Practical synthesis of N-alkyl-N-alkyloxycarbonylaminomethyl prodrug derivatives of acetaminophen, theophylline, and 6-mercaptopurine

Article abstract of DOI:10.1080/00397910600943501

We report a novel synthesis of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of acetaminophen, theophylline, and 6-mercaptopurine by alkylation of the corresponding drug molecule with N-alkyl-N- alkyloxycarbonylaminomethyl chlorides in good yield. Most of the alkylating agents were efficiently synthesized by chloromethylation of N-alkyl carbamic acid alkyl esters, which in turn were made from alkyl amines and alkyl chloroformates. In cases where the alkyl chloroformates were not available, synthesis of N-alkyl carbamic acid alkyl esters was accomplished by converting an alcohol to a chloroformate or to an activated acylating agent such as acyl imidazoles or p-nitrophenylcarbonate esters, followed by their reaction with alkyl amines. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600943501

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Practical Synthesis of
N‐Alkyl‐N‐alkyloxycarbonylaminomethyl
Prodrug Derivatives of Acetaminophen,
Theophylline, and 6‐Mercaptopurine
Susruta Majumdar a & Kenneth B. Sloan a
a Department of Medicinal Chemistry, University of Florida, Gainesville,
Florida, USA
Version of record first published: 24 Nov 2006.
To cite this article: Susruta Majumdar & Kenneth B. Sloan (2006): Practical Synthesis of
N‐Alkyl‐N‐alkyloxycarbonylaminomethyl Prodrug Derivatives of Acetaminophen, Theophylline, and
6‐Mercaptopurine, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:23, 3537-3548
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Synthetic Communicationsw, 36: 3537–3548, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600943501
Practical Synthesis of N-Alkyl-N-
alkyloxycarbonylaminomethyl Prodrug
Derivatives of Acetaminophen,
Theophylline, and 6-Mercaptopurine
Susruta Majumdar and Kenneth B. Sloan
Department of Medicinal Chemistry, University of Florida,
Gainesville, Florida, USA
Abstract: We report a novel synthesis of N-alkyl-N-alkyloxycarbonylaminomethyl
(NANAOCAM) prodrugs of acetaminophen, theophylline, and 6-mercaptopurine by
alkylation of the corresponding drug molecule with N-alkyl-N-alkyloxycarbonylami-
nomethyl chlorides in good yield. Most of the alkylating agents were efficiently syn-
thesized by chloromethylation of N-alkyl carbamic acid alkyl esters, which in turn
were made from alkyl amines and alkyl chloroformates. In cases where the alkyl
chloroformates were not available, synthesis of N-alkyl carbamic acid alkyl esters
was accomplished by converting an alcohol to a chloroformate or to an activated
acylating agent such as acyl imidazoles or p-nitrophenylcarbonate esters, followed
by their reaction with alkyl amines.
Keywords: Prodrugs, acetaminophen, theophylline, 6-mercaptopurine, soft alkyl
INTRODUCTION
Prodrugs are biologically inactive derivatives of a drug that revert to the parent
drug by either enzymatic or chemical hydrolysis. Most prodrugs are esters
because they are easy to make, are economical, yield nontoxic side products,
and are hydrolyzed to the corresponding acid and alcohol (either of which may
be the parent drug) by esterases present in biological organs, tissues, and cells.
Received in the USA May 9, 2006
Address correspondence to Kenneth B. Sloan, Department of Medicinal Chemistry,
University of Florida, Gainesville, FL 32610, USA. E-mail: sloan@cop.ufl.edu
3537

3538
S. Majumdar and K. B. Sloan
Sometimes simple esters (alkyl derivatives of a carboxylic acid) are not
labile, as in the case of penicillin esters.[1] Addition of a CH2O spacer led
to the generation of akylcarbonyloxymethyl (ACOM) or alkyloxycarbonylox-
ymethyl (AOCOM) esters of carboxylic acids. These ACOM and AOCOM
esters are known as soft alkyl prodrugs because they are alkyl derivatives of
the carboxylic acid but can undergo hydrolysis at the alkylcarbonyl or alkylox-
ycarbonyl functional group to leave a hydroxymethyl ester of the carboxylic
acid, which undergoes fast chemical hydrolysis to give the active principle
and formaldehyde.[2–4] Because formaldehyde is normally produced
endogenously by various oxidative demethylation reactions catalyzed by
CYP 450s, low levels of formaldehyde already exist in vivo and low levels
of exogenous formaldehyde should be relatively safe.
