Processes and intermediates for preparing BTK inhibitors

Abstract

Processes for preparing certain intermediates, such as compounds of formula (I) [Formula 1] TIFF2022533747000025.tif60170 A process for preparing a compound of formula (I) is disclosed, wherein R 1 , R 2 , and X 1 is as defined herein, and the intermediates and processes are useful for the preparation of BTK inhibitors such as ibrutinib.

Description

[Technical field]

[0001] The present invention relates to synthetic procedures and intermediates for the synthesis of substituted bicyclic compounds, in particular compounds that are useful as pharmaceutical agents, such as Bruton's tyrosine kinase (Btk) inhibitors, such as ibrutinib. [Background technology]

[0002] Ibrutinib is a small organic molecule with the IUPAC name 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one. It has been described in many published documents, including International Patent Application WO 2008 / 039218 (Example 1b), and is described as an irreversible inhibitor of Btk.

[0003] Btk plays a key role in the B cell signaling pathway that links cell surface B cell receptor stimulation to downstream intracellular responses. Btk is a key regulator of B cell development, activation, signaling, and survival (Kurosaki, Curr Op Imm, 2000, 276-281; ​​Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288). In addition, Btk plays a role in many other hematopoietic cell signaling pathways, such as Toll-like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (FcepsilonRI) signaling in mast cells, inhibition of Fas / APO-1 apoptotic signaling in B lineage lymphocytes, and collagen-stimulated platelet aggregation. See, e.g., CA Jeffries, et al., (2003), Journal of Biological Chemistry 278:26258-26264; NJ Horwood, et al., (2003), The Journal of Experimental Medicine 197:1603-1611; Iwaki et al. (2005), Journal of Biological Chemistry 280(48):40261-40270; Vassilev et al. (1999), Journal of Biological Chemistry 274(3):1646-1656; and Quek et al. (1998), Current Biology 8(20):1137-1140.

[0004] Ibrutinib is approved in several countries, including the United States and the EU, for certain hematologic malignancies and is also being studied in clinical trials for other hematologic malignancies, including chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and multiple myeloma.

[0005] There are many methods for preparing functionalized bicyclic heterocycles and ibrutinib (Example 1b), described inter alia in US Patent Publication No. 2011 / 0082137 and WO 2008 / 039218. With regard to the latter, the latter steps of the ibrutinib synthesis are shown in the following scheme: [ka]

[0006] It is noted that the core heterobicyclic moiety of ibrutinib, i.e., the pyrazolopyrimidine, is already constructed prior to the introduction of the chiral piperidinyl moiety: the bicyclic ring itself is constructed by preparing a pyrazole intermediate substituted at the 3- and 4-positions with amino and cyano groups, respectively, followed by reaction with formamide.

[0007] Other methods of synthesizing ibrutinib are disclosed in International Patent Application WO 2014 / 139970, which includes the following scheme: [ka]

[0008] In this case, the core heterobicycle of ibrutinib, the pyrazolopyrimine, is constructed via an intermediate having a pyrazole ring substituted with amino and cyano groups at positions 3 and 4, respectively. From this intermediate, the pyrimidine portion of the core heterobicycle pyrazolpyrimidine can also be constructed, which is subsequently further functionalized to form ibrutinib.

[0009] The final step for introducing a substituent onto the nitrogen atom of the piperidinyl ring may be carried out according to the above scheme or by reaction with 3-chloropropionyl chloride (e.g., in the presence of aqueous NaHCO3 in Me-THF), thereby introducing a -C(O)-CH2CH2-Cl group onto the nitrogen atom of the piperidinyl, according to the procedure described in International Patent Application WO 2016 / 115356. Such intermediates are subsequently subjected to an elimination reaction in the presence of DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) to give ibrutinib.

