Development of an efficient, scalable route for the preparation of a novel insulin-like growth factor-1 receptor modulator

Article abstract of DOI:10.1021/op300120r

A chromatography-free and efficient synthesis of insulin-like growth factor-1 receptor (IGF-1R) modulator is reported. Herein we describe an improved synthesis for the target compound, which features facile introduction of a novel pyrrolidinyl-pyrimidyl isoxazole 8, via in situ sulfone displacement by fluorine. The overall process consists of six chemical steps and five isolations, with introduction of the expensive triheterocyclic unit 8 towards the end of the synthesis.

Full text of DOI:10.1021/op300120r

Article
pubs.acs.org/OPRD
Development of an Efficient, Scalable Route for the Preparation of a
Novel Insulin-Like Growth Factor‑1 Receptor Modulator
CH Vinod Kumar,*,† Santosh Kavitake,† Sythana Suresh Kumar,† Philip Cornwall,‡ Mithun Ashok,†
Sagar Bhagat,† Sulur G. Manjunatha,† and Sudhir Nambiar†
†Pharmaceutical Development, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560 024, India
‡Medicines Evaluation Chemistry, Pharmaceutical Development, AstraZeneca, Charter Way, Macclesfield SK10 2NA, U.K.
S
* Supporting Information
ABSTRACT: A chromatography-free and efficient synthesis of insulin-like growth factor-1 receptor (IGF-1R) modulator is
reported. Herein we describe an improved synthesis for the target compound, which features facile introduction of a novel
pyrrolidinyl-pyrimidyl isoxazole 8, via in situ sulfone displacement by fluorine. The overall process consists of six chemical steps
and five isolations, with introduction of the expensive triheterocyclic unit 8 towards the end of the synthesis.
INTRODUCTION
DISCOVERY SYNTHESIS
■
■
The medicinal chemistry approach2 for the synthesis of 1
involves the preparation of two key intermediates, 8 and 11,
and then coupling them to attain the intermediate 12 (Scheme
1). Methoxylation of 12 in the subsequent step provides the
target compound 1.
The triheterocyclic unit 8 was synthesized in five steps from
commercially available diethoxy acetonitrile 2 (Scheme 1). The
major drawback of this synthesis was poor regioselectivity
during the formation of intermediate 7. Isoxazole 7 and its
regioisomer 7a were formed in a ratio of 6:4 which required
chromatographic purification to obtain pure 7. The key bicyclic
intermediate 11 was prepared by the reaction of amino pyrazole
10a with commercially available trichloropyrimidine 9 which
resulted in a 7:3 mixture of the desired 11 and undesired
regioisomer 11a (Scheme 1). Chromatography was employed
at this point to separate the pure isomer 11 with 65% isolated
yield.
The insulin-like growth factor (IGF) axis consists of ligands,
receptors, binding proteins and proteases. The two ligands,
IGF-I and IGF-II, are mitogenic peptides that signal through
interaction with the type 1 IGF-1R, a heterotetrameric cell
surface receptor. Binding of either ligand stimulates activation
of a tyrosine kinase domain in the intracellular region of the β-
chain and results in phosphorylation of several tyrosine residues
resulting in the recruitment and activation of various signaling
molecules. The intracellular domain has been shown to
transmit signals for mitogenesis, survival, transformation and
differentiation in cells. The structure and function of the IGF-
1R has been reviewed by Adams et al.1 Since increased IGF
signaling is implicated in the growth and survival of tumor cells
and blocking IGF-1R function can reverse this, inhibition of the
IGF-1R tyrosine kinase domain is a promising approach for
evaluation in the treatment of cancer.
Research activity at AstraZeneca resulted in the discovery of
penta-heterocyclic compound 1, a modulator of the insulin-like
growth factor-1 receptor (Figure 1). In order to evaluate
pharmacological and safety properties of 1, we required an
efficient and chromatography-free synthesis. In this report we
describe our efforts in arriving at a regioselective and scalable
synthesis of 1.
Coupling of intermediate 8 and 11 provided 12 in pure form
after chromatography, which on subsequent reaction with
sodium methoxide under microwave conditions furnished
racemic compound 13 after chromatographic purification.
