Synthesis of deuterium-labeled cyamemazine and monodesmethyl cyamemazine

Article abstract of DOI:10.1002/jlcr.3145

A novel approach is presented for the synthesis of cyamemazine maleate and N-desmethyl cyamemazine maleate using a 10-(amino-2-methylpropyl)phenothiazine derivative. This method was successfully applied to the synthesis of [ ²H₆]cyamemazine maleate and N-desmethyl-[ ²H₃]cyamemazine maleate.

Full text of DOI:10.1002/jlcr.3145

Research Article
Received 29 September 2013,
Revised 24 October 2013,
Accepted 25 October 2013
Published online 18 December 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3145
Synthesis of deuterium-labeled cyamemazine
and monodesmethyl cyamemazine
†
‡
*
R. Sekhar Bolla and I. V. Kasi Viswanath
A novel approach is presented for the synthesis of cyamemazine maleate and N-desmethyl cyamemazine maleate using a
10-(amino-2-methylpropyl)phenothiazine derivative. This method was successfully applied to the synthesis of [2H6]
cyamemazine maleate and N-desmethyl-[2H3]cyamemazine maleate. Copyright © 2013 John Wiley & Sons, Ltd.
Keywords: schizophrenia; [2H6]cyamemazine maleate; N-desmethyl-[2H3]cyamemazine maleate; antipsychotic; cyamepromazine;
deuterium labeled
maleate, and [2H3]monodesmethyl cyamemazine maleate. The
Introduction
commercial synthesis of cyamemazine involves treating the
Cyamemazine (Tercian) also known as Cyamepromazine is a
sodium salt of 3-cyanophenothiazine with 1-dimethyl-amino-
2-methyl-3-chloropropane hydrochloride.7 It was envisaged
phenothiazine aliphatic chain class neuroleptic low-medium
potency first generation typical antipsychotic drug.1 Cyamemazine
differs from other phenothiazine neuroleptics in the nature of its
pharmacological profile. It is used for the management of
that the synthesis of deuterium-labeled cyamemazine
derivatives using the manufacturing route would be difficult.
Therefore, an alternate synthesis was developed in which both
schizophrenia2 but is especially useful as a treatment for
cyamemazine and monodesmethyl cyamemazine could be
psychosis-associated anxiety due to its anxiolytic properties.3 It
prepared from a common intermediate, namely, 10-(amino-2-
methylpropyl)phenothiazine derivative (7).
Scheme 1 depicts the synthetic route for the preparation of
has also been used for the treatment of affective disorders, anxiety
restlessness, and benzodiazepine withdrawal syndrome.2
Although cyamemazine is classed as a typical antipsychotic,
several studies have shown that in addition to acting as a
dopamine D2 antagonist, it has a potent antagonistic effect on
unlabeled cyamemazine maleate (8), and Scheme 2 represents
the synthesis of [2H6]cyamemazine maleate (9). 2-Methyl-1,
3-propanediol (1) was selectively monotosylated10 to give
serotonin receptors (5-HT2A, 5-HT2C, and 5-HT3).4,5 These actions
1-tosyl-2-methyl-3-propanol, which was treated with
are thought to be responsible for its anxiolytic properties. The
potassium phthalimide in DMF at 90 °C to give phthalimido
anxiolytic effects of cyamemazine were studied in mice, but
propanol derivative11 (3). The phthalimido propanol derivative
results were inconclusive.3 This discrepancy was attributed to
the combined activity of cyamemazine on dopamine D2
receptors and 5-HT2C and 5-HT3 receptors. This explains the
activity of cyamemazine in the management of alcohol
was halogenated12 with iodine, triphenylphophine, and imidazole
in THF at 0 °C to yield iodine compound (4), which reacted with the
sodium salt of 3-cyanophenothiazine (5) in DMF at room
temperature to give phthalimido phenothiazine derivative7 (6).
withdrawal and benzodiazepine withdrawal syndrome.
The phthalimide group in compound (6) was deprotected13 with
Cyamemazine is metabolized in liver into two major metabolites,
one of which is monodesmethyl cyamemazine.6 Samples of both
hydrazine monohydrate in ethanol at 70 °C to give the common
intermediate 10-(amino-2-methylpropyl)phenothiazine derivative
(7). The amine (7) was treated with dimethyl sulfate (Scheme 1)
and dimethyl sulfate-d6(Scheme 2) in THF at 60 °C to give the
tertiary amines, which were treated with maleic acid in ethanol
to obtain cyamemazine maleate (8) and [2H6]cyamemazine
maleate (9), respectively, in separate experiments.
compounds labeled with stable isotopes were required as
internal standards for the quantification of cyamemazine and
monodesmethyl cyamemazine in biological samples.
