Communication pubs.acs.org/OPRD
The P‑Chiral Phosphane Ligand (MeO-BIBOP) for Efficient and Practical Large-Scale Rh-Catalyzed Asymmetric Hydrogenation of N‑Acetyl Enamides with High TONs Wenjie Li,* Sonia Rodriguez, Adil Duran, Xiufeng Sun, Wenjun Tang,*,† Ajith Premasiri, Jun Wang, Kanwar Sidhu, Nitinchandra D. Patel, Jolaine Savoie, Bo Qu, Heewon Lee, Nizar Haddad, Jon C. Lorenz, Larry Nummy, Azad Hossain, Nathan Yee, Bruce Lu, and Chris H. Senanayake Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States S Supporting Information *
reactivity for asymmetric hydrogenation have been studied (Figure 1).10 Among these ligands, MeO-BIBOP (1) is the
ABSTRACT: A highly electron-rich P-chiral bis(trialkylphosphane) ligand MeO-BIBOP (1) was efficiently synthesized on large scale. The MeO-BIBOP− rhodium complex exhibited remarkably high reactivities (up to 200,000 TON) for the hydrogenation of N-acetyl enamides to provide chiral acetamides on kilogram scale. In the meantime, a high-yielding, cost-effective, and practical preparation of N-acetyl enamide by reductive acylation of oxime was developed employing an in situ formation of Fe(II) acetate from Fe/AcOH/Ac2O.
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INTRODUCTION The objective for industrial process chemists is to establish efficient, cost-effective, and environmental-friendly manufacturing processes for their target chemical entities.1 For this purpose, the processes involving the use of catalysis have clear advantages over those requiring stoichiometric amounts of reagents.2 For the production of chiral compounds, asymmetric catalytic processes which directly provide the correct enantiomer are highly desirable, and asymmetric catalytic hydrogenation of unsaturated substrates has become one of the most widely used methods.3 Chiral amines are important building blocks in pharmaceutical and agrochemical industry, and their synthesis has attracted a great deal of interest.4 Asymmetric hydrogenation of N-acyl enamides has emerged as a powerful method, and a number of chiral phosphane ligands are found to be effective and highly enantioselective for this transformation.5−8 Despite the significant progress in this field and broad range of catalysis available, the application at industrial scale is limited.9 This is because many current asymmetric catalytic methods suffer from their inherent inefficiency (e.g., low turnover numbers (TONs)) and, thus, are often less cost effective than the conventional methods such as racemic syntheses followed by chemical resolution. Nevertheless, recent advances in asymmetric hydrogenation technology and novel ligand design have provided many opportunities for developing efficient asymmetric catalytic processes. In our efforts to pursue economically viable processes to prepare chiral amines as intermediates for drug substance, a series of P-chiral phosphane ligands have been designed and synthesized, and their selectivity and © XXXX American Chemical Society
Figure 1. BIBOP ligands.
most electron-rich, and we envisioned it would exhibit the best reactivity. Herein we report the application of this ligand to the large-scale asymmetric hydrogenation of enamides with very high TON for the preparation of chiral amines. In addition, a solution to a long-standing problem for the synthesis of Nacetyl enamide was developed, and the method provided a high-yielding, scalable, and cost-effective synthesis for N-(1-(4bromophenyl)vinyl)acetamide on multikilogram scales.
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RESULTS AND DISCUSSION The synthesis of MeO-BIBOP (1) is outlined in Scheme 1. Starting from phosphine oxide (5), the homocoupling was Scheme 1. Synthesis of MeO-BIBOP (1)
Received: March 5, 2013
A
dx.doi.org/10.1021/op400055z | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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and, due to its high instability in air, is difficult to handle at large scale. This prompted us to investigate the in situ generation of Fe(OAc)2 and its direct use in the reductive acylation. Therefore, a revised protocol was developed in which iron powder was stirred in acetic acid and heated to reflux for 3−4 h. At this point most of the iron powder disappeared, and a light-colored suspension was obtained, presumably forming Fe(OAc)2. Acetic anhydride and ketoxime 10 were then charged to this reaction mixture for the reductive acylation to generate N-acetyl enamide (7b). To our knowledge this protocol had not been previously reported in literature, and to our delight, it provided the desired product 7b in 85% assay yield, which was twice as high as the original protocol using iron powder directly (Scheme 2). This newly derived process
initially carried out with LDA/CuCl2 as reported in the literature.10,11 However, the procedure was unreliable upon scale-up, as many undesired byproducts were obtained.12 To overcome this problem, the reaction was extensively studied, and various copper salts were tested. Interestingly, copper(II) acetate was found to be most effective for this reaction and gave the best reaction profile. After reduction with trichlorosilane, the ligand (1) was isolated as an air-stable crystalline solid. The sequence was successfully carried out to prepare MeO-BIBOP (1) on 100-g scale. To examine the catalytic properties of MeO-BIBOP (1), we prepared its rhodium complex (9) and tested it in the hydrogenation of two enamides, 7a and 7b, which were of interest in our development programs. As in the case for many industrial processes, the major focus is the reactivity of the catalyst for economical purposes. The selectivity, although important, is not the most critical factor. As summarized in Table 1, for both substrates, promising results (up to 20,000 TON) were achieved during preliminary studies.
