Review pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
On-Demand Generation and Consumption of Diazomethane in Multistep Continuous Flow Systems Hongwei Yang,*,† Benjamin Martin,‡ and Berthold Schenkel‡ †
Chemical and Analytical Development, Suzhou Novartis Pharma Technology Company Limited, 18 Tonglian Road, Changshu, Jiangsu 215537, China ‡ Chemical and Analytical Development, Novartis Pharma AG, Fabrikstrasse, 4002 Basel, Switzerland 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 in 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 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.
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
In addition, the reactions involving diazomethane show good atomic efficiency due to its low molecular weight and the formation of nitrogen as the sole byproduct. 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
Scheme 1. Synthetic Applications of Diazomethane1,2
Table 1. Safety-Related Properties of Diazomethane3,6 OSHA PEL (10 h time-weighted average) boiling point relative vapor density (air = 1) relative liquid density (water = 1) autoignition temperature (explosion) lower explosion limit (LEL) in nitrogen LEL in air
severe acute and chronic toxicity is especially problematic because of its low boiling point (bp = −23 °C). The Occupational Safety and Health Administration permissible exposure level (OSHA PEL) for a time-weighted average concentration (TWA) for diazomethane is 0.2 ppm (0.4 mg/ m3),3 which makes exposure control very challenging. Furthermore, in both the gaseous and liquid forms 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 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 codistillation of in
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 and C−S nucleophiles. Beyond this, it is applied in the synthesis of diazo ketones, the homologation of ketones and carboxylic acids (Arndt−Eistert reaction), and transition-metalcatalyzed cyclopropanations and as a 1,3-dipole in [3 + 2] cycloadditions to generate N-heterocycles. © XXXX American Chemical Society
0.2 ppm (0.4 mg/m3) −23 °C 1.4 1.5 100 °C 3.9% v/v 14.7% v/v
Received: September 25, 2017 Published: March 26, 2018 A
DOI: 10.1021/acs.oprd.7b00302 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Review
situ-generated diazomethane with anhydrous diethyl ether and condensation into a dry ice-filled cold-finger condenser, leading to the formation of up to 100 mmol of ethereal solution of anhydrous diazomethane.1,5 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, in both the academic and industrial chemical sectors, is becoming popular for enabling chemical reactions that were previously classified as forbidden.10 Overall, flow equipment is regarded as a safer alternative compared with 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 the case that the hazardous reagents are gaseous (e.g., ozone, hydrazoic acid, diazomethane), the lack of headspace 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 multistep 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 Several review articles on the generation and application of diazomethane from a chemistry perspective are available.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 are discussed with a view to industrial applications.
Table 2. Comparison of Different Diazomethane Precursors17−20 NMU onset temperature for decomposition carcinogenic no significant risk level (NSRL) reaction temperature to form diazomethane cost based on the available sources in SciFinder
MNNG
Diazald
∼20 °C
“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) https://oehha.ca.gov/chemicals/n-methyl-n-nitro-nnitrosoguanidine. (20) Arndt, F. Organic Syntheses; Wiley: New York, 1943; Collect. Vol. II, p 461. (21) Archibald, T. G. (Aerojet-General Corporation). Continuous Process for Diazomethane from an N-Methyl-N-nitrosoamine and from Methylurea through N-Methyl-N-nitrosourea. U.S. Patent 5,854,405, 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. (DSM group). Continuous production and reaction of a diazo compound. U.S. Patent 2014/ 0100360 A1, 2014. (24) von Pechman, H. Ber. Dtsch. Chem. Ges. 1894, 27, 1888. (25) Ferstl, W. F.; Schwarzer, M. S.; Loebbecke, S. L. Chem. Ing. Tech. 2004, 76, 1326. K
DOI: 10.1021/acs.oprd.7b00302 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
