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Application of a Rotor–Stator High-Shear System for Cr/ Mn-Mediated Reactions in Eribulin Mesylate Synthesis Takashi Fukuyama, Hiroyuki Chiba, Teiji Takigawa, Yuki Komatsu, Akio Kayano, and Katsuya Tagami Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00383 • Publication Date (Web): 21 Dec 2015 Downloaded from http://pubs.acs.org on December 21, 2015

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Organic Process Research & Development

Application of a Rotor–Stator High-Shear System for Cr/Mn-Mediated Reactions in Eribulin Mesylate Synthesis Takashi Fukuyama,1* Hiroyuki Chiba,2 Teiji Takigawa,1 Yuki Komatsu,2 Akio Kayano,2 and Katsuya Tagami2* 1

API Research, Eisai Pharmaceutical Science & Technology, Eisai Product Creation Systems,

Eisai Co. Ltd. 5-1-3-Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan 2

API Research, Eisai Pharmaceutical Science & Technology, Eisai Product Creation Systems,

Eisai Co. Ltd. 22-Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan

ACS Paragon Plus Environment

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Table of Contents Graphic


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ABSTRACT Potential issues associated with the scale up of a catalytic Nozaki–Hiyama–Kishi reaction and a Cr/Mn-mediated desulfonylation used in eribulin mesylate synthesis were evaluated, and countermeasures were investigated. When stir bar agitation, which is typically used for laboratory-scale reactions, was changed to impeller-type agitation upon scale up of these reactions, the conversion rate and yield decreased considerably. Traditional methods for overcoming such decreases, such as pre-activation of the Mn or the use of fine particles of Mn, did not improve the conversion rate sufficiently, whereas a physical shearing approach was effective. Specifically, we found that the use of a rotor–stator high-shear system as a stirring device afforded the same conversion rate as that observed with a stir bar.

KEYWORDS Eribulin mesylate, catalytic Nozaki-Hiyama-Kishi reaction, Cr/Mn-mediated desulfonylation,

rotor–stator

high-shear


system

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A quarter century after the isolation and the discovery of the anticancer activity of halichondrin B,1,2 a fully synthetic derivative, eribulin mesylate (1), was approved in the United States for the treatment of certain patients with metastatic breast cancer.3 The synthesis of 1 was a significant challenge.4 As of 2015, 1 has been approved for use in more than 50 countries and is being supplied with consistent quality by means of a validated method.5 The final process in the assembly of eribulin mesylate involves SmI2-mediated desulfonylation of α-sulfonyl ketone 2 to give ketone 3 and a subsequent intramolecular Nozaki–Hiyama–Kishi (NHK) reaction6 to afford macrocyclized intermediate 4 (Scheme 1). Although this process can be carried out on a manufacturing scale, it includes features that are undesirable for further scale up, namely, the use of cryogenic conditions for the desulfonylation step and the use of large molar excesses of sensitive to air and/or moisture, expensive reagents (SmI2 and CrCl2). Therefore, we focused on addressing these issues and developed an alternative synthetic route to 4, which includes a catalytic NHK reaction7 of 2 to give macrocyclized α-sulfonyl ketone 5 and subsequent reductive desulfonylation of the Cr–Mn–ligand system.8

Scheme 1. A final assembly of eribulin mesylate


4

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When reactions are scaled up from lab to bench scale, it is generally necessary to switch from stir bar agitation to impeller agitation, and this change often causes problems in the case of heterogeneous reactions. Unfortunately, the two reactions in our alternative route to 1 were no exception. The use of an impeller instead of a stir bar resulted in a substantial decrease in the conversion rates of the scaled-up reactions: specifically, the catalytic NHK reaction of 2 took 3.5 times as long with an impeller as with a stir bar (Figure 1), and the Cr/Mn-mediated desulfonylation of 5 was not complete even after 12 h (Figure 2). (Note that in the latter reaction, the rotation speed was 500 rpm from 0 to 8 h, after which it was increased to 750 rpm, which was the maximum speed of the impeller.) In addition, the yield of each step was worse than expected: with a stir bar, the yields of both the catalytic NHK reaction and the Cr/Mn-mediated desulfonylation were more than 95%, but with an impeller, the yields of the two steps dropped to 93% and 80%, respectively.

c onversion (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


100 90 80 70 60 50 40 30 20 10 0

stir bar impeller

0

1

2

3

4

5

6

7

reac tion t ime (h)

Figure 1. Conversion rate of catalytic NHK reaction of 2. Rotation speed of impeller was 500 rpm (conversion rate was checked by 2 hour).


