triazole Using a Continuous-Flow Reactor - American Chemical Society

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Conversion of 2,4,6-Trimethylaniline to 3(Mesitylthio)-1H-1,2,4-triazole Using a Continuous-Flow Reactor Zhiqun Yu, Jianyang Chen, Jiming Liu, Zhengkang Wu, and Wei-Ke Su Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00362 • Publication Date (Web): 26 Nov 2018 Downloaded from http://pubs.acs.org on November 26, 2018

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Organic Process Research & Development

Conversion of 2,4,6-Trimethylaniline to 3-(Mesitylthio)1H-1,2,4-triazole Using a Continuous-Flow Reactor Zhiqun Yu,† Jianyang Chen,† Jiming Liu,‡ Zhengkang Wu‡ and Weike Su*,†,‡ †National

Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative

Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P.R. China ‡Key

Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of

Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P.R. China * Correspondent. Tel: (+86)57188320899. E-mail: [email protected].

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TOC Graphic:

n-heptane v4 = 4.0 mL/min NH2 T + HCl (aq.)

T T

T

145 psi

v1 = 36.8 mL/min

BPR T1 = 10 oC 1 = 10 S

NaNO2 (aq.)

T2 = 25 oC 2 = 40 S

v2 = 5.4 mL/min N

S HS

N

+ NaOH

HN N in MeOH

N

T

Temperature sensor

v3 = 47.6 mL/min


NH

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Abstract: An expeditious and high efficient continuous-flow process has been developed for the synthesis of 3-(mesitylthio)-1H-1,2,4-triazole. The starting material 2,4,6-trimethylaniline was diazotized to give diazonium chloride, followed by azo-coupling with 1H-1,2,4-triazole-3-thiol and dediazoniation to provide 3-(mesitylthio)-1H-1,2,4-triazole in 85% yield with a productivity of 344 g/h. The side reactions such as hydrolysis, dimerization and intramolecular coupling, were significantly inhibited by the continuous-flow technology. Key Words: Continuous-Flow; Diazotization; Dediazoniation; 3-(Mesitylthio)-1H-1,2,4-triazole.

Introduction Aromatic sulfides play a crucial role in the synthesis of many pharmaceutically active agents[1]. The target molecule 3-(mesitylthio)-1H-1,2,4-triazole is the essential intermediate for the synthesis of Cafenstrole which is an efficient and low toxicity triazole amide herbicide (Scheme 1)[2]. . CON(C2H5)2 N N

O S O

N

Scheme 1. The structural formula of Cafenstrole. In the reported literature, there are mainly three methods for synthesizing the target product 3(mesitylthio)-1H-1,2,4-triazole (Scheme 2). In the first method[3], 2-bromo-1,3,5-trimethylbenzene and 1H-1,2,4-triazole-3-thiol are used as raw materials, and DMF is used as a solvent to synthesize the target product under the action of potassium carbonate. In the second method[4], 2-iodo-1,3,5-trimethylbenzene and 1H-1,2,4-triazole-3-thiol are used as raw materials, and the cuprous oxide is used as a catalyst to synthesize the target product under the action of sodium carbonate. In the third way[5], 2,4,6ACS Paragon Plus Environment


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trimethylaniline is used as a raw material to prepare the target product by diazotization and dediazoniation. Disadvantages in these processes, such as the first process suffers from a high cost of raw materials and a long reaction time. The shortcomings of the second way are harsh reaction conditions and high cost of raw materials. The yield of the target product in the third (78%) is lower than that in the first two methods (excellent yield of 86%), but the raw materials in the third method are much cheaper, and the reaction conditions are milder. However, in the third method, an extremely unstable intermediate diazonium salt is generated and accumulated. The diazonium salt is easily decomposed and released nitrogen, which may lead to accidents.[6] Considering the impact of safety factors and unsatisfied yield, so we chose the third method for further optimization.

