An expeditious synthesis of 6-alkyl-5-(4′ -amino-phenyl)-pyrimidine-2,4-diamines

Article abstract of DOI:10.1081/SCC-120024725

A rapid synthesis of a series of 6-alkyl substituted-5-(4′ -amino-phenyl)-pyrimidine-2,4-diamines is described. These analogs were produced in good yields on moderate scale (ca. 8 g) without chromatography. Furthermore, the methodology described herein al

Full text of DOI:10.1081/SCC-120024725

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An Expeditious Synthesis of 6-Alkyl-5-(4′-amino-
phenyl)-pyrimidine-2,4-diamines
Daniel D. Holsworth a , Michael Stier Jeremy a , J. Edmunds a , Wei He b , Samuel Place b &
Samarendra Maiti b
a Pfizer Global Research and Development, Department of Chemistry , Ann Arbor, Michigan,
USA
b Naeja Pharmaceuticals, Inc., Department of Chemistry , Edmonton, Alberta, Canada
Published online: 15 Aug 2006.
To cite this article: Daniel D. Holsworth , Michael Stier Jeremy , J. Edmunds , Wei He , Samuel Place & Samarendra Maiti
(2003) An Expeditious Synthesis of 6-Alkyl-5-(4′-amino-phenyl)-pyrimidine-2,4-diamines, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:20, 3467-3475, DOI: 10.1081/
SCC-120024725
To link to this article: http://dx.doi.org/10.1081/SCC-120024725
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 20, pp. 3467–3475, 2003
An Expeditious Synthesis of 6-Alkyl-5-(40-amino-
phenyl)-pyrimidine-2,4-diamines
1
1
Daniel D. Holsworth,1, Michael Stier, Jeremy J. Edmunds,
*
Wei He,2 Samuel Place,2 and Samarendra Maiti2
1Pfizer Global Research and Development, Department
of Chemistry, Ann Arbor, Michigan, USA
2Naeja Pharmaceuticals, Inc., Department of Chemistry,
Edmonton, Alberta, Canada
ABSTRACT
A rapid synthesis of a series of 6-alkyl substituted-5-(40-amino-
phenyl)-pyrimidine-2,4-diamines is described. These analogs were
produced in good yields on moderate scale (ca. 8 g) without chroma-
tography. Furthermore, the methodology described herein allows the
production of 6-[ethyl, propyl, isopropyl, and isobutyl]-5-(40-amino-
phenyl)-pyrimidine-2,4-diamines in a more straightforward manner
than previously disclosed.[1d] These novel compounds should aid in
the structure-activity relationship analysis of current pyrimidines that
possess anti-tumor and anti-malarial activities.
*Correspondence: Daniel D. Holsworth, Pfizer Global Research and Development,
Department of Chemistry, Bldg. 28-1, 2800 Plymouth Rd., Ann Arbor, MI 48105,
USA; Fax: 734-622-3107; E-mail: daniel.holsworth@pfizer.com.
3467
DOI: 10.1081/SCC-120024725
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3468
Holsworth et al.
Key Words: 2,4-Diaminopyrimidines; Pyrimidine; Heterocyclic
chemistry.
INTRODUCTION
The 6-alkyl-5-phenyl-pyrimidine-2,4-diamine nucleus has received
considerable attention as agents for cancer chemotherapy and most
notably, as anti-malarials.[1] For instance, Pyrimethamine (1) is commonly
used for malarial infection by acting as an inhibitor of the dihydrofolate
reductase-thymidylate synthase enzyme of Plasmodium Falciparum.[2]
Although many compounds have been disclosed with the 6-ethyl or
methyl moiety,[1,3] none have mentioned the synthesis of other alkyl
groups in this position, as well as, directly incorporating a nitro group at
the 40 position. Finally, reduction of the nitro moiety yields 6-(alkyl)-5-(40-
aminophenyl)-pyrimidine-2,4-diamino analogs that heretofore, have not
been described in the literature. These intermediates are of interest since
pyrimidines incorporating secondary and tertiary amine substituents at
the 40-position have demonstrated activity against dihydrofolate reduc-
tase.[4] These intermediates serve as templates for further structure-activity
relationship investigations of 6-ethyl-5-(30-azido-40-chlorophenyl)-pyrimi-
dine-2,4-diamine; an anti-tumor agent that has completed phase I clinical
trials.[5,1d] Presently, the approach to 40 amino analogs employ compound
1 as starting material.[1d] The synthetic protocol of 6-(alkyl)-5-(40-amino-
phenyl)-pyrimidine-2,4-diamino analogs is outlined in Sch. 1.
The general route mirrors that of Hitchings[3] with two modifications:
(a) The use of triethylorthopropionate with a catalytic amount of sulfuric
acid to induce enolization was much easier/safer to use on large scale
than diazomethane (6–9). Trimethylsilyldiazomethane was tried as a
replacement for diazomethane but was not successful in enol formation;
(b) Nitration with a mixture of sulfuric acid and nitric acid was higher
yielding than with potassium nitrate. Interestingly, Stevens et al.[6] de-
scribed compound 14 as an inseparable mixture of nitro isomers (30 and
40). However, in our hands, nitration of 10 followed by crystallization in
hot methanol afforded the 40 isomer exclusively. Compounds 15, 16, and

