Direct resolution of desacetylketoconazole salt

Abstract

The invention relates to novel achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV). The invention relates to a process for the preparation of novel achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) from racemic desacetyl ketoconazole compound of formula (V) using achiral organic or inorganic acid and its direct resolution to chirally pure salt of desacetyl ketoconazole compound of formula (III). The present invention further relates to a conversion of chirally pure salt of desacetyl ketoconazole compound of formula (III) to levoketoconazole compound of formula (I) using novel achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV).

Description

[0001] DIRECT RESOLUTION OF DESACETYLKETOCONAZOLE SALT

[0002] FIELD OF INVENTION

[0003] The invention relates to novel achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV).

[0004] The invention relates to a process for the preparation of novel achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) from racemic desacetyl ketoconazole compound of formula (V) using achiral organic or inorganic acid and its direct resolution to chirally pure salt of desacetyl ketoconazole compound of formula (III).

[0005] The present invention further relates to a conversion of chirally pure salt of desacetyl ketoconazole compound of formula (III) to levoketoconazole compound of formula (I) using novel achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV).

[0006] BACKGROUND OF THE INVENTION

[0007] Ketoconazole, an antifungal drug, is chemically known as l-[4-(4-{[2-(2,4-Dichlorophenyl)- 2-( IH-imidazol- 1 -ylmethyl)- 1 ,3-dioxolan -4-yl |mcthoxy [ phenyl

[0008] )-l-piperazinyl] ethanone of formula (VI) which is approved in racemate form i.e., Cis (±). Its chemical structure is represented by the following Formula (VI).

[0009] Compund of formula (VI)

[0010] Ketoconazole contain in its structure a substituted 1,3-dioxolane ring, in which carbon atoms C2 and C4 are stereogenic centres, therefore four stereoisomers are possible.

[0011] An optical isomer of ketoconazole i.e., Levoketoconazole (I), chemically is the (-) isomer of cis l-[4-(4-{[(2S, 4R)-2-(2,4-Dichlorophenyl)-2-(lH-imidazol-l-yhnethyl)-l,3-dioxolan-4- yl]methoxyphenyl)- 1 -piperazinyl] ethanone . Levoketoconazole is an approved drug (RECORLEV®), a cortisol synthesis inhibitor, indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.

[0012] Synthesis of (2S, 4R)-ketoconazole , Cis(-), of formula-I was reported in few patent and nonpatent literature, Heeres et al., J. Med. Chem. 22, (8), 1003-1005 (1979); Heel et al., Drugs, 23, 1-36, (1982) and in U.S. Pat. Nos. 4,144,346, 4,223,036 and 4,358,449 the contents of which are hereby incorporated as reference in their entirety.

[0013] D. M. Rotstein et al., J. Med . Chem. , 35, 2818 (1992) described preparation of (+)- and (-)- ketoconazole as depicted below in scheme- 1

[0014] Scheme-1

[0015] As evident, Scheme- 1 mainly requires optically pure S ketal tosylate as key starting material, follows column chromatography to separate intermediate and uses sodium hydride and high temperature to prepare 2S,4R compound of formula (I) which requires further purification using flash chromatography.

[0016] WO 199629325 Al and Tetrahedron Asymmetry Vol. 6 No. 6 pp. 1283-12194, 1995 discloses use of (R)-4-chloromethyl -2, 2-dimethyl- 1,3 -dioxolane as a starting intermediate for the preparation of Levoketoconazole (2S,4R). It mainly differs from above scheme 1 in the use of optically pure S-ketal chloro derivative ((R)-4-chloromethyl-2,2-dimethyl-l, 3- dioxolane) instead of S ketal tosylate. In addition of the use of column chromatography, it further requires purification of intermediates through salt formation using nitric acid and further requires approximately 5 days for completion of reaction. CN102070620 discloses process for the preparation of desacetyl ketoconazole by condensation of cis-[2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-yl methyl) -l,3-dioxolan-4- yl]methylp-tolylsulfonate and l-(4-hydroxyphenyl) piperazine.

[0017] US11760750 B2 discloses two processes to obtain levoketoconazole. One of the process disclosed involves deacetylation, optical resolution of desacetyl ketoconazole and re acetylation to yield crude levoketoconazole (2S, 4R) (96.7% enantiomer) and re resolution of the obtained crude levoketoconazole using resolution agent and repeated purification to finally yield pure levoketoconazole (>99.5 purity by HPLC). It further discloses powder X- ray diffraction of levoketoconazole similar to levoketoconazole disclosed in prior art.

[0018] The described prior art synthesis of levoketoconazole suffers from several drawbacks: a) use of expensive chiral intermediates b) use of flash and column chromatography or re resolution of crude levoketoconazole. Thus, it makes said synthesis low in yield and purity, lengthy, economically unattractive and less industrially feasible.

[0019] The inventors of a present invention surprisingly found that direct resolution of achiral organic or inorganic salt of racemic desacetyl ketoconazole results in specific 2S,4R isomer of ketoconazole (Levoketoconazole) in high enantiomeric purity and is simple, safe, efficient, economical, industrially feasible, scalable process and avoids re-resolution and / or repeated purification of levoketoconazole. It also avoids use of chiral key starting material, lengthy reaction time cycle, pyrophoric reagents like Sodium hydride and chromatographic purification techniques.

[0020] SUMMARY OF THE INVENTION

[0021] In one aspect, the present invention provides a novel achiral salt of racemic desacetyl ketoconazole compound of formula (IV),

[0022] Formula (IV)

[0023] Wherein, R' is achiral organic or inorganic acid.

