Chem. Rev.: application of cross coupling reaction catalyzed by metal Pd in pharmaceutical industry

The 2010 Nobel Prize in chemistry was shared by three distinguished organic chemists, R F heck, e - I Negishi and A Suzuki Their palladium catalyzed cross coupling reactions have become an important reaction for the construction of carbon single bonds in organic compounds The palladium catalyzed cross coupling reactions such as Suzuki reaction, Buchwald Hartwig reaction, Sonogashira reaction and Heck reaction (Figure 1) not only have an important impact on academic research, but also are widely used in the industrial production of complex drugs and bioactive substances Figure 1 common cross coupling reaction sources in pharmaceutical industry: Recently, Andrea Biffis research group of University of Padova, Italy, published a review on the use of metal palladium catalyst in cross coupling reaction on Chemical Reviews The paper focuses on the application of metal palladium catalyst cross coupling reaction in pharmaceutical industry (chem Rev., 2018, DOI: 10.1021/acs.chemrev.7b00443 ）。 Palladium catalyzed carbon carbon bond formation reaction has been widely used for many years, and has become a tool for fine chemical production industry, especially for drug production [1-8] In most of the carbon carbon single bond coupling reactions involved in industrial production, soluble palladium complex or divalent PD (II) salt / ligand system is the most commonly used catalyst at present But other heterogeneous palladium catalysts, such as Pd / C, have higher catalytic efficiency than homogeneous palladium catalysts In principle, the use of this heterogeneous palladium catalyst avoids expensive ligands (as well as additives) and the corresponding inert gas environment In addition, the catalyst is not only easy to obtain, but also easy to recycle Another obvious advantage is that when such heterogeneous catalysts are used, the final product is generally less contaminated by palladium A potential antidepressant (1, figure 2) [9] developed by SmithKline Beecham company has realized kilogram scale preparation The key precursor compound 2 of synthesis 1 was obtained by Suzuki coupling reaction of aryl bromine derivatives and corresponding boric acid The yield of separation was 91% (∼ 6 kg) Figure 2 application source of Suzuki reaction in the pharmaceutical industry of smithklinebeecham company: mk-0359 (3, figure 3) developed by chemical reviews Merck company is a PDE4 inhibitor for the treatment of asthma and chronic obstructive pulmonary disease [10-11] Among them, phenylquinoline intermediate (4) was obtained by Suzuki coupling reaction with commercial boric acid in 92% yield, and the amount of preparation reached kilogram scale Figure 3 Merck's application source of Suzuki reaction in the pharmaceutical industry: etalocib (5, ly293111, vml295) developed by chemical reviews can effectively reduce the proliferation of different cancer cells (Figure 4) The intermediate 6 was prepared by Suzuki coupling reaction of aryl bromine and 4-fluorophenylboronic acid Pd / C is better than PD (OAC) 2 and PPH 3 ligands, which have the same effect Figure 4 Lilly's application source of Suzuki reaction in the pharmaceutical industry: Chemical Reviews, a potential pharmaceutical compound 7 developed by Johnson & Johnson in cooperation with solvias, in which the synthesis of intermediates 8 utilizes Suzuki coupling reaction The precursor of this reaction, 1-bromo-4-iodobenzene, is selectively reacted with C (SP 2) - I bond, while C (SP 2) - Br bond is not involved in the coupling reaction (Figure 5) Using Pd / c-pph 3 as catalyst, compound 8 was obtained with high purity and yield, and palladium residue in the