Development of an SNAr Reaction: A Practical and Scalable Strategy to Sequester and Remove HF

Article abstract of DOI:10.1021/acs.oprd.8b00090

A simple and operationally practical method to sequester and remove fluoride generated through the S_NAr reaction between amines and aryl fluorides is reported. Calcium propionate acts as an inexpensive and environmentally benign in situ scrubbe

Full text of DOI:10.1021/acs.oprd.8b00090

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Full Paper
Development of an SNAr Reaction: A Practical and
Scalable Strategy to Sequester and Remove HF
A. John Blacker, Gabriel Moran Malagon, Lyn Powell,
William Reynolds, Rebecca Stones, and Michael Chapman
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00090 • Publication Date (Web): 31 Aug 2018
Downloaded from http://pubs.acs.org on August 31, 2018
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Development of an SNAr Reaction: A Practical and
Scalable Strategy to Sequester and Remove HF
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A. John Blacker* †, Gabriel Moran-Malagon†, Lyn Powell ‡, William Reynolds †,
Rebecca Stones,† Michael R. Chapman†
† Institute of Process Research and Development, School of Chemistry and School of Chemical
and Process Engineering, University of Leeds, Leeds LS2 9JT, UK.
‡ Chemical Development, AstraZeneca Macclesfield, UK, SK10 2NA
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: j.blacker@leeds.ac.uk
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ABSTRACT
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A simple and operationally practical method to sequester and remove fluoride generated through
the SNAr reaction between amines and aryl fluorides is reported. Calcium propionate acts as an
inexpensive and environmentally benign in situ scrubber of the hydrofluoric acid byproduct,
which is simply precipitated and filtered from the reaction mixture during standard aqueous
workꢀup. The method has been tested from 10 → 100 g scale of operation, showing > 99.5%
decrease in fluoride content in each case. Full mass recovery of calcium fluoride is demonstrated
at both scales, proving this to be a general, efficient and robust method of fluoride abstraction to
help prevent corrosion of glassꢀlined reactors.
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KEYWORDS: SNAr reaction, calcium fluoride, aryl amines, fluoride sequestration, scaleꢀup
INTRODUCTION
The formation of aryl CꢀN bonds is ubiquitous in organic chemistry, and the resulting Nꢀ
arylamines are found in a multitude of natural products and drug molecules.1ꢀ2 In particular, Nꢀ
arylpiperazines are central to many pharmaceutical compounds, such as (i) AZM574670 PDK
inhibitor,3 (ii) AZD4547, a development Fibroblast growth factor receptor (FGFR) tyrosine
kinase family inhibitor,4 (iii) Levofloxacin, Ciprofloxacin and Sparfloxacin antibiotics,5 (iv)
t
etrahydroquinazolinone derivatives such as poly ADPꢀribose polymerase (PARP) inhibitors,6ꢀ7 and
(v) Prazosin, an offꢀpatent antiꢀhypertensive8ꢀ9 (Figure 1). It is therefore unsurprising that aryl
piperazines are considered privileged structures in medicinal chemistry.
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Figure 1. Representative drug molecules comprising the piperazine substructure.
There are several synthetic options to make Nꢀaryl amines. Alkylation of anilines with alkyl
halides is widely used by industry at large scale and overꢀalkylation products can be separated
during workꢀup. An alternative method avoiding the use of Potential Genotoxic Impurities
(PGIs) is catalytic hydrogen transfer using alcohols or alkyl amines though at present only with
uneconomic quantities of precious metalꢀbased catalyst.10ꢀ13 Another option is the direct
amination of aryl halides catalyzed by metals, with copper complexes showing much potential in
place of palladium.14ꢀ17 A commonly employed retrosynthetic option for making these subunits is
the SNAr reaction between an activated aryl fluoride and primary or secondary amine (Scheme
1).18 A preference for this route has already been identified by Moody et al. who made a similar
conclusion when comparing Pdꢀcatalyzed amination and SNAr with heteroaryl chlorides. The
team also evaluated the use of green solvents in this reaction.19
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Scheme 1. Approaches to pꢀelectron withdrawing group (EWG) substituted anilines.
