CA2987708C - A method for preparation of ibrutinib precursor - Google Patents

Abstract

A method for the preparation of ibrutinib's precursor, 3-(4-phenoxypheny1)-1-((3R)-piperidin-3-y1)-1H-pyrazolo[3,4-cillpyrimidin-4-amine, involving arylation of N-protected 1-(piperidin-3-y1)pyrazo1o[3,4-alpyrimidin-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.

Description

A METHOD FOR PREPARATION OF IBRUTINIB PRECURSOR
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.
ONH-11\ C H2 I I N 2 r N 2 NH, NH, (I) OPh (11) OPh Ibrutinib's synthesis scheme involves an intermediate (precursor) of formula (II), that contains main fragments of ibrutinib's structure: pyrazolo[3,4-cflpyrimidine bicyclic system with 4-phenoxyphenyl group at the position 3, as well as N-unsubstituted piperidin-3-y1 substituent at the nitrogen atom N-1 of the pyrazolo[3,4-d]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(1')-protected intermediate (3) by removal of the protecting group (Pg) by known methods.

OR
cl '13g 0-Pg ,I13 Cp-Pg RO

,...õ.....,N H N, OH (2) N (5) OPh ..:rr, N
I I N ______ zio r 1 µ1,1 __________ 4, I..
N ,., / Ph3P, DIAD N -., / Pd(PP113),, base N "-- /
TIE organic solvent, 1120 NII2 NH2 . NH2 Hal (Mitsunobu (Suzuki reaction) (4) reaction) (1) OPh (3) OPh ip

2) 112c ..-1-..x Hal = Br, I
Pg = Boc, Cbz, etc.
I) Deprotection;
Me Me R = H or R+R = mej¨k¨me (I) X = CI, imidazol-1-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-1H-pyrazolo[3,4-d]pyrimidin-4-yDamine (1) and N-protected 3-hydroxypiperidine (2) [1, 211;
2) Suzuki reaction between (3-halo-1H-pyrazolo[3,4-d]pyrimidin-4-yDamine (4) and arylboronic acid derivative (5) [3, 51.
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-d]pyrimidine (3).
/ cN -Pg CN¨Pg 01¨Pg NC OMe HN. .
- NH, H2N iq /1\T NI
NC : (7) H2 / HCON
NC
(6) OPh NH2 Pg = Boc, Cbz, Bn (8) OPh (3) OPh 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 convenient for large-scale synthesis. Thus, introduction of aromatic fragment into molecule of intermediate (3) is performed by Suzuki reaction, that means necessity to use unstable and expensive arylboronic acid, as well as previous halogenation step to obtain 3-halopyrazolo[3,4-alpyrimidine (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 (pip eri din-3 -yl)hydrazine with 1. 1 -di cy ano-2-methoxy -2- (4-phenoxyphenypethylene, it is necessary to use expensive 4-phenoxybenzoic acid and some toxic reagents (e. g. SOC12, 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
In accordance with an aspect of at least one embodiment, there is provided a process for the preparation of ibrutinib's precursor, compound of formula (II) OH
/ N
N

(II) OPh ,comprising arylation of compound (III) Date Recue/Date Received 2021-12-30 ON¨Pgi N
,NH
Pgi (III) ,wherein Pgi and Pg2 are protecting groups, Pgi is Boc, Cbz, or Bn; Pg2 is H, Boc, Cbz, or Bn, withl-bromo-4-phenoxybenzene in the presence of a palladium catalyst, a nitrogen-containing ligand, and a base in an organic solvent, and subsequently isolating a product with formula (IV) ON¨Pgi 'IN/
N
Pg' 2 NH =
(IV) OPh , wherein Pgi is Boc, Cbz, or Bn; Pg2 is H, Boc, Cbz, or Bn, and further comprising deprotecting of compound (IV).
In accordance with at least one embodiment: said catalyst is selected from the group consisting of Pd(OAc)2, PdC12, and Pd(CF3C00)2; said ligand is selected from the group consisting of 1,10-phenanthroline, and 2,2'-bipyridine; said base is selected from the group consisting of Cs2CO3, K2CO3, and K3PO4; and said solvent is selected from the group consisting of xylene, N,N-dimethylacetamide, and diglyme.
In accordance with at least one embodiment: the catalyst for said arylation is Pd(OAc)2, the ligand is 1,10-phenanthroline, the base is Cs2CO3, and the solvent is xylene or N,N-dimethylacetamide.
Direct C-arylation of pyrazolo[3,4-d]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, 131 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-dlpyrimidine, in our case the situation is complicated not only by potentially similar reactivity of C-6 atom in the pirimidine

