Without taking effective protective measures,long-term exposure to ultraviolet radiation will cause different degrees of damage to skin, such as erythema,skin pigmentation, skin tumors, and skin photoaging. [1]Adopting active and effective protective measures to reduce the burden of disease caused by overexposure has become a global consensus. It is well known that the absorption wavelength of isooctyl p-methoxy cinnamate is between 290～320 nm, at a high absorption rate and good solubility in lipophilic raw materials, thus easy to use and can be combined with other UVA absorbers to produce full-band UV sun-screening products. Therefore,among all suns-creenings, the most frequently used in 2007～2015 is isooctyl p-methoxy cinnamate. [2-5]

Although there have been many reports on the synthesis of isooctyl p-methoxy cinnamate, [6-10] most of them use palladium and ligand as catalyst, which is generally costly and the yield is not ideal, making many small and medium enterprises daunting. As a good shrinking agent, titanium tetrachloride has been frequently reported in recent years, [11-15] and industrial grade titanium tetrachloride is 7 yuan/kg, which is cheap and easy to obtain. The author used titanium tetrachloride to catalyze the synthesis of p-methoxybenzaldehyde and isooctyl acetate to obtain isooctyl p-methoxy cinnamate.The synthesis was a one step reaction, and the raw materials p-methoxybenzaldehyde and isooctyl acetate are cheap and easy to obtain, which greatly reduced the cost for industrial production. The synthetic reaction formula is as follows:

（一）流行病学特点 各种年龄、性别的猪都可发生，但以6周龄至6月龄的猪较多发。多呈最急性型或急性型病程，突然死亡，传播迅速。发病率和死亡率通常在50%以上，最急性型的死亡率可高达80%～100%。常发生于4～5月和9～11月。饲养环境突然改变、猪群的转移或混群、拥挤或长途运输、气候骤变等应激因素可使发病率和死亡率增加。

凡此种种，尤其从2015年到现在，每一想起诸如此类的事情，莫名惊诧之外，还有巨大的空茫感与不确定性。我知道，这不是所谓的迷信，尤其是我们或可感知的冥冥中的律定与指派，游离与消失，它们所具备的那种类似被神明操纵的玄学意味，常常使得人心生感慨。

Experimental section

Reagents and instruments

P-methoxybenzaldehyde, isooctyl acetate, titanium tetrachloride, toluene, and sodium hydroxide are all industrial grade. Nexus-470 Fourier Transform Infrared Spectrometer, Nicolet, USA; Bruker 400 NMR spectrometer (with CDCl3 as solvent, TMS as internal standard), Bruker, Switzerland; 6890 Gas Chromatograph,Agilent, USA.

Synthesis of isooctyl p-methoxy cinnamate

Since titanium tetrachloride was added to the system,the temperature rose sharply. In order to prevent bumping and spraying, titanium tetrachloride should be slowly added dropwise. In the case of n(p-methoxybenzaldehyde)∶n (isooctyl acetate)∶n(titanium tetrachloride) = 1∶1.1∶ 0.5, the reaction was carried out at 30℃ for 6 h. The effect of temperature and dropping time on the yield of the target product was shown in Table 1. It can be seen from Table 1 that when the dropping temperature of titanium tetrachloride was 0℃and dropping time was 1 h, the yield reached 98% and the purity was 99.7%.

Results and discussion

The effect of titanium tetrachloride feeding mode on yield

Add 700 g of toluene, 136 g (1 mol) p-methoxybenzaldehyde, 189 g (1.1mol) isooctyl acetate protected by nitrogen flow to a 2,000 mL three-necked flask equipped with an exhaust gas absorption device (aqueous sodium hydroxide solution, hydrogen chloride gas generated by absorption reaction), cooling slowly to 0℃, 95 g (0.5 mol)titanium tetrachloride was added dropwise about 1 h,and then heated to 30℃ for 6 h. After the reaction was completed, adjusting the pH to neutral with 2% sodium hydroxide aqueous solution, washing with water for 1～2 times, protecting the organic layer with nitrogen gas under reduced pressure and slowly heating up, firstly recovering the low boiling point solvent and impurities with water pump, then the internal temperature was 145℃ /-0.099 MPa with oil pump heat preservation distilling for 3 h to remove the unreacted raw materials and high boiling point impurities, the mother liquor was filtered, and filter cake titanium dioxide was recycled for use. The filtrate collected was isooctyl p-methoxy cinnamate with clear transparent colorless to pale yellow. The yield reached 98%,and the purity of GC detection was 99.7%. IR (KBr,σ/cm-1):2,961 (m), 2,872 (m), 1,713(s), 1,607 (s), 1,578 (w),1,513 (s), 1,465 (w), 1,425 (w), 1,255 (s), 1,034 (s), 984 (w),829(s); 1HNMR (400 MHz,CDCl3,δ): 7.64 (d,J=16 Hz,1H,=CH), 7.49 (d, J=8.7 Hz,2H,Ar-H), 6.90(d, J=8.7 Hz,2H,Ar-H), 6.33 (d, J=16 Hz,1H,=CH),4.17～4.07 (m,2H,-OCH2), 3.85 (s,3H,-OCH3), 1.65(q, J=5.9 Hz,1H,-CH), 1.47～1.11 (m,8H,-CH2), 0.93(q, J=7.1 Hz,6H)。

Table 1. Influence of the temperature and time of the titer on the yield of titanium tetrachloride

Temperature/℃ Time/h Yield/g Yield /% Purity/%30 0.5 210 72 95.2 20 0.5 226 78 96.3 10 0.5 238 82 98.6 0 0.5 261 90 99.4 0 0.8 275 95 99.2 0 1.0 284 98 99.7 0 1.5 278 96 99.5

The effect of temperature and time on the yield

In the case of n (p-methoxybenzaldehyde): n (isooctyl acetate): n (titanium tetrachloride) = 1∶1.1∶0.5, the dropping temperature of titanium tetrachloride was 0℃,and dropping time was 1 h, the effects of temperature and time on the yield of the target product were examined,and the results were shown in Table 2. It can be seen from Table 2 that when the temperature was 30℃ and time was 6 h, the yield reached 98% and the purity was 99.7%.

