Development of a Scalable Synthesis of 4-Aminopyrimidin-5-ol, a Versatile Intermediate

Article abstract of DOI:10.1021/acs.oprd.5b00074

A robust process for the preparation of multigram quantities of 4-aminopyrimidin-5-ol (5) in good yield from an inexpensive and readily available pyrimidine starting material is described. An initial evaluation of the reported literature route for this material utilizing a de novo pyrimidine synthesis provided safety concerns over the scalability of several intermediates. In addition, a number of steps proceeded in mediocre yield, and involved chromatographic separations for the desired products. The newly developed route mitigates the safety concerns, reduces the number of steps from five to three, avoids column chromatography, leads to an 8-fold improvement in yield, and utilizes reagents, which are recognized to be more environmentally benign.

Full text of DOI:10.1021/acs.oprd.5b00074

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Full Paper
Development of a Scalable Synthesis of 4-
Aminopyrimidin-5-ol, a Versatile Intermediate
Phuong T Le, Paul F Richardson, Neal W Sach, Shuibo Xin, Shijian Ren, Jiezhan Xiao, and Liangliang Xue
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00074 • Publication Date (Web): 21 May 2015
Downloaded from http://pubs.acs.org on May 24, 2015
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Development of a Scalable Synthesis of 4-
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Aminopyrimidin-5-ol, a Versatile Intermediate
†
†
†
±
±
Phuong T. Le,* Paul F. Richardson,* Neal W. Sach, Shuibo Xin, Shijian Ren, Jiezhan
±
±
Xiao, and Liangliang Xue
†
Pfizer Worldwide Medicinal Chemistry, 10770 Science Center Drive, San Diego, California,
±
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2121, United States, and WuXi App Tec Co., Shanghai, China
Corresponding Author
*
Phuong.Le@pfizer.com Phone: 858-638-6354
*
Paul.F.Richardson@pfizer.com Phone: 858-526-4290
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ABSTRACT. A robust process for the preparation of multigram quantities of 4-aminopyrimidin-
5-ol (5) in good yield from an inexpensive and readily available pyrimidine starting material is
described. An initial evaluation of the reported literature route for this material utilizing a de
novo pyrimidine synthesis provided safety concerns over the scalability of several intermediates.
In addition, a number of steps proceeded in mediocre yield, and involved chromatographic
separations for the desired products. The newly developed route mitigates the safety concerns,
reduces the number of steps from five to three, avoids column chromatography, leads to an 8-
fold improvement in yield, and utilizes reagents, which are recognized to be more
environmentally-benign.
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Keywords: 4-Aminopyrimidin-5-ol, synthetic strategy, O-demethylation, scale-up
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Introduction
Functionalized pyrimidines represent a popular motif in medicinal chemistry owing to their
synthetic versatility based on their predictable reactivity patterns, and their ability to arrange the
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vectors connected to the heterocyclic core in a spatially defined fashion. Examples of
pyrimidine-containing drugs include Uramustine 1, Tegafur 2, Sulfadoxine 3, and Trimethoprim
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(Figure 1). As part of one of our current medicinal chemistry programs, we required a method
to synthesize multigram quantities of 4-aminopyrimidin-5-ol (5), a versatile intermediate for
preparation of novel kinase inhibitors.
Figure 1. Pyrimidine-containing Drugs
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Results and Discussion
Given their popularity, there are numerous methods reported for the synthesis of functionalized
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pyrimidines. These can be crudely broken down into those involving a de novo synthesis of the
pyrimidine ring from suitably functionalized precursors, or those involving functional group
manipulation of a readily available pyrimidine-based starting material. Koskinen has reported a
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synthesis of 5, which is shown in Scheme 1. Initially, we chose to focus our attention on this
route to see if it could be suitably developed to meet our compound needs.
Scheme 1. Literature Synthesis of 5
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Reaction of 6 with methyl formate in the presence of NaH as the base afforded 7, which was
isolated by filtration, and used directly in the Pinner-type condensation with formamidine
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acetate. Scaling of these steps caused some initial concerns. Firstly, the use of NaH is not
attractive, and as such screening for an alternative base to mediate this reaction would be
required to evaluate more attractive options. Secondly, in the Pinner reaction on the laboratory
scale, we observed sublimation of the formamidine acetate from the reaction mixture leading to
build-up and clogging of the condenser. Finally, the overall yield of 30% over the 2 steps and the
required chromatographic separation of 8 were a major obstacle to scale-up this compound.
