Valuable synthetic building blocks: Useful 2-substituted 5-amino-pyrimidines from a stable precursor

Article abstract of DOI:10.1055/s-2005-865338

An efficient large-scale synthesis of 5-aminopyrimidine derivatives is described. The dihexafluorophosphate salt of a vinamidinium cation important in 5-aminopyrimidine synthesis has been prepared as a stable, easily purified intermediate. It has been use

Full text of DOI:10.1055/s-2005-865338

PAPER
1817
Valuable Synthetic Building Blocks: Useful 2-Substituted 5-Amino-
pyrimidines from a Stable Precursor
2
-Substituted 5-A
y
minopyrimi
r
dines fro
i
m
a
Sta
l
ble PrecursorB. Dousson,1 Nicola M. Heron, George B. Hill*
Cancer and Infection Research Area, AstraZeneca Healthcare, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Fax +44(1625)513910; E-mail: george.b.hill@astrazeneca.com
Received 9 February 2005
ous DMF at –10 to –35 °C. Other salts of related vinami-
dinium cations previously described and used by Arnold
and others include tetrafluoroborates,7–9 and hexafluoro-
phosphates.9
Abstract: An efficient large-scale synthesis of 5-aminopyrimidine
derivatives is described. The dihexafluorophosphate salt of a vin-
amidinium cation important in 5-aminopyrimidine synthesis has
been prepared as a stable, easily purified intermediate. It has been
used to prepare several 2-functionalized aminopyrimidines, valu-
able as synthetic building blocks.
Key words: heterocycles, pyrimidines, condensation, amidine, vin-
amidinium
2,5-Disubstituted pyrimidines with have been widely syn-
thesized. However, very few methods are available for the
preparation of otherwise unsubstituted 2-functionalized 5-
aminopyrimidines 1 or related2 compounds. Nevertheless,
such compounds are valuable synthetic building blocks.
Present syntheses are unsuitable for large-scale chemistry,
as they use hazardous precursors such as potentially ex-
plosive nitromalonaldehyde3 or vinamidinium salts. Key
compounds derived from the latter include 2, accessed by
Arnold et al.4 via the vinamidinium diperchlorate 3a5
(Figure 1).
Scheme 1
We were unable to isolate the ditetrafluoroborate salt 3b
usefully owing to its high solubility, and therefore turned
our attention to the dihexafluorophosphate.10
Hexafluorophosphate salts of amines and similar com-
pounds are more easily isolated and less water-soluble
than most other salts, for instance as diazonium salts in the
Balz–Schiemann reaction;11 also, widely used reagents
such as HATU are commonly supplied as stable non-hy-
groscopic hexafluorophosphate salts.
We have prepared the vinamidinium species as its di-
hexafluorophosphate salt 3c and have shown it to be an
easily isolated, stable salt. The vinamidinium species was
prepared, using a modification of Arnold’s conditions,5
from glycine hydrochloride in DMF and phosphorus oxy-
chloride (see safety note12). Research into improved prep-
arations of similar salts from other less volatile
formamides is ongoing.
Figure 1
Recently, we required access to a wide variety of 2-func-
tionalized 5-aminopyrimidines. Some of these were used
in the preparation of potential anti-cancer compounds or
their precursors, by reaction with 4-chloroquinazolines as
described in our recent patent application6 and as exempli-
fied in the conversion of 4 to 5 (Scheme 1).
In our hands Arnold’s original reaction conditions of
125 °C for two hours gave, in addition to the product 3c,
significant amounts of a by-product (Scheme 2) that
formed a hexafluorophosphate salt inseparable from 3c;
data from NMR and mass spectroscopy suggested this im-
purity was the previously undescribed salt 6. This presum-
ably forms by attack on the product by dimethylamine
generated from the decomposition of DMF. At 80 °C the
proportion of this by-product became almost negligible.
