Improved preparation of an epoxy substituted reactive mesogen

Article abstract of DOI:10.1021/acs.oprd.6b00351

An improved manufacturing process was developed for the epoxy substituted mesogen 1 useful for the preparation of liquid crystalline materials. Notable features were telescoping of reactions, replacement of DCC with CDI for formation of a sensitive diaryl

Full text of DOI:10.1021/acs.oprd.6b00351

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Full Paper
Improved Preparation of an Epoxy Substituted Reactive Mesogen
Mark C Wilkinson, and Matthew Higson
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00351 • Publication Date (Web): 06 Dec 2016
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Improved Preparation of an Epoxy Substituted Reactive
Mesogen
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Mark C. Wilkinson,* Matthew Higson
Centec International, The Science Park, Brooks Lane, Middlewich, Cheshire, CW10 0JG, UK.
Mark.C.Wilkinson@centec.uk.com
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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Table of Contents Graphic
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Abstract
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An improved manufacturing process was developed for the epoxy substituted mesogen 1 useful for
the preparation of liquid crystalline materials. Notable features were telescoping of reactions,
replacement of DCC with CDI for formation of a sensitive diaryl ester, and epoxidation using mCPBA
in toluene. The process was validated on 100 kg scale.
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Keywords
Liquid Crystal, Reactive Mesogen, CDI, Diaryl Ester, Process Development
Introduction
Recently Centec became interested in the commercial production of the epoxy substituted reactive
mesogen 1. A mesogen is defined as a compound that under suitable conditions can exist as a
mesophase or in particular as a liquid crystal phase, in which the degree of molecular order is
intermediate between the perfect positional and orientational order found in solid crystals and the
absence of longꢀrange order found in isotropic liquids.1
The initial laboratory synthesis of 1 provided to us gave several issues on kilogram scale, which made
robust commercial manufacture unlikely. A development programme was undertaken which addressed
all issues and led to successful production on 100 kg scale.
Results and Discussion
We were provided with the previous laboratory preparation illustrated in Scheme 1. Alkylation of
methyl 4ꢀhydroxybenzoate in NMP was followed by filtration of the inorganic biproducts. The NMP
solution was treated with 10% NaOH to hydrolyse the methyl ester. The substituted benzoic acid 3 was
neutralized and isolated by precipitation with dilute HCl. Next, a DCC (N,N'ꢀdicyclohexylcarbodiimide)
coupling with 4ꢀmethoxyphenol gave the desired diaryl ester 4, which was crystallised from methanol.
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mCPBA epoxidation in DCM to give the target mesogen 1 was followed by crystallisation from isoꢀ
1
2
3
propanol.
4
i) 5-Bromopent-1-ene
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O
O
NMP, K2CO3,
95 oC, 4h
O H
OCH3
ii) Filter
iii) NaOH
iv) HCl
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O
O
HO
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3
2
92 %th
OCH3
OCH3
4-Methoxyphenol
DCC, DCM
O
O
O
O
92 %th
4
O
mCPBA, DCM
O
80 %th
1
Scheme 1. Previous laboratory preparation, as disclosed to Centec
Whilst the original preparation was successful on small scale, it gave a number of issues. The alkylation
reaction was performed in 5 volumes of NMP, an expensive solvent with toxicity concerns. Filtration of
the potassium bicarbonate and potassium bromide produced in the first alkylation was unattractive on
scale due to the time and equipment required. Washing the inorganic cake with further NMP was
required to avoid product losses. The intermediate acid was precipitated not crystallised, resulting in
small particles which could be slow to filter and wash. This exasperated the risk that efficient cake
washing was necessary to adequately reduce the inorganic content of the cake. Finally, the product had
to be rigorously dried from water, which was incompatible with the following DCC coupling stage.
The DCC esterification gave excellent conversion (> 99% by HPLC), but filtration of the voluminous
DCU (N,N'ꢀdicyclohexylurea) byproduct was tedious, and required extensive washing of the cake to
liberate all the desired product. Handling the potent sensitiser DCC was also not attractive on production
scale.
