An improved process for preparation of lurbinectedin

Abstract

The present invention discloses an improved process for the preparation of Lurbinectedin. The disclosed process is simple, cost effective provides pure Lurbinectedin compound by avoiding use of flash column chromatography in each intermediate stage.

Description

TITLE OF THE INVENTIONAN IMPROVED PROCESS FOR PREPARATION OF LURBINECTEDINFIELD OF THE INVENTION

[0001] The present Invention relates to an improved process for preparation of Lurbinectedin. Particularly, the present invention relates to a commercially feasible, facile and robust process to prepare a pharmaceutically acceptable Lurbinectedin. More particularly, the present invention relates to an improved process for preparation of pure Lurbinectedin compound, as well as use of a novel intermediate compound, which avoids the use of flash column chromatography in each intermediate stage.BACKGROUND OF THE INVENTION

[0082] Lurbinectedin (Brand Name: ZEPZELCA®) from Pharma Mar S.A. was first approved by USFDA in 2020 for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. The chemical name of Lurbinectedin is (1 ’R,6R,6aR,7R, 13S, 14S, 16R)-8, 14-dihydroxy-6\9-dimethoxy-4, 10,23- trimethyl-19-oxo-2’,3’,4’,6,7,9’, 12,13,14,16-decahydro-6aH-spiro[7, 13-azano- 6,16-(epithiopropanooxymethano)[1 ,3]dioxolo[7,8]isoquinolino[3,2- b][3]benzazocine-20, 1 ’-pyrido[3, 4-b] indol]-5-y I acetate.

[0003] The molecular formula of Lurbinectedin is C41H44N4O10S and the molecular weight of Lurbinectedin is 784.87 g / mol. The chemical structure of Lurbinectedin is depicted below as compound of Formula-!:FormiHa~iLwbmectedm

[0004] WO 2003 / 014127 application discloses Lurbinectedin and a process for preparation of Lurbinectedin as depicted in the Scheme-1 below:Scheme-1: Process for preparation of Lurbinectedin

[0005] Lurbinectedin prepared by Scheme-1 has a number of drawbacks. First, the reported process is not efficient to produce pure Lurbinectedin. Additionally, the process does not allow for sufficient control over impurity formation. Further, it requires use of flash column chromatography for purification of Lurbinectedin, which is not desirable.

[0006] WO 2023 / 084329 discloses another process for preparation of Lurbinectedin as depicted in the below Scheme-2:Scheme-2: Process for preparation of Lurbmectedm

[0007] Lurbinectedin prepared by Scheme-2 is disadvantageous in that a reaction of 5-methoxytryptamine with MOM protected cyano a-keto iactone is slower as compared to the present invention.

[0008] IN 202141039393 discloses yet another process for preparation of Lurbinectedin as depicted in the below Scheme-3:Scheme-3: Process for preparation of Lurbmectedm

[0009] Lurbinectedin prepared by Scheme-3 has the following drawbacks. The use of column chromatographic separation in each stage is not desirable. Additionally, the process produces less yield in each stage and the reaction of 5-methoxytryptamine with CN-hydroxy a~keto lactone is slower.

[0010] US 9428524 discloses another process for preparation of Lurbinectedin as depicted in the below Scheme-4:

[0011] Lurbinectedin prepared by Scheme-4 is disadvantageous in that the process is not efficient to produce pure Lurbinectedin and iacks control over the impurity formation.

[0012] Thus, there remains a need to provide an improved process for the preparation of Lurbinectedin.

[0013] The present inventors have found an improved process for preparation of Lurbinectedin, which fulfils the aforesaid objectives.SUMMARY OF THE INVENTION

[0014] A main objective of the present invention is to provide an improved process for preparation of Lurbinectedin, comprising the steps of:

[0015] i) converting cyano compound of formula-!! to hydroxy compound of formula-ill

[0016] ii) coupling of compound of formula-ill with 5-methoxytryptamine(formula-V) to obtain in situ-fomed spiro-lactone compound of formula-IV

[0017] iii) cleaving a methoxymethyl group of the in s / fu-formed compound of formula-IV to form crude Lurbinectedin of formula-l; and

[0018] iv) optionally, purifying crude Lurbinectedin to obtain pure Lurbinectedin.

[0019] Another embodiment of the present invention provides a novel intermediate spiro-iactone derivative of formula~IV:

[0020] In another embodiment, the present invention provides a highly pure Lurbinectedin by avoiding use of flash column chromatography in each intermediate stage.

[0021] In additional embodiment, the present invention provides a purification technique for the purification of crude Lurbinectedin selected from preparative HPLC and crystallization technique.

