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Chemical Structure| 139481-72-4
Chemical Structure| 139481-72-4
Structure of 139481-72-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 139481-72-4 ]

CAS No. :139481-72-4 MDL No. :MFCD08436154
Formula : C43H34N6O3 Boiling Point : -
Linear Structure Formula :- InChI Key :VBMKOTRJWPIKMG-UHFFFAOYSA-N
M.W : 682.77 Pubchem ID :10312563
Synonyms :

Calculated chemistry of [ 139481-72-4 ]

Physicochemical Properties

Num. heavy atoms : 52
Num. arom. heavy atoms : 44
Fraction Csp3 : 0.09
Num. rotatable bonds : 11
Num. H-bond acceptors : 7.0
Num. H-bond donors : 1.0
Molar Refractivity : 200.59
TPSA : 107.95 Ų

Pharmacokinetics

GI absorption : Low
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) : -4.12 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.01
Log Po/w (XLOGP3) : 8.94
Log Po/w (WLOGP) : 8.34
Log Po/w (MLOGP) : 6.44
Log Po/w (SILICOS-IT) : 7.0
Consensus Log Po/w : 6.94

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 1.0
Egan : 1.0
Muegge : 3.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -9.61
Solubility : 0.000000169 mg/ml ; 0.0000000002 mol/l
Class : Poorly soluble
Log S (Ali) : -11.1
Solubility : 0.0000000055 mg/ml ; 0.0 mol/l
Class : Insoluble
Log S (SILICOS-IT) : -14.4
Solubility : 0.0 mg/ml ; 0.0 mol/l
Class : Insoluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 5.14

Safety of [ 139481-72-4 ]

Signal Word:Danger Class:4.1
Precautionary Statements:P240-P210-P241-P264-P280-P302+P352-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313 UN#:1325
Hazard Statements:H315-H319-H228 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 139481-72-4 ]

* 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 [ 139481-72-4 ]
  • Downstream synthetic route of [ 139481-72-4 ]