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On performing the epoxidation stage at 2 kg scale in a 20 L reactor, the aqueous separations from DCM
post reaction were observed to be poor. Even with extended hold periods and filtration to remove trace
fine particles, the separations were compromised. This led to minor entrainment of the coloured aqueous
phase in the organic layer, which gave rise to a darker isolated product. This was clearly unacceptable
for liquid crystal materials where high purity is a prerequisite.
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i) 5-Bromopent-1-ene
NMP, K2CO3,
110 oC, 1h 30
ii) Toluene, H2O
iii) NaOH, TBAB
iv) H2SO4
3
2
81 %th
i) 4-Methoxyphenol
CDI, toluene
ii) mCPBA
1
80 %th
Scheme 2. Centec kilogram scale laboratory preparation
For the next kilogram scale supply (Scheme 2) we first optimised the alkylation reaction with 5ꢀ
bromopentꢀ1ꢀene. We changed the reaction stoichiometry to use bromopentene as the limiting reagent as
this was significantly (200%) more expensive than the hydroxybenzoate 2. We found the volume of
NMP could be reduced to 1.6 volumes, and the reaction time shortened to 1.5 hours at higher
temperature. At first we used the same NMP / NaOH hydrolysis, which was homogeneous and rapid.
However, neutralization of the KHCO3 produced in the alkylation evolved copious CO2 (g) which could
have resulted in pressurisation if not adequately vented on larger scale. We conceived that instead of
filtering off the bicarbonate or neutralising in situ, if the intermediate methyl ester could be extracted
into toluene then the bicarbonate could be removed in an aqueous wash. This obviated the offꢀgassing
risk, and vastly reduced the amount of acid needed for the final neutralization. It would require a
biphasic ester saponification, but fortunately this was readily achieved in a toluene / NaOH (aq) biphase
using TBAB (tetraꢀnꢀbutyl ammonium bromide) as a phase transfer catalyst. A further advantage of this
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process was that we could perform a final controlled crystallisation of the acid 3 from toluene. This
removed previous issues of filtration and inorganic content, as well as offering a useful purification
point. We also moved to neutralize acid 3 with sulfuric acid rather than HCl to allow compatibility with
either glass or stainless steel production vessels.
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Evaluating the esterification / epoxidation stage, and with DCC appearing unattractive an
evaluation of other coupling agents was undertaken. We were initially interested in the water soluble
carbodiimide EDCI (1ꢀethylꢀ3ꢀ[3ꢀdimethylaminopropyl]carbodiimide) as it could potentially remove the
solid filtration / cake washing step. Whilst the coupling to give diaryl ester 4 worked in an analogous
fashion as with DCC, the aqueous separations gave some issues and the cost of the EDCI was
considerably more than DCC. We sought further alternatives and were interested in the precedented use
of CDI (1,1'ꢀcarbonyldiimidazole) for esterification.2 The CDI mediated reaction was sluggish at the
moderate temperatures needed for the carbodiimide reagents (20 ꢀ 40 °C), but we were pleased when the
reaction proceeded smoothly to completion on heating to 85 °C. On production scale, care was required
to balance the rate of heating with the rate of CO2 evolution which appeared to peak midway through
this temperature ramp. Control was achieved by heating to ca. 50 °C at a defined rate, then holding at
this point for 15 minutes before completing the ramp to reaction temperature. Post reaction, washing
with dilute sulfuric acid removed the imidazole byproduct and the solution of the diaryl ester 4 thus
produced could be telescoped into the epoxidation without isolation.
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A focused solvent screen for the epoxidation indicated reactions in DCM, toluene, and
chlorobenzene all went to virtual completion with ethyl acetate, isoꢀpropyl acetate, methyl THF,
acetonitrile and methyl isoꢀbutylketone giving noticeably lower conversion. We focused on toluene as it
was perceived to give better separations than DCM or chlorobenzene. Additionally moving away from a
chlorinated solvent reduced the cost of waste stream disposal and working with an organic upper phase
made the aqueous wash sequence quicker to operate in plant. However, after reaction in any of these
solvents aqueous extractions with bases such as carbonate could still give poor separations. Given the
issues of aqueous entrainment observed in the first kilogram scale run, a more robust solution was
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desirable. It was found that the use of a concentrated aqueous solution of tripotassium phosphate (36
%wt/wt) gave a very dense lower phase which separated cleanly and reproducibly. This removed the
vast majority of the 3ꢀchlorobenzoic acid produced with a facile subsequent wash with a cheaper
potassium carbonate solution accounting for the rest.