The SNAr reaction of amines and activated aryl fluorides is used commonly in scaledꢀup
processes but suffers long reaction times at high temperatures and use of dipolar aprotic solvents,
which cause separation and waste problems during workꢀup. Moreover, the generation of
fluoride salts as byꢀproducts can be detrimental to glassꢀlined reactors, especially with their
repeated use, which occurs via the formation of low levels of hydrofluoric acid (HF) generated
through the intentional or unintentional presence of water.20 The use of mild bases such as
potassium carbonate are well known in SNAr reactions to neutralize the HF generated, however
the product KF can still react with moisture to cause glass etching; the potassium fluoride
dihydrate is highly soluble in water. In this paper, we discuss a number of potential
improvements to processes for making a variety of Nꢀaryl piperazines which includes a screen of
green solvents, overcoming the problem of hydrofluoric glassꢀetching, some scoping of amine
and fluoroaromatic and an exemplar scaleꢀup with an intermediate used in making Linezolid.21
RESULTS AND DISCUSSION
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Evaluation of a Selected SNAr Reaction
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We began our study by evaluating published methods for making Nꢀaryl piperazines (Scheme 2).
It is well known that the SNAr reaction is particularly intolerant of solvents other than dipolar
aprotics. One report of the reaction of 4ꢀfluorobenzonitrile with piperazine employed 2ꢀbutanone
solvent at reflux over 4 days to achieve a 90% conversion.22 The same reaction in DMSO gave
93% conversion of the aromatic using 3 equivalents (eq.) of piperazine, and 1.5 eq. K2CO3 at
95°C for 20 hours. Repeating this experiment, we found that only 40% of the product was Nꢀ
piperazinylꢀ4ꢀcyanobenzene (1a), with 60% being the double addition product, N,N’ꢀdiꢀ(4ꢀ
cyanophenyl)piperazine (3a). Other reports have used a 3ꢀ and 4ꢀfold excess of piperazine in
DMSO at 120°C with 92% and 93% conversion of ethylꢀ4ꢀfluorobenzoate starting material,
respectively.23ꢀ25 Repeating this with 2 eq. piperazine, we found the yield of ethyl Nꢀpiperazinylꢀ
4ꢀbenzoate (1b) was 51%, with the N,Nꢀdiarylated product (4b) the remaining 49%. The use an
excess of the amine was needed to obtain high yields.
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Scheme 2. SNAr reaction of piperazine and aryl fluoride to form monoꢀ and diꢀaryl piperazines.
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Changing to the hindered, unsymmetrical cisꢀ2,6ꢀdimethyl piperazine, the reaction with ethylꢀ4ꢀ
fluorobenzoate and 4ꢀfluorobenzonitrile was regiospecific to the less hindered amine, with the
flanking methyl groups providing an effective steric block (Scheme 2). With 1.5 – 4 eq.
piperazine, the Nꢀarylated piperazine (2a) were produced over several experiments with yields
varying between 82ꢀ97% during the present study (Table 1).
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General comments and observations from repeating these reactions:
• DMSO provides solubility for all the materials and possibly stabilises the intermediate
Meisenheimer complex.
• Heating is required to increase the reaction rate; despite this, long reaction times of 18ꢀ
24 hours are required, and at higher temperatures some decomposition of DMSO is
observed, as evidenced by an increasingly dark solution. It is reported in the DMSO
o
safety data that between 0.1 and 1.0% decomposition may occur below 150 C over 24
h.26,27
• Reactions with piperazine (>4 eq. excess) still lead to mixtures of monoꢀ and diꢀ
arylated products, and reported reactions quote conversion of aromatic rather than yield
of product.