NANAOCAM (N-alkyl-N-alkyloxycarbonylaminomethyl, ROCONR0
CH2) derivatives can also be classed as soft alkyl prodrugs. However, the use
of a NANAOCAM promoiety has only been reported for 6-mercaptopurine.[5]
Since then it has been determined that NANAOCAM derivatives of
phenols, carboxylic acids, and 6-mercaptopurine hydrolyse by a SN1 type of
mechanism.[6] We are interested in synthesizing prodrugs that would
increase the absorption of drugs across the skin. 6-Mercaptopurine (6MP),
theophylline (Th), and acetaminophen (APAP) are three drugs whose
permeability across the skin is limited by their poor solubility properties (i.e.,
solubility in a lipid phase and solubility in an aqueous phase).[7] By transiently
masking the hydrogen bonding groups like –SH in 6MP, –NH in Th, and –OH
in APAP, it should be possible to increase their permeability across the skin.[7]
However, the synthesis of the NANAOCAM prodrugs of 6MP generally
gave poor yields of the desired compounds. Here we report different
approaches to their synthesis, which resulted in greatly improved yields.
SYNTHESIS OF ALKYLATING AGENT
The synthesis of NANAOCAM derivatives of APAP, Th, and 6MP involves
the alkylation of the parent drug with N-alkyl-N-alkyloxycarbonylamino-
methyl chloride (NANAOCAM-Cl).
Method A
Siver et al.[5] reported the synthesis of NANAOCAM-Cl in two steps. 1,3,5-
Trialkylhexahydrotriazene was synthesized from an equimolar amount of
alkyl amine and formaldehyde in the presence of NaOH. The 1,3,5-trialkyl-
hexahydrotriazene was treated with 3 equivalents of the appropriate alkyl
chloroformate to generate NANAOCAM-C1 (RO-CO-NR0-CH2-Cl), which
was then used to derive the desired drug (Scheme 1). NANAOCAM-Cl,
R ¼ CH3, R0 ¼ CH3, was obtained in 90% yield using this protocol. We

NANAOCAM Prodrug Derivatives
3539
also found that the reaction of 1,3,5-trialkylhexahydrotriazenes with alkyl
chloroformates in CH2Cl2 gave the corresponding bis-(N-alkyl-N-alkyloxy-
carbonylamino)methanes (NANAOCA)2M, 2, and unreacted alkyl chlorofor-
mate along with the desired NANAOCAM chlorides, 1. The ratio of
(NANAOCA)2M and unreacted alkyl chloroformate to NANAOCAM-Cl
increased as the alkyloxy chain lengths grew longer (e.g., R ¼ C2H5, C3H7,
C4H9) (Table 1). It was difficult to remove these side products by trituration
with hexanes or ether, and distillation was not possible because of decompo-
sition of the products. The yields of the corresponding alkylated prodrugs were
thus compromised because of the formation of acylated products along with
the alkylated ones and the presence of (NANAOCA)2M in the reaction
mixtures. Furthermore, isolation and purification of the desired prodrug by
crystallization or column chromatography was a cumbersome process.
Therefore alternative procedures for the synthesis of NANAOCAM-
chlorides were developed. Characterizations of NANAOCAM-Cl synthesized
by method A and used to alkylate APAP, Th, and 6MP with little contami-
nation by 2 are as follows.
N-Methyl-N-methyloxycarbonylaminomethyl Chloride
Yield ¼ 90%, 1H NMR (CDCl3): d 2.9 (s, 3H), d 3.75 (s, 3H), d 5.3 (s, 2H).
N-Methyl-N-ethyloxycarbonylaminomethyl Chloride
Yield ¼ 89%, 1H NMR (CDCl3): d 1.3 (t, 3H), d 2.9 (s, 3H), d 4.22 (q, 2H),
d 5.33 (s, 2H).
