Synthesis of 3-hydroxy-4-methoxy cinnamaldehyde as intermediate of advantame

doi:10.16085/j.issn.1000-6613.2022-0153

Abstract

Abstract:

3-Hydroxy-4-methoxy cinnamaldehyde is an important intermediate for the preparation of advantame, which is a novel dipeptide sweetener with super-high potency. At present, this intermediate is mainly synthesized by Aldol condensation reaction of isovanillin and acetaldehyde in the presence of strong base. However, since acetaldehyde is prone to self-condensation, there are problems such as harsh reaction conditions and low yield of 3-hydroxy-4-methoxy cinnamaldehyde. In this paper, a new process for preparation of 3-hydroxy-4-methoxy cinnamaldehyde by using vinyl acetate as a reactant in place of acetaldehyde to react with isovanillin was studied. The influences of reaction temperature, reaction time, NaOH dosage and molar ratio of isovanillin to vinyl acetate on the reaction were investigated by single factor experiments. On the basis of the single factor experiments, the response surface optimization was carried out. Results showed that the yield of 3-hydroxy-4-methoxy cinnamaldehyde was 71.44%±2.21% under optimal conditions: NaOH concentration of 4.5mol/L, reaction temperature of 10℃, reaction time of 12h and the molar ratio of isovanillin to vinyl acetate of 1∶2. In order to further improve the product yield, the strengthening effect of adding a phase transfer catalyst to the reaction system was explored. It was found that PEG-200 had a significant catalytic effect on the reaction, and the yield of 3-hydroxy-4-methoxy cinnamaldehyde achieved 83.12%±2.18%.

Key words: synthesis, 3-hydroxy-4-methoxycinnamaldehyde, vinyl acetate, catalysis, optimization

摘要：

3-羟基-4-甲氧基肉桂醛是制备新型的二肽超高甜度甜味剂爱德万甜的重要中间体。目前制备该中间体的主要方法是通过异香兰素与乙醛在强碱存在下进行羟醛缩合反应，但由于乙醛容易发生自缩合反应从而存在反应条件极为苛刻和3-羟基-4-甲氧基肉桂醛收率低等问题，本文以乙酸乙烯作为反应物替代乙醛与异香兰素发生反应合成3-羟基-4-甲氧基肉桂醛，采用单因素实验考察了反应温度、反应时间、NaOH浓度和异香兰素与乙酸乙烯配比对该反应的影响，并在此基础上进行了响应面优化。在优化的反应条件（NaOH浓度4.5mol/L，反应温度10℃，反应时间12h，异香兰素与乙酸乙烯摩尔比1∶2）下，3-羟基-4-甲氧基肉桂醛收率为71.44%±2.21%。为了进一步提高产品收率，探索了添加相转移催化剂对该反应的强化作用，发现PEG-200对强化该反应有显著作用，3-羟基-4-甲氧基肉桂醛收率可达83.12%±2.18%。

关键词: 合成, 3-羟基-4-甲氧基肉桂醛, 乙酸乙烯, 催化, 优化

CLC Number:

TQ215

FANG Cong, LIU Yixue, LI Sifang. Synthesis of 3-hydroxy-4-methoxy cinnamaldehyde as intermediate of advantame[J]. Chemical Industry and Engineering Progress, 2022, 41(11): 6053-6060.

方聪, 刘怡雪, 黎四芳. 爱德万甜中间体3-羟基-4-甲氧基肉桂醛的合成[J]. 化工进展, 2022, 41(11): 6053-6060.

Figures/Tables 22

References 24

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因素	水平
因素	-1	0	1
A 反应时间/h	8	12	16
B 反应温度/℃	5	10	15
C NaOH浓度/mol·L^-1	0.14	0.18	0.22
D 异香兰素与乙酸乙烯摩尔比	1∶1.5	1∶2	1∶2.5

因素	水平
因素	-1	0	1
A 反应时间/h	8	12	16
B 反应温度/℃	5	10	15
C NaOH浓度/mol·L^-1	0.14	0.18	0.22
D 异香兰素与乙酸乙烯摩尔比	1∶1.5	1∶2	1∶2.5

