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Chemical Structure| 99464-83-2 Chemical Structure| 99464-83-2

Structure of 99464-83-2

Chemical Structure| 99464-83-2

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Product Details of [ 99464-83-2 ]

CAS No. :99464-83-2
Formula : C9H15ClO3
M.W : 206.67
SMILES Code : O=C(OC(Cl)C)OC1CCCCC1
MDL No. :MFCD04038149
InChI Key :ONZWFHWHTYZZLM-UHFFFAOYSA-N
Pubchem ID :11229529

Safety of [ 99464-83-2 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H227-H314
Precautionary Statements:P501-P210-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405
Class:8
UN#:1760
Packing Group:

Computational Chemistry of [ 99464-83-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 0
Fraction Csp3 0.89
Num. rotatable bonds 4
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 50.82
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

35.53 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.89
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

3.45
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.06
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.71
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

2.02
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.63

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.03
Solubility 0.193 mg/ml ; 0.000931 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-3.88
Solubility 0.0274 mg/ml ; 0.000133 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-1.8
Solubility 3.25 mg/ml ; 0.0157 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

Yes
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.11 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.06

Application In Synthesis of [ 99464-83-2 ]

* 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.

  • Downstream synthetic route of [ 99464-83-2 ]

[ 99464-83-2 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 139481-72-4 ]
  • [ 99464-83-2 ]
  • [ 170791-09-0 ]
YieldReaction ConditionsOperation in experiment
100% With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In tetrahydrofuran; at 20 - 65℃; for 6h;Product distribution / selectivity; Example/STEP 1; Preparation of 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (i.e., Candesartan cilexetil trityl); Example/Step 1-ATo a 1 L, three-necked round-bottomed spherical flask equipped with a reflux condenser and a thermometer, were added 100.0 g of 2-ethoxy-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (146.5 mmol), chloroethyl cyclohexyl carbonate (approximately 36.32 g, 175.8 mmol), potassium carbonate (approximately 24.29 g, 175.8 mmol), benzyltriethylammonium chloride (approximately 8.340 g, 36.62 mmol) and tetrahydrofuran (approximately 350 mL). The suspension is heated to reflux (approximately 63-65 C.) over approximately 30 minutes and maintained at this temperature for approximately 5 hours. The heating was stopped, and the suspension was cooled to approximately 20-25 C. over approximately 30 minutes. The suspension was filtered, and the resulting white solid was washed with tetrahydrofuran (2× approximately 100 mL). The solid was discarded, and the yellow mother liquors were concentrated by distilling off the tetrahydrofuran under vacuum. Isopropyl alcohol (approximately 500 mL) was added to the concentrated solution, and the suspension was heated to reflux (approximately 76-78 C.). After reaching reflux temperature, the solution was allowed to cool to approximately 20-25 C. over approximately 3 hours during which time a solid precipitates. The resulting suspension was then stirred at approximately 20-25 C. for approximately 1 hour. The suspension was then filtered, and the resulting solid was washed with isopropyl alcohol (2× approximately 50 mL) to yield 171.0 g (loss on drying (?LOD?)=23.21%, 131.3 g (dry), quantitative yield) of crude 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (i.e., candesartan cilexetil trityl). Table 1 illustrates the results of an HPLC analysis of the crude candesartan cilexetil trityl obtained in Example/Step 1-A.
