Crisaborole

Crisaborole (AN-2728) is a potent inhibitor of PDE4 and cytokine release; inhibit PDE4 with an IC50 of 0.49 μM.

Crisaborole is a member of the class of benzoxaboroles that is 5-hydroxy-1,3-dihydro-2,1-benzoxaborole in which the phenolic hydrogen has been replaced by a 4-cyanophenyl group. A phosphodiesterase 4 inhibitor that is used for treatment of mild to moderate atopic dermatitis in children and adults. It has a role as a phosphodiesterase IV inhibitor, an antipsoriatic and a non-steroidal anti-inflammatory drug. It is a benzoxaborole, an aromatic ether and a nitrile.|Crisaborole is a novel oxaborole approved by FDA on December 14, 2016 as Eucrisa, a topical treatment of for mild to moderate atopic dermatitis. This non-steroidal agent is efficacious in improving disease severity, reducing the risk of infection and reducing the signs and symptoms in patients 2 years old and older. It reduces the local inflammation in the skin and prevents further exacerbation of the disease with a good safety profile. Its structure contains a boron atom, which facilitates skin penetration and binding to the bimetal center of the phosphodiesterase 4 enzyme. It is currently under development as topical treatment of psoriasis.|Crisaborole is a Phosphodiesterase 4 Inhibitor. The mechanism of action of crisaborole is as a Phosphodiesterase 4 Inhibitor.