[0010] The above publications do not disclose alternative methods for synthesizing the key core pyrazolopyrimidine heterobicycles. Moreover, it is difficult to synthesize the NN bond (i.e., two nitrogen atoms are joined) in the context of the ring. In this regard, the formation of indazoles is described in an editorial entitled "A synthesis of 1H-indazoles via a Cu(OAc)2-catalysed NN bond formation" by Chen et al, Organic Letters, 2016, 18, 1690-1693. However, this paper does not disclose any synthesis of the pyrazolopyrimidine heterobicycle core. Summary of the Invention

[0011] A process for preparing a compound of formula (I) is provided, [ka] During the ceremony, R 1 represents a nitrogen protecting group, R 2 represents hydrogen or aryl (e.g., phenyl); X 1 is a leaving group (e.g. halo, -OY 1 etc.) and -N(R 3 )R 4 represents a substituent selected from Y 1 is hydrogen or sulfone (e.g., -S(O)2-R x , where R x is optionally substituted by one or more fluoro atoms 1~3 Alkyl, or optionally halo and C 1~3 Alkyl (The latter group may itself be optionally substituted by one or more fluoro atoms.) may represent aryl (e.g., phenyl) substituted by one or more substituents selected from ( Therefore, X 1 -OY 1 When X represents a sulfonate group may be formed, for example X 1 may represent tosylate, mesylate, or triflate; R 3 and R 4 at least one of represents a nitrogen protecting group and the other represents hydrogen or an independent nitrogen protecting group; This process is An oxidizing agent (e.g., a source of oxygen, such as air, and specifically, O in air) 2 ) and in the presence of a copper-based catalyst, comprising reacting a compound of formula (II) [ka] In the formula, R 1 , R 2 , and X 1 teeth ,above As defined above, This process may be referred to herein as the process of the invention (consisting of one or more embodiments).

[0012] It is noted herein that salts of the compounds may be used and / or produced in the processes of the invention (and in the embodiments described herein). Alternatively (and in preferred embodiments), the free base of the compound may be used and / or produced. Furthermore, where a salt form is used and / or produced, it may be liberated to form the free base form (e.g., for use in further process steps such as those described herein, e.g., for further reactions). It should also be noted that the compounds described herein may exhibit isomerism, e.g., tautomerism.

[0013] For the avoidance of doubt, compounds of formula (I) (and precursors) and downstream products have the (R) configuration at the chiral centres indicated by * in the illustrative examples below; [ka] Here, compounds (e.g., compounds of formula (I), (II), (III), etc.) are shown to be present, in which an atom in the (R) configuration is present, meaning that the (R)-enantiomer is the predominant enantiomer, and the compound has an ee of more than 20% (and in embodiments, a higher ee). For example, enantioenriched compounds (e.g., compounds of formula (I), (II), (III), etc.) can have an enantiomeric excess of more than 40%, such as more than 60%, and in one embodiment, more than 80%. Enantioenriched compounds can even be more than 90% (e.g., they can consist essentially of a single enantiomer, meaning that the ee can be 95% or more, e.g., more than 98% or about 100%). Such enantioenriched compounds (or ees) can be obtained directly or by further purification techniques known to those skilled in the art.

[0014] For example, the process of some embodiments of the present invention produces an enantioenriched product. As an example, the compound of formula (V) used in the process of the present invention described herein (in reaction with the compound of formula (IV) to produce the compound of formula (III)) is enantioenriched, i.e., consists of ee as described herein (e.g., more than 80% ee, etc.). When enantiospecificity is introduced into the process, downstream reaction / process steps can be stereospecific. That is, stereochemistry is maintained in the downstream product, i.e., the ee of the compound of formula (III) is linked to the ee of the precursor compound of formula (V) from which it was derived. Similarly, the ee of the compound of formula (I) is linked to the ee of the compound of formula (III) from which it was derived, etc. Downstream process steps can also be stereospecific and maintain such stereochemistry that is favorable for producing a final pharmaceutical product that is a single enantiomer, such as ibrutinib. The fact that enantioselectivity is introduced early in the reaction scheme is advantageous in terms of efficiency, since less product is wasted. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] In the process of the invention described herein, new N-N bonds are formed during the preparation of the compound of formula (I). To achieve this, in one embodiment, a suitable copper-based catalyst is used. Such reactions are carried out in the presence of an oxidizing agent, such as O2 in air. Suitable catalysts that can be used include Cu(OAc)2, CuBr, and other copper halides, where the halides can be fluoro, iodo, bromo, and chloro, particularly chloro and bromo (especially chloro). Wherein X 1 Compounds of formula (II) where X represents halo (e.g. chloro) can be converted to the corresponding aryl group in the presence of certain copper catalysts (e.g. Cu(OAc)2) by the reaction of formula (II) 1 represents -OH, whereas in the presence of other copper catalysts (e.g. copper halides), X 1 The identity of the parts may potentially be preserved.