target product was very low Figure 5 solvias application source of Suzuki reaction in pharmaceutical industry: Chemical Reviews in all the above-mentioned catalytic reactions, Pd / C belongs to heterogeneous catalyst As we all know, palladium black has low catalytic activity, but it can be used as an accelerant of Suzuki coupling reaction For example, compound 9 (ly503430) developed by Lilly company is a potential Parkinson's disease treatment drug (Figure 6) Through Suzuki coupling reaction, the precursor 10 of the compound can be synthesized with high yield (88%) and purity (99%), and the palladium residue in the target compound 9 is very low (3-8 ppm) Figure 6: source of application of Suzuki reaction in pharmaceutical industry of Lilly company: Chemical Reviews company also uses aromatic iodine compound as starting material (Figure 7) to synthesize compound 11 (ly451395) by Suzuki coupling reaction This is a drug used to treat cognitive impairment in Alzheimer's disease In the reaction, palladium black (1 mol%) was used as catalyst, and the target product was obtained with high yield (93%) Figure 7 about the application source of Suzuki reaction in the synthesis of ly451395: Chemical Reviews boscalid (12) is a widely used bactericide (Figure 8), which was patented by BASF in 1997 [12] and 1999 [13], and is currently being produced in a large scale (> 1000 tons / year) Among them, the key precursor 13 was synthesized by Suzuki coupling reaction catalyzed by Pd (PPH 3) 4 The use of more economical and effective solid palladium catalysts (Pd / C and Pd / molecular sieves) is also described in the above patents Different from the preparation of intermediate 13, intermediate 14 can be prepared by Pd / C catalytic 2-iodoaniline, which avoids the reduction of nitro group Figure 8 BASF's application source of Suzuki reaction in industry: chemical reviews as the most common UV-B sunscreen, the industrial synthesis of 2-ethylhexyl-p-methoxycinnamate 15 (eusolex 2292, uvinul mc80) is obtained by using 2-ethylhexyl-acrylate and p-bromoanisole via the Pd / C catalyzed heck coupling reaction (Figure 9) It was found that [14], a certain amount of water (up to 15%) was beneficial to the reaction rate Figure 9 preparation of 2-ethylhexyl-p-methoxycinnamate by Heck reaction source: Chemical Reviews rilpivirine (16, TMC 278, edurant) is an effective non nucleoside reverse transcriptase inhibitor (Figure 10), which can be used in combination with other antiretroviral drugs to treat HIV infection (FDA approved in 2011) The key intermediate 4-cyanoethylene-2,6-dimethylaniline (17) can be prepared by the coupling reaction of 4-iodo-2,6-dimethylaniline and acrylonitrile The best catalysts are 10% Pd / C (0.5mol%) and 1.2equiv acetate Compared with homogeneous catalysts (PD 2 (DBA) 3 / P (t-Bu) 3 or Pd (OAC) 2 / P (o-Tolyl) 3), Pd / C has the same catalytic performance and low metal residue It is worth noting that although 0.1 mol% catalyst is enough to achieve complete conversion, 0.5 mol% (250 kg scale) will still be used in the factory to ensure the robustness of the reaction Finally, the yield of compound 17 was 81%, and the palladium residue was less than 5 ppm Figure 10 Johnson & Johnson's application source of Heck reaction in the pharmaceutical industry: Chemical Reviews cinacalcet (18) is a calcium mimetic for the treatment of secondary hyperparathyroidism (Figure 11) Medichem has developed a method for the synthesis of its key intermediate 19 [15], which is obtained by the Sonogashira coupling reaction of 1-bromo-3-trifluoromethylbenzene and propargyl alcohol catalyzed by Pd / c-pph 3 and Cui Dipharma Francis SRL [16] also uses this coupling reaction, but the difference is that they use