Despite modern developments in bio-analytical techniques,
compounds labeled with stable isotopes are extremely valuable
as internal standards in the analysis of samples from metabolic
studies. A well-designed labeled compound can provide high
quality information about the identity and quantification of
drug-related compounds in biological samples. This information
can be very useful at key decision points in drug development.
Several synthetic approaches were known for the synthesis
of cyamemazine7–9 and monodesmethyl cyamemazine,6 but the
synthesis of labeled [2H6]cyamemazine maleate and monodesmethyl
[2H3]cyamemazine maleate was not known. In this study, we
developed a novel synthetic approach for the cyamemazine
maleate, [2H6]cyamemazine maleate, monodesmethyl cyamemazine
Department of Chemistry, KL University, Vaddeswaram, Guntur Dist, India
†Research Scholar
‡Assistant Professor
*Correspondence to: R. Sekhar Bolla, Department of Chemistry, KL University,
Vaddeswaram, Guntur Dist, India.
E-mail: rsrbolla@gmail.com
J. Label Compd. Radiopharm 2014, 57 82–85
Copyright © 2013 John Wiley & Sons, Ltd.

R. S. Bolla and I. V. Kasi Viswanath
Scheme 1. Synthesis of cyamemazine maleate.
at same temperature about 3 h. When TLC (4:6, EtOAc/hexanes) showed
complete consumption of the starting material, the reaction mixture was
diluted with water (100 mL), stirred well, separated the organic layer,
washed with 2 M HCl (100 mL) then with sat. NaHCO3 soln (50 mL), dried
over Na2SO4, and evaporated to dryness to give crude, which was
purified by column chromatography to afford 2 (92.0 g, 70%,) as a
colorless solid.
1H NMR (300 MHz, CDCl3): δ 7.79 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.1 Hz,
2H), 4.03–4.00 (m, 2H), 3.58–3.52 (m, 2H), 2.45 (s, 3H), 2.05–1.95 (m, 1H),
0.92 (d, J = 7.2 Hz, 3H); MS (MM) m/z 245 [M + H]+.
Scheme 2. Synthesis of [2H6] cyamemazine maleate.
Synthesis of 2-(3-hydroxy-2-methylpropyl) isoindoline-1, 3-dione (3)
Schemes 3 and 4 illustrate the synthesis of monodesmethyl
cyamemazine maleate (12) and [2H3]monodesmethyl cyamemazine
maleate (14), respectively. The common intermediate (7) was
protected14 with di-tert-butyl dicarbonate. The phenothiazine
carbamate was N-methylated15 with NaH/CH3I and NaH/CD3OTs16,
separately to give N-methyl phenothiazine carbamate derivatives
(11) and (13), respectively. The carbamate deprotetction of N-
methylphenothiazine carbamates (11) and (13) was carried out
separately with HCl in MTBE. The secondary amines were treated
with maleic acid in ethanol to afford monodesmethyl cyamemazine
maleate (12) and [2H3]monodesmethyl cyamemazine maleate (14),
respectively in separate experiments.
To a stirred solution of 2 (50.0 g, 0.204 mol, 1.0 equiv) in DMF (250 mL)
was added potassium phthalimide (45.5 g, 0.245 mol, 1.2 equiv) and
stirred the reaction mixture at 90°C about 16 h under nitrogen
atmosphere. When TLC (2:8, EtOAc/hexanes) showed complete
consumption of the starting material, the reaction mixture was diluted
with water (500 mL) and extracted with EtOAc (500 mL), dried over
Na2SO4, and evaporated to dryness to give crude, which was purified
by column chromatography to afford 3 (27.0 g, 60%,) as a colorless solid.
1H NMR (300MHz, CDCl3): δ 7.87–7.85 (m, 2H), 7.75–7.72 (m, 2H), 3.72
(d, J = 6.0Hz, 2H), 3.54–3.50 (m, 1H), 3.39–3.35 (m, 1H), 2.77 (bs, 1H), 2.11–
2.01 (m, 1H), 0.99 (d, J= 6.9 Hz, 3H). MS (MM) m/z 220 [M + H]+.