[0024] In an aspect, the present invention provides a process for preparation of achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) comprises contacting a racemic desacetyl ketoconazole compound of formula (V) with an achiral organic or inorganic acid in a suitable solvent to obtain an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV).

[0025] In an aspect, the present invention provides a process for preparation of chirally pure salt of desacetyl ketoconazole compound of formula (III) comprises directly resolving an achiral organic or inorganic salt of desacetyl ketoconazole compound of formula (IV) with a chiral resolving agent (counter ion-exchange) in suitable solvent to obtain a chirally pure salt of desacetyl ketoconazole compound of formula (III).

[0026] In an aspect, the present invention provides a process for preparation of chirally pure salt of desacetyl ketoconazole compound of formula (III) comprises a) contacting a racemic desacetyl ketoconazole compound of formula (V) with an achiral organic or inorganic acid in a suitable solvent to obtain an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV); b) directly resolving an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) with a chiral resolving agent in a suitable solvent to obtain a chirally pure salt of desacetyl ketoconazole compound of formula (III).

[0027] In an aspect, achiral organic acid selected from benzoic acid, toluic acid, oxalic acid and p- toluene sulfonic acid or inorganic acid selected from hydrochloric acid.

[0028] Additionally, a person skilled in art may select other achiral organic and inorganic acid suitably and chemically leading to achiral salt of racemic desacetyl ketoconazole of formula (IV).

[0029] In an aspect, the present invention provides counter ion exchange of racemic desacetyl ketoconazole salt compound of formula (IV) by resolving agent, wherein A' is counter ion of resolving agent selected from L- tartaric acid, R-mandelic acid and Di-p-tolyl D-tartaric acid.

[0030] In an aspect, resolving agent is L-(+) tartaric acid.

[0031] Additionally, a person skilled in art may select other resolving agents suitably and chemically leading to chirally pure salt of desacetyl ketoconazole compound of formula (III). In an aspect, the present invention further provides process for the preparation of levoketoconazole compound of formula (I) from achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV).

[0032] In an aspect, the present invention provides process for the preparation of levoketoconazole compound of formula (I), comprising using achiral organic or inorganic salt of racemic desacetyl ketoconazole of compound of formula (IV).

[0033] In an aspect, the present invention provides process for the preparation of levoketoconazole compound of formula (I) comprises a) contacting a racemic desacetyl ketoconazole compound of formula (V) with an achiral organic or inorganic acid in a suitable solvent to obtain an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV); b) directly resolving an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) with a chiral resolving agent in a suitable solvent to obtain a chirally pure salt of desacetyl ketoconazole compound of formula (III); and c) converting a chirally pure salt of desacetyl ketoconazole compound of formula (III) to levoketoconazole compound of formula (I).

[0034] In an aspect, the present invention further comprises optionally purifying a chirally pure salt of desacetyl ketoconazole compound of formula (III).

[0035] In an aspect, a suitable solvent includes but are not limited to methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol; water or mixtures thereof.

[0036] The resolution and preparation of achiral organic or inorganic salts of itraconazole and terconazole can be carried out in a similar manner.

[0037] DETAILED DESCRIPTION OF THE INVENTION

[0038] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0039] The term “reflux temperature” as used herein, refers to an experimental method that involves heating a reaction mixture to the boiling point temperature of the reaction solvent and inducing the solvent to re-condense back into the reaction flask using a condenser. The term “counter ion exchange” refers to the ion that accompanies an ionic species in order to maintain electric neutrality. The counter ion to an anion will be a cation, and vice versa.

[0040] In an aspect, the present invention provides a novel achiral salt of racemic desacetyl ketoconazole compound of formula (IV), wherein R' is achiral organic and inorganic acid.

[0041] In an aspect, achiral organic acid selected from benzoic acid, toluic acid, oxalic acid and p- toluene sulfonic acid or inorganic acid selected from hydrochloric acid.

[0042] In an aspect, the present invention provides a process for preparation of achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) comprises contacting a racemic desacetyl ketoconazole compound of formula (V) with an achiral organic or inorganic acid in a suitable solvent to obtain an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV).

[0043] In an aspect, contacting a racemic desacetyl ketoconazole compound of formula (V) (step a)) comprises dissolving a racemic desacetyl ketoconazole compound of formula (V) and achiral organic or inorganic acid in a suitable solvent. The suitable solvent includes, but are not limited to methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol; water or mixtures thereof.

[0044] The achiral organic acid includes, but are not limited to benzoic acid, toluic acid, oxalic acid and p-toluene sulfonic acid. The inorganic acid includes, but are not limited to hydrochloric acid.

[0045] Additionally, a person skilled in art may select other achiral organic and inorganic acid suitably and chemically leading to achiral salt of racemic desacetyl ketoconazole of formula (IV).

[0046] The temperature for dissolving a racemic desacetyl ketoconazole compound of formula (V) and achiral organic or inorganic acid in a suitable solvent in step a) occurs at room temperature to reflux temperature of the solvent The reaction may be conducted at temperature of about 25 °C to 85 °C, preferably 40 °C to 60 °C.

[0047] The achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) in step a) can be isolated from the reaction mixture. The isolation can be initiated by methods known in the art such as cooling, complete or partial removal of solvent or by addition of a solvent or by both.

[0048] The isolation can be initiated by removing solvent from reaction mixture using any of techniques such as distillation or distillation under vacuum, followed by co-distillation with solvent.

