* 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.
1. Preparation of methyl 6-bromocaproate (methyl 6-bromohe:Kanoate). Hydrogen chloride (gas) was added to a solution of 5.01 g (25.7 mmol) of 6-bromocaproic acid in 250 ml of methanol via vigorous bubbling for 2-3 minutes. The mixture was stirred at 15-25° C. for 3 hours and then concentrated to afford 4.84 g of the product as a yellow oil (90percent): H-NMR (DMSO) 3.58 (3H, s), 3.51 (2H, t), 2.29 (2H, t), 1.78 (2H, pentet), and 1.62-1.27 ppm (4H, m).
To a solution 6-bromohexanoic acid (10 g, 50 mmol) in MeOH was added few drops of concentrated H2SO4. The mixture was then refluxed overnight. Methanol was EPO <DP n="83"/>evaporated and the residue was taken in dichloromethane and washed with saturated solution of sodium bicarbonate and dried over MgSO4. The solvent was then evaporated to give the desired ester (10.7 g) as slightly yellow oil in quantitative yield. 1H NMR: (CDCI3) δ (ppm): 3.6 (s, 3H); 3.3 (m, 2H); 2.4 (m, 2H); 1.5-1.8 (m, 4H); 1.3 (m, 2H).
100%
at 20℃; Cooling with ice
Synthesis of Methyl 6-bromohexanoate [0064] Add 6-bromohexanoic acid (4.1 g, 21.1 mmol) into 100 mL absolute methanol solution and then slowly drop 30 mL thionyl chloride into the solution with an ice bath. Stir the solution at room temperature overnight, concentrate the solution and add chloroform to dissolve. After suction filtration, take and concentrate the filtrate to get the product methyl 6-bromohexanoate (4.4 g, 100percent). Compound Data of the Product: [0065] IR (neat) v 11739 (CO) cm−1. [0066] 1H NMR (CDCl3) δ 3.64 (s, 3H, OCH3), 3.38 (t, 2H, BrCH2), 2.30 (t, 2H, CH2COOCH3), 1.82 (m, 2H, CH2CH2CH2CH2CH2), 1.63 (m, 2H, CH2CH2CH2CH2CH2), 1.46 (m, 2H, CH2CH2CH2CH2CH2). [0067] 13C NMR (CDCl3) δ 173.77 (CO), 51.73 (COOCH3), 33.72 (BrCH2), 33.34 (CH2CH2CH2CH2CH2), 32.30 (CH2CH2 CH2CH2CH2), 27.56 (CH2CH2CH2CH2CH2), 23.98 (CH2CH2CH2CH2CH2).
96%
at 0 - 20℃; for 24 h; Inert atmosphere
To a stirred solution of 6-bromohexanoic acid 24 (5.00 g, 25.6 mmol) in methanol (75 mL) at 0 °C, thionyl chloride (1.86 mL, 25.6 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 24 h. The solvent wasremoved in vacuo and the residue was dissolved in ethyl acetate (20 mL), washedwith water (2 x 10 mL), sat. NaHCO3 (10 mL), brine (10 mL) and dried (MgSO4).The solvent was removed in vacuo to give the title product 23 (5.13 g, 96°h) as ayellow oil which was used without further purification. 1H NMR (300 MHz; CDCI3)1.42-1.52 (2H, m, CH2), 1.56-1.66 (2H, m, CH2), 1.85-1.90 (2H, m, CH2), 2.33(2H, t, J = 3.0 Hz, CH2), 3.41 (2H, t, J = 6.0 Hz, CH2), 3.67 (3H, s, CH3). The 1H values are in agreement with literature.5
96%
for 2 h; Heating / reflux
6-Bromohexanoic acid methyl ester (27a). To a solution of acetyl chloride (1. 0 mL, 14 mmol) in methanol (150 mL) at 0°C was added a solution of 6-bromohexanoic acid (10.0 g, 51 mmol) in methanol (50 mL). The mixture was heated at reflux for 2 hours, then allowed to cool down to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and washed consecutively with saturated aqueous sodium hydrogen carbonate (2 x 50 mL), distilled water (50 mL), and brine (50 mL). The organic layer was dried over anhydrous MgS04, filtered and concentrated under reduced pressure to give the title compound (10.3 g, 96percent) as a colourless oil.
93%
for 8 h; Reflux
6-bromohexanoic acid 18 (4.886 g, 25.100 mmol) was dissolvedin methanol (75 mL). To this solution, Conc. H2SO4 (0.3 mL) was added and reaction mixture refluxed for 8 h. Then solvent evaporatedand residue was dissolved in ethyl acetate (200 mL). Theorganic part was then washed with saturated solution of NaHCO3(50 mL 3), dried and evaporated to give pure ester compound(4.626 g, 22.200 mmol). For making Wittig salt, bromo-estercompound was dissolved in dry CH3CN (70 mL) followed by additiontriphenylphosphine (7.000 g, 26.600 mmol). The reactionmixturewas then refluxed for 36 h. After that solvent evaporated togive gummy residue which was washed with hexanes (20 mL 3)to give compound 19.
