Novel Process for the Preparation of Tavaborole, Its Novel Polymorphic Forms and the Polymorphs Thereof |
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| 申请号 | US16094470 | 申请日 | 2016-07-21 | 公开(公告)号 | US20190119306A1 | 公开(公告)日 | 2019-04-25 |
| 申请人 | Biophore India Pharmaceuticals PVT. Ltd.; | 发明人 | Manik Reddy PULLAGURLA; Mecheril Valsan NANDA KUMAR; Bhasakar Reddy PITTA; Jagadeesh Babu RANGISETTY; | ||||
| 摘要 | 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. | ||||||
| 权利要求 | |||||||
| 说明书全文 | 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. The compound 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Tavaborole) is represented by the formula 1: Tavaborole is an oxaborole antifungal indicated for the topical treatment of onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes. U.S. Pat. Nos. 5,880,188, 7,271,264, 8,115,026 reported various processes for the synthesis of oxaborole—specifically, Tavaborole, the contents of which are hereby incorporated as reference in their entirety. General synthesis of Tavaborole is first described in the U.S. Pat. No. 5,880,188 (Prior art process-1). In this process oxaborole is made by converting an ortho-toluidine under Sandmeyer conditions to an O-substituted halogeno toluene which is then reacted with magnesium or alkyl lithium and the Grignard reagent or aryl lithium so formed is reacted with a borate ester to obtain a toluene boronic acid. This boronic acid is then reacted with NBS in CCl4 solvent to give bromomethylbenzene boronic acid which is hydrolysed in alkali to give the benzaxoborole under acidic conditions. In this process, the reported yield of the bromination stage is ˜15% and the overall yield is less than 5%, which makes the process impractical at a commercial scale production. Another route for the preparation of oxaborole derivatives reported in the U.S. Pat. No. 5,880,188 (Prior art process-2) includes reacting benzaldehyde with p-toluenesulphonylhydrazide and reacting the product obtained subsequently with boron tribromide in the presence of a ferric or aluminium chloride which give the cyclized tosyl compound. The Tosyl compound on subsequent alkaline hydrolysis generates oxaborole compound. In this process, the reported yield of tosylhydrazone to oxaborole conversion is less than 10%. U.S. Pat. No. 7,271,264 presents another route of synthesis for Tavaborole (Prior art process-3). In this process, (2-bromo-5-fluoro-phenyl)-methanol is treated with ethylvinyl ether in presence of PPTS to give 1-bromo-2-(1-ethoxy-ethoxymethyl)-4-fluoro-benzene, which on further treatment with n-BuLi followed by reaction with trimethyl borate, and later with 1N HCl generates Tavaborole. This process involves highly pyrophoric Butyllithium making it unsuitable for industrial scale synthesis. U.S. Pat. No. 8,115,026 patent also describes a general route for the preparation of oxaborole compound including Tavaborole (Prior art process-4). In this process, orthohalo carbonyl compound is treated with bispinacolato diboran or pinacol borane in the presence of Pd catalyst, ligand and a base to give Pinacol borate which on oxidative cleavage with NaIO4 generates boronic acid compound. Reduction of the carbonyl group of boronic acid compound with a suitable reducing agent produces the crude oxaborole compound and that is purified by column chromatography. Even though the process avoids pyrophoric Butyllithium, it requires 30 mole percentage of expensive Palladium catalyst. In addition, this process involves column chromatographic purification of final compound and the overall yield is ˜21%. Therefore, there is a need in the art for a new or improved method for the preparation of Tavaborole in significantly high yield compared to the prior art. In view of this, the present inventors provide a safe, cost-effective and industrially applicable process for the preparation of Tavaborole in significantly high yield. Primary object of the invention is to provide novel process for the preparation of Tavaborole. Another object of the invention is to provide novel polymorphic forms of Tavaborole. Another object of the invention is to provide process for preparation of the novel polymorphic forms of Tavaborole. Another object of the invention is to provide process