* 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.
Stage #1: at 100℃; for 2 h; Heating / reflux Stage #2: With hydrogenchloride In water
To a solution of 3-[5-(2-Fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid methyl ester (3.3 g, 111 mmol) in THF (40 mL) was added 1.5M aqueous NaOH (10 mL, 14 mmol). The reaction mixture was refluxed for 2 h at 100° C. The organic solvent was removed and the aqueous solution was diluted with water (50 mL), and then acidified with aqueous HCl. The white precipitate was filtered off and the white cake was washed with cold water and then dried using lyophilizer. The desired acid (3.0 g, 96percent yield) was obtained as a white powder with 98percent purity (LC/UV). Melting point 242° C.; IR υ 3000 (Aromatic C-H), 1710 (CO); 1H-NMR (D6-DMSO) δ 8.31 (1H), 8.18 (2H), 8.08 (1H), 7.88 (2H), 7.51 (2H); 13C-NMR (D6-DMSO) δ 172.71, 167.38, 166.48, 161.25, 135.80, 132.24, 131.79, 131.79, 131.08, 130.91, 129.81, 127.76, 125.48, 117.38, 111.70; 19F-NMR (D6-DMSO) δ 109.7.
96%
Stage #1: With sodium hydroxide; water In tetrahydrofuran at 100℃; for 2 h; Heating / reflux Stage #2: With hydrogenchloride In water
To a solution of 3-[5-(2-Fluoro-phenyl)-[l,2,4]oxadiazol-3-yl]-benzoic acid methyl ester (3.3g, 11 mmol) in THF (40 mL) was added 1.5M aqueous NaOH (10 mL, 14 mmol). The reaction mixture was refluxed for 2h at 100 °C. The organic solvent was removed and the aqueous solution was diluted with water (50 mL), and then acidified with aqueous HCl. The white precipitate was filtered off and the white cake was washed with cold water and then dried using lyophilizer. The desired acid (3.Og5 96percent yield) was obtained as a white powder with 98percent purity (LC/UV). Melting point 242 °C; IR D 3000 (Aromatic C-H), 1710 (C=O); 1H-NMR (D6-DMSO) δ 8.31 (IH), 8.18 (2H)3 8.08 (IH), 7.88 (2H), 7.51 (2H); 13C- NMR (D6-DMSO) δ 172.71, 167.38, 166.48, 161.25, 135.80, 132.24, 131.79, 131.79, 131.08, 130.91, 129.81, 127.76, 125.48, 117.38, 111.70; 19F-NMR (D6-DMSO) δ 109.7.
96%
Stage #1: With sodium hydroxide; water In tetrahydrofuran at 100℃; for 2 h; Heating / reflux Stage #2: With hydrogenchloride In water
To a solution of 3-[5-(2-Fluoro-phenyl)-[l ,2,4]oxadiazol-3-yl]-benzoic acid methyl ester (3.3g, 1 1 mmol) in THF (40 mL) was added 1.5M aqueous NaOH (10 mL, 14 mmol). The reaction mixture was refluxed for 2h at 100 0C. The organic solvent was removed and the aqueous solution was diluted with water (50 mL), and then acidified with aqueous HCl. The white precipitate was filtered off and the white cake was washed with cold water and then dried using lyophilizer. The desired acid (3.0g, 96percent yield) was obtained as a white powder with 98percent purity (LC/UV). Melting point 242 0C; IR 3000 (Aromatic C-H),ATI-2289908vl 25 <n="27"/>1710 (C=O); 1H-NMR (D6-DMSO) δ 8.31 (IH), 8.18 (2H), 8.08 (IH), 7.88 (2H), 7.51 (2H); 13C-NMR (D6-DMSO) δ 172.71, 167.38, 166.48, 161.25, 135.80, 132.24, 131.79, 131.79, 131.08, 130.91, 129.81, 127.76, 125.48, 1 17.38, 1 11.70; 19F-NMR (D6-DMSO) δ 109.7.
96%
Stage #1: With sodium hydroxide; water In tetrahydrofuran at 100℃; for 2 h; Stage #2: With hydrogenchloride In water
To a solution of 3-[5-(2-Fluoro-phenyl)-[l ,2,4]oxadiazol-3-yl]-benzoic acid methyl ester (3.3g, 11 mmol) in THF (40 niL) was added 1.5M aqueous NaOH (10 niL, 14 mmol). The reaction mixture was refluxed for 2h at 100 0C. The organic solvent was removed and the aqueous solution was diluted with water (50 mL), and then acidified with aqueous HCl. The white precipitate was filtered off and the white cake was washed with cold water and then dried using lyophilizer. The desired acid (3.Og, 96percent yield) was obtained as a white powder with 98percent purity (LC/UV). Melting point 242 0C; IR D 3000 (Aromatic C-H), 1710 (C=O); 1H-NMR (D6-DMSO) δ 8.31 (IH), 8.18 (2H), 8.08 (IH), 7.88 (2H), 7.51 (2H); 13C-NMR (D6-DMSO) δ 172.71, 167.38, 166.48, 161.25, 135.80, 132.24, 131.79, 131.79, 131.08, 130.91, 129.81, 127.76, 125.48, 117.38, 111.70; 19F-NMR (D6-DMSO) δ 109.7.
