CC BY 4.0 · Pharmaceutical Fronts 2022; 04(02): e71-e77
DOI: 10.1055/s-0042-1747641
Original Article

A Novel and Practical Synthesis of Isavuconazonium Sulfate via Anion Exchange Resin

Lei Huang
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2   Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Yi Zhang
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2   Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Hua Chen
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2   Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Wei-Wei Wang
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2   Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Jian-Qi Li
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2   Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Yu Liu
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2   Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
› Author Affiliations
 


Abstract

In this study, an efficient and practical process for the synthesis of isavuconazonium sulfate (compound 1), an antifungal agent, was described. Highlights in the synthesis route are the usage of the ion exchange resin instead of H2SO4 to introduce the HSO4 anion in the formulation of quaternary ammonium salt (1), and the reaction condition was further optimized to facilitate the scale-up. The overall yield of the process was 57.0% and the high-performance liquid chromatography purity of product was 97.25%, which was higher than that of the reference-listed drug.


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Introduction

Isavuconazonium sulfate (1) is a prodrug of isavuconazole (2), which is a broad-spectrum triazole antifungal agent and widely used for the treatment of invasive fungal infections.[1] [2] [3] [4] [5] [6] [7] The water-soluble compound 1 includes a triazolium salt tethered to isavuconazole via an ester moiety ([Fig. 1]). Evidence suggested that many antifungal drugs, such as itraconazole and voriconazole, often used cyclodextrin vehicle, to facilitate the solubility in their intravenous formulation, yet had been speculated to be nephrotoxic in humans.[8] Inspiringly, compound 1 does not require a cyclodextrin vehicle due to its natural water-soluble nature, and thereby can represent a better option in the therapy of fungal infections in comparison to other triazole antifungal agents.[8] [9] [10]

Zoom Image
Fig. 1 Structures of isavuconazonium sulfate (1) and isavuconazole (2).

The current two reported approaches for the synthesis of compound 1 are described in [Scheme 1]. The original preparation of compound 1 was based on Fukuda et al's method using isavuconazonium chloride hydrochloride rather than bisulfate as the key intermediate.[11] Later, Zhou et al reported a new synthetic route in 2017, directly using CuSO4 to introduce SO4 2− to the triazolium salt.[12] The generated key intermediate (7) was acidified by H2SO4 to obtain the target compound. However, these routes had three shortcomings: first, compound 5 degraded a lot owing to basic ion exchange resin in the preparation of compound 6. Second, due to multiple alkaline sites in isavuconazonium, it is difficult to form the HSO4 salt of isavuconazonium in a 1:1 ratio through directly adding H2SO4. Finally, both the reported two routes suffered from purification problems due to the thermal instability of the target product. Thus, developing a method for preparing compound 1 with a high yield and purity is necessary.

Zoom Image
Scheme 1 Reported synthetic routes of isavuconazonium sulfate (1) by Fukuda et al's method (Route 1) and Zhou et al's method (Route 2).

In this study, we first report a novel synthetic route ([Scheme 2]), wherein compound 5 was obtained according to Fukuda et al's method (Route 1 in [Scheme 1]), then neutralized in basic solution to give compound 6. The OH anion of compound 6 was ion exchanged by HSO4 from resin loaded with HSO4 to form the target compound 1.

Zoom Image
Scheme 2 New synthetic route via ion exchange resin reported by this work.

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Results and Discussion

Improved Synthesis of Key Intermediate 4 and the underlying Mechanism

Fukuda et al used a catalytic amount of NaI to prepare key intermediate 4 (Route 1 in [Scheme 1]).[1] However, the yield was too low to be acceptable when the ratio of NaI was below 30% ([Table 1], entries 1–9). Interestingly, this work found that higher equivalents of NaI afforded higher yields of 4 ([Table 1], entries 7–12), and when 1.1 equivalent of NaI was added ([Table 1], entries 12 and 13), compound 2 was reacted completely, indicating that NaI may take a part in the reaction rather than acting as a catalyst. A possible reaction mechanism is proposed in [Scheme 3].

Table 1

Optimization of conditions for the forming of intermediate 4

Entry

Solvent

Temp (°C)

Time (h)

NaI (mol%)

Yield (%)

1

THF

70

3

0.1

10.0

2

Acetone

70

3

0.1

9.7

3

CH3CN

70

3

0.1

9.9

4

CH3CN

50

3

0.1

9.9

5

CH3CN

90

3

0.1

9.8

6

CH3CN

70

5

0.1

9.9

7

CH3CN

70

7

0.1

9.7

8

CH3CN

70

3

20

19.4

9

CH3CN

70

3

30

31.0

10

CH3CN

70

3

50

44.2

11

CH3CN

70

3

90

80.4

12

CH3CN

70

3

110

95.6

13

CH3CN

70

3

130

95.2

Zoom Image
Scheme 3 Proposed mechanism for the synthesis of isavuconazonium iodide 4.

