DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION

PROCESS FOR THE PREPARATION OF MIDOSTAURIN

APPLICANT
HETERO LABS LIMITED
Hetero Corporate 7-2-A2, Industrial Estates, Sanath Nagar, Hyderabad-500 018,
Telangana, India.
Nationality: Indian company.

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

FIELD OF INVENTION

The present invention relates to a process for preparing Midostaurin of compound of Formula-I.

BACK GROUND OF THE INVENTION

Midostaurin is chemically known as N-[(2S,3R,4R,6R)-3-Methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-N-methylbenzamide or N-Benzoylstaurosporine, which has been approved as a capsule having dosage strength 25MG under the trade name RYDAPT® for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy.

Midostaurin was disclosed in US 5,093,330 A of Ciba-Geigy Corporation. Further, US ‘330 disclose the synthesis of Midostaurin as shown below:

US 8,198,435 B2 of Novartis AG, discloses Midostaurin Crystalline Form II, Pure Amorphous and Essentially Amorphous (Mixture of Crystalline & Amorphous) Forms. Further, US ‘435 also discloses the synthesis of Amorphous Midostaurin is as shown below:

However, wherein Staurosporine was purified in different ways and multiple washings with benzyl alcohol and Ethanol have been done to yield Pure Staurosporine. Further, seeding of Pure Staurosporine is needed in purification process to yield Pure Staurosporine.

Further, Pure Staurosporine was treated with benzoic anhydride to yield Midostaurin followed by convertion to Amorphous Form and Crystalline Form II of Midostaurin using different solvents and seeded with Amorphous Form and Crystalline Form II correspondingly.

Further, US ‘435 also disclose the process for preparing Midostaurin Amorphous using spray-drying technique, which is not industrially suitable.

US 9,150,589 B2 of Novartis AG, discloses Crystalline Midostaurin Forms III & Form IV, which were prepared by GAS re-crystallization method.

WO 2018/165071 A1 of Teva Pharmaceuticals, discloses the Crystalline Midostaurin Forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and XVI.

The Journal of Antibiotics 1988, Vol XLII, No 4, Pages 571 to 576, discloses the mixture of hydroxyl epimers UCN-01 & UCN-02. UCN-01 has a hydroxyl group at C-7 of Staurosporine, and UCN-02 is a stereoisomer at C-7 of UCN-01. This article also discloses their purification, physico-chemical properties, structures and biological activities.

WO 2019/215759 A1 of Omgene Life Sciences Pvt. Ltd discloses a process for the preparation of Midostaurin comprising reacting the staurosporine with benzoic acid in presences of condensing agent such as 2-(lH-benzotriazol-l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), N-Hydroxybenzotriazole (HOBt), Diisopropylethylamine (DIPEA).

The present inventors have found that by following the prior-art processes for preparing Midostaurin by reacting Staurosporin, contains the mixture of epimers UCN-01 & UCN-02 with benzoyl chloride yields Midostaurin having the mixture of chloride impurities and are referred as compound of Formula-A, which ultimately leads to a product having less yield and low purity.

Further, the present inventors have noticed that the above obtained Midostaurin, which has low purity, further purified using chromatographic techniques and are not suitable industrially.

Further, the present inventors have found that the prior-art processes involve number of washings which leads to low yield and is not viable industrially.

Further, the present inventors have noticed that the prior-art processes involves purification of Staurosporin and is further converted to Midostaurine, which having low yield and purity.

Further, noticed that prior-art processes involve seeding of the required material to get required compound in its specific polymorphic form.

Further, the present inventors have noticed that the benzoic anhydride has been used for benzoylation and in term the reaction yields benzoic acid as by-product, which cannot be easily washed out using water and further base treatment or column chromatographic techniques were required for removal of benzoic acid.

In view of the above, there is a need for an improved, cost-effective, industrially applicable / viable process for the preparation of Midostaurin having high yield and high purity.

OBJECTIVES

An objective of the present invention is to provide a process for the preparation of Midostaurin, which is free of impurities and is industrially viable, having high yields and high purity.

Another objective of the present invention is to provide a process for the preparation of Midostaurin, which is suitable industrially and cost effective.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is a powder X-ray diffractogram pattern of Amorphous Midostaurin.

Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper-Ka radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA.