92%
Heating / reflux
Example 15a; General Procedure for the Esterification of Bromoalkanoic Acids (I); Appropriate bromo alkanoic acid (1 equiv) was dissolved in methanol and a catalytic amount of conc.H2SO4 (0.1 mL/g) was added and the reaction mixture was refluxed for overnight. Upon reaction completion, methanol was removed in rotary evaporation and the crude product was washed with aq. NaHCO3, brine solution and extracted with ethyl acetate. The product was used further without column purification.; Example 15d; Synthesis of Methyl 6-Bromohexanoate (11); As mentioned in the general procedure (I), 6-bromohexanoic acid (15 g, 76.9 mmol, 1 equiv) was dissolved in methanol (150 mL), and a catalytic amount of conc.H2SO4 (2 mL) was added and the reaction was carried out. The product was taken to next step without column purification. Yield 14.8 g (92percent). 1H NMR (400 MHz, CDCl3): δ 3.66 (s, 3H), 3.42-3.38 (m, 2H), 2.32 (t, J=7.2 Hz, 2H), 1.90-1.83 (m, 2H), 1.68-1.61 (m, 2H), 1.50-1.44 (m, 2H). 13C NMR (100 MHz, CDCl3); δ 173.9, 51.5, 33.8, 33.4, 32.3, 27.6, 24.0. EI/MS m/z (r.i.) 211 (M+2, 98), 210 (M+1, 8), 209 (M+, 100), 178 (16), 161 (33), 129 (51), 97 (28), 87 (9), 74 (23), 69 (23).
91%
at 0 - 20℃;
Step 1 Methyl 6-bromohexanoate: At about 0° C., thionyl chloride (11.9 g; 100 mmol; 1.00 equiv) was added dropwise to a stirred solution of 6-bromohexanoic acid (19.5 g; 100 mmol; 1.00 equiv) in methanol (100 mL). The resulting solution was stirred at ambient temperature for about 1 hour and then concentrated in vacuo, to give the title product as a colorless oil (19 g; 91percent yield). 1H NMR (300 MHz, CDCl3) δ 3.68 (s, 3H), 3.41 (t, J=6.6 Hz, 2H), 2.43 (t, J=6.6 Hz, 2H), 1.88 (m, 2H), 1.64 (m, 2H), 1.49 (m, 2H).
87%
for 16 h; Reflux; Inert atmosphere
General procedure: Typical procedure: After refluxing the mixture of 4a (7.64g, 45.7mmol), methanol (78.4mL), and conc. sulfuric acid (0.77mL) for 16h under a dry argon atmosphere, it was cooled to room temperature. Then, aqueous solution of sodium bicarbonate (78mL) was added to the reaction mixture and the crude product was extracted with ethyl acetate. After washing the combined organic layer with sodium bicarbonate aqueous solution, water, and brine, it was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with a mixed solvent of chloroform/methanol (10/1v/v). The fraction with an Rf value of 0.86 was collected and dried under reduced pressure to afford methyl 4-bromobutanoate (5a)
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[8] Tetrahedron Asymmetry, 2010, vol. 21, # 3, p. 285 - 291
[9] Patent: WO2018/47101, 2018, A1, . Location in patent: Page/Page column 68; 74; 75
[10] Patent: WO2004/46094, 2004, A1, . Location in patent: Page 51
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[37] Patent: US2018/79906, 2018, A1, . Location in patent: Paragraph 0428-0429
4
[ 1110667-71-4 ]
[ 14273-90-6 ]
Reference：
[1] Synthesis, 2008, # 22, p. 3565 - 3568
5
[ 502-44-3 ]
[ 67-56-1 ]
[ 14273-90-6 ]
Reference：
[1] Canadian Journal of Chemistry, 2003, vol. 81, # 8, p. 937 - 960
[2] Journal of the American Chemical Society, 2014, vol. 136, # 41, p. 14389 - 14392
[3] Bulletin de la Societe Chimique de France, 1972, p. 4163 - 4170
[4] Synthesis, 1977, p. 112 - 113
6
[ 186581-53-3 ]
[ 4224-70-8 ]
[ 14273-90-6 ]
Reference：
[1] Carbohydrate Research, 1980, vol. 87, p. 227 - 240
[2] Canadian Journal of Chemistry, 1982, vol. 60, p. 2531 - 2536
[3] Journal of Organometallic Chemistry, 1983, vol. 253, # 1, p. 31 - 38
[4] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1984, vol. 33, # 11, p. 2407 - 2409[5] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1984, # 11, p. 2628 - 2630
[6] Bulletin of the Chemical Society of Japan, 1986, vol. 59, # 11, p. 3535 - 3539
7
[ 4547-43-7 ]
[ 14273-90-6 ]
Reference：
[1] Russian Journal of Bioorganic Chemistry, 2008, vol. 34, # 1, p. 67 - 73
With potassium carbonate In <i>N</i>-methyl-acetamide
29 Preparation of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester
EXAMPLE 29 Preparation of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester A mixture of 5.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.4 g of methyl 6-bromohexanoate and 5.4 g of anhydrous potassium carbonate in 50 ml of anhydrous dimethylformamide was stirred and heated at 75° for 10 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on 125 g of silica gel. Elution with 25% ethyl acetate-hexane gave 7.5 g (90% yield) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester as an oil.
62%
With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 12h;
62%
With potassium carbonate In N,N-dimethyl-formamide
9 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester
EXAMPLE 9 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester A mixture of 2.72 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.72 g of methyl 6-bromohexanoate and 2.90 g of anhydrous potassium carbonate in 30 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 7 hours. The usual workup followed by chromatography on 200 g of silica gel and elution with 10% ethyl acetate-toluene gave 2.77 g (62% yield) of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C18 H26 O5: C, 67.06; H, 8.13. Found: C, 66.92; H, 8.25.