Method B
The synthesis of N-alkyl chloromethylamides has been reported by Moreira
et al.[8] We have extrapolated from that synthesis of tertiary amides to the
synthesis of tertiary carbamates. An alkyl chloroformate was reacted with
alkyl amine in the presence of triethylamine in CH2Cl2 to give
Scheme 1.

3540
S. Majumdar and K. B. Sloan
Table 1. Percentage yields of NANAOCAM-Cl (1) by methods A and B
Structure
Method A
Method B
N-R0
O-R
1
2
3
1
Methyl
Methyl
Methyl
Methyl
Propyl
Butyl
Methyl
Ethyl
90
89
33
17
55
60
35
42
0
0
0
11
49
56
18
22
36
28
Propyl
Butyl
Butyl
18
27
13
12
19
18
85
82
93
92
90
82
Methyl
Propyl
Butyl
Butyl
Butyl
N-alkylcarbamic acid alkyl esters. Chloromethylation of N-alkyl carbamic
acid alkyl ester with paraformaldehyde and trimethylsilyl chloride under
reflux conditions gave the desired NANAOCAM-Cl in excellent yields with
no side products (Scheme 2 and Table 1). A comparison of the yields of the
corresponding prodrug derivatives of APAP, Th, and 6MP using alkylating
agents produced by the two protocols (method A and method B) is shown
in Table 2. In all cases the yields improved substantially using method B
because the reaction mixture containing the alkylating agent was not contami-
nated with any side products. The experimental protocol for the synthesis and
characterization of NANAOCAM-Cl using method B are as follows.
One equivalent of triethylamine (0.033 mol) and alkyl amine (0.033 mol)
was added dropwise to a solution of alkyl chloroformate (0.033 mol) in 75 mL
of CH2Cl2 cooled with an ice bath. The reaction mixture was allowed to warm
to room temperature and stirred overnight. The clear solution was washed
with 3 ꢀ 10 mL of brine, and the organic layer was dried over Na2SO4,
then concentrated to an oil. This oil was purified by trituration with hexane
overnight. The suspension was filtered and the filtrate evaporated to give
the corresponding N-alkyl carbamic acid alkyl ester as a yellow oil. A
mixture of N-alkyl carbamic acid alkyl ester (0.02 mol), 1.7 equivalents of
paraformaldehyde (0.034 mol), and 13 equivalents of trimethylsilyl chloride

NANAOCAM Prodrug Derivatives
3541
Scheme 2.
(0.26 mol) was refluxed for 2.5 h over an oil bath using a CaCl2 drying tube
and a water-cooled reflux condenser. The suspension was diluted with
50 mL of CH2Cl2 and filtered to get rid of unreacted paraformaldehyde. The
clear filterate was concentrated using a rotavapor at 408C under reduced
pressure. The yellow oil obtained was triturated with hexane overnight, the
white suspension was filtered, and the filtrate was concentrated to give the
desired alkylating agent.
N-Methyl-N-propyloxycarbonylaminomethyl chloride: yield ¼ 85%, 1H
NMR (CDCl3): d 0.97 (t, 3H), d 1.7 (m, 2H), d 3.0 (s, 3H), d 4.12 (t, 2H),
d 5.35 (s, 2H).
Table 2. Percent yields of NANAOCAM derivatives by methods A and B and routes
A, B and C
Structure
N-R0
Yields of prodrugs (%)
Drug
O-R
Method A Method B Route A Route B Route C
APAP Methyl Methyl
APAP Methyl Ethyl
APAP Methyl Propyl
APAP Methyl Butyl
APAP Methyl Hexyl
70
65
28
7
76
66
33
39
63
77
45
59
Th
Th
Methyl Methyl
Methyl Ethyl
Methyl Propyl
Methyl Butyl
Methyl Hexyl
Propyl Butyl
73
84
46
33
Th
Th
80
71
Th
6MP
6MP
6MP
6MP
25
26
5
78
57
68
77
Butyl
Butyl
Butyl
Methyl
Propyl
Butyl
16

3542
S. Majumdar and K. B. Sloan
N-Methyl-N-butyloxycarbonylaminomethyl chloride: yield ¼ 82%, 1H NMR
(CDCl3): d 0.95 (t, 3H), d 1.41 (m, 2H), d 1.65 (m, 2H), d 3.0 (s, 3H), d 4.17 (t,
2H), d 5.33 (s, 2H).