Synthesis of 3 2-(3-iodo-2-methylpropyl) isoindoline-1, 3-dione (4)
To a stirred solution of 3 (130 g, 0.593 mol, 1.0 equiv) in THF (800 mL) was
added triphenylphosphine (233 g, 0.89 mol, 1.5 equiv) followed by
addition of imidazole (80.0 g, 1.18 mol, 2.0 equiv) and cooled at 0 °C
under nitrogen atmosphere. Then, solid iodine (180 g, 0.71 mol, 1.2 equiv)
was added portion wise slowly under nitrogen atmosphere. After
completion of addition, the reaction mass was stirred at room
temperature about 3 h. When TLC (4:6, EtOAc/hexanes) showed
complete consumption of the starting material, the reaction mixture
was diluted with water (1000 mL) and extracted with EtOAc
(2 × 500 mL), dried over Na2SO4, and evaporated to dryness to give crude,
which was purified by column chromatography to afford 4 (130 g, 67%,)
as a colorless solid.
Experimental
General
All reagents were purchased from commercial sources and were used
as received. 1H NMR spectra were obtained on a Bruker (Methyl tert
Butylether) AVANCE 300 spectrometer at 300 MHz or Bruker AVANCE
400 spectrometer at 400 MHz with tetramethylsilane used as an
internal reference. Thin layer chromatography (TLC) was performed
using Whatman No. 4500–101 (Diamond No. MK6F silica gel 60 Å)
plates. Visualization of TLC plates was performed using UV light
(254 nm). HPLC was obtained on an Agilent HPLC using ZORBAX
Eclipse XDB-C18, 150mm × 4.6 mm, 5 μm.
1H NMR (300 MHz, CDCl3): δ 7.87–7.84 (m, 2H), 7.75–7.72 (m, 2H), 3.71–
3.57 (m, 2H), 3.27–3.22 (m, 1H), 3.14–3.08 (m, 1H), 2.17–2.10 (m, 1H), 1.06
(d, J = 6.6 Hz, 3H); MS (MM) m/z 329 [M + H]+.
Synthesis of 3-hydroxy-2-methylpropyl 4-methylbenzenesulfonate (2)
To a stirred solution of 1 (50.0 g, 0.554 mol, 1.0 equiv) in CH2Cl2 (500 mL)
was added pyridine (105.26 g, 1.385 mol, 2.5 equiv) and cooled at 0 °C
under nitrogen atmosphere. Then, solid tosyl chloride (94.8 g,
Synthesis of 10-(3-(1, 3-dioxoisoindolin-2-yl)-2-methylpropyl)-10H-
phenothiazine-2-carbonitrile (6)
0.499 mol, 0.9 equiv) was added portion wise slowly under nitrogen To a stirred solution of 60% NaH (8.90 g, 0.223 mol, 2.0 equiv) in DMF
atmosphere. After completion of addition, the reaction mass was stirred (100 mL) at 0 °C was added compound 5 (25.0 g, 0.111 mol, 1.0 equiv)
J. Label Compd. Radiopharm 2014, 57 82–85
Copyright © 2013 John Wiley & Sons, Ltd.
www.jlcr.org

R. S. Bolla and I. V. Kasi Viswanath
Scheme 3. Synthesis of monodesmethyl cyamemazine maleate.
Scheme 4. Synthesis of [2H3]monodesmethyl cyamemazine maleate.
in DMF (100 mL), and stirred under nitrogen for 30 min. Then,
compound 4 (47.5 g, 0.145 mol, 1.3 equiv) in DMF (100 mL) was added
slowly by maintaining a temperature of 0 °C about 30 min. After
completion of addition, the reaction mixture was brought at room
temperature and stirred about 16 h. TLC (2:8, EtOAc/hexanes) showed
10% of the starting material remains in the reaction mixture; the
reaction mixture was diluted with water (500 mL) and extracted with
MTBE (2 × 500 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure to give, crude which was
purified by silica gel column chromatography to afford 6 (6.5 g, 15%)
as pale yellow solid.
1.0 equiv) in ethanol (10 mL) about 30 min. The precipitated solids were
filtered out and dried to afford 8 (250 mg, 35%) as pale yellow solid.
1H NMR (300 MHz, DMSO-d6): δ9.13 (bs, 1H), 7.53–7.47 (m, 1H), 7.45–
7.39 (m, 2H), 7.31–7.23 (m, 2H), 7.15–7.03 (m, 2H), 6.02(s, 2H), 3.98–3.78
(m, 2H), 3.05–2.99 (m, 2H), 2.69 (s, 6H), 2.30–2.27 (m, 1H), 1.03
(d, J = 6.6 Hz, 3H); MS (MM) m/z 324 [M + H]+; HPLC >98%; m.p. 206–208 °C.
