微反应器内邻氨基苯甲酸甲酯的连续重氮化工艺

doi:10.16085/j.issn.1000-6613.2020-2203

摘要/Abstract

摘要：

邻氨基苯甲酸甲酯（MA）的重氮盐是一种典型的重氮化合物，因其具有高化学选择性可高效合成结构复杂分子被广泛应用于现代有机合成领域。传统半间歇合成工艺中的固有缺陷以及MA重氮盐的潜在爆炸性，限制了其在工业规模上的应用。本文基于此提出了在“心形结构”的高通量微通道反应器内合成MA重氮盐的连续流工艺。在单因素实验的基础上，采用Box-Behnken design（BBD）中心组合原理构建响应面模型对工艺进行优化，研究了不同反应条件之间交互效应对反应的影响并与实验室规模的半间歇合成工艺进行了比较。结果表明，微反应器内连续重氮化合成工艺对降低因素交互效应、提高工艺可控性、抑制平行副反应有显著的效果。经优化后的最佳工艺条件为n(MA)∶n(亚硝酸钠)∶n(盐酸)=1∶1.15∶2.67，反应温度为34.62℃，停留时间为45.07s，在此条件下MA重氮盐收率可达92%，相比于半间歇合成工艺提高了10%。这种新的合成方式可有效解决传统半间歇工艺中重氮化合成体系对温度的高敏感性，避免了反应温度控制困难、高潜在热失控风险带来的安全隐患。

关键词: 微反应器, 重氮化反应, 响应面分析法, 连续流工艺, 过程强化

Abstract:

The diazonium salt of methyl anthranilate (MA) is an typical diazo compound, which has been widely used in the field of modern organic synthesis due to its high chemical selectivity and high efficiency in the synthesis of complex molecules. The inherent defects in the traditional semi-batch synthesis process and the potential explosiveness of MA diazonium salt limit its application on industrial scale. In this paper, a continuous flow process for the synthesis of MA diazonium salt was proposed in a high-throughput microchannel reactor with “heart-cell” structure. Based on the single factor experiment, Box-Behnken design (BBD) center combination principle was used to construct the response surface model to optimize the process. The effects of interaction between different reaction conditions on the reaction were studied and compared with the laboratory scale semi-batch synthesis process. The results showed that the continuous diazotization process in micro reactor had significant effect on reducing the interaction effect of factors, improving the process controllability and inhibiting the parallel side reactions. The yield of MA diazonium salt of 92% was achieved under the optimized reaction conditions of n(MA)∶n(sodium nitrite)∶n(hydrochloric acid)= 1∶1.15∶2.67, reaction temperature 34.62℃ and residence time 45.07s, which is 10% higher than the semi-batch synthesis process. The high sensitivity to temperature of the diazotization synthesis system in the traditional semi-batch process can be effectively solved by this new synthesis method, which avoided the security hidden danger caused by the difficulty of reaction temperature control and the risk of high potential thermal runaway.

Key words: microreactor, diazotization, response surface methodology, continuous process, process intensification

中图分类号:

TQ246.4

王犇, 王超, 尹进华. 微反应器内邻氨基苯甲酸甲酯的连续重氮化工艺[J]. 化工进展, 2021, 40(10): 5678-5691.

WANG Ben, WANG Chao, YIN Jinhua. Continuous-flow diazotization of methyl anthranilate in microreactor system[J]. Chemical Industry and Engineering Progress, 2021, 40(10): 5678-5691.

图/表 22

图1 MA重氮盐合成方程式

图2 微通道混合脉冲结构

图3 微通道连续流重氮化反应的实验装置1~4—物料储罐；5~8—原料计量泵；9，10—预处理区；11—反应区；12—反应淬灭区；13—产物收集区

图4 MA与亚硝酸钠摩尔比对重氮化收率的影响

图5 MA与盐酸摩尔比对重氮化收率的影响

图6 反应温度对重氮化收率的影响

图7 反应时间对重氮化收率的影响

图8 流速对重氮化收率的影响

表1 微通道连续流实验因素及水平

水平	因素
水平	A	B	C	D
-1	1∶1.0	1∶2.4	25℃	30s
0	1∶1.1	1∶2.6	35℃	40s
1	1∶1.2	1∶2.8	45℃	50s

