DESC:Field of the invention

The present invention relates to new crystalline solvate form of Ibrutinib and process for the preparation thereof.

Background of the Invention

Ibrutinib is an organic small molecule having IUPAC name 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1-yl] piperidin-1-yl] prop-2-en-1-one.

Ibrutinib is a selective, irreversible inhibitor of BTK first disclosed in WO 2008/039218, which has been shown to be highly clinically efficacious in relapsed/refractory CLL and mantle cell lymphoma (see e.g. Burger et. Leukemia & Lymphoma (2013), 54(11), 2385-91).

Amorphous Ibrutinib is moisture stable. It is therefore a good alternative to crystalline Ibrutinib as amorphous material has a higher solubility, which is connected with better bioavailability, than corresponding crystalline forms. Thus, amorphous Ibrutinib is the preferred physical form for the preparation of pharmaceutical compositions.

CN 103121999 A discloses Ibrutinib of undisclosed form with an HPLC purity of 98.6% and >98% ee by crystallization from toluene.

CN 103923084 A discloses anhydrous, hydrous as well as solvate crystal forms of Ibrutinib, the solvate forms of Ibrutinib being solvates of oxolane and trichloromethane.

Three anhydrous polymorphs and solvates from methanol, methylisobutylketone (MIBK), and toluene of Ibrutinib have been specifically disclosed in WO 2013/184572 including formulations containing them and their use. However, the toluene solvate has been reported as being unstable. Moreover, solvates with methanol and MIBK suffer from low solubility of Ibrutinib in those solvents (about 1 wt% or less), thereby limiting their use for purification and subsequent preparation of amorphous Ibrutinib on industrial scale as this would require very large amounts of solvent. Thus, the solvates from methanol and methylisobutylketone are not suitable for the preparation of amorphous Ibrutinib for use in the manufacture of a medicament.

Furthermore, according to WO 2008/039218 amorphous Ibrutinib can be obtained from material prepared by fast evaporation of solvent from dichloromethane solution. However, material used for this process has been purified by chromatography on silica gel using dichloromethane/alcohol mixtures. This approach bears the disadvantage that the eluent in the final purification step contains unspecified amounts of silica gel leaking from the column. Because such impurities might affect chemical stability in an uncontrolled manner such a material is not appropriate for use in a medicament. Moreover, amorphous Ibrutinib material prepared by fast rotary evaporation as described in WO 2008/039218 features a solid state best described as honey-like, gum, or foam, depending on the amount of residual dichloromethane still present. Such a material is difficult or even impossible to handle and process on a large scale.

WO2015081180 discloses a crystalline form of Ibrutinib, designated as Form I.

WO2015145415 discloses crystalline form III, IV, V, VI, VII, VIII and IX of Ibrutinib.

WO2015145415 also discloses the process for the preparation of amorphous form of Ibrutinib.

WO2016025720A1 discloses Form G, J and K of Ibrutinib.

WO2016079216 discloses anisole, chlorobenzene, 1, 4-dioxane, and pyridine solvates of Ibrutinib.

Summary of Invention

It was thus an object of the present invention to provide a physical form of Ibrutinib and the provision of a process for the preparation of such physical forms of Ibrutinib, which can overcome the disadvantages of the prior art processes.

It has surprisingly been found in the present invention that the above objects can be solved by the provision of new crystalline forms of Ibrutinib. In particular, it has surprisingly been found that new crystalline solvates can be provided.

Studies of solvates of Ibrutinib obtained from solvents such as benzyl alcohol.

Further, it has been surprisingly found that amorphous form of Ibrutinib prepared from these new solvates is essentially free from any chemical impurities, and is essentially free from any crystalline forms of Ibrutinib, such as for example crystalline form A. Moreover, the process of the present invention for the preparation of amorphous Ibrutinib has the advantage over the prior art process that it relies not on any column chromatography, and therefore the resulting product is free from any residual silica. Finally, amorphous Ibrutinib is obtained as a free fluent powder, appropriate for use in the preparation of a medicament on industrial scale. Furthermore, solvates obtained from e.g. benzyl alcohol were found to be useful for the preparation of crystalline, anhydrous form of Ibrutinib on industrial scale.

