* 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.
With sodium hydroxide; water In methanol for 4 h; Heating / reflux
C) 3, 4-Dibenzyloxy benzoic acid; A solution of sodium hydroxide (1.2 g) in methanol (100 ml) was added to a solution of 3,4-dibenzyloxy benzoic acid methyl ester (4.64 g) in methanol (50 ml) and refluxed for 4 hrs. After removal of methanol under reduced pressure the residue was dissolved in water (100 ml) and washed with ethyl acetate (2 x 50 ml). The aqueous layer was acidified with 2N hydrochloric acid to pH 2. The precipitated product was collected by filtration which on drying under vacuum provided 2.4 g of 3,4-benzyloxy benzoic acid. (Yield = 74percent) 'H NMR CDC13 7.7 (2H, b, s) 7.27-7.5 (10H, m) 6.98 (lH, d, J 8Hz) 5.26 (2H, s) 5.22 (2H, s)
32.2 g
With sodium hydroxide In tetrahydrofuran; methanol; water at 80℃; for 1 h;
To a solution of 8b (15.0 g, 97.4 mmol) in MeOH (360 mL) was added SOCl2 (7.9 mL, 48.7 mmol) fordropwise at 60 °C. The reaction mixture was stirred at 60 °C for 10 h. Then, the reaction mixture wasevaporated under reduced pressure. The crude mixture was applied to following reaction without furtherpurification.To a mixture of crude residue and K2CO3 (40.4 g, 0.292 mol) in DMF (162 mL) was added benzylbromide (29.0 mL, 0.244 mol) at 100 °C. The reaction mixture was stirred at 100 °C for 16 h. Then, thereaction mixture was filtered through a pad of Celite, diluted with H2O, and extracted with EtOAc. Theorganic layer was washed with water and brine, dried over anhydrous MgSO4, and evaporated underreduced pressure. The crude mixture was applied to following reaction without further purification.To a stirred solution of crude residue in MeOH/THF (1/1, 324 mL) were added 4 M NaOH aq. (85 mL,0.34 mol) at 80 °C. The reaction mixture was stirred at same temperature for 1 h. Then, the reactionmixture was quenched with 6 M HCl aq., filtered and washed with H2O to give 9b (32.2 g, 96.3 mmol,99percent) as a white solid.Spectral data for 9b were in good agreement with those reported in reference.16
Reference：
[1] Canadian Journal of Chemistry, 2006, vol. 84, # 10, p. 1411 - 1415
[2] Patent: WO2005/113489, 2005, A1, . Location in patent: Page/Page column 90
[3] European Journal of Medicinal Chemistry, 1997, vol. 32, # 5, p. 409 - 423
[4] Heterocycles, 2014, vol. 8, # 2, p. 1371 - 1396
[5] European Journal of Medicinal Chemistry, 2017, vol. 134, p. 24 - 33
2
[ 882427-72-7 ]
[ 1570-05-4 ]
Yield
Reaction Conditions
Operation in experiment
2.81 g
Stage #1: With sodium hydroxide In methanol; water at 20℃; Inert atmosphere Stage #2: With hydrogenchloride In water
General procedure: A solution of hydroxy benzoic acid (1.0 equiv), BnBr (3-5 equiv) and K2CO3 (10-15 equiv) in DMF was stirred overnight under argon. After filtration, the solution was concentrated in vacuo to afford the crude product. The crude product was dissolved in methanol and an aqueous solution of NaOH (75 equiv) was added. The mixture was stirred at room temperature overnight and the solution concentrated in vacuo to remove the methanol. The residue was acidified with 10 percent HCl to pH 2 and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by recrystallization from CH2CH2 / MeOH.