表2 半间歇实验因素及水平

水平	因素
水平	A	B	C	D
-1	1∶1.2	1∶2.8	5℃	10min
0	1∶1.3	1∶3.0	15℃	15min
1	1∶1.4	1∶3.2	25℃	20min

表3 实验设计矩阵及响应值

编号	因素编码值				连续收率/%		半间歇收率/%
编号	A	B	C	D	实测	预测	实测	预测
1	0	0	0	0	90.7	90.40	80.5	80.44
2	-11	0	-11	0	82.5	82.66	68.5	68.11
3	-11	1	0	0	87.8	87.58	78.0	77.98
4	1	-11	0	0	88.4	87.88	78.2	78.08
5	0	0	-11	-11	75.6	74.77	62.4	62.92
6	0	0	1	1	84.3	84.40	71.7	71.05
7	-11	-11	0	0	83.2	82.95	71.1	71.25
8	-11	0	0	1	86.8	86.68	76.2	76.20
9	0	0	0	0	90.0	90.40	80.1	80.44
10	-11	0	1	0	83.9	84.23	69.8	69.65
11	0	1	1	0	88.2	88.21	76.7	77.10
12	0	-11	0	-11	79.2	79.51	73.4	72.98
13	1	0	-11	0	85.5	85.39	69.8	69.80
14	1	0	0	-11	82.3	82.94	76.9	77.19
15	1	1	0	0	90.2	89.72	80.4	80.12
16	0	1	0	1	90.1	90.01	80.6	80.86
17	-11	0	0	-11	79.7	79.81	72.3	72.55
18	0	1	0	-11	82.5	82.99	77.4	77.26
19	0	0	-11	1	89.0	88.98	74.5	74.87
20	1	0	1	0	88.5	88.56	77.0	77.23
21	0	0	0	0	90.9	90.40	80.1	80.44
22	0	-11	-11	0	82.1	82.61	68.2	68.09
23	0	-11	0	1	87.3	87.03	76.4	76.38
24	0	0	0	0	90.1	90.40	80.7	80.44
25	0	0	1	-11	84.8	84.08	76.5	76.00
26	0	-11	1	0	84.1	84.33	69.9	70.42
27	0	0	0	0	90.3	90.40	80.8	80.44
28	0	1	-11	0	84.9	85.19	70.4	70.17
29	1	0	0	1	90.2	90.61	80.5	80.54

表4 连续流重氮化回归方程方差分析和显著性检验结果

来源	平方和和	自由度	均方	F值	P值
模型	446.06	14	31.86	111.65	＜0.0001
A	37.45	1	37.45	131.25	＜0.0001
B	31.36	1	31.36	109.91	＜0.0001
C	16.80	1	16.80	58.89	＜0.0001
D	158.41	1	158.41	555.14	＜0.0001
AB	1.96	1	1.96	6.87	0.0201
AC	0.64	1	0.64	2.24	0.1564
AD	0.16	1	0.16	0.56	0.4664
BC	0.42	1	0.42	1.48	0.2438
BD	0.063	1	0.063	0.22	0.6470
CD	48.30	1	48.30	169.27	＜0.0001
A²	17.04	1	17.04	59.72	＜0.0001
B²	19.77	1	19.77	69.28	＜0.0001
C²	82.71	1	82.71	289.84	＜0.0001
D²	92.23	1	92.23	323.22	＜0.0001
残差	3.99	14	0.27
失拟误差	3.39	10	0.34	2.26	0.2240
纯误差	0.60	4	0.15
总误差	450.02	28
标准偏差		0.53	预测系数R $P r e d 2$		0.9545
确定系数R²		0.9911	变异系数		0.62%
调整系数R $A d j 2$		0.9822	精密度		41.234

