A practical preparation of methyl 2-methoxy-6-methylaminopyridine-3-carboxylate from 2,6-dichloro-3-trifluoromethylpyridine

Article abstract of DOI:10.1248/cpb.49.1621

An effective and practical synthetic route to methyl 2-methoxy-6-methylaminopyridine-3-carboxylate (7), the key intermediate of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), from 2,6-dichloro-3-trifluoromethylpyridine (12) was undertaken. Process improvements were highlighted by regioselectivity of 12 with a nitrogen nucleophile and conversion of the 3- trifluoromethyl group into the methoxycarbonyl group. The reaction of 12 with N-benzylmethylamine provided the 6-(N-benzyl-N-methyl)aminopyridine 26a and the regioisomer 26b in >98: <2 ratio in a quantitative yield. Treatment of 2-methoxy-6-methylamino-3-trifluoropyridine (14a) with a large excess of sodium methoxide followed by acid hydrolysis gave the pyridine-3-carboxylic ester 7 in an excellent yield. The potential application of this reaction is also described.

Full text of DOI:10.1248/cpb.49.1621

December 2001
Chem. Pharm. Bull. 49(12) 1621—1627 (2001)
1621
A Practical Preparation of Methyl 2-Methoxy-6-methylaminopyridine-3-
carboxylate from 2,6-Dichloro-3-trifluoromethylpyridine
Tamaki HORIKAWA, Yoshimi HIROKAWA,* and Shiro KATO
Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Enoki 33–94, Suita, Osaka 564–0053, Japan.
Received August 20, 2001; accepted October 1, 2001
An effective and practical synthetic route to methyl 2-methoxy-6-methylaminopyridine-3-carboxylate (7),
the key intermediate of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), from 2,6-dichloro-3-
trifluoromethylpyridine (12) was undertaken. Process improvements were highlighted by regioselectivity of 12
with a nitrogen nucleophile and conversion of the 3-trifluoromethyl group into the methoxycarbonyl group. The
reaction of 12 with N-benzylmethylamine provided the 6-(N-benzyl-N-methyl)aminopyridine 26a and the regioi-
somer 26b in Ͼ98 : Ͻ2 ratio in a quantitative yield. Treatment of 2-methoxy-6-methylamino-3-trifluoropyridine
(14a) with a large excess of sodium methoxide followed by acid hydrolysis gave the pyridine-3-carboxylic ester 7
in an excellent yield. The potential application of this reaction is also described.
Key words serotonin-3 receptor; dopamine D2, D3 receptor; antiemetic agent; 2-chloro-6-methylamino-3-trimethoxymethyl-
pyridine; regioselective synthesis; 2,6-dichloro-3-trifluoropyridine
Potent and selective serotonin-3 (5-HT3) receptor antago- trifluoromethylpyridine (12) We have previously reported
nists such as DAT-5821) [(R)-N-[1-methyl-4-(3-methylben- a novel synthetic route to 5-bromo-2-methoxy-6-methy-
zyl)hexahydro-1,4-diazepin-6-yl]-1H-indazole-3-carboxam- laminopyridine-3-carboxylic acid (1) from the commercially
ide dihydrochloride], granisetron and ondansetron are known available 2,6-dichloropyridine-3-carboxylic acid with an
to be effective for the control of emesis induced by cancer overall yield of ca. 63% (Chart 1).8) The key reaction of this
chemotherapeutic agents.2) In addition, the traditional an- method is the selective nucleophilic substitution reaction of
tiemetic agent domperidone, a peripheral dopamine D2 re- methyl 2,6-dichloropyridine-3-carboxylate (2) with 4-
ceptor antagonist, has been shown to be effective for the methylbenzenethiolate anion produced from 4-methylben-
treatment of symptoms of chronic upper gastrointestinal dis- zenethiol and potassium tert-butoxide in N,N-dimethyl-
tress and for the prevention of nausea and vomiting resulting formamide (DMF) at Ϫ30 °C. The reaction gave a mixture
from a variety of causes.3) However, domperidone is only of the desired 6-(4-methylbenzenethio)pyridine-3-carboxylic
minimally effective against chemotherapy- or radiation-in- ester (3) and the regioisomer, 2-substituted pyridine deriva-
duced nausea and vomiting.4) In the course of our studies on tive in a ratio of Ͼ97 : Ͻ3 in a quantitative yield. Treatment
the structure–activity relationships of DAT-582,5) novel ben- of the mixture containing 3 as a major product with sodium
zamides with an alkyl group at the nitrogen atom in the hexa- methoxide and purification by recrystallization afforded the
hydro-1,4-diazepine ring such as, 1-ethyl-4-methylhexahy- 2-methoxy-6-(4-methylbenzenethio)pyridine-3-carboxylic
dro-1,4-diazepine ring, were found to show dopamine D2 re- ester 4 in 87% yield. Oxidation of 4 furnished 2-methoxy-6-
ceptor antagonistic activity along with a potent 5-HT3 recep- (4-methylbenzenesulfinyl)pyridine-3-carboxylate (5) along
tor antagonistic activity and to cause only weak central ner- with the corresponding sulfone 6 in a ratio of 11 : 1 in a good
vous system depression and extrapyramidal syndromes.6) yield. After recrystallization of the mixture, the nucleophilic
Thus, these compounds were expected to be broad antiemetic substitution reaction of 5 obtained with methylamine was
agents. These findings had led us to modify the benzoyl moi- carried out to produce methyl 2-methoxy-6-methylaminopy-
ety and to prepare the optically active 6-aminohexahydro- ridine-3-carboxylate (7) in 80% yield from 4. Treatment of 7
1,4-diazepine ring, resulting in the discovery of (R)-5-bromo- with N-bromosuccinimide (NBS) gave methyl 5-bromo-2-
N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)-2- methoxy-6-methylaminopyridine-3-carboxylate (8) in 96%
methoxy-6-methylaminopyridine-3-carboxamide difumarate
(originally AS-8112), a potent dopamine D2 and D3,7) and 5-
HT3 receptors antagonist. AS-8112 was finally selected as a
promising candidate in our search for broad antiemetic
agents.1b) In order to obtain a large amount of AS-8112, an
efficient synthesis of 5-bromo-2-methoxy-6-methylaminopy-
ridine-3-carboxylic acid (1) and 6-amino-1-ethyl-4-methyl-
hexahydro-1,4-diazepine was essential. This paper describes
the efficient synthetic route to methyl 2-methoxy-6-methy-
laminopyridine-3-carboxylate (7), the key intermediate of 1,
from the commercially available 2,6-dichloro-3-trifluoro-
methylpyridine (12).
