Improved chiral synthesis of ravuconazole

Article abstract of DOI:10.1080/00397910802563420

A short, elegant, and high yielding synthesis of ravoconazole is presented. The key step of this synthesis is an enantioselective palladium-catalyzed chiral zinc-allene addition reaction. The starting materials are 2-chloro-1-(2,4-difluorophenyl)-ethanone and (R)-4-phenylbutyn-2-ol obtained from enzymatic resolution of its racemate. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802563420

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Improved Chiral Synthesis of
Ravuconazole
Lin Xu a b , Marc R. Muller c , Xiong Yu b & Bao-Quan
Zhu b
a Basilea Pharmaceutica China Ltd. , Haimen,
Jiangsu, China
b Shanghai Institute of Pharmaceutical Industry ,
Shanghai, China
c Basilea Pharmaceutica International AG , Basel,
Switzerland
Published online: 02 Apr 2009.
To cite this article: Lin Xu , Marc R. Muller , Xiong Yu & Bao-Quan Zhu (2009)
Improved Chiral Synthesis of Ravuconazole, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:9,
1611-1625, DOI: 10.1080/00397910802563420
To link to this article: http://dx.doi.org/10.1080/00397910802563420
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Synthetic Communications1, 39: 1611–1625, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802563420
Improved Chiral Synthesis of Ravuconazole
Lin Xu,1,2 Marc R. Muller,3 Xiong Yu,2 and Bao-Quan Zhu2
1Basilea Pharmaceutica China Ltd., Haimen, Jiangsu, China
2Shanghai Institute of Pharmaceutical Industry, Shanghai, China
3Basilea Pharmaceutica International AG, Basel, Switzerland
Abstract: A short, elegant, and high yielding synthesis of ravoconazole is pre-
sented. The key step of this synthesis is an enantioselective palladium-catalyzed
chiral zinc-allene addition reaction. The starting materials are 2-chloro-1-(2,
4-difluorophenyl)-ethanone and (R)-4-phenylbutyn-2-ol obtained from enzymatic
resolution of its racemate.
Keywords: Azoles, enantioselective addition reaction, enzymatic resolution,
Pd catalysis, propargylic alcohol, zinc-allene derivative
INTRODUCTION
The first azole with antifungal activity was reported in 1944, and the first
azole made available for clinical use in 1958 was chlormidazole.[1]
Currently, the azoles are the most widely used and studied class of
antifungal agent. Fluconazole, itraconazole, voriconazole, and posacona-
zole are the most prominent marketed representatives. Ravuconazole is a
new molecule in this class and is currently in phase II clinical trials. This
compound is a particular challenge for every organic chemist: it contains
two contiguous chiral centers, one being quaternary and the other
tertiary.
Received September 8, 2008.
Address correspondence to Marc R. Muller, Core Chemistry, Basilea Pharma-
ceutica International AG, Grenzacherstrasse 487, Postfach, CH 4005 Basel,
Switzerland. E-mail: marc.muller@basilea.com
1611

1612
L. Xu et al.
RESULTS AND DISCUSSION
The medicinal interest and the synthetic challenge prompted various
approaches to this type of molecule or advanced intermediates
thereof.[2–6] In this context, M. Soukup from Hoffmann-La Roche
developed also a new convergent synthesis of ravuconazole.[7] The
key step of this synthesis is based on a chiral allene addition reaction
catalyzed by palladium, where a zinc–allene derivative generated from
a chiral propargylic mesylate is reacted with a benzophenone derivative
(Scheme 1).
Tamaru et al.[8] described the formation of allylic zinc derivatives
obtained after transmetallation starting from the palladium (p-allyl
species. These allylic zinc species react nicely with carbonyl or thio-
carbonyl partners to form adducts with high diastereoselectivity. Later,
Scheme 1. (a) Chloroacetyl chloride, AlCl3, 80%; (b) PdCl2(CH3CN)2, Et2Zn, 3
equivalents, THF=toluene, rT, 77%; 90% ee; (c) triazole, NaOH=DMSO, 40%;
(d) NaIO4, Ru2O, acetic acid, 88%; (e) carbonyl diimidazole, 74%; (f) aqueous
ammonia, quant. (g) POCl3, 74%; (h) (EtO)2PSSH, 78%; (i) 86%.

Improved Chiral Synthesis of Ravuconazole
1613
Marshall, Adams, and Wallace[9–10] adapted this approach to propargylic
mesylates. Indeed, their treatment with diethyl zinc produces the zinc–
allene derivative via the palladium allene complex (Scheme 2). These
zinc–allene derivatives react readily and in a diastereoselective fashion
with carbonyl partners (anti=syn ratio ranging from 95:5 to 68:32), and
when chiral propargylic mesylates are used, ee values up to 95% for the
main diastereoisomer are observed.
Proposed Reaction Mechanism of the Allene Addition
For the Soukup synthesis of ravuconazole, 2-chloro-1-(2,4-difluoro-
phenyl)-ethanone 1 was reacted with the allene derivative obtained by
the treatment of methanesulfonic acid 1-methyl-prop-2-ynyl ester with
diethyl zinc in presence of palladium(II) catalyst. The adduct 2 was
obtained in a diastereoselective and enantioselective manner. The anti
syn ratio was about 70:30, and the ee was 90%, which are in line with
the Adams and Marshall publications. This primary adduct 2 was then
reacted with triazole to give the stable compound 3. Oxidative cleavage
of the triple bond[11] using sodium periodate in presence of catalytic
amounts of ruthenium dioxide gave the acid 4. The cyano-derivative 7
was obtained via activation of the acid 4 as the b-lactone 5, followed
by ammonia addition to 6 and then dehydration. The thioamide 8 was
obtained in classical fashion and was then submitted to a Hantzsch
reaction with the bromo acetophenone 9 to give ravuconazole 10 in an
8% overall yield in high purity.
Scheme 2.

