WO2009057136A2

WO2009057136A2 - Epimerization by stereoselective synthesis of vitamin d analogues

Info

Publication number: WO2009057136A2
Application number: PCT/IN2008/000480
Authority: WO
Inventors: Mubeen Khan; Gangadhar Patil Dayaghan; Baluram Wagh Ghanshyam
Original assignee: Glenmark Generics Ltd
Current assignee: Glenmark Generics Ltd
Priority date: 2007-08-03
Filing date: 2008-07-30
Publication date: 2009-05-07
Anticipated expiration: 2010-02-03
Also published as: WO2009057136A3

Abstract

A method for epimerization process of C-24 ketones to desired C-24 alcohol by stereo selective reduction using chiral borane reducing agents in the presence of chiral auxillary such as (R)-2-methyl-CBS-oxazaborolidine for the preparation of calcipotriene intermedites and its process to calcipotriene.

Description

EPIMERIZATION BY STEREOSELECTIVE SYNTHESIS OF VITAMIN D ANALOGUES

FIELD OF THE INVENTION

The present invention relates to novel epimerization process of C-24 ketones to desired C-24 alcohols by stereo selective reduction using chiral borane reducing agents for the preparation of calcipotriene.

BACKGROUND OF THE INVENTION

Calcipotriol or calcipotriene (structure I) shows a strong activity in inhibiting undesirable proliferation of epidermal keratinocytes [F. A. CM. Castelijins, M. J. Gerritsen, I. M. J. J. van Vlijmen-Willems, P. J. van Eip, P. C. M. van de Kerkhof; Acta Derm. Venereol. 79, 11, 1999]. The efficiency of calcipotriol in the treatment of psoriasis was shown in a number of clinical trials [D. M. Ashcroft et al.; Brit. Med. J. 320, 963-67, 2000] and calcipotriol is currently used in several commercial drug formulations.

i

In tlie preparation of calcipotriol, the specific stereochemistry for the hydroxyl group at C-24 is necessary for full expression of the biological activity. Under current methodology, the required stereochemistry is introduced by the following methods:

Non diastereoselective reduction of C-24 keto triens and then chromatographic separation of diastereomeric mixtures of C-24 (S) and C-24 (R) hydroxy epimers along with saturated alcohol disclosed in US 4866048 and M. J. Calverley; Tetrahedron, 43 (20), 4609- 19, 1987. This process is most widely used process, but separation of desired C-24 (S) hydroxy epimer from such a mixture by chromatography method is very difficult on large production scale.

M. J. Calverley, Synlett, 157-159, 1990 disclosed a process for the preparation of C- 24 (S) hydroxy epimer by condensing an enantiopure C-24-hydroxyl carrying side chain to the vitamin D skeleton. This process is unfavourable for scale up due to its multi-step nature and production cost.

WO 2003/060094 disclosed method of selectively enzymatically esterifying and selectively enzymatically solvolyzing epimers at C-24 analogs of vitamin D and esters using enzymes. The enzymatic esterification synthesis is not commercially favourable since it requires costly enzymes and depending on the selectivity of enzyme requires additional reaction steps involved.

WO 2005/087719 disclosed a process for preparation of diastereomerically enriched C-24 hydroxyl epimers of calcipotriene derivatives by stereo selective reduction of labile triene system which is protected as sulfur dioxide adduct. This process gives 1 : 1 or more of desired 24 (S)-hydroxyl epimer. This process requires protection of C-24 keto triene compound by sulfur dioxide and deprotection of sulfur dioxide adducts of C-24 (S) and C-24 (R) hydroxyl mixtures followed by separation of desired (S)-epimer from the formed epimer mixtures. This would results in reduced yields, impure products and tedious work-up procedures, especially on large scale.

It would be desirable to provide a novel epimerization process of C-24 ketones to desired C-24 alcohols for preparing intermediates of Calcipotriene and their use in the preparation of Calcipotriene in a convenient and cost efficient manner and on a commercial scale.

SUMMARY OF THE INVENTION In accordance with a first aspect of the present invention, a method of reducing a compound of general structure II,

II wherein Ri and R₂ may be the same or different and represent hydrogen or a hydroxy protecting group, in an inert solvent with a borane reducing agent in the presence of a chiral auxiliary, wherein the chiral auxiliary is (R)-2-methyl-CBS-oxazaborolidine to give a mixture of compounds of general structure Ilia and UIb,

IHa ^• IHb which is enriched with Ilia, wherein Ri and R₂ are as defined above.