1
N-Propyl-N-butyloxycarbonylaminomethyl chloride: yield ¼ 93%, H NMR
(CDCl3): d 0.90–0.95 (2t, 6H), d 1.41 (m, 2H), d 1.65 (m, 4H), d 3.35
(t, 2H), d 4.17 (t, 2H), d 5.33 (s, 2H).
N-Butyl-N-methyloxycarbonylaminomethyl chloride: yield ¼ 92%, 1H NMR
(CDCl3): d 0.94 (t, 3H), d 1.35 (m, 2H), d 1.59 (quintet, 2H), d 3.36 (t, 2H),
d 3.78 (s, 3H), d 5.33 (s, 2H).
1
N-Butyl-N-propyloxycarbonylaminomethyl chloride: yield ¼ 90%, H NMR
(CDCl3): d 0.92 (2m, 6H), d 1.32 (m, 2H), d 1.6–1.71 (2m, 4H), d 3.37 (t, 2H),
d 4.12 (t, 2H), d 5.33 (s, 2H).
1
N-Butyl-N-butyloxycarbonylaminomethyl chloride: yield ¼ 82%, H NMR
(CDCl3): d 0.94 (m, 6H), d 1.3–1.36 (2m, 4H), d 1.57–1.65 (2m, 4H), d
3.36 (t, 2H), d 4.16 (t, 2H), d 5.32 (s, 2H).
Since methods A and B rely on the availability of alkyl chloroformates,
other methods of making the chloroformate (route A) and activated
acylating agents (routes B and C) were evaluated (Scheme 3). Routes A, B,
and C illustrate alternate ways of synthesizing N-alkyl carbamic acid alkyl
ester from an alcohol. The N-alkyl carbamic acid alkyl ester can then be
converted to NANAOCAM-Cl using method B. We chose hexanol as our
model alcohol for this purpose. A comparison of the yields obtained of the
corresponding prodrug derivatives are reported in Table 2.
Route A
This method relies on the conversion of an alcohol to chloroformate. The
chloroformate generated in situ is then reacted with alkyl amine to generate
N-alkyl carbamic acid alkyl ester. The experimental protocol and characteriz-
ation of NANAOCAM-Cl follows.
To an equivalent of triphosgene (2.96 g, 0.01 mol) in 140 mL of CH2Cl2
cooled with an ice bath, was added 3 equivalents of hexanol (3.06 g, 0.03 mol)
and 3 equivalents triethylamine (3.03 g, 0.03 mol) in 10 mL of CH2Cl2
dropwise over a period of 15 min. The reaction mixture was allowed to
warm to room temperature and stirred overnight. The reaction was again
cooled with an ice bath and reacted with 3 equivalents of triethyl amine
(3.03 g, 0.03 mol) and 3 equivalents of aqueous methyl amine (2.25 g,
0.03 mol). The reaction mixture was stirred overnight, then washed with
10 mL of 1 N HCl and 3 ꢀ 15 mL of water. The CH2Cl2 layer was dried

NANAOCAM Prodrug Derivatives
3543
Scheme 3.
over Na2SO4, then concentrated to give the N-methyl carbamic acid hexyl
ester as an oil. The corresponding NANAOCAM-Cl were made from the
N-methyl carbamic acid hexyl ester by reacting it with trimethylsilyl
chloride and paraformaldehyde as in method B. The alkylating agent was sub-
sequently used to synthesize the desired prodrug (Scheme 3).
N-Methyl-N-hexyloxycarbonylaminomethyl chloride: yield ¼ 83%, 1H NMR
(CDCl3): d 0.97 (t, 3H), d 1.3 (m, 6H), d 1.6 (m, 2H), d 3.02 (s, 3H), d 4.15
(t, 2H), d 5.33 (s, 2H).
