A simple method for synthesis of active esters of isonicotinic and picolinic acids

Article abstract of DOI:10.3390/60100047

A method for preparation of the p-nitrophenyl-, N-hydroxysuccinimidyl- and pentafluorophenyl esters of isonicotinic and picolinic acids from the corresponding acids is reported.

Full text of DOI:10.3390/60100047

Molecules 2001, 6, 47-51
molecules
ISSN 1420-3049
2001 by MDPI
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A Simple Method for Synthesis of Active Esters of Isonicotinic
and Picolinic Acids
Jørn B. Christensen*
CISMI, University of Copenhagen, Symbion Science Park, Fruebjergvej 3, DK-2100 Copenhagen,
Denmark.
*
Author to whom correspondence should be addressed. E-mail: j.b.Christensen@symbion.ki.ku.dk
Received: 14 May 2000; in revised form 20 December 2000 / Accepted: 20 December 2000 /
Published: 16 January 2001
Abstract: A method for preparation of the p-nitrophenyl-, N-hydroxysuccinimidyl- and
pentafluorophenyl esters of isonicotinic and picolinic acids from the corresponding acids is
reported.
Keywords: Active esters, pyridine carboxylic acids.
Introduction
In connection with ongoing synthetic work, we needed access to good acylating reagents based on
isonicotinic and picolinic acids. Acylations with isonicotinoyl and picolinoyl chlorides were found to
be troublesome, because the acid chlorides are only prepared or available as the corresponding
hydrochlorides, which are only sparingly soluble in inert solvents. A further complication was, that
upon reaction with polyamines such as poly(propyleneimine) dendrimers incomplete reactions
occurred due to extensive salt formation. Therefore we turned our attention to the so called active
esters [1].
Results and Discussion
Searching the literature we found references to the p-nitrophenyl esters of isonicotinic [2,3] and
picolinic acid [2,3,4], which have been used for the synthesis of potent antagonists of the luteinizing
hormone-releasing hormone (LHRH) [4,5]. The only other ester reported was the pentachlorophenyl

Molecules 2001, 6
48
ester of isonicotinic acid [6], however in the latter case, no experimental details were given. All the
procedures were based on the DCC coupling of the acids with the corresponding phenol, however
especially in the case of picolinic acid the coupling reaction was hampered by the well known
rearrangement of the intermediate O-acylureas to N-acylureas [2]. This problem could be solved by
performing the coupling reaction in CH Cl , but again no experimental details were given [2]. We were
2
2
primarily interested in obtaining the more reactive [1] N-hydroxysuccinimidyl and pentafluorophenyl
esters, and since DCC-coupling mainly gave the corresponding N-acyl-N,N’-dicyclohexylureas, the
present method was developed. Reaction of the corresponding pyridinecarboxylic acid with SOCl2
catalyzed by DMF [7] at room temperature gives the acid chlorides as their hydrochlorides. These were
reacted with 4-nitrophenol, pentafluorphenol and N-hydroxysuccinimide in THF with triethylamine as
base to give the corresponding active esters. The compounds prepared are shown Table 1.
Table 1.
Isonicotinic (1) and Picolinic (2) acid esters prepared.
F
F
O
R (yield):
O N
O
F
O
N O
2
F
F
O
COR
N
1
a (54%)
1b (97%)
2b (92%)
1c (84%)
2a (39%)
2c (67%)
N
COR
Conclusions
A convenient method has been developed for the synthesis of a variety of active esters of
isonicotinic and picolinic acids.
Experimental
General
1
13
H- and C-NMR spectra were obtained using a Varian Gemini 300 NMR or a Varian Unity 400
NMR. Mass spectra were obtained using a Jeol JMS-HX 110 A Tandem Mass Spectrometer. IR-
spectra were recorded on a Perkin Elmer 1760 X. All melting points are uncorrected. The elemental
analyses were performed by Mrs. Karin Linthoe, Department of Organic Chemistry, University of
Copenhagen. All chemicals were used as received.