62%
With potassium carbonate In N,N-dimethyl-formamide
54 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy) hexanoic acid methyl ester
EXAMPLE 54 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy) hexanoic acid methyl ester A mixture of 2.72 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 2.72 g of methyl 6-bromohexanoate and 2.90 g of anhydrous potassium carbonate in 30 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 7 hours. The usual workup followed by chromatography on 200 g of silica gel and elution with 10% ethyl acetate-toluene gave 2.77 g (62% yield) of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy) hexanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C18 H26 O5: C, 67.06; H, 8.13. Found: C, 66.92; H, 8.25.
With potassium carbonate; sodium iodide In acetone for 60h; Heating / reflux;
9
To a mixture of 2-(6-Hydroxy-naphthalen-2-yl)-propionic acid methyl ester 6 (150 g, 652 mmol), anhydrous K2CO3 (480 gr, 3.473 mol) and sodium iodide (22.5 grams, 150 mmol) in anhydrous acetone (2000 ml) was added methyl 6-bromohexanoate (216 g, 1.033 mol) and refluxed for 60 hours. Acetone was distilled off and water (1500 ml) was added. Crude 9 was extracted into ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using hexane as eluant to give pure 2 (130 g, 55.6%) as a light yellow syrup. The structure was confirmed with NMR. 1HNMR (CDCl3) 1.59 (d, 3H, CH3), 1.60 (d, 2H, CH2), 1.75 (m, 2H, CH2), 1.89 (m, 2H, CH2), 2.38 (t, 2H, CH2), 3.69 (s, 6H, ester), 3.88 (q, 1H, CH), 4.08 (t, 2H, OCH2), 7.10 (m, 2H, Ar), 7.40 (d, 1H, Ar), 7.68 (m, 3H, Ar)
55.6%
With potassium carbonate; sodium iodide In acetone for 60h; Heating / reflux;
33 6-[6-(1-Methoxycarbonyl-ethyl)-naphthalen-2-yloxy]-hexanoic Acid Methyl Ester (33)
Example 33 6-[6-(1-Methoxycarbonyl-ethyl)-naphthalen-2-yloxy]-hexanoic Acid Methyl Ester (33) To a mixture of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid methyl ester 30 (150 grams, 652 mmol), anhydrous K2CO3 (480 grams, 3.473 mol) sodium iodide (22.5 grams, 150 mmol) in anhydrous acetone (2000 mL) was added methyl 6-bromo hexanoate (216 grams, 1.033 mol) and refluxed for 60 hours. Acetone was distilled and water (1500 mL) was added. Crude 33 was extracted into Ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using Hexane as eluant to give pure 33 (130 grams, 55.6%) as a light yellow syrup. The structure was confirmed with NMR. IH-NMR (CDCl3) δ 1.59 (d, 3H, CH3), 1.60 (d, 2H, CH2), 1.75 (m, 2H, CH2), 1.89 (m, 2H, CH2), 2.38 (t, 2H, CH2), 3.69 (s, 6H, Ester), 3.88 (q, 1H, CH), 4.08 (t, 2H, OCH2), 7.10 (m, 2H, Ar), 7.40 (d, 1H, Ar), 7.68 (m, 3H, Ar).
With disodium hydrogenphosphate; potassium carbonate; sodium iodide In acetone for 24h; Heating / reflux;
12 6-{2-Methoxy-4-[(8-methyl-non-6-enoylamino)-methyl]-phenoxy}-hexanoic acid methyl ester (1)
To a mixture of Capsaicin (2 g, 6.56 mmol), anhydrous K2CO3 (3 g, 22 mmol), sodium iodide (2 g, 13.3 mmol) and disodium phosphate (2 g, 14.2 mmol) in anhydrous acetone (50 ml) was added methyl 6-bromohexanoate (2 g, 9.6 mmol) and refluxed for 24 hours. Acetone was distilled off and water (15 ml) was added. Crude 12 was filtered, dried and purified by column chromatography on silica gel using benzene:ethyl acetate (9:1) to give pure 12 (1.5 g, 52.8%) as a pale white powder. The melting point was found to be 69.2-70.8° C.
52.8%
With disodium hydrogenphosphate; potassium carbonate; sodium iodide In acetone for 24h; Heating / reflux;
58 6-{2-Methoxy-4-[(8-methyl-non-6-enoylamino)-methyl]-phenoxy}-hexanoic Acid Methyl Ester (58)
Example 58 6-{2-Methoxy-4-[(8-methyl-non-6-enoylamino)-methyl]-phenoxy}-hexanoic Acid Methyl Ester (58) To a mixture of Capsaicin (2 grams, 6.56 mmol), anhydrous K2CO3 (3 grams, 22 mmol), sodium iodide (2 grams, 13.3 mmol) and Disodium phosphate (2 grams, 14.2 mmol) in anhydrous acetone (50 mL) was added methyl 6-bromo Hexanoate (2 grams, 9.6 mmol) and refluxed for 24 hours. Acetone was distilled and water (15 mL) was added. Crude 58 was filtered, dried and purified by column chromatography on silica gel using Benzene:Ethyl acetate (9:1) to give pure 58 (1.5 grams, 52.8%) as a pale white power. The melting point was found to be 69.2-70.8° C.
methyl 6-(2-nitro-5-methoxyphenoxy)hexanoate[ No CAS ]
[ 14273-90-6 ]
[ 704-14-3 ]
[ 244632-93-7 ]
methyl 6-(2-amino-5-methoxyphenoxy)hexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate;palladium; In N-methyl-acetamide;
TB 595 6-(2-isothiocyanoto-5-methoxphenoxy)hexanoic acid, represented as TB595 and shown in FIG. 3Lwas prepared by a number of steps. The first step involves the reaction of <strong>[704-14-3]2-nitro-5-methoxyphenol</strong> (1.69 g, 10 mmol) with methyl 6-bromohexanoate (2.08 g, 10 mmol) in dry dimethylformamide and anhydrous potassium carbonate (2.0 g, 14.5 mmol) at 60 C. for 12 hours to produce the intermediate ester, methyl 6-(2-nitro-5-methoxyphenoxy)hexanoate. Hydrogenation of methyl 6-(2-nitro-5-methoxyphenoxy)hexanoate using palladium-on-carbon as catalyst afforded the isolation of methyl 6-(2-amino-5-methoxyphenoxy)hexanoate which was saponified in 10% water/ethanol (1:1) solution of potassium hydroxide to give 6-(2-amino-5-methoxyphenoxy)hexanoic acid in 95% yield.