A solution of L-tartaric acid (1.94 gms) was prepared in water (28.5 ml) and was heated to 50-55 C. Crisaborole ethanol amine salt (1.9 gms) was added portion wise to aqueous solution of L-tartaric acid at the 50-55 C in 1 hours and the reaction mass was further maintained at same temperature for 1 hour. The obtained solid was filtered, washed with water and dried under vacuum to obtain the tittle compound Crisaborole (1.62 gms) (HPLC purity 99.91%).10.0 gm compound of formula (II) of was added to the stirred solution of methylene chloride (50 ml) at 25C-30C. TBAB (0.5 gm) was added. After the addition of concentrated hydrochloric acid (30 ml), the mixture was stirred for 24 hours at 25C- 30C. After completion of the reaction, the phases were separated. Water (30 ml) was added to the organic layer and phases were separated. The obtained organic layer was cooled to 5C-l0C. The resulting solution was diluted with aqueous sodium hydroxide (4.59 ml 30%) at 5C-l0C and stirred for 15 minutes. The obtained solid was filtered and washed with methylene chloride (10 ml) and suck dried for 20 minutes. The wet cake was added to the water (180 ml) and stirred at 25C-30C for 30 minutes. The obtained solution was filtered and acidified with hydrochloric acid (9.43 ml 10%) at 25C-30C. The obtained solid was filtered and washed with water (10 ml) and dried at 50C under vacuum for 24 hrs to obtain Crisaborole (3.9 gm); Purity = 99.4%.10.0 gm compound of formula (III) of was added to the stirred solution of methylene chloride (50 ml) at 25C-30C. TBAB (0.5 gm) was added. After the addition of concentrated hydrochloric acid (30 ml), the mixture was stirred for 24 hours at 25C- 30C. After completion of the reaction, the phases were separated. Water (30 ml) was added to the organic layer and phases were separated. The organic layer obtained was added 200 ml water followed by aqueous sodium hydroxide (4.49 ml 30%) and stirred for 15 mins. The aqueous layer was filtered and acidified with hydrochloric acid (9.22 ml 10%) at 25C-30C. The obtained solid was filtered and washed with water (10 ml) and dried at 50C under vacuum for 24 hrs to obtain Crisaborole (3.6 gm); Purity = 99.5%.Crisaborole crude (2.0 gms) was added to methanol (40 ml) and stirred at room temperature for 15 minutes to obtain the clear solution. To this clear solution ethanol amine (0.73 gms) was added and the reaction mixture was stirred at 50 C for 60 minutes. The reaction mass was cooled to 25 C to 30 C and stirred for 60 minutes. The obtained solid was filtered and washed with methanol and dried under vacuum at 50 C to 55 C for 6 hours to obtain the Crisaborole ethanol amine salt (1.95 gms) (HPLC purity 99.90%). 1H NMR (DMSO-d6, 400MHz) d (ppm): 2.501-2.505 (s, 2H), 3.768-3.799 (t, 2H), 4.689 (s, 2H), 5.795 (s, 2H), 6.858-6.881 (t, 2H), 7.023-7.045 (d, 2H), 7.400-7.419 (d, 2H), 7.786-7.808 (d, 2H).72.0 g of Crisaborole methyl ester in crystalline Form alpha obtained as disclosed in Examples 10 or 11 are suspended in 1500 ml of water at 15 C. to 20 C. The suspension is stirred for 2 hours, and then the solid is filtered off, washed with water and dried under vacuum at about 50 C. providing 65.1 g of Crisaborole crystalline Form 1 with a HPLC purity of >99.50% at 220 nm.1.00 g of Crisaborole is dissolved at reflux in 10 mL of isopropanol. The solvent is then removed at reduced pressure giving 1.16 g Crisaborole isopropyl ester as a white crystalline solid. 1H-NMR (300 MHz, DMSO-d6) delta (ppm): 7.84 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.1 Hz, 1H), 7.16-7.06 (m, 4H), 5.03 (s, 2H), 4.76-4.68 (m, 1H), 1.26 (d, J=6.0 Hz, 6H).75.0 g of Crisaborole are fully dissolved at 60 C. to 65 C. in 900 ml of methanol. The yellow solution is kept at 60 C. to 65 C. for 30 minutes, then cooled down to 50 C. to 55 C. and maintained under these conditions for 15 to 30 minutes. The mixture is then concentrated to about half the initial volume and cooled down to 0 C. to 5 C. The suspension is filtered off and the solid washed with methanol providing 72.0 g of Crisaborole methyl ester in crystalline Form alpha with a HPLC purity >99.50% (254 nm) and wherein the most intense peaks (expressed in in 2theta) are observed at about 7.4, 12.2, 13.0, 14.1, 16.2, 17.6, 18.8, 19.8, 24.7, 25.5, and 26.6±0.2.1H-NMR (300 MHz, CDCl3) delta (ppm): 7.73 (d, J=7.8 Hz, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.26-6.99 (m, 4H), 5.07 (s, 2H), 3.89 (s, 3H).83.0 g (220 mmol) of 4-(4-bromo-3-trimethylsilanoxymethyl)-benzonitrile of formula (II), prepared as described in Example 5, 540 mL THF and 62.0 g (330 mmol) of B(OiPr)3 are added under nitrogen in a previously anhydrified flask. The mixture is cooled down to -78 C. and then 86 mL of a 2.3 M solution of hexyllithium in hexane is added keeping the temperature below -75 C. After the addition of hexyllithium, the solution is maintained for one further hour at a temperature below -78 C. and then allowed to reach room temperature. A solution of 5% HCl is added until reaching a pH value from 1 to 2. The two phases are separated and the organic phase is concentrated to residue. The residue is dissolved in 240 mL of toluene, then 40 mL of water are added resulting in the formation of solid Crisaborole. The mixture is cooled down to 0 C. and stirred for 10 hours. The solid is then filtered off and washed with toluene providing 42 g of Crisaborole of formula (I) with a yield of 82%. 1H-NMR (DMSO-d6, 300 MHz) delta (ppm): 9.18 (1H, s), 7.85-7.80 (2H, m) 7.76 (1H, d, J=8.1 Hz), 7.14-7.11 (3H, m), 7.07 (1H, dd, J=2.1, J=8.1 Hz), 4.95 (2H, s).

Molecular Weight:251.05
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:251.0753733
Monoisotopic Mass:251.0753733
Topological Polar Surface Area:62.5
Heavy Atom Count:19
Complexity:361
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes