Pyridines: from Lab to Production || Introduction

In the first half of the last century, most pyridines used industrially came from the basic fraction obtained from coal tar distillation. Then the growth in demand for pyridine-based chemicals began to outstrip the supply from natural sources. The demand was driven by the need for 3-pyridine carboxylic Jubilant, India; and Red Sun, China) to manufacture pyridine and methylpyridines are based on this Only recently, by a study using labelled carbons, has the position of each of the carbons in the products been attributed precisely to the carbon in the aldehyde from which it came.7 CO2Et N H CO2Et [Ox] Me EtO2C O MeO NH3 EtO2C Me Me N CO2EtEtO2C Me Me Scheme 1.1 Hantzsch pyridine synthesis. Pyridines: from lab to production � 2013 Elsevier Ltd. ISBN 978-0-12-385235-9, http://dx.doi.org/10.1016/B978-0-12-385235-9.00001-1 All rights reserved. 1 process. Two variations are practised that involve high-temperature vapour phase processes that both yield coproducts which depend on the nature of the feed, catalyst, and conditions. A feed of acet- aldehyde and ammonia gives a mixture of 2- and 4-methylpyridines (Eqn (1.1)); a feed of acetalde- hyde, formaldehyde, and ammonia gives a mixture of pyridine and 3-methylpyridine (Eqn (1.2)). acid (niacin), its amide (niacinamide), and the antituberculosis drug Isoniazid. The discovery that the addition of 2-vinylpyridine to butadieneestyrene latex binder gave a large increase in adhesion of rubber to tirecord drove a dramatic increase in demand for 2-methylpyridine, the precursor of 2-vinylpyridine. The demand created by these factors and others led to the development of a synthetic pyridine process based on Chichibabin’s early vapour phase work. This process was first developed and operated on a large commercial scale, in fluidised bed reactors, by Reilly Tar & Chemical Corporation in the early 1950s.6 Most processes operated today by the three major producers (Vertellus, USA; CHAPTER11 Introduction R. Murugan1, Eric F.V. Scriven2 1 Vertellus Specialties Inc, 1500 South Tibbs Avenue, Indianapolis, IN 46241, USA., 2University of Florida, Gainesville, FL 32611, USA 1. INTRODUCTION Pyridines were first described by Anderson in the 1840s.1 He obtained 2-methylpyridine (beta- picoline) from bone oil distillation, and subsequently pyridine and some dimethylpyridines (lutidines).2 Later (1877), Sir William Ramsey was the first to report a synthesis of pyridine that involved passing a mixture of acetylene and hydrogen cyanide through a hot tube.3 The now well-known Hantzsch synthesis appeared in 1882 (Scheme 1.1),4 and a vapour phase synthesis by Chichibabin in 1906.5 Me OH Me H Me 2 R. Murugan, Eric F. V. Scriven 1.3). Reduction of nitriles under various conditions offers a large range of products. 3. Oxidation of methyl groups to carbinols, aldehydes, and carboxylic acids (Scheme 1.4). Pyri- dine 3-carboxylic acid is not only an important product (niacin) in the vitamin business but it can also be converted to 2-chloropyridine-3-carboxylic acid an important intermediate for production of a number of pharmaceutical and agricultural products (Scheme 1.5). 