Results and Discussion
Large-Scale Synthesis of 5-Bromo-2-methoxy-6-methyl-
aminopyridine-3-carboxylic Acid (1) from 2,6-Dichloro-3-
Fig. 1
To whom correspondence should be addressed. e-mail: yoshimi-hirokawa@dainippon-pharm.co.jp
© 2001 Pharmaceutical Society of Japan

1622
Vol. 49, No. 12
Chart 1. Previous Route8) to the Preparation of 1
yield. Finally, 8 was hydrolyzed under alkaline conditions to
afford the desired carboxylic acid 1 in a quantitative yield
(Chart 1). This route to 1 is quite adequate for the prepara-
tion of a wide variety of 2-alkoxy-6-alkylaminopyridine-3-
carboxylic acids. However, when carried out on a large-scale
(few hundreds gram), the yield of 5 from 3 decreased re-
markably (ca. 25% yield) compared with that in a small-
scale reaction. In addition, in the reaction of 5 with methyl-
amine the unexpected 2-methoxy-N-methyl-6-(4-methylben-
zenesulfinyl)pyridine-3-carboxamide (9a) and/or the corre-
sponding 6-methylaminopyridine 9b were isolated in ca.
20% yield, and the yield of 7 decreased (ca. 50% yield). In
order to improve the overall yield of 1 in large-scale prepara-
tions, a novel and facile synthetic route to the key intermedi-
ate 7 with short steps was examined.
Chart 2
afforded a similar result. The desired 6-methylaminopyridine
Previously, we reported that the nucleophilic substitution 13a was found to be readily separable by washing with
reaction of methyl 2,6-dichloro-3-carboxylate (2) with methyl- hexane. After washing of the mixture of 13a and b with
amine did not show good regioselectivity and gave the unde- hexane, the crystals obtained (60% yield) consisted only of
1
sired 6-chloro-2-methylaminopyridine-3-carboxylic ester as a the isomer 13a by H-NMR spectrum and HPLC. The posi-
major product.8) On the other hand, Dainter et al.9) reported tion of methylamino group of 13a was determined by differ-
that treatment of 2,6-dichloro-3-trichloromethylpyridine (10) ential nuclear Overhauser effect (NOE) experiment; irradia-
having strong electron-withdrawing trichloromethyl group at tion at d 2.97 (N-Me) enhanced signal intensity of the adja-
the 3 position of pyridine ring with 10 mol eq of piperidine cent pyridine 5-proton (d 6.28). Conversion of 13a into 2-
as a nucleophile gave only the 2-chloro-6-piperidino-3-[tri(1- methoxy-6-methylamino-3-trifluoromethylpyridine (14a) was
piperidinyl)methyl]pyridine 11, which underwent displace- then attempted. Reaction of 13a with a large excess of
ment of all three chlorine atoms from the trichloromethyl sodium methoxide in MeOH at reflux temperature gave a
group as well as the ring chlorine atom in a good yield. We, mixture of unexpected two products instead of 14a in a good
1
therefore, expected that commercially available 2,6-dichloro- yield. H-NMR and mass spectra (MS) revealed these two
3-trifluoromethylpyridine (12), which is the starting material products to be 2-chloro-6-methylamino-3-(trimethoxymethyl)-
for the preparation of 2,6-dichloropyridine-3-carboxylic pyridine (15a) and the 2-methoxy counterpart 15b. The ratio
1
acid,10) undergoes the nucleophilic substitution reaction of of 15a and b (ca. 0.9 : 1) was determined by H-NMR spec-
the ring chlorine atom at the 6 position only (Chart 2). 3-Tri- troscopy. Nucleophilic substitution reaction at the 2 position
fluoromethylpyridines show much less activation of the triflu- of 15a with methoxide anion did not proceed to recover the
oromethyl group on the nucleophilic substitution than do starting material 15a. The mixture of 15a and b was then hy-
their trichloromethyl analogues, since the fluorine atom is a drolyzed with a catalytic amount of aqueous hydrochloric
poorer leaving group than the chlorine atom. Thus, nucle- acid or sulfuric acid solution to afford a mixture of the corre-
ophilic substitution reaction of 12 with methylamine was ini- sponding pyridine-3-carboxylic esters 16 and 7 in an excel-
tially examined.
lent yield in a ratio of ca. 0.7 : 1. The structure of 16 was
Treatment of 12 with 1.1 mol eq of methylamine generated confirmed by 1H-NMR and MS, and 7 was identified with the
from methylamine hydrochloride and triethylamine at room sample obtained in a previously reported method,8) on the
temperature gave a mixture of the 2-chloro-6-methylamino- basis of TLC, H-NMR, mass and IR spectra and HPLC
1
3-trifluoropyridine (13a) as a solid and the regioisomer 13b comparison. Once again, the mixture of 16 and 7 thus ob-
as a viscous oil in a ratio of ca. 4 : 1 in Ͼ90% yield. The tained was treated with sodium methoxide in MeOH. The 2-
ratio was determined by 1H-NMR spectroscopy. As expected, methoxylation of 16 with methoxide anion smoothly pro-
the corresponding 3-tri(methylamino)-methylpyridine was ceeded, and the key intermediate 7 was obtained ultimately in
not detected by 1H-NMR spectrum. The reaction at ca. 60 °C an excellent yield (Chart 3). A large amount of methyl 2-

December 2001
1623
Reagents and conditions: i, MeNH2·HCl, Et3N, DMF, ca. 5 °C, 14 h; ii, 28% NaOMe in MeOH, THF,
reflux; iii, 5% aq. H2SO4 solution, MeOH, room temperature, 0.5 h.
