Asymmetric Transfer Hydrogenation: A Suitable Tool for the Synthesis of the Precursors of Pharmaceutical Substances

Transcription

1 Department of Organic Technology Specialized Laboratory for Drug Production programme (N111049) and Organic Technology programme (N111025) Asymmetric Transfer Hydrogenation: A Suitable Tool for the Synthesis of the Precursors of Pharmaceutical Substances Supervisor: Laboratory: Ing. Jiří Vavřík A77b

2 CONTENT 1 INTRODUCTION TASKS Calculation of loadings Progress of the work Sample analysis Results processing...5

3 1 INTRODUCTION Many naturally occurring chiral compounds (sugars, amino acids) are produced exclusively as one enantiomer, because different enantiomers or diastereomers often possess different biological activity. That is very important in case of pharmaceutical substances, where the active pharmaceutical ingredient is only one of the enantiomers, the other one being less active or even harmful. Optical purity is a key parameter of chiral compounds. Separation of racemic mixtures, which are products of classical synthetic approach, is uneconomical and ineffective. That is why asymmetric synthesis, which produces enantiomers in unequal amounts, has become very popular. Nowadays, the asymmetric hydrogenation of ketones and imines is an important and intensively studied field of homogenous catalysis. The reduction can be carried out in two ways, either by gaseous hydrogen (asymmetric hydrogenation, AH), or by hydrogen obtained in situ from a simple organic molecule, such as propan-2-ol or formic acid, which is present in the reaction mixture (asymmetric transfer hydrogenation, ATH). Transfer hydrogenation is a suitable tool in cases, where it is not possible, or practical to use the classical approach (safety risk, expensive set-up). Because of high enantioselectivity of ATH, it can be used for the preparation of various fine chemicals, including active pharmaceutical ingredients or fragrances. Great improvement in the field of ATH came with the discovery of the catalytic complex incorparting chiral diphenylethylenediamine ligand [Ru(II)Cl(η6-arene)(N-tosyl-1,2- diphenylethylene-1,2-diamine)], abbrev. [Ru(II)Cl(η6-arene)Ts-DPEN] in That catalyst was capable of stereoselective reduction of various C=N and C=O double bonds in various types of substrates, including alkyl-, or arylketones, cyclic ketones, and imines, with enantioselectivities over 90 %. 1

4 ATH of dihydroisoquinolines leads to tetrahydroisoquinolines, which are the building blocks of many naturally occurring alkaloids and active pharmaceutical ingredients (for example muscle relaxants: Mivacurium, Doxacurium, Atracurium, Cisatracurium). Mivacurim chloride 2

5 2 TASKS 2.1 Calculation of loadings The reaction mixture consists of: Solvent acetonitrile (ACN) Catalyst precursor [RuCl(p-cymene)(1S,2S)-TsDPEN] Hydrogen donor formic acid (FA) Triethylamine serves as the activator of the precursor by absorption of HCl. Active catalytic hydride is formed from the precursor. Triethylamine also stabilizes ph of the reaction mixture, because catalyst is not stable at low ph level. Substrate 1-methyl-3,4-dihydroisoquinoline 6,7-Dimethoxy-1-methyl-3,4- dihydroisoquinoline [RuCl(p-cymene)TsDPEN] Given values: Substrate weight m(s) = 30 mg Molar ratios: Substrate/catalyst precursor (S/C) = 100 Formic acid/substrate (FA/S) = 6.3 Formic acid/triethylamine (FA/TEA) = 2.5 Cl Ru H 2 N Concentration of the substrate in the reaction mixture: c(s) = mmol/ml Ph N O O S Ph To be calculated: The weight of the catalyst precursor, the volume of formic acid, the volume of triethylamine and the volume of solvent. Note: It is necessary to find densities and molar masses of chemicals used (MSDS, distributors of chemicals etc.). 3

6 2.2 Progress of the work Starting of the reaction, sampling and sample preparation: A reaction flask (10 ml) equipped with a magnetic stirring bar is placed in water bath (30 C). Calculated amounts of the reaction components are added to the flask in an exact order: 1. solvent, 2. the solution of the catalyst precursor, 3. triethylamine, 4. formic acid. The solution of the substrate is added after 5 minutes needed for the activation of the catalyst. From that moment samples (0.1 ml) are being taken in 5, 10, 20, 35. In 55 minutes 0,2 ml is taken. Samples are added to a 1,5 ml of the sat. solution of sodium carbonate. This operation quenches the reaction (neutralization of formic acid). Soda solutions with samples are extracted with diethylether (2x2 ml). Organic phase is separated using Pasteur pipettes. Combined organic phases are dried over anhydrous sodium sulfate (30 min). Sodium sulfate is separated by means of decantation and ether is stripped out by compressed air. Concentrated samples are diluted with 0.8 ml of acetonitrile and transferred to 2 ml GC vials. The last sample is diluted with 1,6 ml of acetonitrile and divided in two vials (0,8 ml each). Then samples are analyzed using gas chromatography. 2.3 Sample analysis Determination of conversion: The samples prepared in labelled vials are placed to an autosampler, H 2 and N 2 bottles are opened and then GC is turned on. First a heating method is chosen. After that a measuring method is chosen from the list and the samples are measured in the order set in the samplelist. Determination of enantiomeric excess (ee): Two methods were developed in our laboratory for the determination of ee: chiral solvation using Pirkle's alcohol (1-anthracen-9-yl-2,2,2-trifluoroethanol) derivatization with (1R)-( )-menthylchloroformate The latter method will be used in this work. Last sample is divided in two fractions, into one of them are added 20 µl of TEA and 10 µl of (1R)-( )-menthylchloroformate. For the 4

7 analysis of this derivatized sample a different GC method is used. GC methods used will be specified in place. 2.4 Results processing Results will be summarized using provided template. After short introduction there will be brief explanation of the main goal, the description of used chemicals, calculations of the loadings and the description of the progress of work and analytic methods for GC. Put in a chart the dependence of conversion (x) on time (t), determine selectivity, that means enantiomeric excess (ee) and calculate the initial reaction velocity in mmol.min -1 (use linear regression function for the first two points of the conversion curve). Summarize the main results in the conclusion part of the protocol. 5