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Structure of 6515-58-8 * Storage: {[proInfo.prStorage]}
* 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 N-Bromosuccinimide; dibenzoyl peroxide In dichloromethane for 2 h; Reflux
Methylmethylbenzoic acid (2.0 g, 14.7 mmol)And benzoyl peroxide (BPO, 0.036 g, 0.15 mmol)Was dissolved in dichloromethane (6 mL) and heated to reflux,NBS (2.6 g, 14.7 mmol) was added in portions,Continue to heat reflux 2h,After cooling to room temperature, the reaction was quenched with water (10 mL), extracted with dichloromethane (50 mL), washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4,Concentrated to give a pale yellow solid 2.7 g, yield 86percent
85%
With N-Bromosuccinimide In tetrachloromethane at 25℃; for 3 h; Reflux
To a suspension of 3-Methyl-benzoic acid (40.0 g, 293 mmol) in carbon tetrachloride (400 mL) were added AIBN (1 g, 0.58 mmol) and N-Bromosuccinamide (52.0 g, 8.07 mmol) at 25 °C. The reaction mixture was refluxed over a period of 3 h. The resulting reaction mixture was filtered when it was hot and the filtrate was diluted with ethyl acetate, washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain 3-Bromomethyl-benzoic acid as a colorless solid (54 g, 85 percent).
85%
With N-Bromosuccinimide In tetrachloromethane at 25℃; for 3 h; Reflux
To a suspension of 3-Methyl-benzoic acid (40.0 g, 293 mmol) in carbon tetrachloride (400 mL) were added AIBN (1 g, 0.58 mmol) and N-Bromosuccinamide (52.0 g, 8.07 mmol) at 25° C. The reaction mixture was refluxed over a period of 3 h. The resulting reaction mixture was filtered when it was hot and the filtrate was diluted with ethyl acetate, washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain 3-Bromomethyl-benzoic acid as a colorless solid (54 g, 85percent).
61%
With N-Bromosuccinimide In chloroform for 2.75 h; 500 W quartz halogen lamp at 75percent power; Heating / reflux
In a 1 L round bottom flask fitted with a reflux condenser, a stirred suspension of 10.00 g m-toluic acid and 14.37 g (1.1 eq.) N-bromosuccinimide in 735 mL chloroform was sparged for 0.5 h with nitrogen. The sparging was discontinued and the stirred suspension was irradiated under a nitrogen atmosphere using a 500 W quartz halogen lamp at 75percent power, causing the solids to dissolve and the reaction to reflux. The red color of the reaction became clear after 1.25 h, and another 14.37 g of N-bromosuccinimide was added. The reaction mixture was stirred and irradiated under nitrogen atmosphere with a 500 W quartz halogen lamp at 75percent power for another 1.5 h, at which time the solution was clear. The solvent volume was reduced in vacuo to about 100 mL, and then the solution was cooled to -20° C., forming crystals. The resultant suspension was vacuum filtered through a bed of dry silica, which was then eluted with 800 mL of chloroform. The chloroform filtrate volume was reduced in vacuo to about 100 mL, and then the chloroform was cooled to -20° C., forming crystals. The crystals were vacuum filtered and washed with 30 mL chloroformn and 50 mL hexanes, then dissolved in 250 mL chloroform and washed in a separatory funnel with 3.x.300 mL volumes of water, followed by one 300 mL volume of brine to remove traces of succinimide. The organic phase was dried over magnesium sulfate, vacuum filtered and concentrated in vacuo to provide 9.56 g (61percent) of Compound 17 as a white crystalline power.
Reference：
[1] Patent: CN106366078, 2017, A, . Location in patent: Paragraph 0229; 0230; 0231
[2] Patent: WO2011/21209, 2011, A1, . Location in patent: Page/Page column 57; 58
[3] Patent: US2012/101099, 2012, A1, . Location in patent: Page/Page column 22
[4] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 7878 - 7889
[5] Collection of Czechoslovak Chemical Communications, 2004, vol. 69, # 12, p. 2239 - 2252
[6] Patent: US2007/72825, 2007, A1, . Location in patent: Page/Page column 32-33
[7] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1914, vol. 46, p. 515[8] Chem. Zentralbl., 1914, vol. 85, # II, p. 1271
[9] Journal of the American Chemical Society, 1985, vol. 107, # 4, p. 898 - 909
[10] Organic letters, 2003, vol. 5, # 9, p. 1407 - 1410
[11] Tetrahedron Letters, 2007, vol. 48, # 15, p. 2679 - 2682
[12] Chemical Communications, 2013, vol. 49, # 95, p. 11155 - 11157
2
[ 99-04-7 ]
[ 6515-58-8 ]
Yield
Reaction Conditions
Operation in experiment
80.5%
With N-Bromosuccinimide In tetrachloromethane
EXAMPLE 1 Preparation of 3-bromomethyl-benzoic acid 10 g (73.4 millimoles) of m-methyl-benzoic acid are dissolved in 75 ml of anhydrous carbon tetrachloride, whereupon 0.2 g of 2,2'-azo-bis-(2-methyl-propiontirile) and 13.72 g (77.07 millimoles) of N-bromo-succinimide are added. The reaction mixture is refluxed for 20 minutes, the formed succinimide is removed by filtering the warm mixture. The organic filtrate is washed with 15 ml of water, dried over sodium sulfate, filtered and the filtrate is evaporated in vacuo. The crude product thus obtained is recrystallized from a fivefold amount of carbon tetrachloride. Thus 12.71 g of the title compound are obtained, yield 80.5percent. Analysis data: Thin layer chromatography Rf =0.38 (a 1:1 mixture of benzene and ethyl acetate). The Rf value of the methyl ester prepared by using diazomethane amounts to 0.38 (a 2:1 mixture of benzene-hexane). 1 H-NMR/CDCl3, δ/:4,51/s, 2H, CH2 / 7.25-7.6 (m, 2H, aromatic protons), 7.75-7.85 (m, 2H, aromatic protons).