The likely thermal- and proven shock-sensitivity of vin-
amidinium perchlorate salts7 made the salt 3a unsuitable
for use by us as a large scale intermediate. It has also to be
isolated by crystallization from a viscous solution in aque-
SYNTHESIS 2005, No. 11, pp 1817–1821
Advanced online publication: 25.04.2005
x
x.
x
x
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2
0
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5
DOI: 10.1055/s-2005-865338; Art ID: P01805SS
© Georg Thieme Verlag Stuttgart · New York

1818
C. B. Dousson et al.
PAPER
Scheme 2
Scheme 3
Preparation of the useful salt 3c was achieved in a
straightforward manner by addition to the quenched reac-
tion mixture at 5 °C of two equivalents of hexafluoro-
phosphoric acid, from which the dihexafluorophosphate
precipitates immediately in good yield. After washing
with ethanol the crude salt (containing a little free acid)
can be air-dried and is sufficiently pure for further chem-
istry. We have stored it for over a year at room tempera-
ture without change, and have shown it by DSC
calorimetry to be thermally stable for chemistry up to at
least 150 °C. The stoichiometric mono-salt 7 was also
prepared with triethylamine analogously to the method
used by Arnold for the mono-perchlorate.4
The facile condensation of 3c with 2-methyl-2-thio-
pseudourea sulfate (Scheme 3) in the presence of sodium
methoxide, as described for the diperchlorate salt,4 gave 8
in comparable yield with that reported; 2 was successfully
prepared from it on large scale. Similarly, the reaction of
other functionalized amidines, via the dimethylamino-
methylene protected 5-aminopyrimidines, followed by
base hydrolysis with either potassium carbonate or hy-
droxide in water or aqueous dioxane, gave novel versatile
building blocks such as 4 and 9, with only slight hydroly-
sis of the Cbz protecting group in 4. These were not fur-
ther deprotected before conversion to aminoquinazolines
as described. The amidines used were commercially avail-
able or (in the case of 413 and 96) readily prepared from
commercially available nitriles by reported Pinner chem-
istry. Glycolamidine hydrochloride14 was used to prepare
the protected 2-pyrimidinemethanol 10. This could readi-
ly be converted either to the aryl ether 11 or to the benzyl
ether 12 (Scheme 4).
Scheme 4
Scheme 5
giving access to a range of 2-functionalized aminopyrim-
idines useful as synthetic building blocks.
A selection of 5-aminopyrimidine ethers 13 were also
made by alkoxide displacement from the known sulfone 2
(Scheme 5; Table 1).
NMR spectra were recorded at 300 (1H) and 75 (13C) MHz, on a
Bruker DPX-300 MHz NMR spectrometer. Mass spectra were de-
termined on a Waters 996 spectrometer. Melting points were mea-
sured using a Büchi B545 melting point apparatus and are
uncorrected. Microanalyses were done by NRM Ltd. DSC Calori-
metry was done on a Mettler Toledo DSC821 instrument. All sol-
The vinamidinium dihexafluorophosphate 3c is a stable,
easily isolated salt. It provides an efficient method for
large-scale synthesis of 5-aminopyrimidine derivatives,
Synthesis 2005, No. 11, 1817–1821 © Thieme Stuttgart · New York

PAPER
2-Substituted 5-Aminopyrimidines from a Stable Precursor
1819
Table 1 Some 2-Alkoxy-5-pyridinamines Prepared from Sulfone 2
Entry
1
ROH
Product
Yield (%)
82
Structure
(m-FC6H4)CH2OH
13a
2
3
(c-Pr)CH2CH2OH
(i-Pr)OCH2CH2OH
13b
13c
73
86
vents (anhydrous where appropriate) and reagents were used as
received.
Yield: 7.27 g (64%); off-white crystals.
1H NMR (DMSO-d6): d = 8.06 (s, 2 H), 7.50 (m, 1 H), 7.32 (m, 5
H), 5.36 (s, 2 H), 5.00 (s, 2 H), 4.19 (d, J = 7 Hz, 2 H).
N-(3-(Dimethylamino)-2-{[(dimethylamino)methylene]ami-
no}prop-2-en-1-ylidene)-N-methylmethanaminium Hydrogen
Dihexafluorophosphate (3c)
MS: m/z = 258 (M+).
Anal. Calcd for C13H14N4O2: C, 60.46; H, 5.46; N, 21.69. Found: C,
60.42; H, 5.52; N, 21.72.
