Development of an Efficient Manufacturing Process for a Key

Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Development of an Efficient Manufacturing Process for a Key Intermediate in the Synthesis of Edoxaban Makoto Michida,*,† Hideaki Ishikawa,† Takeshi Kaneda,† Shinya Tatekabe,‡ and Yoshitaka Nakamura§ †

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Process Technology Research Laboratories (PTRL), Daiichi Sankyo Co., Ltd., 1-12-1 Shinomiya, Hiratsuka-shi, Kanagawa 254-0014, Japan ‡ Plant Management Department, Daiichi Sankyo Chemical Pharma Co., Ltd., 477 Takada, Odawara-shi, Kanagawa 250-0216, Japan § Global Supply Chain - Technology Function, Daiichi Sankyo, Inc., 211 Mt. Airy Road, Basking Ridge, New Jersey 07920, United States S Supporting Information *

ABSTRACT: We report the development of a novel synthetic method to access a key intermediate in the synthesis of edoxaban. The main features of the new synthetic method are an improvement in the approach for the synthesis of a key chiral bromolactone, application of an interesting cyclization reaction utilizing neighboring group participation to construct a differentially protected 1,2-cis-diamine, and implementation of plug-flow reactor technology to enable the reaction of an unstable intermediate on multihundred kilogram scale. The overall yield for the preparation of edoxaban was significantly increased by implementing these changes and led to a more efficient and environmentally friendly manufacturing process. KEYWORDS: process development, enzymatic resolution, flow reactor, 1,2-cis-diamine, rearrangement reaction, aziridine

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INTRODUCTION

As shown in Figure 1, Edoxaban (1) can be accessed via the combination of three structurally distinct units: thiazole carboxylic acid 2, chiral cyclohexane cis-diamine 3, and oxalate 4.4 Notably, 3 features three asymmetric centers on the cyclohexane ring. When designing a synthetic route for 1, our most important consideration was how to efficiently control the stereocenters of 3 while simultaneously installing the differentially protected vicinal cis-diamine moiety. Herein, we describe the establishment of a highly efficient manufacturing procedure of key intermediate 3 which was identified by exploring alternative synthetic approaches to 3 from inexpensive and commercially available starting materials.

Several new direct oral anticoagulants (DOACs) have been approved for the prevention of stroke in patients with atrial fibrillation (AF) and for the treatment and prevention of venous thromboembolism (VTE) recurrence.1 DOACs inhibit Factor Xa (FXa) in the coagulation cascade and represent clinical alternatives to traditional vitamin K antagonists such as warfarin, which possess limitations such as risk of bleeding, strong drug−drug interactions, and the requirement of frequent monitoring.2 Edoxaban (1) is a once-daily DOAC that has been launched under the trade names Lixiana and Savaysa for the prevention of AF and VTE.3

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RESULTS AND DISCUSSION The original manufacturing route for the preparation of 3 is shown in Scheme 1.5 This process started with a classical resolution of rac-5 with (R)-phenylethylamine (PEA) to afford the (S)-5/PEA salt.6 This was followed by a bromolactonization to give the corresponding optically pure lactone 6 (25% isolated yield from rac-5). Then the lactone moiety in 6 was opened by dimethylamine (Me2NH) to form bromohydrin 7, which was converted to amino alcohol 9, with excellent regioselectivity, via the corresponding epoxide 8 following treatment with aqueous ammonia. Boc protection of the resultant amino group gave 10, and subsequent mesylation of the secondary alcohol afforded 11 as a crystalline solid (63% isolated overall yield from 6). Construction of the cis-diamine functionality was achieved by azidation followed by hydrogenation. Although approximately 10% of undesired trans-12 Special Issue: Japanese Society for Process Chemistry Received: November 30, 2018

Figure 1. Synthesis of edoxaban (1). © XXXX American Chemical Society

A

DOI: 10.1021/acs.oprd.8b00413 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Scheme 1. Original Synthetic Route To Prepare cis-Diamine 3

was generated under the optimized reaction conditions, trans12 was converted to the corresponding trans-3 and was effectively removed during the crystallization and isolation of cis-3. As a result, pure cis-diamine 3 was obtained in 64% yield from 11. This process is reproducible and was capable of producing 3 at production scale; however, a critical evaluation of the process indicated that several aspects required improvement due to unsatisfactory processes. Especially, identifying a highly stereoselective synthesis of the cis-diamine moiety was the most important issue from the viewpoint of quality control and cost reduction. In order to solve those problems, we focused on finding alternative routes for the isolable intermediates such as bromolactone 6 and ultimately diamine 3. Preparation of Bromolactone 6. In the original process, (S)-5 is separated from rac-5 by diastereomeric salt crystallization as the (S)-5/(R)-PEA salt. However, to obtain the desired optical purity, repeated recrystallizations of the initially isolated salt (5−6 times) were required to attain >98% ee of bromolactone 6. Screening of additional chiral amines failed to identify an improvement in the optical purity of the corresponding diastereomeric salt. Since the resolution of rac-5 was unavoidable, we examined enzymatic resolution of racemic 6 as an alternative approach (Figure 2). Usually, it is preferable to conduct an optical or enzymatic resolution step as early as possible in the synthetic route to avoid carrying along the undesired isomer. However, since rac-6 is easily prepared from inexpensive rac-5 and a brominating reagent, we focused our efforts on the resolution of rac-6 rather than rac-5. In the original process, bromolactonization of 5 was carried out in dichloromethane followed by a solvent exchange to water for crystallization. To avoid the use of organic solvents and reduce the number of operations, we investigated the bromolactonization in water (Scheme 2). Under these reaction conditions, it was possible to obtain crystalline rac-6 directly from the reaction mixture in moderate yield with high purity. The isolated yield was lower than the original method (50%

