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[ CAS No. 144702-27-2 ] {[proInfo.proName]}

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Chemical Structure| 144702-27-2
Chemical Structure| 144702-27-2
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CAS No. :144702-27-2 MDL No. :MFCD21496234
Formula : C33H29N5 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 495.62 Pubchem ID :-
Synonyms :

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Application In Synthesis of [ 144702-27-2 ]

* 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.

  • Upstream synthesis route of [ 144702-27-2 ]
  • Downstream synthetic route of [ 144702-27-2 ]

[ 144702-27-2 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 144702-27-2 ]
  • [ 144701-48-4 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: With sodium hydroxide; water In ethylene glycol for 8 h; Heating / reflux
Stage #2: With acetic acid In water; ethylene glycol at 20℃;
Example 16 Preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazoI-2-yl)-benzimidazoI- l-yI)-methyl]-biphenyl-2-carboxylic acid (compound 1)A mixture of 2.5 g of compound 3 (5 mmol), 1.0 2 sodium hydroxide (25 mmol). 0.18 g water (10 mmol) and 30 ml etbyleneglycol was refluxed for 8 h. After the reaction was completed, the reaction mixture was cooled to room temperature and HoO (250 ml ) was added. After the pH value of this solution was adjusted to 4 with HOAc ( J 2 ml), the product precipitated and was extracted three times with CHoCIo. The combined organic <n="46"/>layers were washed with brine, dried over NaSψ4 and filtered and the filtrate was concentrated to give 2.55 g of crude compound 1 (yield: 98percent).
98%
Stage #1: With potassium hydroxide; water In ethylene glycol at 140 - 150℃; for 21 h;
Stage #2: With hydrogenchloride In water; ethylene glycol at 20℃;
The mixture of 1.0 g (2.0 mmol) of 4 '-( (1 , 7 ' -dimethyl-2 '- propyl-lH, 3 ' H-2 , 5 ' -dibenzo [d] imidazol-3 ' -yl ) methyl) biphenyl- 2-carbonitrile, 5 ml of ethylene glycol, 0.1 ml of water and 1.03 g (18.4 mmol) of KOH is heated to 140 -1500C for 21 h. Then the solution is cooled to room temperature and 10 ml of water are added. The mixture is neutralized by the addition of 3M HCl to adjust the pH to about 7. The product telmisartan is filtered, washed and dried (1.02 g, 98 percent) .
98.7%
Stage #1: With water; potassium hydroxide In ethylene glycol at 150 - 155℃;
Stage #2: for 2 h;
Example 4.; Telmisartan; A mixture of 2-Cyano-4'-[2"-n-propyl-4"-methyl-6"-(r"-methylbenzimidazole-2'"- yl)benzimidazole-l"-yl methyl]-biphenyl ( 20 gms), ethylene glycol (180 ml), water (3.6 ml) and potassium hydroxide (17.3 gm) were heated to 150- 155 0C for 12- 14 hrs. The completion of the reaction was monitored by TLC, after completion of the reaction the solvent was distilled out under reduced pressure, the concentrated mass was dissolved in 300 ml water, washed with methylene dichloride, pH of the aqueous phase adjusted to 4- 4.5 with 50 percent acetic acid stirred for 2 hours, filtered, the wet cake washed with distilled water ( 3 x 100 ml), and dried in oven at 65 0C to get telmisartan 20.5 gm ( 98.7percent of theory), HPLC purity 99.24percent.
88%
Stage #1: With sulfuric acid In water at 125℃; for 30 h;
Stage #2: With sodium hydroxide In dichloromethane; water
