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Home , Cyclopentyl methyl ether, Tetrahydrofuran

sustainability / green chemistry Industry perspective

Shunji Sakamoto Contribution of Cyclopentyl Methyl (CPME) to Green Chemistry

Shunji sakamoto Specialty Chemicals Division, ZEON CORPORATION, 1-6-2 Marunouchi, Chiyoda-ku, Tokyo, 1008246, Japan

easy peroxide formation and water miscibility, the demand KEYWORDS for CPME has steadily been growing in the pharmaceutical , CPME, Green Chemistry, industry as well as in the electronic and fragrance , process, ICH. industries. Also, CPME has been registered or listed in the corresponding legislations for new chemical substances of United States of America, Canada, European Union, ABSTRACT Japan, South Korea, China and Chinese Taipei, and is commercially available in these countries and regions as Cyclopentyl methyl ether (CPME) is an alternative well as others including India. solvent and has preferable properties including higher In this article, I answer the question why CPME is “Green” hydrophobicity, lower formation of peroxides and better even though it is derived from petroleum. stability under acidic and basic conditions compared to other traditional ether such as . Due to the above unique properties, CPME has particular UNIQUE FEATURES OF CPME 24 advantages and renders some conventional reaction sequences in one pot or easier process as a result of CPME is an asymmetric aliphatic ether having a cyclopentyl solvent unification and facile isolation of the products, group. It has seven unique features attributed to its structure which contribute to Green Chemistry as well as to (Table 1). process innovation. CPME meets eight definitions out of the 12 Principles of Green Chemistry (1) because of Extremely lower miscibility with water the above characteristics as well as its manufacturing The solubility of CPME in water is only 1.1% and that of water process and its applications. in CPME is also only 0.3% (23°C) (2), which gives a very clear separation of organic and water phases and an easy recovery. This immiscibility with water of CPME allows its use as a reaction solvent and extraction solvent as well as a crystallization solvent. INTRODUCTION Lower formation of peroxides n the recent process chemistry for pharmaceutical and The formation of peroxides in CPME is much lower and slower other fine chemical industries, scientists’ demand for than that of other such as MeTHF, IPE and THF (Figure 1). Igreener solvents has been increasing day by day. In view of the circumstances, typical ether solvents, such as tetrahydrofuran (THF), 2-methyl tetrahydrofuran (MeTHF), Diisopropylether (IPE), 1,4-dioxane and methyl t-butyl ether (MTBE), have some inherent properties which are incompatible with Green Chemistry. For example, THF easily forms explosive peroxides (2) and is difficult to recover because of its infinite miscibility with water. MeTHF is the unrivaled replacement for THF because of its high solvency and low miscibility with water as well as renewability (3). However, it generates more peroxides than THF (Figure 1) and is still soluble in water at 14 wt% (20°C) (3). In November, 2005, Cyclopentyl methyl ether (CPME) was commercialized by ZEON CORPORATION with its unique C5 feedstock and synthetic technologies. CPME has been found to be an alternative solvent and has many preferable characteristics for Green Figure 1. Peroxide formation of ethereal solvents Chemistry. Because it is free of drawbacks including

Chimica Oggi - Chemistry Today - vol. 31(6) November/December 2013 sustainability / green chemistry

Table 1. Physical properties of CPME and other ethers

Higher stability under acidic conditions Safer solvents and auxiliaries CPME is more stable to acids than THF and MTBE, ZEON’s production process of CPME is one-step continuous thus it is an excellent alternative solvent for solution system which reduces auxiliaries. of gaseous HCl. Design for energy efficiency Higher and lower Shorter and simpler organic processes with CPME require less The boiling point of CPME is 106°C and the melting point is energy over all. lower than -140°C (2). This wider-temperature liquid range allows its uses from low to high temperature reactions and as a Reduce derivatives crystallization solvent. The simple addition of to without By raising temperature up to the boiling point, rates of reaction protection and deprotection of ZEON’s production process of can be increased. CPME avoids unnecessary derivatization.