[0049] After co-distillation and filtration, isolated solid may be washed with solvent. After washing, achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) can be further dried at suitable temperature. The drying may be conducted at temperature of about 30°C to 70 °C, preferably about 45°C to 65 °C more preferably at about 50 °C.

[0050] The achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) may be used in the next step directly or may be isolated from the reaction medium and then used in the next step.

[0051] In an aspect, the present invention provides a process for preparation of chirally pure salt of desacetyl ketoconazole compound of formula (III) comprises directly resolving an achiral organic or inorganic salt of desacetyl ketoconazole compound of formula (IV) with a chiral resolving agent in suitable solvent to obtain a chirally pure salt of desacetyl ketoconazole compound of formula (III).

[0052] In an aspect, the present invention provides a process for preparation of chirally pure salt of desacetyl ketoconazole compound of formula (III) comprises a) contacting a racemic desacetyl ketoconazole compound of formula (V) with an achiral organic or inorganic acid in a suitable solvent to obtain an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV); b) directly resolving an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) with a chiral resolving agent in a suitable solvent to obtain a chirally pure salt of desacetyl ketoconazole compound of formula (III).

[0053] In an aspect, the present invention provides process for the preparation of levoketoconazole compound of formula (I) comprises a) contacting a racemic desacetyl ketoconazole compound of formula (V) with an achiral organic or inorganic acid in a suitable solvent to obtain an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV); b) directly resolving an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) with a chiral resolving agent in a suitable solvent to obtain a chirally pure salt of desacetyl ketoconazole compound of formula (III); and c) converting a chirally pure salt of desacetyl ketoconazole compound of formula (III) to levoketoconazole compound of formula (I).

[0054] The chirally pure salt of desacetyl ketoconazole compound of formula (III) represented by

[0055] Formula (III),

[0056] Wherein A' is chiral resolving agent.

[0057] In an aspect, the present invention provides counter ion exchange of racemic desacetyl ketoconazole achiral salt compound of formula (IV) by resolving agent, wherein A' is counter ion of resolving agent in step b) selected from L- tartaric acid, R-mandelic acid and Di-p-tolyl D-tartaric acid.

[0058] In an aspect, resolving agent in step b) is L-(+) tartaric acid.

[0059] Additionally, a person skilled in art may select other resolving agents in step b) suitably and chemically leading to chirally pure salt of desacetyl ketoconazole compound of formula (III).

[0060] The molar ratio between resolving agents to compound of formula IV in step b) may be between 0.5 to 2.0 or 0.7 to 1.5 or 1 to 1.5 for preparing compound of formula III.

[0061] The solvent that is used for resolution in step b) can be selected but are not limited to methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secbutyl alcohol or t-butyl alcohol; water or mixtures thereof, more preferably methanol ; water or mixture thereof.

[0062] The resolution of achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) with a chiral resolving agent in a suitable solvent in step b) may be conducted at room temperature to reflux temperature of the solvent The reaction may be conducted at temperature of about 25 °C to 85 °C. The reaction can be conducted as long as required for the completion of the reaction, about 30 minutes to about 5 hours frequently being required.

[0063] After completion of the reaction, chirally pure salt of desacetyl ketoconazole compound of formula (III) formed in step b) may be isolated from the reaction medium and then used in the next step or used in the next step directly.

[0064] According to embodiment, chirally pure salt of desacetyl ketoconazole compound of formula (III) in step b) can be isolated from the reaction mixture. The isolation can be initiated by methods known in the art such as cooling, complete or partial removal of solvent or by addition of a solvent or by both.

[0065] Isolation can be also be initiated by cooling. For example, the reaction mixture can be cooled from about reflux temperature of solvent to room temperature over a period of about 10 minute to about 1 hour, to about 10 hours or longer, preferably 30 to 60 minute.

[0066] The isolation can be initiated by removing solvent from reaction mixture using any of techniques such as filtration by gravity or by suction, centrifugation, slow evaporation, atmospheric distillation or distillation under vacuum and the like, or any other suitable techniques, preferably filtration or distillation under vacuum.

[0067] After isolation, the resulting solid may be optionally treated or washed with solvent. The preferred solvent may be alcohol such as isopropyl alcohol or mixture of methanol and water thereof.

[0068] The resulting solid may be further filtered, washed, and dried.

[0069] Undissolved particles from a mixture comprising compound III can be removed by filtration, centrifugation.

[0070] After washing with suitable solvent, the resulting solid may be further dried. Drying may be suitably carried out using equipment such as a tray dryer (vacuum), vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperature less than about 100° C, less than about 60°C, preferably 50° C. The chirally pure salt of desacetyl ketoconazole compound of formula (III) can be isolated and / or optionally purified.

[0071] In an embodiment, the present invention provides a purification of a chirally pure salt of desacetyl ketoconazole compound of formula (III) comprising; i) providing a slurry or solution of a chiral salt of compound of formula (III); ii) heating the reaction mass; iii) filtering the reaction mass; iv) cooling; v) optionally seeding the solution; vi) isolating a chiral salt of compound of formula (III), wherein A' is as defined above; optionally repeating the purification.

[0072] The solvent that is used in step i) can be selected but are not limited methanol, ethanol, n- propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t- butyl alcohol; water or mixtures thereof, more preferably methanol ; water or mixture thereof.

[0073] Step ii) can be carried out from room temperature to reflux temperature of the solvent. The reaction may be conducted at reflux temperature of the solvent.