Figure 2. Alternative synthetic approach to 6.

Scheme 2. Bromolactonization of rac-5 in Water

versus 80%), and we speculated that this was due to the kinetically formed bromonium intermediate in an approximately 1:1 ratio. Fortunately, the undesired bromonium intermediate was hydrolyzed prior to isomerization when the reaction was conducted in water. Although the isolated yield was lower than the original process, this method appeared to be superior in terms of cost and productivity. We subsequently explored enzymatic kinetic resolution of rac-6 as the substrate via the screening of multiple enzymes (Table 1).7 Using lipases and proteases, poor reactivity and selectivity were attained (entries 1−7). On the other hand, an esterase showed excellent reactivity and selectivity (entry 8). In this reaction system, the corresponding hydrolyzed carboxylic acid 13 was soluble in water, and the desired bromolactone 6 was insoluble, facilitating isolation and B



Article

Table 1. Screening of Enzymatic Resolution of rac-6

entry

enzymes

strain

ee of 6

1 2 3 4 5 6 7 8 9

Lipase 1 Lipase 2 Lipase 3 Lipase 4 Protease 1 Protease 2 Protease 3 Esterase 1 Esterase 2

Burkholderia sp. Pseudomonas sp. Candida sp. Rhizopus sp. Aspergillus sp. Bacillus sp. Bacillus sp. E. coli (Recombinant) E. coli (Recombinant)

0% 0% 0% 0% −48% −5% 4% 100% −100%

Implementation of these improvements resulted in the replacement of a stoichiometric amount of (R)-PEA with a catalytic amount of esterase, decreased the total number of isolations by filtration from 7 to 3, and reduced the amount of organic solvents used by 90%. Although the overall yield and the purity were almost the same, the material cost of 6 was decreased by 50% when compared to the original method. Alternative Synthetic Route Exploration of 3. Another issue in the original route was the introduction of an amino group into the 4-position of the cyclohexane ring to form the vicinal cis-diamine. In the original process, the use of sodium azide, which has a potential to form explosive hydrazoic acid,8 and the use of a transition metal hydrogenation catalyst to produce the 4-amino group were required. Furthermore, even under optimized conditions, more than 10% of the undesired trans-stereoisomer was generated during the displacement of the mesylate. Despite our efforts, the amount of the undesired stereoisomer could not be reduced. While significant progress was made on the preparation of 6, the synthetic route to 3 still had several processes that required improvement in terms of productivity, cost of goods, and the use of hazardous reagents. Before exploring an alternative synthetic route, we considered the potential causes of the low stereoselectivity in the azidation reaction used to convert 11 to cis-12. The generation of trans-12 can be rationalized via neighboring group participation of the Boc group9 as shown in Scheme 4.

purification. After the completion of the reaction, the desired stereoisomer 6 was obtained by filtration. Further optimization of the reaction conditions included the investigation of several parameters such as • the amount of esterase • pH • temperature The reactivity of esterase-1 was influenced by the pH of the reaction media and was readily deactivated under acidic conditions (pH < 5). Since the pH decreased as the reaction progressed owing to the coproduction of carboxylic acid 13, control of the pH with a pH-stat utilizing a K2CO3 aqueous solution for neutralization was implemented. The acceptable range of pH for esterase-1 was determined to be from 6 to 8, and considering the instability of the lactone toward hydrolysis, the target pH value was set to 7 (see Supporting Information). The progress of the reaction was monitored by examining the optical purity of the remaining solids, and when the optical purity reached 95% ee, the addition of the neutralizing K2CO3 solution was stopped. In the isolated crude 6, which was obtained in 49% yield, there remained a small amount of insoluble enzymatic protein derived from esterase-1. To remove this entrained residual protein, crude 6 was dissolved in acetone and filtered which completely removed the residual insoluble protein. Water was added to the acetone solution of 6 to crystallize 6 which was isolated by filtration in 92% isolated yield with 98% ee. The improved manufacturing method for the preparation of optically pure bromolactone 6 is summarized in Scheme 3.

