Green, catalyst-free synthesis of mesalazine conjugates

Article abstract of DOI:10.1055/s-0033-1338532

A greener protocol for the synthesis of mesalazine conjugates is reported. Mesalazine conjugates are prepared in high yields by a one-pot reaction of mesalazine and aminoacyl/peptidoylbenzotriazoles in water under microwave irradiation. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338532

PAPER
▌3255
pGaprereen, Catalyst-Free Synthesis of Mesalazine Conjugates
Green, Catalyst-Free Synthesis of Mesalazine Conjugates
Mohamed A. Ibrahim,a,b Siva S. Panda,a Khalid A. Alamry,c Alan R. Katritzky*a,c
a
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
b
Department of Organic Chemistry, College of Pharmacy, Misr University for Science and Technology, P. O. Box 77, Al-Motamayez District,
Egypt
c
Chemistry Department, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
Fax +1(352)3929199; E-mail: katritzky@chem.ufl.edu
Received: 12.07.2013; Accepted after revision: 22.08.2013
5-ASA, past the small intestine, directly to the large intes-
tine, which is the active site of ulcerative colitis.
Abstract: A greener protocol for the synthesis of mesalazine con-
jugates is reported. Mesalazine conjugates are prepared in high
yields by a one-pot reaction of mesalazine and aminoacyl/pepti-
doylbenzotriazoles in water under microwave irradiation.
An ideal colon-specific prodrug should be chemically and
biochemically stable to be nonabsorbable in the upper in-
Key words: mesalazine, amino acid, prodrug, green chemistry, testine but deliverable to the colonic site. The linkage be-
benzotriazole methodology
tween drug and carrier should then dissociate to release
the drug at the site of action.
Balsalazide (1), sulphasalazine (2), and olsalazine (3) are
Inflammatory bowel disease (IBD) comprises a group of
commercially available as mesalazine prodrugs (Figure 1)
disorders in which the intestines (small and large) become
and are believed to deliver 5-ASA, past the small intes-
inflamed. IBD primarily includes ulcerative colitis and
tine, directly to the large intestine.
Crohn’s disease but the exact etiology of the IBD is not
Amide bonds of various N-aromatic acylamino acid con-
yet known. The most common drugs to relieve the symp-
jugates are stable in the upper intestine but hydrolyzed
toms are corticosteroids and salicylates.1 5-Aminosalicyl-
when they are incubated with the cecal contents of mam-
ic acid (mesalazine, 5-ASA) is used for long-term
mals.4–6 Jung et al. synthesized 5-ASA conjugates with
maintenance therapy to prevent relapses of Crohn’s dis-
glycine, aspartic acid, and glutamic acid by a multistep
ease and ulcerative colitis, but is not suitable as such be-
synthesis. All the conjugates that were incubated in the rat
cause it is absorbed rapidly and extensively in the upper
cecum whose bacterial counts are high as in the human co-
intestine before it reaches to the colonic site.2 In addition,
lon and in vitro experiments, suggested 5-ASA-Gly con-
absorbed 5-ASA is reported to induce nephrotic syn-
jugate as a promising candidate of a colon-specific
drome.3 Several prodrugs aiming at the delivery of 5-ASA
prodrug of 5-ASA.7,8
to the colonic site are available and are believed to deliver
COOH
OH
COOH
OH
N
N
N
N
H
H
N
N
O
N
S
HOOC
O
O
balsalazide (1)
sulphasalazine (2)
COOH
OH
HOOC
HO
N
N
olsalazine (3)
Figure 1 Mesalazine prodrugs
SYNTHESIS 2013, 45, 3255–3258
Advanced online publication: 26.09.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338532; Art ID: SS-2013-M0480-OP
© Georg Thieme Verlag Stuttgart · New York

3256
M. A. Ibrahim et al.
PAPER
Table 1 Preparation of 5-ASA Conjugates 7a–j
Benzotriazole chemistry has been practiced extensively in
our group and has often been found to be superior to con-
ventional routes in various applications.9 In this commu-
nication, we report a novel synthetic route to mesalazine
conjugates through N-acylated benzotriazoles without us-
ing any catalyst or auxiliary reagent. To the best of our
knowledge, this is the first catalyst- and auxiliary-free, en-
vironmentally benign synthesis of 5-ASA conjugates af-
fording good yields under mild reaction conditions.
Product
Yield Mp
(%) (°C)
H
COOH
Cbz
Cbz
Cbz
N
N
H
7a
69
73
72
211–213
O
O
OH
H
N
COOH
N
H
Water was used as the reaction medium for the formation
of 5-ASA conjugates since water (i) is inexpensive, non-
flammable, nontoxic, and safe for use; (ii) it eliminates
additional efforts required to dry the substrates/reagents
before use; and (iii) offers unique physical and chemical
properties that often achieve the reactivity or selectivity
unattainable in organic solvents.10,11
7b
225–227
242–244
OH
H
N
COOH
N
H
7b + 7b′
O
OH
Ph
In continuation of our interest in the synthesis of amino
acid/peptide conjugates of biological interest,12,13 we re-
port herein an efficient, green synthesis of 5-ASA conju-
gates with amino acids and peptides in water in the
absence of any acid/base catalyst. Reaction of N-protected
aminoacyl benzotriazoles, N-protected dipeptidoyl, and
tripeptidoylbenzotriazoles (prepared by our reported pro-
cedures)14,15 with 5-ASA in water under microwave irra-
diation for two hours afforded the desired conjugates in
good yields (67–77%; Scheme 1, Table 1).
H
N
COOH
OH
Cbz
Cbz
7c
74
76
218–220
244–246
N
H
O
O
H
N
COOH
OH
7d
N
H
HN
R2
O
R2
O
7e
7f
71
75
240–242
204–206
H
BtH
SOCl2
H
H
COOH
Pg
Pg
Cbz
N
N
N
N
N
OH
N
N
N
H
H
H
O
O
R1
O
R1
N
OH
n = 0,1,2
4a–j, 4b+4b'
n = 0,1,2
5a–j, 5b+5b'
OBzl
O
H
N
OH
COOH
OH
Cbz
N
H
COOH
O
MW (70 °C, 50 W)
H2O, 2 h
Cbz
NH2
NH
mesalazine (6)
7g
7h
77
74
162–164
182–184
OH
H
R2
O
COOH
Cbz
N
H
N
H
Pg
N
N
N
COOH
O
BtH = benzotriazole
H
H
OH
O
R1
BzlO
Boc
O
n = 0,1,2
7a–j, 7b+7b'
H
N
COOH
OH
Scheme 1 Synthesis of 5-ASA conjugates 7a–j
N
H
O
Synthesis 2013, 45, 3255–3258
© Georg Thieme Verlag Stuttgart · New York

PAPER
Green, Catalyst-Free Synthesis of Mesalazine Conjugates
3257
Table 1 Preparation of 5-ASA Conjugates 7a–j
er was washed with aq 4 M HCl (3 × 30 mL), dried (Na2SO4), fil-
tered, and evaporated to give the desired product 7a–j, respectively.
Product
Yield Mp
(%) (°C)
5-(2-{[(Benzyloxy)carbonyl]amino}acetamido)-2-hydroxyben-
zoic Acid (Cbz-Gly-Mesalazine, 7a)
Yield: 0.31 g (69%); white microcrystals; mp 211–213 °C.
1H NMR (DMSO-d6): δ = 9.93 (s, 1 H), 8.11 (d, J = 2.7 Hz, 1 H),
7.66 (dd, J = 8.9, 2.5 Hz, 1 H), 7.54 (t, J = 6.0 Hz, 1 H), 7.38–7.25
(m, 5 H), 6.92 (d, J = 8.7 Hz, 1 H), 5.05 (s, 2 H), 3.78 (d, J = 6.0 Hz,
2 H).
13C NMR (DMSO-d6): δ = 171.7, 167.7 157.1, 156.6, 137.0, 130.6,
128.3, 127.8, 127.7, 127.4, 120.5, 117.2, 112.4, 65.5, 44.0.
HRMS: m/z [M – H]+ calcd for C17H16N2O6: 343.0936; found:
343.0951.
Ph
O
H
N
H
N
COOH
OH
7i
7j
71
67
249–251
Cbz
N
H
O
OH
NH
COOH
Ph
O
222–224
O
H
N
Cbz
(S)-5-(2-{[(Benzyloxy)carbonyl]amino}propanamido)-2-hy-
droxybenzoic Acid (Cbz-L-Ala-Mesalazine, 7b)
Yield: 0.34 g (73%); white microcrystals; mp 225–227 °C.
