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Process Design and Optimisation in the Pharmaceutical Industry: a Suzuki-Miyaura Procedure for the Synthesis of Savolitinib Neil K Adlington, Lauren R. Agnew, Andrew D. Campbell, Robert J Cox, Andrew Dobson, Cristina Fernandez Barrat, Malcolm A. Y. Gall, William Hicks, Gareth P Howell, Anna Jawor-Baczynska, Lucie Miller-Potucka, Michael Pilling, Katy Shepherd, Ross Tassone, Brian A. Taylor, and Aled Williams J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 23 Oct 2018 Downloaded from http://pubs.acs.org on October 24, 2018
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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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The Journal of Organic Chemistry
Process Design and Optimisation in the Pharmaceutical Industry: a Suzuki-Miyaura Procedure for the Synthesis of Savolitinib Neil K. Adlington, Lauren R. Agnew, Andrew D. Campbell, Robert J. Cox, Andrew Dobson, Cristina Fernandez Barrat , Malcolm A. Y. Gall, William Hicks, Gareth P. Howell,* Anna Jawor-Baczynska, Lucie Miller-Potucka, Michael Pilling, Katy Shepherd, Ross Tassone, Brian A. Taylor, Aled Williams AstraZeneca Pharmaceutical Technology and Development, Macclesfield, UK
[email protected] Abstract A multidisciplinary approach covering synthetic, physical and analytical chemistry, high-throughput experimentation and experimental design, process engineering and solid-state chemistry is used to develop a large-scale (kilomole) Suzuki-Miyaura process. Working against clear criteria and targets, a full process investigation and optimisation package is described highlighting how and why key decisions are made in the development of large-scale pharmaceutical processes.
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Introduction There are clear and obvious differences between the development requirements for industrial-scale chemical processes versus small-scale academic or medicinal chemistry processes. For pharmaceutical manufacturing, the development requirements are often summarised with the acronym “SELECT” as shown in FIGURE 1.1 Although the relative importance of the six SELECT criteria may vary from project to project, there is always a requirement to satisfy most (if not all) of them. Ultimately, these criteria are the reason that only a very small fraction of reported synthetic-organic methodologies are ever utilised in an industrial setting. Many of these criteria are not only of lesser (or no) significance at small-scale but are also either difficult or impossible to properly assess without having access to multi-kilogram quantities of the process components. As a result, rigorous process development against these criteria is not often seen in the “mainstream” organic-synthetic literature.
Safety
• Risk to plant (e.g. explosions) • Risk to operators (COSHH)
Environment
• Volume of wasted natural resources • Environmentally-malign materials
Legal
• Infringement of intellectual property • Use of regulated/controlled materials
Economy
• Cost of goods target for market • Development cost
Control
• Ability to meet purity/quality criteria • Robustness, reproducibility
Throughput
• Material generated per unit time • Availability of raw materials, reagents
FIGURE 1. SELECT Criteria for process development
This manuscript describes a modern process development programme starting from initial process screening and design, through process optimisation to eventual large-scale implementation. With the pharmaceutical application in mind, the importance of the various SELECT criteria is discussed throughout, particularly in relation to decision-making. The approaches and methods used underline the
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The Journal of Organic Chemistry
importance of interdisciplinary research, covering organic synthesis, analytical, physical and solid-state chemistry as well as statistics and process engineering. SCHEME 1. Synthesis of Savolitinib
Br
N H 2N
+
N 2
N
Br
N
N H2
a
3
N N Br
N
NH
N
N H2
Br
b 4
H Cl + N
N
N
N 5
N
N N
+
N N
c, d
N N
–
B O
6
O
N N
N
N
N
N N
1
a) diisopropylethylamine (DIPEA), NMP; b) NaNO2, AcOH, water then HCl; c) Na2PdCl4, 3-(di-tertbutylphosphonium)propane sulfonate (DTBPPS), MeCN, water; d) final recrystallisation and palladium removal using activated carbon, EtOH, water. Savolitinib (1) is a small-molecule c-Met inhibitor2,3currently in advanced clinical trials for the treatment of various cancer types including non-small cell lung4, 5 and advanced or metastatic papillary renal cell carcinoma.6 The route of synthesis shown in SCHEME 1 has been used successfully to manufacture multiple hundreds of kilograms for the purposes of clinical supply over the last five years. The formation
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of 1 (from 5 and 6) via Suzuki-Miyaura coupling appears, on paper at least, to be a suitable candidate for long-term, commercial processing since high chemical yields and purity are obtained using relatively benign solvents. However, a closer comparison against the SELECT criteria reveals a number of shortcomings that might preclude its use in a more highly-regulated commercial setting: i.
As shown in FIGURE 2, Savolitinib exists in various solid forms including anhydrous, hydrated and solvated (acetonitrile amongst others) structures. The anhydrous form I can typically be wellsuspended in solvent allowing for efficient stirring in a reaction vessel, facile transfer to and from said reaction vessel and, most importantly, straight-forward filtration and isolation. The hydrated and acetonitrile-solvated forms II/III/IV, however, form fibrous, intractable gels (see FIGURE 3) that pose significant challenges to large-scale processing. Due to the inherent miscibility of acetonitrile and water, it is highly problematic to reduce the water activity (aw)7 of this system sufficiently (90% 1 by HPLC peak area after twenty hours reaction time are shown in TABLE 1. TABLE 1. Initial high-throughput experimentation results
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H Cl – + N Br
N 5
N
N
N
N
N
O 6
t-Bu
1 cataCXium A
N
Cl
P
Cl P t-Bu t-Bu
N
Pd-132
7a, R = iPrO 7b, R = n-BuO 7c, R = HO 7d, R = s-BuO 7e, R = H Pd source
Cl
N R
N
N
N
t-Bu
N N
Ligand
N
N
N
N
N N
Ph Ph P Cl Pd Fe Cl P Ph Ph
t-Bu
Pd Cl
Pd-166
7a-e Solvent
P
P
N
O – H O + S t-Bu P O t-Bu DTBPPS
P
Pd
Entry
N
N N
O
B
+
N
t-Bu
N
%conv 1 ha
%conv 20 ha
Pd(dppf)Cl2 1b
5b
7a/b
7cb
Σotherb
b
1
Pd-132
none
t-AmOH
35.2
100.0
93.9
nd
-
0.9
5.1
2
Pd-132
none
IPA
79.0
100.0
93.6
nd
1.8
1.5
3.1
3
Pd-132
none
n-BuOH
91.0
100.0
91.0
nd
4.2
1.1
3.7
t-AmOH
38.3
99.5
93.7
0.