Scheme 4. Proposed Mechanism for the Formation of trans12

We postulated that trans-12 can be formed via initial displacement of the mesylate in 11 to form the stabilized carbocation 14, which can then undergo subsequent displacement with azide to form the undesired trans-12. Inspired by this side reaction, we wondered if we could utilize the neighboring group effect to control the stereochemistry during the synthesis of the cis-diamine. Ultimately, we decided on an approach that utilizes an N-protecting group having a tether (structure A) with a terminal nitrogen as a nucleophile, which, in turn, could be used to displace the neighboring mesylate by an intramolecular cyclization (structure B). Finally, removal of the tether would give the desired cis-diamine (structure C). An overview of our proposed strategy is presented in Figure 3. As shown in Scheme 5, we designed and prepared substrate 17 for the proposed cyclization which has a sulfonyl group as a tether. A Burgess-type reagent 15 was used for chemoselective

Scheme 3. New Approach to 6

C



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Figure 3. Synthetic strategy for cis-diamine.

desired product 18 was not observed (entry 1). Instead, the major product was tentatively assigned to be aziridine 19 based on the LC-MS and NMR data obtained on the crude reaction mixture, which was not isolable due to the expected low stability of this strained ring system. Surprisingly, a small amount of regioisomer 20 was also obtained.10 The amount of 20 increased as the reaction progressed, even after 17 had been completely consumed. This result likely indicates that this reaction proceeded via initial formation of 19 as a reactive intermediate, which is converted to 20. In fact, when the reaction time was extended to 8 h, the aziridine 19 was completely consumed, and converged to 20 (entry 2). Based on our observations, we assumed that the reaction proceeds through an intramolecular four-step sequence as shown in Figure 4. Namely: (1) cyclization occurred to form aziridine 19 (2) aziridine ring opening by the pendant dimethylamide group (3) proton transfer (4) recyclization to form 20 All steps in this proposed reaction sequence occurred through intramolecular reactions to form the apparently rearranged product with excellent stereoselectivity. Further support for this proposed mechanism was obtained when an ethyl ester 21 was used under the cyclization conditions, and the corresponding aziridine 23 was also formed (Scheme 6).11 However, 23 remained unchanged and cyclic sulfamides 22 and 24 were not observed which supports our proposal of the participation of the dimethylamide group in the formation of 20. In addition, 23 possessed sufficient stability to be isolated by silica gel column chromatography. This result indicates that the dimethylamide group is essential for the intramolecular cleavage of the aziridine in 19 which ultimately leads to the formation of the desired cis-diamine functionality. As we mentioned earlier, we focused this investigation on finding alternative routes for the isolable intermediates, including intermediate 3, since this approach would minimize the impact on the downstream process and limit the need for

Scheme 5. Preparation of 17

sulfonylation of the aminoalcohol 9. Burgess-type reagents are generally unstable in water; however, due to the solubility of 9 and the use of an aqueous ammonia solution in the previous step, we were unable to avoid performing this reaction in the presence of water. We optimized the reaction conditions by using an aqueous solution of 9. It was found that the sulfonylation reaction proceeded much faster than decomposition of 15, and the desired sulfonamide 16 was obtained exclusively in high yield with excellent chemoselectivity. Mesylation of the hydroxyl group was carried out to obtain substrate 17 for use in the subsequent cyclization reaction. Our initial attempts at the cyclization of 17 are shown in Table 2. In the presence of triethylamine at 80 °C for 1 h, the Table 2. Cyclization of 17

HPLC area% entry

reaction time

18

19

20

1 2

1h 8h

not detected not detected

78% not detected

9% 71%

Figure 4. Plausible mechanism for the formation of 20. D



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Scheme 6. Cyclization of Ethyl Ester 21

Scheme 7. Cyclization of Boc-Protected Substrate

amount of pyridine and water with the goal of telescoping the reaction from the previous step (entry 4). After optimization, it was shown that the four-step cyclization sequence and desulfonylation reactions (27 to 3) could be conducted in one pot and 3 was isolated in 85% yield as the oxalate salt with >99% purity. The revised synthetic route to 3 is shown in Scheme 8. The new optimized reaction sequence resulted in a substantial increase in the overall yield (57% versus 40% from 6) and a significant reduction in the cost of goods when compared to the initial route without any disadvantages such as increase in impurities, reaction steps, number of isolation, or the use of hazardous reagents. Application of Plug-Flow Reactor for Scale-up. In the course of the scale-up studies, a decrease in the yield of 27 was observed (Table 4). We investigated the reason for the low yield and confirmed that the intermediate 30 was not stable under the reaction conditions (Figure 5). Namely, chlorosulfonyl isocyanate (CSI) reacted with t-BuOH to form intermediate 30 having the required Boc group; however, 30 is unstable under acidic conditions and partially decomposed to sulfamoyl chloride and isobutene. Since the addition reaction is highly exothermic, it resulted in an extended reaction time as the scale increased in order to maintain control of the temperature. Furthermore, isobutene generated due to decomposition of 30 reacted with CSI to form reactive byproducts which consumed the amino alcohol 9 in the sulfonylation step.13 A combination of all these side reactions resulted in an increase in the amount of reactive byproducts and a decrease in the yield of 27 upon scale-up as a result of the extended reaction time to prepare 30. To suppress the degradation reactions, it was imperative to add CSI rapidly while keeping the reaction temperature low and to reduce the residence time of 30. However, in the case of multihundred kilogram scale production, the cooling capacity was not sufficient for the needed control of the reaction temperature in a batch mode. Therefore, we sought an alternative approach: utilizing a plug-flow reactor that could offer several advantages for the process from the viewpoint of large scale manufacturing.14 The use of a plug-flow reactor would not only offer highly efficient heat exchange and mixing,

