* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference:
[1] Journal of Organic Chemistry, 2012, vol. 77, # 8, p. 4171 - 4176
2
[ 4117-09-3 ]
[ 29823-21-0 ]
[ 4101-68-2 ]
Reference:
[1] Journal of Organic Chemistry, 2012, vol. 77, # 8, p. 4171 - 4176
3
[ 29823-21-0 ]
[ 17696-11-6 ]
Yield
Reaction Conditions
Operation in experiment
97%
With water; sodium hydroxide In ethanol at 0℃; for 5 h;
To a solution of ethyl 8-bromooctanoate (1.0 g, 3.98mmol) in EtOH (10 mL), 1M NaOH (3.98 mL) was addeddropwise, and the resulting mixture was stirred at 0°C for 5h. The mixture was acidified with 1M HCl and extractedwith ethyl acetate (3 10 mL). The organic layer waswashed with satd NaHCO3 (2 20 mL) and brine (2 20mL), dried over Na2SO4, filtered, and concentrated to getcompound 17 as colorless oil 0.86 g, yield 97percent.
To a solution of 8-bromooctanoic acid (5.0 g, 22 mmol) in ethanol (100 ML) was added H2SO4 (0.36 ML, 7.5 mmol) and the reaction was heated to reflux with stirring for 3 h.The crude reaction mixture was cooled to room temperature and washed H2O (100 ML), sat. NaHCO3 (2*100 ML), H2O (100 ML), dried MgSO4, and evaporated to dryness to afford a clear oil (5.5 g, 98percent yield).
98%
for 3 h; Heating / reflux
To a solution of monodispersed 8-bromooctanoic acid (5.0 g, 22 mmol) in ethanol (100 mL) was added H2SO4 (0.36 mL, 7.5 mmol) and the reaction was heated to reflux with stirring for 3 h. The crude reaction mixture was cooled to room temperature and washed H2O (100 mL), sat. NaHCO3 (2.x.100 mL), H2O (100 mL), dried MgSO4, and evaporated to dryness to afford a clear oil 11 (5.5 g, 98percent yield).
75%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12 h;
To a solution of 8-bromooctanoic acid (0.20 g, 0.89 mmol), DMAP (0.12 g, 0.99 mmol), and ethanol (0.05 g, 0.99 mmol) in methylene chloride (20 mL) was added EDCI (0.19 g, 0.99 mmol) at room temperature. After stirring for 12 h, the reaction mixture was washed with 1 N NaOH aqueous solution (15 mL) and water (30 mL), and the organic layer was dried over Na2SO4 and evaporated to give 8-bromooctanoic acid ethyl ester (0.17 g, 75percent). This bromide reacted with 4-(3-adamantan-l-yl-ureido)butyric acid 822 in the same manner as that used for the preparation of 883 to provide 879 (0.19 g, 65percent) as a solid: 1H EPO <DP n="59"/>NMR (CDCl3) 1.26 (3H, t, J = 6.9 Hz), 1.32-1.35 (6H, m), 1.59-1.66 (1OH, m), 1.82 (2H, quint, J - 6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.28 (2H, t, J = 6.9 Hz), 2.36 (2H, t, J = 6.9 Hz), 3.16 (2H, q, J = 6.9 Hz), 4.05-4.14 (5H, m), 4.31 (IH, s); LC-MS (ESI) m/z calcd for C25H42N2O5 [M + H]+ 451.31, found [M + H]+ 451.20; mp 58-59 C. Anal. (C25H42N2O5) C, H, N.
