A novel one-pot synthesis of 3-[(3-Amino-4-methylaminobenzoyl pyridin-2-yl)amino]propionic acid ethyl ester

Full text of DOI:10.1080/00304948.2014.922383

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Organic Preparations and Procedures
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A Novel One-pot Synthesis of 3-[(3-
Amino-4-methylaminobenzoyl pyridin-2-
yl)amino]propionic Acid Ethyl Ester
Ya-jun Guoa, Yu Huanga, Zhe-dong Yuana & Xue-yan Zhua
a State Key Laboratory of New Drug and Pharmaceutical Process,
Shanghai Institute of Pharmaceutical Industry Shanghai, P. R. China
Published online: 10 Jul 2014.
To cite this article: Ya-jun Guo, Yu Huang, Zhe-dong Yuan & Xue-yan Zhu (2014) A Novel One-pot
Synthesis of 3-[(3-Amino-4-methylaminobenzoyl pyridin-2-yl)amino]propionic Acid Ethyl Ester, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 46:4, 376-380,
DOI: 10.1080/00304948.2014.922383
To link to this article: http://dx.doi.org/10.1080/00304948.2014.922383
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Organic Preparations and Procedures International, 46:376–380, 2014
Copyright © Shanghai Institute of Pharmaceutical Industry
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.922383
OPPI BRIEF
A Novel One-pot Synthesis of
3-[(3-Amino-4-methylaminobenzoyl
pyridin-2-yl)amino]propionic Acid Ethyl Ester
Ya-jun Guo, Yu Huang, Zhe-dong Yuan, and Xue-yan Zhu
State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai
Institute of Pharmaceutical Industry Shanghai, P. R. China
Dabigatran etexilate (N-[2-{4-[N-(hexyloxycarbonyl)amidino]phenylaminomethyl}-1-
methyl-1H-benzimidazol-5-ylcarbonyl]-N-(2-pyridyl)-β-alanine ethyl ester, 9) is a selec-
tive, reversible, and direct inhibitor of thrombin; it has been clinically developed for the
prevention of venous thrombolism and cardioembolic stroke.1–3 A key intermediate in
the preparation of dabigatran etexilate is reported4,5 to be 3-[(3-amino-4-methylamino-
benzoyl)pyridin-2-yl-amino]propionic acid ethyl ester (6), which has been obtained from
4-methylamino-3-nitrobenzoic acid (1) in only 25∼50% overall yield (Scheme 1).4–6
In the reported synthesis of 6 (Scheme 1), the methylamino group in 4-(methylamino)-
3-nitrobenzonic chloride (3) competes with the pyridinylamino group of 4 during the
acylation of 4 by 3. Consequently, this method suffers from undesirable side-reactions,
long reaction time and poor overall yield. Herein we report a one-pot synthesis of 6 in 85%
overall yield from 1 in four steps by introducing the methylamino group at a later stage, as
shown in Scheme 2.
Treatment of 1 with thionyl chloride gave the acid chloride 7 in near quantitative yield.
Coupling of 7 with 4 in the presence of N,N-diisopropylethylamine (DIPEA) afforded the
Submitted by April 8, 2013.
Address correspondence to Zhe-dong Yuan, State Key Laboratory of New Drug and Pharmaceu-
tical Process, Shanghai Institute of Pharmaceutical Industry, 1111 Zhongshanbeiyi Road,Shanghai
200437, P. R. China. E-mail: zhedongyuan@126.com
376

Ethyl 3-[(3-Amino-4-methylaminobenzoyl pyridin-2-yl)amino]propionate
377
Scheme 1
Reagents: (i) 25∼30% MeNH2 in H2O; (ii) SOCl2, DMF, toluene; (iii) Et3N; (iv) H2, Pd/C.
Scheme 2
Reagents: (i) SOCl2, DMF, toluene; (ii) DIPEA; (iii) 27∼30% MeNH2 in EtOH; (iv) HCO2NH4,
Pd/C.
corresponding amide 8 in 93% overall yield from 1. In this route, the most challenging
step is the preparation of compound 5 from 8, as early trials of the methylamination of 8
did not produce satisfactory yields. In this step, we investigated the use of methylamine
hydrochloride, aqueous methylamine, and methylamine in ethanol, as well as the effect of
reaction solvents in order to determine the optimum conditions that would allow maximum

