Syntheses of stable-isotope labeled [M + 7] and [M + 6] 2-(methylamino)imidazole

Article abstract of DOI:10.1002/jlcr.625

Stable isotope-labeled 2-methylaminoimidazole (M + 7 and M + 6) was required as an intermediate in the synthesis of mass labeled drug candidates. These two isotopomers were synthesized with total yields of 24 and 36%, respectively. Labeled 2-aminoimidazol

Full text of DOI:10.1002/jlcr.625

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2002; 45: 1055–1064.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.625
Syntheses of stable-isotope labeled [M+7]
and [M+6] 2-(methylamino)imidazole
Yinsheng Zhang*
Radiochemistry Group, Chemical R&D, Pfizer Global R&D,
Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
Summary
Stable isotope-labeled 2-methylaminoimidazole (M+7 and M+6) was
required as an intermediate in the synthesis of mass labeled drug candidates.
These two isotopomers were synthesized with total yields of 24 and 36%,
respectively. Labeled 2-aminoimidazole (M+4) was prepared from labeled
isothiourea (M+3) and 2-aminoacetaldehyde dimethyl acetal (M+1 and
M+2). The (M+1) version of 2-aminoacetaldehyde dimethyl acetal was
obtained in two steps starting with potassium [15N]phthalimide, while the
(M+2) version was prepared from the reduction of diethoxyacetamide with
LiAlD4. Two different approaches for the preparation of 2-methylaminoimi-
dazole from aminoimidazole were explored. Attempts to prepare protected
2-aminoimidazole to couple with CH3I (M+4) to form the desired labeled
2-methyl-aminoimidazole failed. However, methylation was achieved by
applying N-formamidation followed by deutero-reduction. These successful
syntheses allowed us to selectively label with nitrogen, carbon or hydrogen
isotopes at most of the positions of 2-methylaminoimidazole.
Copyright # 2002 John Wiley & Sons, Ltd.
Key Words: 2-[13C,2H2]Methyl[15N]amino[2-13C–1,3-15N2]imidazole; 2-[2H2]-
methyl[15N]amino[2-13C-1-15N-3-2H]imidazole; N-1H-[2-13C,1,3-15N2] Imida-
zol-2-yl-[13C,15N]formamide; N-1H-[2-13C,4-2H,1,3-15N2]Imidazol-2-yl-forma-
mide; [13C,15N2]thiourea
*Correspondence to: Y. Zhang, Radiochemistry Group, Chemical R&D, Pfizer Global R&D,
Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
E-mail: yinsheng.zhang@pfizer.com
Copyright # 2002 John Wiley & Sons, Ltd.
Received 27 August 2001
Revised 2 April 2002
Accepted 9 May 2002

1056
Y. ZHANG
Introduction
Stable isotope-labeled 2-methylaminoimidazole was required as an
intermediate in the synthesis of mass labeled drug candidates. In this
paper we wish to report efficient syntheses of 2-[13C, 2H2]methyl-
[15N]amino-[2-13C –1,3-15N2]imidazole HCl salt 14 (M+7) and 2-
[2H2]methyl-[15N]amino-[2-13C-1-15N-4-2H]imidazole HCl salt 20
(M+6).
The syntheses of stable isotope-labeled 2-methylaminoimidazole and
2-aminoimidazole were not reported in the literature before, although
unlabeled 2-aminoimidazole was prepared from S-methylisothiourea
and 2-aminoacetaldehyde dimethyl acetal.1 Considering the supply of
labeled starting materials, two routes to synthesize isotope-labeled 2-
methylaminoimidazole (M+7 and M+6) were proposed and studied
(Scheme 1).