• Above 110°C, both Nꢀ(1,4)ꢀpiperazinylꢀ4ꢀbenzonitrile (1a) and ethyl Nꢀ(1,4)ꢀ
piperazinylꢀ4ꢀbenzoate (1b) sublime from the reaction forming a solid above the stirred
level.
• Whilst no specific etching of the glassware was observed, a glass test piece added to
the reaction lost 0.1% of its mass.
• Substantial amounts of water (10 – 15 volume equivalents) are added at the end of
reaction along with a water immiscible solvent such as dichloromethane or ethyl
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acetate to assist in separating the product from DMSO and byꢀproducts. This results in
a sizeable waste stream.
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• Repeated washings of the solid product are required to remove the DMSO, further
lowering the reaction mass efficiency and increasing the waste.
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These problems combine to diminish the efficiency of larger scale SNAr processes.
Process Improvements
Rather than a multiꢀparallel study, we opted to investigate single parameters with overheadꢀ
stirred splitꢀnecked flasks, as this can assist in evaluating more complex issues such as mixing,
glassꢀetching, hetereogeneous sampling and sublimation. The concentration of aromatic used
was 0.7 M, and typically 1.5 eq. of the amine was employed in a total solvent volume of 10 –
1000 mL. Unless stated otherwise, the reaction time was 24 hours which gave full conversion of
starting material in every case.
(a) Solvent Screen
It was decided to evaluate a series of green solvents, with a view to find a dipolar aprotic
alternative for the SNAr reaction.
Table 1. Isolated yield (%) of 2a from various alternative solvents.a
Entry
Solvent
Yield (%)b
1
2
3
Water
0
89
0
Butyl methyl imidazolium chloride [BMIM][Cl]
[BMIM][PF6]
4
5
Dimethylsulfoxide [DMSO]
DMSO/H2O, 2:1
82ꢀ94
76
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DMSO/H2O, 1:1
86
61
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DMSO/H2O, 1:2
90
8
DMSO/pyridine, 9:1
64
9
DMSO/MeCN, 9:1
2ꢀ3
10
Methanol, ethanol, iso-propanol, or tert-butanol
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Ethylene glycol
Methyl ethyl ketone [MEK]
EtOAc
Diethyl carbonate
Ethylene carbonate
THF/toluene, 1:1
Anisole
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5
0
0
0
35
0
<5
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Pyridine
a
The experimental conditions used were those described in the general labꢀscale procedure
replacing DMSO with the solvents indicated. b Isolated mass of 2a.
The SNAr reaction in water was unsuccessful because the fluoroaromatic was insoluble
(entry 1). Interestingly the ionic liquid [BMIM][Cl] proved a good solvent for the reaction of
ethylꢀ4ꢀfluorobenzoate and 2,6ꢀdimethylpiperazine with 89% isolated yield (entry 2).
Surprisingly, the [PF6] analogue was ineffective (entry 3) and the reason for this is unknown.
The cost, separation and potential toxicity issues of ionic liquids precluded their further
evaluation. The aromatics investigated, and piperazine, are completely soluble in DMSO, whilst
2,6ꢀdimethyl piperazine required some heating to fully dissolve. All of the reactions conducted in
DMSO (and mixtures thereof) performed well (entries 4 – 9). With 2:1 (v/v) water/DMSO the
yield of product was ~ 20% lower, and this might reflect destabilisation of the Meisenheimer
intermediate. The addition of 10% pyridine in DMSO gave a 90% yield, possibly because it
assists in deprotonation of this intermediate (entry 8). Since it had been observed that product
sublimed from the reaction, a lower boiling coꢀsolvent was needed that would reflux, dissolve
the amine, and returnꢀit to the reaction mass. A 1:9 combination of MeCN in DMSO (v/v) at
100°C had the desired effect, though the lower temperature slowed the overall rate and resulted
in a lower yield (64%, entry 9). Except for ethylene glycol (entry 11), the alcoholic solvents gave
trace yields (2 – 3%, entry 10). The ketones, esters and carbonates also performed poorly (≤ 5%,
entries 12 – 15). The poor performance of ethylene and diethyl carbonate was disappointing as
these are said to have properties similar to dipolar aprotics. Toluene gave only poor yields, whilst
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reaction rates in THF were low. An equal volume of both toluene and THF at 100°C gave 35%
yield of 2b over 24 hours (entry 16). Both anisole and pyridine were unsuccessful solvents
(entries 19 and 20).
