TECHNICAL FIELD

The present invention relates to a method for the preparation of pharmaceutically active compounds.

More specifically, the present invention relates to a method for the preparation of precursor of anti-cancer drug ibrutinib.

BACKGROUND ART

Ibrutinib is the compound of formula (I) [1] - anti-cancer drug used to treat malignant B-lymphoproliferative disorders.

Ibrutinib's synthesis scheme involves an intermediate (precursor) of formula (II), that contains main fragments of ibrutinib's structure: pyrazolo[3,4-i ]pyrimidine bicyclic system with 4-phenoxyphenyl group at the position 3, as well as N-unsubstituted piperidin-3-yl substituent at the nitrogen atom N-l of the pyrazolo[3,4-^pyrimidine heterocycle. Conversion of the precursor (II) to ibrutinib (I) is performed by trivial methods, using acylation of the piperidine NH group by acrylic acid in the presence of condensing agents or by acryloyl chloride. Precursor (II) is obtained from N(l')-protected intermediate (3) by removal of the protecting group (Pg) by known methods.

(I) X = CI, imidazol-l-yl, etc.

Ibrutinib

Until recent time most of the published methods for synthesis of the precursor (II) can be attributed to one of two general synthetic pathways: 1) Mitsunobu reaction between (3-aryl- lH-pyrazolo[3,4-if]pyrimidin-4-yl)amine (1) and N-protected 3-hydroxypiperidine (2) [1, 2]; 2) Suzuki reaction between (3-halo-lH-pyrazolo[3,4-d]pyrimidin-4-yl)amine (4) and arylboronic acid derivative (5) [3, 5],

Both mentioned synthetic pathways involve Mitsunobu reaction that results in the inversion of the optical configuration of carbon atom C-3 of the piperidine cycle. However, there are reports [11] about partial racemization during Mitsunobu reaction that may lower the optical purity of the product.

Another synthetic pathway leading to the intermediate (3), not involving Mitsunobu reaction, is described in the recently published patent [4]. The method is based on the reaction of compound (6) with (R)-(piperidin-3-yl)hydrazine (7) obtaining pyrazole (8), which then reacts with formamide yielding pyrazolo[3,4-.i]pyrimidine (3).

The starting compound (6) is obtained from 4-phenoxybenzoic acid converting it into the corresponding acyl chloride following by condensation with malononitrile and methylation (e. g. by dimethyl sulfate). However, synthesis of the optically active (piperidin-3-yl)hydrazine (7) in the patent [4] is not disclosed. The known methods of ibrutinib's precursor (II) synthesis are characterized by complicated procedures and by use of some reagents that are not convient for large-scale synthesis. Thus, introduction of aromatic fragment into molecule of intermediate (3) is performed by Suzuki reaction, that means necesssity to use unstable and expensive arylboronic acid, as well as previous halogenation step to obtain 3-halopyrazolo[3,4-<i]pyrimidine (4). Two of the most popular ibrutinib's synthetic routes use Mitsunobu reaction to introduce optically active piperidine moiety. However, Mitsunobu reaction may cause a partial racemization of the chiral reagent, that lowers the optical purity of the product. In another method, involving condensation of optically active (piperidin-3-yl)hydrazine with l,l-dicyano-2-methoxy-2-(4- phenoxyphenyl)ethylene, it is necessary to use expensive 4-phenoxybenzoic acid and some toxic reagents (e. g. SOCl ₂ , dimethyl sulfate). Also, in this method it is necessary to obtain optically active (piperidin-3-yl)hydrazine, that, obviously, is very complicated process, for which a detailed description is not available in the literature.

SUMMARY OF INVENTION

TECHNICAL PROBLEM

Analysis of the background art shows the unsatisfied need of a simple and technologically advantageous alternative method for synthesis of ibrutinib's precursor (II).