Route B
This method relies on the conversion of an alcohol to an activated acylating
agent (acyl imidazole), which can subsequently be used to acylate an amine
to generate N-alkyl carbamic acid alkyl ester. The experimental protocol
follows.
Hexanol (3.06 g, 0.03 mol) was reacted with 1.1 equivalents of
1,10-carbonyl diimidazole (5.34 g, 0.033 mol) in 50 mL of CH2Cl2 overnight
at room temperature, The clear solution was diluted with 50 mL of CH2Cl2
and washed with 20 mL of 1 N HCl and 3 ꢀ 10 mL of water. The CH2Cl2
layer was dried over Na2SO4, then concentrated to an oil: hexyloxycarbonylimi-
dazole. Coupling of the hexyloxycarbonylimidazole with 1.3 equivalents
(2.94 g, 0.039 mol) of aqueous methyl amine in 2-propanol (10 mL) was

3544
S. Majumdar and K. B. Sloan
achieved by refluxing the reaction mixture overnight. The reaction mixture was
then concentrated using a rotavapor under vacuum at 58C. The oily residue
obtained was dissolved in 50 mL of CH2Cl2 and washed with 10 mL of 1 N
HCl and 5 ꢀ 3 mL of water. The CH2Cl2 layer was dried over Na2SO4 and con-
centrated to an oil. The N-methyl carbamic acid hexylester was subsequently
converted to the alkylating agent as reported in method B and used to
generate the desired prodrug (Scheme 3).
Route C
This protocol relies on the conversion of an alcohol to its p-nitrophenyl-
carbonate ester, which is then reacted with alkyl amine to generate N-alkyl
carbamic acid alkyl ester. The experimental protocol for synthesis of
NANAOCAM-Cl follows.
Equimolar equivalents of hexanol(3.06 g, 0.03 mol), p-nitrophenylchlor-
oformate (6.66 g, 0.033 mol), and diisopropylethylamine (4.26 g, 0.033 mol)
were mixed in 50 mL of CH2Cl2, and reaction was run overnight. The clear
solution that resulted was diluted with 25 mL of CH2Cl2 and washed with
10 mL of 1 N HCl, 10 mL of saturated NaHCO3, and 3 ꢀ 10 mL of water.
The CH2Cl2 layer was dried over Na2SO4 and then concentrated to give the
p-nitrophenylcarbonate hexyl ester as an oil. Coupling of the p-nitrophenyl-
carbonate hexyl ester with 1.5 equivalents of methyl amine (3.48 g,
0.045 mol) in dry THF (10 mL) was carried out by refluxing the reaction
mixture overnight. The reaction mixture was concentrated using a rotavapor
under vacuum at 508C. The oily residue obtained was resuspended in
50 mL of CH2Cl2 and washed with 10 mL of 1 N HCl and 3 ꢀ 5 mL with
water. The CH2Cl2 layer was dried over Na2SO4 and concentrated to give
the N-methyl carbamic acid hexylester, which was subsequently converted
to the alkylating agent as reported in method B and used to generate the
desired prodrug.
SYNTHESIS OF EXAMPLES OF PRODRUGS OF
ACETAMINOPHEN, THEOPHYLLINE, AND
6-MERCAPTOPURINE
Acetaminophen (APAP) Prodrugs
Equimolar amounts of APAP (0.01 mol) and triethylamine (0.01 mol) were
refluxed for an hour in 20 mL of CH2Cl2 followed by the addition of 1.1
1
equivalents of the alkylating agent (0.01 mol, as determined by H NMR).
The contents were stirred overnight. The reaction mixture was diluted
with 50 mL of CH2Cl2 followed by washing with 5 ꢀ 3 mL of water.
The CH2Cl2 solution was dried over Na2SO4 for an hour and filtered.

NANAOCAM Prodrug Derivatives
3545
The solution was concentrated using a rotavapor under vacuum at 408C until it
was solvent free. The resulting material was purified by recrystallization and,
if necessary, column chromatography until a sharp melting point was
obtained, a single spot was seen on thin-layer chromatography (TLC) and
an 1H NMR consistent with the desired product was obtained.