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DMSO was selected as the preferred solvent, giving consistently higher yields than all other
solvents tested. Furthermore, it is on the list of solvents preferred by the pharma industry for its
low biological toxicity.28 Nevertheless, this is a problematic solvent since its high boiling point
makes it difficult to separate from products. Moreover, its miscibility with water prevents
disposal to drain, hence requiring incineration, and associated problems of cost and odour
abatement. The use of DMSO translated well to produce the derivative 2b as an alternative
example (94ꢀ97%, see ESI).
(b) Fluoride Sequestration
One of the problems with the use of aryl fluorides in the SNAr reaction is the fluoride salt byꢀ
product that can cause damage to glassꢀlined vessels during repeated batch manufacture.11 The
use of an amine base, or excess amine reactant is often used to neutralize the HF generated,
however the conjugate acid is strong (pKa ~9 in DMSO) and leads to a significant solution
concentration of HF (pKa = 3.2 in water). The reaction of HF with silica is well known and since
even neutral or mildly acidic conditions can generate sufficient concentrations to cause glassꢀ
etching. The use of calcium salts to sequester fluoride is an approach that is widely known in
dentistry/medicine, and calcium gluconate is used as an antidote for accidental contact in
fluorochemical producing industries,29 but appears not to have been used within a fluorideꢀ
generating process, and might be especially useful for protecting standard glassꢀlined assets used
in repeat manufacture. The solubility product (Ksp) of calcium fluoride is 3.9 × 10ꢀ11 in water,
whilst salts such as calcium carbonate and calcium sulfate are higher with Ksp of 4.8 × 10ꢀ9 and
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4.9 × 10ꢀ5 respectively;30 whereas the solubility of calcium fluoride in dipolar aprotic solvents is
much lower. Calcium propionate is much more soluble in water: 49% and 56% (w/v) at 0°C and
at 100°C respectively, with slight solubility in lower alcohols.
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Several calcium salts were initially tested to effectively sequester the fluoride generated in the
reaction. The experiments employed an equimolar stoichiometry of finely divided anhydrous
calcium salt, based on the fluoroaromatic added to the stirred DMSO, amine and aromatic, which
is twice that required if the product is CaF2. The amine in the process may neutralise the acid
released from the reaction of the calcium salt with hydrogen fluoride. Following the reaction,
methyl tertꢀbutyl ether (MTBE) was charged to the reaction vessel, the mixture stirred and
emptied via the bottom runꢀoff to a vacuum filter (optionally coated with filterꢀaid). A further
MTBE wash of the reactor and screened solid ensured full product recovery. The combined
filtrates were washed repeatedly with water, the lower aqueous phase containing DMSO and
other impurities. The level of fluoride in the effluent aqueous washings was measured.
The MTBE solution was concentrated by distillation, before cooling to crystallize the product.
Anhydrous calcium carbonate showed no advantage over calcium sulfate, whilst use of the more
soluble calcium propionate showed similar rates and levels of fluoride sequestration. Calcium
propionate was preferred to the other salts, being more easily charged, dispersed in the reaction,
and recovered. The difference in cost of calcium propionate over other salts is minor. The SNAr
reaction rates with any of the calcium salts tested were identical to that without, and this
indicates the absence of a thermodynamic equilibrium between fluoride, product and the
Meisenheimer complex. Fluoride analysis of the organicꢀaqueous workꢀup solution, using an ion
selective electrode, showed minimum detectable levels compared to the theory amounts, or
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control reactions without Ca(EtCO2)2 (Table 2). The mass balance of CaF2 was based on the
product yield from fluoroaromatic, and compared to the dried solid CaF2 recovered from the
filter, and the fluoride measured in the workꢀup liquors. The remaining mass may be due to
physical losses at this small scale.