[0074] After filtering and cooling (Step iii) and iv), step v) comprises seeding of chiral salt of compound of formula III, seeding material can be added optionally in the reaction mixture i.e. solution.

[0075] The isolation in step vi) can be initiated by removing solvent from reaction mixture using any of techniques such as filtration by gravity or by suction, centrifugation, slow evaporation, atmospheric distillation or distillation under vacuum and the like, or any other suitable techniques, preferably filtration.

[0076] The resulting solid may be as further washed, and dried.

[0077] After washing with suitable solvent as disclosed hereinabove, chiral salt of compound of formula (III) can be further dried at suitable temperature, and atmospheric or reduced pressure, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer (vacuum), vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, preferably tray dryer (Vacuum). The drying may be conducted at temperature of about 30°C to 70°C, preferably about 45°C to 60°C more preferably at about 50°C. Purification optionally can be repeated. Purification can be repeated until the desired chiral purity is obtained. Usually one or two crystallizations may be sufficient with and / or without seeding.

[0078] The chirally pure salt of desacetyl ketoconazole compound of formula (III) can be obtained as a substantially optically pure form. The chiral salt of compound of formula (III) can be obtained as at least 75% or 99% or 99.9% with an enantiomeric purity.

[0079] After a resolution, step c) comprises converting a chirally pure salt of desacetyl ketoconazole compound of formula (III) to levoketoconazole compound of formula (I).

[0080] The process in the step c) comprises a hydrolysing of a chiral salt of compound of formula (III) to obtain a compound of formula (II), converting formula II to levoketoconazole compound of formula (I) by known methods in the prior art.

[0081] The present invention provides process for the preparation of levoketoconazole compound of formula (I) from achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV).

[0082] The racemic desacetyl ketoconazole compound of formula (V) can be prepared by known methods in the prior art e.g., CN102070620.

[0083] The resolution and preparation of achiral organic or inorganic salts of itraconazole and terconazole can be carried out in a similar manner.

[0084] Scheme 2 illustrates the compounds and reaction steps involved in the preparation of a compound of formula I.

[0085]

[0086] Scheme 2

[0087] Scheme 2a illustrates the compounds and process involved in the preparation of a compound of formula I.

[0088] Wherein,

[0089] R= Onganic / ln-orgnic acid

[0090] A is resolving agent

[0091] Scheme 2a

[0092] The present invention is further illustrated by the following examples which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

[0093] EXAMPLES:

[0094] Example 1: Benzoate salt of l-[4-[[(2RS, 4SR)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l- ylmethyl)-l, 3-dioxolan-4-l] methoxy] phenyl] piperazine (Formula-IV) to a round bottom flask, 300 ml of methanol was charged and 150 gm of l-[4-[[(2RS, 4SR)- 2-(2,4-dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4- l]methoxy]phenyl]piperazine (V) and 38.18 gm of benzoic acid were charged and the mass was heated to 45±5°C and stirred it for 15-20 minutes. The reaction mass was distilled as residue by removing the solvent and co-distilled with ethyl acetate. 900 ml of fresh ethyl acetate was charged and stirred for 30 minutes, filtered at 25-30°C the solid and washed with ethyl acetate. The solid material was dried at 50±5°C, to yield title compound. Dry weight : 171 gm. 1H NMR DMSO D6 : 5 7.93-7.68 (2H, m), 7.58-7.55 (1H, s), 7.48-7.39 (4H, m), 7.01 (1H, S), 6.90-6.88 (2H, d), 6.82-6.77 (3H, m), 4.53-4.52 (2H, unresolved d), 4.35-4.30 (2H, complex m), 3.88-3.84 (2H, t), 3.66-3.61 (2H, m), 3.53-3.49 (1H, m), 3.06-3.05 (4H, d), 3.0 (4H, d).

[0095] Example 2: L-Tartrate salt of l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l- ylmethyl)-l, 3-dioxolan-4-l] methoxy] phenyl] piperazine (Formula-Ill).

[0096] To a round bottom flask, 700 ml of methanol and 114 gm of benzoate salt of l-[4-[[(2RS, 4SR)-2-(2, 4-dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4- l]methoxy]phenyl]piperazine (Formula-IV) & 30.64 gm of L-(+) tartaric acid were charged & reaction mass was heated at reflux and slowly 50 ml of water at 65±3°C were added and stirred it for 1 hour , the mass was cooled to 30±3°C and stirred it for 1 hour. The product was filtered and washed with mixture of methanol: water (300 ml) and suck dried. The wet material was dried at 50±5°C to get 56 gm of chiral enriched l-[4-[[(2S,4R)-2-(2,4- dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3-dioxolan-4-l]methoxy]phenyl] piperazine tartrate salt (III) (enantiomeric purity >75%).

[0097] Example 3: Purification of L-Tartrate salt of l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2- (lH-imidazol-l-ylmethyl)-l,3-dioxolan-4-l]methoxy] phenyl] piperazine (Formula-Ill)

[0098] To a round bottom flask, 55 gm of example 2 compound was taken in mixture of methanol (550 ml) and water (110 ml). The contents were heated to reflux and stirred for 1 hour at reflux & cooled to 30±3°C, stirred for 1 hour and filtered the solid & washed with mixture of methanol: water & collected the wet material. The process was repeated to obtain chiral pure l-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-l,3-dioxolan-4- l]methoxy] phenyl] piperazine Tartrate salt (III) (wet weight: 43gm) (enantiomeric purity >99%).