[0016] The compound of formula (II) is a compound of formula (III) [ka] or a salt thereof (wherein, R 1 and X 1 is as defined above) and a compound of formula (IV) [ka] or a salt thereof (wherein, R 2 is as defined, and X 2 represents a halo group in the presence of an organometallic base, in particular an organolithium base, in which case lithium is exchangeable with the halo group, so that (X 2 (in which) a nucleophile is formed which forms a bond with the carbon atom of the cyano moiety of the compound of formula (III) and ultimately forms the imine moiety of the desired compound of formula (II). This reaction, and the key part of forming the organolithium, can be carried out in the presence of a suitable solvent, such as a polar aprotic solvent, for example THF.

[0017] The compound of formula (III) is a compound of formula (V) [ka] or a salt thereof (wherein X 1 is as defined above, and X 3 is halo (e.g., chloro, bromo, or iodo) or -OY 2 and Y 2 is a sulfone (e.g., -S(O)2-R y (R in the formula y is optionally substituted by one or more fluoro atoms 1~3 Alkyl, or optionally halo and C 1~3 Alkyl (The latter group may itself be optionally substituted by one or more fluoro atoms.) may represent aryl (e.g., phenyl) substituted by one or more substituents selected from ( Show and therefore X 3 can form a sulfonate (e.g., tosylate, mesylate, or triflate) ) and, formula Compound (VI) [ka] or a salt thereof (wherein R 1 is defined above) and of, Under nucleophilic aromatic substitution reaction conditions It can be prepared by the reaction of For such a reaction to proceed successfully, X 3 The group acts as a good leaving group and the ortho-cyano substituent acts as a suitable electron-withdrawing moiety to facilitate nucleophilic displacement. The reaction can be carried out in the presence of a suitable base, such as a carbonate base, e.g., an alkali metal carbonate, Na2CO3, or the like.

[0018] Compounds of formula (VI) may be prepared by resolution. In further embodiments of the invention the following processes / methods may be used:

[0019] Certain starting materials and certain intermediates may also be either commercially available or can be prepared according to conventional reaction procedures generally known in the art.

[0020] Every individual feature (e.g., a preferred feature) mentioned in this specification may be taken alone or in combination with any other feature (including a preferred feature) mentioned in this specification (and thus a preferred feature may be taken in conjunction with or independently of other preferred features).

[0021] Those skilled in the art will appreciate that the compounds referred to in the context of the processes of the present invention are stable, i.e., the compounds encompassed herein are compounds that are robust enough to survive isolation to a useful degree of purity, for example from a reaction mixture.

[0022] In one embodiment of the present invention, the process of the present invention provides compounds of formula (I) X 1 is halo (e.g., chloro) or -OY1 and / or Y 1 represents hydrogen.

[0023] In a further embodiment of the invention, the process of the invention provides compounds of formula (I) R 2 represents phenyl (unsubstituted and forms a suitable substituent contained in ibrutinib).

[0024] As used herein, the compounds of formula (I) prepared by the processes described herein are defined as compounds of formula R 1 represents a nitrogen protecting group. In this respect, the following protecting groups are mentioned: - Amides (e.g., N-acetyl) -optionally substituted N-alkyl (e.g., N-allyl or optionally substituted N-benzyl) -N-sulfonyl (e.g., optionally substituted N-benzenesulfonyl) -Carbamates -urea It will be understood that these include those which result in the formation of -trityl (triphenylmethyl), diphenylmethyl, and the like.