Chart 3
Chart 4. Proposed Mechanism for the Conversion of 13a into 15a and b with Methoxide Anion
methoxy-6-methylaminopyridine-3-carboxylate (7) was con- be due to a mechanism similar to that for the formation of
verted into the target 1 via methyl 5-bromo-2-methoxy-6- the 3-trimethoxymethylpyridine 15a from 18a. In path B-2,
methylaminopyridine-3-carboxylate (8) in an excellent yield 20 eliminates a fluoride ion from the trifluoromethyl group
without serious problems according to a method reported rather than a chloride ion from the ring to produce the
previously.8)
reactive intermediate 22, which can give the 3-trimeth-
The speculated mechanism for transformation of the 3- oxymethylpyridine 15b via attack on the methox-ide anion at
trifluoromethylpyridine 13a into the corresponding 3-tri- the side-chain carbon and analogous repeated sequences.
methoxymethylpyridines 15a and b is shown in Chart 4; ini- Transformation of 15a into 15b did not occur, probably
tial deprotonation of the ionizable methylamino group with because of the steric hindrance of the bulky 3-trimeth-
methoxide anion followed by elimination of the fluoro anion oxymethyl group. The high reactivity of the trifluoromethyl
as shown by the arrows (see 17) produce the highly reactive group conjugated with an ortho- or para-hydroxy or amino
key intermediate 18 (path A). Subsequent attack on the CF2 function has been accounted for by activation as in paths A
residue of intermediate 18 with second equivalent of methox- and B-1.11—13) In addition, mechanisms analogous to path B-
ide anion leads to the rearomatization of 18, and the forma- 2 have been proposed to account for the abnormal reactivity
tion of 19 which is capable of eliminating the second and of 3-trifluoromethyl-quinoline and -imidazole.14,15)
ultimately the third fluoro anions to afford the 3-trime-
The development of a shorter route to 1 was desired. One
thoxymethylpyridine 15a. On the other hand, the formation strategy shown in Chart 5 was particularly attractive. Ini-
of 15b might be explained as follows; initial methoxide tially, bromination of 13a with NBS was carried out to give
anion attack at the 2 position of the pyridine ring of 13a the 5-bromo-2-chloro-6-methylamino-3-trifluoropyridine (23)
gives the Meisenheimer-type adduct 20 (path B). In path B-1, in a quantitative yield. Reaction of 23 with a large amount
normal elimination of the chlorine atom at 2 position occurs of sodium methoxide produced a mixture of 2-chloro-3-
(giving 21), but the trifluoromethyl group in the product 21 is trimethoxymethylpyridine 24a and the corresponding 2-
activated by methoxide anion to form the intermediate 18b. methoxypyridine 24b in ca. 0.7 : 1 ratio, which was used in
Conversion of the reactive intermediate 18b into 15b would the next acid-hydrolysis step without further purification.

1624
Vol. 49, No. 12
1
trimethoxymethylpyridines were not detected by H-NMR
The mixture of 24a and b was treated with 2 N HCl solution
to provide a mixture of the pyridine-3-carboxylic esters 25a
and 8 as a crude solid. Once again, the mixture (25a, 8) was
treated with sodium methoxide to give 8 exclusively, which
was hydrolyzed with an alkaline solution without isolation to
produce the desired product 1 in 39% overall yield. The
crude pyridine-3-carboxylic acid 1 was purified twice with
EtOH at reflux temperature for 1 h. Unfortunately, the pyri-
dine-3-carboxylic acid 1 obtained was unacceptably impure
due to the presence of 5-bromo-2-chloro-6-methylaminopyri-
dine-3-carboxylic acid (25b), a nonmethoxylation product of
25a (0.8—0.7% by HPLC). The structure of 25b was specu-
lated by 1H-NMR and MS.
spectrum and the trifluoromethyl group of 27a and b was left
intact. Due to the absence of an acidic proton at the amino
group, the normal nucleophilic substitution reaction was pro-
ceeded at the 2 and 6 positions of the pyridine ring to pro-
duce the corresponding 2- and 6-methoxy derivatives. This
experimental result reveal that path B→B-1 would be exclu-
sive in our proposed two mechanisms for the formation of
15b as shown in Chart 4. After hydrogenolysis of the mixture
of 27a and b, the resulting mixture of 14a and b was reacted
with a large excess of sodium methoxide in MeOH at reflux
temperature to afford only the 3-trimethoxymethylpyridine
1
15b as a solid in a good yield. From H-NMR spectrum and
HPLC, the regioisomer of 15b was not detected in the solid.
Acid hydrolysis of 15b and recrystallization from ethyl ac-
etate gave the key intermediate 7 in 55% overall yield from
the starting material 12 (Chart 6). Preparation of multi-
kirogram amounts of 1 via 7 using this process was carried
out without any significant problems or yield loss.
In order to improve the regioselectivity at position-6 of the
pyridine ring, reaction of 12 with the more bulky N-benzyl-
methylamine was examined. Treatment of 12 with ca. 1.1
mol eq of N-benzylmethylamine in DMF at 60 °C afforded a
mixture of the 6-benzylmethylamino derivative 26a and the
regioisomer 26b as an oil in a ratio of Ͼ98 : Ͻ2 in a quantita-
tive yield. The structure of the major product 26a was con-
Synthesis of Methyl 6-Amino-2-methoxypyridine-3-car-
boxylate (32) from 2,6-Dichloro-3-trifluoromethylpyridine
(12) Coldwell et al.16) reported that methyl 6-amino-2-
methoxypyridine-3-carboxylate (32) was prepared from 2,6-
difluoropyridine via 2-fluoro-6-pivaloylaminopyridine and
ethyl 2-fluoro-6-pivaloylamino-3-pyridinecarboxylate in ca.
20% overall yield. The disadvantage of this method is the
moderate yield (44%) of the ethoxycarboxylation at the 3 po-
sition of 2-fluoro-6-pivaloylaminopyridine at Ϫ78 °C and the
use of silica gel column chromatography for purification. In
order to improve this method, we applied the novel synthetic
route to 7 from 2,6-dichloro-3-trifluoromethylpyridine (12).
Treatment of 12 with more bulky and diprotected amine of
ammonia, dibenzylamine instead of N-benzylmethylamine in
1-methyl-2-pyrrolidone as a solvent at 120 °C gave only
6-dibenzylamino-2-chloro-3-trifluoromethylpyridine (28) in
89% yield. The formation of the regioisomer was not de-
1
firmed by H-NMR and MS, and the position of the benzyl-
methylamino group of 26a was determined by differential
NOE experiment; irradiation at d 3.11 (N-Me) enhanced sig-
nal intensity of the adjacent pyridine 5-proton (d 6.36). With-
out further purification of the oil, the mixture of 26a and b
was treated with sodium methoxide in MeOH to give a mix-
ture of 6-benzylmethylamino-2-methoxy-3-trifluoropyridine
(27a) and the regioisomer 27b as an oil in a ratio of
Ͻ98 : Ͻ2 in 91% yield. In the mixture thus obtained, the 3-
1
tected by H-NMR spectrum. The position of the dibenzyl-
amino group of 28 was determined by NOE experiment; irra-
diation at d 4.80 (CH2Ph) enhanced signal intensity of the
adjacent pyridine 5-proton (d 6.32). When 28 was treated
with sodium methoxide in MeOH, only the 2-methoxy-3-tri-
fluoromethylpyridine 29 was obtained and the non-corre-
sponding 3-trimethoxymethylpyridine was formed owing to
the absence of acidic proton at the 6-amino group. Hy-
drogenolysis of 29 over palladium hydroxide afforded 6-
amino-2-methoxy-3-trifluoromethylpyridine (30) in 98%
yield. In a similar reaction to that described for the pathway
Reagents and conditions: i, NBS, DMF, room temperature, 2 h; ii, 28%
NaOMe in MeOH, THF, reflux, 2 h; iii, 2 N HCl solution, MeOH, ca. 5 °C,
20 min; iv, 28% NaOMe in MeOH, THF, reflux, 10 h; v, H2O, NaOH, room
temperature, 30 min.