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6-Alkyl-5-(40-aminophenyl)-pyrimidine-2,4-diamines
3469
Reaction conditions: (A) NaH, R1-OMe, THF, 0–85ꢀC, 18 h; (B)
Triethylorthopropionate, H2SO4 (cat.), 180–200ꢀC, 18 h; (C) Guanidine hydro-
chloride, NaOEt, EtOH, 130ꢀC, 8 h; (D) H2SO4, HNO3, 0ꢀC-rt, 2 h; (E) Raney-
nickel, H2, MeOH/THF (1:1), 50 psi.
Scheme 1. General route to 6-alkyl-5-(40-nitrophenyl)-pyrimidine-2,4-diamines.
17 were isolated in this manner. It is important to note, however, that in
this situation the separation of nitro regio-isomers is dependent on the
substituent at the 6-position of the pyrimidine ring. For example, when
an ethylmorpholino group was installed at the 6-position of the pyrimi-
dine ring (Sch. 2), the nitration step yielded an inseparable mixture of
1
nitro regio-isomers. These regio-isomers were detected by H NMR, but
appeared as a single compound by TLC and HPLC.
An effort to circumvent the regio-isomer problem by commencing
with 4-nitrophenylacetonitrile or 4-boc-amino-phenylacetonitrile and
employing the route described herein or that of Yuthanvong et al.[1a]
was unsuccessful. Although this methodology will not apply to all
6-position analogs where nitration can cause side reactions or produce
inseparable nitro regio-isomers, the production of a series of 6-alkyl

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3470
Holsworth et al.
Scheme 2. Nitration of 6-ethylmorpholino-5-phenyl-pyrimidine-2,4-diamine
produces an inseparable mixture of regio-isomers.
substituted-5-(40-nitrophenyl) pyrimidine-2,4-diamines were produced in
good yields on moderate scale (ca. 8 g) without chromatography. These
novel compounds should aid in the structure activity relationship analysis
of current pyrimidines that possess anti-tumor and anti-malarial activities.
EXPERIMENTAL SECTION
All reagents were purchased from Aldrich and used without further
purification. Solvents used were of HPLC grade and used without further
purification. NMR spectra were recorded on a Varian 400 MHz spectro-
meter and referenced to the solvent. Melting point values are uncorrected.
General Synthesis of Compounds 2–5
Sodium hydride (8.2 g, (60% in mineral oil), 0.204 mol) in THF
(100 mL) was cooled to 0ꢀC. Benzyl cyanide (20 g, 0.17 mol) was added
via syringe and allowed to stir at 0ꢀC for 30 min. Methyl propionate
(17.97 g, 0.20 mol) previously dissolved in THF (50 mL) was added
slowly [CAUTION! Reaction can become exothermic] via syringe and
allowed to warm to rt (3 h) and then heated to 85ꢀC for 18 h. The reaction
mixture was cooled to rt and water (120 mL) and diethyl ether (400 mL)
were added. The organic and aqueous layers were separated. The aqu-
eous layer was extracted with diethyl ether (3 ꢁ 50 mL) and the etheral
layer combined with the previous organic layer. The pH of the aqueous
layer was adjusted to pH 6 with acetic acid and extracted with diethyl
ether (2 ꢁ 50 mL). The diethyl ether fraction was added to the previous
organic fractions, dried over MgSO4, filtered, and concentrated under
reduced pressure to afford crude compound 2. Compounds 3–6 were

