Facile and regioselective synthesis of novel 2,4-disubstituted-5- fluoropyrimidines as potential kinase inhibitors

Article abstract of DOI:10.1016/j.tetlet.2012.01.088

2,4-Disubstituted-5-fluoropyrimidine is a biologically active molecular core seen in various anticancer agents such as 5-fluorouracil (5-FU). As part of a programme aimed at discovering kinase inhibitors, routes to two series of novel compounds (5-fluorop

Full text of DOI:10.1016/j.tetlet.2012.01.088

Tetrahedron Letters 53 (2012) 1720–1724
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile and regioselective synthesis of novel
2,4-disubstituted-5-fluoropyrimidines as potential kinase inhibitors
Hiroki Wada a, , Lili Cheng b, Ji Jiang b, Zhigan Jiang b, Jun Xie b, Tao Hu b, Hitesh Sanganee c, Tim Luker d
⇑
a Medicinal Chemistry, R&I iMed, AstraZeneca R&D Mölndal, Pepparedsleden 1, Mölndal 43183, Sweden
b Medicinal Chemistry, WuXi AppTec Co., Ltd 288 FuTe Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, China
c New Opportunities iMed, AstraZeneca R&D Alderley Park, Mereside, Macclesfield, Cheshire SK10 4TG, United Kingdom
d Medicinal Chemistry, RIRA AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
2,4-Disubstituted-5-fluoropyrimidine is a biologically active molecular core seen in various anticancer
agents such as 5-fluorouracil (5-FU). As part of a programme aimed at discovering kinase inhibitors,
routes to two series of novel compounds (5-fluoropyrimidine-2-carboxamides and 5-fluoropyrimidine-
4-carboxamides) were successfully executed. For the first series, regioselective substitution at the 4-
position of the pyrimidine with an amine (HNR1R2) was achieved, followed by preparation of the amide
at the 2-position. The route to the second series involved introduction of the methoxy protecting group at
the 4-position, which allowed subsequent amine substitution to occur at the 2-position. The 4-amide
substituent was finally introduced by direct conversion of the 4-methoxy into a 4-chloro group followed
by transformation into an amide by palladium catalysis.
Received 27 October 2011
Revised 11 January 2012
Accepted 20 January 2012
Available online 28 January 2012
Keywords:
5-Fluoro-2,4-disubstituted pyrimidine
5-FU analogues
MeO protecting group
Regioselective synthesis
Pd coupling reaction
Kinase inhibitor
Ó 2012 Elsevier Ltd. All rights reserved.
5-Fluoropyrimidine has been known as a pharmacologically ac-
tive core for over 50 years. For example, 5-FU was first reported by
Dushinsky et al.1 and is now widely used in cancer therapy. Struc-
turally related bioactive derivatives were later found,2 such as
Capecitabine3 and the 5-FU prodrug FT-207 (Fig. 1).4 Since then
other analogues containing the 2,4-disubstituted-5-fluoropyrimi-
dine core have been reported for various therapeutic indications.
Recent uses of 2-anilino-pyrimidine and 2-anilino-5-fluoropyrimi-
dine scaffolds in kinase inhibitor medicinal chemistry5 include pro-
grams targetting Aurora A/B,6 CDK2,7 Trk,8 JNK19 and GSK3b.10
Amongst these compounds, a fluoro group at the pyrimidine 5-po-
sition often demonstrated enhanced kinase inhibitory potency, ex-
plained by the hypothesis of ‘electronegative fluorine acidifying
the aniline NH at the 2-position and thereby increasing H-bond do-
nor strength to the hinge region of the protein’.7a,b Moreover, Kal-
gutkar et al. recently reported that replacement of a disubstituted
pyrazine core with a 2,4-disubstituted-5-fluoropyrimidine in a ser-
ies of 5-HT2c receptor agonists removed the in vitro mutagenicity
in a Salmonella Ames assay.11 Although many 2,4-disubstituted-
5-fluoropyrimidines are known, most either use nitrogen or oxy-
gen links at the 2- and 4-position.5–10a Far less explored are car-
bon-linked analogues,10b such as carbonyl-linked examples, due
to the difficulty of regioselective preparation of the corresponding
acid in the presence of highly reactive halide leaving groups on the
electron-deficient ring system. In addition, the 5-fluoro group was
a better leaving group than the 2-chloro group on the pyrimidine,
resulting in nucleophilic displacement reactions occuring at the 5-
position rather than other positions (see later in Scheme 3). Herein,
we describe facile and regioselective synthetic methods to 5-flu-
oropyrimidine-2-carboxamides 1 and 5-fluoropyrimidine-4-car-
boxamides 2 via the corresponding carboxylic acids, which allow
the synthesis of novel and diverse sets of 5-FU analogues with
the desired 5-fluoropyrimidine core (Fig. 2).
