* 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.
Compound 161a:; 161aTo an ethanol solution (50 mL ) of 6-hydroxy-naphthalene-2-carboxylic acid (5.29 g, 28.0 mmol) was added thionyl chloride (6 mL ) at 0°C. The mixture was stirred at room temperature for 72h. Excess reagents were evaporated. The residue was dissolved in ethyl acetate (100 mL ). The ethyl acetate solution was washed with water (80 ml_), cold 1 M sodium bicarbonate (80 ml.) and brine (80 mL ). It was dried over Na2SO4 and concentrated to give the crude title compound in 99percent yield. 1H NMR (CDCI3): δ 8.53 (1 H, br s), 8.01 (1 H, dd, J=8.5, 1.7Hz), 7.86 (1 H, d, J=8.5Hz), 7.20-7.13 (2H, m), 4.43 (2H, q, J=7.3Hz), 1.43 (3H, t, J=7.1 Hz). LCMS (APCl): 217.1 (M+H+).
85%
for 2 h; Reflux
To the solution of 6-hydroxy-2-naphthaoic acid (10.0 g, 0.053 mol) dissolved in 100 mL of EtOH was added 2.0 mL of H2SO4, and this solution was refluxed for 2 h. The solution was cooled and neutralized with 0.5 M of aqueous NaOH. The solids were collected. The product isolated as white solids were obtained after recrystallization from ethanol. Yield 85percent. 1H NMR (300 MHz, CDCl3): δ 3.95 (s, 3H, -OCH3), 5.74 (s, 1H, Ar-OH), 7.15 (d, 2H, Ar-H, J=7.6 Hz), 7.67 (d, 1H, Ar-H, J=8.6 Hz), 7.83 (d, 1H, Ar-H, J=9.7 Hz), 7.98 (d, 1H, Ar-H, J=8.7 Hz), 8.51 (s, 1H, Ar-H). 13C NMR (75 MHz, CDCl3): δ 50.00, 109.31, 118.52, 125.31, 125.91, 126.53, 127.94, 130.72, 131.24, 136.43, 155.65, 167.00.
Reference：
[1] Patent: WO2006/40646, 2006, A1, . Location in patent: Page/Page column 97
[2] Journal of Physical Chemistry A, 2016, vol. 120, # 33, p. 6563 - 6574
[3] Journal of Medicinal Chemistry, 2004, vol. 47, # 14, p. 3518 - 3536
[4] Molecular Crystals and Liquid Crystals, 2008, vol. 494, p. 282 - 292
[5] Tetrahedron, 2013, vol. 69, # 43, p. 9045 - 9055
[6] Journal of the American Chemical Society, 1950, vol. 72, p. 2112,2114
[7] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 13, p. 4279 - 4290
[8] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2019, vol. 210, p. 266 - 274
2
[ 16712-64-4 ]
[ 17295-12-4 ]
Reference：
[1] Patent: US2003/144329, 2003, A1,
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 8, p. 2465 - 2481
3
[ 67-56-1 ]
[ 16712-64-4 ]
[ 77-76-9 ]
[ 17295-11-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogenchloride In water at 20 - 55℃; for 32 h;
Example 1; Preparation of 6-{ l-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-l- ethylpropyl }naphthalene-2-carboxylic acid; A. 6-Hydroxynaphthalene-2-carboxylic acid methyl ester; Treat a mixture of 6-hydroxy-2-naphthoic acid (4.45g, 23.6 mmol) in 2,2- dimethoxypropane (235 mL) with cone. HCl (24 mL) and then MeOH (60 mL). Stir tlie reaction at RT for 16 h and then at 55 0C for 16 h. Pour the reaction mixture into EtOAc (250 mL) and wash with brine (3 x 100 mL). Dry the organic layer over Na2SO4, concentrate the filtrate, and chromatograph the concentrated filtrate (0.5 kg silica gel, 5:95 to 15:85 EtOAc:hex) to give the title compound (4.77 g, quant). MS (ES) m/e 203 (M+l).
The solution of 6-hydroxy-2-naphthaoic acid (10.0g, 0.053mol) dissolved in CH3OH was slowly added 2.0mL of concentrated H2SO4 and the solution was refluxed for 24h. The solution was cooled to room temperature, and the solids as light brown solids were collected. The solids were purified by recrystallization from methanol. Yield 90percent. 1H NMR (500MHz, CDCl3): δ 3.95 (s, 3H, –OCH3), 5.74 (s, 1H, Ar–OH), 7.15 (d, 2H, Ar–H, J=7.62Hz), 7.67 (d, 1H, Ar–H, J=8.58Hz), 7.83 (d, 1H, Ar–H, J=9.69Hz), 7.98 (d, 1H, Ar–H, J=8.72Hz), 8.51 (s, 1H, Ar–H). 13C NMR (125MHz, CDCl3): δ 50.0, 109.3, 118.5, 125.3, 125.9, 126.5, 127.9, 130.7, 131.2, 136.4, 155.6, 167.0.
84%
for 8 h; Heating / reflux
A solution of 15.7 g (83.4 mmol) of 6-hydroxy-2-naphthoic acid is refluxed for 8 hours in a mixture of 160 ml of methanol and 8 ml of concentrated sulphuric acid. After cooling, the product precipitates out. After filtration and washing with isopropyl ether, 14.1 g of methyl 6-hydroxynaphthalene-2-carboxylate are obtained in the form of a beige-coloured solid in a yield of 84percent.
80%
for 2 h; Reflux
The solution of 6-hydroxy-2-naphthaoic acid (10.0 g, 0.053 mol) dissolved in 100 mL of CH3OH was added 2.0 mL of concentrated H2SO4, and the mixture was refluxed for 2 h.The solution was neutralized with dilute aqueous NaOH(aq). The solids were collected, andt he priduct isolated as white solids were obtained after recrystallization from CH3OH. Yield 80percent.