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6-Alkyl-5-(40-aminophenyl)-pyrimidine-2,4-diamines
3471
synthesized in the exact same manner and scale. All crude compounds
were used directly in the next step.
3-Oxo-2-phenyl-pentanenitrile (2)
25.30 g (86%)
3-Oxo-2-phenyl-hexaenitrile (3)
31.49 g (99%)
4-Methyl-3-oxo-2-phenyl-pentanenitrile (4)
15.90 g (50%)
5-Methyl-3-oxo-2-phenyl-hexanenitrile (5)
22.22 g (65%)
General Synthesis of Compounds 6–9
Compound 2 (25.36 g, 0.146 mol) and molecular sieves (10 g) were
added to a round-bottom flask equipped with a Dean-Stark trap.
Triethylorthopropionate (58 mL, 0.29 mol) and conc. H2SO4 (1 mL)
were added and the mixture heated to 180–200ꢀC for 18 h. The reaction
mixture was cooled to rt, and filtered. Compound 6, (black oil) was used
immediately without further purification in the next step (assume yield
100%). The same procedure and scale was conducted for the production
of compounds 7–9. All samples were used immediately in the next step
without further purification.
General Synthesis of Compounds 10–13
Crude compound 6 (29 g, 0.145 mol, containing residual sulfuric acid,
and triethylorthopropionate) was dissolved in EtOH (70 mL), and 21%
NaOEt (12.72 mL, 0.159 mol). Guanidine hydrochloride (15.30 g,
0.159 mol) was added in solid portions. The resultant mixture was
heated to 130ꢀC for 8 h. The reaction mixture was cooled to rt and
poured into ice-water (300 mL). The mixture was stirred for 30 min at