SUMMARY OF THE INVENTION

A process for the preparation of Midostaurin of Formula-I:

which comprises,
i) benzoylating Staurosporine of Formula-II,

with benzoylating agent in a solvent to yield Midostaurin; and
ii) optionally purifying the Midostaurin of Formula-I.
wherein benzoylating agent is selected from the group comprising of N-benzoylimidazole, N-benzoyltriazole, N-benzoyltetrazole, Benzoyl cyanide, Benzoyl isothiocyanate, 2-benzoylthio-1-methylpyridinium chloride, tert-Butyl Peroxybenzoate (TBPB); benzoyloxybenzotriazole (BBTZ); 2-benzoyloximino-malononitrile, ethyl 2-benzoyloximino-2-cyanoacetate (Oxyma), tert-butyl 2-benzoyloximino-2-cyanoacetate and the like.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Midostaurin of Formula-I, which comprises benzoylating Staurosporine of Formula-II with a benzoylating agent, wherein benzoylating agent is selected from the group comprising of N-benzoylimidazole, N-benzoyltriazole, N-benzoyltetrazole, Benzoyl cyanide, Benzoyl isothiocyanate, 2-benzoylthio-1-methylpyridinium chloride, tert-Butyl Peroxybenzoate (TBPB); benzoyloxybenzotriazole (BBTZ); 2-benzoyloximino-malononitrile, ethyl 2-benzoyloximino-2-cyanoacetate (Oxyma), tert-butyl 2-benzoyloximino-2-cyanoacetate and the like; in a solvent selected from the group comprising of water, halogenated solvents, alcohols, ketonic solvents, ethers, esters, hydrocarbons, nitriles, non-polar solvents, polar aprotic solvents, polar protic solvents or mixture thereof; optionally in presence of a base to give Midostaurin.

In another embodiment of the present invention, optionally purifying the obtained Midostaurin by conventional methods to yield Midostaurin of Formula-I.

In another embodiment throughout the invention, the halogenated solvents are selected from the group comprising of dichloromethane (MDC), ethylene dichloride (EDC), chloroform and the like; alcohols are selected from the group comprising of methanol, ethanol, isopropanol, butanol and the like; ketonic solvents are selected from the group comprising of acetone, methyl isobutyl ketone, dimethylformamide and the like; ethers are selected from the group comprising of tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), diethyl ether, isopropyl ether, methyl isobutylether, methyl t-Butyl ether (MTBE), dioxane and the like; esters are selected from the group comprising of ethyl acetate, isopropyl acetate and the like; hydrocarbons are selected from the group comprising of toluene, xylene and the like; nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, acrylonitrile and the like; non-polar solvents are selected from the group comprising of pentane, cyclopentane, hexane, cyclohexane, n-Heptane, benzene, 1,4-Dioxane and the like; Polar aprotic solvents are selected from the group comprising of dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile, dimethylsulfoxide (DMSO) and the like; Polar protic solvents are selected from the group comprising of Formic acid, acetic acid, n-butanol, n-propanol and the like.

In another embodiment throughout the invention, base is selected from the group comprising of Sodium hydride, Potassium hydride, Sodium hydroxide, Potassium hydroxide, Sodium carbonate, Sodium bicarbonate, Potassium carbonate, Pyridine, Piperidine, Dimethylamino pyridine (DMAP), Triethylamine (Et3N), N,N-Diisopropylethylamine (DIPEA), Morpholine, N-Methyl morpholine, N-Methylpyrrolidine (NMP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN) and the like.

In another embodiment throughout the invention, the mixture of solvents means two or more solvents.

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.

Examples

Reference Example 1: Preparation of Midostaurin
To the stirred solution of Staurosporine (0.5 gm) and dichloromethane (25 ml), added Benzoyl chloride (0.165 gm) at 25 – 35°C and maintained for 30 minutes. To the obtained reaction mixture was added dichloromethane (25 ml) at 25 – 35°C. Added Aq.Sodium bicarbonate solution at 0 to 5°C and stirred for 10 minutes then organic layer was separated and washed with 10% Sodium chloride solution (50 ml) followed by dried with Sodium sulfate and distilled off the solvent. To the obtained solid, added 60% dichloromethane in n-Heptane (25 ml) and stirred for 2 hours at 25 – 30°C. Filtered the solid and washed with 60% dichloromethane in n-Heptane (25 ml) then dried at 40°C for 10 hours to yield Midostaurin (460 mg).
Purity by HPLC: 98.90%
Chloride impurities: 0.7%
Reference Example 2: Preparation of Midostaurin

To the Staurosporine (10 gm), Tetrahydrofuran (180 ml), Benzoic anhydride (5.8 gm) and water (20 ml) were added at 25 – 35°C and the reaction mixture was heated slowly to 65 – 75°C then maintained for 4 hours. The obtained reaction mixture was filtered and washed with tetrahydrofuran (20 ml). Water (500 ml) was added at 55 – 65°C and stirred for 10 hours to 12 hours. Filtered the obtained solid and washed with water (30 ml) then dried at 50°C for 10 hours to yield Midostaurin (12 gm).