表4 连续流重氮化回归方程方差分析和显著性检验结果

来源	平方和和	自由度	均方	F值	P值
模型	446.06	14	31.86	111.65	＜0.0001
A	37.45	1	37.45	131.25	＜0.0001
B	31.36	1	31.36	109.91	＜0.0001
C	16.80	1	16.80	58.89	＜0.0001
D	158.41	1	158.41	555.14	＜0.0001
AB	1.96	1	1.96	6.87	0.0201
AC	0.64	1	0.64	2.24	0.1564
AD	0.16	1	0.16	0.56	0.4664
BC	0.42	1	0.42	1.48	0.2438
BD	0.063	1	0.063	0.22	0.6470
CD	48.30	1	48.30	169.27	＜0.0001
A²	17.04	1	17.04	59.72	＜0.0001
B²	19.77	1	19.77	69.28	＜0.0001
C²	82.71	1	82.71	289.84	＜0.0001
D²	92.23	1	92.23	323.22	＜0.0001
残差	3.99	14	0.27
失拟误差	3.39	10	0.34	2.26	0.2240
纯误差	0.60	4	0.15
总误差	450.02	28
标准偏差		0.53	预测系数R $P r e d 2$		0.9545
确定系数R²		0.9911	变异系数		0.62%
调整系数R $A d j 2$		0.9822	精密度		41.234

表5 半间歇重氮化回归方程方差分析和显著性检验结果

来源	平方和	自由度	均方	F值	P值
模型	661.71	14	47.26	239.50	＜0.0001
A	60.30	1	60.30	305.56	＜0.0001
B	57.64	1	57.64	292.08	＜0.0001
C	64.40	1	64.40	326.35	＜0.0001
D	36.75	1	36.75	186.22	＜0.0001
AB	5.52	1	5.52	27.98	0.0001
AC	8.70	1	8.70	44.10	＜0.0001
AD	0.023	1	0.023	0.11	0.7406
BC	5.29	1	5.29	26.81	0.0001
BD	0.01	1	0.01	0.051	0.8251
CD	71.40	1	71.40	361.82	＜0.0001
A²	23.81	1	23.81	120.64	＜0.0001
B²	18.00	1	18.00	91.21	＜0.0001
C²	348.35	1	348.35	1765.20	＜0.0001
D²	23.50	1	23.50	119.07	＜0.0001
残差	2.76	14	0.20
失拟误差	2.33	10	0.23	2.16	0.2385
纯误差	0.43	4	0.11
总误差	664.47	28
标准偏差		0.44	预测系数R $P r e d 2$		0.9788
确定系数R²		0.9958	变异系数		0.59%
调整系数R $A d j 2$		0.9917	精密度		56.170

表5 半间歇重氮化回归方程方差分析和显著性检验结果

来源	平方和	自由度	均方	F值	P值
模型	661.71	14	47.26	239.50	＜0.0001
A	60.30	1	60.30	305.56	＜0.0001
B	57.64	1	57.64	292.08	＜0.0001
C	64.40	1	64.40	326.35	＜0.0001
D	36.75	1	36.75	186.22	＜0.0001
AB	5.52	1	5.52	27.98	0.0001
AC	8.70	1	8.70	44.10	＜0.0001
AD	0.023	1	0.023	0.11	0.7406
BC	5.29	1	5.29	26.81	0.0001
BD	0.01	1	0.01	0.051	0.8251
CD	71.40	1	71.40	361.82	＜0.0001
A²	23.81	1	23.81	120.64	＜0.0001
B²	18.00	1	18.00	91.21	＜0.0001
C²	348.35	1	348.35	1765.20	＜0.0001
D²	23.50	1	23.50	119.07	＜0.0001
残差	2.76	14	0.20
失拟误差	2.33	10	0.23	2.16	0.2385
纯误差	0.43	4	0.11
总误差	664.47	28
标准偏差		0.44	预测系数R $P r e d 2$		0.9788
确定系数R²		0.9958	变异系数		0.59%
调整系数R $A d j 2$		0.9917	精密度		56.170

图9 残差正态概率图

图10 实测与预测比率图

图11 亚硝酸钠和盐酸交互效应对重氮化收率影响

图12 亚硝酸钠和反应温度交互效应对重氮化收率影响

图13 盐酸和反应温度交互效应对重氮化收率的影响

图14 反应温度和时间交互效应对重氮化收率影响

表6 Corning AFRTM微通道反应器与半间歇反应釜放大数据对比

反应器

单位体积换热面积/m²·m^-3

年产量

产量放大

方式

图15 焦油状副产物的组成及EI质谱谱图

图16 重氮基亲核取代反应

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