Synthesis of enantiomerically pure [14C]-labelled morpholine derivatives for a class of trace amine-associate receptor 1 agonists

Article abstract of DOI:10.1002/jlcr.3403

Various agonists of the trace amine-associate receptor 1, under consideration as potential clinical development candidates, were labelled with carbon-14 for use in preclinical in vitro and in vivo drug metabolism studies. Herein, the [¹⁴C]-radi

Full text of DOI:10.1002/jlcr.3403

Special issue article
Received 24 February 2016,
Revised 29 March 2016,
Accepted 4 April 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3403
14
Synthesis of enantiomerically pure [ C]-
labelled morpholine derivatives for a class of
trace amine-associate receptor 1 agonists
*
Martin R. Edelmann, Thomas Hartung, René Trussardi, Hans Iding,
Guido Galley, Philippe Pflieger and Roger D. Norcross
Various agonists of the trace amine-associate receptor 1, under consideration as potential clinical development candidates,
were labelled with carbon-14 for use in preclinical in vitro and in vivo drug metabolism studies. Herein, the [14C]-
radiosynthesis of 2-phenyl-substituted morpholines 1 is described. After evaluating and optimizing different synthetic
routes, 4-iodonitrobenzene 3 was selected as starting material for the 14-step synthesis. Incorporation of carbon-14 into
the acetyl moiety allowed a safe and efficient synthesis of [14C]-labelled 4-nitroacetophenone 2 in five steps and 38% yield.
Further transformation of 2 to the target compounds 1 was achieved in a 9-step synthesis. In a representative example, [14C]-
labelled 1 was obtained in an overall yield of 11% and was isolated in >99% radiochemical purity and a specific activity of
47 mCi/mmol.
Keywords: radiosynthesis; carbon-14; biocatalysis; enantioselective reduction; cyanation; TAAR1
approaches were investigated. The first approach to be explored
was formation of the ketone functionality via 4-nitrobenzoic acid
Introduction
Trace amines,1 e.g. phenylethylamine, p-tyramine and tryptamine
5, which was intended to be prepared via metalation of 3 by
are amino acid-derived metabolites present in low concentrations
magnesium or lithium followed by carboxylation of the or-
ganometallic intermediate with [14C]-CO2 to generate 4-
in the mammalian central nervous system (CNS). They are
structurally related to the classical biogenic amines such as
dopamine and serotonin and have been shown to be
endogenous agonists for the trace amine-associated receptors
(TAAR). Trace amines are rapidly catabolized by monoamine
nitrobenzoic acid 5. However, all attempts at performing this
reaction using non-labelled carbon dioxide failed completely. A
different concept introducing the carbon-14 atom via a cyanation
reaction7 with potassium cyanide to give 4-nitrobenzonitrile 4
oxidase. Their dysregulation is linked to highly prevalent
proved to be more successful (Scheme 2). After hydrolysis of 4
with sodium hydroxide, 4-nitrobenzoic acid 5 was isolated in
74% yield over two steps.
Subsequent transformation of the benzoic acid 5 into the
psychiatric disorders such as depression, schizophrenia, and
bipolar disorders.2 In recent years, novel synthetic agonists of
TAAR1 have gained attention as potential therapeutic agents for
psychiatric diseases.3–5
acetophenone 2 was tried using the one-pot synthesis
method described by Kangani8 involving methyl–Grignard
In order to perform in vitro and in vivo drug metabolism studies
of potential clinical candidates from a morpholine class of
reaction of in situ-generated Weinreb amides. However, all
compounds 1,6 the synthesis of [14C]-labelled drug was
attempts to reproduce this reaction failed. Based on
published results,9–11 it was considered worthwhile to further
requested by Drug Metabolism and Pharmacokinetics (DMPK)
scientists. Taking into account, the additional requirement to
investigate reactions of the isolated Weinreb amide. A variety
introduce [14C]-carbon into a metabolically stable position of
the molecule, [14C]-labelling of the phenyl ring or the morpholine
moiety was considered as the only viable labelling strategies.
Retrosynthetic analysis of 1 resulted in the selection of
4-nitroacetophenone 2 as the key intermediate (Scheme 1).
Labelling of the acetyl group of 2, in particular of the carbonyl
carbon, seemed to be the most feasible approach.
of methyl Grignard reagents and methyl tin derivatives,12 as
well as different reaction conditions, were explored. Un-
fortunately, none of these attempts led to 4-nitroaceto-
phenone and formation only of unwanted by-products was
observed.