Lower latent heat of vaporization Catalysis CPME has lower latent heat of vaporization than the other The above reaction utilizes a solid acid catalyst. 25 solvents in spite of its higher boiling point (2), which contributes to energy saving. Real-time analysis for pollution prevention The flow reaction process used in the preparation of CPME is Higher efficiency for azeotropic dehydration continuously monitored. CPME makes an with water in a composition of 83.7% of CPME and 16.3% of water at 83°C (2), which enables easy Safer chemistry for accident prevention elimination of water by azeotropic . The formation of peroxides in CPME is much lower and slower than for most of other ether solvents. Medium polarity Because of its polarity, CPME can be used not only as a reaction solvent and an extraction solvent but also as a crystallization REDUCTION OF EMMISIONS solvent in suitable organic processes. Because of higher hydrophobicity and higher boiling point, Lower solubility of salt in CPME CPME can be used not only as a reaction solvent but also as Most salts are difficult to dissolve in CPME. Consequently, an extraction solvent and a crystallization solvent. This means crystalline product precipitates in CPME and is easily separated that additional extraction solvents could be unnecessary from the reaction mixture. for processes using CPME. The unique properties of CPME also give high recovery rate of more than 90%. As a result, plural solvents could be unified to only CPME, and also total THE 12 PRINCIPLES OF GREEN CHEMISTRY amount of solvents used could be reduced. We compare the amount of waste and CO2 emissions in the CPME meets eight definitions out of the widely recognized 12 same model organic process with CPME and THF as a reaction Principles of Green Chemistry, as set out by Paul Anastas and John Warner (1).

Prevention CPME allows significant reduction of water and solvent waste

Atom economy ZEON’s production process of CPME is 100 % atom economical. Total molecular weight of starting materials of cyclopentene and methanol is exactly the same as that Figure 2. Zeon’s Production Process of CPME of CPME (Figure 2).

Chimica Oggi - Chemistry Today - vol. 31(6) November/December 2013 sustainability / green chemistry

slow and limited. For further safety reasons, however, we supply CPME with about 50ppm of (BHT) as a stabilizer, while the commercially available THF usually contains 250ppm of BHT. In case of recovery of CPME by distillation, recharge of BHT to an appropriate percentage is recommended.

TOXICITY

ICH Q3C(R5) (4) is one of the most important guidelines for residual solvents in pharmaceutical chemical process developments, which is now not just a guideline for the tripartite regions (European Union, Japan and United States of America), but also the de facto standard for solvent selection in the world’s pharmaceutical industry. However, CPME is not classified nor does it have recommended human permitted exposure (PDE) within the guideline. This creates a barrier for chemists to use CPME more actively, though it has been begun to be used Figure 3. Calculation of waste and CO emissions 2 in commercial production of several pharmaceuticals. Under this situation, Jeremy P. Scott et al. reported the PDE solvent. In case of the process using THF as a reaction solvent, of 7.4 mg/day for CPME based on their three month repeat- ethyl acetate is additionally necessary for extraction, and much dose toxicity studies in rats as well as a battery of test to waste solvent is generated. On the other hand, CPME reduces asses induction of micronuclei, microbial mutagenicity, and waste solvents because of its high recovery rate from high chromosomal aberrations conducted under GLP (5). hydrophobicity and no necessity for an additional extraction In addition, Kiyoshi Watanabe reported the PDE of 1.5 mg/day solvent. This means that CO2 emission from the process of CPME for the same according to their repeated dose 28-day oral is much less than that of THF according to our calculation from toxicity study in rats. Judging from the result, CPME was incineration of waste solvents in each case (Figure 3). presumed to be classified in Class 2 of ICH Q3C. As also reported, CPME has low acute or sub-chronic toxicity with moderate irritation and negative mutagenicity and skin FORMATION OF PEROXIDES sensitization (Local Lymph Node Assay) (6).

Safety concerns for ether solvent usually stem from its explosive 26 nature arising from formation of peroxides. As shown in Figure IMPROVED PINNER REACTION 1, in the presence of air in a dark place at room temperature without stabilizer, in MeTHF, IPE and THF, there was observed Figure 4 shows “Improved Pinner Reaction” as an example a quick formation of peroxides, while that from CPME is quite of contribution to Green Chemistry (7). The requirements for the solvent of the process are stability to acid, solvency of raw material and insolvency of product. In this case, 4M-HCl in CPME is used because it is stable to gaseous HCl. The raw materials, nitrile and methanol are soluble in CPME. After reaction, white crystalline product is precipitated because it is not soluble in CPME. The product is easily isolated just by filtration and washing. The original process, which consists of 9 steps, is not recommended for scalable preparation of Pinner products, which are often sensitive to moisture and prone to decomposition. The quick work-up sequence with CPME is thus very valuable in handling such sensitive products. CPME obviously shorten and simplify the original process with diethylether and 1,4-dioxane. As a result, CPME contributes to Green Chemistry due to Figure 4. Improved Pinner Reaction reduction of the total amount