Chiral chromatography was employed at this point to obtain
desired enantiomer 1. The synthesis of 1 was achieved in eight
chemical steps and five chromatographic purifications with an
overall yield of 5% starting from diethoxy acetonitrile 2.
One further approach utilized by our medicinal chemistry
colleagues for the synthesis of 1 is depicted in Scheme 2.
Starting from barbituric acid 14, the intermediate 16 was
synthesized in two steps. Reaction of 16 with aminopyrazole
10a under Buchwald conditions furnished a mixture of the
desired 17 (minor isomer) and undesired regioisomer 17a
(Scheme 2). Pure compound 17 was isolated after chromato-
graphic purification. Zinc acetate-mediated coupling of
Received: May 10, 2012
Published: July 20, 2012
Figure 1. Penta-heterocyclic compound.
© 2012 American Chemical Society
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a
Scheme 1. Medicinal chemistry synthesis
a
Reagents and conditions: (a) i) MeOH/H+, ii) NH3; (b) 3-dimethylamino-propenal, NaOMe, EtOH; (c) NH2OH·HCl; (d) i) NaOCl, ii)
chromatography; (e) i) TFA, ii) chromatography; (f) i) Zn(OAc)2, ii) chromatography; (g) i) NaOMe, EtOH, microwave, ii) chromatography; (h)
chiral chromatography; (a′) i) Na2CO3, EtOH, ii) chromatography.
a
Scheme 2. Alternate medicinal chemistry approach
a
Reagents and conditions: (a) BF3·etherate, MeOH, reflux, 3 h; (b) POCl3, reflux, 4 h; (c) 10a, Pd2(dba)2, xanthene, Cs2CO3, dioxane, 80−82 °C,
18 h, ii) chromatography; (d) i) 8, Zn(OAc)2, 2-propanol, reflux, 17 h, ii) chromatography.
triheterocyclic unit 8 with 17 afforded 1 in 23% yield after
chromatography.
tricycle 8 was introduced at an early stage of the synthesis. This
prompted us to consider some alternative approaches.
In another variant, 16 was coupled first with triheterocyclic
unit 8 in the presence of zinc acetate (Scheme 2).
Chromatography was employed at this point to isolate pure
intermediate 18. In the final stage, aminopyrazole 10a was
coupled with 18 using Buchwald methodology. Pure compound
1 was isolated with 17% yield after chromatography.
With the objective of supplying the material for preclinical
evaluation, we assessed the medicinal chemistry approaches
(Schemes 1, 2) for scalability. Both the approaches were
considered unattractive due to low convergence, poor
regioselectivity, low-yielding stages, and multiple chromato-
graphic purifications. Another drawback was that the expensive
RESULTS AND DISCUSSIONS
■
Modified Medicinal Chemistry Route. Our approach
(Scheme 3) to the 2,4-dichloro-6-methoxypyrimidine 16,
utilized the commercially available trichloropyrimidine 9 as
starting material. Initial attempts for the synthesis of 16 using
sodium methoxide, resulted in the formation of the 4-chloro-
2,6-dimethoxypyrimidine impurity at high levels. Later we
examined tetrabutylammonium hydroxide (TBAH)-mediated
methoxylation of 9 in DMSO.3 A stoichiometric quantity of
methanol was used for this reaction, resulting in a 7:3 mixture
of the desired isomer 16 and the undesired regioisomer 16a.
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a
The coupling of aminopyrazole 10a and BOC protected
aminopyrazole 10b with intermediate 18 was attempted using
Buchwald methodology. A quick screen of conditions (Pd
source, solvent, ligand, and temperature) revealed that the
reaction is not promising as maximum conversion of 43% (see
Supporting Information [SI], Table 1, entry 22) was achieved
with a significant amount of starting material left unreacted.
Reactions were maintained at 120 °C for 20 to 24 h.
Incomplete conversion of 18 was attributed to the more
nucleophilic endocyclic nitrogens relative to the exocyclic 5-
amino group in 10a or 10b that inhibits the catalyst activity.