R
Protection
reagents
NH
1) CH I/Base
3
+
2) H O
3
MeO
MeO
N
N R
NH
2
CH NH
2 2
HX
SR
CH
R-X
3
HN
Route I
H N
2
NH
4
N
NH
S
H N
2
H N
2
N
NH
Route II
O
1
2
3
6
NH
NH
H
O
O
BH or LiAlH
3
4
H
O
N
5
Scheme 1. Two possible synthetic approaches to 2-(methylamino)imidazole
Results and discussion
An initial thought was to introduce relatively cheap 13CD3I into 2-
aminoimidazole (Route I, Scheme 1), so that the mass of the methylated
molecule could be increased by 4 units. In order to achieve the goal, the
amino group at the 2 position of imidazole must be activated, while the
amino group in the imidazole ring must be protected. There are several
general methods to introduce a methyl group into a protected amine.2–5
However, most of them are not suitable for making 2-methylaminoi-
midazole from 2-aminoimidazole since the two amino groups give rise
to non-selective methylation.
Protection of imidazole 3 was unsuccessful using t-butyldimethylsilyl
chloride (excess), isobutyl or ethyl chloroformate, or 2-nitrobenzene-
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 1055–1064

SYNTHESES OF STABLE-ISOTOPE
1057
sulfonyl chloride. The treatment of imidazole 3 with excess t-
butyldimethylsilyl chloride only provided mono substituted compound.
The further methylation by MeI in the presence of n-BuLi gave an
undesired 1-methyl-2-aminoimidazole. From the reaction of imidazole 3
with isobutyl chloroformate, a mono N1-substituted compound as a
major by-product was separated in 59% yield. With excess other
reagents, such as ethyl chloroformate and 2-nitrobenzene-sulfonyl
chloride, the reactions afforded a complicated mixture. Considering
the difficulties in preparing a suitable protected imidazole for
methylation by MeI, an alternate route (Route II, Scheme 1) involving
N-formamidation and reduction was studied. Our investigation showed
that the formamidation of 2-aminoimidazole with acetic formic
anhydride provided only 2-formamidoimidazole 5 in good yield.6
Reduction of 2-formamidoimidazole 5 with BH3THF afforded the
desired 2-methylaminoimidazole 6 in high yield.
The entire synthesis of the title compound (M+7) using Route II is
shown in Scheme 2. By using acetamide as solvent instead of DMF in
the N-alkylation of potassium [15N]phthalimide with chloroacetalde-
hyde dimethyl acetal, we were able to obtain product 8 in 86% yield (vs
59% with DMF). Hydrolysis of compound 8 with 20% KOH solution
afforded 2-[15N]aminoacetaldehyde dimethyl acetal 9 with high purity
and yield (84%). Initially, [13C, 15N2]S-methylisothiourea 2a was
synthesized by the treatment of [13C, 15N2]thiourea 1 with methyl
iodide. Compound 2a was then heated with 2-[15N]aminoacetaldehyde
dimethyl acetal in water followed by the treatment with concentrated
H2SO4 to obtain 2-[13C,15N3]aminoimidazole in 30% yield.1 However,
changing reagents from MeI to EtBr, and solvents from H2O to EtOH
allowed us to achieve a higher yield of 2-[13C, 15N3]aminoimidazole 11
(50% vs. 30%). The reaction of 2-[13C, 15N3]aminoimidazole 11 with
mixed anhydride 12 derived from 95% [13C]formic acid in the presence
of MgSO4 provided 2-[13C2, 15N3]formamidoimidazole 13 in 80% yield.
Compound 13 was then reduced using BD3THF to provide the desired
product 14 as the HCl salt in 80% yield.
The synthesis of the (M+6) mass version of 2-methylaminoimidazole
20 is shown in Scheme 3. Commercially available diethoxyacetamide 15
was reduced with LiAlD4 to form 2-amino-[2-2H2]acetaldehyde diethyl
acetal 16 in 98% yield by a modified known procedure.7 The latter was
heated with [13C, 15N2]S-ethylisothiourea in water first and then further
treated with concentrated HCl instead of concentrated H2SO4. The
treatment with HCl provided the desired product in a higher yield
Copyright # 2002 John Wiley & Sons, Ltd.