[0022] In another embodiment, the present invention provides a pure Lurbinectedin having purity of greater than about 99.5% as measured by HPLC.

[0023] Other features and advantages of the present invention will become apparent from the following more detailed description, which illustrate, by way of example, the principle of the invention.DETAILED DESCRIPTION OF THE INVENTION

[0024] The following detailed description is merely exemplary in nature and is not intended to limit the disclosed invention described herein.Furthermore, there is no intention to be bound by any theory presented in the preceding background or the following detailed description.

[0025] The terms “comprising” and "comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited.

[0026] The terms "having" and "including" are to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

[0027] The term “contacting” includes mixing, adding, slurring, or stirring a clear solution or a combination thereof. The term “contacting” as used herein for the purpose of reaction means that one or more reagents are mixed or added with each other and / or solvent(s) in any sequence and further slurried as an insoluble solid mixture or stirred as a clear solution.

[0028] The term “about” is to be construed as modifying a term or value such that it is not an absolute. This term will be defined by the circumstances. This includes, at the very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

[0029] The term “substantially”, as used herein, means at least about 80%, preferably at least about 90%, more preferably at least about 99%, for example at least about 99.9%. In some embodiments, the term substantially can mean completely, or about 100%.

[0030] "At least one”, as used herein, relates to one or more, i.e. , 1 , 2, 3, 4, 5, 6, 7, 8, 9, or more. If used in combination with a compound, the termdoes not relate to the absolute number of molecules but rather to the number of different types of said compound.

[0031] The term “in situ”, as used herein, means a chemical reaction that occurs directly within the reaction mixture, without isolating or removing any intermediates.

[0032] One embodiment of the present invention is to provide an improved process for preparation of Lurbinectedin, comprising the steps of: i) converting a cyano based compound of Formula-I! to a hydroxy based compound of Formula-Ill in presence of a suitable reagent and a suitable organic solventii) coupling the compound of Formula-Ill with 5-methoxytryptamine of Formula~V to in situ formed spiro-lactone derivative of Formula~IV in presence of a suitable acid and a suitable organic solventiii) cleaving a methoxymethyl group of the in situ formed compound of Formula-IV to form Lurbinectedin of Formula-1 in presence of a suitable reagent, a suitable solvent and optionally, in presence of a catalyst; and iv) optionally, purifying crude Lurbinectedin as obtained in step-iii to obtain pure Lurbinectedin.

[0033] The suitable reagent used in step (i) may be silver nitrate.

[0034] The suitable organic solvent used in step (i) may be selected from water; alcohol such as methanol, ethanol, propanol, isopropanol; ester such as ethyl acetate; ether such as tetrahydrofuran, dimethyl ether, diethyl ether; nitrile solvents such as acetonitrile; amide solvents such as dimethyl formamide, dimethyl acetamide; chlorinated solvents such as dichloromethane, dichloroethane and chlorobenzene or mixtures thereof. Preferably, the suitable organic solvent is acetonitrile and tetrahydrofuran, and more preferably, the suitable organic solvent is acetonitrile.

[0035] The suitable acid used in step (II) may be selected from acetic acid, formic acid or its salts like sodium acetate, potassium acetate or mixtures thereof. Preferably, the suitable acid is acetic acid.

[0036] The suitable organic solvent used in step (ii) may be selected from alcohol such as methanol, ethanol, propanol, isopropanol; chlorinated solvents such as dichloromethane, dichloroethane and chlorobenzene or mixtures thereof. Preferably, the suitable organic solvent is selected from dichloromethane, dichloroethane or mixtures thereof, and more preferably, the suitable organic solvent is dichloromethane.

[0037] The suitable reagent used in step (iii) may be selected from trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride, triisopropylsilyl chloride, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and mixtures thereof. Preferably, the reagent is selected from trimethylsilyl chloride or trifluoroacetic acid, and more preferably, the reagent is trim ethylsilyl chloride.

[0038] The suitable solvent used in step (iii) may be selected from water; alcohol such as methanol, ethanol, propanol, isopropanol; ester such as methyl acetate, ethyl acetate; ether such as tetrahydrofuran, dimethyl ether, diethyl ether, dioxane; nitrile solvents such as acetonitrile; amide solvents such as dimethyl formamide, dimethyl acetamide; chlorinated solvents such asdichloromethane, dichloroethane and chlorobenzene or mixtures thereof.Preferably, the solvent used in step (ill) is water, acetonitrile and tetrahydrofuran or mixtures thereof, and more preferably, the solvent is water, acetonitrile or mixtures thereof.

[0039] The suitable catalyst used in step (iii) may be selected from sodium iodide, potassium iodide or mixtures thereof. Preferably, the suitable catalyst is sodium iodide.