In a first aspect, the present invention refers to a solvate of 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1-yl] piperidin-1-yl] prop-2-en-1-one. (Ibrutinib)

In another aspect, the present invention refers to a benzyl alcohol solvate of 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1-yl] piperidin-1-yl] prop-2-en-1-one. (Ibrutinib)

In another aspect, the invention refers to a process for the preparation of a solvate of Ibrutinib, the process comprising the steps of,
a) providing a solution of Ibrutinib in a suitable solvent and benzyl alcohol,
b) optionally adding anti solvent and
c) isolating the crystalline benzyl alcohol solvate.

In another aspect, the invention refers to a process for the preparation of a benzyl alcohol solvate of Ibrutinib, the process comprising the steps of,
a) providing a solution of Ibrutinib in DCM and benzyl alcohol at room temperature,
b) distilling the reaction mass of step (a) and
c) recovering the crystalline form of benzyl alcohol solvate.

In another aspect, the present invention provides a process for the preparation of Ibrutinib of the Formula I,

comprising condensing a compound 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1-yl) piperidine of formula II with formula III to obtain Ibrutinib.

Brief Description of Drawings

Figure 1 illustrates an X-Ray powder diffraction (XRPD) pattern (diffractogram) of the benzyl alcohol solvate of Ibrutinib.
Figure 2 illustrates a TG/DTA thermogram of the benzyl alcohol solvate of Ibrutinib.
Figure 3 illustrates a DSC pattern of the benzyl alcohol solvate of Ibrutinib.

Detailed Description of Invention

In a first embodiment, the present invention refers to a solvate of 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1-yl] piperidin-1-yl] prop-2-en-1-one. (Ibrutinib).

In another embodiment, the present invention refers to a benzyl alcohol solvate of 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1-yl] piperidin-1-yl] prop-2-en-1-one.

In another embodiment, the invention refers to a process for the preparation of a solvate of Ibrutinib, the process comprising the steps of,
a) providing a solution of Ibrutinib in a suitable solvent and benzyl alcohol,
b) optionally adding anti solvent and
c) isolating the crystalline benzyl alcohol solvate.

In another embodiment, the invention refers to a process for the preparation of a benzyl alcohol solvate of Ibrutinib, the process comprising the steps of,
a) providing a solution of Ibrutinib in DCM and benzyl alcohol,
b) optionally adding cyclohexane and
c) isolating the crystalline benzyl alcohol solvate.

In another embodiment, the invention refers to a process for the preparation of a benzyl alcohol solvate of Ibrutinib, the process comprising the steps of,
a) providing a solution of Ibrutinib in DCM and benzyl alcohol at room temperature,
b) distilling the reaction mass of step (a) and
c) isolating the crystalline form of benzyl alcohol solvate.

In another embodiment, the invention refers to a process for the preparation of amorphous Ibrutinib comprising the steps of:
a) providing a solution of Ibrutinib in suitable solvents,
b) stirring the solution, or submitting the solution to one or more of temperature cycling, crash cooling, distillation, stripping, evaporation, or anti-solvent addition, to form a slurry,
c) optionally isolating the crystalline solvate in solid form,
d) optionally drying the crystalline solvate,
e) desolvating the solvate, and
f) optionally drying the product.

In another embodiment, the invention refers to a process for the preparation of amorphous Ibrutinib comprising the steps of:
a) providing a solution of Ibrutinib benzyl alcohol solvate in suitable solvents,
b) filtering the reaction mass,
c) adding the reaction mass to the suitable solvent,
d) drying the product to obtain amorphous form of Ibrutinib.

In another embodiment, the invention refers to a process for the preparation of amorphous Ibrutinib comprising the steps of:
a) providing a solution of Ibrutinib benzyl alcohol solvate in dimethyl sulfoxide,
b) filtering the reaction mass,
c) adding the reaction mass to the water,
d) drying the product to obtain amorphous form of Ibrutinib.

In another embodiment, the invention refers to a process for the preparation of form A Ibrutinib comprising the steps of:
a) drying Ibrutinib benzyl alcohol solvate under vacuum product to obtain form A Ibrutinib.

