WO2025046257A1

WO2025046257A1 - A substantially pure propentofylline and preparation thereof

Info

Publication number: WO2025046257A1
Application number: PCT/IB2023/058436
Authority: WO
Inventors: Rakesh Ramesh GANORKAR; Malhari Deoram Bhor; Samir Shanteshwar Shabade; Vishal Gautam Gaikwad; Suresh Maruti Doke; Manish Chandra SRIVASTAVA
Original assignee: Hikal Ltd
Current assignee: Hikal Ltd
Priority date: 2023-08-25
Filing date: 2023-08-25
Publication date: 2025-03-06
Anticipated expiration: 2026-02-25

Abstract

The present invention relates to substantially pure Propentofylline formula (I). The substantially pure Propentofylline comprises at least one or more impurities selected from O-Hexoyl impurity formula (1), Valerate impurity formula (2), Methane impurity formula (3) and isopropyl impurity formula (4). The present invention further relates to a process for the preparation of substantially pure Propentofylline by using a mixture of alcoholic and hydrocarbon solvent with good yield and greater purity.

Description

“A SUBSTANTIALLY PURE PROPENTOFYLLINE AND PREPARATION

THEREOF”

FIELD OF THE INVENTION

The present invention relates to substantially pure Propentofylline formula (I). The substantially pure Propentofylline comprises at least one or more impurities selected from O-Hcxoyl impurity formula (1), Valerate impurity formula (2), Methane impurity formula (3) and isopropyl impurity formula (4). The present invention further relates to a process for the preparation of substantially pure Propentofylline by using a mixture of alcoholic and hydrocarbon solvent with good yield and greater purity.

O-Hexoyl impurity (1) Valerate impurity (2)

Methane impurity (3) Isopropyl impurity (4)

BACKGROUND OF THE INVENTION

Propentofylline is chemically known as 3-methyl-l-(5-oxohexyl)-7-propylpurine-2,6- dione. It is used in pharmaceutical industry as an intermediate in the production of peripheral vasodilators and xanthine-type haemorheologies. It is a drug widely used as an effective remedy for motivational and emotional disorders associated with cerebrovascular disorders. For several years it has been well established in the geriatric therapy of the dog improving hemodynamics in cerebral and peripheral compartments. In human medicine clinical development of this pharmaceutical has already entered an advanced stage for the long-term therapy of patients with Alzheimer's disease and vascular dementia.

The various patent publications such as, US4289776, CS270545B1, CN102718764A, CS270546, CA1075690A, and CS270547 discloses the preparation of Propentofylline which involves numerous drawbacks for example: i) use of expensive catalyst; ii) use of multiple and carcinogenic solvents; iii) multiple and tedious operations; iv) multiple purification processes; v) expensive and explosive solvents for recrystallization; vi) low overall process yield.

The research article Sci. Pharma, 58, (1990) 55-67 discloses that the Propentofylline exists in four different crystal modifications such as modification I, II, III and IV. The article further discloses the melting point for modification I (71 °C), modification II (69°C), modification III (61°C) and modification IV (53°C), but fail to disclose the preparation, isolation, and purification of modification I, which is a more stable at room temperature.

The Japanese patent JPH05246850A and CS270545 discloses crystallization of Propentofylline using solvent isopropyl ether, Z-butyl methyl ether, respectively.

Another Japanese patent JPH09316075A disclose the preparation of type-I crystal of Propentofylline by heating Propentofylline with acetone or ethanol at 56°C to 78°C and adding an anti-solvent hexane, with overall recovery 95%; but failed to disclose the purity of type-I crystal and a process of preparing pure polymorph type-I crystal.

The prior art documents disclose the process(es) resulting to low yield, it might be due to the presence of process impurities but, the impurities are not explicitly disclosed. In the present scenario it is a requirement from regulatory agencies that the drug manufacturers isolate, identify, and characterize the process impurities in their products.

Furthermore, it is required to control and ensure the lowest possible level of impurities in the final drug compound, even if impurities are not identified. It becomes easy to control the process impurities to a great extent by understanding the chemical structures and synthetic pathways, particularly by identifying the parameters that influence the development of impurities in the final product. The inventors of instant invention have developed a process to overcome the limitations of the prior-art process. Further, the present invention provides a process to obtain substantially pure propentofylline having a polymorph of type-I crystal.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a substantially pure Propentofylline of formula (I).