In accordance with a second aspect of the present invention, a process for preparing calcipotriene, comprises the following steps a. reducing a compound of general structure II,

II wherein Rj and R₂ may be the same or different and represent hydrogen or a hydroxy protecting group, in an inert solvent with a borane reducing agent in the presence of a chiral auxiliary, wherein the chiral auxiliary is (R)-2-methyl-CBS-oxazaborolidine to give a mixture of compounds of general structure Ilia and HIb,

Ilia HIb which is enriched with Ilia, wherein Ri and R₂ are as defined above. b. isolating the compound of formula-IIIa and converted to calcipotriene.

In accordance with a third aspect of the present invention, a pharmaceutical composition is provided comprising at least one pharmaceutically acceptable excipient and calcipotriene obtained through the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein a "hydroxy protecting group" is any group which forms a derivative that is stable to the projected reactions wherein said hydroxy protecting group can be selectively removed by reagents that do not attack the regenerated hydroxy group. Silyl derivatives, such as tert-butyldimethylsilyl forming silyl ethers are examples of hydroxy protecting groups; Silyl chlorides such as tert-butyldimethylsilyl chloride (TBSCI), trimethylsilylchloride, triethylsilylchloride, diphenylmethylsilylchloride, triisopropylsilylchloride, and tert-butyldiphenylsilylchloride are examples of hydroxy protecting agents. Ethers or esters are also used as hydroxy protecting groups for example ethers such as tetrahydropyranyl (THP) ether, alkoxyalkyl ethers (acetals) such as methoxymethyl (MOM) ether; esters such as chloroacetate ester, trimethylacetate, acetate or benzoate ester.

As used herein "borane reducing agent" is a borane containing compound which is capable of enantioselectively or diastereoselectively reducing the C24 keto group of formula-II to alcohol of formula-IIIa and IHb.

As used herein, "chiral auxiliary" means any chiral compound or optically active catalyst, e.g. a compound comprising asymmetrically substituted carbon atoms or axially chiral compounds, or mixtures of chiral compounds and/or optically active catalysts, which will improve the yield of a compound of general structure Ilia with respect to its epimer (increase the molar ratio IHa: IHb) in the reduction of a compound of general formula II with the reducing agent.

A mixture of compounds of general structure IHa and HIb₅ which is enriched with IHa, means a mixture, were the molar ratio (diastereomer ratio) of IIIa/HIb is one (50: 50) or larger than one, thus that the mixture contains at least 50% of the compound of general structure HIa (containing 50% or less of the compound of general structure IHb). Where compound of general structure Ilia means C24 (S)-hydroxy epimer of calcipotriene intermediate and general structure IHb means C24 (R)-hydroxy epimer of calcipotriene intermediate. As used herein "separating a compound" means the purification and/or isolation of a compound more than 90% purity, such as at least 95% purity. It also means increasing the concentration of required isomer in a mixture of compounds.

In one embodiment, the process for preparing compounds of formula-IIIa and/or HIb includes

a) reducing a compound of the formula-II

II wherein Rj and R₂ may be the same or different and represent hydrogen, or a hydroxy protecting group, with a borane reducing agent in the presence of a chiral auxiliary in an inert solvent to form a compounds of Formula-IIIa and IIIb

Ilia IIIb wherein Ri and R₂ may be the same or different and represent hydrogen, or a hydroxy protecting group, preferably Rj and R₂ are both tert-butyl dimethyl silyl group. The compound of Formula II is known in the art and can be prepared by any known method, for example, a compound of Formula II can be synthesized by the process mentioned in US 4866048 and "MJ Calverley, tetrahedron 43(20), 4609-4619, 1987, the contents of each of which are incorporated herein by reference.

A suitable inert solvent for use herein may be, for example any organic solvent compatible with said reducing agent under the reaction conditions employed, or mixtures of such solvents. Non limiting examples of inert solvents include hydrocarbons, such as toluene, xylenes and the like; and ethers, such as tert-butyl methyl ether, diisopropyl ether or tetrahydrofuran and the like and mixtures thereof; halogenated hydrocarbon solvent such as methylene chloride, ethylene chloride and the like; acetates such ethyl acetate and the like. In one embodiment the solvent is toluene, tetrahydrofuran or mixtures thereof, preferably mixture of toluene and tetrahydrofuran.