The synthetic method to 1 is outlined in Scheme 1. Regioselective
displacement of 2,4-dichloro-5-fluoropyrimidine (3) was achieved
with representative aryl and alkyl amines under mild conditions.
The products 4 were then converted into pyrimidine-2-carboxylic
acid 5 via Pd-catalysed carbonylation. The desired acid 5 was then
coupled with various amines to afford amides 1. The yields of the
reactions with representative reagents for the parallel library chem-
istry are listed in Table 1.
Secondly, we investigated the preparation of the alternative
regioisomer 2 as shown in Scheme 2. However, initial attempts
to introduce a carboxylic acid moiety at the pyrimidine 4-position
failed due to difficulties preparing the cyano intermediate 6. While
the same reaction can be achieved without the presence of a 5-flu-
oro group on pyrimidine as reported previously with Zn(CN)2 in
the presence of Pd catalyst,15 no desired product was obtained
with 2,4-dichloro-5-fluoropyrimidine (3). This is possibly due to
⇑
Corresponding author. Tel.: +48 31 7761882; fax: +48 31 7763818.
E-mail address: hiroki.wada@astrazeneca.com (H. Wada).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.088

H. Wada et al. / Tetrahedron Letters 53 (2012) 1720–1724
1721
O
OH
F
F
F
O
O
N
N
NH
OH
O
N
H
N
O
O
N
H
O
O
N
O
H
FT-207
Capecitabine
Figure 1. Anticancer agents with a 5-fluoropyrimidine core.
5-FU
n-BuLi at À78 °C in the presence of diethyl carbonate.17 Trial nucle-
ophilic substitution of the 2-chloro group was carried out with the
ester 12, however, selective displacement did not take place due to
the high reactivity of the 5-fluoro group, with the reaction afford-
ing undesired product 13 with the amine at the 5-position. No
reaction took place with aniline in the presence of palladium catal-
ysis to afford the desired product 14. Therefore, this route was
abandoned.
F
3
R
F
8
R
N
N
1
R
6
R
N
4
R
N
7
R
N
N
N
N
2
5
R
O
O
R
2
1
Figure 2. Structures of 5-fluoropyrimidine-2-carboxamide 1 and 5-fluoropyrimi-
dine-4-carboxamide 2.
Our successful route to regioisomer 2, suitable for a parallel
synthesis is outlined in Scheme 4. Due to the higher reactivity of
the 4-chloro over the 2-chloro group, a methoxy group was intro-
duced selectively as a protecting group at the 4-position. This in
turn allowed introduction of the amino moiety at the 2-position.
The methoxy group was then converted into a chloro group via
hydrolysis and subsequent chlorination with POCl3 to afford 4-
chloropyrimidine 17. The chloride 17 was readily converted into
the corresponding acid 18 via a palladium coupling reaction. Vari-
ous amides 2 were synthesized by an amide coupling reaction at
the end of this reaction scheme. The methoxy group was a very
useful protecting group in the case of electron poor rings such as
5-fluoropyrimidine and the application of this key intermediate
for various analogue syntheses is currently ongoing. The yields of
the reaction are shown in Table 2 and it is useful to note that this
route allowed the introduction not only of an aniline group but
also secondary and primary amines at the 2-position of the pyrim-
idine ring, affording the products 17a, b and c.
the high reactivity of the intermediate 4-cyanopyrimidine 6: the
introduction of three electron-withdrawing groups on to the elec-
tron-deficient pyrimidine ring may make nucleophilic decomposi-
tion a problem under the reaction conditions.
An alternative attempt to afford the 4-pyrimidine carboxylic
acid ester 10 via the key intermediate 8 was carried out by using
Pd coupling with tributyl(1-ethoxyvinyl)stannane16 as shown in
Scheme 3. The ethoxyvinyl intermediate 8 was then reacted with
nucleophiles such as ammonia at the 2-position of pyrimidine.