123 mg
With water; sodium hydroxide In ethanol at 20℃; for 3 h;
General procedure: To a solution of methyl ester 13 (228 mg, 0.76 mmol) in EtOH: H2O (3:2, 10 mL) was added crushed NaOH (91 mg, 2.27 mmol) and the solution was stirred at rt for 3h. The volatiles were evaporated under reduced pressure and the residue obtained was acidified with 1N aqueous HCl (pH ~ 4). This solution was then transferred to a separatory funnel and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried Na2SO4 and concentrated under reduced pressure to afford the title acid 14 (123 mg, 54percent) as a white solid.
3 g
With water; sodium hydroxide In tetrahydrofuran at 100℃; for 2 h;
A solution of 33 g of methyl 3- [5- (2-fluorophenyl) - [1,2,4-oxadiazol-3-yl] -benzoic acid methyl ester was dissolved in 400 mlOf tetrahydrofuran,To this was added 100 ml of a 1.5 M aqueous solution of sodium hydroxide.The reaction mixture was heated at 100 ° C for 2 hours. The solvent was removed under reduced pressure,The aqueous solution was stirred at 5 ° C for 2 hours.The organic solvent was removed, the aqueous solution was diluted with 50 ml of water,Followed by acidification with hydrochloric acid to pH 1. Filter out a white precipitate, wash the filter cake with cold water,And then dried with a freeze drier.To obtain 3. 0 g of 3- [5- (2_ fluorophenyl) - [1,2,4] oxadiazol-3-yl] benzoic acid. (1H), 8.18 (2H), 08.8 (1H), 7.88 (2H), 7.11 (2H). Show that the sample prepared in Preparation Example 1 was incubated with TO2004091502A2 Example 2 prepared ataluren
Reference：
[1] Patent: US2004/204461, 2004, A1, . Location in patent: Page 54
[2] Patent: WO2007/117438, 2007, A2, . Location in patent: Page/Page column 261
[3] Patent: WO2008/45566, 2008, A1, . Location in patent: Page/Page column 25-26
[4] Patent: WO2006/110483, 2006, A1, . Location in patent: Page/Page column 21
[5] Advanced Synthesis and Catalysis, 2017, vol. 359, # 5, p. 772 - 778
[6] Patent: WO2008/30570, 2008, A1, . Location in patent: Page/Page column 20-21
[7] Patent: WO2008/30570, 2008, A1, . Location in patent: Page/Page column 21-23
[8] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 11, p. 2473 - 2476
[9] Patent: CN105461650, 2016, A, . Location in patent: Paragraph 0075; 0082
2
[ 1141475-82-2 ]
[ 393-52-2 ]
[ 775304-60-4 ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate In acetone at 20℃; for 24 h;
General procedure: 2 mmol of either amidoxime 1 [30] or 2 [26] were dissolved in acetone (200 mL) in a round-bottomed flask; then, K2CO3 (0.35 g; 2.5 mmol) and the corresponding aroyl chloride (2.5 mmol), were added to the reaction mixture and stirred for 24 h at room temperature. The solvent was removed under vacuum and the residue treated with water and refluxed for 30 min 1,2,4-Oxadiazoles products were obtained by filtration and further purified by chromatography.
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 101, p. 236 - 244
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 11, p. 2473 - 2476
3
[ 775304-80-8 ]
[ 775304-60-4 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 5 - 130℃; for 22 h;
44g of 3-(N-2-Fluorobenzoylcarbamimidoyl)-benzoic acid methyl ester in toluene (500 mL) was refluxed for 4h at 130 °C using Dean-Stark apparatus. The reaction mixture was stirred at 5 °C for 18h. The white precipitate was filtered off and the filtrate was concentrated, crystallized again in toluene. The desired oxadiazole (38g, 92percent yield) was obtained as a white solid with 99percent purity (LC/UV). 1H-NMR (CDCl3) S 8.91 (IH)5 8.38 (IH)3 8.15 (2H), 7.62 (2H)3 7.35 (2H)3 3.95 (3H).
