Efficient one-step synthesis of a key intermediate for the synthesis of azole antifungals using the Mitsunobu protocol

Article abstract of DOI:10.1080/00397910500297461

A simple and single-step process for coupling (2R,1S)-1-[2-(2,4- difluorophenyl)-2-oxiranyl]ethanol and various 1,2,4-triazolones utilizing the Mitsunobu protocol is described. The product so formed is a key intermediate in the synthesis of azole antifung

Full text of DOI:10.1080/00397910500297461

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Efficient One‐Step Synthesis
of a Key Intermediate for the
Synthesis of Azole Antifungals
Using the Mitsunobu Protocol
Jitendra A. Sattigeri a , Jasbir S. Arora a , Ashwani K.
Verma a , Sanjay Malhotra a & Mohammad Salman a
a Medicinal Chemistry, New Drug Discovery
Research , Ranbaxy Research Laboratory , Gurgaon,
Haryana, India
Published online: 22 Aug 2006.
To cite this article: Jitendra A. Sattigeri , Jasbir S. Arora , Ashwani K. Verma ,
Sanjay Malhotra & Mohammad Salman (2005) Efficient One‐Step Synthesis of a Key
Intermediate for the Synthesis of Azole Antifungals Using the Mitsunobu Protocol,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:22, 2939-2943
To link to this article: http://dx.doi.org/10.1080/00397910500297461
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Synthetic Communicationsw, 35: 2939–2943, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500297461
Efficient One-Step Synthesis of a Key
Intermediate for the Synthesis of Azole
Antifungals Using the Mitsunobu Protocol
Jitendra A. Sattigeri, Jasbir S. Arora, Ashwani K. Verma,
Sanjay Malhotra, and Mohammad Salman
Medicinal Chemistry, New Drug Discovery Research, Ranbaxy Research
Laboratory, Gurgaon, Haryana, India
Abstract: A simple and single-step process for coupling (2R,1S)-1-[2-(2,4-difluoro-
phenyl)-2-oxiranyl]ethanol and various 1,2,4-triazolones utilizing the Mitsunobu
protocol is described. The product so formed is a key intermediate in the synthesis
of azole antifungals with potent and broad-spectrum activity against yeast and filamen-
tous fungi.
Keywords: Azole antifungal, Mitsunobu coupling
BACKROUND
We have identified 2[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-yl)propyl]-4-[4-(4-chlorophenyl)-1-piperizinyl]phenyl]-3-
(2H,4H)-1,2,4-thiotriazolone (1) as an azole antifungal with potent and
broad-spectrum activity against yeast and filamentous fungi. The in vitro
activity correlated well with in vivo protection, indicating adequate pharma-
cokinetic properties in mouse, the efficacy model used. Further preclinical
development necessitated a robust and simple synthesis to generate this
compound in multigram quantities. Synthesis of 1 involves Lawesson’s[1a,b]
(or modified Lawesson’s,[1c]
)
reagent–mediated transformation of
Received in India May 13, 2005
Address correspondence to Mohammad Salman, Medicinal Chemistry, New Drug
Discovery Research, Ranbaxy Research Laboratory, Gurgaon, Haryana, India.
E-mail: mohammad.salman@ranbaxy.com
2939