Reference：
[1] Synthesis (Germany), 2018, vol. 50, # 7, p. 1560 - 1568
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 23, p. 7486 - 7494
[3] ChemMedChem, 2010, vol. 5, # 9, p. 1577 - 1593
[4] Tetrahedron, 2013, vol. 69, # 21, p. 4226 - 4235
[5] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 10, p. 1403 - 1408
[6] Patent: WO2004/52840, 2004, A1, . Location in patent: Page 33
[7] Tetrahedron, 2012, vol. 68, # 36, p. 7331 - 7337
[8] Journal of Medicinal Chemistry, 1997, vol. 40, # 8, p. 1186 - 1194
[9] Organic Letters, 2017, vol. 19, # 7, p. 1808 - 1811
[10] Synthetic Communications, 2012, vol. 42, # 17, p. 2526 - 2539
[11] MedChemComm, 2014, vol. 5, # 8, p. 1247 - 1253
[12] Letters in Drug Design and Discovery, 2011, vol. 8, # 1, p. 26 - 31
[13] Journal of Medicinal Chemistry, 2001, vol. 44, # 18, p. 2869 - 2878
[14] Journal of the American Chemical Society, 2010, vol. 132, # 32, p. 11288 - 11305
[15] Journal of Medicinal Chemistry, 2013, vol. 56, # 3, p. 761 - 780
[16] Journal of Organic Chemistry, 2014, vol. 79, # 15, p. 7132 - 7140
[17] Journal of Medicinal Chemistry, 2015, vol. 58, # 2, p. 560 - 576
[18] Carbohydrate Research, 2017, vol. 446-447, p. 76 - 84
[19] Patent: JP2018/2689, 2018, A, . Location in patent: Paragraph 0075; 0076
5
[ 16712-64-4 ]
[ 17295-11-3 ]
Reference：
[1] Patent: US6087304, 2000, A,
[2] Patent: US5773421, 1998, A,
[3] Patent: US5061399, 1991, A,
General procedure: 6-Hydroxy-2-naphthoic acid (1) (2.44 g, 13 mmol, 1 equiv.) and KOH (1.46 g, 26 mmol, 2equiv.) were dissolved in ethanol/water (25 mL, 9/1) and the solution was stirred for 20 min;corresponding n-alkyl bromide (32.50 mmol, 2.5 equiv.) was then added and the mixture isheated under reflux for 24 hr. When the reaction was complete, KOH (0.73 g, 13 mmol, 1equiv.) was added and the mixture is heated under reflux for further 4 hr. The ethanol wasevaporated, and the mixture is poured into water and acidified to approximately pH = 2?3with acetic acid. The precipitatewas filtered and washed with water and ether, and then recrystallizedtwice from glacial acetic acid, then from ethanol to give 71%?80% yield. (IR) (KBr):upsilonmax/cm-1: 3061, 2930, 2828, 1680, 1603, 1311, 1472, 1450, 1383, 1216, 1060, and 721.
Compound 161a:; 161aTo an ethanol solution (50 mL ) of 6-hydroxy-naphthalene-2-carboxylic acid (5.29 g, 28.0 mmol) was added thionyl chloride (6 mL ) at 0C. The mixture was stirred at room temperature for 72h. Excess reagents were evaporated. The residue was dissolved in ethyl acetate (100 mL ). The ethyl acetate solution was washed with water (80 ml_), cold 1 M sodium bicarbonate (80 ml.) and brine (80 mL ). It was dried over Na2SO4 and concentrated to give the crude title compound in 99% yield. 1H NMR (CDCI3): delta 8.53 (1 H, br s), 8.01 (1 H, dd, J=8.5, 1.7Hz), 7.86 (1 H, d, J=8.5Hz), 7.20-7.13 (2H, m), 4.43 (2H, q, J=7.3Hz), 1.43 (3H, t, J=7.1 Hz). LCMS (APCl): 217.1 (M+H+).
85%
With sulfuric acid; for 2h;Reflux;
To the solution of 6-hydroxy-2-naphthaoic acid (10.0 g, 0.053 mol) dissolved in 100 mL of EtOH was added 2.0 mL of H2SO4, and this solution was refluxed for 2 h. The solution was cooled and neutralized with 0.5 M of aqueous NaOH. The solids were collected. The product isolated as white solids were obtained after recrystallization from ethanol. Yield 85%. 1H NMR (300 MHz, CDCl3): delta 3.95 (s, 3H, -OCH3), 5.74 (s, 1H, Ar-OH), 7.15 (d, 2H, Ar-H, J=7.6 Hz), 7.67 (d, 1H, Ar-H, J=8.6 Hz), 7.83 (d, 1H, Ar-H, J=9.7 Hz), 7.98 (d, 1H, Ar-H, J=8.7 Hz), 8.51 (s, 1H, Ar-H). 13C NMR (75 MHz, CDCl3): delta 50.00, 109.31, 118.52, 125.31, 125.91, 126.53, 127.94, 130.72, 131.24, 136.43, 155.65, 167.00.
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0℃;
To a stirred suspension of NaH (60%, 1.37 g, 34.3 mmol) in DMF (40 mL) at 0 C. under nitrogen was added 6-hydroxy-2-naphthoic acid (3.0 g, 15.6 mmol). The resulting brown mixture was stirred for 30 min before benzyl bromide (5.99 g, 34.3 mmol) was added. After stirring overnight, the reaction mixture was poured into water and the aqueous layer was extracted with ethyl acetate (3*100 mL). The combined organic extracts was washed with brine (4*100 mL), dried (Na2SO4) and evaporated to give the crude product which upon fractionation with flash chromatography (hexane/ethyl acetate, 10:1) gave JRL01001 as a white solid (4.3 g, 75%); Rf (hexane/ethyl acetate, 10:1) 0.42; deltaH (400 MHz, CDCl3) 5.19 (2H, s), 5.41 (2H, s), 7.20-7.60 (12H, m), 7.74 (1H, d, J=8.6 Hz), 7.85 (1H, d, J=9.0 Hz), 8.06 (1H, dd, J 1.9 and 8.6 Hz) and 8.57 (1H, s); deltaC (100 MHz, CDCl3) delta 7.1 (t), 70.5 (t), 107.2 (d), 120.2 (d), 125.5 (s), 126.3 (d), 127.2 (d), 127.5 (d), 128.2 (s), 128.4 (d), 128.5 (d), 128.6 (d), 128.9 (d), 131.2 (d), 136.5 (s), 136.7 (s), 137.4 (s), 158.6 (s), 166.8 (s).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
Reference Example 43; Benzyl 6-(benzyloxy)-2-naphthoate [] To a solution of 6-hydroxy-2-naphthoic acid (17.9 g) in N,N-dimethylformamide (200 ml) was added potassium carbonate (32.9 g) and benzyl bromide (22.6 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by recrystallization (hexane - ethyl acetate) to obtain an objective product (26.1 g) as crystals. Melting point 97 - 98C; 1H-NMR (CDCl3) delta 5.18 (2H, s), 5.40 (2H, s), 7.21-7.27 (2H, m), 7.31-7.49 (10H, m), 7.72 (1H, d), 7.84 (1H, d), 8.04 (1H, dd), 8.54 (1H, s).