The chlorination of heteroaromatic compounds with POCl is a well-established procedure,
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which presents a number of challenges to develop on scale. Typically in the research setting, a
large excess of POCl at reflux is employed to serve as both the reagent and the solvent leading
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to a hazardous exothermic quenching operation being required to neutralize the excess reagent in
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the presence of a potentially sensitive reaction product. Numerous studies have been published
investigating this chlorination process, and it is known that the reaction only requires a slight
excess of POCl to proceed. However, the development of the optimal methodology to employ
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stoichiometric quantities of POCl is both labor intensive, and is critically dependent on a
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number of key parameters such as reaction solvent, substrate solubility, use of additives, and the
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order of reagent addition. In our initial studies on multigram scale, we utilized the Koskinen
methodology, and removed the bulk of the excess POCl through distillation under reduced
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pressure. This method somewhat mitigates the hazard in quenching a large excess of reagent.
The issue now becomes carrying out the controlled quench on the residual gum. In addition, the
POCl distillate still needs to be suitably handled for disposal, and will lead to a large
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environmental burden from a waste perspective. While the current reaction proceeds in a
moderate yield to provide 9, development of a stoichiometric POCl -based methodology for 8
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would be highly advantageous.
Introduction of the amino functionality in the conversion of 9 to 10 is achieved through direct
displacement of the chloride utilizing a solution of ammonia. The reaction proceeds in high yield
but requires extended heating in an autoclave at 130 °C, as well as an extractive work-up in the
isolation of 10 as a solid. The final step in the sequence to form 5 is the O-demethylation of 10.
The literature conditions utilize an excess of n-BuSH with NaH as base at 110 °C and
reproduction of these on scale presents issues. Firstly, there are concerns with handling n-BuSH
based on its toxicity, flammability and the fact that it is a known irritant. In addition, this
substance generates an extremely unpleasant odor with a low perception threshold. In human
odor tests conducted on thiols, n-BuSH was ranked at 5 on a scale of 0 to 5 in which 5 represents
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the most malodorous and 0 refers to a thiol essentially possessing no detectable odor. Secondly,
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the use of DMF and NaH is known to present a thermal hazard on scale with the possibility of a
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runaway reaction at elevated temperature. Finally, the demethylation reaction only provides a
modest yield with a work-up, chromatographic separation and crystallization necessary to obtain
the desired product in good purity. In considering sourcing options, this last step presented the
greatest challenge with approximately a two-fold increase in both cost and lead-time being
obtained for similar quantities of 10 and 5.
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With the problems associated with the final demethylation step, we evaluated whether an
alternative reagent could be utilized to overcome the key issues of safety and odor associated
with generation of the thiolate in situ. The possibility of utilizing a pre-formed thiolate reagent
such as NaSMe was considered. As shown in scheme 2, the reaction proceeds in a significantly
better yield on laboratory scale. However, this reagent is a flammable solid and also has
significant toxicity concerns. In addition, it is typically available as a technical grade (> 90%
purity), and still presents an odor issue due to the residual malodorous parent thiol utilized in its
preparation. From a cost perspective, the preformed thiol reagent also presents an issue (as
MeSH has been discontinued by Aldrich, the corresponding EtSH reagent was used as a
comparator. This analysis demonstrated that roughly on a per gram basis, the technical grade of
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the thiolate was ca. 40 times more costly than the parent thiol). Again, an aqueous work-up and
chromatographic separation were utilized to obtain the desired pure compound.
Scheme 2. Alternative conditions for the demethylation of 10
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Although the literature route was able to deliver gram quantities for our program, environmental,
economic and safety concerns as well as the low yields and long lead time prompted us to
consider alternative synthetic routes for the preparation of 5. A central theme within our
considerations was to investigate routes which did not involve construction of the pyrimidine
ring. Instead we wanted to utilize a readily available and relatively inexpensive pyrimidine-based
starting material, which through a simple set of functional group interconversions could lead to
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. A range of possible starting materials can be envisioned to fit these criteria, and as such our
feasibility studies focused not only on the availability/cost of the material but also on the
precedence for, or rapid ability to evaluate the proposed chemistry. Our first consideration was
the use of 4-aminopyrimidine (11), which is available from a wide range of suppliers. Despite
being somewhat costly on gram scale, this material was also reported to be available in bulk. The
proposed chemistry to evaluate this substrate as a potential starting material is illustrated in
Figure 2.
Figure 2. Strategies to utilize 11 to access 5
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The bromination of 11 has been reported, and readily affords 4-amino-5-bromopyrimidine 12,
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which is also commercially available. From our perspective, this represents a versatile starting
material with the correct regiochemistry already in place. We envisioned that a Buchwald or
Ullmann type coupling would enable the installation of suitable oxygen protected functionality in
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the 5-position to access a precursor to 5.