Reference：
[1] Synthetic Communications, 2006, vol. 36, # 5, p. 587 - 597
[2] Angewandte Chemie - International Edition, 2010, vol. 49, # 52, p. 10210 - 10213
[3] Inorganic Chemistry, 2010, vol. 49, # 8, p. 3737 - 3745
[4] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 20, p. 11081 - 11089
[5] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 7, p. 2191 - 2194
[6] European Journal of Medicinal Chemistry, 2011, vol. 46, # 6, p. 2386 - 2396
[7] Patent: CN105596337, 2016, A, . Location in patent: Paragraph 0106; 0107
3
[ 99-50-3 ]
[ 100-39-0 ]
[ 1570-05-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 4, p. 1080 - 1083
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 15, p. 4575 - 4580
[3] Patent: US2015/342984, 2015, A1, . Location in patent: Paragraph 0175
4
[ 5447-02-9 ]
[ 1570-05-4 ]
Reference：
[1] Archiv der Pharmazie, 1997, vol. 330, # 9-10, p. 313 - 316
[2] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 9, p. 1873 - 1882
[3] Yakugaku Zasshi, 1952, vol. 72, p. 1081,1083[4] Chem.Abstr., 1953, p. 10536
[5] Helvetica Chimica Acta, 1962, vol. 45, p. 270 - 276
[6] Archives of Pharmacal Research, 2011, vol. 34, # 7, p. 1065 - 1070
5
[ 99-50-3 ]
[ 100-44-7 ]
[ 1570-05-4 ]
Reference：
[1] Canadian Journal of Biochemistry and Physiology, 1959, vol. 37, p. 1439,1442
[2] Patent: US5498748, 1996, A,
[3] Patent: EP636941, 1995, A1,
6
[ 3943-89-3 ]
[ 100-39-0 ]
[ 584-08-7 ]
[ 1570-05-4 ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium hydroxide In methanol; water; butanone
(B) 3,4-DIBENZYLOXYBENZOIC ACID To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-185° C. The NMR and IR spectra were consistent with the assigned structure.
92%
With potassium hydroxide In methanol; water; butanone
3,4-Dibenzyloxybenzoic Acid To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-5° C. The NMR and IR spectra were consistent with the assigned structure.
92%
With potassium hydroxide In methanol; water; butanone
(b) 3,4-Dibenzyloxybenzoic Acid To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-185° C. The NMR and IR spectra were consistent with the assigned structure.
Reference：
[1] Patent: US4582855, 1986, A,
[2] Patent: US4402974, 1983, A,
[3] Patent: US4798892, 1989, A,
With thionyl chloride;pyridine; for 4h;Heating / reflux;
3, [4-DIBENZYLOXYBENZOIC] acid (3.1 g. 9.3 mmol) was combined with pyridine (5 drops, catalytic) and thionyl chloride (15 ml, 205 [MMOL).] The solution was heated at reflux for 4 h, cooled, and excess thionyl chloride removed under reduced pressure. The crude product was dissolved in benzene (50 [ML),] and stripped of solvent under vacuum. The benzoyl chloride (theoretical yield 3.4 g) was then dissolved in dichloromethane and used directly in the next step.
With oxalyl dichloride; In dichloromethane; at 20℃; for 2h;
Reference Example 1; General syntheis methods of side chain amines (a)-(n); As illustrated in the synthesis route above, an equivalent mole of oxalyl chloride was added to a methylene chloride (10 V) solution (suspension) of benzoic acid derivative (A), which corresponds to side chains (a)-(n), followed by stirring at room temperature for 2 hours. After concentration in vacuo until reaching about-half volume, the resultant was added to an amine (1.0 equivalent/Et3N (1.2 equivalent)/THF solution), which corresponds to side chains (a)-(n), that had been cooled to - 20°C, subsequently stirring for 30 minutes. Diluting with methylene chloride, washing with water, drying, and then concentrating the filtrate yielded desired amine (C) (side chains (a)-(n)) (90percent or higher yield). Physical constans of side chains (a)-(n) are shown below.Side chain (a) [Show Image] 1H-NMR (CDCl3) delta(delta): 1.72-1.88 (6H, m), 2.50-2.62 (4H, m), 2.68 (2H, t, J = 5.7 Hz), 3.52-3.57 (2H, m), 5.19 (4H, s), 6.90 (1H, d, J =8.7 Hz), 7.21-7.60 (11H, m), 7.56 (1H, d, J = 1.8 Hz), 8.49 (1H, bs). LC/MS (ES +) : 445 (M+H+)
General procedure: A solution of hydroxy benzoic acid (1.0 equiv), BnBr (3-5 equiv) and K2CO3 (10-15 equiv) in DMF was stirred overnight under argon. After filtration, the solution was concentrated in vacuo to afford the crude product. The crude product was dissolved in methanol and an aqueous solution of NaOH (75 equiv) was added. The mixture was stirred at room temperature overnight and the solution concentrated in vacuo to remove the methanol. The residue was acidified with 10 percent HCl to pH 2 and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by recrystallization from CH2CH2 / MeOH.