4 Date Recue/Date Received 2021-12-30 cycle, but also by presence of amino group 4-NH2. We unexpectedly found, that compound with protected piperidine NH and 4-NH2 groups (III, Pg2 H), as well as compound with unprotected 4-NH2 group (III, Pg2 = H), reacts withl-bromo-4-phenoxybenzene in the presence of palladium catalyst (e. g., Pd(OAc)2-1,10-phenanthroline-Cs2CO3 system) with formation of compound (IV). Deprotection of the latter by known methods leads to the ibrutinib's precursor (II). For example, 4-(benzyloxy carbonyl)amino-1 - [1-(benzyl oxy carbonyl)piperi din-3 -yl derivative (III) (Pgl = Pg2 = Cbz) reacts with 1-bromo-4-phenoxybenzene with high conversion, selectively forming compound (IV) (Pgl = Pg2 = Cbz) with good yield (76%). Further hydrogenation (H2, Pd/C, Me0H) results in removal of both Cbz protecting groups, thus obtaining ibrutinib's precursor (II) with free NH2 group in 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).
0"¨Pgi CN¨Pgi CNH

6 icr/1,.1 6 1\1,1 6 ,N Alp Pg2 PgcH NH2 (III) Pgi = Boc, Cbz, Bn, etc. (IV) OPh (II) OPh Pg2 = H, Boc, Cbz, Bn, etc.
Continuing our study of direct C-arylation we surprisingly found that compound (III) with unprotected 4-NH2 group (Pgi = Boc, Pg2 = H) reacts with 1-bromo-4-phenoxybenzene in the presence of palladium catalyst forming compound (IV) (Pgi = Boc, Pg2 = H) with good yield (65% or higher). However, arylation of compound (III) with protected 4-NH2 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 physico-chemical and NMR spectral characteristics of the compound (IV) obtained by the above described direct C-arylation of compound (III) with unprotected 4-NH2 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-NH2 group arylation of the unprotected compound (III) surprisingly occurs with desired regioselectivity and in the direct arylation 4a Date Recue/Date Received 2021-12-30 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-NH2 group (e.g., Pg2 = Boc or Cbz) react with 1-bromo-4-phenoxybenzene even faster, the reaction occurs at lower temperature and with less amount of impurities than in the case of unsubstituted compound (III).
After removal of both protecting groups (Pgi and Pg2) by the appropriate procedure we obtained compound (II). Acylation of the latter by acryloyl chloride in standard conditions [1]
leads to ibrutinib (I) which is identical with the standard ibrutinib's sample by the physico-chemical and spectral characteristics.
4b Date Recue/Date Received 2021-12-30

5 PCT/LV2015/000009 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] 1-(piperidin-3-yl)pyrazolo[3,4-dlpyrimidin-4-amine bearing protecting group at the piperidine nitrogen atom and, preferably, also at the 4-NH2 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-d]pyrimidine 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. Cs2CO3, 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) (Pgi = Boc, Pg2 = H) and its unprotected analogue (Pgi = H) are described in the patent [6]. Starting from these compounds, N4,1\11'-(Boc)2-protected compound (III) (Pgi = Pg2 = Boc), as well as N4,N1-(Cbz)2-protected compound (III) (Pgi = Pg2 = Cbz) were also synthesized by known methods.

