Lercanidipine Impurity 26 synthesis

Yield:890045-70-2 58%

Reaction Conditions:

Stage #1: 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acidwith thionyl chloride in dichloromethane;N,N-dimethyl-formamide at -2 - 2; for 1 h;
Stage #2: 3-chloro-2-methylpropan-2-ol in dichloromethane;N,N-dimethyl-formamide at -5 - 20; for 27 h;

Steps:

1

Example 1; l-Chloro-2-methyl-2-propyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)- 1 -pyridine-3 , 5 -dicarboxylate; 31 g (0.26 moles) of thionyl chloride were added dropwise under stirring to a mixture of 78 g (0.235 moles) of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl)-l,4-dihydropyridine-3-carboxylic acid, 420 ml methylene dichloride and 110 ml dimethyl formamide kept at temperature of -2⁰C - +2° under nitrogen. After terminating the addition of the thionyl chloride the stirring was continued under nitrogen for a further hour. To the above mixture a solution of 26 g (0.24 moles) of l-chloro-2-methyl-2-propanol in 60 ml methylene dichloride was added dropwise while stirring under nitrogen at a temperature of -5⁰C - O⁰C. The stirring was continued for 3 EPO hours at O⁰C, afterwards the mixture was allowed to stand for 24 hours at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in 1200 ml of ethylacetate. The organic solution was washed with saturated solution of sodium chloride and afterwards with a solution of 5% Na₂CO_3. The organic layer was separated and dried with Na₂SO₄. The organic solution was evaporated to 500 ml and allowed to stand at O⁰C for 24 hours. The l-Chloro-2-methyl-2-proρyl methyl 1,4- dihydro-2,6-dimethyl-4-(3-nitrophenyl)-l-pyridine-3,5-dicarboxylate thus obtained was filtered and dried at 5O⁰C under vacuum. The weight was 58 g ( 58 % yield) of about 98% purity as determined by HPLC analysis, shown in Figure 1.The method for performing the HPLC was as follows:HPLC: Merck-Hitachi with autosamplerColumn: Symmetry C 18, 4,6 x 250mm (Waters)Detector: UV 237nmMobile Phase: 60% Acetonitrile + 40% buffer pH 4.0Flow rate: lml/minInjection Volume: 20μlTemparature: 3O⁰CThe buffer pH 4.0 was prepared by dissolving 5.14g potassium di- hydrogen phosphate and 2.4 ml triethylamine in 980 ml water with mixing. The pH of the solution was adjusted to 4.0 with phosphoric acid and distilled water was added to make 1 liter, and the solution was mixed.The product has the following ¹H NMR Spectrum (300 MHz, CDCI₃): 8.11 (lH,m), 8.04 (lH,m), 7.64 (lH,d, J=7.5Hz), 7.37 (lH,t, J=8.1Hz), 3.64 (3H,s), 2.97 (lH,s) 2.90 (lH,s) 2.35 (3H,s) 2.34 (3H,s), 1.47 (3H,s), 1.44 (3H,s).

References:

WO2006/59332,2006,A1 Location in patent:Example 1