Process for the preparation of tavaborole, its novel polymorphic forms and the polymorphs thereof

Abstract

The invention relates to novel process for preparation of Tavaborole. The invention also relates to novel polymorphic forms of Tavaborole and process for preparation of those polymorphic forms. The invention also relates to process for purification of Tavaborole to obtain the Tavaborole in significantly high yield and substantially pure form.

Claims

1. A process for preparation of a crystalline forms of Tavaborole comprising the steps of: (a) contacting Tavaborole with a solvent or mixture of solvents; (b) heating the solvent or solvents mixture with Tavaborole to reflux; and (c) precipitating Tavaborole from solvent or solvents mixture by using conventional techniques selected from slow or fast cooling, addition of crystallization solvent, drying at atmospheric or reduced pressure, so as to obtain the desired crystalline form of Tavaborole; wherein the solvent or solvents mixture can be selected from water, methanol, Ethanol, Isopropyl alcohol, Methyl tertiary butyl alcohol, Toluene, acetone Tetrahydrofuran, Ethyl acetate, dichloromethane, acetonitrile, methyl tertiary butyl ether or mixtures thereof; and wherein the obtained crystalline forms of Tavaborole are any of crystalline form Form-I, Form-II, Form-III, Form-IV and Form V.

2. The crystalline Form I of Tavaborole as claimed in claim 1, characterized by X-ray powder diffraction (XRPD) pattern comprising one or more of the reflections at value 6.30, 12.66 and 25.5±0.2 degrees 2 theta (2θ°).

3. The crystalline Form I of Tavaborole as claimed in claim 2, further characterized by XRPD pattern comprising one or more of the reflections at value: 5.70, 11.43, 14.25, 14.83, 16.33, 20.31, 26.23, 26.98, 28.84, 30.95, 32.06, 33.44, 36.96, 38.71, 41.40±0.2 degrees 2 theta (2θ°).

4. A process for preparing crystalline Form I of Tavaborole as claimed in claim 2 comprising refluxing Tavaborole in a mixture of acetonitrile and toluene and isolating Tavaborole by cooling to 0-5° C.

5. The crystalline Form II of Tavaborole as claimed in claim 1, characterized by X-ray powder diffraction (XRPD) pattern comprising one or more of the reflections at value 6.31, 14.35, 14.91, 16.44 and 27.08±0.2 degrees 2 theta (2θ°).

6. The crystalline Form II of Tavaborole as claimed in claim 5 further characterized by XRPD pattern comprising one or more of the reflections at value: 12.68, 12.91, 20.41, 24.95, 25.51, 25.85, 26.33, 26.68, 27.08, 27.68, 28.93, 30.51, 31.74+0.2 degrees 2 theta (2θ°).

7. The crystalline Form III of Tavaborole as claimed in claim 1, characterized by X-ray powder diffraction (XRPD) pattern comprising one or more of the reflections at value 6.21, 12.55, 14.23, 14.82, 16.36, 25.37, and 26.99±0.2 degrees 2 theta (2θ°).

8. The crystalline Form III as claimed in claim 7 further characterized by XRPD pattern comprising one or more of the reflections at value 5.56, 12.88, 20.27, 24.17, 24.83, 25.37, 26.23, 26.99, 28.81, 30.05, 30.33, 30.9, 31.9, 33.37, 36.88 and 38.56±0.2 degrees 2 theta (2θ°).

9. The crystalline Form IV of Tavaborole as claimed in claim 1, characterized by X-ray powder diffraction (XRPD) pattern comprising one or more of the reflections at value: 6.35, 7.55, 8.25, 8.46, 14.2, 14.6, 14.9, 16.5, 25.46, 25.84, 26.38 and 26.63±0.2 theta degree (2θ°).

10. The crystalline Form IV of Tavaborole as claimed in claim 9 further characterized by XRPD pattern comprising one or more of the reflections at value 7.09, 10.23, 12.74, 13.17, 13.76, 15.27, 15.55, 17.07, 17.72, 18.15, 19.31, 19.90, 20.51, 21.88, 22.8, 23.08, 24.29, 24.92, 27.09, 27.67, 29.42, 30.19 and 31.66±0.2° 2θ.

11. The crystalline Form V of Tavaborole as claimed in claim 1, characterized by X-ray powder diffraction (XRPD) pattern comprising one or more of the reflections at 6.3, 7.48, 8.21, 8.37, 14.16, 14.35, 14.54, 14.88, 15.55, 16.41, 25.37, 25.78, 26.29, 26.5 and 27.03±0.2° 2θ.

12. The crystalline Form V of Tavaborole as claimed in claim 11 further characterized by XRPD pattern comprising one or more of the reflections at value 7.01, 10.16, 10.68, 12.64, 13.14, 15.2, 16.07, 16.67, 17.05, 17.64, 18.08, 19.88, 20.43, 22.77, 24.3, 24.87, 26.29, 27.37, 28.90, 29.39±0.2° 2θ.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1: represents a characteristic X-Ray powder diffraction pattern of Tavaborole Form I

(2) FIG. 2: represents a characteristic differential scanning calorimetry (DSC) of Tavaborole of Form I

(3) FIG. 3a and FIG. 3b: represents a characteristic X-Ray powder diffraction pattern of Tavaborole Form II

(4) FIG. 4a and FIG. 4b: represents a characteristic X-Ray powder diffraction pattern of Tavaborole Form III

(5) FIG. 5a and FIG. 5b: represents a characteristic X-Ray powder diffraction pattern of Tavaborole Form IV

(6) FIG. 6a and FIG. 6b: represents a characteristic X-Ray powder diffraction pattern of Tavaborole Form V

DETAILED DESCRIPTION OF THE INVENTION

(7) The present invention relates to processes for the preparation of Tavaborole in significantly high yield and substantially pure form. The invention also comprises novel polymorphic forms of Tavaborole and processes for their preparation. The invention also provides processes for purification of Tavaborole to obtain substantially pure Tavaborole, comprising purity more than or equal to 99% and devoid of process related impurities represented as Impurity A and Impurity B.

(8) The methods for the preparation of Tavaborole are schematically represented by Scheme-1 and Scheme-2.

