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[ CAS No. 68291-97-4 ] {[proInfo.proName]}

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Chemical Structure| 68291-97-4
Chemical Structure| 68291-97-4
Structure of 68291-97-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 68291-97-4 ]

CAS No. :68291-97-4 MDL No. :MFCD00865316
Formula : C8H8N2O3S Boiling Point : -
Linear Structure Formula :- InChI Key :UBQNRHZMVUUOMG-UHFFFAOYSA-N
M.W : 212.23 Pubchem ID :5734
Synonyms :
CI 912;AD 810;Excegram;Exceglan;PD 110843

Calculated chemistry of [ 68291-97-4 ]

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 50.65
TPSA : 94.57 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.42 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.25
Log Po/w (XLOGP3) : 0.24
Log Po/w (WLOGP) : 1.55
Log Po/w (MLOGP) : -0.46
Log Po/w (SILICOS-IT) : 0.28
Consensus Log Po/w : 0.37

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.65
Solubility : 4.74 mg/ml ; 0.0224 mol/l
Class : Very soluble
Log S (Ali) : -1.79
Solubility : 3.47 mg/ml ; 0.0164 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.89
Solubility : 0.272 mg/ml ; 0.00128 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.72

Safety of [ 68291-97-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P201-P202-P264-P270-P280-P301+P312+P330-P308+P313-P405-P501 UN#:N/A
Hazard Statements:H302-H361 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 68291-97-4 ]

* 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.

  • Upstream synthesis route of [ 68291-97-4 ]
  • Downstream synthetic route of [ 68291-97-4 ]

[ 68291-97-4 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 73101-65-2 ]
  • [ 68291-97-4 ]
YieldReaction ConditionsOperation in experiment
91.25% With ammonia In toluene at 2 - 15℃; B) Preparation of crude Zonisamide; A 0.25 ml three necked flask was charged with BOS-Cl (13 g) and toluene(130 ml) to obtain a solurion. The obtained solution was then cooled to -20C, and ammonia gas is bubbled through the solution until the pH was about 9, leading to a precipitate of zonisamide and ammonium chloride. The temperature was naturally increased to room temperature followed by adding 43 ml water and 3.4 ml HCl 32percent, and stirring for 30 minutes. Filtration and washing with water (13 ml) and ethanol tech.(13 ml) afforded the wet product. Drying at 5O0C gave crude Zonisamide (10.6 g, yield 91.6percent).; Example 3: Preparation of Zonisamide with Anhydrous Ammonia according to WO 03/072552; A 2 L reactor was charged with the solution of BOS-Cl in toluene. The mixture was cooled to 10-15°C and anhydrous ammonia gas was bubbled through the mixture. The temperature of the mixture was maintained at 10-15 °C. The amidation reaction was monitored by HPLC. After the reaction was completed the inorganic EPO <DP n="18"/>salts were filtered out. The solid was reslurried (triturated)in water at room temperature, filtered and washed with 95percent ethanol to provide crude product zonisamide (wet crude:166 grams; yield: 91.25 percent; content of BOS- NH4:2.5percent(wt/wt)).
91.6% With ammonia In toluene at 2℃; B) Preparation of crude ZonisamideA 0.25 ml three necked flask was charged with BOS-Cl (13 g) and toluene (130 ml) to obtain a solution. The obtained solution was then cooled to ~2°C, and ammonia gas was bubbled through the solution until the pH was of about 9, leading to a precipitate of zonisamide and ammonium chloride. The temperature naturally increased to room temperature followed by adding 43 ml water and 3.4 ml HCl 32percent, and stirring for 30 minutes. Filtration and washing with water (13 ml) and ethanol tech. (13 ml) afforded the wet product. Drying at 5O0C gave the crude zonisamide (10.6 g, yield 91.6percent).
77.8% With ammonium carbonate In butanone for 1 h; Heating / reflux A three-necked flask was charged with BOS-Cl (10 grams), ammonium carbonate (20 grams) and MEK (100 mL). The reaction mixture was stirred at reflux for about 1 hour. [0059] After cooling, the product was filtered out and washed with MEK. After drying, the zonisamide product weighed 7.13 grams (yield about 77.8percent) and the purity on HPLC was 87percent. [0060] Other reaction solvents including acetone, MIBK, ethyl-acetate, butyl-acetate were used instead of MEK and were found to yield similar zonisamide products. [0061] The crude zonisamide product was then crystallized from ethanol (95percent) to yield pure zonisamide.
181.40 g at 10 - 15℃; for 1 h; Green chemistry 2), vacuum suction for 0.5 hours to remove the excess unreacted phosgene, and then control the temperature at 10-15 access to anhydrous ammonia, when the pH = 9-10 end of the end of ammonia, the same temperature reaction 1 Hour after the test pH, maintain pH = 9-10, or addammonia;3), the solid was centrifuged at 10-15 ° C and the solid was rinsed with 200 g of toluene. The wet solid was added with 600 g of waterand stirredat20-25 ° C for 1 hour. Centrifuge and dry to give crude oxazepam 240.3 g HPLC purity of 94.60percent), the driedsolid was recrystallized from 1500 g of methanol to obtain 181.40 g of the qualified zonisamide crystal, the purity was more than 99.70percent, themaximum single product was 0.04percent, the total yield of the two steps was 85.50 percent.