Chart 5
Reagents and conditions: i, N-benzylmethylamine, Et3N, DMF, 60 °C, 2 h; ii, 28% NaOMe in MeOH, THF, reflux, 12 h;
iii, Pd/C, H2, aq. EtOH, ca. 50 °C; iv, 28% NaOMe in MeOH, reflux, 0.5 h; v, 2 N HCl solution, MeOH, room tempera-
ture, 30 min.
Chart 6

December 2001
1625
Reagents and conditions: i, dibenzylamine, Et3N, 1-methyl-2-pyrrolidone, 120 °C, 8.5 h; ii, 28% NaOMe in MeOH,
THF, reflux, 10 h; iii, Pd (OH)2/C, H2, aq. MeOH, AcOH, 3.2 kg/cm2, room temperature; iv, 28% NaOMe in MeOH, re-
flux, 0.5 h; v, 5% aq. H2SO4 solution, MeOH, room temperature, overnight.
Chart 7
to 7 from 15a, the trifluoromethyl group of 30 was converted NMe), 5.15 (1H, br, NHMe), 6.28 (1H, d, Jϭ8.6 Hz, Py-5), 7.67 (1H, d,
Jϭ8.6 Hz, Py-4). Anal. Calcd for C7H6ClF3N2: C, 39.93; H, 2.87; Cl, 16.84;
into the corresponding methoxycarbonyl group (giving 32)
F, 27.07; N, 13.30. Found: C, 39.85; H, 2.92; Cl, 16.75; F, 26.95; N, 13.05.
via the 3-trimethoxymethylpyridine 31 in an excellent yield.
IR cmϪ1 3296, 1612, 1385, 1319. HPLC [(A : Bϭ65 : 35), detection,
1
The H-NMR spectrum of 32 thus obtained was identical to
245 nm]; the retention times of 13a and b were 5.5 and 6.4 min, respectively.
that of the sample reported by Coldwell et al. The total yield
of 32 from 12 was 59% (Chart 7).
2-Chloro-6-methylamino-3-trimethoxymethylpyridine (15a) and 2-
Methoxy-6-methylamino-3-trimethoxymethylpyridine (15b) A mixture
of 13a (70.0 g, 0.33 mol), 28% sodium methoxide in MeOH (321 g,
1.65 mol) and tetrahydrofuran (THF) (210 ml) was heated to reflux for 13 h
and cooled to room temperature. After evaporation of the solvent, the
residue was poured into ice-water (300 ml). The resulting precipitates were
collected by filtration and dried to give a mixture of 15a and b (87 g) as a
white solid. 1H-NMR d: 2.92 (3H, d, Jϭ5.4 Hz, NMe of 15b), 2.94 (ca. 3H,
d, Jϭ5.9 Hz, NMe of 15a), 3.11 (9H, s, (OMe)3 of 15b), 3.14 (ca. 9H, s,
(OMe)3 of 15a), 3.90 (3H, OMe of 15b), 4.52 (1H, br, NH of 15b), 5.07 (ca.
0.9H, br, NH of 15a), 5.92 (1H, d, Jϭ8.3 Hz, Py-5 of 15b), 6.28 (ca. 0.9H,
d, Jϭ8.6 Hz, Py-5 of 15a), 7.72 (1H, d, Jϭ8.3 Hz, Py-4 of 15b), 7.87 (ca.
0.9H, d, Jϭ8.6 Hz, Py-4 of 15a). MS (APCI) m/z: 243 (MHϩ of 15b), 247
(MHϩ of 15a). IR cmϪ1 3373, 2945, 1609, 1508, 1375, 1275.
Methyl 2-Chloro-6-methylaminopyridine-3-carboxylate (16) and
Methyl 2-Methoxy-6-methylaminopyridine-3-carboxylate (7) Five per-
cent aqueous H2SO4 solution (20 ml) was added dropwise to a solution of
15a and b (87 g) in a mixture of MeOH (435 ml) and water (12 ml) at room
temperature. The mixture was stirred at the same temperature for 0.5 h and
concentrated to dryness to give 63 g of a mixture of 16 and 7 as a white
solid. 1H-NMR d: 2.97 (ca. 2H, d, Jϭ5.1 Hz, NMe of 7), 2.98 (3H, d,
Conclusion
We have established an efficient route for the synthesis of
1, the carboxylic acid moiety of a novel promising broad
antiemetic agent AS-8112, from 2,6-dichloro-3-trifluoropyri-
dine (12). Synthesis of methyl 2-methoxy-6-methylaminopy-
ridine-3-carboxylate (7), the key intermediate of 1, by a se-
quence containing regioselective nucleophilic substitution re-
action of 12 with N-benzylmethylamine, methoxylation of 3-
trifluoromethyl group conjugated with a para-methylamino
function, and acid hydrolysis of the orthoester group was ac-
complished. The novel route with seven steps, which was ap-
plied to a large-scale synthesis of 1 improved significantly
the overall yield (Ͼ50%).