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 24h;Inert atmosphere;
(A) A 300 ml four-necked flask was charged with 40.6 g of 6-hydroxy-2-naphthoic acid, 59.7 g of potassium carbonate and 121.8 g of N, N-dimethylformamide (DMF), purged with nitrogen under stirring , 81.3 g of benzyl bromide was added dropwise and the mixture was reacted at 25 C. for 24 hours. Thereafter, water was added to the reaction solution to precipitate a solid matter, followed by filtration.
The solution of 6-hydroxy-2-naphthaoic acid (5.0g, 0.027mol) and KOH (3.0g, 0.053mol) was gently heated in 100mL of C2H5OH/ H2O (10/1) for 30min under nitrogen atmosphere. The solution was then added 1-bromododecane (13.92g, 0.056mol), and the mixture was refluxed for 24h. The solution was neutralized with dilute 1.0M HCl to pH equal to 6.0. The white solids were collected. The products isolated as white crystals were obtained after recrystallized from CH2Cl2/CH3OH. Yield 88%. 1H NMR (CDCl3): delta 0.85-0.90 (t, 3H, -CH3), 1.29-1.50 (m, 12H, -CH2), 1.83-1.85 (m, 2H, -CH2), 4.08-4.11 (t, 2H, -OCH2), 7.14 (s, 1H, Ar-H), 7.18-7.20 (d, 1H, Ar-H, J=8.94Hz), 7.23 (s, 1H, Ar-H) 7.73-7.75 (d, 1H, Ar-H, J=8.68Hz), 7.83-7.85 (d, 1H, Ar-H, J=8.92Hz), 8.04-8.06 (d, 1H, Ar-H, J=8.89Hz), 8.59 (s, 1H, Ar-H). 13C NMR (CDCl3): delta 13.91, 22.55, 26.05, 29.15, 29.28, 29.35, 31.75, 68.30, 106.72, 119.97, 121.29, 124.16, 126.05, 126.85,127.85, 130.95, 131.80, 137.75, 159.51.
General procedure: <strong>[16712-64-4]6-Hydroxy-2-naphthoic acid</strong> (1) (2.44 g, 13 mmol, 1 equiv.) and KOH (1.46 g, 26 mmol, 2equiv.) were dissolved in ethanol/water (25 mL, 9/1) and the solution was stirred for 20 min;corresponding n-alkyl bromide (32.50 mmol, 2.5 equiv.) was then added and the mixture isheated under reflux for 24 hr. When the reaction was complete, KOH (0.73 g, 13 mmol, 1equiv.) was added and the mixture is heated under reflux for further 4 hr. The ethanol wasevaporated, and the mixture is poured into water and acidified to approximately pH = 2?3with acetic acid. The precipitatewas filtered and washed with water and ether, and then recrystallizedtwice from glacial acetic acid, then from ethanol to give 71%?80% yield. (IR) (KBr):upsilonmax/cm-1: 3061, 2930, 2828, 1680, 1603, 1311, 1472, 1450, 1383, 1216, 1060, and 721.
With potassium carbonate; sodium iodide; In DMF (N,N-dimethyl-formamide); at 70℃; for 4h;
To a solution of 6-hydroxy-2-naphthoic acid (0.50 g, 2.66 mmol) and [BENZYLCHLORIDE] [(1.] 01 g, 7.97 mmol) in [N, N-DIMETHYLFORMAMIDE] (15 mL) was added potassium carbonate [(1.] 10 g, 7.97 mmol) and sodium iodide (0.12 g, 0.80 [RNMOL),] and the mixture was stirred at [70C] for 4 hours. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The separated organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica-gel (n-hexane : ethyl acetate, 4: [1)] to give benzyl [6- (BENZYLOXY)-2-NAPHTHOATE (1. 01] g, 103 %) as yellowish granules.
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃;
To a solution of 6-hydroxy-2-naphthoic acid (300 mg), DL-phenylalanine methyl ester (344 mg), 1-hydroxybenzotriazole [(HOBT,] 280mg), and triethylamine (0.3 ml) in [N, N-DIMETHYLFORMAMIDE (DMF,] 8 ml) was added [1-ETHYL-3- (3-DIMETHYLAMINO-] propyl) carbodiimide (EDCI, 396 mg). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate and evaporated to give colorless viscous oil, that was purified by silica gel column chromatography (hexane/ethyl acetate = 1: 1) to give N- (6-hydroxy-2-naphthoyl) phenylalanine methyl ester (475 mg, 85%) as a colorless foam.
(6-hydroxy-naphthalen-2-yl)-piperidin-1-yl-methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;
A mixture of 0.5 g (0.003 mol) <strong>[16712-64-4]6-hydroxy-2-naphtoic acid</strong>, 1.2 g (0.003 mol) 2- ( l H-benzotriazol- I -yl) - I>1>3>3-tetramethyl uronium tetrafluoroborate, 2.3 ml (0.013 mol) N-ethyldiisopropylamine and 0.29 ml (0.030 mol) piperidine in 10 ml DMF was stirred for 16 h at room temperature. The mixture was concentrated to dryness and 50 ml ethyl acetate, 30 ml water and 20 ml NaHC03 aq. (10%) was added. The aqueous phase was extracted with 50 ml ethyl acetate and the combined organic layers were purified with column chromatography on silica. The product fractions were concentrated to dryness and titurated twice with 20 ml diethyl ether/ heptane 1 / 1. The residue was dried under vacuum at 50 C to yield 0.58 g (0.0227 mmol; 85 %) of the title compound as light brown solid. MS (m/e): 254.3 (MH-, 100%)
With hydrogenchloride; In water; at 20 - 55℃; for 32h;
Example 1; Preparation of 6-{ l-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-l- ethylpropyl }naphthalene-2-carboxylic acid; A. 6-Hydroxynaphthalene-2-carboxylic acid methyl ester; Treat a mixture of 6-hydroxy-2-naphthoic acid (4.45g, 23.6 mmol) in 2,2- dimethoxypropane (235 mL) with cone. HCl (24 mL) and then MeOH (60 mL). Stir tlie reaction at RT for 16 h and then at 55 0C for 16 h. Pour the reaction mixture into EtOAc (250 mL) and wash with brine (3 x 100 mL). Dry the organic layer over Na2SO4, concentrate the filtrate, and chromatograph the concentrated filtrate (0.5 kg silica gel, 5:95 to 15:85 EtOAc:hex) to give the title compound (4.77 g, quant). MS (ES) m/e 203 (M+l).
