WO2022034427A1 - An improved process for the preparation of 4-oxoisotretinoin - Google Patents

Abstract

The present invention relates to an improved process for the preparation of 4-Oxoisotretinoin and purification process of 4-Oxoisotretinoin (I) and crystalline 5 form of 4-Oxoisotretinoin (I).

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF 4- OXOISOTRETINOIN FIELD OF THE INVENTION The present invention relates to an improved process for the preparation and purification of 4-Oxoisotretinoin. The present invention also relates to a crystalline polymorph of 4-Oxoisotretinoin. BACKGROUND OF THE INVENTION 4-Oxoisotretinoin is chemically known as (2Z,4E,6E,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-3-oxocyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid, as shown below a Compound of Formula (I). 4-OxoIsotretinoin is a metabolite of Isotretinoin.

4-Oxoisotretinoin (I) disclosed in GB 2156676, and discloses a process for the preparation of 4-Oxoisotretinoin, wherein esterification of 4-oxo-11,13-di-cis retinoic acid (A) with methanol to produce 4-oxo-11,13-di-cis retinoic acid methyl ester (B). Isomerization of the obtained ester to 4-Oxoisotretinoin methyl ester, which is hydrolyzed to 4-Oxoisotretinoin (I). The process as shown in Scheme-I below:

It is observed that this procedure is especially problematic for large-scale operations with few disadvantages, like use of highly toxic diazomethane and use of expensive use of palladium catalyst. Further, this process involves an additional step of esterification and isomerization step. Advanced Materials Research (2011), 236-238 (Pt. 3, Application of Chemical Engineering), 2794-2797 and Hecheng Huaxue, 15(5), 591-594; 2007 reported a process of 4-Oxoisotretinoin, wherein esterification of Isotretinoin (II) with methanol to produce Isotretinoin methyl ester (III). Oxidation of Compound (III) using MnO₂ to 4-Oxoisotretinoin methyl ester (IV). Hydrolysis of (IV) to produce 4-Oxoisotretinoin (I). The process as shown in Scheme-II below:

However, the above route suffer from inconsistence in yields and longer hours required for oxidation and produces several impurities, which gives lower yield and purity. Considering the importance of 4-Oxoisotretinoin (I), there is always a need for an alternative and improved preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity. Moreover, the prior art processes do not disclose about the polymorphic forms and preparation of pure 4-Oxoisotretinoin (I), substantially free from impurities. The removal of the impurities from the final API is very essential as the compound is known to have impurities. In view of this, our inventors have developed the present invention; it has now surprisingly been found that the pure 4-Oxoisotretinoin (I), have numerous advantages over the reported processes. Further, polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviours (e.g. measured by thermogravimetric analysis—“TGA”, or differential scanning calorimetry— “DSC”), Powder x-ray diffraction (PXRD) pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound. Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional polymorphs of 4-Oxoisotretinoin. OBJECTIVE OF THE INVENTION The main objective of the present invention is an improved process for the preparation of 4-Oxoisotretinoin (I), and its intermediates with high purity and good yield on commercial scale. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 – Shows a PXRD of crystalline 4-Oxoisotretinoin (I) Figure 2 – Shows a DSC thermogram of crystalline 4-Oxoisotretinoin (I) The Powder X-ray diffraction (PXRD) pattern measured on an X-ray diffractometer (Instrument name Bruker D8 Advance) with measured using CuKα radiation. Methodology of X-ray diffraction is as follows: Time/Step: 0.5 sec Detector: Lynx Eye Voltage: 40kV Current: 40mA Scan range: 3-40° Step size: 0.02° The Differential Scanning Calorimetry (DSC) thermograms were obtained on a DSC Q2000. Methodology of DSC is as follows: Mass flow: 50.0 mL/min Equilibrate: 25.00°C Ramp: 10.00°C/min to 265.00°C SUMMARY OF THE INVENTION In one embodiment, the present invention provides a crystalline form of 4- Oxoisotretinoin (I) having a Powder X-ray Diffraction (PXRD) pattern shown in