[0099] Example 4: l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-l,3- dioxolan-4-1] methoxy] phenyl] piperazine L-Tartrate (Formula-Ill).

[0100] To a round bottom flask, example-3 compound was charged in mixture of 440 ml of methanol and 220 ml of water and the mixture was heated to reflux to get solution. To the solution, enantiomerically pure l -|4-| |(2.S'. 4R)-2-(2.4-dichlorophcnyl)-2-( I H-imidazol- 1 - ylmethyl)-l,3-dioxolan-4-l] methoxy] phenyl] piperazine tartrate as seed material was charged, then cooled to 28±3°C and stirred for 1 hour and the reaction mass was filtered and washed with mixture of methanol: water and dried the wet solid to obtain pure title compound l-[4-[[(25', 4R)-2-(2, 4-dichlorophcnyl)-2-( I H-imidazol- 1 -ylmethyl)- 1, 3- dioxolan-4-1] methoxy]phenyl] piperazine Tartrate (Formula-Ill). Dried weight: 36 gram (enantiomeric purity of desired isomer >99.9%) Tartaric acid content : 24.6%w / w. NMR DMSO D6 : 5 7.69-7.68 (1H, bs), 7.58-7.56 (1H, d), 7.48 (1H, Unresolved s), 7.47-7.44 (1H, dd), 7.01 (1H, Unresolved d), 6.94-6.92 (2H, d), 6.82 (1H, Unresolved s), 6.82-6.79 (2H, d), 4.57-4.48 (2H, unresolved d), 4.37-4.31 (1H, q), 3.95 (2H, s), 3.88-3.84 (1H, t), 3.66-3.61 (2H, m), 3.53-3.50 (1H, m), 3.18 (8H, Unresolved m).

[0101] Example 5: Preparation of l-[4-[4-[[(2S, 4R)-2-(2,4-dichlorophenyl)-2-(lH-imidazol-l- ylm ethyl)- l,3-dioxolan-4-yl] methoxy] phenyl] - 1-piperazinyl] -ethanone (F ormula (I))

[0102] To a round bottom flask, 30 gm of example-4 compound and 150 ml of Dichloromethane was charged. Stirred reaction mass for 15-20 minutes at room temperature and Aq. NaOH solution was charged to the reaction mass & stirred for 10-15 minutes. Payers were separated, aqueous layer was extracted with Dichloromethane. Combined Dichloromethane layers and washed with Brine solution. Collected organic layer & Aq. NaOH solution (5.62 gm of sodium hydroxide in water) was charged. 10.53 gm of acetic anhydride was added & stirred. After completion of reaction, water (150 ml) was added and stirred. Layers were separated, aqueous layer was extracted with dichloromethane. Combined both organic layers, washed with water (50 ml), Collected organic layer and subjected for activated charcoal treatment and filter through hyflow. Collected filtrate in clean round bottom flask and distilled under vacuum, Acetone (150 ml) was charged, stirred at 28±3°C for ~1 hour. Filtered the solid and washed with acetone to get wet material, which was dried at 50±5°C to get pure Levoketoconazole compound of formula (I); Dried weight: 18gm (HPLC Purity: >99.5% and Chiral Purity: >99.9%).

[0103] Example 6: Hydrochloride salt of l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2-(lH- imidazol-l-ylmethyl)-l, 3-dioxolan-4-l] methoxy] phenyl] piperazine (Formula IV).

[0104] To a round bottom flask, 100 ml of methanol, 50 gm of l-[4-[[(2RS, 4SR)-2-(2,4- dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3-dioxolan-4-l]methoxy]phenyl]piperazine (V) and 12.6 ml of cone, hydrochloric acid were charged and reaction mass was heated to 45- 50°C and stirred for 15-20 minutes. Distilled a reaction mass to a residue by removing the solvent and co-distilled with ethyl acetate. Then 250 ml of fresh ethyl acetate was charged & stirred for 30 minute. The precipitated solid was filtered at 25-30°C and washed with ethyl acetate. The solid material was dried at 50°C, to obtain title compound. Dry weight : 55 gm. 'H NMR DMSO D6 : 5 9.00 (2H, bs), 7.70-7.69 (2H, d), 7.59-7.57 (1H, d), 7.48-7.45 (1H, Unresolved m), 7.09 (1H, Unresolved s), 6.95-6.92 (3H, Unresolved m), 6.82-6.80 (2H, d), 4.57-4.56 (2H, unresolved d), 4.36-4.33 (1H, t), 3.95 (2H, s), 3.88-3.85 (1H, m), 3.66-3.61 (3H, m), 3.57-3.53 (1H, m), 3.21 (10H, Unresolved m).

[0105] Example 7: L-Tartrate salt of l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l- ylmethyl)-l, 3-dioxolan-4-l] methoxy] phenyl] piperazine (Formula III).

[0106] To a round bottom flask, 350 ml of methanol and 50 gram of hydrochloride salt of l-[4- [[(2RS, 4SR)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-l,3-dioxolan-4- l]methoxy]phenyl]piperazine (IV) & 15.32 gm of L-(+) tartaric acid were charged & reaction mass was heated to 45-50°C & stirred for 10-15min., 9.60 gm of triethylamine was added & further reaction mass was heated at reflux and slowly added 50 ml of water at 65±3°C and stirred for 1 hour. The reaction mass was cooled to 30±3°C and stirred it for 1 hour. The solid was filtered and washed with mixture of methanol: water (75ml) & dried the material at 50°C to get 26.5 gm of l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)- 1, 3 -dioxolan-4-1] methoxy] phenyl] piperazine tartrate salt (III) (enantiomeric purity >80%).