N-Methyl-N-methyloxycarbonylaminomethyl-APAP: Purified by recrys-
tallization from CH2Cl2–hexane (1:3) twice to give white crystals. Yield
1
70%, mp 86–888C, H NMR (CDCl3): d 7.6 (s, lH), d 7.39 (d, 2H), d
6.96–6.87 (2d, 2H), d 5.28–5.21 (2s, 2H), d 3.72–3.7 (2s, 3H), d 3.0–2.97
(2s, 3H), d 2.0 (s, 3H). Anal. calcd. for C12H16N2O4: C, 57.13; H, 6.39; N,
11.1%. Found: C, 56.81; H, 6.34; N, 11.1.
N-Methyl-N-ethyloxycarbonylaminomethyl-APAP: Purified by trituration
with hexane overnight to give yellow crystals, which were recrystallized
from ethyl acetate–hexane (1:3) to give white crystals. Yield 65%, mp
1
75–778C, H NMR (CDCl3): d 7.38 (d, 2H), d 7.12 (s, 1H), d 6.96 (2d,
2H), d 5.3 (2s, 2H), d 4.15 (2q, 2H), d 3.0 (2s, 3H), d 2.15 (s, 3H), d 1.25
(2t, 3H). Anal. calcd. for C13H18N2O4: C, 58.64; H, 6.81; N, 10.52. Found:
C, 58.53; H, 6.93; N, 10.47.
N-Methyl-N-propyloxycarbonylaminomethyl-APAP: Purified by silica-gel
chromatography in ethyl acetate–hexane (3:2) followed by trituration in
hexane overnight to give pale white crystals. These crystals were further
recrystallized from ethyl acetate–hexane (3:2) to give white crystals. Yield
1
76%, mp 58–598C, H NMR (CDCl3): d 7.38 (d, 2H), d 7.14 (s, 1H), 6.96
(2d, 2H), d 5.3 (2s, 2H), d 4.05 (2t, 2H), d 3.0 (2s, 3H), d 2.15 (s, 3H),
d1.65 (m, 2H), d 0.91 (2t, 3H). Anal. calcd. for C14H20N2O4: C, 60.01; H,
5.45; N, 12.73. Found: C, 60.1; H, 5.35; N, 12.58.
N-Methyl-N-butyloxycarbonylaminomethyl-APAP: Purified by silica-gel
chromatography using 70% ethyl acetate–hexane as an eluent to give an
1
yellow oil. Yield 66%, H NMR (CDCl3): d 7.39 (d, 2H), d 7.14 (s, lH),
6.97–6.88 (2d, 2H), d 5.29–5.22 (2s, 2H), d 4.10 (2t, 2H), d 3.03–2.97
(2s, 3H), d 2.15 (s, 3H), d 1.65 (m, 2H), d 1.4 (m, 2H), d 0.91 (2t, 3H).
Anal. calcd. for C15H22N2O4: C, 61.21; H, 7.53; N, 9.52. Found: C, 61.16;
H, 7.65; N, 9.24.
N-Methyl-N-hexyloxycarbonylaminomethyl-APAP: Purified by silica-gel
column chromatography in ethyl acetate–hexane (4:l) followed by trituration
1
in hexane overnight to give a colorless oil. Yield 63%, H NMR (CDCl3): d
7.38 (d, 2H), d 7.29 (s, 1H), d 6.95–6.89 (2d, 2H), d 5.29–5.23 (2s, 2H),
d 4.11–4.07 (m, 2H), d 3.02–2.98 (2s, 3H), d 2.15 (s, 3H), d 1.63 (m, 2H),
d 1.3 (m, 6H), d 0.89 (m, 3H). Anal. calcd. for C17H26N2O4: C, 62.33;
H, 8.13; N, 8.69. Found: C, 61.96; H, 8.14; N, 8.36.

