LV15201A - The method for the preparation of ibrutinib intermediate - Google Patents

Abstract

Invention relates to method for producing pharmacologically active substances, in particular to the method for the preparation of ibrutinib intermediate (II) by arylation of N-protected 1-(piperidin-3-yl)pyrazolo[3,4-d]pyrimidine-4-amine by 1-bromo-4-phenoxybenzene in the presence of Pd catalyst, nitrogen-containing ligand, and a base, followed by removal of protecting groups by known procedures is reported.

Description

DESCRIPTION OF THE INVENTION

Engineering industry

The invention relates to methods for obtaining pharmacologically active substances.

In particular, the invention relates to a method for obtaining the raw material for the ibrutinib synthesis of a cancer preparation.

Level of technique

Ibrutinib is a compound of formula (I) [1], an anticancer drug used to treat malignant B-lymphoproliferative diseases.

The starting material or the last intermediate in the synthesis of ibrutinib (I) - a compound (Π) that contains the basic structure of ibrutinib - the bicyclic system of pyrazolo [3,4-d] pyrimidine with the (4-phenoxyphenyl) group at the 3rd position and the N-unsubstituted (piperidine-3-) il) a substituent at the nitrogen atom N1. The preparation of Ibrutinib (I) from compound (II) is carried out by trivial methods, acylating it with acrylic acid in the presence of condensing agents or with acryloyl chloride. The compound (II) is obtained from N (l ') - a protected intermediate (3) by removing the protecting group Pg by known techniques.

Methods of synthesis of intermediate (3) described so far with minor variations can be grouped in two ways: 1) Micunobes reaction between (3-aryl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) amine (1) and N- protect 3-hydroxypiperidine (2) [1,2]; 2) Suzuki reaction between (3-halo-1H-pyrazolo [3,4-d] pyrimidin-4-yl) amine (4) and an arylboronic acid derivative (5) [3, 5].

In both variants of ibrutinib starting material (II) synthesis, Micunobu reaction is used, resulting in a change in the optical configuration of the carbon atom in position 3 of the piperidine moiety. However, in the literature [11] there is information about partial racemization during the Micunobu reaction, which may impair the optical purity of the product.

In the literature [4] another synthesis pathway for the counter product (3), which does not include the Micunob reaction, is described. It is based on the reaction of the compound (6) with (II) - (piperidin-3-yl) hydrazine (7) to form the pyrazole (8) from which pyrazolo [3,4-d] pyrimidine (3) is obtained by reaction with formamide:

The raw material (6) is obtained from 4-phenoxybenzoic acid by conversion to chloride, then condensed with malondinitrile and methylation (e.g. dimethyl sulfate). The method for obtaining an optically active hydrazine (7) is not detailed in the patent [4].

Certain methods are characterized by complexity and the use of non-industrial reagents. Thus, the Suzuki reaction used to introduce an aromatic fragment into the synthesis of the interconnection (3) involves the use of unstable and expensive arylboronic acid, as well as prior to the addition of a halogen atom (Br or I) in the pyrazolo [3,4-d] pyrimidea substrate, which requires an additional step and work with specific, toxic halogenating reagents. Two of the most popular ibrutinib synthesis pathways for administering the optically active piperidine fumarate are Micunobu's reaction, which may result in partial racemization which may impair product quality. Another method of using the optically active (piperidin-3-yl) hydrazine condensation to form the pyrazole ring with 1,1-dicyano-2-methoxy-2- (4-phenoxyphenyl) ethylene involves the use of relatively expensive substituted benzoic acid and toxic reagents; also the synthesis of optically active (piperidin-3-yl) hydrazma is a complex process because its detailed description is not available.

Summary of Invention Technical Problem

Assessment of the state of the art shows that there is an unmet need for a simpler and more technologically advantageous alternative raw material extraction process (II).