Synthesis of [2H6]10-(3-(dimethylamino)-2-methylpropyl)-10H-
phenothiazine-2-carbonitrile maleate (9)
To a stirred solution of 7 (500 mg, 1.69 mmol, 1.0 equiv) in THF (30 mL)
was added dimethyl sulfate-d6(250 mg, 1.86 mmol, 1.1 equiv) refluxed
at 70 °C about 2 h. Then, the reaction mixture was cooled at 0 °C and
was added a solution of NaOH (200 mg, 5.08 mol, 3.0 equiv) in water
(2.0 mL) followed by dimethyl sulfate-d6(250 mg, 1.86 mmol, 1.1 equiv)
and refluxed the contents about 2 h. When TLC (1:9, MeOH/CH2Cl2)
showed completion of the starting material, the reaction mixture was
cooled at room temperature and diluted with water (50 mL) and
extracted with EtOAc (2 × 50 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure to give
crude, which was purified by silica gel column chromatography to obtain
the tertiary amine, which was stirred in a solution of maleic acid (200 mg,
1.69 mmol, and 1.0 equiv) in ethanol (10 mL) about 30 min. The
precipitated solids were filtered out and dried to afford 9 (0.28 g, 38%)
as pale yellow solid.
1H NMR (300 MHz, CDCl3): δ 7.73–7.70 (m, 2H), 7.63–7.61 (m, 2H), 7.11–
7.04 (m, 3H), 6.99–6.75 (m, 4H), 3.90–3.83 (m, 1H), 3.76–3.69 (m, 1H), 3.66–
3.52 (m, 2H), 2.56–2.47 (m, 1H), 0.99 (d, J = 6.9 Hz, 3H); MS (MM) m/z 426
[M + H]+.
Synthesis of 10-(3-amino-2-methylpropyl)-10H-phenothiazine-2-
carbonitrile (7)
To a stirred solution 6 (6.50 g, 15.3 mmol, 1.0 equiv) in ethanol (100 mL)
was added 35% hydrazine hydrate(20 mL) and stirred under nitrogen
for 70 °C about 4 h. When TLC (3:7, EtOAc/hexanes) showed completion
of the starting material, the reaction mixture was diluted with MTBE
(100 mL), and the precipitated solids were filtered and washed with MTBE
(50 mL). The organic layer was dried over anhydrous Na2SO4 and
concentrated under reduced pressure to afford 7 (4.00 g, 85%) as yellow solid.
1H NMR (300 MHz, DMSO-d6): δ 7.48–7.33 (m, 3H), 7.27–7.17 (m, 2H),
7.11–6.97 (m, 2H), 4.00–3.93 (m, 1H), 3.68–3.61 (m, 1H), 2.64–2.58 (m,
1H), 2.46–2.44 (m, 1H), 1.97–1.86 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H); MS
(MM) m/z 296 [M + H]+.
1H NMR (300MHz, DMSO-d6): δ 9.06 (bs, 1H), 7.53–7.45 (m, 1H), 7.43–7.39
(m, 2H), 7.31–7.23 (m, 2H), 7.15–7.03 (m, 2H), 6.02(s, 2H), 3.98–3.78 (m, 2H),
3.04–2.99 (m, 2H), 2.30–2.29 (m, 1H), 1.03 (d, J= 6.6Hz, 3H); MS (MM) m/z
330 [M+ H]+; HPLC >98%; m.p. 207–209 °C; isotopic abundance >99%.
