HETEROCYCLES

Short Paper | Regular issue | Vol. 83, No. 10, 2011, pp. 2343-2352
Received, 24th June, 2011, Accepted, 2nd August, 2011, Published online, 9th August, 2011.
DOI: 10.3987/COM-11-12290

■ Convenient Synthesis of Aminopyridinecarboxylic Acids

Iwao Okamoto,* Masayuki Terashima, Rempei Yoshioka, Tomonori Muramatsu, Satomi Kojima, Haruka Inoue, Mio Takahashi, Nobuyoshi Morita, and Osamu Tamura

Showa Pharmaceutical University, 3-3165, Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan

Abstract

6-(Alkylamino)pyridine-2-carboxylic acids and 5-(alkylamino)pyridine-3-carboxylic acids were conveniently synthesized from dibromopyridine in satisfactory yields.

Pyridine, especially aminopyridinecarboxylic acids, are important structural units of both natural and synthetic bioactive compounds and many types of functional molecules,1,2 so efficient synthesis of these compounds is an important issue. Many synthetic studies of pyridine derivatives have been reported, and some of them also work well for aminopyridines.3 However, alkylaminopyridinecarboxylic acids are generally expensive, and their synthesis is troublesome because of their high polarity and water solubility. Herein we report a convenient synthesis of 6-(alkylamino)pyridine-2-carboxylic acids 1 and 5-(alkylamino)pyridine-3-carboxylic acids 2 from dibromopyridines.

As potential synthetic routes to pyridinecarboxylic acids with various alkylamino groups, we considered two simple approaches using commercially available compounds (Scheme 1). Route A, direct amination of bromopyridinecarboxylic acid 3 or 4, is expected to be a one-step synthesis, whereas route B, amination and carbonylation, can be started from dibromopyridine 7 or 8, which is relatively inexpensive. First, we examined route A (Scheme 2). This route is considered to be used generally in syntheses of many kinds of alkylaminopyridinecarboxamides. In order to synthesize in large scale with aqueous solution of amine, such as methylamine, we tried with simple conditions.

The amination of 3 and 4 was performed by heating the compounds with an aqueous solution of excess alkyl amine in a sealed tube, to avoid the need to separate a metal catalyst or other additive from the product. Although the amination of 6-bromopyridine-2-carboxylic acid 3 proceeded under this condition, the reaction gave amides 9 instead of carboxylic acids. The reaction of methyl 6-bromopyridine-2-carboxylate, instead of 3, with butylamine also gave the amide 9a in quantitative yield. These amides can be purified by chromatography, but their hydrolysis products can not be easily isolated from aqueous solution after acidic or basic hydrolysis. The methyl derivative 1b, obtained from 9b, could be isolated by crystallization from the neutralized solution (52%), but (butylamino)pyridinecarboxylic acid 1a, obtained from 9a, could not be isolated as a solid. Therefore, in this method, the amides should be converted to methyl esters 10, which can be purified by chromatography, then hydrolyzed to carboxylic acids 1 (Scheme 2).4 The reaction with ammonia solution afforded the aminated product 9c, however the yield was poor. As we can see from these results, the yield varies depending on the amine, probably because of polarity of the amine solution.
In the case of 3-bromopyridine derivatives, it is well known that similar amination requires a copper salt.4,5 The amination of 5-bromopyridine-3-carboxylic acid 4 in the presence of CuSO4 gave the desired amino acids 2. However, these compounds could not readily be purified from the copper-containing residue, and had to be converted to the methyl ester 11, chromatographed, then hydrolyzed to afford the amino acids 2. Thus, although it is possible to synthesize aminopyridinecarboxylic acids from bromopyridinecarboxylic acid derivatives, purification and handling of the products and intermediates are troublesome.