This chemistry also presents an additional element
of versatility in being able to directly couple an alcohol into the pyrimidine, and thus potentially
avoid a downstream alkylation step when constructing more complex molecular architectures
within the projects chemical space. For the purposes of accessing multigram quantities of 5, we
utilized benzyl alcohol for our model studies with the view that this resulting ether product (13)
would be easily deprotected via a simple hydrogenolysis, and thus avoid the problematic O-
demethylation chemistry. A screen of both Pd- and Cu-mediated couplings using a range of
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ligands/catalysts were evaluated using our high throughput reaction screening platform.
However in none of these reactions could synthetically useful levels of the product be detected
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even under forcing conditions. We hypothesized that perhaps the aminopyrimidine was
inhibiting the desired reaction through competing complexation of the metal catalyst. With this
as a working hypothesis, we evaluated the same series of reactions conditions on the bis-Boc
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protected precursor, 14. Across the series of reaction conditions evaluated, the desired product
was readily observed; however, competing loss of one of the Boc protecting groups lead to both
a complex analysis and the gradual retardation of the desired reaction over time. Synthetic
designs employing a more robust amino protecting group were considered, but concerns over
potential problems with its removal later in the synthesis prioritized execution on these.
An alternative possibility using 5-bromo-4-aminopyrimidine (12) would be to carry out a Pd-
mediated borylation with bis-pinacol ester to access the boronate ester (16), which could be
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subjected to a range of mild oxidative conditions to access the desired phenol. One advantage
of this approach would be that this would enable direct access to the unprotected alcohol thus
avoiding the problematic demethylation reaction encountered in the original synthesis. However,
perhaps unsurprisingly based on the results from the screen of the Buchwald coupling described
above, screening of a series of catalysts/bases/solvents for the proposed borylation failed to yield
appreciable levels of the desired product, and as such further attempts on this approach were
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abandoned.
At this time, we switched our attention to utilize 4,6-dichloro-5-methoxypyrimidine 17 as an
alternative pyrimidine-based starting material. This compound is readily available in bulk
quantities and inexpensive from a wide range of vendors.
From our perspective, we envisioned the following retrosynthetic approach in enabling 17 as a
starting material to access our desired 5 as shown in Figure 3. Initial displacement with
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ammonia or a suitable surrogate allows displacement of the initial chloride to afford 18.
Halogen removal under reductive conditions from aromatic systems is also well precedented.
The major drawback from our proposed sequence is that we would need to revisit the O-
demethylation chemistry, which caused significant problems in the initial synthesis.
Figure 3. Proposed Retrosynthesis of 5 starting from 17
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Investigating the aminolysis reaction, we found that heating 17 with 28% aqueous ammonia in n-
butanol at 90 °C allowed for the clean formation of 18. Although on scale, an autoclave was still
used, a lower temperature was required from the initial synthesis. Additionally, the opportunity
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to utilize flow to further optimize this step exists. On cooling the desired mono-substituted
product precipitated from the reaction enabling direct isolation by filtration, thus obviating the
need for chromatography. Whereas, using an ammonia surrogate such as benzylamine may allow
milder conditions to be employed for this transformation, and could conceivably be cleaved
during the hydrogenation step, employment of ammonia is the most atom-economical option for
this transformation. Deschlorination of the intermediate 18 to afford the 4-amino-5-
methoxypyrimidine was effected with hydrogenation using 10% Pd/C as the catalyst at 50 psi at
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50 °C for 3 hours. Hydrogenation also took place at ambient temperatures and pressure, but
lead to longer reaction time. As such, the optimized conditions utilized mild heating. No base
additive was required in the reaction. The work-up required simple filtration followed by
addition of aqueous ammonia and solvent evaporation. The concentrate was then slurried in
THF and CH Cl resulting in the precipitation of the ammonium chloride and a second filtration.
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Concentration of the filtrate afforded the desired product 10 as a colorless solid in ca. 90% yield.
The material was used directly in the next step.
Finally, we attempted to address the problems encountered in the O-demethylation step by
systematically evaluating alternative reagents and conditions used on scale to alleviate the odor,
safety and toxicity concerns. Initial tests using the classical demethylating reagent BBr lead to
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both a sluggish reaction, and large excesses of reagent being required to obtain a decent
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conversion. In addition, a complex work-up and the necessity for chromatography lead us to
pursue alternative options. Methanesulfonic acid in combination with methionine has also been
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reported as an effective combination to carry out O-demethylation on scale with advantages
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being a simple extractive work-up. However, in our case, this combination failed to afford the
desired product following the reported literature conditions. Reports suggest that alkanethiols
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with a chain length of 12 carbons or more are considered odorless. For example, 1-dodecathiol
has boiling point of 266-283 °C and is both inexpensive and available in large quantities. Its use
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has been reported for O-demethylation on scale. Given our previous positive results with both
sodium methanethiolate and butane-1-thiol in combination with NaH, we were confident that the
use of 1-dodecanthiol and a suitable base would provide the desired product. Indeed switching
NaH for NaOMe and reacting 5-methoxypyrimidin-4-amine 10 in the presence of 1-
dodecanethiol in DMF at 120 °C for 12 h provided the desired product 4-aminopyrimidin-5-ol 5
as a gray white solid in 87% yield and 100% purity by HPLC with no column chromatography.