[0025] Therefore, R 1 can represent: -C(O)R t1 (In the formula, R t1 is C 1~6 alkyl, or optionally substituted aryl), C 1~6 alkyl, where the alkyl group is optionally substituted with one or more substituents selected from optionally substituted aryl (which may, for example, form a benzyl moiety); -S(O)2R t2 (In the formula, R t2 may represent optionally substituted aryl), or, in one embodiment, -C(O)OR t3 (In the formula, R t3is optionally substituted aryl, or in a further embodiment, optionally substituted C 1~6 (For example, C 1~4 ) alkyl, such as tert-butyl (thus forming, for example, a tert-butoxycarbonyl protecting group, which when combined with an amino moiety forms a tert-butyl carbamate group), or a -CH2 phenyl group (thus forming a carboxybenzyl protecting group); -C(O)N(R t4 )R t5 wherein in one embodiment, R t4 and R t5 are independently hydrogen, C 1~6 Alkyl, optionally substituted aryl, or -C(O)R t6 R t6 is C 1~6 represents an alkyl, or an optionally substituted aryl.

[0026] In one embodiment, R 1 -C(O)OR t3 (In the formula, R t3 is C 1~6 alkyl, which may represent tert-butyl, and therefore in one embodiment, R 1 The protecting group is tert-butoxycarbonyl (also known as the BOC or Boc group, and referred to herein as the BOC or Boc group).

[0027] However, R 1 The choice of protecting groups that R may represent in the processes described herein is flexible. Furthermore, in any of the compounds described herein, it is possible to select a protecting group that is not a protecting group, for example, when it is advantageous for a particular protecting group to be used in a particular process step (and for a different protecting group to be used in a subsequent or preceding process step). 1 The protecting group is replaced by another R 1 It can be converted to a protecting group.

[0028] (For example, in the formula X 1 is halo (e.g., chloro) or -OY 1Compounds of formula (II) that may be used in the process of the invention to provide compounds of formula (I) representing 1 In particular, those in which X is halo (e.g. chloro). 1 Compounds of formula (II) in which X represents halo (e.g. chloro) can be prepared (according to the procedures described herein) by 1 Compounds of formula (I) (i.e., in which Y 1 represents hydrogen -OY 1 )

[0029] In further embodiments, depending on the desired downstream product to be synthesized, certain compounds of formula (I) can be converted to other compounds of formula (I). For example, in the processes described herein, 1 In the case where compounds of formula (I) are provided in which X represents -OH, 1 The group can be made into a better leaving group, for example, X 1 -OY 1 represents Y 1 represents a sulfone group (i.e., -S(O)2-R x where R x where X is defined above. Such a conversion can be done, for example, by 1 It may be useful to provide further downstream products (e.g., via nucleophilic aromatic substitution reactions) to introduce other substituents (a more varied array) at the X position. 1 -OY 1 In the formula Y 1 -S(O)2-R x represents the formula X 1 represents -OH and the corresponding compound of formula LG-S(O)2-R x (wherein R x is as defined above, LG represents a suitable leaving group such as halo, and -OS(O)2-R x R may also represent a group, x is as defined herein, and two R xThe groups may be the same or different, but preferably the same. Such reactions may take place in the presence of a base and, optionally, a suitable solvent (for example, they may take place in the presence of pyridine). As an example, 1 Compounds of formula (I) in which represents -OH can be reacted with trifluoromethanesulfonic anhydride, i.e. (CFSO)O or F-C-S(O)-OS(O)CF, for example in the presence of pyridine, to form a triflate leaving group and in a similar manner other leaving groups such as mesylate and tosylate can also be formed.

