# Skin Depigmenting Agents in Anti-Aging Cosmetics: A Medicinal Perspective on Emerging Ingredients
## 3 Results and Discussion
### Medicinal Chemistry Perspective of New Skin Depignetting Ingredients in Anti-Aging Products
#### 3.2.3 4-Butylresorcinol
After eight weeks, the 4-\(n\)-butylresorcinol formula significantly reduced senile hyperpigmentation intensity, measured by spectrometry and digital photography, contrary to both 0.5% phenylethylresorcinol and the vehicle control. Further improvements were assessed after 12 weeks. [PERSON] et al. reported the effects of the application of three cosmetic products containing 4-butylresorcinol and glycyrrhetinic acid for 4 weeks, with or without a previous fractional laser photothermolysis, for lightening hand solar lentigines [60]. The 4-butylresorcinol and glycyrrhetinic acid skincare regimen were well tolerated and efficacious at reducing solar lentigo colors and dimensions measured by dermatoscopic imaging, both for the treatment and control groups. There were no significant differences when fractional laser photothermolysis was performed after product application. Recently, another resorcinol derivative named thiamidiol (isobutylamido thiazolyl resorcinol) was synthesized, showing a greater efficacy over 4-butylresorcinol [13]. This compound has shown positive results for the treatment of UVB-induced hyperpigmentation [61; 62]. However, being a proprietary ingredient, it is not predictable thiamidiol will replace 4-butylresorcinol in the near future. Several patents have also been granted for methodologies for the industrial preparation of 4-butylresorcinol since 2018 [63; 64; 65; 66; 67; 68]. The large majority of these procedures comprise only a few steps, use resorcinol (**34**) as a raw material, and vary mainly on the secondary building block, always with the aim of significantly improving the yield, to reduce the use of accessory substances and reduce production costs [63; 64; 66; 69]. Method A (Scheme 6) discloses a multi-step procedure for preparing 4-butylresorcinol which comprises the initial addition of resorcinol (**34**) to \(N\),\(N\)-dimethylformamide with phosphorus oxychloride to obtain 2,4-dihydroxybenzaldehyde (**35**). Condensation with acetone under alkaline conditions to obtain 2,4-dihydroxybenzylideneacetone (**36**) and hydrogenation under acidic conditions gives 4-butylresorcinol. The main advantage of this methodology is the environmentally-friendly character due to the reduced generation of high-toxicity wastes [65]. Another methodology for preparing 4-butylresorcinol by a one-pot method comprises a reaction of resorcinol (**34**) with \(n\)-butyl alcohol to obtain intermediate monopholate (Method B, Scheme 6). Then, reaction with a Lewis acid in a one-pot dehydration to obtain a crude product after acidosis and recrystallization produces 4-butylresorcinol. The advantages of this procedure include mild conditions, low cost, and high yield and purity [66]. Three different methodologies were reported for the acylation of resorcinol (**34**) with aliphatic acid (**38**) to afford the corresponding acylated resorcin. A further reduction to 4-butylresorcinol can be achieved using (1) a triethylsilane/trifluoroacetic acid system (Method C, Scheme 6) [64], (2) hydrogen to avoid the use of a zinc amalgam (Method D,Scheme 6) [63], or (3) zinc dust in the presence of concentrated hydrochloric acid (Method E, Scheme 6) [69]. Other methodologies towards the preparation of 4-butylresorcinol include the use of different starting materials. As an example, a method that involves microchannel plates for the reduction of the carbonyl group of 2'4'-dihydroxybutyrophenone (**44**) using NaBH\({}_{4}\) and Raney Nickel as reducing agents was recently reported (Scheme 7) [67]. The overall production has a low catalyst cost, mild reaction conditions, slowly released hydrogen gas, simple operational procedures, and high yields [67]. Another procedure reports the bis-\(O\)-benzylation of 2,4-dihydroxybenzaldehyde (**39**) with benzyl chloride (**40**) being carried out under alkaline conditions to obtain 2,4-dibenzylox benzaldehyde (**41**) (Scheme 7) [68].