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The cumulative benefits of the process improvements described above were demonstrated in the
further kilogram scale run depicted in Scheme 2. A minor decrease in yield (ca. 3%) was traded off for a
process that would be much more robust to operate in a production plant.
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i) 5-Bromopent-1-ene
NMP, K2CO3,
110 oC, 1h 30
ii) Toluene, H2O
iii) NaOH, TBAB
iv) H2SO4
2
4
v) 4-Methoxyphenol, CDI
87 %th
mCPBA, toluene
90 %th
1
Scheme 3. Final manufacturing route
Thus significant progress had been made in improving the process from the first kilogram scale run.
However as we headed towards production plant we observed in further trials inconsistent reaction
profiles in the epoxidation with minor variations in reaction completion and more significant variations
in impurity generation. This was compounded by the fact that residual starting olefin 4 could be difficult
to purge in the crystallization of the epoxide 1.
We screened a number of potential influences on the reaction, but were unable to demonstrate a causal
link to spiking with acid, base (inorganic or organic), additional water or reaction temperature. We did
demonstrate that carry over into the epoxidation of the DCU byproduct of DCC mediated esterification
reduced conversion giving another driver to change coupling agent.
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The variable epoxidation results posed a significant challenge to process robustness. The
solution proved to be moving the isolation point. In the process depicted in Scheme 2, post
neutralization of acid 3 we had a solution in toluene which was also the solvent for the CDI coupling.
Thus instead of isolating acid 3 and telescoping the esterification and epoxidation, we instead combined
the bromopentene alkylation with the CDI esterification. The isolation and purification of the alkene 4
gave a more consistent starting point for the epoxidation reaction which went on to perform as desired.
Whilst the change in isolation point was made to aid robustness it also gave the addition benefit of
increasing the overall yield. These changes were combined to form the final manufacturing route
(Scheme 3) which was proved successfully on 100 kg scale.
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Conclusions
In conclusion, an improved manufacturing process for the epoxy substituted reactive mesogen 1 was
developed and validated on 100 kg. A three stage process involving a DCC coupling was replaced by
two stages utilising a CDI esterification, and overall yield increased from 67% to 78% theory.
Experimental Section
1
Reagents and solvents were purchased from commercial sources and were used as received. H NMR
spectra were recorded on a Bruker AVANCE III 400 MHz spectrometer operating at 400.2 MHz. Data
are presented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, m = multiplet), and
integration. HPLC analysis was performed using an Agilent 1220 LCUV system, Phenomex Luna
C18(2) 50 mm x 2 mm, 3 µm column, column temperature 40 °C, eluent: 0ꢀ100% MeCN (+ 0.05%
TFA) in 0.05% TFA, linear gradient over 8 min then 100% MeCN (+ 0.05% TFA) for 2 min, 1 mL/min
flow rate with UV detection at 220 nm.
4’-(Pent-1-enyloxy)benzoic acid (3)
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To a slurry of K2CO3 (69.9 g, 0.506 mol, 1.08 eq) and methy 4ꢀhydroxybenzoate (72.7 g, 0.478 mol,
1.02 eq) in NMP (112 ml, 1.6 vol) was added 5ꢀbromopentꢀ1ꢀene (70 g, 0.469 mol). The reaction
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mixture was heated to 80
°C, at which point an exotherm was observed. The batch was further heated to
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110 C for 1 h 30. After cooling to 80
°
°C, toluene (245 ml, 3.5 vol) was added, followed by water (160
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ml, 2.3 vol). A lower aqueous phase was removed at 75
°
C.3 NaOH (47 %wt/wt, 42 ml, 0.6 vol) was
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premixed with water (84 ml, 1.2 vol), and added to the reaction, followed by TBAB (Et4NBr, 0.7 g, 1
wt%). After 1 h, the reaction temperature was increased to 80 C. The reaction was stirred for 2 h, or
°
until saponification of the ester was complete by HPLC analysis. The pH was cautiously adjusted to
below 2 by addition of 14 M sulfuric acid (105 ml, 1.5 vol). The stirring was stopped, and a lower
aqueous layer removed. The upper organic phase was washed at 70 ꢀ 75 °C with water (140 ml, 2 vol).