序列	因素				收率/%
序列	A：反应时间	B：反应温度	C：NaOH 浓度	D：异香兰素与乙酸乙烯摩尔比	实际值	预测值
1	-1	0	1	0	37.94	38.92
2	0	-1	1	0	31.55	29.23
3	1	-1	0	0	36.61	37.56
4	-1	-1	0	0	34.17	35.31
5	1	1	0	0	30.57	30.59
6	-1	1	0	0	28.88	29.09
7	0	1	-1	0	25.36	25.66
8	-1	0	-1	0	41.13	40.71
9	0	0	0	0	69.23	71.44
10	0	0	0	0	71.25	71.44
11	0	0	0	0	70.98	71.44
12	1	0	-1	0	43.95	43.83
13	0	1	1	0	23.25	22.44
14	0	0	0	0	72.54	71.44
15	0	0	0	0	73.21	71.44
16	0	-1	-1	0	33.29	32.07
17	1	0	1	0	39.59	40.21
18	-1	0	0	1	45.82	44.61
19	0	1	0	1	28.79	28.75
20	0	0	-1	1	40.77	41.27
21	0	-1	0	1	33.98	34.52
22	1	0	0	1	46.78	46.12
23	0	0	1	1	37.02	37.89
24	0	0	-1	-1	39.11	39.40
25	0	-1	0	-1	32.93	33.83
26	0	0	1	-1	36.07	36.73
27	1	0	0	-1	45.78	44.97
28	0	1	0	-1	26.07	26.40
29	-1	0	0	-1	44.10	42.73

序列	因素				收率/%
序列	A：反应时间	B：反应温度	C：NaOH 浓度	D：异香兰素与乙酸乙烯摩尔比	实际值	预测值
1	-1	0	1	0	37.94	38.92
2	0	-1	1	0	31.55	29.23
3	1	-1	0	0	36.61	37.56
4	-1	-1	0	0	34.17	35.31
5	1	1	0	0	30.57	30.59
6	-1	1	0	0	28.88	29.09
7	0	1	-1	0	25.36	25.66
8	-1	0	-1	0	41.13	40.71
9	0	0	0	0	69.23	71.44
10	0	0	0	0	71.25	71.44
11	0	0	0	0	70.98	71.44
12	1	0	-1	0	43.95	43.83
13	0	1	1	0	23.25	22.44
14	0	0	0	0	72.54	71.44
15	0	0	0	0	73.21	71.44
16	0	-1	-1	0	33.29	32.07
17	1	0	1	0	39.59	40.21
18	-1	0	0	1	45.82	44.61
19	0	1	0	1	28.79	28.75
20	0	0	-1	1	40.77	41.27
21	0	-1	0	1	33.98	34.52
22	1	0	0	1	46.78	46.12
23	0	0	1	1	37.02	37.89
24	0	0	-1	-1	39.11	39.40
25	0	-1	0	-1	32.93	33.83
26	0	0	1	-1	36.07	36.73
27	1	0	0	-1	45.78	44.97
28	0	1	0	-1	26.07	26.40
29	-1	0	0	-1	44.10	42.73

方差来源	平方和	自由度	均方	F	P	显著性
回归方程	6249.78	14	446.41	223.75	< 0.0001	+ +
A	10.53	1	10.53	5.28	0.0376
B	130.75	1	130.75	65.53	< 0.0001	+ +
C	27.57	1	27.57	13.82	0.0023	+
D	6.90	1	6.90	3.46	0.0841
AB	0.14	1	0.14	0.070	0.7945
AC	0.34	1	0.34	0.17	0.6850
AD	0.13	1	0.13	0.065	0.8025
BC	0.034	1	0.034	0.017	0.8977
BD	0.70	1	0.70	0.35	0.5638
CD	0.13	1	0.13	0.063	0.8052
A²	979.04	1	979.04	490.72	< 0.0001	+ +
B²	4391.39	1	4391.39	2201.09	< 0.0001	+ +
C²	2118.43	1	2118.43	1061.82	< 0.0001	+ +
D²	1372.84	1	1372.84	688.11	< 0.0001	+ +
残差	27.93	14	2.00	—	—
失拟项	18.46	10	1.85	0.78	0.6603
纯误差	9.47	4	2.37	—	—
总和	6277.71	28	—	—	—