(9) ##STR00016##

(10) One of the reported procedures of the invention (Scheme—1), comprises i. Conversion of compound 2 into compound 3 using a suitable hydroxyl protecting agent. Non limiting examples of the suitable hydroxyl protecting groups/agents are as defined under “definitions”. In one aspect of the invention, the hydroxyl protecting group is the acyl protecting agent preferably acetic anhydride and the reaction is carried out in dichloromethane as solvent at room temperature in the presence of catalytic amount of pyridine. In another aspect of the invention, the hydroxyl protecting group is the silyl protecting agent preferably TBDMSCl and the reaction is carried out in THF solvent in the presence of imidazole base. ii. Conversion of compound 3 into borate compound 4 via a transition metal catalyzed cross-coupling reaction. Non limiting examples of the borylation reagent, transition metal catalyst, ligands and the solvent employed are as defined hereunder. Compound 3 is treated with 1 to 2 equivalents of borylation reagent in the presence of 1 to 4 mol % (0.01 to 0.04 equivalents with respect to compound 3, transition metal catalyst, 1 to 5 equivalents of base and/or with the use of appropriate ligand in a suitable solvent. Occasionally these metal catalyst reactions may be conducted in the presence of additive or co-catalyst. Reaction temperatures range from 70° C. to 120° C., preferably 80° C. to 90° C. Reaction completion times range from 10 minutes to 24 hrs, preferably 6-8 hrs. Suitable solvent used for this reaction step is selected from the group comprising toluene, xylene, N,N-dimethylformamide, dimethylsufoxide, tetrahydrofuran, 1,4-dioxane or mixtures thereof. In one aspect of the invention, the most preferred solvent used for the reaction is 1,4-dioxane. iii. Conversion of compound 4 into Tavaborole (1) a) either by simultaneous deprotection of hydroxyl protecting group and the borate group (ester or acid, when R.sup.2, R.sup.3=‘H’) of compound 4 using a suitable deprotecting agent optionally in the presence of an acid or base; or b) by sequential deprotection of hydroxyl protecting group and boronate ester group under suitable conditions followed by cyclization in the presence of an acid or a base, the most preferred acid is HCl and the most preferred base is NaOH.

(11) Compound 4 can be converted to Tavaborole by an alternate route via the formation of 6A. The reaction stage includes oxidative cleavage of compound 4 by treating with 1 to 3 equivalents of NaIO.sub.4 or Pb(OAc).sub.4 in a suitable solvent followed by dehydrative cyclization in the presence of an acid or a base. Suitable solvent is selected from the group comprising H.sub.2O, tetrahydrofuran, 1,4-dioxane, methanol, ethanol or mixtures thereof.

(12) Another route of synthesis of Tavaborole is as represented in Scheme—2 below:

(13) ##STR00017##

(14) wherein the substituents X, R.sup.2, R.sup.3 are as defined above and the process comprises i. Conversion of compound 2 into compound 5 via a Nickel catalyzed cross-coupling reaction.

(15) Compound 2 is treated with 1 to 2 equivalents of borylation reagent in the presence of 5 to 15 mol % (0.05 to 0.15 equivalents with respect to compound 2) of Nickel catalyst, 2 to 5 equivalents of base in a suitable solvent, optionally with the use of appropriate ligand.

(16) Reaction temperatures may range from 25° C. to 95° C., preferably 35° C. to 40° C. Reaction completion times range from 1 hr to 24 hr, preferably 10 to 12 hr.

(17) Suitable solvent is selected from the group comprising methanol, ethanol, IPA, N,N-dimethylformamide, dimethylsufoxide, tetrahydrofuran, 1,4-dioxane or mixtures thereof.

(18) The non limiting examples of the Nickel catalyst, base and the ligand is as described hereunder. ii. In step-2, compound 5 is converted into Tavaborole (1) under acid or base mediated hydrolysis conditions.

(19) The acid used for the hydrolysis is selected from the group comprising HCl, H.sub.2SO.sub.4, AcOH, HCOOH, BF.sub.3Et.sub.2O, AlCl.sub.3, BBr.sub.3 or the like and the base is selected from the group comprising NaOH, KOH, LiOH, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, LiCO.sub.3, CsCO.sub.3, NaOMe, EtOMe. iii. In step-3, alternatively the borate ester of compound 5 is oxidatively cleaved by treating with 1 to 3 equivalents of NaIO4 or Pb(OAc).sub.4 in a suitable solvent. Suitable solvent is selected from the group comprising H.sub.2O, tetrahydrofuran, 1,4-dioxane, methanol, ethanol or mixtures thereof. iv. In step-4, compound 6 is converted into Tavaborole (1) under acidic or basic conditions by dehydrative cyclization. Suitable acid is selected from the group comprising HCl, H.sub.2SO.sub.4, AcOH, HCOOH, BF.sub.3Et.sub.2O, AlCl.sub.3, BBr3 or the like. Suitable base is selected from the group comprising NaOH, KOH, LiOH, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, LiCO.sub.3, CsCO.sub.3, NaOMe, EtOMe.

(20) Tavaborole obtained by the above two syntheses is 92-95% pure. When the reaction is performed as exemplified in examples 4 and 10 supra, Tavaborole obtained is substantially pure, with purity greater than or equal to 99% and hence doesn't require further purification. Tavaborole isolated from the instant processes or from any other process can be further purified from solvents selected from the group comprising alkanes like hexanes, toluene, cyclohexane; alcohols like methanol, ethanol, IPA; water; acetonitrile; tetrahydrofuran; acetone; ethyl acetate; dichloromethane or mixtures thereof.

(21) Tavaborole can be purified by any of the following procedures: i. Mixing it in any of the above said suitable solvents or mixtures thereof and treating the thus obtained solution with an anti-solvent, which is water in many of the cases; ii. Mixing Tavaborole in any of the above said solvents or mixtures, optionally heating the solution to dissolve the compound and isolating the pure compound by cooling the solution; iii. Treating Tavaborole with silica gel in any of the above suitable solvents followed by crystallization in any of the solvents or mixtures thereof, and iv. Dissolving Tavaborole in aqueous alkali solution followed by washing with ethyl acetate, adjusting the pH of the aqueous layer to acidic with HCl, and filtering the precipitated solid.