[0107] Example 8: Purification of L-Tartrate salt of l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2- (lH-imidazol-l-ylmethyl)-l,3-dioxolan-4-l]methoxy] phenyl] piperazine (III).

[0108] To a round bottom flask, 25 gm of example-7 compound was taken in mixture of methanol (250 ml) and water (50 ml). The mixture was heated to reflux and stirred for 1 hour at reflux (67°C), & cooled to 30±3°C, stirred for 1 hour. The solid was filtered & washed with mixture of methanol: water & collected the wet material. The process was repeated to obtain chiral pure l-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-l,3-dioxolan-4- l]methoxy]phenyl] piperazine tartrate salt (wet weight: ~20gm) (enantiomeric purity >99%).

[0109] Example 9: Pure 1- [4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-l,3- dioxolan-4-1] methoxy] phenyl] piperazine L-Tartrate (Formula-Ill).

[0110] To a round bottom flask, compound of example 8 was charged in mixture of 200 ml of methanol and 100 ml of water. The mixture was heated to reflux and to get solution. To the solution, enantiomerically pure l -|4-| |(2.S'.4R)-2-(2.4-dichlorophcnyl)-2-( lf / -imidazol- l- ylmethyl)-l,3-dioxolan-4-l] methoxy] phenyl] piperazine tartrate as seed material was charged , then cooled to 28±3°C, stirred for 1 hour and the reaction mass was filtered and washed with mixture of mixture of methanol: water and dried to obtain pure title compound l-[4-[[(25', 4R)-2-(2.4-dichlorophcnyl)-2-( IH-imidazol- l -ylmcthyl)- 1,3 -dioxolan-4-1] methoxy]phenyl] piperazine tartrate (Formula-Ill), Dried weight: 17gm (enantiomeric purity of desired isomer >99.9%). Example 10: l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-l,3- dioxolan-4-1] methoxy] phenyl] piperazine L-Tartrate (Formula-Ill)

[0111] To a round botom flask, 300 ml of methanol was charged and 150 gm of l-[4-[[(2RS,4SR)- 2-(2,4-dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4- l]methoxy]phenyl]piperazine compound -V and 38.18 gm of benzoic acid were charged and the mass was heated to 45±5°C and stirred it for 15-20 minutes. The reaction mass was distilled to residue by removing the solvent and co-distilled with ethyl acetate. 900 ml of fresh ethyl acetate was charged & stirred for 30 minute. The obtained wet solid was filtered at 25-30°C & washed with ethyl acetate. The wet material of benzoate salt of l-[4-[[(2RS, 4SR)-2-(2, 4-dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4- l]methoxy]phenyl]piperazine (Formula-IV), 1050 ml of methanol and 45.97 gm of L-(+) tartaric acid were charged & reaction mass was heated at reflux and slowly 75 ml of water at 65±3°C was added and stirred for 1 hour, the reaction mass was cooled at 30±3°C and stirred for 1 hour. The obtained material was filtered and washed with mixture of methanol: water (300 ml) and suck dried. The solid material was dried at 50-55°C.

[0112] Example 11: Preparation of l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l-yl methyl)-l ,3-dioxolan-4-l] methoxy] phenyl] piperazine (F ormula-II)

[0113] 20 gm of L-tartrate salt of l-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(lH-imidazol-l- ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]-piperazine (III) was charged in 60 ml of water at 25±3°C and stirred. To this, solution of 4.8 gm of sodium hydroxide in 60 ml of water was charged at 25±3°C., stirred it for 15-20 minutes. The product was extracted in 100 ml of dichloromethane and aqueous layer was washed with 40 ml of dichloromethane. Dichloromethane layer was combined and washed with sodium chloride solution (6.66 gram sodium chloride in 40 ml of water), dichloromethane layer was collected and distilled out solvent under vacuum at below 40°C. 100 ml of ethyl acetate was slowly charged and stirred for 15-20 minutes at 35-40°C, cooled to 25-30°C and stirred it for 30-60 minutes at 25-30°C. The product was filtered and washed with 20 ml of ethyl acetate to get wet material. The wet material was dried in a vacuum tray dryer at 45°C to get 12.4 gm of solid compound of formula (II) (Enantiomeric purity of desired isomer >99.9%). Example 12: Preparation of l-[4-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(lH-imidazol-l- ylm ethyl)- l,3-dioxolan-4-yl] methoxy] phenyl] - 1-piperazinyl] -ethanone (F ormula (I))

[0114] 25 gm of pure L-tartrate salt of l-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(lH-imidazol-l- ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]-piperazine (III) in 8% sodium hydroxide solution was charged and stirred for 15-20 minutes at room temperature. 125 ml of dichloromethane was charged in reaction mass. The reaction was stirred for 10-15 minutes, settled and separated organic layer. Aqueous layer was washed with 50 ml of dichloromethane. The organic layer i.e. Dichloromethane layer was combined and washed with brine solution and collected dichloromethane layer. Dichloromethane layer was cooled at 20±3°C. Charged 16.16 gm of potassium carbonate and stirred 5-10 minutes and slowly added 4.59 gm of acetyl chloride at 20 ±3°C and stirred it for 30-60 minutes. After completion of reaction, water (125 ml) was added, stirred, and separated out dichloromethane layer, aqueous layer was washed with 50 ml of dichloromethane. Combined both organic layer i.e. dichloromethane layer , washed with water (50 ml), organic layer i.e. dichloromethane layer was collected and treated with activated charcoal treatment, filtered through hyflow and washed with dichloromethane. The filtrate was collected in clean round bottom flask and distilled out under vacuum at below 40°C up to 1.0-2.0 volume, added acetone (125 ml) and stirred, cooled the mass to 28±3°C under stirring for 30-60 minutes. The product was filtered and washed with acetone (25 ml) to get wet material. The wet material was dried at 50±5°C in vacuum tray dryer to get pure compound of formula (I) (18.5 gram).

