Hyperpolarisation of Mirfentanil by SABRE in the Presence of Heroin

Article abstract of DOI:10.1002/cphc.202100165

Mirfentanil, a fentanyl derivative that is a μ-opioid partial agonist, is hyperpolarised via Signal Amplification By Reversible Exchange (SABRE), a para-hydrogen-based technique. [Ir(IMes)(COD)Cl] (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene, C

Full text of DOI:10.1002/cphc.202100165

Articles
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ChemPhysChem
Hyperpolarisation of Mirfentanil by SABRE in the Presence
of Heroin
Thomas B. R. Robertson,[a, c] Nicolas Gilbert,[a, b] Oliver B. Sutcliffe,*[a, b] and Ryan E. Mewis*[a, b]
Mirfentanil, a fentanyl derivative that is a μ-opioid partial
agonist, is hyperpolarised via Signal Amplification By Reversible
(IMes)(H)2(mirfentanil)2(MeOH)]+ is proposed to form based on
the observation of two hydrides at δ À 22.9 (trans to mirfentanil)
and À 24.7 (trans to methanol). In a mixture of mirfentanil and
heroin, the former could be detected using SABRE at concen-
trations less than 1% w/w. At the lowest concentration
analyzed, the amount of mirfentanil present was 0.18 mg
(812 μM) and produced a signal enhancement of À 867-fold
(P=0.42%). following polarisation transfer at 6.5 mT.
Exchange (SABRE),
a para-hydrogen-based technique. [Ir-
(IMes)(COD)Cl] (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazole-2-
ylidene, COD=cyclooctadiene) was employed as the polar-
isation transfer catalyst. Following polarisation transfer at 6.5
mT, the pyrazine-protons were enhanced by 78-fold (polar-
isation,
P=0.04%).
The
complex
[Ir-
1. Introduction
Mirfentanil, 1 (Figure 1), is a fentanyl derivative that appears to
be a μ-opoid partial agonist.[1] Studies have shown 1 possesses
moderate selectivity for μ-opioid receptors (IC50 =7.99 nM)
compared to k- or δ-receptors (IC50 =480 nM and 1428 nM
respectively).[2] Despite being a promising analgesic,[3] inducer
of antinociception (without suppressing splenic natural killer
activity),[4] and having a limited effect on the ventilatory
response to hypercarbia (25–150 μg KgÀ 1),[5] significant adverse
effects were found at higher doses (>2000 ngmLÀ 1 in blood
plasma) that was linked to increased heart rates (greater than
130 bpm), epileptiform EEG potentials and a convulsion in
volunteers studied.[6]
Morphine (3a) and heroin (3b) are both opiates and as such
are analgesics. They both possess euphoric properties. 3b is
more potent than 3a due to greater brain penetration and
rapid enzyme-catalysed deacetylation in the blood to form 6-
acetylmorphine, which is then subsequently hydrolysed to 3a.[7]
Therefore, 3b is a drug of abuse. A number of reports have
cited an increase in 3b-related overdose due to the fact that 3b
is often “cut” with other drugs such as 2 or one of its
derivatives, known as fentalogs, due to their euphoria inducing
Figure 1. Chemical structures of mirfentanil (1), fentanyl (2), morphine (3a)
and heroin (3b)
effects.[8] Some countries, such as the USA, have seen a sharp
rise in 3b-linked deaths.[9]
The concentration of 2 or a fentalog in a sample of 3b is
typically low (ca. mg) and so commonly used methods such as
GC-MS struggle to detect them against the strong background
of 3b, although methods have been developed to combat
this.[10]
Polarisation methodologies could aid in the detection of 2
or a fentalog, despite their low concentration in bulk samples.