Reference：
[1] Patent: US4638002, 1987, A,
3
[ 614-45-9 ]
[ 99-04-7 ]
[ 6515-58-8 ]
Yield
Reaction Conditions
Operation in experiment
53%
With N-Bromosuccinimide In tetrachloromethane
a) 3-bromomethylbenzoic Acid A mixture of 3-toluic acid (15.0 g, 110 mmol), N-bromosuccinimide (19.60 g, 110 mmol) and t-butyl peroxybenzoate (2.1 mL, 110 mmol) in carbon tetrachloride (50 mL) was heated at reflux overnight. The mixture was cooled and concentrated under reduced pressure. The residue obtained was washed with carbon tetrachloride and filtered under vacuum. The filtrate was evaporated to dryness to yield a white solid (12.57 g, 53percent). 1H NMR (400 MHz, CDCl3) d 7.93 (m, 2H), 7.43 (m, 2H), 4.55 (s, 2H).
Reference：
[1] Patent: US2002/49316, 2002, A1,
4
[ 128-08-5 ]
[ 99-04-7 ]
[ 123-56-8 ]
[ 6515-58-8 ]
Yield
Reaction Conditions
Operation in experiment
61%
for 2.75 h; Irradiation; Heating / reflux
Synthesis of 3-bromomethylbenzoic acid: In a 1 L round bottom flask fitted with a reflux condenser, a stirred suspension of 10.00 g of m-toluic acid and 14.37 g (1.1 eq.) N-bromosuccinimide in 735 mL chloroform was sparged for 0.5 h with nitrogen. The sparging was discontinued, and the suspension was stirred and irradiated under nitrogen atmosphere using a 500 W quartz halogen lamp at 75percent power, causing the solids to dissolve and the chloroform to reflux. The red color of the reaction mixture disappeared after 1.25 h, and 14.37 g of N-bromosuccinimide was added. The reaction mixture was stirred and irradiated under nitrogen atmosphere with a 500 W quartz halogen lamp at 75percent power for another 1.5 h, at which time the solution became colorless. The solvent volume was reduced in vacuo to about 100 mL, and then cooled to-20 °C. The resultant suspension was vacuum filtered through a bed of dry silica. The silica was washed with 800 mL of chloroform. The chloroform filtrate was reduced in vacuo to about 100 mL, and then cooled to-20 °C. The resultant crystals were vacuum filtered, washed with 30 mL of chloroform followed by 50 mL of hexanes, then dissolved in 250 mL chloroform and washed in a separatory funnel with 3 x 300 mL volumes of water followed by one 300 mL volume of brine to remove traces of succinimide. The organic phase was dried with magnesium sulfate, vacuum filtered, and the solvent was removed in vacuo to provide 9.56 g (61percent) of 3- bromomethylbenzoic acid as a white crystalline power.