1614
L. Xu et al.
The beauty of this synthesis is the simultaneous construction of the
two contiguous chiral centers, one being quaternary and the other
tertiary, in a diastereoselective and enantioselective manner.
The scarce availability of the chiral (R)-2-butynol in large quantities
and its price are nevertheless problematic. It can be obtained by chiral
reduction of butynone, a compound that is prone to polymerize very
easily and therefore is delicate to handle. The enzymatic resolution of
a racemic 2-butynol ester despite extensive efforts was not successful.
The reason for this failure is that the triple bond has to be substituted
by a bulky group (for instance, trimethylsilyl) to get a good enzymatic
resolution.
This prompted us to use easily accessible racemic 4-phenyl-3-butyn-
2-ol 11 as starting material in our synthesis. This compound 11 was
synthesized from phenyl-acetylene and acetaldehyde. The chiral resolu-
tion was performed via enzymatic esterification using the lipase AK.
After transesterification with vinyl acetate catalyzed by lipase AK, the
formed chiral ester (R)-11 was isolated and subsequently hydrolyzed.
The ee of the obtained (R)-4-phenyl-3-butyn-2-ol (R)-11 was up to
96% (Scheme 3), and the overall yield starting from phenyl-acetylene
was 35%.
(R)-4-Phenyl-3-butyn-2-ol (R)-11 was easily converted to the
corresponding mesylate 13. Based on the proposed mechanism (see
Scheme 2), we did not anticipate that the presence of the phenyl group
in the 4-position would have a negative impact on the allene addition
reaction because no steric interactions were expected from this extra phe-
nyl group in the transition state. Indeed, the reaction proceeded
smoothly, and the yield and enantioselectivity of the reaction were in
the same range as those of unsubstituted butynol. Merely the diastereos-
electivity (determined by NMR to be 16:1) seemed better.
As expected, the chloro-alcohol 14 was not very stable and therefore
converted directly to the triazole derivative 15, which was purified by chro-
matography to afford the desired compound with an ee of 93%. Simple
recrystallization in ethanol improves the optical purity of compound 15
Scheme 3. (a) n-BuLi, CH3CHO, 81%; (b) lipase AK, vinyl acetate, 47.8%; and
(c) NaOH, 92%; 96% ee.

Improved Chiral Synthesis of Ravuconazole
1615
Scheme 4. (a) MsCl, Et3N, 83%, 92% ee; (b) PdCl2 (CH3CN)2, Et3Zn, 3 equiva-
lents, THF=toluene, Rt, 87%; 85% ee; (c) triazole, NaOH=DMSO, 72.5%; and
(d) NaIO4, Ru2O, acetic acid, 71%.
up to 99%. Despite the higher steric congestion, the oxidative cleavage of
the triple bond worked quite smoothly; interestingly about 30% of the
corresponding tertiary benzoyl ester was obtained (Scheme 4). This ester
could be converted to the acid 4 by simple hydrolysis under basic condi-
tions. The overall yield of this step was 71%. This acid 4 was then con-
verted to ravuconazole in the way previously described (Scheme 1).
CONCLUSIONS
4-Phenyl-3-butyn-2-ol proved to be a suitable starting material for the
synthesis of ravuconazole. The overall yield of this eight-step synthesis
was 12.5%. The purity of the obtained product is 99%, and the ee was
more than 99.5%.
The chiral 4-phenyl-3-butyn-2-ol (R)-11 was obtained by enzymatic
resolution in an easy and efficient fashion.
EXPERIMENTAL
General Methods
Starting materials and solvents were obtained from commercial suppliers
and used without further purifications unless otherwise stated. Lipase
AK was purchased from Amano Co.

1616
L. Xu et al.
NMR spectra were recorded on a Varian Mercury Plus 400. Chemical
shifts are reported as d ppm relative to tetramethylsilane (TMS) in CDCl3
(d ¼ 0), used as internal standard for 1H NMR. For 13C NMR spectra, the
solvent peak of dimethyl sulfoxide (DMSO-d6) (d ¼ 39.52 ppm) is used as
the internal standard. Mass spectral analysis (ESI-MS) were recorded on a
Varian 1200 L Quadrupole. GC=MS were recorded Varian CP-3800 GC
system fitted with a Varian Saturn 2200 mass selective detector (El, 70
ev) and a DB-17MS column (30 m ꢀ 250 mm). [TGC(injector) ¼ 250 ꢁC,
time program (oven): T0min ¼ 80 ꢁC, T1min ¼ 80 ꢁC, T6min ¼ 250 ꢁC (20 ꢁC,
(min), T15.5min ¼ 250 ꢁC]. Analytical high-performance liquid chromato-
graphy (HPLC) was performed on an Agilent 1100 series using Chiralcel
OJ-H, Chiralcel OD-H, Chiralpak AS-H, and Chiralpak AD-H (each
4.6 ꢀ 250 mm, Daicel Chem. Ind.) as chiral columns. IR spectra were taken
on a Shimadzu FTIR-8400S. Optical rotations were measured on a PE341
polarimeter. Melting points were measured on a Buchi B-540 melting-
¨
point apparatus and are uncorrected. Elemental analyses were performed
on a CarloErba-1106.
Synthesis of 4-Phenyl-3-butyn-2-ol 11
Phenyl acetylene (89.6 mL, 817 mmol) was dissolved in dry ether (300 mL).
The mixture was cooled to ꢂ 20 ꢁC and a butyl lithium solution (509 mL,
1.6 M solution in hexane, 814 mmol) was added slowly. The reaction
mixture was warmed to 0 ꢁC, and acetaldehyde (40 g, 870 mmol) was
added. The reaction was stirred at 0 ꢁC for 2 h, then the mixture was
quenched with a saturated aqueous ammonium chloride solution
(120 mL). The mixture was extracted three times with ethyl acetate
(3 ꢀ 200 mL). The combined organic phases were washed with brine and
dried over sodium sulfate. The solids were filtered off, and the solvent
was removed under reduced pressure to give 4-phenyl-3-butyn-2-ol 11
(100.2 g, 686 mmol, yield 83%) as light yellow liquid. IR (film): 3329,
1599, 1489, 1105, 756, 690 cmꢂ1 1H NMR (DMSO-d6) d: 7.40–7.33
.
(m, 5H), 5.44 (d, J ¼ 5.2 Hz, 1H), 4.57 (q, J ¼ 6.4 Hz, 1H), 1.36 (d,
J ¼ 6.4 Hz, 3H). 13C NMR (DMSO-d6) d: 131.89, 129.34, 129.06,
123.20, 94.11, 82.80, 57.36, 25.29. GC=MS: Rt ¼ 6.34 min: m=z (%) ¼ 145
(94.4) [Mþ ꢂ 1].
Synthesis of (1R)-acetic Acid 1-Methyl-3-phenyl-prop-2-ynyl Ester 12
4-Phenyl-3-butyn-2-ol 11 (30 g, 187 mmol) was dissolved in hexane
(600 mL). Vinyl acetate (52.8 mL, 561 mmol, 3.0 equiv.) and lipase AK