2. VALUE CHAINS The reactions below have formed the basis for production of high-volume pyridine derivatives available commercially from the major pyridine producers or via other companies that buy pyridines, the methyl- and cyano-pyridines from the major pyridine producers. These reactions are: 1. Ammoxidation e vapour phase conversion of a methyl groups to nitriles (Eqn (1.3)). The main use of pyridine 3-carbonitrile is for production of niacinamide in a large scale commercial process that involves a controlled hydrolysis. NN NH3 / Air / 450oC V2O5 cat. Me CN Gas phase (1.3) 2. Reduction of nitriles to carbinols, aldehydes, and hydrolysis to amides, carboxylic acids (Scheme N NH3 N Me CH3CHO Me ++ Vap. phase Cat. 400-500oC (1.1) N NH3 N CH3 +OHC + Vap. phase Cat. 400-500oC + HCHO Me (1.2) The pyridine/3-picoline process is operated at greater volume driven largely by the demand for pyridine that is converted to the herbicide paraquat (demand 26,000 MTY) and the insecticide chlorpyrifos (35,000 MTY) obtained from 3-picoline in a multistep process, these volumes refer to sales in 2008. Worldwide, over 100 to 1000 tons of pyridine and products containing a pyridine ring are produced annually. The coproduct ratios in these processes can be varied to some extent by changes in feeds, operating conditions, and use of different catalysts to promote formation of one coproduct over the other. However, coproduct mixtures are always formed. Commercial success, therefore, also depends on response to demand for each of the coproducts and their downstream derivatives by low- cost synthetic routes based on best technology. Pyridine value-added chains based on the two major vapour phase coproduct reactions are illustrated (Figure 1.1). One important liquid phase reaction is operated commercially by Lonza and provides a significant source of niacin (Scheme 1.2).8 N N Me NN Me Me N NMe2 DMAP N N Me Me Paraquat N CCl3Cl Nitrapyrin (P) N ClCl Cl O P OS O Chlorpyrifos NCl Imidacloprid N NH N NO2 N N NCl Br HN O Cl Me O H N Me Chlorantraniliprole N NH2 N O + _ N H N N CN N COOH Polymers PVNO N H Ph PH OH Azacyclonol N CN N CONH2 N NH2 N COOH N Me N Me NH2 H2N + N Latex N ClCl Cl Cl 2Cl- + + Figure 1.1 Pyridine and picoline value-added chains. Introduction 3 N COOH N N COOH HOOCMe Me CH3CHO + NH3 HOAc (cat.) HNO3 -CO2 Scheme 1.2 Liquid phase pyridine synthesis. N N OH O NH2 N OH N NH2 O N H O N CN N N H N N NH R RNH2 Scheme 1.3 Catalytic reduction of pyridine nitriles. N N N N CH3 CH2OH CHO COOH 2-methylpyridine (2-picoline) 3-methylpyridine (3-picoline) 4-methylpyridine (4-picoline) Pyridine-2-carboxylic acid (Picolinic acid) Pyridine-3-carboxylic acid (Nicotinic acid) Pyridine-4-carboxylic acid (Isonicotinic acid) Scheme 1.4 Oxidation of methyl pyridines. 4 R. Murugan, Eric F. V. Scriven Introduction 5 N COOH N COOH N COOH O _ + H2O2 Cl POCl3 N CONMe2 S HN HN O N N OMe OMe O O N O N H O F F N NH CF3 OH O O MeNH Nicosulfuron Niflumic acid 4. Reduction of the pyridine ring to piperidines (Eqn (1.4)) or partially reduced pyridines. N N H H2 Cat. (1.4) 5. Ring aminations at the 2-position by treatment of various pyridines with sodamide (Eqn (1.5)), or at positions 3- and 4- by Hofmann reaction on the respective amide (Eqn (1.6)). NNN NaNH2 NaNH2 NH2 H2N NH2 (1.5) NNN NaOH, H2O NaOCl CN CONH2 NH2 NaOH (1.6) Diazonium salts, formed from pyridinamines, provide an important way to functionalise pyridine ring positions, comparable with benzene chemistry. This is exemplified by a step in the synthesis of CF3 N N N Diflufenican BI-RG-587 Scheme 1.5 Some medicinal and agricultural products based on 2-chloropyridine-3-carboxylic acid. Rynaxypyr (Scheme 1.6) (and also in a route to Imidacloprid, Section 1.3) that also includes a Hofmann rearrangement step.9 Now other options are available for synthesis of pyridines especially those based on cross-coupling reactions. These starting materials for these reactions usually depend on the availability of chloro- or bromo-pyridines (see Chapter 3). Several dichloropyridines are available as by-products from the Cl N N O Me Br Rynaxypyr Scheme 1.6 Synthesis of Rynaxypyr. 