POCl3 (70 mL, 0.75 mol) was added dropwise to DMF (150 mL) at
10 °C, and the mixture was then stirred for 20 min at 20 °C. This so-
lution was cooled to 5 °C and powdered glycine hydrochloride (27.9
g, 0.25 mol) was added in portions; the temperature of the reaction
mixture was maintained at 20 °C. The mixture was then heated to
80 2 °C (internal temperature). The solid rapidly disappeared and
there was a slight effervescence. After 4 h, the still hot, dark brown
solution was poured directly in a fine stream into H2O (400 mL),
pre-cooled to 5 °C, the temperature of the solution was kept below
20 °C with a dry ice/i-PrOH bath. After stirring the solution for 5
min, it was cooled to –5 °C and treated from a plastic vessel with
60% aq HPF6 (74 mL, 0.5 mol). A thick precipitate formed imme-
diately and was filtered off, washed with EtOH (500 mL), and air-
dried to constant weight over 2 h. In subsequent runs the product
contained up to 0.2 extra equiv of HPF6.
Benzyl [(5-{[6-Methoxy-7-(3-morpholin-4-ylpropoxy)quinazo-
lin-4-yl]amino}pyrimidin-2-yl)methyl]carbamate (5)
A stirred slurry of 4-chloro-6-methoxy-7-(3-morpholin-4-ylpro-
poxy)quinazoline6 (8.61 g, 25.5 mmol) in H2O (34 mL) was main-
tained at 20 °C while a solution of 4 M HCl in 1,4-dioxane (10.5
mL, 42 mmol) was added over 3–4 min, giving a clear orange solu-
tion. This was treated in one portion with a solution of 4 (3.87 g, 15
mmol) in a mixture of 1,4-dioxane (40 mL) and H2O (20 mL). The
mixture was heated to 60 °C for 40 min. The reaction mixture was
cooled, basified with aq NaHCO3, and then extracted with EtOAc
(3 × 100 mL). The combined organic extracts were extracted with
20% aq NaCl (5 × 50 mL) and then evaporated. The residue was
taken up in CH2Cl2–MeOH (5:1, 50 mL), dried (MgSO4), and evap-
orated. After purification by chromatography on silica gel (CH2Cl2–
MeOH, 100:8→100:15), the product was crystallized from CH2Cl2–
MeOH–EtOAc (3:1:1).
Yield: 73.1 g (60%); off-white solid; mp 165–185 °C (dec.).
1H NMR (DMSO-d6): d = 10.15 (d, J = 12 Hz, 1 H), 8.05 (d, J = 12
Hz, 1 H), 7.67 (s, 2 H), 3.27 (m, 9 H), 3.15 (m, 9 H).
13C NMR (DMSO-d6): d = 161.11, 158.53, 100.85, 49.17, 43.96, ca.
40 (under DMSO), 36.97.
MS: m/z = 197 (M+).
Yield 5.96 g (71%); off-white powder.
1H NMR (DMSO-d6): d = 9.71 (br s, 1 H), 9.14 (s, 2 H), 8.47 (s, 1
H), 7.80 (s, 1 H), 7.74 (t, J = 6 Hz, 1 H), 7.26–7.40 (m, 5 H), 7.21
(s, 1 H), 5.05 (s, 2 H), 4.40 (d, J = 6 Hz, 2 H), 4.18 (t, J = 6.4 Hz, 2
H), 3.96 (s, 3 H), 3.57 (m, 4 H), 2.44 (t, J = 7.1 Hz, 2 H), 2.37 (m,
4 H), 1.95 (m, 2 H).
Anal. Calcd for C10H22N4PF6·1.2HPF6: C, 23.2; H, 4.29; N, 10.82.
Found: C, 23.46; H, 4.26; N, 10.60.
MS: m/z = 560 (M+).
Benzyl [(5-Aminopyrimidin-2-yl)methyl]carbamate (4)
Anal. Calcd for C29H33N7O5: C, 62.24; H, 5.94; N, 17.52. Found: C,
61.9; H, 5.94; N, 17.2.
