A Scalable Balz-Schiemann Reaction Protocol in a Continuous Flow Reactor

Podsumowanie

A detailed scalable continuous flow protocol is presented to synthesize an aryl fluoride from an aryl amine through the Balz-Schiemann reaction.

Streszczenie

The demand for aromatic fluorides is steadily increasing in the pharmaceutical and fine chemical industries. The Balz-Schiemann reaction is a straightforward strategy for preparing aryl fluorides from aryl amines, via the preparation and conversion of diazonium tetrafluoroborate intermediates. However, significant safety risks exist in handling the aryl diazonium salts when scaling up. In order to minimize the hazard, we present a continuous flow protocol that has been successfully performed at a kilogram scale that eliminates the isolation of aryl diazonium salts while facilitating efficient fluorination. The diazotization process was performed at 10 °C with a residence time of 10 min, followed by a fluorination process at 60 °C with a residence time of 5.4 s with about 70% yield. The reaction time has been dramatically reduced by introducing this multi-step continuous flow system.

Wprowadzenie

The Balz−Schiemann reaction is a classic method for replacing the diazonium group with fluorine by heating ArN₂⁺BF₄⁻ without a solvent^1,2. The reaction can be applied to a wide variety of aryl amine substrates, making it a generally applicable approach to synthesize aryl amines, which are frequently utilized for advanced intermediates in pharmaceutical or fine chemical industries^2,3. Unfortunately, harsh reaction conditions are often employed in the Balz-Schiemann reaction, and the reaction generates potentially explosive aryldiazonium salts^4,5,6,7,8. Other challenges associated with the Balz-Schiemann reaction are the formation of side products during the thermal decomposition process and its modest yield. In order to minimize the side product formation, thermal dediazotization can be performed in nonpolar solvents or using neat diazonium salts^9,10, which means the aryldizanium salts should be isolated. However, the diazotization of aromatic amines is generally exothermic and fast, which is a risk associated with the isolation of the explosive diazonium salt, especially in large-scale production.

In recent years, continuous flow synthesis technologies have helped to overcome the safety issues associated with the Balz-Schiemann reactions^11,12. Although there are some examples of diazotization of aromatic amines using continuous microreactors for deamination at positions para to aryl-chlorides, 5-azodyes, and chlorosulfonylation, these contributions were only reported on a laboratory scale^{13,14,15,16,17}. Yu and co-workers developed a continuous kilo-scale process for the synthesis of aryl fluorides¹⁸. They have shown that the improved heat and mass transfer of a flow system would benefit both the diazotization process and the fluorination process. However, they used two separate continuous flow reactors; therefore, the diazotization and thermal decomposition processes were investigated separately. A further contribution was published by Buchwald and co-workers¹⁹, where they presented a hypothesis that if the product formation was proceeding through the SN2Ar or SN1 mechanism, then the yield may be improved by increasing the concentration of the fluoride source. They developed a flow-to-continuous stirred tank reactor (CSTR) hybrid process in which the diazonium salts were generated and consumed in a continuous and controlled manner. However, the heat and mass transfer efficiency of a CSTR is not good enough as a tube flow reactor, and a large CSTR cannot be expected to be used with explosive diazonium salts in large-scale production. Subsequently, Naber and co-workers developed a fully continuous flow process to synthesize 2-fluoroadenine from 2,6-diaminopurine²⁰. They found that the exothermic Balz-Schiemann reaction was easier to control in a continuous flow manner and that the tubing dimensions of the flow reactor would influence the heat transfer and temperature control aspects - a tube reactor with large dimensions shows a positive improvement. However, the tube reactor's scaled-up effect will be notable, and the poor solubility of the polar aryl diazonium salt in organic solvents is troublesome for static tube reactors, which face a blockage risk. Even though remarkable progress has been established, there are still some problems associated with large-scale Balz-Schiemann reactions. Thus, the development of an improved protocol that would provide rapid and scalable access to aryl-fluorides is still significant.