Signal Amplification By Reversible Exchange[11] (SABRE) is one
such technique. SABRE utilizes para-hydrogen (p-H2) as the
source of polarisation. An iridium centred catalyst is typically
employed to facilitate polarisation from p-H2 derived hydrides,
and the spin-1/2 nuclei of the analyte molecule being polarised,
through the established J-coupling network. A number of N-
heterocycles, inclusive of drug molecules, have been polarised
by SABRE.[11–12]
[a] Dr. T. B. R. Robertson, Dr. N. Gilbert, Dr. O. B. Sutcliffe, Dr. R. E. Mewis
Department of Natural Sciences
Manchester Metropolitan University
John Dalton Building, Chester St., Manchester, M1 5GD, UK
E-mail: o.sutcliffe@mmu.ac.uk
In a previous report, three pyridyl fentalogs were success-
fully polarised via SABRE.[13] 2 was also appraised in this
previous report but was not polarised due to lack of sufficient
donor atoms to the iridium catalyst used. Even a combined
SABRE-relay[14] and catalyst separated hyperpolarisation (CASH)-
SABRE[15] approach did not facilitate the polarisation of 2.
Although these fentalogs have, to date, not been encountered
on the recreational drug scene, proof-of-concept for the
detection of fentalogs using SABRE has been established.
However, 1 is a known fentalog with known toxicity that could
be encountered. Therefore, development of technique to detect
r.mewis@mmu.ac.uk
[b] Dr. N. Gilbert, Dr. O. B. Sutcliffe, Dr. R. E. Mewis
MANchester DRug Analysis and Knowledge Exchange (MANDRAKE)
Manchester Metropolitan University
John Dalton Building, Chester St., Manchester, M1 5GD, UK
[c] Dr. T. B. R. Robertson
Current address: School of Chemistry, University of Southampton, SO17 1BJ,
Southampton, UK
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cphc.202100165
An invited contribution to a Special Collection on Parahydrogen En-
hanced Resonance.
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this fentalog at low concentration in a seized drug sample is
desirable. In terms of harm reduction point-of-care services,
being able to quickly analyse and detect materials at a low
threshold in a seized drug sample is very important for safe-
guarding vulnerable individuals. In the light of this, a route by
which 1 can be detected, via SABRE, against a strong back-
ground signal of 3b, is described to potentially aid harm
reduction point-of-care services.
2. Results and Discussion
2.1. Synthesis of 1
The synthesis of 1 is outlined in Scheme 1. The synthetic
pathway is adapted from a procedure reported by Bagley
et al.[16] and utilizes 1-phenethyl-4-piperidone as the starting
material. The overall yield of this four-step pathway was 62%.
Briefly, 1-phenethyl-4-piperidone was converted into the hy-
droxylamine, 4, before being reduced in the presence of LiAlH4
to give 5.HCl, following an acidic work-up. A copper-mediated
coupling was then utilized to form 6 in 34% yield; this step was
the lowest yielding step of the synthetic pathway. Acylation of
6 with 2-furoyl chloride formed the target compound, 1. The 1H,
13C and IR data for all of these compounds is reported in the SI
and is consistent with their molecular structures.
Figure 2. 1H NMR spectra of 1 and 4 in the ratio of 4:1 (4.7 mg of 1) in the
presence of p-H2 in d4-methanol following polarisation transfer in a magnetic
field of 6.5 mT (A) or earth’s magnetic field (B) compared to the sample at
thermal equilibrium (C). Multiplication factors indicate scaling of the vertical
axis.
protons (δ 8.62) were enhanced by 78-fold (Figure 2A). This
equates to a polarisation (P) level of 0.04%. Conducting
polarisation transfer in earth’s magnetic field resulted in a much
lower enhancement of only 11-fold (P=0.005%) for the
pyrazine protons (Figure 2B). This contrasts with previous para-
substituted pyridyl fentalogs[13] and endothelial nitric oxide
synthase (eNOS) substrates[12a] that were polarised optimally at
earth’s magnetic field.