In another aspect, the present invention provides a substantially pure Propentofylline comprising at least one or more impurity(es) is selected from O-Hcxoyl impurity formula (1), Valerate impurity formula (2), Methane impurity formula (3) and isopropyl impurity formula (4).

In another aspect, the present invention provides a substantially pure Propentofylline having purity greater than 99.5% comprising (?-Hexoyl impurity formula less than 0.10%, Valerate impurity less than 0.10%, Methane impurity less than 0.10%, and isopropyl impurity less than 0.10% as measured by HPLC.

In another aspect, the present invention provides a process for the preparation of substantially pure Propentofylline formula (I)

having one or more impurity(es) selected from O-Hcxoyl impurity, Valerate impurity,

Methane impurity, and isopropyl impurity comprising the step of: a) reacting 3-methyl xanthine (II) with n-propyl halide in presence of base, a polar aprotic solvent to obtain 3-methyl-7-propyl- xanthine of formula (III);

b) reacting 3-methyl-7-propyl-xanthine (III) with 6-halo-2-hexanone in presence of base, a polar aprotic solvent to obtain Propentofylline of formula (I), c) isolating Propentofylline comprising one or more impurity(es) selected from O- Hexoyl impurity, Valerate impurity, Methane impurity, and isopropyl impurity; d) purifying Propentofylline consisting steps of:

1) dissolving Propentofylline in 1:1 to 1:5 volume ratio of alcoholic and hydrocarbon solvent at temperature 50°C to 70°C for 15 min to 2 hrs,

2) cooling and optionally seeding,

3) filtering to obtain substantially pure Propentofylline.

In another aspect, the present invention provides a process for the preparation of substantially pure Propentofylline by purification in a mixture of alcoholic and hydrocarbon solvents.

In another aspect of the present invention is to provide a substantially pure

Propentofylline in a crystal form -I by seeding with a form -I crystal.

BRIEF DESCRIPTION OF DRAWINGS

Fig 1 : is a characteristic powder X-ray diffraction (XRPD) pattern of substantially pure Propentofylline.

Fig 2: is a characteristic infra-red (IR) spectrum of substantially pure Propentofylline. Fig 3: is a characteristic Differential Scanning Calorimetric (DSC) thermogram of substantially pure Propentofylline.

Fig 4: is a Thermogravimetric Analysis (TGA) of substantially pure Propentofylline.

Fig 1, Fig 2, Fig 3, and Fig 4 of the present invention resemble Crystal form-I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a,” “an,” “the,” include plural referents unless the context clearly indicates otherwise.

The term solvent used herein refers to the single solvent or mixture of solvents.

For the purpose of the specification, the term “substantially pure” used herein, refers to Propentofylline with purity more than 99.5%, more particularly more than 99.8%.

The term “substantially free” used herein, refers to a substantial percentage of one or more impurity(es) as measured by HPLC.

The substantial percentage used herein refers to a maximum acceptable percentage by the regulatory authority for known or unknown impurity(es).

The “purification” step mentioned herein specification is carried out by using different purification techniques well known in prior art.

The present invention relates to a “substantially pure Propentofylline” comprising impurities, namely:

3-methyl-6-((5-oxohexyl)oxy)-7-propyl-3,7-dihydro-2H-purin-2-one,

O-Hexoyl impurity (1) methyl 5-(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-lH-purin-l-yl) pentanoate

l,r-methylenebis(3-methyl-7-propyl-3,7-dihydro-lH-purine-2, 6-dione)

And

7-isopropyl-3-methyl-l-(5-oxohexyl)-3,7-dihydro-lH-purine-2, 6-dione

Isopropyl impurity (4)

The instant invention provides substantially pure Propentofylline wherein the substantially pure Propentofylline is substantially free from one or more impurity(es) selected from O-Hcxoyl impurity (1), Valerate impurity (2), Methane impurity (3), and isopropyl impurity (4).