The thiol by-products were removed by simple aqueous extractive work-up.
Scheme 3. Modified Synthesis of 5 from 17
Conclusion
In summary, we have identified an alternative scalable 3 step synthesis to the literature reported
route (5 steps, 6% overall yield in our hands) of 4-aminopyrimidin-5-ol (5) which proceeded in
52% yield from a known, commercially available, inexpensive starting material, 4,6-dichloro-5-
methoxypyrimidine (17). On > 100 g scale, the new synthesis presented several advantages with
no chromatography being required, and a number of safety concerns present in the original route
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eliminated. The common step between the two routes involved the O-demethylation with the
new route using 1-dodecanethiol as an odorless replacement to n-BuSH and NaOMe as the base.
The newly developed route significant reduced the lead time to access 100g of the substrate by a
factor of at least 4 (1-1.5 weeks) compared to the original route (6 -7 weeks).
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Experimental
General. Starting materials and other reagents were purchased from commercial suppliers and
were used without further purification unless otherwise noted. All reactions were performed
under a positive pressure of nitrogen, argon, or with a drying tube, at ambient temperature
(
unless otherwise stated), and in anhydrous solvents, unless otherwise indicated. Analytical thin-
layer chromatography was performed on glass-backed Silica Gel 60_F 254 plates (Analtech (0.4-
.5 mm)) and eluted with the appropriate solvent ratios (v/v). The reactions were assayed by
0
high-performance liquid chromatography (HPLC) or thin-layer chromatography (TLC) and
terminated as judged by the consumption of starting material. The TLC plates were visualized by
1
UV. H NMR spectra were recorded on a Bruker instrument operating at 400 MHz unless
1
otherwise indicated. H NMR spectra are obtained as DMSO-d or CDCl solutions as indicated
6
3
(reported in ppm), using DMSO-d (2.50 ppm) or chloroform (7.25 ppm) as the reference
6
standard. Other NMR solvents were used as needed. When peak multiplicities are reported, the
following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br =
broadened, dd = doublet of doublets, dt = doublet of triplets. Coupling constants are reported in
hertz. The mass spectra were obtained using liquid chromatography mass spectrometry (LC-MS)
on an Agilent instrument using atmospheric pressure chemical ionization (APCI) or electrospray
ionization (ESI). High performance liquid chromatography (HPLC) conditions were as indicated.
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Initial Route to 4-aminopyrimidin-5-ol (5).
Preparation of methyl (E)-2,3-dimethoxyacrylate (7). This reaction was set up in two batches
2 x 83.2 g) with the batches being combined for work-up. To a mixture of compound methyl 2-
(
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methoxyacetate (6, 83.2 g, 0.8 mol) and methyl formate (57.6 g, 0.96 mol) in anhydrous THF
°
(1.5 L) was added NaH (44.8 g, 1.12 mol, 60% in oil) in portions at 0 C. The resulting mixture
was stirred at room temperature for 12 h during which formation of a white solid was observed.
MTBE (1 L) was added and the mixture was filtered. The filter cake (assume 100% yield ~1.6
mol) was dried under reduced pressure and then used without purification in the next step.
Preparation of 5-methoxypyrimidin-4-ol (8). This reaction was set up in two batches (2 x 0.8
mol) with the batches being combined for work-up and purification. The solid obtained from the
previous step (~0.8 mol) was added to a solution of formamidine acetate (83.2 g, 0.8 mol) in
EtOH (1.6 L). The resulting mixture was stirred at room temperature for 12 h, and then refluxed
for a further 24 h. During the reflux period, a build-up of solids was observed in the condenser
leading to a potential clogging issue. After being allowed to cool, water (400 mL) was added,
and the mixture was acidified with AcOH (250 mL) to adjust the pH from 10 to ~ 5. The
solution was concentrated in vacuo to give a residue, which was purified by column
chromatography on silica gel (CH Cl /MeOH = 50:1 to 10:1, R = 0.2 in CH Cl /MeOH = 10:1)
2
2
f
2
2
1
to give 5-methoxypyrimidin-4-ol (8, 60 g, 30%) as an off-white solid. H NMR (400 MHz,
DMSO-d ) δ 12.52 (br s, 1 H), 7.81 (s, 1 H), 7.52 (s, 1 H), 3.72 (s, 3 H).