a. 6-Hydroxy-naphthalene-2-carboxylic acid ethyl ester. A solution of 6-hydroxy-2-naphthoic acid (75.9 g, 0.40 mol) in ethanol (1.0 L) and sulfuric acid (5.0 mL) was heated to reflux under an atmosphere of nitrogen. After 16 hours, the volume was removed to approximately half via simple distillation and the resulting solution was diluted with water. The resulting cloudy mixture was extracted with EtOAc (4*) and the combined organics were successively washed with NaHCO3 (0.25 M, twice), water, brine and dried (MgSO4). The mixture was filtered and evaporated to give 6-hydroxy-naphthalene-2-carboxylic acid ethyl ester, 85.4 g (98%). 1H NMR (300 MHz; CDCl3) 1.44 (t, J=7.5 Hz, 3 H), 4.45 (q, J=7.5 Hz, 2 H), 6.48 (brs, 1 H), 7.10-7.25 (m, 2 H), 7.66 (d, J=8.4 Hz, 1 H), 7.84 (dd, J1=9.0 Hz, J2=1.0 Hz, 1 H), 8.00 (dd, J1=9.0 Hz, J2=1.5 Hz, 1 H), 8.53 (d, J=1.0 Hz, 1 H).
(1) Synthesis of 6-acetoxy-2-naphthoic acid 25 Grams (133 mmol) of 6-hydroxy-2-naphthoic acid and 68 g (265 mmol) of acetic anhydride were placed in a reactor, and while the mixture was stirred, 0.05 g of concentrated sulfuric acid was added. The mixture was stirred until heat generation ceased, and the mixture was further heated and stirred at 80 C. for 1 hour and then gradually cooled to room temperature. While the reaction mixture was cooled in an ice bath, 500 g of water was gradually added, and the mixture was stirred at room temperature for 3 hours to quench unreacted acetic anhydride. A precipitated white solid was recovered by filtration, washed with water to remove acetic acid, and dried with a vacuum dryer, to give 30.3 g of an end compound (yield 99%)
74.4%
With potassium hydroxide; acetic anhydride; In water;
Step i) STR229 In a 100 ml-reaction vessel, 16.7 g (2.53*10-1 M) of potassium hydroxide and 85 ml of water were placed, followed by cooling to 0 C. To the mixture, 20.0 g (1.06*10-1 M) of 6-hydroxy-2-naphthoic acid was added and dissolved therein. To the solution, 10.9 g (1.07*10-1 M) of acetic anhydride was added dropwise in 40 minutes at 0 C. followed by stirring for 2 hours. After stirring, the reaction mixture was acidified with 6N-hydrochloric acid to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and drying to obtain 18.3 g of 6-acetoxy-2-naphthoic acid (Yield: 74.4%).
60.5%
With sulfuric acid; acetic anhydride; In water;
STR31 In a 30 ml-round-bottomed flask, 2.00 g (10.6 mM) of 6-hydroxy-2-naphthoic acid, 4.0 ml of acetic anhydride and two drops of concentrated sulfuric acid were placed, followed by heat-stirring for 1 hour at about 90 C. The reaction mixture was cooled to room temperature and poured into 100 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and recrystallization from ethanol to obtain 1.48 g of 6-acetoxy-2-naphthoic acid (Yield: 60.5%).
With acetic anhydride; In sodium hydroxide;
EXAMPLE 1 20.4 parts (0.2 mole) of acetic anhydride are stirred at a temperature between 20 and 25 C. into a solution of 37.6 parts (0.2 mole) of 6-hydroxy-2-naphthoic acid in 750 parts of 2.2% strength aqueous sodium hydroxide solution (this starting solution has a pH of about 12.5). The reaction batch is afterwards stirred for a further hour and is then brought to a pH of 4.5-5 with dilute aqueous sulfuric acid. The precipitated product is filtered off with suction, is washed with water and is dried. Yield of 6-acetoxy-2-naphthoic acid: 45.2 parts of about 99% purity, which corresponds to 98% of theory.
With acetic anhydride; In sodium hydroxide;
EXAMPLE 2 61.2 parts (0.6 mole) of acetic anhydride are stirred at a temperature between 20 and 25 C. into a solution of 37.6 parts of 6-hydroxy-2-naphthoic acid in 750 parts of 2.2% strength aqueous sodium hydroxide solution. The reaction batch is afterwards stirred for a further hour and the product which has precipitated at pH 4.5-5.5 is filtered off with suction, is washed with water and is dried. Yield of 6-acetoxy-2-naphthoic acid: 44.4 parts of about 99.5% purity, which corresponds to 96.5% of theory.
With pyridine; hydrogenchloride; acetic anhydride; In water;
EXAMPLE 19 Synthesis of 6-acetoxy-2-naphthoic acid Into a 0.25 L, 3-necked roundbottom flask, fitted with a magnetic stirbar and addition funnel were added 6-hydroxy-2-naphthoic acid (20.0 g, 106 mmol) and pyridine (100 mL, 1.24 mol). The reaction mixture was cooled to 0 C. in an ice water bath. Acetic anhydride (10.9 g, 106 mmol) was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was poured into 1.1 L of a 10:1 mixture of water and concentrated hydrochloric acid. The white precipitate was isolated by vacuum filtration and washed with an additional 1 L of water. The white solid was allowed to air dry over 48 hours. 22.5 g (92%) were obtained as a white powder. 1H NMR (500 MHz, DMSO-d6): delta 13.10 (s, br, 1H), 8.65 (s, 1H), 8.17 (d, 1H, J=10), 8.05 (dd, 2H, J=10, 20), 7.75 (s, 1H), 7.40 (m, 1H), 2.38 (s, 3H). 13C NMR (125 MHz, DMSO-d6): delta 169.5, 167.5, 150.0, 135.5, 131.0, 130.5, 130.2, 127.9, 127.8, 126.0, 122.6, 118.6, 21.0.
General procedure: A solution of 6-hydroxy-2-naphthoic acid (11) (5.0 g, 26.6 mmol) and KOH (6.0 g, 107.1 mmol) in EtOH/H2O (10:1, 100 mL) was refluxed under N2 for 30 min. Then, 1-bromohexane (8.77 g, 53.2 mmol) was added and the resulting mixture was refluxed for 24 h. After cooling, the pH value of the solution was adjusted to 6.0 by dilute HCl. The solid was filtered and recrystalized in MeOH and CH2Cl2 to afford 12a (5.66 g, yield 78.2%) as white solid.
75.7%
General procedure: A solution of 6-hydroxy-2-naphthoic acid (11) (5.0 g, 0.027 mol) and KOH (6.0 g, 0.106 mol) in EtOH-H2O (10:1, 100 mL) was refluxed under N2 for 30 min. Then, 1-bromopentane (8.03 g, 0.053 mol) was added to reaction solution and the resulting mixture was refluxed for 24 h. After cooling, the pH value of the solution was adjusted to 6.0 by dilute HCl. The precipitation was filtered and recrystalized in MeOH and CH2Cl2 to afford 12a (5.52 g, yield 80.4%) as white solid.
