Liu Wei, Wang Naixing, Ren Chunxia
(Technical Institute of Physics and Chemistry, The Chinese Academy of Sciences, Beijing, 100101, China)

Received Oct.16, 2002.

Abstract p-Butyramidophenyl acetate was an important organic compound, herein its synthetic methods were reported, and the results of the orthogonal experiments were given.
Keywords p-butyramidophenyl acetate, synthetic methods, orthogonal experiments

1 INTRODUCTION
p-Butyramidophenyl acetate is an important organic compound, which has not been sold in most chemical companies, such as Aldrich, Acros and TCI. Therefore, it is valuable for us to find out an efficient method to synthesize this compound in a large scale. Some papers described its synthesis previously. Wooldridge et al reported that p-butyramidophenyl acetate was synthesized by the reaction of p-butyramidophenol and acetyl chloride,^[1] but the purification of the product was difficult and the yield was very low. Amidate was also obtained from the reaction of amino-group and acid anhydride.^[2,3] But butyric anhydride was lack and the price was high, so it was not often used to synthesize the amidate even though sometimes it was also utilized to obtain the butyramide.^[4] p-Aminophenol is abundant^[6-11] and the price is low. So in our experiment, p-aminophenol as a starting material was amidated by n-butyric acid to get p-butyramidopenol and then p-butyramidophenol reacted with esterifying agent acetic anhydride to get the title compound. Moreover, orthogonal design was used to optimize the reaction conditions and a high yield was obtained. This synthetic method was convenient and easy to use in a large scale.

2 EXPERIMENTAL
Melting points were uncorrected and were determined on the X-4 melting point instrument. IR spectra were recorded on a BIO-RAD FTS165 Spectrograph. ¹H NMR spectra were measured on a Varian Gemini-300MHz spectrometer. MS data was determined on a VG TRID-2000 mass spectrograph.
2.1 Preparation of p-butyramidophenol
Orthogonal experiments were carried out as the reaction temperature(A), mole ratio of p-aminophenol and n-butyric acid (B) and reaction time(C) shown in Table.1. The crude product was recrystallized by toluene and ethanol. IR (KBr) u: 3319, 3160, 1645, 1608, 1557, 1511, 1448; ¹H NMR (CD₃COCD₃, 300MHz) d: 0.90 (t, J=7.40 Hz, 3H), 1.64 (m, J=7.35 Hz, 2H), 2.26 (t, J=7.14 Hz, 2H), 6.72-7.42 (q, J=8.72 Hz, 4H), 9.18 (s, 1H).
2.2 Synthesis of p-butyramidophenyl acetate
A mixture of p-butyramidophenol, pyridine, toluene and acetic anhydride was stirred for several hours. After completion of the reaction, water was added to the reaction mixture. Acetic ester was used in the extraction of the crude product and the crude product was purified by recrystallization. m.p. 104-105ºC; IR (KBr) u: 3298, 1766, 1657, 1607, 1537, 1508, 1465; ¹H NMR (CDCl₃, 300MHz) d: 1.00 (t, J=7.28 Hz, 3H), 1.76(m, J=7.26Hz, 2H), 2.29 (s, 3H), 2.33 (t, J=7.14 Hz, 2H), 7.03-7.52 (q, J=8.61 Hz, 4H).

3 RESULTS AND DISCUSSIONS
3.1 The optimization of the reaction conditions of amidization           
Orthogonal design was used to optimize the reaction conditions (Table.1) and the results were shown as Table.2.

Table 1 The scheme of L₉(3³) orthogonal experiment

Table 2 L₉(3³) Results in the orthogonal experiment

3.1.1 The influence of reaction temperature: As Table.2 shown, the higher the temperature was, the better the yield was. It showed that the forward reaction was endothermal one and the high temperature benefited for the production of p-butyramidophenol. But if the temperature was too high, n-butyric acid was easy to evaporate and it was unfavorable to the reaction. Moreover, p-aminophenol was easy to be oxidized under high temperature. Therefore our experiments showed that 140-150ºC was suitable.
3.1.2 The influence of mole ratio of p-aminophenol and n-butyric acid: The reaction was reversible, so excessive n-butyric acid was favorable for the production of p-butyramidophenol. When the mole ratio of p-aminophenol and n-butyric acid was more than 1:4, as Table 2 shown, the mole ratio of the two materials had less influence than before one. Considering the cost of the production, we chose 1:4 as the mole ratio of the starting materials.
3.1.3 The influence of reaction time: As Table.2 shown, 6.5 h was enough for the reaction. The yield was about constant even though the reaction was continued for 9.5 h. So the experiments showed that 6.5 h was suitable.

3.2 Esterification         
The synthetic method in the previous papers was the reaction of p-butyramidophenol and acetyl chloride. However, acetyl chloride resulted in many side reactions and by-products because of its high activity. Acetic anhydride, as an esterfying agent, showed much lower reactivity than acetyl chloride. When acetic anhydride was used instead of acetyl chloride to react with p-butyramidophenol, there were few side reactions and it was easy to purify the product. Moreover, the reaction was not affected greatly by temperature, time as well as other factors. For example, under the same conditions the yield varied from 74.5% to 72.3% when the reaction temperature changed from room temperature to 60ºC. So it was convenient to be used in the large-scale production. In our experiment, the yield of this reaction was 70-78% .

4 CONCLUSION  
The yield of amidization was affected by many factors. The mole ratio of p-aminophenol and n-butyric acid affected the yield greatly. The temperature also had some influences on the yield and the reaction time had little effect on it. Considering the cost of the production as well as other factors, we demonstrated that the optimal reaction conditions were 140-150ºC, 6.5 h and n(p-aminophenol):n(n-butyric acid) = 1:4. The yield was 74.6% under this optimal reaction conditions. In the second step, the yield of the reaction was basically constant at 70-78%.

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