crystals Crystals Crystals Crystals 2073-4352 MDPI 10.3390/cryst2041455 crystals-02-01455 Short Note Improved Synthesis and Crystal Structure of Dalcetrapib Laus Gerhard 1 * Kahlenberg Volker 2 Richter Frank 3 Nerdinger Sven 3 Schottenberger Herwig 1 Faculty of Chemistry and Pharmacy, University of Innsbruck, 6020 Innsbruck, Austria; Email: herwig.schottenberger@uibk.ac.at Institute of Mineralogy and Petrography, University of Innsbruck, 6020 Innsbruck, Austria; Email: volker.kahlenberg@uibk.ac.at Sandoz GmbH, 6250 Kundl, Austria; Email: frank.richter@sandoz.com (F.R.); sven.nerdinger@sandoz.com (S.N.) Author to whom correspondence should be addressed; Email: gerhard.laus@uibk.ac.at; Tel.: +43-512-507-57080; Fax: +43-512-507-57099. 19 10 2012 12 2012 2 4 1455 1459 15 08 2012 05 09 2012 14 09 2012 © 2012 by the authors; licensee MDPI, Basel, Switzerland. 2012

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An improved synthesis of the Cholesteryl Ester Transfer Protein inhibitor dalcetrapib is reported. The precursor disulfide was reduced (a) by Mg/MeOH or (b) by EtSH/DBU/THF. The resulting thiol was acylated (a) by a known procedure or (b) in a one-pot process. Impurities were removed (a) by dithiothreitol (DTT) or (b) by oxidation using H2O2. Dalcetrapib crystallized in space group P21/c.

 CETP inhibitor dalcetrapib disulfide thioester 1. Introduction

Cholesteryl Ester Transfer Protein (CETP) inhibitors [1] are investigated as high density lipoprotein-cholesterol (HDL-C) raising agents with beneficial effects on atherosclerosis. A series of S-(2-(acylamino)phenyl) alkanethioates was evaluated, and S-(2-((1-(2-ethylbutyl)cyclohexane)carbonyl-amino)phenyl) 2-methylpropanethioate was found to exhibit significant inhibition of CETP activity in animals [2,3] and clinical trials [4,5]. It was first synthesized by reduction of the disulfide 1 using triphenylphosphine and subsequent acylation of the resulting thiol 2 to give the title compound, dalcetrapib 3 (Figure 1) [2]. A one-pot process for the preparation of 3 comprising acylation in the presence of a reducing agent such as phosphine, phosphinite, phosphonite, or phosphite was patented [6].

 2. Results and Discussion

The synthesis of dalcetrapib involves two key steps (Figure 1): Reduction and acylation. The patented use of phosphorus(III) compounds as reducing agents [6] showed several disadvantages. The excess phosphines and resulting phosphine oxides are difficult to remove, and we intended to avoid chromatography. Methyl or ethyl phosphites (and the resulting phosphates) are alkylating agents giving rise to thioether byproducts. In addition, a patent-free synthesis was desired.

Synthesis of dalcetrapib (3). Step A: reduction; Step B: acylation (see text).

The reduction of disulfide 1 to thiol 2 using magnesium in methanol [7] seemed to be a good option for the first step and proceeded smoothly. The thiol is, however, very sensitive to oxygen. The final product dalcetrapib was therefore always contaminated by a few percent of the corresponding disulfide. Purification was effected by treatment with dithiothreitol (DTT), a reagent capable of reducing disulfides and maintaining thiols in the reduced state [8]. The use of this reagent gave a perfectly pure product. It is, however, rather expensive. Water-soluble phosphines, such as tris(2-carboxyethyl)-phosphine or trisodium tris(3-sulfonatophenyl)phosphine, also worked well for this purpose, but they carry an even steeper price. Consequently, a process was sought which did not require the isolation of the sensitive intermediate 2.

A one-pot method to obtain thiol esters directly from disulfides and acyl chlorides in the presence of zinc and aluminum trichloride [9] was tried, but a new byproduct was observed. Therefore, this route was not pursued further. A thiol-disulfide interchange reaction employing inexpensive ethanethiol in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was found to produce thiols in a very short time [10]. This concept has been successfully applied to the one-pot synthesis of dalcetrapib and has been reported by an anonymous author in an online journal [11]. In our hands, however, a much higher yield was obtained (reported 52%, found 82%). A modified workup was necessary to remove an unidentified impurity beyond the limit of detection.

In the search for polymorphs, crystalline dalcetrapib was obtained from several solvents (ethanol, heptane, tetrahydrofuran). Powder X-ray diffraction showed that they were identical crystalline forms. The molecular structure is shown in Figure 2. The cyclohexane ring adopts a typical chair conformation. The molecules are arranged in chains by N–H...O=C hydrogen bonds in the direction of the crystallographic b axis (Figure 3). The pertinent distances are H...O 2.02(2) Å and N...O 2.905(2) Å. The N...H...O angle is 159(2)°.

ORTEP plot of dalcetrapib (thermal ellipsoids drawn at the 50% level).

Packing diagram of dalcetrapib (3). Atoms engaged in hydrogen bonding are drawn as balls, and all other hydrogen atoms are omitted for clarity.

 3. Experimental Section

The disulfide 1 [211513-15-4] has been prepared according to the literature [2]. 1H NMR spectra of thiol 2 [211513-21-2] and dalcetrapib 3 [211513-37-0] have been previously published [2].