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1058
Y. ZHANG
MeO
MeO
O
O
CH Cl
2
MeO
MeO
20% KOH
84%
*
NCH CH(OMe)
CH NH
2 2
*
2
2
NK
*
MeCONH /KI
2
O
O
9
8
7
86%
1) MeI/H2O
or
2) EtBr/EtOH
HBr
SR
*
*
HN
H N
2
H O
2
S
*
H N
2
*
H N
2
*
*
1
2a R=Me, 2b R=Et
O
80%
1) NH (gas)
*
*
NH
2
NH
HBr
*
H
*
H SO
2
3
4
HN
*
*
*
*
*
*
N
NH
NHCH CH(OMe)
2
*
2
N
NH
*
H N
2
2) HC*CO Ac
2
50%
H SO
2
*
4
12
10
13
11
1) BH -THF
3
2) HCl
80%
*
HD C
2
HCl
C* = 13C, N* = 15
N
NH
*
*
*
*
N
NH
14
Scheme 2. Synthesis of 2-(methylamino)imidazole (M+7)
O
D
D
H O
HBr
NHCD CH(OMe)
*
2
LIAlD
98%
4
EtO
HN
EtO
NH
NH
2
2
2
2
*
HBr
SEt
H N
2
*
OEt
OEt
15
HN
*
16
17
*
H N
2
*
2b
60%
HCl
O
HD C
1) NH (gas)
2
3
*
1) BH -THF
3
2) HCl
*
NH
2
NH
NH
*
HCl
H
2) HCO Ac
2
HCl
*
*
*
*
NH
*
*
N
N
NH
N
NH
80%
85%
D
D
D
18
20
19
Scheme 3. Synthesis of 2-(methylamino)imidazole (M+6)
Copyright # 2002 John Wiley & Sons, Ltd.
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SYNTHESES OF STABLE-ISOTOPE
1059
2
(60%) of [13C, H, 15N2]2-aminoimidazole hydrochloride 18 than the
H2SO4 treatment. The formamidation and reduction reactions of
compound 18 were carried out applying the same procedures as for
the preparation of compound 14. The final compound 20 was easily
isolated as a HCl salt by the addition of 1 M HCl in ether to the free
base of 20.
Experimental
All reactions were carried out under an atmosphere of nitrogen unless
1
otherwise stated. H and 13C NMR spectra were recorded on a Varian
Gemini 200 or 400 MHz. Chemical purity of all labeled compounds was
determined by HPLC and GC-MS or LC-MS. Purifications were done
by flash column chromatography on Biotage Flash 40 system. LiAlD4
(98 at% D), and BD3-THF (1 M, 99 at% D) were purchased from
Cambridge Isotope Lab. [15N] potassium phthalimide (98 at% 15N),
[13C, 15N2]thiourea (99 at% 13C, 99 at% 15N) and [13C]formic acid
(95–96%, 99 at% 13C) were purchased from Isotec. All prepared stable-
isotope labeled compounds contained less, 0.1% of unlabeled material
based on LC-MS analysis, unless otherwise stated.
N-(1,1-Dimethoxylethyl-[15N]phthalimide 8
%
A mixture of acetamide (26.0 g, 440 mmol), potassium iodide (7.50 g,
45 mmol) and [15N] potassium phthalimide (10.15 g, 54.5 mmol) was
heated to 1108C with stirring. To this suspension was added slowly
chloroacetaldehyde dimethyl acetal (7.0 ml, 61.5 mmol) for 40 min. The
reaction temperature was raised to 1508C for 1 h. The mixture was
stirred at 1508C for another 1 h. After the reaction mixture was cooled
to room temperature, water (50 ml) was added to the mixture. The off-
white solid product 8 was collected by filtration, washed with water
1
(3 ꢀ 5 ml), and dried under vacuum (11.09 g, 86%). M.P. 98–1008C; H
NMR (CDCl3) d 7.87-7.82 (m, 2H), 7.73-7.69 (m, 2H), 4.76 (t,
J ¼ 5:82 Hz, 1H), 3.81 (dd, J ¼ 1:11 Hz, J ¼ 5:68 Hz, 2H) 3.37 (s,
6H); 13C NMR (CDCl3) d 168.52 (d, J ¼ 12:7 Hz), 134.49, 132.50 (d,
J ¼ 7:9 Hz), 123.84, 100.50, 53.68, 39.25 (d, J ¼ 10:4 Hz); MS (ESI):
237 [(M+1)+1], 236, 205, 147, [M+0]51%.