N
H
N
H
O
1H NMR (DMSO-d6): δ = 9.95 (s, 1 H), 8.13 (d, J = 2.4 Hz, 1 H),
7.67 (dd, J = 8.8, 2.3 Hz, 1 H), 7.57 (d, J = 7.1 Hz, 1 H), 7.38–7.20
(m, 5 H), 6.92 (d, J = 9.0 Hz, 1 H), 5.06 (d, J = 12.6 Hz, 1 H), 5.00
(d, J = 12.9 Hz, 1 H), 4.15 (t, J = 7.2 Hz, 1 H), 1.29 (d, J = 6.9 Hz,
3 H).
13C NMR (DMSO-d6): δ = 171.7, 171.3, 157.1, 155.8, 137.0, 130.7,
128.3, 127.7, 127.4, 120.6, 117.6, 117.1, 112.6, 65.4, 50.8, 18.0.
To elucidate the range of applicability, 5b (Cbz-Ala-Bt)
was selected for coupling with 5-ASA in organic solvents
(EtOH, DMF, THF), tap and distilled water, and also un-
der solvent-free conditions. Tap and distilled water gave
essentially identical results, whereas the other solvents
gave inferior results to water. We also tried the reaction
with different times (5 min to 3 h under microwave irradi-
ation and up to 6 h under conventional heating). Optimi-
zation of reaction conditions revealed best results under
microwave heating at 70 °C for two hours; conventional
heating was less efficient.
HRMS: m/z [M – H]+ calcd for C18H18N2O6: 357.1092; found:
357.1102.
5-(2-{[(Benzyloxy)carbonyl]amino}propanamido)-2-hydroxy-
benzoic Acid (Cbz-DL-Ala-Mesalazine, 7b + 7b′)
Yield: 0.34 g (72%); white microcrystals; mp 242–244 °C.
1H NMR (DMSO-d6): δ = 9.95 (s, 1 H), 8.13 (d, J = 2.4 Hz, 1 H),
7.67 (dd, J = 8.8, 2.3 Hz, 1 H), 7.58 (d, J = 7.2 Hz, 1 H), 7.38–7.20
(m, 5 H), 6.92 (d, J = 9.0 Hz, 1 H), 5.06 (d, J = 12.6 Hz, 1 H), 5.00
(d, J = 12.9 Hz, 1 H), 4.15 (d, J = 7.1 Hz, 1 H), 1.29 (d, J = 6.9 Hz,
3 H).
In summary, we have reported novel, facile, and green
conditions for the synthesis of mesalazine conjugates
without the use of catalysts, synthetic auxiliaries, or or-
ganic solvent. The heterogeneous reaction run in water
produces good yields of mesalazine conjugates without
loss of chirality.
13C NMR (DMSO-d6): δ = 171.7, 171.3, 157.0, 155.8, 137.0, 130.7,
128.3, 127.8, 127.5, 120.6, 117.2, 112.4, 65.4, 50.7, 18.0.
(S)-5-(2-{[(Benzyloxy)carbonyl]amino}-3-phenylpropanami-
do)-2-hydroxybenzoic Acid (Cbz-L-Phe-Mesalazine, 7c)
Yield: 0.42 g (74%); white microcrystals; mp 218–220 °C.
Commercial reagents were purchased from Sigma-Aldrich and
were used without purification. Solvents were purified by distilla-
tion. Melting points were determined on a capillary point apparatus
equipped with a digital thermometer. NMR spectra were recorded
in DMSO-d6 on Mercury or Gemini NMR spectrometers operating
at 300 MHz for 1H (with TMS as an internal standard) and 75 MHz
for 13C. Elemental analyses were performed on a Carlo Erba-
EA1108 instrument. All microwave assisted reactions were carried
out with a single mode cavity Discover Microwave Synthesizer
(CEM Corporation, NC, USA). The reaction mixtures were trans-
ferred into a 10 mL glass pressure microwave tube equipped with a
magnetic stirrer bar. The tube was closed with a silicone septum and
the reaction mixture was subjected to microwave irradiation (Dis-
cover mode; run time: 60 sec.; PowerMax-cooling mode.
