On-demand Generation and Consumption of Diazomethane in

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE

On-demand Generation and Consumption of Diazomethane in Multistep Continuous Flow Systems Hongwei Yang, Benjamin Martin, and Berthold Schenkel Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00302 • Publication Date (Web): 26 Mar 2018 Downloaded from http://pubs.acs.org on March 26, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Organic Process Research & Development

On-demand Generation and Consumption of Diazomethane in Multistep Continuous Flow Systems Hongwei Yanga*, Benjamin Martinb, Berthold Schenkelb a Chemical and Analytical Development, Suzhou Novartis Pharma Technology Company Limited, 18 Tonglian Road, Changshu, Jiangsu, China. b Novartis Pharma AG, Chemical and Analytical Development, Fabrikstrasse, 4002 Basel, Switzerland. * Corresponding author. Tel.: +86 512 5225 6829; fax: +86 512 5225 6912. E-mail address: [email protected] (Hongwei Yang).

1 ACS Paragon Plus Environment

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 30

Table of contents


Page 3 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Abstract: Diazomethane is an exceptionally versatile C1 building block in organic synthesis. However, reactions involving the use of diazomethane impose significant challenges for safe scale-up. This review aims to highlight the recent developments on the processes and equipment concepts for the generation and consumption of diazomethane in continuous mode. We focus specifically on the continuous processes and equipment solutions that have, either individually or together, enabled the entire sequence consisting of synthesis of the diazomethane precursor, subsequent generation and purification of diazomethane, and the downstream reaction to achieve the target product. The discussions are performed mainly from an industrial perspective, and the processes are categorized by the capability to generate the specific forms of diazomethane: as a neat gas; gas-diluted; or in organic solution. Lab processes and pilot processes are reviewed separately to demonstrate the options available to process diazomethane on different scales.

Keywords. Diazomethane; Diazomethane precursor; Flow reactor; Continuous manufacturing; Process Analytical Technology; Scale-up



Page 4 of 30

1. Introduction Diazomethane is one of the most versatile reagents for constructing carbon-carbon and carbon-heteroatom bonds in synthetic organic chemistry, as shown in Scheme 1.1, 2 The most well-known example is the conversion of carboxylic acids into the corresponding methyl esters. Diazomethane is also a strong methylating reagent for phenols, enols and other C-N or C-S nucleophiles. Beyond this it is applied in the synthesis of diazo ketones, the homologation

of

ketones

and

carboxylic

acids

(Arndt-Eistert

reaction),

transition

metal-catalyzed

cyclopropanations, and as a 1,3-dipole in [3+2] cycloadditions to generate N-heterocycles.

Scheme 1 Synthetic applications of diazomethane.1,2 In addition, the reactions involving diazomethane show good atomic efficiency due to its low molecular weight and the formation of nitrogen as the sole by-product. However, the disparity between utility and marginal application especially in industry is in large part due to the associated hazards of diazomethane. Similar to many strong alkylation agents, diazomethane is a potent carcinogen and is extremely poisonous, Table 1. The severe acute and chronic toxicity is especially problematic because of its low boiling point (bp = -23 °C). The OSHA PEL (Occupational Safety and Health Administration Permissible Exposure Level) for a timeweighted average concentration (TWA) for diazomethane is 0.2 ppm (0.4 mg/m³),3 which makes exposure control very challenging. Furthermore, in both gaseous and liquid form, it is exceedingly sensitive to detonation via heat, shock and light,4 and thus diazomethane is virtually exclusively used as a solution in diethyl ether or a diluted


Page 5 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


mixture in an inert gas. As a result, safe generation and handling of diazomethane in batch-mode is difficult and requires specific safety precautions and dedicated equipment even at lab scale. The commercialized kit for diazomethane preparation employs the co-distillation of in-situ generated diazomethane with anhydrous diethyl ether, and the condensation into a dry ice filled cold-finger condenser leading to the formation of up to 100 mmol ethereal solution of anhydrous diazomethane. 1,5 OSHA PEL (10 hour timeweighted average) Boiling point Relative vapor density (air = 1) Relative liquid density (water = 1) Auto-ignition temperature: (explosion) Lower explosion limit (LEL) in nitrogen Lower explosion limit (LEL) in air