(22) In one aspect crude Tavaborole is dissolved in acetonitrile at 25-60° C., preferably at 45-50° C., and isolation step is performed by adding the anti-solvent water.

(23) In the second aspect, crude Tavaborole is dissolved in mixture of IPA and toluene at 40-80° C., preferably at 60-70° C., and the pure product is isolated by cooling the solution.

(24) In another aspect crude Tavaborole is treated with silica gel in toluene and recrystallized in hexane.

(25) In another aspect crude Tavaborole is recrystallized from a mixture of toluene and acetonitrile solvents, which comprises the steps of dissolving the crude Tavaborole in toluene—acetonitrile mixture while heating, followed by gradual cooling during which pure Tavaborole solid precipitates.

(26) The major process impurities which are eliminated during the purification of Tavaborole according to the present invention are depicted below (A & B), thus obtaining Tavaborole in substantially pure form with a purity greater than 99%.

(27) ##STR00018##

(28) In one aspect of the invention, crystalline polymorphic forms I, II, III, IV and V of Tavaborole are reported whose X-ray diffraction pattern are represented by FIG. 1, FIG. 3a and FIG. 3b, FIG. 4a and FIG. 4b, FIG. 5a and FIG. 5b, and FIG. 6a and FIG. 6b respectively and whose 2-theta values are tabulated in Table—1, Table—2, Table—3, Table—4 and Table—5 respectively.

(29) The polymorphic crystalline Form I of Tavaborole may produce an X-ray diffraction pattern comprising one or more of the following reflections: 6.30, 12.66 and 25.5, ±0.2° 2θ or that produces an X-ray powder diffraction pattern further comprising one or more of the following reflections: 5.70, 11.43, 14.25, 14.83, 16.33, 20.31, 26.23, 26.98, 28.84, 30.95, 32.06, 33.44, 36.96, 38.71, 41.40±0.2° 2θ or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table—1.

(30) The polymorphic crystalline Form I of Tavaborole may also be identified by the DSC as depicted in FIG. 2. The X-ray diffraction pattern of Tavaborole polymorphic Form I is represented by FIG. 1.

(31) The polymorphic crystalline Form II of Tavaborole may produce an X-ray diffraction pattern comprising one or more of the following reflections: 6.31, 14.35, 14.91, 16.44 and 27.08±0.2° 2θ or that produces an X-ray powder diffraction pattern further comprising one or more of the following reflections: 12.68, 12.91, 20.41, 24.95, 25.51, 25.85, 26.33, 26.68, 27.08, 27.68, 28.93, 30.51, 31.74±0.2° 2θ or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table—2. The X-ray diffraction pattern of Tavaborole polymorphic Form II is represented by FIG. 3a and FIG. 3b.

(32) The polymorphic crystalline Form III of Tavaborole may produce an X-ray diffraction pattern comprising one or more of the following reflections: 6.21, 12.55, 14.23, 14.82, 16.36, 25.37, and 26.99±0.2° 2θ or that produces an X-ray powder diffraction pattern further comprising one or more of the following reflections: 5.56, 12.88, 20.27, 24.17, 24.83, 25.37, 26.23, 26.99, 28.81, 30.05, 30.33, 30.9, 31.9, 33.37, 36.88 and 38.56±0.2° 2θ or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table—3. The X-ray diffraction pattern of Tavaborole polymorphic Form III is represented by FIG. 4a and FIG. 4b.

(33) The polymorphic crystalline Form IV of Tavaborole may produce an X-ray diffraction pattern comprising one or more of the following reflections: 6.35, 7.55, 8.25, 8.46, 14.2, 14.6, 14.9, 16.5, 25.46, 25.84, 26.38 and 26.63±0.2° 2θ or that produces an X-ray powder diffraction pattern further comprising one or more of the following reflections: 7.09, 10.23, 12.74, 13.17, 13.76, 15.27, 15.55, 17.07, 17.72, 18.15, 19.31, 19.90, 20.51, 21.88, 22.8, 23.08, 24.29, 24.92, 27.09, 27.67, 29.42, 30.19 and 31.66±0.2° 2θ or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table—4. The X-ray diffraction pattern of Tavaborole polymorphic Form IV is represented by FIG. 5a and FIG. 5b.

(34) The polymorphic crystalline Form V of Tavaborole may produce an X-ray diffraction pattern comprising one or more of the following reflections: 6.3, 7.48, 8.21, 8.37, 14.16, 14.35, 14.54, 14.88, 15.55, 16.41, 25.37, 25.78, 26.29, 26.5 and 27.03±0.2° 2θ or that produces an X-ray powder diffraction pattern further comprising one or more of the following reflections: 7.01, 10.16, 10.68, 12.64, 13.14, 15.2, 16.07, 16.67, 17.05, 17.64, 18.08, 19.88, 20.43, 22.77, 24.3, 24.87, 26.29, 27.37, 28.90, 29.39±0.2° 2θ or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table—5. The X-ray diffraction pattern of Tavaborole polymorphic Form V is represented by FIG. 6a and FIG. 6b.

(35) Generally, the crystalline forms of the present invention are prepared by contacting Tavaborole with a solvent, or mixture of solvents, one preferred method is refluxing Tavaborole in a mixture of solvents and then precipitating Tavaborole from the solvent using conventional techniques (e. g. slow or fast cooling, addition of crystallization solvent, drying at atmospheric or reduced pressure), so as to form the desired crystalline form Tavaborole.

(36) The solvent components used in producing the crystalline forms of the present invention include methanol, ethanol, IPA, methyl tertiary butyl alcohol, toluene, acetone tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile or mixtures thereof.

(37) According to the process of preparing crystalline Tavaborole Form I, the process comprising contacting Tavaborole with mixture of solvents; heating the solvents with Tavaborole to reflux; isolating Tavaborole by cooling the solvent to 0-5° C. and thereby obtaining the crystalline Tavaborole Form I. Suitable mixture of solvent for the preparation of crystalline tavaborole Form-I are selected from the group comprising ethyl acetate, toluene, acetonitrile, IPA.