In another embodiment, the present invention provides an improved process for the preparation of 4-Oxoisotretinoin (I):

which comprises: (i) oxidation of Isotretinoin alkyl ester of a compound of Formula (III) using an oxidizing agent in presence of an acid;

to produce 4-Oxoisotretinoin alkyl ester of a Compound of Formula (IV);

wherein R is a carboxyl protecting group comprises substituted or unsubstituted alkyl group; (ii) optionally, hydrolysis of a Compound of Formula (IV) to produce 4- Oxoisotretinoin of a Compound of Formula (I). In another embodiment, the present invention provides an improved process for the preparation of 4-Oxoisotretinoin (I):

which comprises: (i) oxidation of Isotretinoin alkyl ester of a compound of Formula (III) using an alpha form of MnO₂;

to produce 4-Oxoisotretinoin alkyl ester of a Compound of Formula (IV);

wherein R is a carboxyl protecting group comprises substituted or unsubstituted alkyl group; (ii) optionally addition of an acid; (iii) hydrolysis of a Compound of Formula (IV) to produce 4-Oxoisotretinoin of a Compound of Formula (I). In another embodiment, the present invention provides purification process of 4-Oxoisotretinoin (I):

which comprises: (a) providing a solution of 4-Oxoisotretinoin (I) in a suitable solvent; (b) optionally, filtering the resulting solution; (c) adding an anti-solvent to the resulting solution; and (d) isolating the pure 4-Oxoisotretinoin (I). DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the present invention provides a crystalline form of 4- Oxoisotretinoin (I):

In another embodiment of the present invention, crystalline form of 4- Oxoisotretinoin (I) is characterized by Powder X-ray diffraction pattern, made using CuKαl radiation, which comprises peaks at degrees 2 θ (±0.02 degrees) as shown in FIG.1. Furthermore, the crystalline form of 4-Oxoisotretinoin (I) is characterized by DSC (determined via DSC; evaluated as onset -temperature; heating rate 10 K/min). The obtained DSC curve is shown in FIG.2. In another embodiment, the present invention provides an improved process for the preparation of 4-Oxoisotretinoin (I):

which comprises: (i) esterification of Isotretinoin (II);

to produce Isotretinoin alkyl ester of a compound of Formula (III);

wherein R is a carboxyl protecting group comprises substituted or unsubstituted alkyl group; (ii) oxidation of Isotretinoin alkyl ester of a compound of Formula (III) using an oxidizing agent in presence of an acid to produce 4- Oxoisotretinoin alkyl ester of a Compound of Formula (IV);

(iii) hydrolysis of a Compound of Formula (IV) to produce 4-Oxoisotretinoin (I). In still another embodiment, step (i) is carried out using an alkylating agent and a dehydrating agent in presence of a base and a solvent. In still another embodiment, alkylating agent comprises methanol, ethanol, propanol, isopropanol, 2-butanol and dehydrating agent comprises aluminum phosphate, Burgess reagent, calcium oxide, cyanuric chloride, N,N'- cicyclohexylcarbodiimide, Iron(III) chloride, ortho formic acid, Phosphorus pentoxide, phosphoryl chloride, sulfuric acid. In still another embodiment, R is an alkyl group comprises methyl, ethyl, propyl, isopropyl, butyl. In still another embodiment, solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, methylene chloride (CH₂Cl2) and/or mixtures thereof. In still another embodiment, the base comprises 4-dimethylaminopyridine (DMAP), pyridine; diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and/or mixtures thereof. In still another embodiment, oxidizing agent used in step (ii) of conversion of Isotretinoin alkyl ester of a compound of Formula (III) to 4-Oxoisotretinoin alkyl ester of a compound of Formula (IV) comprises Oxygen (O₂), hydrogen peroxide (H₂O₂), potassium permanganate (KMnO₄), sodium dichromate (Na₂Cr₂O₇), peroxydisulfuric acid (H₂S₂O₈), peroxymonosulfuric acid (H₂SO5), MnO₂ and/or alpha form of MnO₂. In still another embodiment, oxidizing agent used in step (ii) of conversion of Isotretinoin alkyl ester of a compound of Formula (III) to 4-Oxoisotretinoin alkyl ester of a compound of Formula (IV) specifically alpha form of MnO_2. In still another embodiment, step (ii) is carried out in presence of an acid to produce 4-Oxoisotretinoin alkyl ester of a compound of Formula (IV). In still another embodiment, acid comprises oxalic acid, hydrochloric acid, sulfuric acid or nitric acid. The advantage of using alpha form of MnO₂ in step (ii) is the oxidation reaction is completed within 4 hours and ~15% of higher yield is obtained for isolation of product. The advantage of using an acid like oxalic acid is the formation of critical impurity at 0.84 RRT is controlled during oxidation. In one more embodiment, the step (ii) reaction is carried out at a temperature ranging from about 0 degrees Celsius to about 80 degrees Celsius depending upon the solvent used in the reaction for a time period of 1-4 hours In still another embodiment, hydrolysis of a compound of Formula (IV) in step (iii) is carried out using an alkali or an acid or metal alkoxides in a suitable solvent. In still another embodiment, alkali comprises sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or acid comprises hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, metal alkoxides comprises sodium methoxide, sodium ethoxide and/or mixtures thereof. In still another embodiment, as the solvent used in hydrolysis, comprises water; a lower alcohol comprises methanol, ethanol, propanol, isopropyl alcohol; a water soluble organic solvent such as acetone, tetrahydrofuran, dioxane and the like, and a mixture of solvents selected from the same can be illustrated. In still another embodiment, the hydrolysis reaction may be performed usually at from 0° C to a boiling point of used solvent for 30 minutes to 48 hours, and then 4-Oxoisotretinoin (I) can be obtained by a usual procedure. In still another embodiment, after completion of the reaction pH can be adjusted by adding appropriate acid / base. In another embodiment, the present invention provides purification process of 4-Oxoisotretinoin (I):