Improved Chiral Synthesis of Ravuconazole
1617
(0.5 mass equiv.) were added at room temperature, and the reaction
mixture was stirred for 7 h. The solids were filtered off, and the solvent
was evaporated. The residue was purified by silica-gel column chromato-
graphy (eluent: petroleum ether=ethyl acetate ¼ 20:1) to give (1R)-acetic
acid 1-methyl-3-phenyl-prop-2-ynyl ester 12 (17.9 g, 95 mmol, yield:
47.8%) as a light yellow liquid. Enantiomeric excess: 98.5% as determined
by HPLC on a Chiralcel OD-H column (n-hexane=2-propanol, 98:2),
23
Rt¼5.32 min. [a]D ¼ 171.8 ꢁ (c ¼ 1, MeOH). IR (film): 2989, 1747,
1
1490, 1232, 758, 692 cmꢂ1. H NMR (CDCl3) d: 7.41–7.43 (m, 2 H),
7.26–7.28 (m, 3 H), 5.67 (q, J ¼ 6.4 Hz, 1H), 2.06 (3H, s), 1.56 (d,
J ¼ 6.8 Hz, 3 H). 13C NMR (CDCl3) d: 170.14, 132.08, 128.81, 21.73,
128.47, 122.49, 87.65, 84.78, 61.03, 29.92, 21.33. GC=MS: Rt ¼ 7.44 min;
min; m=z (%) ¼ 188 (23.9) [Mþ].
Synthesis of (R)-4-Phenyl-3-butyn-2-ol (R)-11
(1R)-Acetic acid 1-methyl-3-phenyl-prop-2-ynyl ester 12 (17.8 g,
88.8 mmol) was dissolved in a potassium hydroxide solution in (6.37 g,
113 mmol) in methanol (100 mL) at ꢂ10 ꢁC. The reaction mixture was
stirred at 0 ꢁC for 1 h, and then water (30 mL) was added. The mixture
was extracted with methylene chloride (100 mL ꢀ 3). The combined
organic phases were washed with brine and dried over sodium sulfate.
The solids were filtered off, and the solvent was removed under
reduced pressure to give (R)-4-phenyl-3-butyn-2-ol (R)-11 (12.4 g,
84.4 mmol, yield 95.0%) as a light yellow liquid. The enantiomeric excess
was determined to be 94.0% by HPLC on Chiralpak OD-H (n-hexane=
2-propanol, 95:5).
23
Rt¼13.32 min. [a]D ¼ 31.9ꢁ (c ¼ 1, MeOH). IR (film): 3329, 1599,
1
1490, 1103, 756, 690 cmꢂ1. H NMR (DMSO-d6) d: 7.33–7.40 (m, 5 H),
5.44 (s, 1 H), 4.57 (q, J ¼ 6.4 Hz, 1H), 1.36 (d, J ¼ 6.4 Hz, 3H). 13C
NMR (DMSO-d6) d: 131.89, 129.34, 129.06, 123.20, 94.11, 82.80,
57.36, 25.29. GC=MS: Rt ¼ 6.29 min; m=z (%) ¼ 145 (68.2) [Mþ ꢂ 1].
Methanesulfonic Acid 1(R)-Methyl-3-phenyl-prop-2-ynyl Ester 13
(R)-4-Phenyl-3-butyn-2-ol (R)-11 (3.00 g, 20.2 mmol) and triethylamine
(5.76 mL, 40.4 mmol) were dissolved in dichloromethane (30 mL) at ꢂ
78 ꢁC. Mesylchloride (2.40 mL, 30.4 mmol) was added slowly. The
reaction mixture was stirred at ꢂ 78 ꢁC for 1 h and then warmed to room
temperature slowly. The mixture was quenched with saturated aqueous
sodium bicarbonate solution (50 mL). The organic phase was separated,

