A general procedure for the synthesis of acylguanidines derived from aliphatic and aromatic amines

Article abstract of DOI:10.1081/SCC-100105128

Condensation of aliphatic and aromatic amines with 1-aroyl-S-methylisothiourea in the presence of triethylamine affords acylguanidines in moderate to good yields. An improved procedure for the generation of 1-aroyl-S-methylisothiourea derivatives is descr

Full text of DOI:10.1081/SCC-100105128

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A GENERAL PROCEDURE FOR THE SYNTHESIS OF
ACYLGUANIDINES DERIVED FROM ALIPHATIC AND
AROMATIC AMINES
Seetharamaiyer Padmanabhan a , Ruth C. Lavin a , Paresh M. Thakkar b & Graham J.
Durant a
a Cambridge NeuroScience Inc., One Kendall Square, Bldg. 700, Cambridge, MA, 02139,
U.S.A.
b Genetics Institute, 85 Bolton Street, Cambridge, MA, 02140, U.S.A.
Available online: 09 Nov 2006
To cite this article: Seetharamaiyer Padmanabhan, Ruth C. Lavin, Paresh M. Thakkar & Graham J. Durant (2001):
A GENERAL PROCEDURE FOR THE SYNTHESIS OF ACYLGUANIDINES DERIVED FROM ALIPHATIC AND AROMATIC AMINES,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:16,
2491-2497
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SYNTHETIC COMMUNICATIONS, 31(16), 2491–2497 (2001)
A GENERAL PROCEDURE FOR THE
SYNTHESIS OF ACYLGUANIDINES
DERIVED FROM ALIPHATIC AND
AROMATIC AMINES
Seetharamaiyer Padmanabhan,* Ruth C. Lavin,
Paresh M. Thakkar,{ and Graham J. Durant
Cambridge NeuroScience Inc., One Kendall Square,
Bldg. 700, Cambridge, MA 02139, USA
ABSTRACT
Condensation of aliphatic and aromatic amines with 1-aroyl-
S-methylisothiourea in the presence of triethylamine affords
acylguanidines in moderate to good yields. An improved
procedure for the generation of 1-aroyl-S-methylisothiourea
derivatives is described.
Acylguanidines are an important group of molecules exhibiting vari-
ous biological activities e.g. amiloride [1-(3,5-diamino-6-chloropyrazinoyl)-
guanidine] and derivatives1,2 as Naþ/Hþ antiporter inhibitors and multiple
ion channel blockers, and guanfacine3 [N-(2,6-dichlorophenacetyl)guani-
dine] as an a2-adrenoreceptor agonist for the treatment of hypertension.
*Corresponding author.
{Current address: Genetics Institute, 85 Bolton Street, Cambridge, MA 02140.
2491
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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PADMANABHAN ET AL.
Work on guanidine based derivatives as ion channel blockers and potential
treatments for stroke and other neurological disorders, has been a
long-standing interest in our laboratories. As part of this work, we
became interested in the preparation of a small library of acylguanidines
and here we disclose our results on a general procedure for acylguanidines
derived from both aromatic and aliphatic amines.
Initially we studied the condensation of acylcyanamides with aryl-
amine hydrogen halide salts which led to the isolation of the desired acyl-
guanidine derivatives in good yields and high purities.4 However,
condensation of acylcyanamides with aliphatic amines as hydrogen halide
salts or as free amines led to the isolation of highly impure reaction mix-
tures.
Synthetic utility of substituted S-methylisothiourea derivatives like N,N0-
bis(benzyloxycarbonyl)-S-methylisothiourea5,6 and other aroyl S-methyl-
isothiourea derivatives have been reported7,8,9 for the preparation of guani-
dine derivatives. The former involves the use of mercury salts while in the latter
cases the products were isolated in low yields or after longer reaction times
with repeated crystallizations. The isolated protected guanidines were sub-
sequently subjected to deprotection affording mono substituted guanidine
derivatives. Based on these reports we investigated the preparation of 1-
aroyl-S-methylisothiourea derivatives as starting materials for synthesis of
acylguanidines.
Addition of 4-methylbenzoyl chloride (Ia) as a solution in ether with
S-methylisothiouronium sulfate (II) was carried out at room temperature in
the presence of sodium hydroxide solution following the reported pro-
1
cedure10 and resulted in the isolation of a product. The H-NMR spectrum
in deuterated chloroform and the HPLC analysis of this product indicated
the presence of two components. Dissolution of the product in methanol
and filtration of the insoluble impurity easily separated the components. The
desired product, 1-(4-methylbenzoyl)-S-methyl-isothiourea (IIIa) was iso-
lated in high purity (ꢀ96% by HPLC) by the removal of the solvent. The
methanol insoluble product was identified as the N,N-diacylated derivative