which comprises: (a) providing a solution of 4-Oxoisotretinoin (I) in a suitable solvent; (b) optionally, filtering the resulting solution; (c) adding an anti-solvent to the resulting solution; and In still another embodiment, suitable solvent used in step (a) comprises, methylene chloride, ethylene chloride, methyl tert-butyl ether (MTBE), dimethyl sulfoxide (DMSO), N,N-dimethylacetamide, N-methyl-pyrrolidine, tetrahydrofuran, or N,N-dimethylformamide and/or mixtures thereof. In yet another embodiment of the present invention, after the solvent addition in step (a), which is optionally concentrated to remove water and striped of with same or different solvent before the addition of anti-solvent. In still another embodiment, anti-solvent used in step (c) comprises acetonitrile, ethanol, methanol, isopropyl alcohol, n-butanol and/or mixtures thereof. In still another embodiment, after adding suitable solvent in step (a) heating the reaction mixture to 10-50°C, preferable 20-30°C and further stirred the reaction mixture up to 30 minutes, preferable 20 minutes. Filtering the resulting solution. In another embodiment, after adding anti-solvent in step (c) stirred the reaction mixture up to 1-2 hours, preferably 1 hour and cooled to 20-30°C. In still another embodiment, the present invention provides 4- Oxoisotretinoin (I) obtained is in crystalline form. The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention. EXAMPLES: EXAMPLE 1: PREPARATION OF ISOTRETINOIN METHYL ESTER (III) N,N-Dimethylaminopyridine (0.4 g) and 1,3-dicyclohexylcarbodiimide (7.5 g) were added to a stirred suspension of Isotretinoin (II) (10 g) in a mixture of methanol (50 ml) and methylene chloride (50 ml) at 20-30°C under nitrogen atmosphere. The reaction mass was stirred for 2 h and concentrated under reduced pressure. Ethyl acetate (100 ml) and DM water (50 ml) were added to this concentrated mass. The resultant slurry was cooled to 0-5°C and stirred for 30 min. The insolubles were removed by filtration and washed with ethyl acetate (10 ml). The organic layer was separated and acetified with ~5% w/w aqueous hydrochloric acid. The organic layer was separated and washed with DM water (30 ml). The organic layer was concentrated completely under reduced pressure to afford Isotretinoin methyl ester (11 g). PREPARATION OF 4-OXOISOTRETINOIN METHYLESTER (IV) Oxalic acid (8.3 g) and α-MnO₂ (250 g) were added to a stirred solution of Isotretinoin methyl ester (III) (11 g) in methylene chloride (1000 ml), at 20-30°C. The resultant slurry was stirred for 4 h at 20-30°C. The insolubles were removed by filtration and washed with methylene chloride (5 × 200 ml). The wet cake was unloaded and suspended in methylene chloride (1000 ml). The resultant slurry was stirred for 30 min. The insolubles were removed by filtration and washed with methylene chloride (5 × 200 ml). The combined filtrate was concentrated completely under reduced pressure at <30 °C to afford brownish syrup. (8 g). PREPARATION OF 4-OXOISOTRETINOIN (I) 2,6-Di-tert-butyl-4-methylphenol (0.1 g) was added to a stirred solution of 4-oxoisotretinoin methyl ester (IV) (8 g) in a mixture of methanol (100 ml) and sodium hydroxide solution (6.6 g of sodium hydroxide in 100 ml DM water) was added slowly over 40 min. The reaction mass was warmed to 20-30°C and stirred for 16h at 20-30°C. The solvent was removed from the reaction mass under reduced pressure. The pH of the reaction mass was adjusted to 3.0-3.5 with ~5% w/w aqueous hydrochloric acid. The product was extracted twice with ethyl acetate (2 × 100 ml). The organic layers were combined and washed with DM water (50 ml). The organic layer was concentrated completely under reduced pressure. Ethyl acetate (20 ml) was added to the concentrated mass. The slurry was stirred for 1 h at 20-30°C. The resultant slurry was cooled to 0-5°C and stirred for 2 h. The product was filtered under nitrogen atmosphere and dried to afford 4-oxoisotretinoin (5 g). PURIFICATION OF 4-OXOISOTRETINOIN (I) 4-Oxoisotretinoin (5 g) was added to methylene chloride (17.5 ml) at 20- 30°C under nitrogen atmosphere. Acetonitrile (175 ml) was added slowly over 1 h at 20-30°C. The resultant slurry was stirred 1 h at 20-30°C. Further, the slurry was cooled to -10 to -20°C and stirred for 2 h. The product was filtered under nitrogen atmosphere and dried to afford 4-oxoisotretinoin (3 g). The PXRD obtained is shown in Fig.1.