Reference：
[1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 2, p. 457 - 480
6
[ 209743-33-9 ]
[ 6515-58-8 ]
Reference：
[1] Journal of the Chemical Society, 1924, vol. 125, p. 1315
7
[ 99-36-5 ]
[ 6515-58-8 ]
Reference：
[1] Chemistry - A European Journal, 2004, vol. 10, # 19, p. 4673 - 4684
8
[ 120-33-2 ]
[ 6515-58-8 ]
Reference：
[1] Chemical Communications, 2013, vol. 49, # 95, p. 11155 - 11157
9
[ 62290-17-9 ]
[ 6515-58-8 ]
Reference：
[1] Chemical Communications, 2013, vol. 49, # 95, p. 11155 - 11157
10
[ 75-25-2 ]
[ 7726-95-6 ]
[ 99-04-7 ]
[ 6515-58-8 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1914, vol. 46, p. 515[2] Chem. Zentralbl., 1914, vol. 85, # II, p. 1271
11
[ 67-56-1 ]
[ 6515-58-8 ]
[ 1129-28-8 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 25℃; for 1 h; Reflux
To a solution of 3-Bromomethyl-benzoic acid (1 g, 4.6 mmol) in methanol (20 mL) was added thionyl chloride (1.1 g, 9.3 mmol) drop wise at 25 °C. The reaction mixture was refluxed over a period of 1 h and methanol was removed under reduced pressure to obtain crude sticky mass. The crude mass was diluted with ethyl acetate and washed with water and dried over sodium sulphate. Ethyl acetate was evaporated under reduced pressure to obtain 3-Bromomethyl-benzoic acid methyl ester as light yellow oil (1.0 g, 94.0 percent)
94%
at 25℃; for 1 h; Reflux
To a solution of 3-Bromomethyl-benzoic acid (1 g, 4.6 mmol) in methanol (20 mL) was added thionyl chloride (1.1 g, 9.3 mmol) drop wise at 25° C. The reaction mixture was refluxed over a period of 1 h and methanol was removed under reduced pressure to obtain crude sticky mass. The crude mass was diluted with ethyl acetate and washed with water and dried over sodium sulphate. Ethyl acetate was evaporated under reduced pressure to obtain 3-Bromomethyl-benzoic acid methyl ester as light yellow oil (1.0 g, 94.0percent)
Reference：
[1] Advanced Synthesis and Catalysis, 1998, vol. 340, # 4, p. 367 - 374
15
[ 6515-58-8 ]
[ 32194-76-6 ]
Yield
Reaction Conditions
Operation in experiment
92.3%
With sodium methylate In methanol; water; ethyl acetate
EXAMPLE 2 Preparation of 3-methoxymethyl-benzoic acid 12 g (55.75 millimoles) of 3-bromomethyl-benzoic acid are dissolved in 10 ml of anhydrous methanol and to the solution 22.30 ml of sodium methylate (concentration 5 millimoles/ml) are added dropwise at room temperature. The reaction mixture is stirred for 5-10 minutes, the methanol is removed in vacuo. The residue is dissolved in 10 ml of ethyl acetate, to the solution 2 ml of water are added and the pH of the mixture is adjusted to 2-3 with a 2N sodium hydrogen sulfate solution at 0° C. The layers are separated, the organic phase is dried, filtered and the solvent is distilled off in vacuo. Thus 8.55 g of the title compound are obtained, yield 92,3percent. Analysis data: TLC: Rf =0.13 (a 1:1 mixture of benzene and ethyl acetate), Rf =0.61 (a 20:10:1 mixture of benzene, dioxane and acetic acid).
3-{(1S,2S,3S,4R,6R)-6-[(S)-1-((S)-1-Carbamoyl-3-methyl-butylcarbamoyl)-2-carboxy-ethylcarbamoyl]-2,3,4-trihydroxy-cyclohexylsulfanylmethyl}-benzoic acid[ No CAS ]
3-{(1S,2S,3S,4R,6R)-6-[(S)-1-((S)-1-Carbamoyl-3-methyl-butylcarbamoyl)-3-carboxy-propylcarbamoyl]-2,3,4-trihydroxy-cyclohexylsulfanylmethyl}-benzoic acid[ No CAS ]
(E)-3-[3-((E)-1-Cyano-2-dimethylamino-2-phenyl-vinyl)-phenyl]-2-[3-((E)-2-cyano-1-dimethylamino-2-phenyl-vinyl)-phenyl]-3-dimethylamino-acrylonitrile[ No CAS ]
In chloroform; for 2.75h;Irradiation; Heating / reflux;
Synthesis of 3-bromomethylbenzoic acid: In a 1 L round bottom flask fitted with a reflux condenser, a stirred suspension of 10.00 g of m-toluic acid and 14.37 g (1.1 eq.) N-bromosuccinimide in 735 mL chloroform was sparged for 0.5 h with nitrogen. The sparging was discontinued, and the suspension was stirred and irradiated under nitrogen atmosphere using a 500 W quartz halogen lamp at 75% power, causing the solids to dissolve and the chloroform to reflux. The red color of the reaction mixture disappeared after 1.25 h, and 14.37 g of N-bromosuccinimide was added. The reaction mixture was stirred and irradiated under nitrogen atmosphere with a 500 W quartz halogen lamp at 75% power for another 1.5 h, at which time the solution became colorless. The solvent volume was reduced in vacuo to about 100 mL, and then cooled to-20 C. The resultant suspension was vacuum filtered through a bed of dry silica. The silica was washed with 800 mL of chloroform. The chloroform filtrate was reduced in vacuo to about 100 mL, and then cooled to-20 C. The resultant crystals were vacuum filtered, washed with 30 mL of chloroform followed by 50 mL of hexanes, then dissolved in 250 mL chloroform and washed in a separatory funnel with 3 x 300 mL volumes of water followed by one 300 mL volume of brine to remove traces of succinimide. The organic phase was dried with magnesium sulfate, vacuum filtered, and the solvent was removed in vacuo to provide 9.56 g (61%) of 3- bromomethylbenzoic acid as a white crystalline power.
b) tert-butyl 3-bromomethylbenzoate Followiong the procedure of Exmaple 39(a), except substituting <strong>[6515-58-8]3-bromomethylbenzoic acid</strong> for 4-bromomethylbenzoic acid, the title compound was prepared as a yellow oil (7.9 g, 100%). 1H NMR (400 MHz, CDCl3) d 7.93 (m, 2H), 7.43 (m, 2H), 4.55 (s, 2H), 1.55 (s, 9H).