Experimental
All melting points were determined on a Yanagimoto micromelting point Jϭ5.1 Hz, NMe of 16), 3.82 (3H, s, OMe of 7), 3.87 (3H, s, CO2Me of 16),
apparatus without correction. IR spectra were recorded on a Shimadzu 3.97 (ca. 2H, CO2Me of 7), 4.87 (ca. 0.7H, br, NH of 7), 5.35 (1H, br, NH of
FTIR-8200PC spectrometer with KBr disks. Atmospheric pressure chemical 16), 5.94 (ca. 0.7H, d, Jϭ8.4 Hz, Py-5 of 7), 6.29 (1H, d, Jϭ8.6 Hz, Py-5 of
ionization (APCI) and fast atom bombardment (FAB) MS were obtained on 16), 8.01 (ca. 0.7H, d, Jϭ8.4 Hz, Py-4 of 7), 8.04 (1H, d, Jϭ8.6 Hz, Py-4 of
a
Hitachi M-1000 spectrometer and JEOL JMS-SX 102A QQ, 16). IR cmϪ1 3356, 1693, 1601, 1269. MS (APCI) m/z: 197 (MHϩ of 7), 201
respectively. 1H-NMR spectra were recorded on a Varian Gemini-200 (MHϩ of 16).
(200 MHz) or a JEOL JNM-LA300 (300 MHz) spectrometer using dilute so-
5-Bromo-2-chloro-6-methylamino-3-trifluoromethylpyridine (23)
A
lution in CDCl3. Chemical shifts were expressed as d (ppm) values from solution of NBS (59.5 g, 0.33 mol) in DMF (160 ml) was added dropwise to
tetramethylsilane as an internal standard. Organic extracts were dried over a solution of 13a (64.0 g, 0.30 mol) in DMF (500 ml) at room temperature
anhydrous MgSO4. The solvents were evaporated under reduced pressure. for about 20 min. The mixture was stirred at the same temperature for 2 h.
Flash chromatography was carried out on 60 mm mesh silica gel (Fuji Silysia After addition of water (2000 ml), the reaction mixture was extracted with
FL60D). 2,6-Dichloro-3-trifluoromethylpyridine (12) was purchased from ethyl acetate (1000 mlϫ2). The extract was washed successively with water
Ishihara Sangyo Kaisha, Ltd. (Japan); 97.76% purity. HPLC [column, CAP- (500 ml) and brine (500 ml). The solvent was evaporated to give 88 g (quan-
1
CELL PAK C18 (Shiseido Industries, Ltd., Japan); 4.6 mm fϫ250 mm; elu- titative yield) of 23 as a pale yellow oil. H-NMR d: 3.08 (3H, d, Jϭ5 Hz,
ent, CH3CN (A)–0.05% aqueous CF3CO2H (B); flow rate, 0.8 ml/min; col- NMe), 5.53 (1H, br, NHMe), 7.81 (1H, s, Py-4). MS (APCI) m/z: 290
umn temperature, 25 °C].
2-Chloro-6-methylamino-3-trifluoromethylpyridine (13a) and 6- was 12.1 min.
(MHϩ). HPLC [(A : Bϭ65 : 35), detection, 245 nm]; the retention time of 23
Chloro-2-methylamino-3-trifluoromethylpyridine (13b) Triethylamine
(151 g, 1.50 mol) was added dropwise to a solution of 2,6-dichloro-3-trifluo-
5-Bromo-2-chloro-6-methylamino-3-trifluoromethylpyridine (24a) and
5-Bromo-2-methoxy-6-methylamino-3-trifluoromethylpyridine (24b)
A
romethylpyridine (12, 108 g, 0.50 mol) and methylamine hydrochloride mixture of 23 (88 g, 0.30 mol) and 28% sodium methoxide in MeOH (703 g,
(37.1 g, 0.54 mol) in DMF (500 ml) at ca. 5 °C. The mixture was stirred at 3.6 mol) was heated to reflux for 2 h and cooled to room temperature. The
room temperature for 14 h and then poured into ice-water. The resulting solvent was concentrated to dryness and the residue was triturated with
clammy crystals were collected by filtration and dried to give a mixture of water to give 113 g of the mixture of 24a and b as a white solid. 1H-NMR d:
13a and b. 1H-NMR d: 2.96 (3H, d, Jϭ5.1 Hz, NMe of 13a), 3.04 (ca. 0.7H, 3.07 (3H, d, Jϭ5 Hz, NMe of 24b), 3.04 (d, Jϭ5 Hz, NMe of 24a), 3.11
d, Jϭ5 Hz, NMe of 13b), 5.10 (ca. 0.25H, br, NHMe of 13b), 5.53 (1H, br,
NHMe of 13a), 6.30 (1H, d, Jϭ8.6 Hz, Py-5 of 13a), 6.60 (ca. 0.25H, d,
Jϭ8.6 Hz, Py-5 of 13b), 7.56 (ca. 0.25H, d, Jϭ8 Hz, Py-4 of 13b), 7.65 (1H,
(9H, s, (OMe)3 of 24b), 3.15 (ca. 6H, s, (OMe)3 of 24a), 3.95 (3H, s, OMe
of 24b), 4.95 (1H, br, NHMe of 24b), 5.19 (ca. 0.6H, br, NHMe of 24a),
7.85 (1H, s, Py-4 of 24b), 8.03 (0.7H, s, Py-4 of 24a). MS (APCI) m/z: 322
d, Jϭ8.6 Hz, Py-4 of 13a). MS (APCI) m/z: 211 (MHϩ). The pure 13a (MHϩ of 24b), 326 (MHϩ of 24a). IR cmϪ1 3385, 2936, 1597, 1379, 1263.
(64.0 g, 60%) was obtained as a colorless crystal by washing of the mixture HPLC [(A : Bϭ65 : 35), detection, 245 nm]; the retention times of 24b and a
with hexane (500 ml), mp 92—94 °C. 1H-NMR d: 2.97 (3H, d, Jϭ5.1 Hz, were 6.5 and 7.6 min, respectively.