Br

K2CO3, DMF

i

S

SH

N

N N

NH

excllent yield

HN N

I ii

Na2CO3, Cu2O N

S

SH

N N

86%

NH

HN N

NH2 iii

NaNO2 HCl

N 2+

N SH , NaOH 1) HN N 2) H

S

+

N N

NH

78%

Scheme 2. Methods for synthesizing the target product. Recently, continuous-flow technology has been widely reported and researched in both industry and academia[7]. Compared with the traditional batch reactor technology, the continuous-flow technology has great advantages, such as precise control of reaction parameters (reaction temperature, reaction time and molar flow ratio), excellent heat and mass transfer efficiency which provides better safety profile [8]. The production of diazonium salts and other intermediates related to diazonium salts using a batch reactor ACS Paragon Plus Environment

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requires a lot of time (cooling, sodium nitrite addition, low-temperature reaction, diazonium salt storage) and there are safety hazards in the process (reaction exothermic, unstable intermediate). However, continuous-flow technology can reduce overall reaction time, since a series of reactions can be conducted continuously. Meanwhile, the continuous-flow process can greatly inhibit the occurrence of consecutive side reaction because of the plug-flow reactor which there are almost no back mixing[9]. Therefore, we hope to design an expeditious and high efficient continuous-flow process to obtain the target product. Results and Discussion Adapting the Batch Chemistry to Continuous-Flow. The synthesis of 3-(mesitylthio)-1H-1,2,4-triazole in a batch process is usually divided into two steps, diazotization and dediazoniation. Diazotization usually requires a low temperature of -5~0 oC, followed by a higher temperature of 10 oC for the dediazoniation reaction. The yield of the target product in the literature is around 78%[5], however, the yield that we could obtain was about 60%. Subsequently, LCMS detection and structural identification reveled that there were three main by-products (Scheme 3). Byproduct a (10%) is produced by hydrolysis of diazonium salt, b (5%) is created from the reaction of diazonium salt with unreacted 2,4,6-trimethylaniline. The reason for the formation of these two byproducts in the batch process is that diazotization temperature is low, and the reactants are in a solid-liquid state, resulting in competing side reactions. Decomposition via hydrolysis of the diazonium salt produces a. And under severe back mixing, a consecutive side reaction occurs, resulting in b. By-product c (15%) is formed during dediazoniation which is caused by intramolecular displacement of the diazonium moiety. Theoretically, the continuous-flow reactor has high heat transfer efficiency, and the heat released by diazotization reaction can be removed in time to avoid hydrolysis of the diazonium salt. And the continuous-flow reactor is very close to the plug-flow reactor in which the back mixing can be ignored. ACS Paragon Plus Environment


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Thus consecutive by-products a and b can be inhibited by continuous-flow process. As for the by-product c, the proposal formation mechanism is shown in Scheme 4. In alkaline condition, hydroxide ions attack hydrogen on the ortho-methyl group to form a carbon anion, and then attack the diazo group to undergo an intramolecular coupling reaction[10]. The alkaline condition has an important effect on this side reaction, so in order to inhibit the reaction, we did the following experiments to investigate the effect of equivalent of sodium hydroxide. As shown in Figure 1, when the amount of sodium hydroxide was 2.5 equiv., the yield arrived at a maximum value of 63%. When the amount of sodium hydroxide was too low or too high, the yield was not high. It was because that the weaker alkalinity led to the weak nucleophilic ability of sulfur anion, and stronger alkalinity resulted in increasing of intramolecular coupling by-product c. In batch manner, the diazo solution was slowly added to the triazole solution. And it could be considered that the sodium hydroxide was in a large excess, which was advantageous for the intramolecular coupling side reaction. Although the problem of excessive sodium hydroxide could be avoided by one-off feeding, a large amount of diazonium salt accumulated in dediazoniation reaction, which could easily lead to runaway or even explosion accident. In the continuous-flow process, diazonium salt and triazole solution entered flow reactor at the same time, which could effectively avoid the safety risk because of the excellent control ability of the reactor.


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N

N

H N

b NH2

N 2+

NaNO2

NH2

H N

OH-

HCl

N c H 2O

OH

a

Scheme 3. Main by-products HO-

H

CH2 N

N

CH2 -H

+

N

N

N N

N NH

Scheme 4. Proposal formation mechanism of 4,6-dimethyl-1H-indazole

Figure 1. Effect of the equivalent of sodium hydroxide on the yield of the product. Continuous-Flow Process for Diazotization Reaction. The continuous-flow setup for diazotization reaction was shown in Figure 2. Commercially available 2,4,6-trimethylaniline was combined with hydrochloric acid as one feed stream (material A) and sodium ACS Paragon Plus Environment


