LV15201B - The method for the preparation of ibrutinib intermediate - Google Patents

Abstract

A method for the preparation of ibrutinib's precursor, 3-(4-phenoxyphenyl)-1-((3R)-piperidin-3-il)-1H-pyrazolof [3,4-d]|pyrimidin-4-amine, involving arylation of N-protected 1-(piperidin-3-yl)pyrazolo[3,4-d]pyrimidin-4-amine in the presence of palladium catalyst, nitrogen-containing ligand, and base, with subsequent removal of the protecting groups by known methods, is reported. (Formula (II))

Description

Ibrutinib is a compound of formula (I) [1], an anticancer agent used to treat B-lymphoproliferative malignancies

The starting material, or the last intermediate in the synthesis of ibrutinib (I), is the compound (II) which contains the basic structure of ibrutinib, a pyrazolo [3,4-d] pyrimidine bicyclic system with a (4-phenoxyphenyl) group at the 3-position and an N-unsubstituted (piperidin-3-yl) a substituent at the nitrogen atom Nl. The preparation of ibrutinib (I) from compound (II) is carried out by trivial methods by acylating it with acrylic acid in the presence of condensing agents or with acryloyl chloride. Compound (II) is obtained from N (l ') - protected intermediate (3) by removal of the protecting group Pg in known manner.

(i)

Ibrutinib

X = Cl, imidazol-1-yl, u.c.

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

Both variants of the synthesis of the ibrutinib starting material (II) employ the Micunobu reaction, which results in a change in the optical configuration of the carbon atom at position 3 of the piperidine moiety. However, partial racemization during the Micunobu reaction has been reported in the literature [11], which may impair the optical purity of the product.

In the literature [4], another route for the synthesis of strapproduce (3), which does not involve a Micunobu reaction, is described. It is based on the reaction of compound (6) with (?) - (piperidin-3-yl) hydrazine (7) to form the pyrazole (8), which, on reaction with formamide, produces pyrazolo [3,4-d] pyrimidine (3):

The starting material (6) is obtained from 4-phenoxybenzoic acid by conversion to the chloride then condensation with malondinitrile and methylation (eg dimethylsulfate). The authors of the patent [4] do not provide detailed information on the method of obtaining optically active hydrazine (7).

Known methods are characterized by their complexity and the use of non-industrial reagents. Thus, the Suzuki reaction used to introduce the aromatic moiety in the synthesis of the intermediate (3) involves the use of an unstable and expensive arylboronic acid, and prior to this the introduction of a halogen atom (Br or I) into the pyrazolo [3,4d] pyrimidine substrate and work with specific, toxic halogenation reagents. Two of the most popular routes for the synthesis of ibrutinib are the Micunobu reaction for the administration of the optically active piperidine moiety, which may lead to partial racemization, which may impair the quality of the product. Another method of optically active (piperidin-3-yl) hydrazine condensation with 1,1-dicyano-2-methoxy-2- (4-phenoxyphenyl) ethylene to form the pyrazole ring involves the use of relatively expensive substituted benzoic acids and toxic reagents; also synthesis of optically active (piperidin-3-yl) hydrazine is a complex process as no detailed description is available.

Summary of the Invention

Technical problem

The state of the art indicates that there is an unmet need for a simpler and more technologically advantageous alternative route to the raw material (II).

Solution of the problem

The direct pyrazole pyrimidine Carylation at the 3-position of the pyrazole ring has not been used to date in the synthesis of the ibrutinib starting material (II). Some works are known which show the possibility of directly arylating the C-3 atom of the pyrazole ring in the indazole ring [7-10, 12, 13]. There is no known arylation of indazoles containing an amino group in the benzene ring. Similarly, the 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 ring, but also by the amino group 4-NH2. We unexpectedly found that both the protected NH and NH 2 protected group (III, Pg 2 ψ H) and the unprotected NH 2 protected group (III, Pg 2 - H) react with l-bromo-4-phenoxybenzene in the presence of a palladium catalyst (e.g. , Pd (OAc) in the 2-1,10-phenanthroline-Cs2CO3 system) to form the compound (IV) from which the ibrutinib starting material (II) can be readily obtained by deprotection. For example, the 4- (benzyloxycarbonyl) amino-1- [1- (benzyloxycarbonyl) piperidin-3-yl] derivative (III) (Pgi = Pg 2 = Cbz) reacts with 1-bromo-4-phenoxybenzene with high conversion to selectively form compound (IV) (Pgi-Pg2-Cbz) with good yield (76%). Further hydrogenation (H2, Pd / C, MeOH) removes both Cbz-protecting groups to give the ibrutinib starting material (II) with a free NH2 group in the pyrimidine ring and a free NH group in the piperidine moiety which is easily converted to ibrutinib by acylation ).