Molecules 2001, 6
49
Isonicotinoylchloride hydrochloride
Thionylchloride (60 mL) was added carefully to a stirred mixture of isonicotinic acid (24.6 g; 0.2
mol) and DMF (1 mL). A lively gas evolution started, and after 30 minutes all of the acid had gone into
solution and the temperature had risen to about 40°C. Excess thionyl chloride was removed in vacuo,
and diethyl ether (200 mL) was stirred into the residue. The crude product was filtered, washed with
diethyl ether and dried in vacuo at 40°C. Yield: 35.0 g (98%) of white crystals sufficiently pure for the
preparation of the activated esters.
Picolinoylchloride hydrochloride
Prepared analogously to isonicotinoylchloride hydrochloride.
General procedure for the preparation of active esters
Isonicotinic acid pentafluorophenyl ester
To a stirred suspension of isonicotinoylchloride hydrochloride (8.9 g; 0.05 mol) and
pentafluorophenol (9.2 g; 0.05 mol) in THF (100 mL) was added triethylamine (20 mL; 0.14 mol) over
1
0 minutes. The suspension was stirred at room temperature for 12 hrs, filtered and concentrated in
vacuo. The residue was dissolved in hexane (300 mL), treated with activated carbon and filtered. The
hexane was removed to give the pentafluorophenyl ester as a slightly brownish oil, which crystallized
1
to give a creme colored solid melting 52-54°C. Yield: 14.0 g (97%); H-NMR (300 MHz; CDCl ) δ:
3
1
3
8
1
.93 (m; 2 H); 8.01 (m; 2 H). C-NMR (100 MHz; CDCl ) δ: 161.2; 150.9; 142.3 (m); 141.1 (m);
3
+
39.8 (m); 139.2 (m); 138.5 (m); 136.6 (m); 134.2; 123.3. MS (EI): M/Z: 290 (M ); 155; 106; 78; 51.
IR (KBr pellet): 3132, 3087, 3063, 2644, 2132, 1765, 1741, 1651, 1592, 1520, 1457, 1436, 1391, 1298,
241, 1163, 1098, 1067, 1042, 980, 865, 821, 787, 785, 714, 691, 621, 608. An analytical sample was
recrystallized from hexane. Found: C: 49.31; H: 1.40 ; N: 4.79. (Calcd. for C H F NO : 49.84% C;
1
1
2
4
5
2
1
.39% H; 4.84% N.)
Isonicotinic acid 4-nitrophenyl ester
This compound was prepared according to the general procedure with the exception, that the crude
product was crystallized from 2-propanol to give the ester in 54% yield. Mp. 137-138°C (137-139°C
1
13
[
5]). H-NMR (300 MHz; CDCl ) δ: 8.88 (m; 2 H); 8.35 (m; 2 H); 7.99 (m; 2 H); 7.44 (m; 2H). C-
3
NMR (63 MHz; CDCl ) δ: 162.80; 154.91; 150.88; 146.0; 135.76; 125.31; 123.05; 122.32. MS(EI):
3
+
M/Z: 245 (M ); 106; 78; 51. IR (KBr pellet): 3462, 3116, 3086, 3053, 3024, 1746, 1615, 1594, 1567,
1
7
525, 1489, 1408, 1357, 1326, 1312, 1272, 1210, 1163, 1109, 1087, 1061, 1012, 884, 864, 847, 833,
50, 699, 677, 624.