In another embodiment, the present invention refers to a benzyl alcohol solvate of Ibrutinib. The solvate is typically characterized by having one or more of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1;
(b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.41±0.2, 12.52±0.2, 16.29±0.2, 16.53±0.2, 19.09±0.2 ,20.69±0.2, and 20.85±0.2° 2-Theta;
(c) a thermogravimetric/differential thermal analysis (TG/DTA) thermogram substantially similar to the one set forth in Figure 2;and
(d) DSC pattern as shown in Figure 3.

In another embodiment, the present invention provides a process for the preparation of Ibrutinib of the Formula I,

comprising condensing a compound of formula II or a salt thereof with formula III to obtain Ibrutinib.

In another embodiment, the present invention provides a process for the preparation of Ibrutinib of the Formula I,

comprising condensing a compound of formula II or a salt thereof with formula III in the presence of suitable base ,suitable condensing agent and suitable solvent to obtain Ibrutinib.

In another embodiment, the present invention refers to the compound of formula IV.

In another embodiment, the present invention refers to the compound of formula V.


In another embodiment, the present invention refers to the compound of formula VI.

Crash cooling is typically performed by directly and rapidly cooling the solution from a temperature of between 25-50°C to a temperature of 2°C or below, such as a temperature between 0°C and -18°C, depending on the type of solvate, and keeping the solution at this temperature for example for 4 h to 24 h, such as for example 16-20 h.

Evaporation is typically performed at reduced pressure, but may also be achieved at atmospheric pressure.

Stripping is a physical separation process where one or more components are removed from a liquid stream by a vapor stream.

Temperature cycling is the process of cycling through two temperature extremes, typically at relatively high rates of change.

Suitable solvent of the present invention may be selected from the group consisting of water, alkanol, esters, ketones, ethers, polar aprotic solvents, or mixtures thereof. Examples of alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, 2-propanol, ethylene glycol, PEG, benzyl alcohol butanol. Examples of ester solvents include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include tetrahydrofuran and the like. A suitable polar aprotic solvent includes N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1, 2-dichloroethane. Examples of hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene, perfluorobenzene and the like; polar solvents" such as water; and/or their mixtures, nitro solvents like nitro methane, nitro ethane and the like.

Anti solvent of the present invention may be selected from the group consisting of n-hexane, n-heptane, cyclohexane, benzene, toluene and xylene.

R is selected for the present invention from the group comprising of acetyl, benzoyl, substituted benzoyl, benzyl, substituted benzyl, dimethoxy trityl, methoxy trityl, tetrahydro pyranyl, trityl, ß-methoxyethoxymethyl ether, methoxymethyl ether , p-methoxybenzyl ether, methylthiomethyl ether, silyl ether (such as trimethylsilyl, tert-butyldimethylsilyl, tri-iso-propylsilyloxymethyl , trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, triphenylsilyl and triisopropylsilyl), methyl ethers, ethoxyethyl ethers, t-butyl, t-butoxymethyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, p-chlorophenyl, 2,4- dinitrophenyl, diphenylmethyl, , benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, 9-fluorenyl-methyl carbonate, mesylate, tosylate, triflate, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, substitutedpixyl, carbobenzyloxy, p-methoxybenzyl carbonyl , tert-butyloxycarbonyl, 9-fluorenylmethyloxy carbonyl, carbamate , p-methoxybenzyl, 3,4-dimethoxybenzyl , p-methoxyphenyl, besyl, fluorosulfonyl,nosyl, brosyl, acryloyl, nitrate; alkyl phosphate; alkyl borate; trialkylammonium; dialkylsulfonium; 2,4,5-trichlorophenoxy; 2,4-dinitrophenoxy; succinimido-n-oxy, imidazolyl, halo amides, hydroxides, alkoxides, phenoxides, carboxylates, amines, ammonia, thiolate, dialkyl ether and the like.