6
Preparation of 4-chloro-5-methoxypyrimidine (9). A suspension of compound 5-
methoxypyrimidin-4-ol (5, 57 g, 0.452 mol) in POCl (751 g, 4.69 mol) was heated at reflux for
3
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h. After being allowed to cool, the excess POCl was removed under reduced pressure, and the
3
remaining residue was poured into ice-water (~300 ml). The pH was then adjusted to ~ 7 with
K CO (ca. 250 g), and the mixture was extracted with EtOAc:MTBE (3:1, 4 x 250 mL). The
2
3
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organic layers were combined, washed with brine (100 mL) and dried over Na SO , filtered and
2
4
concentrated in vacuo to give 4-chloro-5-methoxypyrimidine as a yellow solid (9, 35 g, 53%, Rf
1
=
0.5 in EtOAc). H NMR (400 MHz, CDCl ) δ 8.64 (s, 1 H), 8.33 (s, 1 H), 4.03 (s, 3 H).
3
Preparation of 5-methoxypyrimidin-4-amine (10). This reaction was set up in two batches (2 x
6 g) with the batches being combined for work-up and purification. A suspension of 4-chloro-5-
1
methoxypyrimidine (9, 16 g, 0.109 mol) in EtOH (800 mL) saturated with ammonia gas was
poured into an autoclave, which was heated to 130 °C with stirring for 12 h. After being allowed
to cool, evaporation of the solution provided a tan residue, which was partitioned between
CH Cl (1 L) and brine (250 mL). The organic layer was separated and the aqueous layer was
2
2
extracted with CH Cl (6 x 100 ml). The organic layers were dried over Na SO , filtered and
2
2
2
4
concentrated in vacuo to give 5-methoxypyrimidin-4-amine as a yellow solid (10, 24 g, 86%, Rf
1
=
0.4 in CH Cl /MeOH = 10:1). H NMR (400 MHz, DMSO-d ) δ 8.01 (s, 1 H), 7.81 (s, 1 H),
2
2
6
6.72 (br s, 2 H), 3.81 (s, 3 H).
Preparation of 4-aminopyrimidin-5-ol (5). To a solution of compound 5-methoxypyrimidin-4-
amine (10, 38 g, 0.3 mol) in anhydrous DMF (2 L) was added NaH (28.7 g, 1.2 mol, 60% in
mineral oil pre-washed with hexanes) at room temperature. The resulting mixture was cooled
using an ice bath to 0 °C before addition of n-BuSH (36.8 g, 0.405 mol). The resulting reaction
mixture was stirred at 110 °C for 12 h. TLC (CH Cl /MeOH = 10:1, R = 0.1) indicated that
2
2
f
compound 10 had been consumed and a new unknown spot was detected, which did not co-elute
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with authentic 5. A further charge of n-BuSH (12 g, 0.135 mol) was added to the reaction, which
was then stirred at 110 °C for 12 h. TLC (CH Cl /MeOH = 10:1) indicated that the unknown
2
2
spot was almost consumed. The mixture was concentrated in vacuo to dryness. AcOH (35 ml)
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and H O (200 mL) were added, and the reaction concentrated again. The residue was purified by
2
column chromatography on silica gel (CH Cl /MeOH = 50:1 to 10:1), and then the product
2
2
recrystallized from MeOH (100 mL) to give 4-aminopyrimidin-5-ol (5) as a yellow solid. (17 g,
1
4
4%). H NMR (400 MHz, DMSO-d ) δ 9.64 (br s, 1 H), 7.91 (s, 1 H), 7.63 (s, 1 H), 6.42 (br s, 2
6
+
H). MS-ESI: m/z 112.6 [M+H] . HPLC: Column: YMC-pack ODS-A 150 x 4.6 mm, 5 µm.
Retention Time: 3.418 min. Mobile phase: 0.1% TFA in water (solvent A) and 0.1% TFA in
acetonitrile (solvent B), holding at 0% (solvent B) for 4 minutes, and then using the elution
gradient 0% - 30% over 6 min, and holding at 30% for 5 minutes at a flow rate of 1.0 ml/minutes
showed 99.3% purity.