378
Yuan et al.
conversion of 8 while minimizing the formation of undesirable by-products. The reaction
of 8 even with excess methylamine hydrochloride under strong alkali conditions was
incomplete, and treatment of 8 with aqueous methylamine led to partial hydrolysis of 8.
Methylamine in ethanol was found to give the best result. Solvents such as DMA, DMF and
NMP were more effective than THF and toluene. When methylamine in ethanol and DMF
was used, the reaction was complete in 5 h at room temperature and the yield was 85% from
8. Reduction of the NO2 group using ammonium formate as the hydrogen donor afforded
the final product 6 in 90% yield. This route gave compound 6 71% overall yield from 1.
At the same time, we were contemplating if a one-pot strategy would be more amenable
toward industrial production. To our surprise, when 8 was used without any work-up, the
methylamination was nearly quantitative and the reaction was complete within 30 min in
DMF. It appears that the N,N-diisopropylethyl- amine (DIPEA) hydrochloride generated
from the previous step acts as a catalyst for the methylamination. The catalytic action of
N,N-diisopropylethylamine hydrochloride was confirmed by the independent reaction of 8
with MeNH2 in the presence of the salt. Thus, compound 6 was obtained in 85% overall
yield from 1 using a one-pot synthetic approach by carrying out the reduction step without
isolation of 5 as illustrated above.
In conclusion, a highly efficient one-pot synthesis of 6 has been developed, and the
targeted critical intermediate 6 was obtained in 85% overall yield in four steps. Executing
four reaction steps in just one reactor and purifying only at the final stage significantly
improves the efficiency and the overall yield of the synthesis.
Experimental Section
All chemicals were reagent grade and available commercially. Melting points were ob-
tained on a capillary melting point apparatus and are uncorrected. 1H NMR spectras were
determined in DMSO-d6 on a Bruker-AV400 (400 MHz) instrument with TMS as inter-
nal standard. ESI-MS analyses were performed on a Q-Tomicro YA019 ion trap mass
spectrometer. The progress of the reactions was monitored by TLC and/or HPLC.
3-[(3-Amino-4-methylaminobenzoyl)-pyridin-2-ylamino]propionic Acid Ethyl Ester (6)
To a solution of 4-chloro-3-nitrobenzoic acid (1, 80 g, 0.40 mol) in a mixture of toluene
(650 ml) and N,N-dimethylformamide (2 ml) at 70◦C, thionyl chloride (34 ml, 0.47 mol)
was added dropwise and the mixture was stirred for 2 h. After the volatiles were removed
in vacuo at 55◦C, the remaining liquid was dissolved in anhydrous dichloro- methane
(400 ml). A solution of 3-(pyridin-2-ylamino)propionic acid ethyl ester 4 (77 g, 0.40 mol)
in anhydrous dichloromethane (400 ml), and N,N-diisopropylethylamine (131 ml) were
added, and the reaction temperature was maintained between 0 and –5◦C. The mixture was
stirred for 1 h at 0◦C, and then the solvents were removed in vacuo at 30◦C to give an
off-white powder. HPLC analysis of an aliquot of the powder indicated a purity of 93%
(determined by peak areas).
N,N-dimethylformamide (DMF, 740 ml) was added and the mixture was stirred at
70◦C for 15 min. Then a solution of 27∼30% methylamine in ethanol (140 ml) was added