Roche Pharma Research and Early Development, Therapeutic Modalities, Roche
Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124,
4070 Basel, Switzerland
Results and discussion
Synthesis of [14C]-4-nitroacetophenone 2
*Correspondence to: Martin R. Edelmann, pRED Therapeutic Modalities, F.
Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
E-mail: martin.edelmann@roche.com
For the synthesis of [14C]-labelled 4-nitroacetophenone 2,
starting from 4-iodonitrobenzene 3, a number of different
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M. R. Edelmann et al.
Scheme 1. Retrosynthetic analysis of the potential development candidates 1.
Scheme 2. Synthesis of [14C]-4-nitrobenzoic acid 5 via cyanation.
As a potential explanation for the failure of all Grignard or
metal-mediated reactions, vicarious nucleophilic substitution,
described by Mąkosza13,14 and Ricci,15 can be proposed as a
competing side reaction (Scheme 3). Mąkosza reported that
Grignard reagents are able to attack ortho to a nitro group. As this
unwanted reaction occurs with nitrobenzenes, which are para
substituted with halogen, cyanide, and esters, it is most probably
the main reason for the formation of multiple by-products.
Another one-pot conversion of carboxylic acids to methyl
ketones by alkylation of the corresponding Meldrum’s acid
derivatives has been published by Tsolomitis.16 Although the
identical substrate to ours was mentioned in the paper, we were
unable to reproduce the yield of 81% as described.
An alternative method for preparing the acetophenone 2, as
described by Armati,17 was investigated next (Scheme 4). Thus,
acid chloride 6 was reacted with the dimorpholino ethene 7, to
give intermediate 8, which upon hydrolysis with aqueous
hydrochloric acid yielded the 4-nitroacetophenone 2. By
employing this reaction sequence, the desired product 2 could
be isolated in 44% yield over three steps (78% yield over three
steps based on recovered starting material).
Scheme 4. Synthesis of [14C]-4-nitroacetophenone 2.
in the reduction step was achieved by employing an enzymatic
approach,20 which made the subsequent enantiomeric
enrichment via racemic resolution of the tartrate salts obsolete
(Scheme 5).
Thus, enzymatic reduction of bromoketone
9 to the
Synthesis of [14C]-1
corresponding alcohol (S)-10 was carried out using the NADH
dependent alcohol dehydrogenase (ADH-A11). The NADH
cofactor is recycled in situ by an additional auxiliary enzyme,
glucose dehydrogenase (GDH-105), and its natural substrate
glucose, as final hydride donor. The biocatalytical reduction
afforded alcohol (S)-10 in an excellent enantiomeric excess of
98.9% and a high yield of 95%. As a secondary product, the
enantiomerically pure (S)-11 epoxide was formed in 1.4% area
The initial step of the synthesis route to the target compounds 1
is the bromination of [14C]-4-nitroacetophenone 2, which was
carried out according to the reaction conditions described by
Fan et al.18 After dropwise addition of bromine dissolved in
glacial acetic acid to 2, the bromoacetophenone 9 was obtained
in a yield of 71%.
The key step of the synthesis route is an asymmetric reduction
of the ketone group in 9 to afford the chiral alcohol 10. The
original medicinal chemistry route included an asymmetric
Corey–Bakshi–Shibata reduction19 to introduce the chiral center,
followed by formation and separation of the diastereometric tartrate
salt by crystallization to further improve the enantiomeric excess
of 85%. A breakthrough in achieving excellent enantioselectivities
(Scheme
5 and Figure 1), which is advantageously an
intermediate of the subsequent ethanolamine addition.
The formation of the morpholine ring of 13 was performed in
two steps. First, introduction of ethanolamine and in situ Boc
protection of the secondary amine with Boc anhydride furnished
diol 12 in 91% overall yield (Scheme 6).
Scheme 3. Vicarious nucleophilic substitution. R = Me, Et, n-Bu; X = H, F, Cl, Br, I, CN, COOi-Pr.
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M. R. Edelmann et al.
Scheme 5. Biocatalytical reduction of ketone 9.
Figure 1. Chiral HPLC analysis. Column: Chiralcel OZ-H, 250 mm × 4.6 mm, 5 μm. Mobile phase: n-heptane + 5% EtOH, flow: 1.0 mL/min, isocratic.