Preparation of di-tert-butyl (5-bromopyrimidin-4-yl)imidodicarbonate (14)
To a solution of compound 5-bromopyrimidin-4-amine 12 (800 mg, 4.60 mmol), (BOC)2 (3310
mg, 15.2 mmol) and DMAP (191 mg, 1.56 mmol) in anhydrous THF (6 mL) was added Et3N
(2000 mg, 19.8 mmol). The mixture was stirred under N2 at RT for 16 h. LC-MS showed the
reaction was completed. The reaction mixture was evaporated under reduced pressure. The
residue was dissolved in chloromethane (40 mL), and purified by Biotage (petroleum ether/ ethyl
acetate=100/1 to 8/1) to give the desired product 14 as a white solid (810.4 mg, 47.1%). 1H
NMR (400 MHz, DMSO-d ): 9.23 (s, 1 H), 9.19 (s, 1 H), 1.37 (s 18 H). MS-ESI: m/z 397.9
6
+
[
M+23] .
Modified preparation of 4-aminopyrimidin-5-ol (5). To a solution of compound 5-
methoxypyrimidin-4-amine (10, 40 g, 0.32mol) in anhydrous DMF (2.5L) was added CH SNa
3
(40.3 g, 575 mmol, 95% Aldrich, powdered solid) at room temperature. The resulting mixture
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was heated at 120 °C for 12 h. TLC (CH Cl /MeOH = 10:1, R = 0.1) showed the reaction was
2
2
f
complete. The mixture was concentrated in vacuo to give a residue, to which was added AcOH
35 mL) and H O (100 mL). The mixture was again evaporated in vacuo to give the crude
(
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product, which was purified by column chromatography on silica gel (CH Cl /MeOH = 50:1 to
2
2
1
5:1) to give 4-aminopyrimidin-5-ol as a brown solid (5, 29 g, 82%). H NMR (400 MHz,
DMSO-d ) δ 9.64 (br s, 1 H), 7.91 (s, 1 H), 7.63 (s, 1 H), 6.42 (br s, 2 H).
6
Optimized Route to 4-aminopyrimidin-5-ol (5).
Preparation of 6-chloro-5-methoxypyrimidin-4-amine (18). A suspension of compound 4,6-
dichloro-5-methoxypyrimidine (17, 550.00 g, 3070 mmol) in 28% aqueous ammonia (2 L) and
n-butanol (1.5 L) was heated at 90 °C for 10 h in a 5 L autoclave. The mixture was cooled to
room temperature. The precipitate, which had formed, was filtered, and the filter cake washed
with EtOH (2 x 200 mL). The solid was collected and dried under high vacuum to give 6-chloro-
1
5-methoxypyrimidin-4-amine as a white solid (21, 330 g, 67%). H NMR (400 MHz, DMSO-d )
6
+
δ 7.97 (s, 1 H), 7.32 (br s, 2 H), 3.71 (s, 3 H). LC-MS: m/z [M+H] 160.1. HPLC column:
HPLC-BC (4-220) Ultimate XB-C18, 3.0 x 50mm, 3 µm. Retention Time: 2.37 min; Mobile
phase: from 1 % MeCN in water (0.1% TFA) to 100 % MeCN in water (0.1% TFA) over 8
minutes Wavelength: 220 nm showed purity of 99.8%.
Preparation of 5-methoxypyrimidin-4-amine (10). To a suspension of 6-chloro-5-
methoxypyrimidin-4-amine (18, 160 g, 10.03 mol) in methanol (1.6 L) was added Pd/C (32.0 g,
1
0% w/w Degussa grade containing ~50% H O). The mixture was degassed three times with N
2
2
and then placed under 50 psi of hydrogen pressure at 50 °C for 3 h. TLC (CH Cl /MeOH = 10/1)
2
2
indicated the reaction was complete. The mixture was filtered through a pad of celite, and the
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filter cake was washed with MeOH (3 x 100 mL). To the filtrate was added aqueous ammonia
(25 mL), and the resulting mixture was concentrated in vacuo. The residue was dissolved in THF
(
1.0 L) and CH Cl (1.0 L), and stirred for 1 h. The suspension was filtered, and the filtrate
2
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0
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concentrated and dried under high vacuum to give 5-methoxypyrimidin-4-amine as a white solid.
1
(10, 111.3 g, 90%). H NMR (400 MHz, DMSO-d ) δ 8.01 (s, 1 H), 7.81 (s, 1 H), 6.71 (br s, 2
6
H), 3.81 (s, 3 H).