a) 3-bromomethylbenzoic Acid A mixture of 3-toluic acid (15.0 g, 110 mmol), N-bromosuccinimide (19.60 g, 110 mmol) and t-butyl peroxybenzoate (2.1 mL, 110 mmol) in carbon tetrachloride (50 mL) was heated at reflux overnight. The mixture was cooled and concentrated under reduced pressure. The residue obtained was washed with carbon tetrachloride and filtered under vacuum. The filtrate was evaporated to dryness to yield a white solid (12.57 g, 53%). 1H NMR (400 MHz, CDCl3) d 7.93 (m, 2H), 7.43 (m, 2H), 4.55 (s, 2H).
EXAMPLE 1 Preparation of 3-bromomethyl-benzoic acid 10 g (73.4 millimoles) of m-methyl-benzoic acid are dissolved in 75 ml of anhydrous carbon tetrachloride, whereupon 0.2 g of 2,2'-azo-bis-(2-methyl-propiontirile) and 13.72 g (77.07 millimoles) of N-bromo-succinimide are added. The reaction mixture is refluxed for 20 minutes, the formed succinimide is removed by filtering the warm mixture. The organic filtrate is washed with 15 ml of water, dried over sodium sulfate, filtered and the filtrate is evaporated in vacuo. The crude product thus obtained is recrystallized from a fivefold amount of carbon tetrachloride. Thus 12.71 g of the title compound are obtained, yield 80.5%. Analysis data: Thin layer chromatography Rf =0.38 (a 1:1 mixture of benzene and ethyl acetate). The Rf value of the methyl ester prepared by using diazomethane amounts to 0.38 (a 2:1 mixture of benzene-hexane). 1 H-NMR/CDCl3, delta/:4,51/s, 2H, CH2 / 7.25-7.6 (m, 2H, aromatic protons), 7.75-7.85 (m, 2H, aromatic protons).
With sodium methylate; In methanol; water; ethyl acetate;
EXAMPLE 2 Preparation of 3-methoxymethyl-benzoic acid 12 g (55.75 millimoles) of 3-bromomethyl-benzoic acid are dissolved in 10 ml of anhydrous methanol and to the solution 22.30 ml of sodium methylate (concentration 5 millimoles/ml) are added dropwise at room temperature. The reaction mixture is stirred for 5-10 minutes, the methanol is removed in vacuo. The residue is dissolved in 10 ml of ethyl acetate, to the solution 2 ml of water are added and the pH of the mixture is adjusted to 2-3 with a 2N sodium hydrogen sulfate solution at 0 C. The layers are separated, the organic phase is dried, filtered and the solvent is distilled off in vacuo. Thus 8.55 g of the title compound are obtained, yield 92,3%. Analysis data: TLC: Rf =0.13 (a 1:1 mixture of benzene and ethyl acetate), Rf =0.61 (a 20:10:1 mixture of benzene, dioxane and acetic acid).
With potassium fluoride; In ethyl acetate; acetonitrile;
EXAMPLE 3 Preparation of 3-fluoromethyl-benzoic acid 2.945 g (11.15 millimoles) of 1,4,7,10,13,16-hexanona-cyclooctadecane (18-Crown-6) are dissolved in 30 ml anhydrous acetonitrile, whereupon 6.48 g (111.54 millimoles) of anhydrous potassium fluoride are added. The mixture is stirred for half an hour and 12 g (55.77 millimoles) of <strong>[6515-58-8]3-bromomethyl benzoic acid</strong> are added. The reaction mixture is stirred at 50 C. for 3 hours, whereupon it is filtered and the filtrate is evaporated in vacuo. The residue is taken up in 100 ml of ethyl acetate and the suspension is washed with 15 ml of water, 15 ml of a saturated sodium chloride solution, dried over sodium sulfate, filtered and the organic solvent is distilled off in vacuo. Thus 7.3 g of the title compound are obtained, yield 85%. TLC: Rf =0.3 (in a 50:10:1 mixture of benzene, dioxane and acetic acid). The Rf value of the methyl ester prepared with diazomethane in ether as medium amounts to 0.37 (in a 2:1 mixture of benzene and hexane). 1 H-NMR/CDCl3, delta/:5.46(s, 2H, CH2 F), 7.28-7.7 (m, 2H, aromatic protons), 7.8-8.3 (m, 2H, aromatic protons).
A. Preparation of 3-[4-(6-fluoro-1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic Acid Methyl Ester This compound was prepared following the procedure described in example 1 (part D) starting with 0.5 g (2.3 mmol) of 6-fluoro-3-piperidin-4-yl-1H-indole and 0.7 g (3 mmol) of 3-bromomethyl-benzoic acid. After the standard purification, 0.842 g (93% of yield) of 3-[4-(6-fluoro-1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester were obtained.
m-carboxyphenyl-methyl-triphenylphosphonium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.3%
In acetonitrile; for 2h;Heating / reflux;
To a solution of 3- (bromomethyl) benzoic acid (16.50 g, 76.73 itimol) in acetonitrile (76.7 ml) was added triphenylphosphine (22.14 g, 84.40 mmol) . After heating the mixture under reflux for 2 hr, the reaction mixture was cooled to room temperature. The precipitate was collected by filtration and dried under reduced pressure to give (3- carboxybenzyl) (triphenyl) phosphoniumbromide (30.13 g, 63.12 mmol, yield 82.3%) as a white solid.