SOLUTION TO PROBLEM

Direct C-arylation of pyrazolo[3,4-cT]pyrimidine at C-3 position was not used in the synthesis of ibrutinib's precursor (II) until now. Some works are published [7-10, 12, 13] describing direct arylation of indazole at C-3 position. However, there are no reports on direct C-arylation of amino-substituted indazoles, also direct C-arylation of pyrazolopyrimidines is not known at all. Regarding direct C-3 arylation of pyrazolo[3,4-<i]pyrimidme, in our case the situation is complicated not only by potentially similar reactivity of C-6 atom in the pirimidine cycle, but also by presence of amino group 4-NH ₂ . We unexpectedly found, that compound with protected piperidine NH and 4-NH ₂ groups (III, Pg ₂ ≠ H), as well as compound with unprotected 4-NH ₂ group (III, Pg ₂ = H), reacts with l-bromo-4- phenoxybenzene in the presence of palladium catalyst (e. g., Pd(OAc) ₂ - 1 , 10-phenanthroline- Cs ₂ C0 ₃ system) with formation of compound (IV). Deprotection of the latter by known methods leads to the ibrutinib's precursor (II). For example, 4-(benzyloxycarbonyl)amino- 1- [l-(benzyloxycarbonyl)piperidin-3-yl derivative (III) (Pgi = Pg ₂ = Cbz) reacts with 1-bromo- 4-phenoxybenzene with high conversion, selectively forming compound (IV) (Pgi = Pg ₂ = Cbz) with good yield (76%). Further hydrogenation (H ₂ , Pd/C, MeOH) results in removal of both Cbz protecting groups, thus obtaining ibrutinib's precursor (II) with free NH ₂ group ar the pyrimidine cycle and free NH group in the piperidine fragment; the obtained compound (II) can be easily acylated to give the final product ibrutinib (I).

Pg ₂ = H, Boc, Cbz, Bn, etc.

Continuing our study of direct C-arylation we surprisingly found that compound (III) with unprotected 4-NH ₂ group (Pg _! = Boc, Pg ₂ = H) reacts with l-bromo-4-phenoxybenzene in the presence of palladium catalyst forming compound (IV) (Pgi = Boc, Pg ₂ = H) with good yield (65% or higher). However, arylation of compound (III) with protected 4-NH ₂ group has certain preparative advantages, such as higher conversion and yield of the product, as well as more easy isolation of the arylated compound (III).

We investigated physically-chemical and NMR spectral characteristics of the compound (IV) obtained by the above described direct C-arylation of compound (III) with unprotected 4-NH ₂ group. Comparing these characteristics with the corresponding characteristics of the standard sample of compound (IV) obtained by other method, we found that these compounds are identical. So, despite the presence of the unprotected 4-NH ₂ group arylation of the unprotected compound (III) surprisingly occurs with desired regioselectivity and in the direct arylation experiments we obtained exactly C(3)-arylated product (IV) instead of the possible 4-arylamino- or 6-aryl-substituted isomers. Compounds (III) with the protected 4-NH ₂ group (e. g., Pg ₂ = Boc or Cbz) react with l-bromo-4-phenoxybenzene even faster, the reaction occurs at lower temperature and with less amount of impurities than in the case of unsubstituted compound (HI).

After removal of both deprotecting groups (Pgi and Pg ₂ ) by the appropriate procedure we obtained compound (II). Acylation of the latter by acryloyl chloryde in standard conditions [ 1 1 leads to ibrutinib (I) which is identical with the standard ibrutinib's sample by the physically-chemical and spectral characteristics. ADVANTAGEOUS EFFECTS OF INVENTION

The described method allows to obtain the ibrutinib's precursor (II) with good yields by direct C-arylation of protected derivatives (III) of known [6] l-(piperidin-3-yl)pyrazolo[3,4- </]pyrimidin-4-amine bearing protecting group at the piperidine nitrogen atom and, preferably, also at the 4-NH ₂ group. Performing synthesis of the ibrutinib's precursor (II) by the method described in this invention eliminates work with unstable and expensive arylboronic acid derivatives and toxic phosphine ligands. The most preferable ligands for direct C-arylation are nitrogen-containing heterocycles, e. g. 1,10-phenanthroline, derivatives of 2,2'-bipyridine, etc., that are more available, less toxic, stable in air and moisture, and recoverable (if necessary). Palladium(II) salts used as the catalysts in the direct C-arylation reactions are easily separable from the reaction mixture in the form of amorphous Pd(0). Performing ibrutinib's large-scale synthesis, the palladium catalyst also might be recovered by converting of the precipitated Pd(0) to the corresponding Pd(II) salt. In the described direct C(3)- arylation of pyrazolo[3,4-<flpyrimidine cycle, the chiral centre - C-3 atom of the piperidine moiety - is not affected, so the optical purity of the product is not compromised. The convient method for aryl group introduction in the final steps of the ibrutinib's (I) synthesis opens a possibility to synthesize series of ibrutinib's analogues by varying the aryl halide used in the C-arylation.