Preparation of 4-aminopyrimidin-5-ol (5). Sodium (25.7 g, 1.12 mol) was added in portions to
anhydrous MeOH (700 mL) at room temperature, and the reaction stirred until the sodium had
dissolved completely. The resulting solution was then concentrated under vacuum. To a
suspension of 5-methoxypyrimidin-4-amine (10, 70.0 g, 559.4 mmol) and NaOMe (prepared as
described above) in anhydrous DMF (1.3 L) was added 1-dodecanthiol (226 g, 1.12 mol). The
suspension was heated to 120 °C to give initially a light yellow clear solution in which a white
solid started to form after 30 min. The mixture was stirred at 120 °C for a further 12 h. TLC
(
CH Cl /MeOH = 10/1) showed the reaction was complete. The reaction mixture was
2 2
concentrated to remove DMF. To the reaction mixture was added acetic acid (70 mL) and H O
2
(150 mL) (pH = 5~6). The mixture was then concentrated under vacuum for over 10 minutes.
EtOAc (400 mL) and H O (120 mL) were added to the reaction mixture. The majority of the
2
supernatant from the organic layer (dodecanthiol and EtOAc) was decanted, the remaining
suspension was filtered. The solid was washed with H O (2 x 30 mL), EtOAc (2 x 50 mL), and
2
dried under high vacuum to give 4-aminopyrimidin-5-ol (5, 53.8 g, 87%) as a gray-white solid.
1
H NMR (400 MHz, DMSO-d ) δ 9.65 (br s, 1 H), 7.91 (s, 1H), 7.63 (s, 1 H), 6.44 (br s, 2 H).
6
13
+
C NMR (100 MHz, DMSO-d ) δ 155, 149, 137.6, 136. MS-ESI: m/z 112.1 [M+H] . HPLC
6
column: Atlantis HILIC Silica 150 x 4.6mm, 5 µm; Mobile phase: 0.1% TFA in water (solvent
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A) and 0.1% TFA in acetonitrile (solvent B), using the elution gradient 90% - 60% (solvent B)
over 10 minutes and holding at 60% for 5 minutes at a flow rate of 1.0 mL/minute. Wavelength:
220 nm showed a purity of 100%.
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AUTHOR INFORMATION
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
REFERENCES
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Fan, E. J. Org. Chem., 2011, 76, 4149. (d) Wang, H.; Wen, K.; Wang, L.; Xiang, Y.; Xu,
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A.; Harris, J. C.; Haas, O. W.; Jass, P. A.; Kim, D. H.; Kodersha, G. A.; Kotnis, A. S.;
LaJeuness, J.; Lust, D. A.; Madding, G. D.; Modi, S. P.; Moniot, J. L.; Nguyen, A.;
Palaniswamy, V.; Phillipson, D. W.; Simpson, J. H.; Thoraval, D.; Thurston, D. A.; Tse,
K.; Polomski, R. E.; Wedding, D. L.; Winter, W. J. Org. Process. Res. Dev., 1997, 1,
0
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0
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00.
7
. Node, M.; Kumar, K., Nishide, K.; Ohsugi, S-I.; Miyamoto,T. Tetrahedron Lett. 2001,
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. (a) Buckley, J.; Webb, R. L.; Laird, T.; Ward, R. J. Chem. Eng. News 1982, 60, 5. (b) De
Wall, G., Chem. Eng. News 1982, 60, 5, 43.
9
. As a simple comparison (www.sigmaaldrich.com – accessed February 2015). 100mL of
9
7% ethanethiol (cat. E3708) costs $26.90. 10g of ~ 90% sodium ethanethiolate (cat.
71208) costs $121. These calculations are very crude, and more competitive pricing
would most likely be available from alternative bulk vendors.
1
0. (a) Paudler, W. W.; Jovanovic, M. V., J. Org. Chem., 1083, 48, 1064. (b) Reigan, P.;
Gbaj, A.; Chinje, E.; Stratford, I. J.; Douglas, K. T.; Freeman, S. Biorg. Med. Chem. Lett.,
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004, 14, 5247. (c) Coombs, T. C.; Tanega, C.; Shen, M.; Wang, J. L.; Auld, D. S.;
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1. (a) Maligres, P. E.; Li, J.; Krska, S. W.; Schreier, J. D.; Raheem, I. T. Angew. Chem. Int.
Ed., 2012, 51, 9071. (b) Wu, X.; Forrs, B.; Buchwald, S. L. Angew. Chem. Int. Ed. 2011,
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0, 9943.
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1
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2. (a) Thomas, A. W.; Ley, S. V. Angew. Chem. Int. Ed., 2003, 42, 5400. (b) Beletskaya, I.
P.; Cheprakov, A. V. Coord. Chem. Rev., 2004, 248, 2337.
