Concise Synthesis of 1,3-Diacetoxy-2-[2′-(2′′,4′′-difluorophenyl)prop-2′-en-1′-yl]propane: An Intermediate for Posaconazole

Article abstract of DOI:10.1080/00397911.2014.929147

A concise process of 1,3-diacetoxy-2-[2′-(2″,4″-difluorophenyl)prop-2′-en-1′-yl]propane has been developed. Diethyl malonate was C-alkylated with 2,3-dichloropropene and then the ester groups were reduced by LiAlH₄ followed by acylation to provide 2-(2′-chloroprop-2′-en-1′-yl)-1,3-diacetoxypropane. The chloropropene was finally coupled with 2,4-difluorophenylmagnesium bromide and catalyzed by Fe(acac)₃ to afford the title compound in good total yield. GRAPHICAL ABSTRACT.

Full text of DOI:10.1080/00397911.2014.929147

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A Concise Synthesis of 1,3-diacetoxy-2-[2′-(2”,4″-
difluorophenyl)prop-2′-en-1′-yl]propane: An
Intermediate for Posaconazole
Yunxiang Chen a , Yangwei Huang b , Xueqing Zhao b & Zhongming Li a
a College of Chemistry and environment, Jianghan University , Wuhan , China
b Synthetic Group, Fujian Institute of Microbiology , Fuzhou , China
Accepted author version posted online: 10 Sep 2014.
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To cite this article: Yunxiang Chen , Yangwei Huang , Xueqing Zhao & Zhongming Li (2014): A Concise Synthesis
of 1,3-diacetoxy-2-[2′-(2”,4″-difluorophenyl)prop-2′-en-1′-yl]propane: An Intermediate for Posaconazole,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2014.929147
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A concise synthesis of 1,3-diacetoxy-2-[2’-(2”,4”-difluorophenyl)prop-2’-en-1’-
yl]propane: an intermediate for posaconazole
Yunxiang Chen1, Yangwei Huang2, Xueqing Zhao2, Zhongming Li1
1College of Chemistry and environment, Jianghan University, Wuhan, China 2Synthetic
Group, Fujian Institute of Microbiology, Fuzhou, China
Corresponding author. Xueqing Zhao: E-mail: zhaogangzhao@163.com; Zhongming Li:
E-mail: lizhongm@jhun.edu.cn
Abstract
A concise process of 1,3-diacetoxy-2-[2’-(2”,4”-difluorophenyl)prop-2’-en-1’-yl]propane
has been developed. Diethyl malonate was C-alkylated with 2,3-dichloropropene and
then the ester groups were reduced by LiAlH4, followed by acylation to provide 2-(2´-
chloroprop-2´-en-1´-yl)-1,3-diacetoxypropane.The chloropropene was finally coupled
with 2,4-difluorophenylmagnesium bromide catalyzed by Fe(acac)3 to afford the title
compound in good total yield.
KEYWORDS: 2,3-Dichloropropene; 2,4-Difluorobromobenzene;
Tris(acetylacetonato)iron(III); Posaconazole
INTRODUCTION
Posaconazole (1) has been marketed as a novel extended-spectrum triazole antifungal
agent for the treatment and prevention of life-threatening invasive fungal infection
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induced by many yeasts and moulds.[1] Due to its complicated structure, exploration for
its novel synthetic process still attracted the attention of the synthetic organic chemists.
POSACONAZOLE (1)
The 2,2,4-trisubstituted tetrahydronfuran skeleton with two chiral centers (2 in the
Scmeme 1) is a critical unit for posaconazole as well as other analogs.[2-4] Early these two
chiral centers were built via asymmetric synthesis involving tedious procedures or
expensive chiral auxiliary agents.[5-6] Later a novel synthesis was developed with
enzymatically catalyzed process as a key step for the conversion of 6 into 7 (Scheme 1).[7-
8]
Compared with the asymmetric synthetic methods reported, this enzymatic process
undoubtedly prevailed in highly efficiency and environment-friendliness. However, the
preparation of precursor 5 still remained complicated and tedious as disclosed in the
following four patents: (1) in the first patent, Friedel-Crafts reaction of 1,3-
difluorobenzene and chloroacetyl acid chloride gave 2-chloro-2’,4’-difluoroacetophenone.