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Preparation of Compound 6

Removing the Boc of compound 4 in HCl (aq) solution obtained compound 5, and the I of which was replaced with OH to obtain compound 6. Fukuda et al used an ion-exchange resin to introduce OH. However, under basic conditions, the ester groups in compound 5 were easy to hydrolyze, and the hydrolyzed products (2, 8, 9) are shown in [Scheme 4]. Even if compound 5 was suspended in 5% NaHCO3 solution and extracted with dichloromethane (DCM), the hydrolysis of compound 5 was still unstoppable. In this work, the process of obtaining compound 6 was improved. Compound 5 was added into a two-phase DCM/water solvent system at a low temperature, followed by HCl neutralization and the replacement of I with OH under basic conditions. The generated compound 6 was immediately transferred into an organic phase, thus avoiding degradation. This solution was used for the next step without further work-up.

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Scheme 4 Degradation mechanism of compound 5 under basic conditions.

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Preparation of Target Compound 1 (Isavuconazonium Sulfate)

To obtain the target compound 1, Fukuda et al replaced the OH group of compound 6 with HSO4 by addition of H2SO4. However, it was found that when H2SO4 was added to the reaction mixture, compound 6 was degraded into impurity 8 and isavuconazole (2), and the product precipitated as a syrup, which could not be purified because of its poor solid form and thermal instability. Given above, the introduction of HSO4 anion via a medium that would provide a pure convenient ion pair is significantly important.

Evidence suggested that some I-containing imidazolium ionic liquids can be anion-exchanged with anion–exchange resin loaded with different anions.[13] Considering that isavuconazonium has a similar quaternary ammonium moiety to these imidazolium ionic liquids, we used the anion-exchange resin loading with HSO4 as a medium for the introduction of HSO4 into isavuconazonium, and the ion-exchange reaction is described in [Scheme 5]. Our explored method thereby achieved better outcomes compared with the use of H2SO4 (aq) solution.

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Scheme 5 Ion exchange between ionic compound and the specific resin.

The conditions for the ion-exchange reaction were also explored. Initially, a strongly basic anion-exchange resin Amberlyst A-26 (OH form) was used. The resin was treated with ammonium hydrogen sulfate (NH4HSO4) solution to retain HSO4 in the resin. The solution of compound 6 in DCM was concentrated and the residue was re-dissolved in methanol and stirred with A-26 resin (HSO4 form) according to a reported study.[13] However, the reaction outcome was disappointing, with a formation of a complex product mixture. We assumed that the concentration process may contribute to the degradation of isavuconazonium, because compound 6 was thermally sensitive in solution. Besides, an additional stability experiment also indicated that compound 1 was unstable in methanol. Therefore, DCM solution of compound 6 was moved to the next procedure directly instead of using after concentration. Ion exchange was performed directly using DCM solution of compound 6, unfortunately, the residue was found again to contain a complex mixture, which was hard to be purified.

Then, a biphasic system was trialed in this step. The approach was based on the excellent water solubility of the expected product, with the expectation that performing anion exchange in a biphasic system would partition the targeted water-soluble products (mostly generated from the coordination of isavuconazonium with HSO4 in the aqueous phase), and the lipophilic impurities were reserved in the organic phase. Excitingly, after the reaction, the resulting aqueous solution was washed with DCM and lyophilized to give the target product in 97.0% purity, without requiring additional purification.

Due to the importance of the anion-exchange resin in this process, three types of commercially available strongly basic anion-exchange resins were screened to compare the resulting product purity and yield. The results indicated that resin Amberlite IRA410 gave the optimal results with a good yield (60.0%) and high-performance liquid chromatography (HPLC) purity (98.03%), as shown in [Table 2].

Table 2

Effect of the type of different resins on the reaction outcome

Entry

Resin type

Yield

HPLC purity

1

D301

24.0%

97.65%

2

IRA402

34.0%

96.70%

3

IRA410

60.0%

98.03%

Abbreviation: HPLC, high-performance liquid chromatography.


Based on this novel and improved process, the batch was scaled up to 100 g and the results were reproduced in three validation productions. Furthermore, results from HPLC analysis showed that the peak position of compound 1 was consistent with that of RLD isavuconazonium sulfate for injection, of which the inactive ingredient was mannitol ([Fig. 2]); however, the purity by measuring area percentage of the main peak according to the area normalization method showed that the purity of compound 1 was much higher (97.25%) in comparison to that of RLD isavuconazonium sulfate for injection (94.10%) ([Figs. S6] and [S7] [online only]).

Zoom Image
Fig. 2 Overlay map of RLD isavuconazonium sulfate for injection and compound 1 from HPLC analysis. HPLC, high-performance liquid chromatography; RLD, reference listed drug.

