A convenient synthesis of 4-aminomethyl-4,5,6,7-tetrahydro-1,3-benzothiazole arginine side-chain mimetics

Article abstract of DOI:10.1016/S0040-4039(01)01939-6

A convenient synthesis of novel 4-aminomethyl-4,5,6,7-tetrahydro-1,3-benzothiazole arginine side-chain mimetics designed for incorporation into thrombin inhibitors is reported.

Full text of DOI:10.1016/S0040-4039(01)01939-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8911–8913
A convenient synthesis of
4-aminomethyl-4,5,6,7-tetrahydro-1,3-benzothiazole arginine
side-chain mimetics
Petra Marinko, Jozˇe Kastelic, Alesˇ Krbavcˇicˇ and Danijel Kikelj*
University of Ljubljana, Faculty of Pharmacy, Asˇkercˇeva 7, 1000 Ljubljana, Slovenia
Received 29 August 2001; revised 2 October 2001; accepted 12 October 2001
Abstract—A convenient synthesis of novel 4-aminomethyl-4,5,6,7-tetrahydro-1,3-benzothiazole arginine side-chain mimetics
designed for incorporation into thrombin inhibitors is reported. © 2001 Elsevier Science Ltd. All rights reserved.
During the last 3 years there has been a growing
interest in heterocyclic arginine mimetics, comprising
heterocyclic amines and aza-heterocycles as synthons
for the preparation of trypsin-like serine protease
inhibitors.1 The reduced basicity of these heterocyclic
compounds and the rigidity of the heterocyclic ring as
compared to the guanidinoalkyl side-chain of arginine
contribute to the increased bioavailability and selectiv-
ity of thrombin inhibitors containing heterocyclic
arginine mimetics.2–4 These peptidomimetic building
blocks generally possess an amino group by which they
are coupled to the rest of the inhibitor molecule by an
amide bond. It has been demonstrated several times
that a methylene linker between the heterocycle and the
amino group, allowing substantial conformational free-
dom of the heterocycle, is crucial for the design of
potent thrombin inhibitors.5–7
Recently, we have reported a general synthetic
approach to the aminomethyl substituted heterobicyclic
arginine side-chain mimetic 1, which, through a syn-
thetic strategy based on N-[(4-oxocyclohexyl)-
methyl]acetamide as the key intermediate, provided
compounds bearing an aminomethyl group at the
meta/para position relative to the ring junction, in-
cluding
5-aminomethyl-4,5,6,7-tetrahydroindazole,
methyl-4,5,6,7-tetrahydro-1,3-benzothiazole and 6-
5-aminomethyl-4,5,6,7-tetrahydroisoindole,
6-amino-
aminomethyl-5,6,7,8-tetrahydroquinazoline
deriva-
tives.8,9 Among them, 6-(aminomethyl)-4,5,6,7-tetra-
hydro-1,3-benzothiazol-2-amine (2) was shown to be
one of the most promising arginine side-chain mimetics
providing potent and selective thrombin inhibitors.10 In
order to optimize interactions of the P1 part of the
inhibitors with the S1 pocket of thrombin, modification
Keywords: arginine mimetics; peptidomimetics; 4-aminomethyl-4,5,6,7-tetrahydro-1,3-benzothiazole derivatives.
* Corresponding author. Tel.: +386-1-476-9561; fax: +386-1-425-8031; e-mail: danijel.kikelj@ffa.uni-lj.si
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01939-6