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nitrite in water as a separate stream (material B). And then the two streams were pumped into a tubular reactor (Hastelloy C276[11], 3.3mm i.d., 5.5mm o.d.) via a T-joint (Hastelloy C276, 3.3mm i.d.) by two plunger metering pumps (PTFE, BOOK). After a certain residence time, the reaction solution was collected in a thermostatic container where urea had been added in advance to quench the diazotization reaction. And then the diazo solution is slowly added to a vessel containing the 1H-1,2,4-triazole-3-thiol sodium hydroxide methanol solution. In the reaction vessel, the reaction mixture was stirred for 0.5 h and then samples were analyzed by HPLC, the reaction yield was calculated by the external standard method. NH2 T + HCl (aq.)

T

T

T1, 1

NaNO2 (aq.) T

Temperature sensor

urea

Figure 2. Continuous-flow process for diazotization reaction. Material A is 1.7 mol/L 2,4,6trimethylaniline aqueous hydrochloric acid with a flow rate of 36.8 mL/min; Material B is 12.0 mol/L aqueous sodium nitrite with a flow rate of 5.1 mL/min. The related parameters of diazotization, such as residence time (τ1), reaction temperature (T1), molar flow ratio of 2,4,6-trimethylaniline and NaNO2 (FA : FN), were investigated systematically. The result was shown in Figure 3. The yield increased with prolonged residence time τ1, but after more than 20 s, the yield no longer increased but instead decreased because of the decomposition of diazonium salt. And the increasing in temperature accelerated the degradation rate of diazonium salt, resulting in the ACS Paragon Plus Environment

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occurrence of side reactions and the decrease of yield. And the optimum molar flow ratio of NaNO2 and 2,4,6-trimethylaniline was 1.05 : 1. Consequently, the most appropriate conditions for diazotization reaction were decided as follows: τ1 = 10 s, T1 = 10 oC, FA : FN = 1 : 1.05. These conditions resulted in an increased yield from 60% to 72% with the by-products a and b reduced from 15% to less than 3% (Figure 4), indicating that the effect of the continuous flow diazotization reaction was achieved.

Figure 3. Effect of residence time (τ1), temperature (T1) and molar flow ratio of sodium nitrite and 2,4,6-trimethylaniline (FN : FA) on the yield of product.

Figure 4. Content of a and b in two manners. ACS Paragon Plus Environment


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Continuous-Flow Process for Dediazoniation Reaction. By-products a and b were greatly reduced by continuous-flow diazotization, which proved that the previous speculation was correct. Next, we focused on optimization of continuous-flow dediazoniation process to reduce by-product c. As shown in Figure 5, the setup used two plunger metering pumps to introduce the feed streams of combination of 2,4,6-trimethylaniline in hydrochloric acid (material A) and aqueous sodium nitrite (material B). A T-joint (Hastelloy C276, 3.3mm i.d.) was used as a mixer to connect reacting tube (Hastelloy C276, 3.3mm i.d., 5.5mm o.d.). And then the diazo solution was mixed with the third stream of a combination of 1H-1,2,4-triazole-3-thiol in methanol and sodium hydroxide (material C) via the T-joint, and pumped into the second tubular reactor for the dediazoniation reaction. After a period of residence time, the reaction solution was collected, and then after removing methanol, the crude product was obtained by adjusting the pH to 3~4, filtering, washing and drying. Samples were analyzed by HPLC and the yield was calculated by the external standard method. The related parameters of dediazoniation, such as residence time (τ2), reaction temperature (T2), molar flow ratio of triazole and 2,4,6-trimethylaniline (FT : FA), were investigated systematically, and the results were shown in Figure 6. The conversion rate was slow at lower temperature, and due to the instability of the diazonium salt at a higher temperature, resulting in decreased reaction yield. The reason was that diazonium salt was prone to decomposition or other side reactions occurred with increasing temperature (Figure 6a). As the residence time was prolonged, the conversion rate and the yield were increased. After 40 s, the yield was almost unchanged, so the appropriate residence time was 40 s (Figure 6b). The equivalent of triazole had a significant effect on the yield of the reaction. When FT : FA was increased from 1.05 to 1.2, the yield increased by 14%, but continued to increase, the yield remained unchanged, so FT : FA = 1.2 : 1 was chosen (Figure 6c). Therefore, a maximum yield of 85% was obtained ACS Paragon Plus Environment