change control. Considering these unexpected results, we decided to employ the Boc-protected substrate 27 instead of continuing to explore the use of Cbz-protected 17 to determine if this new approach could be used to our advantage to prepare the intermediate 3 directly. This would produce 3 in fewer steps because the Boc group would be installed via the Boc-protected Burgess type reagent 25 which can be easily prepared by using t-BuOH in situ. Based on our working hypothesis, the Boc-protected substrate 27 was prepared from 9 in good yield in two steps, and the key reaction proceeded smoothly to produce 28 in 86% yield with excellent regio- and stereoselectivity (Scheme 7). With an expeditious route to 28 in hand, we turned our attention to the development of the desulfonylation of 28 (Table 3) to produce 3. Recently, desulfonylation of cyclic Table 3. Desulfonylation of 28

volume vs 28 entry

pyridine

H2O

1 2 3 4

1 5 5 1

5 5 1 0.5

HPLC area% CH3CN none 5

28

3

29

12.5 N.D. 0.1 0.4

0.25 40.6 96.3 96.5

62.5 13.5 0.4 0.3

sulfonamides has been reported using pyridine in the presence of water or alcohols for the synthesis of diamines.12 In the course of the optimization study for the reaction, it was found that the chemoselectivity between the Boc carbonyl group and the sulfonyl group depended on the ratio of pyridine and water. Interestingly, when the amount of water was decreased, the amount of the Boc-deprotected byproduct 29 also decreased (entries 1−3). Further optimization was achieved by performing the desulfonylation in CH3CN, with a reduced E



Article

Scheme 8. Improved Synthetic Route of 3 from 6

mixer at constant flow rates with syringe pumps, and then intermediate 30 was passed through a tube in an ice bath into a Et3N/CH3CN solution to produce 25. Residence time could be adjusted easily by varying the tube length and the flow rates. The effect of the flow system was evaluated by comparing the results to the reaction performed in a batch reactor (Table 5). In the case of the conventional batch mode, the yield of 26 decreased when the reaction time of Step-1 was extended (entries 1 and 2). On the other hand, the flow system provided high yields by shortening the residence time of 30 (entries 3 and 4). Even when the total reaction time (Step-1 + Step-2) increased, the amount of impurities were significantly reduced (entry 4) in the flow system. These results indicate that the application of a plug-flow reaction system can be an effective alternate for scale-up. Prior to implementation on large-scale we performed a scaleup study. The key point of the process design was to control the decomposition of the unstable intermediate 30 and produce 25 in an acceptable yield. However, to determine the appropriate conditions for the continuous plug-flow reactor, not only the various process parameters such as flow rate, temperature, and reagent concentration needed to be considered, but also equipment specifications such as the piping, heat exchanger, and mixer. We determined these interactive parameters by process modeling and simulation. The conceptual flowchart of our approach is shown in Figure 7. The criterion of the yield for production of 30 was set to more than 99% since circumventing the decomposition was critical to the yield and quality of 26. On the other hand, the yield of 25 was set to more than 95% because the decomposition of 25 did not have a critical impact on the quality of 26. In addition, from an engineering point of view, the total operating time for preparation of 25 was set to 10−15 h to consider the limitation of the cooling capacity in the temperature control system and to ensure an efficient time schedule to enable sequential commercial manufacturing. The schematic diagram of process modeling used for predicting the correlations of the yield of 30 and 25 with the operating time is shown in Figure 8. Commercially available and inexpensive equipment, such as general piping, an inline static mixer, a double pipe heat exchanger, and a standard batch reactor, were selected to minimize the required investment in the manufacturing plant if this process was implemented. The overall process could be divided into three steps:

Table 4. Yields of 27 in Scale-up Study

scale

yield of 27

10 g 100 g 1 kg 100 kg

70% 67% 66% 63%

Figure 5. Side reactions in preparation of 25.

but the residence time of unstable reaction intermediates such as 30 could be significantly reduced. To obtain a proof-ofconcept for this approach, we conducted a preliminary investigation of the process using simple equipment (Figure 6). CSI and t-BuOH/CH3CN solutions were supplied to a T-

(i) flow reaction step (ii) cooling step (iii) batch reaction step

Figure 6. Experimental apparatus for preliminary investigation. F



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Table 5. Comparison of Experimental Results between Batch Mode and Flow Mode

addition time entry

mode

Step-1

Step-2

reaction yield of 26 from 9

1 2 3 4

batch batch flow flow

1h 5h 17 sa 17 sa

1.5 h 1.5 h 1.0 h 10 h

91% 85% 94% 93%

a

Residence time of Step-1.

