药物中的还原反应_op2003826

Large-Scale Carbonyl Reductions in the Pharmaceutical Industry Javier Magano* and Joshua R. Dunetz* Chemical Research and Development, Pharmaceutical Sciences, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States ABSTRACT: Herein we present a review on methods for carbonyl reductions on large scale (≥100 mmol) applied to the synthesis of drug candidates in the pharmaceutical industry. We discuss the most common and reliable methods for the reduction of aldehydes, ketones, carboxylic acids, esters, amides, imides, and acid chlorides. Representative examples illustrate detailed reaction and workup conditions and highlight the advantages and limitations of each reducing agent with special emphasis on safety, cost, and amenability to scale-up. ■ CONTENTS 1. Introduction 1156 2. Aldehyde Reduction 1157 2.1. Aldehyde Reduction to Alcohol 1157 2.2. Aldehyde Reduction to Alkane 1157 3. Ketone Reduction 1158 3.1. Nonasymmetric Ketone Reduction to Alcohol 1158 3.2. Substrate-Controlled, Diastereoselective Ketone Reduction to Alcohol 1158 3.3. Reagent-Controlled, Asymmetric Ketone Reduction to Alcohol 1160 3.4. Ketone Reduction to Alkane 1164 4. Carboxylic Acid Reduction to Alcohol 1164 5. Ester Reduction 1166 5.1. Acyclic Ester Reduction to Aldehyde 1166 5.2. Acyclic Ester Reduction to Alcohol 1167 5.3. Lactone Reduction to Lactol 1170 5.4. Lactone Reduction to Diol 1172 6. Amide Reduction 1172 6.1. Amide Reduction to Aldehyde 1172 6.2. Amide Reduction to Alcohol 1173 6.3. Amide Reduction to Saturated Amine 1174 7. Imide Reduction 1176 7.1. Imide Reduction to Saturated Amine 1176 7.2. Imide Reduction to Hemiaminal 1177 8. Acid Chloride Reduction to Aldehyde 1178 9. Conclusions 1179 Author Information 1180 Corresponding Author 1180 Notes 1180 Acknowledgments 1180 Abbreviations 1180 References 1180 1. INTRODUCTION Reductions and oxidations are among the most important and prevalent transformations in organic chemistry. In the pharmaceutical industry, the synthesis of drug candidates often requires functional group manipulations via reductants or oxidants during the early stages of compound preparation. Successful compound progression requires greater quantities of active pharmaceutical ingredient (API), and process chemists are responsible for the manufacture of high-quality API under the guidelines of current Good Manufacturing Practices (cGMP) to meet the stringent requirements for clinical testing. As a result, early synthetic routes are often revised for safe and efficient implementation on large scale. One goal of process development is redox economy,1 or the minimization of changes to oxidation states throughout a synthesis. For this reason, there is a strong preference to design process routes from raw materials having the desired oxidation states; however, the increasing complexity of drug candidates makes it impossible to avoid reductions or oxidations in process chemistry. Reductions are preferred to oxidations on large scale, as the latter can be more difficult to implement due to process safety and toxicity concerns surrounding many oxidants (which can make the disposal of waste streams difficult and expensive).2 As a result, reductions are much more frequent than oxidations for the synthesis of pharmaceuticals on large scale and, as many examples in this review will showcase, can be implemented reliably on multikilogram scale. Both industry and academia place special emphasis on carbonyl reductions due to the versatility of this transformation for the generation of a wide range of products.3 Hydrogen gas is the ideal reducing agent in terms of cost and atom efficiency, and has very broad applicability for the reduction of carbonyls. Hydrogenation chemistry is well established (first catalytic example reported in 1874 for olefin reduction4) and reliable, and typically affords reduction products in high yield and purity with minimal workup.5 Its drawbacks include the flammability of H2 gas, the frequent need for specialized equipment, and the lack of reactivity toward certain carbonyl groups (e.g., carboxylic acids, esters, amides). The discovery of LiAlH4 in 1947 (prepared by treating AlCl3 with LiH) 6 and NaBH4 in 1953 (prepared by treating B(OMe)3 with NaH) 7 set the foundation for the development of new and more chemo- selective reagents that have considerably expanded the scope of reducing agents.8 For example, reductions using boron- based reagents now comprise a mature technology routinely Received: December 23, 2011 Published: February 14, 2012 Review pubs.acs.org/OPRD © 2012 American Chemical Society 1156 dx.doi.org/10.1021/op2003826 | Org. Process Res. Dev. 2012, 16, 1156−1184 implemented in the pharmaceutical industry with numerous applications in process chemistry where robustness and reliability are fundamental.9 Further research in this field has led to the development of chiral reagents for asymmetric reductions.10 To the best of our knowledge, a