Enabling the Multigram Synthesis of (2-Cyclooctyn ... - ACS Publications

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Enabling the Multi-gram synthesis of (2-Cyclooctyn-1-yloxy)acetic acid Matthew T. Burk, Sarah Rothstein, and Pascal Dubé Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00275 • Publication Date (Web): 12 Dec 2017 Downloaded from http://pubs.acs.org on December 12, 2017

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Organic Process Research & Development

Title: Enabling the Multi-gram Synthesis of (2-Cyclooctyn-1-yloxy)acetic acid Authors: Matthew Burk,*† Sarah Rothstein‡ & Pascal Dubé§ *[email protected] †Nalas Engineering Services, 85 Westbrook Rd, Centerbrook CT 06409, USA. ‡Metals and additives Corp. 10665 N State Road 59 Brazil, IN 47834, USA. §Matsys, Inc. 45490 Ruritan Circle Sterling, VA 20164, USA.

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Abstract: The synthesis of (2-cyclooctyn-1-yloxy)acetic acid was enabled to allow for the simple and safe production of this material on multi-gram scale. Keywords: Click Chemistry, Cyclooctyne, Electrocyclic, Carbene Introduction Cyclooctynes have become a ubiquitous part of bioconjugation strategies by the opportunities they offer for linking biomacromolecules with small, organic molecules.1 Accordingly, strainpromoted [3+2] Huisgen cycloadditions are well-suited to bioconjugation, such as oxygen and water tolerance, favorable kinetics, bio-orthogonality, and low toxicity in living systems.2 (2-Cyclooctyn-1-yloxy)acetic acid (1) was one of the first cyclooctynes developed for the use in bioconjugate chemistry.3 Although second generation cyclooctynes featuring additional ring strain or electronic deactivation4 were found to achieve higher cycloaddition rates, the structural simplicity and straightforward synthesis of 1 still make it attractive for numerous applications. Although previous methods have been sufficient to provide small amounts (110 mg or less) of material required for biological testing, a program at Nalas required the use multi-gram quantities of this cyclooctyne. As external sourcing was not an option, the expedited timeline associated with our program led us to enable the existing chemistry to (2-cyclooctyn-1yloxy)acetic acid (1) on multi-gram scale, and develop a process not requiring the use of chromatography. The standard preparation of 1 proceeds via a three step sequence from cycloheptene and the original conditions prior to our work are presented in Scheme 1. Accordingly, the dibromocyclopropanation of cycloheptene 2 followed by a silver perchlorate-mediated



electrocyclic ring opening of dibromocyclopropane 3 and final base-promoted elimination of the resulting trans vinyl bromide 4 produces the desired cyclooctyne 1 in synthetically practical yields.5 This original synthesis suffers from several limitations for its application to multi-gram quantities, including the need for chromatography at every step. In addition, step 2 presented a considerable safety hazard for which details are given below. Scheme 1. Original synthetic route to 1

The synthetic method described herein thus retains the same basic synthetic sequence as the original work, while addressing several shortcomings of previously published procedures. As such, our goal was first to develop processes that would allow for either telescoping streams directly into the following step or enabling purification methods based on crystallizations, thus bypassing entirely the need for chromatographic separations. As a secondary objective, we sought to address the safety concerns associated with the use of silver perchlorate in toluene, a known explosive hazard, especially if the chemistry had to be scaled to multi-gram quantities. Results and Discussion The dibromocyclopropanation of cycloheptene was found to be an efficient transformation which only required minor modifications. Accordingly, a detailed analysis of the crude product stream by NMR revealed that the starting cycloheptene was the main contaminant as the result of an


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incomplete conversion. We found that a slight increase in the base stoichiometry coupled with the use of efficient mechanical stirring to facilitate mass transfer limitations directly led to improved conversion. Moreover, pentane was replaced with hexane with the intent to reduce the hazards associated with the flammability and volatility of this solvent. These seemingly minor improvements however translated in our ability to use crude 3 directly in the next step without further purification after a standard aqueous workup and evaporation of the organic layer to a crude residue (see Experimental Section for details). The existing procedure for silver perchlorate-mediated ring expansion of 3 posed several practical and safety issues. First, the reported solvent, toluene, forms a potentially explosive complex with silver perchlorate.6 Specifically, silver perchlorate containing 9% toluene is known to explode releasing 3.51 kJ per gram, a value that represents 84% of the energy output of TNT. Moreover, the original procedures disclosed no provision for the removal of the perchloric acid byproduct or the excess silver perchlorate prior to concentration of the reaction mixture, thus making this operation especially problematic for multi-gram scale reactions. This was judged to be unacceptably hazardous in light of the well-known hazards of perchloric acid and silver perchlorate,6 as well as a likely cause of the observed instability of crude 4, which required immediate purification by chromatography. In addition to the impracticality of chromatographic purification on large scale, our experience with this method of purification of 4 resulted in poor recovery and partial isomerization to the more stable cis isomer. Cis-4 was further difficult to purgea and observed to be inert in the subsequent elimination, thus draining the yield for the last step.