1618
L. Xu et al.
and the aqueous layer was extracted with methylene chloride (30 mL ꢀ 3).
The combined organic phases were washed with water and dried over
sodium sulfate. The solids were filtered off, and the solvent was removed
under reduced pressure to give methanesulfonic acid 1(R)-methyl-3-
phenyl-prop-2-ynyl ester 13 (4.23 g, 84.4 mmol, yield: 89.3%) as a light
brown liquid. Enantiomeric excess was 91.5% as determined by HPLC
on Chiralpak AS-H column (n-hexane=2-propanol, 95:5); Rt¼19.01 min.
min. IR (film): 2939, 2233, 1490, 1175, 760, 692 cmꢂ1. 1H NMR (DMSO-
d6) d: 7.39–7.48 (m, 5H), 5.62 (q, J ¼ 6.6 Hz, 1 H), 3.28 (s, 3 H), 1.64 (d,
J ¼ 6.8 Hz, 3H). 13C NMR (DMSO-d6) d: 132.25, 130.12, 129.43, 121.55,
87.28, 87.01, 68.83, 39.04, 23.17.
Synthesis of (2R,3S)-1-chloro-2-(2,4-difluorophenyl)-3-methyl-5-
phenyl-pent-4-yn-2-ol 14
Bis-acetonitrile palladium chloride (0.27 g, 1.03 mmol) and triphenylpho-
sphine (0.67 g, 2.57 mmol) were suspended in THF (80 mL). The mixture
was stirred at 20 ꢁC for 1 h. Methanesulfonic acid 1(R)-methyl-3-phenyl-
prop-2-ynyl ester 13 (10.4 g, 46.3 mmol) and 2-chloro-1-(2,4-difluoro-
phenyl)-ethanone (5.0 g, 25.7 mmol) in THF (50 mL) were added in
sequence. A diethyl zinc solution in toluene (70.1 mL, 1.1 M, 77.1 mmol)
was added slowly to the reaction mixture, and the temperature of the
reaction mixture was kept between 35 ꢁC and 38 ꢁC. After 40 min, the
mixture was quenched with cold brine (50 mL). Ethyl acetate (25 mL)
and concentrated hydrochloric acid (10 mL) were added. The organic
phase was separated, and the aqueous layer was extracted with ethyl acet-
ate (50 ml ꢀ 3). The combined organic phases were washed with a satu-
rated aqueous sodium bicarbonate solution (30 mL ꢀ 3) and water
(30 mL) and dried over sodium sulfate. The solids were filtered off, and
the solvent was removed under reduced pressure to give the crude pro-
duct, which was purified by silica-gel column chromatography (eluent:
petroleum ether=ethyl acetate ¼ 25:1) to give (2R,3S)-1-chloro-2-(2,4-
difluorophenyl)-3-methyl-5-phenyl-pent-4-yn-2-ol 14 (6.48 g, 20.2 mmol,
yield 78.6%). White solid, melting point: 62.8 to 63.8 ꢁC. Enantiomeric
excess: 85.0% as determined by HPLC on Chiralcel OD-H column
20
(n-hexane=2-propanol, 99.5:0.5, Rt¼14.46 min. [a]D ¼ 35.3 ꢁ (c ¼ 1,
1
MeOH). IR (KBr): 1616, 1500, 1138, 756, 690 cmꢂ1. H NMR (DMSO-
d6) d: 7.64–7.71 (m, 1H), 7.42–7.44 (m, 2 H), 7.33–7.35 (m, 3 H), 7.17–
7.23 (m, 1 H), 7.09–7.13 (m, 1 H), 6.01 (s, 1 H), 4.30 (d, J ¼ 12Hz, 1H),
4.17 (d, J ¼ 12Hz, 1H), 3.23 (q, J ¼ 6.8 Hz, 1H), 0.98 (d, J ¼ 6.8 Hz,
3H). 13C NMR (DMSO-d6) d: 162.47 (dd, 1JCF ¼ 244 Hz, 3JCF ¼ 12.1Hz),
158.91 (dd, 1JCF ¼ 245 Hz, 3JCF ¼ 12.1Hz), 132.33, 132.09, 129.20, 128.87,