5

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c onversion (%)


100 90 80 70 60 50 40 30 20 10 0

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stir bar impeller 0

2

4

6

8

10

12

reac tion t ime (h)

Figure 2. Conversion rate of Cr/Mn-mediated desulfonylation of 5. Rotation speed of impeller was 500 rpm (0h to 8 h) and 750 rpm (from 8 h) (conversion rate was measured every 2 hours)

In these two reactions, degradation of the product and substrate (caused by the longer reaction time) and the presence of residual 2 and 5 affected the yield and purity of 4. Accordingly, the development of scalable versions of these two Cr/Mn-mediated reactions with good conversion rates is critical to assure a reliable process for manufacture of 1. Herein, we report that we have developed a scalable approach for these consecutive heterogeneous reactions. The mechanisms of the two reactions are shown in Scheme 2.7a,7d Ni–neocuproine complex 6 and Cr ligand 7 (Scheme 1) were soluble in the reaction medium, but the Mn was insoluble. Therefore, one of the keys to the success of the two reactions was to increase the efficiency of the reduction of Cr(III) to Cr(II) by the insoluble Mn. Scheme 2. Reaction mechanism for both catalytic NHK reaction and Cr/Mn-mediated desulfonylation


6

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Cr(II)

Cr(III) Catalytic NHK reaction

Ni(0)

Ni(I)

RCHO OCr(III)Cl2

X

Ni(II)X

Cr(III)Cl2 1/2Mn(0)

R Cp2ZrCl2

1/2Mn(II)

OZr(Cp)2Cl

Cr(II)Cl2 Cr(III)Cl3

R Desulfonylation Mn(0)

Mn(II)

2Cr(II)

2Cr(III)

Cr(III)SO2Ph

SO2Ph OCr(III)

O

The surface of Mn powder is known to be partially coated with manganese oxide (MnO).9 This MnO coating interferes with the Cr(III)/Cr(II) redox cycle. Iodine (I2) is known to promote metal-mediated reactions by removing the oxide layer from metal surfaces.10 Therefore, we initially attempted to activate the Mn in situ by adding I2 to the catalytic NHK reaction of 2, and we found that the conversion rate in the early stage of the reaction was improved. However, the conversion rate then gradually decreased, and full conversion required a reaction time of 12 h. Because the redox cycle involving Mn and Cr(III) occurred at the Mn surface, we expected that the conversion rate would increase if the surface area of the Mn could be increased. To confirm this hypothesis, we investigated a reaction using Mn with a particle size of 10 µm.11 As expected, the use of these fine particles of Mn did improve the conversion rate (the reaction was complete after 5 h), but the conversion rate was still not as high as that with a stir bar. The use of fine Mn particles was also investigated in the subsequent Cr/Mn-mediated desulfonylation of 5, but complete conversion was not achieved.