0.2 ppm (0.4 mg/m³) –23 °C 1.4 1.5 100 °C 3.9 % (v/v) 14.7 % (v/v)

Table 1 Safety-related properties of diazomethane.3, 6 To take full advantage of the versatility of diazomethane on scale, innovative processes are needed that provide improvement in both the yield of the reagent and the production throughput, without increasing the risk of exposure and injury to plant operators. It is therefore not surprising that much attention has been focused on developing safe and sustainable methods.2,7,8 When the synthesis of hazardous reagents is contemplated, it would be highly desirable to have a continuous reaction system that encompasses the whole life-cycle of the toxic and explosive material. An optimal scenario is in-situ generation from benign starting materials followed by separation and immediate consumption in the formation of the desired product.9 Continuous manufacturing, both in the academic and industrial chemical sectors, is becoming popular for enabling chemical reactions that were previously referred to as forbidden.10 Overall, flow equipment is regarded as a safer alternative compared to the batch counterpart. These types of reactors demonstrate a high surface-to-volume ratio and short diffusion path, which results in high heat transfer and mixing efficiency. In particular the superior control over heat transfer makes possible chemical pathways that would typically be considered too dangerous to pursue using standard techniques. Relevant to highly toxic and explosive compounds, the total volume of material being processed at any time is drastically reduced; therefore the safety of the process is significantly increased. In



Page 6 of 30

case the hazardous reagents are gaseous (e.g. ozone, hydrazoic acid, diazomethane), the lack of head space under flow conditions eliminates the risk of forming an explosive atmosphere. Furthermore, advances in continuous separation technology and on-line analytical technology have allowed the integration of all unit operations of a multi-step synthesis into a fully continuous and closed sequence under automatic control. 11,12 One of the key benefits of such an automated system is that the human operator has less risk of exposure to the toxic components.13 There are several review articles available on the generation and application of diazomethane from a chemistry perspective.1,2,8,10e,14 In this review, we focus specifically on the continuous processes and equipment solutions that have, either individually or together, enabled the entire sequence consisting of synthesis of the diazomethane precursor, subsequent generation and purification of diazomethane, and the downstream reaction to achieve the target product. Pros and cons for individual processes and equipment concepts have will be discussed with a view to industrial applications.

2. Typical Precursors for generating diazomethane The intrinsic hazard of diazomethane imposes significant risk during its storage and transport, thus diazomethane is exclusively generated by treating various N-methyl-N-nitrosoamines derivatives with a strong base.1 Even though a wide variety of compounds can serve as the diazomethane precursors, the majority of the reports in the fields are only focused on three compounds due to availability and shelf-life. A comparison of safety-related properties for these compounds is shown in Table 2, with structures shown in Scheme 2. The lower molecular weight precursors typically show good atom efficiency, with N-nitroso-N-methylurea (NMU) being the first choice in this regard. Additionally its fast conversion to diazomethane at a low temperature makes it ideally suited for the continuous processes for which the formed diazomethane is finally extracted into organic solution. However this molecule is itself unstable at temperatures above 20 °C, and highly toxic methyl isocyanate is one of the decomposition products.6 In addition, NMU is classified as a carcinogen,15 mutagen, and teratogen,16 and mediates its toxicity by transferring a methyl group to nucleobases in nucleic acids. As a result, NMU is scarcely available from chemical suppliers in quantities above 10 kg.17


