Synthesis and Applications of Valeryl Chloride

Physicochemical Properties

Valeryl chloride (also known as n-pentanoyl chloride or n-valeryl chloride) is a colorless, transparent, fuming oily liquid with an irritating odor. Its chemical formula is C₅H₉ClO, and its structural formula is CH₃CH₂CH₂CH₂COCl. It decomposes on contact with water and is soluble in organic solvents such as ether. It is strongly acidic, and its vapor is a strong irritant to the eyes and respiratory mucosa. Furthermore, this substance is corrosive to metals, therefore, it requires corrosion-resistant packaging such as lined iron drums or glass/plastic containers with corrosion-resistant coatings. It should be stored in a dry, well-ventilated, rainproof, and sun-protected environment. It is prohibited to store or transport it with water, ethanol, strong alkalis, or oxidizing agents. It should be transported according to the regulations for strong acid and strong alkali hazardous materials [₁].

Synthesis

Method 1: Obtained by the reaction of valeric acid and phosphorus trichloride. The reaction formula is as follows:

3CH₃CH₂CH₂CH₂COOH + PCl₃→3CH₃CH₂CH₂CH₂COCl+H₃PO₄

Method 2: Obtained by the reaction of valeric acid and thionyl chloride. Valeric acid and thionyl chloride are respectively pumped from storage tanks into an enamel reaction kettle via metering pumps. Then, 1-5 w‰ of DMF (based on the weight of valeric acid) is added, and the temperature is raised to 50-90℃ until no more gas is released. The above chlorination reaction liquid is then vacuum-sucked into a distillation kettle, and 1-5‰ of a stabilizer (based on the weight of valeric acid) is added. Vacuum distillation is performed, controlling the distillation kettle temperature to ≤90℃. The fore-fraction thionyl chloride is collected into a receiving tank, and the valeryl chloride is collected into a finished product tank. This method, by adding a stabilizer with an electron-rich structure, allows the acyl cation to preferentially bind to the stabilizer, avoiding the formation of valeric anhydride [₂].

Uses

Valeryl chloride is a chemical used in the chemical, chemical engineering, and pharmaceutical synthesis fields. In organic synthesis, it is used as an acylating agent and is a raw material for the preparation of valeric amide. It can also be used to synthesize liquid crystals and pesticides.

1. As a pharmaceutical synthesis raw material. For example, in the synthesis of the antihypertensive drug valsartan, N-[(2'-cyanobiphenyl-4-yl)methyl]-L-valine methyl ester is acylated with valeryl chloride in toluene using DMAP as a catalyst and sodium carbonate as an acid binder to obtain N-(1-oxopentyl)-N-[(2'-cyanobiphenyl-4-yl)methyl]-L-valine methyl ester. Then, after reaction with sodium azide under the action of the phase-transfer catalyst bis(trimethylsilyl)polyethylene glycol, and subsequent hydrolysis, the antihypertensive drug valsartan is obtained [₃].

2. As an organic synthesis raw material. Using valeryl chloride and m-dichlorobenzene as raw materials, hexaconazole and its derivatives are synthesized through Friedel-Crafts acylation, carbonyl epoxidation, and ring-opening reaction [₄], and then used for the preparation of fungicides [₅].

References

[1]Ju Chao, Yuan Kunpeng, Liu Qiongyang. A method for directly producing valeryl chloride and its preparation method: CN202110142220.8[P]. CN112939769A.

[2]Fang Yongqin, Chu Junxuan, Wu Anbang, et al. Production process of pharmaceutical grade valeryl chloride: CN201210432079.6[P]. CN102942470A.

[3]Wang Xiaodong, Guo Yekun, Pan Lu, et al. Synthesis of Valsartan[J]. Chinese Journal of Pharmaceutical Industry, 2012, 43(6):3. DOI: 10.3969/j.issn.1001-8255.2012.06.006.

[4]Wang Bei. Synthesis of hexaconazole derivatives and study on their wood preservation performance[D]. Nanjing Forestry University, 2015.

[5]Wang Hongxue, Li Zhengming. Process improvement of 2,4-dichlorobenzoyl pentane[J]. Tianjin Chemical Industry, 2007(005):021.