Pg ₂ = H, Boc, Cbz, Bn, etc.

^0m

Further investigation of the direct C-arylation reaction, it is surprisingly found that compound (III) with an unprotected 4-NH 2 group (Pgi = Boc, Pg 2 = H) also reacts with 1-bromo-4-phenoxybenzene in the presence of palladium catalyst to form compound (IV). (Pgi = Boc, Pg2 = H) with good yield (65% and above). However, arylation of compound (III), although requiring the introduction of 2 protecting groups, has a preparative advantage, since the product (IV) with two protecting groups is easier to isolate and purify, and the reaction has a better outcome.

Comparison of the physico-chemical properties and NMR spectra of the compound (II) obtained by these direct arylation processes with the corresponding standard sample characteristics showed that these compounds are identical. Thus, despite the presence of an unprotected 4-NH 2 group, the arylation of compound (III) surprisingly occurs with the desired regioselectivity, as the parent product is the 3-aryl derivative (IV) (Pg 2 = H), rather than the possible 4-arylamino or 6-aryl isomers. . Compounds (III) with a protected 4-NH 2 group (e.g. Boc- or Cbz-protected) react more readily with l-bromo-4-phenoxybenzene, reaction is faster and at lower temperatures. In this case, a smaller amount of by-products in the reaction mixture is also observed.

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

Advantages of the Invention

The proposed process allows the preparation of ibrutinib starting material (II) with good yield by direct arylation from protected [6] 1- (piperidin-3-yl) pyrazolo [3,4-d] pyrimidin-4-amine protected derivatives containing a piperidine protecting group nitrogen atom or its analogue with an additional protected 4-NH 2 group. The synthesis of the ibrutinib starting material (II) according to the method of the present invention does not involve the handling of unstable and expensive arylboronic acid or its derivatives, as well as 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, non-toxic, stable in air and moisture and can be recovered from the reaction if necessary. of the mixture. Palladium (II) salts, used as catalysts in Carylation, 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 C-3 arylation reaction does not affect the chiral center, the C-3 piperidine ring attached to the N-1 atom of the pyrazole ring, so that the optical purity of the product is not impaired. A convenient method for introducing an aryl group into the final stage of ibrutinib synthesis also makes it easy to obtain a library of ibrutinib analogs for further biological studies, varying with the reaction aryl halides.

Description of embodiments of the invention

The proposed process can be carried out in various solvents, e.g., toluene, xylene, dimethylacetamide, diglyme, dioxane, 1,2-dimethoxyethane or mixtures thereof. Palladium complexes or salts, such as Pd (OAc) 2, PdCh, Pd (CF 3 COO) 2, etc., may be used as catalysts. Various complexing compounds can be used as ligands, preferably nitrogen containing heterocycles (1,10-phenanthroline, 2,2'-bipyridyl derivatives, etc.). A variety of alkali metal carbonates, phosphates, alkoxides such as CS2CO3, ABuOK, and the like can be used as bases in the reaction. The reaction temperature, depending on the reagents and solvent selected, is between 80 and 180 ° C and the reaction time is 4 to 48 hours. Examples of method implementation are provided below.

Examples

The Boc-protected compound (III) (Pgi = Boc, Pg2 = H) and the unprotected analog (Pgi = Pg2 = H) are described in [2]. From these starting materials N ⁴ , № (Boc) 2-protected compound (III) (Pgi = Pg 2 - Boc) and N ⁴ , N ^r - (Cbz) 2-protected compound (III) (Pgi) are also synthesized by known procedures. = Pg2 = Cbz).

(III)

Pg _p Pg ₂ = H, Boc, Cbz

Example 1:

tert-butyl (3R) -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) (318 mg, 1.00 mmol), Pd (OAc) 2 (22 mg, 0.10 mmol), 1,10-phenanthroline (18 mg, 0 , 10 mmol), CS2CO3 (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 is poured into EtOAc (20 mL), stirred vigorously for 5 min, filtered through celite and evaporated in vacuo. The product is purified by column chromatography (eluent: CH 2 Cl 2 -MeOH 20: 1, Rt ~ 0.5). Yield 234 mg (48%), a viscous yellow oil.

Example 2:

tert -butyl (3A) -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) was charged to the reactor. , 20 mmol), K 2 CO 3 (304 mg, 2.20 mmol), 1bromo-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 in analogy to Example 1. Yield 642 mg (66%), a viscous yellow oil. The analytical data of the product corresponds to the product obtained in Example 1.