The described method can be performed in different solvents, e. g. toluene, xylene, dimethylacetamide, diglyme, dioxane, 1,2-dimethoxyethane or in a mixture of solvents. Different complex-forming compounds can be used as the catalyst, more preferable - nitrogen-containing heterocycles such as 1,10-phenanthroline, derivatives of 2,2'-bipyridine, etc. As the base, alkali metal carbonates, phosphates, alkoxides can be used, e. g. Cs ₂ C0 ₃ , t- BuOK, etc. The reaction temperature, depending on the solvent used, may vary from 80 to 180°C; the reaction time is from 4 to 48 h. In the following examples, the process which is the object of the present patent application is described by way of examples; these examples are not intended to limit the scope of protection of the same.

EXAMPLES

Boc-protected compound (III) (Pg _t = Boc, Pg ₂ = H) and its unprotected analogue (Pgi = Pg ₂ = H) are described in the patent [6 J. Starting from these compounds, N ⁴ ,N' -(BOC) ₂ - protected compound (III) (Pgi = Pg ₂ = Boc), as well as N ⁴ ,N ¹ -(Cbz) ₂ -protected compound (HI) (Pgi = Pg ₂ = Cbz) were also synthesized by known methods.

Example 1

(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-^pyrimid in-l-yl]piperidine-l- carboxylic acid tert-butyl ester (IV, Pgi = Boc, Pg ₂ = H)

A mixture of compound (III) (Pgi = Boc, Pg ₂ = H) (318 mg, 1.00 mmol), Pd(OAc) ₂ (22 mg, 0.10 mmol), 1,10-phenanthroline (18 mg, 0.10 mmol), Cs ₂ C0 ₃ (358 mg, 1.10 mmol), 1- bromo-4-phenoxybenzene (274 mg, 1.10 mmol) and xylene (5 ml) was heated in a sealed tube under argon atmosphere at 160°C for 24 h with intensive stirring. After completion of the reaction the tube was cooled to room temperature, carefully opened, and the reaction mass was poured into EtOAc (20 ml). After intensive stirring for 5 min the obtained suspension was filtered through celite un evaporated in vacuum. The product was purified by column chromatography (eluent CH ₂ Cl ₂ -MeOH 20:1, R _f 0.5). Yield 234 mg (48%), viscous yellowish oil.

Example 2

(3R)-3-[4-Amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-<f]pyrimidin- 1 -yl]piperidine- 1 - carboxylic acid tert-butyl ester (IV, Pgi = Boc, Pg ₂ = Η)

A mixture of compound (III) (Pg _! = Boc, Pg ₂ = Η) (636 mg, 2.00 mmol), Pd(OAc) ₂ (44 mg, 0.20 mmol), 1,10-phenanthroline (36 mg, 0.20 mmol), K ₂ C0 ₃ (304 mg, 2.20 mmol), 1- bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and Ν,Ν-dimethylacetamide (DMA) (10 ml) was heated in a sealed tube under argon atmosphere at 150°C for 16 h with intensive stirring. The product (III) was isolated and purified similarly to that described in the Example 1. Yield 642 mg (66%), viscous yellowish oil. The analytical data of the obtained compound (III) correspond to that of the product obtained in the Example 1.

Example 3

(3/?)-3-|4-Amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-c/]pyrimidin- 1-ylJpiperidine-l- carboxylic acid tert-butyl ester (IV, Pgi = Boc, Pg ₂ = Η) A mixture of compound (III) (Pgi = Boc, Pg ₂ = H) (636 mg, 2.00 mmol), Pd(OAc) ₂ (44 mg, 0.20 mmol), 4,4'-di(tert-butyl)-2,2'-bipyridine (54 mg, 0.20 mmol), K ₃ P0 ₄ (467 mg, 2.20 mmol), 1 -bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and DMA (10 ml) was heated in a sealed tube under argon atmosphere at 150°C for 48 h with intensive stirring. The product (III) was isolated and purified similarly to that described in the Example 1. Yield 428 mg (44%), viscous yellowish oil. The analytical data of the obtained compound (III) correspond to that of the product obtained in the Example 1.