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Table 2. The effect of calcium propionate sequestration of fluoride
Entry Product Theory level Fluoride level in Fluoride level in
Mass
recovery
of fluoride
in washa
1414
wash (no
wash (with
Ca(EtCO2)2)/ppm Ca(EtCO2)2)/ppm CaF2/%a
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2
3
4
1349b
1473
1053
1752
9b
7
74
70
2a
2b
3a
4b
1248
1201
1260
3
4
69
87c
a Based on 100% reaction of aromatic charged. b Average of 3 experiments. c Average of 2 experiments.
The ion selective electrode cannot be used in organic solvent, so to assess the effect of calcium
sequestration of fluoride in the reaction mass prior to workꢀup, careful observation of the glass
was done under the microscope and showed no etching. Using Ca(EtCO2)2, the pH of both the
reaction mass and MTBE wash were neutral.
Reaction Scope
(a) Varying the fluoroaromatic
With a method to remove fluoride in hand, we set out to investigate the scope of the process
using a range of fluoroaromatics and amine substrates. Initially, 2,6ꢀdimethylpiperazine was
reacted with various 4ꢀsubstituted fluoroaromatic compounds in the presence of calcium
propionate, Scheme 3. Good isolated yields of carboxylateꢀbased aromatics (2cꢀ2f, 85ꢀ90%)
were obtained under the standard reaction conditions, with excellent yields of 94 and 90%
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observed for cyanoꢀ and nitroꢀ substituted aromatics, 2a and 2c, respectively. For all examples,
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fluoride content was measured to be ≤ 10 ppm, with no apparent change in reaction rate.
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Scheme 3. A fluoroaromatic scoping study with isolated yields of amine. The fluoride content is
given in parentheses.
(b) Varying the amine
To complement our scope study, the amine coupling partner was varied under otherwise
analogous conditions to those outlined above, Scheme 4. Primary and secondary amines were
1
employed, and reaction conversion was monitored by H NMR spectroscopy. In general, less
hindered primary amines were converted in moderate to good yields of 38 – 90%, whilst more
encumbered secondary amines (2h, 2i, 2m) afforded low conversion to product (34 – 66%).
However, only trace levels of fluoride were detected for each example postꢀreaction (≤ 10 ppm),
demonstrating the generality of calcium propionate as a sequestering agent.
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Scheme 4. Scoping study with isolated yields of amine. The fluoride content given in
parentheses.
Process Scale-up
To finalize our study, we next evaluated the scalability of fluoride sequestration by conducting
two parallel SNAr reactions at 10 and 100 g scales. Reaction between 4ꢀfluorobenzonitrile and
piperazine was selected as model system. Carrying out the process on a 0.1 L scale with 11.5 g
piperazine, 5.5 g CaF2 was precipitated from the reaction mixture during workꢀup. Linearly
scaling the reaction by an order of magnitude, 115 g piperazine yielded 55 g of CaF2 during
workꢀup, highlighting the robustness of our method. Following removal of solvent, the small and
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largeꢀscale reaction mixtures showed 8 and 2 ppm fluoride content, respectively (Table 3), with
quantitative conversion of piperazine in both cases. Importantly, a full mass recovery of CaF2
was obtained to allow simple removal of fluoride by filtration.
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Table 3. Fluoride mass balance for scaleꢀup of 1a.
Entry Scale/mL
Theory level of
fluoride in washa
1273
Fluoride level in wash (with
Mass recovery
CaF2/%a
105
Ca(EtCO2)2)/ppm
1
2
100
1000
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1273
104
aBased on 100% reaction of aromatic charged.