The reduction reaction of a prochiral ketone is usually carried out in a temperature interval between about -50 and 5O⁰C, preferably between about -20 and 20⁰C, more preferably between about -10 and 10⁰C, most preferably between 0 and 5°C. The temperature of the reduction reaction will depend on the specific reaction conditions, reagents and solvents used.

The reducing agent, optionally dissolved or mixed with an inert solvent, may be added to the compound of general structure II optionally dissolved or mixed with an inert solvent, e.g. under an inert atmosphere, such as nitrogen. Alternatively the compound of general structure II, optionally dissolved or mixed with an inert solvent, may be added to the reducing agent, optionally dissolved or mixed with an inert solvent. The sequence of addition of reducing agent and/or compound of general structure II is not particularly critical.

The "Borane reducing agent" for use herein may be, for example borane or any borane derivatives, such as borane complexes with amines or ethers. Non-limiting examples of borane reducing agents e.g. include but are not limited to N, N-diethylaniline-borane, borane-tetrahydrofuran, 9-borabicyclononane (9-BBN)₅ or borane dimethylsulfide. In a preferred embodiment the borane reducing agent is borane dimethylsulfide or N, N- diethylaniline-borane. In a most preferred embodiment the borane reducing agent is N, N- diethylaniline-borane.

The "chiral auxiliary" for use herein may be, for example chiral oxazaborolidine reagents selected from but are not limited to (lR,2S)-cis-l-amino-2-indanol, (lS,2R)-cis-l- amino-2-indanol, (S)-prolinol, (R)-prolinol, B-(3-pinanyl)-9-borabicyclo [3.3.2] nonane (alpine-borane), 5,5-diphenyl-2-methyl-3,4-propano-l ,3,2-oxazaborolidine, (S)-2-methyl- CBS-oxazaborolidine, (R)-2-methyl-CBS-oxazaborolidine. In a preferred embodiment the chiral auxiliary is (R)-2-methyl-CBS-oxazaborolidine.

The reducing agent may be used about 2.0 to 3.5 mol equivalents to the starting prochiral ketone compound of formula-II, preferably 2.2 to 2.6 mol equivalents and most preferably 2.4 mol equivalents. The chiral auxiliary may be present in catalytic amounts, such as substoichiometric, or equimolar or in molar excess referring to a prochiral ketone compound of formula-II. The ratio of chiral auxiliary and prochiral ketone compound of formula-II may be 1 :1.5 mol equivalents, preferably 1 :1.1 mol equivalents.

After completion of the reduction reaction any byproducts formed in reaction, for example N,N-diethyI aniline can be removed by conventional techniques for example extraction of reaction mixture with aqueous acid solution. Aqueous acids are selected from acetic acid, hydrochloric acid, hydrobromic acid and the like and mixtures thereof, preferably hydrochloric acid can be used.

Advantageously the compound of formula-IIIa and HIb present in crude reaction mixture may be with the ratio of about 60:40, preferably with the ratio of about 65:35. The separation, isolation and/or purification methods for separating Ilia and IHb include, but are not limited to solvent crystallization, distillation, chromatography method such as adsorption chromatography (including column chromatography and simulated moving bed (SMB)). The separation, isolation and purification methods may be used subsequently and in combination.

In another aspect of the present invention, compounds Ilia and IHb thus obtained may be purified by dissolving the crude mixture in an organic solvent selected from the group consisting of Cj_-4 alcohols, ethers and mixtures thereof to form a solution. Ethers are selected but are not limited to diisopropyl ether, diethyl ether, and methyl tert-butyl ether. Ci_-4 alcohols are selected but are not limited to methanol, ethanol, propanol, isopropanol, and butanol. In a preferred embodiment the organic solvent is methanol, diisopropyl ether and mixtures thereof, most preferably the organic solvent is mixture of methanol and diisopropyl ether.

The solution may be heated to dissolve the compounds of general structure Ilia and IHb. The temperature suitable for dissolving the compounds of general structure Ilia and IHb depends on the solvent used and the amount of the compounds of general structure IHa and IHb in the solution. Typically, the compounds of general structure Ilia and IHb solution is heated at a temperature of at least about 35⁰C to about 55⁰C. Preferably, the solution is heated at about 40⁰C to about 50⁰C and more preferably at about 40⁰C to about 45⁰C. The compound of general structure Ilia can be recovered from the solution by any known method for example concentration under vacuum to obtain the residue or cooling the resultant solution to -20 to 20⁰C, preferably from 5 to 15⁰C. The resulting solid can then be filtered and washed with an organic solvent such as methanol, diisopropyl ether or mixtures thereof. Optionally, the isolated crystals can then be dried. If, desired repeat the purification step by one or more times to achieve the desired purity.