2.2. SABRE-based hyperpolarisation of 1
1
Initial studies were focused on the hyperpolarisation of 1 solely
using [Ir(IMes)(COD)Cl] (IMes=1,3-bis(2,4,6-trimethylphenyl)
imidazole-2-ylidene, COD=cyclooctadiene), 7, as the polarisa-
tion transfer catalyst in a ratio of 4:1. Following polarisation
transfer in a 6.5 mT magnetic field, the sample was transferred
rapidly to a measurement field of 1.4 T. Resultantly, the pyrazine
The hyperpolarised H NMR spectrum of 1 in the presence
of 7 produced two observable hydride resonances at À 22.9 and
À 24.7 ppm (Figure 2B and 2 C). Based on previous studies,[17]
the latter is due to a hydride trans to coordinated methanol
whilst the former is a due to a hydride trans to 1. The complex
[Ir(IMes)(H)2(1)2(MeOH)]+ (Figure 3A) is proposed to account for
Scheme 1. Synthetic pathway for the preparation of 1. Conditions; (i) NH2OH.HCl, KOH, MeOH, RT, 24 hr; (ii) LiAlH4, THF, reflux, 1 hr; (iii) NaOH (aq) (to form 5)
°
then Cu, 2-chloropyrazine, 180 C, 6 hr; (iv) diisopropylamine, 2-furoyl chloride, RT, 2 hr.
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not polarised by 7,[21] (unless co-ligands are used[22]) due to
steric hindrance around the nitrogen. Furthermore, these
observations and hydride chemical shift data rule out the
possibility of the furan-oxygen from acting as a ligand to the
metal centre.
Figure 3. Chemical structures of [Ir(IMes)(H)2(1)2(MeOH)]+, [Ir-
(IMes)(mtz)2(pz)(H)2]Cl, [Ir(IpClC6H2Me2)(pz)2(BnNH2)(H)2]Cl and [Ir-
(IpClC6H2Me2)(pz)(BnNH2)2(H)2]Cl (A–D respectively). L1 =IMes,
L2 =IpClC6H2Me2, mir=1, mtz=1-methyl-1,2,3-triazole and pz=pyrazine
2.3. SABRE of a simulated sample of 1and 3b
A series of simulated samples were produced whereby the
amount of 1 present relative to 3b was varied from 0.63% to
3.80% w/w. This translates to 0.18 mg to 1.15 mg of 1 in an
NMR sample, which is lower than the dose required to produce
an adverse effect in an adult male (assuming a blood plasma
volume of 2.5 L, 5 mg of 1 would be required to cause an
adverse effect). From a harm-reduction point-of-care perspec-
tive, being able to detect this small amount of 1 in a seized
drug sample is advantageous in terms of safe-guarding, and it
avoids the need for biological sample testing.
7 was again used as the polarisation transfer catalyst and
was present in a 1:4 ratio of 7:1. A control was also prepared
in which 1 was replaced for 3b. These samples were all
subjected to SABRE utilizing polarisation transfer fields of 6.5
mT and earth’s magnetic field. The control sample was found
not to polarise, despite 3a having been reported to be
polarised previously, albeit using [Ir(COD)(PCy3)(py)][PF6] as the
polarisation transfer catalyst.[12c] Steric interactions between 3a
and 7 may have prevented ligation; no hydride ligands were
observed to suggest activation of 7 into the active form of the
polarisation transfer catalyst.
Following polarisation transfer at earth’s magnetic field, the
sample consisting of 3.80% w/w of 1 relative to 3b produced
an enhancement of À 6-fold (P=0.003%). This enhancement
was calculated via internal reference to a heroin aromatic signal.
The sample consisted of 1.15 mg of 1 relative to 29.1 mg of 3b.
A larger enhancement of À 42-fold (P=0.02%) was obtained
when polarisation transfer was conducted at 6.5 mT. These
results are consistent with the hyperpolarisation of 1 solely with
respect to the enhancement linked magnetic field dependency.
An internal reference signal was utilised here because the
amount of 1 present in the 0.63% w/w sample was only visible
after acquiring 128 transients (ca. 15 min acquisition, see
Figure 4A).