Intermediate 21 : 3-Carboxymethylbenzoic acid; To a solution of 3-bromomethylbenzoic acid (2.29 g, 10 mmol) in methanol (30 ml_) is added sodium cyanide (0.49 g, 10 mmol) and the mixture is stirred at 70 0C for 2 hrs. The solvent is removed under reduced pressure and water is added to the residue. The mixture is extracted with ether and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by column chromatography using CH2CI2 as eluent to give 3-cyanomethylbenzoic acid.Next, a mixture of the 3-cyanomethylbenzoic acid (950 mg, 5.42 mmol) in water (2.5 ml_) and sulfuric acid (2.5 ml_, d 1 .84) is heated at 1 15 0C for 18 hrs. The mixture is cooled to room temperature and the resulting precipitate is filtered, washed with water and dried under reduced pressure to give 3-carboxymethylbenzoic acid.
To a solution of 3-Bromomethyl-benzoic acid (1 g, 4.6 mmol) in methanol (20 mL) was added thionyl chloride (1.1 g, 9.3 mmol) drop wise at 25 C. The reaction mixture was refluxed over a period of 1 h and methanol was removed under reduced pressure to obtain crude sticky mass. The crude mass was diluted with ethyl acetate and washed with water and dried over sodium sulphate. Ethyl acetate was evaporated under reduced pressure to obtain 3-Bromomethyl-benzoic acid methyl ester as light yellow oil (1.0 g, 94.0 %)
94%
With thionyl chloride; at 25℃; for 1h;Reflux;
To a solution of 3-Bromomethyl-benzoic acid (1 g, 4.6 mmol) in methanol (20 mL) was added thionyl chloride (1.1 g, 9.3 mmol) drop wise at 25 C. The reaction mixture was refluxed over a period of 1 h and methanol was removed under reduced pressure to obtain crude sticky mass. The crude mass was diluted with ethyl acetate and washed with water and dried over sodium sulphate. Ethyl acetate was evaporated under reduced pressure to obtain 3-Bromomethyl-benzoic acid methyl ester as light yellow oil (1.0 g, 94.0%)
With sodium hydride; tetra-(n-butyl)ammonium iodide; In tetrahydrofuran; water;
Step 2: methyl 3-((1-(5-nitropyridin-2-yl)piperidin-4-yloxy)methyl)benzoate (C-22) To Compound C-21 (1.00 g, 4.48 Mmol) in Dry Thf (20 Ml) Under Nitrogen was added sodium hydride (0.215 g of 60 wt % in oil, 5.38 mmol). The mixture was stirred at room temperature for 20 mins then added 3-(bromomethyl)benzoate (1.54 g, 6.72 mmol) and tetrabutylammonium iodide (0.41 g, 1.12 mmol). The reaction mixture was heated at reflux for 4 h then cooled and concentrated. Water (50 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined extracts were dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: CH2Cl2 to 6% EtOAc-CH2Cl2) gave the product C-22 (0.96 g, 58% yield) as a yellow oil. MS (M+1): 372
Preparation 5: Synthesis of 5-bromo-3-(5-(3-(bromomethyl)phenyl)-l,3,4-oxadiazol-2- y l)pyrazin-2 -aminer[00164] Step 1 : Dibromo(triphenyl)phosphorane (9.0 g, 20.46 mmol) was added to a suspension of <strong>[6515-58-8]3-(bromomethyl)benzoic acid</strong> (1.0 g, 4.65 mmol) in anhydrous acetonitrile (31 mL). The reaction mixture was stirred for 1 h at room temperature and then cooled at 0 C upon which DIEA (8.0 mL, 45.9 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Water (50 mL) was added dropwise to the stirring solution and was allowed to stir for an additional 20 min. The reaction mixture was filtered and the resulting solid was washed with a 10%water/acetonitrile mixture until the dark color disappeared. The solid was dried to yield 5- bromo-3-(5-(3-(bromomethyl)phenyl)-l,3,4-oxadiazol-2-yl)pyrazin-2-amine as a yellow solid (1.9 g, 99% yield). XH NMR (400 MHz, DMSO-i¾) delta 8.46 (s, 1H), 8.20 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.64 (dd, J = 19.0, 11.0 Hz, 1H), 4.90 (s, 2H).
Intermediate la: 3-(acetylthiomethyl benzoic acid. Into a 250-mL round bottom flask, was placed a solution of <strong>[6515-58-8]3-(bromomethyl)benzoic acid</strong> (7 g, 32.56 mmol, 1.00 equiv) in ethanol (80 mL), and potassium ethanethioate (9.65 g, 84.65 mmol, 2.60 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 80 mL of water and adjusted to pH 3-4 with 10% hydrochloric acid. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined, washed with 1x50 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 4.4 g (64%) of 3-(acetylthiomethyl)benzoic acid as a brown solid.