A solution of <strong>[603-86-1]2-chloro-6-nitro-phenol</strong> (0.046 mol) in N,N-dimethylformamide (150 ml) was heated to 50 C., then K2CO3 (0.069 mol) was added and the reaction mixture was stirred for 15 min. 6-Bromo-, methyl ester hexanoic acid (0.069 mol) was added and the mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated and the residue was used as such in the next step, yielding 13.88 g of intermediate 6.
A solution of <strong>[603-86-1]2-chloro-6-nitro-phenol</strong> (0.046 mol) in N, N-DIMETHYLFORMAMIDE (150 ML) was heated to 50 C, then K2CO3 (0.069 mol) was added and the reaction mixture was stirred for 15 min. 6-Bromo-, methyl ester hexanoic acid (0.069 mol) was added and the mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated and the residue was used as such in the next step, yielding 13.88 g of intermediate 6.
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 24h;Product distribution / selectivity;
Di-tert-butyliminodiacetate (1.35 g, 5.50 mmol) was dissolved in anhydrous DMF (10 mL). Potassium carbonate (0. 78 g, 5.64 mmol), potassium iodide (0.79 g, 5.27 mmol) and methyl 6-bromohexanoate (1. 15 g, 5.50 mmol) were added and the resulting suspension was stirred at room temperature for 24h under N2 atmosphere. The reaction was diluted with methylene chloride (around 50 mL) and washed with water (3 x 50 mL). The organics were dried (Na 2SO4) and the solvent was removed under reduced pressure. The product was isolated by column chromatography (silica gel' ; Hexanes : EtOAc 7: 1) as clear oil. The isolated yield was 686 mg (1.84 mmol, 33%). 'H NMR and LC/MS data identical to the ones for the product of method A.
With sodium iodate; potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16h;
1
Sarcosine tert-butyl ester hydrochloride (10.0 g, 5.50 mmol) was suspended in anhydrous DMF (10 mL) under N2. Potassium carbonate (1.9 g, 13.7 mmol) and sodium iodate (0. 82 g, 5.47 mmol) were added, followed by methyl 6-bromohexanoate (1.41g, 6.78 mmol). The solution was stirred at 60°C for 16h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL) and washed with water and sat. NaHCO3. The organic phase was dried on Na 2SO4 and the solvent was removed. The product was isolated by column chromatography (silica gel; Hexanes: EtOAc 4: 1-> 1: 1) as clear oil. The isolated yield was 1.24 g (4.54 mmol, 82%). 'H NMR (CDC13) : 8 3.87 (s, 3H), 3.34 (s, 2H), 2.68 (t, J= 7. 4 Hz, 2H), 2.56 (s, 3H), 2.52 (t, J= 7. 0 Hz, 2H), 1.94-1. 46 (m, 6H), 1.67 (s, 9H). MS (CI) : m/z= 274 (M+1), 218 (M+1-t- Bu).
With disodium hydrogenphosphate; potassium carbonate; sodium iodide In acetone for 16h; Heating / reflux;
22 6-[2-Methoxy-4-(2-methoxycarbonyl-vinyl)-phenoxy]-hexanoic Acid Methyl Ester (22)
Example 22 6-[2-Methoxy-4-(2-methoxycarbonyl-vinyl)-phenoxy]-hexanoic Acid Methyl Ester (22) To a mixture of methyl ferulate (44 grams, 211 mmol), anhydrous K2CO3 (102 grams, 738 mmol), Sodium iodide (8.8 grams, 59 mmol), disodium phosphate (8.8 grams, 62 mmol) in anhydrous acetone (900 mL) was added methyl 6-bromo hexanoate (61 grams, 292 mmol) and refluxed for 16 hours. Acetone was distilled and water (600 mL) was added. Crude 22 was filtered, dried and recrystallized from methanol to give pure 22 (52 grams, 73.2%) as a white fluffy powder. The melting point was found to be 90-91.8° C. The structure was confirmed with IR and NMR. IH-NMR (CDCl3) δ 1.53 (m, 2H, -CH2-), 1.72 (m, 2H, -CH2), 1.91 (m, 2H, -CH2-), 2.38 (q, 2H, CH2), 3.65 (s, 3H, ester), 3.80 (s, 3H, -OCH3), 3.89 (s, 3H, ester), 6.30 (d, 1H, J=17 Hz, CH=CH), 6.81 (d, 1H, Ar), 7.02 (d, 2H, Ar), 7.12 (dd, 1H, Ar), 7.62 (d, 1H, J=17 Hz, CH=CH).