1H NMR (DMSO-d6): δ = 10.09 (s, 1 H), 8.10 (d, J = 2.6 Hz, 1 H),
7.72–7.65 (m, 2 H), 7.37–7.16 (m, 11 H), 6.93 (d, J = 8.7 Hz, 1 H),
4.97 (s, 2 H), 4.41–4.15 (m, 1 H), 3.11–3.01 (m, 1 H), 2.89–2.80 (m,
1 H).
13C NMR (DMSO-d6): δ = 171.6, 170.1, 157.1, 155.9, 137.8, 136.9,
130.5, 129.2, 129.0, 128.2, 128.1, 128.0, 127.7, 127.5, 126.3, 120.7,
117.2, 112.4, 65.3, 56.9, 55.5.
HRMS: m/z [M – H]+ calcd for C24H22N2O6: 433.1405; found:
433.1419.
(S)-5-(2-{[(Benzyloxy)carbonyl]amino}-3-methylbutanamido)-
2-hydroxybenzoic Acid (Cbz-L-Val-Mesalazine, 7d)
Yield: 0.38 g (76%); white microcrystals; mp 244–246 °C.
1H NMR (DMSO-d6): δ = 10.01 (s, 1 H), 8.13 (d, J = 2.3 Hz, 1 H),
7.68 (dd, J = 8.9, 2.4 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.37–7.22
(m, 5 H), 6.92 (d, J = 8.9 Hz, 1 H), 5.04 (s, 2 H), 3.94 (t, J = 8.4 Hz,
1 H), 2.04–1.95 (m, 1 H), 0.90 (d, J = 6.7 Hz, 6 H).
Protected Aminoacyl/Peptidoylbenzotriazoles 5a–j; General
Procedure
The compounds were synthesized following our established proce-
dure.14,15
13C NMR (DMSO-d6): δ = 171.7, 170.2, 157.1, 156.2, 137.0, 130.5,
128.3, 127.8, 127.7, 127.5, 120.6, 117.2, 112.4, 65.5, 61.1, 30.2,
19.2, 18.5.
HRMS: m/z [M – H]+ calcd for C20H22N2O6: 385.1405; found:
385.1413.
Protected Aminoacyl/Peptidyl-Mesalazine Conjugates 7a–j;
General Procedure
A mixture of respective protected aminoacyl/peptidoylbenzotri-
azolide 5a–j (1.0 mmol) and mesalazine (6; 184 mg, 1.2 mmol) in
H2O (3 mL) was irradiated in microwave at 70 °C and 50 W for 2 h.
After completion of the reaction, the mixture was diluted with aq 4
M HCl (5 mL) and extracted with EtOAc (50 mL). The organic lay-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3255–3258

3258
M. A. Ibrahim et al.
PAPER
(S)-5-[2-{[(Benzyloxy)carbonyl]amino}-3-(1H-indol -3-
yl)propanamido]-2-hydroxybenzoic Acid (Cbz-L-Try-Mesala-
zine, 7e)
13C NMR (DMSO-d6): δ = 172.4, 171.6, 169.5, 157.2, 155.8, 137.4,
136.9, 130.4, 129.2, 128.3, 128.1, 127.8, 127.7, 127.5, 126.4, 120.6,
117.2, 112.5, 65.5, 54.5, 50.3, 37.5, 18.0.
HRMS: m/z [M – H]+ calcd for C27H27N3O7: 504.1776; found:
504.1799.
Yield: 0.44 g (71%); white microcrystals; mp 240–242 °C.
1H NMR (DMSO-d6): δ = 8.11 (br s, 1 H), 7.72–7.67 (m, 2 H), 7.57
(d, J = 7.8 Hz, 1 H), 7.35–6.91 (m, 11 H), 4.98 (br s, 2 H), 4.46–4.39
(m, 1 H), 3.21–3.14 (m, 1 H), 3.05–2.98 (m, 1 H).
13C NMR (DMSO-d6): δ = 171.7, 170.6, 157.2, 155.9, 137.0, 136.1,
130.7, 128.3, 128.1, 127.7, 127.6, 127.2, 123.9, 120.9, 118.6, 118.2,
117.1, 112.4, 111.3, 109.9, 65.4, 56.2, 27.8.
5-[(5S,8S)-5-Benzyl-8-methyl-3,6,9-trioxo-1-phenyl-2-oxa-
4,7,10-triazadodecan-12-amido]-2-hydroxybenzoic Acid (Cbz-
L-Phe-L-Ala-Gly-Mesalazine, 7j)
Yield: 0.49 g (67%); white microcrystals; mp 222–224 °C.