Copyright # 2002 John Wiley & Sons, Ltd.
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Y. ZHANG
[15N]Aminoacetaldehyde dimethyl acetal 9
%
Compound 8 (7.0 g, 29.7 mmol) was suspended in KOH aqueous
solution (20%, 100 ml), and heated at 1008C for 2 h. After cooling to
room temperature, the reaction mixture was extracted with CHCl3
(5 ꢀ 15 ml). The CHCl3 extracts were washed with brine (10 ml), and
dried over MgSO4. The solvent was evaporated under vacuum to give
[15N]aminoacetaldehyde dimethyl acetal 9 as a colorless liquid (2.65 g,
1
84%). H NMR (CDCl3) d 4.28 (t, J ¼ 5:13 Hz, 1H), 3.38 (s, 6H), 3.77
(dd, J ¼ 5:13 Hz, J ¼ 1:06 Hz, 2H), 1.15 (2H); 13C NMR (CDCl3)
d 106.27, 54.50, 44.14 (d, J ¼ 3:8 Hz); MS (ESI): 107 [(M+1)+1].
S-Ethyl-[13C, 15N2]isothiouronim 2b
A suspension of [13C, 15N2]thiourea (2.0 g, 25.3 mmol) in EtOH (20 ml)
and bromoethane (16 ml) was heated at 558C for 5 h to form a clear
solution. Additional bromoethane (16 ml) was added, and the mixture
was stirred overnight at 558C. The solution was cooled to room
temperature, and then poured into 500 ml of dry ether with stirring. The
oily residue solidified after cooling in an ice bath. The precipitate was
filtered off and washed with cold ether (2 ꢀ 10 ml) to give S-ethyl-[13C,
15N2]isothiouronim 2b as white crystals (4.54 g, 96%). M.P. 88-908C; 1H
NMR (DMSO-d6) d 9.26 (bd, J ¼ 15:2 Hz, 2H), 8.81 (bd, J ¼ 8:43 Hz,
2H), 3.43-3.13 (m, 2H), 1.27 (t, 3H, J ¼ 7:33 Hz); 13C NMR (DMSO-
d6) d 170.09 (t, J ¼ 17:0 Hz), 25.04, 14.34 (d, J ¼ 1:8 Hz); MS (ESI): 108
[(M+3)+1].
[13C, 15N]2-Aminoimidazole hydrosulfate 11
To a solution of S-ethyl-[13C, 15N2]isothiouronim 2b (2.875 g,
15.4 mmol) in water (10 ml) was added [15N] aminoacetaldehyde
dimethyl acetal 9 (1.689 g, 15.5 mmol). The mixture was heated at
908C for 1.5 h, and then distilled to remove EtSH. Water (10 ml) was
added to the residue. The aqueous phase was extracted with CHCl3
(3 ꢀ 10 ml), and evaporated and dried under vacuum to give crude
N-(2,2-dimethyloxyethyl)guanidine hydrobromide 10 as a glassy semi-
solid (3.512 g). 1H NMR (DMSO-d6) d 4.481 (t, 1H), 3.33 (s, 6H), 3.274
(t, 2H); 13C NMR (DMSO-d6) d 157.33 (q, J ¼ 21:2 Hz), 101.81, 54.26,
42.78 (d, J ¼ 10:5 Hz); MS (ESI): 152 [(M+3)+1], 120, 102.
Copyright # 2002 John Wiley & Sons, Ltd.
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SYNTHESES OF STABLE-ISOTOPE
1061
This crude product was dissolved in water (50 ml) and concentrated
H2SO4 (1.0 ml), and heated at 1108C for 40 min. The mixture was
evaporated with EtOH (3 ꢀ 5 ml) and dried under vacuum to give [13C,
15N3]2-aminoimidazole H2SO4 salt 11 as a semi-solid (1.42 g, 50%),
1
which was used for the next reaction without further purification. H
NMR (DMSO-d6/TFA) d 6.85 (m, 2H); 13C NMR d 147.19 (q,
J ¼ 20:80 Hz), 113.60 (m); MS (ESI): 88 [(M+4) +1].