-
1.2
4.6
Pd(OAc)2
t-BuPPh2
-
1.2
3.8
Pd(OAc)2
cataCXium A -
1.3
4.9
Pd(OAc)2
t-BuPPh2
-
1.0
2.6
Pd-132
none -
1.4
4.1
-
1.0
3.1
4
5
5 MeCN
11.9
99.3
93.5
0. 7
6
MeCN
7
32.3
98.9
92.8
1. 0
MeCN
45.2
98.0
93.1
1. 9
8
Pd(dppf)Cl2
none
MeCN
30.5
97.8
90.0
2. 0
9
t-AmOH Pd(OAc)2
5.5
97.4
93.5
2.
cataCXium A 5
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10
MeCN Pd(OAc)2
t-Bu2PMe.HBF4
Na2PdCl4
DTBPPS
Pd-166
none
11
97.0
91.1
2.
-
1.7
3.2
-
1.2
2.7
-
1.2
3.6
8 t-AmOH
12
8.7
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19.0
96.5
92.8
3. 3
t-AmOH
15.8
95.1
90.5
4. 7
100 ∗ (Product Area%)
a) Conversion measured by (Ar ― Br(SM)Area%) + (Product Area%) using HPLC at 220 nm b) Peak area by HPLC at 220 nm
A number of catalyst/solvent systems were shown to be effective, giving 95% conversion or higher within twenty hours. The best catalysts appeared to be Pd-132 (entries 1-3,7) or Pd(OAc)2 with various ligands (entries 4-6, 9, 10). Other catalysts including Pd(dppf)Cl2 (entry 8) and Pd-166 (entry 12) showed slightly lower activity. One system employing the original catalyst showed high conversion (entry 11). The measured conversions after one hour give an indication of rates of reaction, which generally decreased in the following way: 1° or 2° alcohol solvents > MeCN~t-AmOH > other solvents. Competing solvolysis of aryl-bromide 5 leading to products such as 7a and 7b was observed when using 1° or 2° alcohol solvents, indicating that there is a trade-off to be made with solvent selection. It was also envisaged that future attempts to lower catalyst loading would further promote the rate of uncatalyzed solvolysis versus the desired Suzuki-Miyaura coupling. Hydrolysis of the starting material 5 leading to 7c was also noted in most cases,13 perhaps due to the relatively high concentration of K2CO3(aq) used (4.0 M); it was expected that this side-reaction could be reduced with future development. A second ninety-six experiment screen was conducted using the following: i.
Three of the most active catalysts from the screen above, including Pd-132, Pd(OAc)2/t-BuPPh2 and Pd(OAc)2/cataCXium A. The original catalyst system was included for reference.
ii.
Three 2°/3° alcohol solvents were selected, iPrOH, t-AmOH and s-BuOH. Primary alcohols were not selected due to the aforementioned issue with solvolysis. Acetonitrile was not included due to the requirement to isolate the anhydrous form of Savolitinib 1.
iii.
Four bases: K3PO4, K2CO3, KHCO3 and DIPEA.
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A solvent/water volume ratio of either 1:1 or 9:1.
K2CO3 K3PO4 KHCO3
1:1 solvent/ water
DIPEA K2CO3 K3PO4 KHCO3 DIPEA
9:1 solvent/ water
Pd(OAc)2 CataCXium A
Pd(OAc)2 t BuPPh2
Pd-132
Na2PdCl4 DTBPPS
s-BuOH
Pd(OAc)2 CataCXium A
Pd-132
Na2PdCl4 DTBPPS
Pd(OAc)2 CataCXium A
IPA
Pd(OAc)2 t BuPPh2
Pd-132
t-AmOH
Pd(OAc)2 t BuPPh2
iv.
Na2PdCl4 DTBPPS
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1
2
3
4
5
6
7
8
9
10
11
12
A
91.7
74.9
50.1
0.8
98.2
98.2
93.3
10.1
100
98.9
60.5
30.2
B
91.3
85.4
52.7
3.5
96.8
95.6
91.3
87.8
97.2
98.8
67.4
37.6
C
60.1
52.4
20.1
4.8
80.6
94.0
47.8
30.3
64.0
66.3
31.5
1.3
D
66.3
72.2
18.0
6.4
99.3
100
59.4
52.4
54.7
100
42.5
3.8
E
9.5
21.4
16.9
1.1
43.3
60.2
29.6
8.8
28.8
36.4
14.7
0
F
8.7
28.9
36.6
12.2
38.3
43.8
31.1
8.6
30.9
32.7
30.7
4.5
G
4.6
13.6
13.6
1.2
9.3
24.5
8.4
0
8.4
15.3
6.6
0
H
1.4
10.0
3.2
0
2.0
11.4
3.0
0
1.8
11.7
4.5
0
>2.5% hydrolysis
>2.5% solvolysis
>2.5% hydrolysis >2.5% solvolysis
