Ethyl (R)-4-chloro-3-hydroxybutyrate ((R)-CHBE) is a versatile fine chemistry intermediate. It is used as a precursor in the synthesis of several pharmacologically valuable products, including L-carnitine. It is usually produced by means of stereoselective biotechnology methods in enzymatic reactions. An alternative preparation strategy towards ethyl (R)-4-chloro-3-hydroxybutyrate is based on the asymmetric hydrogenation of ethyl 4-chloro-acetoacetate (ECAA) to the optically pure product ((R)-CHBE) over ((S)-Ru-BINAP) catalytic complex. The reaction conditions were optimised first using (R)-Ru-BINAP yielding the (S)-CHBE isomer. All reactions were performed under continuous regime in a microfluidic chip reactor. Three different solvent phases were employed. The methanol/water phase, the ethanol/water phase, and the [N8,222][Tf2N]/methanol/water phase. The attained conversions were total in all cases already at 408 K. The parameter of enantioselectivity ee was 99.4% towards the (S)-CHBE for the system in which (R)-Ru-BINAP was accommodated in [N8,222][Tf2N]/methanol/water phase. In the case of methanol/water experiment the ee parameter reached 92.5%. For ethanol/water ee was 91.8%. The (R)-CHBE isomer over (S)-Ru-BINAP was obtained with ee = 99.3% in the [N8,222][Tf2N]/methanol/water phase at 408 K. For the reactions leading to (S)-CHBE apparent activation energies were evaluated. They were similar for MeOH/water and EtOH/water (110.5 and 110.7 kJ.mol−1). The apparent activation energies corresponding with the [N8,222][Tf2N]/MeOH/water system were much higher (of about 90 kJ.mol−1) reaching the level of 200 kJ.mol−1. The impact of the molecular structure of the main reactant was negligible as appeared from the comparison with hydrogenation of methylacetoacetate (MAA, ~ 200 kJ.mol−1). The effect of the presence of the [N8,222][Tf2N] ionic liquid on the sum of the activation energy dominated. The effectiveness of the enantioselective synthesis was additionally assessed by nuclear magnetic resonance employing the method of enantioselective complexation of the chiral compound with a chiral solvating agent.