92%
at 5 - 130℃; for 22 h; Dean-Stark apparatus
44g of 3-(N-2-Fluorobenzoylcarbamimidoyl)-benzoic acid methyl ester in toluene (500 mL) was refluxed for 4h at 130 0C using Dean-Stark apparatus. The reaction mixture was stirred at 5 0C for 18h. The white precipitate was filtered off and the filtrate was EPO <DP n="22"/>concentrated, crystallized again in toluene. The desired oxadiazole (38g, 92percent yield) was obtained as a white solid with 99percent purity (LC/UV). 1H-NMR (CDCl3) δ 8.91 (IH), 8.38 (IH), 8.15 (2H), 7.62 (2H)3 7.35 (2H), 3.95 (3H).
44g of 3-(N-2-Fluorobenzoylcarbamimidoyl)-benzoic acid methyl ester in toluene (500 mL) was refluxed for 4h at 130 0C using Dean-Stark apparatus. The reaction mixture was stirred at 5 0C for 18h. The white precipitate was filtered off and the filtrate was concentrated, crystallized again in toluene. The desired oxadiazole (38g, 92percent yield) was obtained as a white solid with 99percent purity (LC/UV). 1H-NMR (CDCl3) δ 8.91 (IH), 8.38 (IH), 8.15 (2H), 7.62 (2H), 7.35 (2H), 3.95 (3H).
38 g
at 5 - 130℃; for 22 h; Dean-Stark
At 130 ° C with Dean-StarkThe solution was heated to dissolve 44 grams of toluene in 500 ml3- (N-2-fluorobenzoylamidino) -benzoic acid methyl ester for 4 hours.The reaction mixture was stirred at 5 ° C for 18 hours. The white precipitate was filtered off, the filtrate was concentrated,And then crystallized in toluene.To obtain 38 g of methyl 3- [5- (2-fluorophenyl) - [1,2,4-oxadiazol-3-yl] -benzoic acid methyl ester.
Reference：
[1] Patent: WO2008/45566, 2008, A1, . Location in patent: Page/Page column 25
[2] Patent: CN105461650, 2016, A, . Location in patent: Paragraph 0075; 0081
5
[ 348-52-7 ]
[ 775304-60-4 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 5, p. 772 - 778
6
[ 394-47-8 ]
[ 775304-60-4 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 10, p. 1708 - 1716
7
[ 13531-48-1 ]
[ 775304-60-4 ]
Reference：
[1] Patent: CN105461650, 2016, A,
[2] Advanced Synthesis and Catalysis, 2017, vol. 359, # 5, p. 772 - 778
[3] Patent: WO2006/110483, 2006, A1,
8
[ 1141475-82-2 ]
[ 775304-60-4 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 5, p. 772 - 778
[2] Patent: WO2006/110483, 2006, A1,
9
[ 1877-72-1 ]
[ 775304-60-4 ]
Reference：
[1] Patent: CN105461650, 2016, A,
10
[ 15676-11-6 ]
[ 775304-60-4 ]
Reference：
[1] Patent: CN105461650, 2016, A,
11
[ 1129-28-8 ]
[ 775304-60-4 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 10, p. 1708 - 1716
In water; tert-butyl alcohol; at 81 - 86℃; for 18.8333 - 21.5333h;Product distribution / selectivity;
Methyl 3-[5-(2-fluorophenvn-[l,2,41oxadiazol-3-yll-benzoate [0153] Batch 1[0154] Methyl 3-cyanobenzoate (105 kg) and molten terf-butanol were charged to a dry reactor. 50% aqueous hydroxylamine (43L, 47.4 kg) was added to the clear solution of methyl 3-cyanobenzoate in molten ter/-butanol in an inert atmosphere over about 2 hours and 48 minutes. The maximum batch temperature during the addition of 50% aqueous hydroxylamine was about 430C. The addition rate of 50% aqueous hydroxylamine varied from about 9L per hour at the onset of addition to about 30L per hour. The batch temperature was maintained by alteration of the jacket set point on the reactor. In particular, the set point was changed from about 40.50C at the beginning of the addition to <n="18"/>about 29.6C as the addition rate increased. The reaction was deemed complete (i.e., less than about 0.5% ester) after stirring for about 4 hours at about 40-450C. [0155] The batch was transferred to a dry reactor and chased through with about 1 OL of molten /erf-butanol. The jacket set point was decreased from about 33C when the batch was received by the dry reactor to about 27C after transfer was complete. Partial crystallization of the batch was observed which did not adversely affect stirring. The batch was cooled to about 34.4C and triethylamine (72.6 kg, 100L) was charged to the reactor. The jacket temperature set point was raised from about 20.40C to about 31.00C to maintain the batch temperature with the range of about 30-350C. Following a line rinse with molten /er/-butanol (1 OL), the batch was charged with 2-fluorobenzoyl chloride (113.7 kg, 86.0L). The addition rate over the first third of the charge was about 25L per hour. The jacket inlet temperature was lowered to about 15C during this period and the batch temperature remained at about 34.6C. The addition was complete after about 5.5 hours. The maximum batch temperature during the addition was about 38.8C. The addition rate was slowed towards the end of the addition with the final 27 liters of 2-fluorobenzoyl being added at about 1 IL per hour. The