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

The reactor is charged with 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 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 in analogy to Example 1. Yield 428 mg (44%), a viscous yellow oil. The analytical data of the product corresponds to the product obtained in Example 1.

Example 4. .....

Benzyl (3R) -3- [4- (benzyloxycarbonylamino) -3- (4-phenoxyphenyl) -1H-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) is charged into the reactor mmol), CS2CO3 (716 mg, 2.20 mmol), 1bromo-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 is poured into EtOAc (40 mL), stirred vigorously for 5 min, filtered through celite and evaporated in vacuo. The product is purified by column chromatography (eluent: EtOAc-hexane 1: 2, Rt ~ 0.4 of product). Yield: 995 mg (76%), white amorphous powder.

Example 5.

Tert-Butyl (3R) -3- [4- (tert-butoxycarbonylamino) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] piperidine-1-carboxylate) (IV, Pgi = Pg2 = Boe)

The compound (III) (Pgi = Pg 2 = Boc) (837 mg, 2.00 mmol), PdCl 2 (35 mg, 0.20 mmol), 4,4'-di (tert-butyl) -2,2 'is charged into the reactor. -bipyridine (54 mg, 0.20 mmol), CS2CO3 (717 mg, 2.20 mmol), 1-bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and diglimus (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 is cooled to room temperature, carefully opened, the reaction mass is poured into EtOAc (40 mL), stirred vigorously for 5 min, filtered through celite and evaporated in vacuo. The product is purified by column chromatography (eluent: EtOAc-hexane 1: 4, Rf ~ 0.3 of product). Yield: 727 mg (62%), white amorphous powder.

Example 6.

- (4-Phenoxyphenyl) -1 - [(3 R) -piperidin-3-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine (II) Compound (IV) (Pgi = Pg 2 = Boc) (2.93 g, 5.00 mmol) is suspended in methanol (15 mL). Add 33% HCl (3 mL), heat the reaction mass for 4 h at 50 ° C with vigorous stirring (gas evolved during the reaction!). At the end of the reaction, cool the solution and evaporate to dryness (attention! Vapors contain HCl!). To the residue is added saturated aqueous solution (5 mL) 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 N ⁴ , № '- (Cbz) 2-protected compound (IV) (Pgi = Pg 2 = Cbz) by standard hydrogenation procedure in the presence of Pd / C catalyst gives compound (II), which is identical to that obtained above from N, with 99% yield. ⁴ , N ¹ '- (Boc) 2-protected compound (IV) (Pgi = Pg 2 = Boc).

Industrial Applicability

The method is feasible under pharmaceutical conditions and equipment. This allows the product to be purified by routine methods up to pharmaceutical grade (> 99% base content), easily separable impurities and recyclable waste.

LIST OF LITERATURE

Patent literature [1] WO2008 / 121742.

[2] US2008 / 007621.

[3] WO2012 / 158795.

[4] WO20 / 14/139970.

[5] WO2009 / 062118.

[6] WO2012 / 05 8645.

Other literature [7] A. Ben-Yahia, M. Naas, S. El 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. Set, 4, 2374 (2013).

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

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

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

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

Claims (5)

A process for preparing ibrutinib starting material - a compound of formula (II): for the preparation of a compound of formula (III): wherein Pgi and Boc, Cbz, Bn; Pg 2 is the arylation of H, Boc, Cbz, Bn with l-bromo-4-phenoxybenzene in the presence of a Pd catalyst, nitrogen-containing Uganda and a base in an organic solvent, with the following product of formula (IV): wherein Pgi and Boc, Cbz, Bn; Pg 2 is H, Boc, Cbz, Bn, deprotection and deprotection by known techniques. The process of claim 1, wherein the arylation catalyst is selected from the group consisting of: Pd (OAc) 2, PdCl 2, Pd (CF 3 COO) 2, the ligand selected from the group consisting of 1,10-phenanthroline, 2,2'-bipyridyl or derivatives thereof. , and base selected from the series: CS2CO3, K2CO3, K3PO4, solvent selected from the group: xylene, Ν, Ν-dimethylacetamide, diglyme. The process 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 CS 2 CO 3 and the preferred solvent is xylene or N, N-dimethylacetamide. A process according to any one of the preceding claims, further comprising arylation At 80-180 ° C for 4 to 48 hours. Intermediate of formula (IV, Pgi = Pg 2 = Cbz) for carrying out the process of claim 1.