To the above obtained Solid, Tetrahydrofuran (180 ml) was added at 25 – 35°C and heated to 65 – 75°C. The obtained clear solution was cooled to 25 – 35°C and stirred for 3 hours to 4 hours then cooled to 15 – 20°C and maintained for 30 minutes. Filter the obtained solid and washed with tetrahydrofuran (10 ml) then dried at 50°C for 10 hours to yield Midostaurin (8 gm).

To the above obtained solid, added Dichloromethane (80 ml) and Ethanol (24 ml) at 25 – 35°C and stirred for 10 minutes. To the obtained clear solution, added charcoal (0.8 gm) and stirred for 5 minutes. Filtered the reaction mixture and washed with Dichloromethane (16 ml) and Ethanol (16 ml). Distilled at 50°C under vacuum pressure and co-distilled with Ethanol (24 ml) at 50°C under vacuum pressure. Dried the solid at 55°C for 24 hours to yield Midostaurin (7.5 gm).
PXRD: Amorphous as shown in Figure 1

Example 1: Preparation of Midostaurin

To the Staurosporine (0.5 gm), N-Benzoylimidazole (461 mg), tetrahydrofuran (9 ml) and water (1 ml) were added at 25 – 35°C and the reaction mixture was heated slowly to 65 – 75°C then maintained for 12 hours. The obtained reaction mixture was filtered and washed with tetrahydrofuran (1 ml). Water (25 ml) was added at 55 – 65°C and stirred for 10 hours to 12 hours at 25 – 35°C. Filtered the obtained solid and washed with water (1 ml) then dried at 50 – 55°C to yield Midostaurin (0.6 gm).
Chloride impurities: Not detected

To the above obtained Solid, Tetrahydrofuran (9 ml) was added at 25 – 35°C and heated to 70 – 75°C and maintained for 30 minutes. The obtained clear solution was cooled to 25 – 35°C and stirred for 3 hours to 4 hours then cooled to 15 – 25°C and maintained for 30 minutes. Filter the obtained solid and washed with tetrahydrofuran (0.6 ml) the dried at 50°C for 10 hours to yield Midostaurin (0.3 gm).

To the above obtained solid, added Dichloromethane (3 ml) and Ethanol (0.9 ml) at 25 – 35°C and stirred for 10 minutes. To the obtained clear solution, added charcoal (0.3 gm) and stirred for 5 minutes. Filtered the reaction mixture and washed with Dichloromethane (0.6) and Ethanol (0.6 ml). Distilled at 50°C under vacuum pressure and co-distilled with Ethanol (0.9 ml) at 50°C under vacuum pressure. The obtained solid was dried at 55°C for 24 hours to yield Midostaurin (0.3 gm).
PXRD: Amorphous as shown in Figure 1
Purity by HPLC: 99.24%
Chloride impurities: Not detected

,CLAIMS:
We Claim:
1. A process for the preparation of Midostaurin of Formula-I:

which comprises,
i) benzoylating Staurosporine of Formula-II,

with benzoylating agent in a solvent to yield Midostaurin; and
ii) optionally purifying the Midostaurin of Formula-I.
wherein benzoylating agent is selected from the group comprising of N-benzoylimidazole, N-benzoyltriazole, N-benzoyltetrazole, Benzoyl cyanide, Benzoyl isothiocyanate, 2-benzoylthio-1-methylpyridinium chloride, tert-Butyl Peroxybenzoate (TBPB); benzoyloxybenzotriazole (BBTZ); 2-benzoyloximino-malononitrile, ethyl 2-benzoyloximino-2-cyanoacetate (Oxyma), tert-butyl 2-benzoyloximino-2-cyanoacetate and the like.

2. The process as claimed in claim 1, wherein solvent used in benzoylation is selected from the group comprising of water, halogenated solvents, alcohols, ketonic solvents, ethers, esters, hydrocarbons, nitriles, non-polar solvents, polar aprotic solvents, polar protic solvents or mixture thereof.

Dated this 10th day of March, 2020

Dr. RATHNAKAR REDDY KURA
DIRECTOR
HETERO LABS LIMITED