2940
J. A. Sattigeri et al.
corresponding triazolone 2a to the desired thio analogue 1. We undertook
development of a simple and efficient synthesis of the key intermediate
required for the generation of penultimate triazolone 2a (Scheme 1).
Analogous triazolones have been synthesized following a general literature
procedure[2] (Scheme 2) involving conversion of (2R,1S)-1-[2-(2,4-difluoro-
phenyl)-2-oxiranyl]ethanol[3] (3) to the key intermediate 4, in ꢀ20–60%
yields (conversion of 3 to the corresponding activated triflate intermediate
followed by nucleophillic displacement with the anion of triazolone 5 at
low temperatures). Intermediate 4 is then converted to the desired triazolone
2 following standard protocol for epoxide ring opening with 1,2,4-triazole.
This reported sequence, however, could not be applied efficiently for the
synthesis of desired candidate molecule 2a, partly because of the inherent
labile nature of the triflate intermediate (as reflected in only low to
moderate yields for 4) and more importantly the highly insoluble nature of
the triazolone side chain 5a in solvents used for this transformation at low
temperatures. Hence, an alternate and more efficient route to generate 2a in
multigram quantities was required.
PRESENT WORK
Discrete generation of amide anion followed by addition of an alkylating
group has been the most widely used methodology in literature[4] for alkylat-
ing amidic nitrogen. Several variations of bases, additives, and cosolvents
have been used to effect this transformation. Interestingly, there has been
very limited[5] application of the Mitsunobu protocol for the alkylation of
amidic nitrogen.
Although the Mitsunobu protocol offers distinct advantages for
N-alkylation because it does not require discrete generation of nucleophilic
anions or an activated displaceable group (e.g., halide or sulfonate) because
the anion and the necessary electrophile are generated in situ, the use of this
methodology has not been explored in the synthesis of azole antifungals.
We report successful utilization of the Mitsunobu protocol as an efficient
alternative for the conversion of epoxy alcohol 3 to the key intermediate 4
in a simple one-pot process[6] (Scheme 3). Thus, diisopropylazodicarboxylate
(DIAD) was added slowly to a suspension of epoxy alcohol 3, triphenylphos-
phine, and triazolone 5a in DMF at 08C. The clear solution thus obtained
Scheme 1.

Key Intermediate for Azole Antifungals
2941
Scheme 2.
(after the complete addition of DIAD) was stirred overnight at ambient tempe-
rature to afford, after workup and purification, 4a in ꢀ35% isolated yield
with complete inversion of stereochemistry at the 28 carbon, as desired
(Scheme 1).
We have further successfully applied this protocol (Scheme 4) to the
synthesis of other analogous triazolones (4b–g) and pyrimidinone analogs
4h in moderate to good yields (Table 1).
In conclusion, we have demonstrated the utility of the Mitsunobu protocol
for the synthesis of the key intermediate 4a required for the generation of 1.
This alternate procedure is simple and offers distinct advantages as
compared to earlier methods used for the synthesis of analogous triazolones.
EXPERIMENTAL
General Procedure for Alkylation of Triazolones
Under nitrogen and stirring, nucleophile (1.1 mmol) and triphenylphosphine
(1.2 mmol) were added to dry DMF (5 mL) in a three-neck round-bottom
flask, and the mixture was cooled to 08C. A solution of epoxy alcohol 3
(1.0 mmol) in DMF (1 mL) was added at 08C followed by DIAD
(1.2 mmol). The reaction mixture was stirred at 25–308C and the progress
Scheme 3.

2942
J. A. Sattigeri et al.
Scheme 4.
was monitored by TLC. The reaction mixture was poured into ice-cold water
(100 mL) and extracted with ethyl acetate (3 ꢀ 25 mL). The combined organic
layer was washed with brine and dried over anhydrous Na2SO4, and the
solvent removed in vacuo. The residue was purified by column chromography
(silica gel, 100–200 mesh) to afford the desired product 4. [1H NMR data for
Table 1. Mitsunobu protocol in the synthesis of azole antifungals
Entry
Nucleophile 3a
Product 4
Yield
75%
5e
4e
1
5f
4f
2
41%
5g
4g
3
4
53%
34%
5h
4h
aProducts 4b–d were obtained as inseparable mixtures with reduced DIAD. They
were thus subjected to epoxide ring opening with 1,2,4-triazole, and yields were calcu-
lated over two steps.

Key Intermediate for Azole Antifungals
2943
4a: MS (þve ion mode; m/z) 539 (Mþ þ 1); (CDCl3; 300 MHz): d 1.46
(d, J ¼ 7.0 Hz, 3H), 2.87 (d, J ¼ 4.6 Hz, 1H), 3.15 (d, J ¼ 4.6 Hz, 1H),
3.29–3.35 (m, 8H), 4.95 (q, J ¼ 7.0 Hz, 1H), 6.80–7.68 (m, 12 H).]
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