Polarisation of the 0.63% w/w sample also led to polar-
isation of 1 with the enhancement again being greater at
6.5 mT (Figure 4). The amount of 1 in the sample equated to
0.18 mg or 81 μM. The enhancement obtained at 6.5 mT was
À 867-fold (P=0.42%). These data highlight that 1 can be
readily detected against a strong background of 3b. Further-
more, the two hydride signals are still visible at À 22.9 and
À 24.7 ppm, which is indicative of the same catalytic species
being present in solution.
these observations. Thus, only a single molecule of 1 is trans to
hydride; trans couplings have been shown to facilitate efficient
transfer of hyperpolarisation when compared to cis couplings,[18]
which are often negligible or zero.[19]
Hyperpolarisation studies of pyrazine solely (Figures S15–
17), gave a number of hydrides in the region À 21.7 to
À 24.7 ppm. The appearance of the hydride region did not
change when the ratio of pyrazine:7 was changed from 20:1 to
4:1 (Figure S19). The most prominent hydrides are those at
À 22.8 and À 24.7 ppm, which account for ca. 50% of the total
integral area and possess a common JHH coupling of À 12.9 Hz.
Hydride resonances trans to pyrazine (pz) have been reported
at À 22.7, À 21.9 and À 23.0 ppm in [Ir(IMes)(mtz)2(pz)(H)2]Cl
(mtz=1-methyl-1,2,3-triazole),[20]
(IpClC6H2Me2)(pz)2(BnNH2)(H)2]Cl
[Ir-
[Ir-
and
(IpClC6H2Me2)(pz)(BnNH2)2(H)2]Cl[12b] respectively (Figure 3B-3D
respectively). The pyrazine protons of the 4:1 pyrazine:7 sample
were enhanced by À 1313-fold (P=0.63%), following polar-
isation transfer at 6.5 mT. For the analogous 20:1 pyrazine:7
sample, the pyrazine protons were only enhanced by À 414-fold
(P=0.20%) at the same transfer field. Both of these enhance-
ments, and polarisation values, are significantly larger than the
enhancement observed for 1.
Addition of 50 μL of water to the 4:1 pyrazine:7 sample
resulted in the most upfield hydride signal shifting by 0.3 ppm
to À 25 ppm. The complex [Ir(IMes)(H)2(1)2(H2O)]+ is proposed
to account for this change in hydride region; the change in
chemical shift of the most upfield hydride signal is consistent
with previous recorded observations.[17] The remainder of the
hydride region is unchanged upon the addition of water
(Figure S19). The addition of water to the sample caused the
enhancement of the pyrazine protons to diminish to À 370-fold
(P=0.18%) following polarisation transfer at 6.5 mT.
It should be noted that the previously reported para-
substituted pyridyl fentalogs led to the production of a single
observable hydride due to the formation of [Ir-
(IMes)(H)2(fentalog)3]Cl.[13] Evidently, the substitution of the
pyrazine ring ortho to one of the nitrogen atoms in 1 causes
steric encumbrance such that only a single molecule of 1 can
bind trans to hydride in [Ir(IMes)(H)2(1)2(MeOH)]+. Evidence for
the formation of [Ir(IMes)(H)2(1)2(MeOH)]+ is obtained from the
SABRE-enhanced 1H NMR spectra (figures 2A and 2B), which
possess two hydride signals, due to the lack of symmetry in the
complex. The unhindered nitrogen atom of the pyrazine ring is
proposed to act as the donor atom to the iridium centre as
previous studies have shown that 2-picoline and 2,6-lutidine are
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without further purification as an off-white solid (8.18 g, 76% yield);
1H NMR (400 MHz, CDCl3) δ 9.05 (s (br), 1H), 7.32–7.09 (m, 5H), 2.90–
2.30 (m, 12H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.42, 140.13,
128.73, 128.47, 126.16, 60.08, 53.68, 52.44, 33.76, 31.39, 24.41; ATR-
FTIR vmax/cmÀ 1: 3060.4, 2908.0, 2821.5, 1666.4, 1600.8, 1495.7; HRMS
(C13H18N2O): predicted mass=219.1497 [M+H]+; experimental
mass=219.1498 [M+H]+.