The said ‘C-Hexoyl impurity (l)’is characterized by: ^JH NMR: (DMSO-d6, 400 MHz): 8 (ppm); 0.805 - 0.841 (3H, t), 1.583 - 1.636 (2H, m), 1.695 - 1.795 (4H, m), 2.081 (3H, s), 2.50 - 2.533 (2H, t), 3.421 (3H, s), 4.128 - 4.163 (2H, t), 4.375 - 4.387 (2H, t), 8.135 (1H, s). LCMS; m/z= 307 (M+l) and HPLC purity: > 93 %.

The said ‘Valerate impurity (2)’is characterized by: ' H NMR: (DMSO-d6, 400 MHz): 6 (ppm); 0.798 - 0.835 (3H, t), 1.497 - 1.559 (4H, m), 1.726 - 1.816 (2H, m), 2.314 - 2.349 (2H, t), 3.410 (3H, s), 3.565 (3H, s), 3.836 - 3.869 (2H, t), 4.174 - 4.209 (2H, t), 8.082 (1H, s). LCMS; m/z = 323 (M+l) and HPLC purity: > 97%. The said ‘Methane impurity (3)’ is characterized by: ^JH NMR: (DMS0-d6, 400 MHz): 6 (ppm); 0.799 - 0.836 (6H, t), 1.724 - 1.814 (4H, m), 3.330 - 3.352 (6H, d), 4.163 - 4.197 (4H, t), 6.057 (2H, s), 8.077 (2H, s). LCMS; m/z = 429 (M+l) and HPLC purity: > 99 %.

The said ‘isopropyl impurity (4)’is characterized by: ' H NMR: (DMSO-d6, 400 MHz): 8 (ppm); 1.373 - 1.455 (4H, m), 1.473 - 1.489 (6H, d), 2.058 (3H, s), 2.437 - 2.471 (2H, t), 3.404 (3H, s), 3.821 - 3.855 (2H, t), 4.844 - 4.944 (1H, septet), 8.187 (1H, s). LCMS; m/z = 307 (M+l) and HPLC purity: > 98 %.

The impurities such as ‘O-Hcxoyl impurity’, ‘Valerate impurity’, ‘Methane impurity’ and ‘isopropyl impurity’ are formed during the process for the preparation of Propentofylline and they are isolated in pure form using column chromatography / prep HPLC and further characterized.

The inventors of the present invention found the formation of ‘O-Hcxoyl impurity,’ ‘Valerate impurity,’ ‘Methane impurity’ during the preparation of Propentofylline formula (I), and ‘isopropyl impurity’ during the preparation of compound formula (III).

The present said ‘O-Hcxoyl impurity,’ ‘Valerate impurity,’ ‘Methane impurity’ and ‘isopropyl impurity’ have not yet reported so far. Thus, there is also a need for a process which controls or removes these impurities to obtain substantially pure Propentofylline to meet regulatory standard.

The inventors of present invention developed an industrial process which avoid the O- alkylation and favour the N-alkylation to obtain desired substantially pure

Propentofylline.

N-alkylation O-alkylation The inventors of present invention developed an industrial process which does not require critical and/or multiple purification steps for removal of the said impurities and obtained a substantially pure Propentofylline in a single purification step.

The inventor of the present invention developed a HPLC method for determination of Propentofylline, key starting compounds/intermediates and impurities formed.

HPLC Method: For determination of compounds of formula (II), (III), (I) and impurity (1), impurity (2), impurity (3), and impurity (4).

Instrument: High performance liquid chromatography equipped with UV detector/ PDA detector, (Thermo Scientific and Agilent).

Chromatographic conditions:

Table 1:

Gradient elution program (values in volume %):

Mobile Phase Preparation:

Buffer Solution: Prepare a solution of 4 g of sodium perchlorate monohydrate in 1000 mL of Milli-Q-water., add 2.0 mL Triethylamine and 2.0 mL Perchloric acid, sonicate for 3 minutes at ambient temperature to degas.

Mobile phase A: 100% buffer preparation.