Page 7 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Similarly, N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) is toxic, and has been classified as a severe irritant, a carcinogen, and a potent mutagen. Due to the toxicity concerns, the use of MNNG has historically been limited to small-scale production of diazomethane (approximately 1 mmol) even though it demonstrates a long shelf life (for years) and needs only a low temperature for the liberation of diazomethane.1,17 As an alternative, N-methyl-N-nitroso-para-toluenesulfonamide (Diazald®) shows better thermal stability and less toxicity compared to NMU and MNNG, and has been applied as the precursor of diazomethane in commercial manufacturing processes.6 However, the conversion of Diazald® to diazomethane typically needs a higher temperature than NMU and MNNG, which is an issue considering the decrease of diazomethane solubility with the increase of temperature. Diazald® has therefore predominantly been used as the precursor in cases where the formed diazomethane is processed as a gas in the following operation.2

On-set temperature for decomposition Carcinogenic No Significant Risk Level (NSRL) Reaction temperature to form diazomethane Cost based on the available sources in SciFinder

NMU ~20 °C 0.006 µg/day

MNNG ”commercial sources” ; b) Based on a search in SciFinder with the following criteria: Substance Identifier " CAS 70-25-7">”substances” >”commercial sources” ; c) Based on a search in SciFinder with the following criteria: Substance Identifier " CAS 80-11-5">”substances” >”commercial sources”. 18 https://oehha.ca.gov/chemicals/n-nitroso-n-methylurea. 19 HYPERLINK "https://oehha.ca.gov/chemicals/n-methyl-n-nitro-n-nitrosoguanidine" https://oehha.ca.gov/chemicals/n-methyl-n-nitro-n-nitrosoguanidine”. 20 Arndt, F. Organic Syntheses; Wiley: New York, 1943; Collect. Vol. II, p 461. 21 Archibald, T. G. Continuous Process for Diazomethane from an N-Methyl-N-nitrosoamine and from Methylurea through N-Methyl-N-nitrosourea. (Aerojet-General Corporation). U.S. Patent 5854405, 1998. 22 Lehmann, H. Green Chem. 2017, 19, 1449. 23 Poechlauer, P.; Reintjens, R. W. E. G.; Dielemans, H. J. A.; Thathagar, M.; Konings, J. H. G. Continuous production and reaction of a diazo compound. (DSM group). U.S. Patent 2014/0100360 A1, 2014. 24 Von Pechman, H. Chem. Ber. 1894, 27, 188. 25 Ferstl, W. F.; Schwarzer, M. S.; Loebbecke, S. L. Chemie Ingenieur Technik 2004, 76, 132. 26 Struempel, M.; Ondruschka, B.; Daute, R.; Stark, A. Green Chem. 2008, 10, 41 27 Rossi, E.; Woehl, P.; Maggini, M. Org. Process Res. Dev. 2012, 16, 1146 28 de Boer, T. H. J. ; Backer, H. J. ; Recueil des Travaux Chimiques des Pays-Bas 1954, 73, 229 29 Carlson E.; Duret G.; Blanchard N.; Tam W. Synth. Commun. 2016, 46, 55. 30 Hong H.; Tao J.; Guo X.; Jiao J. Reactor for continuous safe mass production of diazomethane and its working method.(Asymchem Laboratories (Tianjin) Co., Ltd.). CN patent CN 101844063, 2010. 2