With potassium carbonate; In acetone; for 6h;Heating / reflux;
Example 9 3-Methoxy-4-(5-methoxycarbonyl-pentyloxy)-benzoic Acid Ethyl Ester (9) To a mixture of Ethyl vanillate (40 grams, 204 mmol), anhydrous K2CO3 (120 grams, 868 mmol) in anhydrous acetone (750 mL) was added methyl 6-bromo hexanoate (56 grams, 268 mmol) and refluxed for 6 hours. Acetone was distilled and water (600 mL) was added. Crude 9 was filtered, dried, and recrystallized from a mixture of Toluene:Hexane (1:6) to give pure 9 (46 grams, 96.6%) as a white powder. The melting point was found to be 42.5-43.5 C. The structure was confirmed by I.R and NMR. IH-NMR (CDCl3) delta 1.38 (t, 3H, -OCH2CH3), 1.52 (m, 2H, CH2), 1.69 (m, 2H, CH2), 1.85 (m, 2H, CH2), 2.32 (t, 2H, CH2), 3.62 (s, 2H, OCH3), 3.84 (s, 2H, Ester), 4.02 (t, 2H, -OCH2), 4.34 (q, 2H, -OCH2CH3), 6.83 (d, 1H, Ar), 7.28 (dd, 1H, Ar), 7.58 (dd, 1H, Ar).
With disodium hydrogenphosphate; potassium carbonate; sodium iodide In acetone for 18h; Heating / reflux;
44 6-(7-Oxo-7H-furo[3,2-g]chromen-9-yloxy)-hexanoic Acid Methyl Ester (44)
Example 44 6-(7-Oxo-7H-furo[3,2-g]chromen-9-yloxy)-hexanoic Acid Methyl Ester (44) To a mixture of Xanthotoxol (10 grams, 49.5 mmol), anhydrous K2CO3 (25 grams, 180 mmol), sodium iodide (15 grams, 100 mmol), disodium phosphate (25 grams, 177 mmol) in anhydrous acetone (500 mL) was added methyl 6-bromo hexanoate (15 grams, 72 mmol) and refluxed for 18 hours. Acetone was distilled and water (200 mL) was added. Crude 44 was extracted into ethyl acetate, solvent distilled and purified by column chromatography on silica gel using benzene as a eluant to give pure 44 (1.5 grams, 9.2%) as a white powder. The melting point was found to be 49-50.5° C. The structure was confirmed with IR and NMR. IH-NMR (CDCl3) δ 1.63 (m, 6H, -CH2), 2.35 (t, 2H, -CH2-), 3.62 (s, 3H, Ester), 4.42 (t, 2H, OCH2) 6.31 (d, 1H, J=12.6 Hz, Pyran), 6.79 (d, 1H, J=1 Hz, Furan), 7.31 (s, 1H, Ar), 7.65 (d, H, J=1 Hz, Furan), 7.73 (d, 1H, J=12.6 Hz, Pyran).
With disodium hydrogenphosphate; potassium carbonate; sodium iodide In acetone for 28h; Heating / reflux;
51 6-[3-(4-Methoxy-phenyl)-4-oxo-4H-chromen-7-yloxy]-hexanoic Acid Methyl Ester (51)
Example 51 6-[3-(4-Methoxy-phenyl)-4-oxo-4H-chromen-7-yloxy]-hexanoic Acid Methyl Ester (51) To a mixture of 7-hydroxy-4'-methoxy isoflavone (10 grams, 37.3 mmol), anhydrous K2CO3 (30 grams, 217 mmol), sodium iodide (2 grams, 13.3 mol), disodium phosphate (3 grams, 21.2 mmol) in anhydrous acetone was added methyl 6-bromo hexanoate (13 grams, 62.2 mmol) and refluxed for 28 hours. Acetone was distilled and water (150 mL) was added. Crude 51 was filtered, dried and purified by column chromatography on silica gel using chloroform as eluant to give pure 51 (8 grams, 54.2%) as a white powder. The melting point was found to be 130-133° C. The structure was confirmed with IR and NMR. IH-NMR (CDCl3) δ 1.56 (m, 2H, CH2), 1.74 (m, 2H, CH2), 1.84 (m, 2H, CH2), 2.38 (t, 2H, CH2), 3.66 (s, 3H, ester), 3.82 (s, 3H, OCH3), 4.04 (t, 2H, OCH2), 6.86 (s, 1H, Ar), 6.92 (d, 2H, Ar), 7.24 (d, 2H, Ar), 7.84 (s, 1H, Pyran), 8.16 (d, 1H, Ar).
With disodium hydrogenphosphate; potassium carbonate; sodium iodide; In acetone; for 8h;Heating / reflux;
Example 41 6-(7-oxo-7H-furo[3,2-g]chromen-4-yloxy)-hexanoic Acid Methyl Ester (41) To a mixture of <strong>[486-60-2]Bergaptol</strong> (5 grams, 24.7 mmol), anhydrous K2CO3 (12.5 grams, 90 mmol), Sodium iodide (7.5 grams, 50 mmol), disodium phosphate (12.5 grams, 88 mmol) in anhydrous acetone (250 mL) was added methyl 6-bromo hexanoate (7.5 grams, 35.9 mmol) and refluxed for 8 hours. Acetone was distilled and water (100 mL) was added. Crude 41 was filtered and recrystallized in methanol to give pure 41 (3 grams, 36.8%) as a white powder. The melting point was found to be 98.8-101.8 C. The structure was confirmed with IR and NMR. IH-NMR (CDCl3) delta 1.62 (m, 3H, -CH2), 1.75 (m, 2H, -CH2), 1.92 (m, 2H, -CH2), 2.38 (t, 2H, -CH2), 3.68 (s, 3H, ester), 4.45 (t, 2H, OCH2), 6.22 (d, 1H, J=12.5 Hz, pyran), 6.90 (s, 1H, furan), 7.11 (s, 1H, Ar), 7.55 (s, 1H, furan), 8.19 (d, 1H, J=12.5 Hz, pyran).
