Organic Process Research & Development 2008, 12, 96–100
Implementation on Pilot-Plant Scale of the Titanocene-Catalyzed Reduction of a Lactone with Poly(methylhydrosiloxane) Dominique Depré,*,† András Horváth,† Walter Snissaert,‡ Leo Van Den Bergh,‡ and Wim Dermaut§ Johnson and Johnson Pharmaceutical Research and DeVelopment, a DiVision of Janssen Pharmaceutica, API DeVelopment, Turnhoutseweg 30, B-2340 Beerse, Belgium
Abstract: The titanocene-catalyzed reduction of the lactone 1 into the lactol 2 was studied. This process uses poly(methylhydrosiloxane) as stoichiometric reductant. Thermodynamic and safety data was collected in order to develop a reliable, safe and scalable process that was successfully implemented in the pilot plant. Using this new process, the target lactol was obtained on 30-kg scale with better yield and purity than with a former process using DIBALH, while decreasing the amount of waste.
Introduction The selective reduction of esters and lactones into aldehydes or acetals and lactols, respectively, is often a challenging reaction and requires generally the use of diisobutylaluminum hydride (DIBALH) in a nonchelating solvent, generally dichloromethane (DCM). Any alternative method to achieve this goal in a practical manner, without using pyrophoric reagents and environmentally problematic solvents, should deserve the consideration of the process chemists. In this article, we would like to report the development of a safe and scalable process for the selective reduction of the lactone 1 into the corresponding lactol 2 using poly(methylhydrosiloxane) (PMHS) as the stoichiometric reducing agent. As part of a project on Selective Estrogen Receptor Modulators (SERMs), several batches of RWJ-443931 (Figure 1) were needed for toxicological and clinical studies.1 The synthesis of this drug substance required the reduction of the lactone 1 into the lactol 2. For the synthesis of the non-GMP batch and of the first GMP batch, the reduction was performed using DIBALH in dichloromethane (Scheme 1). After optimization of the reaction conditions and the workup, compound 2 could be obtained in fair yield and purity. However, this process presented several drawbacks. First, the use of pyrophoric DIBALH together with large amounts of DCM was necessary, which led to high peak volume (up to 15 L/mol 1) and produced a large amount of waste (60-90 kg waste per kg lactol 2). Also, the quantity of DIBALH had to be precisely controlled in order to maximize the conversion of 1 and to avoid the over-reduction of 2 into the diol 3 and/or the ether 4. Finally, * To whom correspondence should be addressed. E-mail: ddepre@ prdbe.jnj.com. † Process Research. ‡ Pilot Plant. § Safety Testing Laboratory.
(1) (a) Kanojia, R. M.; Jain, N. F.; NG, R.; Sui, Z.; Xu, J. Patent WO 03/053977 A1. (b) Jain, N.; Kanojia, R. M.; Xu, J.; Jian-Zhong, G.; Pacia, E.; Lai, M.-T.; Du, F.; Musto, A.; Allan, G.; Hahn, D. W.; Lundeen, S.; Sui, Z. J. Med. Chem. 2006, 49, 3056. 96 • Vol. 12, No. 1, 2008 / Organic Process Research & Development Published on Web 12/01/2007
Figure 1. Structure of RWJ-443931. Scheme 1
the presence of traces of aluminium salts in the isolated lactol 2 led to the formation of undesired side products in the following step of the API synthesis. Results and Discussion Screening of Reducing Agents. To improve the synthesis of the desired lactol 2 and to reduce the environmental impact of our processes, we screened several reducing agents (Table 1) and first focused our efforts on the morpholine-modified RedAl system described in the literature as a possible alternative to DIBALH.2 However, no selectivity in the reduction could be observed in our case, and even with only 1 equiv of reducing agent, substantial amounts of diol 3 and of several unknown degradation products were produced beside the desired lactol 2 while 1 was still present (entry 1). We then turned our attention to some catalytic hydrosilylation systems, hoping that more selectivity could be observed. The triethylsilane-ruthenium catalyst combination in refluxing toluene gave no reaction, presumably due to the very low solubility of the starting material in this solvent (entry 2).3 Changing the solvent from toluene to THF and/or using more active silanes such as phenylsilane or PMHS led either to almost no reaction or to degradation (entries 3–5). Using Mimoun’s hydrosilylation system4 was also unsuccessful in our case, giving only slow degradation of the starting lactone without yielding (2) Kanazawa, R.; Tokoyorama, T. Synthesis 1976, 526. (3) Igarashi, M.; Mizuno, R.; Fuchikami, T. Tetrahedron Lett. 2001, 42, 2149. (4) (a) Mimoun, H. J. Org. Chem. 1999, 64, 2582. (b) Mimoun, H. Patent WO 96/12694, 1995. 10.1021/op700207m CCC: $40.75 2008 American Chemical Society
Table 1. Screening of reducing agents LC (UV 254 nm, area %) entry
conditionsa
1
1
1.2 equiv Red-Al + 1.1 equiv morpholine (premixed), toluene-DCM, 0–5 °C 1.5 equiv Et3SiH, 0.33 mol % Ru3(CO)12, toluene, ∆ 1.5 equiv Et3SiH, 0.33 mol % Ru3(CO)12, THF, ∆ 1.5 equiv PhSiH3, 0.33 mol % Ru3(CO)12, THF, ∆ ∼5 equiv PMHS,b 0.33 mol % Ru3(CO)12, THF, ∆ ∼1.1 equiv PMHS,b 5 mol % Et2Zn-eda, THF, ∆ ∼1.1-5 equiv PMHS,b 5 mol % Zn(EH)2, 5 mol % NaBH4, DIPE, ∆ 3 equiv PhSiH3, 5 mol % Cp2TiF2, THF, ∆ 5 equiv PMHS,b 5 mol % Cp2TiF2, THF, ∆
10.1
14.2
7.4
68.3
100 94.3 80.0 50.8 81.0 96.8
0 93.0
0 0