a

This isomerization occurred even when the excess silver perchlorate and perchloric acid were removed by aqueous workup.



Our first concern was alleviated by the use of dichloromethane as a reaction solvent. We were unable to find any reports of explosive mixtures or complexes between dichloromethane and silver perchlorate. Perchloric acid and excess silver perchlorate were removed by quenching the reaction with sodium bicarbonate and sodium chloride prior to filtration of silver halides and aqueous extraction. These modifications had the additional benefits of allowing more complete silver recovery and removing the excess methyl glycolate by taking advantage of its solubility in water. As a result, chromatographic purification of 4 was simply unnecessary thus avoiding cis/trans isomerization. Telescoping this new crude material into the final step was thus found to be the most efficient path forward. The established conditions worked well with the crude incoming vinyl bromide 4, allowing the desired elimination in presence of sodium methoxide. Interestingly, adventitious water was sufficient to promote an in-situ saponification, resulting in the formation of 1 in 75% yield. Scheme 2. Enabled route to 1

Conclusions: We have reported an improved procedure for the preparation of 1 on multi-gram scale. Compared to the previously reported procedure, the protocol presented herein offers improved yields, reduced safety hazards and the elimination of chromatography. This work has enabled our


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program directed at the development of environmentally benign binders for rocket propellant applications, which will be reported in a separate publication. General Experimental Methods All reagents were used as received without further purification. All reactions were performed under an atmosphere of ambient air. 1H NMR and 13C NMR spectra were acquired in CDCl3 at 300 MHz. Spectra were referenced to residual CHCl3 (7.26 ppm 1H; 77.00 ppm 13C). Dibromocyclopropanation of cycloheptene. Preparation of 8,8-dibromobicyclo[5.1.0]octane (3). A 100-mL EasyMax™ reactor, equipped with an anchor-style mechanical stirrer and a thermocouple probe was charged with potassium tert-butoxide (14.5 g, 130 mmol, 2.50 equiv). Hexanes (9.8 mL) was added, followed by cycloheptene (6.10 mL, 52 mmol, 1.00 equiv). The resulting suspension was stirred and cooled to -10 °C. Bromoform (6.8 mL, 78 mmol, 1.5 equiv) was added as a solution in hexane (10 mL) over 1 h via dosing unit. Upon completion of the addition, the reaction temperature was increased to 20 °C in a continuous ramp over 3 h. The resulting suspension was stirred at 20 °C for 64 h. Water (39 mL) and 1 M HCl (50 mL) were added. The resulting biphasic mixture was transferred to a separatory funnel where it was diluted with hexane (15 mL). The phases were separated and the aqueous phase was extracted with hexane (2 x 25 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under a stream of dry air to provide 13.18 g (95% mass recovery) of crude 3 as an oil which was used in the next step without further purification. The spectra were in accordance with those previously reported.5 1H NMR (300 MHz, CDCl3) δ 1.11-1.25 (m, 3H); 1.28-1.46 (m, 2H); 1.65-1.75 (m, 2H); 1.75-1.93 (m, 3H); 2.20-2.31 (m, 2H).



Ring opening of 3. Preparation of [(Z)-2-bromo-2-cycloocten-1-yloxy]acetic acid, methyl ester (4) A 100-mL EasyMax™ reactor, equipped with a mechanical stirrer and a thermocouple probe was charged with CH2Cl2 (26.3 mL) and crude 3 (13.13 g, 36.3 mmol, 1.0 equiv). Methyl glycolate was added (33.9 mL, 326 mmol, 9.0 equiv). The internal temperature was regulated at 23 °C, and the reactor was protected from light using Al foil. Silver perchlorate (20.31 g, 98 mmol, 2.00 equiv) was added in a single portion. The resulting solution was allowed to stir at 23 °