general review covering large- scale processes for carbonyl reduction has not been published. Herein we intend to describe technologies that are reliable and well- established or have the possibility of being useful for carbonyl reduction on large scale. For easy reference, this review has been divided into sections and subsections based on functional group conversion (e.g., aldehyde to alcohol). Each subsection contains an introduction citing all the examples we found for a given trans- formation that meet the following two criteria: (a) implementation on at least 100 mmol scale and (b) the presence of a detailed experimental procedure. The body of each subsection then contains representative examples which highlight the most commonly employed methods for substrate reduction. These examples have been selected because the researchers provided details on decisions leading to the development of reaction and quench conditions. We captured this information in the schemes and text of this review and, where appropriate, commented on the advantages and limitations of processes with respect to safety, cost, and amenability to scale-up. In reaction schemes, Roman numerals indicate steps performed within a single process (e.g., i. LAH; ii. MeOH quench), whereas Arabic numerals designate discrete transformations separated by reaction workups or product isolations. We have thoroughly reviewed the mainstream, large-scale literature from the early 1990s through December 2011 and believe that we have captured most of the examples from the past 20 years. The patent literature has not been covered in this review since, in our opinion, the most representative examples have been reported in the mainstream literature. 2. ALDEHYDE REDUCTION 2.1. Aldehyde Reduction to Alcohol. Surprisingly, the reduction of aldehydes to alcohols is not commonly found in the process literature.11 Sodium borohydride is the preferred reagent for this transformation on large scale since it is reliable, commercially available in bulk and in various forms (powder, pellets, caustic solution), and cost efficient (least expensive metal hydride on a hydride equivalent basis).12 NaBH4 reductions of aldehydes are typically carried out in THF, alcohols (MeOH, EtOH), or combinations thereof, and may be performed under aqueous or anhydrous conditions. Other solvent combinations include toluene/MeOH11j and MTBE/H2O (biphasic mixture with n-Bu4NCl as phase-transfer agent). 11i Sodium hydroxide is sometimes added to stabilize the reagent and avoid decomposition (and the need for a large excess) in protic solvents such as MeOH. An aqueous quench, sometimes acidic depending on product stability (e.g., HCl,11b,d H2SO4 11j), typically follows NaBH4 reduction to destroy residual borohydride. Safety concerns with aqueous quench include hydrogen gas evolution and concurrent exotherm, and acetone may be employed as an alternative quench reagent to avoid offgassing and minimize heat generation.11i,13 Acetic acid is another alternative when anhydrous quench conditions are required. The versatility of NaBH4 for the large-scale reduction of aldehydes to alcohols has been demonstrated in the literature.11 For example, NaBH4 has been used to convert the aldehyde generated from alkene ozonolysis directly to the alcohol.11f,g This reagent has also been employed for the reduction of a lactol to the corresponding diol (CH2Cl2/MeOH mixture at reflux).14 Cabaj and co-workers at Cedarburgh Pharmaceuticals have described the synthesis of anabolic steroid oxandrolone (3), a compound to promote weight gain and relieve the bone pain caused by osteoporosis (Scheme 1).11d The lactone of the molecule was assembled in a one-pot, three-step sequence that started with the sodium salt formation of acid 1 via treatment with aqueous, ethanolic NaOH. The resulting solution was dosed with NaBH4 at 0−10 °C (added in four portions) to reduce the aldehyde group to the corresponding alcohol. Alternatively, a commercially available caustic solution of NaBH4 could be employed, which is more easily handled on scale. After complete reduction of aldehyde to alcohol, 6 M aqueous HCl was added to quench excess NaBH4 and promote the cyclization to the lactone. Oxandrolone (3) was then collected by filtration in 94% yield. This material could be further purified by performing a charcoal treatment in MeOH followed by recrystallization from MeOH/H2O (85% yield). The researchers mentioned that when the reduction was carried out in water, product filtration after acidification was very slow. In addition to sodium borohydride, both LAH (conversion of an α,β-unsaturated aldehyde to the allylic alcohol; THF, −78 °C, basic quench)15 and catalytic hydrogenation (conversion of furan-2-carbaldehyde to 2-hydroxymethyltetra- hydrofuran, 60 psig, Ra-Ni, MeOH, 60 °C)16 have been employed for the large-scale reduction of aldehydes to alcohols. The Meerwein−Ponndorf−Verley reduction (IPA/Al(Oi-Pr)3) 