reaction was deemed complete (i.e., less than about 0.5% methyl 3-amidinobenzoate) after stirring for about 2 hours at 30-350C. [0156] The batch was then heated to reflux temperature (about 82C) over about 1 hour and 42 minutes and stirred for about an additional 18 hours. During stirring, some product partially crystallized to form a slurry. The slurry was cooled to bout 400C to allow for sampling, during which full crystallization occurred. The batch was reheated to reflux temperature and stirred for about 1 hour and 50 minutes. The batch was then cooled over about 2 hours to about 69C and 630L of purified water was slowly added over about 4 hours and 15 minutes while the batch temperature was maintained at between about 66- 69C. The slurry was cooled to about 22.4C over about 3 hours and 14 minutes and transferred to 2X200L ceramic filters fitted with 25-30mu mesh polypropylene filter cloths. Transfer of the material from the vessel onto the filters was complete after about 55 minutes. The filter cakes were washed with 50% aqueous t°r/-butanol (210L), allowing about 10 minutes for the wash to soak into each cake. The cakes were then dried in vacuo over about 5-10 minutes. Purified water was applied to the filter cakes as a secondary wash (158L per cake) to remove residual terr-butanol and triethylammonium chloride salt. <n="19"/>Liquors were removed after drying in vacuo for about 5 minutes. The cakes were dried in vacuo for about an additional 2 hours and then sampled using liquid chromatography. The purity of the cakes was determined to be about 99.6% by liquid chromatography. [0157] After drying the cakes in vacuo for about 8 hours and 25 minutes, the wet cake (207.4kg) was transferred to an air oven. Drying in the air oven was performed at about 50-550C for about 52 hours. The overall yield of isolated product was about 89.9 % (174.65kg), which can be adjusted to about 90.7% after accounting for material consumed by sampling. [0158] Batch 2[0159] Methyl 3-cyanobenzoate (105 kg) and molten rerf-butanol were charged to a dry reactor. 50% aqueous hydroxylamine (47.85 kg) was charged to the reactor in an inert atmosphere over about 3 hours and 29 minutes. The temperature was maintained at about 40-450C during addition. The reaction was deemed complete (i.e., less than about 0.5% ester) after stirring for about 3 hours and 16 minutes at about 40-450C. [0160] The batch was transferred to a dry reactor as described for Batch 1. The batch was cooled to about 34.4C and charged with triethylamine (72.6kg, 100L). The addition was performed over a period of about 45 minutes while maintaining the batch temperature at about 30-350C. The jacket inlet temperature was raised from about 31.40C to about 32.6C during the addition. After line rinse with molten ter/-butanol, the batch was charged with 2-fluorobenzoyl chloride (113.7kg, 86.0L). The acid chloride was ...
To a solution of 3-[5-(2-Fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid methyl ester (3.3 g, 111 mmol) in THF (40 mL) was added 1.5M aqueous NaOH (10 mL, 14 mmol). The reaction mixture was refluxed for 2 h at 100 C. The organic solvent was removed and the aqueous solution was diluted with water (50 mL), and then acidified with aqueous HCl. The white precipitate was filtered off and the white cake was washed with cold water and then dried using lyophilizer. The desired acid (3.0 g, 96% yield) was obtained as a white powder with 98% purity (LC/UV). Melting point 242 C.; IR upsilon 3000 (Aromatic C-H), 1710 (CO); 1H-NMR (D6-DMSO) delta 8.31 (1H), 8.18 (2H), 8.08 (1H), 7.88 (2H), 7.51 (2H); 13C-NMR (D6-DMSO) delta 172.71, 167.38, 166.48, 161.25, 135.80, 132.24, 131.79, 131.79, 131.08, 130.91, 129.81, 127.76, 125.48, 117.38, 111.70; 19F-NMR (D6-DMSO) delta 109.7.
96%
To a solution of 3-[5-(2-Fluoro-phenyl)-[l,2,4]oxadiazol-3-yl]-benzoic acid methyl ester (3.3g, 11 mmol) in THF (40 mL) was added 1.5M aqueous NaOH (10 mL, 14 mmol). The reaction mixture was refluxed for 2h at 100 C. The organic solvent was removed and the aqueous solution was diluted with water (50 mL), and then acidified with aqueous HCl. The white precipitate was filtered off and the white cake was washed with cold water and then dried using lyophilizer. The desired acid (3.Og5 96% yield) was obtained as a white powder with 98% purity (LC/UV). Melting point 242 C; IR D 3000 (Aromatic C-H), 1710 (C=O); 1H-NMR (D6-DMSO) delta 8.31 (IH), 8.18 (2H)3 8.08 (IH), 7.88 (2H), 7.51 (2H); 13C- NMR (D6-DMSO) delta 172.71, 167.38, 166.48, 161.25, 135.80, 132.24, 131.79, 131.79, 131.08, 130.91, 129.81, 127.76, 125.48, 117.38, 111.70; 19F-NMR (D6-DMSO) delta 109.7.