Reference:
[1] Tetrahedron Letters, 2001, vol. 42, # 2, p. 301 - 303
[2] Patent: US2003/228275, 2003, A1, . Location in patent: Page 42
[3] Patent: US2003/229009, 2003, A1, . Location in patent: Page 38
[4] Journal of Medicinal Chemistry, 2002, vol. 45, # 3, p. 563 - 566
[5] Synthesis, 1998, # 11, p. 1662 - 1669
[6] Synthesis, 2007, # 22, p. 3489 - 3496
[7] Carbohydrate Research, 2001, vol. 330, # 3, p. 295 - 307
[8] Journal of Medicinal Chemistry, 2004, vol. 47, # 8, p. 2110 - 2122
[9] Patent: WO2006/45119, 2006, A2, . Location in patent: Page/Page column 57-58
[10] Bulletin de la Societe Chimique de France, 1956, p. 1345,1350
[11] Chinese Journal of Chemistry, 2014, vol. 32, # 2, p. 157 - 162
[12] ACS Chemical Neuroscience, 2017, vol. 8, # 9, p. 1949 - 1959
5
[ 17696-11-6 ]
[ 29823-21-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
With phosphoric acid In ethanol; water; benzene
(4) Production of ethyl 8-bromocaprylate A 500-ml flask equipped with a liquid-liquid separating device for separation of water was charged with 100 g (0.45 mole) of 8-bromocaprylic acid, 100 ml of ethanol, 300 ml of benzene and 10 g of phosphoric acid, and the reaction was allowed to proceed under azeotropic removal of water for 6 hours. Thereafter, 200 ml of water and 200 ml of benzene were added to the liquid reaction mixture for extraction. The benzene layer was washed with two 100-ml portions of water and then dried over anhydrous sodium sulfate. After the benzene was distilled off, the residual liquid was distilled under reduced pressure to give 106 g (94percent yield based on the charged 8-bromocaprylic acid) of ethyl 8-bromocaprylate as a fraction boiling at 124°-125° C./4 mmHg.
Reference:
[1] Patent: US4510331, 1985, A,
6
[ 67-56-1 ]
[ 17696-11-6 ]
[ 29823-21-0 ]
Yield
Reaction Conditions
Operation in experiment
93%
at 20℃; Inert atmosphere
To an ice-salt-cooled solution of 10 g (45 mmol) of 8-bromooctanoic acid in 180 mL of ethanol is added slowly 9 mL of acetyl chloride (127 mmol) under Ar. The resulting mixture was stirred for 20 min before removing the cooling bath. The solution is allowed to stand overnight at room temperature (20 h). Solvent was removed under reduced pressure. The residual oil was dissolved in hexanes (200 mL) and washed with dilute sodium bicarbonate twice (2 x 70 mL). The aqueous phase was extracted with hexanes (100 mL). The combined organic solution was washed with brine (2 x 70 mL), dried over sodium sulfate, filtered and concentrated to give a corlorless oil (10.49 g, 41.8 mmol, 93percent).
8-(2-methoxy-phenylsulfanyl)-octanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
Example 1 - Preparation of 8-(2-Methoxy-phengammalsulfanyl)-octanoic acid (Compound 1); [94] To a 250 niL flask, equipped with a magnetic stir bar, was added ethyl 8-bromo- octanoate (13.8 mL, 66 mmol), 2-methoxybenzenethiol (8.0 mL, 66 mmol), and 80 mL ethyl alcohol. The reaction vessel was cooled with an external ice bath while potassium hydroxide (5.2g 93 mmol) was added. The reaction was allowed to warm to room temperature and stirred 16 hours under a nitrogen atmosphere. The white precipitate was removed by suction filtration and solvent removed under reduced pressure. The concentrate was then dissolved in 10 mL ethyl alcohol, treated with 90 mL of aqueous 1 N sodium hydroxide solution and heated for 1 hour at reflux. The solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4C. The product (16.2 g, 87%) was isolated by filtration as an off-white powder, mp 62-630C.SUBSTITUTE SHEET (RULE 26) <n="38"/>Found: C: 63.79 %, H: 7.91 % S: 11.25 %; C15H22O3S requires C: 63.80 %, H: 7.85 %, S: 11.35 %; IH NMR (d6-DMSO): delta 7.21, d, IH (aryl H); delta 7.15 td, IH (aryl H); delta 6.96, d, IH (aryl H); delta 6.92 td, IH (aryl H); delta 3.8, s, 3H (OCH3); delta 2.85, t, 2H (CH2 alpha to S); delta 2.2, t, 2H (CH2 alpha to COOH); delta 1.6-1.2, multiplet, 1OH (rest of CH2's).
