Benzeneboronic acid

Example 7

Catalysis of the Suzuki Reaction

The coupling of bromobenzene and benzeneboronic acid (dihydroxyphenylborane) to biphenyl was investigated. The typical reaction conditions were based on studies of the Suzuki reaction which were taken from the current literature.

To carry out the Suzuki cross-coupling, a mixture of bromobenzene and 1.2 equivalents of benzeneboronic acid in toluene was admixed with 2 equivalents of bis(N-pivaloyl-N′-butyl-benzamidine)palladium(II) chloride auxiliary base and as the catalyst. The reactions were carried out at from 85 to 110° C. To monitor the progress of the reaction, samples were taken regularly for was chromatography (GC). After from 1 to 72 hours, the reactions were terminated. The product yields were determined by GC using the internal standard diethylene glycol di-n-butyl

Table 2 summarizes the coupling experiments of bromobenzene and benzeneboronic acid to give biphenyl under bis(N-pivaloyl-N′-butylbenzamidine)palladium(II) chloride catalysis.

EXAMPLE 12

[Figure (not displayed)]

To a solution of benzeneboronic acid (1.9 g; 15.8 mmol) dissolved in CH₂Cl₂ (250 mL) was added 2-chloro-5-methylphenol (36; 2.5 g; 17.5 mmol), cupric acetate (3.5 g; 19.3 mmol), TEA ((12.3 mL; 87.7 mmol) and 12.5 g of 4 Å molecular sieves. The reaction was stirred for 24 h and an additional aliquot of benzeneboronic (2.4 g; 19.3 mmol) was added and stirring continued for an additional 48 hr. The reaction mixture was filtered through a bed of CELITE® and the filtered solids were washed thoroughly with CH₂Cl₂. The combined organic extracts were washed with 2N HCl, H₂O, sat'd NaHCO₃, H₂O and brine, dried (MgSO₄) filtered and evaporated. The crude product was purified by silica gel chromatography and eluted with hexane:EtOAc (9:1) to yield 37b (1.6 g; 47.1%) as a clear oil.

Example 6

157.2 mg of progesterone and 105.0 mg of 3-nitrophthalic acid were weighed, mixed and placed in an agate mortar, 40 μl of an ethanol-water (volume ratio=1:1) mixed solvent was added dropwise, grinding was then performed, an additional ethanol-water (volume ratio=1:1) mixed solvent was continuously added during the grinding process, and after grinding was performed for 45 min at room temperature, the solution was dried in a vacuum drying cabinet at 65° C. to obtain a cocrystal of progesterone. The obtained cocrystal was subjected to powder X-ray diffraction analysis. Its diffraction pattern is shown in FIG. 3-2, indicating that the obtained crystal is a progesterone-3-nitrophthalic acid cocrystal.

The structure of each of the cocrystals of progesterone prepared in Examples 1-6 was characterized by infrared absorption spectrum, X-ray diffraction and differential scanning calorimetry. The results are shown in the drawings and Table 1.

1. The Results of Infrared Absorption Spectrum

The progesterone monomer, the cocrystal former monomers and the cocrystals of progesterone prepared in Examples 1-6 were analyzed by Fourier infrared spectroscopy. The results are shown in FIGS. 1-1, 2-1 and 3-1. This analysis mainly studied the changes in the stretching vibration frequencies of —C═O and —OH within the range of 1600 to 1710 cm⁻¹ and 2500 to 3500 cm⁻¹. It is found that after progesterone forms a cocrystal with isophthalic acid, 4-benzeneboronic acid or 3-nitrophthalic acid, due to the effect of hydrogen bonds, the characteristic wave number and waveform within the above wavelength ranges are apparently changed, proving the formation of cocrystals of progesterone.

2. The Results of X-Ray Diffraction

The cocrystals of progesterone prepared in Examples 1-3 were analyzed by single-crystal X-ray diffraction respectively. The crystal data and structural parameters of the cocrystals of progesterone are shown in Table 1 below.

Single-crystal X-ray diffraction measurement confirmed that the cocrystals of progesterone are formed by bonding progesterone to the cocrystal formers via hydrogen bonds, and belong to pharmaceutical cocrystals.

The progesterone monomer, the cocrystal former monomers and the cocrystals of progesterone prepared in Examples 4-6 were subjected to powder X-ray diffraction analysis. The results are shown in FIGS. 1-2, 2-2 and 3-2. By comparison, the powder X-ray diffraction pattern of the cocrystal of progesterone is significantly different from that of the progesterone monomer and that of the corresponding cocrystal former monomer in such aspects as the number of diffraction peaks, the position of the diffraction peaks, and the intensity of the diffraction peaks, which indicates the cocrystals of progesterone show new diffraction peaks which were obviously different from those of the monomers. The powder X-ray diffraction patterns of the cocrystals of progesterone are consistent with the theoretical patterns (SC simulated) of the cocrystals simulated through software with the crystal data obtained from single-crystal X-ray diffraction, indicating that the obtained cocrystals of progesterone have relatively high crystallinity and purity.