8912
P. Marinko et al. / Tetrahedron Letters 42 (2001) 8911–8913
of the arginine mimicking part of the inhibitor molecule
by a different point of attachment of the aminomethyl
group seemed to be a logical choice.
Interestingly, reduction of 6b to 7b with lithium alu-
minum hydride was accompanied by deguanylation
yielding4,5,6,7-tetrahydro-1,3-benzothiazol-4-ylmethan-
amine (7c) in 36% yield and by scission of an NꢀC
bond in the guanidino group giving 7a in 45% yield.17
Although deaminations of similar substituted 1,3-thia-
zol-2-amines are known, according to the literature
they are performed by reduction with sodium in liquid
ammonia or mercury(II) oxide and generally give a
mixture of products.12b By reducing the excess of
lithium aluminum hydride from 1.6 to 1.3 equiv., the
formation of 7a and 7c was completely suppressed and
7b was obtained in 72% yield.
We report here a synthetic strategy leading to novel
4 - aminomethyl - 4,5,6,7 - tetrahydro - 1,3 - benzothiazole
arginine side-chain mimetics 3 which were designed as
building blocks for the preparation of thrombin
inhibitors.
Starting from commercially available ethyl 2-oxocyclo-
hexanecarboxylate (4), bromination with bromine in
diethyl ether afforded the 3-bromo derivative 511
(Scheme 1). In the next step, a classical Hantzsch
thiazole synthesis12a applying thiourea or amidinoth-
iourea as an SꢀCꢀN synthon afforded fused thiazoles
6a13a,b and 6b.20 Reduction of the esters 6a and 6b with
lithium aluminum hydride and subsequent tosylation
with p-toluenesulfonyl chloride in pyridine afforded
tosylates 8a and 8b. In the case of the 2-amino deriva-
tive 7a, in addition to the tosylate 8a, the N-tosyl
derivative was obtained as a by-product in 25% yield.14
Nucleophilic substitution of tosylates 8a and 8b with
sodium azide in N,N-dimethylformamide produced the
azides 9a and 9b. Catalytic hydrogenation of the azide
9b using 10% palladium on charcoal as a catalyst
afforded the arginine side-chain mimetic 3b.18,21 In con-
trast, when the azide 9a was subjected to reduction
under various conditions (hydrogenation over palla-
dium on charcoal,15 reduction with tin(II) chloride16),
the reaction was not successful due to formation of
numerous by-products. Therefore, a direct substitution
of the tosylate 8a in liquid ammonia was attempted and
this successfully produced the target arginine side-chain
mimetic 3a in 40% yield.19,21
For conversion of 7c to arginine side-chain mimetic
3c,21 the same strategy as described above for the
synthesis of 3a and 3b was applied.
In conclusion, we have developed a straightforward
synthetic pathway to novel 4-(aminomethyl)-4,5,6,7-tet-
rahydro-1,3-benzothiazole arginine side-chain mimetics
bearing either an amino group or a guanidino residue
at carbon 2. They were used as synthons for the prepa-
ration of non-covalent thrombin inhibitors which will
be reported elsewhere.
Acknowledgements
This work was financially supported by the Ministry of
Science and Technology of the Republic of Slovenia.
The authors wish to thank Dr. Anthony R. Byrne for
critical reading of the manuscript.
Scheme 1. (a) Br2, ether, rt, 2 h, 98%; (b) H2NCSNH2, abs. EtOH, rt, 16 h, 98%; (c) H2NCSNHC(ꢁNH)NH2, DMF, rt, 16 h,
73%; (d) LiAlH4, THF, ice bath then reflux, 16 h, 31–72%; (e) TsCl, pyridine, rt, 16 h, 34–62%; (f) NaN3, DMF, reflux, 3 h,
65–77%; (g) SnCl2·2H2O, MeOH, rt, 16 h, 15%; (h) H2, Pd/C, MeOH, 55%; (i) liq. NH3, abs. EtOH, 50°C, 16 h, 40%.

