The Development of an Effective Synthetic Route of Belinostat

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The Development of an Effective Synthetic Route of Belinostat Xuefei Bao, Dake Song, Xuejun Qiao, Xuan Zhao, and Guoliang Chen Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00170 • Publication Date (Web): 12 Jul 2016 Downloaded from http://pubs.acs.org on July 13, 2016

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Organic Process Research & Development

The Development of an Effective Synthetic Route of Belinostat Xuefei Bao, Dake Song, Xuejun Qiao, Xuan Zhao, Guoliang Chen* Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China

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Table of Contents Graphic: O O S ONa OH Na2S2O5

inexpensive starting materials HOSO2Cl K2SO4

hundreds gram scale 5 total steps, 33% overall yield

CHO CHO

H N

O S

O SO2Cl Belinostat


O N H

OH

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ABSTRACT: A practical synthetic route of belinostat is reported. Belinostat was obtained via a five-step process starting from benzaldehyde and including addition reaction with sodium bisulfite, sulfochlorination with chlorosulfonic acid, sulfonamidation with aniline, Knoevenagel condensation, and the final amidation with hydroxylamine. Key to the strategy is the preparation of 3-formylbenzenesulfonyl chloride using an economical and practical protocol. The main advantages of the route include inexpensive starting materials and acceptable overall yield. The scale-up experiment was carried out to provide 169 g of belinostat with 99.6% purity in 33% total yield.

KEYWORDS: Belinostat, Synthesis, chlorosulfonation, histone deacetylase inhibitor.



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INTRODUCTION Belinostat (1, Figure. 1), a small molecule histone deacetylase (HDAC) inhibitor developed by CuraGen/TopoTarget, has been approved in the U.S for the treatment of relapsed or refractory peripheral T-cell lymphoma in July 2014.1 Recently, the drug is in clinical development for the treatment of cutaneous T-cell (CTCL), other T-cell non-Hodgkin's lymphomas (NHL) and thymic epithelial tumors.2

Figure 1. The chemical structure of belinostat (1). Several research-scale synthetic methods have been reported for the preparation of 1 (Scheme 1). Initially, Andrianov et al. disclosed a method for its synthesis in the early stage of drug discovery (Route A).3 In this method, benzaldehyde was used as starting material and first sulfonylated with oleum, followed by six steps process to provide 1 with a 12% total yield. Qian et al. developed another method (Route B) to obtain 1 from sodium 3-sulfo-benzoic acid via six steps with total yield of 13%.4 These two methods suffered from long synthetic procedure, low yield and laborious workups. Besides, the use of extremely corrosive oleum required tedious separation and caused a large amount of wastewater. Yang et al. reported a synthetic route (Route C) of 1 starting from 3-nitrobenzaldehyde with the overall yield of 33% and the key step in this procedure involved the conversion of (E)-3-(3-aminophenyl)acrylic acid methyl ester to (E)-3-(3-chlorosulfonylphenyl) acrylic acid methyl ester via diazotization and sulfonylation.5 The method, producing sub-gram scale 1 in a single batch, had two drawbacks, limiting the largescale synthesis of 1: (a) complicated purification process, (b) the employment of environmentally unfriendly SO2. Recently, Wang et al. reported a process (Route D) for the preparation of 4 Environment ACS Paragon Plus

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belinostat cis-isomer starting from 3-formyl-N-phenylbenzenesulfonamide 5.6 In the process, belinostat would be the main by product, but starting material 5 was not commercially available. Scheme 1. Reported Research-scale Synthetic Route of Belinostat



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For the large-scale preparation of 1, Reisch et al. used 3-bromobenzenesulfonyl chloride as starting material (Scheme 2).7 By the method, 1 was obtained with high yield on hundreds gram scale, but expensive palladium acetate was used and no industrial-scale 3-bromobenzenesulfonyl chloride was commercially available. These drawbacks made it unsuitable for industrial-scale production. Luo et al. developed a manufacturing route of 1 based on route B (Scheme 1) by changing some reagents.8 Some issues of the method for large-scale synthesis are described below: (1) the employment of expensive oxidant 1-hydroxy-1-oxide-1, 2-Benziodoxol-3(1H)one; (2) long synthetic procedure and laborious workups; (3) the relatively low 21.6% overall yield. In this report, we discuss our attempts to develop an effective process for the hundredgram scale preparation of belinostat. Scheme 2. Reported Large-scale Synthetic Route of Belinostat.