Hence, we decided to terminate further investigations on this
approach.
Scheme 3. Modified medicinal chemistry approach
Improved Synthesis of Triheterocyclic Unit (8). The
original medicinal chemistry synthesis was unsuitable for
supplying multikilogram quantities of triheterocyclic unit 8
(Scheme 1) due to poor regioselectivity and low-yielding
stages. Therefore, a better route was sought. A novel and
efficient process for the synthesis of functionalized Boc-
pyrolidine isoxazoles such as 7 was demonstrated by our
colleagues at AstraZeneca (Scheme 4).2 Reaction of hydroxyl-
amine hydrochloride with acetyl pyrimidine 20 furnished oxime
21, which was subsequently treated with the proline-derived
Weinreb amide 22 in the presence of n-butyllithium and
diisopropylamine to obtain hydroxyisoxazole 23.4,5 Dehydra-
tion of hydroxyisoxazole 23 with thionyl chloride in dichloro-
methane, afforded Boc-isoxazole 7 that, on deprotection,
furnished the triheterocyclic unit 8 in good yields and high
enantiomeric purity.
Final Choice of Route. In the new synthetic strategy we
wanted to introduce the expensive triheterocyclic unit 8
towards the end of the synthesis. With an appropriately
functionalized, commercially available pyrimidine9 such as 24,
nucleophilic substitutions can be achieved at the 4 and 6
positions in the beginning of the synthesis (Scheme 5).
Subsequent oxidation of the sulfide function to sulfone was
envisaged to facilitate nucleophilic displacement at the 2-
position of pyrimidine with the triheterocyclic unit 8, towards
the end of the synthesis.
a
Reagents and conditions: (a) 20% w/w TBAH in methanol, DMSO,
55%; (b) 8, DIPEA, NMP, 55%; (c) 10a or 10b, Buchwald screening,
120 °C, 20−24 h, 43% (conversion by HPLC area %); (d)
chromatography.
Recrystallization of this mixture from isopropyl alcohol afforded
pure 16 in 55% yield.
The tricyclic fragment 8 was then reacted with 16 in NMP
resulting in a 56% yield of the desired product 18 after
crystallization from isopropyl alcohol. For the investigation of
this approach we utilized key intermediate 8 synthesized as
shown in Scheme 4.
Scheme 4. Alternative approach for the synthesis of
intermediate 8
In the first step, Boc-aminopyrazole 10b was coupled with
the substituted pyrimidine 24 in DMSO medium, resulting in
the formation of intermediate 25b in high yield. It was found
that the Boc group of intermediate 25b was very labile under
the subsequent methoxylation conditions. Hence, we decided
Scheme 5. Final route for the synthesis of 1
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to couple aminopyrazole 10a with 24 which resulted in the
formation of intermediate 25a in high yield.
compound 1 was obtained in an overall yield of 20% and high
optical purity.
A screen of various solvents, temperatures, molar ratios of
sodium methoxide, etc. was followed to maximise the
conversion of 25a to 26. The use of sodium methoxide in
methanol at reflux temperature was identified as the best
condition (see SI, Table 2, entry 6) for this transformation. The
crude intermediate 26 (contaminated with 29) was taken into
the oxidation6 without purification. Complete conversion of 26
to 27 was achieved using the combination of hydrogen
peroxide−sodium tungstate in NMP within 4 h. At this point
we were able to purify sulfone 27 from dimethoxy impurity 29
by employing a hot methanol slurry to get pure 27 with 75%
isolated yield. A solution of 27 in NMP was then treated with
potassium carbonate followed by di-tert-butyldicarbonate
(Boc2O) to afford a 9:1 mixture of desired mono-Boc 28 and
di-Boc protected compound 30 (Figure 2) in high yield. This
mixture was taken for downstream processing without
purification.
CONCLUSION
■
A practical, highly regioselective synthesis of an insulin-like
growth factor-1 receptor (IGF-1R) inhibitor was developed. In
the new approach, metal-mediated coupling reactions were
replaced by simple displacement reactions, and the expensive
tricyclic unit 8 was introduced towards the end of the synthesis
with just one equivalent being used.10 The project was
discontinued before a scale-up campaign in our kilo lab could
be carried out.