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3472
Holsworth et al.
which time a precipitate formed. The oily solid was filtered and washed
three times with diethyl ether to afford compound 10 (14.08 g, 45%) as a
white solid. The same procedure and scale was conducted for the
production of compounds 13–15.
6-Ethyl-5-phenyl-pyrimidine-2,4-diamine (10). Yield: 45%: M.p. ¼
244–246ꢀC (Lit,[3] m.p. ¼ 237–240ꢀC): H NMR (400 MHz, d6-DMSO):
1
ꢀ 7.39 (m, 2H), 7.32–7.15 (m, 1H), 7.16–7.10 (m, 2H), 5.79 (s, 2H), 5.33
(brs, 2H), 2.01 (q, J ¼ 7.6, 2H), 0.92 (t, J ¼ 7.2, 3H): 13C NMR (100 MHz,
d6-DMSO): ꢀ 167.1, 162.7, 162.6, 136.7, 131.2, 129.6, 127.8, 107.2, 28.1,
13.8. MS (APCI) m/z 215.0 (M þ 1): Anal. cald. for C12H12N4(%): C,
67.26; H, 6.58; N, 26.15. Found: C, 66.98; H, 6.58; N, 26.25.
5-Phenyl-6-propyl-pyrimidine-2,4-diamine (11). Yield: 28%: M.p. ¼
174–175ꢀC (Lit,[7] m.p. ¼ 171–173ꢀC): H NMR (400 MHz, d6-DMSO):
1
ꢀ 7.41 (m, 2H), 7.32 (m, 1H), 7.15 (m, 2H), 5.80 (s, 2H), 5.35 (brs, 2H),
2.05 (m, 2H), 1.42 (m, 2H), 0.68 (t, J ¼ 7.32, 3H): 13C NMR (100 MHz,
d6-DMSO): ꢀ 165.8, 162.7, 162.0, 136.8, 131.3, 129.5, 127.8, 107.8, 36.8,
22.1, 14.6. MS (APCI) m/z 229.1 (M þ 1): Anal. calcd. for C13H16N4 (%):
C, 68.39; H, 7.06; N, 24.54. Found: C, 68.07; H, 7.18; N, 24.61.
6-Isopropyl-5-phenyl-pyrimidine-2,4-diamine (12). Yield: 20%: M.p. ¼
185–187ꢀC (Lit,[8] m.p. ¼ 184–186ꢀC): H NMR (400 MHz, d6-DMSO): ꢀ
1
7.40 (m, 2H), 7.32 (m, 1H), 7.15 (m, 2H), 5.78 (s, 2H), 5.36 (brs, 2H), 2.47
(hept, J ¼ 2, 1H), 0.95 (d, J ¼ 7.2, 6H): 13C NMR (100 MHz, d6-DMSO):
ꢀ 170.4, 162.9, 162.7, 136.8, 131.2, 129.6, 127.8, 106.7, 31.3, 22.17. MS
(APCI) m/z 229.15 (M þ 1).
6-Isobutyl-5-phenyl-pyrimidine-2,4-diamine (13). Yield: 25%: M.p. ¼
144–145ꢀC (Lit,[8] m.p. ¼ 141–143ꢀC): H NMR (400 MHz, d6-DMSO): ꢀ
1
7.40 (m, 2H), 7.31 (m, 1H), 7.11 (m, 2H), 5.85 (s, 2H), 5.48 (brs, 2H), 1.98
(m, 2H), 1.92 (m, 1H), 0.66 (d, J ¼ 7.6, 6H): 13C NMR (100 MHz,
d6-DMSO): ꢀ 165.14, 162.7, 162.5, 136.8, 131.5, 129.5, 127.7, 108.4,
43.5, 27.8, 23.1. MS (APCI) m/z 243.12 (M þ 1).
General Synthesis of Compounds 14–17
Compound 10 (14 g, 0.065 mol) was added to concentrated sulfuric
acid (60 mL) at rt. Once the compound was dissolved, the mixture was
cooled to 0ꢀC. Concentrated nitric acid (13.79 mL, 3 equiv.) was added
dropwise via an addition funnel. [CAUTION! Do not allow reaction mix-
ture to warm above 15ꢀC]. The mixture was stirred at 0ꢀC for 1 h and then
at rt for an additional hour. The reaction mixture was poured into ice-
water (400 mL) and the pH of the mixture adjusted to 12 with 50%
NaOH. The resultant yellow precipitate was collected, added to hot

