C1 (5 mL) carefully. The mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were dried over MgS04, concentrated under reduced pressure to give 6-bromo-l,2,3,4-tetrahydro-l,8-naphthyridine (180 mg. 85% yield). LC-MS (ESI) m/z 212, 214 (M + H)+.
9.3 g
With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 16h;
To a cooled (0 C.) solution of <strong>[129686-16-4]6-bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one</strong> (10.0 g, 44.0 mmol) in THF (500 mL) is added sodium borohydride (8.3 g, 220 mmol) followed by boron trifluoride diethyl ether complex (38.7 mL, 308 mmol), dropwise. The resulting mixture is allowed to warm and stir at room temperature for 16 h. The reaction is carefully quenched with the dropwise addition of 1N HCl (15 mL). Once quenched, additional 1N HCl (85 mL) is added and the mixture is stirred at room temperature for 16 h. The mixture is concentrated, diluted with water and made basic (pH 8) with the addition of powdered sodium bicarbonate. The mixture is extracted with EtOAc and the combined organic layers are washed with brine, dried (Na2SO4) and concentrated to obtain the title compound (9.3 g).
With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
To a mixture of NaBH4 (950 mg, 25.0 mmol) and a solution of 6-bromo-3,4- dihydro-l,8-naphthyridin-2(lH)-one (1.135 g, 5.0 mmol) in anhydrous THF (100 mL) was added a solution of BF3-Et20 (9.5 mL, 35.0 mmol, 47%) dropwise at 0 C under nitrogen atmosphere. The mixture was stirred at rt for 2 hours, quenched with saturated NH4C1 aqueous solution (25 mL), and the resulted mixture was extracted with DCM/MeOH (10/1, 50 mL x 3). The combined organic layers were dried over anhydrous Na2S04, and concentrated in vacuo to give the title compound as a white solid (2.8 g. >100%). The crude product was used directly in the next step without further purification. MS (ESI, pos. ion) m/z: 213.0 (M+l); 1H NMR (400 MHz, DMSO-de): delta 1.70-1.87 (m, 2H), 2.76 (t, J = 6.1 Hz , 2H), 3.38 (t, J = 5.6 Hz, 2H), 7.84 (d, J= 0.9 Hz, 1H), 8.03 (d, J= 2.0 Hz, 1H), 8.18 (br, 1H).
9.3 g
With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 16h;
To a cooled (0 C) solution 6-bromo-3,4-dihydro-lH-[l,8]naphthyridin-2-one (10 g, 44 mmol) in THF (500 mL) is added sodium borohydride (8.3 g, 220 mmol) followed by boron trifluoride diethyl ether complex (39 mL, 310 mmol) dropwise. The resulting mixture is allowed to warm to room temperature and it is stirred for 16 hr. The reaction is carefully quenched with the dropwise addtion of 1.0 N HC1 aquous solution (15 mL). Once quenched, additional 1.0 N HC1 aqueous solution (85 mL) is added and the mixture is stirred at room temperature for 16 hr. The mixture is then concentrated, diluted with water and made basic (pH 8) with the addition of powdered sodium bicarbonate. The mixture is extracted with EtOAc and the combined organic layers are washed with brine, dried over Na2S04 and concentrated to give 9.3 g of 6-bromo- 1,2,3,4- tetrahydro- [ 1,8] naphthyridine .
With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere;
The compound NaBH4 (950 Mg, 25.0 mmol), 6 - bromo - 3, 4 - dihydro - 1, 8 - naphthyridine -2 (1 H) - one (1.135 g, 5.0 mmol) and anhydrous THF (100 ml) mixture is cooled to 0 C, then under the protection of nitrogen, added dropwise to the reaction solution in the BF3 ·Et2 O (9.5 ml, 35.0 mmol, 47%), room temperature stirring for 2 hours, add saturated NH4 Cl aqueous solution (25 ml) quenching the reaction, DCM/MeOH mixture (10/1, 50 ml x 3) extraction, the combined organic phase with anhydrous Na2 SO4 Drying, concentrated under reduced pressure, to obtain the title compound as a white solid (2.8 g,>100%). The crude product without further purification, is directly used for the next step of the reaction.
With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 16h;
To a solution of <strong>[129686-16-4]6-bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (5.0 g, 21.80 mmol) and NaBH4 (4.18 g, 110.49 mmol) in THF (140 mL) was added BF3-Et20 (20 mL, 157.83 mmol) dropwise at 0 C. The reaction mixture was stirred for 16 h at room temperature. iN HC1 solution (100 mL) was added and the reaction mixture was stirred for an additional 16 h at room temperature. The pH value of the mixture was then adjusted to 8 with aq. sat. NaHCO3 solution. The resulting mixture was extracted with ethyl acetate (3 x 150 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 6-bromo-1,2,3,4-tetrahydro-1,8-naphthyridine as a white solid. MS: (ESI, m/z): 213, 215 [M+H]t
With palladium diacetate; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; acetonitrile; at 180℃; for 0.583333h;Inert atmosphere; Microwave irradiation;
A. Synthesis of the intermediates Example A.1 a) Preparation of intermediate (1) A solution of 6-bromo-3,4-dihydro-lH-[l,8]naphthyridin-2-one (1.0 g, 4.4 mmol), tert- butyl acrylate (2.56 ml, 17.62 mmol) and N,N-diisopropylethylamine (1.46 ml, 8.81 mmol) in acetonitrile (20 ml) and DMF (7 ml) was stirred and degassed with nitrogen gas for 10 minutes. Tri-o-tolylphosphine (0.27 g, 0.88 mmol) and palladium (II) acetate (47% on Pd) (0.099 g, 0.44 mol) were added and the resulting mixture was microwaved (1600 W, 180C, 35 minutes). The reaction mixture was evaporated till dryness, taken up in a mixture of DCM/methanol (8/2) (50 ml), filtered through a short pad of celite and washed with DCM. The organic layer was washed with water, dried (MgS04), filtered and evaporated to dryness. The residue was taken up in cold ethanol (10 ml) and stirred at 5C for 5 minutes, the precipitate was filtered off, washed with cold ethanol (3 ml) and dried under vacuum to yield 950 mg intermediate (1).