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2493
(IVa) and not the N,N0-diacylated product based on the aromatic region of
1
the H-NMR spectrum.
It was found that the reported reaction conditions were unsuitable for
synthesis of IIIa in gram quantities due to the formation of increased amounts
of diacylated product. The amount of diacylated product formed depends on
various factors, namely, amount of ether used, rate of addition of acid chlor-
ide, rate of evaporation of ether from the reaction mixture, etc. We were
therefore obliged to explore other methods for preparing acylmethyl-
isothiourea derivatives in good yields and high purity. Various modifications
in the reaction conditions, such as molar proportions of the reactants, time,
temperature, and the bases used viz. aqueous sodium hydroxide, sodium
carbonate, sodium bicarbonate (saturated) were attempted. Best results
were obtained by reacting acid chloride (Ia, 1 eq) in ether with S-methyl-
isothiouronium sulfate (II, 2 eq) in sodium hydroxide (1N) under ice-cold
conditions. The isolated product, IIIa was found to be pure both by NMR
and HPLC (> 90%). Using these reaction conditions, different acyliso-
thiourea derivatives IIIa–g (Table 1) were synthesized in high purity and
were subsequently converted to acylguanidine derivatives.
Initially condensation of IIIa with aromatic amine hydrochlorides in
refluxing xylenes gave the acylguanidine hydrogen halides in good yields.3
As in the case of acylcyanamides, reaction of IIIa with hydrochloride salts of
arylalkylamines and aliphatic amines did not take place in refluxing xylenes.
Under fusion conditions (160–170ꢁC and 3 h) condensation of IIIa with
benzylamine hydrochloride occurred and the desired product was isolated
in moderate yield. However, other aliphatic amines gave complex reaction
mixtures under fusion conditions.
Successful condensation of IIIa with aromatic and aliphatic amines
(Vh–n) was achieved in the presence of triethylamine in refluxing xylenes and
the desired acylguanidines (VIh–n) were isolated in high purity in 48 to 74%
yields (Table 2).

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PADMANABHAN ET AL.