Improved Chiral Synthesis of Ravuconazole
1619
2
2
125.89, 123.56, 111.66 (d, JCF ¼ 21.3 Hz), 104.62 (t, JCF ¼ 26Hz), 90.99,
83.66, 77.20 (d, 3JCF ¼ 5 Hz), 52.61, 35.78, 16.70. M=S (ESI) (real intensity)
m=z 321. Anal. calcd. for C18H15ClF2O: C, 67.40; H, 4.71; Cl, 11.05;
F,11.85. Found: C, 67.50; H, 4.55; Cl, 11.01; F, 11.90.
Synthesis of (2R,3S)-2-(2,4-difluoro-phenyl)-3-methyl-5-phenyl-1-[1,2,4]-
triazol-1-yl-pent-4-yn-2-ol 15
1,2,4-Triazole (6.65 g, 96.3 mmol) and sodium hydroxide (3.85 g,
96.3 mmol) were dissolved in DMSO (25 mL). The mixture was heated
at 70 ꢁC for 30 min and then cooled to room temperature. Compound
14 (15.0 g, 30.4 mmol) dissolved in DMSO (5 mL) was added slowly over
a period of 20 min. The resulting solution was stirred at 70 ꢁC for 3 h.
After cooling to room temperature, the reaction mixture was quenched
with water (100 mL) and extracted with toluene (50 mL ꢀ 4). The com-
bined organic phases were washed with an aqueous 2 N HCl solution
(25 mL) and water (25 mL) and dried over sodium sulfate. The solids
were filtered off, and the solvent was removed under reduced pressure;
the residue was purified by silica-gel column chromatography (eluent:
petroleum ether=ethyl acetate ¼ 5:1) to give (2R,3S)-2-(2,4-difluoro-
phenyl)-3-methyl-5-phenyl-1-[1,2,4] triazol-1-yl-pent-4-yn-2-ol 15 (8.2 g,
22.0 mmol, yield 72.5%). White solid, melting point: 111.2 to 112.2 ꢁC.
Enantiomeric excess over 99.5% as determined by HPLC on Chiralpak
20
OD-H column (n-hexane=2-propanol, 90:10, Rt ¼ 20.76 min. [a]D ¼ 25.1ꢁ
(c ¼ 1, MeOH). IR (KBr): 1499, 1420, 1138, 758 cmꢂ1. 1H NMR (DMSO-
d6) d: 8.34 (s, 1 H), 7.66 (s, 1 H), 7.64–7.71 (m, 1 H), 7.42–7.44 (m, 2 H),
7.33–7.35 (m, 3 H), 7.13–7.17 (m, 1 H), 6.90-6.94 (m, 1 H), 5.97 (s, 1 H),
4.30 (d, J ¼ 12 Hz, 1 H), 4.86 (d, J ¼ 12Hz, 2 H), 3.43 (q, J ¼ 6.8 Hz, 1 H),
0.99 (d, J ¼ 6.8 Hz, 3 H). 13C NMR (DMSO-d6) d: 162.55 (dd,
3
1
3
1JCF ¼ 246 Hz, JCF ¼ 12.1Hz), 159.27 (dd, JCF ¼ 246 Hz, JCF
¼
12.1Hz), 151.12, 145.45, 132.21, 131.31 (m), 129.19, 128.90, 124.86 (d,
2JCF ¼ 12.0Hz), 123.64, 111.49 (d, JCF ¼ 21.3Hz), 104.56 (t, JCF
¼
2
2
27.3 Hz), 91.06, 84.05, 76.62 (d, 3JCF ¼ 4.6 Hz), 56.99, 34.72, 16.28. MS(ESI)
m=z (real intensity) 354. Anal. calcd. for C20H17F2N3O: C, 67.98; H, 4.85;
F, 10.75; N, 11.89. Found: C, 67.86; H, 4.84; F, 10.86; N, 11.84.
Synthesis of (2R,3R)-3-(2,4-difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]-
triazol-1-yl-butyric Acid 4
Ruthenium (IV) oxide hydrate (0.188 mmol) and sodium periodate
(9.68 g, 45.3 mmol) were dissolved in water (160 mL). After addition of

1620
L. Xu et al.
adogene 464 (0.2 mL), compound 15 (4.00 g, 11.3 mmol) dissolved in
acetic acid (100 ml) and water (20 ml) was added slowly at 5 ꢁ to 10 ꢁC.
The reaction mixture was warmed to room temperature and stirred for
3 h. After addition of 2-propanol (25 mL), the reaction mixture was stir-
red for an additional 30 min at room temperature. Then the pH of the
reaction mixture was adjusted to pH4 by the addition of aqueous sodium
hydroxide solution (4 N, 80 mL). The resulting solution was diluted with
water (100 mL) and extracted with ethyl acetate (30 mL ꢀ 6). The com-
bined organic phases were dried over sodium sulfate. The solids were fil-
tered off, and the solvent was removed under reduced pressure. The
residue was purified by silica-gel column chromatography (eluent: ethyl
acetate=petroleum ether ¼ 5:1) to give (2R,3R)-3-(2,4-difluoro-phenyl)-
3-hydroxy-2-methyl-4-[1,2,4] triazol-1-yl-butyric acid 4 (1.56 g, 5.20 mmol,
yield 46%) and the corresponding tertiary benzylated ester 4a (1.32 g,
yield 29%).
Ester 4, white solid, melting point: 215.0 to 215.6 ꢁC. Enantiomeric
excess: 98.5% as determined by HPLC on Chiralpak AS-H column
20
[n-hexane (0.1% TFA)=ethanol, 87:13], Rt ¼ 6.50 min. [a]D ¼ ꢂ50.9 ꢁ
1
(c ¼ 1, MeOH). IR (KBr): 2920, 1657, 1497, 1421, 1128 cmꢂ1. H NMR
(DMSO-d6) d: 12.77 [s (br), 1H], 8.29 (s, 1 H), 7.58 (s, 1 H), 7.11–7.21
(m, 2 H), 6.84–6.88 (m, 1 H), 5.84 [s (br), 1 H], 4.77 (d, J ¼ 14.4 Hz,
1 H), 4.69 (d, J ¼ 14.4 Hz, 1 H), 3.08 (q, J ¼ 6.8 Hz, 1 H), 0.82
(d, J ¼ 6.8 Hz, 3 H). 13C NMR (DMSO-d6) d: 175.49, 162.42
(dd, 1JCF ¼ 245 Hz, 3JCF ¼ 12.1 Hz), 159.12 (dd, 1JCF ¼ 244 Hz,
2
3JCF ¼ 12.1 Hz), 150.91, 145.42, 130.60, 125.17 (d, JCF ¼ 12.2 Hz),
2
2
111.35 (d, JCF ¼ 19.8 Hz), 104.45 (t, JCF ¼ 27.4 Hz), 76.21 (d,
3JCF ¼ 4.6 Hz), 56.58, 45.65, 13.19. MS(ESI) m=z (real intensity) 298.
Anal. calcd. for C13H13F2N3O: C, 52.53; H, 4.41; F, 12.78; N, 14.14.
Found: C, 52.74; H, 4.44; F, 12.83; N, 14.08.
(2R,3R)-3-(2,4-difluoro-phenyl)-3-benzoyloxy-2-methyl-4-[1,2,4]-triazol-
1-yl-butyric Acid 4a
White solid, melting point: 162.6–164.6 ꢁC. IR (KBr): 3435, 1728, 1716,
1
1275, 1109, 878, 712 cmꢂ1. H NMR (DMSO-d6) d: 12.54 [s(br), 1H],
8.30 (s, 1 H), 7.90–7.92 (m, 3H), 7.63–7.67 (m, 1H), 7.48–7.52 (m, 2H),
7.41–7.47 (m, 1H), 7.10–7.23 (m, 2H), 5.53 (d, J ¼ 14.8 Hz, 1H), 5.32
(d, J ¼ 14.8, 1H), 3.24 (q, J ¼ 6.8 Hz, 1H), 1.09 (d, J ¼ 6.8 Hz, 3H). 13C
1
NMR (DMSO-d6) d: 173.76, 165.04, 162.58 (dd, JCF ¼ 245.9 Hz,
1
3
3JCF ¼ 13.6 Hz ), 160.16 (dd, JCF ¼ 248.7 Hz, JCF ¼ 11.8 Hz), 152.30,
146.38, 134.25, 130.61, 130.29, 130.09, 129.37, 121.06 (d, 2JCF ¼ 10.1 Hz),
2
2
111.65 (d, JCF ¼ 21.9 Hz), 105.27 (t, JCF ¼ 25.2 Hz), 84.40 (d,