for preparation of Tavaborole with high yield and purity. Another object of the invention is to provide process for purification of Tavaborole to obtain highly purified Tavaborole. A further object of the invention is to provide Tavaborole without the impurities represented as Impurity A and Impurity B. Accordingly, the present invention provides novel synthetic methods for the preparation of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Tavaborole 1). In one aspect of the invention, synthesis of Tavaborole is reported which result in significantly high yield, greater than 80%. In one aspect of the invention methods of purification of Tavaborole to obtain a substantially pure compound, whose purity is greater than or equal to 99% is reported. In another aspect of the invention, Tavaborole obtained by the reported purification procedures of the invention has purity greater than or equal to 99% and is devoid of the major reaction impurities (A&B). One of the processes for the preparation of Tavaborole according to the invention comprises three steps as depicted in Scheme-1. Wherein X is a member selected from Br, I, OTf; R1 is hydroxyl protecting group; and R2, R3 are members independently selected from H; substituted or unsubstituted C1-C8 alkyl; substituted or unsubstituted heteroalkyl C1-C8; substituted or unsubstituted aryl C5-C10; substituted or unsubstituted heteroaryl C5-C10; substituted or unsubstituted cycloalkyl C3-C8; substituted or unsubstituted heterocycloalkyl C3-C8; together with the atoms to which they are attached may be optionally joined to form a 4- to 8-membered ring.
In another embodiment of the invention Tavaborole is synthesized by the reaction depicted in Scheme-2. wherein the substituents X, R2, R3 are as defined above.
In yet another aspect of the invention, crystalline polymorphic Forms I, II, III, IV & V of Tavaborole and processes for their preparation are reported. In one embodiment the invention provides a process for preparation of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Tavaborole) comprising the steps of:
The borate compound 4 in step (iii) is converted into Tavaborole either by simultaneous deprotection of hydroxyl protecting group and boronate ester group using a hydroxyl deprotecting agent, or by sequential deprotection of hydroxyl protecting group and boronate ester group of compound 4 followed by cyclization in presence of an acid or a base. The hydroxyl protecting agent comprises acyl protecting agent selected from the group consisting of acetyl chloride, acetic anhydride, and benzoyl chloride or Silyl protecting agents selected from the group consisting of trimethyl silyl chloride, triethyl silyl chloride, and tertiary butyl dimethyl silyl chloride (TBDMSCl). The transition metal catalyzed cross-coupling reaction of step (ii) is carried out in presence of Pd catalyst selected from PdCl2(dppf), [PdCl2dppf]CH2Cl2, PdCl2(PPh3)2, Pd(PPh3)4, Pd(OAc)2, [Pd2dba3], [Pd(allyl)Cl]2, Pd(acac)2, PhPd(OAc)(PPh)2 or any Palladium catalyst that generates in situ Pd(O) and combinations thereof or Ni catalyst selected from NiCl2(dppp), NiCl2(dppf), NiCl2(dppe), NiCl2.glyme, NiBr2.glyme, NiCl2(PPh3)2, NiCl2(PCy3)2, Ni(PPh3)4, Ni(PPh3)4, Ni(COD)2, NiCl2, NiBr2 or any Nickel catalyst that generates in situ Ni(O) and combinations thereof. The borylation reagent is selected from the group consisting of Bis(neopentylglycolato)diboron, Bis(catecholato)diboron, Bis(hexyleneglycolato)diboron, Bis(pinacolato)diboron, Tetrahydroxydiboron, Pinacolborane, Methylpentanediolborane, Catecholborane, Neopentylglycoborane and Trialkyl borate. The reaction of step (ii) is carried out in presence of a solvent selected from toluene, xylene, N,N-dimethylformamide, dimethylsufoxide, tetrahydrofuran and 1,4-dioxane or mixtures thereof. The reaction of step (ii) is carried out in presence of a ligand selected from the group consisting of Xphos, MeO-CM-Phos, Sphos, DavePhos, RuPhos, tBu3P—HBF4, QPhos, JohnPhos, Me4-tBu-XPhos, Ad2PBu, BrettPhos, AmPhos, PPh3 and tri(o-tolyl)phosphine. The transition metal catalyst in step (ii) further comprises co-catalyst selected from the group consisting of Cu(OTf)2, Cu(OAc)2, CuCl, CuBr, CuI, ZnCl2 and Ag2CO3. The deprotection of hydroxyl protecting group is carried out by a hydroxyl deprotecting agent comprising an inorganic base selected from potassium hydroxide, lithium hydroxide and sodium hydroxide, metal carbonates selected from potassium carbonate, sodium carbonate and cesium carbonate, metal alkoxides selected from sodium methoxide and sodium ethoxide. The deprotection of hydroxyl protecting group is carried out by a hydroxyl deprotecting agent comprising an acid deprotecting agent selected from HCl, H2SO4, HNO3, AcOH, HCOOH, BF3Et2O, AlCl3 and BBr3. The cyclization is carried out using an acid selected from the group consisting of HCl, H2SO4, HNO3, AcOH, HCOOH, BF3Et2O, AlCl3 and BBr3. In another embodiment, the invention provides a process for preparation of Tavaborole comprises the steps of:
In another embodiment, the invention provides a process for preparation of Tavaborole comprising following steps:
In another embodiment, the invention provides a process for preparation of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Tavaborole) comprising the steps of:
The conversion of borate ester compound 5 into Tavaborole in step (ii) comprises the sub-steps of:
The above said compounds 2, 5 and 6 and their substituents are as described above for Scheme-2. The transition metal catalyzed cross-coupling reaction of step (i) is carried out in presence of Pd catalyst selected from PdCl2(dppf), [PdCl2dppf]CH2Cl2, PdCl2(PPh3)2, Pd(PPh3)4, Pd(OAc)2, [Pd2dba3], [Pd(allyl)Cl]2, Pd(acac)2, PhPd(OAc)(PPh)2 or any Palladium catalyst that generates in situ Pd(O) and combinations thereof; or Ni catalyst selected from NiCl2(dppp), NiCl2(dppf), NiCl2(dppe), NiCl2.glyme, NiBr2.glyme, NiCl2(PPh3)2, NiCl2(PCy3)2, Ni(PPh3)4, Ni(PPh3)4, Ni(COD)2, NiCl2, NiBr2 or any Nickel catalyst that generates in situ Ni(O) and combinations thereof. The borylation reagent is selected from the group consisting of Bis(neopentylglycolato)diboron, Bis(catecholato)diboron, Bis(hexyleneglycolato)diboron, Bis(pinacolato)diboron, Tetrahydroxydiboron, Pinacolborane, Methylpentanediolborane, Catecholborane, Neopentylglycoborane and Trialkyl borate. The reaction of step (i) is carried out in a solvent selected from MeOH, EtOH, IPA, toluene, xylene, N,N-dimethylformamide, dimethylsufoxide, tetrahydrofuran and 1,4-dioxane or mixtures thereof. The reaction of step (i) is carried out in presence of a base comprising an inorganic base selected from the group consisting of KOPh, KOAc, NaOAc, NH4OAc, Cu(OAc)2, Cs2CO3, K2CO3, Na2CO3, Ag2CO3, K3PO4, NaOH, KOH, CsOH, KOMe, NaOMe, LiOtBu, NaOtBu and KOtBu or an organic base selected from the group consisting of pyridine, triethyl amine, leutidine, DABCO, DBU, 1,2,2,6,6-pentamethylpipiridine, 1,1,3,3-tetramethylguanidine, iPr2NEt, NBu3 and Cy2NMe. The reaction of step (i) is carried out in presence of a ligand selected from the group consisting of Xphos, MeO-CM-Phos, Sphos, DavePhos, RuPhos, tBu3P—HBF4, QPhos, JohnPhos, Me4-tBu-XPhos, Ad2PBu, BrettPhos, AmPhos, PPh3 and tri(o-tolyl)phosphine. The transition metal catalyst in step (i) further comprises co-catalyst selected from the group consisting of Cu(OTf)2, Cu(OAc)2, CuCl, CuBr, CuI, ZnCl2 and Ag2CO3. The oxidative cleaving in step (i) comprises treating the compound of formula 5 with NaIO4 or Pb(OAc)4 in presence of a solvent selected from the group consisting of H2O, tetrahydrofuran, 1,4-dioxane, methanol and ethanol or mixtures thereof. The acid in step (ii) is selected from the group consisting of HCl, H2SO4, AcOH, HCOOH, BF3Et2O, AlCl3 and BBr3. The above said processes further comprises purification of the Tavaborole with solvents comprising alkanes consisting of Hexanes, Toluene and cyclohexane, alcohols consisting of Methanol, Ethanol and Isopropyl alcohol, water, Acetonitrile, Tetrahydrofuran, Acetone, Ethyl acetate, and Dichloromethane or mixtures thereof. In one embodiment, the invention provides a process for purification of Tavaborole comprising the steps selected from:
In another embodiment, the invention provides process for purification of Tavaborole comprising the steps selected from:
In another embodiment, the invention provides process for purification of Tavaborole to obtain purified Tavaborole with more than 99% purity comprising the steps of:
In another aspect, the invention provides purified 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Tavaborole 1) with greater than 99% purity and without the impurities represented as Impurity-A and Impurity-B. In another aspect, the invention provides a process for preparation of crystalline forms of Tavaborole comprising the steps of:
The invention further provides:
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. The methods for the preparation of Tavaborole are schematically represented by Scheme-1 and Scheme-2. One of the reported procedures of the invention (Scheme-1), comprises
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 NaIO4 or Pb(OAc)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 H2O, tetrahydrofuran, 1,4-dioxane, methanol, ethanol or mixtures thereof. Another route of synthesis of Tavaborole is as represented in Scheme-2 below: wherein the substituents X, R2, R3 are as defined above and the process comprises
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. 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. Suitable solvent is selected from the group comprising methanol, ethanol, IPA, N,N-dimethylformamide, dimethylsufoxide, tetrahydrofuran, 1,4-dioxane or mixtures thereof. The non limiting examples of the Nickel catalyst, base and the ligand is as described hereunder.
The acid used for the hydrolysis is selected from the group comprising HCl, H2SO4, AcOH, HCOOH, BF3Et2O, AlCl3, BBr3 or the like and the base is selected from the group comprising NaOH, KOH, LiOH, Na2CO3, K2CO3, LiCO3, CsCO3, NaOMe, EtOMe.
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. Tavaborole can be purified by any of the following procedures:
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. 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. In another aspect crude Tavaborole is treated with silica gel in toluene and recrystallized in hexane. 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. 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%. 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 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. The polymorphic crystalline Form I of Tavaborole may also be identified by the DSC as depicted in 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 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 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 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 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. 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. 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. In another embodiment,
The X-Ray diffraction data of the Tavaborole crystalline forms obtained are tabulated below. The following terms shall have for the purpose of this application, including the claims appended hereto, the respective meanings set forth below: “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 comprising 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. 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 PdCl2(dppf), [PdCl2dppf].CH2Cl2, PdCl2(PPh3)2, Pd(PPh3)4, Pd(OAc)2, [Pd2dba3], [Pd(allyl)Cl]2, Pd(acac)2, PhPd(OAc)(PPh)2 any Palladium catalyst that generates in situ Pd(0) and combinations thereof. In one aspect of the invention, Pd catalyst used is PdCl2(dppf). Non limiting examples of Ni catalyst selected from group of NiCl2(dppp), NiCl2(dppf), NiCl2(dppe), NiCl2.glyme, NiBr2.glyme, NiCl2(PPh3)2, NiCl2(PCy3)2, Ni(PPh3)4, Ni(COD)2, NiCl2, NiBr2 or any Nickel catalyst that generates in situ Ni(0) and combinations thereof. In one aspect of the invention, Ni catalyst used is NiCl2(dppp). Appropriate ligand is selected from the group comprising of Xphos, MeO-CM-Phos, Sphos, DavePhos, RuPhos, tBu3P—HBF4, QPhos, JohnPhos, Me4-tBu-XPhos, Ad2PBu, BrettPhos, AmPhos, PPh3, tri(o-tolyl) phosphine or the like. In one aspect of the invention, the ligand used is tri(o-tolyl)phosphine. 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. 