1H NMR (DMSO-d6): δ = 8.31–8.15 (m, 2 H), 7.69 (d, J = 6.9 Hz,
1 H), 7.50 (d, J = 8.1 Hz, 1 H), 7.40–7.16 (m, 10 H), 6.92 (d, J = 7.5
Hz, 1 H), 4.94 (s, 2 H), 4.32 (br s, 2 H), 3.88 (br s, 2 H), 3.09–2.99
(m, 1 H), 2.79–2.69 (m, 1 H), 1.28 (d, J = 6.3 Hz, 3 H).
13C NMR (DMSO-d6): δ = 172.5, 171.7, 171.6, 167.3, 157.1, 155.9,
138.1, 137.0, 130.5, 129.2, 128.3, 128.0, 127.7, 127.4, 126.2, 120.5,
117.3, 112.4, 109.6, 65.2, 56.0, 48.5, 37.4, 18.0.
HRMS: m/z [M – H]+ calcd for C26H23N3O6: 472.1514; found:
472.1537.
(S)-5-(4-Benzyloxy-2-{[(benzyloxy)carbonyl]amino}-4-oxobu-
tanamido)-2-hydroxybenzoic Acid [Cbz-L-Asp(Cbz)-Mesala-
zine, 7f]
Yield: 0.48 g (75%); white microcrystals; mp 204–206 °C.
1H NMR (DMSO-d6): δ = 8.14 (br s, 1 H), 7.79–7.66 (m, 2 H), 7.42–
7.23 (m, 10 H), 6.95–6.90 (m, 1 H), 5.11–5.06 (m, 4 H), 4.59 (s, 1
H), 2.93–2.69 (m, 2 H).
HRMS: m/z [M – H]+ calcd for C29H30N4O8: 561.1991; found:
561.2004.
13C NMR (DMSO-d6): δ = 171.7, 170.0, 168.9, 157.3, 155.8, 136.8,
136.0, 130.5, 128.4, 128.0, 127.8, 127.7, 121.0, 117.1, 112.5, 65.7,
65.7, 52.0, 36.3.
HRMS: m/z [M – H]+ calcd for C26H24N2O8: 491.1460; found:
491.1483.
Acknowledgment
We thank the University of Florida and the Kenan Foundation for
financial support. This paper was also funded in part by generous
support from King Abdulaziz University, under grant No. (D-
006/431). The authors, therefore, acknowledge the technical and fi-
nancial support of KAU. We also thank Dr. C. D. Hall for useful
suggestions and English checking.
(S)-5-(2,6-Bis{[(benzyloxy)carbonyl]amino}hexanamido)-2-hy-
droxybenzoic Acid [Cbz-L-Lys(Cbz)-Mesalazine, 7g]
Yield: 0.55 g (77%); white microcrystals; mp 162–164 °C.
1H NMR (DMSO-d6): δ = 8.14 (s, 1 H), 7.70 (dd, J = 9.0, 2.4 Hz, 1
H), 7.53 (d, J = 7.5 Hz, 1 H), 7.38–7.23 (m, 11 H), 6.93 (d, J = 8.7
Hz, 1 H), 5.05 (s, 2 H), 5.00 (s, 2 H), 4.13–4.05 (m, 1 H), 3.01–2.97
(m, 2 H), 1.68–1.61 (m, 2 H), 1.42–1.30 (m, 4 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
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13C NMR (DMSO-d6): δ = 171.7, 170.8, 157.1, 156.1, 137.3, 137.0,
130.7, 128.3, 128.1, 128.0, 127.9, 127.8, 127.8, 127.7, 127.5, 120.6,
117.2, 112.4, 65.5, 65.1, 64.9, 55.4, 31.5, 29.1, 22.9.
HRMS: m/z [M – H]+ calcd for C29H31N3O8: 548.2038; found:
548.2059.
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Yield: 0.47 g (71%); white microcrystals; mp 249–251 °C.
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Hz, 1 H), 7.58 (d, J = 7.2 Hz, 1 H), 7.47–7.40 (m, 5 H), 7.38–7.31
(m, 5 H), 7.02 (d, J = 9.0 Hz, 1 H), 5.12 (m, 2 H), 4.74–4.67 (m, 1
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