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when reaction temperature T2 = 25 oC, residence time τ2 = 40 s and molar flow ratio of triazole and diazo solution FT : FA = 1.2 : 1 were picked. The dediazoniation reaction by continuous-flow solved the problems of pH control and hidden trouble of material clashing by batch process, which also inhibited the intramolecular coupling by-product c significantly. However, since the reaction must be carried out under alkaline condition, the intramolecular coupling side reaction could not be completely avoided. But, compared with batch dediazoniation process, by-product c was greatly reduced from 15% to less than 2%, and the reaction yield increased to 85%. Within this two-step continuous-flow process, the reaction yield was improved to greater than 85% After isolation, the crude product was obtained in 94% yield with a purity of 91%. However, qualified product (98% purity) was obtained only by the further purification process. NH2 T

T + HCl (aq.)

T

T

145 psi

A

BPR o

T1 = 10 C 1 = 10 S

NaNO2 (aq.)

T2, 2

B N

HS

+ NaOH HN N in MeOH

T

Temperature sensor

C

Figure 5. Continuous-flow dediazoniation process. Material A is 1.7 mol/L 2,4,6-trimethylaniline aqueous hydrochloric acid with a flow rate of 36.8 mL/min; Material B is 12.0 mol/L aqueous sodium nitrite with a flow rate of 5.4 mL/min. Material C is 1.5 mol/L 1H-1,2,4-triazole-3-thiol methanol and aqueous sodium hydroxide with a flow rate of 40.0 mL/min. T1 = 10 oC，τ1 = 10 s.



a

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b

c Figure 6. Effect of temperature (T2), residence time (τ2) and molar flow ratio of triazole and diazo solution (FT : FA) on the yield of product. Advanced continuous-flow process. After dediazoniation reaction, target product was in the form of sodium salt in reaction solution with a good water solubility, while the water solubility of by-products was poor. Therefore, we considered adding inert solvent with poor water solubility in the dediazoniation reaction to extract the by-products in situ, which was also beneficial to inhibit fouling of reacting tube. As shown in Figure 7, in comparison with the previous process, a new stream of inert solvent was introduced into the second joint. For the selection rules of inert solvent, we considered good solubility of by-products, poor water solubility, and low price and toxicity. Therefore, n-heptane was chosen, and the impurities could be extracted in situ. The flow rate of n-heptane should be chosen without changing the flow pattern so as not to affect the reaction and satisfy the requirement of impurity extraction. We had tried the n-heptane flow rate of 2 mL/min, 4 mL/min, 6 mL/min to 20 mL/min. It was found that when the flow rate was below 4 mL/min, ACS Paragon Plus Environment

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the extraction effect was not very good and the extraction effect above 4 mL/min was the same, and the flow pattern would not be destroyed, so the flow rate of n-heptane was set at 4 mL/min. These changes resulted in a 86% isolated yield with a product purity of 98% without further purification. n-heptane D NH2 T

T + HCl (aq.)

T

T

A

145 psi

BPR o

T1 = 10 C 1 = 10 S

NaNO2 (aq.)

o

T2 = 25 C 2 = 40 S

B N

S HS

+ NaOH HN N in MeOH

N N

T

NH

Temperature sensor

C

Figure 7. Advanced continuous-flow process. Material A is 1.7 mol/L 2,4,6-trimethylaniline aqueous hydrochloric acid with a flow rate of 36.8 mL/min; Material B is 12.0 mol/L aqueous sodium nitrite with a flow rate of 5.4 mL/min. Material C is 1.5 mol/L 1H-1,2,4-triazole-3-thiol methanol and aqueous sodium hydroxide with a flow rate of 47.6 mL/min. Material D is n-heptane with a flow rate of 4.0 mL/min. T1 = 10 oC, τ1 = 10 s, T2 = 25 oC, τ2 = 40 s. The comparisons in the different operation manners were summarized to underline the advantages of continuous-flow process. As shown in Figure 8, the main by-products (a, b and c) was significantly inhibited in this two-step continuous-flow process. As shown in Table 1, the reaction time was greatly reduced in continuous-flow process. The superior mass and heat transfer advantages and excellent control over reaction temperature would minimize the side reactions. In a word, the synthesis of the target product by continuous-flow process not only increased the yield, but also improved the purity. ACS Paragon Plus Environment


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Table 1. Comparison of batch and continuous-flow process. reaction attribute

batch

advanced continuous-flow

reaction yield/%a

60

85

reaction time

3h

50 s

diazotization

0

10

dediazoniation

10

25

91

98

temperature/oC

purity of crude product/% a

Reaction yield was determinate by external standard method.