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6-Alkyl-5-(40-aminophenyl)-pyrimidine-2,4-diamines
3473
MeOH and filtered. Washings with hot MeOH (two or three times)
were continued until all para isomer was isolated (monitored by
1H NMR). 8.65 g (51%) of compound 14 was isolated as a yellow solid.
The same procedure and scale was conducted for the production of
compounds 15–17.
6-Ethyl-5-(40-nitrophenyl)-pyrimidine-2,4-diamine (14). Yield: 51%:
M.p. ¼ 345–347ꢀC (dec): 1H NMR (400 MHz, d6-DMSO):
ꢀ 8.22
(d, J ¼ 8.78, 2H), 7.44 (d, J ¼ 8.78, 2H), 5.92 (s, 2H), 5.66 (brs, 2H),
2.46 (q, J ¼ 3.6, 2H), 0.93 (t, J ¼ 7.3, 3H): 13C NMR (100 MHz, d6-
DMSO): ꢀ 165.4, 161.75, 161.70, 146.5, 143.8, 132.2, 123.9, 104.9, 27.2,
13.0. MS (APCI) m/z 260.1 (M þ 1): Anal. calcd. for C12H13N5O2 (%): C,
55.39; H, 5.05; N, 27.01. Found: C, 55.50; H, 4.87; N, 26.95.
5-(40-Nitrophenyl)-6-propyl-pyrimidine-2,4-diamine (15). Yield: 48%:
M.p. ¼ 282–284ꢀC: H NMR (400 MHz, d6-DMSO): ꢀ 8.24 (d, J ¼ 8.78,
1
2H), 7.43 (d, J ¼ 8.54, 2H), 5.93 (s, 2H), 5.67 (brs, 2H), 2.06 (t, J ¼ 7.6,
2H), 1.44 (q, J ¼ 7.6, 2H), 0.70 (t, J ¼ 7.2, 3H): 13C NMR (100 MHz,
d6-DMSO): ꢀ 165.7, 163.0, 162.3, 147.1, 145.0, 132.9, 124.6, 106.0, 36.8,
22.0, 14.5. MS (APCI) m/z 274.1 (M þ 1): Anal. calcd. for C13H15N505
(%): C, 57.13; H, 5.53; N, 25.63. Found: C, 56.82; H, 5.31; N, 25.63.
6-Isopropyl-5-(40-nitrophenyl)-pyrimidine-2,4-diamine (16). Yield:
40%: M.p. ¼ >300ꢀC: 1H NMR (400 MHz, d6-DMSO)
ꢀ
8.23
(d, J ¼ 8.8, 2H), 7.42 (d, J ¼ 8.8, 2H), 5.87 (s, 2H), 5.65 (brs, 2H), 2.43
(m, 1H), 0.98 (d, J ¼ 6.4, 6H): 13C NMR (100 MHz, d6-DMSO) ꢀ 170.3,
163.3, 162.2, 147.2, 145.1, 132.9, 124.6, 31.6, 22.1; MS (APCI) m/z 274.01
(M þ 1): Anal. calcd. for C13H15N502 ꢂ 0.3 H2O (%): C, 57.13; H, 5.53; N,
25.63. Found: C, 56.03; H, 5.64; N, 25.13. Found: C, 56.0; H, 5.52; N,
25.24.
6-Isobutyl-5-(40-nitrophenyl)-pyrimidine-2,4-diamine (17). Yield: 35%:
M.p. ¼ 259–261ꢀC: H NMR (400 MHz, d6-DMSO) ꢀ 8.24 (d, J ¼ 8.0,
1
2H), 7.41 (d, J ¼ 8.0, 2H), 5.93 (s, 2H), 5.68 (brs, 2H), 1.98 (s, 2H),
1.93 (m, 1H), 0.67 (d, J ¼ 6, 6H): 13C NMR (100 MHz, d6-DMSO) ꢀ
165.0, 162.9, 162.3, 147.1, 145.1, 133.2, 124.5, 106.6, 43.6, 27.9, 23.0.
MS (APCI) m/z 288.21 (M þ 1): Anal. calcd. for C14H17N502 ꢂ 0.9 H20
(%): C, 55.40; H, 6.24; N, 23.07. Found: C, 55.44; H, 5.57; N, 22.65.
General Synthesis of Compounds 18–21
Compound 14 (8.0 g, 0.030 mol) was dissolved in a mixture of MeOH
and THF (1:1, 200 mL). Raney nickel (9.3 g) was added and placed under
an atmosphere of hydrogen at 50 psi for 18 h. The solution was filtered
and concentrated under reduced pressure. The resultant solid was washed