[0030] R in the formula 2 Compounds of formula (I) in which R represents aryl (e.g. phenyl) can be prepared, for example, from 2a -L xa (R in the formula 2a represents aryl, e.g., phenyl, L xa -B(OH)2, -B(OR w )2, or -Sn(R w )3, wherein each R w is independently C 1~6 represents an alkyl group, or -B(OR w ) In the case of 2, each R w The groups can be joined together to form a 4- or 6-membered cyclic group (e.g., a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group, thereby forming, for example, a pinacolato boronate group), and where such groups can be prepared from the corresponding compound having a halo atom, by reacting a compound of formula R 2represents hydrogen, and such reactions may be carried out in the presence of a suitable catalytic system (preferred catalysts include palladium), such as metals (or salts or complexes thereof), for example Pd, CuI, Pd / C, Pd(OAc)2, Pd(Ph3P)2Cl2, Pd(Ph3P)4, Pd2(dba)3 and / or NiCl2, and ligands such as PdCl2(dppf).DCM, t-Bu3P, optionally in the presence of a suitable base (e.g. a carbonate base, a hydroxide base, etc.) and a suitable solvent.

[0031] A compound of formula (I) (e.g., where X 1 is halo (e.g., chloro), or 1 -S(O)2-R x Represents -OY 1 group), followed by X in the formula 1 -N(R 3 )R 4 (R in the formula 3 and R 4 Such compounds can be converted to other compounds of formula (I) representing, for example, compounds of formula (I) (wherein X is as defined above). 1 represents an appropriate "leaving group"), 3 )R 4 (wherein R 3 and R 4 is as defined above) (and preferably, both represent hydrogen or at least one represents hydrogen and the other represents hydrogen or a nitrogen protecting group as defined above). Protecting groups that may be mentioned include those defined above and may in one embodiment represent benzyl or PMB (4-methoxy-benzyl). If desired, such protecting groups may be removed using methods described herein / known to those skilled in the art.

[0032] In one embodiment, a compound prepared according to the described procedure (e.g., of formula X 1 represents -NH2, and R 2represents unsubstituted phenyl; R 1 A compound of formula (I), wherein R represents hydrogen or a nitrogen protecting group, in which case the nitrogen protecting group may be removed as described herein, can then be used to prepare ibruintib. For example, such a compound may be reacted with Cl-C(O)-C(H)=CH2 under conditions described in either WO 2014 / 139970 or WO 2016 / 115356, or a two-step process may be carried out by reacting with 3-chloropropionyl chloride (e.g. in the presence of aqueous NaHCO3 in Me-THF), thereby producing a compound of formula (VII). [ka] or a derivative thereof, and such intermediate may undergo an elimination reaction, for example in the presence of DBU (1,8-diazabicyclo(5.4.0)undec-7-ene), to provide ibrutinib.

[0033] For the avoidance of doubt, the formula for ibrutinib (as prepared in an embodiment of the present invention) is as follows: [ka]

[0034] Unless otherwise specified, alkyl groups as defined herein may be straight chain or, if there is a sufficient number (i.e., a minimum of three) carbon atoms, may be branched chain and / or cyclic. Furthermore, if there is a sufficient number (i.e., a minimum of four) carbon atoms, such alkyl groups may also be partially cyclic / acyclic. Furthermore, such alkyl groups may be saturated or, if there is a sufficient number (i.e., a minimum of two) carbon atoms, may be unsaturated (and thus include, for example, a "vinyl" moiety).

[0035] The process of the present invention produces enantioenriched forms or products, which means that the products produced have an enantiomeric excess of more than 20%, such as more than 40%, such as more than 60%, and in one embodiment more than 80%. Enantioenriched products can even be more than 90% (e.g., they can consist essentially of a single enantiomer, meaning that the ee can be 95% or more, such as more than 98% or about 100%). Such enantioenriched products (or ees) can be obtained directly or by further purification techniques known to those skilled in the art.

[0036] For the avoidance of doubt, when reference is made to equivalents it is intended that this means molar equivalents.