Mobile phase B: A homogenous mixture of Methanol, Acetonitrile and 1 -Propanol in ratio (80:10:10) NININ. Mix well and sonicate for 5 minutes at ambient temperature to degas.

Diluent: A mixture of Water, Methanol and Perchloric acid in ratio (70:30:0.1) NININ.

Rinsing port solution: A homogenous mixture of Water and Methanol in ratio (70:30) v/v. Standard solution: (150pg/mL of Propentofylline)

Retention time of Propentofylline peak is about 7.6 minutes.

HPLC analysis:

Table 2:

The process is illustrated in the following general synthetic scheme.

The present invention is more broadly elaborated in following embodiment.

In one embodiment, the instant invention provides substantially pure Propentofylline of formula (I) having ‘D-Hexoyl impurity’ of formula (1) less than 0.10%; preferably less than 0.05%.

In an embodiment the instant invention provides substantially pure Propentofylline of formula (I) having ‘Valerate impurity’ of formula (2) less than 0.10%; preferably less than 0.05%. In an embodiment the instant invention provides substantially pure Propentofylline of formula (I) having ‘Methane impurity’ of formula (3) less than 0.10%; preferably less than 0.05%.

In an embodiment the instant invention provides substantially pure Propentofylline of formula (I) having ‘isopropyl impurity’ of formula (4) less than 0.10%; preferably less than 0.05%.

In another embodiment of present invention states the formation of below impurities:

Dimer impurity (5) Uracil ring opened Base Hydrolysis impurity (7) i.e. 1,1’-Trimethylenebis impurity (6)

In an embodiment, the present invention results in Crystalline substantially pure Propentofylline, starting from compound of formula (II) and using commercially available, economical reagent and solvent, avoiding critical and/or multiple purification processes and resulting into less effluent generation, thus makes process environment friendly, safe, and commercially viable.

In another embodiment of the present invention, the n-propyl halide is selected from n- propyl bromide, n-propyl chloride, and n-propyl iodide and used in 1.3 to 1.5 mol equivalent.

In another embodiment of the present invention, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate and used in 0.8 to 1.75 mol equivalent.

In another embodiment of the present invention, wherein the polar aprotic solvent is selected from N, N ’-dimethyl formamide, acetone, acetonitrile, dichloromethane, dimethyl sulfoxide, ethyl acetate, hexamethyl phosphoric triamide, pyridine, sulfolane, and tetrahydro furan and used in 4 to 7 volumes. In another embodiment of present invention, 6-halo-2-hexanone is selected from 6- chloro-2-hexanone, 6-bromo-2-hexanone and 6-iodo-2-hexanone and used in 1.0 to 1.3 mol equivalent.

In another embodiment of the invention, wherein, the preparation compound of formula (III) is performed at temperature 70°C to 90°C.

In another embodiment of the invention, wherein, the preparation compound of formula (I) is performed at temperature 70°C to 95 °C.

In another embodiment of present invention, wherein isolation of Propentofylline of formula (I), involve the steps of: a) filtering the reaction solution, b) removing solvent, c) dissolving reaction residue in an alcoholic solvent, d) cooling and adding hydrocarbon solvent, and e) filtering.

In another embodiment of present invention, wherein alcoholic solvent is selected from methanol, ethanol, isopropanol, n-butanol, iso-butanol, and the like and mixture thereof.

In another embodiment of present invention, wherein hydrocarbon solvent is selected from propane, butane, pentane, n-hexane/hexane, cyclohexane, n-heptane / heptane, toluene, xylene, and mixture of solvents.

In another embodiment of present invention, wherein mixture of alcoholic solvent, and hydrocarbon solvent may be used in a 1:1 to 1:8 volume ratio respectively, and the total volume ratio is 3 to 15 volumes.

In another embodiment of present invention, wherein said heating is performed at temperature 50°C to 110°C.

In another embodiment of present invention, wherein said cooling temperature is -5°C to 35°C. In another embodiment of present invention, wherein said cooling temperature is maintained for 0 to 8 h.

In another embodiment of the present invention, wherein purification step is performed by simple sequential step such as addition of mixture of solvent(s), heating, filtering, cooling, seeding, and finally filtering the substantially pure Propentofylline.

