A practical synthesis of deuterated methylamine and dimethylamine

Article abstract of DOI:10.1177/1747519820969636

In recent years, several deuterated drugs have entered clinical trials and have been approved for use. Deuterated methylamine and dimethylamine as important intermediates play significant roles in the preparation of deuterated drugs. In this study, we have developed a new method to prepare deuterated methylamine and dimethylamine. This method employs Boc-benzylamine as the starting material and TsOCD₃ as the deuterated methylation reagent. Our method gives relatively high yields and involves simple purifications, which provide a favourable supplement for the development and synthesis of deuterated drugs in the future.

Full text of DOI:10.1177/1747519820969636

969636CHL0010.1177/1747519820969636Journal of Chemical ResearchLiu et al.
research-article2020
Research Paper
Journal of Chemical Research
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A practical synthesis of deuterated
methylamine and dimethylamine
https://doi.org/10.1177/1747519820969636
DOI: 10.1177/1747519820969636
journals.sagepub.com/home/chl
Zhaogang Liu1,2, Xiangyu Ren1 and Peng Wang1
Abstract
In recent years, several deuterated drugs have entered clinical trials and have been approved for use. Deuterated
methylamine and dimethylamine as important intermediates play significant roles in the preparation of deuterated drugs.
In this study, we have developed a new method to prepare deuterated methylamine and dimethylamine. This method
employs Boc-benzylamine as the starting material and TsOCD3 as the deuterated methylation reagent. Our method
gives relatively high yields and involves simple purifications, which provide a favourable supplement for the development
and synthesis of deuterated drugs in the future.
Keywords
deuterated drugs, deuteration, dimethylamine, methylamine, methylation
Date received: 27 July 2020; accepted: 9 October 2020
of a single administration while not affecting the pharma-
Introduction
cological activity of the drug.4,5 The first deuterated drug
Deuterated drugs are small molecule drugs in which the
Austedo (deutetrabenazine), (Figure 1) was approved by
hydrogen atoms are replaced by the heavier stable iso-
tope deuterium. In modern clinical medicine, deuterated
drugs play an important role in the field of drug discovery
and disease treatment. Compared with traditional drugs,
deuterated drugs have better metabolic stability and
improved efficacy.1 Moreover, deuteration can slow
down the system clearance rate and prolong the half-life
of the drug in the body.2,3 Therefore, deuterated drugs can
reduce the toxicity and side effects by reducing the dose
1School of Engineering, China Pharmaceutical University, Nanjing, P.R.
of China
2Jiangsu Simcere Pharmaceutical Company, Nanjing, P.R. of China
Corresponding author:
Peng Wang, School of Engineering, China Pharmaceutical University,
Nanjing 210009, P.R. of China.
Email: wangpeng@cpu.edu.cn
Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons
Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,
reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and
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2
Journal of Chemical Research 00(0)
N
N
N
O
D
3C CD3
O
O
D
D
3C
3C
N
D
3C
HN
O
N
N
O
N
N
D
3C
N
H
N
H
O
N
N
F
N
N
N
H
F
deutetrabenazine
BMS-986165
CTP-354
O
N
H
D
CF3
O
D
D
N
Cl
O
D
N
N
D
N
N
O
H
N
N
N
H
N
H
N
H
Donafinil
VX-984
Figure 1. The chemical structures of deuterium-containing drugs.
the US Food and Drug Administration (FDA) in 2017 for the nucleophilic substitution reaction between the amine
the treatment of involuntary movements or chorea in and deuteroiodomethane is relatively low due to the high
patients with Huntington’s disease.6 Many pharmaceuti- activity of deuteroiodomethane. The amino compounds can
cal companies and research institutions have committed go on to react with the deuterated methylation reagent to
to the development of deuterium-containing drugs. form a mixture of secondary, tertiary, and quaternary
Several deuterium-containing drugs have entered clinical ammonium salts. Furthermore, the reductive amination of
trials, such as BMS-986165, VX-984, and CTP-354.7–9 formaldehyde is another efficient and feasible method;
Recently, the clinical study of Donafinil showed signifi- however, this method did not lead to deuterated methyl-
cant overall survival in the treatment of advanced hepato- amine and dimethylamine because deuterated formalde-
cellular carcinoma, and this new drug application was hyde is difficult to obtain and very expensive.16 Hence,
formally accepted by the State Food and Drug Adminis- there is a requirement to develop a new approach to the
tration of China in May 2020.
synthesis of deuterated methylamine and dimethylamine.
In this study, we report a novel synthetic method towards
Among these deuterium drugs, the deuteration of methyl
groups is a common method in the design of deuterated deuterated methylamine and dimethylamine. Boc-protected
drugs.10 Taking the JAK inhibitor BMS-986165 as an exam- benzylamine as the starting material, reacted with the deu-
ple, it exhibits a unique ability to selectively bind to the pseu- terated methylation reagent TsOCD3 at low temperature in
dokinase (JH2) domain of tyrosine kinase 2 (TYK2) and the presence of NaH or n-butyllithium. Next, the Boc and
inhibits the TYK2 function through an allosteric mecha- benzyl protecting groups were removed to afford the tar-
nism.11 The deuteration of the N-methyl group was shown to geted deuterated methylamine and dimethylamine. This
slow down the generation of a less selective primary amide novel method exhibits relatively high yields, a simple oper-
metabolite in vivo by suppressing an N-demethylation meta- ation, and satisfactory purity.
bolic pathway via a deuterium kinetic isotope effect
(DKIE).11 Similarly, Donafinil was designed from Sorafenib
Results and discussion
with a deuteriated methyl group. From the structures of
BMS-986165 and Donafinil, we find that deuterated methyl- Initially, we attempted to synthesize deuterated methyl-
amine and dimethylamine, as the important intermediates, amine by utilizing benzylamine as the starting material and
play significant roles in the preparation of deuterated drugs. n-butyllithium as a strong base. Although there were no ter-
Generally, methylation of amino compounds can be tiary amine or quaternary ammonium salt by-products, the
achieved by nucleophilic substitution reactions with methyl yield of deuterated methylamine was relatively low. Next,
iodide12 or by reductive amination with aldehydes.13,14 we selected Boc-benzylamine as the starting material for
Therefore, the deuterated methylation of amino compounds the reaction. As shown in Scheme 1, Boc-benzylamine
can be achieved with deuterated methylating agents such as reacted with TsOCD3 to give intermediate 2 quantitatively
deuteroiodomethane and TsOCD3.15 However, the purity of in the presence of sodium hydride. The hydrochloride form