Solution to the problem

So far, the direct C-arylation of pyrazolpyrimidine at position 3 of the pyrazole cycle has not been used in the synthesis of Ibrutinib starting material (II). There are some works that show the possibility to directly arylate the C-3 atom of the pyrazole ring in the indazole ring [7-10, 12, 13]. The arylation of indazoles containing the amino group in the benzene ring is not known. Also, arylation of pyrazolpyrimidines is not known. In our case, the problem is complicated not only by the potentially reactive C-6 atom in the pyrimidine cycle, but also by the amino group 4-NH2. We unexpectedly discovered that both the compound protected by NH and NH2 (III, Pg2 φ H) and the compound with an unprotected NH2 group (ΠΙ, Pg2 = H) reacted with 1-bromo-4-phenoxybenzene in the presence of a palladium catalyst (e.g. , Pd (OAc) 2 -10-phenanthroline-Cs2CO3 system) to form compound (IV), from which after removal of the protecting groups by known methods it is easy to obtain ibrutinib starting material (Π). For example, 4- (benzyloxycarbonyl) amino-1- [1- (benzyloxycarbonyl) piperidin-3-yl] derivative (III) (Pgi = Pg2 = Cbz) reacts with 1-brom-4-phenoxybenzene with high conversion, selectively forming a compound (IV) (Pgi = Pg2 = Cbz) with good result (76%). Further hydrogenation (H2, Pd / C, MeOH) results in the removal of both Cbz-protecting groups, thereby obtaining ibrutinib feedstock (II) with free NH2 group in the pyrimidine cycle and free NH-group in the piperidine moiety, which is easily converted to ibrutinib by the acylation reaction (I ).

Continuing the study of direct C-arylation reaction, we surprisingly discovered that compound (III) with an unprotected 4-NH 2 group (Pgi = Boc, Pg 2 = H) reacts with 1-bromo-4-phenoxybenzene.

Palladium in the presence of a catalyst to form compound (IV) (Pgi-Boc, Pg2 = H) with good yield (65% and more). However, arylation of the compound (ΙΠ), although it requires the introduction of 2 protecting groups, has a preparatory advantage as the product (IV) with the two protecting groups is easier to isolate and purify, and the reaction has a better outcome.

By comparing the physico-chemical properties and NMR spectra of the compound (II) obtained in these direct arylation processes with the corresponding standard sample characteristics, we found that these compounds were identical. Thus, despite the presence of an unprotected 4-NH2-group, the arylation of compound (III) is surprisingly with the desired regioselectivity as the 3-aryl derivative (IV) (Pg2 = H), rather than the possible 4-arylamino or 6-aryl aromers as the main product. . Compounds (ΙΠ) with a protected 4-NH 2 group (e.g., with Boc- or Cbz-protection) react more easily with 1-bromo-4-phenoxybenzene, the reaction is faster and at a lower temperature. In this case, the lower content of the by-products in the reaction mixture is also observed.

Acylation of the intermediate (II) with acryloyl chloride under known conditions [1] yields ibrutinib, which by its nature is identical to the standard compound.

Advantages of the invention

The proposed technique allows to obtain ibrutinib feedstock (II) with good yield through direct arylation from the known [6] 1- (piperidin-3-yl) pyrazolo [3,4-d] pyrimidine-4-amine protected derivatives containing the piperidine protecting group a nitrogen atom or an analog thereof with an additional protected 4-NH 2 group. The synthesis of ibrutinib raw material (II) according to the present invention does not need to work with unstable and expensive arylboronic acid or its derivatives, as well as with toxic phosphine ligands. The most suitable ligands for the direct C-arylation reaction are nitrogen-containing heterocycles, such as: 1,10-phenanthroline, ....... 2,2'-bipyridyl derivatives, etc., which are readily available, toxic, stable in air and humidity, and if necessary, it can be recovered from the reaction mixture. Palladium (II) salts used as catalyst in C-arylation are reduced during reaction to amorphous Pd (0), which is readily separable from the reaction mixture. If necessary, palladium can be converted back to the desired Pd (II) salt by industrial scale synthesis. The described arylation reaction of the C-3 atom does not affect the chiral center, the C-3 atom of the piperidine ring attached to the N-1 atom of the pyrazole ring, thus the optical purity of the product is not impaired. A convenient method of administering an aryl group at the end of ibrutinib synthesis also makes it easy to obtain ibrutinib analogue libraries for further biological studies by varying the aryl halides used in the reaction.

Description of embodiments of the invention

The proposed process can be carried out in a variety of solvents, such as toluene, xylene, dimethylacetamide, diglyme, dioxane, 1,2-dimethoxyethane or mixtures thereof. Palladium complexes or salts such as Pd (OAc) 2, PdCh, Pd (CF3COO) 2, etc. may be used as catalyst. Various complexing compounds, preferably nitrogen-containing heterocycles (1,10-phenanthroline, 2,2'-bipyridyl derivatives, etc.) can be used as ligands. A variety of alkali metal carbonates, phosphates, alkoxides such as CS2CO3, r-BuOK, etc. may be used as a base for the reaction. The reaction temperature, depending on the selected reagents and solvent, is between 80 and 180 ° C, the reaction time is 4-48 hours. Examples of how to implement the technique are given below.