64%
Intermediate 4a: 3-(acetylthiomethyl)benzoic acid. Into a 250-mL round-bottom flask, was placed a solution of <strong>[6515-58-8]3-(bromomethyl)benzoic acid</strong> (7 g, 32.56 mmol, 1.00 equiv) in ethanol (80 mL), and potassium thioacetate (9.65 g, 84.65 mmol, 2.60 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 80 mL of water and adjusted to pH 3-4 with 10% hydrochloric acid. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x50 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 4.4 g (64%) of 3-(acetylthiomethyl)benzoic acid as a brown solid.
64%
In ethanol; at 20℃;
Into a 250-mL round-bottom flask, was placed a solution of <strong>[6515-58-8]3-(bromomethyl)benzoic acid</strong> (7 g, 32.56 mmol, 1.00 equiv) in ethanol (80 mL), and potassium ethanethioate (9.65 g, 84.65 mmol, 2.60 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 80 mL of water and adjusted to pH 3-4 with 10% hydrochloric acid. The resulting solution was extracted with 3*50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1*50 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. This resulted in 4.4 g (64%) of 3-(acetylthiomethyl)benzoic acid as a brown solid.
With potassium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 90℃; for 2h;
Intermediate 7a: 3-(((2-(diethylamino ethyl)(methyl amino)methvnben2oic acid.; Into a 1000-mL round bottom flask, was placed a solution of Nl,Nl-diethyl-N2- methylethane-l,2-diamine (9.1 g, 63.00 mmol, 1.50 equiv, 90%) in N,N- dimethylformamide (500 mL), <strong>[6515-58-8]3-(bromomethyl)benzoic acid</strong> (10 g, 46.51 mmol, 1.00 equiv), potassium carbonate (7.8 g, 56.12 mmol, 1.20 equiv), and potassium iodide (1.55 g, 9.34 mmol, 0.20 equiv). The resulting solution was stirred for 2 h at 90C in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (10 g) was purified by reverse phase HPLC eluting with 0.05% TFA in a water/CH3CN gradient. The product was obtained as 6 g (46%) of a white solid. -NMR (300MHz, COCh, ppm) delta 8.01(m, 1H), 7.89-7.87(m, 1H), 7.28- 7.22(m, 2H), 3.99(s, 2H), 2.97-2.72(m, 8H), 2.28(s, 3H), 1.13-1.01(m, 6H). MS (ES, m/z): 265 [M+H]+.
46%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 90℃; for 2h;
Intermediate 12a: 3-(((2-("diethylamino)ethyl')('methyl)amino methyl benzoic acid. Into a 1000-mL round bottom flask, was placed a solution of Nl,Nl-diethyl-N2- methylethane-l,2-diamine (9.1 g, 63.00 mmol, 1.50 equiv, 90%) in N,N- dimethylformamide (500 mL), <strong>[6515-58-8]3-(bromomethyl)benzoic acid</strong> (10 g, 46.51 mmol, 1.00 equiv), potassium carbonate (7.8 g, 56.12 mmol, 1.20 equiv), and potassium iodide (1.55 g, 9.34 mmol, 0.20 equiv). The resulting solution was stirred for 2 h at 90C in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (10 g) was purified by reverse phase HPLC eluting with 0.05% TFA in a water/CH3CN gradient. The product was obtained as 6 g (46%) of a white solid. 1H-NMR (300MHz, COC , ppm) delta 8.01(m, 1H), 7.89-7.87(m, 1H), 7.28- 7.22(m, 2H), 3.99(s, 2H), 2.97-2.72(m, 8H), 2.28(s, 3H), 1.13-1.01(m, 6H). MS (ES, m/z): 265 [M+H]+.
46%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 90℃; for 2h;
Into a 1000-mL round bottom flask, was placed a solution of N1,N1-diethyl-N2-methylethane-1,2-diamine (9.1 g, 63.00 mmol, 1.50 equiv, 90%) in N,N-dimethylformamide (500 mL), <strong>[6515-58-8]3-(bromomethyl)benzoic acid</strong> (10 g, 46.51 mmol, 1.00 equiv), potassium carbonate (7.8 g, 56.12 mmol, 1.20 equiv), and potassium iodide (1.55 g, 9.34 mmol, 0.20 equiv). The resulting solution was stirred for 2 h at 90 C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (10 g) was purified by reverse phase HPLC eluting with 0.05% TFA in a water/CH3CN gradient. The product was obtained as 6 g (46%) of a white solid. 1H-NMR (300 MHz, CDCl3, ppm): delta 8.01 (m, 1H), 7.89-7.87 (m, 1H), 7.28-7.22 (m, 2H), 3.99 (s, 2H), 2.97-2.72 (m, 8H), 2.28 (s, 3H), 1.13-1.01 (m, 6H). MS (ES, m/z): 265 [M+H]+.