(38) In another embodiment, the crystalline Form I of Tavaborole is obtained by refluxing Tavaborole in a mixture of acetonitrile and toluene and isolating Tavaborole by cooling to 0-5° C.; the crystalline Form II of Tavaborole is obtained by the crystallizing Tavaborole from toluene or mixture of toluene and methanol; the crystalline Form III of Tavaborole is obtained by the crystallizing Tavaborole from water or mixture of water and methanol; the crystalline Form IV of Tavaborole is obtained by the crystallizing Tavaborole from acetone or THF or melting of solid Tavaborole Form I at 136° C. and cooling; and the crystalline Form V of Tavaborole is obtained by crystallizing Tavaborole from ethyl acetate, dichloromethane, acetonitrile or methyl tertiary butyl ether solvents.

(39) The X-Ray diffraction data of the Tavaborole crystalline forms obtained are tabulated below.

(40) TABLE-US-00001 TABLE 1 X-ray diffraction data for Tavaborole Polymorphic Form I d value Peak no. Angle 2θ (°) Angstrom Intensity % 1. 5.70 15.46 4.7 2. 6.30 13.99 100 3. 11.43 7.73 1.7 4. 12.66 6.98 36 5. 14.25 6.20 13.5 6. 14.83 5.96 3.2 7. 16.33 5.42 4.8 8. 20.31 4.36 1.7 9. 25.52 3.48 26.5 10. 26.23 3.39 8.7 11. 26.98 3.30 12.1 12. 28.84 3.09 2 13. 30.95 2.88 3.3 14. 32.06 2.78 3.3 15. 33.44 2.67 2.3 16. 36.96 2.42 3.2 17. 38.71 2.32 6.5 18. 41.40 2.17 2.1

(41) TABLE-US-00002 TABLE 2 X-ray diffraction data for Tavaborole Polymorphic Form II d value Peak no. Angle 2θ (°) Angstrom Intensity % 1. 6.31 13.97 30 2. 8.24 10.71 16.6 3. 8.43 10.47 7.1 4. 12.68 6.97 10.9 5. 12.91 6.85 5.6 6. 14.35 6.16 100 7. 14.91 5.93 27.5 8. 16.44 5.38 33 9. 20.41 4.34 5.6 10. 24.95 3.56 5.1 11. 25.51 3.48 10.4 12. 25.85 3.44 12.7 13. 26.33 3.38 10 14. 26.68 3.33 6.7 15. 27.08 3.28 14.7 16. 27.68 3.21 4.7 17. 28.93 3.08 9.5 18. 30.51 2.92 5.5 19. 31.74 2.81 5.1

(42) TABLE-US-00003 TABLE 3 X-ray diffraction data for Tavaborole Polymorphic Form III d value Peak no. Angle 2θ (°) Angstrom Intensity % 1. 5.56 15.87 4.4 2. 6.21 14.21 68.9 3. 12.55 7.04 36.7 4. 12.88 6.86 5.1 5. 14.23 6.21 100 6. 14.82 5.97 38.6 7. 16.36 5.41 60.8 8. 20.27 4.37 10.9 9. 24.17 3.67 4.2 10. 24.83 3.58 6.5 11. 25.37 3.5 46.9 12. 26.23 3.39 14 13. 26.99 3.3 23.2 14. 28.81 3.09 12.3 15. 30.05 2.97 4.8 16. 30.33 2.94 9.2 17. 30.9 2.89 9.8 18. 31.9 2.8 5.2 19. 33.37 2.68 4.6 20. 36.88 2.434 7 21. 38.56 2.33 12

(43) TABLE-US-00004 TABLE 4 X-ray diffraction data for Tavaborole Polymorphic Form IV Peak d value no. Angle 2θ (°) Angstrom Intensity % 1. 6.35 13.89 23.6 2. 7.09 12.45 9.6 3. 7.55 11.68 51.9 4. 8.25 10.7 95.7 5. 8.46 10.43 38.6 6. 10.23 8.63 9.3 7. 12.74 6.94 12.2 8. 13.17 6.71 6.1 9. 13.76 6.4 7.8 10. 14.2 6.2 100 11. 14.6 6.06 57.9 12. 14.91 5.9 29.7 13. 15.27 5.79 14.6 14. 15.55 5.69 10.1 15. 16.5 5.36 25.1 16. 17.07 5.18 12.4 17. 17.72 5 10.2 18. 18.15 4.88 9.3 19. 19.31 4.59 6 20. 19.9 4.45 19.3 21. 20.51 4.32 12.5 22. 21.88 4.05 4.2 23. 22.8 3.89 7.7 24. 23.08 3.84 8.7 25. 24.29 3.66 4.7 26. 24.92 3.56 9.8 27. 25.46 3.49 47 28. 25.84 3.44 59 29. 26.38 3.37 22 30. 26.63 3.34 33.1 31. 27.09 3.28 19.2 32. 27.67 3.22 18.4 33. 29.42 3.03 5.7 34. 30.19 2.95 5.1 35. 31.66 2.82 4.6

(44) TABLE-US-00005 TABLE 5 X-ray diffraction data for Tavaborole Polymorphic Form V d value Peak no. Angle 2θ (°) Angstrom Intensity % 1. 6.3 14.01 29.7 2. 7.01 12.58 8.9 3. 7.48 11.8 56.2 4. 8.21 10.74 55.9 5. 8.37 10.55 22.2 6. 10.16 8.69 15.2 7. 10.68 8.27 4.9 8. 12.64 6.99 10.8 9. 13.14 6.72 7.9 10. 14.16 6.24 99 11. 14.35 6.16 100 12. 14.54 6.08 98.4 13. 14.88 5.94 34.8 14. 15.2 5.82 17.3 15. 15.55 5.69 24.6 16. 16.07 5.5 10.5 17. 16.41 5.39 42.2 18. 16.67 5.31 16.5 19. 17.05 5.19 8.2 20. 17.64 5.02 7.9 21. 18.08 4.9 14.2 22. 19.88 4.46 15.7 23. 20.43 4.34 11.4 24. 22.77 3.9 9.1 25. 24.3 3.65 7.4 26. 24.87 3.57 13.9 27. 25.37 3.5 52.4 28. 25.78 3.45 25.1 29. 26.29 3.38 26 30. 26.5 3.36 24.9 31. 27.03 3.29 32.3 32. 27.37 3.25 14.1 33. 28.9 3.08 9.5 34. 29.39 3.03 9