[0040] The purification technique for the purification of crude Lurbinectedin used in step (iv) may be selected from preparative HPLC or crystallization techniques.

[0041] In another embodiment, the invention provides a new intermediate spiro-lactone compound of Formula-IV:Formula-IV

[0042] Surprisingly, the inventors observed that hydrolysis when performed before Pictet-Spengler reaction leads to formation of a pure lurbinectedin compound of Formula-I having no contamination of its startingmaterial — i.e., compound of formula-ill and other process impurities. The hydrolysis refers to conversion of CN-Hydroxy protected by MOM based a- keto lactone of Formula-Il to Hydroxy-Hydroxy protected by MOM based a- keto lactone of Formula-Ill. The Pictet-Spengler reaction refers to reaction of compound of Formula-Ill with 5-methoxytryptamine of Formula-V. This improved process avoids the flash chromatographic purification at intermediate stage(s). Additionally, the reaction proceeds at a higher speed as compared to similar reaction step (i.e., reaction of 5-methoxytrptamine with CN-Hydroxy based a-keto lactone or CN-Hydroxy protected by MOM based a-keto lactone) disclosed in the prior art.

[0043] The following nonlimiting examples illustrate the methods for preparing the Lurbinectedin and related compounds as discussed in the present invention.

[0044] EXAMPLES

[0045] Example 1: Preparation of hydroxy compound of Formula-Ill from CN compound of Formula-IkFormula-!! Formula-Hi

[0046] 1.0 g of cyano-based compound of Formula-Il was dissolved in 80 mL of acetonitrile at 20°C to 30°C and 120 mL of purified water was slowly added, and the reaction mass was stirred for 10 to 20 minutes at 20° to 30°C. 6.15 g of silver nitrate was added into the reaction mass at 20°C to 30°C andthe reaction mass was stirred for 6 to 10 hrs. After completion of the reaction, the reaction mass was cooled at 10°C to 15°C and saturated sodium bicarbonate solution was added into the reaction mass and the organic layer was extracted with dichloromethane solvent. Organic solvent was removed under vacuum at low temperature to get crude hydroxy based compound of Formula-Il!, which was purified with methanol.

[0047] Example 2: Preparation of lurbinectedin compound of Formula-! from reaction between hydroxy compound of Formula-Ill and 5- methoxytryptamine compound of Formula-V involving in situ formation of spirolactone derivative of compound of Formula-IV:Formula-!Lurbmectedm

[0048] 450 mg of 4-Hydroxy diketone (Formula-Ill) was dissolved in 9.0 ml of Dichloromethane. 391 mg of 5-methoxy tryptamine (Formula-V) was added and stirred for about 10 m in to about 15 m in. 411 mg acetic acid was charged into the reaction mass and stirred for about 120 min to about 180 min. After completion of the reaction, the mass was basified with 5.0 % of sodium bicarbonate solution and the reaction mass was filtered through celite bed. The organic layer was separated from the filtrate ml and the organic layer having the product was kept aside. 513 mg of sodium iodide was dissolved in 13.5 mlacetonitrile. The organic layer was charged into the sodium iodide solution and stirred for about 15 min at ambient temperature. The reaction mass was further cooled at about 0° to about 5CC. 312 mg of trimethylsilyl chloride was added into the reaction mass and the reaction mass was stirred for about 60 min to about 120 min. After completion of the reaction, 2.25 ml of dichloromethane and 4.5 ml of 10% sodium dithionate solution were added into the reaction mass and the mass temperature was raised up to about 20°C to about 25°C. The organic layer was separated and washed with water. The organic layer was dried over sodium sulphate and solvent was distilled out under vacuum to get crude Lurbinectedin (380 mg). The obtained crude lurbinectedin solid was purified with the preparative HPLC to get pure lurbinectedin (100 mg).

[0049] Example 3: Preparation of spiro-lactone derivative of compound of Formula-IV from reaction between hydroxy based compound of Formula-Ill and 5-methoxytryptamine compound of Formula-V(5):

[0059] 500 mg of hydroxy based compound of Formula-Ill was dissolved in 50 ml of dichloromethane and then 420 mg of 5-methoxy tryptamine compound of Formula-V was added into the reaction mass and stirred for 15 to 20 minutes. 450 mg of acetic acid was added into the reaction mass and stirred for 120 to 180 minutes. After completion of the reaction, sodium bicarbonate solution (5%) was added into the reaction mass and the reactionmass was filtered through celite bed. The solvent was removed under vacuum at low temperature to get crude spiro-lactone derivative compound of Formula- IV, which was purified with ethyl acetate and n-hexane.