1-Phenethylpiperidin-4-amine Hydrochloride (5.HCl)
Lithium aluminium hydride (47.2 mmol, 1.25 eq.) was slowly
°
dissolved in anhydrous THF (75 mL) at 0 C. To this mixture was
slowly added 4 (37.49 mmol) in anhydrous THF (85 mL) with
stirring. After gas evolution had subsided, the reaction mixture was
carefully heated to reflux for 1 h. The mixture was then cooled to
room temperature and placed in an ice bath. The reaction was
quenched by slow addition of water (1.8 mL), aqueous NaOH (15%
w/v, 1.8 mL) and then water again (5.4 mL). The resulting mixture
was stirred until it turned from dark grey to a light yellow. The
resulting mixture was filtered to remove the white precipitate. The
filtrate was concentrated in vacuo. The resulting oil was dissolved in
diethyl ether (10 mL) and 3 M HCl in cyclopentyl methyl ether
(13.0 mL) was added. The resulting salt was isolated by filtration
and dried under vacuum. Compound 5.HCl was obtained as a light
Figure 4. 1H NMR spectra 1 and 7 in the ratio of 4:1 (0.183 mg of 1) in the
presence of heroin (29.1 mg) and p-H2 in d4-methanol at thermal equilibrium
(A – 128 transients, B – 1 transient) or following polarisation transfer at
earth’s magnetic field (C) or at 6.5 mT (D). All spectra are shown to the same
vertical scale, except where indicated.
1
yellow solid (7.5 g, 83% yield); H NMR (400 MHz, DMSO-d6) δ 8.21
3. Conclusions
(s(br), 3H), 7.35–7.13 (m, 5H), 3.46 (s(br), H2O), 2.97–2.94 (m, 3H),
2.73–2.70 (m, 2H), 2.02 (t, J=11.4 Hz, 2H), 1.89 (d, J=11.8 Hz, 2H),
1.55 (q, J=11.5 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 140.80,
129.16, 128.78, 126.41, 59.79, 51.43, 48.25, 33.30, 30.03; ATR-FTIR
To conclude, SABRE could be used in a forensic context to
qualitatively detect low amounts of 1 (<1 mg) against a strong
background signal of 3b via 1H NMR spectroscopy. Only a single
transient is required for detection. Polarisation transfer occurred
optimally at 6.5 mT, although it should be noted that only two
polarisation transfer fields were utilized in the study. Employ-
ment of 100% p-H2 would improve the signal intensity further
(by a factor of three), as only 50% p-H2 was utilized in this
study. The selective hyperpolarisation of 1 in the presence of
3b highlights that SABRE could be a potentially powerful
forensic tool for aiding harm-reduction point-of-care services.
v
max/cmÀ 1: 3399.2, 2948.8, 2822.5, 2569.9, 2101.2, 1630.0, 1600.9,
1515.6; HRMS (C13H20N2): predicted mass=205.1705 [M+H]+;
experimental mass=205.1702 [M+H]+.
N-(1-Phenethylpiperidin-4-yl)pyrazin-2-amine (6)
Compound 5.HCl (2.81 mmol, 2.0 eq.) was dissolved in water. The
resulting solution was made basic (pH=12) by the addition of
aqueous NaOH. The solution was transferred to a separation funnel
and the aqueous layer was extracted three times with dichloro-
methane (325 mL). The combined organic layers were dried over
magnesium sulfate and concentrated in vacuo to obtain the free-
base form of compound 5 as a yellow oil.
Experimental Section
Copper powder (1.41 mmol, 1.0 eq.) and 2-chloropyrazine
All reagents were of commercial quality (Sigma-Aldrich, Gillingham,
UK or Fluorochem Limited, Hadfield, UK) and used without further
purification. Solvents (Fisher Scientific, Loughborough, UK) were
dried, where necessary, using standard procedures. Complex 7 was
prepared according to the procedure reported by Sola and co-
workers.[23] 1H NMR and 13C NMR spectra were acquired on a JEOL
JMN-ECS-400 (JEOL, Tokyo, Japan) NMR spectrometer operating at
a proton resonance frequency of 400 MHz and referenced to the
residual solvent peak. Infrared spectra were obtained in the range
4000–400 cmÀ 1 using a Thermo Scientific Nicolet iS10ATR-FTIR
instrument (Thermo Scientific, Rochester, USA). High-resolution
mass spectrometry (HRMS) data were obtained on an Agilent 6540
LC-QToF spectrometer in positive electrospray ionization mode.