98% With potassium carbonate; In ISOPROPYLAMIDE; at 60℃; for 4h; 20.40 g (30 mmol) of trityl candesartan (III), 30 mL of dimethylacetamide (DMA); 4.95 g (235.9 mmol) K2CO3 and 10.2 g (49.4 mmol) of 1 -chloroethyl cycfohexyf carbonate are heated at 600C for 4 hours. The reaction mixture is cooled to room temperature, and 240 ml of isopropyl acetate and 240 mi of water are added. The organic phase is separated from the aqueous phase and the aqueous phase is <n="22"/>extracted again with 240 m. of isopropyi acetate. The combined organic phases are washed with 2x240 ml of water, filtered and the volatile components are evaporated in vacuum. To the oily residue 150 m. of tert-butyl methyl ether are added and the mixture is stirred at room temperature for at least 15 hours. The precipitate is filtered and dried for 2 hours at 400C in a vacuum dryer. 25.09 g (98%) of compound (II) are obtained (HPLC: more than 98%).
96% With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4h;Flow reactor; Alkaline conditions; Large scale; II.The reactor was charged with DMF (68 kg), triphenyl candesartan prepared in Step I (14 kg, 20.50 mol), sodium iodide (1.5 kg, 10.00 mol) and anhydrous potassium carbonate (3.8 kg, 27.53 mol) were added. ,Then add chloroethyl cyclohexyl carbonate (5.6kg, 27.18mol), warmed to 60 C, incubated for 4 hours;TLC (dichloromethane:methanol=20:1) was detected and the reaction was completed. The temperature was lowered to 25 C., 35 L of ethyl acetate and 93 L of water were added to the reactor, and 152 L of ethyl acetate was added for extraction to separate the organic layer. , add anhydrous sodium sulfate to dry;The desiccant was filtered off, the filtrate was transferred to a vacuum oven, and the ethyl acetate was recovered by distillation under reduced pressure at 35 C. The residue in the kettle was viscous.Add 70kg of anhydrous ethanol, raise the temperature to 45C, stir for 3 hours, reduce to room temperature, until a large amount of solids are generated; filter rejection, solid drying at 50C for 12 hours to obtain triphenylcandesartan cilexetil (white sticky solid () 16.8kg. Calculated according to the following formula, the yield of this step is 96%.
95% With potassium carbonate; In N,N-dimethyl-formamide; at 55 - 60℃; for 3h; A mixture of trityl Candesartan, dimethylformamide (DMF) and potassium carbonate at was heated at 60-70 C. Cyclohexyl 1-chloroethylcarbonate was added at 55-60 C. to the reaction mixture and maintain for 3 hours at 55-60 C. The reaction mixture was cooled at ambient temperature. The reaction mixture was poured in water at 0-10 C. and stirred for one hour at 0-10 C. The mixture was filtered and washed with D. M. water. A mixture of wet cake and acetone was stirred and heated for 30 minutes at 55-60 C. The reaction mixture was cooled and stirred at ambient temperature for 30 minutes. The mixture was filtered and washed with acetone. The solid was dried to obtain tritylated Candesartan cilexetil.Yield: 92-95%
92 - 95% With potassium carbonate; In N,N-dimethyl-formamide; at 55 - 70℃; for 3h; Exaniples-4; Preparation of tritylated Candesartan cilexetilA mixture of trityl Candesartan, dimethylformamide (DMF) and potassium carbonate at was heated at 60-700C. Cyclohexyl 1-chloroethylcarbonate was added at 55-600C to the reaction mixture and maintain for 3 hours at 55-600C. The reaction mixture was cooled at ambient <n="16"/>temperature. The reaction mixture was poured in water at 0-100C and stirred for one hour at 0-100C. The mixture was filtered and washed with D. M. water. A mixture of wet cake and acetone was stirred and heated for 30 minutes at 55-600C. The reaction mixture was cooled and stirred at ambient temperature for 30 minutes. The mixture was filtered and washed with acetone. The solid was dried to obtain tritylated Candesartan cilexetil. Yield: 92-95 %