96%
To a solution of 3-[5-(2-Fluoro-phenyl)-[l ,2,4]oxadiazol-3-yl]-benzoic acid methyl ester (3.3g, 1 1 mmol) in THF (40 mL) was added 1.5M aqueous NaOH (10 mL, 14 mmol). The reaction mixture was refluxed for 2h at 100 0C. The organic solvent was removed and the aqueous solution was diluted with water (50 mL), and then acidified with aqueous HCl. The white precipitate was filtered off and the white cake was washed with cold water and then dried using lyophilizer. The desired acid (3.0g, 96% yield) was obtained as a white powder with 98% purity (LC/UV). Melting point 242 0C; IR 3000 (Aromatic C-H),ATI-2289908vl 25 <n="27"/>1710 (C=O); 1H-NMR (D6-DMSO) delta 8.31 (IH), 8.18 (2H), 8.08 (IH), 7.88 (2H), 7.51 (2H); 13C-NMR (D6-DMSO) delta 172.71, 167.38, 166.48, 161.25, 135.80, 132.24, 131.79, 131.79, 131.08, 130.91, 129.81, 127.76, 125.48, 1 17.38, 1 11.70; 19F-NMR (D6-DMSO) delta 109.7.
96%
To a solution of 3-[5-(2-Fluoro-phenyl)-[l ,2,4]oxadiazol-3-yl]-benzoic acid methyl ester (3.3g, 11 mmol) in THF (40 niL) was added 1.5M aqueous NaOH (10 niL, 14 mmol). The reaction mixture was refluxed for 2h at 100 0C. The organic solvent was removed and the aqueous solution was diluted with water (50 mL), and then acidified with aqueous HCl. The white precipitate was filtered off and the white cake was washed with cold water and then dried using lyophilizer. The desired acid (3.Og, 96% yield) was obtained as a white powder with 98% purity (LC/UV). Melting point 242 0C; IR D 3000 (Aromatic C-H), 1710 (C=O); 1H-NMR (D6-DMSO) delta 8.31 (IH), 8.18 (2H), 8.08 (IH), 7.88 (2H), 7.51 (2H); 13C-NMR (D6-DMSO) delta 172.71, 167.38, 166.48, 161.25, 135.80, 132.24, 131.79, 131.79, 131.08, 130.91, 129.81, 127.76, 125.48, 117.38, 111.70; 19F-NMR (D6-DMSO) delta 109.7.
3-[5-(2-fluorophenvIHl,2,41oxadiazo--3-yll-benzoie acid [0168] Batch 1[0169] A reaction vessel was charged with methyl 3-[5-(2-fluorophenyl)- [l,2,4]oxadiazol-3-yl]-benzoate (74.0kg), the vessel was sealed, evacuated and purged. The jacket set-point was set to about 35C and the agitator was started in the vessel. Molten tert-butanol (222L, 3 vol.) and purified water (355L, 4.8 vol.) were charged into the vessel. These charges were followed by the addition of 25.1%w/w aqueous sodium hydroxide solution (43.5kg, 1.1 mol equiv.) and a line rinse with additional purified water (10OL, 1.35 mol). The batch temperature dropped from about 39.00C to about 38.8C during the addition. The batch temperature was raised to about 63-67C over about 1 hour and 54 minutes and then adjusted to about 68-72C over about 30 minutes. The mixture was stirred for about 3 hours at about 68-72C. The solution was then cooled to about 40- 450C over about 5 hours and 11 minutes. The solution was then reheated to about 68-720C following the above procedure over about 3 hours and 33 minutes. [0170] The jacket temperature on the reaction vessel was set to about 600C, the agitator was started and the hot liquor was transferred through a 1 micron filter at about 700C under slight positive pressure of nitrogen (1.5 to 5.6 psig). The product temperature dropped to about 64.30C during the transfer, which was completed in about 45 minutes. The vessel was charged with purified water (61 L, 0.82 vol.) and the contents were heated to about 68-72C. <n="22"/>[0171] The batch temperature was adjusted to about 69.4C and treated with13.9%w/w sulfuric acid (100.7kg, 1.15 mol equiv.) over about 4 hours and 18 minutes.The batch temperature was maintained at about 68.0-70.80C during the addition. Acid addition was followed by a line rinse with purified water (50L, 0.68 vol.) and stirring at about 68-72C was continued for about an additional 31 minutes.[0172] The batch was cooled in a linear fashion from about 69.20C to about 41.20C over about 4 hours and 10 minutes. The stirrer on a Rosenmund filter/dryer was raised to the highest position and the jacket set point was set at about 400C. The slurry was transferred into the filter/dryer in two parts. Constant nitrogen pressure was applied to the first part (less than about 15 psig). The pressure ranged from about 23.9 to about 28.8 psi during the transfer, which was completed in about 1 hour and 5 minutes. The second part of the slurry was transferred on top of the filter cake and the composite was stirred briefly to homogenize the batch. The second part was filtered using about 26.1 to about 29.1 psi nitrogen pressure and the cake was pushed free of liquor after about 3 hours. The cake was washed with hot aqueous /e/7-butanol solution (352kg, 5 vol.) at about 38-42C and 3X hot purified water (370L, 5 vol.) at about 65-700C.[0173] The filter/dryer jacket temperature was set to about 43C and the product was dried in vacuo with periodic stirring over about 26 hours. Purity was determined to be about 99.7%. The overall yield of isolated product was about 74.4 % (52.45kg).