A slurry of 3c (23.0 g, 44 mmol) and benzyl (2-amino-2-iminoeth-
yl)carbamate hydrochloride13 (11.88 g, 49 mmol) in MeOH (70 mL)
was stirred under nitrogen while NaOMe in MeOH (31.7 mL, 146
mmol, 25% w/w) was added dropwise at r.t. The mixture was heated
slowly to 60 °C over 40 min and was then maintained at that tem-
perature for 10 min. The mixture was cooled, diluted with CH2Cl2
(100 mL), washed with H2O (150 mL), and the aqueous phase
washed with CH2Cl2 (2 × 50 mL). The combined organic solutions
were dried and evaporated to an oil. This was dissolved in CH2Cl2–
MeOH (100:10), filtered through silica gel (40 g) and evaporated
once more to an oil, which contained a little benzyl alcohol. The oil
was taken up in dioxane (100 mL) and 5% aq K2CO3 (200 mL) and
the mixture refluxed for 6 h, cooled, treated with brine (50 mL), and
extracted with EtOAc–MeOH (4:1, 1 × 100 mL) and EtOAc (2 ×
100 mL); the combined organic solutions were dried and evaporat-
ed. After purification by column chromatography on silica gel
(CH2Cl2–MeOH, 100:3→100:10), the product was recrystallized
from EtOAc–isohexane (1:1).
N-[3-(Dimethylamino)-2-{[(dimethylamino)methylene]ami-
no}prop-2-en-1-ylidene]-N-methylmethanaminium Hydrogen
Monohexafluorophosphate (7)
A suspension of the crude dihexafluorophosphate 3c (10 g, 19.3
mmol) in EtOH (80 mL) was treated with Et3N (8 mL, 58 mmol)
and heated to 70 °C giving a clear solution which was cooled imme-
diately. The solution was cooled to –20 °C and the heavy, cream-
colored solid was filtered off, washed with very cold EtOH (50 mL)
and Et2O (50 mL), and air-dried under a nitrogen blanket.
Yield: 6.6 g (94%).
1H NMR (DMSO-d6): d = 7.33 (s, 1 H), 7.13 (s, 2 H), 3.16 (s, 12 H),
2.95 (s, 3 H), 2.89 (s, 3 H).
MS: m/z = 197 (M+).
Synthesis 2005, No. 11, 1817–1821 © Thieme Stuttgart · New York

1820
C. B. Dousson et al.
PAPER
Anal. Calcd for C10H21N4PF6: C, 35.09; H, 6.18; N, 16.37. Found:
C, 35.1; H, 6.17; N, 16.1.
MS: m/z = 255, 253 (M+).
Anal. Calcd for C11H9ClFN3O: C, 52.09; H, 3.58; N, 16.57. Found:
C, 51.90; H, 3.53; N, 16.43.
2-(Diethoxymethyl)pyrimidin-5-amine (9)
A slurry of 3c (125.8 g, 242 mmol) and 2,2-diethoxyethanimid-
amide hydrochloride6 (51.6 g, 283 mmol) in EtOH (500 mL) was
stirred under nitrogen while NaOMe in MeOH (186.6 g, 864 mmol,
25% w/v) was added dropwise, the mixture was heated to reflux
halfway through the addition. After refluxing for 135 min, the mix-
ture was cooled to 0 °C, the inorganic precipitate was filtered off,
washed with EtOH (2 × 50 mL), and the filtrate evaporated. The
residue was taken up in CH2Cl2 (700 mL), extracted with H2O (3 ×
150 mL), dried (MgSO4), and evaporated to an oil. This in turn was
taken up in CH2Cl2–MeOH (10:1, 170 mL), filtered through silica
gel (30g) and evaporated to an orange oil.
2-{[(3-Fluorobenzyl)oxy]methyl}pyrimidin-5-amine (12)
A solution of 10 (0.9 g, 5 mmol) in DMF (3 mL) was treated with
NaH (60% dispersion in oil; 220 mg, 5.5 mmol) with stirring under
nitrogen. 3-Fluorobenzyl bromide 1.04 g, 5.5 mmol) was added
dropwise and the mixture stirred for 1 h. The reaction was quenched
with H2O (10 mL) and evaporated to dryness. The residue was taken
up in dioxane (5 mL), H2O (1 mL) and EtOH (10 mL), treated with
2 M aq NaOH (9 mL, 18 mmol), and refluxed for 18 h. The mixture
was cooled, extracted with EtOAc (3 × 10 mL), the organic solu-
tions dried (MgSO4), evaporated, and the product purified by chro-
matography on silica gel (CH2Cl2→CH2Cl2–MeOH, 100:10). The
product was recrystallized from CH2Cl2–isohexane (1:5).