With sodium hydroxide; In water; dimethyl sulfoxide; ethyl acetate;
Preparation 11 To a solution of 6-hydroxy-2-naphthoic acid (1 g) in the mixture of 10% sodium hydroxide aqueous solution (4.25 ml) and dimethylsulfoxide (17 ml) was added octyl bromide (0.918 ml). The mixture was stirred for 6 hours at 60 C. The reaction mixture was added to a mixture of water and ethyl acetate and adjusted to pH 3 with conc. hydrochloric acid. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 6-octyloxy-2-naphthoic acid (0.91 g). IR (Nujol): 1670, 1620, 1210 cm-1 NMR (DMSO-d6, delta): 0.86 (3H, t, J=6.7 Hz), 1.2-1.6 (10H, m), 1.78 (2H, m), 4.10 (2H, t, J=6.7 Hz), 7.19 (1H, dd, J=2.3 and 8.8 Hz), 7.36 (1H, d, J=2.3 Hz), 7.83 (1H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.52 (1H, s)
General procedure: <strong>[16712-64-4]6-Hydroxy-2-naphthoic acid</strong> (1) (2.44 g, 13 mmol, 1 equiv.) and KOH (1.46 g, 26 mmol, 2equiv.) were dissolved in ethanol/water (25 mL, 9/1) and the solution was stirred for 20 min;corresponding n-alkyl bromide (32.50 mmol, 2.5 equiv.) was then added and the mixture isheated under reflux for 24 hr. When the reaction was complete, KOH (0.73 g, 13 mmol, 1equiv.) was added and the mixture is heated under reflux for further 4 hr. The ethanol wasevaporated, and the mixture is poured into water and acidified to approximately pH = 2?3with acetic acid. The precipitatewas filtered and washed with water and ether, and then recrystallizedtwice from glacial acetic acid, then from ethanol to give 71%?80% yield. (IR) (KBr):upsilonmax/cm-1: 3061, 2930, 2828, 1680, 1603, 1311, 1472, 1450, 1383, 1216, 1060, and 721.
Example 3 1.5 1 of water were initially introduced into a 5 1 three-necked flask at room temperature, and 461 g of 6-hydroxy-2-naphthoic acid were then introduced. A pH of 11.5 was then established with 50% strength by weight aqueous sodium hydroxide solution and 710 g of dimethyl sulfate were subsequently allowed to run in, while cooling at 18 to 25 C., in the course of 6 hours, the pH being kept between 11.2 and 11.8 by metering in very finely divided sodium hydroxide solution via a two-component atomizing nozzle. When the reaction had ended, the solid product was filtered off with suction. 899.2 g of methyl 6-methoxy-2- naphthoate were thus obtained. This corresponds to a yield of 97.2%, based on the methylatable compounds employed.
The methyl 6-methoxy-2-naphthoate thus obtained had a purity of more than 57% (HPLC) and contained less than 0.1% by weight of 6-hydroxy-2-naphthoic acid.
Step A(i) 6-n-Octoxynaphthalene-2-carboxylic acid 6-Hydroxynaphthalene-2-carboxylic acid (39.8 g), 1-bromooctane (61.3 g), potassium hydroxide (23.7 g), ethanol (900 ml) and water (120 ml) were stirred and refluxed for 16 hours. 10% Aqueous potassium hydroxide (200 ml) was added and refluxing was continued for a further 2 hours, when the solution was poured into water (5 liter) and acidified to ph 1. The solid was filtered, washed with water, dried and recrystallized from acetic acid to give the product (49.0 g, 77.2% theory) as a white crystalline solid, mpt 150-153 C. (98.2% pure by hplc).
77.2%
With potassium hydroxide; In ethanol; water;
Step A(i) 6-n-octoxynaphthalene-2-carboxylic acid 6-Hydroxynaphthalene-2-carboxylic acid (39.8 g), 1-bromooctane (61.3 g), potassium hydroxide (23.7 g), ethanol (900 ml) and water (120 ml) were stirred and refluxed for 16 hours. 10% Aqueous potassium hydroxide (200 ml) was added and refluxing was continued for a further 2 hours, when the solution was poured into water (5 litre) and acidified to ph 1. The solid was filtered, washed with water, dried and recrystallized from acetic acid to give the product (49.0 g, 77.2% theory) as a white crystalline solid, mpt 150-153C (98.2% pure by hplc).
With sodium borohydrid; dimethyl sulfate; In tetrahydrofuran; water;
Example 7 Under a nitrogen atmosphere, 3.90 g (101 mmol) of sodium borohydride (purity: 98%) and 60 mL of anhydrous tetrahydrofuran were introduced into a 300-mL four-neck flask equipped with a dropping funnel, a gas inlet pipe, a condenser and a thermometer and stirred. The mixture was added dropwise with 13.21 g (105 mmol) of dimethyl sulfate at 0C over 5 minutes and stirred for 2 hours with ice cooling. The mixture was further added with 40 mL of anhydrous tetrahydrofuran and stirred at room temperature for 3 hours, and the stop of gas generation was observed. Subsequently, the reaction mixture was added with a solution of 9.73 g (51.71 mmol) of 6-hydroxy-2-naphthalenecarboxylic acid in anhydrous tetrahydrofuran (50mL) at room temperature over 25 minutes by using a dropping funnel. The reaction mixture solidified during the addition. This reaction mixture was stirred at the same temperature for 7 hours. After the reaction was completed, the reaction mixture was cooled, added with 150 mL of water with ice cooling and vigorously stirred at room temperature for 30 minutes. The resulting reaction mixture was analyzed by liquid chromatography using the internal standard method. As a result, it was found that the conversion of the 6-hydroxy-2-naphthalenecarboxylic acid was 68.53% and the yield of the 6-hydroxy-2-naphthylcarbinol was 26.8%.