The 2-ethoxyvinyl moiety of 9 was subsequently converted into
ethyl ester 10 by oxidative cleavage. Although the ester 10 was
successfully obtained, the low yield of the final oxidative cleavage
reaction (36% yield) and the introduction of the harsh reaction con-
ditions towards the end of this reaction scheme were not ideal for
parallel library synthesis. Hence, modification of the route was re-
quired. The intermediate 8 was converted into ester 12, which can
also be prepared from 2-chloro-5-fluoropyrimidine (11) with
F
F
F
3
R
F
N
N
N
N
(iii)
(i)
(ii)
1
R
1
R
1
R
OH
N
4
R
N
2
N
N
2
N
N
2
N
Cl
Cl
N
Cl
R
O
R
O
R
4
5
3
1
Scheme 1. Synthesis of 5-fluoropyrimidine-2-carboxamides 1. Reagents and conditions: (i) DIEA/EtOH, amine or aniline, reflux; (ii) (a) Pd(dppf)Cl2, Et3N, CO, MeOH; (b)
NaOH, MeOH/H2O, rt; (iii) amine, HOBt/EDC, Et3N, DMF, 50 °C.
Table 1
Representative structures and yields of reactions i, ii and iii in Scheme 1
R1
R3
N
N
Product
Yield (%)
Products
Yields (%)
2
R4
R
H
N
4a
89
95
96
5aa, 1aa
44, 86
76, 75
76, 81
N
H
H
N
N
4b
5bb, 1bb
5cc,13 1cc14
O
H
N
N
H
4c12

1722
H. Wada et al. / Tetrahedron Letters 53 (2012) 1720–1724
F
F
8
R
F
F
N
N
N
N
(i)
6
N
7
R
HO
N
Cl
R
N
N
5
NC
N
Cl
Cl
N
Cl
O
O
R
3
7
2
6
Scheme 2. Cyanation at the 4-position of 2,4-dichloro-5-fluoropyrimidine (3). Reagents and conditions: (i) Zn(CN)2, Pd(PPh3)4, DMF, 60 °C or 120 °C.
F
F
F
F
N
N
N
N
(i)
(vi)
(v)
O
O
O
N
NH2
N
NH2
N
Cl
Cl
N
Cl
3
8
9
O
10
(ii)
HN
N
F
(iii)
F
N
O
O
N
(iv)
N
13
Cl
O
O
F
N
Cl
N
Cl
11
12
O
N
N
N
H
14
O
Scheme 3. Preparation of pyrimidine-4-carboxylate 10. Reagents and conditions: (i) tributyl(1-ethoxyvinyl)stannane, Pd(PPh)3Cl2, K2CO3, 1,4-dioxane, 100 °C, 1 h (92%); (ii)
NaIO4, KMnO4, 1,4-dioxane/H2O, 1 h (75%); (iii) methylamine, Et3N/CH2Cl2, rt (80%); (iv) diethyl carbonate, n-BuLi, tetramethylpiperazine, À78 °C to rt;16 (v) NH3/EtOH (30%);
(vi) NaIO4, KMnO4, 1,4- dioxane/H2O (36%).
F
F
F
N
N
N
(i)
(iii)
(ii)
R6
O
N
N
R5
O
N
15
Cl
Cl
N
3
Cl
16
F
F
F
8
R
N
N
N
6
R
(iv)
6
R
(v)
6
HO
N
R
7
R
Cl
N
N
N
N
N
N
5
5
5
R
O
R
O
R
17
18
2
Scheme 4. Synthesis of 5-fluoropyrimidine-4-carboxamides 2. Reagents and conditions: (i) NaOMe, MeOH, rt;18 (ii) (a) aniline, Pd2(dba)3/BINAP, Cs2CO3, 1,4-dioxane, reflux,
12 h;19 (ii) (b) amine, DIEA, MeCN, 80 °C, 12 h;20 (iii) (a) 6 M HCl, 80 °C, 12 h; (b) POCl3, 100 °C, 5 h; (iv) (a) Pd(dppf)Cl2, Et3N, MeOH, CO, 50 °C, 24 h; (b) NaOH, MeOH/H2O, rt;
(v) amine, HOBt, EDC, Et3N, DMF, rt.