[ 139481-72-4 ] Synthesis Path-Upstream   1~13

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YieldReaction ConditionsOperation in experiment
94% With triethylamine In dichloromethane at 15 - 23℃; for 3.5 h; Flow reactor; Large scale I. Candesartan (10kg) and methylene chloride (100kg) were added to the reactor, and the temperature was lowered to 15°C. Triethylamine (4.5kg) was slowly added dropwise; after the addition was completed, the temperature of the reaction system was raised to 23°C. Triphenylchloromethane (7kg) was added in portions; after the addition, the reaction system temperature was maintained at 23°C for 3.5 hours; TLC monitoring (developer dichloromethane:methanol = 10:1 (V/V),Rf = 0.78) After the reaction is complete, add 0.1 mol/L HCl 30L (system pH = 5.4) at a time, add 5L 9mol/L HCl slowly to pH = 2.2, and separate the aqueous and organic layers by standing. 60L for the organic layer. The saturated saline solution was washed, transferred to a vacuum vessel, and the dichloromethane was recovered under reduced pressure.The residue in the kettle was added with 65 L of ethanol, and the temperature was raised to 45° C. and stirred for 3 hours until a large amount of white solid precipitated. The heating was stopped, and the temperature was lowered to room temperature. The filter cake was washed with a small amount of ethanol and dried at normal pressure at 50° C. for 12 hours to obtain three. Phenyl candesartan (white crystalline powder, 14.5 kg). Calculated according to the following formula, the yield of this step is 94.0percent.
90% With triethylamine In acetone at 55 - 60℃; for 4 - 8 h; Examples-l; Preparation of tritylated Candesartan acid (acetone) A mixture of Candesartan acid, triethylamine and acetone was heated to reflux temperature at 55-600C. To this trityl chloride solution in acetone was added and refluxed it for 4-8 hours. The reaction mixture was cooled at ambient temperature followed by addition of D. M. water and stirred for one hour. The reaction mixture was filtered and washed with mixture of acetone and D. M. water. To the solid, D. M water was added and stirred for 30 minutes at ambient temperature. The mixture was filtered and washed with D. M. water. The solid was dried to obtain tritylated Candesartan acid. Yield: 90 percent Purity: 99percent
90% With triethylamine In acetone at 55 - 60℃; A mixture of Candesartan acid, triethylamine and acetone was heated to reflux temperature at 55-60° C. To this trityl chloride solution in acetone was added and refluxed it for 4-8 hours. The reaction mixture was cooled at ambient temperature followed by addition of D. M. water and stirred for one hour. The reaction mixture was filtered and washed with mixture of acetone and D. M. water. To the solid, D. M water was added and stirred for 30 minutes at ambient temperature. The mixture was filtered and washed with D. M. water. The solid was dried to obtain tritylated Candesartan acid.Yield: 90percentPurity: 99percent
89% With triethylamine In methyl iso-butyl ketone (MIBK) at 55 - 60℃; for 4 - 8 h; ExampIes-2; Preparation of tritylated Candesartan acid (MIBK)A mixture of Candesartan acid, triethylamine and methyl isobutyl ketone (MIBK) was heated to reflux temperature at 55-600C. To this trityl chloride solution in MIBK was added and refluxed it for 4-8 hours. The reaction mixture was cooled at ambient temperature followed by addition of D. M. water and stirred for one hour. The reaction mixture was filtered and washed with mixture of acetone and D. M. water. To the solid, D. M water was added and stirred for 30 minutes at ambient temperature. The mixture was filtered and washed with D. M. water. The solid was dried to obtain tritylated Candesartan acid. Yield: 89 percent Purity: 98.5percent
88% With triethylamine In butanone at 55 - 60℃; for 4 - 8 h; Examples-3; Preparation of tritylated Candesartan acid (MEK) A mixture of Candesartan acid, triethylamine and methyl ethyl ketone (MEK) was heated to reflux temperature at 55-600C. To this trityl chloride solution in MEK was added and refluxed it for 4-8 hours. The reaction mixture was cooled at ambient temperature followed by addition of D. M. water and stirred for one hour. The reaction mixture was filtered and washed with mixture of acetone and D. M. water. To the solid, D. M water was added and stirred for 30 minutes at ambient temperature. The mixture was filtered and washed with D. M. water. The solid was dried to obtain tritylated Candesartan acid. Yield: 88 percent .bul. Purity: 98percent
83.8% With triethylamine In dichloromethane at 25 - 30℃; for 2 h; Heating / reflux Example-1: Preparation of Candesartan cilexetil (with isolation of cilexetil trityl candesartan); Step-I: Preparation of Trityl candesartanTo solution of Candesartan (10Og in 350 ml MDC) and triethyl amine (34.3 g) Trityl chloride (76.8g in 150 ml MDC) is added slowly at temperature of 25 - 3O0C. Temperature of the reaction mass is raised and maintained at reflux temperature for 2 hrs. Reaction mass is cooled to temperature of 30 - 350C, water (100 ml) is added, stirred for about 15 min, allowed to settle and separated the layers. Aqueous layer is extracted with MDC (2x 100 ml), combined organic layer is washed with water and MDC is removed below 5O0C from organic layer. Ethyl acetate (600 ml) is added, raised and maintained the temperature of the reaction mass at reflux temperature for 2hrs. The temperature of the mass is cooled, maintained for 1 hr at 25 - 3O0C and isolated the product by filtration. Wet cake is washed with ethyl acetate (100 ml) and dried at temperature of 45 - 5O0C to constant weight. <n="7"/>The weight of trityl candesartan is 130 g (Yield 83.8percent)
53% With triethylamine In dichloromethane at 20℃; for 2.5 h; To a solution of 2-ethoxy-1-[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}-benzimidazole-7-carboxylic acid (78 mg) in methylene chloride (1ml) were added trityl chloride (63 mg) and triethylamine (0.03ml). The mixture was stirred at room temperature for two hours thirty minutes. The reaction mixture was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica (eluant: cyclohexane /ethyl acetate: from to 90/10 to 0/100) to give 2-ethoxy-1-[{2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-1,1'-biphenyl-4-yl}methyl]-benzimidazole-7-carboxylic acid (60mg, 53percent yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ 1.40 (t, J=7Hz, 3H), 4.62 (q, J=7Hz, 2H), 5.59 (s, 2H), 6.76 (d, J=8Hz, 2H), 6.92-6.96 (m, 8H), 7.14 (t, J=8Hz, 1 H), 7.19-7.30 (m, 10H), 7.38 (m, 2H), 7.64 (d, J=8Hz, 1 H), 7.76-7.83 (m, 2H) ppm.
125.5 g With triethylamine In dichloromethane at 25 - 35℃; for 20 h; 250 g of tributyl tin azide was added into 600 ml of xylene. 100 g of candesartan cyclic compound (in formula II, R is ethyl) was added, heated to 140-150° C., and refluxed to react for 20 h. After the end of the reaction, the reaction mixture was cooled to 40-50° C. 600 ml of sodium hydroxide solution (48 g of sodium hydroxide dissolved in 600 ml of water) was added, and stirred under 20-35° C. (0032) The organic layer was removed. (0033) The alkaline aqueous layer was heated to 70-80° C. to completely hydrolyze candesartan ethyl ester. The temperature of the mixture was controlled at 25-35° C. 400 ml of dichloromethane was added. Glacial acetic acid was added dropwise to adjust pH of the mixture to 5-6 to precipitate candesartan. (0034) Triethylamine was added dropwise into the mixture until the candesartan solid was dissolved completely. The dichloromethane layer was separated. The aqueous layer was extracted by adding 200 ml of dichloromethane once again. The organic layers were combined. 68 g of triphenyl chloromethane was added into the organic layer. The temperature of the mixture was controlled at 25-35° C. to react until the content of candesartan was reduced to less than 1.0percent monitored by HPLC. After the end of the reaction, 100 ml of water was added for washing. The aqueous layer was removed. The organic layer was dried under reduced pressure. 600 ml of anhydrous ethanol was added to crystallize. The resulting crystals were collected by filtration, and dried to provide 125.5 g of trityl candesartan, yield 78.2percent, purity 97