(1.41 mmol, 1 eq.) were suspended along with 5. The reaction
°
mixture was refluxed at 180 C under inert atmosphere for 6 h. The
reaction was then cooled to room temperature and a solid formed.
The solid was broken up and suspended in aqueous HCl (10% v/v).
The solid was removed by filtration. The filtrate was washed once
with diethyl ether (50 mL). The aqueous layer was made basic
(pH=12) by the addition of aqueous NaOH. The aqueous layer was
then extracted twice with dichloromethane (250 mL). The com-
bined organic layers were washed with water (50 mL) and brine
(50 mL). The organic layers were then dried over magnesium sulfate
and concentrated in vacuo. The crude product was purified by flash
column chromatography (SiO2, 0–10% v/v MeOH in DCM) to obtain
1
compound 6 as a light yellow solid (139 mg, 34% yield); H NMR
(400 MHz, CDCl3) δ 7.95 (dd, J=2.7, 1.5 Hz, 1H), 7.85 (d, J=1.3 Hz,
1H), 7.77 (d, J=2.8 Hz, 1H), 7.30–7.18 (m, 5H), 4.47 (d, J=7.7 Hz,
1H), 3.84–3.72 (m, 1H), 3.00 (d, J=11.7 Hz, 2H), 2.85–2.81 (m, 2H),
2.66–2.60 (m, 2H), 2.27 (t, J=11.0 Hz, 2H), 2.10 (d, J=12.0 Hz, 2H),
1.95–1.45 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.98, 141.98,
141.10, 141.08, 134.02, 131.16, 129.15, 129.13, 129.12, 128.71,
128.70, 128.69, 126.30, 126.28, 60.40, 52.52, 51.49, 34.98, 33.61,
33.55, 32.03; ATR-FTIR vmax/cmÀ 1: 3261.6, 3062.3, 3030.8, 2952.8,
2761.6, 2638.3, 2480.1, 1645.3, 1597.2, 1582.8, 1518.6, 1503.5; HRMS
1-Phenethylpiperidin-4-one Oxime (4)
1-Phenethyl-4-piperidone
(49.3 mmol)
and
hydroxylamine
hydrochloride (74.0 mmol, 1.5 eq.) were dissolved in methanol
(82 mL). Aqueous potassium hydroxide was added (54.0 mmol KOH
in 15 mL water) and the mixture was stirred at room temperature
for 24 The combined organic layers were dried over magnesium
sulfate and concentrated in vacuo. Compound 4 was obtained
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(C17H22N4): predicted mass=283.1923 [M+H]+; experimental
mass=283.1927 [M+H]+.
Acknowledgements
REM is grateful to Manchester Metropolitan University for a Vice
Chancellor studentship for TBRR. The Natural Sciences and
Engineering Research Council of Canada (396154510) and Fonds
de Recherche du Québec – Nature et Technologie (206375) are
thanked for funding for NG. Oxford Instruments are thanked for
their technical support.
N-(1-phenethylpiperidin-4-yl)-N-(pyrazin-2-yl)
furan-2-carboxamide (Mirfentanil, 1)
Compound 6 (1.0 mmol) was dissolved in dichloromethane (10 mL)
and treated with diisopropylethylamine (2.0 mmol). The mixture
was cooled in an ice bath and 2-furoyl chloride (2.0 mmol) was
added dropwise. The resulting solution was stirred at room temper-
ature for 2 h. The mixture was diluted with water (30 mL) and the
organic layer washed sequentially with brine (30 mL) and saturated
aqueous sodium bicarbonate (30 mL). The organic layer was dried
with magnesium sulfate and concentrated in vacuo. The crude oil
was purified using a Biotage Isolera One Flash Purification System
(eluent: 0–10% MeOH in DCM). Mirfentanil, 1, was obtained as a
Conflict of Interest
The authors declare no conflict of interest.