With potassium carbonate; In ethanol; at 20℃; for 17h;
A mixture of 3-bromomethylbenzoic acid (4.30 g, 20 mmol), <strong>[59702-07-7]1-<strong>[59702-07-7]methylpiperazin-2-one</strong></strong> (2.3 g, 20 mmol),38 and powdered potassiumcarbonate (2.76 g, 20 mmol) in ethanol (50 mL) was stirredfor 17 h at room temperature. The solvent was evaporated off underreduced pressure to give a residue which was treated with HCl(10 mL of 2 M) and extracted with EtOAc. The combined extractswere washed with water, dried and the solvent was evaporatedoff under reduced pressure to give 8, which was recrystallised fromEtOAc/hexane to give a cream crystalline solid, mp 161?166 C; 1HNMR (DMSO-d6) d 2.63 (t, J = 5.5 Hz, 2H), 2.80 (s, 3H), 2.96 (s, 2H),3.26 (t, J = 5.5, 2H), 3.61 (s, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.90 (d,J = 8.0 Hz, 2H), 12.9 (br s, 1H).
3-(3-(2-pyridyl)pyrazol-1-ylmethyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With tetra(n-butyl)ammonium hydroxide; sodium hydroxide; In water; benzene; at 80℃;
2-(1H-Pyrazol-3-yl)pyridine (0.339 g, 2.33 mmol) and 3-bromomethylbenzoic acid (0.500 g, 2.33 mmol) were added to a solution of 40% aqueous NaOH (3.5 mL), benzene (10 mL), and Bu4NOH (4 drops), and the resulting solution was refluxed at 80 C overnight. After cooling to room temperature, the colourless organic layer was separated from the yellow aqueous layer. The aqueous layer was then washed with ethyl acetate (2 * 10 mL) before being acidified to pH 3 using aqueous HCl (6 M), at which point a yellow precipitate formed. This precipitate was extracted into ethyl acetate (3 * 60 mL) that was then washed with water (2 * 50 mL) and brine (50 mL). The organic layer was then dried over magnesium sulfate before having the solvent removed under reduced pressure. Recrystallization from ethyl acetate/petroleum ether (40-60 C) gave L2 as a pale brown solid (0.224 g, 34%). Anal. Calc. for C16H13N3O2·0.25H2O C, 67.71; H, 4.80; N, 14.80. Found: C, 67.94; H, 4.67; N, 14.72%. 1H NMR (400 MHz, dmf-d7): delta (ppm) = 5.61 (2H, s, Hg), 6.95 (1H, d, J = 2.3 Hz, He), 7.30 (1H, ddd, J = 7.4, 4.8, 1.2 Hz, Hb), 7.54 (1H, t, J = 7.7 Hz, Hh), 7.64 (1H, dt, J = 7.7, 1.5 Hz, Hk), 7.83 (1H, td, J = 7.7, 1.8 Hz, Hc), 8.01-7.95 (3H, m, Hd, Hj and Hi), 8.05 (1H, d, J = 2.3 Hz, Hf), 8.60 (1H, dt, J = 4.9, 1.3 Hz, Ha). HRESI-MS (dmf/MeOH): m/z calcd for C16H12N3O2-: 278.0935 [L2-H]-: found: 278.0930. Selected IR numax/cm-1: 2415, 1690, 1598, 1566, 1492, 1294, 768.
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine[ No CAS ]
m-BrCH<SUB>2</SUB>PhCOHN-IKPEAPGEDASPEELNRYYASLRHYLNL(hC)TRQ(psi-R35Y36)-CONH<SUB>2</SUB>[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1. Synthesis of H2N-IKPEAPGEDASPEELNRYYASLRHYLNL(hC) TRQ(psi-R35Y36)-Sieber Resin (0425) Amino acid extensions onto the pre-loaded (psi-R35, Y36)-Sieber resin from Example 1, step 2 (0.1 mmol) were performed as described in Example 1, step 3 with the modification of using a 5-fold excess of protected amino acids. 2. Synthesis of m-BrCH2PhCOHN-IKPEAPGEDASPEELNRYYASLRHYLNL(hC) TRQ(psi-R35Y36)-Sieber Resin (0426) m-Bromomethylbenzoic acid was coupled onto the above resin according to the procedure described in Example 1, step, with the modification that the coupling was carried out at 50 C. instead of 75 C.