3.1. Two-Step Synthesis of Dalcetrapib (<bold>3</bold>)

Mg turnings (1.1 g) were added to a solution of the disulfide 1 (10.0 g) in MeOH (100 mL). The reaction mixture was stirred under argon for 9 h in a water bath to keep the temperature below 50 °C. The solvent was removed and the residue partitioned between 1M HCl (100 mL) and EtOAc (100 mL). The organic phase was washed with brine (60 mL), then dried over MgSO4, and taken to dryness to give the thiol 2 as a foul-smelling oil, which solidified overnight (yield 98%). This intermediate was dissolved in anhydrous CH2Cl2 (70 mL). Pyridine (6 mL) was added and, dropwise, isobutyryl chloride (3.4 mL). The mixture was stirred at room temperature for 3 h. After removal of the solvent, the residue was redissolved in EtOAc (100 mL) and washed with H2O (100 mL), 1M HCl (100 mL), 1M NaOH (100 mL), and brine (100 mL). The solvent was evaporated, and the crude product was dissolved in Et2O (200 mL) and vigorously stirred with a solution of DTT (0.8 g) and NaHCO3 (0.5 g) in H2O (40 mL) at room temperature for 45 min. The organic phase was separated, washed with 1M NaOH (140 mL) and H2O (100 mL), and the solvent was evaporated. The residue was dissolved in EtOH (40 mL) and precipitated by slow addition of H2O (40 mL) with stirring for 1 h. The crystalline product 3 was filtered off, washed with H2O (40 mL), and dried over P2O5 in vacuum. Yield: 77%. The single crystals were obtained by cooling of a hot solution in EtOH (from 80 °C to 20 °C in 3 h).

 3.2. One-Pot Synthesis of Dalcetrapib (<bold>3</bold>)

Isobutyryl chloride (2.0 mL) was added to a stirred solution of the disulfide 1 (2.0 g), DBU (2.8 mL), and EtSH (0.7 mL) in THF (15 mL) at room temperature. After 10 min, the precipitated DBU hydrochloride was filtered off and washed with Et2O (25 mL). The filtrate was stirred with H2O (25 mL) for 20 min. The organic phase was shaken with H2O (25 mL) and saturated NaHCO3 solution (25 mL). After removal of the volatiles, the residue was dissolved in heptane/MeOH (20/14 mL) and stirred with 1% H2O2 (6 mL) at 35 °C for 1 h. The organic phase was separated, washed four times with a mixture of MeOH (3 mL) and H2O (1 mL), and taken to dryness. The residue was crystallized as described above. Yield: 82%.

 3.3. Spectroscopic and Crystal Structure Data

Disulfide (1): 1H NMR (300 MHz, CDCl3): δ 0.70 (t, J = 7.3 Hz, 6H), 1.2–1.6 (m, H), 2.0 (m, 2H), 6.91 (Td, J = 6.9 Hz, J = 1.2 Hz, 1H), 7.12 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.41 (Td, J = 7.7 Hz, J = 1.5 Hz, 1H), 8.48 (dd, J = 8.3 Hz, J = 1.1 Hz, 1H), 8.59 (br s, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ 11.2, 23.5, 26.4, 27.2, 35.4, 36.2, 45.3, 48.3, 120.9, 122.8, 123.9, 132.6, 136.8, 140.3, 175.4 ppm. IR (neat): ν 3387 w, 2956 m, 2924 m, 2855 m, 1686 m, 1576 m, 1503 s, 1459 m, 1425 s, 1290 m, 753 s cm−1.

Thiol (2): 1H NMR, see [2]. 13C NMR (75 MHz, CDCl3): δ 11.1, 23.5, 26.4, 27.2, 35.5, 36.3, 45.6, 48.2, 116.5, 121.3, 124.1, 129.7, 135.5, 139.6, 175.2 ppm. IR (neat): ν 3377 w, 2957 m, 2927 m, 2869 m, 2850 m, 2507 w, 1644 s, 1507 s, 1459 m, 1439 s, 1287 m, 748 s·cm−1.

Dalcetrapib (3): 1H NMR, see [2]. 13C NMR (75 MHz, CDCl3): δ 11.1, 19.7, 23.4, 26.3, 27.2, 35.6, 36.2, 43.5, 45.7, 48.1, 116.9, 122.1, 124.4, 131.8, 136.4, 140.5, 175.1, 201.5 ppm. IR (neat): ν 3302 w, 2965 m, 2922 m, 2862 m, 1697 s, 1644 m, 1506 m, 1475 s, 959 s, 856 m, 754 s cm−1.

Oxford Diffraction Gemini R Ultra diffractometer, Cu-Kα radiation; ω scans; T = 100(2) K; θmax = 67.2°; indices: −12 ≤ h ≤ 12, −11 ≤ k ≤ 10, −21 ≤ l ≤ 24; Dx = 1.20 g·cm−3; 13476 reflections measured, 3624 independent with Rint = 0.048, F(000) = 848, μ = 1.46 mm−1. Crystal data for C23H35NO2S (M = 389.6 g·mol−1). Monoclinic, P21/c, a = 10.7572(3), b = 9.7154(3), c = 20.5873(6) Å, β = 90.003(3)°, V = 2151.59(11) Å3, Z = 4. R1 = 0.039 and wR2 = 0.089 for 2668 reflections with I > 2σ(I), 251 parameters, R1 = 0.058 and wR2 = 0.094 for all data; S = 0.93; ∆ρmax = 0.21 and ∆ρmax = −0.32 e Å−3. CCDC reference number: 895592.

 4. Conclusions

The new synthetic procedures are superior to the patented processes in terms of purity and yield. Remarkably, the flexible alkyl chains did not exhibit any disorder in the crystal.

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