(2) Reaction heats for the preparation of 30 and 25 were measured respectively in batch mode with a reaction calorimeter. (3) Physical properties required for process modeling such as density, viscosity, and specific heat were measured. (4) Process modeling including reaction rate analysis was performed by using process data obtained above, and a model was developed which was capable of calculating the predicted yields of 30 and 25 and the operating time by input of the operating conditions and equipment specifications. (5) Model validation was conducted. Namely, the appropriateness was confirmed by the comparison of the representative experimental results in flow mode and the simulation results. (6) Case studies were conducted under each condition. The effect of operating conditions and equipment specifications on process results was investigated in a systematic manner. Consequently, we were able to determine what conditions would lead to a robust process for large-scale manufacturing. In addition, since numerous literature references indicated that the effect of mixing would be quite important especially in the case of instantaneous reactions,15 we evaluated the ratio of

Figure 7. Conceptual flowchart for determination of process.

The process parameters in each step could be derived respectively by well-known conventional equations. The yield of 30 and 25 and the operating time could be quantitatively predicted by simultaneous differential equations describing the reaction rate and the heat balance. For the determination of process parameters, we did the following: (1) Decomposition rates for 30 and 25 were measured respectively in batch mode under several temperature conditions.

Figure 8. Schematic diagram for process modeling. G



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Table 6. Case Study of Manufacturing Conditions and Results with Scale-up Simulation Casea

1

2

3

4

5

6

7

CSI flow rate t-BuOH/CH3CN temperature t-BuOH/CH3CN concentration t-BuOH/CH3CN flow rate maximum temperature of 30 reaction Heat exchanger temperature of 25 reaction

0.73 L/min 0 °C 0.18 wt.fr 4.87 L/min 78 °C no 0 °C

0.74 L/min 0 °C 0.18 wt.fr 4.98 L/min 78 °C install 0 °C

0.62 L/min 0 °C 0.13 wt.fr 5.53 L/min 62 °C no 0 °C

0.62 L/min −15 °C 0.13 wt.fr 5.43 L/min 50 °C no 0 °C

0.74 L/min −15 °C 0.13 wt.fr 6.55 L/min 50 °C install 0 °C



operating time: criteria ≥10 h, ≤ 15 h 30 yield: criteria ≥99% 25 yield: criteria ≥95%

10.2 h 81.40% 96.20%

10.0 h 97.10% 96.30%

12.1 h 96.10% 95.60%

12.1 h 99.10% 95.60%

10.0 h 99.90% 96.30%

16.2 h 99.80% 94.10%

13.0 h 99.80% 93.70%

Other conditions: CSI temperature 10 °C, brine temperature −20 °C, piping diameter 15 mm, piping length 20 m.

a

Scheme 9. Summary of Improvements

the reaction rates between the main reaction and the decomposition of 30. As a result, it was found that the degradation rate of 26 was much slower (400 000 times) than the main reaction. The results implied that the reaction would not be mixing-sensitive.16 To confirm this possibility, we conducted several experiments with changing hydrodynamics (see Supporting Information). Since the differences in the yield or purity were not observed across all the conditions evaluated, we concluded that a general plug-flow system would be sufficient for scale-up The summary of results from the case studies with simulation are shown in Table 6. In Case Study 1, the reaction conditions employed were based on the current batch conditions and provided 30 in low yield. By installing a heat exchanger (Case Study 2), it was expected that the yield of 30 would be increased by suppression of the decomposition of 30 in the piping. However, it was found that optimization of the reaction conditions was more effective than the installation of a heat exchanger. Namely, increasing the amount of CH3CN used for the dilution of t-BuOH effectively reduced the maximum temperature of a synthesis reaction (MTSR, Case Study 3). In addition, a lower initial temperature of the tBuOH/CH3CN mixture (Case Study 4) further reduced the MTSR. As a result, the yield of 30 was drastically increased and the criteria for a suitable reaction were met even without the installation of a heat exchanger. Although addition of a heat exchanger could provide further improvement (Case Study 5), the return on equipment investment would be expected to be low. Therefore, we decided not to use a heat exchanger in this process. The conditions that used a more dilute reaction (Case Study 6) and an increased reaction temperature for the

formation of 25 (Case Study 7) did not meet the criteria. Consequently, the reaction conditions investigated in Case Study 4 were selected as the manufacturing conditions. Based on the above modeling study, we subsequently evaluated the process robustness with scale-down lab experiments, by mimicking the commercial plant, to determine the reaction parameters. The acceptable range of process parameters such as flow rate, temperature, volume, and operating time were appropriately defined by determining the isolation yield and quality of 27 based on the criteria of ≥75% yield and ≥96% purity. Regarding the equipment factors such as mixing, heat transfer, and fluctuation of flow rate which would not correspond to the actual manufacturing system, we designed a series of experiments under more severe conditions to address these variables. Furthermore, another improvement that was also applied was the use of anhydrous dimethylamine for the aminolysis of 6 to avoid undesired competitive hydrolysis of the lactone ring in 6. As a result, the overall yield of 27 from 6 was significantly improved from 63% to 78%. We summarized the changes to the manufacturing process to prepare 3 in Scheme 9. Although the total number of reaction steps was not decreased, the revised operations were significantly simplified by telescoping the key reaction steps such as the conversion of 27 to 3. Also, the overall yield for the revised manufacturing process for the preparation of 3 from 6 was increased from 40% to 66%, which enabled an increase in the amount of 3 generated by more than 1.5 times per batch. In addition, the material cost of 3 was reduced by 40% due to these improvements, which effectively reduced the cost to produce edoxaban. H