Improved Chiral Synthesis of Ravuconazole
1621
3JCF ¼ 3.3 Hz), 50.68, 45.59, 12.86. MS(ESI) m=z (real intensity) 402. The
ester 4a (1.32 g, 3.29 mmol) was hydrolyzed in aqueous sodium hydroxide
solution (4 N, 10 mL) under reflux temperature for 3 h. The pH of the
reaction solution was adjusted to pH4 by the addition of hydrochloric
acid (4 N, 9.3 mL). The resulting solution was extracted with ethyl acetate
(30 mL ꢀ 6). The combined organic phases were dried over sodium sul-
fate. The solids were filtered off, and the solvent was removed under
reduced pressure. The residue was purified by silica-gel column chroma-
tography (eluent: ethyl acetate=petroleum ether ¼ 5:1) to give the corre-
sponding acid 4 (0.83 g, 2.79 mmol, yield 85%).
The overall yield of the alkyne cleavage reaction (directly formed
acid combined with the acid obtained after hydrolysis of the benzoyl
group) was 70.7%.
Synthesis of (3R,4R)-4-(2,4-difluoro-phenyl)-3-methyl-4-[1,2,4]-triazol-1-
ylmethyl-oxetan-2-one 5
`
Compound 4 (1.6 g, 5.17 mmol) and 1,1-carbonyl diimidazole (1.13 g,
6.72 mmol) were dissolved in THF (30 mL). The reaction mixture was
heated at 60 ꢁC for 3 h and then cooled to room temperature. The sol-
vent was partially evaporated. The residue was poured into a 0.5 N
hydrochloric acid solution (50 mL). The aqueous layer was extracted
with ethyl acetate (30 mL ꢀ 3). The combined organic layers were
washed with water (30 mL ꢀ 2) and saturated aqueous sodium bicarbo-
nate solution (30 mL ꢀ 3) and dried over sodium sulfate. The solids
were filtered off, and the solvent was removed under reduced pressure.
The residue was purified by silica-gel column chromatography
(eluent: petroleum ether=ethyl acetate ¼ 2:1) to give (3R,4R)-4-(2,4-
difluoro-phenyl)-3-methyl-4-[1,2,4]triazol-1-ylmethyl-oxetan-2-one 5
(1.36 g, 4.77 mmol, yield 92.2%). White solid, melting point: 61.3 to
63.5 ꢁC. Enantiomeric excess: 98.3% as determined by HPLC on
Chiralpak AS-H column (n-hexane=2-propanol, 90:10), Rt¼25.72 min.
20
[a]D ¼ 44.9 (c ¼ 1, MeOH). IR (KBr): 1832, 1504, 1276 cmꢂ1
.
1H
ꢁ
NMR (DMSO-d6) d: 1.11 (d, J ¼ 7.6 Hz, 3 H), 3.96 (q, J ¼ 7.6 Hz, 1
H), 4.85 (s, 2H), 4.85 (d, J ¼ 12 Hz, 2 H), 6.91–6.96 (m, 2 H), 7.32–
7.37 (m, 1 H), 7.85 (s, 1 H), 8.13 (s, 1 H). 13C NMR (DMSO-d6) d:
1
3
168.64, 163.83 (dd, JCF ¼ 251 Hz, JCF ¼ 12.1 Hz), 158.95 (dd,
1JCF ¼ 246 Hz, JCF ¼ 12.1 Hz), 152.20, 144.92, 129.32 (m), 118.05 (d,
3
2JCF ¼ 13.7 Hz), 112.68 (d, JCF ¼ 21.3 Hz), 104.92 (t, JCF ¼ 25.1 Hz),
2
2
3
80.95, 54.94 (d, JCF ¼ 3.1 Hz), 52.41, 9.83. MS(ESI) m=z (real intensity)
280.0. Anal. calcd. for C13H11F2N3O2: C, 55.92; H, 3.97; F,13.61; N,
15.05. Found: C, 56.08; H, 3.99; F, 13.70; N, 15.01.