84.8% With potassium carbonate; In acetonitrile; at 40℃; for 8h;Product distribution / selectivity; EXAMPLES; Example 1: Method of Making Cilexetil Trityl Candesartan in a Low Boiling Solvent; A suspension of trityl candesartan (2.0 g, 2.93 mmol), cilexetil chloride (1.21 g, 5.86 mmol), potassium carbonate (0.81 g, 5.86 mmol) and acetonitrile (19 g) was stirred at 40C for about 8 h, and the reaction was monitored by TLC. The acetonitrile was removed at 30C to 35 C under reduced pressure (10 mbar), and the residue was mixed with water (20 ml) and ethyl acetate (30 ml). The water layer was separated and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (10 ml x 2), dried over sodium sulfate, and evaporated to give cilexetil trityl candesartan crude, as a semi-solid, 94.38 % pure by HPLC. The crude product was triturated with hexane (30 ml) at 25C to 27C for about 3 h. Thereafter, the solids were filtered off, washed on the filter with hexane (5 g x 2) and dried at 25 C to 27C under reduced pressure (10 mbar) to give cilexetil trityl candesartan (12 g, 84.8 %) 94.64% pure by HPLC.
67.2% With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate; In toluene; at 50 - 55℃; for 8.5h;Product distribution / selectivity; Example 2: Method of Making Cilexetil Trityl Candesartan with a PTC; A suspension of trityl candesartan (2.0 g, 2.93 mmol), cilexetil chloride (1.21 g, 5.86 mmol), potassium carbonate (1.22 g, 8.83 mmol), and tetrabutylammoniumhydrogensulfate (0.2 g) in toluene (20 ml) was stirred at 50C to 55 C for about 8. 5 h. The reaction progress was monitored by TLC. The mixture was poured into water (100 ml) and neutralized with citric acid (solid). The organic layer was separated, washed with water, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, and evaporated. The residue was triturated with hexane (20 ml) at 20-25C for about 30 min, filtered and dried at 40C and at less than about 30mbar to give white powder (1.68 gr, 67.2%), with 97.90% purity by HPLC.
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 25 - 65℃; 13,6 kg candesartan is dissolved 43,3 kg DMF at temperature bellow 25C; thereto add 4,1 kg Threeethylamine and 10,4 kg trityl chloride and heat up to 60-650C. After the reaction has completed the reaction mixture is poured into ethanol preheated to 50 +/-2C and thereto water is added. Upon cooling pH is adjusted with aqueous HCI to 4.6. Isolated tritylcandesartan is dissolved in 50kg DMF, and mixed at 25C; whereupon 2,2 kg potassium iodide, 4,4 kg potassium carbonate and 6,6 kg cilexetil chloride are added and mixture is heated to 60-65 0C until the reaction is completed. The product is isolated.
With potassium carbonate; potassium iodide; In dimethyl sulfoxide; at 60 - 65℃; for 2.5h;Product distribution / selectivity; Step-2: Preparation of Trityl candesartan cilexetil; Carbohexyl 1-chloroethyl carbonate (36 g) is added to a suspension of trityl candesartan (100 g), potassium carbonate (24 g) and potassium iodide (12 g) in DMSO (500 ml) at temperature of 60 - 65C over 30 min. Reaction mass is maintained at 60-650C for 2 hrs, added toluene (300 ml) and water (300 ml). Reaction mass is mixed for 15 min., allowed to settle, the layers are separated at 60 - 650C and aqueous layer is extracted with toluene (200 ml). Water (200 ml) washings are given to the combined organic layer and toluene extractions twice at temperature of 60 - 650C. Toluene is distilled off from water washed organic layer at temperature below 6O0C under vacuum, ethanol (100 ml) is added, mixed for about 30 min and distilled off solvents under vacuum at temperature below 600C under vacuum. Residue is cooled to 30 - 35C, ethanol (300 ml) is added, mixed for 2 hrs at 25 - 300C and filtered the product. Wet cake is washed with ethanol (100 ml) and suck dried. Wet weight of Cilexetil trityl candesartan is 180 g; Example 2: Preparation of Candesartan cilexetil (without isolation of cilexetil trityl candesartan); Carbohexyl 1-chloroethyl carbonate (36 g) is added to a suspension of trityl candesartan (100 g), potassium carbonate (24 g) and potassium iodide (12 g) in DMSO (500 ml) at <n="8"/>temperature of 60 - 65C over 30 min. Reaction mass is maintained at 60-650C for 2 hrs, added toluene (300 ml) and water (300 ml). Reaction mass is mixed for 15 min., allowed to settle, the layers are separated at 60 - 650C and aqueous layer is extracted with toluene (200 