Next, we examined route B (Scheme 3). This method employs 2,6-dibromopyridine 7 or 3,5-dibromopyridine 8 as a starting material. The amination was carried out in a sealed bottle with 1 equivalent of alkylamine and 3 equivalents of triethylamine. The presence of water as a solvent is essential to obtain a good yield. 6-Bromo-2-(alkylamino)pyridines, 5a and 5b, were obtained from 7 in this simple way, but 3,5-dibromopyridine 8 reacted more slowly. In the latter case, the use of excess amine gave (butylamino)pyridine 6a in 48% yield, with 41% recovery of the starting material 8; and amination to (methylamino)pyridine 6b proceeded in good yield. These amination reactions were not accompanied with significant formation of the diamino product or other by-product, so this method may be suitable for large-scale synthesis.
Carbonylation of the amines 5 and 6 was performed by Albaneze-Walker’s method.6 Carbon monoxide insertion using (BINAP)PdCl2 afforded the corresponding methyl esters 10 and 11 in almost quantitative yield. These methyl esters were easily purified by chromatography with CH2Cl2 then AcOEt as eluents. The amino acids 1 and 2, which can not be easily purified by chromatography, are obtained by hydrolysis of the methyl esters with LiOH and acidification with an equimolar amount of hydrochloric acid, followed by recrystallization from water. Thus, these simple sequences afforded (alkylamino)pyridinecarboxylic acids 1 and 2 from dibromopyridine.
In conclusion, we have examined two simple methods for the synthesis of (alkylamino)pyridinecarboxylic acids. Monoamination of dibromopyridine followed by carbonylation using carbon monoxide was found to be convenient, and should be suitable for the synthesis of many alkylaminopyridine compounds.

EXPERIMENTAL
Melting points were determined by using a Yanaco melting point apparatus MP-S3 and are uncorrected. Autoclave reaction was performed in a TVS-1 (Taiatsu Techno Corporation) with a pressure gauge. Elemental analyses were carried out on Thermo Finnigan Flash EA1112, and antipyrine was used as a standard. 1H and 13C NMR spectra were recorded on JEOL AL-300, and chemical shifts are expressed in ppm relative to tetramethylsilane. IR spectra were recorded on Shimadzu FTIR-8200A. Mass spectra were measured on JEOL MS700 or HX110. Silica gel [silica gel 40-50 °C µ neutral, (Kanto Chemical Co., Inc.)] was used for all chromatographic procedures. Starting materials, 6-bromopyridine-2- carboxylic acid (3, from TCI), 5-bromopyridine-3-carboxylic acid (4, from TCI), 2,6-dibromopyridine (5, from TCI), 3,5-dibromopyridine (6, from TCI), (MeCN)2PdCl2 (from Aldrich) and rac-BINAP (from TCI), were commercial products and were used as received.

(rac-BINAP)PdCl2 7
A mixture of (MeCN)2PdCl2 (5.19 g, 20.0 mmol), rac-BINAP (12.46 g, 20.0 mmol) and acetonitrile (160 mL) was stirred at 50 °C for 15 h, then at ambient temperature for 6 h. The bright yellow powder was collected by filtration and washed with acetonitrile to give the complex quantitatively. This complex was used for CO insertion without further purification.

2-(Butylamino)-6-bromopyridine (5a)
A mixture of 2,6-dibromopyridine (20.1 g, 84.8 mmol), triethylamine (40 mL, 287 mmol), butylamine (10 mL, 101 mmol) and water (50 mL) was heated in a sealed bottle with stirring at 190 °C for 23 h. After cooling, the mixture was poured into sat. NaHCO3 aq., and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and evaporated with a rotary evaporator to give the crude product, which was chromatographed (CH2Cl2) to give the amine 5a (18.8 g, 96%) as a pale yellow oil. 1H NMR (CDCl3) 7.25 (1H, t, J = 7.7), 6.70 (1H, d, J = 7.3), 6.27 (1H, d, J = 8.1), 4.65 (1H, br-s), 3.20 (2H, q, J = 7.0), 1.59 (2H, quint, J = 7.0), 1.41 (2H, sext, J = 7.0), 0.95 (3H, t, J = 7.3). 13C NMR (CDCl3) 159.0, 140.3, 139.5, 115.5, 103.9, 42.0, 31.4, 20.1, 13.8. IR (KBr) 3360, 2958, 1550, 1433 cm-1. LR-MS (EI) 228, 230 [M+]. HR-MS (EI) Calcd for C9H13N2Br: 228.0262, 230.0243; Found: 228.0270, 230.0216.