Synthesis of 10-(3-(dimethylamino)-2-methylpropyl)-10H-phen- Synthesis of tert-butyl (3-(2-cyano-10H-phenothiazin-10-yl)-2-
othiazine-2-carbonitrile maleate (8) methylpropyl)carbamate (10)
To a stirred solution of 7 (500 mg, 1.69 mmol, 1.0 equiv) in THF (50 mL) To a stirred solution of 7 (1.50 g, 5.08 mmol, 1.0 equiv) in CH2Cl2 (25 mL)
was added dimethyl sulfate (250 mg, 1.86 mmol, 1.1 equiv) refluxed at at 0 °C was added triethylamine(1.40 mL, 1.016 mmol, 2.0 equiv) followed
70 °C about 2 h. Then, the reaction mixture was cooled at 0 °C and was by di-tert-butyl dicarbonate (1.10 g, 5.08 mmol, 1.0 equiv) and stirred
added a solution of NaOH (200 mg, 5.08 mmol, 3.0 equiv) in water
(2.0 mL) followed by dimethyl sulfate(0.250 g, 1.86 mmol, 1.1 equiv) and
under nitrogen at room temperature about 3 h. When TLC (2:8, EtOAc/
hexanes) showed completion of the starting material, the reaction
refluxed the contents about 2 h. When TLC (1:9, MeOH/CH2Cl2) showed mixture was diluted with water (50 mL) and extracted with CH2Cl2
completion of the starting material, the reaction mixture was cooled at (2 × 100 mL). The organic layer was dried over anhydrous Na2SO4 and
room temperature and diluted with water (50 mL) and extracted with concentrated under reduced pressure to give crude, which was purified by
EtOAc (2 × 100 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure to give crude, which was
silica gel column chromatography to afford 10 (1.80 g, 90%) as pale yellow oil.
1H NMR (300 MHz, DMSO-d6): δ 7.26–7.15 (m, 4H), 7.05–7.6.99 (m, 2H)7.98,
purified by silica gel column chromatography to obtain the tertiary 6.91–6.88 (m, 1H), 4.80 (bs, 1H), 3.84–3.64 (m, 2H), 3.20–3.05 (m, 2H), 2.30–2.22
amine, which was stirred in a solution of maleic acid (200 mg, 1.69 mmol, (m, 1H), 1.38 (s, 9H), 1.00 (d, J= 6.6 Hz, 3H); MS (MM) m/z 396 [M + H]+.
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R. S. Bolla and I. V. Kasi Viswanath
(m, 1H),3.03–2.97 (m, 1H), 2.86–2.79 (m, 1H), 2.30–2.29 (m, 1H), 0.99
(d, J = 6.6 Hz, 3H); MS (MM) m/z 313 [M + H]+; HPLC >98%; m.p. 205–
206 °C; isotopic abundance >98%.
Synthesis of tert-butyl (3-(2-cyano-10H-phenothiazin-10-yl)-2-
methylpropyl)(methyl)carbamate (11)
To a stirred solution of 60% NaH (330 mg, 8.22 mmol, 2.5 equiv) in DMF
(10 mL) at 0 °C was added compound 10 (1.30 g, 3.29 mmol, 1.0 equiv)
in DMF (5 mL), stirred under nitrogen for 30 min. Then, methyliodide
(0.50 mL, 8.22 mmol, 2.5 equiv) in DMF (10 mL) was added slowly by
maintaining a temperature of 0 °C about 30 min. After completion of
addition, the reaction mixture was brought at room temperature and
stirred about 5 h. When TLC (2:8, EtOAc/hexanes) showed completion
of the starting material, the reaction mixture was diluted with water
(50 mL) and extracted with Methyl tert Butylether (2 × 50 mL). The organic
layer was dried over anhydrous Na2SO4 and concentrated under reduced
pressure to give crude, which was purified by silica gel column
chromatography to afford 11 (1.20 g, 90%) as pale yellow oil.
Results and discussion
The identity and purity of the cyamemazine derivatives synthesized
were confirmed by 1H NMR, MS, and HPLC analyses. After
recrystallization from ethanol, all cyamemazine maleate derivatives
were obtained as pale yellow needles with melting points in the
expected range. The deuterium incorporation in [2H6]cyamemazine
was >99% and in [2H3] monodesmethyl cyamemazine was >98%.
This corresponds well with the reported deuterium abundance for
the labeled starting material (CD3OTs, >98% atom D) and indicates
that there was no loss of deuterium by exchange during the
syntheses. These compounds were considered to be of acceptable
quality for use as internal standards in bio-analytical studies
1H NMR (300 MHz, CDCl3): δ 7.19–7.06 (m, 4H), 6.94–6.91 (m, 2H), 6.81–6.78
(m, 1H), 3.77–3.74 (m, 1H), 3.59–3.52 (m, 1H), 3.29–3.26 (m, 1H), 3.06–3.04
(m, 1H), 2.73 (s, 3H) 2.36–2.26 (m, 1H), 1.37 (s, 9H), 0.91 (d, J=6.6Hz, 3H);
MS (MM) m/z 410 [M + H]+.