Reference: [1] Patent: WO2007/16208, 2007, A2, . Location in patent: Page/Page column 16-17
[2] Patent: WO2007/16209, 2007, A2, . Location in patent: Page/Page column 13
[3] Patent: US2004/14983, 2004, A1, . Location in patent: Page 4
[4] Journal of Medicinal Chemistry, 1979, vol. 22, p. 180 - 183
[5] Patent: US2004/14983, 2004, A1, . Location in patent: Page 4
[6] Patent: US2004/14983, 2004, A1, . Location in patent: Page 4
[7] Patent: US2006/84814, 2006, A1, . Location in patent: Page/Page column 3; 4
[8] Patent: US2007/142644, 2007, A1, . Location in patent: Page/Page column 7
[9] Patent: WO2005/44808, 2005, A1, . Location in patent: Page/Page column 10
[10] Patent: CN106810507, 2017, A, . Location in patent: Paragraph 0040; 0042-0043; 0047; 0049-0050; 0054; 0056-0057
  • 2
  • [ 73101-64-1 ]
  • [ 68291-97-4 ]
YieldReaction ConditionsOperation in experiment
75%
Stage #1: at 10 - 40℃; for 2 h;
Stage #2: With oxalyl dichloride In DMF (N,N-dimethyl-formamide); toluene at 10 - 18℃; for 2 h;
Stage #3: With ammonia In DMF (N,N-dimethyl-formamide); toluene at 10 - 18℃; for 2 h;
A 500 ml three necked flask, equipped with mechanical stirrer, Dean-Stark trap and condenser, was charged with BIOS-Na monohydrate (20 grams, prepared as described in Reference Example 1 above) and toluene (220 ml). The resulting suspension was heated to reflux so that water was azeotropically distilled during 4 hours. The resulting suspension was cooled under nitrogen atmosphere to 10° C. and DMF (6.4 ml, 1.04 equivalents) was added into the mixture. Oxalyl chloride (10.5 grams, 1.04 equivalents) was added dropwise to the mixture at 10-15° C. during 1 hour and the reaction mixture heated to 40° C. for 1 hour. Ammonia gas (5.5 grams, 4 equivalents) was bubbled into the reaction mixture at 10-18° C. during 2 hours. The resulting precipitate was collected by filtration and slurried in water (80 ml) at ambient temperature for 2 hours. A solid was collected from the slurry by filtration, washed with water and dried under reduced pressure at 50° C. overnight to obtain crude zonisamide (15.6 grams) in 93percent yield, (purity by HPLC: 99.05percent). The crude zonisamide (15.6 grams) was dissolved with heating in a mixture of methanol (150 ml) and water (20 ml) and the solution was thereafter filtered. A portion of the methanol (about 65 ml) was distilled from the filtrate. The residual solution was cooled to ambient temperature and maintained at 10-15° C. for 16 hours. The resulting colorless crystals were collected by filtration, washed with a cool mixture of water and methanol and dried under reduced pressure at 50° C. overnight to obtain pure zonisamide (12.6 grams) in 75percent overall yield (purity by HPLC: 99.94
74.5%
Stage #1: at 10 - 40℃; for 1.5 h;
Stage #2: With oxalyl dichloride In DMF (N,N-dimethyl-formamide); toluene at 10 - 18℃; for 2 h;
Stage #3: With ammonia In DMF (N,N-dimethyl-formamide); toluene at 10 - 18℃; for 2 h;