8-(2-chloro-phenylsulfanyl)-octanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: 2-chlorothiphenol; Ethyl 8-bromooctanoate With potassium hydroxide In ethanol at 20℃; for 1h;
Stage #2: With ethanol; water at 20 - 45℃; for 99.5h;
Stage #3: With hydrogenchloride; water at 4℃; for 0.75h;
30
Example 30 -- Preparation of 8-(2-Chloro-phenylsulfanyl)-octanoic acid (Compound 30); [123] To a mini-tube equipped with a magnetic stir bar, was added 2-chlorobenzene thiol (1.0 mL, 8.2 mmol), ethyl 8-bromooctanoate (1.8 mL, 8.2 mmol), and 45 mL ethyl alcohol. Potassium hydroxide (1.5 g, 26 mmol) was added at room temperature and the reaction was allowed to stir at room temperature for 1 hr under a nitrogen atmosphere. Water (10 mL) was added and the stirring continued for 3 hours. The reaction was heated to 45°C for 0.5 hr, cooled to room temperature and stirred for an additional 96 hours. Solvent was removed under reduced pressure and the resulting solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 40C for 45 min. Product (2.24 g, 88%) was isolated as a white powder by filtration. IH NMR (d-DMSO): δ 11.96, broad s, IH (COOH); δ 7.42, dd, IH (aryl H); δ 7.33, multiplet,SUBSTITUTE SHEET (RULE 26) 2H (aryl H); δ 7.16, dt, IH (aryl H); δ 2,97, t, 2H (CH2 α to S); δ 2.17, t, (CH2 α to COOH); δ 1.6-1.25, complex, 1OH (rest of CH25S).
9 1-(7-ethoxycarbonylheptyl)-2,4,5-triphenylimidazole
EXAMPLE 9 1-(7-ethoxycarbonylheptyl)-2,4,5-triphenylimidazole A mixture of 2,4,5-triphenylimidazole (11 g), ethyl 8-bromooctanoate (18.64 g), anhydrous potassium carbonate (51.3 g) and dry butanone (350 ml) was heated at reflux for 26 h. The cooled reaction mixture was filtered to remove inorganics and the filtrate was evaporated to dryness in vacuo. The residue was stirred in hexane and unreacted 2,4,5-triphenylimidazole was collected by filtration (3.1 g). The filtrate was cooled and a white precipitate was collected. Recrystallisation from hexane gave 1-(7-ethoxy-carbonyl-heptyl)-2,4,5-triphenylimidazole (8.37 g, 48.4%) as a white solid, m.p. 65°-7°. Found C, 79.97; H, 7.32; N, 6.39%; C31 H34 N2 O2 requires: C, 79.79; H, 7.34; N, 6.00%.
To a solution of the monodispersed compound 10 (3.0 g, 8.8 mmol) in ether (90 mL) was added potassium t-butoxide (1.2 g, 9.6 mmol) and the reaction mixture was stirred for 1 h. Then dropwise addition of the monodispersed compound 11 (2.4 g, 9.6 mmol), dissolved in ether (10 mL), was added and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, 200 mL) and evaporated to dryness. The resultant oil was dissolved in ethyl acetate and washed H2O ( 2×200 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate to ethyl acetate/methanol, 10:1) was performed and afforded the monodispersed compound 12 as a clear oil (0.843 g, 19% yield).
To a solution of the non-polydispersed compound 25 (3.0 g, 8.8 mmol) in ether (90 mL) was added potassium t-butoxide (1.2 g, 9.6 mmol) and the reaction mixture was stirred for 1 h. Then dropwise addition of the non-polydispersed compound 26 (2.4 g, 9.6 mmol), dissolved in ether (10 mL), was added and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, 200 mL) and evaporated to dryness. The resultant oil was dissolved in ethyl acetate and washed H2O (2×200 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate to ethyl acetate/methanol, 10:1) was performed and afforded the non-polydispersed title compound as a clear oil (0.843 g, 19% yield).