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, NH4OAc, Cu(OAc)2, Cs2CO3, K2CO3, Na2CO3, Ag2CO3, K3PO4, 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, iPr2NEt, NBu3, Cy2NMe or the like. In one aspect of the invention, suitable organic base used is iPr2Net. “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, H2SO4, HNO3, AcOH, HCOOH, BF3Et2O, AlCl3, BBr3 or the like. These deprotecting agents are most suitable for simultaneously removing the boronate ester protecting groups. Additive or co-catalyst that is employed is selected from the group comprising Cu(OTf)2, Cu(OAc)2, CuCl, CuBr, CuI, ZnCl2, Ag2CO3 or the like. The dehydrating agent used for the cyclization of Tavaborole is an organic or an inorganic acid selected from the group comprising HCl, H2SO4, HNO3, AcOH, HCOOH, BF3Et2O, AlCl3, 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, Na2CO3, K2CO3, LiCO3, CsCO3, NaOMe, EtOMe. The following examples further illustrate the present invention, but should not be construed in any way as to limit its scope. Wherein in compound 2, X=Br and in compound 3, R1=Ac 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 NaHCO3 (100 mL), 0.1 N HCl (50 mL) and water (100 mL) and dried over Na2SO4. Evaporation of the solvent gave 2-bromo-5-fluorobenzyl acetate (Yield: 97%; Purity: 99.3%). Wherein in compound 4, R1=Ac, R2& R3 together=borate ester 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 H2O and extracted with EtOAc. The organic layer is dried over Na2SO4 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%). 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 Na2SO4 and evaporated in vacuo to yield 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Yield: 93%; Purity: 92%). 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%). 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%. 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 Na2SO4 and evaporated in vacuo to yield 5-fluoro-1,3-dihydrobenzo[c][1,2]oxaborole (Yield: 93%; Purity: 92%). 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 H2O and extracted with EtOAc. The organic layer was dried over Na2SO4 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%. To a solution of (2-bromo-5-fluorophenyl) methanol (10.05 g, 0.049 mol) in Ethanol 100 mL), NiCl2(dppp) (2.67 g, 0.0049 mol), (HO)2B—B(OH)2 (6.62 g, 0.074 mol), PPh3 (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 H2O and extracted with EtOAc. The organic layer is dried over Na2SO4 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%). Wherein compound-5, R2& R3=borate ester 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%). A mixture of crude (4-fluoro-2-(hydroxymethyl) phenyl)boronic acid (3 g) and 10% H2SO4 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%). 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%). 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%). 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%). 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%). 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%). 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%). a. Preparation of Tavaborole Form I: 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. b. Preparation of Tavaborole Form II: 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. c. Preparation of Tavaborole Form III: 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. d. Preparation of Tavaborole Form IV: 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. The above Form IV can be obtained by melting polymorphic Form I of Tavaborole at 136° C. and cooling down to 25-30°. e. Preparation of Tavaborole Form V: 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. Wherein in compound 2, X=I and in compound 3, R1=TBDMS To a solution of (5-fluoro-2-iodophenyl)methanol (3.78 g, 0.015 mol) in CH2Cl2 (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 CH2Cl2, and the organic layer is dried over Na2SO4, and concentrated to give tert-butyl((5-fluoro-2-iodobenzyl)oxy)dimethylsilane (Yield-88%). Wherein in compound 4, R1=TBDMS, R2& R3 together=borate ester To a solution of tert-butyl((5-fluoro-2-iodobenzyl)oxy)dimethylsilane (4.76 g, 0.013 mol) in Acetonitrile (40 mL), Pd(OAc)2 (292 mg, 0.0013 mol), Tri-O-tolylphosphine (395 mg, 0.0013 mol), Bis(pinacolato)diboron (4.98 g, 0.0196 mol), Cs2CO3 (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 H2O and extracted with EtOAc (120 mL). The organic layer is dried over Na2SO4 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%). 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%). |
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