EXPERIMENTAL SECTION
■
1
General. H NMR spectra were obtained at 300 MHz, 13C
NMR spectra were obtained at 100 MHz at 25 °C in DMSO-d6
or CDCl3, and coupling constants are quoted in hertz. HPLC
monitoring of most reactions was carried out with the use of
commercially available reverse-phase columns (Zorbax XDB-
C18 150 mm × 4.6 mm, 5 μ), eluted with ammonium acetate
(aq) and acetonitrile. LC−MS spectra were run using the same
HPLC system described above connected to an Agilent 1100
series LC-MSD, using APCI + ES ion source. Chiral analysis for
enantiomers of compound 1 was carried out with commercially
available chiral column (Chiralpak AS-H 250 mm × 4.6 mm, 5
μ), eluted with n-hexane, ethanol, and diethylamine. Melting
points were determined by closed cell DSC.
Figure 2. Impurities observed during synthesis of 1.
Procedures. 6-Chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-
(methylsulfanyl)pyrimidine-4-amine (25a). To a solution of
4,6-dichloro-2-(methylsulfanyl)pyrimidine 24 (25.0 g, 0.128
mol) in DMSO (150 mL) was charged aminopyrazole 10a
(18.68 g, 0.192 mol) and N,N-diisopropylethylamine (24.85 g,
0.192 mol) at 20−25 °C. The progress of the reaction was
monitored by HPLC. After completion of the reaction, the
reaction mass temperature was raised to 40−45 °C and
maintained for 5 h. The reaction vessel contents were cooled to
20−25 °C and diluted with water (1 L). The mixture was
stirred for 30 min, and the resulting solid was collected by
filtration and dried under vacuum to afford product 25a as
white solid. Yield: 27.6 g (84.2%); 1H NMR assay: 98% (w/w)
using DMSO-d6 as a solvent and maleic acid as an internal
Intermediates 27 and 28 were assessed for crucial sulfone
group displacement with the triheterocyclic unit 8. A screen of
conditions (temperature, base, and solvent) was conducted to
ascertain the best conversion. Initial screening (see SI, Table 3)
revealed that the sulfone displacement reaction is sluggish and
the best conversion achieved was about 10% with DMSO and
potassium carbonate even with an excess of the triheterocyclic
unit 8. Prolonged heating at an elevated temperature led to a
complex mixture.
To our surprise, we were able to achieve facile displacement
of the sulphone group in the intermediate 28 with less bulky
amines7 such as benzylamine and morpholine. At this point we
reasoned that steric hindrance could be the major factor that
slows down the sulphone displacement reaction. A thought on
sulfone group displacement by fluoride, which could reduce the
steric hindrance for the triheterocyclic unit 8 substitution,
prompted us to use tetrabutylammonium fluoride (TBAF)
during the reaction. Reaction of 28 with a stoichiometric
amount of TBAF in DMSO furnished the fluoro intermediate
31 (Figure 2) in 85% isolated yield. The reaction of 31 with
triheterocyclic unit 8 resulted in the much higher conversions
to the final compound 1 via fluoride displacement.8 In a
subsequent experiment, the desired transformation was
accomplished without isolating the fluoro intermediate 31.
Eventually, addition of stoichiometric amount of TBAF to the
reaction mixture containing 28 and triheterocyclic unit 8 in
DMSO dramatically improved the reaction profile with the best
conversion observed (>90%) to 19 (see SI, Table 3, entry 6).
Deprotection of the Boc group in compound 19 was
accomplished utilizing 6.0 N HCl solution at 20−25 °C. In a
further iteration, the isolation of intermediate 19 was avoided,
which allowed us to telescope the process from 28 to obtain the
target molecule 1 in 60% yield. Thus, starting from 24, the final
1
standard. H NMR: (300 MHz, DMSO-d6) δ 12.15 (s, 1H),
10.13 (s, 1H), 7.01 (s, 1H), 6.17 (s, 1H), 2.49 (s, 3H), 2.21 (s,
3H); LC−MS: m/z 257 (M+ + 1); Melting point: 153−155
°C.