Stage #1: 4-bromo-2-nitrophenol With potassium carbonate In ISOPROPYLAMIDE at 40℃; for 0.25h; Heating / reflux;
Stage #2: methyl 6-bromohexanoate In ISOPROPYLAMIDE at 40℃; for 2h;
A6.a Example A6; a) Preparation of hexanoic acid, 6- (4-BROMO-2-NITROPHENOXY)-, methyl ester (intermediate 22)
A mixture of 4-bromo-2-nitrophenol (0.046 mol) in DMA (100 ml) was heated to 40°C and then K2C03 (0.046 mol) was added. The reaction mixture was stirred for 15 min. 6-Bromo-hexanoic acid methyl ester (0.046 mol) was added and the mixture was stirred overnight at 40 °C. Extra 6-bromo-hexanoic acid methyl ester (2 g) was added and the reaction mixture was stirred for another 2 hours. The mixture was cooled to RT and poured into ice water (400 ml). The resulting precipitate was filtered, dissolved in DCM, dried (MGS04) and filtered again. Finally, the filtrate was evaporated, yielding 14.24 g (90 %) of intermediate 22.
A mixture of 2-methyl-6-nitro-phenol (0.0065 mol) and K2CO3 (0.026 mol) in N, N dimethyl-formamide (DMF) (80 ML) was stirred at 50 C for 15 min. , then 6-bromo- , methyl ester hexanoic acid (0.0195 mol) was added dropwise and the reaction mixture was stirred for 18 hours at 50C. After completion, the reaction was quenched with ice-water and the mixture was extracted 3 times with toluene. The organic layer was separated, dried (MGS04), filtered and concentrated. The residue was used as such in the next step, yielding 100% of intermediate 1.
Stage #1: di(pyridin-2-yl)amine With sodium hydride In N,N-dimethyl-formamide at 20℃;
Stage #2: methyl 6-bromohexanoate With potassium iodide In N,N-dimethyl-formamide at 20 - 90℃;
2
NaH (112 mg, 2.92 mmol) was added to di-pyridin-2-yl-amine (500 mg, 2.92 mmol) in DMF (10 ml.) at it After 10 min, Kl (485 mg, 2.92 mmol) and methyl 6- bromohexanoate, I (0.464 ml_, 2.92 mmol) were added, and the reaction mixture was stirred at 9O0C for 21 h. Brine (200 mL) and EtOAc (200 mL) were then added, the phases were separated, and the aqueous phase was extracted with EtOAc (100 mL). The organic phases were combined, dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using CH2CI2/Me0H (100:0.5 to 100:1) as eluant to furnish Il as a colourless oil (206 mg, 24%). 1H NMR (400 MHz, CDCI3) δH: 8.35 (dd, J=2.5, 1.8Hz, 2H), 7.47-7.56 (m, 2H), 7.07 (d, J=9.2Hz, 2H), 6.86 (dd, J=6.4, 5.6Hz, 2H), 4.15-4.21 (m, 2H), 3.65 (s, 3H), 2.29 (t, J=7.5Hz, 2H), 1.61-1.77 (m, 4H), 1.34-1.45 (m, 2H). MW: 299.37. LCMS (ES): found 300.3 [MH]+, 322.3 [MNa]+.
Example 37; Preparation of Compound 37; Methyl 4-carboxymethylpyridine (5 g) and methyl 6-bromohexanoate (8 g) are heated in 1,2-dichlorobenzene (50 ml) until the reaction is complete as indicated by TLC. After cooling to room temperature, the mixture is filtered to collect the solid that is washed with ether and air-dried. The crude product is directly used for next step reaction without further purification.
Stage #1: 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere;
Stage #2: methyl 6-bromohexanoate With potassium iodide In N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere;
40%
Stage #1: 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere;
Stage #2: methyl 6-bromohexanoate With potassium iodide In N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere;
[0217] 6-(2-Methyl-l,2,3,4-tetrahydro-pyrido[4,3-i&]indol-5-yl)hexanoic acid methyl ester (18): 2-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole (17) (0.50 g, 2.7 mmol) was placed under argon and dissolved in 5 mL of anhydrous DMF. Potassium tert-butoxide (0.32 g, 2.8 mmol) was dissolved in 3 mL of anhydrous DMF and added slowly to the reaction at room temperature. The reaction turned from orange to dark brown. After 15 min, 6- bromohexanoic acid methyl ester (0.56 g, 2.7 mmol) and 5 mg of potassium iodide were added to the reaction at room temperature. The reaction was heated to 80 0C for 2 h upon which a precipitate formed and the reaction turned from dark brown to dark orange. The reaction was then diluted with 30 mL of ethyl acetate and 30 mL of water. The organic layer was isolated and the aqueous layer extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with water (2 x 20 mL), brine (15 mL), dried (Na2SO4) and concentrated in vacuo. Purification by MPCC (0-80% gradient of ethyl acetate in hexane) afforded the title compound (0.35 g, 40%) as a yellow oil. 1H NMR (400 MHz, DMSO): δ 7.46 (m, 2H), 7.17 (m, IH), 7.06 (m, IH), 4.46 (m, 2H), 4.10 (t, 2H, J= 7.0 Hz), 3.66 (m, 2H), 3.56 (s, 3H), 3.16 (m, 2H), 3.00 (s, 3H), 2.28 (t, 2H, J= 7.4 Hz), 1.66 (m, 2H), 1.55 (m, 2H), 1.29 (m, 2H). 13C NMR (100 MHz, DMSO): S 173.7, 136.7, 131.3, 124.7, 121.9, 119.7, 118.0, 110.3, 101.8, 51.6, 51.0, 50.5, 42.9, 42.2, 33.6, 29.8, 26.1, 24.6, 19.8. ESI- HRMS (m/z): [M+H]+ calcd. for Ci9H26N2O2, 315.1959; found, 315.1945.