This water wash was repeated twice more. The organic layer was refluxed through a DeanꢀStark head to
remove all water, then toluene (35 ml, 0.5 vol) removed by distillation. The solution was cooled to 60 ꢀ
63 °C, seeded with authentic material (0.21 g, 0.3 wt%) and cooled to 15 ꢀ 18 °C over 3 h. After stirring
at this temperature for 0.5 h, the product was isolated by filtration, and washed with further toluene (3 x
25 ml, 3 x 0.35 vol). The product was dried to constant weight in a vacuum oven to give the product as a
white crystalline solid. (78.3 g, 81 %th). 1H NMR (400 MHz, CDCl3): δ 8.14 (2H, d), 6.95 (2H, d), 5.88
(1H, m), 5.05 (2H, m), 4.08 (2H, t), 2.25 (2H, m), 1.91 ppm (2H, m). HPLC = 4.35 min, 99.3 % a/a. mp
= 122 – 125 °C. The data was in accordance with the published literature.4,5
4’-Methoxyphenyl 4’’-(pent-1-enyloxy)benzoate (4)
To a slurry of K2CO3 (69.9 g, 0.506 mol, 1.08 eq) and methy 4ꢀhydroxybenzoate (72.7 g, 0.478 mol,
1.02 eq) in NMP (112 ml, 1.6 vol) was added 1ꢀbromopentꢀ4ꢀene (70 g, 0.469 mol). The reaction
mixture was heated to 80
110 C for 1 h 30. After cooling to 80
ml, 2.3 vol). A lower aqueous phase was removed at 75
°
C, at which point an exotherm was observed. The batch was further heated to
C, toluene (350 ml, 5 vol) was added, followed by water (160
C. NaOH (47 %wt/wt, 42 ml, 0.6 vol) was
°
°
°
premixed with water (84 ml, 1.2 vol), and added to the reaction, followed by TBAB (Et4NBr, 0.7 g, 1
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wt%). After 1 h, the reaction temperature was increased to 80 °C. The reaction was stirred for 2 h, or
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until saponification of the ester was complete by HPLC analysis. The pH was cautiously adjusted to
below 2 by addition of 14 M sulfuric acid (105 ml, 1.5 vol). The stirring was stopped, and a lower
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aqueous layer removed. The upper organic phase was washed at 70 ꢀ 75
This water wash was repeated twice more. The organic layer was refluxed through a DeanꢀStark head to
remove all water, then cooled to 30 C. DMAP (3.5 g, 5 wt%) was charged followed by 4ꢀ
°C with water (140 ml, 2 vol).