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The difference between the results for the two reactions indicates that the composition of the Mn salt formed by reduction of Cr(III) to Cr(II) differed under the two reaction conditions. In the catalytic NHK reaction of 2, the Mn formed a salt with Cl or I, whereas in the Cr/Mn-mediated desulfonylation of 5, the Mn formed a salt with Cl or sulfinate. The Mn sulfinate probably remained on the surface of Mn to a greater extent than did the Mn halide, inhibiting further reduction of Cr(III) to Cr(II). Therefore, we concluded that the critical factor in these reactions was how the Mn salt was removed from the Mn surface. Chemical activation of the Mn surface by the addition of I2 or by micronization of the Mn powder had limited effects, especially for the desulfonylation reaction. However, in situ grinding of the Mn surface by the stir bar seemed to be very effective. Even when the rotation speed of the stir bar was set to a minimum, the conversion rate remained unchanged. These findings indicate that physical shearing of the Mn in situ was the most important factor for the success of these reactions. Therefore, we turned to an investigation of physical shearing. First, we examined the use of ultrasonic waves12 in the Cr/Mn-mediated desulfonylation of 5. We found that although the early stage of the reaction proceeded at the same conversion rate as that of the reaction conducted with stir bar agitation, conversion was incomplete (95%), and the unidentified byproducts were produced, probably because of excess local heating. Nevertheless, the results of this experiment confirmed that the use of physical shearing was appropriate and that a more practical, milder, and controllable shearing system was necessary. Rotor–stator high-shear systems are known to be useful for breaking down tissues, forming emulsions, dispersing pigments, controlling particle size in crystallization processes,13 wet milling,14 and so on. Recently, applications of such systems for chemical reactions have been reported.15 We expected that a rotor–stator high-shear system would shear the Mn salt from the


8

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Mn surface, and we therefore carried out the Cr/Mn-mediated desulfonylation reaction with a rotor–stator tissue homogenizer. As expected, the conversion rate was improved: the rate was the same as that observed with the stir bar. This promising result proved that stirring with a rotor– stator high-shear system was useful, and further investigations with the system were carried out. In our initial trial, we used a tissue homogenizer (not industrial system) with 20 µm of clearance and a tip speed of 1.57 m/s. If such a system is to be used for chemical reactions on a practical scale, two important system characteristics must be considered: the clearance between the rotor and stator and the tip speed of the rotor. In fact, among the available industrial-use rotor–stator high-shear systems, the minimum rotor–stator clearance is 500 µm,16 and the maximum practical tip speed is 15 m/s.16 To assess the feasibility of using a rotor–stator highshear system in our manufacturing process, we investigated a system with a 500 µm clearance (tip speed 5.34 m/s) and found that the result was the same as that for the system with the 20 µm clearance (Table 1).

Table 1. The results of using different clearance of rotor–stator high-shear systems for Cr/Mnmediated desulfonylation of 5.

a

Determined by HPLC. bPhyscotron NS-7 was used as stirring device (tip speed was 1.57 m/s). c IKA T25 ULTRA TURRAX S25N-25F was used as stirring device (tip speed was 5.34 m/s).

Having confirmed that the 500 µm clearance was acceptable for the desulfonylation reaction, we also performed the catalytic NHK reaction of 2 using the same device and tip speed (5.34


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m/s) as desulfonylation reaction (Table 2, entry 1). The conversion rate was comparable to that achieved with magnetic stirring. Next, we scaled up the reaction further and investigated the effect of tip speed on the conversion rate. When we scaled up the reaction approximately 6-fold and halved the tip speed, there was no difference in conversion rate (entry 2).

Table 2. Further scale up and comparison of tip speed at catalytic NHK reaction of 2.

entry

2 (g)

tip speed (m/s)

time (min)

conversiona (%)

1b 2b

2.5 16

5.34 2.85

120 120

100 100

a

Determined by HPLC. bIKA T25 ULTRA TURRAX S25N-25F (clearance: 500 µm) was used as stirring device.

Next, we conducted similar investigations of the Cr/Mn-mediated desulfonylation of 5 (Table 3). In contrast to the catalytic NHK reaction, a 12 g scale desulfonylation reaction exhibited a lower late-stage conversion rate and incomplete conversion (98%) when the tip speed was set at 2.85 m/s (entry 2). However, when the tip speed was raised to 3.74 m/s, the conversion rate improved, and the reaction went to completion (100%, entry 3). This result implies that the minimum tip speed required for completion of the desulfonylation reaction is between 2.85 and 3.74 m/s.