RESULTS AND DISCUSSION The synthetic route of 1, from commercially available benzaldehyde 2 and aniline, involved addition reaction with sodium bisulfite to afford adduct 3. Then 3 was reacted with chlorosulfonic acid to yield 3-formylbenzenesulfonyl chloride 4. The reaction between 4 and aniline in the presence of pyridine furnished 3-formyl-N-phenylbenzenesulfonamide 5. Compound 5 was transformed into (E)-3-(3-((phenylamino)sulfonyl) phenyl)acrylic acid 6 by


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Knoevenagel condensation. 2-Propenoyl chloride obtained from 6 was reacted with hydroxylamine to afford belinostat (Scheme 3). Scheme 3. Novel Effective Synthetic Route of Belinostat O O S ONa CHO

CHO

chlorosulfonic acid

Na2S2O5 EtOH, H2O

K2SO4

92%

69%

2

pyridine, EA SO2Cl

3 COOH malonic acid

SOCl2, DBU then NH2OH

piperidine, pyridine

EA, THF, H2O

SO2NHPh 6

83%

5

93%

4

CHO

SO2NHPh

aniline

OH

1

66%

Initially, in order to shorten the preparation process, our study was focused on the directly preparation of 4 via the reaction between chlorosulfonic acid and benzaldehyde. As shown on Table 1, however, only a small amount of 4 was obtained. The poor results were due to the generation of benzal chloride as reported in literatures.9 Benzal chloride 7 and 8 were obtained via column chromatography on silica gel, and they were generated in a low yield at low temperature (entris 1-3). A plausible mechanism for the generation of 7 and 8 was shown in Scheme 4. Besides, some unidentified strong-polarity impurities were not eluted out from the column. Table 1. Reaction of Benzaldehyde with Chlorosulfonic Acid a

entry

solvent

temp.(oC)


4

yield(%) b 7

8


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1

-

40

14

19

23

2c

-

20

10

7

11

3

-

60

9

24

47

4

DCM

40

12

20

23

5

CHCl3

40

10

23

28

6

THF

40

0

0

0

7d

-

40

17

25

28

a

Standard conditions: benzaldehyde (6.7 mmol), chlorosulfonic acid (53.4 mmol), solvent (10 ml). b Isolated yield after chromatography. c Benzaldehyde 2 was recovered in 31% yield. d Chlorosulfonic acid was increased to 80.0 mmol. Scheme 4. Possible Mechanism for the Generation of Benzal Chloride.

The poor results from initial attempt compelled us to protect aldehyde before chlorosulfonation and the protected benzaldehyde, 2-phenyl-1,3-dioxolane 9, was prepared according to a literature procedure.10 It was noteworthy that, when chlorosulfonic acid was dropped into 9, the conversion of compound 9 was 100%, but the product was not the target compound 4. Rather, the main product was unexpected 10 (Scheme 5). However, when 9 was dropped into chlorosulfonic acid, we obtained a mixture containing 4, 7 and 8. The amount of chlorosulfonic acid influenced the generation of products. When there was only a small amount of chlorosulfonic acid, acetal 9 8 Environment ACS Paragon Plus

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converted to hemiacetal which was oxidized to ester 10 before additional chlorosulfonic acid was added. And when there was enough chlorosulfonic acid, generated hemiacetal was hydrolysis to aldehyde immediately. Scheme 5. Attempted Synthesis of 4 from 9

Aldehyde bisulfite adducts were often employed for the purification of aldehydes, we tested benzaldehyde bisulfite adduct 3 in several experiments (Table 2). Starting material 3 was obtained according to a literature procedure.11 When the reaction was deemed to be complete monitored by TLC, the product was isolated by column chromatography. As shown in Table 2, the reaction with incremental amount of chlorosulfonic acid afforded a higher yield, but the amounts of 7 and 8 also increased (entries 1-4). Meanwhile, we investigated the influence of the temperature: by lowering the temperature, a remarkable increase of 4 and decrease of 7 and 8 were observed (entries 6-9). When the amount of chlorosulfonic acid was less than 10 equiv, the isolated yield was low (

The Development of an Effective Synthetic Route of Belinostat

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