Ethyl 3-[(3-Amino-4-methylaminobenzoyl pyridin-2-yl)amino]propionate
379
dropwise. The mixture was cooled to 25◦C. After 30 min, ananlysis by HPLC indicated
that it was the complete consumption of 8.
To the above solution, 10% Pd/C (11.1 g) and ammonium formate (65.1 g, 1.03 mol)
were then added. The mixture was stirred for 12 h at room temperature. The resulting
mixture was filtered through Celite by gravity and the filtrate was evaporated to yield an
oil which was dissolved in ethyl acetate (500 ml), and the solution was washed with water
(300 ml × 3) and brine (300 ml), respectively. The organic layer was dried over anhydrous
Na2SO4, evaporated in vacuo at 35◦C. The residual solid was recrystallized from toluene
(350 ml) to give 6 (116.1 g, 85% overall yield from 1) as a white powder, mp. 103–104◦C.
3-[(4-Chloro-3-nitrobenzoyl)pyridin-2-yl-amino]propionic Acid Ethyl Ester (8)
Crude compound 8 was prepared as described above. The solution was washed with water,
dried over anhydrous Na2SO4, evaporated in vacuo at 20◦C and recrystallized from 1-
methoxy-2-methylpropane to give a white powder, mp. 64–65◦C; ESI-MS (m/z): 378
([M+H]+), 400 ([M+Na]+); 1H-NMR: δ 1.19 (t, J = 7.2 Hz, 3H), 2.70 (t, J = 7.2 Hz, 2H),
3.95 (q, J = 7.2 Hz, 2H), 4.20 (t, J = 7.2 Hz, 2H), 7.22 (m, 2H), 7.25 (m, 1H), 7.44 (dd, J =
2.0, 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.75 (m, 1H), 7.92 (d, J = 2.0 Hz, 1H), 8.35
(m, 1H).
Anal. Calcd for C17H16ClN3O5: C, 54.05; H, 4.27; N, 11.12. Found: C, 54.16; H, 4.15;
N, 11.33.
3-[(4-Methylamino-3-nitrobenzoyl)pyridin-2-yl-amino]propionic Acid Ethyl Ester (5)
Crude compound 5 was prepared following the procedure described above. The solution
was evaporated in vacuo at 90◦C, and the residue was dissolved with ethyl acetate. The
solution was washed with water and brine and dried with anhydrous Na2SO4. The solvent
was removed in vacuo to afford 5 as a yellow powder, mp. 86–88◦C (lit.4 mp. 86–88◦C);
1
ESI-MS m/z: 373 ([M+H]+); H-NMR: δ 1.11 (t, J = 6.8 Hz, 3H), 2.66 (t, J = 7.2 Hz,
2H), 2.91 (t, J = 5.2 Hz, 3H), 3.96 (q, J = 7.2 Hz, 2H), 4.18 (t, J = 7.2 Hz, 2H), 6.83 (d,
J = 9.2 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.21 (m, 1H), 7.32 (dd, J = 2.0, 8.8 Hz, 1H),
7.69 (m, 1H), 7.93 (d, J = 2.0 Hz, 1H), 8.36 (m, 1H), 8.43 (m, 1H).
Anal. Calcd for C18H20N4O5: C, 58.06; H, 5.41; N, 15.05. Found: C, 58.19; H, 5.53;
N, 14.83.
3-[(3-Amino-4-methylaminobenzoyl)pyridin-2-yl-amino]propionic Acid Ethyl Ester (6)
Compound 6 was prepared as described above, was crystallized from toluene to a white
powder, mp. 103–104◦C. ESI-MS (m/z): 365 ([M+Na]+); 1H-NMR: δ 1.14 (t, J = 7.2 Hz,
3H), 2.62 (t, J = 7.2 Hz, 2H), 2.69 (d, J = 4.4 Hz, 3H), 3.96 (q, J = 7.2 Hz, 2H), 4.17
(t, J = 7.2 Hz, 2H), 4.49 (s, 2H), 5.07 (s, 1H), 6.12 (d, J = 8.4 Hz, 1H), 6.35 (dd, J = 8.4,
2.0 Hz, 1H), 6.69 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 7.12 (m, 1H), 7.55 (m, 1H), 8.39 (m,
1H).
Anal. Calcd for C18H22N4O3: C, 63.14; H, 6.48; N, 16.36. Found: C, 63.32; H 6.55;
N, 16.15.

380
Yuan et al.
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