From the results of single-crystal and powder X-ray diffraction, it is clear that each of the cocrystals of progesterone has the following morphological characteristics.

(1) The basic structural unit of the progesterone-isophthalic acid cocrystal is formed by bonding two progesterone molecules and one isophthalic acid molecule together via intermolecular hydrogen bonds, wherein the carbonyl group in the progesterone molecule acts as a hydrogen bond acceptor, and the carboxyl group in the isophthalic acid molecule acts as a hydrogen bond donor. The cocrystal belongs to a triclinic system with a space group of P1 and unit cell parameters of a=21.889(6) Å, b=7.4735(17) Å, c=16.423(4) Å, α=γ=90°, β=125.052(14), V=2199.3(9) ų and Z=4. Powder X-ray diffraction characteristic peaks of the progesterone-isophthalic acid cocrystal, expressed as 2θ angles, appear at 6.56°±0.2°, 10.96°±0.2°, 13.14°±0.2°, 16.17°±0.2°, 19.76°±0.2°, 20.32°±0.2°, 21.04°±0.2°, 22.20°±0.2°, 24.17°±0.2°, 26.45°±0.2°, 28.05°±0.2°, and 28.55°±0.2°.

(2) The basic structural unit of the progesterone-4-formylbenzeneboronic acid cocrystal is formed by bonding one progesterone molecule and one 4-formylbenzeneboronic acid molecule together via an intermolecular hydrogen bond, wherein the carbonyl group in the progesterone molecule and the carbonyl group in the 4-formylbenzeneboronic acid molecule act as hydrogen bond acceptors, and the hydroxyl group in the 4-formylbenzeneboronic acid molecule and the six-membered ring in the progesterone molecule act as hydrogen bond donors. The cocrystal belongs to an orthorhombic system with a space group of P2₁2₁2₁, and unit cell parameters of a=9.2744(17)Å, b=14.001(3)Å, c=19.632(4)Å, α=β=γ=90°, V=2549.2(8)ų and Z=4. Powder X-ray diffraction characteristic peaks of the progesterone-4-formylbenzeneboronic acid cocrystal, expressed as 2θ angles, appear at 9.04°±0.2°, 10.55°±0.2°, 12.64°±0.2°, 13.44°±0.2°, 16.48°±0.2°, 16.99°±0.2°, 18.22°±0.2°, 19.11°±0.2°, 19.66°±0.2°, 20.70°±0.2°, 21.18°±0.2°, 22.12°±0.2°, 23.48°±0.2°, 24.68°±0.2°, 26.63°±0.2°, and 27.85°±0.2°.

(3) The basic structural unit of the progesterone-3-nitrophthalic acid cocrystal is formed by bonding one progesterone molecule and one 3-nitrophthalic acid molecule together via an intermolecular hydrogen bond, wherein the carbonyl group in the progesterone molecule acts as a hydrogen bond acceptor, and the hydroxyl group in the 4-formylbenzeneboronic acid molecule and the carboxylc group in the 3-nitrophthalic acid molecule acts as hydrogen bond donors. The cocrystal belongs to an orthorhombic system with a space group of P2₁2₁2₁, and unit cell parameters of a=7.7804(8)Å, b=15.6533(15)Å, c=22.414(2)Å, α=β=γ=90°, V=2729.8(5)ų and Z=4. Powder X-ray diffraction characteristic peaks of the cocrystal, expressed as 2θ angles, appear at 9.08°±0.2°, 13.01°±0.2°, 13.39°±0.2°, 13.78°±0.2°, 15.88°±0.2°, 16.55°±0.2°, 18.78°±0.2°, 19.29°±0.2°, 20.87°±0.2°, 23.34°±0.2°, 26.27°±0.2°, 27.33°±0.2°, and 29.79°±0.2°.

The modes of bonding via hydrogen bonds in the cocrystals of progesterone are Pro-IPA mode, shown in FIG. 8, Pro-BBA mode, shown in FIG. 9, and Pro-NPA mode, shown in FIG. 10.

3. Results of Differential Scanning Calorimetry

The progesterone monomer, the cocrystal former monomers and the cocrystals of progesterone prepared in Examples 1-6 were analyzed by differential scanning calorimetry at the same heating rate of 10° C./minute. The results, as shown in FIGS. 1-3, 2-3 and 3-3, indicate that the progesterone-isophthalic acid cocrystal has an endothermic peak at 140.1° C.±3° C., and the progesterone-4-formylbenzeneboronic acid cocrystal has an endothermic peak at 114.7° C.±3° C. and the progesterone-3-nitrophthalic acid cocrystal has an endothermic peak at 169.0° C.±3° C. The comparison between the DSC patterns shows that the cocrystals of progesterone are significantly different from the progesterone monomer and the cocrystal former monomers in such aspects as the temperature and position of the endothermic peak, which also indicates the formation of new cocrystals of progesterone.