3546
S. Majumdar and K. B. Sloan
Theophylline Prodrugs
Equimolar amounts of theophylline (0.01 mol) and triethylamine (0.01 mol) in
20 mL of CH2Cl2 were stirred for 20 min. A white suspension was seen, and
the alkylating agent (0.011 mol, as determined by 1H NMR) was added to the
suspension. An exothermic reaction occured, and the suspension cleared to
give a solution, which was stirred overnight at room temperature. The
reaction mixture was diluted with 40 mL of CH2Cl2 and extracted with
5 mL of 1 N HCl, 5 mL of NaHCO3 saturated solution, and 5 ꢀ 3 mL of
water. The CH2Cl2 layer was dried over Na2SO4 and concentrated to give
white solids, which were crystallized from CH2Cl2–ether or CH2Cl2–
hexanes to give pure white crystals.
N7-(N-Methyl-N-methyloxycarbonyl)aminomethyl theophylline: Purified by
recrystallization with CH2Cl2–hexane (1:4) to give white crystals. Yield
73%, mp 165–1668C, NMR (CDCl3): d 7.98 (2s,lH), d 5.8 (2s, 2H), d
3.75 (2s, 3H), d 3.61 (s, 3H), d 3.43 (s, 3H), d 3.0 (2s, 3H). Anal. calcd.
for C11H15N5O4: C, 46.97; H, 5.38; N, 24.9. Found: C, 46.88; H, 5.22; N,
24.77.
N7-(N-Methyl-N-ethyloxycarbonyl)aminomethyl theophylline: Purified by
recrystallization with CH2Cl2–ether (1:4) followed by CH2Cl2–hexane
1
(1:4) to give pure white crystals. Yield 84%, mp 115–1178C, H NMR
(CDCl3): d 7.99 (2s,lH), d 5.8 (2s, 2H), d 4.2 (2q, 3H), d 3.61 (s, 3H),
d 3.43 (s, 3H), d 3.1 (2s, 3H), d 1.28 (t, 3H). Anal. calcd. for C12H17N5O4:
C, 48.81; H, 5.8; N, 23.72. Found: C, 48.8; H, 5.84; N, 23.67.
N7-(N-Methyl-N-propyloxycarbonyl)aminomethyl theophylline: Purified by
recrystallization with CH2Cl2–hexane (1:4) followed by hot EtOH to give
white crystals. Yield 80%, mp 128–1298C, 1H NMR (CDCl3): d 7.98
(2s, lH), d 5.8 (2s, 2H), d 4.08 (2t, 2H), d 3.6 (s, 3H), d 3.43 (s, 3H), d 3.1
(2s, 3H), d 1.7 (m, 2H), d 0.94 (2t, 3H). Anal. calcd. for C13H19N5O4: C,
50.48; H, 6.19; N, 22.64. Found: C, 50.60; H, 6.29; N, 22.62.
N7-(N-Methyl-N-butyloxycarbonyl)aminomethyl theophylline: Purified by
recrystallization with CH2Cl2–hexane (l:3) to give white crystals. Yield
1
71%, mp 1038C, H NMR (CDCl3): d 7.98 (2s,1H), d 5.8 (2s, 2H), d 4.12
(2t, 2H)), d 3.61 (s, 3H), d 3.42 (s, 3H), d 3.01 (2s, 3H), d 1.63 (m, 2H),
d 1.39 (m, 2H), d 0.94 (2t, 3H). Anal. calcd. for C14H21N5O4; C, 52.0;
H, 6.55; N, 21.66. Found: C, 52.17; H, 6.73; N, 21.68.
N7-(N-Methyl-N-hexyloxycarbonyl)aminomethyl theophylline: Purified by
recrystallization with CH2Cl22 petroleum ether (1:3) to give white crystals.
1
Yield 77%, mp ¼ 74–758C, H NMR(CDCl3): d 7.99 (2s,1H), d 5.8 (2s,
2H), d 4.2–4.12 (2t, 2H), d 3.61 (s, 3H), d 3.42 (s, 3H), d 3.01 (2s, 3H), d

NANAOCAM Prodrug Derivatives
3547
1.63 (m, 2H), d 1.31 (m,6H), d 0.89 (m, 3H). Anal. calcd. for C16H25N5O4: C,
54.6; H, 7.17; N, 19.93. Found: C, 54.18; H, 7.13; N, 19.53.