A 500 ml three-necked flask, equipped with mechanical stirrer, Dean-Stark trap and condenser, was charged with BIOS-Na monohydrate (20 grams, prepared as described in Reference Example 1 above), toluene (100 ml) and DMF (6.4 ml, 1.04 equivalents). The resulting suspension was heated to 70° C. forming a jelly-like mixture. The resulting jelly-like mixture was heated to reflux so that water was azeotropically distilled during 2 hours. Toluene (100 ml) was added and the reflux with azeotropic distillation continued for 2 hours The suspension was cooled under nitrogen atmosphere to 10° C. Oxalyl chloride (10.5 rams, 1.04 equivalents) was added dropwise to the mixture at 10-15° C. during 1 hour and the reaction mixture was heated to 40° C. for 0.5 hour. Ammonia gas (5.5 grams, 4 equivalents) was then bubbled into the reaction mixture at 10-18° C. during 2 hours. The resulting precipitate was collected by filtration and slurried in water (80 ml) at ambient temperature for 2 hours. A solid was collected from the slurry by filtration, washed with water and dried under reduced pressure at 50° C. overnight to obtain crude zonisamide (14.8 grams) in 88.8percent yield (purity by HPLC: 98.53percent). The crude zonisamide (14.9grams) was dissolved with heating in a mixture of methanol (140 ml) and water (15 ml) and the solution was thereafter filtered. A portion of the methanol (about 60 ml) was distilled from the filtrate. The residual solution was cooled to ambient temperature and maintained at 10-15° C. for 16 hours. The resulting colorless crystals were collected by filtration, washed with a cool mixture of water and methanol and dried under reduced pressure at 50° C. overnight to obtain pure zonisamide (12.5 grams) in 74.5percent overall yield (purity by HPLC: 99.95
Reference: [1] Patent: US2006/9644, 2006, A1, . Location in patent: Page/Page column 10
[2] Patent: US2006/9644, 2006, A1, . Location in patent: Page/Page column 10
[3] Patent: US2005/215796, 2005, A1, . Location in patent: Page/Page column 3
[4] Patent: CN106810507, 2017, A,
  • 3
  • [ 73101-65-2 ]
  • [ 68291-97-4 ]
  • [ 81534-20-5 ]
YieldReaction ConditionsOperation in experiment
85% With ammonia In toluene at 10 - 15℃; A 2 L reactor was charged with the solution of BOS-Cl in toluene prepared in example 6(a). The mixture was cooled to 10-15° C. and anhydrous ammonia gas was bubbled through the mixture. The temperature of the mixture was maintained at 10-15° C. The amidation reaction was monitored by HPLC. [0067] After the reaction was completed the inorganic salts were filtered out. The solid was reslurried (triturated) in water at room temperature, filtered and washed with 95percent ethanol to provide crude product zonisamide (wet crude: 166 grams; yield: 91.25percent; content of BOS-NH4: 2.5percent (wt/wt)).c) Preparation of Zonisamide With Dry Ammonia [0076] A 2L reactor was charged with the solution of BOS-Cl in toluene prepared in example 7(b). The mixture was cooled to 10-15° C. and anhydrous ammonia gas was bubbled through the mixture. The temperature of the mixture was maintained at 10-15° C. The amidation reaction was monitored by HPLC. [0077] After the amidation reaction was completed, the inorganic salts and zonisamide were filtered out. The solid was reslurried (triturated) in water at room temperature, filtered and washed with 95percent ethanol to provide the crude product zonisamide (yield: 85percent; BOS-NH4: 2.4percent (wt/wt)).
Reference: [1] Patent: US2004/14983, 2004, A1, . Location in patent: Page 4-5
[2] Patent: WO2007/16209, 2007, A2, . Location in patent: Page/Page column 14
  • 4
  • [ 4865-84-3 ]
  • [ 68291-97-4 ]
Reference: [1] Patent: US2007/66830, 2007, A1, . Location in patent: Page/Page column 5
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