1626
Vol. 49, No. 12
Methyl 5-Bromo-2-chloro-6-methylaminopyridine-3-carboxylate (25a) of the theoretical hydrogen (ca. 5 h), the catalyst was filtered off. The filtrate
and Methyl 5-Bromo-2-methoxy-6-methylaminopyridine-3-carboxylate was concentrated to leave a residue, which was dissolved in ethyl acetate
(8) 2 N HCl solution (500 ml) was added dropwise to a suspension of a
(990 ml). The solution was washed with 5% aqueous Na2CO3 solution (300
mixture of 24a and b (113 g) in MeOH (400 ml) at ca. 5 °C. The mixture and 150 ml) and concentrated to dryness to give ca. 220 g (quantitative
was stirred at the same temperature for 20 min. After neutralization with yield) of a mixture of 14a and b as a yellow oil, which was used in the next
1
NaHCO3 powder, the insoluble materials were collected by filtration to give step without further purification. H-NMR d: 2.93 (3H, d, Jϭ4.9 Hz, NMe
130 g of a mixture of methyl 5-bromo-2-chloro-6-methylaminopyridine-3- of 14a), 3.03 (Ͻ0.1H, d, Jϭ4.9 Hz, NMe of 14b), 3.93 (3H, s, OMe of 14a),
carboxylate (25a) and methyl 5-bromo-2-methoxy-6-methylaminopyridine- 4.02 (Ͻ0.1H, s, OMe of 14b), 4.73 (1H, br, NHMe of 14a), 5.89 (1H, d,
3-carboxylate (8) as a white solid. 1H-NMR d: 3.08 (3H, d, Jϭ5 Hz, NMe of Jϭ8.3 Hz, Py-5 of 14a), 5.99 (Ͻ0.05H, d, Jϭ8.3 Hz, Py-5 of 14b), 7.55
8), 3.10 (ca. 2H, d, Jϭ5 Hz, NMe of 25a), 3.82 (3H, s, CO2Me of 8), 3.88 (1H, d, Jϭ8.3 Hz, Py-4 of 14a), 7.72 (Ͻ0.05H, d, Jϭ8.3 Hz, Py-4 of 14b).
(ca. 2H, s, CO2Me of 25a), 4.02 (3H, s, OMe of 8), 5.38 (1H, br, NHMe of MS (APCI) m/z: 207 (MHϩ). HPLC [(A : Bϭ65 : 35), detection, 245 nm];
8), 5.52 (ca. 0.6H, br, NHMe of 25a), 8.15 (1H, s, Py-4 of 8), 8.20 (ca. the retention times of 14a and b were 7.1 and 8.6 min, respectively.
0.7H, s, Py-4 of 25a). MS (APCI) m/z: 276 (MHϩ of 8), 280 (MHϩ of 25a).
HPLC [(A : Bϭ65 : 35), detection, 245 nm]; the retention times of 8 and 25a
were 6.5 and 7.0 min, respectively.
2-Methoxy-6-methylamino-3-trimethoxymethylpyridine (15b) A so-
lution of a mixture of 14a and b (388 g, 1.9 mol) in MeOH (388 ml) was
added dropwise to 28% sodium methoxide in MeOH (2540 g, 12.1 mol) at
ca. 60 °C for 1 h. The mixture was heated to reflux for 0.5 h, cooled to room
Methoxylation of 25a and 8 and Acid Hydrolysis A mixture of 25a
and 8 (130 g), 28% sodium methoxide in MeOH (289 g, 1.5 mol) and THF temperature and poured into ice-water (9000 ml). The resulting solid was
(1000 ml) was heated to reflux for 10 h and cooled to room temperature. collected by filtration and dissolved in a mixture of CHCl3 (2000 ml) and
After addition of water (1000 ml), the mixture containing only 8 was stirred water (500 ml). The organic layer was separated, dried over anhydrous
at room temperature for 30 min and acidified with 30% HCl solution under MgSO4 and evaporated to leave 347 g (76%) of 15b as a white solid, mp
ice-cooling. The resulting precipitates were collected by filtration to give 148—150 °C. 1H-NMR d: 2.92 (3H, d, Jϭ5.1 Hz, NMe), 3.11 (9H, s,
54 g of 1 as a solid [5-bromo-2-chloro-6-methylaminopyridine-3-carboxylic (OMe)3), 3.91 (3H, s, OMe), 4.46 (1H, br, NHMe), 5.92 (1H, d, Jϭ8.2 Hz,
acid (25b) was detected in ca. 5% by HPLC]. After concentration of the fil- Py-5), 7.72 (1H, d, Jϭ8.2 Hz, Py-4). MS (APCI) m/z: 243 (MHϩ). IR cmϪ1
trate, the precipitates were collected by filtration to afford 18 g of 1. EtOH 3381, 2947, 1609, 1510, 1373, 1281. HPLC [(A : Bϭ55 : 45), detection,
(250 ml) was added to the solid (72 g) and the suspension was heated to re-
319 nm]; the retention time of 15b was 5.1 min.
flux for 1 h and cooled to room temperature. The insoluble 1 was collected
Methyl 2-Methoxy-6-methylaminopyridine-3-carboxylate (7) 1) A
by filtration. Once again, a suspension of 1 in EtOH (200 ml) was heated to solution of a mixture of 16 and 7 (60 g) and 28% sodium methoxide in
reflux for 1 h and cooled to room temperature. The insoluble 1 was collected MeOH (1731 g, 9.0 mol) in THF (180 ml) was heated to reflux for 24 h and
by filtration and dried to give 51 g (65% from 13a) as a white solid (25b was cooled to room temperature. After evaporation of the solvent, the residue
detected in 0.7—0.8% by HPLC). Compound 1 was identified with the sam- was poured into ice-water (500 ml). The resulting solid was collected by fil-
ple obtained in an alternative synthesis,8) on the basis of HPLC and 1H- tration and dried to give 74 g of crude 7 as a white solid, which was recrys-
NMR comparison. 1H-NMR d: 3.10 (3H, d, Jϭ5 Hz, NMe of 1), 3.82 (s,
NMe of 25b), 4.13 (3H, s, OMe of 1), 5.58 (1H, br, NHMe of 1), 8.15 (s, colorless crystals, mp 126.5—127.5 °C. H-NMR d: 2.97 (3H, d, Jϭ5.1 Hz,
Py-4 of 25b), 8.29 (1H, s, Py-4 of 1). MS (APCI) m/z: 262 (MHϩ of 25b), NMe), 3.81 (3H, s, OMe), 3.97 (3H, s, CO2Me), 4.85 (1H, br. d, NHMe),
266 (MHϩ of 1). HPLC [(A : Bϭ35 : 65), detection, 245 nm]; the retention 5.94 (1H, d, Jϭ8.5 Hz, Py-5), 8.01 (1H, d, Jϭ8.5 Hz, Py-4). IR cmϪ1 3393,
tallized from ethyl acetate/hexane to furnish 41.0 g (63% from 13a) of 7 as
1
times of 25b and 1 were 10.3 and 11.0 min, respectively.