Figure 8. Content of the by-products a, b and c in different manners. Conclusion In summary, an expeditious and high-yielding process for synthesis of 3-(mesitylthio)-1H-1,2,4triazole from 2,4,6-trimethylaniline via a continuous-flow reactor has been set up. The consecutive side reaction and intramolecular coupling side reaction were significantly inhibited by continuous-flow process. The final product was obtained with an isolated yield of 86% and a purity of 98%. ACS Paragon Plus Environment

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Experimental section All chemicals were purchased from commercial sources and used without purification. Highperformance liquid chromatography (HPLC) analysis was carried out a FULI 2200 high-performance liquid chromatography. HPLC conditions: C18 chromatographic column; 85% HPLC methanol and 15% ultrapure water as mobile phase; mobile phase flow rate 1 mL/min; detection wavelength at 254 nm. Batch Experiment 2,4,6-Trimethylaniline (13.5 g, 0.1 mol) was dissolved in H2O (40 mL) and placed in a 100 mL glass jar, then hydrochloric acid (30%, 27.25 g, 0.22 mol) added with stirring. The mixture was heated to 60 oC into a clarification solution and then cooled. After that, aqueous sodium nitrite was prepared from sodium nitrite (7.2 g, 0.105 mol) and 10 mL water at r.t.. After 2,4,6-trimethylaniline hydrochloric was cooled to -5 oC, the aqueous sodium nitrite was added in. Diazotization was initiated by the slow addition of aqueous sodium nitrite, and the temperature was kept between -5 ~ 0 oC. And then, the reaction mixture continued to stir for 20 min while the temperature was between -5 ~ 0 oC. Then the mixture was added to a 500 mL flask with well-mixed 1H-1,2,4-triazole-3-thiol (11 g, 0.11 mol), sodium hydroxide (13 g, 0.25 mol), and 40 mL H2O in it at 10 oC. After addition, the mixture was maintained at 10 oC for 30 min. Finally, the methanol was removed out, and the pH was adjusted to 3~4, and the crude product was filtered. About 13.9 g of crude product in 64% yield and 91% purity was obtained. 1H NMR (400 MHz, DMSO-d6) δ/ppm: 13.95 (s, 1H), 8.48 (s, 1H), 7.03 (s, 2H), 2.38 (s, 6H), 2.28 (s, 3H). Advanced Continuous-flow Process. As shown in Figure 7, a mixture of 2,4,6-trimethylaniline (135 g, 1.0 mol), hydrochloric acid (30%, 272.5 g, 2.2 mol), and 400 mL H2O was prepared. Aqueous sodium nitrite was prepared from sodium nitrite (72 g, 1.05 mol), and 100 mL of water. The aniline hydrochloride (36.8 mL/min) and aqueous ACS Paragon Plus Environment


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sodium nitrite (5.4 mL/min) were pumped into the reacting tube in the thermostat (10 oC) through a Tjoint. After a residence time of 10 s, a mixture of 1H-1,2,4-triazole-3-thiol (120 g, 1.2 mol), sodium hydroxide (130 g, 2.5 mol) in 400 mL methanol (47.6 mL/min) and n-heptane (4.0 mL/min) were pumped into the second reacting tube via a cross mixer. Then the mixture flowed into the second tube reactor which was immersed in a thermostat (25 oC). A back pressure regulator (BPR) was installed at the end of pipe adjusting the pressure value of 145 psi. After a residence time of 40 s, the mixture was collected in a collecting vessel with stirring. After liquid separation, removing the organic phase, and taking aqueous phase to adjust the pH to 3~4, filtering, washing and drying, about 188 g yellow solid was obtained in a yield of 86% and a purity of 98%.

Acknowledgment We are grateful to the Zhejiang Provincial Key R&D Project (No. 2018C03074) and the National Natural Science Foundation of China (No. 21776254) for financial support.

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triazole Using a Continuous-Flow Reactor - American Chemical Society

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