Catalytic transfer hydrogenation of 7-ketolithocholic acid to ursodeoxycholic acid with Raney nickel

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Abstract

Ursodeoxycholic acid was produced by the stereoselective reduction of 7-ketolithocholic acid. This hydrogenation reaction was catalyzed by the T-1 Raney nickel and potassium borohydride was used as hydrogen donor instead of inflammable hydrogen gas. Potassium tert-butoxide was introduced to improve yield of ursodeoxycholic acid from about 70% to a maximum of 94% by inducing the stereoselectivity on hydroxyl group at 40 °C and atmospheric pressure. Reduction reaction conditions such as amount of reactants, temperature and stirring speed were optimized. The whole process is safe and low-cost. Eventually, the product, ursodeoxycholic acid was characterized by IR, 1H NMR and 13C NMR spectra.

Introduction

Ursodeoxycholic acid (3α,7β-2-hydroxy-5β-cholanic acid, UDCA, Fig. 1) is an important clinical drug in the treatment of gallstones, cholecystitis, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) [1], [2], [3], [4]. It was originally derived from the bile of Chinese bear [5]. In 1954, Kanazawa et al. [6] chemically synthesized ursodeoxycholic acid by reducing 7-ketolithocholic acid (3α-hydroxy-7-oxo-5β-cholanic acid, 7K-LCA, Fig. 2) in n-propyl alcohol by using metal sodium. Because UDCA and its epimer chenodeoxycholic acid (3α,7α-2-hydroxy-5β- cholanic acid, CDCA, Fig. 3) are both reduction products of 7K-LCA, and CDCA is favorable, currently the industrial production of ursodeoxycholic acid is based on the synthesis process outlined by Kanazawa. Nevertheless, this process requires special safety measures because of the known danger of the alkali metals. Researchers have also attempted to reduce 7K-LCA to UDCA by using milder methods. Bharucha and Slemon [7] demonstrated that 7K-LCA could be electrochemically reduced to UDCA in the electrolyte containing short chain alcohol preferably with weakly acidic dipolar additives such as hexamethylphosphoric triamide (HMPA) with ruthenized titanium or mercury electrodes, and 91% yield of UDCA could be obtained. Magni et al. [8] stated that 97% yield of UDCA could be obtained by catalytic hydrogenation of 3α-hydroxy-7-oxo-5β-cholanate using Raney nickel as the catalyst and beta-branched alcohols as the solvent in the presence of a base at 40 °C and atmospheric pressure. 3α-Hydroxy-7-oxo-5β-cholanate dissolved in alcohols also could be reduced to UDCA by hydrogen at pressure 0.5 MPa and temperature 80 °C catalyzed by Raney nickel, and the yield of UDCA is 92.5% [9]. Herein 3α-hydroxy-7-oxo-5β-cholanate was formed by adding hydrate to 7K-LCA. However, these methods cannot successfully substitute the alkali metals reduction in industrial scale for UDCA production. Thus, a stable, safe and convenient way needs to be found for the chemical synthesis of UDCA.

Our interest in producing UDCA by the method of catalytic transfer hydrogenation (CTH) is in introducing hydrogen-containing organic compounds as the hydrogen donor instead of molecular hydrogen, in order to avoid pressure vessels for hydrogen gas being applied to such reactions. Raney nickel catalyzed transfer hydrogenations utilizing 2-propanol have been reported for the reduction of olefins [10], aldehydes [11], ketones [10], [12], [13], phenols [10], aromatic alcohols [14], nitriles [15], aromatic nitro compounds [16], [17], [18], and certain aromatic hydrocarbons [10], [19]. Other commonly used hydrogen donors for Raney nickel are ethanol, cyclohexanol [20], formic acid [21], hydrazine [22], etc. To our knowledge, studies on borohydride together with Raney nickel in CTH are scarce. An example was reported by Wu et al. [23], various aliphatic and aromatic nitriles were reduced to primary amines in Raney Ni/KBH4 system at mild temperature and up to 93% isolated yields were achieved.

Here we focus on Raney Ni/KBH4 asymmetric CTH reaction of 7K-LCA to generate UDCA. As far as is known, molecular hydrogen is replaced by KBH4 as the hydrogen donor together with Raney Ni catalyst is never reported in the reduction of steroids. Compared to the aforementioned catalytic hydrogenation reactions, the temperature and the pressure were mild and hydrogen gas is avoided. The process is safer and facile in industry.

Section snippets

Materials

UDCA standard (>98%) was purchased from China Aroma Chemical Co., Ltd. (Hangzhou, China). 7K-LCA was prepared according to our previous work [24], via indirect electrooxidation of CDCA using the medium of Br/Br2. Nickel–aluminum alloy (40–50% Ni) was from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Acetonitrile of HPLC grade was from Shanghai Xingke Biochemistry Co., Ltd. Other reagents were analytical grade. HPLC (LC-20A, Shimadzu Corporation, Kyoto, Japan) with a UV detector

Results and discussion

UDCA was the main product of the reaction (Scheme 1). The C-7 carbonyl group of 7K-LCA was stereoselectively reduced to 7β-hydroxyl group by Raney nickel catalyzing transfer hydrogenation. In the reaction, potassium borohydride was used as the hydrogen donor, and 2-propanol as the solvent. Potassium tert-butoxide was a stereoselective reagent and a higher yield of UDCA could be obtained.

As is shown in Table 1, no UDCA is found in the absence of potassium borohydride, and this reveals that

Conclusions

In this study, 7K-LCA was stereoselectively reduced to UDCA catalyzed by Raney nickel using potassium borohydride as the hydrogen donor. The CTH reaction specifically converted the C-7 carbonyl group to 7β-hydroxy group. Especially, potassium tert-butoxide improved the yield of UDCA. By process conditions optimized, up to 94% yield of UDCA was obtained. Its purity was 97% after purification by column chromatography. The product was confirmed as UDCA through IR, 1H NMR and 13C NMR spectra. The

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