Liu et al.
3
H
N
Boc
HN
Boc
N
D
3C
D
3C
H
2, 5% Pd/C
CH3OH, 40 oC
NaH, DMF
3 M HCl/EtOAc
rt
.
.
NH2
HCl
HCl
D
3C
TsOCD
3, rt
4
2
1
3
96%
100%
100%
H
N
CD3
N
D
3C
D
3C
CD3
NH
n-BuLi /THF
TsOCD
oC~rt
H
2, 5% Pd/C
CH3OH, 40 oC
.
.
HCl
HCl
.
HCl
D
3C
3, -20
3
6
5
91%
100%
Scheme 1. The synthetic routes to deuterated methylamine hydrochloride 4 and deuterated dimethylamine hydrochloride 6.
of deuterated N-methylbenzylamine 3 was obtained by NMR spectrometer in CDCl3 or dimethyl sulfoxide
removal of the Boc group under acidic conditions. Finally, (DMSO)-d6. The chemical shifts are reported in δ (ppm)
considering that methylamine and dimethylamine are gase- relative to tetramethylsilane (TMS) as the internal standard.
ous at normal temperature and pressure, deuterated methyl- Electrospray ionization mass spectrometry (ESI-MS) spectra
amine hydrochloride 4 was obtained by removing the were recorded on a Thermo MSQ PLUS mass spectrometer.
benzyl group of compound 3 in the presence of Pd/C.
High-resolution mass spectroscopy (HRMS) spectra were
Similar to the deuterated methylamine hydrochloride 4, obtained on a Bruker Solarix 94 FT mass spectrometer.
deuterated dimethylamine hydrochloride 6 was synthesized
from intermediate 3. Reaction of compound 3 with n-butyl- tert-Butyl benzyl(methyl-d3)carbamate (2). At 0 ℃, com-
lithium and TsOCD3 afforded compound 5. After the subse- pound 1 (24.12 mmol) was added to dimethylformamide
quent hydrogenation was completed, Pd/C was removed by (DMF) (25 mL) under a nitrogen atmosphere. Next, NaH
filtration. Finally, the filtrate was concentrated to afford (60% in mineral oil, 26.54 mmol) was added dropwise to
deuterated dimethylamine hydrochloride 6.
the solution, and after 30 min, TsOCD3 (24.12 mmol) in
DMF (5 mL) was added dropwise. The reaction mixture
was warmed to room temperature. After completion of
the reaction as determined by thin layer chromatography
(TLC) analysis, the reaction was quenched with satu-
rated ammonium chloride (40 mL) at room temperature.
The organic layer was separated and the aqueous layer
was extracted with EtOAc (3 × 50 mL). The combined
organic layers were dried over anhydrous Na2SO4, fil-
tered, and evaporated to obtain the crude product. Com-
pound 2 was obtained by flash chromatography over
silica gel (EtOAc: petroleum ether, 1:10). Yield 96%. 1H
NMR (400 MHz, CDCl3): δ 1.47 (s, 9H, -CH3), 4.41 (s,
2H, -CH2), 7.23–7.35 (m, 5H, -ArH); 13C NMR (100
MHz, CDCl3): δ 28.5, 51.9, 52.5, 79.1, 127.2, 127.7,
128.5, 138.1.
Conclusion
Deuterated methylamine and deuterated dimethylamine are
important deuterated intermediates that are employed in the
synthesis of various deuterated drug molecules. Convenient
and controllable methods for synthesizing deuterated meth-
ylamine and dimethylamine are of great significance. In
this study, an efficient and practical route conducive to the
reduction of production costs of deuterium methylamine
hydrochloride and deuterium dimethylamine hydrochloride
is described. This novel method exhibits relatively high
yields, a simple operation, and satisfactory purity.
Experimental
N-Benzylmethan-d3-amine hydrochloride (3). Compound 2
(12.06 mmol) in EtOAc was added dropwise to a solution
Materials and instruments
All chemicals and reagents used in this work were of analyti- of HCl/EtOAc (3 M, 15 mL) at 0 ℃. The reaction mixture
cal grade and obtained from commercial suppliers without was warmed to room temperature and a completion of the
further purification. 1H nuclear magnetic resonance (NMR) reaction as determined by TLC analysis, the mixture was
and 13C NMR spectra were recorded on a Bruker AM-400 concentrated to afford the hydrochloride of compound 3