P. Marinko et al. / Tetrahedron Letters 42 (2001) 8911–8913
8913
References
16. Maiti, S. N.; Singh, M. P.; Micetich, R. G. Tetrahedron
Lett. 1986, 27, 1423–1424.
1. Peterlin-Masˇicˇ, L.; Kikelj, D. Tetrahedron 2001, 57,
7073–7105.
2. Rewinkel, J. B. M.; Adang, A. E. P. Curr. Pharm. Design
1999, 5, 1043–1075.
3. Steinmetzer, T.; Hauptmann, J.; Stu¨rzebecher, J. Exp.
Opin. Invest. Drugs 2001, 10, 845–864.
17. Compounds 7a (Rf=0.27; mp 62–65°C), 7b (Rf=0.00;
mp 81–85°C) and 7c (Rf=0.47; yellow oil; previously
described in Ref. 11) were separated by column chro-
matography on silica gel using CHCl3/MeOH (9:1) as
eluant and fully characterized by NMR, IR, mass spec-
trometry and CHN analysis.
4. Coburn, C. A. Exp. Opin. Ther. Pat. 2001, 11, 721–738.
5. Feng, D. M.; Gardell, S. J.; Lewis, S. D.; Bock, M. G.;
Chen, Z.; Freidinger, R. M.; Naylor-Olsen, A. M.;
Ramjit, H. G.; Woltmann, R.; Baskin, E. P.; Lynch, J. J.;
Lucas, R.; Shafer, J. A.; Dancheck, K. B.; Chen, I.-W.;
Maso, S. S.; Krueger, J. A.; Hare, T. A.; Mulichak, A.
M.; Vacca, J. P. J. Med. Chem. 1997, 40, 3726–3733.
6. Wiley, M. R.; Lepore, S. D. PCT Int. Appl. WO
0,027,199, 2000; Chem. Abstr. 2000, 132, 347944.
7. Sanderson, P. E.; Lyle, T.; Dorsey, B.; Stanton, M. G.;
Naylor-Olsen, A. M. PCT Int. Appl. WO 0,026,210,
2000; Chem. Abstr. 2000, 132, 334472.
18. Compound 3b: yield 55%, yellow solid; mp 149–153°C;
IR (KBr): w 3347, 2928, 1606, 1547, 1451, 1255, 967, 735
cm−1 1H NMR (300 MHz, DMSO-d6): l 1.55–1.70 (m,
;
2H, CH2), 1.75–1.87 (m, 2H, CH2), 2.40–2.55 (m, 3H,
CH, CH2), 2.89–2.97 (AX part of an ABX system, JAB
=
11.50 Hz, JAX=3.20 Hz, 1H, CH2-N), 6.72 (br s, 4H,
NHC(NH)NH2); 1H NMR (300 MHz, CDCl3): l 1.50–
1.70 (m, 2H, CH2), 1.87–2.01 (m, 2H, CH2), 2.58–2.67
(m, 2H, CH2), 2.68–2.79 (m, 1H, CH), 2.90–2.98 (ABX
system, 2H, JAB=18.08 Hz, JAX=5.27 Hz, JBX=6.41 Hz,
CH2-N); MS (70 eV, EI): m/z (%) 225 (M+, 20), 196
(100). Anal. calcd for C9H15N5S·0.5H2O: C, 46.13; H,
6.88; N, 29.89. Found: C, 46.52; H, 6.99; N, 29.76%.
19. Compound 3a: yield 40%, brownish solid; mp 89–92°C;
8. Peterlin-Masˇicˇ, L.; Kikelj, D. Tetrahedron Lett. 2000, 41,
5589–5592.
9. Peterlin-Masˇicˇ, L.; Jurca, A.; Marinko, P.; Jancˇar, A.;
Kikelj, D. Tetrahedron, accepted for publication.
10. Kikelj, D.; Peterlin-Masˇicˇ, L.; Marinko P.; Breznik, M.;
Stegnar, M.; Trampusˇ-Bakija, A.; Fortuna, M. Patent
Appl. PCT/GB01/01997 (04.05.2001).
11. Maillard, J.; Delaunay, P.; Langlois, M.; Portevin, B.;
Legeai, J.; Benharkate, M. Eur. J. Med. Chem. 1984, 19,
457–460.
12. (a) Liebscher, J. In Houben-Weyl: Methoden der Organis-
chen Chemie; Schaumann, E., Ed.; Georg Thieme: Stutt-
gart, 1994; Vol. E8b/Part 2, pp. 23–110; (b) Liebscher, J.
In Houben-Weyl: Methoden der Organischen Chemie;
Schaumann, E., Ed.; Georg Thieme: Stuttgart, 1994; Vol.
E8b/Part 2, pp. 217–220.
1
IR (NaCl): w 3310, 2933, 1623, 1524, 1311, 1111 cm−1; H
NMR (300 MHz, DMSO-d6): l 1.43–1.68 (m, 2H, CH2),
1.71–1.88 (m, 2H, CH2), 2.35–2.48 (m, 2H, CH2), 2.52–
2.60 (m, 2H, 2×CH), 2.75–2.85 (AX part of an ABX
system, JAB=12.25 Hz, JAX=4.70 Hz, 1H, CH2-N), 3.05
(br s, NH2+H2O), 6.60 (br s, 2H, NH2); MS (70 eV,
FAB): m/z (%) 184 (MH+, 100); HRMS calcd for
C8H13N3S: 183.083019. Found: 183.083650.
20. Ethyl 2-{[amino(imino)methyl]amino}-4,5,6,7-tetrahydro-
1,3-benzothiazole-4-carboxylate hydrobromide (6b): To a
solution of compound 5 (19.2 g, 77 mmol) in 40 mL of
anhydrous DMF was added 2-imino-4-thiobiuret (10.0 g,
85 mmol). After being stirred at room temperature for 12
h, the solvent was removed in vacuo. The resulting oily
residue was treated with ether, and the precipitate dried
in vacuo over P2O5 giving 19.6 g (73%) of the title
compound as a white solid, mp 190–193°C; IR (KBr): w
3298, 3174, 2868, 1717, 1675, 1606, 1510, 1377, 1297,
13. Compound 6a has been previously prepared by
a
modified procedure described in two patents. See: (a)
Wei, P. H. L. US Patent 3,859,280, 1975; Chem. Abstr.
1975, 82, 140120; (b) Caprathe, B. W.; Jaen, J. C.; Wise,
L. D. US Patent 4,988,699, 1991; Chem. Abstr. 1991, 115,
8786.
1185, 1087, 1012, 930, 703, 613 cm−1 1H NMR (300
;
MHz, DMSO-d6): l 1.19 (t, 3H, J=7.16 Hz, CH3),
1.72–1.90 (m, 2H, CH2), 1.94–2.08 (m, 2H, CH2), 2.65–
2.74 (m, 2H, CH2), 3.69–3.78 (m, 1H, CH), 4.11 (q, 2H,
14. The O-tosyl (Rf=0.36; mp 131–134°C) and the N-tosyl
(Rf=0.27; mp 73–76°C) derivatives were separated by
column chromatography on silica gel using CH2Cl2/
MeOH (20:1) as eluant and fully characterized by NMR,
IR, mass spectrometry and CHN analysis.
15. Hydrogenation was carried out in methanol using 10%
Pd/C as a catalyst at room temperature and normal
pressure or in abs. ethanol at 90°C and 9 bar.
J=7.16 Hz, CH6 2
-OH), 8.17 (br s, 5H, NHC(NH)NH3+);
MS (70 eV, EI): m/z (%) 268 [(M−HBr)+, 100]; Anal.
(free base) calcd for C11H16N4O2S·0.75H2O: C, 46.86; H,
6.26; N, 19.87. Found: C, 47.33; H, 6.25; N, 19.48%.
21. The target compounds were obtained as racemates.