In another embodiment of present invention, wherein the seeding is performed using Crystal form-I.

In another embodiment of the present invention, wherein the substantially pure Propentofylline Crystal form-1, is obtained after seeding with Crystal form-1.

In another embodiment of the present invention, wherein seeding temperature is 30°C to 45°C.

In another embodiment of the invention, wherein the substantially pure Propentofylline formula (I) qualify ICH Q3C for OVI content, having HPLC purity >99.5% along with (9-Hexoyl impurity of formula (1) < 0.10%, Valerate impurity of formula (2) < 0.10 % and Methane impurity of formula (3) < 0.10%; and isopropyl impurity (4) < 0.10% single maximum unknown impurity < 0.10%.

In another embodiment of the present invention, the substantially pure Propentofylline obtained by the said process is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 3.750, 7.454, 9.079, 10.575, 13.740, 17.141 and 18.659+0.2 degrees substantially in accordance with FIG. 1; an infra-red (FT-IR) spectrum having main bands at about 3111.61, 1696.56 and 1651.80^cm-1±2 substantially in accordance with FIG. 2; and a Differential Scanning Calorimetric (DSC) thermogram having a sharp endotherm peak at about 71.79°C substantially in accordance with FIG. 3, and a Thermogravimetric Analysis (TGA) having % loss as straight line up to 200°C substantially in accordance with FIG. 4 and resemble with Crystal form -I.

The preparation of the starting materials used in the present invention are well known in prior art. The present invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in any way.

EXPERIMENTAL

1) Preparation of 3-methyl-7-propyl- xanthine formula (III).

To the solvent N, A ’-dimethyl formamide (4-6 vol) a 3-methyl Xanthine (1.0 eq) and sodium carbonate (1-1.5 eq) was added at 20°C to 30°C. To the reaction mixture n- propyl halide (1.2 to 1.5 eq) was added and heated at 70°C to 85°C for 8-12 hrs. The completion of reaction is monitored by HPLC. After completion, the reaction mixture was cooled, and solvent was removed by simple distillation. To the reaction mixture water was added and stirred for 1-2 hrs at 70°C to 85°C.

The reaction mixture was cooled, filtered, and washed with water. To this residue again water and caustic lye solution was added and stirred for 1-2 hrs at 50°C to 70°C. The pH 6-9 of reaction solution was maintained using cone, hydrochloric acid. The reaction mixture was cooled gradually up to 10°C within 1-2 hrs, filtered and dried under vacuum to obtain 3-methyl-7-propyl-xanthine as an off-white to white solid (90% yield, HPLC purity 99.5%).

2) Preparation of Propentofylline (I).

To the 3-methyl-7-propyl- xanthine (1.0 eq.) in N, A’-dimethyl formamide (4-6 vol) potassium carbonate (1.5-2.0 eq) was added at 20°C to 30°C. To the reaction mixture 6- halo-2-hexanone (1-1.3 eq) was added and heated at 80°C to 100°C. Stirred for 4-8 hrs. The completion of reaction is monitored by HPLC. After completion, the reaction mixture was filtered. The solvent was distilled under vacuum and to the reaction mixture isopropyl alcohol (2-3 Vol) was added at 50°C to 70°C and stirred for 10-15 min. The reaction mixture was cooled to room temperature and n-heptane (2-3 Vol) was added. The reaction mixture was further cooled to -10°C to 10°C and maintained for 1-2 hrs. The reaction mixture was filtered, washed with isopropyl alcohol and n-heptane mixture (1-3 Vol), and dried under vacuum. The crude compound was purified by adding a mixture of isopropyl alcohol and n-heptane (1:5, 12 vol), heating at 50°C to 70°C for 15-60 min. The clear solution was gradually cooled to 35°C to 45°C within 1-2 hrs and seeded with crystal form-I. The precipitated polymorphic crystals were further cooled to -10°C to 10°C and maintained for 1-2 hrs. The precipitated polymorphic crystals were filtered, washed with isopropyl alcohol in n-heptane, dried to obtain substantially pure crystal form-I of Propentofylline as an off-white to white solid (85% yield, HPLC purity 99.9%) with (?-Hexoyl impurity of formula (1) 0.05%, Valerate impurity of formula (2) 0.05 % as determined by HPLC.