Definitions

(45) The following terms shall have for the purpose of this application, including the claims appended hereto, the respective meanings set forth below:

(46) “Hydroxyl or Hydroxy protecting groups”, the terms are used synonymously, means those groups that one skilled in the field would recognize as being suitable to protect the —OH substituent on an alkyl or ringed system as described herein and which may be removed under deprotection conditions known to those skilled in the field as set forth. Non-limiting examples of hydroxy protecting groups include ether protecting groups comprising benzyl ethers, silyl ethers, alkyl ethers including methyl ethers, ethyl ethers, propyl ethers, butyl ethers or the like; esters including benzoate, acetate or the like; acetals including MOP, BOM, THP or the like. Suitable acyl protecting agents used are selected from the group comprising of acetyl chloride, acetic anhydride, benzoyl chloride or the like; Suitable Silyl protecting agents used is selected from a group comprisisng of trimethyl silyl chloride, triethyl silyl chloride, and tertiary butyl dimethyl silyl chloride (TBDMSCl) or the like. In one aspect of the invention, the silyl protecting group employed is TBDMSCl.

(47) Suitable Transition Metal catalysts that can be employed in the present invention are Pd catalyst or Ni catalysts. The Pd catalyst is selected from the group comprising of PdCl.sub.2(dppf), [PdCl.sub.2dppf].CH.sub.2Cl.sub.2, PdCl.sub.2(PPh.sub.3).sub.2, Pd(PPh.sub.3).sub.4, Pd(OAc).sub.2, [Pd.sub.2dba.sub.3], [Pd(allyl)Cl].sub.2, Pd(acac).sub.2, PhPd(OAc)(PPh).sub.2 any Palladium catalyst that generates in situ Pd(0) and combinations thereof. In one aspect of the invention, Pd catalyst used is PdCl.sub.2(dppf). Non limiting examples of Ni catalyst selected from group of NiCl.sub.2(dppp), NiCl.sub.2(dppf), NiCl.sub.2(dppe), NiCl.sub.2.glyme, NiBr.sub.2.glyme, NiCl.sub.2(PPh.sub.3).sub.2, NiCl.sub.2(PCy.sub.3).sub.2, Ni(PPh.sub.3).sub.4, Ni(COD).sub.2, NiCl.sub.2, NiBr.sub.2 or any Nickel catalyst that generates in situ Ni(0) and combinations thereof. In one aspect of the invention, Ni catalyst used is NiCl.sub.2(dppp).

(48) Appropriate ligand is selected from the group comprising of Xphos, MeO-CM-Phos, Sphos, DavePhos, RuPhos, tBu.sub.3P-HBF.sub.4, QPhos, JohnPhos, Me.sub.4-tBu-XPhos, Ad.sub.2PBu, BrettPhos, AmPhos, PPh.sub.3, tri(o-tolyl) phosphine or the like. In one aspect of the invention, the ligand used is tri(o-tolyl)phosphine.

(49) Suitable borylation reagent used is selected from the group comprising of boronic acids, Bis(neopentyl glycolato)diboron, Bis(catecholato)diboron, Bis(hexylene glycolato)diboron, Bis(pinacolato)diboron, Tetrahydroxydiboron, Pinacolborane, Methylpentanediolborane, Catecholborane, Neopentylglycoborane, Trialkyl borate. In one aspect of the invention, borylation reagent used is Bis(pinacolato)diboron.

(50) Suitable base that can be employed in step 2 of Scheme—1 is an organic base or an inorganic base. Suitable inorganic base used is selected from the group comprising of KOPh, KOAc, NaOAc, NH.sub.4OAc, Cu(OAc).sub.2, Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, Na.sub.2CO.sub.3, Ag.sub.2CO.sub.3, K.sub.3PO.sub.4, NaOH, KOH, CsOH, KOMe, NaOMe, LiOtBu, NaOtBu, KOtBu or the like. In one aspect of the invention, the inorganic base used is KOAc. Suitable organic base used is selected from the group comprising of pyridine, triethyl amine, leutidine, DABCO, DBU, 1,2,2,6,6-pentamethylpipiridine, 1,1,3,3-tetramethylguanidine, iPr.sub.2NEt, NBu.sub.3, Cy.sub.2NMe or the like. In one aspect of the invention, suitable organic base used is iPr.sub.2Net.

(51) “hydroxyl deprotecting agents or deprotecting agents” means those reagents that one skilled in the field would recognize as being suitable to remove the protecting groups of a hydroxyl moiety as described herein. Suitable hydroxyl deprotecting agents may be acid or base. Non-limiting examples being inorganic bases like potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate or the like; metal alkoxides like sodium methoxide, sodium ethoxide; metal carbonates like sodium carbonate, potassium carbonate, cesium carbonate or the like; acid deprotecting agent selected from the group comprising HCl, H.sub.2SO.sub.4, HNO.sub.3, AcOH, HCOOH, BF.sub.3Et.sub.2O, AlCl.sub.3, BBr3 or the like.

(52) These deprotecting agents are most suitable for simultaneously removing the boronate ester protecting groups.

(53) Additive or co-catalyst that is employed is selected from the group comprising Cu(OTf).sub.2, Cu(OAc).sub.2, CuCl, CuBr, CuI, ZnCl.sub.2, Ag.sub.2CO.sub.3 or the like.

(54) The dehydrating agent used for the cyclization of Tavaborole is an organic or an inorganic acid selected from the group comprising HCl, H.sub.2SO.sub.4, HNO.sub.3, AcOH, HCOOH, BF.sub.3Et.sub.2O, AlCl.sub.3, BBr3 or the like. HCl being the most preferred acid. The base employed for cyclization of Tavaborole is selected from the group comprising NaOH, KOH, LiOH, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, LiCO.sub.3, CsCO.sub.3, NaOMe, EtOMe.