[0115] Example 13: Toluic acid salt of l-[4-[[(2RS, 4SR)-2-(2, 4-dichlorophenyl)-2-(lH- imidazol-l-ylmethyl)-l, 3-dioxolan-4-l] methoxy] phenyl] piperazine (Formula-IV).

[0116] To a round bottom flask,, 100 ml of methanol was charged and 20 gm of l-[4-[[(2RS, 4SR)- 2-(2,4-dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4- l]methoxy]phenyl]piperazine and 5.68 gm of Toluic acid were charged and the mass was heated to 45 ±5°C and stirred it for 15-20 minutes. The reaction mass was distilled to residue by removing the solvent and co-distilled with ethyl acetate. Then 120 ml of fresh ethyl acetate was charged and stirred for 30 minute, filtered at 25-30°C the solid and washed with ethyl acetate. The solid material was dried at ~50°C, obtained title compound, dry weight : 25.5 gm. ^ NMR DMSO D6 : 57.82-7.80 (2H , d) 7.68 (1H, d), 7.57-7.55 (1H, d), 7.48-7.44 (2H, m) 7.23-7.21, (2H d), 7.01 (1H, S), 6.89-6.87 (2H, d), 6.82-6.77 (3H, m), 4.53-4.52 (2H, unresolved d), 4.33 (1H, complex), 3.88-3.84 (1H, m), 3.66-3.63 (2H, m), 3.62-3.52 (1H, m), 3.01 (4H, d), 2.94 (4H, d), 2.34 (3H, s).

[0117] Example 14: L-Tartrate salt of l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l- ylmethyl)-l, 3-dioxolan-4-l] methoxy] phenyl] piperazine (Formula-Ill).

[0118] To a round bottom flask, 140 ml of methanol and 25gram of toluic acid salt of l-[4-[[(2RS, 4SR)-2-(2, 4-dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4- l]methoxy]phenyl]piperazine (Formula-IV) (obtained in Ex- 13) & 6.1 gm of L-(+) tartaric acid were charged and reaction mass was heated at refluxand slowly added 10 ml of water at 65±3°C and stirred it for 1 hour , cooled the mass at 30±3°C and stirred it for 1 hour and filtered the product and washed with mixture of methanol: water and suck dried and followed by drying at 50±5°C to get 12.5 gm of chiral enriched l-[4-[[(2S,4R)-2-(2,4- dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3-dioxolan-4-l]methoxy]phenyl] piperazine Tartrate salt (Formula-Ill) (enantiomeric purity 86.4%).

[0119] Example 15: Oxalate salt of l-[4-[[(2RS, 4SR)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l- ylmethyl)-l, 3-dioxolan-4-l] methoxy] phenyl] piperazine (Formula-IV).

[0120] To a round bottom flask, 100 ml of methanol was charged and 20 gm of l-[4-[[(2RS, 4SR)-2- (2, 4-dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3-dioxolan-4- l]methoxy]phenyl]piperazine and 5.25 gm of oxalic acid were charged and the mass was heated to 45±5°C and stirred it for 15-20 minutes. Distilled reaction mass to residue by removing the solvent and co-distilled with ethyl acetate. Then 120 ml of fresh ethyl acetate was charged & stirred for 30 minute, filtered at 25-30°C the, solid was washed with ethyl acetate. The solid material was dried at ~50°C to to obtain the title compound, dry weight : 24 gm. 'H NMR DMSO D6 : 5 7.69-7.68 (1H, unresolved d), 7.58-7.56 (1H, d), 7.49-7.44 (2H, m), 7.01 (1H, S), 6.95-6.93 (2H, d), 6.82-6.80 (3H, m), 4.53-4.49 (2H, unresolved d), 4.35-4.32 (1H, complex m), 3.88-3.84 (1H, m), 3.66-3.61 (2H, m), 3.54-3.50 (1H, m), 3.2 8H, unresolved s).

[0121] Example 16: L-Tartrate salt of l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l- ylmethyl)-l, 3-dioxolan-4-l] methoxy] phenyl] piperazine (Formula-Ill).

[0122] To a round bottom flask, 140 ml of methanol and 22 gm of oxalate salt of l-[4-[[(2RS, 4SR)- 2-(2, 4-dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4- l]methoxy]phenyl]piperazine (Formula-IV) (obtained from Ex-15) & 6.1 gm of L-(+) tartaric acid were charged & reaction mass was heated to 45-50°C & stirred for 10-15minute, 4.5 gm of triethylamine was added & further reaction mass was heated at reflux and slowly added 10 ml of water at 65±3°C and stirred it for 1 hour , cooled the mass at 30±3°C and stirred it for 1 hour and filtered the product and washed with mixture of methanol: water(300 ml) and suck dried followed by drying the material at 50±5°C to get 11.5 gm of chiral enriched l-[4- [[(2S,4R)-2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-l,3-dioxolan-4-l]methoxy] phenyl ] piperazine Tartrate salt (Formula-Ill) (enantiomeric purity 91%).