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PADMANABHAN ET AL.
In summary, a general procedure for the synthesis of acylguanidines
involving condensation of aromatic and aliphatic amines with 1-aroyl-S-
methylisothiourea has been developed and we improved the reported
method of generating 1-aroyl-S-methylisothiourea derivatives.
EXPERIMENTAL
Melting points were determined in open capillary tubes on a Mel-
Temp II apparatus and are uncorrected. Yields are of pure homogenous
1
products and are not optimized. H-NMR spectra were run on a Varian
Gemini 300 MHz spectrophotometer using CDCl3 or CD3OD as solvents
with tetramethylsilane as internal standard. Elemental analyses of the prod-
ucts were obtained from Atlantic Microlab, Norcross, GA.
1,1-Bis-(4-methylbenzoyl)-S-methylisothiourea (IVa): m. p. 158–160ꢁC
1
(EtOH); H-NMR (CDCl3) d 2.40 (s, 3H, SMe), 2.61 (s, 3H, Me), 7.33 (d,
2H, Ar), 7.27 (d, 2H, Ar), 7.93 (d, 2H, Ar), 8.24 (d, 2H, Ar); Anal. Calcd. for
C18H18N2O2S: C, 66.26; H, 5.52; N, 8.59. Found: C, 66.26; H, 5.51; N, 8.63%.
General procedure for preparation of 1-aroyl-S-methylisothiourea deri-
vatives (IIIa–g): To a well cooled solution of S-methylisothiouronium sulfate
(6.9g, 0.025 mole) in aqueous sodium hydroxide (1N, 30 ml) at 5–10 ꢁC in an
ice bath, aroyl chloride (Ia–g, 0.01 mole) in ether (10 ml), was added slowly
over 5–10 min. The reaction mixture was stirred as such for 4 hours. The
solid, which had separated, was filtered, washed with water, followed by
hexanes and dried. The isolated products were found to be pure by both 1H-
NMR and HPLC and were used without further purification and analyti-
cally pure samples were obtained by crystallization from appropriate
solvents. Various acylisothiourea derivatives synthesized and their physical
characteristics are given in Table 1.

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General procedure for the preparation of acylguanidine derivatives
2497
(VIh–n): A mixture of the S-methylisothiourea derivative, IIIa (208 mg,
1 mmole) and amine derivatives (Vh–n, 1 mmole) with triethylamine
(1 mmole) in xylenes (5 ml) was heated to reflux for 3 to 4 hours. The reac-
tion mixture was worked up by filtering the solid separated or by removal
of solvent, after washing and repeated coevaporation with hexanes solid
separated was filtered, crystallized from appropriate solvents. In the case
of VIk, VII and VIn the guanidine free bases isolated were converted to
the corresponding hydrochloride salts. Yields, m.p. and physical character-
istics of various acylguanidine derivatives prepared are given in the Table 2.
ACKNOWLEDGMENT
The authors wish to thank M. E. Perlman, Lu Zhang, Aine Cullinan
and Deke Moore for the HPLC purity determination of the products.
REFERENCES
1. Bicking, J.B.; Mason, J.W.; Woltersdorf Jr. O.W.; Jones, J.H.; Kwong,
S.F.; Robb, C.M.; Cragoe Jr. E.J. J. Med. Chem. 1965, 8, 638.
2. Baumgarth, M.; Beier, N.; Gericke, R. J. Med. Chem. 1998, 41,
3736–3747.
3. Bream, J.B.; Picard, C.W. Swiss 511816 (1969); Chem, Abstr. 1972, 76,
72286.
4. Padmanabhan, S.; Durant, G.J. (unpublished results).
5. Su, W. Synth. Commun. 1996, 26, 407.
6. Chandrakumar, N.S. Synth. Commun. 1996, 26, 2613.
7. Budesinsky, Z.; Emr, A.; Musil, V.; Perina, Z.; Zikmund, E., Ceskoslove.
farm. 1959, 8, 129; Chem. Abstr. 1960, 54, 3197.
8. Bream, J.B.; Leuener, H.; Picard, C.W.; Scholtysik, G.; White, T.G.
Arzneim.-Forsch. (Drug Res.) 1975, 25, 1477.
9. Barron, D.I.; Bavin, P.M. G.; Durant, G.J.; Natoff, I.L.; Spickett, R.
G.W.; Vallance, D.K. J. Med Chem. 1963, 6, 705.
10. Hegarty, A.F.; Hegarty, C.N.; Scott, F.L. J. Chem. Soc. Perkin Trans
II 1973, 2054.
11. Wheeler, H.L.; Merriam, H.F. J. Amer. Chem. Soc. 1903, 29, 479.
12. Johnson, T.B.; Jamieson, G.S. J. Amer. Chem. Soc. 1906, 35, 299.
13. Free base of this compound is reported in Ref. 7.
Received in the USA November 10, 2000

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