(55) TABLE-US-00006 Reagent Name Definition NBS N-Bromosuccinimide Pd Palladium MOP Methoxypropyl acetal BOP Benzyloxymethyl acetal TBDMSCl tert-Butyldimethylsilyl chloride n-BuLi n-Butyllithium BF.sub.3Et.sub.2O Boron trifluoride etherate NaIO.sub.4 Sodium periodate Pb(OAc).sub.4 Lead tetraacetate [PdCl.sub.2dppf]•CH.sub.2Cl.sub.2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II), complex with dichloromethane PdCl.sub.2(PPh.sub.3).sub.2 Dichlorobis(triphenylphosphine)palladium(II) Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium(0) Pd(OAc).sub.2 Palladium(II) acetate [Pd.sub.2dba.sub.3] Tris(dibenzylideneacetone)dipalladium [Pd(allyl)Cl].sub.2 Allylpalladium(II) chloride dimer Pd(acac).sub.2 Palladium(II) acetylacetonate PhPd(OAc)(PPh.sub.3).sub.2 Bis(triphenylphosphine)phenyl palladium acetate PdCl.sub.2(dppf) [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) NiCl.sub.2(dppp) Dichloro[1,3-bis(diphenylphosphino)propane]nickelc NiCl.sub.2(dppf) [1,1′-Bis(diphenylphosphino)ferrocene]dichloronickel(II) NiCl.sub.2(dppe) 1,2-Bis(diphenylphosphino)ethane nickel(II) chloride NiCl.sub.2•glyme dichloronickel; 1,2-dimethoxyethane NiBr.sub.2•glyme Nickel(II) bromide 2-methoxyethyl ether complex NiCl.sub.2(PPh.sub.3).sub.2 Bis(triphenylphosphine)nickel(II) dichloride NiCl.sub.2(PCy.sub.3).sub.2 Bis(tricyclohexylphosphine)nickel(II) chloride Ni(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)nickel(0) Ni(COD).sub.2 Bis(cyclooctadiene)nickel(0) NiCl.sub.2 Nickel(II) chloride NiBr.sub.2 Nickel(II) bromide Xphos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl MeO-CM-Phos N-Methyl-2-(2′-dicylohexylphosphino-5′-methoxyphenyl)indole Sphos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl DavePhos 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl tBu.sub.3P-HBF.sub.4 Tributylphosphonium tetrafluoroborate QPhos 1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene JohnPhos (2-Biphenyl)di-tert-butylphosphine, (2-Biphenylyl)di-tert- butylphosphine Me.sub.4-tBu-XPhos 2-Di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl- 1,1′-biphenyl Ad.sub.2PBu di(1-adamantyl)-n-butylphosphine BrettPhos 2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl- 1,1′-biphenyl AmPhos Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) PPh.sub.3 Triphenylphosphine KOPh Potassium phenoxide KOAc Potassium acetate NaOAc Sodium acetate NH.sub.4OAc Ammonium acetate Cu(OAc).sub.2 Copper(II) acetate Cs.sub.2CO.sub.3 Caesium carbonate K.sub.2CO.sub.3 Potassium carbonate Na.sub.2CO.sub.3 Sodium carbonate Ag.sub.2CO.sub.3 Silver carbonate K.sub.3PO.sub.4 Tripotassium phosphate NaOH Sodium hydroxide KOH Potassium hydroxide CsOH Cesium hydroxide KOMe Potassium methoxide NaOMe Sodium methoxide LiOtBu Lithium tert-butoxide NaOtBu Sodium-t-butoxide KOtBu Potassium tert-butoxide DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene iPr.sub.2NEt N,N-Diisopropylethylamine NBu.sub.3 N-tributylamine Cy.sub.2NMe N,N-Dicyclohexylmethylamine HNO.sub.3 Nitric acid Cu(OTf).sub.2 Copper (II) triflate Cu(OAc).sub.2 Copper(II) acetate CuCl Copper(I) chloride CuBr Copper(I) bromide CuI Copper(I) iodide ZnCl.sub.2 Zinc chloride AlCl.sub.3 Aluminium chloride BBr.sub.3 Boron tribromide Ag.sub.2CO.sub.3 Silver carbonate NaHCO.sub.3 Sodium hydrogen carbonate LiCO.sub.3 Lithium carbonate LiOH Lithium hydroxide Na.sub.2SO.sub.4 Sodium sulfate H.sub.2O Water CH.sub.2Cl.sub.2 Dichloromethane MTBE Methyl tert-butyl ether IPA Isopropyl alcohol MeOH Methanol EtOH Ethanol EtOAc Ethyl acetate CCl.sub.4 Carbon tetrachloride HCl Hydrochloric acid H.sub.2SO.sub.4 Sulfuric acid AcOH Acetic acid HCOOH Formic acid Ac Acetyl

(56) The following examples further illustrate the present invention, but should not be construed in any way as to limit its scope.

Example-1

Preparation of 2-bromo-5-fluorobenzyl Acetate (3a)

(57) ##STR00019##

(58) Wherein in compound 2, X═Br and in compound 3, R.sup.1=Ac

(59) To a solution of (2-bromo-5-fluorophenyl)methanol (10.25 g, 0.05 mol) and acetic anhydride (7.1 mL; 0.075 mol) in dichloromethane (50 mL) two drops of pyridine is added and the mixture is stirred at room temperature until complete disappearance of starting material (reaction is monitored by TLC). After completion, the reaction mixture is quenched with water (100 ml), and the mixture is extracted by dichloromethane (120 mL). The organic layer is separated, and washed with saturated NaHCO.sub.3 (100 mL), 0.1 N HCl (50 mL) and water (100 mL) and dried over Na.sub.2SO.sub.4. Evaporation of the solvent gave 2-bromo-5-fluorobenzyl acetate (Yield: 97%; Purity: 99.3%).

Example-2

Preparation of 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Benzyl Acetate (4a)

(60) ##STR00020##

(61) Wherein in compound 4, R.sup.1=Ac, R.sup.2& R.sup.3 together=borate ester

(62) To a solution of 2-bromo-5-fluorobenzyl acetate (5 g, 0.02 mol) in 1,4-dioxane (60 mL), bis(pinacolato)diboron (5.6 g, 0.022 mol) and potassium acetate (5.6 g, 0.06 mol) are added. The resulting mixture is degassed using a stream of nitrogen and to this is added [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (250 mg, 0.34 mmol). The reaction mixture is then heated at 80° C. for 10 hrs. The mixture is cooled to room temperature, diluted with H.sub.2O and extracted with EtOAc. The organic layer is dried over Na.sub.2SO.sub.4 and evaporated in vacuo to yield 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl acetate that is used in the next reaction step without further purification (Yield: 95%; Purity: 99.9%).