The challenges associated with large-scale Balz−Schiemann reaction processing include the following:(i)the thermal instability of an accumulated diazonium intermediate over a short time period²¹; (ii) the long processing times; and (iii) the non-uniform heating or the presence of water in the diazonium fluoroborate, leading to uncontrollable thermal decomposition and increased by-product formation^22,23. Additionally (iv) in some flow processing modes, an isolation of the diazonium intermediate is still required due to its low solubility¹⁴, which is then fed into a uncontrolled rate decomposition reaction. The risk of handling a large quantity of in-line diazonium salt cannot be avoided. Thus, there is significant benefit in developing a continuous flow strategy to solve the abovementioned problems and avoid both the accumulation and the isolation of the unstable diazonium species.

In order to establish an inherently safer production of chemicals in pharmaceuticals, our group has focused on multi-step continuous flow technology. In this work, we apply this technology to the Balz−Schiemann synthesis on a kilogram scale in a way that eliminates the isolation of aryl diazonium salts, while facilitating efficient fluorination.

Protokół

CAUTION: Carefully check the properties and toxicities of the chemicals described here for the appropriate chemical handling of the relevant material as per the material safety data sheets (MSDS). Some of the chemicals used are detrimental to health, and special care must be taken. Avoid inhalation and contact with skin of these materials. Please wear the proper PPE during the whole process.

1. Preparation of feeds for continuous flow protocol

1. Purchase BF₃·Et₂O with a concentration of 8.1 mmol/mL. Label the glass bottle with 2.5 kg of BF₃·Et₂O as Feed A.
2. Prepare a solution of substrate 1 as Feed B. Add 12.7 L of tetrahydrofuran (THF) to a clean 50 L vessel with a mechanical stirrer. Start the stirrer at 150 rpm, and then add 2-Methylpyridin-3-amine (0.5 kg) carefully to the above vessel. Visually check for complete dissolution. Then stop the stirrer and transfer the solution into a container and label as Feed A.
   NOTE: Ensure that the water content on the Karl Fischer (KF) reaction of THF is below 0.5% w/w. The water content influences the generation of by-products, such as hydrolyzed OH Imp-1; therefore, anhydrous THF was used. If the water content of the reaction mixture is over 1%, the by-product percentage will increase up to 5%. THF with a <0.5% water content is a normal standard, not strictly for the anhydrous THF standard.
3. Prepare a solution of tert-butyl nitrite as Feed C. Add 10.7 L of THF to a clean 50 L vessel with a mechanical stirrer. Start the stirrer with moderate rpm and add tert-butyl nitrite (0.53 kg) to the above vessel. Stir for 10 min. Then transfer the solution into a container and label as Feed C.
4. Label a container with 25 L heptane as Feed D.
   ​NOTE: Ensure that the water content on the KF reaction of heptane is below 0.5%. There are two roles that heptane plays in this protocol: i) to dilute the diazonium salt slurries, which can slow down the gas stream during the diazonium decomposition process; and ii) to remove nonpolar impurities in the distillation process during the first-time phase separation.
5. Label a container with 2 L of THF as Feed E, which will be used as washing solution.

2. Continuous flow equipment setup

1. Prepare two modules of a microflow reactor with 9 mL of internal reaction volume, one dynamic mixing tube reactor with 500 mL of internal reaction volume, one constant flow pump with a PTFE pump head, and three constant flow pumps with a 316 L pump head.
2. Assemble the equipment according to the process flow sheet shown in Figure 1. Check the mechanical integrity of all the connections between pumps, pipelines, and flow reactors before use.
3. For the pumps, set up the following flow rates: pump A at 23.8 mL/min; pump B at 3.4 mL/min; pump C at 22.8 mL/min; and pump D at 50 mL/min.
4. Maintain the temperature regulation by setting the jacket outlet temperature of the premixing and diazonium salt formation zone at -5 °C and the jacket outlet temperature of the thermal decomposition zone at 60 °C.
5. For an equipment safety check and a leak-test, perform the following steps.
   1. Place the dosing pipelines of pumps A, B, C, and D into the Feed E bottle. Place the discharging pipeline into the waste collecting bottle.
   2. Start the pumps A, B, C, and D . Regulate the back pressure up to 3 bars, slowly.
   3. Observe the stability of each pump, and check all the joints, pipelines, and reactors for any solvent leakage.
   4. Observe the jacket inlet and outlet temperature of each zone and the real-time inlet pressure of each pump and check whether they are within the target ranges.
   5. Stop the pumps A, B, C, and D after 10 min of steady state equilibrium.

