Application of Continuous Flow-Flash Chemistry to Scale-up Synthesis

Article Cite This: Org. Process Res. Dev. 2019, 23, 1420−1428

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Application of Continuous Flow-Flash Chemistry to Scale-up Synthesis of 5‑Cyano-2-formylbenzoic Acid Masaki Seto,*,† Shinichi Masada,† Hirotsugu Usutani,‡,∥ David G. Cork,‡,⊥ Koichiro Fukuda,†,§ and Tetsuji Kawamoto*,†,§ †

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Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan ‡ Process Chemistry, Pharmaceutical Sciences, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan S Supporting Information *

ABSTRACT: Efficient scale-up synthesis of 5-cyano-2-formylbenzoic acid or its cyclic isomer 6-cyano-3-hydroxy-2-benzofuran1(3H)-one (1) as a key intermediate for various biologically important compounds has been achieved from isopropyl 2-bromo5-cyanobenzoate (8c) by means of continuous flow-flash chemistry using flow microreactors. It was found that Br/Li exchange reaction of 8c, bearing both a carboisopropoxy group and a cyano group, with BuLi took place within 0.1 s at −50 °C, and the resulting highly reactive aryllithium intermediate underwent formylation with DMF to afford 1, which is extremely difficult to achieve by a conventional batch process. Optimization of the continuous flow-flash reaction conditions and modification of the reaction system brought about the production of 237 g of 1 from 897 g of 8c in 270 min, without purification by column chromatography. The results suggest that phthalaldehydic acid derivatives bearing electrophilic group(s) can be synthesized conveniently from the corresponding 2-bromobenzoic acid esters by means of flow-flash chemistry using flow microreactors. KEYWORDS: flow synthesis, flash chemistry, flow microreactor, 5-cyano-2-formylbenzoic acid, alkoxycarbonyl group, cyano group

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INTRODUCTION Phthalaldehydic acid1 derivatives have been used widely as key intermediates for various heterocyclic compounds of biological importance, such as isoindolin-1-one,2 dihydroisoindolo[2,1a]quinolin-11-one,3 benzo[c]thiophen-1(3H)-one,4 phthalazin-1(2H)-one,5 6H-isochromeno[4,3-b]pyridin-6-one,6 and 2-benzofuran-1(3H)-one7 derivatives. Among them 5-cyano-2formylbenzoic acid or the cyclic 6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1) derivatives2e−g,3a,b have been reported to be employed as key intermediates for synthesis of the 3-cyanodihydroisoindolo[2,1-a] quinolin-11-one derivative (2)3 as an inhibitor of tyrosyl-DNA phosphodiesterase I (Tdp1) and topoisomerase I (Top1), and they would also be potential key intermediates for various biologically active compounds bearing an isoindolin-1-one pharmacophore substituted at the C(6) position with a cyano group (3)8a and (4)8d or a 1,2,4-oxaziazol-3-yl group (5)9a and (6)9c (Figure 1).8,9 It is well-known that various phthalaldehydic acid derivatives are synthesized conveniently from 2-bromobenzaldehyde protected with lithium morpholide1c or 2-bromobenzoic acid2a−c,4b,10 derivatives through their treatments with BuLi followed by carboxylation or formylation of the resulting aryllithium intermediates with CO2 or DMF, respectively. However, the above methods have generally been limited to the syntheses of phthalaldehydic acid derivatives without electrophilic functional group(s) because highly reactive aryllithium intermediates bearing electrophilic functional group(s) are very difficult to generate. Therefore, some of the phthalaldehydic acid derivatives2d−g,3a,b involving (1) have been synthesized via the corresponding phthalide derivatives © 2019 American Chemical Society

