Elsevier

Tetrahedron

Volume 73, Issue 25, 22 June 2017, Pages 3536-3540
Tetrahedron

Breathing air as oxidant: Optimization of 2-chloro-2-oxo-1,3,2-dioxaphospholane synthesis as a precursor for phosphoryl choline derivatives and cyclic phosphate monomers

https://doi.org/10.1016/j.tet.2017.05.037Get rights and content

Abstract

Phosphoryl choline derivatives are important compounds for drug development. Also other phosphoesters have received increased demand in recent years. Many of such compounds rely 2-chloro-2-oxo-1,3,2-dioxaphospholane (COP) as an intermediate. COP is available in a two-step reaction from the cyclic adduct of phosphorus chloride and ethylene glycol after oxidation. Although commercially available, in-house synthesis of COP is often required due to pricing, purity, and delivery issues. Air is a convenient and economical oxidizing agent, yet not used for synthesis of COP. While slow consumption of the P(III)-precursor 2-chloro-1,3,2-dioxaphospholane with molecular oxygen from a gas bottle, high amounts of unreacted oxygen are lavished and even may cause an explosion. Oxygen from air is a reasonable and safer alternative. Additionally, catalytic amounts of cobalt(II)chloride increase the reaction kinetics remarkably. The results presented allow a controlled and fast access to a variety of phosphoesters by optimized reaction conditions of COP and its derivatives.

Introduction

2-Chloro-2-oxo-1,3,2-dioxaphospholane (COP) (also known as ethylene chlorophosphate or ethylene phosphochloridate) is an essential precursor and a key building block for mainly two purposes: the synthesis of (i) phosphorylcholine (PC) derivatives, a polar zwitterion naturally present in phospholipids of cell membranes, which are used in diverse drug delivery applications. A popular synthetic representative is the monomer 2-methacryloyloxyethyl phosphorylcholine (MPC), which produces the water-soluble and biocompatible polymer PMPC, mimicking the phospholipids.1, 2, 3, 4, 5 Also the synthesis of small molecule PC's for different polymers has been reported.6, 7, 8, 9 However also the preparation of (ii) cyclic phosphate monomers for the ring-opening polymerization to produce poly(phosphoester)s (PPEs)10, 11, 12, 13, 14, 15, 16, 17, 18, 19 is a valuable reaction pathway of COP (Scheme 1). Synthetic PPEs are inspired by desoxyribose nucleic acid (DNA) and a versatile class of polymers ranging from hydrophobic to water-soluble materials. They find currently an increased attention as potential materials for biomedical applications13, 20, 21 or as flame retardant additives.22

The most common route for the synthesis of COP refers to protocols from Scully et al.23 and Edmundson24 from the 1950's and 1960's. Nowadays, COP is still synthesized via this route in a two-step reaction: (i) esterification of phosphorus trichloride with ethylene glycol generates 2-chloro-1,3,2-dioxaphospholane (CP) (1a), which is (ii) oxidized by molecular oxygen in refluxing organic solvent to prepare 2-chloro-2-oxo-1,3,2-dioxaphospholane (1) (Scheme 2). For the oxidation reaction slight modifications are reported, substituting the reaction solvent benzene using toluene5, 25 or dichloromethane26 instead. Also the reaction times from 8 h to 4d24, 27 and temperatures from room temperature5, 26 to reflux24, 27 vary. However, moderate yields from 37 to 83%5, 27 are reported so far, often lacking high purity of the product. Additionally, molecular oxygen from a gas bottle in large excess is used in all cases as reagent and bubbled through the reaction, showing only poor and slow consumption with unreacted oxygen being released in large amounts (note: in a well-ventilated fume hood this should be unproblematic, however flying sparks need to be prevented). Several attempts in our group conducting the oxidation in a closed system were sparsely satisfying and can cause unwelcome overpressure in the system due to reflux conditions.10 In our search for alternative routes, reported literature protocols include the use of dinitrogen tetroxide (N2O4)28 or ozone (O3)29 as oxidants, also resulting in poor yields in the case of N2O4 and challenging handling of reactant. Also phosphorus oxychloride, ethylene glycol and catalytic amounts of copper(I)chloride (CuCl) were reported to produce COP in a one-step reaction, but several attempts of this protocol in our group did not produce COP in reasonable yields or purity.30

There is a high demand in COP. Although commercially available, price, delivery time and purity of the commercial product are often unsatisfactory. Therefore an efficient, inexpensive and safer in-house preparation is indispensable. Herein, we present a facilitated synthesis protocol using the oxygen from air as oxidant, instead of molecular oxygen from a gas bottle. Still used in excess, large amounts of wasted unreacted molecular oxygen can be avoided. Additionally, cobalt(II)chloride has been found to be an efficient catalyst that accelerates the reaction from days to several hours, resulting in COP with a very high purity and overall acceptable yields of 70%.

Section snippets

Materials

All reagents were used without further purification, unless otherwise stated. Solvents, dry solvents (over molecular sieves) and deuterated solvents were purchased from Acros Organics, Sigma-Aldrich, Deutero GmbH (Germany) or Fluka. Ethylene glycol was purchased from Sigma-Aldrich, dried prior to use with NaH, distilled and stored over molecular sieves. PCl3 was purchased from Acros Organics. Cobalt(II)chloride hexahydrate was purchased from Sigma Aldrich, and dried at reduced pressure at

Results and discussion

Following the protocol of Edmundson,24 the oxidation of 2-chloro-1,3,2-dioxaphospholane (CP) with molecular oxygen from a gas bottle bubbled through the reaction in benzene under reflux shows slow consumption and requires several days (4d) for the reaction to reach full conversion to 2-chloro-2-oxo-1,3,2-dioxaphospholane (COP) (yields up to 83%, 98% purity, Table 1, entry 1). The major disadvantage of the set-up is the waste of unreacted molecular oxygen and the potential risk with high amounts

Conclusion

High demands on purity, pricing and delivery issues of COP still require in-house synthesis of this precursor molecule. Using oxygen from air instead of pure oxygen from a gas tank, has a strong economical impact, is easy to perform and avoids wasting of oxygen. Additionally, this is the first report on the acceleration of this reaction by the addition of catalytic amounts of CoCl2 to reduce the reaction times from days to hours. A screening of different solvents revealed that the highest

Conflict of interest

The authors declare no competing financial interest.

Acknowledgments

G.B. is recipient of a fellowship through funding of the Excellence Initiative (DFG/GSC 266) in the context of the graduate school of excellence “MAINZ” (Material Sciences in Mainz). F.R.W. is grateful to the Max Planck Graduate School (MPGC) for support.

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