Claims

WE CLAIM: 1. An improved process for the preparation of 4-Oxoisotretinoin (I):

which process comprises the steps of: (i) oxidation of Isotretinoin alkyl ester of a compound of Formula (III) using an oxidizing agent in presence of an acid;

to produce 4-Oxoisotretinoin alkyl ester of a compound of Formula (IV);

wherein R is a carboxyl protecting group; (ii) optionally, hydrolysis of a compound of Formula (IV) to produce 4-Oxoisotretinoin (I).

2. The process as claimed in claim 1, oxidizing agent used in step (i) comprises oxygen (O₂), hydrogen peroxide (H₂O₂), potassium permanganate (KMnO₄), sodium dichromate (Na₂Cr₂O₇), peroxydisulfuric acid (H₂S₂O₈), peroxymonosulfuric acid (H₂SO₅), MnO₂, alpha form of MnO₂ and/or mixtures thereof.

3. The process as claimed in claim 1, acid used in step (i) comprises oxalic acid, hydrochloric acid, sulfuric acid, nitric acid and/or mixtures thereof.

4. An improved process for the preparation of 4-Oxoisotretinoin (I):

which comprises: (i) oxidation of Isotretinoin alkyl ester of a compound of Formula (III) using an alpha form of MnO₂;

to produce 4-Oxoisotretinoin alkyl ester of a compound of Formula (IV);

wherein R is a carboxyl protecting group; (ii) optionally addition of an acid; (iii) hydrolysis of a compound of Formula (IV) to produce 4- Oxoisotretinoin (I).

5. The process as claimed in claim 1 and claim 4, R is a carboxyl protecting group comprises methyl, ethyl, propyl, isopropyl and/or butyl.

6. The process as claimed in claim 4, acid used in step (ii) comprises oxalic acid, hydrochloric acid, sulfuric acid, nitric acid and/or mixtures thereof.

7. The process as claimed in claim 1 and claim 4, hydrolysis of a compound of Formula (IV) is carried out using an alkali comprises sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or acid comprises hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, metal alkoxides comprises sodium methoxide, sodium ethoxide and/or mixtures thereof.

8. An improved purification process of 4-Oxoisotretinoin (I):

which comprises: (a) providing a solution of 4-Oxoisotretinoin (I) in a suitable solvent; (b) optionally, filtering the resulting solution; (c) adding an anti-solvent to the resulting solution; and (d) isolating the pure 4-Oxoisotretinoin (I).

9. The process as claimed in claim 8, suitable solvent used in step (a) comprises, methylene chloride, ethylene chloride, methyl tert-butyl ether (MTBE), dimethyl sulfoxide (DMSO), N,N-dimethylacetamide, N-methyl- pyrrolidine, tetrahydrofuran, or N,N-dimethylformamide and/or mixtures thereof and anti-solvent used in step (c) comprises acetonitrile, ethanol, methanol, isopropyl alcohol, n-butanol and/or mixtures thereof.

10. A crystalline form of 4-Oxoisotretinoin (I), which is characterized by a Powder X-ray Diffraction (PXRD) pattern, comprises peaks at degrees 2 θ