Scheme 6. Formation of morpholine ring.
The second step of the ring closure is the activation of the intermediate 14, the target aryl (phenyl or pyridyl derivatives)
primary hydroxyl group with mesyl chloride at À10 °C followed amides 1 were now readily accessible.20
by addition of sodium hydroxide to close the morpholine ring
Different amidation methods to obtain the desired aryl amides
to give 13 in an overall yield of 72%.
16 were investigated. The first attempt by directly reacting an aryl
Palladium-catalyzed hydrogenation of the nitrobenzene 13 ester 15a with aniline 14 in THF and potassium butylate at 50 °C
gave the aniline 14 in 90% yield (Scheme 7). From this key overnight gave yields of >80%. Using aryl acids 15b, which were
first activated with T3P in the presence of Hünig’s base, the amides
16 could be obtained in 70–80% yield after 16 h at room
temperature. However, the best results were achieved using the
corresponding acid chlorides 15c in ethyl acetate and triethylamine.
Under these conditions, the target products could be isolated in up
to 90% yield after 1 h reaction time at room temperature.
The final step in the synthesis is the Boc deprotection of 16
using acidic cleavage conditions. Among the conditions tested,
trifluoroacetic acid in dichloromethane at room temperature
proved to be the most efficient method to deprotect the
morpholines 16. After half an hour, the final products 1 were
isolated in yields of >90%.
Conclusion
Scheme 7. Synthesis to [14C]-1 from 13. Ar: phenyl or pyridyl derivatives. 15a:
R = OEt, 15b: R = OH; 15c: R = Cl.
Starting from 4-iodonitrobenzene 3, the key intermediate 4-
nitroacetophenone 2 was prepared in five steps in an overall
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M. R. Edelmann et al.
reaction to be complete. The solution was diluted with 10 mL DCM and
washed with 12 mL 0.1 N aq. NaOH and 12 mL saturated brine. The
organic layer was dried with Na2SO4, filtered, and then concentrated to
dryness to give 385 mg (83%, 58 mCi) of 8, which was used in the
following reaction without further purification.
yield of 38%. After nine subsequent steps, the final compounds 1
were isolated in a range of 20% to 30% yield. In summary, for a
representative example, this 14-step synthesis could be
completed in 11% overall yield, which means an average yield
of 85% for each step. The target compound 1 was prepared in
a specific activity of 47 mCi/mmol, a radiochemical purity of
>99% and an enantiomeric excess of 98.9%.
[
14C]-4-nitroacetophenone 2: 385 mg (1.10 mmol, 70 mCi) 8 was
treated with 12 mL (98.7 mmol) 25% aqueous HCl and the mixture stirred
over night at 125 °C. After cooling, a precipitate was formed. The mixture
was extracted sequentially with 30 mL EtOAc. The organic layer was
separated and extracted with 20 mL 1 N aq. HCl and 15 mL 1 N aq. NaOH.
After drying with Na2SO4 and filtered, the organic layer was evaporated
to yield 4-nitroacetophenone 2 as a colorless solid (90.3 mg, 45%,
31 mCi). TLC: Rf = 0.62 in dichloromethane. Radiochemical purity: 98.3%.
Experimental
Materials and methods
Carbon-14 labelled potassium cyanide was obtained from ViTrax Specific activity: 58 mCi/mmol. Additional 30 mCi was recovered as
Radiochemicals (Placentia, CA, USA) as solid. Enzymes for biocatalytical
reduction, ADH-A11 was obtained from Xzyme (Duesseldorf, Germany)
and GDH-105 from Codexis Inc. (Redwood City, CA, USA). Liquid
scintillation counting was accomplished using a HIDEX 300 SL and
[
14C]-4-nitrobenzoic acid 5 from the basic aqueous layer after extraction.