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Table 3. Further scale up and comparison of tip speed at Cr/Mn-mediated desulfonylation of 5.

a

Determined by HPLC. bIKA T25 ULTRA TURRAX S25N-25F (clearance: 500 µm) was used as stirring device. cEntry 3 is the result of additional 30 min stirring within tip speed 3.74 m/s using the reaction of entry 2. Because the experimental results described so far were obtained for reactions at a maximum scale of 16 g, further scale up of the two reactions was investigated with a batch-type rotor–stator high-shear system (IKA T65 digital ULTRA TURRAX S65-KG-HH-G65F was used, see the experimental section). The catalytic NHK reaction of 2 on a 367 g scale proceeded smoothly over the course of 2 h at a tip speed of 5.0 m/s. In contrast, the Cr/Mn-mediated desulfonylation of 327 g of 5 showed a slight decline in reaction speed with this agitation system. The variation of the conversion rate with reaction time is shown in Figure 3. The tip speed was initially set at 5.0 m/s, but after 3 h, the tip speed had to be increased to 7.6 m/s to achieve full conversion. 100 90 80 conversion (%)

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70 60 50 40 30 20 10 0 0

1

2

3

4

5

reaction time (h)


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Figure 3. Conversion rate of Cr/Mn-mediated desulfonylation of 5 in 327 g scale. Tip speed 5.0 m/s (0 h to 3 h), 7.6 m/s (3 h to 5 h) (conversion rate was checked by the hour)

In these experiments, the same reaction vessel was used for both reactions, and the reaction volume of the Cr/Mn-mediated desulfonylation was a little less than half that of the catalytic NHK reaction. Therefore, the rotor–stator was completely immersed in the reaction solution for the catalytic NHK reaction but not for the Cr/Mn-mediated desulfonylation reaction (Figure 4). This difference between the reaction volumes may be one reason for the decline in the conversion rate of the desulfonylation. This is one potential drawback of instruments design for multiple purposes.

Figure 4. Comparison of the state of reaction solution

There are two types of rotor–stator high-shear systems: the batch type and the in-line type (Figure 5). The in-line type is generally superior in performance because it exhibits efficient shearing due to efficient cycling of the reactor content. If the in-line type is used, the reaction volume does not need to be considered.


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Figure 5. Two types of the rotor–stator high-shear systems We compared the conversion rates achieved with the batch and in-line type systems for the catalytic NHK and desulfonylation reactions (Figures 6 and 7, respectively). As expected, conversion with the in-line type system was as good as or better than that with the batch-type system for both reactions. Accordingly, like an appropriately set up batch-type system, an in-line type system would undoubtedly be suitable on a manufacturing scale. 100 90 80 c onversion (%)

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70 60 50 40

a)

30

b)

20

c)

10 0 0

60

75

90

105

120

reac tion t ime (m in)

Figure 6 Conversion rate of catalytic NHK reaction of 2. a) Batch type (IKA T25 ULTRA TURRAX S25N-25F), tip speed 2.85 m/s. b) In-line type (IKA magic LAB MK module), tip speed 10.2 m/s. c) Impeller stirring, 500 rpm. (conversion rate were measured after the addition of 2 in THF solution for 1 h)


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c onversion (%)


100 90 80 70 60 50 40 30 20 10 0

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a) b) c)

0

15 30 45 60 75 90 105 120 reac tion t ime (m in)

Figure 7. Conversion rate of Cr/Mn-mediated desulfonylation of 5. a) Batch type (IKA T25 ULTRA TURRAX S25N-25F), tip speed 2.85-3.74 m/s. b) In-line type (IKA magic LAB MK module), tip speed 10.2 m/s. c) Impeller stirring, 500 rpm.

Conclusion We investigated a promising method for scale up of two Cr/Mn-mediated reactions used to synthesize eribulin mesylate. The decrease in conversion rate observed when an impellor rather than a stir bar was used for agitation, a change that is traditionally implemented in scaling up a reaction from the laboratory scale to the bench plant scale, could be prevented by the use of a rotor–stator high-shear system for agitation. Two types of such systems were compared, and the in-line type was found to be better for the manufacturing scale. This approach can be expected to solve problems with scale up of similar types of metal-mediated heterogeneous reactions.