C for 50 min, during which time a white precipitate formed. Saturated aq. NaHCO3 solution was

added (65 mL), followed by saturated aq. NaCl solution (30 mL). The precipitated Ag salts were filtered off and washed with MTBE (40 mL). The filtrate was transferred to a separatory funnel, where it was diluted with MTBE (20 mL). The phases were separated. The organic phase was washed with water (2 x 20 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil (13.5 g, 99% mass recovery) was used in the next step without further purification. The spectra were in accordance with those previously reported.5 1H NMR (300 MHz, CDCl3) δ 1.09 (m, 1H); 1.21-1.36 (m, 1H); 1.41-1.58 (m, 1H); 1.64-1.78 (m, 1H); 1.83-2.14 (m, 4H); 2.29 (m, 1H); 2.73 (dq, J = 5.5, 11.8, 1H); 3.97 (d, A of AB, J = 16.6 Hz, 1H); 4.13 (dd, J = 5.0, 10.1 Hz); 4.24 (d, B of AB, J = 16.5 Hz); 6.22 (dd, J = 4.0, 11.7 Hz). Preparation of (2-Cyclooctyn-1-yloxy)acetic acid (1). A 100-mL EasyMax™ reactor, equipped with a mechanical stirrer and a thermocouple probe was charged with DMSO (24 mL) and crude 4 (9.55 g, 34.5 mmol, 1.0 equiv). Sodium methoxide (30 % in methanol, 43.5 mL, 234 mmol, 6.8 equiv) was added. The resulting mixture was stirred for 45 min at 20 °C and then was transferred to a separatory funnel, where it was diluted with water (250 mL) and DCM (100 mL). The phases were separated and the aqueous


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phase was extracted with DCM (2 x 50 mL). The organic phases were discarded. The aqueous phase was acidified with 1 M HCl (200 mL, pH < 2) and extracted with MTBE (50 mL). The resulting organic phase was washed with water (2 x 50 mL), dried over MgSO4, filtered, and concentrated in vacuo, providing 1 as a tan solid (4.68 g, 75%). The spectra were in accordance with those previously reported5 and contained only trace impurities. Quantitative 1H NMR indicated 90% potency.

1

H NMR (300 MHz, CDCl3) δ 1.40-1.50 (m, 1H); 1.60-1.70 (m, 2H);

1.73-2.32 (m, 7 H); 4.09 (d, A of AB, J = 16.9 Hz, 1H); 4.24 (B of AB, J = 16.9 Hz); 4.38 (m, 1H); 8.79 (br s, 1H).

Acknowledgement: This work was supported by the Strategic Environmental Research and Development Program (SERDP).

References: 1

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Desai, A.; Gordon, C.L.; Leroueil, P.R.; Baker, J.R. Bioorg. Med. Chem. Lett, 2012, 22, 3152-3156. d) Bernardin, A.; Cazet, A.; Guyon, L.; Delannoy, P.; Vinet, F.; Bonnaffé, D.; Texier, I. Bioconjugate Chem. 2010, 21, 583-588. 4 For examples, see: a) Codelli, J. A.; Baskin, J. M.; Agard, N. J.; Bertozzi, C. R. J. Am. Chem. Soc. 2008, 130, 11486. b) Schultz, M. K.; Parameswarappa, S. G.; Pigge, F. C. Org. Lett. 2010, 12, 2398-2401. c) Ren, X.; Gerowska, M.; El-Sagheer, A. H.; Brown, T. Bioorg. Med. Chem. 2014, 22, 4384-4390. 5 a) van Dongen, M. A.; Silpe, J. E.; Dougherty, C. A.; Kanduluru, A. K.; Choi, S. K.; Orr, B. G.; Low, P. S.; Banaszak Holl, M. M. Mol. Pharm. 2014, 11, 1696-1706. b) Kent, A. D.; Spiropulos, N. G.; Heemstra, J. M. Anal. Chem. 2013, 85, 9916-9923. c) Evans, H. L.; Slade, R. L.; Carroll, L.; Smith, G.; Nguyen, Q.; Iddon, L.; Kamaly, N.; Stöckmann, H.; Leeper, F. J.; Aboagye, E. O.; Spivey, A. C. Chem. Commun. 2012, 48, 991-993. 6 Urben, P. G., Ed. Bretherick’s Handbook of Reactive Chemical Hazards, 7th ed.; Academic Press: Burlington MA, 2006.


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