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CONCLUSION We have developed a highly efficient manufacturing route to the key intermediate 3 in the synthesis of edoxaban. During the investigation of an alternative route, we identified an enzymatic resolution approach that avoided the use of a stoichiometric amount of a chiral amine and repetitious diastereomeric salt recrystallizations. Furthermore, in the course of the synthetic route interrogation, an interesting cascade, cyclization reaction was discovered and applied to design a more efficient route to the cis-diamine intermediate. Although the method initially had some challenges for the application to large scale processing, the finalized procedure was reproducible and robust once the application of a plug-flow reactor was incorporated into the process. These technologies were highly effective in terms of cost reduction and increase in productivity.

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method was dried under full vacuum, 165.5 g of dry rac-6 were obtained in 51% yield. 1H NMR (CDCl3) 4.81 (t, J = 5.0 Hz, 1H), 4.41 (t, J = 4.4 Hz, 1H), 2.66 (d, J = 12.2 Hz, 1H), 2.08− 2.58 (m, 4H). 1.80−2.08 (m, 2H). (1S,4S,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (6). The previously prepared rac-6 wet cake (289.6 g) was charged to water (480 mL) and stirred at 30 °C. Esterase (Esterase AC “Amano”, 8.0 g) was added, and then the pH was controlled between 7 to 8 using a 1 M potassium carbonate aqueous solution (264 mL) with a pH-stat for 11 h. The resulting solids were filtered, washed with water (200 mL), and dried at room temperature to give crude 6 (86.4 g, 26.5% yield, 95% ee). The crude 6 (80 g) was charged to acetone (480 mL) and dissolved at 50 °C. The resulting insoluble protein was filtered, and the filtrate was concentrated to 320 mL. The mixture was warmed to 50 °C, and water (480 mL) was added to induce crystallization. The resulting slurry was cooled to 5 °C, stirred for 1 h, and filtered. The wet cake was washed with 40% acetone/water (200 mL) and dried to give 6 (75.0 g, 93.8% yield, 99% ee). (1R,2R,4S)-2-[(tert-Buthoxycarbonyl)amino]-4[(dimethylamino)carbonyl]cyclohexylmethanesulfonate (11). Compound 6 (20 g, 0.098 mol) was mixed by addition of acetonitrile (125 mL) and an aqueous solution of dimethyl amine (50%, 35.2 g, 0.39 mol). The reaction mixture was stirred at 10 °C for 15 h and then concentrated under reduced pressure maintaining the temperature below 15 °C. An aqueous ammonia solution (28%, 125 mL, 2.06 mol) was added, and the mixture was stirred at 40 °C for 8 h and then concentrated under reduced pressure. Deionized water (88 mL), di-tert-butyl dicarbonate (31.9 g, 0.146 mol), and NaOH aqueous solution (48%, 20.3 g) were added and stirred for 2 h at 40 °C. After reaction completion, 4-methyl-2-pentanone (175 mL) was added, and the layers were separated. The aqueous layer was extracted again with 4-methyl-2-pentanone (175 mL), and the combined organic phases were concentrated under reduced pressure to a volume of 175 mL. 4Methyl-2-pentanone (75 mL) and methane sulfonyl chloride (17.9 g, 0.156 mol) were added to the solution. Triethyl amine (18.8 g, 0.186 mol) was added dropwise, and the reaction mixture was stirred for 1 h at 25 °C. Methanol (43 mL) and deionized water (63 mL) were added to the mixture, and stirring was continued for 15 min. The organic layer was washed with 5% sodium bicarbonate aqueous solution (50 mL), and the separated organic phase was concentrated under reduced pressure to a volume of 100 mL. The resulting slurry was stirred at 0 °C for 3 h and filtrated. The cake was washed with 4-methyl-2-pentanone (25 mL) and dried under full vacuum to give 11 (22.4 g, 62.9% yield). 1H NMR (CDCl3) 4.69−4.82 (m, 2H), 4.00−4.08 (m, 1H), 3.07 (s, 3H), 3.04, (s, 3H), 2.94 (s, 3H), 2.75−2.81 (m, 1H), 2.17−2.26 (m, 1H), 2.04−2.15 (m, 1H), 1.84−1.96 (m, 2H), 1.67−1.76 (m, 1H), 1.58−1.66 (m, 1H), 1.45 (s, 9H). tert-Butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate Oxalate (3). Dodecylpyridinium chloride (15.58 g, 0.055 mol), toluene (40 mL), and NaN3 aqueous solution (13.56 g/40 mL, 0.207 mol) were charged, and the mixture was stirred at 30 °C for 1 h. Toluene (147 mL) was added, and a Dean−Stark trap was attached to the flask. The mixture was refluxed under reduced pressure at 50 °C for 7 h to reduce the water content (0.05%, specification: < 0.17%). The mesylate 11 (40 g, 0.110 mol) was added at 20 °C, and the mixture was stirred at 70 °C for