CONCLUSIONS
We report a systematic study of the factors which impact the process development of the SNAr
reaction between amines and aryl fluorides. This is a useful strategy to generate anilines, though
is compromised by the generation of stoichiometric equivalents of hydrofluoric acid byꢀproduct
which often leads to glassꢀetching of industrial reactor vessels. In this study, we employ calcium
propionate as an effective in-situ HF scrubber, generating calcium fluoride byꢀproduct which is
simply removed by precipitation/filtration postꢀreaction. This method appears to avoid
hydrofluoric glassꢀetching, showing trace ppm levels of fluoride content on both 10 and 100 g
reaction scale. Full mass recovery of CaF2 is observed at both reaction scales, suggesting that
this strategy translates linearly and efficiently to kilogram scale.
EXPERIMENTAL SECTION
General SNAr procedure (laboratory scale). Fluoroaromatic (6.7 mmol) was added to a
suspension of amine (13.4 mmol) and calcium propionate (1.25 g, 6.7 mmol) in DMSO (10 mL).
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The mixture was heated to 100 °C for 23 hours without any observed darkening of the
solution.26,27 The reaction was allowed to cool to ambient temperature, and MTBE (30 mL) was
added in a single portion. The resulting calcium precipitate was collected by vacuum filtration
and ovenꢀdried overnight. The filtrate was washed with water (3 × 30 mL) to remove the excess
amine/propionic acid, and the organic phase dried over MgSO4 and concentrated under reduced
pressure to give the crude reaction product as the freeꢀbase. At this point, conversion was
determined by 1H NMR spectroscopy and/or the pure products isolated by recrystallization from
a methanol/water combination (30:20 mL).
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10 g scale SNAr procedure. 4ꢀFluorobenzonitrile (8.1 g, 67 mmol) and piperazine (11.5 g, 134
mmol) were added to a suspension of calcium propionate (12.5 g, 67 mmol) in DMSO (100 mL),
°
and heated to 100 C for 23 hours without any observed darkening of the solution.26,27 The
reaction mixture was then cooled to room temperature and MTBE (300 mL) was added to cause
precipitation of CaF2. The precipitate was collected via vacuum filtration and dried in the oven
overnight, to give a mass of 5.51 g. The filtrate was washed with water (3 × 300 mL) and the
organic phase dried with MgSO4, filtered and the solvent removed under vacuum to give 13.1 g
1
of product. H NMR spectroscopic analysis of the crude reaction mixture showed quantitative
conversion to 40% 1a and 60% 3a, and residual fluoride in the aqueous phase was measured to
be 8 ppm.
100 g scale SNAr procedure. 4ꢀFluorobenzonitrile (81 g, 0.67 mol) and piperazine (115 g, 1.34
mol) were added to a suspension of calcium propionate (125 g, 0.67 mol) in DMSO (1000 mL),
and heated to 100°C for 23 hours without any observed darkening of the solution.26,27 The
reaction mixture was then cooled to room temperature and MTBE (3000 mL) was added to cause
precipitation of CaF2. The precipitate was collected via vacuum filtration and dried in the oven
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overnight, to give a mass of 54.71 g. The filtrate was washed with water (3 × 3000 mL) and the
organic phase dried with MgSO4, filtered and the solvent removed under vacuum to give 130g of
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product. H NMR spectroscopic analysis of the crude reaction mixture showed quantitative
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conversion to 40% 1a and 60% 3a and residual fluoride in the aqueous phase was measured as 2
ppm.
ACKNOWLEDGMENTS
The authors wish to thank AstraZeneca for support and the EPSRC Higher Educational
Investment Funding for contributing to Dr Reynolds’ position.
ASSOCIATED CONTENT
Supporting Information. This material is available free of charge via the Internet at
http://pubs.acs.org.
Information on general experimental and analytical, fluoride measurements, 1H NMR
characterization data for compounds 1a, 1b, 2aꢀ2m, supplementary references.
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