2-(Methylamino)-6-bromopyridine (5b)
A mixture of 2,6-dibromopyridine (2.59 g, 10.9 mmol), triethylamine (5.0 mL, 35.9 mmol), methylamine solution in water (1.0 mL, 12 mmol) and water (5.0 mL) was heated in a sealed bottle with stirring at 190 °C for 23 h. After cooling, the mixture was poured into sat. NaHCO3 aq. and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and evaporated in a rotary evaporator to give the crude product, which was chromatographed (CH2Cl2) to give the amine 5b (1.47 g, 72%) as colorless needles. Mp 62.0-63.0 °C (hexane). 1H NMR (CDCl3) 7.27 (1H, t, J = 7.7), 6.72 (1H, dd, J = 7.5, 0.6), 6.28 (1H, dd, J = 8.3, 0.4), 4.87 (1H, br-s), 2.90 (3H, d, J = 5.3). 13C NMR (CDCl3) 159.8, 140.2, 139.5, 115.5, 103.7, 29.1. IR (KBr) 3311, 1596, 1558, 1448 cm-1. LR-MS (EI) 186, 188 [M+]. Anal. Calcd for C6H7N2Br: C, 38.53; H, 3.77; N, 14.98. Found: C, 38.53; H, 3.56; N, 14.74.

Methyl 6-(butylamino)pyridine-2-carboxylate (10a)
An autoclave was charged with a solution of 5a (18.8 g, 82.1 mmol), triethylamine (15 mL, 108 mmol) MeOH (100 mL), and a stirrer bar, then nitrogen gas was bubbled through for 1 min, followed by addition of (rac-BINAP)PdCl2 (115 mg, 0.144 mmol). The autoclave was sealed and air was replaced with CO (by means of several cycles of evacuation and flushing with CO) at a pressure of 0.4 MPa.6 The mixture was heated at 100 °C with stirring and continuous addition of CO gas to maintain the pressure for 23 h. After cooling, the mixture was filtered and the filtrate was evaporated to give the crude product, which was chromatographed (AcOEt/hexane 1:3) to give the ester 10a (13.8 g, 87%) as a pale yellow oil. 1H NMR (CDCl3) 7.56 (1H, t, J = 8.1), 7.40 (1H, d, J = 7.3), 6.56 (1H, d, J = 8.4), 4.86 (1H, br-s), 3.95 (3H, s), 3.23 (2H, q, J = 7.0), 1.61 (2H, quint, J = 7.7), 1.44 (2H, sext, J = 7.7), 0.95 (3H, t, J = 7.3). 13C NMR (DMSO-d6) 165.8, 158.7, 145.7, 137.0, 112.7, 111.7, 51.8, 40.3, 30.9, 19.6, 13.6. IR (KBr) 3400, 2954, 1725, 1528, 1270 cm-1. LR-MS (EI) 208 [M+]. HR-MS (EI) Calcd for C11H16N2O2: 208.1212; Found: 208.1220.

Methyl 6-(methylamino)pyridine-2-carboxylate (10b)
Product 10b was obtained in 94% yield from 5b (1.125 g, 6.01 mmol) by using a similar method to that employed for 10a. Mp 49.0-51.0 °C (hexane). 1H NMR (DMSO-d6) 7.51 (1H, dd, J = 8.4, 7.2), 7.17 (1H, dd, J = 7.2, 0.8), 6.79 (1H, br-q, J = 4.3), 6.64 (1H, dd, J = 8.4, 0.8), 3.79 (3H, s), 2.77 (3H, d, J = 4.9). 13C NMR (DMSO-d6) 165.8, 159.2, 145.8, 137.1, 112.8, 111.5, 51.8, 27.8. IR (KBr) 3334, 3278, 2949, 1718, 1602, 1521 cm-1. LR-MS (EI) 166 [M+]. Anal. Calcd for C8H10N2O2: C, 57.82; H, 6.07; N, 16.86. Found: C, 57.78; H, 6.07; N, 16.88.