Table 2
Representative structures and yields of reactions i, ii, iii (combined), iv and v in Scheme 4
R6
R8
N
N
Product
Yield (%)
Product
Yields (%)
R5
7
R
N
17a
17b
63
50
18aa, 2aa
18bb, 2bb
37, 72
56, 80
N
H
H
N
N
H
O
N
O
H
17c21
42
18cc22, 2cc23
86, 86
N
H

H. Wada et al. / Tetrahedron Letters 53 (2012) 1720–1724
1723
12. Typical procedure for amination (Table 1, Product 4c):
(2-Chloro-5-fluoropyrimidin-4-yl)isobutylamine:
In conclusion, this work highlights the preparation of novel
5-fluoropyrimidine-4-carboxamide analogues 2 by use of a meth-
oxy protecting group. This methodology avoids nucleophilic
decomposition due to highly electron-deficient heterocycles and
has the potential to facilitate the synthesis of novel 5-fluoropyrim-
idine analogues. The biological evaluation of these compounds as
kinase inhibitors is currently in progress.
To a stirred solution of 2,4-dichloro-5-fluoropyrimidine (8.0 g, 48 mmol) and
isobutylamine (3.5 g, 48 mmol) in EtOH (50 ml) was added dropwise DIEA
(15.4 g, 120 mmol) and the mixture was stirred at room temperature for
30 min. At the end of the reaction, the mixture was evaporated under reduced
pressure to remove the solvent. The residue was diluted with CH2Cl2 (100 ml),
washed with water (60 mL) and brine (60 mL), dried over Na2SO4 and
concentrated under reduced pressure to yield 9.4 g (96% yield) of the
product as a light yellow oil.
1H NMR (400 MHz, CDCl3) d 7.88 (d, J = 2.8 Hz, 1H), 5.29 (br s, 1H), 3.37 (t,
J = 6.4 Hz, 2H), 1.97 (m, 1H), 1.05 (d, J = 6.8 Hz, 6H).
Acknowledgements
13. Typical procedure for carboxylation and hydrolysis (Table 1, Product 5cc):
5-Fluoro-4-isobutylaminopyrimidine-2-carboxylic acid
We are grateful to the department of Analytical Sciences at WuXi
AppTec Co., Ltd for their assistance in NMR and MS studies. We also
thank Teyrnon Jones from AstraZeneca Charnwoodand Mark Furber,
Cristina Gardelli, Peter Sjö and John Steele from AstraZeneca
Mölndal for helpful suggestions regarding this manuscript and
Matthew Perry from the Department of Chemistry, AstraZeneca
Mölndal for helpful suggestions regarding library synthesis.
A
mixture of (2-chloro-5-fluoropyrimidin-4-yl)isobutylamine (10.9 g,
54.0 mmol), Pd(dppf)Cl2 (1.1 g, 1.1 mmol) and Et3N (13.6 g, 135.0 mmol) in
MeOH (300 ml) was heated at 140 °C under 3 MPa of carbon monoxide
pressure for 16 h. At the end of the reaction, the mixture was cooled to room
temperature and then evaporated under reduced pressure to remove the
solvent. The residue was purified by flash column chromatography on silica
gel, eluting with 10% EtOAc/PE, yielding 10.4 g of the ester product as a white
solid. The obtained ester was then treated with NaOH (1.9 g, 48.5 mmol) in 50%
MeOH/H2O (100 ml) at room temperature for 1 h. At the end of the reaction,
MeOH was removed by evaporation. The aqueous residue was washed with
MTBE (50 ml), then acidified to pH = 3–4 with conc. HCl. The resulting
precipitate was collected by filtration and dried to give 8.6 g (76% yield) of
the acid product as a white solid.
Supplementary data
1H NMR (400 MHz, DMSO-d6) d 8.15 (d, J = 3.6 Hz, 1H), 7.88 (br s, 1H), 3.21 (t,
J = 6.4 Hz, 2H), 1.91 (m, 1H), 0.86 (d, J = 6.8 Hz, 6H).
Supplementary data (representative experimental procedures
and compound characterisation data) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.
2012.01.088.