Scheme 2. Kilogram-scale synthesis of enamide 7b
Table 1. Asymmetric hydrogenation of enamides using 9 as catalysta
S. M.
R
S/C (TON) 5,000
7a
CF3
7b
Br
100% conv,b 97.5:2.5 erc,d 100% conv,b 95:5 erc,d
S/C (TON) 10,000 100% conv,b 97.5:2.5 erc,d 100% conv,b 95.5:4.5 erc,d
invloving the in situ generation of Fe(OAc)2 and its direct use in the reductive acylation provided a solution to a long-standing problem for the large-scale synthesis of N-acetyl enamides, as it was successfully scaled up on multikilogram scale and the product was consistently isolated in 77−80% yields. More importantly, the N-acetyl enamide (7b) produced by this method had high purity and was suitable for efficient asymmetric hydrogenation. For the hydrogenation of enamide 7b, detailed development work was carried out using [Rh(nbd)(MeO-BIBOP)]BF4 catalyst 9. It was found that factors such as hydrogen pressure and reaction temperature played insignificant roles in terms of enantioselectivity and reactivity. The reaction proceeded well in both methanol and dichloromethane, but methanol was chosen due to its better solubility of substrate and process friendliness. While the [Rh(nbd)(MeO-BIBOP)]BF4 complex (9) could be prepared and isolated in pure form, we preferred to generate it in situ prior to hydrogenation, and such freshly prepared solution of catalyst appeared to have better reactivity. Under the optimized conditions, several batches of asymmetric hydrogenation were performed on kilogram scale, and the catalyst loading was reduced to as low as 0.0005 mol % (200,000 TON, Table 2). During the course of the hydrogenation, the enantioselectivity remained consistent (95:5 er) throughout the reaction, demonstrating the remarkable robustness of the catalyst system (Figure 2). At such low catalyst
S/C (TON) 20,000 100% conv,b 97.5:2.5 erc,d 100% conv,b 95:5 erc,d
a
The hydrogenation was done in CH2Cl2/MeOH (4:1) under 300 psi H2 for 20 h. bThe conversion was measured with LC/MS. cThe enantioselectivity was determined by GC using Chirasil-L-Val (for 8a) or by HPLC using Kromasil 3-CelluCoat Rp column (for 8b). dThe racemic samples were prepared by hydrogenation on Pd/C in methanol (from 7a) or with Wilkinson’s catalyst in methanol (from 7b).
Encouraged by these initial results, we focused our attention to the development of a kilogram-scale process for 8b (R = Br). Before we could carry out the hydrogenation studies, a reliable process for the large-scale synthesis of enamide 7b was needed. Although a number of synthetic methods were reported,13−15 most of them suffered from high reagent cost, narrow substrate scope, and poor scalability. Among these methods, reductive acylation of ketoximes with iron powder in acetic acid and acetic anhydride has been widely used in large-scale synthesis due to its low material cost. This procedure, however, usually showed an uncontrollable exothermic behaviour and gave low yield as multiple byproducts were typically generated. Recently, several methods have been discovered by us,16 including an Fe(II) acetate-mediated reductive acylation of oximes.16a This protocol had clear advantages over the traditional Fe/AcOH/ Ac2O method, and offered cleaner reaction profiles, mild reaction conditions, and consistently high yields for the synthesis of various functionalized N-acetyl enamides. Unfortunately, Fe(II) acetate has limited commercial availability
Table 2. Asymmetric hydrogenation of 7b with high TONs
B
entry
S/C (TON)
h
conv. (%)
er
1 2 3
50,000 100,000 200,000
10 36 40
100 100 100
95.3:4.7 95.4:4.6 95.3:4.7
dx.doi.org/10.1021/op400055z | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Figure 2. Conversion and er during the hydrogenation of 7b at various S/C.