Examples

Boc-protected compound (III) (Pgi = Boc, Pg2 = H) and unprotected analogue (Pgi = Pg2 = H) are described in the patent [2]. N4, N- (Boc) 2-protected compound (III) (Pgi = Pg2 = Boc) as well as N4, N- (Cbz) 2-protected compound (III) are also synthesized from these starting materials by known procedures Pg2 = Cbz).

Example 1: tert-butyl- (3 R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-ylpiperidine-1-carboxylate) (IV, Pgi = Boc, Pg2 = H)

The compound (III) (Pgi = Boc, Pg2 = H) (318 mg, 1.00 mmol), Pd (OAc) 2 (22 mg, 0.10 mmol), 1,10-phenanthroline (18 mg, 0 mg) is placed in the reactor. , 10 mmol), CS 2 CO 3 (358 mg, 1.10 mmol), 1-bromo-4-phenoxybenzene (274 mg, 1.10 mmol) and xylene (5 mL). The ampoule is filled with argon, sealed and heated at 160 ° C for 24 h with vigorous stirring. At the end of the reaction, the reactor is cooled to room temperature, carefully opened, the reaction mass poured into EtOAc (20 mL), stirred vigorously for 5 min, filtered through celite and evaporated in vacuo. The product is purified by columns

by chromatography (eluent CH2Cl2-MeOH 20: 1, product Rf-0.5). Yield: 234 mg (48%), viscous yellowish oil. Example 2: tert-butyl- (3 R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-ylpiperidine-1-carboxylate) (IV, Pgi = Boc, Pg2 = H)

The compound (III) (Pgi = Boc, Pg 2 = H) (636 mg, 2.00 mmol), Pd (OAc) 2 (44 mg, 0.20 mmol), 1,10-phenanthroline (36 mg, 0 mg) is placed in the reactor. , 20 mmol), K 2 CO 3 (304 mg, 2.20 mmol), 1-bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and Ν, Ν-dimethylacetamide (DMA) (10 mL). The reactor is filled with argon, sealed and heated at 150 ° C for 16 h with vigorous stirring. The product is isolated and purified analogously to that described in Example 1. Yield: 642 mg (66%), viscous yellowish oil. The product analytical data corresponds to the product data of Example 1. Example 3: ? -butyl- (3?) - 3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-ylpiperidine-1-carboxylate) (IV, Pgi = Boc, Pg2 = H)

In the reactor, compound (III) (Pgi = Boc, Pg2 = H) (636 mg, 2.00 mmol), Pd (OAc) 2 (44 mg, 0.20 mmol), 4,4'-di (tert-butyl) is added. ) -2,2'-bipyridine (54 mg, 0.20 mmol), K 3 PO 4 (467 mg, 2.20 mmol), 1-bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and DMA (10 mL) ). The reactor is filled with argon, sealed and heated at 150 ° C for 48 h with vigorous stirring. The product is isolated and purified analogously to that described in Example 1. The yield was 428 mg (44%), a viscous yellowish oil. The product analytical data corresponds to the product data of Example 1. Example 4: .. ______

Benzyl- (3 R) -3- [4- (Benzyloxycarbonylamino) -3- (4-phenoxyphenyl) -1 H -pyrazolo [3,4-d] pyrimidin-1-yl] piperidine-1-carboxylate) (IV, Pgi = Pg2 = Cbz)

The compound (III) (Pgi = Pg2 = Cbz) (973 mg, 2.00 mmol), Pd (OAc) 2 (44 mg, 0.20 mmol), 1,10-phenanthroline (54 mg, 0.20 mg) is placed in the reactor. mmol), CS2CO3 (716 mg, 2.20 mmol), 1-bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and xylene (10 mL). The reactor is filled with argon, sealed and heated at 140 ° C for 16 h with vigorous stirring. At the end of the reaction, the rector is cooled to room temperature, carefully opened, the reaction mass poured into EtOAc (40 mL), stirred vigorously for 5 min, filtered through celite and evaporated in vacuo. The product was purified by column chromatography (eluent EtOAc-hexane 1: 2, product Rf = 0.4). Yield: 995 mg (76%), white amorphous powder. Example 5: tert-Butyl- (3 R) -3- [4- (tert-Butoxycarbonylamino) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] piperidine -carboxylate) (IV, Pgi = Pg2 = Boc)