N-1H-[2-13C, 1,3-15N2]Imidazol-2-yl-[13C, 15N]formamide 13
To acetic anhydride (2.0 ml) was added [13C]formic acid (95–96%,
0.8 ml) and MgSO4 (0.2 g) at 08C. The resulting suspension was warmed
to 508C, and stirred for 5 h. After cooling to room temperature,
the anhydride 12 was used in the following reaction without
purification.
2-[13C, 15N3]Aminoimidazole H2SO4 salt 11 (crude, 2.85 g, ca.
15 mmol) was suspended in a mixture of THF and MeOH (40 ml/
5 ml). Dry NH3 gas was passed through the suspension for 2 h. The
precipitate was removed by filtration and the filtrate was concentrated
under vacuum to give free 2-[13C, 15N3]aminoimidazole. To a solution
of [13C]acetic formic anhydride in dry THF (10 ml) was added a solution
of 2-[13C, 15N3]aminoimidazole in THF (40 ml). The mixture was stirred
at room temperature for 25 h, and then concentrated to dryness. The
residue was dissolved in water (18 ml), and extracted with ether (10 ml)
and CHCl3 (10 ml). The aqueous solution was evaporated under
vacuum to form about 10 ml of solution, which was neutralized (pH
7) with saturated aqueous K2CO3 solution. The resulting solid was
collected by filtration. Drying under vacuum afforded N-1H-[2-13C,
1,3-15N2]imidazol-2-yl-[13C, 15N]formamide 13 (1.39 g, 80%). M.P. 203-
1
2058C; H NMR (DMSO-d6/TFA) d 8.515 (dq, 1H, JN2C ¼ 207 Hz,
JC2N2C ¼ 9:44 Hz), 7.321 (m, 2H) [1H NMR for unlabeled compound
(DMSO-d6/TFA) d 8.20 (br S, 1H), 6.70 (S, 2H)]; 13C NMR (DMSO-
d6/TFA) d 160.84 (d, J ¼ 9:1 Hz), 137.22 (q, J ¼ 21:3 Hz), 115.10 (m);
MS (ESI): 117 [(M+5)+1], 115, 108.
2
2-[13C, H2]Methyl[15N]amino[2-13C –1,3-15N2]imidazole HCl salt 14
To a cold suspension of [13C2, 15N3]2-formamidoimidazole 13 (0.330 g,
2.84 mmol) was injected a solution of BD3THF (1 M, 5.6 ml, 5.6 mmol)
for 30 min at 0–28C. The resulting suspension was warmed to room
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Y. ZHANG
temperature, and stirred overnight. After the reaction mixture was
cooled to 08C, MeOH (anhydrous, 8 ml) was added. The reaction
solution was adjusted to pH=2 by adding a solution of 2 M HCl in
MeOH. The solution was then heated to reflux for 3 h. After cooling, the
mixture was filtered through Celite and concentrated under vacuum.
The oily residue was repeatedly concentrated under vacuum from
methanol (3 ꢀ 5 ml) and then dissolved in ethyl acetate (10 ml). A dry
solution of 1 M HCl in ether was added to the mixture to afford 2-[13C,
2H2]methyl[15N]amino[2-13C –1,3-15N2]imidazole HCl salt 14 as a white
powder (0.318 g, 80%), which was collected by filtration, and dried
1
under vacuum at 408C. M.P. 141–1438C; H NMR (DMSO-d6/TFA) d
7.92 (d, 1H), 6.91 (b, 2 H), 3.53 (dt, 1H) [1H NMR for unlabeled
compound (DMSO-d6/TFA) d 7.90 (d, 1H), 6.90 (S, 2H), 2.8 (d, 3H)];
13C NMR (DMSO-d6/TFA) d 148.03 (q), 113.50 (m), 29.20 (m); MS
(ESI): 105 [(M+7)+1].