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere;
3.1 Synthesis of compound 2a
General procedure: Ethylbromoacetate (1 equiv) was added dropwise to a solution of apigenin(1 equiv) with anhydrous K2CO3(1 equiv) in anhydrous N,N-Dimethylformamide in ice bath under an atmosphere of argon, and stirring was continued for 8 h at room temperature. The product was purified by silica gel chromatography (normal phase, 15-25% ethyl acetate in hexanes gradient). Compounds 2b-f were synthesized according to the method for 2a.
ethyl 8-(2-fluoro-4-nitrophenylamino)octanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.1%
With potassium carbonate; In acetonitrile;Reflux;
<strong>[369-35-7]2-Fluoro-4-nitroaniline</strong> (0.400 g, 2.56 mmol),Ethyl-8-bromoctanoate (0.523 g, 0.385 mmol),Potassium carbonate (1.60 g, 2.32 mmol),15 ml of acetonitrile was added to the three-necked flask and refluxed overnight.Intermediate additional potassium carbonate (0.271 g, 1.95 mmol),After completion of the reaction,Work-up gave ethyl 8- (2-fluoro-4-nitrophenylamino) octanoate as a yellow solid 0.384 g,The yield was 70.1%.
benzyl 2-(8-ethoxy-8-oxooctyloxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With potassium carbonate; In acetonitrile;Reflux;
General procedure: The corresponding alkyl bromide (2.0eq) and potassium carbonate (2.0eq) were added to a solution of benzyl 2-hydroxybenzoate (1.0eq) in CH3CN, and the mixture was refluxed. After completion of the reaction, the residue was purified by silica gel column chromatography (EtOAc/Hexane) to afford the product.
ethyl 8-(4-formyl-2,6-dimethylphenoxy)octanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With potassium carbonate In acetonitrile at 80℃; for 24h;
ethyl 4-(4-formyl-2,6-dimethylphenoxy)butanoate (14aa)
General procedure: 4-hydroxy-3,5-dimethylbenzaldehyde(13a)(1.5 g, 10 mmol) and ethyl4-bromobutanoate (1.95g, 10mmol) were dissolved in acetonitrile (100 mL) andtreated with K2CO3 (5.52g, 40mmol). The reaction mixturewas stirred at 80 °C for 24 h.Water was added to thereaction,and the aqueouslayer was extracted with EA (3 × 20 mL). The organic layers were combined,washed with water (3 × 25 mL),dried over anhydrous Na2SO4,and concentrated in vacuo to give compound 14aa(1.87g,71%).
Multi-step reaction with 3 steps
1: 18 h / 20 °C
2: sodium phosphinate / 2 h / 40 °C
3: sodium hexamethyldisilazane / tetrahydrofuran / 2 h / -78 - 20 °C
With sodium carbonate; In N,N-dimethyl-formamide; at 70℃;
Add 45 ml DMF and ethyl 8-bromooctanoate 14.50 g to a 250 ml reaction flask with a magnetic particle and a thermometer.(0.058 mol), compound 110.36 g (0.064 mol), anhydrous sodium carbonate 13.03 g (0.123 mol), stirred, warmed to 70The reaction is carried out at ±5 ° C for 2 to 2.5 hours. The temperature was lowered to room temperature, filtered, and the filtrate was poured into 420 ml of water under stirring, stirring was continued for 1 to 1.5 hours, filtered, and the filter cake was rinsed with purified water, and dried in a blast drying oven at 35 to 40 ° C for 24 hours to obtain a pale pink solid of 18.3 g. The yield was 95.1percent.
Stage #1: (S)-(+)-1-bromo-2-methylbutane With iodine; magnesium In tetrahydrofuran at 30℃; for 3h; Inert atmosphere;
Stage #2: Ethyl 8-bromooctanoate With copper(I) bromide In tetrahydrofuran at 10℃; for 3h; Inert atmosphere;
4.1.2. Ethyl 10-methyldodecanoate (6)
General procedure: To a mixture of Mg turnings (2.80 g, 115 mmol) and a piece of I2 in THF (42.0 g), a solution of 3 (14.5 g, 96.0 mmol) in THF (43.5 g)was added dropwise at 30 °C. After stirring for 3 h, the resulting Grignard reagent was added dropwise to a solution of 4 (20.1 g, 80.0 mmol) and CuBr (0.29 g, 2.0 mmol) in NMP (31.7 g, 320 mmol) and THF (71.1 g) at 10 °C. After stirring for 3 h, the reaction mixture was poured into 20 % aq. NH4Cl solution and extracted with hexane. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was distilled to give 6 (18.7 g, 96 % yield).