4
Journal of Chemical Research 00(0)
(12.06 mmol, yield 100%).17 1H NMR (400 MHz, D2O): δ Declaration of conflicting interests
4.08 (s, 2H, -CH2), 7.36–7.39 (m, 5H, -ArH); 13C NMR
The author(s) declared no potential conflicts of interest with
(100 MHz, D2O): δ 31.4, 52.2, 129.2, 129.6, 129.7, 130.7.
HRMS(ESI): m/z [M+H]+ calcd for C8H8D3N: 125.1158;
found: 125.1152.
respect to the research, authorship, and/or publication of this
article.
Funding
Methan-d3-amine hydrochloride (4). Compound 3 (12.06
mmol) and 5% Pd/C (200 mg) were added to 25 mL of
MeOH under a hydrogen atmosphere. The reaction was
heated to 40 ℃, After completion of the reaction as deter-
mined by TLC analysis, the reaction mixture was filtered
and evaporated to obtain compound 4 (12.06 mmol, yield
100%).18 1H NMR (400 MHz, DMSO-d6):δ 8.10 (s, 2H,
-NH2); 13C NMR (100 MHz, DMSO-d6): δ: 23.5.
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
Peng Wang
https://orcid.org/0000-0003-2359-908X
Supplemental material
The Supporting Information is available free of charge at HRMS
spectrum and 1H and 13C (PDF).
N-benzyl-N-(methyl-d3)methanamine-d3 hydrochloride (5). At
-20℃, N-benzylmethan-d3-amine hydrochloride 3 (16.10
mmol) was added in 16 mL of anhydrous tetrahydrofuran
(THF) under a nitrogen atmosphere. Next, n-butyllithium
(16.10 mmol) was added dropwise to the solution, and after
30 min, TsOCD3 (16.10 mmol) in anhydrous THF (20 mL)
was added dropwise. The reaction was stirred for another
30 min. Then the reaction mixture was warmed to room
temperature and reacted overnight. After completion of the
reaction as determined by TLC analysis, the mixture was
quenched with saturated ammonium chloride (20 mL) at
room temperature. The organic layer was separated and the
aqueous layer was extracted with EtOAc (3 × 30 mL). The
combined organic layers were dried over anhydrous
Na2SO4, filtered, and evaporated to obtain the crude prod-
uct. After purified by flash chromatography over silica gel
(CH2Cl2: MeOH 20:1), the obtained compound was dis-
solved in 15 mL of EtOH. Then HCl/EtOH (3 M, 2 mL)
was added to the solution. After removing the solvents,
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1
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