[0221] 4-(2-Methyl-l,2^,4-tetrahydro-pyrido[4,3-6]indol-5-ylmethyl)beiizoic acid methyl ester (20): Potassium te/t-butoxide (0.95 g, 8.5 mmol) was placed under argon and suspended in 1 mL of anhydrous DMF. To it was added 2-methyl-2,3,4,5-tetrahydro-l/i- pyrido[4,3-]indole (17) (1.5 g, 8.1 mmol) dissolved in 3 mL of DMF upon which the reaction turned a deep orange in color. The reaction was stirred at room temperature for 15 min after which 4-bromomethyl-benzoic acid methyl ester (1.8 g, 8.1 mmol) was added in 1 mL of DMF along with approximately 5 mg of potassium iodide. The reaction then turned a light orange in color. The reaction was stirred at 80C for two hours after which the reaction was quenched by the addition of 15 mL of water. The pH was adjusted to approximately 12 with 2N NaOH and the organic products were extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (0-80% gradient of ethyl acetate in hexane) afforded the title compound (1.7 g, 61%) as a yellow oil. 1E NMR (400 MHz, CD3OD): delta 7.83 (d, 2H, J= 8.3 Hz), 7.33 (d, IH, J= 7.8 Hz), 7.23 (m, 3H), 7.07 (m, IH), 6.97 (m, IH), 4.59 (s, 2H), 4.01 (s, 2H), 3.82 (s, 3H), 2.90 (t, 2H, J= 5.5 Hz), 2.84 (t, 2H, J= 5.3 Hz), 2.48 (s, 3H). 13C NMR (100 MHz, MeOD): delta 167 '.1, 147.5, 134.9, 130.4, 129.2, 128.1, 128.0, 127.4, 120.4, 119.2, 177.7, 108.3, 108.1, 65.4, 51.0, 50.0, 40.2, 29.2, 20.3. ESI-MS (m/z): [M+H]+ 335.2 m/z.
A solution of LDA (1.07 mmol, 1.1 equiv) [prepared from diisopropylamine (0.15 mL, 1.07 mmol) in THF (2.5 mL) and n-BuLi (1.5 M in hexane, 0.7 mL, 1.07 mmol) stirred at -78 C for 30 min] was added to a solution of 4 (200 mg, 0.97 mmol, 1 equiv) in THF (1.4 ml), cooled to -78 C. The reaction mixture was allowed to warm up to -65 C (l h), cooled again to -78 C and a mixture of methyl 6-bromohexanoate (0.46 mL, 2.92 mmol, 3 equiv) and HMPA (1.1 mL, 6.14 mmol, 6.3 equiv) in THF (2.3 mL) was added. The solution was allowed to warm to rt and then stirred for 16 h. Then the reaction was quenched with saturated aqueous NH4Cl and was extracted with Et2O (3×3 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (AcOEt/petroleum ether, 1:9 to 1:1) to afford 18 (45 mg, 14%) as a pale yellow oil. TLC Rf 0.67 (silica gel, AcOEt/petroleum ether, 1:2); IR (film) 1724 cm-1; 1H NMR (300 MHz, CDCl3) delta 7.35-7.15 (m, 5H, Ph), 3.75 (s, 3H, CO2Me), 3.66 (s, 3H, CO2Me), 3.67-3.62 (m, 2H, CH2Ph), 3.19-3.05 (m, 2H, H-4), 2.52 (m, 1H, H-3a), 2.30 (t, 2H, J=7.43 Hz, H-5'), 2.04-1.86 (m, 2H, H-3b+H-1'a), 1.79 (m, 1H, H-1'b), 1.70-1.56 (m, 2H, H-4'), 1.43-1.02 (m, 4H, H-2', H-3'); 13C NMR (75 MHz, CDCl3) delta 174.3 (CO), 174.2 (CO), 138.7 (Cq-Ar), 128.7 (2CH-Ar), 128.4 (2CH-Ar), 127.0 (1CH-Ar), 72.3 (C-2), 56.1 (CH2Ph), 51.61 (OCH3), 51.56 (OCH3), 49.8 (C-4), 34.1 (C-5'), 29.6 (C-1'), 26.3 (C-2', C-4'), 25.0 (C-3), 23.7 (C-3'); HRMS (ESI) [M+H]+ calcd for C19H28NO4: 334.201, found 334.201.