17 is another useful method that has not yet been reported in the mainstream literature for the large-scale reduction of aldehydes, although an example for ketone reduction has been reported (section 3.2). As a special case of aldehyde reduction, an interesting example of diastereoselective pinacol homocoupling of an aldehyde to a vicinal diol mediated by VCl3 has been described by researchers at Hoechst AG.18 2.2. Aldehyde Reduction to Alkane. Aldehydes can also be reduced to alkanes, although this transformation rarely appears in the large-scale literature. An example is the reduction of benzaldehyde 4 to toluene 6, reported by Connolly and co- workers at Roche Palo Alto LLC en route to benzoic acid 9 (Scheme 2).19 Aldehyde 4 was hydrogenated at 5 psig with 10% Pd/C (5 wt%; 50% water-wet) in EtOAc to provide transient benzylic alcohol 5, which upon further reduction afforded dimethoxytoluene 6. Initial experiments with only 2.5 wt% catalyst showed quick reduction to alcohol 5 followed by slow conversion to the alkane over 48 h. The amount of catalyst was Scheme 1. Synthesis of oxandrolone (3) via aldehyde reduction with NaBH4 followed by lactonization Organic Process Research & Development Review dx.doi.org/10.1021/op2003826 | Org. Process Res. Dev. 2012, 16, 1156−11841157 doubled in the plant to decrease the reaction time; as a result, the aldehyde was fully consumed after 3 h with only 4% residual alcohol 5. After 15 h, essentially complete reduction of 5 to toluene 6 was observed (only 0.4% of residual 5). After filtration through Celite or Solka-Floc (cellulose), the EtOAc solution of 6 under- went bromination with 1,3-dibromo-5,5-dimethylhydantoin (7) to provide aryl bromide 8. This material was isolated via crystallization from H2O/MeOH in 96% yield on multikilogram scale. 3. KETONE REDUCTION The large-scale reduction of ketones to alcohols in both non- asymmetric and asymmetric fashion is a very general practice and numerous examples can be found in the literature. In particular, the preparation of chiral, secondary alcohols with high optical purity from prochiral ketones is of paramount importance, and many methods are currently available to medicinal and process chemists,20 including biocatalysis.20h,21 In this review, the asymmetric reductions have been divided into two categories: substrate-controlled and reagent-controlled. 3.1. Nonasymmetric Ketone Reduction to Alcohol. Sodium borohydride12 is the preferred reagent for large-scale ketone reductions22 for the same reasons described in section 2.1. LAH has been employed as an alternative to NaBH4 for large-scale ketone reduction,23 but the lower chemical selectivity of this reagent limits its application to relatively simple substrates. Dowpharma reported ketone hydrogenation in IPA using (diphosphine)RuCl2(diamine) precatalysts and KOt-Bu 24 as a practical alternative to NaBH4. Ikemoto and co-workers at Takeda Chemical Industries in Japan have reported the preparation of non-peptide CCR5 antagonist candidate 13 for the therapy of HIV-1 (Scheme 3).22h During the one-pot preparation of α,β-unsaturated acid 12 from cycloheptanone 10, an intermediate β-keto ester (not shown) was synthesized by treating 10 with dimethyl carbonate and NaOMe at reflux. Initial conditions (NaBH4 in CH2Cl2) for ketone reduction produced the desired β-hydroxy ester 11 with 1,3-diol as a byproduct from ester reduction, and as a result, the purification of 11 required chromatography. Alternatively, ketone reduction in a 10:1 THF/H2O mixture at −15 to −5 °C provided alcohol 11 without diol after water dilution and product extraction into diisopropyl ether.25 Dehydration of the β-hydroxy ester via mesylate elimination and subsequent saponification via aqueous NaOH in MeOH provided acid 12 in 54% yield from 10 on kilogram scale. 3.2. Substrate-Controlled, Diastereoselective Ketone Reduction to Alcohol. NaBH4 is also the most widely used reagent for the substrate-controlled, diastereoselective reduction of ketones.26 This reagent has been used in combination with additives such as CeCl3 (Luche reduction of an enone to allylic alcohol)27 and Et3B 28 or Et2BOMe 11c (reduction of β-hydroxy ketone to syn-1,3-diol). NaBH4 has also been employed for the kinetic resolution of a mixture of diastereomeric, α-substituted cyclopentanones.26c Acyloxyborohydrides, prepared from the reaction of NaBH4 and carboxylic acids, are also useful reagents for diastereose- lective, substrate-controlled reductions.29,30 An attractive feature of these reductants is that their reactivity can be fine-tuned by adjusting the stoichiometry of carboxylic acid (1−3 equiv). Among them, Me4N(OAc)3BH is known to reliably afford anti-1,3-diols with high diastereoselectivity via reduction of the corresponding β-hydroxy ketones,31 but we only found a single application of this technology in the process literature.32 LAH is a cost-effective reagent, but it is less frequently used for the