Into a reaction vessel 2Og (40 mmol) cyanotelmisartan and 20 ml (lδOmmol) H2SO4 (1:1) were added. The reaction mixture was heated to around 125°C and stirred at this temperature for 30 h. A sample of the reaction mixture was analyzed by Areapercent HPLC (cyanotelmisartan below 0.1 percent, intermediate amide of telmisartan less than 0,2percent, telmisartan over 97percent) . The reaction mix- ture was cooled below 8O0C and 250 ml of water were added. Then, 200 ml of dichloromethane were added and pH value of mixture was adjusted to 5.3 by addition of 6M NaOH. The mixture was stirred for approximately 5 min and then the phases were separated. The water phase was reextracted with 136 ml of dichloromethane. Collected organic phases were washed with water (2χl36ml) and then treated with activated charcoal (5.3 g) . Subsequently, the organic phase was evaporated to an oily residue (26g) . 264 ml of acetone were added. The mixture was stirred at room temperature for at least 6 hours. The precipi- tated product was separated and washed with fresh acetone and dried at 65°C under reduced pressure for 3hours . Yield: 18g (88percent) Area percent HPLC: Telmisartan 99.86percent
87.37%
Stage #1: With potassium hydroxide In ethylene glycol at 150 - 155℃;
Stage #2: With acetic acid In methanol; water; ethylene glycol at 25 - 30℃; for 1.5 h;
Add potassium hydroxide 80g in 500ml of ethylene glycol then add 2-cyano-4'- [2-n-propyl-4-methyl-6-( 1 -methyl benzimidazol-2-yl) benzimidazol- 1 -ylmethyl] biphenyl lOOgm at room temperature. Stir the reaction mixture and raise temperature to 150- 155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C then diluted with 800 ml methanol then telmisartan precipitates by adding of acetic acid at 25 to 30°C and further diluted with water. Then stirred for further 90min at 25 to 30°C. After the crystals have been suction filtered. The wet material dissolve in 500ml methanol with 12gm potassium hydroxide then after treatment of charcoal crystallize the telmisartan to adjusting of pH 6.0 to 6.4 by acetic acid then dilute with 400ml water. Filtered and then dried in a vacuum tray drier at 85°C. Yield: 90g (87.37percent of theory); HPLC: 99.91percent.
63% for 136 h; Heating / reflux The mixture of 1.0 g (2.0 mmol) of 4 '-(( 1 , 7 ' -dimethyl-2 '- propyl-lH, 3 ' H-2 , 5 ' -dibenzo [d] imidazol-3 ' -yl ) methyl ) biphenyl- 2-carbonitrile, 4 ml of water and 4 ml of cone. HCl is heated at reflux temperature for 136 h. Then the mixture is cooled to room temperature and IM NaOH is added to adjust the pH to about 5 to 7. The product is filtered, washed and dried. 0.65 g (63percent) of telmisartan is isolated.
107 g
Stage #1: With sodium hydroxide In butan-1-ol at 123 - 126℃; for 15 h;
Stage #2: With hydrogenchloride In water at 80℃;
Stage #3: With acetic acid In water at 80 - 85℃;
Example 4: 4'-[2-n^ropyl-4-methyl-6-(l-methylbenzi idazol-2-yl)benzi idazol-ylmethyl]bipheny carboxylic acid 126 gm of 2-cyano-4'-(2"-n-propyl-4"-methyl-6"-(l "'-methylbenzimidazol-2"'-yl) benzimidazol-1"- ylmethyl) biphenyl was dissolved in 750 ml of n-butanol and 83 gm sodium hydroxide added. The reaction mass was heated to reflux and maintained for 15 hours at 123 to 126 °C. The completion of the reaction was monitored by TLC using mobile phase chloroform: methanol (9: 1). The solvent was distilled out at atmospheric pressure till the mass temperature reached 140 °C. The residual mass was cooled to 100 °C and 300 ml water was added. The solvent was distilled out azeotropically till the mass temperature reached 120 °C. To the reaction mass 750 ml of water was added, the solution warmed to 80 °C. The pH of the reaction mass was adjusted to 8.0 with hydrochloric acid. Finally the pH was adjusted to 6.0 with acetic acid, and the reaction mass maintained at 80 to 85 °C for one hour. The product obtained was filtered, washed with water and dried