EXPERIMENTAL SECTION

General. All reactions were performed in an atmosphere of nitrogen. Nuclear magnetic resonance (NMR) spectra were obtained using a Bruker 400 MHz spectrometer in the indicated solvents. Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. Water content was measured by Karl Fischer titration. All the yields were calculated by weight without assay unless otherwise noted. All reaction yields were quantified using a standard sample to determine % weight by high performance liquid chromatography (HPLC). Analytical conditions are described below. Compound 5 to 6. HPLC conditions (reaction monitoring and evaluation of impurities). Buffer solution: Phosphate buffer (pH = 2.5). Eluent A: Buffer and acetonitrile (7:3) v/v. Eluent B: Buffer and acetonitrile (9:11) v/v. Column: X Bridge C8 (150 × 4.6) mm, 3.5 μm. Flow rate: 1.0 mL/min. Detector: UV at 210 nm. Column oven temperature: 40 °C. Sample tray temp: 5 °C. Injection volume: 10 μL. Run Time; 65 min. Gradient Time (Min) Solution A (%)/Solution B (%): 0 min; 100:0, 10 min; 100:0, 35 min; 0:100, 45 min; 0:100, 60 min; 100:0. Enantiomeric Purity of 6. HPLC conditions; Eluent: premixed and degassed solution of n-hexane/2-propanol in the ratio of 98:2 (%v/v). Column: CHIRALPAK AD-H (250 × 4.6) mm, 5 μm. Flow rate: 1.0 mL/min. Detector: UV at 215 nm. Injection volume: 40 μL. Column oven temperature: 35 °C. Sample tray temperature: 25 °C. Run time: 30 min. Compound 6 to 3. Column: L-Column C8 (4.6 mm I.D. × 150 mm, 5 μm). Eluent: (0.02 M KH2PO4/CH3CN = 2:1) + 0.5 mol % Sodium dodecyl sulfate (SDS). Mode: Isocratic. Column temp: 30 °C. Detector: UV at 210 nm. Flow rate: 1 mL/min. Time: 30 min. Sample cooler: 5 °C. Injection sample was diluted with the same eluent. 4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (rac-6). Water (200 mL) and potassium hydroxide solution (48% aqueous solution 123.9 mL, 1.590 mol) were treated by the addition of rac-5 (200 g, 1.585 mol). 1,3-Dibromo-5,5dimethylhydantoin (226.7 g, 0.793 mol) was added over 3 h while maintaining the reaction temperature below −10 °C and then stirred at 0 °C for 1 h. Sodium sulfite (40.0 g 0.317 mol) was dissolved in water (200 mL) and added to the reaction solution. This was stirred at 30 °C for 1 h and filtered. The cake was washed with water (400 mL) to give rac-6 (289.6 g as a wet cake) and then used in the next step. When the wet cake prepared with the same I



Article

(CDCl3) 7.39 (s, 1H), 5.37 (d, J = 5.5 Hz, 1H), 4.72−4.75 (m, 1H), 3.99 (m, 1H), 3.10 (s, 3H), 3.06 (s, 3H), 2.94 (s, 3H), 2.82−2.86 (m, 1H), 2.35 (ddd, J = 4.8, 8.9, 14.4 Hz, 1H), 1.98−2.05 (m, 2H), 1.84−1.91 (m, 1H), 1.61−1.69 (m, 2H), 1.49 (s, 9H). HRMS: calculated for C15H29N3O8S2, M − H− m/z 442.1318, found 442.1326. tert-Butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate Oxalate (3) from 27. Mesylate 27 (1430 kg, 3.224 kmol) was charged to a reactor, followed by the addition of acetonitrile (6435 L) and triethylamine (503 L, 3.579 kmol). The mixture was stirred at 70 °C for 2 h. After the reaction completion, water (358 L) and pyridine (1287 L, 15.98 kmol) were added, and the mixture was stirred at 75 °C for 5 h. NaCl aqueous solution (20%, 1430 L), water (200 L), toluene (14 300 L), and NaOH aqueous solution (25%, 2145 L) were added, and the mixture was stirred at 50 °C; then the layers were separated. The organic layer was washed with NaCl aqueous solution (20%, 1430 L) and NaOH aqueous solution (25%, 286 L). The organic layer was concentrated under reduced pressure to a volume of 4290 L, and then acetonitrile (8580 L) was added and filtered to give the solution of 3. Oxalic acid (406 kg, 4.510 kmol), water (601 L), and acetonitrile (10 100 L) were charged to another reactor, followed by the addition of 3 solution at 35 °C for 2 h. The mixture was stirred at 50 °C for 2 h, then cooled to 25 °C, and filtrated. The cake was washed with an aqueous acetonitrile solution (93%, 5434 L) to give the crude crystalline 3 as a hydrate. Then the crude 3 was charged into acetonitrile (10 010 L), and the mixture was concentrated under reduced pressure to remove most of the water. The slurry was filtrated at 30 °C and then dried under full vacuum at 60 °C to give 3 (1010.8 kg, 2.692 kmol, 83.5% yield) as a white crystalline solid.