With water; potassium hydroxide; In ethanol; at 20 - 70℃;
Take 1.5g (3.53mmol) compound 16a in 50mL round bottom flask, was added 20mL of ethanol, taking 1g (17.85mmol) of potassium hydroxide was dissolved in 10mL of water and slowly added to the flask and the reaction stirred until the reaction mixture was homogeneous at 70 status.The reaction mixture was evaporated to an excess of ethanol, add 100mL water, cooled to room temperature.4mol·L-1 was added dropwise to acidified till no white precipitate (pH3 ~ 4), filtered, washed with water, suction filtered and dried to give a white solid.
<i>N</i>-{4-[3-(3,4-dihydroxy-benzoylamino)-propylamino]-butyl}-2-({4-[3-(3,4-dihydroxy-benzoylamino)-propylamino]-butylcarbamoyl}-methyl)-2-hydroxy-succinamic acid; compound with GENERIC INORGANIC NEUTRAL COMPONENT[ No CAS ]
<i>N</i>-(4-{benzyl-[3-(3,4-bis-benzyloxy-benzoylamino)-propyl]-amino}-butyl)-2-[(4-{benzyl-[3-(3,4-bis-benzyloxy-benzoylamino)-propyl]-amino}-butylcarbamoyl)-methyl]-2-hydroxy-succinamic acid[ No CAS ]
(3R,4R)-3-(3,4-Bis-benzyloxy-benzoylamino)-4-[3,5-bis-benzyloxy-4-(2-benzyloxy-6-benzyloxycarbonyl-benzoyl)-benzoyloxy]-pyrrolidine-1-carboxylic acid benzyl ester[ No CAS ]
(1) 2-Amino-4-[1-(3,4-dibenzyloxybenzoyl)-4-piperidinyl]-6-(4-methoxyphenylmethyl) pyrimidine STR73 To a solution of 2-amino-4-(4-methoxyphenylmethyl)-6-(4-piperidinyl)pyrimidine (160 mg, 0.54 mmol), <strong>[1570-05-4]3,4-dibenzyloxybenzoic acid</strong> (179 mg, 0.54 mmol) and 1-hydroxybenzotriazole (72 mg, 0.54 mmol) in dichioromethane (150 ml) were added 1-ethyl-3-(N, N'-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. After stirring for about 30 minutes, the mixture was washed successively with saturated sodium hydrogen carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and then evaporated. The residue was purified by column chromatography (chloroform:methanol=99:1) to give the titled compound (477 mg). 1 H-NMR (CDCl3): delta 1.77 (4H, m), 2.59 (1H, m), 2.84 (2H, m), 3.78 (3H, s), 3.82 (2H, s), 3.90 (1H, m), 4.70 (1H, m), 5.11 (2H, s), 5.17 (2H, s), 5.18 (2H,s), 6.24 (1H, s), 6.84-7.00 (5H, m), 7.14-7.44 (12H, m).
(2) A mixture of 3,4-dibenzyloxybenzoic acid (10 g, 30 mmole) obtained in above (1) and thionyl chloride (10.7 g, 90 mmole) was heated slowly, reacted with stirring for 1 hour at 85° C. and then evaporated in vacuo to give 10.3 g of 3,4-dibenzyloxy benzoyl chloride as white crystals having a melting point of 92.5°-94.5° C.
(2) A mixture of 3,4-dibenzyloxybenzoic acid (10 g, 30 mmole) obtained in above (1) and thionyl chloride (10.7 g, 90 mmole) was heated slowly, reacted with stirring for 1 hour at 85°C and then evaporated in vacuo to give 10.3 g of 3,4-dibenzyloxy benzoyl chloride as white crystals having a melting point of 92.5-94.5°C. (3) Using 3,4-dibenzyloxybenzoyl chloride (5.2 g, 14.6 mmole) obtained in above (2) and 2,6-dihydroxy-9-anthrone (1 g, 4.4 mmole), the reaction was carried out in the same manner as described in Synthesis Example 1,
54
[ 3943-89-3 ]
[ 100-39-0 ]
[ 584-08-7 ]
[ 1570-05-4 ]
Yield
Reaction Conditions
Operation in experiment
101 g (92%)
With potassium hydroxide; In methanol; water; butanone;
(B) 3,4-DIBENZYLOXYBENZOIC ACID To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-185° C. The NMR and IR spectra were consistent with the assigned structure.