reduction of ketones to alcohols due to its lower chemical selectivity.33 Solid LAH is highly flammable and may ignite in moist or heated air. Commercial LAH solutions in various solvents (e.g., THF, 2-methoxyethyl ether, DME) are safer and more practical alternatives for large-scale manufactur- ing, but careful quenching of LAH reductions with protic solvent is still required to control the rate of H2 evolution and accompanying exotherm. In addition, aluminum salts often complicate reaction workup and product isolation, but the Fieser conditions34 generally precipitate these salts from solution as a granular solid that can be easily removed by filtration. Diisobutylaluminum chloride (DIBAC)35 is a less known alternative to DIBAL, and only one example has been found in the large-scale literature for substrate-controlled, diastereose- lective ketone reduction.36 Another technology that has received little attention from the process community, despite being cost-effective and environmentally friendly, is the Meerwein−Ponndorf−Verley reduction.17,37 This method employs Al(Oi-Pr)3 as catalyst and IPA (a readily oxidized secondary alcohol) as solvent to generate acetone as byproduct, which can be easily removed by distillation to drive the reaction to completion. Other reagents and methods implemented on large-scale for substrate-controlled, diastereoselective ketone reduction to Scheme 2. Benzaldehyde 4 reduction to alkane 6 via catalytic hydrogenation Scheme 3. NaBH4 reduction of β-keto ester intermediate en route to α,β-unsaturated acid 12 Organic Process Research & Development Review dx.doi.org/10.1021/op2003826 | Org. Process Res. Dev. 2012, 16, 1156−11841158 alcohol are L-Selectride (cyclohexenone reduction to allylic alcohol during the synthesis of anti-Alzheimer drug (−)-gal- anthamine),38 catalytic hydrogenation in the presence of PtO2 (cyclohexanone reduction in steroid substrate), 39 and Li(Ot-Bu)3AlH (aliphatic ketone reduction during the synthesis of HIV protease inhibitor atazanavir).40 Beck and co-workers at Hoechst AG in Germany combined NaBH4 with Et3B (1 M in hexanes) to reduce β-hydroxy ester 14 to syn-1,3-diol 15, an intermediate to side-chain 16 for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reduc- tase inhibitors (Scheme 4).28 Similarly, Fuenfschilling and co-workers at Novartis combined NaBH4 with Et2B(OMe) (50% in THF) to prepare the racemic syn-1,3-diol 18 for the synthesis of racemic fluvastatin (19, Scheme 5).11c Both cases required cryogenic temperatures and provided syn-1,3-diols with high diastereoselectivities after aqueous quench and oxidative workup to cleave the initial boronate from reduction. The Evans−Saksena reduction31 of β-hydroxy ketone 20 was implemented by researchers at Novartis for the large-scale prep- aration of the anticancer marine natural product discodermolide (22, Scheme 6).32 The highly functionalized and advanced intermediate 20 was treated with Me4N(OAc)3BH at −25 °C in a mixture of THF and glacial AcOH. After an 18-h period at 0 °C, the reaction was quenched with an aqueous solution of sodium potassium tartrate (Rochelle salt). Workup and chromatography afforded anti-1,3-diol 21 in 73% yield and high diastereoselectivity (exact information on stereoselectivity was not provided in the article). Watson and co-workers at the Hoechst Marion Roussel Research Institute used LAH to effect the diastereoselective reduction of cyclopentenone 23 to allylic alcohol 24 for their synthesis of 25 (MDL 201449A), a candidate for the treatment of multiple inflammatory diseases (Scheme 7).33b A solution of cyclopentenone 23 in MTBE was added to a mixture of LAH and LiI in toluene while maintaining batch temperature between −30 and −20 °C. The additive LiI served two purposes: (a) it suppressed 1,4-hydride addition to 23, thus minimizing olefin reduction byproducts; and (b) it allowed the raising of reaction temperature from −78 to −30 °C. After reaction completion, the mixture was quenched with aqueous NH4Cl at a rate to maintain an internal temperature below 10 °C. The aluminum salts were removed by filtration, and concentration of the organic layer provided alcohol 24 in 76% yield as a 37:1 mixture of cis/trans isomers. Ethereal cosolvents were required for LAH solubility, and initial studies using Et2O/toluene gave more favorable cis/trans ratios; however, the highly flammable and peroxide-forming Et2O was replaced with MTBE to avoid the process safety risks associated with the diethyl ether. Furthermore, to minimize the handling risks associated with flammable LAH and anhydrous LiI (hygro- scopic), both materials were purchased in preweighed, toluene- soluble bags and charged directly to the tank. Singh and co-workers at Bristol-Myers Squibb employed DIBAC for the reduction of cyclobutanone 26 to alcohol 27 during the preparation of lobucavir (28), a potent antiviral agent for the treatment of herpes, hepatitis B, and HIV (Scheme 8).36 T