6-(Butylamino)pyridine-2-carboxylic acid (1a)
To a solution of ester 10a (9.91 g, 47.6 mmol) in MeOH (120 mL), a solution of LiOH monohydrate (2.20 g, 52.4 mmol) in water (60 mL) was added. The resulting mixture was stirred at ambient temperature under an argon atmosphere for 17 h. After the addition of 1 mol/L hydrochloric acid (52.4 mL, 52.4 mmol) and stirring for 15 min, volatile materials were removed, first with a rotary evaporator, then under vacuum. Water (10 mL) was added, then the residue was collected by filtration and washed with water to give the product 1a (8.74 g, 95%) as a pale yellow powder. Mp 153.0-156.0 °C (water). 1H NMR (DMSO-d6) 7.49 (1H, t, J = 8.1), 7.13 (1H, d, J = 7.3), 6.74 (1H, br-t, J = 5.9), 6.66 (1H, d, J = 8.4), 3.27 (2H, q, J = 6.6), 1.51 (2H, quint, J = 7.0), 1.36 (2H, sext, J = 7.0), 0.90 (3H, t, J = 7.3). 13C NMR (DMSO-d6) 166.3, 158.3, 146.0, 137.4, 112.1, 111.8, 40.3, 31.0, 19.7, 13.7. IR (KBr) 3280, 3057, 1658, 1586 cm-1. LR-MS (EI) 194 [M+]. Anal. Calcd for C10H14N2O2+1/2H2O: C, 59.10; H, 7.44; N, 13.78. Found: C, 59.18; H, 7.54; N, 13.69.

6-(Methylamino)pyridine-2-carboxylic acid (1b)
1b was obtained from 10b in 91% yield by using a similar method to that employed for 1a. Mp 195.0-196.0 °C (water). 1H NMR (DMSO-d6) 7.51 (1H, dd, J = 8.4, 7.1), 7.16 (1H, d, J = 7.1), 6.74 (1H, br-q, J = 4.6), 6.65 (1H, d, J = 8.4), 2.80 (3H, d, J = 4.6). 13C NMR (DMSO-d6) 166.3, 158.9, 146.1, 137.5, 112.3, 111.7, 27.8. IR (KBr) 3481, 3274, 3101, 1647, 1541, 1400 cm-1. LR-MS (EI) 152 [M+]. Anal. Calcd for C7H8N2O2: C, 55.26; H, 5.30; N, 18.41. Found: C, 55.22; H, 5.43; N, 18.26.

3-(Butylamino)-5-bromopyridine (6a)
A mixture of 3,5-dibromopyridine (1.015 g, 4.28 mmol), butylamine (4.3 mL, 43.5 mmol) and water (4.3 mL) was heated in a sealed bottle with stirring at 190 °C for 46 h. After cooling, the mixture was poured into sat. NaHCO3 aq. and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and evaporated in a rotary evaporator to give the crude product, which was chromatographed (CH2Cl2) to give the amine 6a (474 mg, 48%), together with recovery of the substrate (413 mg, 41%). Mp 61.0-62.0 °C (hexane). 1H NMR (CDCl3) 7.96 (1H, d, J = 1.8), 7.91 (1H, d, J = 2.4), 6.99 (1H, t, J = 1.8), 3.76 (1H, br-s), 3.10 (2H, q, J = 6.9), 1.62 (2H, quint, J = 7.5), 1.43 (2H, sext, J = 7.8), 0.97 (3H, t, J = 7.5). 13C NMR (CDCl3) 145.3, 138.6, 134.3, 121.1, 120.1, 43.1, 31.2, 20.1, 13.8. IR (KBr) 3261, 2924, 1583 cm-1. LR-MS (EI) 228, 230 [M+]. Anal. Calcd for C9H13N2Br: C, 47.18; H, 5.72; N, 12.23. Found: C, 47.20; H, 5.71; N, 12.00.

3-(Methylamino)-5-bromopyridine (6b)
6b was obtained in 89% yield (17.59 g) from 3,5-dibromopyridine (25.0 g, 105 mmol) and methylamine solution (40%, 150 mL) by a similar method to that employed for 6a. Mp 91.5-93.5 °C (hexane), colorless flakes. 1H NMR (CDCl3) 7.99 (1H, d, J = 1.8), 7.93 (1H, d, J = 2.5), 7.00 (1H, t, J = 2.2), 3.88 (1H, br-s), 2.85 (3H, d, J = 5.3). 13C NMR (CDCl3) 146.1, 138.8, 134.1, 121.1, 119.9, 30.0. IR (KBr) 3261, 2924, 1583 cm-1. LR-MS (EI) 186, 188 [M+]. Anal. Calcd for C6H7N2Br: C, 38.53; H, 3.77; N, 14.98. Found: C, 38.60; H, 3.65; N, 14.92.