This ketone was treated with acetate sodium, reacted with a Wittig reagent, and finally
hydrolyzed to afford 3, which could be convert into 5 as described in Scheme 1;[5] (2) in
the second patent, the preparation of the precursor 5 started from Friedel-Cratfs reaction
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of 1,3-diflurobenzene and acetic anhydride and was followed by Wittig reaction, radical
substitution reaction and final C-alkylation of diethyl malonate. A tough problem in the
radical reaction was that it was difficult to separate several bromo-substituted byproducts
when scaled up;[9] (3) in the third patent, a single step for preparing 5 was disclosed by
condensation of 2,4-diflurobromobenzene, allene and diethyl malonate catalyzed by
Pd(PPh3)4 in the presence of sodium hydride;[10] (4) in the last patent, the ene reaction of
2-chloro-2’,4’-difluoroacetophenone with (trimethylsilyl)methylmagnesium chloride
gave 2-(2,4-difluorophenyl)-3-chloroprop-1-ene, which was condensed with diethyl
malonate to afford 5.[11] However, all the reported methods are often involved in one or
more drawbacks at least, such as tedious steps, rare or expensive materials, and harsh
conditions.
Herein we report a novel and straightforward synthesis of 1,3-Diacetoxy-2-[2’-(2”,4”-
difluorophenyl)prop-2’-en-1’-yl]propane (12), which could be enzymatically resolved to
yield chiral compound 7, a key intermediate to posaconazole (Scheme 2).
RESULTS AND DISCUSSION
In our initial approach diethyl malonate was C-alkylated in ethanol with inexpensive 2,3-
dichloropropene (8) in the presence of sodium ethoxide, to give diethyl 2-(2’-chloroprop-
2’-en-1’-yl)-1,3-propandioate (9) in 89% yield[12]; further reduction of the ester groups of
9 with LiAlH4 in refluxing THF afforded the diol 10 in 91% yield, which was further
acylated with Ac2O to quantitatively provide the diacetoxy 11..
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The key step of 11 to 12 was involved in Kumada cross-coupling[13-14] of a vinyl chloride
with Grignard reagent of an aryl bromide. Usually, Kumada cross-coupling between aryl
magnesium bromides and a vinyl chloride was performed with air-sensitive nickel (0), or
palladium as a catalyst, both metals respectively with phosphine compounds as its
ligand.[15-22] In the past decade, iron (III) complexes have been successfully applied to
catalyze the coupling and numerous functional groups are tolerated (alkyl and aryl
bromides, amides, esters and even ketones.[23-29] Due to its ready availability, low cost,
and environmental friendliness, iron complexes have been attracting attention of chemists
in the field of catalysts.
In our case, tris(acetylacetonato) iron(III) [Fe(acac)3] was applied to catalyze cross-
coupling of 11 with 2,4-difluorophenyl magnesium bromide in THF-NMP (3:2 v/v) [23,30]
to give the title product 12 in a moderate yield (76%).
CONCLUSION
A novel and concise synthesis of 1,3-diacetoxy-2-[2’-(2”,4”-difluorophenyl)prop-2’-en-
1’-yl]propane has been developed in four steps from 2,3-dichloropropene and diethyl
malonate in an overall yield of 60%. The key cross-coupling of 2,4-
difluorophenylmagnesium bromide with 2-(2´-chloroprop-2´-en-1´-yl)-1,3-
diacetoxypropane was catalyzed by inexpensive and nonpoisonous Fe(acac)3 to give the
title compound in an excellent yield. The trace byproducts can be easily removed by
extraction or vacuum distillation This method may be a useful approach for the synthesis
of its 2-(2-substituted prop-2-en-1-yl)-1,3-diactoxypropane derivatives.
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EXPERIMENTAL SECTION
All reactions were performed in oven-dried (120 °C) glassware. Tetrahydrofuran (THF)
was distilled from sodium under N2. NMP (N-methylpyrrolidin-2-one) and Et3N
(triethylamine) were distilled from CaH2 under N2. Absolute ethanol was distilled from
magnesium under N2. Melting points were determined with a Büchi 540 Melting Point
apparatus and were uncorrected. TLC was performed on glass plates (GF254, 50 mm ×
100 mm, Marine Chemical Company of Qingdao, China) and compounds were stained
with aqueous solution of 0.05% KMnO4 after developed. NMR spectra were taken on
Bruker AVANCE III (500M Hz) with TMS as an internal standard. Mass spectra were
recorded using Agilent 1100 Series LC/MSD Trap. IR spectra were recorded using
Perkin–Elmer 1600 series FTIR. Elemental analyses were performed on Leco CHNS-932
Elemental Analyzer, Leco Corporation (USA).
4.2 Diethyl 2-(2’-Chloroprop-2’-En-1’-Yl)-1,3-Propandioate(9)
A glass reactor was charged with diethyl malonate (1.15 kg, 7.19 mol) and potassium
iodide (300 mg). Then a solution of sodium ethoxide (490.0 g, 7.21 mol) in alcohol (2.50
L) was added dropwise under stirring at room temperature. After the resulting solution
had refluxed for 10 min, 2,3-Dichloropropene (780.0 g, 7.03 mol) was added dropwise
over a period of two hours. The mixture was continued to reflux for two hours and then
cooled down to room temperature. The reaction mixture evaporated under reduced
pressure via a rotavapor to leave oily residue, to which water (3 L) was added. The
mixture was extracted with ethyl acetate (2 × 2 L). The combined organic layers were
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washed with brine (2 L), dried over anhydrous Na2SO4 (0.1 Kg) overnight and filtered.
The solvent was removed via a rotavapor and the residual oil was distilled under reduced
pressure to give the compound 9 (1.47 kg, 89.1%) as colorless oil, which could be used
directly in the next step. Rf = 0.65 (petroleum ether-ethyl acetate = 5:1); (bp：94-100
ºC/2-3 mbar); IR (KBr) ν/cm-1 2965, 1734, 1638, 1370, 1240, 632; 1H NMR (500 MHz,
CDCl3) δ 5.23 (s, 1H), 5.20 (s, 1H), 4.22 – 4.15 (m, 4H), 3.73 (t, J = 7.5 Hz, 1H), 2.91 (d,
J = 7.6 Hz, 2H), 1.25 (t, 6H); MS (ESI+) m/z: 235 [M+1]+, 257 [M+Na]+.
4.3 2-(2´-Chloroprop-2´-En-1´-Yl)-1,3-Propanediol (10)
A glass reactor was charged with THF (3.65 L) and LiAlH4 (365 g, 9.62 mol). A solution
of 9 (1.50 kg, 6.40 mol) in THF (2.50 L) was added at 0 ºC over 2 h under stirring. After
complete addition, the reactants were stirred for 10 min at this temperature and then
allowed to reflux 8 hours. After cooled down by ice-water, the reaction mixture was
slowly poured with agitations into the dilute hydrochloric acid (10 L) [prepared by
mixing conc. hydrochloric acid (1.75 L) with ice water (8.50 L)]. The resulting mixture
was extracted with CH2Cl2 (2 × 5 L). The combined organic layers were washed with
saturated brine, dried over anhydrous Na2SO4 (1.5 kg) overnight, and filtered. The
solvent was evaporated under reduced pressure to afford the crude compound 10 (880 g,
91.4%) as pale-yellow solid, which can be used without purification in the next step. Rf =
0.35 (petroleum ether-acetone = 3:1); mp 32-38 ºC; IR (KBr) ν/cm-1 3306, 2940, 1637,
1150, 1034, 895, 660; 1H NMR (500 MHz, MeOD-d4): δ 5.26 (d, 1H, J=1.0), 5.22 (d, 1H,
J=1.1), 3.60 (d, 4H, J=5.5), 2.42 (dd, 2H, J=7.2, 0.6), 2.06–1.98 (m, 1H); MS (ESI+) m/z:
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151 [M+1]+, 173 [M+Na]+. Anal. Calcd for C6H11ClO2 (150.60): C 47.85, H 7.36; Found:
C 47.74, H 7.15.
4.4 2-(2´-Chloroprop-2´-En-1´-Yl)-1,3-Diacetoxypropane (11)
In a glass reactor was added a solution of 10 (1.00 kg, 6.64mol) and Et3N (2 L, 14.4 mol)
in CH2Cl2 (8 L). Then Ac2O (1.40 kg, 13.7 mol) was added dropwise under stirring
during 1.5 h under ice-water cooling. The resulting mixture was stirred at room
temperature for 4 h and then treated cautiously with sat. aq. NaHCO3 (15.0 L). The
organic layer was separated and washed with brine (10 L) and dried over anhydrous
Na2SO4 (1 kg). The solvent was removed under vacuum to give the compound 11 (1.51
kg, 96.8%) as pale-yellow oil. Rf = 0.69 (petroleum ether-ethyl acetate = 5:1); IR (KBr)
ν/cm-1 3110, 2960, 1745, 1637, 1435, 1368,1232, 1158, 1043, 890, 635; 1H NMR (500
MHz, CDCl3) δ 5.24 (d, 1H, J=1.3), 5.18 (d, 1H, J=1.1), 4.10 (dd, 2H, J=11.2, 4.6), 4.05
(dd, 2H, J=11.2, 5.6), 2.46–2.40 (m, 3H), 2.05 (s, 6H); MS (ESI+) m/z: 235 [M+1]+, 257
[M+Na]+. Anal. Calcd for C10H15ClO4 (234.68): C 51.18, H 6.44; Found: C 51.11, H
6.27.