Reactor (III) (Pgi = 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 CO 3 (717 mg, 2.20 mmol), 1-bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and diglyme (10 mL). The reactor is filled with argon, sealed and heated at 110 ° C for 20 h with vigorous stirring. At the end of the reaction, the ampoule was cooled to room temperature, carefully opened, the reaction mass poured into EtOAc (40 mL), stirred vigorously for 5 min, filtered through celite and evaporated in vacuo. The product was purified by column chromatography (eluent EtOAc-hexane 1: 4, product Rf = 0.3). Result: 727 mg (62%), white amorphous powder. Example 6. 3- (4-Phenoxyphenyl) -1 - [(3 R) -piperidin-3-yl] -1 H -pyrazolo [3,4-d] pyrimidine-4-amine (II) Compound (IV) (Pgi = Pg 2) = Boc) (2.93 g, 5.00 mmol) is suspended in methanol (15 mL). 33% HCl (3 ml) is added, the reaction mass is heated for 4 h at 50 ° C with vigorous stirring (gas is released during the reaction). At the end of the reaction, the solution is cooled and evaporated to dryness (the vapor contains HCl!). Saturated Na 2 CO 3 solution (5 mL) is added to the residue and extracted with EtOAc (3 x 10 mL). The extract is dried over Na2SO4 and evaporated in vacuo. Yield 1.89 g (98%). White amorphous mass.

From N4, N '- (Cbz) 2-protected compound (IV) (Pgi = Pg2 = Cbz) with a standard hydrogenation procedure in the presence of a Pd / C catalyst, 99% yield of compound (II) identical to that obtained from N4 above. N1 '- (Boc) 2-protected compound (TV) (Pgi = Pg2 = Boc). Industrial applicability

The technique is practicable in pharmaceutical industry conditions and apparatus. This allows a product to be purified by routine methods to pharmaceutical quality (> 99% base material content), readily separable impurities and waste for disposal.

LIST OF LITERATURE

Patent Literature [1] WO2008 / 121742.

[2] US2008 / 007621.

[3] WO2012 / 158795.

[4] WO2014 / 139970.

[5] WO2009 / 062118.

[6] WO2012 / 058645. Other Literature [7] A. Ben-Yahia, M. Naas, S. E1 Kazzouli, E. M. Essassi, G. Guillaumet, Eur. J. Org. Chem., 7075 (2012).

[8] M. Naas, S. E1 Kazzouli, E. M. Essassi, M. Bousmina, G. Guillaumet, J. Org. Chem., 79,7286 (2014).

[9] M. Ye, A.J.F. Edmunds, J.A. Morris, D. Sale, Y. Zhang, J.-Q. Yu, Chem. Sci., 4, 2374 (2013).

[10] A. Unsinn, P. Knochel, Chem. Commun., 48, 2680 (2012).

[11] T. S. Kaufman, Tetrahedron Lett., 37, 5329 (1996).

[12] M.M. Engle, J.-Q. Yu, J. Org. Chem., 78, 8927 (2013).

[13] M. Ye, G.-L. Gao, A.J. Edmunds, A.A. Worthington, J.A. Morris, J.-Q. Yu, J. Am. Chem. Soc., 133,19090 (2011).

Claims (5)

1. Method of ibrutinib feedstock - compound of formula (II): containing a compound of formula (III): wherein Pgi is Boc, Cbz, Bn; Pg2 is H, Boc, Cbz, Bn, arylation with 1-bromo-4-phenoxybenzene Pd in the presence of a nitrogen-containing ligand and base in an organic solvent with the following product of formula (IV): wherein Pgi is Boc, Cbz, Bn; Pg2 is the release of H, Boc, Cbz, Bn, and deprotection by known techniques. A process according to claim 1, wherein the arylation catalyst is selected from the group consisting of Pd (OAc) 2, PdCh, Pd (CF3 COO) 2, ligand selected from the group: 1,10-phenanthroline, 2,2'-bipyridyl or derivatives thereof and the base selected from the group consisting of: CS2CO3, K2CO3, K3PO4, solvent selected from xylene, Ν, dimet-dimethylacetamide, diglims. The method according to any one of the preceding claims, wherein the desired arylation catalyst is Pd (OAc) 2, the preferred ligand is 1,10-phenanthroline, the preferred base is CS2CO3 and the preferred solvent is xylene or N, N-dimethylacetamide. The process according to any one of the preceding claims, wherein the arylation is carried out at a temperature of 80-180 ° C for 4-48 hours. An intermediate of formula (IV, Pgi = Pg2 = Cbz) for the method of claim 1.