Molecules 2001, 6
50
Isonicotinic acid N-hydroxysuccinimidyl ester
Prepared according to the general procedure with the exception that the crude product was
1
crystallized from 2-propanol to give the ester in 84% yield. Mp. 140-141°C. H-NMR (300 MHz;
1
3
CDCl ) δ: 8.81 (m; 2 H); 7.87 (m; 2 H); 2.88 (d; J = 8.6 Hz; 4 H). C-NMR ( 63 MHz; CDCl ) δ:
3
3
+
1
68.54; 160.62; 150.79; 132.39; 122.95; 25.46. MS(EI): M/Z: 220 (M ); 106; 78; 51. Found C: 54.14;
H: 3.80; N: 12.49. IR (KBr pellet): 3501, 3064, 2991, 2939, 1806, 1779, 1736, 1596, 1563, 1409,
1
3
367, 1326, 1238, 1201, 1074, 1018, 844, 806, 747, 698, 651, 603. (Calcd. for C H N O : 54.55.% C;
10 8 2 2
.66% H; 12.72 % N.)
Picolinic pentafluorophenyl ester
Prepared according to the general procedure, and crystallized twice from hexane. Transparent
1
crystals. Yield: 92%. Mp. 61-63°C. H-NMR (300 MHz; CDCl ) δ: 8.78 (m; 1 H); 8.21 (m; 1 H); 7.89
3
1
3
(
m; 1 H); 7.56 (m; 1 H). C-NMR (100 MHz; CDCl ) δ: 160.93; 150.14; 144.89; 140.75; 139.80;
3
+
1
39.00; 138.20; 137.29; 136.50; 128.11; 126.38. MS(EI): M/Z: 290 (M ); 242; 212; 183; 155; 106; 78.
IR (KBr pellet): 3518, 3054, 2467, 1768, 1715, 1654, 1616, 1593, 1520, 1473, 1411, 1330, 1263, 1212,
161, 1078, 1056, 995, 857, 845, 806, 764, 748, 728, 699, 622, 576.
1
Picolinic acid p-nitrophenyl ester
Prepared according to the general procedure, and crystallized from 2-propanol. White needles.
1
Yield: 39%. Mp. 147-149°C (dec.). (155-157°C [5]). H-NMR (300 MHz; CDCl ) δ: 8.86 (m; 1 H);
3
1
3
8
1
2
1
.31 (m; 3 H); 7.96 (m; 1 H); 7.60 (m; 1 H); 7.45 (m; 2 H). C-NMR (63 MHz; CDCl ) δ: 162.87;
3
+
55.44; 150.13; 146.40; 145.48; 137.25; 127.78; 126.01; 125.16; 122.56; MS (EI): M/Z: 245 (M );
00; 106; 78. IR (KBr pellet): 3455, 3114, 3079, 1764, 1740, 1615, 1591, 1520, 1489, 1437, 1350,
293, 1245, 1218, 1160, 1094, 1072, 1045, 995, 887, 865, 836,749, 740, 712, 696, 681, 617.
Picolinic acid N-hydroxysuccinimidyl ester
Prepared according to the general procedure, and crystallized from 2-propanol. White crystals.
1
Yield: 67%. Mp. 172-174°C. H-NMR (300 MHz; CDCl ) δ: 8.84 (m; 1 H); 8.23 (m; 1 H); 8.12 (m; 1
3
1
3
H); 7.82 (m; 1 H); 2.91 (s; 4 H). C-NMR (63 MHz; CDCl ) δ: 169.04; 150.06; 143.5; 137.4; 128.5;
3
+
1
1
26.2; 25.4. MS (EI): M/Z: 220 (M ); 106; 78. IR (KBr pellet): 3493, 3093, 2955, 1799, 1776, 1742,
587, 1471, 1440, 1419, 1359, 1265, 1236, 1200, 1066, 1009, 851, 814, 744, 698, 642, 620, 598.
References
1
2
. Bodanzsky, M. Peptide Chemistry, 2nd ed., Springer-Verlag, Berlin-Heidelberg-New York 1993.,
pp. 60.
. Folkers, K.; Ljungqvist, A. The Reaction of Pyridinecarboxylic Acids with Dicyclohexyl-
carbodiimide and p-Nitrophenol. Acta Chem. Scand. 1988, B42, 408.

Molecules 2001, 6
51
3
4
. Fife, T. H.; Przystas, T. J. Divalent Metal Ion Catalysis in the Hydrolysis of Esters of Picolinic
Acid. Metal Ion Promoted Hydroxide Ion and Water Catalyzed Reactions. J. Am. Chem. Soc.
1
985, 107, 1041.
. Flouret, G.; Mahan, K.; Majewski, T. Decreased Histamine Release by Luteinizing Hormone-
Releasing Hormone Antagonists Obtained upon Translocation of the Cationic Amino Acid from
Position 8 to Position 7. J. Med. Chem. 1992, 35, 636.
5
6
7
. Janecka, A.; Janecki, T.; Shan, S.; Bowers, C.; Folkers, K. Novel, Potent Luteinizing Hormone-
Releasing Antagonistwith Improved Solubility in Water. J. Med. Chem. 1994, 37, 2238.
. Solárzano, C.; Davis; M. A. Preparation of Arene Ruthenium(II) Complexes with Activated
Ligands for Protein Labeling. Inorg. Chim. Acta 1985, 97, 135.
. Bosshard, H. H.; Mory, R.; Schmid, M.; Zollinger, H. Eine Methode zur katalysierten Herstellung
von Carbonsäure- und Sulfosäure-chloriden mit Thionylchlorid. Helv. Chim. Acta 1959, 42, 1653.
Sample Availability: Available from the author.
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