[0123] Example 17: p-Toluene sulfonate salt of l-[4-[[(2RS, 4SR)-2-(2, 4-dichlorophenyl)-2- (lH-imidazol-l-ylmethyl)-l,3-dioxolan-4- IJmethoxy] phenyl] piperazine (Formula-IV).

[0124] To a round bottom flask,-, 100 ml of methanol was charged and 20 gm of l-[4-[[(2RS, 4SR)- 2-(2,4-dichlorophenyl)-2-( IH-imidazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4- l]methoxy]phenyl]piperazine and 7.93 gm of p-toluene sulfonic acid were charged & the mass was heated to 45±5°C and stirred it for 15-20 minutes. Distilled the reaction mass to residue by removing the solvent and co-distilled with ethyl acetate. Then 120 ml of fresh ethyl acetate was charged and stirred for 30 minute, filtered at 25-30°C, the solid was washed with ethyl acetate. The solid material was dried at ~50°C, obtained the title compound, dry weight : 26 gm. 'H NMR DMSO D6 : 5 8.6 (1H, bs), 7.69-7.68 (1H, m), 7.58-7.56 (1H, s), 7.50-7.44 (4H, m), 7.12-7.10 (2H, d), 7.02 (1H, S), 6.95-6.92 (2H, m), 6.82-6.80 (3H, m), 4.53-4.52 (2H, d), 4.35-4.32 (1H, complex m), 3.88-3.84 (1H, t), 3.66-3.61 (2H, m), 3.54- 3.50 (1H, m), 3.21 (8H, unresolved s), 2.28 (3H, s).

[0125] Example 18: L-Tartrate salt of l-[4-[[(2S, 4R)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l- ylmethyl)-l, 3-dioxolan-4-l] methoxy] phenyl] piperazine (Formula-Ill)

[0126] To a round bottom flask, 140 ml of methanol and 25 gm of p-toluene sulphonic acid salt of 1- [4-[[(2RS, 4SR)-2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-l,3-dioxolan-4- l]methoxy]phenyl]piperazine (Formula-IV A) (obtained from Ex-17) and 6.1 gm of L-(+) tartaric acid were charged and reaction mass was heated to 45-50°C & stirred for 10-15min., 4.5 gm of triethylamine was added & further reaction mass was heated at reflux and slowly added 10 ml of water at 65±3°C and stirred it for 1 hour , cooled the mass at 30±3°C and stirred it for 1 hour and filtered the product and wash with mixture of methanol: water(300 ml) and suck dried followed by drying the material at 50±5°C to get 10.5 gm of chiral enriched l-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(lH-imidazol-I-yhnethyl)-l,3-dioxolan-4- l]methoxy]phenyl] piperazine tartrate salt (Formula-Ill) (enantiomeric purity 90.3%).

Claims

We Claim:

1. A novel achiral salt of racemic desacetyl ketoconazole compound of formula (IV), wherein R' is achiral organic or inorganic acid.

2. The compound of claim 1, wherein achiral organic acid selected from benzoic acid, toluic acid, oxalic acid and p-toluene sulfonic acid or inorganic acid selected from hydrochloric acid.

3. A process for preparation of achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) comprises contacting a racemic desacetyl ketoconazole compound of formula (V) with an achiral organic or inorganic acid in a suitable solvent to obtain an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV).

4. A process for preparation of chirally pure salt of desacetyl ketoconazole compound of formula (III) comprises directly resolving an achiral organic or inorganic salt of desacetyl ketoconazole compound of formula (IV) with a chiral resolving agent in suitable solvent to obtain a chirally pure salt of desacetyl ketoconazole compound of formula (III).

5. A process for preparation of chirally pure salt of desacetyl ketoconazole compound of formula (III) comprises a) contacting a racemic desacetyl ketoconazole compound of formula (V) with an achiral organic or inorganic acid in a suitable solvent to obtain an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV); b) directly resolving an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) with a chiral resolving agent in a suitable solvent to obtain a chirally pure salt of desacetyl ketoconazole compound of formula (III).

6. A process for process for preparation of levoketoconazole compound of formula (I) comprises a) contacting a racemic desacetyl ketoconazole compound of formula (V) with an achiral organic or inorganic acid in a suitable solvent to obtain an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula(IV); b) directly resolving an achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV) with a chiral resolving agent in a suitable solvent to obtain a chirally pure salt of desacetyl ketoconazole compound of formula (III); and c) converting a chirally pure salt of desacetyl ketoconazole compound of formula (III) to levoketoconazole compound of formula (I).

7. The process according to claim 3, 4, 5 and 6, wherein achiral organic acid selected from benzoic acid, toluic acid, oxalic acid and p-toluene sulfonic acid or inorganic acid selected from hydrochloric acid.

8. The process according to claim 4,5 and 6, wherein resolving agent selected from L- tartaric acid, R-mandelic acid and Di-p-tolyl D-tartaric acid.

9. The process according to claim 3 to 6, wherein the solvent includes but are not limited to methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol ; water or mixtures thereof.

10. The process according to claim 4, 5 and 6 further comprises optionally purifying a chirally pure salt of desacetyl ketoconazole compound of formula (III).

11. A process for the preparation of levoketoconazole compound of formula (I) from achiral organic or inorganic salt of racemic desacetyl ketoconazole compound of formula (IV)

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