6- Methoxy- N-(3- met hy l- 1H -pyrazol-5 -yl)-2-
(methylsulfanyl)pyrimidin-4-amine (26). To a suspension of
25a (27.0 g, 0.106 mol) in methanol (270 mL), was charged
sodium methoxide (20.04 g, 0.371 mol) at 20−25 °C. The
reaction mass temperature was then raised to 60−65 °C and
the mixture stirred for 22 h. After completion of the reaction,
the contents were cooled to 20−25 °C and diluted with water
(270 mL). The mixture was stirred for 60 min, and the resulting
solid was collected by filtration and dried under vacuum to
1
afford product 26 as a white solid. Yield: 19.90 g (75%). H
NMR: (300 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.52 (s, 1H),
6.39 (s, 1H), 5.96 (s, 1H), 3.84 (s, 3H), 2.49 (s, 3H), δ 2.19 (s,
3H); LC−MS: m/z 252 (M+ + 1); Melting point: 187−190
°C.
6-Methoxy-N-(3-methyl-1H-pyrazol-5-yl)-2-(methanyl
sulfonyl)pyrimidin-4-amine (27). To a solution of 26 (20 g,
0.079 mol) in NMP (200 mL) was charged Na2WO4·2H2O
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(2.34 g, 0.1 mol) at 20−25 °C. The reaction mass temperature
was then raised to 40−45 °C and H2O2 (23.20 g, 35% (w/w),
0.238 mol) was added dropwise over a period of 30 min. The
reaction was held for 4.0 h at 40−45 °C. After completion of
the reaction (by HPLC), the reaction was cooled to 20−25 °C,
and water (300 mL) was charged over a period of 15 min.
Excess of H2O2 was destroyed by charging a solution of
Na2S2O5 (5% w/w aqueous) until a peroxide test-strip showed
no peroxide. The reaction mixture was stirred for a further
hour, and the resulting solid was collected by filtration and
dried under vacuum at 50 °C for 10 h to afford pure 27 as an
off-white solid. Yield: 16.90 g (75%); 1H NMR assay: 98% (w/
w) using DMSO-d6 as a solvent and maleic acid as an internal
(300 MHz, CDCl3) δ 6.43 (s, 1H), 6.28 (s, 1H), 4.74 (br, 1H),
3.86 (s, 3H), 2.44 (s, 3H), 1.55 (s, 9H); 13C NMR: (100 MHz,
CDCl3) δ 172.52, 172.36, 172.44, 162.03, 161.31, 161.22,
161.14, 160.97, 159.91, 148.6, 147.5, 143.6, 101.6, 85.89, 83.93,
53.4, 26.9, 13.7; 19F NMR: (300 MHz, CDCl3) δ −45.19 ppm;
LC−MS: m/z 324 (M+ + 1).
ASSOCIATED CONTENT
* Supporting Information
■
S
Tables of results. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*vinod.kumar@astrazeneca.com
1
■
standard. H NMR: (300 MHz, DMSO-d6) δ 12.10 (s, 1H),
10.26 (s, 1H), 7.01 (s, 1H), 5.98 (s, 1H), 3.39 (s, 3H), 3.31 (s,
3H), 2.19 (s, 3H); LC−MS: m/z 284 (M+ + 1); Melting point:
188−190 °C.
Notes
The authors declare no competing financial interest.
tert-Butyl-5-{[6-methoxy-2-(methylsulfonyl)pyrimidin-4-
yl]amino}-3-methyl-1H-pyrazole-1-carboxylate (28). To a
solution of 27 (15.0 g, 0.053 mol) in NMP (150.0 mL) was
charged potassium carbonate (10.26 g, 0.074 mol) at 20−25 °C
followed by Boc2O (13.88 g, 0.064 mol) dropwise over a period
of 5.0 min, and the reaction contents were stirred for 3 h. After
completion of the reaction (by HPLC), the inorganic salts were
separated, and the reaction solution was diluted with water
(200 mL). The resulting solid was collected by filtration and
dried under vacuum to afford product 28 as an off-white solid.
