First chemoenzymatic stereodivergent synthesis of both enantiomers of promethazine and ethopropazine

Abstract

Enantioenriched promethazine and ethopropazine were synthesized through a simple and straightforward four-step chemoenzymatic route. The central chiral building block, 1-(10H-phenothiazin-10-yl)propan-2-ol, was obtained via a lipase-mediated kinetic resolution protocol, which furnished both enantiomeric forms, with superb enantioselectivity (up to E = 844), from the racemate. Novozym 435 and Lipozyme TL IM have been found as ideal biocatalysts for preparation of highly enantioenriched phenothiazolic alcohols (up to >99% ee), which absolute configurations were assigned by Mosher's methodology and unambiguously confirmed by XRD analysis. Thus obtained key-intermediates were further transformed into bromide derivatives by means of PBr3, and subsequently reacted with appropriate amine providing desired pharmacologically valuable (R)- and (S)-stereoisomers of title drugs in an ee range of 84-98%, respectively. The modular amination procedure is based on a solvent-dependent stereodivergent transformation of the bromo derivative, which conducted in toluene gives mainly the product of single inversion, whereas carried out in methanol it provides exclusively the product of net retention. Enantiomeric excess of optically active promethazine and ethopropazine were established by HPLC measurements with chiral columns.

Keywords: Mosher methodology; ethopropazine; lipase-catalyzed kinetic resolution; promethazine; stereodivergent synthesis.

Scheme 1

Chemoenzymatic synthesis of enantioenriched enantiomers of promethazine 9 and ethopropazine 10. Reagents and conditions: (i) n-BuLi (1.5 equiv), dry THF, 1 h at −78 °C, then propylene oxide 2 (2 equiv), 12 h at rt; (ii) CH₃COCl (1.5 equiv) or C₃H₇COCl (1.5 equiv) or C₉H₁₉COCl (1.5 equiv), NEt₃ (1.5 equiv), DMAP (0.1 equiv), dry CH₂Cl₂, 12 h at rt; (iii) vinyl ester (3 equiv), lipase [20% (w/w)], MTBE, 25 °C, 500 rpm (magnetic stirrer); (iv) NaOH (1.1 equiv), MeOH, 1 h at rt; (v) PBr₃ (1 equiv), CH₂Cl₂, 2 h at rt; (vi) Me₂NH (5 equiv) or Et₂NH (20 equiv), MeOH, sealed tube, 4 d at 90 °C (temperature of oil bath); (vii) Me₂NH (25 equiv) or Et₂NH (50 equiv), PhCH₃, sealed tube, 7 d at 140 °C (temperature of oil bath).

Figure 1

Dependence of optical purities (% ee) of (R)-(−)-6a (red curve, ■) and (S)-(+)-5 (blue curve, ▲) on the conversion degree of (±)-3 during lipase-catalyzed acetylation with vinyl acetate in a MTBE solution at 25 °C (magnetic stirrer, at 500 rpm).

Scheme 2

Assignment of the stereochemistry of enantiopure alcohol (+)-5 resulting from derivatization with (R)- and (S)-MPA 11 and 12, respectively.

Figure 2

Description of substituents for determination of the absolute configuration of (+)-5 and Δδ^RS values obtained for the MPA esters 11 and 12.

Figure 3

¹H NMR (CDCl₃, 400 MHz) spectra of the (R)-MPA 11 (red colored line) and (S)-MPA and 12 (blue colored line) derivatives of enantiopure alcohol (+)-5 (>99% ee). Additionally, with red color are marked protons shielded by the phenyl ring of chiral auxiliary, blue labels stand for unaffected protons. Green arrows indicate the shielding effect caused by the aromatic system.

Figure 4

An ORTEP plot of (S)-(+)-1-(10H-phenothiazin-10-yl)propan-2-ol (S)-(+)-5. The following crystal structure has been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC-1018655.

Scheme 3

Amination of optically active bromo derivatives (R)-(+)-8 or (S)-(−)-8 in toluene.

Scheme 4

Amination of optically active bromo derivatives (R)-(+)-8 or (S)-(−)-8 in methanol.

Scheme 5

The proposed reaction mechanism for amination of optically active (S)-(−)-8 in methanol.