目前，南海航海保障中心已启动海区MF-DSC电路改造工作，计划于2018年底完成并正式启动广州通信中心统一值守海区MF-DSC电路工作。

Table 2. Influence of reaction time and reaction temperature on the yield

Temperature /℃ Time/h Yield/g Yield/% Purity/%0 4 203 70 94.5 10 4 220 76 96.5 20 4 232 80 97.6 30 4 261 90 98.3 30 5 275 95 98.8 30 6 284 98 99.7 30 7 282 97.5 99.4

The effect of raw material ratio on yield

The titanium tetrachloride was added dropwise at 0℃for 1 h, then the reaction was continued at 30℃ for another 6 h. The effect of the ratio of raw materials on the yield was examined. The results were shown in Table 3. As can be seen from Table 3, the yield was as high as 98% when the molar ratio of p-methoxybenzaldehyden,isooctyl acetate and titanium tetrachloride was 1∶1.1∶0.5.

Table 3. Influence of the ratio of raw materials on the yield

Ratio/mol Yield/g Yield/% Purity/%1∶0.9∶1 250 86 98.6 1∶1.0∶1 258 89 97.3 1∶1.1∶1 267 92 99.0 1∶1.2∶1 261 90 98.9 1∶1.1∶1.1 252 87 97.6 1∶1.1∶0.8 270 93 98.5 1∶1.1∶0.6 275 95 98.9 1∶1.1∶0.4 249 86 95.6 1∶1.1∶0.5 284 98 99.7

Conclusion

The optimal condition for the synthesis of isooctyl p-methoxycinnamate using titanium tetrachloride as catalyst are as follows: n (p-methoxybenzaldehyde): n(isooctyl acetate): n (titanium tetrachloride) = 1∶1.1∶ 0.5,titanium tetrachloride was added dropwise, the dropping temperature was 0℃ and dropping time was 1 h, the reaction temperature was 30℃ and time was 6 h. The yield at this condition was 98%, and the purity tested by GC was 99.7%. This method has the advantages of low cost and easy availability, simple operation, high yield,high product purity, excellent quality and high efficiency.

References

[1] Zhou Hongfei; Huang Wei; Shou Lu. Research progress of sunscreen agents. Journal of Zhejiang Normal University(Natural Science) 2017, 40(2), 206-213.

[2] Li Zhu; Cui Wenguang; Su Wei. Analysis of characteristics of 1172 sunscreen cosmetics. Occupation and Health 2017,33(13),1814-1822.

[3] Cai Lunhua; Kang Xiaoxi; Wan Li; et al. Investigation on the use of sunscreens in cosmetics. Journal of Preventive Medicine Information 2017, 33(3), 288-290.

[4] Zhang Zhuona; Zhang Weiqiang;yang yanwei. Analysis of the use of sunscreens in cosmetics. Chinese Journal of Health Inspection, 2017, 27(6), 902-904.

[5] Ding yi. Changes in the use of sunscreens in sunscreen cosmetics from 2007 to 2015. Chinese Journal of Health Inspection 2016, 26(6), 882-884.

[6] leyva-perez A; Oliver-meseguer J; Rubio-marques P; et al.Water-stabilized three- and four-atom palladium clusters as highly active catalytic species in ligand-free CC cross-coupling reactions. Angewandte Chemie: International Edition 2013,52(44), 11554-11559.

[7] Roberts G M. Improving reactivity and selectivity of aqueousbased Heck reactions by the local hydrophobicity of phisphine ligands. Tetrahedron 2015, 71(43), 8263-8270.

[8] Villa C. Eco-friendly methodologies for the synthesis of some aromatic esters, well-known cosmetic ingredients.International Journal of Cosmetic Science 2005, 27(1), 11-16.

[9] yadav VG;Chandalia S B. An efficient method for synthesis of 2-ethylhexyl 4-methoxycinnamate, a raw material for the cosmetics industry. Indian Journal of Chemical Technology 1999, 6(1),19-23.

[10] Littke A F; FU G C A. Versatile catalyst for heck reactions of aryl bromides under mild conditions. Journal of the American Chemical Society 2001, 123(29), 6989-7000.

[11] Berger M. Discovery of new selective glucocorticoid receptor agonist leads. Bioorganic & Medicinal Chemistry Letters 2017,27(3),437-442.

[12] Paula B R S. Bioreduction of α-acetoxymethyl enones: Proposal for an SN2' mechanism catalyzed by enereductase.Advanced Synthesis & Catalysis 2016, 358(22),3555-3571.

[13] Nageswara R K. Total synthesis of the anticancer marine natural product mycalol. European Journal of Organic Chenistry 2018(3), 398-412.

[14] Duan Jingwu. Tricyclic sulfones as RORy modulators and their preparations: 2016179460. 2016-11-10.

[15] Perla R. First total synthesis of the proposed structure of cryptorigifoliol B. Tetrahedron Letters 2016, 57(19),2100-2102.