3. Continuous flow reaction processing

1. Place dosing pipelines A, B, C, and D into pumps A, B, C, and D, respectively. Place the discharging pipeline into the waste collecting bottle.
2. Start pumps A and B simultaneously and record the time. Start pump C after 30 s and pump D after 8 min.
3. Place the discharging pipeline into the product collecting vessel after 10 min of steady state equilibrium.
4. Observe and record the temperature of each zone and the pressure of each pump.
5. Place dosing pipeline B into Feed E at the completion of Feed B pumping.
6. Place the discharging pipeline into the waste collecting bottle. Place dosing pipelines A, C, and D into the Feed E bottle.
7. Stop pumps A, B, C, and D after 10 min of the washing process.

4. Distillation of organic solvents

1. Adjust the pH value to 1-2 by adding 4 M HCl into the product collecting vessel at 20-30 °C.
2. Separate the aqueous layer to an interim vessel.
   NOTE: After adding 4 M HCl to adjust the pH value, there are two layers in the vessel. The product was acidified in hydrochloride salt form, which can be dissolved in the bottom aqueous layer, while some nonpolar impurities were dissolved in the upper heptane layer.
3. Adjust the pH value of the above separated aqueous layer to 9-10 by adding 20% NaOH aqueous at 20-30 °C.
4. Add tert-butyl methyl ether (5.4 L) to the above vessel.
5. Stir the mixture for 10 min before letting the mixture stand for another 10 min.
6. Partition the mixture between the organic layer and the aqueous layer. Collect the organic layer into a container and discharge the aqueous layer into the separator vessel.
7. Add ter-butyl methyl ether (4.6 L) to the separator vessel.
8. Stir the mixture for 10 min before letting the mixture stand for another 10 min.
9. Partition the mixture between the organic layer and the aqueous layer. Keep the organic layer in the separator vessel and collect the aqueous layer in the waste container.
10. Add the first part of the separated organic layer into the separator vessel.
11. Wash the combined organic phase with 4% citric acid to pH 4-5.
12. Partition the above mixture and transfer the organic layer to distillation equipment.
13. Distill the organic solvents at 1 atm and 60 °C, and then vacuum distill (25 mmHg) at 60 °C to obtain the product.

Wyniki

The model reaction is shown in Figure 2. 2-Methylpyridin-3-amine (compound 1 in Figure 2) was chosen as the starting material to prepare 2-methylpyridin-3-fluoride (compound 3 in Figure 2) via the Balz-Schiemann reaction. The experimental parameters were systematically investigated by varying reaction temperature and residence time. Feed A is 0.35 M 2-methylpyridin-3-amine in THF. Feed B is pure BF₃·Et_2...

Dyskusje

A continuous flow protocol of the Balz-Schiemann reaction has been successfully performed through a combination of a micro-channel flow reactor and a dynamically mixed flow reactor. This strategy features several advantages compared with the batch process: (i) it is safer with controlled diazonium salt formation; (ii) it is more amenable to a higher reaction temperature, 10 °C versus -20 °C; and (iii) it is more efficient without isolation of the diazonium intermediate, two steps in one continuous process. Spec...

Materiały

Name	Company	Catalog Number	Comments
2-Methylpyridin-3-amine	Raffles Pharmatech Co. Ltd	C2021236-SM5-H221538-008	HPLC: >98%, Water by KF ≤0.5%
316L piston constant flow pump	Oushisheng (Beijing) Technology Co.,Ltd	DP-S200
BF3.Et2O	Whmall.com	B802217
Citric acid	Titan Technology Co., Ltd	G83162G
con.HCl	Foshang Xilong Huagong	1270110101601M
Dynamically mixed flow reactor	Autichem Ltd	DM500	316L reator with 500 mL of internal volume
Heptane	Shenzhen Huachang	HCH606	Water by KF ≤0.5%
Micro flow reactor	Corning Reactor Technology Co.,Ltd	G1 Galss AFR	Glass module with 9 mL of internal volume
PTFE piston constant flow pump	Sanotac China	MPF1002C
Sodium hydroxide	Foshang Xilong Huagong	1010310101700
tert-Butyl methyl ether	Titan Technology Co., Ltd	01153694
tert-Butyl nitrite	Whmall.com	XS22030900060
Tetrahydrofuran	Titan Technology Co., Ltd	1152930	Water by KF ≤0.5%