1622
L. Xu et al.
Synthesis of (2R,3R)-3-(2,4-difluoro-phenyl)-3-hydroxy-2-methyl-4-
[1,2,4]-triazol-1-yl-butyramide 6
Compound
5
(0.62 g, 2.21 mmol) and 4-dimethyl-aminopyridine
(19.9 mg, 0.16 mmol) were dissolved in 25% aqueous ammonium hydro-
xide solution (70 mL). The reaction mixture was stirred for 5 h at room
temperature. The solution was evaporated, and the residue was taken
up in methylene chloride. The organic phase was dried over magnesium
sulfate, the solids were filtered off, and the solvent was removed under
reduced pressure. The residue was purified by silica-gel column chroma-
tography (eluent: ethyl acetate=petroleum ether ¼ 2:1) to give (2R,3R)-3-
(2,4-difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-yl-butyramide
6 (0.64 g, 2.12 mmol, yield: 96.7%). White solid, melting point: 161.3 to
162.7ꢁC. Enantiomeric excess: 99.5% as determined by HPLC on
Chiralpak AD-H column [n-hexane (0.1% TFA)=ethanol], Rt¼
20
17.68 min. [a]D ¼ ꢂ 74.8ꢁ (c ¼ 0.42, MeOH). IR (KBr): 3339, 3300,
1
1666, 1618, 1500, 1417, 1136 cmꢂ1. H NMR (DMSO-d6) d: 8.28 (s, 1
H), 8.15 [s (br), 1 H], 7.59 [s (br), 1 H], 7.57 (s, 1 H), 7.12–7.24 (m,
1 H), 6.84–6.88 (m, 1 H), 6.64 (s, 1 H), 4.70 (d, J ¼ 14 Hz, 1 H), 4.40
(d, J ¼ 14 Hz, 1 H), 3.12 (q, J ¼ 6.8 Hz, 1 H), 0.81 (d, J ¼ 6.8 Hz, 3
1
H). 13C NMR (DMSO-d6) d: 178.58, 161.96 (dd, JCF ¼ 243 Hz,
1
3
3JCF ¼ 12.1 Hz), 158.65 (dd, JCF ¼ 260 Hz, JCF ¼ 12.1 Hz), 144.97,
2
2
130.31, 124.10 (d, JCF ¼ 12 Hz), 111.03 (d, JCF ¼ 18.3 Hz), 104.03 (t,
2JCF ¼ 26.6 Hz), 75.85 (d, JCF ¼ 3 Hz), 56.72, 41.79, 13.89. MS (ESI)
3
m=z (real intensity) 297.0. Anal. calcd. for C13H14F2N4O2: C, 52.70;
H, 4.76; F, 12.82; N, 18.91. Found: C, 52.51; H, 4.71; F, 13.11; N,
18.61.
Synthesis of (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-[1,2,4]-
triazol-1-yl-butyronitrile 7
(2R,3R)-3-(2,4-Difluorophenyl)-3-hydroxy-2-methyl-4-[1,2,4]-triazol-1-yl-
butyramide 6 (1 g, 3.38 mmol) was dissolved in phosphorous oxychloride
(1.26 mL, 13.5 mmol). The mixture was stirred at 40 ꢁC for 3 h. After
cooling the mixture to room temperature, excess of phosphorous oxy-
chloride was removed under high vacuum. The oily residue was purified
by silica-gel column chromatography (eluent: petroleum ether=ethyl acet-
ate ¼ 1:1) to give (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-
[1,2,4]-triazol-1-yl-butyronitrile 7 (0.89 g, 3.20 mmol, yield 94.6%). White
solid, melting point: 182.9 to 184.2 ꢁC. Enantiomeric excess: >99.5% as
determined by HPLC on Chiralpak AD-H [n-hexane column (0.1%

Improved Chiral Synthesis of Ravuconazole
1623
20
TFA)=ethanol], 80:20, Rt ¼11.41 min. [a]D ¼ 28.8ꢁ (c ¼ 1, MeOH). IR
(KBr): 2245, 1502, 1421, 1136, 1070 cmꢂ1 1H NMR (DMSO-d6) d:
.
8.32 (s, 1 H), 7.71 (s, 1 H), 7.29–7.35 (m, 1 H), 7.16–7.21 (m, 1 H),
6.95–7.00 (m, 1 H), 6.63 (s, 1 H), 4.78 (d, J ¼ 14.0 Hz, 1 H), 4.66 (d,
J ¼ 14.0 Hz, 1 H), 3.59 (q, J ¼ 7.2 Hz, 1 H), 1.02 (d, J ¼ 7.2 Hz, 3 H).
1
3
13C NMR (DMSO-d6) d: 162.92 (dd, JCF ¼ 246 Hz, JCF ¼ 13.7 Hz),
1
3
159.22 (dd, JCF ¼ 246 Hz, JCF ¼ 13.7 Hz), 151.43, 145.79, 131.15 (d,
3JCF ¼ 13.7 Hz), 123.17 (d, JCF ¼ 13.7 Hz), 121.39, 111.93 (d,
2
2JCF ¼ 21.3 Hz), 104.76 (t, JCF ¼ 26.6 Hz), 75.54 (d, JCF ¼ 4.6 Hz),
56.40, 134.26, 3.63. MS(API-ES) m=z 279.1. Anal. calcd. for C13H12F2
N4O: C, 56.11; H, 4.35; F, 13.65; N, 20.13. Found: C, 55.96; H, 4.31;
F, 13.62; N,19.95.
2
3
Synthesis of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-[1,2,4]-
triazol-1-yl-thiobutyramide 8
(2S,3R)-3-(2,4-Difluorophenyl)-3-hydroxy-2-methyl-4-[1,2,4]-triazol-1-yl-
butyronitrile 7 (1.0 g, 3.41 mmol) was dissolved in ethanol (20 mL). The
mixture was stirred at room temperature for 10 min, and aqueous ammo-
nium sulfide solution (48 wt.%, 14.6 mL, 85.4 mmol) was added. The
mixture was stirred at 50 ꢁC for 7 h. The reaction mixture was poured into
water (30 mL) and extracted with ethyl acetate (30 mL ꢀ 3). The com-
bined organic phases were washed with water (30 mL ꢀ 3) and dried over
sodium sulfate. The solids were filtered off, and the solvent was removed
under reduced pressure. The crude product was purified by silica-gel
column chromatography (eluent: ethyl acetate=petroleum ether ¼ 2:1)
to give (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-[1,2,4]-tria-
zol-1-yl-thiobutyramide 8 (0.76 g, 2.43 mmol, yield 70.4%). White solid,
melting point: 131.5ꢁ to 133.6 ꢁC. Enantiomeric excess: >99.5% as deter-
mined by HPLC on Chiralpak AD-H column [n-hexane (0.1%
20
TFA)=ethanol]. [a]D ¼ ꢂ 145.8 ꢁ (c ¼ 1.0, MeOH). IR (KBr): 1500,
1423, 1136, 1101 cmꢂ1 1H NMR (DMSO-d6) d: 10.11 (s (br), 1 H),
;
9.95 [s (br), 1 H], 8.27 (s, 1 H), 7.57 (s, 1 H), 7.23–7.27 (m, 1 H), 7.15–
7.20 (m, 1 H), 6.84–6.89 (m, 1 H), 6.53 (s, 1 H), 4.80 (d, J ¼ 14.4 Hz, 1
H), 4.49 (d, J ¼ 14.4 Hz, 1 H), 3.56 (q, J ¼ 6.8 Hz, 1 H), 0.89 (d,
J ¼ 6.8 Hz, 3 H). 13C NMR (DMSO-d6) d: 209.03, 162.47 (dd,
3
1
3
1JCF ¼ 246 Hz, JCF ¼ 12 Hz), 159.13 (dd, JCF ¼ 246 Hz, JCF ¼ 12 Hz),
2
2
150.89, 145.32, 131.06, 124.50 (d, JCF ¼ 12 Hz), 111.50 (d, JCF
¼
2
3
19.7 Hz), 104.69 (t, JCF ¼ 26.6 Hz), 76.11 (d, JCF ¼ 5 Hz), 56.70,
50.19,16.73. MS (API-ES) m=z 313.0. Anal. calcd. for C13H14F2 N4OS:
C, 49.99; H, 4.52; F, 12.17; N, 17.94; S, 10.27. Found: C, 49.96; H,
4.54; F, 12.20; N, 17.72; S, 10.23.