Page 30 of 30

31

a) Roda, N. M. ; Tran, D. N. ; Battilocchio, C. ; Labes, R. ; Ingham, R. J. ; Hawkins, J. M. ; Ley, S. V. Org. Biomol. Chem. 2015, 13, 2550. b) Kralj, J. G.; Sahoo, H. R.; Jensen, K. F. Lab Chip 2007, 7, 256. c) Cervera-Padrell, A. E.; Morthensen, S. T.; Lewandowski, D. J., Skovby T., Kiil S., Gernaey K. V. Org. Process Res. Dev. 2012, 16, 888. d) Nord, L.; Karlberg, B. Anal. Chim. Acta 1980, 118, 285. e) Joensson J. A.; Mathiasson L. J. Chromatogr. A 2000, 902, 205. f) Cai Z.; Fang Q.; Chen H.; Fang Z. Anal. Chim. Acta 2006, 556, 151. g) Yang L.; Jensen K. F. Org. Process Res. Dev. 2013, 17, 927. 32 Maurya, R. M.; Park, C. P.; Lee, L. H.; Kim, D.-P. Angew. Chem., Int. Ed. 2011, 50, 5952. 33 Mastronardi, F., Gutmann, B., and Kappe, C. O. Org. Lett. 2013, 15, 559. 34 Pinho V. D., Gutmann B., Miranda L. S. M., de Souza R. O. M. A., Kappe C. O. J. Org. Chem. 2014, 79, 155. 35 Dallinger D., Pinho V. D., Gutmann B., Kappe C. O. J. Org. Chem. 2016, 81, 5814. 36 Resnick R. P. R. Polymers of fluorinated dioxoles.( E. I. Du Pont de Nemours and Company). U.S. Patent 3978030, 1976. 37 Pinnau, I.; Toy, L. G. J. Membr. Sci. 1996, 109, 125. 38 O’Brien, M., Baxendale, I., Ley, S. V. Org. Lett. 2010, 12, 1596. 39 Petersen, T. P.; Polyzos, A.; O’Brien, M.; Baxendale, I. R.; Ley, S. V. ChemSusChem 2012, 5, 27. 40 Bourne, S. L.; Koos, P.; O’Brien, M.; Martin, B.; Schenkel, B.; Baxendale, I. R.; Ley, S. V. Synlett 2011, 18, 264. 41 Polyzos, A.; O’Brien, M.; Petersen, T. P.; Baxendale, I. R.; Ley, S. V. Angew. Chem., Int. Ed. 2011, 50, 119. 42 Brzozowski, M.; O’Brien, M., Ley S. V.; Polyzos, A. Acc. Chem. Res. 2015, 48, 34. 43 Dallinger, D.; Kappe, C. O. Nat. Protoc. 2017, 12, 2138. 44 Martin, L. J.; Marzinzik, A. L.; Ley, S. V.; Baxendale, I. R. Org. Lett. 2011, 13, 320. 45 Flow Liquid Liquid Extraction machine, available from Syrris, http://www.syrris.com. 46 Poechlauer, P.; Braune, S.; Dielemans, B.; Kaptein, B.; Obermüller, R.; Thathagar, M. Chim. Oggi/Chem. Today 2012, 30, 51. 47 Britton, J.; Jamison, T. F. Nat. Protoc. 2017, 12, 2423. 48 Hu, D. X.; O’Brien, M.; Ley, S. V. Org. Lett. 2012, 12, 4246. 49 Cervera-Padrell, A. E.; Morthensen, S. T.; Lewandowski, D. J.; Skovby, T.; Kiil S.; Gernaey, K. V. Org. Process Res. Dev. 2012, 16, 888. 50 Moore, C. B.; Pimentel, G. C. J. Chem. Phys. 1964, 40, 32. 51 Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Wittkamp, B.; Goode, J. G.; Gaunt, N. L. Org. Process Res. Dev. 2010, 14, 39. 52 Roda, N. M.; Tran, D. N.; Battilocchio, C.; Labes, R.; Ingham, R. J.; Hawkins, J. M.; Ley, S. V. Org. Biomol. Chem. 2015, 13, 2550. 53 Archibald, T.G.; Huang, D.-S.; Pratton, M. H.; Barnard, J. C. Large scale batch process for diazomethane.(AerojetGeneral Corporation). EU patent EP0916649 A1, 1998. 54 Archibald, T. G. Chim. Oggi/Chem. Today 2000, 18, 34. 55 Warr A. J.; Proctor M., Process for the preparation of diazomethane.(Phoenix Chemicals Limited). U.S. patent US6962983B2, 2005. 56 Website of Asymchem Laboratorie Inc. http://www.asymchem.com/en/tech.aspx?cid=21. 57 Website of Zaiput Flow Technologies. http://www.zaiput.com/?q=liquid-liquid-separators.


On-demand Generation and Consumption of Diazomethane in

Recommend Documents