Pgi

6 rfrt 1 Pg ,NH (III) Pgi, Pg2 = H, Boc, Cbz Example 1 (3R)-3 -14-Amino-3-(4-phenoxypheny1)-1H-pyrazolo13,4-d1py rimidin-l-yll piperidine-l-carboxylic acid tert-butyl ester (IV, Pgt = Boc, Pg2 = H) A mixture of compound (III) (Pgi = Boc, Pg2 = H) (318 mg, 1.00 mmol), Pd(OAc)2 (22 mg, 0.10 mmol), 1,10-phenanthroline (18 mg, 0.10 mmol), Cs2CO3 (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 Et0Ac (20 m1). After intensive stirring for 5 min the obtained suspension was filtered through celite and evaporated in vacuum. The product was purified by column chromatography (eluent CH2C12-Me0H 20:1, Rf 0.5). Yield 234 mg (48%), viscous yellowish oil.
Example 2 (3R)-3-14-Amino-3-(4-phenoxypheny1)-1H-pyrazolo13,4-0 pyrimidin-l-yll piperidine-1 -carboxylic acid tert-butyl ester (IV, Pgt = Boc, Pg2 = H) A mixture of compound (III) (Pgt = Boc, Pg2 = H) (636 mg, 2.00 mmol), Pd(OAc)2 (44 mg, 0.20 mmol), 1,10-phenanthroline (36 mg, 0.20 mmol), K2CO3 (304 mg, 2.20 mmol), 1- bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and N,N-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 (3R)-3-14-Amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-0 pyrimidin-l-yll piperidine-1 -carboxylic acid tert-butyl ester (IV, Pgt = Boc, Pg2 = H) Date Recue/Date Received 2021-12-30 A mixture of compound (III) (Pgi = Boc, Pg2 = H) (636 mg, 2.00 mmol), Pd(OAc)2 (44 mg, 0.20 mmol), 4,4'-di(tert-buty1)-2,2'-bipyridine (54 mg, 0.20 mmol), K3PO4 (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-(B enzyloxy carb onyl amino)-3 -(4-phenoxypheny1)-1H-py razol o [3,4-dlpyrimi din-1-yllpiperidine-l-carboxylic acid benzyl ester (IV, Pgi = Pg2 = Cbz) A mixture of compound (III) (Pgi = Pg2 = Cbz) (973 mg, 2.00 mmol), Pd(OAc)2 (44 mg, 0.20 mmol), 1,10-phenanthroline (36 mg, 0.20 mmol), Cs2CO3 (716 mg, 2.20 mmol), 1-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 Et0Ac (40 m1). After intensive stirring for 5 min the obtained suspension was filtered through celite and evaporated in vacuum. The product was purified by column chromatography (eluent Et0Ac-hexane 1:2, Rf 0.4). Yield 995 mg (76%), white amorphous powder.
Example 5 (3R)-3 - [4-(tert-Butoxy carbonylamino)-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d] py rimi din-1-yllpiperidine-l-carboxylic acid tert-butyl ester (IV, Pgi = Pg2 = Boc) A mixture of compound (III) (Pgi = Pg2 = Boc) (837 mg, 2.00 mmol), PdC12 (35 mg, 0.20 mmol), 4,4'-di(tert-buty1)-2,2'-bipyridine (54 mg, 0.20 mmol), Cs2CO3 (716 mg, 2.20 mmol), 1-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 Et0Ac (40 m1). After intensive stirring for 5 min the obtained suspension was filtered through celite and evaporated in vacuum. The product was purified by column chromatography (eluent Et0Ac-hexane 1:4, Rf 0.3). Yield 727 mg (62%), white amorphous powder.
Example 6 3 -(4-Phenoxypheny1)-1 -((3R)-piperidin-3 -y1)-1H-pyrazolo [3,4-d] py rimidin-4-amine (II)

7 Date Recue/Date Received 2021-12-30 Compound (IV) (Pgi = Pg2 = Boc) (2.93 g, 5 mmol) was dissolved in Me0H (15 ml), then 33% HC1 (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 HCl). Saturated Na2CO3 solution (5 ml) was added to the dry residue and the mixture was extracted with Et0Ac (3 x 10 ml).
The extract was dried over Na2SO4 and evaporated in vacuum. Yield 1.89 g (98%), white amorphous mass.
From N4,N1.-(Cbz)2-protected compound (IV) (Pgi = Pg2 = 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 N4,1\1'-(Boc)2-protected compound (IV) (Pgi = Pg2 =
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.

8 CITATION LIST
PATENT LITERATURE
[1] W02008/121742.
[2] U52008/007621.
[3] W02012/158795.
[4] W02014/139970.
[5] W02009/062118.
[6] W02012/058645.
NON PATENT LITERATURE
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Claims (5)

1. A process for the preparation of ibrutinib's precursor, compound of formula (II) comprising aiylation of compound (III) , wherein Pgi and Pg2 are protecting groups, Pgi is Boc, Cbz, or Bn; Pg2 is H, Boc, Cbz, or Bn, with 1-bromo-4-phenoxybenzene in the presence of a palladium catalyst, a nitrogen-containing ligand, and a base in an organic solvent, and subsequently isolating a product with formula (IV) , wherein Pgi is Boc, Cbz, or Bn; Pg2 is H, Boc, Cbz, or Bn, and further comprising deprotecting of compound (IV).

2. The process according to claim 1, wherein: said catalyst is selected from the group consisting of Pd(OAc)2, PdC12, and Pd(CF3C00)2; said ligand is selected from the group consisting of 1,10-phenanthroline, and 2,2'-bipyridine; said base is selected from the group consisting of Cs2CO3, K2CO3, and K3PO4; and said solvent is selected from the group consisting of xylene, N,N-dimethylacetamide, and diglyme.

3. The process according to claim 1 or 2, wherein the catalyst for said arylation is Pd(OAc)2, the ligand is 1,10-phenanthroline, the base is Cs2CO3, and the solvent is xylene or N,N-dimethylacetamide.

4. A process according to claim 1, 2, or 3, wherein said arylation is performed at a temperature within the range of 80-180 C and the reaction time is 4-48 h.

5. A compound of formula (IV) , wherein Pgi = Pg2 = Cbz.