14C]-2-bromo-1-(4-nitrophenyl)ethanone 9: Two different batches of
14C]-labelled 2 (90 mg, 0.53 mmol, 31 mCi, 58 mCi/mmol and 112 mg,
[
[
0.68 mmol, 25 mCi, 37 mCi/mmol) were combined and dissolved in
ULTIMATE GOLD™ cocktail (PerkinElmer Inc., Waltham, MA, USA). 3.5 mL acetic acid. 62 μL (1.2 mmol) Bromine was added dropwise to
Precoated thin-layer chromatography sheets (TLC) were obtained from
the reaction solution, and the resulting mixture was stirred at room
Merck KGaA (Darmstadt, Germany). Developed plates were visualized temperature overnight. 10 mL water was added, and the mixture was
using Automatic TLC-linear Analyzer (Berthold Technologies, Bad
Wildbad, Germany). Analytical HPLC was performed using an Agilent
1200 series HPLC system (Santa Clara, CA, USA) using an XBridge C18
extracted with MTBE (3 × 5 mL). The organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The crude material was
purified by flash chromatography (24 g silica gel column heptane: EtOAc
column (4.6 mm × 150 mm, 3.5 μm), injection activity: 1 μCi, HPLC 7:1 isocratic) to yield 211 mg (71%, 40 mCi) solid of 9. TLC: Rf = 0.71 in
conditions: mobile phase gradient 10% to 70% (MeCN/H2O) over
12 min. Preparative purification was made with an XBridge C18 column
(10 mm × 300 mm, 5 μm). Radiochemical purity was measured using the
β Radioactivity HPLC detector RAMONA with internal solid scintillator
dichloromethane. Radiochemical purity: 98%. New specific activity:
47 mCi/mmol.
[
14C]-(S)-2-bromo-1-(4-nitrophenyl)ethanol (S)-10: A slurry of 211 mg
(0.86 mmol, 40 mCi) of 9 in 20 mL MeS buffer (100 mM, 2 mM MgCl2,
(raytest, Straubenhardt, Germany). Disposable RediSep™ silica gel pH 7) was warmed to 30 °C. After reaching this temperature, 2.58 g
columns of different sizes were purchased from Isco, Inc. (Lincoln, NE,
(0.43 mmol) PEG6000 and 1.06 g (5.3 mmol) D-glucose monohydrate
USA) and used for flash column chromatography using Isco Combiflash® were added, and the mixture was stirred slowly for 10 min. 10.7 mg
Rf+. Specific activity was determined by mass spectrometric isotopic
peak intensity distribution, using 4000QTRAP System (AB Sciex GmbH,
Zug, CH), flow injection mode with a CTC PAL and an Agilent 1100
(16.1 μmol) NADH, 11.4 mg (860 μmol) GDH-105 enzyme and 5.5 mg
(860 μmol) A11-ADH enzyme were added to the reaction mixture and
stirring continued slowly at 30 °C for 16 h. The mixture was diluted with
microLC pump without any separation. Reaction products were identified 15 mL water and extracted with MTBE (3 × 10 mL). The organic phases
by HPLC comparison with commercially available materials or
intermediates from Roche pharma research and early development
(pRED).
were separated, combined, dried with Na2SO4, filtered, and concentrated
in vacuo to give 202 mg (38 mCi) crude alcohol (S)-10 with
radiochemical purity of 91%, which was used in the next synthesis step
a
[
14C]-4-cyanonitrobenzene 4: [14C]-Potassium cyanide was previously without further purification. TLC: Rf = 0.52 in dichloromethane.
dried under vacuum at 80 °C for 5 h. After this, 110 mg (1.64 mmol,
95 mCi) of [14C]-KCN was dissolved in 4 mL THF under an argon
atmosphere. 420 mg (1.69 mmol) of 4-iodonitrobenzene 3 and 90 mg
Enantiomeric excess: >98%.
14C]-t-butyl N-(2-hydroxyethyl)-N-[(2S)-2-hydroxy-2-(4-nitrophenyl)et-
hyl]carbamate 12: 202 mg (0.82 mmol, 38 mCi) of 10 was dissolved in
[
(0.078 mmol) of tetrakis (triphenylphosphine) palladium (0) were added. 1 mL ethanolamine, and the solution was stirred for 3 h at room
The mixture was stirred at 75 °C for 8 h at which time TLC analysis
showed the reaction was nearly complete. The solvent was concentrated
to 1 mL and diluted with 14 mL EtOAc. A precipitate was formed, which
was removed by filtering over a short silica gel column and concentrated
temperature. The solution was diluted with 20 mL water and put on a
short column, filled with LiChroprep RP-18 (40–63 μm, Merck, Darmstadt,
Germany), and washed with 80 mL water. The intermediate product was
eluted from the column with 80 mL EtOH, evaporated and dried in vacuo.
to dryness to give 246 mg (98%, 94 mCi) of a colorless solid. TLC: Rf = 0.43 The residual oil was dissolved in 5 mL THF, 190 mg (0.85 mmol) of di-tert-
in heptane: EtOAc 5:1. Radiochemical purity: 98%.
