Continuous Flow Production of 3-Chloropropionyl Chloride

3-Chloropropionyl chloride is an important bifunctional reagent. It is capable of acylation and possesses a 2-chloroethyl fragment (CH2CH2Cl), which can be subjected to nu­cleophilic substitution and serves as a masked vinyl group. It can be used as a starting material in many reactions to construct a variety of (hetero)cyclic compounds. 3-Chloropropionyl chloride is mainly used as a chemical intermediate, widely used in many fields: 1. Organic synthesis:Used as a precursor for the synthesis of other compounds, such as drugs, pesticides and dyes.  It plays an important role in the synthesis of amino acids, esters and amides. 2. Pharmaceutical chemistry: Used in the preparation of biologically active molecules, especially in drug development. Can be used as modifiers to improve the biocompatibility or potency of active compounds. 3. polymer production: 3-Chloropropionyl chloride can be used as monomers in certain polymerization reactions to produce polymeric materials with specific properties.

Atom- and Mass-economical Continuous Flow Production of3-Chloropropionyl Chloride

Miniaturized systems have emerged as powerful tools to con-duct various types of chemistry, including the use and generation of hazardous compounds in a safe manner. We have recently demonstrated the acid chloride formation of saturated, unsaturated and heterocyclic carboxylic acids. Labile acid chlorides were safely and continuously generated via an on-demand and on-site procedure by using a continuous flow microreactor set-up. Building on this experience, we have investigated alternative routes and technologies for obtaining 3-chloropropionyl chloride, a compound with broad use in adhesives, pharmaceuticals, herbicides and fungicides. The current large-scale syn-thesis of 3-chloropropionyl chloride poses safety issues give the use of large amounts of chlorinating reagents for long re-action times. We report a highly efficient procedure for the preparation of 3-chloropropionyl chloride from acrylic acid in-volving the formation of and 1,4-addition across acryloyl chloride.[1]

The screening of phosphoryl chloride and oxalyl chloride as chlorinating reagents resulted in moderate conversions, and can be found in the supporting information. The best results for the POCl3-mediated acid chloride formation and 1,4-addi-tion were obtained with 0.5 equivalents of catalyst, equimolar amounts of POCl3, at 80 8C and within 25 minutes, giving a conversion of 77 % towards 3-chloropropionyl chloride. On the other hand, a maximum of 68 % conversion into 3-chloro-propionyl chloride was reached with oxalyl chloride as chlorinating reagent. Via a simple continuous setup, it was possible to achieve a conversion up to 94 % towards 3-chloropropionyl chloride. Using this process in a tubular flow reactor of 3 mL with an internal diameter of 0.5 mm, an output of 3-chloropropionyl chloride of approximately 4.6 grams per hour can be achieved, with room for fast scale-up by first smart dimensioning (scale-out of internal diameter and volume) and further using the numbering-up principle. The neat conditions and the simplicity of the setup furthermore allow a scale-up for industrial applications. Purification on the thus obtained 3-chloropropionyl chloride on scale can be accomplished via a vacuum distillation, for example, with a wiped film evaporator.

As mentioned earlier, 3-Chloropropionyl chloride is a chemically versatile building block with applications in the field of adhesives, pharmaceuticals, herbicides and fungicides. Its current production entails problems concerning safety, prolonged reaction times and the use of excessive amounts of chlorinating reagents. We developed a continuous flow procedure for acid chloride formation from acrylic acid and a consecutive 1,4-addition of hydrogen chloride generating 3-chloropropionyl chloride, as presented in this paper. Up to 94 % conversion was reached in 25 minutes at mild temperatures and pressures. This continuous flow method offers a safer alternative and is highly efficient in terms of consumption of starting product and shorter residence time. Valorization of this building block is exemplified by the synthesis of beclamide, a compound with sedative and anticonvulsant properties. Over 80 % conversion towards this drug was achieved in 1 minute in a continuous flow setup. Further research is needed to telescope the synthesis of 3-chloropropionyl chloride and subsequent beclamide formation without intermediate purification.

References

[1]Movsisyan M, Heugebaert TSA, Roman BI, Dams R, Van Campenhout R, Conradi M, Stevens CV. Atom- and Mass-economical Continuous Flow Production of 3-Chloropropionyl Chloride and its Subsequent Amidation. Chemistry. 2018 Aug 9;24(45):11779-11784. doi: 10.1002/chem.201802208. Epub 2018 Jul 13. PMID: 29879290.

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