soluble palladium salt (PdCl2 or Pd (OAC) 2) as catalyst Figure 11 medichem application source of Sonogashira reaction in pharmaceutical industry: Chemical Reviews conclusion: palladium catalyzed cross coupling reaction is an important chemical reaction used to form carbon carbon bond, which is widely used in organic synthesis Through coupling reaction, special functional groups can be effectively introduced and reaction steps can be shortened There is no doubt that the use and development of excellent, stable and cheap palladium catalyzed cross coupling reaction for the industrial synthesis of drugs and active natural products can reduce costs and improve efficiency It is believed that further research in this area will make palladium catalyzed cross coupling reaction have a more extensive application prospect in the field of pharmaceutical industry References: [1] magnao, J.; duetz, J R large scale applications of transition metal catalyzed couplings for the synthesis of pharmaceuticals Chem Rev 2011, 111, 2177-2250 [2] torborg, C.; Beller, M recentapplications of palladium catalyzed coupling reactions in the pharmaceutical, agricultural, and Fine Chemical Industries Adv Synth Catal 2009, 351 , 3027-3043 [3] Blaser, H.-U.; Indolese, A.; Naud, F.; Nettekoven, U.; Schnyder, A.Industrial R&D on Catalytic C-C and C-N Coupling Reactions: A PersonalAccount on Goals, Approaches and Results Adv Synth Catal 2004, 346 , 1583-1598 [4] de Vries, J G The Heck Reaction in the Production of Fine Chemicals Can J Chem 2001, 79 , 1086-1092 [5] Zapf, A.; Beller, M FineChemical Synthesis with Homogeneous Palladium Catalysts: Examples, Status andTrends Top Catal 2002, 19 , 101-109 [6] Lipton, M F.; Mauragis, M A.; Maloney, M T.; Veley, M F.; VanderBor, D.W.; Newby, J J.; Appell, R B.; Daugs, E D The Synthesis of OSU 6162:Efficient, Large-Scale Implementation of a Suzuki Coupling Org Process Res.Dev 2003, 7 , 385-392 [7] Doucet, H.; Hierso, J C Palladium Coupling Catalysts for PharmaceuticalApplications Curr Opin Drug Discovery Devel 2007, 10 , 672-690 [8] Budarin, V L.; Shuttleworth, P S.; Clark, J H.; Luque, R IndustrialApplications of C-C Coupling Reactions Curr Org Synth 2010, 7 , 614-627 [9] Environmental Health Criteria 226: Palladium International Programmeon Chemical Safety (IPCS); World HealthOrganization: Geneva, 2002 [10] Macdonald, D.; Mastracchio, A.; Perrier, H.; Dube, D.; Gallant, ́ M.; Lacombe, P.; Deschenes,D.; Roy, B.; Scheigetz, J.; Bateman, K.; et al Discovery of a Substituted 8-ArylquinolineSeries of PDE4 Inhibitors: Structure-Activity Relationship, Optimization, andIdentification of a Highly Potent, Well Tolerated, PDE4 Inhibitor Bioorg Med Chem.Lett 2005, 15 , 5241-5246 [11] Conlon, D A.; Drahus-Paone, A.; Ho, G.-J.; Pipik, B.; Helmy, R.;McNamara, J M.; Shi, Y.-J.; Williams, J M.; Macdonald, D.; Deschenes, D.; etal Process Development and Large-Scale Synthesis of a PDE4 Inhibitor Org Process Res.Dev 2006, 10 , 36-45 [12] Dey, R.; Sreedhar, B.; Ranu, B C Molecular Sieves-Supported Palladium(II)Catalyst: Suzuki Coupling of Chloroarenes and an Easy Access to UsefulIntermediates for the Synthesis of Irbesartan, Losartan and Boscalid Tetrahedron 2010, 66 , 2301-2305 [13] Jingquan, S.; Xiangshan, W.; Xianzhen, Z Preparation Method of Boscalid.China Patent CN103073489 A, 2013 [14] Eisenstadt, A Utilization of the Heterogeneous Palladium-onCarbonCatalyzed Heck Reaction in Applied Synthesis In Catalysis of organic reactions; Herkes, F E., Ed.; Chemical Industries Series; Marcel Dekker:New York, 1998; Vol 75, pp 415-427 [15] Szekeres, T.; Repa ́ si, J.; Szabo ́ , A.; Mangion, B Processes for ́ Preparing IntermediateCompounds Useful for the Preparation of Cinacalcet World Patent WO20080352