950 mg
With N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; acetonitrile; at 180℃; for 0.583333h;Microwave irradiation;
A solution of 6-bromo-3,4-dihydro-lH-[l,8]naphthyridin-2-one (l .Og, 4.4 mmol), tert- butyl acrylate (2.56 ml, 17.62 mmol) and N,N-diisopropylethylamine (1.46 ml, 8.81 mmol) in acetonitrile (20 ml) and DMF (7 ml) was stirred and degassed with nitrogen gas for 10 minutes. Tri-o-tolylphosphine (0.27 g, 0.88 mmol) and palladium (II) acetate (47% on Pd) (0.099 g, 0.44 mol) were added and the resulting mixture was microwaved (1600 W, 180C, 35 minutes). The reaction mixture was evaporated till dryness, taken up in a mixture of DCM/methanol (8/2) (50 ml), filtered through a short pad of celite and washed with DCM. The organic layer was washed with water, dried over MgS04, filtered and evaporated to dryness. The residue was taken up in cold ethanol (10 ml) and stirred at 5C for 5 minutes, the precipitate was filtered off, washed with cold ethanol (3 ml) and dried under vacuum to yield 950 mg intermediate (1).
950 mg
With palladium diacetate; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; In 1,2-dimethoxyethane; acetonitrile; at 180℃; for 0.583333h;Inert atmosphere; Microwave irradiation;
Example A.1 a) Preparation of intermediate (1)A solution of 6-bromo-3,4-dihydro-lH-[l,8]naphthyridin-2-one (1.0 g, 4.4 mmol), tert- butyl acrylate (2.56 ml, 17.62 mmol) and N,N-diisopropylethylamine (1.46 ml, 8.81 mmol) in acetonitrile (20 ml) and DMF (7 ml) was stirred and degassed with nitrogen gas for 10 minutes. Tri-o-tolylphosphine (0.27 g, 0.88 mmol) and palladium (II) acetate (47% on Pd) (0.099 g, 0.44 mol) were added and the resulting mixture was microwaved (1600 W, 180C, 35 minutes). The reaction mixture was evaporated till dryness, taken up in a mixture of DCM/methanol (8/2) (50 ml), filtered through a short pad of celite and washed with DCM. The organic layer was washed with water, dried over MgS04, filtered and evaporated to dryness. The residue was taken up in cold ethanol (10 ml) and stirred at 5C for 5 minutes, the precipitate was filtered off, washed with cold ethanol (3 ml) and dried under vacuum to yield 950 mg intermediate (1).
950 mg
A solution of <strong>[129686-16-4]6-bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one</strong> (1.0 g, 4.4 mmol), tert-butyl acrylate (2.56 ml, 17.62 mmol) and N,N-diisopropylethylamine (1.46 ml, 8.81 mmol) in acetonitrile (20 ml) and DMF (7 ml) was stirred and degassed with nitrogen gas for 10 minutes. Tri-o-tolylphosphine (0.27 g, 0.88 mmol) and palladium (II) acetate (47% on Pd) (0.099 g, 0.44 mol) were added and the resulting mixture was microwaved (1600 W, 180 C., 35 minutes). The reaction mixture was evaporated till dryness, taken up in a mixture of DCM/methanol (8/2) (50 ml), filtered through a short pad of celite and washed with DCM. The organic layer was washed with water, dried over MgSO4, filtered and evaporated to dryness. The residue was taken up in cold ethanol (10 ml) and stirred at 5 C. for 5 minutes, the precipitate was filtered off, washed with cold ethanol (3 ml) and dried under vacuum to yield 950 mg intermediate (1).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In N,N-dimethyl-formamide; acetonitrile; at 120℃; for 0.666667h;Inert atmosphere; Microwave irradiation;
Example A.6 a) Preparation of intermediate (21) Reaction done on 4 batches of 0.5g of 6-bromo-3,4-dihydro-lH-[l,8]naphthyridin-2- one each. A solution of 6-bromo-3,4-dihydro-lH-[l,8]naphthyridin-2-one (0.5 g, 2.20mmol), bis(pinacolato)diboron (0.67 g, 2.64 mmol) and potassium acetate (0.648 g, 6.61 mmol) in DMF (5 ml) and CH3CN (10 ml) was stirred and degassed with nitrogen for 10 minutes. 1 , -Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.161 g, 0.22mmol) was added and the resulting mixture was heated at 120C using a microwave (Biotage initiator 60) with a power output ranging from 0 to 400 W for 40 minutes. The mixture was evaporated till dryness, the residue was taken up in DCM and water, filtered through a short pad of celite. The organic layer of the filtrate was separated, washed with water, dried (MgS04) and evaporated till dryness. The residue was taken up in EtOH, filtered off and dried to give 0.36 g of intermediate (21).
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