6 R. Murugan, Eric F. V. Scriven chlorpyrifos process (Scheme 1.7).10 N N ClCl2 N Cl OVap. Phase Cl Cl Cl N ClCl Cl OH NaOH Cl Cl PO N CONH2 NaOCl N NH2 Cl2 N NH2 Cl N ClNaNO2 HCl Cl N O NH Cl Me NH NaOH 2.1. Routes to 3,5-Dimethyl-4-Methoxy-2-Pyridylcarbinol The pyridine derivative, 3,5-dimethyl-4-methoxy-2-pyridylcarbinol, is an intermediate used to make Omeprazole, a proton pump acid inhibitor. Two approaches are shown (Scheme 1.8) one from 2,3,5- collidine and the other from 3,5-lutidine. The first three steps of each involve; N-oxidation, nitration, and replacement of the 4-nitro substituent by methoxide. In one case, the 2-hydroxymethyl group is installed by the reaction of 2,3,5-trimethyl-4-methoxypyridine N-oxide with acetic anhydride11 to form the 3,5-dimethyl-4-methoxy-2-acetoxymethylpyridine, which on hydrolysis gives the final OS Me Me Chlorpyrifos Scheme 1.7 Synthesis of Chlorpyrifos. Introduction 7 Ac2O MeMe OMe MeMe OMe N MeMe NO2 Me O + -NaOMe N MeMe Me 1. N-oxidation 2. Nitration 2-pyridylcarbinol product. In the other route, the intermediate 3,5-dimethyl-4-methoxypyridine N-oxide on methylation with dimethyl sulphate gave theN-methoxypyridinium salt which undergoes the Minisci reaction12 (radical substitution) to introduce the CH2OH group at the 2-positon with the elimination of theN-methoxy group. The second approach has proved more economical than the first approach.13 It should be noted that of these two approaches, treatment of N-oxide with Ac2O or Minisci reaction sometimes do not work as well for less substituted pyridine N-oxides, owing to lack of regiospecificity or low yields. N Me Minisci Rxn. Hyd. Me OMe OH N OAc N Me O + - N MeMe OMe OMe + MeOSO3- N MeMe OMe O + - Me2SO4 N MeMe 1. N-Oxidation 2. Nitration 3. NaOMe N Me Me OMe S N H N O MeO Omeprazole Scheme 1.8 Synthetic routes to Omeprazole. 3. STRATEGIC CONSIDERATIONS e RING SYNTHESIS VS SUBSTITUENT MANIPULATION When considering approaches to a target pyridine, it is important to identify a high-yield synthetic route based on the lowest cost readily available starting material which usually appears earliest in the value-added chains (Figure 1.1). Examples given of commercial routes (1 to 5 above) offer a further indication of availability of starting materials and technology involved. Then a comparison should be made of the pyridine-based route with costs of routes based on pyridine-ring synthesis from the cheapest building blocks available. It is interesting to make the above comparison for a specific case. A large volume insecticide Imidacloprid was developed by Bayer AG in the 1990s. Several synthetic routes to the key intermediate 2-chloro-5-methylpyridine, or the subsequent intermediate 2-chloro- 5-chloromethylpyridine were developed (Scheme 1.9). Three of these routes have been operated commercially. Two routes are based on 3-picoline, a first-generation pyridine, the lowest cost starting material. Initial work focused on chlorination of the N-oxide which always gave a mixture of 2- and 6-chlo- rination, and no way was found to change this to exclusively 6-chlorination.14 The Chichibabin amination of 3-picoline, similarly, favoured 2 over 6-substitution by 9:1. However, further work on this reaction proved more fruitful. It was