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methoxyphenol (61.1 g 0.492 mol, 1.05 eq). CDI (83.7 g, 0.516 mol, 1.1 eq) was added cautiously
portionwise to avoid pressurising the reactor with liberated CO2. The reaction was heated slowly to 50 ꢀ
55 °C over ca. 45 minutes, held for 15 minutes, then heated and held at 80 ꢀ 84 °C for 90 min. On
completion of the esterification, the reaction was cooled to 45 ꢀ 55 °C and water (70 ml, 1 vol) added,
followed by 14 M sulfuric acid (140 ml, 2 vol). The lower aqueous layer was removed, and the organic
phase washed with water (140 ml, 2 vol). The organic phase was vacuum distilled to 190 ml (2.7 vol)
and isoꢀpropanol added (140 ml, 2 vol) keeping the temperature above 55 °C. The vacuum distillation to
190 ml (2.7 vol) was repeated. isoꢀPropanol was added (280 ml, 4 vol) and the batch heated to above 58
°C to produce a solution. The solution was cooled to 56 ꢀ 57 °C, seeded with authentic material (0.35 g,
0.5 wt%) and cooled to 15 ꢀ 18 °C over 4 h. After stirring at this temperature for 1 h, the product was
isolated by filtration, and washed with further isoꢀpropanol (2 x 70 ml, 2 x 1 vol). The product was dried
to constant weight in a vacuum oven giving the title product as a white crystalline solid (127.3 g, 87
1
%th). H NMR (400 MHz, CDCl3): δ 8.16 (2H, d), 7.15 (2H, d) 6.98 (2H, d), 6.96 (2H, d), 5.89 (1H,
m), 5.01 (2H, m), 4.10 (2H, t), 3.85 (3H, s) 2.29 (2H, m), 1.97 ppm (2H, m). HPLC = 5.88 min, 97.6 %
a/a. mp = 85 – 86 °C. The data was in accordance with the published literature.6
4’-Methoxyphenyl 4’’-(1,2-epoxypentyloxy)benzoate (1)
To a slurry of 4’ꢀmethoxyphenyl 4’’ꢀ(pentꢀ1ꢀenyloxy)benzoate 4 (80 g, 0.2564 mol) in toluene (320 ml,
4 vol) was added mCPBA (75% wt/wt, 4 x 17.55 g, 0.305 mol, 1.19 eq) portionwise over 2 h, with
cooling to keep the reaction temperature below 40 °C. Stirring was continued for 20 h. Tripotassium
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phosphate (90 g) was dissolved in water (160 ml) then charged to the reactor. The biphasic mixture is
stirrer at 38 ꢀ 42 °C for 5 min, settled and the lower aqueous layer removed. The organic layer is washed
with a 10 %wt/wt solution of potassium carbonate (120 ml, 1.5 vol), then water (120 ml, 1.5 vol). The
organic phase was vacuum distilled to 160 ml (2 vol) and isoꢀpropanol added (160 ml, 2 vol) keeping
the temperature above 55 °C. The vacuum distillation to 160 ml (2 vol) was repeated. isoꢀPropanol was
added (200 ml, 2.5 vol) and the batch heated to above 65 °C to produce a solution. The solution was
cooled to 61 ꢀ 63 °C, seeded with authentic material (0.4 g, 0.5 wt%) and cooled to 15 ꢀ 18 °C over 4 h.
After stirring at this temperature for 1 h, the product was isolated by filtration, and washed with further
isoꢀpropanol (2 x 56 ml, 2 x 0.7 vol). The product was dried to constant weight in a vacuum oven giving
the title product as a white crystalline solid (75.68 g, 90 %th). 1H NMR (400 MHz, CDCl3): δ 8.16 (2H,
d), 7.15 (2H, d), 7.00 (2H, d), 6.96 (2H, d), 4.13 (2H, m), 3.85 (3H, s) 3.05 (1H, m), 2.83 (1H, m), 2.55
(1H, dd), 2.01 ppm (2H, m), 1.91 ppm (1H, m), 1.87 ppm (1H, m). HPLC = 5.01 min, 96.3 % a/a. mp =
97 – 98 °C.
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Acknowledgements
Sandra van Meurs (University of Sheffield) is gratefully acknowledged for analytical assistance.
References
1 Barón, M.; Stepto, R.F.T. Pure Appl. Chem. 2002, 74, 493
2 Staab, H.A. Angew. Chem. 1959, 71, 194
3
The aqueous washes were performed at elevated temperature to maximise throughput. Increasing the temperature above
ambient decreases the volume of solvent required (to dissolve the product / intermediate) and water required (to dissolve the
inorganic components). This operation was risk assessed on production scale and appropriate controls and PPE applied.
4 a) Arehart, S.V.; Pugh, C. J. Am. Chem. Soc. 1997, 119, 3027
5 Kelly, S.M.; Buchecker, R. Helv. Chim. Acta 1988, 71, 461
6 Chen, CꢀC.; Lin, CꢀH.. Asian J. Chem. 2016, 28, 1270
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