6-Mercaptopurine Prodrugs
To 6MP (0.01 mol) in 5 mL of DMSO was added N-alkyl-N-alkyloxycarbo-
nylaminomethyl chloride (0.011 mol). The yellow solution was stirred at
room temperature for 1.5 h. Triethyl amine (0.025 mol) and 15 mL of
CHCl3 were added, and stirring continued for one more hour. The reaction
mixture was diluted with 100 mL of CH2Cl2 and was washed with 20 mL
of 1 N HCl, 20 mL of saturated NaHCO3 solution, and 15 ꢀ 3 mL of brine
solution. The organic layer was dried over Na2SO4 and concentrated to give
a yellow oil. The oil was triturated with petroleum ether to give yellow
solids, which were further recrystallized with CH2Cl2–hexane or ethyl
acetate–hexanes to give yellow crystals.
S-(N-Propyl-N-butyloxycarbonylaminomethyl)-6MP: Purified using ethyl
acetate–hexane (1:3) to give yellow crystals. Yield 78%, mp 144–1468C
(lit. mp ¼ 143–1448C)[5]
;
1H NMR (CDCl3): d 8.76 (s,1H), d 8.62–8.2
(2s,1H), d 5.75 (2s, 2H), d 4.24–4.17 (2t, 2H), d 3.42–3.35 (2t, 2H),
d 1.68–1.61 (m,4H), d 1.4–1.3 (m, 2H), d 0.9 (m,6H). Anal. calcd. for
C14H21N5O2: C, 51.99; H, 6.55; N, 21.65. Found: C, 52.09; H, 6.31; N,
21.69.
S-(N-Butyl-N-methyloxycarbonylaminomethyl)-6MP: Purified using ethyl
acetate–hexane (1:1) to give yellow crystals. Yield 57%, mp 133–1358C
1
(lit. mp ¼ 134–1358C)[5]; H NMR (CDCl3): d 8.71 (s, 1H), d 8.42–8.2
(2s,1H), d 5.68 (2s, 2H), d 3.85–3.76 (2s, 3H), d 3.47–3.38 (2t, 2H), d
1.55–1.48 (m, 2H), d 1.34–1.24 (m, 2H), d 0.9 (t, 3H). Anal. calcd. for
C12H17N5O2: C, 48.80; H, 5.8; N, 23.71. Found: C, 48.69; H, 5.78; N,
23.65.
S-(N-Butyl-N-propyloxycarbonylaminomethyl)-6MP: Purified using ethyl
acetate–hexane (1:4) to give yellow crystals. Yield 68%, mp 75–778C
1
(lit. mp ¼ 74–778C)[5]; H NMR (CDCl3): d 8.71 (s,1H), d 8.42–8.2 (2s,
1H), d 5.68 (2s, 2H), d 4.19–4.1 (2t, 2H), d 3.47–3.38 (2t, 2H), d 1.78–
1.64 (m, 2H), d 1.54–1.51 (m, 2H), d 1.28 (m, 2H), d 1.0 (m, 6H). Anal.
calcd. for C14H21N5O2: C, 51.99; H, 6.55; N, 21.65. Found: C, 51.76; H,
6.4; N, 21.57.
S-(N-Butyl-N-butyloxycarbonylaminomethyl)-6MP: purified using ethyl
acetate–hexane (1:4) to give yellow crystals. Yield 77%, mp 85–878C
(lit. mp ¼ 87–898C);[5] 1H NMR (CDCl3): d 8.72 (s,1H), d 8.44–8.2
(2s,1H), d 5.69 (2s, 2H), d 4.23–4.15 (2t, 2H), d 3.47–3.39 (2t, 2H), d

3548
S. Majumdar and K. B. Sloan
1.7–1.2 (m, 8H), d 0.9 (m, 6H). Anal. calcd. for C14H21N5O2: C, 53.39; H,
6.87; N, 20.75. Found: C, 53.42; H, 6.59; N, 20.77.
CONCLUSION
A practical general synthesis of N-alkyl-N-alkyloxycarbonylaminomethyl
chlorides has been reported. The N-alkyl-N-alkyloxycarbonylaminomethyl
chloride derivative can further be used to alkylate 6-MP, APAP, and Th to
make useful prodrug derivatives whose purification and yields are higher
than has been reported before.
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