Hydrochloric Acid → 2'-(1H-Tetrazol-5-yl)-1,1'-biphenyl-4-carboxaldehyde (Losartan Impurity)

HRID 550043Notes

Reaction equation

HRID 550043 reaction equation
OC[C:3]1[CH:4]=[C:5]([C:15]#[N:16])[C:6]([C:9]2[CH:14]=[CH:13]C=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[H-].[Li+].[N-:19]=[N+:20]=[N-:21].C([Al+][CH2:25][CH3:26])C.[Cl-].C([Al+]CC)C.[N-]=[N+]=[N-].[Na+].N([O-])=[O:38].[Na+].[OH-].[Na+].Cl.[N+]([O-])(O)=O>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[NH:19]1[C:15]([C:5]2[CH:4]=[CH:3][CH:8]=[CH:7][C:6]=2[C:9]2[CH:14]=[CH:13][C:26]([CH:25]=[O:38])=[CH:11][CH:10]=2)=[N:16][N:21]=[N:20]1

Participants

12

Reactant 9

HCID 313Hydrochloric AcidHCID 944Nitric AcidHCID 14798Sodium HydroxideHCID 33557Sodium AzideHCID 62714Lithium hydrideHCID 16686102Diethyl aluminum chlorideHCID 187797454-Hydroxymethylbiphenyl-2-carbonitrileHCID 22336426Et2AlN3HCID 23668193Sodium Nitrite

Product 1

HCID 1785194042'-(1H-Tetrazol-5-yl)-1,1'-biphenyl-4-carboxaldehyde (Losartan Impurity)

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 7237O-XyleneSolvent2×

Conditions

Temperature
120 °C

Procedure

16.74 g (80 mmol) of the “4-hydroxymethyl-biphenyl-2-carbonitrile” is suspended in 100 ml of dry xylene (isomer mixture) under argon. To this suspension is added at room temperature under stirring 0.636 g (80 mmol) of lithium hydride. The suspension is stirred for an additional 4 hours at 120° C. external temperature and a solution of 160 mmol diethylaluminium azide in toluene (which is prepared separately by stirring 160 mmol of diethylaluminium chloride and 160 mmol of sodium azide in xylene [isomer mixture] at room temperature overnight) is added via syringe. The reaction mixture is heated to reflux (˜120° C.), external temperature ca. 140° C. Conversion is controlled by HPLC analysis. After refluxing for 24 hours the reaction mixture is cooled to room temperature and finally quenched with a solution of 300 mmol of sodium nitrite and of 15% sodium hydroxide (240 mmol). Finally 95 ml of conc. HCl is added under stirring. To the resulting suspension is added at room temperature under stirring 31 g (320 mmol) of 65% nitric acid. The suspension is stirred for an additional 6 hours at 60° C. external temperature (internal Temperature=55° C.). Finally the product is isolated by filtration. The crude 2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde is obtained.

Workup

  1. additionTo this suspension is added at room temperature
  2. additionis added via syringe
  3. temperatureThe reaction mixture is heated
  4. temperatureto reflux (˜120° C.), external temperature ca. 140° C
  5. temperatureAfter refluxing for 24 hours the reaction mixture
  6. temperatureis cooled to room temperature
  7. stirringunder stirring
  8. additionTo the resulting suspension is added at room temperature
  9. stirringThe suspension is stirred for an additional 6 hours at 60° C. external temperature (internal Temperature=55° C.)
  10. customFinally the product is isolated by filtration

Sources & evidence

ORD record
ord-fff77c8389404e4495f82372b24e20b1
Source dataset
uspto-grants-2011_05
Patent number
US07943647B2

Reaction notes

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