Suitable base of the present invention includes but not limited to an inorganic base or organic base selected from the group comprising of carbonates, bicarbonates, hydroxides, hydrides and alkoxides of alkali or alkaline earth metals and the like, phosphates such as dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diammonium monohydrogen phosphate, ammonium dihydrogen phosphate and triammonium phosphate; acetates such as potassium acetate, sodium acetate and ammonium acetate; formates such as potassium formate and sodium formate; n-butyllithium, n-hexyllithium, sodium hydride and lithium diisopropylamide. These inorganic bases may be used singly, or in combination of two or more kinds thereof. The organic base is selected from the group comprising of lutidine, diisopropylethylamine, dimethylaminopyridine, triethylamine, tri-n-propylamine, tri-n-butylamine, piperidine, pyridine, 2-picoline, 3-picoline, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N,N-diethylaniline, N-ethyl-N-methylaniline, diisopropylethylamine, 3-methylimidazole, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane and 4-dimethylaminopyridine; and metal alcoholates such as sodium methoxide and sodium ethoxide. Other bases are known to the person skilled in the art.

Suitable condensing agent of the present invention includes but not limited to phenylsilane, 1,1'-carbonyldiimidazole (CDI), benzotriazol-1-yloxytris (dimethylamino) phophonium hexafluorophosphate (BOP), 1-hydroxy benzotriazole hydrate (HOBt), PyBOP (Analog of the BOP), 1,3-dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), N,N-diisopropylethylamine (DIEA), 4-dimethylaminopyridine (DMAP), 1,4-dithio-L-threitol (DTT), N-ethyl-N'-(3-dimethylaminopropyl) carbodidimide hydrochloride (EDC HCl), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosp- hate (HATU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluoroph- osphate (HCTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetra methyluronium tetrafluoroborate (TBTU), tetramethylfluoroformamidiniunhexafluorophosphate (TFFH), Diisopropyl carbodiimide (DIPC), and mixtures thereof.

In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

Examples

Example 1: Preparation of Ibrutinib benzyl alcohol solvate
Ibrutinib (280.0 g), benzyl alcohol (200 ml) and MDC (2240 ml) were charged in to round bottom flask. The mixture was stirred at 25 to 30oC. Solvents were distilled and striped with cyclohexane. Cyclohexane (5600 ml) was charged, stirred at 25 to 30oC. The obtained reaction mass was filtered and washed with cyclohexane. The obtained product was dried under vacuum at 25 to 40oC to obtain benzyl alcohol solvate of Ibrutinib (271.0 g).

Example 2: Preparation of Ibrutinib benzyl alcohol solvate
Ibrutinib (5.0 g) and benzyl alcohol (2.5 ml) were charged in to round bottom flask. The mixture was stirred for 12 hours at 25 to 30oC. Solvents were distilled and then striped with cyclohexane (20 ml). Cyclohexane (200 mL) was charged and stirred at 25 to 30oC. The obtained reaction mass was filtered and washed with cyclohexane. The obtained product was dried under vacuum at 25 to 40oC for 48 hours to obtain benzyl alcohol solvate of Ibrutinib (4.6 g).

Example 3: Preparation of Ibrutinib benzyl alcohol solvate
Ibrutinib (9.0 g), benzyl alcohol (9.0 ml) and MDC (100 ml) were charged in to round bottom flask. The mixture was stirred for 12 hours at 25 to 30oC. Solvents were distilled and then striped with cyclohexane. Cyclohexane (400 mL) was charged and stirred at 25 to 30oC. The obtained reaction mass was filtered and washed with cyclohexane. The obtained product was dried under vacuum at 25 to 40oC for 10 to 12 hours to obtain benzyl alcohol solvate of Ibrutinib (8.1 g).

Example 4: Preparation of Ibrutinib benzyl alcohol solvate
Ibrutinib (5.0 g) and benzyl alcohol (5.0 ml) were charged in to round bottom flask. The mixture was stirred at 25 to 30oC. Cyclohexane (250 mL) was charged and stirred at 25 to 30oC. The obtained reaction mass was filtered and washed with cyclohexane. Product obtained was dried under vacuum at 30 to 40oC for 24 hours to obtain benzyl alcohol solvate of Ibrutinib (4.5 g).