ml). Water (200 ml) washings are given to the combined organic layer and toluene extractions twice at temperature of 60 - 650C. Toluene is distilled off from water washed organic layer at temperature below 6O0C under vacuum, ethanol (100 ml) is added, mixed for about 30 min and distilled off solvents under vacuum at temperature below 6O0C under vacuum. Residue is cooled to 30 - 350C, ethanol (1000ml) and boric acid (9.0 g) is added at temperature of 25 - 300C, temperature of reaction mass is raised and maintained at reflux temperature for 8 hrs. Reaction mass is concentrated to one third of its original volume by distillation of solvent and cooled the solution to 25 - 3O0C.n-Hexane (500 ml) is added to the reaction mass, mixed for 8hrs at 25 - 3O0C and filtered the product. Wet cake is washed with n-hexane (100 ml) and dried the material at temperature of 45-500C till becomes constant weight. Dry weight of Cilexetil candesartan is 65 g (Yield: 72.5%)
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20 - 75℃; Potassium carbonate (60 gm), 1-chloroethylcyclohexyl carbonate (60 gm) and potassium iodide (20 gm) were added to the solution of 2-Ethoxy-1-[[2'-(N- triphenylmethyltetrazole-5-yl)biphenyl)-4-yl]methyl]benzimidazole-7-carboxylic acid (100 gm) in dimethylformamide (500 ml) at room temperature. Raised the temperature to 750C, stirred for 2 hours, cooled to room temperature and 5% sodium chloride solution (2000 ml) was added. Maintained for 15 minutes, ethyl acetate (400 ml) was added, stirred and separated the layers. Aqueous layer was extracted with ethyl acetate (400 ml), organic layer was taken, washed with 10% sodium chloride solution (400 ml), concentrated, and co-distilled with ethyl acetate (100 ml). Mixture of ethyl acetate (500 ml) and n-hexane (500 ml) were added to the residual mass, stirred for 6 hours at room temperature, cooled to 50C, stirred for 1 hour, filtered, then washed with mixture of ethyl acetate (50 ml) and n-hexane (200 ml) and dried for 6 hours to obtain 1-(Cyclohexyloxy <n="6"/>carbonyloxy)ethyl-2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl] benzimidazole-7-carboxylate (110 gm, HPLC Purity: 99%).
With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 65℃; for 2.5h; Step I: Preparation of N-trityl candesartan cilexetilA mixture of N-trityl candesartan (Form A: 120 gm), potassium carbonate (48.58 gm), cilexetil chloride (54.48 gm) and dimethyl formamide (180 mL) at ambient temperature was heated to 60 C to 65 C followed by stirring at the same temperature for 2 hours and 30 minutes. The reaction mixture was cooled to 25 C to 30 C followed by addition of dichloromethane (600 mL) and ice cooled de-ionized water (1200 mL) at 10 C to 15 C to the reaction mass. The reaction was further stirred at 15 C to 20 C for 30 minutes followed by extraction of the aqueous layer with dichloromethane (120 mL) at 15 C to 30 C and washing with de-ionized water (2x600 mL) at ambient temperature.The organic layer was concentrated completely under vacuum at 30 C to 35 C followed by removal of traces of dichloromethane with cyclohexane (120 mL) and the further addition of cyclohexane (360 mL) to the residue at the ambient temperature. The reaction mixture was stirred at the same temperature for 14 hours followed by filtration and washing of the solid with cyclohexane (120 mL) which was suck dried under vacuum for 1 hour. Dichloromethane was again added (360 mL) at ambient temperature to the isolated solid followed by heating and stirring of the reaction mass at 30 C to 35 C for 30 minutes. The organic layer was concentrated under vacuum at 30 C to 35 C, cyclohexane (300 mL) added and the reaction mass was stirred further for 5 hours at the same temperature. The solid was filtered, washed with cyclohexane (120 mL) and suck dried under vacuum for 1 hour followed by further drying under vacuum for 16 hours at 35 C to 40 C.Chromatographic purity: 98.8%N-trityl desethylcandesartan cilexetil- 0.28%

 

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Technical Information

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