through their bromination, followed by hydrolysis of the resulting 3-bromophthalide derivatives (Scheme 1). Yoshida et al. reported that by means of flow-flash chemistry11 using flow microreactors, aryl bromides bearing alkoxycarbonyl,12 nitro,13 cyano,14 and other electrophilic functional groups15 generate highly reactive aryllithium intermediates through Br/Li exchange reaction on treatment with BuLi, which can then react with various electrophiles without affecting the electrophilic functional groups and giving compounds that are generally difficult to obtain by conventional batch processes. The method was anticipated to be applicable for an efficient synthesis of 1 from 2-bromo-5-cyanobenzoic acid ester (8) by Br/Li exchange reaction followed by formylation of the resulting highly reactive aryllithium intermediate with DMF and its scale-up synthesis through the continuous operation of flow-flash synthesis using flow microreactors (Scheme 1). Generation and reaction of aryllithium compounds bearing an alkoxycarbonyl12 or a cyano14 group have been reported so far; however, flow-flash syntheses of those possessing both an alkoxycarbonyl and a cyano group have not been reported. From these points of view, it should be intriguing to investigate Br/Li exchange reactions of 8 followed by formylation of the resulting aryllithium intermediate with DMF for efficient synthesis of 1. The present paper describes investigation of efficient synthesis of 5-cyano-2-formylbenzoic acid or its cyclic isomer Received: May 1, 2019 Published: May 30, 2019 1420

DOI: 10.1021/acs.oprd.9b00180 Org. Process Res. Dev. 2019, 23, 1420−1428

Organic Process Research & Development

Article

Figure 1. Biologically important compounds derived from 5-cyano-2-formylbenzoic acid or 6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1).

Scheme 1. Conventional Synthesis of 1 from 7 and Investigation of Efficient Synthesis of 1 from 8 by Means of Flow-Flash Chemistry Using Flow Microreactorsa

a

(i) Bromination followed by hydrolysis;3 (ii) BuLi then DMF (flow).

Figure 2. Set-up of the lithiation-formylation flow-flash reaction system for synthesis of 1 and 9 from 8.

Initially, continuous streams of solutions of a series of 2bromo-5-cyanobenzoic acid ester (8a−d, 0.2 M in THF) and BuLi (0.22 M in hexane) were delivered into T-shaped mixer (M1) by syringe pumps, and the resulting highly reactive phenyl lithium intermediate was provided into T-shaped mixer (M2) for formylation with a solution of DMF (2.0 M in THF), provided by a syringe pump at −50 °C. The reaction solution obtained from tube reactor (L2) was treated with aqueous 1 N HCl solution at 0 °C before measurements of the ratios of 8, 1, 9, and byproducts including 10 and 11 were carried out by HPLC. The results are shown in Table 1.

6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1), from 2bromo-5-cyanobenzoic acid ester (8) as well as scale-up synthesis using continuous flow-flash chemistry with flow microreactors.

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RESULTS AND DISCUSSION Investigation of Continuous Flow-Flash Synthesis of 1 from 8 Using Flow Microreactors. To investigate synthesis of 1 from 8 by means of flow-flash chemistry using flow microreactors, a flow-flash chemistry reaction system composed of two T-shaped mixers (M1 and M2) and two microtube reactors was set up (Figure 2). 1421



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Table 1. Feasibility Study for Synthesis of 1 and 9 from 8 by Flow-Flash Chemistry Using Flow Microreactorsa HPLC area (%)c entry

substrate

A (M)

B (mL/min)

C (M)

D (mL/min)

E (M)

F (mL/min)

τ (ms)

8x

1

9x

byproductsd

1 2 3 4 5 6

8a 8b 8b 8c 8c 8d

0.1 0.1 0.1 0.2 0.2 0.2

10 10 5.0 6 6.0 6.0

0.1 0.1 0.1 0.22 0.22 0.2

10 10 5.25 6.0 6.0 6.0

1.0 1.0 1.0 2.0 2.0 0.2

10 10 10 6.0 6.0 6.0

80 80 160 160 240 240

30 36 14 13 N.D. 1.5

6 12 14 42 30 8

0 0 0 9 3 58

62 50 66 10 21 −

b

At −50 °C (bath temperature). bResidence time. cProducts and byproducts were not isolated. dTotal of byproducts 10 and 11, identified by their HPLC retention time. Various amounts of unidentified byproducts were also produced. a

Table 2. Effects of Reaction Temperature and Residence Time on Flow-Flash Synthesis of 1 and 9c from 8c Using Flow Microreactorsa

HPLC area (%) entry

temp (°C)b

G (mL/min)

Hc (mm)

τd (ms)

Ie (mm)

8c

1

9c

byproductsf

1 2 3 4 5 6 7

0 0 −25 −50 −80 −80 −80

10 20 10 10 10 10 20

1.0 1.0 1.0 1.0 1.0 0.5 0.5

70.7 35.3 70.7 70.7 70.7 17.7 8.8

1.0 1.0 1.0 1.0 1.0 0.5 0.5

N.D. N.D. N.D. N.D. 28.8 53.2 16.5

3.8 9.6 14.6 36.8 15.8 14.1 24.0

N.D. N.D. N.D. N.D. N.D. N.D. N.D.

12.6 13.1 13.4 21.1 17.5 9.9 18.5

a

[8c] = 0.2 M in THF; [BuLi] = 0.2 M in hexane; [DMF] = neat, 2.0 mL/min. bBath temperature. cInner diameter of microtube reactor (L1). Residence time. eInner diameter of microreactor (M2). fTotal of byproducts 10c and 11c, identified by their HPLC retention time. Various amounts of unidentified byproducts were also produced.

d

It was found that the flow-flash chemistry reactions at −50 °C gave rise to almost completion of the Br/Li exchange reaction of 8 within 240 ms, to afford a mixture of 1 and 9 concomitant with byproducts including 10 and 11 depending on the alkoxycarbonyl group of 8:12 Compounds 8a and 8b gave 1 in lower yield than 8c, with significant formation of byproducts even in the Br/Li exchange reactions of 80 and 160 ms at −50 °C (entries 1−3). On the other hand, 8d was found to afford 9d as the major product (entry 6), which would need purification by column chromatography on silica gel. Considering that 8c is available more easily than 8d as a substrate for scale-up synthesis and purification of 1 without column chromatography is possible

by back extraction of the reaction mixture and crystallization, flow-flash synthesis of 1 from 8c using flow microreactors was investigated for a scale-up synthesis. Thus, continuous streams of solutions of 8c (0.2 M in THF) and BuLi (0.2 M in hexane) were delivered into a T-shaped mixer (M1, ϕi.d. = 0.25 mm) and the resulting aryllithium intermediate was provided into a second T-shaped mixer (M2) under varying reaction conditions (reaction temperature, reaction tube (L1), residence time (τ), and T-shaped mixer (M2)) where a continuous stream of DMF was delivered without dilution to enhance formylation of the aryllithium intermediate with DMF. The reaction solution was treated with an aqueous 1 N HCl solution at 0 °C before 1422



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Table 3. Effects of the Concentrations of the 8c and BuLi Solutions and Residence Times on the Flow-Flash Synthesis of 1 and 9c from 8c Using Flow Microreactorsa

HPLC area (%) entry 1 2 3 4 5 6

f

J (M)

K (mL/min)

L (M)

M (mL/min)

N (mm)

O (cm)

τ (ms)

8c

1

9c

byproductse

0.2 0.2 0.2 0.4 0.4 0.8

10 10 10 10 20 10

0.2 1.6 1.6 1.6 1.6 1.6

10 1.25 1.25 2.5 5 5

1.0 0.5 0.5 0.5 0.5 0.5

3.0 3.0 12.5 3.0 3.0 3.0

70.7 31.4 131 28.3 14.1 23.6

N.D. 4.6 N.D. 1.5 N.D. 1.5

36.8 27.0 16.7 28.4 33.5 10.1

N.D. 2.2 2.6 2.0 5.1 3.3

21.1 16.4 12.2 12.2 18.3 11.3

b

c

d

At −50 °C (bath temperature); DMF (neat), 2.0 mL/min. bInner diameter of microtube reactor (L1). cLength of microtube reactor (L1). Residence time. eTotal of byproducts 10c and 11c, identified by their HPLC retention time. Various amounts of unidentified byproducts were also produced. fData from Table 2 entry 4. a

d

employed and optimization of the flow-flash reaction condition at −50 °C was investigated. To deliver the highly reactive aryllithium intermediate rapidly into T-shaped mixer (M2) for formylation with DMF, a reaction tube (L1) with a smaller diameter (ϕi.d. = 0.5 mm) was employed. Thus, continuous streams of varying concentration of solution of 8c in THF and a solution of BuLi (1.6 M in hexane) were delivered into Tshaped mixer (M1) by syringe pumps and the resulting highly reactive phenyl lithium intermediate was provided into Tshaped mixer (M2) for formylation with DMF provided by a syringe pump at −50 °C. The reaction solution was treated with aqueous 1 N HCl solution at 0 °C before measurements of the ratios of 1, 9c, and byproducts including 10c and 11c were carried out by HPLC. The results are shown in Table 3. Although 8c was almost totally consumed in the flow-flash reactions using a higher concentration BuLi solution (1.6 M in hexane), lower yields of 1 and 9c than those of entry 1 were observed in the experiments with shorter and longer residence times for the Br/Li exchange reactions of 8c (entries 2 and 3). Higher concentration of the 8c solution (0.4 M in THF) gave 1 and 9c in as low yield as those for entry 2 (entry 4) and higher flow rates of the solutions brought about similar yields of 1 and 9c to those in entry 1 (entry 5). In contrast to these results, higher concentration of the 8c solution (0.8 M in THF) than used in entries 4 and 5 resulted in significant decrease in the yield of 1 (entry 6).

measurements of the ratios of 8c, 1, 9c, and byproducts including 10c and 11c were carried out by HPLC. The results are shown in Table 2. The Br/Li exchange reactions of 8c with BuLi have been found to be completed within 100 ms at 0 °C to afford 1 concomitant with byproducts (entry 1). The flow-flash reaction with higher flow rates of the solutions of 8c and BuLi (entry 2) and those at lower reaction temperature, brought about increased yield of 1 (entries 2−4). Significant recovery of 8c was observed for the flow-flash reaction at −80 °C, with decreased yield of 1 (entry 5), and the reaction using tube reactor (L1) and flow micromixer (M2) with smaller diameter, resulted in increased recovery of 8c and similar yield of 1 to that for entry 5 (entry 6). Higher flow rate of the solutions of 8c and BuLi at the same temperature enhanced the Br/Li exchange reaction to give 1 in better yield than for the entries 5 and 6 (entry 7), which was lower than that in entry 4. Therefore, further optimization of the reaction condition for flow-flash synthesis of 1 from 8c using flow microreactors was investigated, based on the experimental result in entry 4, for a scale-up synthesis. Optimization of the Reaction Condition for Continuous Flow-Flash Synthesis of 1 and 9c from 8c Using Flow Microreactors. To improve the productivity of the flow-flash synthesis of 1 from 8c using flow microreactors, higher concentrations of the solutions of 8c and BuLi than those used in the experiments in Tables 1 and 2 were 1423



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Table 4. Scale-up Synthesis of 1 from 8c by Means of Continuous Flow-Flash Chemistry Using Flow Microreactorsa

HPLC area (%) entry e

1 2e 3f 4f 5f

8c (g)

operation time (min)

P (mL/min)

Q (mL/min)

R (mL/min)

τ (ms)

8c

1

9c

byproductsc

yield 1 (g (%))d

22.3 53.6 197 216 408

5.2 12.5 61 68 124

40 40 30 30 30

12 12 9 9 9

9 9 9 7 7

22.6 22.6 30.2 30.2 30.2

11.0 7.1 6.8 6.8 4.0

17.9 18.7 18.1 16.1 16.3

19.1 14.9 16.6 16.3 17.2

11.7 11.0 10.7 10.9 9.9

6.9 (47) 15.2 (44) 46 (36) 55 (39) 114 (42)

b

a

[8c] = 0.4 M, [BuLi] = 1.6 M, DMF (neat). bResidence time. cTotal of byproducts 10c and 11c, identified by their HPLC retention time. Various amounts of unidentified byproducts were also produced. dIsolated yield. eAt −50 °C (bath temperature). fAt −60 °C (bath temperature).

Scale-up Synthesis of 1 from 8c by Means of Continuous Flow-Flash Chemistry Using Flow Microreactors. Considering the experimental results of the optimization studies in Table 3, scale-up synthesis of 1 from 8c by means of continuous flow-flash chemistry using flow microreactors was investigated. Thus, continuous streams of solutions of 8c (0.4 M in THF) and BuLi (1.6 M in hexane) were delivered into a T-shaped mixer (M1, ϕi.d. = 0.25 mm) at flow rates of 40 mL/min and 12 mL/min, respectively, by gear pumps and the resulting highly reactive aryllithium intermediate was provided into a T-shaped mixer (M2, ϕi.d. = 0.25 mm) for formylation with DMF, provided at a flow rate of 9.0 mL/min by a gear pump at −50 °C. The reaction solution was treated with aqueous 2 N HCl solution at 0 °C before measurements of the ratios of 8c, 1, 9c, and byproducts including 10c and 11c were carried out by HPLC. The results are shown in Table 4. In preliminary experiments for continuous flow-flash synthesis of 1 at −50 °C, a significant rise in temperature of the cooling bath and increase in internal pressure of the flow-flash reaction system was observed (entries 1 and 2). Therefore, to address safety concerns for the flow-flash reaction system, continuous streams of the solutions of 8c, BuLi and DMF were delivered at lower flow rates into flow microreactors at −60 °C for all subsequent continuous flow-flash syntheses of 1, while employing longer operation times (entries 3−5). The collected reaction mixture was extracted with aqueous saturated NaHCO3 solution and the aqueous layer was acidified with aqueous 2 N HCl solution at pH = 2 under cooling, before it was extracted back with EtOAc. It was found that 9c was

converted easily into 1 during the treatment, to afford crude 1 as crystals in ca. 40% yield with sufficient purity (>98% HPLC area) for use in the subsequent step. Thus, scale-up synthesis of 1 to give 237 g from 897 g of 8c was achieved in 270 min by means of flow-flash chemistry using flow microreactors, without purification by column chromatography, which was then provided to drug research and development programs.

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CONCLUSIONS

Efficient scale-up synthesis of 5-cyano-2-formylbenzoic acid or its cyclic isomer 6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1) as a key intermediate for various biologically important compounds has been achieved from isopropyl 2-bromo-5cyanobenzoate (8c) by means of continuous flow-flash chemistry using flow microreactors. It was found that the Br/Li exchange reaction of 8c bearing both a carboisopropoxy group and a cyano group with BuLi took place within 0.1 s at −50 °C, and the resulting highly reactive aryllithium intermediate underwent formylation with DMF to afford 1, which is extremely difficult to achieve in a conventional batch process. Optimization of the continuous flow-flash reaction conditions and modification of the reaction system brought about the production of 237 g of 1 from 897 g of 8c in 270 min, without the need for purification by column chromatography. The results suggest that further optimization of the continuous flow-flash reaction conditions should give rise to even higher yields of 1 from 8c for its practical synthesis, and phthalaldehydic acid derivatives bearing electrophilic group(s) 1424



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with water, aqueous saturated sodium bicarbonate solution and brine before being dried over Na2SO4. The solvent was removed by evaporation under reduced pressure to give crude isopropyl-2-bromo-5-cyanobenzoate (2.0 kg, 89%) as a red oil. To a solution of crude isopropyl-2-bromo-5-cyanobenzoate (3.0 kg, 8.13 mol) in DMF (30 L) was added zinc cyanide (992.8 g, 8.45 mol) at room temperature and the mixture was flushed with N2 for 1 h before (triphenylphosphine)palladium(0) (187.8 g, 0.162 mol) was added at room temperature. The mixture was stirred at 70 °C for 16 h under N2 and the reaction mixture was diluted with water and EtOAc. The undissolved materials were removed by filtration and the solid was washed with EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 times). The combined organic layers were washed with water and brine solution before being dried over Na2SO4. The solvent was removed by evaporation under reduced pressure to give crude compound. The crude compound was purified by flash column chromatography on silica gel (100−200 mesh) (eluted with 3−5% EtOAc/Petrol) to afford isopropyl 2bromo-5-cyanobenzoate (8c, 1.247 kg, 57%) as a white solid. 1 H NMR (300 MHz, Me2SO-d6) δ 1.36 (6H, d, J = 6.3 Hz), 5.18 (1H, spt, J = 6.3 Hz), 7.93 (1H, dd, J = 8.3, 2.0 Hz), 7.98 (1H, dd, J = 8.3, 0.5 Hz), 8.20 (1H, dd, J = 2.0, 0.5 Hz). 13C NMR (75 MHz, Me2SO-d6) δ 21.4, 70.1, 111.0, 117.3, 125.4, 133.8, 134.4, 135.0, 135.6, 163.9. Anal. Calcd for C11H10BrNO2: C, 49.28; H, 3.76; N, 5.22. Found: C, 49.21; H, 3.93; N, 5.49. mp 47.0−48.9 °C. tert-Butyl 2-bromo-5-cyanobenzoate (8d). 1,1-Di-tertbutoxytrimethylamine (24.88 mL, 104.00 mmol) was added dropwise to a solution of 2-bromo-5-iodobenzoic acid (8.5 g, 26.00 mmol) in toluene (40 mL) at 80 °C under N2. The mixture was stirred at 80 °C under N2 for 28 h. The solvent was removed in vacuo and the residue was purified by column chromatography (NH silica gel, eluted with 5−40% EtOAc in hexane) to give tert-butyl 2-bromo-5-iodobenzoate (9.26 g, 24.18 mmol, 93%) as a colorless oil. A mixture of tert-butyl 2-bromo-5-iodobenzoate (9.26 g, 24.18 mmol), Pd(Ph3P)4 (0.559 g, 0.48 mmol) and zinc cyanide (1.611 mL, 25.39 mmol) in DMF (dry) (90 mL) was stirred at 70 °C under Ar for 18 h. Water and EtOAc were added to the reaction mixture at room temperature and undissolved materials were removed by filtration. The filtrate was separated, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine before being dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10−60% EtOAc in hexane) to give tert-butyl 2bromo-5-cyanobenzoate (8d, 5.77 g, 20.45 mmol, 85%) as a white amorphous solid.17 1 H NMR (400 MHz, CDCl3) δ 1.62 (9H, s), 7.54 (1H, dd, J = 8.3, 2.2 Hz), 7.76 (1H, d, J = 8.3 Hz), 7.96 (1H, d, J = 2.0 Hz). 13C NMR (101 MHz, CDCl3) δ 28.1, 84.0, 111.6, 117.3, 126.6, 134.3, 134.3, 135.3, 135.5, 163.6. HRMS (m/z) [M(−C4H9)−H]− calcd. for C8H4NO2Br, 223.9353, found 223.9376. Typical Procedure for Feasibility Study of Synthesis of 1 and 9 from 8 by Flow-Flash Chemistry Using Flow Microreactors (Table 1, Entry 5). The flow-flash reaction system in Figure 2 was set up according to reports in the literature,11 composed of precooling loops (stainless tube, ϕi.d. = 1.0 mm, L = 50 cm), T-shaped mixers (M1, stainless tee pieces, ϕi.d. = 0.25 mm, Sannkouseikikougyou) and (M2 (ϕi.d. =

can be synthesized conveniently from the corresponding 2bromobenzoic acid esters by means of flow-flash chemistry using flow microreactors, as key intermediates for biologically important compounds, which will facilitate enhanced drug research and development programs.

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EXPERIMENTAL SECTION General Methods. 1H NMR spectra were recorded on a Bruker AVANCE III (300 MHz), chemical shifts are given in parts per million (ppm) downfield from tetramethysilane (δ) as the internal standard in deuterated solvent, and coupling constants (J) are in Hertz (Hz). Data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, brs = broad singlet), and coupling constants. All solvents and reagents were obtained from commercial suppliers and used without further purification. LC−MS analysis was performed on a Shimadzu UFLC-Mass Spectrometer System, operating in ESI (+ or −) ionization mode. Analyses were obtained using a linear gradient of 0.05% TFA containing water/acetonitrile, 0.1% TFA containing water/acetonitrile or 5 mM ammonium acetate containing water/acetonitrile mobile phase. The purities of compounds were determined by LC− MS analysis (detection at 220 or 254 nm). HPLC was performed on an Agilent 1200 series instrument (Column: ZORBAX (SB-C18, ϕ 4.6 × 50 mm, 1.8 μm, 40 °C)). Flow rate = 1.0 mL/min. Mobile phase = 0.05% TFA in CH3CN and 0.05% TFA in H2O. Ethyl 2-bromo-5-cyanobenzoate (8b). A mixture of 2bromo-5-iodobenzoic acid (5.0 g, 15.29 mmol), iodoethane (1.479 mL, 18.35 mmol) and K2CO3 (3.17 g, 22.94 mmol) in DMF (50 mL) was stirred at room temperature for 16 h. Water was added to the reaction mixture at room temperature and the mixture was extracted with EtOAc. The organic layer was washed with water, aqueous saturated NaHCO3 solution/water (v/v, 1:1), water and brine, and was dried over Na2SO4. The solution was concentrated in vacuo to give ethyl 2-bromo-5iodobenzoate (5.40 g, 15.20 mmol, 99%) as a pale yellow oil. A mixture of ethyl 2-bromo-5-iodobenzoate (3.0 g, 8.45 mmol), zinc cyanide (0.590 mL, 9.30 mmol), Pd(Ph3P)4 (0.195 g, 0.17 mmol) in DMF (dry) (30 mL) was stirred at 70 °C under Ar for 17 h. Water was added to the reaction mixture at room temperature and undissolved materials were removed by filtration. The filtrate was extracted with EtOAc. The organic layer was washed with water three times and brine, and was dried over Na2SO4. The solution was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10−50% EtOAc in hexane) to give ethyl 2-bromo-5-cyanobenzoate (8b, 1.820 g, 7.16 mmol, 85%) as a white amorphous solid.16 1 H NMR (400 MHz, CDCl3) δ 1.43 (3H, t, J = 7.1 Hz), 4.44 (2H, q, J = 7.3 Hz), 7.58 (1H, dd, J = 8.3, 2.0 Hz), 7.80 (1H, d, J = 8.3 Hz), 8.07 (1H, d, J = 2.0 Hz). 13C NMR (101 MHz, CDCl3) δ 14.1, 62.4, 111.7, 117.2, 127.2, 133.8, 134.7, 134.8, 135.6, 164.3. Isopropyl 2-bromo-5-cyanobenzoate (8c). To a mixture of 2-bromo-5-iodobenzoic acid (2.0 kg, 6.12 mol) and potassium carbonate (2.52 kg, 18.41 mol) in DMF (7.7 L), was added a solution of 2-iodopropane (920 mL, 9.18 mol) in DMF (3.0 L) at room temperature over the period of 1.5 h and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3 times). The combined organic layers were washed 1425



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HCl solution (408 mL) and extracted back with EtOAc (2040 mL). The organic layer was washed with brine and dried over anhydrous MgSO4. The solvent was removed in vacuo to give crude 5-cyano-2-formylbenzoic acid (6-cyano-3-hydroxy-2benzofuran-1(3H)-one, 1, 82 g, 57.4%) as a dark red solid. The crude solid was treated with a mixture of IPE (240 mL) and EtOAc (40 mL) and collected by filtration. The obtained solid was washed with IPE and dried to give 5-cyano-2formylbenzoic acid (6-cyano-3-hydroxy-2-benzofuran-1(3H)one, 1, 55.0 g, 314 mmol, 38.5%)3a,b as an orange solid.

0.5 mm, Shimadzu-GLC tee piece, part no. 6010-72357), microtube reactors (stainless tube, ϕi.d. = 1.0 mm, L1 (3.0 cm) and L2 (283 cm)), syringe pumps (ISIS Ltd., Osaka Japan, Fusion 100), and a cooling bath (PSL-2000, EYELA). Continuous streams of solutions of 8c and BuLi (0.2 M in THF and 0.22 M in hexane, respectively) were provided into the T-shaped mixer (M1) at flow rates of 6.0 mL/min, respectively, by the syringe pumps at −50 °C. The resulting solution of 2-bromophenyllithium intermediate was delivered into the next T-shaped mixer (M2) for formylation with a continuous stream of a solution of DMF (2.0 M in THF), provided at a flow rate of 6.0 mL/min by the syringe pump, at −50 °C. The reaction solution obtained from L2 was poured into aqueous 1 N HCl at −0 °C and extracted with EtOAc. The organic layer was concentrated and subjected to an HPLC analysis to determine the ratio of 8c, 1, 9c, and byproducts. Typical Procedure for Optimization of Reaction Condition of Continuous Flow-Flash Synthesis of 1 and 9c from 8c Using Flow Microreactors (Table 3, Entry 4). The above-described flow-flash reaction system was set up, composed of precooling loops (stainless tube, ϕi.d. = 1.0 mm, L = 50 cm), T-shaped mixers (M1, stainless tee pieces, ϕi.d. = 0.25 mm, Sannkouseikikougyou) and (M2 (ϕi.d. = 0.5 mm, Shimadzu-GLC tee piece, part no. 6010−72357), microtube reactors (stainless tube, L1 (ϕi.d. = 0.5 mm, 3.0 cm) and L2 (ϕi.d. = 0.5 mm, 283 cm), syringe pumps (ISIS Ltd., Osaka Japan, Fusion 100), and a cooling bath (PSL-2000, EYELA). Continuous streams of solutions of 8c and BuLi (0.4 M in THF and 1.6 M in hexane, respectively) were provided into the T-shaped mixer (M1), at flow rates of 10 and 2.5 mL/ min, respectively, at −50 °C by syringe pumps. The resulting solution of 2-bromophenyllithium intermediate was delivered into the next T-shaped mixer (M2) for formylation with a continuous stream of DMF (neat) provided at a flow rate of 2 mL/min, at −50 °C by a syringe pump. The reaction solution obtained from L2 was poured into aqueous 1 N HCl at −0 °C and extracted with EtOAc. The organic layer was concentrated and subjected to an HPLC analysis to determine the ratio of 8c, 1, 9c, and byproducts. 5-Cyano-2-formylbenzoic Acid (6-Cyano-3-hydroxy2-benzofuran-1(3H)-one, 1) (Table 4, Entry 4). The above-described flow-flash reaction system was set up composed of precooling loops (stainless tube, ϕi.d. = 1.0 mm, L = 50 cm), T-shaped mixers (M1 and M2, stainless tee pieces, ϕi.d. = 0.25 mm, Sannkouseikikougyou), microtube reactors (stainless tube, L1 (ϕi.d. = 0.5 mm, 10 cm) and L2 (ϕi.d. = 1.0 mm, 300 cm), gear pumps equipped with mass flow meters (mini-CORI-Flow, Bronkhost), and a cooling bath (PSL-2000, EYELA). Continuous streams of solutions of 8c and BuLi (0.4 M in THF and 1.6 M in hexane, respectively) were provided into the T-shaped mixer (M1), at flow rates of 30 and 9.0 mL/ min, respectively, by gear pumps equipped with mass flow meters, at −60 °C. The resulting solution of 2-bromophenyllithium intermediate was delivered into the next T-shaped mixer (M2) for formylation with a continuous stream of a solution of DMF (4.0 M in THF), provided at a flow rate of 20 mL/min by the gear pumps equipped with mass flow meters, at −60 °C. The reaction solution obtained from L2 was poured into aqueous 2 N HCl solution at 0 °C and extracted with EtOAc (3060 mL). The separated organic layer was extracted with aqueous 1 N NaOH solution (1632 mL), aqueous 1 N NaOH solution (408 mL), and water (400 mL × 2). The combined aqueous layers were made acidic with aqueous 6 N

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.9b00180. Copies of 1H and 13C NMR spectra for compounds 1, 8b, 8c, and 8d (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Phone: +81-466-32-1194. *E-mail: [email protected]. Phone: +81-466-321193. ORCID

Tetsuji Kawamoto: 0000-0002-4319-6934 Present Addresses §

Chemistry Research Division, Axcelead Drug Discovery Partners, Inc. 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-0012, Japan. ∥ Kyoto University Original Co., Ltd., Kyoto University, Yoshida-Hommachi, Sakyo-ku, Kyoto 606-8501, Japan. ⊥ 2-4-56 Ueno Higashi, Toyonaka, Osaka, 560-0013, Japan. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to Mr. Shotaro Miura for his helpful discussion regarding preparation of the manuscript. ABBREVIATIONS BuLi, n-butyl lithium; DMF, N,N-dimethylformamide; IPE, diisopropyl ether. REFERENCES

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(15) Kim, H.; Nagaki, A.; Yoshida, J. A flow-microreactor approach to protecting-group-free synthesis using organolithium compounds. Nat. Commun. 2011, DOI: 10.1038/ncomms1264. (16) HRMS of 8b did not give molecular ion peak (m/z) nor its fragment ion peaks (m/z). (17) HRMS of 8d did not give molecular ion peak (m/z) but gave its fragment ion peak (m/z).

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Application of Continuous Flow-Flash Chemistry to Scale-up Synthesis

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