[0051] Example 4: Preparation of Lurbinectedin of Formula-I from spirolactone derivative compound of Formula~IV:Formula-IV Formula-ILurbinectedin

[0052] 360 mg of Sodium iodide was dissolved in mixture of 30 mL of acetonitrile and 0.6 ml of water 200 mg of spiro-lactone derivative compound of Formula-IV was added, followed by dissolution in dichloromethane. The reaction mass was stirred for 10 to 15 minutes and then 524 mg chlorotrimethylsilane was added into the reaction mass. After completion of the reaction, 10% of sodium dithionate solution was added into the reaction mass and stirred for 10 to 15 minutes and extracted with dichloromethane. The organic layer was washed with purified water and organic solvent was removed under vacuum at low temperature to get crude Lurbinectedin, which was purified by preparative HPLC to get pure Lurbinectedin having a purity of about 99.6%.

[0053] It should be noted that the invention in its broader aspects is not limited to the specific details, representative compositions, methods, and processes, and Illustrative examples described in connection with the preferredembodiments and preferred methods. Modifications and equivalents will be apparent to practitioners skilled in this art and are encompassed within the spirit and scope of the appended claims.

Claims

What is claimed is:1 . A process for preparation of lurbinectedin, comprising the steps of: i) converting a cyano-based compound of Formula-Il to a hydroxy compound of Formula-Ill in presence of at least one reagent and at least one organic solventFormtda-H FormuSa-lh ii) coupling the compound of Formula-Ill with a 5-methoxytryptamine compound of Formula-V to yield an in situ formed a spiro-lactone compound ofFormula-IV in presence of at least one acid and at least one organic solventiii) cleaving a methoxymethyl group of the in situ formed compound of Formula-IV to form a lurbinectedin compound of Formula-1 in presence of at least one reagent and at least one solventLurbmectedm2. The process according to claim 1 , wherein the at least one reagent used in step (i) is silver nitrate.

3. The process according to claim 1 , wherein the at least one organic solvent used in step (I) is selected from water, methanol, ethanol, propanol, isopropanol, ethyl acetate, tetrahydrofuran, dimethyl ether, diethyl ether, acetonitrile, dimethyl formamide, dimethyl acetamide, dichloromethane, dichloroethane, chlorobenzene, and mixtures thereof.

4. The process according to claim 3, wherein the at least one organic solvent is acetonitrile.

5. The process according to claim 1 , wherein the at least one acid used in step (ii) is selected from acetic acid, formic acid or its salts, and mixtures thereof.

6. The process according to ciaim 5, wherein the at least one acid is acetic acid.

7. The process according to claim 1 , wherein the at least one organic solvent used in step (ii) is selected from methanol, ethanol, propanol, isopropanol, dichloromethane, dichloroethane, chlorobenzene, and mixtures thereof.

8. The process according to claim 7, wherein the at least one organic solvent is dichloromethane.

9. The process according to claim 1 , wherein the at least one reagent used in step (iii) is selected from trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride, triisopropylsilyl chloride, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and mixtures thereof.

10. The process according to claim 9, wherein the at least one reagent is trimethylsilyl chloride.

11. The process according to claim 1 , wherein the at least one organic solvent used in step (iii) is selected from water, methanol, ethanol, propanol, isopropanol, methyl acetate, ethyl acetate, tetrahydrofuran, dimethyl ether, diethyl ether, dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, dichloromethane, dichloroethane, chlorobenzene, and mixtures thereof.

12. The process according to claim 11 , wherein the at least one organic solvent is water, acetonitrile or a mixture thereof.

13. The process according to claim 1 , wherein the step (iii) further comprises use of at least one catalyst.

14. The process according to ciaim 13, wherein the at ieast one catalyst used in step (iii) is selected from sodium iodide, potassium iodide, and mixtures thereof.

15. The process according to claim 14, wherein the at least one catalyst is sodium iodide.

16. The process according to claim 1 , further comprising a step (iv) of purifying crude lurbinectedin obtained in step (iii) to obtain a pure lurbinectedin.

17. The process according to claim 15, wherein the step (iv) comprises a purification technique selected from preparative HPLC and crystallization technique.

18. An intermediate for synthesis of lurbinectedin, the intermediate being a compound of Formula~IV:Formula-IV19. A process for preparation of the intermediate according to claim 18, comprising the steps of: i) converting a cyano compound of Formula-Il to a hydroxy compound of Formula-Ill in presence of at least one reagent and at least one organicsolventFormula-H Formula-Ill and ii) coupling the compound of Formula-Ill with a 5-methoxytryptamine compound of Formula-5 in presence of at least one acid and at least one organic solvent to obtain the intermediate of Formula-IVFormula-Ill Formula-IV

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