Synthesis of 10-(2-methyl-3-(methylamino)propyl)-10H-phenothi-
azine-2-carbonitrile maleate (12)
Conclusion
We have reported a novel procedure for the synthesis of maleate
derivatives of cyamemazine and monodesmethyl cyamemazine.
This was successfully applied in the synthesis of deuterium-
labeled derivatives [2H6]cyamemazine and [2H3]monodesmethyl
cyamemazine maleate.
To a stirred solution of 11 (500 mg, 1.21 mmol, 1.0 equiv) in Methyl tert
Butylether (5 mL) was added 20% solution of HCl in Methyl tert Butylether
(20 mL) at 0 °C and stirred at room temperature about 16 h. The precipitated
solids were filtered and neutralized with sat. NaHCO3 solution (30 mL) and
extracted with EtOAc (2 × 50 mL). The organic layer was dried over anhydrous
Na2SO4 and concentrated under reduced pressure to obtain secondary amine
residue, which was stirred in a solution of maleic acid (140 mg, 1.21 mmol,
1.0equiv) in ethanol (10 mL) about 30 min. The precipitated solids were
filtered out and dried to afford 12 (150 mg, 30%) as pale yellow solid.
1H NMR (300 MHz, DMSO-d6): δ 8.22 (bs, 1H), 7.49–7.39 (m, 3H), 7.30–7.23
(m, 2H), 7.13–7.02 (m, 2H), 6.01(s, 2H), 3.99–3.92 (m, 1H),3.84–3.77
(m, 1H),3.03–2.97 (m, 1H),2.86–2.79 (m, 1H), 2.54 (s, 3H), 2.30–2.29 (m, 1H),
0.99 (d, J= 6.6Hz, 3H); MS (MM) m/z 310 [M + H]+; HPLC >98%; m.p. 203–205 °C.
Acknowledgement
We would like to thank Dr K.R.S. Prasad, Head Department of
Chemistry, KL University, for the valuable guidance, encouragement,
and valuable support.
Conflict of Interest
Synthesis of [2H3] tert-butyl (3-(2-cyano-10H-phenothiazin-10-yl)-
2-methylpropyl)(methyl)carbamate (13)
The authors did not report any conflict of interest.
To a stirred solution of 60% NaOH (130 mg, 3.16 mmol, 2.5 equiv) in DMF
(10 mL) at 0 °C was added compound 10 (500 mg, 1.26 mmol, 1.0 equiv)
in DMF (5 mL), stirred under nitrogen for 30 min. Then, CD3OTs (5.94 g,
3.16mol, 2.5equiv) in DMF (10 mL) was added slowly by maintaining a
temperature of 0 °C about 30 min. After completion of addition, the reaction
mixture was brought at room temperature and stirred about 5 h. When TLC
(2:8, EtOAc/hexanes) showed the completion of the starting material
remains in the reaction mixture, the reaction mixture was diluted with
water (50 mL) and extracted with Methyl tert Butylether (2× 50 mL). The
organic layer was dried over anhydrous Na2SO4 and concentrated under
reduced pressure to give crude, which was purified by silica gel column
chromatography to afford 13 (300 mg, 57%) as pale yellow oil.
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Synthesis of [2H3]10-(2-methyl-3-(methylamino)propyl)-10H-phen-
othiazine-2-carbonitrile maleate (14)
To a stirred solution of 13 (250 mg, 0.605mmol, 1.0 equiv) in Methyl tert
Butylether (5mL) was added 20% solution of HCl in MTBE(10 mL) at 0°C
and stirred at room temperature about 16h. The precipitated solids were
filtered and neutralized with sat. NaHCO3 solution (15 mL) and extracted
with EtOAc (2× 20 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure to obtain secondary amine
residue, which was stirred in a solution of maleic acid (70 mg, 0.605 mmol,
1.0 equiv) in ethanol (5mL) about 30 min. The precipitated solids were
filtered out and dried to afford 14 (70mg, 30%) as pale yellow solid.
1H NMR (300 MHz, DMSO-d6): δ 8.26 (bs, 1H), 7.50–7.39 (m, 3H), 7.31–
b)W. Feng, et al., WO2011113366, 22 Sept. 2011.
Supporting information
Additional supporting information may be found in the online
7.23 (m, 2H), 7.13–7.02 (m, 2H), 6.02(s, 2H), 3.99–3.93 (m, 1H),3.84–3.77 version of this article at the publisher’s web-site.
J. Label Compd. Radiopharm 2014, 57 82–85
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