NOVEL PROCESS FOR THE PREPARATION OF CRISABOROLE AND ITS INTERMEDIATES

Abstract

The present invention provides a novel and improved process for the preparation of Crisaborole of Formula (I) and its pharmaceutically acceptable salts. The present invention also provides novel intermediates and process for the preparation of intermediates used in the preparation of Crisaborole. The present invention also provides an improved process for the preparation of Crisaborole and pharmaceutically acceptable salts thereof, that is commercially and industrially scalable.

Claims

1. A process for preparation of crisaborole of formula (I) comprising steps of: a) treating 4-(4-halo-3-hydroxymethyl-phenoxy)-benzonitrile of formula (V) with trityl chloride in presence of a base and a suitable solvent to give 4-{4-halo-3 [(trityloxymethyl)]phenoxy}benzonitrile of formula (IV); ##STR00013## b) reacting of the compound of formula (IV) with pinacolborane or bis(pinacolato)diboron in presence of a transition metal catalyst and the base in suitable solvent to give 4-[4-(4,4,5,5-tetramethyl-(1,3,2]dioxaborolan-2-yl) 3-trityloxymethyl-phenoxy]-benzontirile of formula (III); ##STR00014## c) optionally transesterifying the compound of formula (III) with diethanolamine in suitable solvent to provide a compound of formula (II); ##STR00015## d) deprotecting and cyclizing the compound of formula (II) or (III) in presence of a suitable acid and solvent to give the crisaborole of formula (I); and ##STR00016## e) optionally purifying the crisaborole of formula (I).

2. The process according to claim 1, wherein the solvent used in step a) or step d) is selected from a group consisting of methanol, ethanol, propanol, isopropanol, butanol, methylene chloride, chloroform, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, acetone, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, water, and mixtures thereof.

3. The process according to claim 1, wherein the base used in step a) is selected from a group consisting of triethylamine, diisopropylamine, diisopropylethylamine, piperidine, pyridine N-methyl morpholine N, N-dimethylbenzylamine, picoline, lutidine, lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, magnesium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, and magnesium hydroxide.

4. The process according to claim 1, wherein the transition metal catalyst used in step b) is selected from a group consisting of Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf).CH.sub.2Cl.sub.2, P(i-Pr), P(cyclohexyl).sub.3, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (X-Phos), 2-dicyclohexyl phosphino 2,6-dimethoxybiphenyl (S-Phos), (2,2-bis(diphenylphosphino)-1,1 binaphthyl)(BINAP), and Ph2P(CH2),PPh2 with n is 2 to 5.

5. The process according to claim 1, wherein the base used in step b) is selected from a group consisting of potassium acetate, potassium phosphate, potassium carbonate, trimethylamine, and triethylamine.

6. The process according claim 1, wherein the suitable solvent used in step b) or step c) is selected from a group consisting of acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphsophoric triamide, sulforan, N-methylpyrrolidone, benzene, toluene, xylene, ethylbenzene, diethylbenzene, styrene, vinyltoluene, divinylbenzene, alpha-methylstyrene, and mixtures thereof.

7. The process according to claim 1, wherein the acid used in step d) is selected from a group consisting of formic acid, oxalic acid, acetic acid, trimethyl acetic acid, trifluoroacetic acid, methanesulfonic, p-toluene sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, pivalic acid, and phosphoric acid.

8. (canceled)

9. (canceled)

10. (canceled)

11. Use of a compound of formula (IV), (III) or (II) for the preparation of crisaborole of a compound of formula (I), wherein the compound of formula (IV) is, ##STR00017## where X=Cl, Br, I, F or Triflate, wherein the compound of formula (III) is, ##STR00018## wherein the compound of formula (II) is, ##STR00019##

12. A process for preparing highly pure crisaborole comprising: a) reacting crisaborole with mono-ethanolamine in a suitable solvent to obtain ethanolamine salt of the crisaborole, b) isolating the mono-ethanolamine salt of the crisaborole obtained in step a), and c) converting the obtained mono-ethanolamine salt of crisaborole to a highly pure crisaborole.

13. (canceled)

Description

EXAMPLES

Example-1

Preparation of 4-(4-bromo-3-[(trityloxymethyl)]phenoxy)benzonitrile [Compound of Formula (W), Wherein X=Br]

[0097] Trityl chloride (68.75 gm) was added to a stirred solution of methylene chloride (100 ml) at 25 C.-30 C. DIPEA (45.8 ml) was added to the reaction mixture and heated to 40 C.-45 C. The solution of 2-bromo-5-(4-cyanophenoxy)benzyl alcohol (50 gm) in methylene chloride (400 ml) was added to the reaction mixture at 40 C.-45 C. over a 1 hour period and stirred for 5 hours at the same temperature. The reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, reaction mixture was cooled to 25 C.-30 C. and water (200 ml) was added slowly to the reaction mixture and stirred for 15 to 20 minutes. Organic layer was added with water and stirred for 15 to 20 minutes. The phases were separated and organic phase was distilled under vacuum at 40 C.-45 C. Methanol (250 ml) was added to the obtained reaction mass and heated up to the reflux temperature for 2 hour. The reaction mixture was cooled to 25 C.-30 C., stirred for 30 minutes and filtered. The solid was washed with methanol (252 ml) and dried at 50 C. in ATD for 2 hours and further dried at 25 C.-30 C. under vacuum for 12 hrs to obtain crude 4-(4-halo-3-[(trityloxymethyl)]phenoxy) benzonitrile (85.5 gm); Purity=88%.

