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

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 and catalyzed by Fe(acac)3 to afford the title compound in good total yield. GRAPHICAL ABSTRACT


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 induced by many yeasts and molds. [1] Because of its complicated structure, exploration for a novel synthetic process still attracts the attention of synthetic organic chemists.
Posaconazole (1) The 2,2,4-trisubstituted tetrahydronfuran skeleton with two chiral centers (2 in Scheme 1) is a critical unit for posaconazole as well as other analogs. [2][3][4] Previously 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 high efficiency and environmental 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 0 ,4 0difluoroacetophenone. This ketone was treated with acetate sodium, reacted with a Wittig reagent, and finally hydrolyzed to afford 3, which could be converted into 5 as described in Scheme 1. [5] (2) In the second patent, the preparation of the precursor 5 started from Friedel-Crafts reaction of 1,3-diflurobenzene and acetic anhydride and was followed by Wittig reaction, radical substitution reaction, and C-alkylation of diethyl malonate. A tough problem in the radical reaction was that it was difficult to separate several bromo-substituted by-products 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(PPh 3 ) 4 in the presence of sodium hydride. [10] (4) In the last patent, the ene reaction of 2-chloro-2 0 ,4 0difluoroacetophenone with (trimethylsilyl)methylmagnesium chloride gave 2-(2,4difluorophenyl)-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

SYNTHESIS OF POSACONAZOLE INTERMEDIATE
drawbacks at least, such as tedious steps, rare or expensive materials, and harsh conditions.
the title compound in an excellent yield. The trace by-products 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.

EXPERIMENTAL
All reactions were performed in oven-dried (120 C) glassware. THF was distilled from sodium under N 2 . NMP and Et 3 N (triethylamine) were distilled from CaH 2 under N 2 . Absolute ethanol was distilled from magnesium under N 2 . Melting points were determined with a Bü chi 540 melting-point apparatus and were uncorrected. Thin-layer chromatography (TLC) was performed on glass plates (GF 254 , 50 mm Â 100 mm, Marine Chemical Company of Qingdao, China) and compounds were stained with aqueous solution of 0.05% KMnO 4 after development. NMR spectra were taken on Bruker Avance III (500 M Hz) with tetramethylsilane (TMS) as an internal standard. Mass spectra were recorded using Agilent 1100 Series LC=MSD Trap. Infrared (IR) spectra were recorded using Perkin-Elmer 1600 series FTIR. Elemental analyses were performed on a Leco CHNS-932 Elemental Analyzer, Leco Corporation (USA).

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 2 h. The mixture was continued to reflux for 2 h and then cooled down to room temperature. The reaction mixture evaporated under reduced pressure via a rotavapor to leave an oily residue, to which water (3 L) was added. The mixture was extracted with ethyl acetate (2 Â 2 L). The combined organic layers were washed with brine (2 L), dried over anhydrous Na 2 SO 4 (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 a colorless oil, which could be used directly in the next step.

2-(2'-Chloroprop-2'-en-1'-yl)-1,3-propanediol (10)
A glass reactor was charged with THF (3.65 L) and LiAlH 4 (365 g, 9.62 mol). A solution of 9 (1.50 kg, 6.40 mol) in THF (2.50 L) was added at 0 C over 2 h under stirring. After complete addition, the reactants were stirred for 10 min at this temperature and then allowed to reflux 8 h. After cooling by ice water, the reaction mixture was slowly poured with agitations into the dilute hydrochloric acid (10 L) [prepared by mixing concentrated hydrochloric acid (1.75 L) with ice water (8.50 L)]. The resulting mixture was extracted with CH 2 Cl 2 (2 Â 5 L). The combined organic layers were washed with saturated brine, dried over anhydrous Na 2 SO 4 (1.5 kg) overnight, and filtered. The solvent was evaporated under reduced pressure to afford the crude compound 10 (880 g, 91.4%) as a pale yellow solid, which can be used without purification in the next step. In a 500-mL, three-necked flask a little of I 2 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 mmol) and THF (350 mL) were added slowly, and the reaction temperature was kept between 40 and 50 C.
This solution of 2,4-difluorophenylmagnesium bromide was added dropwise 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 vessel at À5 C over 1.5 h. Stirring was continued for 30 min at this temperature, and then the reaction mixture was quenched with aqueous 1 M HCl (8 L). After the organic layer was isolated, the aqueous layer was extracted with CH 2 Cl 2 (2 Â 3 L). The combined organic layer was washed with saturated aqueous NaHCO 3 (6 L) and brine (2 Â 6 L) and dried (MgSO 4

FUNDING
We thank Scientific Foundation of Fujian Province (2011J01095) for the support of this work.

SUPPLEMENTAL INFORMATION
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