ACKNOWLEDGMENTS
■
We thank David Heaton, Robin Wood and Andrew Thomas
from Medicinal Chemistry and Gair Ford from Pharmaceutical
Development at AstraZeneca for providing initial inputs during
development of the chemistry. We also thank Paul Murray and
Ed Turp from Pharmaceutical Development at AstraZeneca
who supported us with catalyst screening during route
exploration. We acknowledge the contribution of AstraZeneca
Pharmaceutical Development colleagues Debra Ainge, Alison
Foster, Phil Keegan, Luis Vaz, and Ben McKeever Abbas to the
development of the optimized synthesis of functionalized
isoxazoles.
1
Yield: 14.21 g (70%). H NMR: (300 MHz, DMSO-d6) δ
10.78 (s, 1H), 7.15 (s, 1H), 6.39 (s, 1H), 3.96 (s, 3H), 3.35 (s,
3H), 2.47 (s, 3H), 1.58 (s, 9H); LC−MS: m/z 384 (M+ + 1);
Melting point: 152−155 °C.
6-Methoxy-N-(3-methyl-1H-pyrazol-5-yl)-2-[(2S)-2-(3-pyri-
midin-2-ylisoxazol-5-yl)-pyrrolidin-1-yl]pyrimidin-4-amine
(1). To a solution of 28 (5.0 g, 0.013 mol) in DMSO (25.0
mL), was charged TBAF hydrate (6.80 g, 0.026 mol) and
triheterocyclic unit 8 (3.10 g, 0.014 mol) at 20−25 °C. The
reaction temperature was raised to 75−80 °C and stirred for 5
h. After completion of the reaction (by HPLC), the reaction
contents were cooled down to 20−25 °C; HCl solution (6 N
aqueous, 45 mL) was added, and the mixture was stirred at 25
°C for 14−16 h. Then the pH of the solution was adjusted to
7.0−7.5 using NaOH (5.0 N) solution. After stirring at 20 °C
for an hour, the precipitated solid was filtered, washed with
water (20 mL), and dried under vacuum at 60 °C for 22 h to
afford 3.90 g of crude 1. The crude material was suspended in
acetone (10 mL) and stirred for 1 h. The resulting crystals were
filtered, washed with cold (0 °C) acetone (5 mL), and dried
under vacuum at 60 °C for 12 h to afford pure 1 as an off-white
ABBREVIATIONS
■
Boc, tert-butoxy carbonyl; Boc2O, di-tert-butyl dicarbonate
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completion of the reaction (by HPLC), the vessel contents
were cooled to 20−25 °C and diluted with water (20 mL). The
mixture was stirred for 10 min, and the resulting solid was
collected by filtration and dried under vacuum to afford product
1
31 as a pale-yellow solid. Yield: 360 mg (85.3%). H NMR:
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V.; Leznoff, C. C.; Miller, J. M. J. Heterocycl. Chem. 1985, 22, 149.
(g) Klauke, E.; Oehlmann, L.; Baasner, B. J. Fluorine Chem. 1982, 21,
495.
(9) Trifluoropyrimidine was also considered during the route
scouting exercise. However, it was expensive and not commercially
available.
(10) All approaches considered for the synthesis compound 1,
employ the tricyclic fragment 8 at some point. Although the
improvement in the synthesis of 8 is a major factor, it still remains
the most expensive fragment, and any process or route would look to
utilise this material as efficiently as possible. Our work introduces the
fragment cleanly at the final bond-forming step, without any heavy
metal catalysis (one could imagine that removal of metals from such a
potentially complex structure such as the API would be difficult),
consuming only one equivalent. From the process efficiency
calculations we estimated the quantity of tricyclic fragment 8 required
for making 1.0 kg of final compound 1 is around 11.0 kg for the earlier
approaches, while it is only 2.2 kg for the new approach.
NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was published on the Web July 25, 2012, with errors
in Schemes 1, 3, and 5 and errors in reference 10 and in the
Supporting Information. The corrected version was reposted
on August 3, 2012.
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