With borane; In tetrahydrofuran; water;
Example 4 Under a nitrogen atmosphere, 100 mL of about 1 M borane/tetrahydrofuran complex solution in tetrahydrofuran obtained by the same procedure as in Example 1 and 13.86 g trimethyl borate were introduced into a 500 mL four-neck flask equipped with a dropping funnel, a gas inlet pipe, a condenser and a thermometer, and added dropwise with a solution of 12.56 g (66.74 mmol) of 6-hydroxy-2-naphthalenecarboxylic acid in anhydrous tetrahydrofuran (70 mL) at room temperature over 40 minutes by using a dropping funnel. This reaction mixture was stirred at the same temperature for 4 hours. After the reaction was completed, the reaction mixture was cooled, added with 150 mL of water with ice cooling and vigorously stirred at room temperature for 30 minutes. After the tetrahydrofuran was evaporated under reduced pressure, white crystals were deposited. The resulting white crystals were washed with water (200 mL) by filtration and dried under reduced pressure at 80C for 8 hours to obtain 11.23 g of 6-hydroxy-2-naphthylcarbinol as white crystals. The composition of the resulting white crystals was analyzed by liquid chromatography using the internal standard method. As a result, it was found that the conversion of the 6-hydroxy-2-naphthalenecarboxylic acid was 99.95% and the purity of the 6-hydroxy-2-naphthylcarbinol was 99.26% (64.47 mmol, yield: 96.6%).
(2)Two moles of a borane/tetrahydrofuran complex solution was added dropwise at room temperature, over a period of 25 minutes to a solution of one mole of 6-hydroxy-2- naphthalenecarboxylic acid and 3,9 mole of trimethyl borate in anhydrous tetrahydrofuran. This mixture was then stirred for 3.5 hours at room temperature. After completion of the reaction, the mixture was cooled with ice-water, and vigorously stirred at room temperature for 30 minutes. Evaporation of the solvent produced the product 6-Hydroxy-2- Hydroxymethyl-Naphthalene (6-hydroxy-2-naphthyl carbinol) as white plates.
With sulfuric acid; In methanol; hexane; water; ethyl acetate;
To a 1-L round bottomed flash equipped with a nitrogen inlet and magnetic stir bar was added 50 g (0.27 mol) of 6-hydroxy-2-naphthoic acid and 400 mL of methanol. The suspension was treated slowly with 1 mL of con. H2SO4 and stirred at room temperature overnight. The resulting solution was evaporated, taken up in 500 mL of ethyl acetate and washed sequentially with 3*300 mL of saturated NaHCO3, 2*300 mL of water and brine. The pale yellow solution was dried over MgSO4, reduced in volume to about 100 mL and slowly treated with hexane. The resulting crystalline precipitate was collected and dried under a stream of nitrogen to yield 52 g (95%) of the title compound as fine, white plates, mp 196 C. Preparation of 6-hydroxymethyl-2-naphthol:
EXAMPLE 4. Preparation of 6-carboxy-2-naphthol. The palladium-on-charcoal used in the carbonylation process of Example 3, was recovered by filtration, washing with water and ethyl acetate followed by drying at room temperature under water-pump vacuum. The recovered catalyst was reused for a second alkoxycarbonylation of 6-bromo-1-naphthol (BHN). 5.12g BHN (0.0231M), 2.16g Na2CO3, 45ml 2-ethyl-1-hexanol and the recovered Pd/C from Example 3, were reacted under the same conditions as mentioned therein. A conversion of 94% to the ester was observed after 4.5 hrs. and 96% after 6 hrs.
19
[ 15231-91-1 ]
[ 104-76-7 ]
[ 16712-64-4 ]
Yield
Reaction Conditions
Operation in experiment
90.3%
With sodium hydroxide; sodium carbonate;palladium-carbon; In ethanol; water;
EXAMPLE 3. Preparation of 6-carboxy-2-naphthol (CHN). A four-necked flask was charged with: 16.4g of 6-bromo-2-naphthol (0.074 moles), 6.33g Na2CO3(0.06 moles), 351.4mg Pd/C (3.2%) and 120 ml 2-ethyl-1-hexanol. Nitrogen was flushed through the system for 20 mins., then replaced by CO at atmospheric pressure (20 ml/min. flow). The carbonylation process was carried out at 160oC for 7 hrs. with stirring whereupon the conversion of 6-bromo-2-naphthol to the 2-ethyl-1-hexyl ester of 2-hydroxy-6-naphthol acid was 96.2%, and only 0.3% of starting material was detected. After the reaction, the flask was cooled and vented. 50cc water was added to the reaction mixture, which was then filtered in order to remove the heterogeneous catalyst. The excess of octanol was distilled from the organic layer. The product, a viscous oil, was dissolved in 80cc 95% ethanol. 8.9 g NaOH in 40 ml water was added, and the mixture was refluxed for 2.5 hrs. The hydrolysis mixture was allowed to cool and the ethanol was stripped off by distillation followed by the addition of 40cc water. The resulting 2-phase system was separated. The aqueous layer was further extracted with ethyl acetate (20ml) to remove all traces of organic materials, then acidified with aqueous HCl (37%), to bring the pH to 3.0-3.5. The heavy white-grey precipitate was filtered, washed with water and dried in an oven under vacuum to give 12.6 g of 2-hydroxy-6-naphthoic acid (90.3%). Crystallization from hot water and acetone yielded a white solid with a melt-. ing of of 250oC. The above ester, as well as the acid, were characterised by IR, NMR and Gas Chromatography-Mass Spectrometry.
EXAMPLE 5. Preparation of 6-carboxy-2-naphthol . The catalyst used in Example 4 was recovered, washed with water and ethyl acetate and reused directly in a third reaction mixture, using the following reagents: 6 g BHN (0.027M), 2.27 g Na2CO3,48cc 2-ethyl-1-hexanol, under the same conditions. Gas Chromatography analysis showed 92.4% conversion by weight to the desired ester after 7 hrs. reaction and 95% after 8 hrs.
General procedure: A solution of 6-hydroxy-2-naphthoic acid (11) (5.0 g, 26.6 mmol) and KOH (6.0 g, 107.1 mmol) in EtOH/H2O (10:1, 100 mL) was refluxed under N2 for 30 min. Then, 1-bromohexane (8.77 g, 53.2 mmol) was added and the resulting mixture was refluxed for 24 h. After cooling, the pH value of the solution was adjusted to 6.0 by dilute HCl. The solid was filtered and recrystalized in MeOH and CH2Cl2 to afford 12a (5.66 g, yield 78.2%) as white solid.
74.3%
General procedure: A solution of 6-hydroxy-2-naphthoic acid (11) (5.0 g, 0.027 mol) and KOH (6.0 g, 0.106 mol) in EtOH-H2O (10:1, 100 mL) was refluxed under N2 for 30 min. Then, 1-bromopentane (8.03 g, 0.053 mol) was added to reaction solution and the resulting mixture was refluxed for 24 h. After cooling, the pH value of the solution was adjusted to 6.0 by dilute HCl. The precipitation was filtered and recrystalized in MeOH and CH2Cl2 to afford 12a (5.52 g, yield 80.4%) as white solid.