Example-3

Preparation of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Tavaborole 1)

(63) ##STR00021##

(64) A mixture of 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl acetate (3 g) and HCl (4N HCl, 30 mL) is stirred at 80° C. for 10 hrs. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with water (until water layer becomes neutral), dried over Na.sub.2SO.sub.4 and evaporated in vacuo to yield 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Yield: 93%; Purity: 92%).

Example-4

Preparation of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Tavaborole 1)

(65) ##STR00022##

(66) To a solution of 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (5 g) in Methanol (40 mL), NaOH (2 eq) is added and stirred for 4 hrs at RT. Solvent is removed at reduced pressure. The obtained crude is taken in mixture of THF (30 mL) and water (15 mL), and treated with concentrated HCl (7.5 ml). After completion of the reaction (usually completes in 12 hrs at RT), product is extracted with ethyl acetate and concentrated at reduced pressure to give the solid. The obtained compound is dissolved in aqueous NaOH solution (30 mL, 1 eq NaOH), washed with ethyl acetate, then acidified with aqueous HCl. The precipitated white solid is filtered, washed with water and dried (Yield: 80%; Purity: 99.8%).

Example-5

Preparation of 2-(acetoxymethyl)-4-fluorophenylboronic Acid (6A)

(67) ##STR00023##

(68) To a solution of 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (5.13 g, 0.014 mol) in Acetone (50 mL), sodium periodate (8.9 g, 0.042 mol), ammonium acetate (2.4 g, 0.031 mol) in water is added. After stirring at room temperature for 10 hr, 2.5N HCl (40 mL) is added, and the mixture is stirred at 0-5° C. for 20 minutes. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried on anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue is treated with MTBE to afford 2-(acetoxymethyl)-4-fluorophenylboronic acid (Yield: 83%; Purity: 94%.

Example-6

Preparation of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Tavaborole 1)

(69) ##STR00024##

(70) A mixture of 2-(acetoxymethyl)-4-fluorophenylboronic acid (3 g) and HCl (4N HCl, 30 mL) is stirred at 80° C. for 10 hrs. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with water (until water layer becomes neutral), dried over Na.sub.2SO.sub.4 and evaporated in vacuo to yield 5-fluoro-1,3-dihydrobenzo[c][1,2]oxaborole (Yield: 93%; Purity: 92%).

Example-7

Preparation of (5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (5)

(71) ##STR00025##

(72) To a solution of (2-bromo-5-fluorophenyl) methanol (5 g, 0.02 mol) in 1,4-dioxane (60 mL), bis(pinacolato)diboron (5.6 g, 0.022 mol) and potassium acetate (5.6 g, 0.06 mol) were added. The resulting mixture was degassed using a stream of nitrogen and to this was added [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (250 mg, 0.34 mmol). The reaction mixture was then heated at 80° C. for 10 hrs. The mixture was cooled to room temperature, diluted with H.sub.2O and extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4 and evaporated in vacuum to yield (5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol that was used in the next reaction step without further purification. Yield-95%; Purity-99.9%.

Example-8

Preparation of (4-fluoro-2-(hydroxymethyl)phenyl)boronic Acid (6)

(73) ##STR00026##

(74) To a solution of (2-bromo-5-fluorophenyl) methanol (10.05 g, 0.049 mol) in Ethanol 100 mL), NiCl.sub.2(dppp) (2.67 g, 0.0049 mol), (HO).sub.2B—B(OH).sub.2 (6.62 g, 0.074 mol), PPh.sub.3 (0.01 mol), (DIPEA (25.7 mL, 0.148 mol) are added. The resulting mixture is degassed using a stream of nitrogen. The reaction mixture is stirred at reflux for 4 hrs, then cooled to room temperature, diluted with H.sub.2O and extracted with EtOAc. The organic layer is dried over Na.sub.2SO.sub.4 and evaporated in vacuo to yield (4-fluoro-2-(hydroxymethyl)phenyl)boronic acid that is used in the next reaction step without further purification (Yield: 62%).

Example-9

Preparation of 4-fluoro-2-(hydroxymethyl)phenylboronic Acid (6)

(75) ##STR00027##

(76) Wherein compound-5, R.sup.2& R.sup.3=borate ester

(77) To a solution of 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (5.0 g, 0.02 mol) in Acetone (50 mL), sodium periodate (10.6 g, 0.05 mol), ammonium acetate (2.7 g, 0.035 mol) in water is added. After stirring at room temperature for 10 hr, the reaction mass is concentrated to give crude 4-fluoro-2-(hydroxymethyl)phenylboronic acid (Yield: 80%; Purity: 95%).

Example-10

Preparation of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Tavaborole 1)

(78) ##STR00028##

(79) A mixture of crude (4-fluoro-2-(hydroxymethyl) phenyl)boronic acid (3 g) and 10% H.sub.2SO.sub.4 solution (20 mL) is stirred at room temperature for 4 hrs. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried on anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue is treated with MTBE to afford benzo[c][1,2]oxaborole-1,5(3H)-diol (Yield: 81%; Purity: 95%).

Example-11

Preparation of 5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (Tavaborole 1)

(80) ##STR00029##

(81) To a solution of 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl methanol (5 g) in 1,4-dioxane (30 mL) and water (15 mL), and treated with concentrated HCl (7.5 ml). After completion of the reaction (usually completes in 5-6 hrs at RT), product is extracted with ethyl acetate and concentrated at reduced pressure to give the solid. The obtained compound is dissolved in aqueous NaOH solution (30 mL, 1 eq NaOH), washed with ethyl acetate, then acidified with aqueous HCl. The precipitated white solid is filtered, washed with water and dried (Yield: 77%; Purity: 99.6%).

Example-12

(82) Purification of Tavaborole (1)

(83) a. Crude Tavaborole is treated with a mixture of IPA:ethyl acetate (3:4) at 60-65° C., then cooled to 0-5° C. sand maintained for 1 hr. Solid is filtered under vacuum, washed with 0.5 volumes of chilled 3:4 mixture of IPA and ethyl acetate solution. The resulting solid is dried under vacuum (Yield: 77%; Purity: 99.5%).