observed that by running the amination under a high initial N CH3 NaNH2 H2O2Cat. N NH NNO2 8 R. Murugan, Eric F. V. Scriven N N NN Cl CCl3 CH3 CH3 Cl Cl Cl N CH3 O H2N + - N O H N CH3 O CH3 C6H5 POCl3 NaNO2/HCl DMF/POCl3Cl2 H2 Cat. Cl2 NCl Imidacloprid Scheme 1.9 Synthetic routes to Imidacloprid. ammonia pressure, the product ratio was switched in the desired direction to >4:1.15 Therefore, 2-amino-5-methylpyridine became the intermediate of choice for development of a manufacturing process. Conversion to 2-chloro-5-methylpyridine was achieved by a high-yield non-aqueous diazotisation followed by chlorination with gaseous HCl. A further high-yield chlorination at the 5-methyl group, using chlorine and sodium bicarbonate, afforded 2-chloro-5-chloromethylpyridine again in high yield.16 These two chlorinations would seem to have promise of extension for chlori- nation of related pyridines and other heterocycles. Two ring synthesis reactions have proved to be competitive with the above 3-picoline-based process. One involves a Vilsmeier cyclisation (Scheme 1.10)17 similar to some developed by Meth- Cohn.18 This process utilises benzylamine and the coproduct benzyl chloride is available for recycle (by conversion to benzylamine) or reuse in other ways. The third commercial process is based on reaction of acrolein with acrylonitrile; cyclopentadiene, which can be recycled, acts as a protecting group (Scheme 1.11).19 Another ring synthesis based on cis-pentenonitrile (a nylon by-product) has been claimed but it has never been operated commercially.20 O Me H Me Me Me N Me ClVilsmeierH Scheme 1.10 Formation of 2-chloro-5-methylpyridine by a Vilsmeier ring closure. O CN Introduction 9 H O H O H NC OHC CN OHC CN Cl Cl N Cl Cl + Base Heat Heat + Recycled Cl2HCl/PCl5 Scheme 1.11 Formation of 2-chloro-5-chloromethylpyridine from acrolein and acrylonitrile. H2N N + NaOH N O Cl + Ac2O Reaction DMF/POCl3 competitive differentiation, as it often does, depends on access to low cost raw materials and required 10 R. Murugan, Eric F. V. Scriven manufacturing technology available to the competitors rather than on just synthetic chemistry considerations. Patent protection of the lowest cost process can, of course, also be the key factor in competitive differentiation. It is hoped the consideration of value chains in the section and the above case study will prove helpful for those evaluating routes to pyridine intermediates. The application of directed ortho metallation and cross-coupling reactions have had a great influence on the best methods for synthesis of multiply substituted pyridines, particularly those of medicinal importance. Snieckus has combined in a one-pot reaction a directed ortho-metal- lationeboronation and a SuzukieMiyaura coupling of a pyridine derivative (Scheme 1.12).21 In another case, the same group combined a directed ortho metallation with a halogen dance.22 The 2-, 3-, and 4-pyridyl O-carbamates below were used to introduce electrophiles in high yields to give trisubstituted pyridines (Scheme 1.13). The electrophiles used included methanol, TMS, and iodine. 4. CHALLENGES AND NEEDS The comparative economics of the three commercial processes above is obviously very close and N CONEt2 N CONEt2 R2 R1 Br R2 R1 Na2CO3 / Pd(PPh3)4 (cat.) (i) 1. B(OiPr)3; 2. LDA; 3. Pinacol or diethanolamine; 4. concentrate R1 = H, OMe R2 = OMe, CN, H Toluene / reflux / 12 hN CONEt2 B OO(i) Scheme 1.12 One pot directed-ortho-metallation, Suzuki-Miyaura coupling. Most pyridines produced commercially are required for their bioactivity. Especially, the pharmaceutical industry has stringent specifications for products, and the requirement that late-stage intermediates and final products are manufactured by FDA approved processes in FDA regulated equipment. All chemical processes developed today need to be not only lowest cost but also sustainable. This presents a challenge particularly to process development chemists. Process development techniques have become very specialised. They are not dealt with in this book as they have been well covered in a recent book.23 Some of the successful methods used to develop the best processes for a series of products, including many pyridines continue to appear in Organic Process Research and Development. The above consider- ations among others have led to the study especially of catalytic reactions with a great deal of intensity and success.24 This has resulted in several new reactions in pyridine chemistry that involve specific CeH activation and have the advantage of eliminating several steps, for example, halogenation and formation of a boronic ester before palladium cross coupling. A direct arylation of 2-picoline by rhodium-catalysed CeH activation is a case in point (Eqn (1.7)).25 N N Br + (i) 6 : 1 (i) [RhCl(CO)2]2 (0.05 eq), dioxane, 175-190oC, 24 h 53% (1.7 An interesting iron-catalysed oxidation that employs oxygen allows preferential oxidation at the benzylic CH2 rather than at the methyl group, in contrast copper-catalysed oxidation results in oxidation of both substituents (Eqn (1.8)).26 It should be noted that the temperature at which these oxidations are run can have a big influence on the nature of the products formed. N NR (i) (i) AcOH (1 eq) cat (10 mol %), O2, DMSO, 130oC, 24 h O FeCl2.4H2O R = CH3 yield 85% CuI R = CHO yield 62% (1.8 Introduction 11 N E N I OCONEt2 I OCONEt2 E = H, CONEt2, Cl, I E = TMS, CONEt2, Cl, I Scheme 1.13 Synthesis of trisubstituted pyridines by directed-ortho-metallation and halogen dance. N OCONEt2 N OCONEt2 N I N E OCON(iPr)2 OCON(iPr)2 I I E I E = D, Et, Cl, I ) ) Arylation of pyridine 2-benzylic amines using arylboronates has been achieved with ruthenium (1.9) 12 R. Murugan, Eric F. V. Scriven The chemical processes (outlined in 1.2) and recently reported reactions (1.4), e.g. DoM,29 cross- coupling,30 and CeH bond activation,31 combined with the availability of modern flow reactor technology32 offer synthetic chemists the advantage of easier scale up from laboratory to plant and safer handling of energetic intermediates, e.g. in nitrations and Hofmann rearrangements. Progress in pyridine chemistry over 150 years has been reviewed in a comprehensive manner.33 Several other works deal with aspects of synthetic pyridine chemistry old34,35 and new.36 REFERENCES 1. Anderson, T. Liebigs Ann. 1846, 60, 86. 2. Anderson, T. Liebigs Ann. 1851, 80, 44. 3. Ramsey, W. Ber. 1877, 10, 736. 4. Hantzsch, A. Liebigs Ann. 1882, 215, 72. 5. Chichibabin, A. E. Russ. J. Phys. Chem. 1905, 37, 1229. 6. Cislak, F. E.; Wheeler, W. R. US Patent 2,744,904. 1956. 7. Calvin, J. R.; Davis, R. D.; McAteer, C. H. Appl. Catal. 2004, 1. The move away from high cost toxic heavy metals to the use of base metals as alternative catalysts is illustrated by the copper-catalysed amidation of 2-phenylpyridine. Moderate to good yields have been obtained (Eqn (1.10)).28 N N TosHN (i) + Tos NH2 (0.35 mmol) (0.70 mmol) O2 Cu(OAc)2 (0.07 mmol) 20 mol% (i) Anisole (ca. 2mL), DMSO (2.5 mol%), 160oC, 48h (1.10) Conditions: Pinacolone (8 eq), 140oC, 24-36h R Me Yield % (Conversion %) 64 86 Ph 90 100 (0)- sp3 CeH bond activation, however a sterically demanding 3-substituent (methyl or phenyl) is critical for attaining high yields (Eqn (1.9)).27 N OO B N NH R NH Ph H Ph R Ph Ph + Ru3(CO)12 5 mol % 8. Stocker, A.; Marti, O.; Pfammatter, T.; Schreiner, G.; Brander, S. German Patent 2,046,556 and British Patent GB 1,276,776. 1971. 9. Shapiro, R. US Patent Appl. 2007/0161797. 10. Muller, K. Agrochemicals: Composition, Production, Toxicology, Applications; Wiley-VCH: Toronto, 2000; 541. 11. Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286. 12. Minisci, F.; Fontanna, F.; Serri, A.; Baima, R. US Patent 5,763,624. 1988. 13. Brandstrom, A. E.; Lamm, B. R. US Patent 4,544,750. 1985. 14. Gallenkamp, B.; Knops, H. US Patent 4,897,488. 1990. 15. McGill, C. K.; Sutor, J. J. US Patent 4,386,209. 1983. Lawin, P. B.; Sherman, A. R.; Grendze, M. P. US Patent 5,808,081. 1998. 16. Gunther, A. US Patent 5,198,549. 1993. 17. Jelich, K.; Lindel, H.; Mannheims, C.; Lantzsch, R.; Merz, W. US Patent 5,648,495. 1997. 18. Meth-Cohn, O.; Westwood, K. T. J. Chem. Soc. Perkin Trans. 1984, 1, 1173. 19. Zhang, T. Y.; Scriven, E. F. V. US Patent 5,229,519. 1993. 20. Murugan, R.; Scriven, E. F. V.; Zhang, T. Y. US Patent 5,508,410. 1996. 21. Alessi, M.; Larkin, A. L.; Ogilvie, K. A.; Green, L. A.; Lai, S.; Lopez, S.; Snieckus, V. J. Org. Chem. 2007, 72, 1588. Introduction 13 22. Miller, R. E.; Rantanen, T.; Ogilvie, K. A.; Groth, U.; Snieckus, V. Org. Lett. 2010, 12, 2198. 23. Anderson, L. G. Practical Process Research and Development, 2nd ed.; Elsevier: Amsterdam, 2012. 24. Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Senanayake, C. H. Adv. Synth. Catal. 2011, 353, 1825. 25. Berman, A. M.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2010, 75, 7863. 26. De Houwer, J.; Tehrani, K. A.; Maes, B. U. W. Angew. Chem. Int. Ed. 2012, 51, 2745. 27. Dastbaravardeh, N.; Schnuerch, M.; Mihovilovic, M. D. Org. Lett. 2012, 14, 1930. 28. John, A.; Nicholas, K. M. J. Org. Chem. 2011, 76, 4158. 29. Snieckus, V. Chem. Rev. 1990, 90, 879. 30. Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. 31. Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. 32. Wiles, C.; Watts, P. Micro Reaction Technology in Organic Synthesis; CRC Press: Boca Raton, 2011. 33. Boulton, A. J.; McKillop, A. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds. Comprehensive Heterocyclic Chemistry; Pergamon: Oxford, 1984; Vol. 2; Boulton, A. J. Vol. Ed.; Comprehensive Heterocyclic Chemistry II, Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds.; Pergamon: Oxford, 1996; Vol. 6. Black, D. St.C. Vol. Ed.; Comprehensive Heterocyclic Chemistry III, Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. Eds. Elsevier: Oxford, 2008; Vol. 7. 34. Meier-Bode, H.; Altpeter, J. Das Pyridin und seine Derivate in Wissenschaft und Technik; Wilhelm Knapp: Halle, 1934; Ferles, M.; Jizba, J. Chemie Pyridinu, Ceskoslovenske Akademie Ved: Praha, 1955. 35. Pyridine and Its Derivatives; Klingsberg, E., Ed.; Interscience: New York, 1960; Abramovitch, R. A., Ed., Pyridine and Its Derivatives, Wiley: New York, 1974. Newkome, G. R., Ed., Pyridine and Its Derivatives, Interscience: New York, 1984. 36. Pyridines, Science of Synthesis; Black, D. StC, Ed.; Thieme: Stuttgart, 2005. 1. Introduction 1. Introduction 2. Value Chains 2.1. Routes to 3,5-Dimethyl-4-Methoxy-2-Pyridylcarbinol 3. Strategic Considerations – Ring Synthesis Vs Substituent Manipulation 4. Challenges and Needs References