2949, 1709, 1597, 1566, 1263, 1236. HPLC [(A : Bϭ55 : 45), 319 nm]; the
6-(N-Benzyl-N-methyl)amino-2-chloro-3-trifluoromethylpyridine
retention time of 7 was 4.9 min. The crystals obtained were identified with
1
(26a) and 2-(N-Benzyl-N-methyl)amino-6-chloro-3-trifluoromethylpyri- the sample obtained in an alternative synthesis,8) on the basis of TLC, H-
dine (26b) A mixture of 12 (100 g, 0.46 mol), N-benzylmethylamine (61.0 NMR, and HPLC comparison.
g, 0.50 mol), triethylamine (93.5 g, 0.93 mol) and DMF (500 ml) was heated
to 60 °C for 2 h then cooled to room temperature. The resulting precipitates
2) Compound 15b (350 g, 1.4 mol) was dissolved in hot MeOH (1750 ml)
and cooled to room temperature. After addition of water (52 ml, 2.9 mol), 2 N
of triethylamine hydrochloride were filtered off, and water (500 ml) and HCl solution (72 ml, 0.14 mol) was added dropwise at room temperature.
ethyl acetate (300 ml) were added to the filtrate. The organic layer was sepa- The mixture was stirred at the same temperature for 0.5 h and concentrated
rated, washed with water, and concentrated to dryness to give ca. 150 g to ca. 1200 ml. The resulting precipitates were collected by filtration to give
(quantitative yield) of a mixture of 26a and b as an orange oil. This oil was a powder (250 g), which was recrystallized from ethyl acetate to afford 224 g
used in the next step without further purification. 1H-NMR d: 2.94 (Ͻ0.1H, (79%) of 7. The crystals obtained were identified with the sample described
s, NMe of 26b), 3.11 (3H, s, NMe of 26a), 4.68 (ca. 0.05H, s, CH2Ph of above, on the basis of TLC, 1H-NMR, and HPLC comparison.
26b), 4.80 (2H, s, CH2Ph of 26a), 6.36 (1H, d, Jϭ8.8 Hz, Py-5 of 26a), 6.80
6-Dibenzylamino-2-chloro-3-trifluoromethylpyridine (28) A mixture
(Ͻ0.05H, d, Jϭ8.8 Hz, Py-5 of 26b), 7.20—7.36 (ca. 5H, m, arom. H), 7.63 of 12 (50.0 g, 0.23 mol), dibenzylamine (46.9 g, 0.24 mol), triethylamine
(1H, d, Jϭ8.8 Hz, Py-4 of 26a), 7.76 (Ͻ0.05H, d, Jϭ8.8 Hz, Py-4 of 26b). (45.7 g, 0.45 mol) and 1-methyl-2-pyrrolidone (300 ml) was heated at 120 °C
MS (APCI) m/z: 301 (MHϩ). HPLC [(A : Bϭ65 : 35), detection, 270 nm]; for 8.5 h and cooled to room temperature. The reaction mixture was poured
the retention times of 26a and b were 18.8 and 24.8 min, respectively.
6-(N-Benzyl-N-methyl)amino-2-methoxy-3-trifluoromethylpyridine
into ice-water and extracted with ethyl acetate. The extract was washed with
brine and evaporated to give a brown oil, which was chromatographed on
(27a) and 2-(N-Benzyl-N-methyl)amino-6-methoxy-3-trifluoromethyl- silica gel with hexane/ethyl acetateϭ5 : 1 to afford 77.7 g (89%) of 28 as a
pyridine (27b) Twenty-eight percent sodium methoxide in MeOH (1307 g, fawn oil. The oil solidified on standing at room temperature, mp 74—79 °C.
6.8 mol) was added dropwise to a solution of a mixture of 26a and b (680 g, 1H-NMR d: 4.80 (4H, s, CH2Phϫ2), 6.32 (1H, d, Jϭ8.8 Hz, Py-5), 7.16—
2.3 mol) in THF (2040 ml) at room temperature. The mixture was heated to 7.45 (10H, m, arom. Hϫ2), 7.59 (1H, d, Jϭ8.8 Hz, Py-4). FAB-high resolu-
reflux for 12 h and cooled to room temperature. After evaporation of the sol- tion (HR)-MS m/z: 377.1029 (MHϩ) (Calcd for C20H16ClF3N2: 377.1032).
vent, water (1360 ml) and ethyl acetate (1360 ml) were added to the residue. MS (APCI) m/z: 377 (MHϩ). IR cmϪ1 1601, 1504, 1319.
The organic layer was separated and concentrated to dryness to give 630 g
6-Dibenzylamino-2-methoxy-3-trifluoromethylpyridine (29) Twenty-
(91%) of a mixture of 27a and b as an orange oil, which was used in the
eight percent sodium methoxide in MeOH (473 g, 2.45 mol) was added
next step without further purification. 1H-NMR d: 3.07 (3H, s, NMe of 27a), dropwise to a solution of a mixture of 28 (307.8 g, 0.84 mol) in THF
3.11 (Ͻ0.1H, s, NMe of 27b), 3.81 (Ͻ0.1H, s, OMe of 27b), 3.91 (3H, s, (4000 ml) at room temperature. The mixture was heated to reflux for 10 h
OMe of 27a), 4.68 (ca. 0.05H, s, CH2Ph of 27b), 4.82 (2H, s, CH2Ph of
27a), 6.02 (1H, d, Jϭ8.4 Hz, Py-5 of 27a), 6.37 (Ͻ0.05H, d, Jϭ8.4 Hz, Py-5
of 27b), 7.19—7.38 (ca. 5H, m, arom. H), 7.57 (1H, d, Jϭ8.4 Hz, Py-4 of
and cooled to room temperature. After evaporation of the solvent, water
(800 ml) and CHCl3 (600 ml) were added to the residue. The organic layer
was separated, washed with brine and concentrated to dryness to give a
27a), 7.64 (Ͻ0.05H, d, Jϭ8.4 Hz, Py-4 of 27b). MS (APCI) m/z: 297 pale brown oil, which was recrystallized from iso-PrOH to afford 250.2 g
(MHϩ). HPLC [(A : Bϭ65 : 35), detection, 245 nm]; the retention times of (67.5%) of 29 as colorless crystals. After concentration of the mother liquid,
27a and b were 18.3 and 25.1 min, respectively.
the residue was chromatographed on silica gel with hexane/ethyl acetateϭ
2-Methoxy-6-methylamino-3-trifluoromethylpyridine (14a) and 6- 9 : 1 to 4 : 1 to give a pale yellow oil. The oil was crystallized from iso-PrOH
1
Methoxy-2-methylamino-3-trifluoromethylpyridine (14b) A solution of
to afford 22.2 g (7.3%) of 29 as colorless crystals, mp 88—89 °C. H-NMR
a mixture of 27a and b (315 g, 1.5 mol) in a mixture of EtOH (990 ml), d: 3.91 (3H, s, OMe), 4.81 (2H, s, CH2Phϫ2), 6.05 (1H, d, Jϭ8.8 Hz, Py-5),
water (60 ml), and acetic acid (6.6 ml) was hydrogenated over 10% palla- 7.22—7.42 (10H, m, arom. Hϫ2), 7.55 (1H, d, Jϭ8.4 Hz, Py-4). Anal.
dium on carbon (33 g) at ca. 50 °C at atmosphere pressure. After absorption Calcd for C21H19F3N2O: C, 67.73; H, 5.14; N, 7.52; F, 15.31. Found: C,

December 2001
1627
67.58; H, 5.08; N, 7.61; F, 15.57. MS (APCI) m/z: 373 (MHϩ). IR cmϪ1
1614, 1574, 1504, 1452, 1398, 1333.