14. Typical procedure for amide formation (Table 1, Product 1cc):
5-Fluoro-4-isobutylaminopyrimidine-2-carboxylic acid phenylamide
A mixture of 5-fluoro-4-isobutylaminopyrimidine-2-carboxylic acid (43.0 mg,
0.20 mmol), HOBt (13.5 mg, 0.10 mmol), EDC (46.1 mg, 0.24 mmol) and Et3N
(60.6 mg, 0.60 mmol) in DMF (2 ml) was stirred at room temperature for
10 min. Phenylamine (22.3 mg, 0.24 mmol) was added and the reaction
mixture was heated at 50 °C for 6 h. At the end of the reaction, the solvent
was removed by evaporation and the residue was purified by preparative TLC
to give 46.6 mg (81% yield) of the product as a colorless oil.
References and notes
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J = 8.0 Hz, 2H), 7.40 (m, 2H), 7.16 (m, 1H), 5.44 (br s, 1H), 3.50 (t, J = 6.0 Hz, 2H),
2.02 (m, 1H), 1.06 (d, J = 6.0 Hz, 6H).
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18. Typical procedure for displacement with MeO (compound 15):
2-Chloro-5-fluoro-4-methoxypyrimidine
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V.; Fisher, E.; Gingell, H. H. J.; Green, C. P.; Heaton, D. W.; Nash, I. A.;
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To a stirred solution of 2,4-dichloro-5-fluoropyrimidine (30.0 g, 180.7 mmol) in
MeOH (200 ml) cooled to 0 °C was slowly added NaOMe (19.5 g, 361.4 mmol).
The mixture was stirred at room temperature for 12 h. At the end of the
reaction, the solvent was removed by evaporation. The residue was partitioned
between CH2Cl2 (200 ml) and H2O (200 ml). The CH2Cl2 layer was washed with
brine (200 ml), dried over Na2SO4 and concentrated in vacuo to give 22.0 g
(75% yield) of the product as a white solid.
1H NMR (400 MHz, CDCl3) d 8.20 (d, J = 2.4 Hz, 1H), 4.11 (s, 3H).
19. Typical procedure for amination with an aniline (compound 16a):
(5-Fluoro-4-methoxypyrimidin-2-yl)phenylamine
To
a stirred solution of 2-chloro-5-fluoro-4-methoxypyrimidine (16.0 g,
98.8 mmol) and phenylamine (13.8 g, 141.8 mmol) in 1,4-dioxane (500 ml)
was added Cs2CO3 (97.8 g, 296.3 mmol) followed by Pd2(dba)3 (2.7 g,
2.9 mmol) and BINAP (3.1 g, 4.9 mmol) under N2. The mixture was heated at
reflux for 12 h. On completion, the mixture was filtered to remove the
inorganic salts and the filtrate was partitioned between CH2Cl2 (500 ml) and
H2O (500 ml). The CH2Cl2 layer was washed with brine (500 ml), dried over
NaSO4 and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel, eluting with 5% EtOAc/PE, to afford 13.0 g (63%
yield) of the product as a yellow solid.
1H NMR (400 MHz, CDCl3) d 8.07 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.34
(m, 2H), 7.16 (br s, 1H), 7.07 (m, 1H), 4.06 (s, 3H).
20. Typical procedure for amination with an aliphatic amine (compound 16c):
(5-Fluoro-4-methoxypyrimidin-2-yl)isobutylamine
10. (a) Lum, C.; Kahl, J.; Kessler, L.; Kucharski, J.; Lundström, J.; Miller, S.;
Nakanishi, H.; Pei, Y.; Pryor, K.; Roberts, E.; Sebo, L.; Sullivan, R.; Urban, J.;
Wang, Z. Bioorg. Med. Chem. Lett. 2008, 18, 3578; (b) Tavares, F. X.; Boucheron, J.
A.; Dickerson, S. H.; Griffin, R. J.; Preugschat, F.; Thomson, S. A.; Wang, T. Y.;
Zhou, H. J. Med. Chem. 2004, 47, 4716.
To
a stirred solution of 2-chloro-5-fluoro-4-methoxypyrimidine (10.0 g,
61.7 mmol) and isobutylamine (6.8 g, 92.6 mmol) in MeCN (200 ml) was
added DIEA (11.9 g, 92.6 mmol). The mixture was stirred at 80 °C for 12 h. At
the end of the reaction, the resulting mixture was cooled and partitioned
11. Kalgutkar, A. S.; Bauman, J. N.; McClure, K. F.; Aubrecht, J.; Cortina, S. R.;
Paralkar, J. Bioorg. Med. Chem. Lett. 2009, 19, 1559.