10 h. An aqueous solution of 2.5% sodium bicarbonate (120 mL) and toluene (28 mL) were added, the mixture was stirred at 50 °C for 15 min, and the organic layer was separated. The remaining aqueous layer was extracted with toluene (3 × 40 mL). The organic layers were combined and washed with water (20 mL) and then concentrated to 120 mL under reduced pressure. Toluene (40 mL), MeOH (4 mL), and Pd/ C (7.5%, 5.60 g) were added to the mixture, and an ammonium formate (7.60 g, 0.121 mol) solution in toluene (60 mL) and MeOH (44 mL) was added dropwise while the reaction was stirred at 40 °C for 1 h and then filtrated. The filtrate was concentrated under reduced pressure to 60 mL, and acetonitrile (280 mL) and water (20 mL) were added. An acetonitrile solution of oxalic acid (6.9%, 128.89 g, 0.099 mol) was added dropwise to the solution at 50 °C and stirred for 3 h. The resulting slurry was filtrated at 30 °C. The wet crystalline mass and CH3CN (280 mL) were charged to a flask, and then the mixture was concentrated under reduced pressure to remove water. The slurry was filtrated at 30 °C and dried under full vacuum to give 3 (26.33 g, 0.0701 mol, 63.8%). 1H NMR (CDCl3) 4.10 (br, 1H), 3.32 (d, J = 12.2 Hz, 1H), 2.96 (m, 3H), 2.80 (t, J = 12.4 Hz, 1H), 2.77 (s, 3H), 1.72−1.83 (m, 3H), 1.63 (t, J = 22.7 Hz, 1H), 1.37−1.49 (m, 2H), 1.30 (s, 9H). Preparation of Burgess Reagent 25. Chlorosulfonyl isocyanate (737 kg, 5.207 kmol) and t-BuOH (465 kg, 6.274 kmol) in acetonitrile (3897 L) were reacted through the plugflow system, and the mixture was continuously added into a mixture of triethylamine (2117 L, 15.06 kmol) and acetonitrile (1477 L) while maintaining the temperature below 5 °C for 13 h. (1R,2R,4S)-2-{[(tert-Butoxycarbonyl)sulfamoyl]amino}-4-(dimethylcarbamoyl)cyclohexyl Methanesulfonate (27) from 6.17 (1S,4S,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (890 kg, 4.340 kmol) was charged followed by dimethylamine in THF (24%, 2092 L). The mixture was stirred at 25 °C for 14 h. NaCl (409 kg), citric acid (584 kg), water (2252 L), and ethyl acetate (3560 L) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 1780 L). The organic phases were combined and concentrated under reduced pressure to a volume of 2225 L. Water (1780 L) was added, and the solution was concentrated under reduced pressure to a volume of 2225 L. Water (1638 L), ammonia aqueous solution (28%, 5563 L, 82.37 kmol), and NaOH aqueous solution (25%, 547 L) were added, and the mixture was stirred at 40 °C for 4 h and concentrated under reduced pressure to a volume of 4450 L to afford a 9 solution. The solution was added to the previously prepared 25 solution, and the mixture was stirred at 5 °C for 1 h. Citric acid (334 kg) and ethyl acetate (9790 L) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3193 L). The organic layers were combined and washed with a NaCl aqueous solution (20%, 3382 L), and the solvent was replaced to give an acetonitrile solution of 26 (2670 L). Methane sulfonyl chloride (488 kg, 4.261 kmol) and 4-methylmorpholine (531 kg, 5.250 kmol) were added, and the mixture was stirred at 5 °C for 3 h. Sulfuric acid (5% aqueous solution, 757 L) was added, and the mixture was transferred into water (12 990 L). The slurry was stirred at 5 °C for 3 h and then filtrated. The cake was washed with aqueous acetonitrile (28%, 2848 L) and then dried under full vacuum at 50 °C to give the corresponding mesylate 27 (1529.9 kg, 3.449 kmol, 79.5% yield) as a white crystalline solid. 1H NMR

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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.8b00413. Optimization studies of enzymatic reaction, confirmatory experiments, effect of hydrodynamics and process modeling in plug-flow reactor (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Makoto Michida: 0000-0003-1281-3300 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Mr. Tomohiro Shiohara, Yasuhisa Kuwahara, Takuma Nishizawa, and the staff of Manufacturing/Engineering Department of the Odawara plant (Daiichi Sankyo Chemical Pharma Co., Ltd.) for their valuable support during our scale up runs. In addition, we thank Dr. David Conlon (Daiichi Sankyo, Inc.) for helpful discussions during the preparation of the manuscript.

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REFERENCES

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Development of an Efficient Manufacturing Process for a Key

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