mm, 2.7 μm) for reaction monitoring or Kromasil 3-CelluCoat Rp column (4.6 mm × 150 mm, 2.7 μm) for chiral purity. Synthesis of (2R,2′R,3R,3′R)-3,3′-Di-tert-butyl-4,4′-dimethoxy-2,2′,3,3′-tetrahydro-2,2′-bibenzo[d][1,3]oxaphosphole (MeO-BIBOP, 1). To a solution of (S)-3-tert-butyl-4-methoxy2,3-dihydrobenzo[d][1,3]oxaphosphole oxide (5, 114 g, 97%, 0.46 mol, chiral purity >99.5%) in THF (2 L) at −78 °C was added 1.8 M LDA (383.6 mL, 0.69 mol) over 15 min. The mixture was stirred at −70 °C for 1 h before the addition of anhydrous Cu(OAc)2 (334 g, 1.84 mol) in one portion. The resulting mixture was stirred at −70 °C for 10 min before it was warmed to rt over 1 h. To the mixture was added 15% NH4OH (1.8 L). The mixture was stirred for 10 min and allowed to settle. The two layers were separated, and the aqueous layer was extracted with dichloromethane (3 L). The first organic layer was concentrated under vacuum. The residue was combined with the dichloromethane extract, washed with water (2 × 1 L), and concentrated under vacuum. To the residue was added ethyl acetate (250 mL). A slurry was obtained. It was stirred at ambient temperature for 1 h and filtered. The solid was rinsed with a mixed solvent (methyl tertbutyl ether/ethyl acetate = 1:1) and dried under vacuum to give (2R,2′R,3S,3′S)-3,3′-di-tert-butyl-4,4′-dimethoxy-2,2′,3,3′-tetrahydro-2,2′-bibenzo[d][1,3]oxaphosphole bisoxide (6, 72.5 g, 0.15 mol, 66%) as a white solid. Chiral purity >99.5% by HPLC. 1H NMR and 31P NMR data are consistent with those reported in literature.10 To a solution of (2R,2′R,3S,3′S)-3,3′-di-tert-butyl-4,4′dimethoxy-2,2′,3,3′-tetrahydro-2,2′-bibenzo[d][1,3]oxaphosphole bisoxide (6, 10 g, 20.9 mmol) and triethylamine (16.9 g, 167.2 mmol) in toluene (160 mL) was added trichlorosilane (11.3 g, 83.6 mmol). The mixture was heated to 80 °C for 4 h, then cooled to 0 °C and quenched with addition of degassed 30% NaOH solution (160 mL) over 30 min. The
loading, the price of catalyst was only a very small portion of the cost, and this process turned out to be the most efficient and economical way to prepare the desired product (8b). In addition, the metal content (rhodium) was not a concern during the drug development. After hydrogenation, the product (8b) was crystallized by addition of water and isolated by filtration. The isolated yield was 84%, and the enantiomeric ratio of the product reached 99.9:0.1. In summary, we have developed a practical and economical asymmetric hydrogenation of N-acetyl enamides with in situ prepared [Rh(nbd)(MeO-BIBOP)]BF4 complex (9) and a TON up to 200,000 was achieved. In conjunction with an improved protocol for the preparation of N-acetyl enamide by reductive acylation of oxime employing an in situ formation of Fe(II) acetate from Fe/HOAc/Ac2O, the process provided a highly economical synthesis of N-(1-(4-bromophenyl)vinyl)acetamide (8b), which is an important building block for our drug candidate synthesis. With proper modification and optimization, this method should offer general utilities for the synthesis of various important chiral amines for the pharmaceutical, chemical, and agro-chemical industries.
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EXPERIMENTAL SECTION General. Starting materials, reagents, and solvents were obtained from commercial suppliers and used without further purification. 1H and 13C NMR data were recorded on a BrukerBiospin DRX500 or DRX400 NMR spectrometer. Highresolution mass spectral data were acquired using an Agilent 1100 HPLC interfaced with a time-of-flight mass spectrometer (TOF-MS). Samples were introduced to the mass spectrometer by flow injection, and ionized by electrospray positive ionization. HPLC analyses were performed on Hewlett-Packard 1200 system using Halo Rp-Amide column (4.6 mm × 150 C
dx.doi.org/10.1021/op400055z | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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mixture was further stirred at 50 °C for about 1 h until the two layers became clear. The toluene layer was separated under N2 and washed with degassed water (80 mL). It was dried over sodium sulfate and concentrated under N2. Degassed heptane (100 mL) was added. The mixture was heated to 90 °C and stirred for 30 min. It was cooled to ambient temperature, stirred for 1 h, and filtered under N2 to give (2R,2′R,3R,3′R)-3,3′-ditert-butyl-4,4′-dimethoxy-2,2′,3,3′-tetrahydro-2,2′-bibenzo[d][1,3]oxaphosphole (1, 6.5 g, 14.6 mmol, 70%) as white solid. Chiral purity >99.5% by HPLC. 1H NMR and 31P NMR data are consistent with those reported in literature.10 Kilogram-Scale Synthesis of N-(1-(4-Bromophenyl)vinyl)acetamide 7b. A stirred mixture of iron powder (2.20 kg, 39.35 mol), acetic anhydride (5.62 kg, 55.14 mol) in acetic acid (12.56 kg, 209.35 mol) was heated to 116−120 °C for 3.5−4 h. The reaction mixture was then cooled to 40 °C. A solution of 1(4-bromophenyl)ethanone oxime (10, 4.00 kg, 18.63 mol) in ethyl acetate (14 L) was added to the reaction mixture over 30 min, keeping the reaction temperature below 50 °C. The reaction mixture was then stirred at 50 °C for 2.5−3 h until the reaction was complete (by HPLC). Slurry of Celite (0.60 kg) in ethyl acetate (6 L) was charged, followed by toluene (6 L). The reaction mixture was then stirred for 30 min at 50 °C before it was filtered to remove the solid. The filter cake was washed with ethyl acetate (20 L). The combined filtrate was washed with 0.5% NaCl (16 L). Water (12 L) was charged to the organic phase, and pH was adjusted to 7−9 with 50% NaOH at