Methyl 5-(butylamino)pyridine-3-carboxylate (11a)
11a was obtained in 95% yield from 6a by a similar method to that employed for 10a. 11a: Mp 111.5-113.0 °C (AcOEt/hexane), colorless needles. 1H NMR (DMSO-d6, 60 °C) 8.26 (1H, br-s), 8.16 (1H, br-s), 7.33 (1H, dd, J = 2.6, 1.8), 6.02 (1H, br-t, J = 5.1), 3.84 (3H, s), 3.06 (2H, q, J = 6.6), 1.55 (2H, quint, J = 7.0), 1.39 (2H, sext, J = 7.0), 0.92 (3H, t, J = 7.3). 13C NMR (DMSO-d6, 150 °C) 165.2, 114.2, 138.4, 136.5, 125.2, 116.6, 50.7, 41.7, 30.1, 18.7, 12.3. IR (KBr) 3269, 2928, 1724, 1601 cm-1. LR-MS (EI) 208 [M+]. Anal. Calcd for C11H16N2O2: C, 63.44; H, 7.74; N, 13.45. Found: C, 63.51; H, 7.89; N, 13.31.

Methyl 5-(methylamino)pyridine-3-carboxylate (11b)
11b was obtained in 97% yield from 6b by a similar method to that employed for 10a. 11b: Mp 124.0-124.5 °C (AcOEt/hexane), pale yellow prisms. 1H NMR (CDCl3) 8.48 (1H, br-s), 8.11 (1H, br-s), 7.37 (1H, dd, J = 2.8, 1.6), 4.11 (1H, br-s) 3.86 (3H, s), 2.83 (3H, s). 13C NMR 166.5, 144.8, 139.5, 139.3, 126.1, 117.9, 52.2, 30.2. IR (KBr) 3271, 3065, 1716, 1593 cm-1. LR-MS (EI) 166 [M+]. Anal. Calcd for C8H10N2O2: C, 57.82; H, 6.07; N, 16.86. Found: C, 58.02; H, 6.02; N, 16.63.

5-(Butylamino)pyridine-3-carboxylic acid (2a)
2a was obtained in 91% yield from 11a by a similar method to that employed for 1a. 2a: Mp 168.0-170.5 °C (water). 1H NMR (DMSO-d6, 60 °C) 8.25 (1H, br-s), 8.12 (1H, br-d, J = 2.2), 7.32 (1H, dd, J = 2.6, 1.8), 5.95 (1H, br-s), 3.06 (2H, t, J = 7.0), 1.55 (2H, quint, J = 7.3), 1.39 (2H, sext, J = 7.3), 0.92 (3H, t, J = 7.3). 13C NMR (DMSO-d6, 120 °C) 166.1, 144.3, 138.1, 136.9, 126.2, 117.0, 41.8, 30.2, 18.9, 12.7. IR (KBr) 3300, 2960, 1701, 1597 cm-1. LR-MS (EI) 194 [M+]. Anal. Calcd for C10H14N2O2: C, 61.84; H, 7.27; N, 14.42. Found: C, 61.72; H, 7.34; N, 14.25.

5-(Methylamino)pyridine-3-carboxylic acid (2b)
2b was obtained in 93% yield from 11b by a similar method to that employed for 1a. 2b: Mp 262.0-266.5 °C (water). 1H NMR (DMSO-d6, 60 °C) 8.24 (1H, d, J = 1.5), 7.82 (1H, d, J = 3.0), 7.32 (1H, br-t, J = 1.5), 5.45 (1H, d, J = 4.5), 2.70 (3H, d, J = 4.8). 13C NMR (DMSO-d6) 167.0, 145.6, 138.3, 137.2, 126.5, 116.9, 29.2. IR (KBr) 3298, 1608 cm-1. LR-MS (EI) 152 [M+]. Anal. Calcd for C7H8N2O2: C, 55.26; H, 5.30; N, 18.41. Found: C, 55.25; H, 5.20; N, 18.33.