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3474
Holsworth et al.
with ethyl acetate/hexanes (1:1), filtered, and dried to obtain compound
18 as a white solid. The same procedure and scale was conducted for the
production of compounds 19–21.
5-(40-Amino-phenyl)-6-ethyl-pyrimidine-2,4-diamine (18). Yield: 98%:
M.p. ¼ 183–185ꢀC: H NMR (400 MHz, d6-DMSO) ꢀ 6.76 (d, J ¼ 8.8,
1
2H), 6.57 (d, J ¼ 8.4, 2H), 5.67 (brs, 2H), 5.05 (brs, 2H), 2.09 (q, J ¼ 8,
2H), 0.93 (t, J ¼ 3.6, 3H): 13C NMR (100 MHz, d6-DMSO) ꢀ 167.4, 163.3,
162.3, 148.3, 131.5, 123.0, 115.1, 107.6, 28.1, 13.9. MS (APCI) m/z 230.1
(M þ 1): Anal. calcd. for C12H15N5 ꢂ 0.9 H2O (%): C, 58.71; H, 6.90; N,
28.53. Found: C, 58.51; H, 6.66; N, 28.47.
5-(40-Amino-phenyl)-6-propyl-pyrimidine-2,4-diamine (19). Yield:93%:
M.p. ¼ 103–105ꢀC: H NMR (400 MHz, d6-DMSO) ꢀ 6.76 (d, J ¼ 8.3,
1
2H), 6.59 (d, J ¼ 8.3, 2H), 5.69 (s, 2H), 5.30 (brs, 2H), 5.06 (s, 2H),
2.07 (m, 2H), 1.41 (m, 2H), 0.73 (m, 3H): 13C NMR (100 MHz,
d6-DMSO) ꢀ 166.1, 163.3, 162.2, 148.2, 131.6, 123.1, 115.0, 108.1, 36.9,
22.2, 14.7; MS (APCI) m/z 244.1 (M þ 1): Anal. calcd. for
C13H17N5 ꢂ 1.0 H2O (%): C, 59.75; H, 7.33; N, 26.80. Found: C, 60.00;
H, 7.49; N, 26.46.
5-(40-Amino-phenyl)-6-isopropyl-pyrimidine-2,4-diamine (20). Yield:
85%: M.p. ¼ 218–219ꢀC: 1H NMR (400 MHz, d6-DMSO): ꢀ 6.76 (d,
J ¼ 8.4, 2H), 6.59 (d, J ¼ 8.4, 2H), 5.64 (brs, 2H), 5.06 (brs, 2H), 2.58
(hept, J ¼ 6.8, 1H), 0.93 (d, J ¼ 6.4, 6H): 13C NMR (100 MHz, d6-
DMSO): ꢀ 170.7, 163.3, 162.5, 148.3, 131.5, 123.1, 115.1, 107.1, 31.1,
22.2; MS (APCI) m/z 244.1 (M þ 1): Anal. calcd. for C13H17N5 ꢂ 0.6
H20 (%): C, 61.44; H, 7.22; N, 27.56. Found: C, 61.36; H, 7.14; N, 27.48.
5-(40-Amino-phenyl)-6-isobutyl-pyrimidine-2,4-diamine (21). Yield:
99%: M.p. ¼ 65–67ꢀC: H NMR (400 MHz, CDCl3): ꢀ 6.96 (d, J ¼ 8.5,
1
2H), 6.74 (d, J ¼ 8.8, 2H), 4.97 (brs, 2H), 4.60 (brs, 2H), 3.76 (brs, 2H),
2.20 (d, J ¼ 7.2, 2H), 2.06 (hept, J ¼ 6.8, 1H), 0.78 (d, J ¼ 6.8, 6H):
13C NMR (100 MHz, CDCl3): ꢀ 167.5, 163.8, 161.9, 146.1, 131.9, 124.5,
115.8, 109.9, 68.0, 42.9, 28.3, 22.6; MS (APCI) m/z 258.2 (M þ 1): Anal.
calcd. for C14H19N5 ꢂ 0.2 C4H8O2 (%): C, 64.34; H, 7.55; N, 25.47.
Found: C, 64.24; H, 7.80; N, 25.36.
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6-Alkyl-5-(40-aminophenyl)-pyrimidine-2,4-diamines
3475
3753; (d) Griffin, R.J.; Meek, M.A.; Schwalbe, C.H.; Stevens, M.F.G.
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Received in the USA April 17, 2003

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