Example 5: Preparation of Ibrutinib amorphous from Ibrutinib Benzyl alcohol solvate
Ibrutinib benzyl alcohol solvate (5.0 g) and dimethyl sulfoxide (25 ml) were charged in to round bottom flask and stirred to get clear solution. The reaction mass was filtered and added to water (100 ml). The reaction mixture was stirred for 1 hour. The reaction mass was filtered and washed with water. The obtained product was dried under vacuum at 30 to 35oC to obtain amorphous Ibrutinib (4.4 g).
Example 6: Preparation of Ibrutinib
(R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo [3, 4-d] pyrimidin-4-amine (5.0 g) and MDC (50.0 ml) were charged in to a round bottom flask. Acrylic acid (0.93g), 1-(3-Dimethyl aminopropyl)-3-ethyl carbodiimide hydrochloride (EDC-HCl) (2.98 g) and MDC (30 ml) were added to the reaction mixture and stirred for 2 hrs at 20 to 25oC.The reaction mass was washed with water, aqueous citric acid solution and was neutralized with aqueous sodium carbonate solution. The reaction mass was washed with brine solution. The layers were separated and MDC was distilled to obtain Ibrutinib (4.2 g).

Example 7: Preparation of Ibrutinib
(R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo [3, 4-d] pyrimidin-4-amine (5.0 g), MDC (50.0 ml) and Diisopropyl ethyl amine (DIPEA) (1.7 g) were charged in to a round bottom flask. Acrylic acid (0.93g), 1-(3-Dimethyl aminopropyl)-3-ethyl carbodiimide hydrochloride (EDC-HCl) (2.98 g) and MDC (30 ml) were added to the reaction mixture and stirred for 2 hrs at 20 to 25oC.The reaction mass was washed with water, aqueous citric acid solution and was neutralized with aqueous sodium carbonate solution. The reaction mass was washed with brine solution. The layers were separated and MDC was distilled to obtain Ibrutinib (4.2 g).

Example 8: Preparation of Ibrutinib
(R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo [3, 4-d] pyrimidin-4-amine (5.0 g) and acetonitrile (50.0 ml) were charged in to a round bottom flask. Acrylic acid (0.78g), 1-(3-Dimethyl aminopropyl)-3-ethyl carbodiimide hydrochloride (EDC-HCl) (2.98 g) and acetonitrile (30 ml) were added to the reaction mixture and stirred for 2 hrs at 20 to 25oC.The reaction mass was washed with water, aqueous citric acid solution and was neutralized with aqueous sodium carbonate solution. The reaction mass was washed with brine solution. The layers were separated and acetonitrile was distilled to obtain Ibrutinib (4.2 g).
,CLAIMS:1. A process for the preparation of a benzyl alcohol solvate of Ibrutinib comprising the steps of :
a) providing a solution of Ibrutinib in a suitable solvent and benzyl alcohol;
b) isolating the crystalline benzyl alcohol solvate.
2. The process of claim 1 where in crystalline benzyl alcohol solvate was isolated by distilling the reaction mass of step (a).
3. The process of claim 1 where in crystalline benzyl alcohol solvate was isolated by adding anti solvent to the reaction mass of step (a).
4. The process according to the claim 1, wherein the suitable solvent is selected from methanol, ethanol, n-propanol, 2-propanol,water, ethyl acetate, n-propyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, N-methylpyrrolidone, dichloromethane, chloroform,1,2-dichloroethane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene, perfluorobenzene, nitro methane and nitro ethane, preferably dichloromethane.
5. The process according to the claim 3, where in anti solvent is selected from n-hexane, n-heptane, cyclohexane, benzene, toluene and xylene.
6. Use of the solvate as claimed in any one claims of 1 to 5 for preparing amorphous form of Ibrutinib.
7. Benzyl alcohol solvate of Ibrutinib having an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.41±0.2, 12.52±0.2, 16.29±0.2, 16.53±0.2, 19.09±0.2 ,20.69±0.2, and 20.85±0.2° 2-theta values.
8. Benzyl alcohol solvate of Ibrutinib characterized by X-ray powder diffraction pattern as shown in Figure-1.
9. Benzyl alcohol solvate of Ibrutinib characterized by DSC pattern as shown in Figure-2.
10. Benzyl alcohol solvate of Ibrutinib characterized by TGA pattern as shown in Figure- 3.

Dated this 15th day of June 2017