3425, 3346, 3248, 1695, 1682, 1651, 1593, 1564.
6-Amino-2-methoxy-3-trifluoromethylpyridine (30) A solution of 29
(38.0 g, 0.10 mol) in a mixture of 10% aqueous MeOH (600 ml) and acetic
acid (100 ml) was hydrogenated over 20% palladium hydroxide on carbon
(wet, 3.8 g) at room temperature under a pressure of 3.2 kg/cm2. After ab-
sorption of the theoretical hydrogen, the catalyst was filtered off. The filtrate
was concentrated to leave an aqueous solution, which was neutralized with
solid K2CO3 and extracted with CHCl3. The extract was washed with brine
and concentrated to give 19.3 g (98%) of 30 as a pale yellow oil, which so-
References and Note
1) a) Kato S., Morie T., Ito T., Yoshida N., Jpn. Kokai Tokkyo Koho JP
05,230,057 [93,230,57] [Chem. Abstr., 120, 164242c (1994)]; b) Kato
S., Fujiwara I., Yoshida N., Med. Res. Rev., 19, 25—73 (1999).
2) King F. D., Jones B. J., Sanger G. J. (eds.), “5-Hydroxytryptamine-3
Receptor Antagonists,” CRC Press Inc., Boca Raton, 1994.
3) a) Brogden R. N., Carmine A. A., Heel R. C., Speight T. H., Avery G.
S., Drugs, 24, 360—400 (1982); b) Davis R. H., Clench M. H., Math-
iae J. R., Dig. Dis. Sci., 33, 1505—1511 (1988).
1
lidified on standing at room temperature, mp 51—55 °C. H-NMR d: 3.92
(3H, s, OMe), 4.61 (2H, br s, NH2), 5.88 (1H, d, Jϭ8.2 Hz, Py-5), 7.56 (1H,
d, Jϭ8.2 Hz, Py-4). HRFAB-MS m/z: 192.0517 (Calcd for C7H7F3N2O:
192.0510). MS (APCI) m/z: 193 (MHϩ). IR cmϪ1 3508, 3369, 1643, 1605,
1585, 1406, 1323.
4) Triozzi P. L., Laszlo J., Drugs, 34, 136—149 (1987).
5) Harada H., Morie T., Hirokawa Y., Yoshida N., Kato S., Chem. Pharm.
Bull., 43, 1364—1378 (1995).
6) Hirokawa Y., Yoshida N., Kato S., Bioorg. Med. Chem. Lett., 8,
1551—1554 (1998).
7) The dopamine D3 receptors in the area postrema play an important role
in the regulation of emesis. See: Yoshikawa T., Yoshida N., Hosoki K.,
Eur. J. Pharmacol., 301, 143—149 (1996).
8) Hirokawa Y., Horikawa T., Kato S., Chem. Pharm. Bull., 48, 1847—
1852 (2000).
9) Dainter R. S., Suschitzky H., Wakefield B. J., Hughes N., Neslon A. J.,
J. Chem. Soc., Perkin Trans. 1, 1988, 227—233.
10) Haga T., Koyanagi T., Nakajima T., Ohshima T., Eur. Pat. Appl. EP
92117 (1983) [Chem. Abstr., 100, 68179 (1983)].
11) Jones R. G., J. Am. Chem. Soc., 69, 2346—2350 (1947).
12) Belcher R., Stacey M., Sykes A., J. Chem. Soc., 1954, 3846—3851.
13) Kiselyov A. S., Strekoxski L., Org. Prep. Proc. Int., 28, 291—318
(1996).
14) Kobayashi Y., Kumadaki I., Acc. Chem. Res., 11, 197—204 (1978).
15) Kimoto H., Cohen L. A., J. Org. Chem., 44, 2902—2906 (1979).
16) Coldwell M. C., Gadre A., Jerman J., King F. D., Nash D., Bioorg.
Med. Chem. Lett., 5, 39—42 (1995).
Methyl 6-Amino-2-methoxypyridine-3-carboxylate (32) A solution of
a mixture of 30 (86.5 g, 0.45 mol) in MeOH (450 ml) was added dropwise to
28% sodium methoxide in MeOH (608 g, 3.15 mol) at ca. 65 °C for 2.5 h.
The mixture was heated to reflux for 0.5 h and cooled to room temperature.
The solvent was evaporated and the residue was dissolved in H2O and
CHCl3. The organic layer was separated and washed with brine and the
aqueous layer was extracted with ethyl acetate. The extract was again
washed with brine. The solvent of CHCl3 and ethyl acetate extracts was
evaporated to give an yellow solid containing 6-amino-2-methoxy-3-
trimethoxymethylpyridine (31). The solid was dissolved in a mixture of
MeOH (500 ml) and water (250 ml). After addition of 5% aqueous H2SO4
solution (25 ml), the mixture was stirred overnight at room temperature. The
mixture was concentrated and then the resulting precipitates were collected
by filtration, washed with EtOH and dried to give 73.6 g (90%) of 32 as col-
1
orless crystals, mp 162—164 °C. H-NMR d: 3.83 (3H, s, OMe), 3.96 (3H,
s, CO2Me), 4.75 (2H, br s, NH2), 6.05 (1H, d, Jϭ8.3 Hz, Py-5), 8.01 (1H, d,
Jϭ8.3 Hz, Py-4). MS (APCI) m/z: 183 (MHϩ). Anal. Calcd for C8H10N2O3:
C, 52.74; H, 5.53; N, 15.38. Found: C, 52.64; H, 5.56: N, 15.21. IR cmϪ1