Batch 2[0175] A reactor vessel was charged with methyl 3-[5-(2-fluorophenyl)-[1 ,2,4]oxadiazol-3-yl]-benzoate (47 kg, wet cake) and molten /e/7-butanol (1 1 1.4 kg). The vessel was sealed and the batch temperature was set to 30- 400C and the agitator was started. Purified water (51.6 kg.) was charged into the vessel. This charge was followed by the addition of 3.47% w/w aqueous sodium hydroxide solution (202.4 kg). The batch temperature was raised to about 67-73C over about 1 hour and then stirred for about 3 hours at about 700C.[0176] The batch was filtered with 1 micron polypropylene filter bag under slight positive pressure of nitrogen and then transferred to a new reactor. The vessel was charged with purified water (146 kg) and the batch was heated to about 68-72C. <n="23"/>[0177] The batch was charged with 10.7% aqueous hydrochloric acid over about 4 hours. The batch temperature was maintained at about 68-72C during the addition. The pH of the batch was determined to be about 2.2, by a pH meter and stirring at about 700C was continued for about an additional 1 hour.[0178] The batch was cooled in a linear fashion from 70C to about 60 0C over about 2 hours. The batch at about 60 0C was cooled in a linear fashion from 600C to about 40 0C over about 2 hours. The batch was stirred for further 2 hours at 40 0C and the slurry was transferred into a centrifuge filter. Filtration was complete after about 30 minutes. The filter cakes were washed with about 42% w/w aqueous terf-butanol (165 kg) over about 30 minutes. Purified water (118 kg, 400C) was applied to the cakes as the final wash. The cakes were dried at about 900 rpm for about 1 hour and then discharged into a drum. [0179] The wet cakes were transferred into a paddle dryer (a double-cone dryer is also suitable for this step) and the jacket temperature was set to about 700C. The product was dried in vacuo at about 700C with periodic stirring over about 48 hours. Purity was determined to be about 99.8%. The overall yield of isolated product was about 74% (68.5 kg).[0180] Batch 3[0181] A reaction vessel was charged with methyl 3-[5-(2-fluorophenyl)- [ 1 ,2,4]oxadiazol-3-yl]-benzoate ( 10 g) and molten ter/-butanol ( 128 mL). The batch temperature was set to 30- 400C and the agitator was started. 4.48% w/w aqueous sodium hydroxide solution (32.5 g) was charged into the vessel over about 30 minutes. The batch temperature was maintained at about 40-500C. The batch temperature was raised to about 78-82C over about 1 hour and then stirred for about an additional 1 hour at about 78- 82C. The batch was filtered with 5 mum polyethylene filter under slight positive pressure of nitrogen and then transferred to a new reactor. The batch temperature was maintained at about 78-820C.[0182] A new vessel was charged with 37% aqueous hydrochloric acid (4 mL) and molten ter/-butanol (8 mL). The temperature was maintained at about 30-400C and the mixture was stirred for about 30 minutes.[0183] The batch was charged with the hydrochloric acid in terr-butanol over about 4 hours using a metering pump. The first half of the charge was added over about 20-30 <n="24"/>minutes. The agitator speed was set to about 200 rpm. The remaining charge was added over about 3.5 hours. The agitator speed was set to about 100 rpm. The batch temperature was maintained at about 78-82C during the addition. The pH of the final batch was adjusted to be about 1.2, by a pH meter and stirring at about 78-82C was continued for about an additional 1 hour.[0184] The batch was cooled in a linear fashion from 78-82C to about 700C over about 1 hour. The batch at about 70 0C was cooled in a linear fashion from 700C to about500C over about 4 hours and the agitator speed was set to about 80 rpm. The batch at about 500C was cooled in a linear fashion from 500C to about 400C over about 4 hours and the agitator speed was set to about 60 rpm. The batch was stirred for further 4 hours at400C.[0185] The filter temperature was set to about 40-450C. The slurry was transferred into a filter. Filtration was complete after about 1 minute. The filter cakes were washed with /erf-butanol (50 mL, 500C) over about 2 minutes. Purified water (100 mL x 2, 600C) was applied to the cakes as the final wash. The cakes were dried at about 60-700C under vacuum for about 12 hours and then discharged in to a container.[0186] HPLC purity was determined to be about 99.9% area. The yield of isolated product was about 94% (9.Og).[0187]
123 mg
With water; sodium hydroxide; In ethanol; at 20℃; for 3h;
General procedure: To a solution of methyl ester 13 (228 mg, 0.76 mmol) in EtOH: H2O (3:2, 10 mL) was added crushed NaOH (91 mg, 2.27 mmol) and the solution was stirred at rt for 3h. The volatiles were evaporated under reduced pressure and the residue obtained was acidified with 1N aqueous HCl (pH ~ 4). This solution was then transferred to a separatory funnel and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried Na2SO4 and concentrated under reduced pressure to afford the title acid 14 (123 mg, 54%) as a white solid.