4.5 1,3-Diacetoxy-2-[2’-(2”,4”-Difluorophenyl)Prop-2’-En-1’-Yl]Propane (12)
In a 500 mL three necked flask a little of I2 was added to the mixture of flame-dried
magnesium turnings (5.82 g, 240 mmol) and 15 ml of absolute THF, several minutes later
about 0.5 mL of 2,4-difluorobromobenzene was injected. After initiation of the reaction
warmed by means of a heat gun, the rest of 2,4-difluorobromobenzene (44.4 g, 230
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mmol) and THF (350 mL) was added slowly, and the reaction temperature was kept
between 40-50 °C.
A 20 L glass reactor was charged with magnesium turnings (52.4 g, 2.16 mol), absolute
THF (1 L), and the solution of the above 2,4-difluorophenylmagnesium bromide. Then
2,4-difluorobromobenzene (400 g, 2.07 mol) and THF (2.3 L) were added during the
reaction temperature between 40-50 °C, to give a solution of 2,4-
difluorophenylmagnesium bromide.
To a solution of 11 (492 g, 2.10 mol) and tris(acetylacetonato) iron(III) [Fe(acac)3] (22.0
g, 62.3 mmol, 3% equiv. referred to compound (11) in a mixed solution of THF ( 3 L)
and NMP (2 L) in a glass reaction was added the above solution of 2,4-
difluorophenylmagnesium bromide dropwise at -5 ºC over 1.5 h. Stirring was continued
for 30 min at this temperature, and then the reaction mixture was quenched with aq. 1 M
HCl (8 L). After the organic layer was isolated, the aqueous layer was extracted with
CH2Cl2 (2 × 3 L). The combined organic layer was washed with sat. aq. NaHCO3 (6 L)
and brine (2 × 6 L), and dried (MgSO4). Solvents were removed via a rotavapor and the
residue was distilled under vacuum to afford the title compound 12 (498 g, 76.0% based
on compound 11) as light yellow oil. Rf = 0.46 (petroleum ether-ethyl acetate = 87:13);
(bp: 136-141°C/ 1-2 mbar); IR (KBr) ν/cm-1 3081, 2961, 1741, 1616, 1504, 1368, 969,
851, 607; 1H NMR (500 MHz, CDCl3): δ 7.23 (td, 1H J 8.6, 6.5), 6.87–6.82 (m, 1H),
6.79 (ddd, 1H, J=11.2, 8.8, 2.5), 5.24 (d, 1H, J=1.1), 5.21 (s, 1H), 4.05 (dd, 2H, J=11.1,
13
5.0), 4.00 (dd, 2H, J=11.1, 6.3), 2.57 (d, 2H, J=7.4), 2.04–1.95 (m, 7H); C NMR (126
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MHz, CDCl3) δ 170.93 (s), 162.37 (dd, 1JCF = 249.5 Hz, 3JCF = 11.3 Hz), 159.86 (dd, 1JCF
= 249.5 Hz, 3JCF = 11.3 Hz), 141.00 (s), 130.82 (dd, 2JCF = 9.4, 5.9 Hz), 124.84 (dd, J =
14.3, 3.9 Hz), 118.70 (s), 111.40 (dd, 2JCF = 21.0, 4JCF = 3.6 Hz), 104.21 (t, 3JCF = 26.5),
63.66 (s), 35.59 (s), 35.23 (d, 4JCF = 3.7 Hz), 20.78 (s). MS (ESI+) m/z: 335 [M+Na]+.
Anal. Calcd for C16H18F2O4 (312.31): C 61.53, H 5.81; Found: C 61.33, H 5.63.
FUNDING
We would like to thank Scientific Founds of Fujian Province (2011J01095) for the
support of this work.
SUPPLEMENTAL INFORMATION
Supplemental data for this article can be accessed on the publisher's website.
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Scheme 1. The chemoenzymatic route of literatures to the intermediate (2) of
posaconazole
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Scheme 2. New synthetic route of compound 12
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