101 g (92%)
With potassium hydroxide; In methanol; water; butanone;
3,4-Dibenzyloxybenzoic Acid To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-5° C. The NMR and IR spectra were consistent with the assigned structure.
101 g (92%)
With potassium hydroxide; In methanol; water; butanone;
(b) 3,4-Dibenzyloxybenzoic Acid To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil. This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-185° C. The NMR and IR spectra were consistent with the assigned structure.
3-t-butylamino-2-hydroxypropyl 3,4-dibenzyloxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; In tetrahydrofuran; pyridine; toluene;
3-t-Butylamino-2-hydroxypropyl 3,4-dibenzyloxybenzoate To 20 g (0.06 mole) of the <strong>[1570-05-4]3,4-dibenzyloxybenzoic acid</strong> in 200 ml of toluene was added 60 g (0.33 mole) of thionyl chloride. The reaction mixture was evaporated to dryness in vacuo to give a solid; m.p. 85°-86°. The solid was dissolved in 100 ml of dry THF and added dropwise into a solution of 17.7 g (0.06 mole) 3-(t-butylamino)-1,2-propanediol in 50 ml of pyridine and 50 ml of toluene. The reaction mixture was stirred for 1 hour at 25° C. and partitioned between ether and 5percent K2 CO3 solution. The ether layer was evaporated to dryness to give 30 g of solid.
Compound 12 was prepared according a procedure reported by Tranchimand et al.33 and spectral data were in accordance with literature. Briefly, benzyl bromide (14 mL, 117 mmol) and K2CO3 (10.7 g, 78 mmol) were added over a solution of 3,4-dihydroxybenzoic acid (11) (2.00 g, 13 mmol) in dry DMF (30 mL) under an argon atmosphere and heated to 60 °C for 20 h. The reaction mixture was cooled to room temperature, filtered and the solvent was removed under reduced pressure. The residue was dissolved in AcOEt (10 mL) and washed with 1 M HCl (3 x 5 mL) and brine (5 x 5 mL). The combined organic extracts were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was dissolved in CH3OH (38 mL), and treated with 2.3 MNaOH (14 mL) and the mixture was heated under reflux for 1 h. Then, solvents were evaporated under reduced pressure and the residue was treated with H2O (5 mL) and then extracted with Et2O (3 6 mL). The aqueous phase was made acidic (pH 1?2) with 1 M HCl and extracted with AcOEt (3 x 5 mL). The organic extracts were dried over MgSO4, filtered and the solvent was removed under reduced pressure. Mp 187?188 °C as reported inliterature.33
With potassium carbonate; In acetonitrile; for 18h;Reflux;
Preparation of 3,4-bis(benzyloxy)benzoic acid (0175) 3,4-Dihydroxy benzoic acid, benzyl bromide, and potassium carbonate were dissolved in acetonitrile, and the solution was refluxed for 18 hours. The reaction solution was then cooled to room temperature and filtered. The solution was then concentrated and diluted with hexanes, resulting in a solid that was collected by filtration. The solid was then recrystallized in the mixture of THF and hexanes, giving rise to a pure product.
With dmap; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃;
General prodedure: A mixture of appropriate benzoic acid (1.2 equiv), 2-(1-Hydroxy-1-methyl-ethyl)-2,3-dihydro-benzofuran-6-ol 37 or 2,2-dimethyl-chroman-3,7-diol 39 (1 equiv), DCC (3 equiv) and 4-dimethylaminopyridine (DMAP) (0.2 equiv) in DMF was stirred overnight at room temperature. Then the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 3h;Inert atmosphere;
General procedure: Methylation of bergenin with iodomethane (5 equiv) in the presence of potassium carbonate (5 equiv) in DMF produced tri-O-methylnorbergenin (97percent yield). To a solution of tri-O-methylnorbergenin in dry THF (2 mL/mmol), corresponding benzoic acids (1 equiv) and Ph3P (2 equiv) were dissolved. DIAD (1.7 equiv) was added the solution under 0 °C. The mixture was stirred for 3h on rt under nitrogen and monitored by TLC. It was concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/EtOAc, 2:8) to afford the analogue as a white power (72?93percent total yield).
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