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Experimental Section All reagents and solvents were obtained from commercial sources, except for 25c and Ni– neocuproine complex 6.7b The HPLC conditions for the catalytic NHK reaction were as follows: Shimadzu Prominence HPLC, Hypersil column (4.6 × 250 mm, 5 µm), flow rate 1.3 mL/min, column temperature 35 °C, detection wavelength 210 nm, eluent n-hexane/methyl t-butyl ether (870/130, v/v), run time 30 min. The procedures for the batch-type catalytic NHK reaction and the Cr/Mn-mediated desulfonylation reaction can be found in the supporting information of ref 7b, along with the NMR data for the reaction products. Catalytic NHK reaction of 2: The stirring device used for this reaction was a T65 digital ULTRA TURRAX (IKA) homogenizer with an S65-KG-HH-G65F (IKA) dispersing element (tip speed 5.0 m/s). Reaction temperature was controlled with room-temperature water bath. Tetrahydrofuran (7.34 L) was added to a mixture of 4,4′-di-tert-butyl-2,2′-bipyridyl (6.20 g, 23.1 mmol), CrCl3 (3.66 g, 23.1 mmol), (cyclopentadienyl)2ZrCl2 (74.3 g, 254 mmol), and Mn powder (50.8 g, 924 mmol) in a sealed reactor that had been purged with Ar, and the mixture was stirred with the rotor–stator high-shear system at room temperature for 30 min. To the resulting mixture was added a suspension of Ni–neocuproine complex 6 (7.80 g, 23.1 mmol) in THF (300 mL). After the mixture was stirred for 10 min at room temperature, a solution of 2 (367 g, 231 mmol) in THF (6.97 L) was added over the course of 1 h, and the resulting mixture was stirred for 3 h at room temperature. n-Heptane (7.34 L) was added to the reaction mixture, and then the reaction was quenched with 10% aqueous citric acid (3.67 kg). After separation of


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the n-heptane layer, the aqueous layer was extracted with n-heptane (3.67 L). The combined nheptane layers were washed with a solution containing 5% NaHCO3 and 10% Na2SO4 (3.67 kg) and were then concentrated in vacuo to give 5 (327 g, 224 mmol, 97.0% yield) as a pale yellow amorphous solid.

Cr/Mn-mediated desulfonylation of 5: The stirring device used for this reaction was a T65 digital ULTRA TURRAX (IKA) homogenizer with an S65-KG-HH-G65F (IKA) dispersing element (tip speed 5.0–7.6 m/s). Reaction temperature was controlled with room-temperature water bath. A solution of 5 (327g, 224 mmol) in THF (6.54 L) was added to a mixture of 4,4′-ditert-butyl-2,2′-bipyridyl (72.0 g, 268 mmol), CrCl3·6H2O (71.5 g, 268 mmol), and Mn powder (49.2 g, 895 mmol) in a sealed reactor that had been purged with Ar, and the mixture was stirred for 5 h at room temperature. The reaction was quenched with n-heptane (6.54 L), MeOH (1.64 L), and 10% aqueous citric acid (3.27 kg), and the resulting mixture was stirred for 30 min. After separation of the aqueous layer, the organic phase was washed with an aqueous solution containing 5% NaHCO3 and 10% Na2SO4 (3.27 kg) and then concentrated in vacuo to afford 4 (279 g, 211 mmol, 94.3% yield) as a pale yellow amorphous solid.

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] *E-mail: [email protected]


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Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We are grateful to IKA Japan for mechanical support. REFERENCES (1) For the original isolation and structural elucidation of halichondrins, see: (a) Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C.; Tanaka, J.; Okumura, Y.; Hirata, Y. J. Am. Chem. Soc. 1985, 107, 4796. (b) Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701. (2) For total synthesis of halichondrin class natural products, see: (a) halichondrin B and norhalichondrin B: Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162. (b) norhalichondrin B: Jackson, K. L.; Henderson, J. A; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346. (c) halichondrin C: Yamamoto, A.; Ueda, A.; Brémond, P.; Tiseni, P. S.; Kishi, Y. J. Am. Chem. Soc. 2012, 134, 893. (d) halichondrin A, norhalichondrin A and homoholichondrin A: Ueda, A.; Yamamoto, A.; Kato, D.; Kishi, Y. J. Am. Chem. Soc. 2014, 136, 5171. (3) Lin, N. U.; Burstein, H. J. Lancet 2011, 377, 878. and references therein. (4) (a) Towle, M. J.; Salvato, K. A.; Budrow, J.; Wels, B. F.; Kuznetsov, G.; Aalfs, K. K.; Welsh, S.; Zheng, W.; Seletsky, B. M.; Palme, M. H.; Habgood, G. J.; Singer, L. A.; DiPietro, L. V.; Wang, Y.; Chen, J. J.; Quincy, D. A.; Davis, A.; Yoshimatsu, K.; Kishi, Y.; Yu, M. J.; Littlefield, B. A. Cancer Res. 2001, 61, 1013 (b) Wang, Y.; Habgood, G. J.; Christ, W. J.; Kishi,