A 37 g sample of this oil was taken up in dioxane (230 mL), treated
with 5% aq K2CO3 (385 mL), and refluxed for 6 h. The solution was
evaporated to dryness, co-evaporated with toluene (300 mL), taken
up in CH2Cl2–MeOH (10:1, 330 mL), filtered through silica gel
(30g) evaporated to dryness and the solid washed with Et2O.
Yield: 0.37 g (32%); off-white crystals.
1H NMR (DMSO-d6): d = 8.10 (s, 2 H), 7.37 (m, 1 H), 7.15 (m, 1
H), 6.95 (m, 1 H), 5.52 (s, 2 H), 4.56 (s, 2 H), 4.48 (s, 2 H).
MS: m/z = 233 (M+).
Yield: 20.27 g (65%); off-white solid.
1H NMR (DMSO-d6): d = 8.08 (s, 2 H), 5.58 (s, 2 H), 5.28 (s, 1 H),
3.53 (m, 4 H), 1.09 (t, J = 7 Hz, 2 H).
Anal. Calcd. for C12H12FN3O: C, 61.79; H, 5.19; N, 18.02. Found:
C, 61.49; H, 5.23; N, 17.67.
13C NMR (DMSO-d6): d = 142.94, 154.37, 141.99, 102.86, 62.02,
2-Alkoxy-5-aminopyrimidines 13a–c; General Procedure
To a solution of the required commercially available alcohol (24
mmol) in THF (30 mL) was added NaH (60% dispersion in oil; 22
mmol) portionwise. After stirring for 5 min, the milky solution was
treated over 2 min with a solution of the sulfone 2 (20 mmol) in
DMF (30 mL). After 10 min, the mixture was poured into 5% aq
NaHCO3 (200 mL). A solid which formed was filtered off and
washed with H2O. The solid was dissolved in dioxane (50 mL) and
treated with 2 M aq KOH (40 mL), followed by addition of 50% aq
dioxane until the mixture was almost homogeneous. The mixture
was refluxed for 4 h, cooled, extracted with EtOAc (3 × 100 mL),
the organic layer dried (MgSO4), and evaporated to an oil which
was purified by column chromatography on silica gel (50g;
CH2Cl2–MeOH, 100:10). The product was recrystallized from
CH2Cl2–isohexane.
15.99.
MS: m/z = 197 (M+).
Anal. Calcd for C9H15N3O2: C, 54.59; H, 7.67; N, 21.22. Found: C,
54.42; H, 7.62; N, 20.98.
N¢-[2-(Hydroxymethyl)pyrimidin-5-yl]-N,N-dimethylimidofor-
mamide (10)
A slurry of 3c (21.3 g, 41 mmol) and glycolamidine hydrochloride14
(5.0 g, 45 mmol) in EtOH (80 mL) was heated to reflux and NaOMe
in MeOH (34.1 mL, 158 mmol, 25% w/w) was added dropwise. Af-
ter refluxing for 2 h, the mixture was cooled to 0 °C, the inorganic
precipitate was filtered off, washed with EtOH (2 × 50 mL), the fil-
trate evaporated, and the residue purified by chromatography on sil-
ica gel, (EtOAc–MeOH, 100:10→100:25) to give the product as an
oil, 5.32 g (72%). From a solution in tert-butyl methyl ether was ob-
tained a sample of analytically pure white crystals.
13a
1H NMR (DMSO-d6): d = 7.96 (s, 2 H), 7.39 (m, 1 H), 7.20 (m, 1
Yield: 5.32 g (72%); mp 62–63 °C.
H), 7.10 (m, 1 H), 5.24 (s, 2 H), 4.99 (s, 2 H).
1H NMR (DMSO-d6): d = 8.36 (s, 2 H), 7.93 (s, 1 H), 5.06 (t, J = 6.2
Hz, 1 H), 4.49 (d, J = 6.2 Hz, 2 H), 3.05 (s, 3 H), 2.96 (s, 3 H).
MS: m/z = 180 (M+).
MS: m/z = 219 (M+).