to yield 120 gm of 4'-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid. Example 5: Purification of 4'-[2-n^ropyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l- ylmethyl]biphenyl-2-carboxytic acid In a 3 litre reaction flask, 1000 ml of methanol was added followed by the addition of 120 gm of 4'-[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl- 2-carboxylic acid obtained by procedure described in Example 4. The solution was warmed to 50 °C and pH adjusted to 10.0 to 10.5 with 100 ml of a 10percent methanolic potassium hydroxide solution. The reaction mass became a clear solution, and 6 gm activated carbon was added. The mass was maintained at 50 to 55 °C for one hour and filtered through hyflo supercel to remove the activated carbon. The clear filtrate obtained was collected and its pH adjusted to 6.0 to 6.5 with 130 ml of acetic acid, maintaining the temperature between 50 to 55 °C. The mass was cooled to 15 °C and maintained one hour at 10 to 15 °C. The product which precipitated out was filtered, washed with 50 ml of methanol followed by 500 ml of water. The wet product was dried to yield 107 gm of 4'-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid. C 76.49percent; H 5.74percent, N 11.02percent; m/z 515.45.; 1H NMR DMSO d6 400 Mhz : 5ppm 0.97 - 1.01 (t, 3H) 1.76 - 1.85 (m, 2H) 2.62 (s, 3H) 2.90 - 2.94 (t, 3H) 3.81 (s, 3H) 5.61 (s, 2H) 7.15 - 7.71 (14H aromatic); Melting point of purified telmisartan: 269 °C.
120 g With sodium hydroxide In butan-1-ol at 123 - 126℃; for 15 h; EXAMPLE 4 4′-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-ylmethyl]biphenyl-2-carboxylic acid [0026] 126 gm of 2-cyano-4′-(2″-n-propyl-4″-methyl-6″-(1′″-methylbenzimidazol-2′″-yl) benzimidazol-1″-ylmethyl) biphenyl was dissolved in 750 ml of n-butanol and 83 gm sodium hydroxide added. The reaction mass was heated to reflux and maintained for 15 hours at 123 to 126° C. The completion of the reaction was monitored by TLC using mobile phase chloroform: methanol (9:1). [0027] The solvent was distilled out at atmospheric pressure till the mass temperature reached 140° C. The residual mass was cooled to 100° C. and 300 ml water was added. The solvent was distilled out azeotropically till the mass temperature reached 120° C. To the reaction mass 750 ml of water was added, the solution warmed to 80° C. The pH of the reaction mass was adjusted to 8.0 with hydrochloric acid. Finally the pH was adjusted to 6.0 with acetic acid, and the reaction mass maintained at 80 to 85° C. for one hour. The product obtained was filtered, washed with water and dried to yield 120 gm of 4′-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid.

Reference: [1] Patent: WO2009/4064, 2009, A1, . Location in patent: Page/Page column 44-45
[2] Patent: WO2007/147889, 2007, A2, . Location in patent: Page/Page column 30
[3] Patent: WO2009/116089, 2009, A2, . Location in patent: Page/Page column 16
[4] Patent: WO2010/146187, 2010, A2, . Location in patent: Page/Page column 37
[5] Patent: WO2011/77444, 2011, A1, . Location in patent: Page/Page column 7-8
[6] Patent: WO2007/147889, 2007, A2, . Location in patent: Page/Page column 30
[7] Patent: WO2009/4064, 2009, A1, . Location in patent: Page/Page column 45
[8] Patent: WO2014/27280, 2014, A1, . Location in patent: Page/Page column 7-8
[9] Patent: US2015/197495, 2015, A1, . Location in patent: Paragraph 0026; 0027
[10] Patent: CN104768936, 2017, B, . Location in patent: Paragraph 0132-0133
[11] Patent: WO2007/147889, 2007, A2, . Location in patent: Page/Page column 30-31
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