[
butyl dicarbonate was added and stirred over night at room temperature.
TLC (SiO2, DCM: MeOH 9:1) showed the reaction was complete with an
14C]-4-nitrobenzoic acid 5: To 246 mg (1.63 mmol, 94 mCi) dried 4 was
added 4 N aq. NaOH (10 mL, 40 mmol) and the mixture stirred for 2 h at 88% radiochemical purity. The solution was concentrated and purified
80 °C. The mixture was diluted with 5 mL water and extracted with EtOAc by flash chromatography (24 g silica gel column, heptane: EtOAc 1:1
(6 × 10 mL). The aqueous phase was treated with 5 N aq. HCl and a
precipitate was formed. The mixture was extracted with EtOAc (8 × 5 mL). of 98%. TLC: Rf = 0.53 in dichloromethane: MeOH 9:1.
The combined organic extracts were dried with Na2SO4, filtered and
14C]-t-butyl (2S)-2-(4-nitrophenyl)morpholine-4-carboxylate 13: To a
concentrated under reduced pressure to give 200 mg (74%, 70 mCi) of solution of 245 mg (0.75 mmol, 35 mCi) of 12 in 2.5 mL of THF was added
isocratic) to give 245 mg (92%, 35 mCi) of 12 with a radiochemical purity
[
foam.TLC: Rf = 0.08 in heptane: EtOAc 1:1. Radiochemical purity: 97%.
[
tion of 200 mg (1.2 mmol, 70 mCi) of 5 in 5 mL DCM and one drop of
DMF was added 210 μL (304 mg, 2.39 mmol) oxalyl chloride, and the
mixture was stirred at room temperature for 3 h. The solvent was
evaporated to dryness, and the residue 6 was dissolved in 3 mL DCM.
240 μL (1.72 mmol) triethylamine, and the mixture was cooled under an
argon atmosphere to À13 °C. A solution of 75 μL (0.96 mmol) mesyl
chloride, dissolved in 0.5 mL of THF was added dropwise to the reaction
solution. After 15 min, 1.21 mL (4.85 mmol) 4 N aq. NaOH was added, and
the mixture was stirred at room temperature overnight. THF was
removed by evaporation and the aqueous residue was extracted with
14C]-3,3-dimorpholino-1-(4-nitrophenyl)prop-2-en-1-one 8: To a solu-
252 μL (1.44 mmol) Hünig’s base was added, and the mixture was cooled MTBE (3 × 10 mL). The combined extracts were dried over Na2SO4,
to 0 °C. Under an argon atmosphere, 262 mg (1.1 mmol) of 4,4′-(ethene-
1,1-diyl)dimorpholine 7 dissolved in 3 mL DCM was added dropwise to
the reaction solution. The reaction mixture was warmed gradually to
room temperature and was stirred for 2 h. HPLC analysis showed the
filtered, and concentrated in vacuo. Purification by flash chromatography
(24 g silica gel column, heptane: EtOAc 7:1 isocratic) gave 166 mg (72%,
25 mCi) of 13 as a colorless powder. TLC: Rf = 0.62 in heptane: EtOAc
1:1. Radiochemical purity: 98%.
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M. R. Edelmann et al.
Figure 2. Chiral HPLC analysis. Column: Chiralcel OZ-3, 150 mm × 4.6 mm, 3 μm. Mobile phase: n-heptane + 0.1% diethylamine: EtOH 70:30, flow: 1.0 mL/min, isocratic.
[
14C]-t-butyl (2S)-2-(4-aminophenyl)morpholine-4-carboxylate 14:
References
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chromatography (24 g silica gel column, heptane: EtOAc 2:1 isocratic)
to afford 135 mg (90%, 23 mCi) of a colorless oil. TLC: Rf = 0.35 in heptane:
EtOAc 1:1. Radiochemical purity: 99%.
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Acknowledgements
The authors would like to thank Mathias Müller and Georg Etter
for technical assistance in synthesis experiments and for helpful
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Conflict of interest
The authors did not report any conflict of interest.
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