1624
L. Xu et al.
Synthesis of 4-[2-[(1R,2R)-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-
(1,2,4-triazol-1-yl)propyl]thiazol-4-yl]benzonitrile (Ravuconazole)
(2R,3R)-3-(2,4-Difluorophenyl)-3-hydroxy-2-methyl-4-[1,2,4]-triazol-1-yl-
`
thiobutyramide 8 (100 mg, 0.32 mmol) and 2-bromo-4-cyanoacetophe-
none (789 mg, 0.35 mmol) were dissolved in ethanol (10 mL). The mixture
was heated under reflux for 3 h. After cooling to room temperature, water
(10 mL) was added. The mixture was extracted with ethyl acetate
(30 mL ꢀ 3). The combined organic phases were washed with saturated
aqueous sodium bicarbonate solution (10 mL ꢀ 3) and brine (10 mL ꢀ 3)
and dried over sodium sulfate. The solids were filtered off, and the sol-
vent was removed under reduced pressure. The crude product was puri-
fied by silica-gel column chromatography (eluent: petroleum ether=ethyl
acetate ¼ 1:1) to give 4-[2-[2(R)-(2,4-difluorophenyl)-2-hydroxy-1(R)-
methyl-3-(1,2,4-triazol-1-yl)propyl]thiazol-4-yl]benzonitrile (ravucona-
zole) (0.11 g, 0.25 mmol, yield: 79.5%). White solid; melting point: 161.6
to 163 ꢁC. Enantiomeric excess: >99.5% as determined by HPLC on
20
Chiralpak AD-H column [n-hexane (0.1% TFA)=ethanol]. [a]D
¼
ꢂ 30.2ꢁ (c ¼ 1, MeOH). IR (KBr): 2226, 1608, 1500, 1138 cmꢂ1
.
1H
NMR (DMSO-d6) d: 8.41 (s, 1 H), 8.20 (s, 1 H), 8.18 (d, J ¼ 8.4 Hz, 2
H), 7.91 (d, J ¼ 8.4 Hz, 2 H), 7.61 (s, 1 H), 7.26–7.30 (m, 1 H), 7.18–
7.23 (m, 1 H), 6.91–6.95 (m, 1 H), 6.07 (s, 1 H), 4.85 (d, J ¼ 14.4 Hz, 1
H), 4.35 (d, J ¼ 14.4 Hz, 1 H), 4.07 (q, J ¼ 7.2 Hz, 1 H), 1.12 (d, J ¼
7.2 Hz, 3 H). 13C NMR (DMSO-d6) d: 172.45, 162.57 (dd, 1JCF ¼ 245 Hz,
3JCF ¼ 12.1 Hz), 159.33 (dd, JCF ¼ 245 Hz, JCF ¼ 12.1 Hz), 152.02,
1
3
2
151.12, 138.99, 145.41, 133.58, 130.90, 127.39, 125.30 (d, JCF ¼ 14 Hz),
2
3
119.61, 119.09, 111.57 (d, JCF ¼ 19.7 Hz), 110.78, 104.70 (d, JCF
¼
2
6 Hz), 76.89 (d, JCF ¼ 26.6 Hz), 56.64, 45.21,17.25. MS (API-ES) m=z
438.0. Anal. calcd. for C22H17F2 N5OS: C, 60.40; H, 3.92; F, 8.69; N,
16.01; S, 7.33. Found: C, 60.56; H, 3.93; F, 8.76; N, 15.76; S, 7.36.
ACKNOWLEDGMENTS
We are grateful for the important contribution of the analytical services of
Basilea China, especially to Xianzheng Liang and Jianxia Zhou for the
determinations of the ee of the produced compounds. Skillful technical assis-
tance by other analytic chemists in Basilea China is greatly acknowledged.
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Improved Chiral Synthesis of Ravuconazole
1625
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