Chimica Oggi - Chemistry Today - vol. 31(6) November/December 2013 of solvent used, waste disposal and energy. CPME also contributes Integrated Chemical and to process innovation and allows both fixed and variable cost reductions. Analytical Development Services COMMERCIALLY AVAILABLE CPME REAGENTS

Prepared CPME reagents are convenient for chemists especially in Navigate your API to success laboratory use. Several companies such as Watanabe Chemical Industries, Ltd., Kokusan Chemical Co., Ltd., Sigma-Aldrich and Tokyo Chemical Industries, Co., Ltd. have commercialized gaseous HCl in CPME solution. Traditionally, the solution has been supplied in many kinds of solvents such as THF, 1,4-dioxane, etc. In case of such solvents, chemists have to take care about peroxides in THF, and about toxicity for 1,4-dioxane. On the other hand, CPME generates less peroxides and is less toxic. As a consequence, HCl solution in CPME has been recognized as a very useful reagent for deprotection of the Boc group, chlorination with easier precipitation. As for basic reagents, lithium t-amoxide (LTA) and sodium t-amoxide (NTA) in CPME are available from Rockwood Lithium. CPME shows better solubility than THF and MeTHF for NTA. In addition, some Grignard reagents in CPME are available from Pentagon Chemical Specialties and Acros Organics, including Methylmagnesium bromide, , Phenylmagnesium chloride, etc. They are useful for medicinal chemistry and other research and developmental use in other industries and academia.

CONCLUSION

CPME contributes to Green Chemistry in its own production by the atom economical and energy saving process, and in its applications because of reduction of the total amount of solvents used, waste water, waste solvents and CO2 emissions due to its unique properties including high hydrophobicity, high boiling point and low formation of peroxides. This means that CPME is thoroughly environmentally friendly from cradle to grave even if it is not from renewable source. CPME also contributes to Process Innovation because it can save process time and facilities by shortening work-up time and simplifying the total process, which leads to fixed cost reduction. In addition, CPME can reduce variable cost due to its high recovery rate and unnecessary need forextraction and crystallization solvents. A good stability under acidic and basic conditions of CPME contributes to Process innovation as well. These unique properties Process research and development of CPME, which traditional ethereal solvents do not have, give Comprehensive analytical support innovations such as one-pot synthesis and telescoping. Solid-state development Process optimization – Fit for purpose REFERENCES Scale-up – Proof of concept 1. American Chemical Society Green Chemistry Institute, The Twelve Principles of Green Chemistry: http://www.acs.org/content/acs/en/greenchemistry/ Manufacturing of about/principles/12-principles-of-green-chemistry.html > tox material (non-GMP/GMP) 2. Kiyoshi Watanabe, Noriyuki Yamagiwa and Yasuhiro Torisawa, Org. Proc. Res. Dev. 2007, 11, 251. > GMP starting materials 3. David F. Aycock, Org. Process Res. Dev., 2007, 11 (1), pp 156–159. 4. ICH Harmonized Tripartite Guideline for residual solvent Q3C (R5) was > API for clinical studies up to phase II established by International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH): http://www.ich.org/fileadmin/Public_Web_Site/ICH_ Products/Guidelines/Quality/Q3C/Step4/Q3C_R5_Step4.pdf 5. Vincent Antonucci, John Coleman, James B. Ferry, Neil Johnson, Michelle Mathe, Jeremy P. Scott, Jing Xu, Org. Process Res. Dev., 2011, 15 (4), pp 939–941. 6. Kiyoshi Watanabe, Molecules 2013,18, 3183-3194. 7. Kiyoshi Watanabe, Naoto Kogoshi, Hideaki Miki and Yasuhiro Torisawa, www.solvias.com Synth commun .2009, 39, 2008.