The process of the present invention advantageously provides compound Ilia in relatively high chiral purity, e.g., a purity of greater than or equal to about 90%, preferably greater than or equal to about 95%, and more preferably greater than or equal to about 97.5%. In another aspect of the present invention, compounds of general structure IHa and IHb₅ which is enriched with general structure Ilia for example having the ratio of about 97.5:2.5 may be converted into calcipotriene by any known methods, for example isomerization of general structure Ilia and when Ri and R₂ are not hydrogen, removing the hydroxyl protecting groups by reaction conditions as disclosed in US 4866048 and "MJ Calverley, tetrahedron 43(20), 4609-4619, 1987, the contents of each of which are incorporated herein by reference.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.

EXAMPLES

Example 1 : Preparation of (lα,3β,5E,7E,20R)-l,3-bis-(tert-butyldimethylsiloxy)-20-(- cyclopropyl-3S-hydroxy-prop-lE-enyl )-9, lO-Secopregna-5, 7, 10(19), triene (Structure HIa, wherein Ri & R₂ are tert- butyl dimethyl silyl) and (lα ,3β,5E,7E,20R)-l,3-bis-(tert- butyldimethylsiloxy)-20-(-cycIopropyl-3R-hydroxy-prop-lE-enyl)-9, 10-Secopregna-5, 7, 10(19), triene (Structure HIb, where in Ri & R₂ are tert- butyl dimethyl silyl). (R)-2-methyl-CBS-oxazaborolidine (16.97 ml, IM solution in toluene) was added to 200 ml of tetrahydrofuran at 0-5⁰C under nitrogen atmosphere and stirred for 15-20 minutes. Added 6.92 ml of N,N-diethylaniline borane at 0-5°C over a period of 20-30 minutes to the (R)-2- methyl-CBS-oxazaborolidine solution to form a chiral ligand mixture and maintained for 25- 30 min at same temperature. Then solution of (lα,3β,5E,7E,20R)-l,3-bis-(tert-butyl dimethylsiloxy)-20-(cyclopropyl-3-oxo-l-proρenyl)-9, 10-Secopregna-5, 7, 10(19), triene (Structure II, where in Ri & R₂ are tert-butyl dimethyl silyl, prepared according to the method described by M.J. Calverley, Tetrahydron, Vol. 43, No. 20, pp 4609-4619,1987), 10 gm in 100 ml THF was added to the above obtained chiral ligand mixture over a period of 40-45 minutes at temperature 0-5 °C and maintained the reaction at temperature 0-5⁰C for 60-90 minutes. Added saturated sodium bicarbonate solution at 0-5 °C and extracted the reaction product with ethyl acetate (2x200 ml) and separated the organic layer. Washed organic layer with water and then washed with IN aqueous hydrochloric acid at 0-5°C at pH 5-6. Washed the ethyl acetate layer with water (200 ml), 5% sodium bicarbonate solution (200 ml) followed by brine solution (200 ml). The organic phase was dried with over anhydrous sodium sulfate and concentrated under vacuum at below 4O⁰C to give the oily residue of structural formula-Ilia and IHb (Ratio of HIa and HIb by HPLC purity: 65:35). The obtained oily residue (mixture of Ilia and UIb) was purified by passing through short path column to remove the unwanted impurities to give the pure compound.

Weight: 11.0 gm

HPLC purity (chiral): 65:35 % ratio of Ilia and IHb

Example 2: Purification of compound formula-IIIa and HIb (where in Ri & R₂ are tert- butyl dimethyl silyl).

1 1 gm of mixture of structure Ilia and IHb (obtained from exarriple-1) was dissolved in 11 ml of di-isoproρyl ether at temperature 40-45⁰C and added 110 ml of Methanol. Cooled the solution to 20-25⁰C and stirred for 5 hours again cooled the solution to 10-15⁰C, stirred for 30 minutes. Filtered the material and washed with chilled Methanol to give the compound, Ilia with enriched ratio of the desired isomer. Optionally the compound, IHa with enriched ratio of the desired isomer was further purified in a mixture of diisopropyl ether and methanol to give the pure compound, Ilia with enriched ratio of the desired isomer.