Example 4

(3R)-3-[4-(Benzyloxycarbonylamino)-3-(4-phenoxyphenyl)-lH-py razolo[3,4- ]pyrimidin-l- yl]piperidine-l-carboxylic acid benzyl ester (IV, Pgi = Pg ₂ = Cbz)

A mixture of compound (III) (Pgi = Pg ₂ = Cbz) (973 mg, 2.00 mmol), Pd(OAc) ₂ (44 mg, 0.20 mmol), 1,10-phenanthroline (36 mg, 0.20 mmol), Cs ₂ C0 ₃ (716 mg, 2.20 mmol), l-bromo-4- phenoxybenzene (548 mg, 2.20 mmol) and xylene (10 ml) was heated in a sealed tube under argon atmosphere at 140°C for 16 h with intensive stirring. After completion of the reaction the tube was cooled to room temperature, carefully opened, and the reaction mass was poured into EtOAc (40 ml). After intensive stirring for 5 min the obtained suspension was filtered through celite un evaporated in vacuum. The product was purified by column chromatography (eluent EtOAc-hexane 1:2, R _f 0.4). Yield 995 mg (76%), white amorphous powder.

Example 5

(3 ?)-3-[4-(tret-Butoxycarbonylamino)-3-(4-phenoxyphenyl)-lH-py razolo[3,4-<i]pyrimidin-l- yl]piperidine-l-carboxylic acid tert-butil ester (IV, Pgi = Pg ₂ = Boc)

A mixture of compound (III) (Pg _! = Pg ₂ = Boc) (837 mg, 2.00 mmol), PdCl ₂ (35 mg, 0.20 mmol), 4,4'-di(tert-butyl)-2,2'-bipyridine (54 mg, 0.20 mmol), Cs ₂ C0 ₃ (716 mg, 2.20 mmol), l-bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and diglyme (10 ml) was heated in a sealed tube under argon atmosphere at 110°C for 20 h with intensive stirring. After completion of the reaction the tube was cooled to room temperature, carefully opened, and the reaction mass was poured into EtOAc (40 ml). After intensive stirring for 5 min the obtained suspension was filtered through celite un evaporated in vacuum. The product was purified by column chromatography (eluent EtOAc-hexane 1:4, R _f 0.3). Yield 727 mg (62%), white amorphous powder.

Example 6

3 -(4-Phenoxyphenyl)- 1 -((3R)-piperidin-3 -il)- lH-pyrazolo[3,4-i |pyrimidin-4-amine (II) Compound (IV) (Pg] = Pg? = Boc) (2.93 g, 5 mmol) was dissolved in MeOH (15 ml), then 33% HQ (3 ml) was added, and the reaction mass was heated at 50°C for 4 st with intensive stirring (note: a foam is forming during the reaction due to isolation of gaseous by-products!). After completion of the reaction the resulting solution was cooled to room temperature and evaporated to dryness (note: the vapor contains HC1). Saturated Na ₂ C0 ₃ solution (5 ml) was added to the dry residue and the mixture was extracted with EtOAc (3 x 10 ml). The extract was dried over Na ₂ S0 ₄ and evaporated in vacuum. Yield 1.89 g (98%), white amorphous mass.

From N ⁴ ,N ^! -(Cbz) ₂ -protected compound (IV) (Pg _! = Pg ₂ = Cbz) using standard hydrogenation conditions in the presence of Pd/C catalyst, compound (II) was obtained in 99% yield. The analytical data of this product correspond to that of the above mentioned product (II) obtained from N ⁴ ,N ^J -(Boc) ₂ -protected compound (IV) (Pg _\ = Pg ₂ = Boc).

INDUSTRIAL APPLICABILITY

The invented method may be realized in pharmaceutical industry using the corresponding equipment and conditions. The method allows to obtain the product, which can be purified to pharmaceutical quality (>99%) by routine procedures. The process is characterized by utilizable waste and easily separable impurities in the target product.

CITATION LIST

PATENT LITERATURE

[ 1 | WO2008/121742.

[2] US2008/007621.

[3] WO2012/158795.

[4] WO2014/139970.

[5] WO2009/062118.

[6] WO2012/058645.

NON PATENT LITERATURE

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