Claims

CLAIM:

1. A substantially pure Propentofylline of formula (I) comprising at least one or more impurity(es) selected from O-Hcxoyl impurity of formula (1), Valerate impurity of formula (2), and Methane impurity of formula (3) and isopropyl impurity formula (4).

O-Hexoyl impurity (1 ) Valerate impurity (2)

Methane impurity (3) Isopropyl impurity (4)

2. The substantially pure Propentofylline as claimed in claim 1 , wherein the purity is greater than 99.5% as measured by HPLC.

3. The substantially pure Propentofylline as claimed in claim 1 , wherein the purity is greater than 99.5% comprising O-Hexoyl impurity less than 0.10%, Valerate impurity less than 0.10%, Methane impurity less than 0.10% and isopropyl impurity less than 0.10% as measured by HPLC.

4. The substantially pure Propentofylline of formula (I) as claimed in claim 1 comprising the step of: a) reacting 3-methyl xanthine (II) with n-propyl halide where halide is chloride, bromide, and Iodide, in presence of base, a polar aprotic solvent to obtain 3-methyl-

7-propyl-xanthine of formula (III);

b) reacting 3-methyl-7-propyl-xanthine (III) with 6-halo-2-hexanone where halo is chloro, bromo and Iodo in presence of base, a polar aprotic solvent to obtain Propentofylline of formula (I), c) isolating Propentofylline comprising one or more impurity(es) selected from O- Hexoyl impurity, Valerate impurity, Methane impurity, and isopropyl impurity, d) purifying Propentofylline consisting steps of: i) dissolving in 1:1 to 1:5 volume ratio of alcoholic and hydrocarbon solvent at temperature 50°C to 70°C for 15 min to 2 hrs, ii) cooling and optionally seeding, iii) filtering to obtain substantially pure Propentofylline.

5. The process as claimed in claim 4, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, and sodium bicarbonate.

6. The process as claimed in claim 4, wherein polar aprotic solvent is selected from N,N- Dimethyl formamide, acetone, acetonitrile, dichloromethane, dimethyl sulfoxide, ethyl acetate, hexamethyl phosphoric triamide, pyridine, sulfolane, and tetrahydrofuran.

7. The process as claimed in claim 4, wherein alcoholic solvent is selected from methanol, ethanol, isopropanol, n-butanol, and iso-butanol.

8. The process as claimed in claim 4, wherein hydrocarbon solvent is selected from propane, butane, pentane, n-hexane/hexane, cyclohexane, n-heptane / heptane, toluene, and xylene.

9. The process as claimed in claim 4, wherein n-propyl halide is used in 1.3 to 1.5 mol equivalent and 6-halo-2-hexanone is used in 1.0 to 1.3 mol equivalent.

10. The process as claimed in claim 4, wherein isolation of Propentofylline of formula (I), comprising the steps of: a) filtering the reaction solution, b) removing solvent, c) dissolving reaction residue in an alcoholic solvent, d) cooling and adding hydrocarbon solvent, and e) filtering the propentofylline.

11. The process as claimed in claim 4, wherein mixture of alcoholic solvent and hydrocarbon solvent is used in 3 to 15 volumes.

12. The substantially pure Propentofylline obtained by using a process as claimed in claim 4 is Crystal form -I and characterized by atleast one of the following parameters: a) atleast one characteristic 2-theta value (±0.2) at 3.750, 7.454, 9.079, 10.575, 13.740, 17.141 and 18.659; b) DSC endotherm peak at about 71.79°C; c) TGA % loss as straight line up to 200°C; d) peak maxima in the FTIR spectrum with wave numbers at about 3111.61, 1696.56 and 1651.80 cm^-1±2

13. A substantially pure Propentofylline comprising a compound of formula of formula (1).

14. A substantially pure Propentofylline comprising a compound of formula of formula (2).

15. A substantially pure Propentofylline comprising a compound of formula of formula (3).

16. A substantially pure Propentofylline comprising a compound of formula of formula (4).

Isopropyl impurity (4)