With hydrogenchloride; potassium hydroxide; sodium iodide; In ethanol; water;
First step A mixture of 3.76 g (20 mmol) of 6-hydroxy-2-naphthoic acid, 5.38 g (30 mmol) of 1-bromoheptane, 2.64 g (40 mmoll of potassium hydroxide having purity of 85 %, 0.11 g (0.7 mmol) of sodium iodide, 40 ml of ethanol and 5 ml of water was allowed to undergo reaction at a reflux temperature for 10 hours in a nitrogen atmosphere. To the reaction mixture was added 20 ml of 10 % aqueous solution of potassium hydroxide to perform reaction for 2 hours at the same temperature. After the reaction mixture was cooled to room temperature, 80 ml of water was added to the mixture and was then acidified using 20 % hydrochloric acid. Then, the deposited solid was isolated from the mixture through filtration. The obtained solid was washed with water, then dried and recrystallized using ethanol of 10 times (by weight) of the solid, so as to obtain 4.26 g (14.9 mmol) of 6-n-heptyloxy-2-naphthoic acid in the form of a white solid.
General procedure: <strong>[16712-64-4]6-Hydroxy-2-naphthoic acid</strong> (1) (2.44 g, 13 mmol, 1 equiv.) and KOH (1.46 g, 26 mmol, 2equiv.) were dissolved in ethanol/water (25 mL, 9/1) and the solution was stirred for 20 min;corresponding n-alkyl bromide (32.50 mmol, 2.5 equiv.) was then added and the mixture isheated under reflux for 24 hr. When the reaction was complete, KOH (0.73 g, 13 mmol, 1equiv.) was added and the mixture is heated under reflux for further 4 hr. The ethanol wasevaporated, and the mixture is poured into water and acidified to approximately pH = 2?3with acetic acid. The precipitatewas filtered and washed with water and ether, and then recrystallizedtwice from glacial acetic acid, then from ethanol to give 71%?80% yield. (IR) (KBr):upsilonmax/cm-1: 3061, 2930, 2828, 1680, 1603, 1311, 1472, 1450, 1383, 1216, 1060, and 721.
[Synthesis Example 4] Synthesis of Compound No. 15; Compound No. 15 was synthesized according to the procedure of Steps 1 to 7 in the following manner.; <Step 1> Synthesis of 6-acroyloxy-2-naphthoic acid; 6-Acroyloxy-2-naphthoic acid was synthesized according to the reaction formula given by [Formula 76] in the following manner. [Show Image] To a stirred mixture of 3.00 g (16 mmol) of 6-hydroxy-2-naphthoic acid, 40 mmol of sodium hydroxide, and 16 g of water, 1.59 g (18 mmol) of acryloyl chloride was added at 20C, and the reaction was performed for 3 hours. After the reaction, the mixture was acidified by adding 4-mol/l hydrochloric acid dropwise and chilled with ice-water. The resultant precipitate was collected by filtration, dried in an oven at 40C, and recrystallized from methanol-THF (2:3) mixed solvent to yield the desired product, 6-acryloyloxy-2-naphthoic acid, as while solid (2.07 g, Yield: 53.6%).
<strong>[16712-64-4]6-Hydroxy-2-naphthoic acid</strong> [MA31-1] (300 g, 1.59 mol) was added to a 2L four-necked flask,Potassium hydroxide (205g, 3.66mol),Distilled water (1200g),Heat stirring at 100C.6-chloro-1-hexanol (261 g, 1.91 mol) was added dropwise thereto.After the addition,Reaction tracing by HPLC,After confirming the end of the reaction,After cooling the reaction solution to near room temperature,The reaction solution was poured into ice water (3L),Neutralization was performed by adding 35% hydrochloric acid.after that,The precipitated solid is filtered,After cleaning with distilled water,Dry the solid under reduced pressureThus, 275 g of compound [MA31-2] was obtained (yield 60%).
56.5%
[Synthesis Example 5] Synthesis of Compound No. 16; Compound No. 16 was synthesized according to the procedure of Steps 1 to 5 in the following manner.; <Step 1> Synthesis of 6-(6-hydroxy-hexa-1-yloxy)-2-naphthoic acid; 6-(6-Hydroxy-hexa-1-yloxy)-2-naphthoic acid was synthesized according to the reaction formula given by [Formula 84] in the following manner. [Show Image] To a stirred mixture of 25.00 g (133 mmol) of 6-hydroxy-2-naphthoic acid, 2.21 g (13 mmol) of potassium iodide, 4.28 g (13 mmol) of tetrabutylammonium bromide, and 77 g of ethanol, was added dropwise 18.63 g (332 mmol) of potassium hydroxide dissolved in 38 g of water. The mixture was heated to 60C, 19.07 g (146 mmol) of 6-chloro-1-hexanol was added dropwise here, and the solution was refluxed for 34 hours. After adding hydrochloric acid dropwise, the reaction mixture was chilled with ice-water, and the precipitate was collected by filtration. Water was added to the precipitate, and the mixture was stirred for 30 minutes and filtered to recover the precipitate, which was dried in an oven at 40C overnight. The dried product was recrystallized from THF to yield the desired product, 6-(6-hydroxy-hexa-1-yloxy)-2-naphthoic acid as white solid (21.63 g, Yield: 56.5%).
General procedure: A solution of 6-hydroxy-2-naphthoic acid (11) (5.0 g, 26.6 mmol) and KOH (6.0 g, 107.1 mmol) in EtOH/H2O (10:1, 100 mL) was refluxed under N2 for 30 min. Then, 1-bromohexane (8.77 g, 53.2 mmol) was added and the resulting mixture was refluxed for 24 h. After cooling, the pH value of the solution was adjusted to 6.0 by dilute HCl. The solid was filtered and recrystalized in MeOH and CH2Cl2 to afford 12a (5.66 g, yield 78.2%) as white solid. 1H NMR (DMSO-d6, 500 MHz) delta: 12.87 (s, 1H), 8.51 (s, 1H), 8.01 (d, 1H, 9.05 Hz), 7.92 (dd, 1H, J=1.65 Hz), 7.86 (d, 1H, J=8.65 Hz), 7.39 (d, 1H, J=2.35 Hz), 7.23 (dd, 1H, J=2.45 Hz), 4.11 (t, 2H, J=6.55 Hz), 1.78 (m, 2H), 1.34 (m, 2H), 1.20 (m, 4H), 0.89 (m, 3H). Anal. calcd for C17H20O3: C, 75.00; H, 7.35; found: C, 75.21; H, 7.33. The synthetic procedure for compounds 12b-c was similar to the preparation of compound 12a except using other 1-bromoalkanes instead of 1-bromopentane.39
78.2%
General procedure: A solution of 6-hydroxy-2-naphthoic acid (11) (5.0 g, 0.027 mol) and KOH (6.0 g, 0.106 mol) in EtOH-H2O (10:1, 100 mL) was refluxed under N2 for 30 min. Then, 1-bromopentane (8.03 g, 0.053 mol) was added to reaction solution and the resulting mixture was refluxed for 24 h. After cooling, the pH value of the solution was adjusted to 6.0 by dilute HCl. The precipitation was filtered and recrystalized in MeOH and CH2Cl2 to afford 12a (5.52 g, yield 80.4%) as white solid.