3 g
With water; sodium hydroxide; In tetrahydrofuran; at 100℃; for 2h;
A solution of 33 g of methyl 3- [5- (2-fluorophenyl) - [1,2,4-oxadiazol-3-yl] -benzoic acid methyl ester was dissolved in 400 mlOf tetrahydrofuran,To this was added 100 ml of a 1.5 M aqueous solution of sodium hydroxide.The reaction mixture was heated at 100 C for 2 hours. The solvent was removed under reduced pressure,The aqueous solution was stirred at 5 C for 2 hours.The organic solvent was removed, the aqueous solution was diluted with 50 ml of water,Followed by acidification with hydrochloric acid to pH 1. Filter out a white precipitate, wash the filter cake with cold water,And then dried with a freeze drier.To obtain 3. 0 g of 3- [5- (2_ fluorophenyl) - [1,2,4] oxadiazol-3-yl] benzoic acid. (1H), 8.18 (2H), 08.8 (1H), 7.88 (2H), 7.11 (2H). Show that the sample prepared in Preparation Example 1 was incubated with TO2004091502A2 Example 2 prepared ataluren
3-(N-2-fluorobenzoylcarbamimidoyl)-benzoic acid methyl ester[ No CAS ]
[ 775304-60-4 ]
Yield
Reaction Conditions
Operation in experiment
92%
In toluene; at 130℃; for 4h;Heating / reflux;
44 g of 3-(N-2-Fluorobenzoylcarbamimidoyl)-benzoic acid methyl ester in toluene (500 mL) was refluxed for 4 h at 130 C. using Dean-Stark apparatus. The reaction mixture was stirred at 5 C. for 18 h. The white precipitate was filtered off and the filtrate was concentrated, crystallized again in toluene. The desired oxadiazole (38 g, 92% yield) was obtained as a white solid with 99% purity (LC/UV). 1H-NMR (CDCl3) delta 8.91 (1H), 8.38 (1H), 8.15 (2H), 7.62 (2H), 7.35 (2H), 3.95 (3H)
3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid sodium salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium hydroxide; water; In tetrahydrofuran; at 5 - 100℃; for 4h;Heating / reflux;
The sodium salt can be prepared as follows. To a solution of 3-[5-(2-Fluoro-phenyl)-[l,2,4]oxadiazol-3- yl]-benzoic acid methyl ester (33g3 111 mol) in THF (400 mL) was added 1.5M aqueous NaOH (100 mL, 144 mmol). The reaction mixture was refluxed for 2h at 100 C. The organic solvent was removed under reduced pressure and the aqueous solution was stirred 2 h at 5 C. The white precipitate was filtered off and the filtrate was concentrated and precipitated again in water. The white cake was washed with cold water and then dried using lyophilizer. The desired salt (33g, 96% yield) was obtained as a white powder with 98.6% purity (LC/UV).
96%
With sodium hydroxide; water; In tetrahydrofuran; at 5 - 100℃; for 4h;Heating / reflux;
To a solution of 3-[5-(2-Fluoro-phenyl)- [l ,2,4]oxadiazol-3-yl]-benzoic acid methyl ester (33g, 11 1 mol) in THF (400 mL) was added 1.5M aqueous NaOH (100 mL, 144 mmol). The reaction mixture was refluxed for 2h at 100 0C. The organic solvent was removed under reduced pressure and the aqueous solution was stirred 2 h at 5 0C. The white precipitate was filtered off and the filtrate was concentrated and precipitated again in water. The white cake was washed with cold water and then dried using lyophilizer. The desired salt (33g, 96% yield) was obtained as a white powder with 98.6% purity (LCAJV).