[2-2H2]Aminoacetaldehyde diethyl acetal 16
To a suspension of LiAlD4 (10.0 g, 238 mmol) in dry THF (90 ml)
was added dropwise a solution of 2,2-diethoxylacetamide (20.0 g,
135.8 mmol) in dry THF (50 ml) at 08C. The resulting mixture was
stirred at 258C for 30 min, then heated at 758C for 15 h. The mixture
was cooled and quenched with H2O (10 ml), 15% NaOH(10 ml)
and H2O (30 ml). After stirring for 30 min, the mixture was filtered
to remove the white precipitate. The mother liquor was evaporated
to give [2-2H2]aminoacetaldehyde diethyl acetal 16 as a colorless
liquid (18.0 g, 98%). The product was used in the next reaction with-
out further purification. 1H NMR (CDCl3) d 4.39 (s, 1H), 3.68
(m, 2H), 3.3.53 (m, 2H), 1.58 (bs, 2H), 1.20 (t, 6H); C NMR (CDCl3)
104.03, 62.66, 44.12 (t), 15.59; MS (ESI): 136 [(M+2)+1],
[M+0]51%.
2
[13C, H, 15N2]2-Aminoimidazole hydrochloride 18
To a solution of S-ethyl-[13C, 15N2]isothiouronim 2b (18.7 g, 99.5 mmol)
in water (10 ml) was added [2H2] aminoacetaldehyde dimethyl acetal 16
(18.0 g, 133.3 mmol). The mixture was heated at 908C for 1.5 h, and then
distilled to remove EtSH. Water (30 ml) was added to the residue. The
aqueous phase was extracted with CHCl3 (3 ꢀ 10 ml), and evaporated
2
and dried under vacuum to give N-(2,2-dimethyloxyethyl)[13C, H2,
Copyright # 2002 John Wiley & Sons, Ltd.
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SYNTHESES OF STABLE-ISOTOPE
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1
15N2]guanidine hydrobromide 17 as a glassy foam (25.1 g, 98%). H
NMR (DMSO-d6) d 4.52 (s, 1H), 3.60 (m, 2H), 3.46 (m, 2H), 1.09
(t, 6H); 13C NMR (DMSO-d6) d 157.8 (t, J ¼ 21:2 Hz), 119.1 (t), 100.3,
62.8, 15.9; MS (ESI): 181 [(M+5)+1].
This crude product was dissolved in concentrated HCl (40 ml),
and heated at 1108C for 20 min. The mixture was evaporated
under vacuum with EtOH (3 ꢀ 5 ml) to give [13C, 2H, 15N2]2-
aminoimidazole hydrochloride 18 (7.38 g, 60%) as a foam, which
1
was used for the next reaction without further purification. H NMR
(D2O) d 6.82 (bs, 1H); 13C NMR (D2O) d 147.5 (t); MS (ESI): 88
[(M+4)+1].
N-1H-[2-13C, 4-2H, 1,3-15N2]Imidazol-2-yl-formamide 19
The same procedure as for the preparation of N-1H-[2-13C,
1,3-15N2]imidazol-2-yl-[13C, 15N]formamide 13 was followed. From
crude 18 (8 g, 64.8 mmol) product 19 was obtained as a brownish
1
powder (5.96 g, 80%). H NMR (DMSO-d6) d 8.18 (bs, 1H), 6.71 (m,
1H); 13C NMR (DMSO-d6) d 140.5 (bm); MS (ESI): 116 [(M+4)+1].
2
2-[2H2]Methyl[[13C, H, 15N2]aminoimidazole HCl salt 20
The same procedure was followed as for the preparation of 2-[13C, 2H2,
15N]methyl[[13C, 15N2] aminoimidazole HCl salt 14. From 19 (2.0 g,
17.4 mmol) product 20 was obtained as a white solid (2.06 g, 85%). M.P.
1
142–1438C; H NMR (DMSO-d6) d 12.29 (t, 1H), 7.80 (db, 1H), 6.88
(m, 1H), 2.81 (m, 1H); 13C NMR (DMSO-d6) d 148.4 (t); MS (ESI): 104
[(M+6) 1].
Acknowledgements
The author thanks Dr C.C. Huang and Dr Om P. Goel for helpful
discussions and valuable remarks concerning this work.
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Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 1055–1064