3. (a) Higginson, P. D.; Sach, N. W. Org. Process. Res. Dev., 2004, 8, 1009. (b) Higginson,
P. D.; Sach, N. W. Org. Process. Res. Dev., 2001, 5, 331. For an example of the
utilization of this platform, see : Huang, Q.; Richardson, P. F.; Sach, N. W.; Zhu, J.; Liu,
K-C, Smith, G. L.; Bowles, D. M. Org. Process. Res. Dev., 2011, 15, 556.
1
4. For the Buchwald-type conditions, a screen was designed to evaluate 12 Pd-based
catalysts x 4 bases x 3 solvents across 144 reactions. Each reaction was run at a
0
.002mmol scale at 0.01M concentration and 110 °C for 18 h. Both the bromide and
iodide were evaluated as substrates. In a similar manner for the Ullmann coupling, a
screen was designed using the iodide as the substrate to evaluate 36 ligands using CuI
t
with either K PO or KO Pn as base and DMAc or Dioxane as solvent in a matrix of 108
3
4
conditions. Each reaction was run at a 0.004 mmol scale at 0.02 M concentration and 120
C for 18 h. As noted, in the text, limited success was realized through these screens with
°
the most promising result showing a ~ 30% LC-MS yield in the Buchwald-based screen
using a similar ligand to that reported in reference 11 (b).
1
5. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem., 1995, 60, 7508.
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6. For selected examples, see : (a) Guo, S.; Lu, L.; Cai, H. Synlett, 2013, 24, 1712. (b)
Gogoi, A.; Bora, U. Synlett, 2012, 23, 1079. (c) Chen, G.; Zeng, X.; Cui, X. Synthesis,
2
014, 46, 263. (d) Qi, H-L.; Chen, D-S.; Ye, J-S.; Huang, J-M. J. Org. Chem., 2013, 78,
482. (e) Chen, D-S.; Huang, J-M. Synlett, 2013, 24, 499. (f) Molander, G. A.;
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Cavalcanti, L. N. J. Org. Chem., 2011, 76, 623. (g) Zhu, C.; Wang, R.; Falck, J. R. Org.
Lett., 2012, 14, 3494. (h) Xu, J.: Wang, X.; Shao, C.; Su, D.; Cheng, G.; Hu, Y. Org.
Lett., 2010, 12, 1964.
17. For the boronate formation on these substrates, a screen was designed to examine 12
catalysts x 2 solvents x 4 bases. In total there were 96 reactions. Each was run at a 0.001
mmol scale with 3 equivalents of bis(pinacolato)diboron at 0.01 M concentration at 100
°
C for 18 h. As noted, in the text, synthetically useful-levels of product were not
observed in this screen.
18. (a) Bretschneider, H.; Richter, W.; Klötzer, W. Monatshefte für Chemie, 1965, 96, 1661.
(b) Bretschneider, H.; Klötzer, W.; Schantl, J. US Patent 3,132,139 (1964).
1
9. For use of gaseous ammonia in flow in a “tube in tube” reactor system, see Browne, D.
L.; O’Brien, M.; Koos, P.; Cranwell, P. B.; Polyzos, A.; Ley, S. V. Synlett, 2012, 23,
1
402.
2
0. See for example (a) Storer, R. I.; Brennan, P. E.; Brown, A. D.; Bungay, P. J.; Conlon, K.
M.; Corbett, M. S.; DePianta, R. P.; Fish, P. V.; Heifetz, A.; Ho, D. K. H.; Jessiman, A.
S.; McMurray, G.; de Oliveira, C. A. F.; Roberts, L. R.; Root, J. A.; Shanmugasundaram,
V.; Shapiro, M. J.; Skerten, M.; Westbrook, D.; Wheeler, S.; Whitlock, G. A.; Wright, J..
J. Med. Chem., 2014, 57, 5258. (b) Engelhardt, H.; Schultes, S.; de Graaf, C.; Nijmeijer,
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S.; Vischer, H. F.; Zuiderveld, O. P.; Dobler, J.; Stachurski, K.; Mayer, M.; Arnhof, H.;
Scharn, D.; Haaksma, E. E. J.; de Esch, I. J. P.; Leurs, R.. J. Med. Chem., 2013, 56, 4264.
2
1. For the use of BBr on scale, see for example : (a) Lim, C. W.; Tissot, O., Mattison, A.;
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Hooper, M. W.; Brown, J. M.; Cowley, A. R.; Hulmes, D. I.; Blacker, A. J. Org. Process.
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Ashwood, M. S.; Brande, K. M. J.; Brewer, S. E.; Cowden, C. J.; Dolling, U-H.;
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2. (a) Dillon, B. R.; Roberts, D. F.; Entwistle, D. A.; Glossop, P. A.; Knight, C. J.; Laity, D.
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