N-Butyl-6-(butylamino)pyridine-2-carboxamide (9a)
A mixture of 6-bromopyridine-2-carboxylic acid (10.05 g, 49.8 mmol), butylamine (40 mL, 4.5 mmol), CuSO4 (1.25 g, 5.0 mmol) and water (40 mL) was heated in a sealed bottle with stirring at 170 °C for 22 h. After cooling, the mixture was poured into sat. NaHCO3 aq. and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and evaporated in a rotary evaporator to give the crude product, which was chromatographed (AcOEt/CH2Cl2 0:1 then 1:1) to give the product 9a (4.85 g, 39%) as a brown oil. 1H NMR (DMSO-d6, 60 °C) 8.13 (1H, br-s), 7.47 (1H, dd, J = 8.4, 7.3), 7.11 (1H, d, J = 7.3), 6.61 (1H, d, J = 8.1), 6.53 (1H, br-t, J = 5.9), 3.30 (4H, m), 1.54 (2H, quint, J = 7.3), 1.51 (2H, quint, J = 7.3), 1.35 (4H, m), 0.92 (3H, t, J = 7.3), 0.91 (3H, t, J = 7.3). 13C NMR (DMSO-d6) 164.2, 157.7, 147.8, 137.3, 111.3, 109.1, 40.1, 38.1, 31.3, 31.1, 19.7, 19.5, 13.7, 13.5. IR (KBr) 3347, 2958, 1670, 1608, 1508 cm-1. LR-MS (EI) 249 [M+]. HR-MS (EI) Calcd for C14H23N3O: 249.1841; Found: 249.1846.

N-Methyl-6-(methylamino)pyridine-2-carboxamide (9b)
A mixture of 6-bromopyridine-2-carboxylic acid (10.2 g, 50.3 mmol) and methylamine solution in water (160 mL, 1.8 mol) was heated in a sealed bottle with stirring at 200 °C for 19 h. After cooling, the mixture was poured into sat. NaHCO3 aq. and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and evaporated in a rotary evaporator to give the crude product, which was chromatographed (AcOEt/hexane 1:1) to give the product 9b (6.55 g, 78%) as a colorless solid. Mp 69.0-70.0 °C (AcOEt/hexane). 1H NMR (CDCl3) 8.34 (1H, br-s), 7.47 (1H, dd, J = 8.4, 7.2), 7.11 (1H, dd, J = 7.2, 0.7), 6.67 (1H, br-s), 6.58 (1H, dd, J = 8.3, 0.7), 2.84 (3H, d, J = 4.9), 2.80 (3H, d, J = 4.9). 13C NMR (DMSO-d6) 165.0, 158.3, 148.0, 137.2, 111.2, 109.2, 27.6, 25.7. IR (KBr) 3388, 3323, 2896, 1668, 1602 cm-1. LR-MS (EI) 165 [M+]. Anal. Calcd for C8H11N3O: C, 58.17; H, 6.71; N, 25.44. Found: C, 58.30; H, 6.72; N, 25.42.

6-Aminopyridine-2-carboxamide (9c)
A mixture of 6-bromopyridine-2-carboxylic acid (5.2 g, 25.6 mmol) and ammonia solution in water (160 mL, 2.6 mol) was heated in a sealed bottle with stirring at 200 °C for 17 h to give the product 9c (456 mg, 13%), using a similar method to that employed for 9b. Mp 149.5-153.0 °C (AcOEt/hexane). 1H NMR (DMSO-d6) 7.62 (1H, br-s), 7.50 (1H, t, J = 8.1), 7.43 (1H, br-s), 7.14 (1H, dd, J = 7.2, 0.9), 6.60 (1H, dd, J = 8.4, 0.9), 6.08 (2H, s). 13C NMR (DMSO-d6) 166.4, 158.5, 148.3, 137.9, 111.1, 109.9. IR (KBr) 3361, 3200, 1705, 1680, 1618 cm-1. LR-MS (EI) 137 [M+]. HR-MS (EI) Calcd for C6H7N3O: 137.0589; Found: 137.0585.