Stage #1: (4S,4’S)-2,2’-ethylidenebis[4,5-dihydro-4-phenyloxazole] With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 0.5h;
Stage #2: methyl 6-bromohexanoate In tetrahydrofuran at 0 - 20℃; for 6h; Reflux;
Stage #1: (4R,4’R)-2,2’-ethylidenebis[4,5-dihydro-4-phenyloxazole] With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 0.5h; Reflux;
Stage #2: methyl 6-bromohexanoate In tetrahydrofuran at 0 - 20℃; for 6h; Reflux;
1,1-di-tert-butyl 6-methyl 1-methylhexane-1,1,6-tricarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
[00140] A lOOmL three-necked flask was charged with 5.7g (17.8 mmol, 1.0 eq.) 2- methyl di-tert-butyl malonate, 30ml dry tetrahydrofurane and the resulting solution was cooled to 0C. Into the well stirred reaction mixture 783mg (19.6 mmol, 1.1 eq.) of sodium hydride were added in portions at 0C. After the addition the reaction mixture was allowed to warm to room temperature and a solution of 3.7 g (17.8 mmol, 1.0 eq.) 6- bromohexanoic acid methyl ester dissolved in tetrahydrofurane (10ml) was added and the reaction mixture was refluxed overnight. Monitoring of the reaction: a small sample of the well-stirred reaction mixture was added into a mixture of water and ethyl acetate and the organic phase was analyzed by TLC (silica plate, eluent was hexane/MTBE = 5/1). The reaction was complete. Into the reaction mixture water (30ml) and ethyl acetate (50ml) was added. The layers were separated and the aqueous phase was extracted with ethyl acetate (2x 50 ml). The combined organic phases was washed with brine (50ml), dried over Na2S04 and evaporated to dryness. The crude product (7.6g) was purified by vacuum distillation (128-132C/0.9 mbar). Yield of product: 2.7g (7.5 mol, 42%) colorless oil. Analysis: GC: 98.3%
1-(6-methoxy-6-oxohexyl)pyridazinium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
In toluene at 70℃; for 5h; Sonication; Green chemistry;
General Procedure for the Synthesis of N-alkylpyridazinium Halides 1-8 with Ultrasonic Irradiation
General procedure: Pyridazine (1.0 eq.) and an alkyl halide (1.1 eq.) were added totoluene (15 mL) and placed in a closed vessel and exposed to irradiation for 5 h at 70 °C in a sonicator until a precipitate was formed. The obtained solid was filtered and washed with ethyl acetate to afford the desired pyridazinium IL
6-methoxy-6-oxohexyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.42 g
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2h;
Step 1:- Synthesis of 6-methoxy-6-oxohexyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoate (53)
To a stirred solution of acid 18 (0.500 g, 1.10 mmol) in DMF (6 mL) was added K2CO3 (0.305g, 2.21 mmol) and methyl 6-bromohexanoate 52 (0.231g, 1.10 mmol) at RT and the reaction mixture was heated at 60 °C for 2h. The reaction mixture was diluted with ice cold water and extracted with ethyl acetate (23X3mL). Organic layer was washed with brine solution, dried over anhydrous sodium sulfate, evaporated under vacuum and was purified by normal phase silica gel chromatography to afford 0.42g of 53.LCMS: 580.2 (M+1)+
methyl 6-((5-hydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)hexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 6h; Inert atmosphere;
Ethyl-2-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)acetate (7a)
General procedure: To a solution of Chrysin (1.00g, 3.93mmol) in DMF (40mL) was added K2CO3 (1.09g, 7.86mmol) and compound 6a (1.31g, 7.86mmol) under Ar. The mixture was stirred at 70°C for 6h. The mixture was then diluted with EtOAc (200mL) and washed with saturated NaCl solution (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (CH2Cl2: CH3OH=90:1) to afford compound 7a (1.08g, 81%) as a pale yellow solid.
20%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6h;
7.1 1) Preparation of Compound (7-1)
The apigenin (400.0 mg, 1.48 mmol) was dissolved in N,N-dimethylformamide (14 mL).Potassium carbonate (410 mg, 2.96 mmol), methyl 6-bromohexanoate (371 mg, 1.78 mmol) was added to the above mixture, and the system was heated to 80 ° C for 6 hours, 1N HCl (20 mL × 3), The ester was extracted (20 mL × 2), and the organic phase was washed with brine (20 mL)(light yellow solid, 600.0 mg, yield: 20%).
1-hexyl-3-(6-methoxy-6-oxohexyl)-1H-imidazol-3-ium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
In toluene; at 80℃; for 0.333333h;Microwave irradiation;
General procedure: 1-Hexylimidazole (1 eq) and the appropriate alkyl halide (1 eq) were placed in a closed vessel and exposed to irradiation for 20 min at 80 C using a microwave irradiation. The product was then collected as described in the conventional procedure outlined earlier.
methyl 6-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)hexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 6h; Inert atmosphere;
Ethyl-2-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)acetate (7a)
General procedure: To a solution of Chrysin (1.00g, 3.93mmol) in DMF (40mL) was added K2CO3 (1.09g, 7.86mmol) and compound 6a (1.31g, 7.86mmol) under Ar. The mixture was stirred at 70°C for 6h. The mixture was then diluted with EtOAc (200mL) and washed with saturated NaCl solution (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (CH2Cl2: CH3OH=90:1) to afford compound 7a (1.08g, 81%) as a pale yellow solid.
methyl 6-((5-hydroxy-2-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)hexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 6h; Inert atmosphere;
Ethyl-2-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)acetate (7a)
General procedure: To a solution of Chrysin (1.00g, 3.93mmol) in DMF (40mL) was added K2CO3 (1.09g, 7.86mmol) and compound 6a (1.31g, 7.86mmol) under Ar. The mixture was stirred at 70°C for 6h. The mixture was then diluted with EtOAc (200mL) and washed with saturated NaCl solution (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (CH2Cl2: CH3OH=90:1) to afford compound 7a (1.08g, 81%) as a pale yellow solid.
B Step B - Synthesis of intermediate A-2
To a solution of A-1 (500 mg, 2.66 mmol) in acetonitrile (2 mL) was added methyl 6- bromohexanoate (1.67 g, 7.97 mmol). The reaction mixture was stirred at 50 °C for 16 h then concentrated under reduced pressure. The residue was diluted with Et2O, stirred at RT for 1 h, filtered, washed with Et2O and dried to afford A-2. LC/MS: [M]+ = 317.2.
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