Weight: 2.75 gm.

HPLC purity (chiral): 97.0 / 2.5% ratio of Ilia and HIb.

Example 3 : Preparation of Calcipotriene A solution of alcohol of structure HIa with Ri = R₂ ^ert-butyl dimethyl silyl (10 gm) Anthracene (1.7 g), Triethyl amine (1.7 ml) and toluene (750ml) contained in a photochemical reactor at 20-25⁰C was irradiated with light from a high pressure ultra violet lamp to completion. Cooled the reaction mixture and filtered the unwanted products and concentrated the toluene completely under vacuum to yield crude tert-butyl dimethyl silyl protected Calcipotriene. The tert-butyl dimethyl silyl protected calcipotriene was dissolved in 400 ml of Tetrahydrofuran (THF) and tetra-butyl ammonium fluoride (24 gm). The resulting mixture was heated at 60-65°C for 2 hours.. Quenched the reaction mass into 2% sodium bicarbonate solution (1200 ml) and ethyl acetate (1200 ml) and stir for 15 minutes. Separated the ethyl acetate layer and washed with water followed by organic phase was dried over sodium sulfate. Evaporating the organic phase under vacuum at below 4O⁰C to give the calcipotrien as an oily residue. The calcipotriene residue was passed through short path of column and eluted by ethyl acetate. The fractions were concentrated and crystallized from methyl formate to give pure calcipotriene.

Weight: 2 gm

DSC endotherm: 166-167°C

NMR: 0.15-0.65 (4H, m); 0.56 (3H,s); 0.75-1.1 (lH,m); 1.05 (3H,d, J-07 Hz); 3.45 (IH, m);

4.2 (lH,m); 4.4 (lH,m); 4.99(lH,m); 5.31(lH,m); 5.47 (2H,m); 5;99 (IH, d, J-I l Hz); 6.36

(IH₁ In, J-I l Hz)

Claims

1. A method of reducing a compound of general structure II,

II wherein Ri and R₂ may be the same or different and represent hydrogen, or a hydroxy protecting group, in an inert solvent with a borane reducing agent in the presence of a chiral auxiliary, wherein the chiral auxiliary is (R)-2-methyl-CBS-oxazaborolidine to give a mixture of compounds of general structure Ilia and IHb,

ilia nib which is enriched with Ilia; wherein R] and R₂ are as defined above.

2. The method as claimed in claim 1, wherein the borane reducing agent is N₅N- diethylaniline-borane, borane-tetrahydrofuran, 9-borabicyclononane, or borane dimethylsulfide.

3. The method as claimed in claim 1, wherein the inert solvent is toluene, tertahydrofuran, tert-butyl methyl ether or mixtures thereof.

4. The method as claimed in claim 1, wherein the reduction is carried out at a temperature between -10 to + 1O⁰C.

5. The method as claimed in claim 2, wherein the borane reducing agent is N₅N- diethylaniline-borane.

6. A process for preparing calcipotriene, comprises the following steps a. reducing a compound of general structure II,

II wherein R₁ and R₂ may be the same or different and represent hydrogen, or a hydroxy protecting group, in an inert solvent with a borane reducing agent in the presence of a chiral auxiliary, wherein the chiral auxiliary is (R)-2-methyl-CBS-oxazaborolidine to give a mixture of compounds of general structure Ilia and IHb,

iiia nib which is enriched with IHa; wherein Ri and R₂ are as defined above. b. isolating the compound of formula-IIIa and converting to calcipotriene.

7. The process as claimed in claim 1 and 4, wherein Ri and/or R₂ represents tert-butyl dimethyl silyl.

8. The process as claimed in claim 4, wherein the process further comprises the steps of a) providing a solution of mixture of compounds of general structure Ilia and IHb, which is enriched with Ilia in an organic solvent, wherein the organic solvent is selected from Ci_-4 alcohols, ethers and mixtures thereof. b) crystallizing and isolating from the resulting suspension the compound of general structure Ilia in chirally pure form.

9. The process as claimed in claim 6, wherein the Ci_-4 alcohol is selected from methanol, ethanol, propanol, and isopropanol and ethers are selected from diisopropyl ether, diethyl ether, and methyl tert-butyl ether.

10. The process as claimed in claim 7, wherein the Ci_-4 alcohol is methanol and ether solvent is diisopropyl ether.

11. The process as claimed in claim 6, wherein the crystallization is carried out at temperature between about 10 and about 15° C.