Anal. Calcd for C11H10FN3O: C, 60.27; H, 4.60; N, 19.17. Found:
C, 60.29; H, 4.64; N, 19.19.
Anal. Calcd for C8H12N4O: C, 53.32; H, 6.71; N, 31.09. Found: C,
53.0; H, 6.74; N, 30.8.
13b
1H NMR (DMSO-d6): d = 7.95 (s, 2 H), 4.92 (s, 2 H), 4.18 (t, J = 0.7
Hz, 2 H), 1.58 (m, 2 H), 0.68 (m, 1 H), 0.44 (m, 2 H), 0.09 (m, 2 H).
2-[(3-Chloro-4-fluorophenoxy)methyl]pyrimidin-5-amine (11)
A solution containing 10 (1.8 g, 10 mmol), 3-chloro-4-fluorophenol
(1.54 g, 10.5 mmol) and PPh3 (3.93 g, 15 mmol) in THF (50 mL)
was treated, with stirring at –15 °C over 20 min, with a solution of
DIAD (3.13 g, 15.5 mmol) in THF (10 mL). The mixture was al-
lowed to warm to r.t. and stirred for 2 h. The solution was evaporat-
ed to dryness, the product was chromatographed on silica gel
(EtOAc–MeOH, 100:5→100:7.5). This gave 1.73 g of an off-white
solid, which was hydrolyzed in dioxane and aq K2CO3 as described
for 6a, giving after recrystallization from THF–isohexane an off-
white solid.
MS: m/z = 179 (M+).
Anal. Calcd for C9H13N3O: C, 60.32; H, 7.31; N, 23.45. Found: C,
60.23; H, 7.30; N, 23.57.
13c
1H NMR (DMSO-d6): d = 7.96 (s, 2 H), 4.94 (s, 2 H), 4.23 (m, 2 H),
3.62 (m, 3 H), 1.09 (d, J = 8 Hz, 6 H).
MS: m/z = 197 (M+).
Anal. Calcd for C9H15N3O2: C, 54.81; H, 7.67; N, 21.30. Found: C,
54.77; H, 7.58; N, 21.26.
Yield: 1.13 g (45%).
1H NMR (DMSO-d6): d = 8.09 (s, 2 H), 7.26 (m, 1 H), 7.19 (m, 1
H), 6.95 (m, 1 H), 5.60 (s, 2 H), 5.00 (s, 2 H).
Synthesis 2005, No. 11, 1817–1821 © Thieme Stuttgart · New York

PAPER
2-Substituted 5-Aminopyrimidines from a Stable Precursor
1821
(7) Ragan, J. A.; McDermott, R. E.; Jones, B. P.; am Ende, D.
J.; Clifford, P. J.; McHardy, S. J.; Heck, S. D.; Lira, S.;
Segelstein, B. E. Synlett 2000, 1172.
Acknowledgment
We wish to thank Phil Walker for DSC calorimetry, Madeleine
Vickers for mass spectra and Chris de Savi for useful comments du-
ring the preparation of the manuscript.
(8) Arnold, Z.; Dvorak, D.; Havranek, M. Collect. Czech. Chem.
Commun. 1996, 61, 1637.
(9) (a) Davies, I. W.; Marcoux, J.-F.; Wu, J.; Palucki, M.;
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(10) Hexafluorophosphoric acid is nearly the only common acid
with a reported pKa as low as perchloric acid. See:
Hendrickson, J. B.; Cram, D. J.; Hammond, G. S. Organic
Chemistry, 3rd ed.; McGraw Hill: New York, 1970.
(11) Fieser, L. F. Reagents for Organic Synthesis, Vol. 1; Wiley:
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(12) Safety Note: It should be noted that the combination of
POCl3 and DMF is now presumed to generate small
quantities of the potent carcinogen N,N-dimethylcarbamoyl
chloride (DMCC). See: Levin, D. Org. Process Res. Dev.
1997, 1, 182; and references therein.
(13) Mengelberg, M. Chem. Ber. 1956, 89, 1185.
(14) McCasland, G. E.; Tarbell, D. S. J. Am. Chem. Soc. 1946, 68,
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Synthesis 2005, No. 11, 1817–1821 © Thieme Stuttgart · New York