96%
Pharmaceutically acceptable salts of 3-[5-(2-Fluoro-phenyl)-[l ,2,4]oxadiazol-3-yl]-benzoic acid can be prepared using methods known to those skilled in the art. The sodium salt can be prepared as follows. To a solution of 3-[5-(2-Fluoro-phenyl)- [l,2,4]oxadiazol-3-yl]-benzoic acid methyl ester (33g, 111 mol) in THF (400 mL) was added 1.5M aqueous NaOH (100 mL, 144 mmol). The reaction mixture was refluxed for 2h at 100 0C. The organic solvent was removed under reduced pressure and the aqueous solution was stirred 2 h at 5 0C. The white precipitate was filtered off and the filtrate was concentrated and precipitated again in water. The white cake was washed with cold water and then dried using lyophilizer. The desired salt (33g, 96% yield) was obtained as a white powder with 98.6% purity (LC/UV).
44g of 3-(N-2-Fluorobenzoylcarbamimidoyl)-benzoic acid methyl ester in toluene (500 mL) was refluxed for 4h at 130 C using Dean-Stark apparatus. The reaction mixture was stirred at 5 C for 18h. The white precipitate was filtered off and the filtrate was concentrated, crystallized again in toluene. The desired oxadiazole (38g, 92% yield) was obtained as a white solid with 99% purity (LC/UV). 1H-NMR (CDCl3) S 8.91 (IH)5 8.38 (IH)3 8.15 (2H), 7.62 (2H)3 7.35 (2H)3 3.95 (3H).
92%
In toluene; at 5 - 130℃; for 22h;Dean-Stark apparatus;
44g of 3-(N-2-Fluorobenzoylcarbamimidoyl)-benzoic acid methyl ester in toluene (500 mL) was refluxed for 4h at 130 0C using Dean-Stark apparatus. The reaction mixture was stirred at 5 0C for 18h. The white precipitate was filtered off and the filtrate was EPO <DP n="22"/>concentrated, crystallized again in toluene. The desired oxadiazole (38g, 92% yield) was obtained as a white solid with 99% purity (LC/UV). 1H-NMR (CDCl3) delta 8.91 (IH), 8.38 (IH), 8.15 (2H), 7.62 (2H)3 7.35 (2H), 3.95 (3H).
In toluene; at 5 - 130℃; for 22h;Heating / reflux;
44g of 3-(N-2-Fluorobenzoylcarbamimidoyl)-benzoic acid methyl ester in toluene (500 mL) was refluxed for 4h at 130 0C using Dean-Stark apparatus. The reaction mixture was stirred at 5 0C for 18h. The white precipitate was filtered off and the filtrate was concentrated, crystallized again in toluene. The desired oxadiazole (38g, 92% yield) was obtained as a white solid with 99% purity (LC/UV). 1H-NMR (CDCl3) delta 8.91 (IH), 8.38 (IH), 8.15 (2H), 7.62 (2H), 7.35 (2H), 3.95 (3H).
38 g
In toluene; at 5 - 130℃; for 22h;Dean-Stark;
At 130 C with Dean-StarkThe solution was heated to dissolve 44 grams of toluene in 500 ml3- (N-2-fluorobenzoylamidino) -benzoic acid methyl ester for 4 hours.The reaction mixture was stirred at 5 C for 18 hours. The white precipitate was filtered off, the filtrate was concentrated,And then crystallized in toluene.To obtain 38 g of methyl 3- [5- (2-fluorophenyl) - [1,2,4-oxadiazol-3-yl] -benzoic acid methyl ester.
With potassium carbonate; In acetone; at 20℃; for 24h;
General procedure: 2 mmol of either amidoxime 1 [30] or 2 [26] were dissolved in acetone (200 mL) in a round-bottomed flask; then, K2CO3 (0.35 g; 2.5 mmol) and the corresponding aroyl chloride (2.5 mmol), were added to the reaction mixture and stirred for 24 h at room temperature. The solvent was removed under vacuum and the residue treated with water and refluxed for 30 min 1,2,4-Oxadiazoles products were obtained by filtration and further purified by chromatography.
With boron trifluoride diethyl etherate; In 1,4-dioxane; at 0℃; for 12.5h;Reflux;
General procedure: To a solution of benzamidoxime (500 mg, 3.67 mumol) in dioxane (35 mL) at 0 C was added 2,4-dichlorobenzoyl chloride (770 mg, 3.67 mmol) and BF3?OEt2 (114 muL, 0.80 mmol). The reaction mixture was stirred at rt for 30 min and heated to reflux for 12 h. The volatiles were evaporated under reduced pressure and the residue was cooled in an ice bath and diluted with ice-water (25 mL). This solution was then transferred to a separatory funnel and the aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (10% EtOAc in hexanes) to yield bis-aryl oxadiazole 1 (850 mg, 80%) as a colorless solid.
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