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1986, 108, 6048. (d) Wan, Z.-K.; Choi, H.; Kang, F.-A.; Nakajima, K.; Demeke, D.; Kishi, Y. Org. Lett. 2002, 4, 4431. (e) Austad, B.; Chase, C. E.; Fang, F. G. Intermediates For The Preparation Of Halichondrin B. WO 2005118565, 2005. (7) (a) Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533. (b) Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349. (c) Namba, K.; Kishi, Y. Org. Lett. 2004, 6, 5031. (d) Namba, K.; Cui, S.; Wang, J.; Kishi, Y. Org. Lett. 2005, 7, 5417. (e) Namba, K.; Wang, J.; Cui, S.; Kishi, Y. Org. Lett. 2005, 7, 5421. (f) Namba, K.; Kishi, Y. J. Am. Chem. Soc. 2005, 127, 15382. (8) (a) Inanaga K.; Kubota, M.; Kayano, A.; Tagami, K. Novel Intermediate For Halichondrin B Analog Synthesis And Novel Desulfonylation Reaction Used For The Intermediate. PCT Int. Appl. WO2009064029, 2009. (b) Inanaga, K.; Fukuyama, T.; Kubota, M.; Komatsu, Y.; Chiba, H.; Kayano, A.; Tagami, K. Org. Lett. 2015, 17, 3158. (9) The Merck Index, 13.4 [CD-ROM]; Wiley: New York, 2005. (10) Hiyama, T.; Sawahata, M.; Obayashi, M. Chem. Lett. 1983, 1237. (11) Mn with a particle size of 10 µm was made to order by Wako Pure Chemical Industries, Ltd. Unless otherwise specified, Mn with a particle size of 75 µm (also manufactured by Wako Pure Chemical Industries) was used for the reactions described in this paper. (12) BRANSON Yamato 5200 was used. (13) (a) Kamahara, T.; Takasuga, M.; Tung, H. H.; Hanaki, K.; Fukunaka, T.; Izzo, B.; Nakada, J.; Yabuki, Y.; Kato, Y. Org. Process. Res. Dev. 2007, 11, 699. (b) Lo, E.; Mattas, E.; Wei, C.; Kacsur, D.; Chen, C.-K. Org. Process. Res. Dev. 2012, 16, 102.


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(14) (a) Lee, I.; Variankaval, N.; Lindemann, C.; Starbuck, C. Am. Pharm. Rev. 2004, 7, 120123 and 128. (b) Harter, A.; Schenck, L.; Lee, I.; Cote, A. Org. Process. Res. Dev. 2013, 17, 1335. (c) Luciani, C. V.; Conder, E. W.; Seibert, K. D. Org. Process. Res. Dev. 2015, 19, 582. (15) (a) Kryukov, Y. A.; Vasilishin, M. S.; Ivanov, O. S.; Karpov, A. G.; Surmacheva, I. A.; Akhmadeev, I. R.; Sysolyatin, S. V. Pharm. Chem. J. 2010, 44, 456. (b) Meeuwse, M.; Lempers, S.; Schaaf, J. Van Der; Schouten, J. C. Ind. Eng. Chem. Res. 2010, 49, 10751. (c) Beutner, G. L.; Desai, L.; Fanfair, D.; Lobben, P.; Anderson, E.; Leung, S. W.; Eastgate, M. D. Org. Process. Res. Dev. 2014, 18, 1812. (16) The minimum clearance and maximum tip speed are specified in the IKA catalog. www.ikaprocess.com (accessed Aug 31, 2015).


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Mn-Mediated

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