Methyl 6-aminopyridine-2-carboxylate (10c)
A mixture of 9c (457 mg, 3.34 mmol) and conc. hydrochloric acid (20 mL) was heated at reflux with stirring for 19 h, and volatile materials were removed under reduced pressure to give a colorless solid. This crude product was dissolved in MeOH (5 mL), and a mixture of MeOH (12 mL) and acetyl chloride (1.65 mL, 23 mmol) was added, followed by the addition of trimethyl orthoacetate (1.65 mL, 13.0 mmol). The resulting mixture was heated at reflux for 17 h, then evaporated under reduced pressure. Sat. NaHCO3 aq. was added to the residue, and the mixture was extracted with CH2Cl2. The organic solution was dried over MgSO4, then evaporated to give the crude product, which was chromatographed (AcOEt) to give the ester 10c in 81% yield. Mp 88.0-91.5 °C (AcOEt/hexane). 1H NMR (DMSO-d6) 7.50 (1H, dd, J = 8.0, 7.3), 7.17 (1H, dd, J = 7.1, 0.7), 6.63 (1H, dd, J = 8.4, 0.7), 6.28 (2H, s), 3.78 (3H, s). 13C NMR (DMSO-d6) 165.7, 159.6, 145.7, 137.6, 113.1, 112.2, 51.8. IR (KBr) 3437, 3300, 3166, 1714, 1629 cm-1. LR-MS (EI) 152 [M+]. Anal. Calcd for C7H8N2O2: C, 55.26; H, 5.30; N, 18.41. Found: C, 55.04; H, 5.25; N, 18.27.

Methyl 5-(ethylamino)pyridine-3-carboxylate (11d)
A mixture of 5-bromonicotinic acid (9.44 g, 46.7 mmol), ethylamine solution (70% in water, 100 mL) and CuSO4 (0.76 g, 3.05 mmol) was heated in a sealed bottle with stirring at 170 °C for 21 h. After cooling, the mixture was evaporated to give a green viscous oil. To this crude mixture, MeOH (30 mL) and then a mixture of 100 mL of MeOH and 25 mL of acetyl chloride were added, followed by the addition of trimethyl orthoacetate (20 mL). The resulting solution was heated at reflux for 17 h, then evaporated under reduced pressure. Sat. NaHCO3 aq. was added to the residue, and the mixture was extracted with CH2Cl2. The organic solution was dried over MgSO4, then evaporated to give the crude product, which was chromatographed (CH2Cl2 then AcOEt/hexane 1:1) to give the ester 11d in 81% yield. Mp 104.0-106.5 °C (AcOEt/hexane), colorless needles. 1H NMR (CDCl3) 8.54 (1H, d, J = 1.5), 8.15 (1H, d, J = 2.6), 7.43 (1H, dd, J = 2.9, 1.8), 3.93 (3H, s), 3.81 (1H, br-s), 3.22 (2H, dq, J = 7.0, 5.5), 1.30 (3H, t, J = 7.0). 13C NMR (CDCl3) 166.4, 144.0, 139.5, 139.1, 126.1, 118.2, 52.1, 38.0, 14.5. IR (KBr) 3273, 1716, 1598 cm-1. LR-MS (EI) 180 [M+]. Anal. Calcd for C9H12N2O2: C, 59.99; H, 6.71; N, 15.55. Found: C, 59.86; H, 6.82; N, 15.49.

5-(Ethylamino)pyridine-3-carboxylic acid (2d)
2d was obtained in 93% yield from 11d by a similar method to that employed for 1a. 2d: Mp 199-245 °C (dec) (water), colorless powder. 1H NMR (DMSO-d6) 8.25 (1H, br-s), 8.11 (1H, br-s), 7.30 (1H, dd, J = 2.6, 1.8), 6.07 (1H, br-s), 3.08 (2H, dq, J = 7.0, 4.8), 1.17 (3H, t, J = 7.0). 13C NMR (DMSO-d6) 167.0, 144.7, 138.5, 137.1, 126.5, 117.2, 36.9, 14.0. IR (KBr) 3319, 2977, 1608 cm-1. LR-MS (EI) 166 [M+]. Anal. Calcd for C8H10N2O2: C, 57.82; H, 6.07; N, 16.80. Found: C, 57.57; H, 6.01; N, 16.65.

ACKNOWLEDGEMENTS
This work was supported by Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, and Sasakawa Grants for Science Fellows from the Japan Science Society.

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