(84) b. Crude Tavaborole is dissolved in mixture of toluene: IPA (5:1; 6 V) at 60° C., the obtained clear solution is slowly allowed to room temperature, then cooled to 0-5° C., filtered and dried (Yield 53%; Purity 99.2%).

(85) c. Crude Tavaborole is dissolved in mixture of toluene: acetonitrile (4:2; 6 V) at 70-80° C., the obtained clear solution is slowly allowed to room temperature, then cooled to 0-5° C., filtered and dried (Yield 81%; Purity 99.9%).

(86) d. Crude Tavaborole is treated with a mixture of ethanol: water (1:5) at 50-60° C., then cooled to 0-5° C. and maintained for 4 hrs. Solid is filtered, washed with 1 volume of chilled 1:5 mixture of IPA and water solution. The resulting solid is dried under vacuum (Yield: 78%; Purity: 99.7%).

(87) e. Crude Tavaborole is dissolved in acetonitrile (2V) at 50° C. and water (20 V) is added drop wise. The solution is slowly allowed to reach room temperature, then cooled to 0-5° C., filtered, washed with a chilled mixture of acetonitrile: water; 1:10 (1V) and dried (Yield: 62%; Purity: 99.96%).

Example-13

Preparation of Tavaborole Polymorphic Forms

(88) a. Preparation of Tavaborole Form I:

(89) To 5.0 g of Tavaborole is added 13 ml of toluene and the mixture is heated at reflux conditions to attain clear solution. To this 1.0 ml of acetonitrile is added and cooled to 25-30° C. The solution is further cooled 0-5° C. and then stirred for 1.0 hr and the solid is filtered under vacuum, dried at 25-30° C. for overnight to get crystalline Tavaborole polymorphic Form I.

(90) b. Preparation of Tavaborole Form II:

(91) In 100 ml round bottom flask equipped with a reflux condenser, Tavaborole 2.0 g and toluene 5.0 ml are charged at 25-30° C., the solution is heated to 50-57° C. to get a clear solution and then cooled to 25-30° C. The solution is further cooled to 0-5° C. and the resulting solid (320 mg) is filtered, washed with chilled toluene and dried under vacuum to get crystalline Tavaborole Form II.

(92) c. Preparation of Tavaborole Form III:

(93) In 100 ml of round bottom flask equipped with a reflux condenser, Tavaborole 2.0 g and 10 ml of water are charged and heated to reflux at 97° C. The solution is cooled to 25-30° C. and further to 0-15° C. The precipitated solid is filtered (1.4 g) and washed with water, filtered and dried under vacuum to get crystalline Tavaborole Form III.

(94) d. Preparation of Tavaborole Form IV:

(95) In a 100 ml of round bottom flask equipped with a reflux condenser, Tavaborole (1.0 g) and 2.0 ml of acetone are charged and stirred to get clear solution. To this 18 ml of acetone is added and concentrated on rotatory evaporator. The solid that is scratched (0.62 g) from the wall of the round bottom flask after removal of entire solvent is crystalline Tavaborole Form IV.

(96) The above Form IV can be obtained by melting polymorphic Form I of Tavaborole at 136° C. and cooling down to 25-30°.

(97) e. Preparation of Tavaborole Form V:

(98) In a 100 ml of round bottom flask, Tavaborole (1.0 g) and 3.0 ml of methyl tertiary butyl ether are charged and the mixture is stirred to get clear solution at 25-30° C. The solution is concentrated using rotatory evaporator to obtain Tavaborole as crystalline Form V.

(99) Alternative Routes:

Example-14

Preparation of tert-butyl((5-fluoro-2-iodobenzyl) oxy) Dimethylsilane (3b)

(100) ##STR00030##

(101) Wherein in compound 2, X═I and in compound 3, R.sup.1=TBDMS

(102) To a solution of (5-fluoro-2-iodophenyl)methanol (3.78 g, 0.015 mol) in CH.sub.2Cl.sub.2 (40 mL), imidazole (3.0 g, 0.045 mol) and TBDMS chloride (2.5 g, 0.016 mol) are added successfully, the reaction mass is stirred at room temperature for 8 hrs. After completion, reaction mass is quenched with water, washed with brine solution, extracted with CH.sub.2Cl.sub.2, and the organic layer is dried over Na.sub.2SO.sub.4, and concentrated to give tert-butyl((5-fluoro-2-iodobenzyl)oxy)dimethylsilane (Yield-88%).

Example-15

Preparation of tert-butyl((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)dimethylsilane (4b)

(103) ##STR00031##

(104) Wherein in compound 4, R.sup.1=TBDMS, R.sup.2& R.sup.3 together=borate ester

(105) To a solution of tert-butyl((5-fluoro-2-iodobenzyl)oxy)dimethylsilane (4.76 g, 0.013 mol) in Acetonitrile (40 mL), Pd(OAc).sub.2 (292 mg, 0.0013 mol), Tri-O-tolylphosphine (395 mg, 0.0013 mol), Bis(pinacolato)diboron (4.98 g, 0.0196 mol), Cs.sub.2CO.sub.3 (6.39 g, 0.0196 mol), CuI (0.49 g, 0.0026 mol) are added. The resulting mixture is degassed using a stream of nitrogen. The reaction mixture is stirred at room temperature for 36 hrs. The mixture is cooled to room temperature, diluted with H.sub.2O and extracted with EtOAc (120 mL). The organic layer is dried over Na.sub.2SO.sub.4 and evaporated in vacuo to yield tert-butyl((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)dimethylsilane and that is used in the next reaction step without further purification (Yield-87%).

Example-16

Preparation of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Tavaborole 1)

(106) ##STR00032##

(107) To a solution of tert-butyl((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)dimethylsilane (5.13 g, 0.014 mol) in Acetone (50 mL), sodium periodate (8.9 g, 0.042 mol), ammonium acetate (2.4 g, 0.031 mol) in water is added. After stirring at room temperature for 10 hr, 2.5N HCl (40 mL) is added, and the mixture is stirred at room temperature overnight. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried on anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue is treated with MTBE to afford 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Yield: 83%; Purity: 94%).