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Conclusion

In this study, an improved method for the synthesis of isavuconazonium sulfate (1) was reported. An anion-exchange resin was first used to introduce HSO4 to the target compound with the major advantages as the following: (1) only dissociation and ion exchange were mentioned in the new synthetic route, indicating the mild and facile reaction conditions in the whole preparation of the target compound; (2) high HPLC purity (97.25%) of compound 1 was obtained without the need for techniques such as recrystallization and column chromatography; (3) the process met the requirements of “green chemistry” based on the conversion of the starting material isavuconazole, and the overall yield of the synthetic route was 57%; and (4) the used resin could be recycled via acid–base neutralization reactions.

In summary, the novel and practical synthesis of isavuconazonium sulfate (1) was explored in this study, and this may also provide guidance for the synthesis other HSO4 salt analogues in the future. It is a promising reference of application of ion-exchange resins in organic synthesis.


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Experimental Section

General

Unless otherwise noted, reagents were commercially available (obtained from Titan, Energy Chemical, Meryer, etc.) and used without purification. NMR data were obtained using a Bruker V-400 instrument (Bruker BioSpin AG, Industriestrasse 26, CH-8117, Fallanden) at 400 MHz for 1H and 100 Hz for 13C in either CDCl3 or DMSO-d 6. The chemical shifts are reported in δ ppm relative to tetramethylsilane. HPLC analysis was performed on Agilent 1200 (Agilent Technologies, California, United States) using a Dionex U3000, a Symmetry Shield RP C18 HPLC column (4.6 mm × 250 mm, particle size 5 μm) under the following conditions: mobile A (0.05% TFA aqueous solution) and mobile B (acetonitrile) with gradient condition of 0–17 minutes: mobile A 75%; 17–23 minutes, mobile A 25%, and detection wavelength was 289 nm.


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General Procedure to Load HSO4 Anion in Resin IRA410

NH4HSO4 aqueous solution (1 mol/L) was passed through a glass column (Shanghai Heqi Glassware Co., Ltd., Shanghai, China) packed with commercial resin IRA410 (OH form) (Titan) until the pH of the eluent reached the same value as that of the original solution. The process was performed at room temperature using gravity as the driving force.


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Preparation of 4-(1-(((3-(((N-(tert-butoxycarbonyl)-N-methylglycyl)oxy)methyl)pyridin-2-yl)(methyl)carbamoyl)oxy)ethyl)-1-((2R,3R)-3-(4-(4-cyanophenyl)thiazol-2-yl)-2-(2,5-difluorophenyl)-2-hydroxybutyl)-1H-1,2,4-triazol-4-ium Iodide (4)

A solution of compound 2 (100 g, 228.83 mmol), sodium iodide (51.5 g, 343.25 mmol), and compound 3 (142.4 g, 343.25 mmol) was stirred in acetonitrile (1,000 mL) for 3 hours at 70°C under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (3 L), and then washed with HCl solution (2%, 1.5 L × 2) and H2O (1.5 L). The organic layer was dried over MgSO4, filtered, and the filtrate was evaporated under vacuum to give the crude product 4 as a light-yellow oil (211.7 g, 98% yield). b.p. 86°C (decomposed). 1H NMR (400 MHz, DMSO-d 6) δ 10.16 (brd, J = 4.9, 1H), 9.01 (brd, J = 3.6, 1H), 8.49 (s, 1H), 8.24–8.20 (m, 2H), 7.96–7.91 (m, 2H), 7.44–7.26 (m, 6H), 7.15–7.05 (m, 1H), 6.66–6.61 (m, 1H), 6.17–5.90 (m, 2H), 5.76 (s, 2H), 5.09 (d, J = 14.8, 2H), 4.91–4.79 (m, 3H), 4.15 (q, J = 7.3, 1H), 3.15 (s, 1H), 3.12 (s, 2H), 1.99 (s, 3H), 1.42 (s, 9H), 1.20 (d, J = 6.9, 3H). ESI-MS (m/z): calcd. for C40H43F2IIN8O7S [M − I]+ 817.2938; found 817.70.


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Preparation of 1-((2R,3R)-3-(4-(4-cyanophenyl)thiazol-2-yl)-2-(2,5-difluorophenyl)-2-hydroxybutyl)-4-(1-((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl)-1H-1,2,4-triazol-4-ium Iodide Hydrochloride (5)

To a solution of compound 4 (211.7 g, 224.25 mmol) in ethyl acetate (1 L) was added hydrogen chloride ethyl acetate solution (2 N, 1121.3 mL) at room temperature. After stirring for 2 hours, the precipitate was filtered and washed with ethyl acetate. The precipitate was dried to afford the crude product 5 as a yellow solid (199.3 g, 97%). b.p. 95°C (decomposed). 1H NMR (DMSO-d6 ) δ 10.62–10.35 (m, 1H), 9.39–9.08 (m, 3H), 8.48 (s, 1H), 8.20 (d, J = 7.92 Hz, 2H), 7.99 (d, J = 8.25 Hz, 2H), 7.49–7.02 (m, 5H), 6.84–6.59 (m, 1H), 5.22–4.56 (m, 5H), 4.28–3.79 (m, 2H), 3.30–3.10 (m, 3H), 1.64–1.10 (m, 12H). ESI-MS (m/z): calcd. For C35H35F2IN8O5S [M − I]+ 717.2414; found 717.60.