[0098] .sup.1H NMR (CDCl3, 400 MHz) (ppm): 4.235 (s, 2H), 6.806-6.834 (dd, J=8.4, 2.8 Hz, 1H), 7.051-7.073 (dd, J=6.8, 2.0 Hz, 2H), 7.211-7.309 (m, 9H), 7.439-7.463 (m, 7H), 7.545-7.552 (d, J=2.8 Hz, 1H), 7.620-7.643 (dd, J=6.8, 2.0 Hz, 2H).

Example-2

Preparation of 4-[4-(4,4,5,5-tetramethyl-(1,3,2]dioxaborolan-2-yl)-3-trityloxy Methyl phenoxy]-benzontirile (III)

[0099] A mixture of compound of formula (IV-A) (50 gm), PdCl2(dppf)CH2Cl2 (1.49 gm), potassium acetate (26.90 gm) and bis(pinacolato)diboron (27.90 mg) in 1,4-dioxane (1000 ml) was heated at 90 C. and maintained for 25 hours. The reaction mixture cooled to 25 C.-30 C., filtered and washed the bed with 1,4-dioxan (50 ml). The solvent was distilled under vacuum at 50 C.-60 C. and obtained mass was added with isopropanol (350 ml) at 55 C.-60 C. and stirred for 30 minutes at the same temperature. The obtained mass was cooled to 25 C.-30 C. within 1-2 hrs and maintained for 1 hr. The obtained solid was filtered and washed with isopropanol (502 ml) and dried at 25 C. to 30 C. under vacuum for 14 hrs to obtain the title compound (42 gm); Purity=98.11%.

[0100] .sup.1H NMR (CDCl3, 400 MHz) (ppm): 1.165 (s, 12H), 4.490 (s, 2H), 6.904-6.930 (dd, J=8.2, 2.4 Hz, 1H), 7.102-7.125 (dd, J=7.2, 2.0 Hz, 2H), 7.213-7.303 (m, 9H), 7.449-7.467 (m, 6H), 7.626-7.655 (dd, J=6.8, 2.0 Hz, 2H), 7.666-7.672 (d, J=2.4 Hz, 1H), 7.775-7.795 (d, J=8.0 Hz, 1H).

Example-3

Preparation of Crisaborole [Compound of Formula (1)]

[0101] 10.0 gm compound of formula (III) of was added to the stirred solution of methylene chloride (50 ml) at 25 C.-30 C. TBAB (0.5 gm) was added. After the addition of concentrated hydrochloric acid (30 ml), the mixture was stirred for 24 hours at 25 C.-30 C. 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 25 C.-30 C. The obtained solid was filtered and washed with [0102] water (10 ml) and dried at 50 C. under vacuum for 24 hrs to obtain Crisaborole (3.6 gm); Purity=99.5%.

Example-4

Preparation of Compound of Formula (II)

[0103] A mixture of compound of formula (IV-A) (50 gm), PdCl2(dppf). CH2Cl2 (1.49 gm), potassium acetate (26.9 gm) and bis(pinacolato)diboron (27.9 gm) in 1,4-dioxane (1000 ml) was heated at 90 C. and maintained for 25 hours. The reaction mixture was cooled to 25 C.-30 C., filtered and washed the bed with 1,4-dioxan (50 ml). Diethanolamine (19.2 gm) was added and stirred for 24 hrs at 25 C.-30 C. The solid was filtered, washed with 1,4-dioxane (50 ml) and dried at 25 C. to 30 C. under vacuum for 24 hrs to obtain the compound of formula (U) (40 gm); purity=99.88%.

[0104] .sup.1H NMR (CDCl3, 400 MHz) (ppm): 2.543-2.573 (m, 2H), 2.766-2.852 (m, 2H), 3.700-3.754 (m, 2H), 3.931-3.991 (m, 2H), 4.306 (s, 2H), 6.377 (s, 1H), 6.952-6.957 (d, J=2.0 Hz, 1H), 6.987-6.993 (d, J=2.4 Hz, 1H), 7.011-7.033 (d, J=8.8 Hz, 2H), 7.252-7.430 (m, 15H), 7.573-7.595 (d, J=8.8 Hz, 2H), 7.850-7.870 (d, J=8.0 Hz, 1H)

Example-5

Preparation of Crisaborole (Compound of Formula (I)]

[0105] 10.0 gm compound of formula (II) of was added to the stirred solution of methylene chloride (50 ml) at 25 C.-30 C. TBAB (0.5 gm) was added. After the addition of concentrated hydrochloric acid (30 ml), the mixture was stirred for 24 hours at 25 C. was 30 C. 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 5 C.-10 C. The resulting solution was diluted with aqueous sodium hydroxide (4.59 ml 30%) at 5 C.-10 C. 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 25 C.-30 C. for 30 minutes. The obtained solution was filtered and acidified with hydrochloric acid (9.43 ml 10%) at 25 C.-30 C. The obtained solid was filtered and washed with water (10 ml) and dried at 50 C. under vacuum for 24 hrs to obtain Crisaborole (3.9 gm); Purity=99.4%.

Example-6

Preparation of Crisaborole Ethanolamine Salt

[0106] 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 gins) (HPLC purity 99.90%).

[0107] .sup.1H NMR (DMSO-d6, 400 MHz) (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).

Example-7

Preparation of Crisaborole from Crisaborole Ethanolamine Salt

[0108] A solution of L-tartaric acid (1.94 gins) was prepared in water (28.5 ml) and was heated to 50-55 C. Crisaborole ethanol amine salt (1.9 gins) 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 gins) (HPLC purity 99.91%).