Reference: [1] Patent: CN105153124, 2018, B, . Location in patent: Paragraph 0005; 0054; 0055; 0076; 0090
[2] Patent: WO2009/7986, 2009, A1, . Location in patent: Page/Page column 13
[3] Patent: US2010/210852, 2010, A1, . Location in patent: Page/Page column 5
[4] Patent: WO2009/7986, 2009, A1, . Location in patent: Page/Page column 14
[5] Patent: WO2009/7986, 2009, A1, . Location in patent: Page/Page column 14
[6] Patent: WO2007/94015, 2007, A1, . Location in patent: Page/Page column 5-6
[7] Patent: EP1833801, 2008, B1, . Location in patent: Page/Page column 18
[8] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 23, p. 7971 - 7977
[9] Patent: WO2006/50922, 2006, A1, . Location in patent: Page/Page column 12
[10] Patent: WO2009/157001, 2009, A2, . Location in patent: Page/Page column 4
[11] Patent: WO2011/92666, 2011, A1, . Location in patent: Page/Page column 12
[12] Patent: WO2011/145100, 2011, A1, . Location in patent: Page/Page column 7-8
[13] Patent: US2018/155326, 2018, A1, . Location in patent: Paragraph 0031-0034
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YieldReaction ConditionsOperation in experiment
66% With triethylamine In dichloromethane WORKING EXAMPLE 6
2-Ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid
To a solution of 2-ethoxy-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (2.07 g) in methylene chloride (10 ml) were added trityl chloride (1.59 g) and triethylamine (0.8 ml).
The mixture was stirred at room temperature for one hour.
The reaction mixture was washed with water, dried and concentrated to dryness.
The residue was purified by column chromatography on silica gel to give crystals.
Recrystallization of crude crystals thus obtained from ethyl acetate-benzene gave colorless crystals (2.12 g, 66percent), m.p. 168°-170° C.
1 H-NMR(200 MHz, CDCl3) δ: 1.40(3H,t), 4.61(2H,q), 5.58(2H,s), 6.76(2H,d), 6.91-6.96(8H,m), 7.12(1H,t), 7.17-7.41(12H,m), 7.60(1H,dd), 7.73-7.82(2H,m)
Reference: [1] Patent: US5196444, 1993, A,
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Reference: [1] Patent: US6177587, 2001, B1,
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Reference: [1] Patent: WO2011/145100, 2011, A1,
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Reference: [1] Patent: WO2011/145100, 2011, A1,
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Reference: [1] Patent: WO2011/145100, 2011, A1,
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Reference: [1] Patent: US2018/155326, 2018, A1,
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