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Preparation of 1-((2R,3R)-3-(4-(4-cyanophenyl)thiazol-2-yl)-2-(2,5-difluorophenyl)-2-hydroxybutyl)-4-(1-((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl)-1H-1,2,4-triazol-4-ium OH (6)

Compound 5 (199.3 g, 217.5 mmol) was dissolved in a mixture of DCM (1.5 L) and H2O (500 mL). Then, NaHCO3 solution (aq, 5%) was slowly added at 0°C until the pH of the mixture was 7.8 to 8.0. The organic layer was separated and maintained at 0°C for the next procedure without further work-up. The product was not isolated and structure conformed.


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Preparation of the Target Product (1)

To a solution of the organic layer above (1.5 L) and deionized water (100 mL) was added resin IRA410 (HSO4 form, 1.36 L). The mixture was stirred for 1.5 hours. Water layer was separated, washed with DCM (200 mL × 2), and then lyophilized to give the target compound 1 (106.3 g, 60%) as a white solid. HPLC purity: 97.25%. b.p. 100°C (decomposed); m.p. 143.6–146.2°C. 1H NMR (400 MHz, D2O) δ 8.85 (d, J = 30.5 Hz, 1H), 8.66 (s, 1H), 8.44–8.29 (m, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.89–7.70 (m, 3H), 7.51 (ddd, J = 21.7, 18.0, 6.9 Hz, 3H), 6.87 (ddd, J = 47.0, 19.8, 14.0 Hz, 3H), 5.37–4.99 (m, 3H), 4.99–4.74 (m, 3H), 4.67–4.50 (m, 2H), 4.29–4.10 (m, 1H), 4.01 (d, J = 16.0 Hz, 2H), 3.29–3.06 (m, 3H), 2.80–2.62 (m, 3H), 1.58–1.42 (m, 1H), 1.84 (s, 1H), 1.12 (dd, J = 23.0, 6.9 Hz, 3H). [α]D 24 +3.505° (c 1.0, H2O). 13C NMR (151 MHz, D2O) δ 171.76, 166.98, 159.40, 157.79, 155.35, 153.78, 152.95, 151.86, 151.23, 150.70, 149.13, 142.45, 140.19, 137.80, 132.64 (×2), 128.12, 126.45, 125.01, 124.69, 119.15, 117.62, 115.38, 110.06, 79.36, 76.41, 63.04, 59.08, 50.53, 48.63, 43.90, 35.98, 33.00, 19.09, 16.69. ESI-MS (m/z): calcd. For C35H36F2N8O9S2 [M − HSO4]+ 717.2414; found 717.60.


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Supporting Information

Spectroscopic characterization processes (NMR and ESI-MS) for 4 and 1, as well as HPLC results for the purities of compound 1 following the improved synthesis route, are included in the Supporting Information ([Figs. S1–S7] [online only]).


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Conflict of Interest

None.

Acknowledgments

We are grateful for the structure conformation provided by Instrumental Analysis and Research Centre of China State Institute of Pharmaceutical Industry.

Supplementary Material


Address for correspondence

Jian-Qi Li, PhD
Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry
285 Gebaini Road, Shanghai 201203
People's Republic of China   
Yu Liu, PhD
Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry
285 Gebaini Road, Shanghai 201203
People's Republic of China   

Publication History

Received: 20 December 2021

Accepted: 25 February 2022

Article published online:
04 July 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


Zoom Image
Fig. 1 Structures of isavuconazonium sulfate (1) and isavuconazole (2).
Zoom Image
Scheme 1 Reported synthetic routes of isavuconazonium sulfate (1) by Fukuda et al's method (Route 1) and Zhou et al's method (Route 2).
Zoom Image
Scheme 2 New synthetic route via ion exchange resin reported by this work.
Zoom Image
Scheme 3 Proposed mechanism for the synthesis of isavuconazonium iodide 4.
Zoom Image
Scheme 4 Degradation mechanism of compound 5 under basic conditions.
Zoom Image
Scheme 5 Ion exchange between ionic compound and the specific resin.
Zoom Image
Fig. 2 Overlay map of RLD isavuconazonium sulfate for injection and compound 1 from HPLC analysis. HPLC, high-performance liquid chromatography; RLD, reference listed drug.