General procedure: <strong>[16712-64-4]6-Hydroxy-2-naphthoic acid</strong> (1) (2.44 g, 13 mmol, 1 equiv.) and KOH (1.46 g, 26 mmol, 2equiv.) were dissolved in ethanol/water (25 mL, 9/1) and the solution was stirred for 20 min;corresponding n-alkyl bromide (32.50 mmol, 2.5 equiv.) was then added and the mixture isheated under reflux for 24 hr. When the reaction was complete, KOH (0.73 g, 13 mmol, 1equiv.) was added and the mixture is heated under reflux for further 4 hr. The ethanol wasevaporated, and the mixture is poured into water and acidified to approximately pH = 2?3with acetic acid. The precipitatewas filtered and washed with water and ether, and then recrystallizedtwice from glacial acetic acid, then from ethanol to give 71%?80% yield. (IR) (KBr):upsilonmax/cm-1: 3061, 2930, 2828, 1680, 1603, 1311, 1472, 1450, 1383, 1216, 1060, and 721.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
Step 1; To a stirred mixture of 6-hydroxy-2-napthoic acid (100 mg, 0.531 mmol) in anhydrous dimethylormamide (5 mL) was added triethylamine (163 mul, 1.168 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (112 mg, 0.584 mmol), and 1-benzyl-piperidine-4-amine (100 mul, 0.531 mmol). The mixture was allowed to stir at room temperature overnight, then poured into water. The resulting solids were collected by filtration and purified by column chromatography to yield N-(1-benzylpiperidin-4-yl)-6-hydroxy-2-naphthamide as a light brown solid (0.191 g, 80%).
A 1:2 stoichiometric amount of 6-hydroxy-2-naphthoic acid (0.0188 g, 0.1 mmol) and <strong>[3977-29-5]2-amino-4-hydroxy-6-methyl pyrimidine</strong> (0.0250 g, 0.2 mmol) was dissolved in 5 mLethanol. Another five milliliter of distilled water was added to theabove solution with stirring for 10e15 min until gained a homogeneoussolution. Upon slow evaporation of the clear, homogeneoussolution, colorless, irregular, block crystals were producedover ten days. Single crystals suitable for X-ray diffraction wereculled from the mother liquor by filtration, and dried under vacuum.Yield: 82percent. Anal. calcd for C21H24N6O6: C, 56.76; H, 5.41; N,16.22percent. Found: C, 54.75; H, 5.68; N, 16.03percent. Infrared spectrum (KBrdisc, cm1): 3327 s, 3135 s, 2925 s, 2744 m, 1660 s, 1513 s, 1483 s,1395 s, 1360 s, 1213 s, 1157 m, 1084 w, 972 w, 835 m, 816 m, 772 w,657 w, 552 m.
Slow evaporation of a 1:1 ethanol/distilledwater solution (10 mL) containing 6-hydroxy-2-naphthoic acid(0.0376 g, 0.2 mmol) and 2-amino-4,6-dimethyl pyrimidine(0.0123 g, 0.1 mmol) yielded colorless crystals of 7 after ten days.Good quality single crystals, suitable for diffraction, were gatheredfrom their mother solution by filtration and dried under vacuum.Yield: 84percent.Anal. calcd for C28H27N3O7: C, 64.99; H, 5.22; N, 8.12percent.Found: C, 65.32; H, 5.57; N, 8.36percent. Infrared spectrum (KBr disc,cm1): 3193 s, 2912 m, 2598 m, 2338 w, 1921 w, 1684 s, 1628 s,1483 s, 1438 m, 1354 s, 1285 s, 1209 s, 1152 s, 1098 m, 971 w, 868 m,814 m, 770 m, 521 m.
General procedure: 6-Hydroxy-2-naphthoic acid (1) (2.44 g, 13 mmol, 1 equiv.) and KOH (1.46 g, 26 mmol, 2equiv.) were dissolved in ethanol/water (25 mL, 9/1) and the solution was stirred for 20 min;corresponding n-alkyl bromide (32.50 mmol, 2.5 equiv.) was then added and the mixture isheated under reflux for 24 hr. When the reaction was complete, KOH (0.73 g, 13 mmol, 1equiv.) was added and the mixture is heated under reflux for further 4 hr. The ethanol wasevaporated, and the mixture is poured into water and acidified to approximately pH = 2?3with acetic acid. The precipitatewas filtered and washed with water and ether, and then recrystallizedtwice from glacial acetic acid, then from ethanol to give 71%?80% yield. (IR) (KBr):upsilonmax/cm-1: 3061, 2930, 2828, 1680, 1603, 1311, 1472, 1450, 1383, 1216, 1060, and 721.
In a reaction vessel equipped with a Dean-Stark apparatus and a condenser, 10.0 g of the compound represented by the formula (C-4-1)15.2 g of the compound represented by the formula (C-4-2), 0.8 g of phosphoric acid,150 mL of mesitylene was added,And heated under reflux for 20 hours while removing water.After cooling, the solid was filtered and dispersed and washed with water. And dried to obtain 21.8 g of a compound represented by the formula (C-4). Under a nitrogen atmosphere,2.0 g of the compound represented by the formula (C-4) produced in Example 1-7,4.0 g of the compound represented by formula (D-2-1)0.1 g of 4-dimethylaminopyridine,40 mL of dichloromethane was added.2.1 g of diisopropylcarbodiimide was added dropwise while cooling with ice, and the mixture was stirred at room temperature for 10 hours.The precipitate was removed by filtration, and the filtrate was washed successively with 1percent hydrochloric acid, water and brine.After recrystallization (dichloromethane / methanol), purification was carried out by column chromatography (silica gel, dichloromethane) and recrystallization (dichloromethane / methanol) to obtain 4.6 g of the compound represented by the formula (D-2) .The obtained compound had a purity of 98.644percent (impurity content represented by formula (C-4) of 0.006percent, impurity content represented by formula (F1-2) and formula (F2-2) 0.120percent).
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