1
light yellow solid (145 mg, 54% yield); H NMR (400 MHz, CDCl3) δ
Keywords: Mirfentanil · hyperpolarisation · SABRE · NMR ·
8.53 (s, 2H), 8.38 (s, 1H), 7.30–7.07 (m, 5H), 6.56–6.52 (m, 1H), 6.27–
6.25 (m, 1H), 4.78 (tt, J=11.9, 3.0 Hz, 1H), 3.07 (d, J=11.1 Hz, 2H),
2.78–2.74 (m, 2H), 2.60–2.56 (m, 2H), 2.22 (t, J=11.6 Hz, 2H), 1.97 (d,
J=11.9 Hz, 2H), 1.85–1.52 (m, 2H); 13 C{1H} NMR (100 MHz, CDCl3)
δ 158.81, 150.13, 147.56, 145.93, 144.74, 143.49, 143.43, 140.12,
128.73, 128.51, 126.19, 117.64, 111.43, 60.44, 54.39, 53.14, 33.81,
30.39; ATR-FTIR vmax/cm-1: 3134.8, 3112.9, 3036.2, 3010.0, 2948.8,
2903.6, 2851.9, 2809.8, 1651.1, 1600.1, 1575.2, 1519.0; HRMS
(C22H24 N4O2): predicted mass=377.1978 [M+H]+; experimental
mass=377.1973 [M+H]+.
opioid
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SABRE Measurements
1H NMR spectra collected for the hyperpolarised samples were
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1
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0.473 mmol of 3b, was dissolved in 3.6 mL of d4-methanol and
sonicated for 30 s. For the lowest concentration (812 μM), 1.1 mg of
1 and 0.5 mg of the SABRE pre-catalyst, 7, were added to this stock
and sonicated for 30 seconds. 0.6 mL of this solution was then
taken up by syringe and transferred into a Young’s tap NMR tube.
The sample was then degassed on a high-vacuum line via three
‘cool’-pump-thaw cycles (using a acetone/CO2 slush bath). Para-
hydrogen, at a pressure of 3.0 atmospheres was then admitted to
the NMR tube. Parahydrogen was produced by cooling hydrogen
gas to 77 K over charcoal (50% parahydrogen produced). The
sample was then shaken to form the catalytically active species in
solution prior to collecting a thermal 1H NMR spectrum. For the
collection of SABRE measurements, the hydrogen in the head-space
of the tube was replenished with parahydrogen prior to shaking for
10 s in either earth’s magnetic field (ca. 0.5 G) or in a hollow tube
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vertical magnetic field of up to 150 G could be generated (see
Figure S14). The sample was then rapidly inserted into the NMR
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spectrometer and a H NMR spectrum acquired using a π/2 pulse.
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1: 7. Following the addition of more 1 and 7 the stock was
sonicated for 30 seconds before removal of a fresh aliquot and
acquisition repeated in this way for the total four concentrations
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Articles
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Manuscript received: March 1, 2021
Revised manuscript received: April 5, 2021
Accepted manuscript online: April 19, 2021
Version of record online: ■■■, ■■■■
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ARTICLES
Mirfentanil detection: Mirfentanil, a
fentanyl derivative and μ-opioid
partial agonist, is hyperpolarised via
the hyperpolarisation technique
Signal Amplification By Reversible
Exchange (SABRE). In a series of
simulated samples consisting of mir-
fentanil and heroin, the amount of
mirfentanil was varied from 0.63%
w/w–3.80% w/w. Mirfentanil was
readily detected in the 1H NMR
spectrum (single transient) at all the
concentrations studied when SABRE
was employed.
Dr. T. B. R. Robertson, Dr. N. Gilbert,
Dr. O. B. Sutcliffe*, Dr. R. E. Mewis*
1 – 7
Hyperpolarisation of Mirfentanil by
SABRE in the Presence of Heroin