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H. Wada et al. / Tetrahedron Letters 53 (2012) 1720–1724
between EtOAc (200 ml) and H2O (200 ml). The EtOAc layer was washed with
4.92 mmol) in MeOH (50 ml) was added Pd(dppf)Cl2 (0.7 g, 0.98 mmol) and
Et3N (1.5 g, 14.80 mmol). The mixture was stirred at 50 °C for 24 h under 50 psi
of carbon monoxide pressure. On completion, the mixture was concentrated
and the residue purified by flash column chromatography on silica gel, eluting
with 5% EtOAc/PE, to give 0.7 g (63% yield) of the ester product as a yellow
solid. The obtained ester (0.6 g, 2.64 mmol) was treated with NaOH (0.3 g,
7.93 mmol) in MeOH (15 ml) and H2O (5 ml) at room temperature for 5 h.
MeOH was removed by evaporation. The aqueous residue was washed with
MTBE (10 ml) and then acidified to pH = 6 with 3 M aq. HCl. The precipitate
was collected by filtration and dried to give 0.5 g (86% yield) of the acid
product as a white solid.
brine (200 ml), dried over Na2SO4 and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel, eluting with 2-5%
EtOAc/PE to afford 5.2 g (42% yield) of the product as a yellow solid.
1H NMR (400 MHz, CDCl3) d 7.92 (d, J = 2.8 Hz, 1H), 5.03 (br s, 1H), 3.99 (s, 3H),
3.21 (t, J = 6.4 Hz, 2H), 1.91 (m, 1H), 0.99 (d, J = 6.4 Hz, 6H).
21. Typical procedure for de-methylation and chlorination (Table 2, Product 17c):
(4-Chloro-5-fluoropyrimidin-2-yl)isobutylamine
A
mixture of (5-fluoro-4-methoxypyrimidin-2-yl)isobutylamine (1.5 g, 7.52
mmol) in 6 M aq. HCl (20 ml) was heated at 100 °C for 12 h. On completion, the
mixture was concentrated to dryness. The residue was dissolved in POCl3
(10 ml) and heated at 100 °C for 12 h. At the end of the reaction, the mixture
was cooled to room temperature and concentrated to remove POCl3. The
residue was poured into ice-water (10 ml) and then basified to pH = 8–9 with
ammonia. The aqueous solution was extracted with CH2Cl2 (10 ml  3). The
combined CH2Cl2 layers were dried over anhydrous Na2SO4 and concentrated.
The residue was purified by flash column chromatography on silica gel, eluting
with 5% EtOAc/PE to give 1.2 g (42% yield) of the product as a yellow solid.
1H NMR (400 MHz, CDCl3) d 8.11 (s, 1H), 5.34 (br s, 1H), 3.21 (t, J = 6.4 Hz, 2H),
1.91 (m, 1H), 0.94 (d, J = 6.4 Hz, 6H).
1H NMR (400 MHz, DMSO-d6) d 8.47 (s, 1H), 7.55 (br s, 1H), 3.03 (t, J = 6.4 Hz,
2H), 1.82 (m, 1H), 0.86 (d, J = 6.8 Hz, 6H).
23. Typical procedure for amide formation (Table 2, Product 2cc):
5-Fluoro-2-isobutylaminopyrimidine-4-carboxylic acid (4-methoxyphenyl)
amide
By following the typical procedure for the synthesis of product 1cc, treatment
of 5-fluoro-2-isobutylaminopyrimidine-4-carboxylic acid (43.0 mg, 0.20
mmol) with p-methoxyaniline (29.5 mg, 0.24 mmol) gave 54.7 mg (86%
yield) of the product as a light yellow solid.
22. Typical procedure for carboxylation and hydrolysis (Table 2, Product 18cc):
5-Fluoro-2-isobutylaminopyrimidine-4-carboxylic acid
1H NMR (400 MHz, CDCl3) d 9.47 (br s, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.65 (d,
J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.36 (br s, 1H), 3.84 (s, 3H), 3.29 (t,
J = 6.4 Hz, 2H), 1.97 (m, 1H), 1.07 (d, J = 6.4 Hz, 6H).
To a stirred solution of (4-chloro-5-fluoropyrimidin-2-yl)isobutylamine (1.0 g,