(S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-((S)-5-tert-butoxy-5-oxo-4-palmitamidopentanamido)hexanoic acid[ No CAS ]
C52H67N6O9PolS[ No CAS ]
[ 71989-31-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 71989-35-0 ]
[ 132388-59-1 ]
[ 132327-80-1 ]
[ 109425-51-6 ]
[ 6515-58-8 ]
[ 167015-23-8 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine[ No CAS ]
m-BrCH<SUB>2</SUB>PhCOHN-ISPEAPGEDASPEELNRYYASLRHYLN-K(γ-Glu-Pal)-(hC)TRQ(psi-R35Y36)-CONH<SUB>2</SUB>[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The title compound was prepared according to the procedures described in Example 9, using Fmoc-Lys(Pal-Glu-OtBu)-OH (from Active Peptide) in place of Fmoc-Leu-OH at position 30 and Fmoc-Ser(tBu)-OH in place of Fmoc-Lys(Boc)-OH at position 4, in step 1. 60% EtOH/H2O was used as solvent in place of MeCN/H2O and sat'd aq. NaHCO3 was used in place of the NH4OAc buffer in step 4 to effect cyclization. Product purification was performed using a Waters XBridge C18 OBD column (50×250 mm, 5 mum) at rt. The mobile phase consisted of a gradient elution of Buffer A (10 mM NH4OH in water, pH -9) and Buffer B (MeCN) ranging from an initial concentration of 10% B to an intermediate concentration of 20% B (100 mpm) over 5 min, and then to a final concentration of 30% B (100 mpm) over 40 min. Impure fractions were re-chromatographed using a gradient comprised of an initial concentration of 10% B to an intermediate concentration of 20% B (100 mpm) over 5 min, and then to a final concentration of 30% B (100 mpm) over 60 min.
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine[ No CAS ]
m-BrCH<SUB>2</SUB>PhCOHN-IKPEAPGEDASPEELNRYYASLRHYLNL(hC)TRQRY-CONH<SUB>2</SUB>[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1. Synthesis of H2N-IKPEAPGEDASPEELNRYYASLRHYLNL(hC) TRQRY-PAL-PEG Resin (0402) The protected peptidyl resin was synthesized using Fmoc strategy as described above on a CEM Liberty Blue Microwave peptide synthesizer using low loading Rink amide resins, preferably, Fmoc-PAL-PEG PS resin (ca., 0.16-0.2 meq/g, supplied by Applied Biosystems) on a scale of 0.1 mmol, as depicted in Scheme 1. Standard Fmoc-protected amino acids were coupled in 5-fold excess relative to resin loading using DIC/Oxyma as the coupling agents and a reaction temperature of ca., 90 C. for 4 min. Fmoc-Arg(Pbf)-OH was double coupled at 90 C. for 4 min each and Fmoc-His(Trt)-OH was coupled using a two-stage protocol: 4 min at rt followed by 8 min at 50 C. Single Fmoc deprotections were carried out using 20% piperidine in DMF (deprotection solution) at 90 C. for 1.5 min. 2. Synthesis of m-BrCH2PhCOHN-IKPEAPGEDASPEELNRYYASLRHYLNL(hC) TRQRY-PAL-PEG Resin (0403) The Fmoc-deprotected peptide-resin (0.1 mmol) from above was treated with a solution of m-bromomethylbenzoic acid (20 eq.) and DIC (10 eq.) in DMF (4 mL) in a microwave reactor at 75 C. for 15 min, by which time the reaction was generally determined to be complete, as per a Kaiser ninhydrin test (Kaiser, et al., Anal. Biochem., 1970, 34, 595-598). In cases where the coupling was determined to be incomplete, the coupling was repeated with fresh reagents. The reaction was drained, and the resin was washed extensively with DMF and DCM. 3. Synthesis of m-BrCH2PhCOHN-IKPEAPGEDASPEELNRYYASLRHYLNL(hC) TRQRY-CONH2: Deprotection and Cleavage from Resin The resin from above was then treated with a cleavage cocktail (10 mL/0.1 mmol scale) consisting of TFA/water/phenol/TIPS (88:5:5:2) and heated in a microwave reactor at 38 C. for 40 min, then filtered. The resin was washed with TFA and the combined filtrates were concentrated under a stream of nitrogen to a volume of ca. 2.5 mL and the peptide was precipitated by the addition of cold diethyl ether (40 mL). The peptide/ether suspension was centrifuged and the ether layer was decanted. The peptide pellet was re-suspended in ether, centrifuged and decanted, and this process was repeated a third time. The crude peptide thus obtained was dried under a mild nitrogen stream.
Fmoc-N-Me-Arg(Pbf)-OH, Pbf=pentamethyldihydrobenzofuran-5-sulfonyl[ No CAS ]
[ 35661-60-0 ]
[ 35661-39-3 ]
[ 71989-31-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 71989-26-9 ]
[ 71989-35-0 ]
[ 132388-59-1 ]
[ 132327-80-1 ]
[ 109425-51-6 ]
[ 6515-58-8 ]
[ 167015-23-8 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine[ No CAS ]
m-BrCH<SUB>2</SUB>PhCOHN-IKPEAPGEDASPEELNRYYASLRHYLNL(hC)TRQ-(N-Me-R35)-Y-CONH<SUB>2</SUB>[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The title compound was prepared according to the procedure as described in Example 2 substituting Fmoc-N-Me-Arg(pbf)-OH in place of Fmoc-Arg(pbf)-OH at position 35 in step 1 and with the modification that a 1M NaHCO3 buffer was used in place of the NH4OAc buffer to effect cyclization. Product purification was performed using a Varian Pursuit XRs C18 column (30×250 mm, 100A, 5 m) at rt. The mobile phase consisted of a gradient elution of Buffer A (0.1% TFA in water) and Buffer B (0.1% TFA in MeCN) ranging from 10-60% B (30 mpm) over 36 min.
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