[0037] In a further aspect of the invention, there is provided a process for separating the product (compound of formula (I)) obtained from the process of the invention (which may be referred to herein as the "compound of the invention"). Thus, the compound of the invention (or the product obtained by the process of the invention) can be separated / isolated. This can be achieved in several ways: -Flash column chromatography -Precipitation / crystallization -Derivatization, optionally followed by precipitation / crystallization - Extraction (e.g., derivatization followed by extraction) -distillation.

[0038] In a further embodiment of the present invention there is provided a process of the present invention as described herein followed by yet further process steps.

[0039] The compounds of formula (I) (in enantiomerically enriched form) may be used to prepare further compounds, for example further medicinal products (or intermediates thereof), such as medicinal products useful in the treatment of cancer (such as hematological malignancies), in particular the medicinal product may be ibrutinib.

[0040] Further transformations (of the products obtained directly by the process of the invention or of further products obtained from downstream processes, e.g. as may be described herein) can be carried out according to standard techniques and processes of the prior art, e.g. amide formation reactions (where possible conditions and coupling reagents will be known to the skilled person), esterifications, nucleophilic substitution reactions, and aromatic nucleophilic substitution reactions.

[0041] There is further subsequently provided a process for preparing a pharmaceutical formulation comprising ibrutinib, which comprises bringing ibrutinib (or a pharma- ceutically acceptable salt thereof) prepared according to the process described above into association with a pharma- ceutically acceptable excipient, adjuvant, diluent, and / or carrier.

[0042] In general, the processes described herein may have the advantage that the compounds prepared may be produced in a manner that utilizes fewer reagents and / or solvents and / or requires fewer reaction steps (e.g., different / separate reaction steps) compared to processes disclosed in the prior art.

[0043] The process of the present invention may also have the advantage that the compounds prepared are produced in higher yield, higher purity, higher selectivity (e.g., higher regioselectivity), in shorter time, in a more convenient (i.e., easier to handle) form, from more convenient (i.e., easier to handle) precursors, at lower cost, and / or with less usage and / or loss of materials (including reagents and solvents) compared to procedures disclosed in the prior art. Additionally, there may be several environmental advantages of the process of the present invention. EXAMPLES

[0044] The following examples are intended to illustrate the present invention and should not be construed as limiting the scope of the invention.

[0045] Preparation of compounds 6 and 7: Compound number 5 is prepared according to the general procedure of the following scheme (from compounds 1, 2, 3, and 4). Compound 5 is then converted to compounds 6 and 7 under the following specific conditions: (i) Under dry air, CuBr as catalyst, and DMA as solvent, compound 6 is the major product, with 10-20% of compound 7 as a by-product. The isolated yield of compound 6 is about 55.8%. (ii) Under air (dried / not dried), Cu(OAc)2 as catalyst, and DMSO as solvent, compound 7 is the major product with only a trace of compound 6. The isolated yield of compound 7 is 44.2%. [ka]

[0046] Route from compound 7 to compound 11: The reaction was successful, but the yield was low due to the instability of compound 8. The -OH group was activated by reaction with TfO (to form the corresponding triflate, compound 8), which was subsequently displaced in three different ways. [ka]

[0047] Compound 8 was reacted in three different ways (with three different amines) with amines as shown above: (i) NHBn (benzylamine); (ii) NH (ammonia); and (iii) NHPMB (4-methoxybenzylamine). These are shown in the scheme below. The substitution reaction (i) with NHBn was successful, but the deprotection, or "de-Bn" step showed that the main product was over-hydrogenation and the yield of compound 9 was very low. The above substitution reactions (ii) and (iii) with NH and NHPMB, respectively, were successful but did not proceed in very high yields. Hence the low yields to obtain compounds 10 and 12 from reactions (ii) and (iii). [ka]

[0048] Route from compound 6 to compound 11: There are three routes from compound 6 to compound 10 according to the scheme below. The first route involves bubbling NH3 into a solution of compound 6 in DMA (dimethylacetamide) in the presence of CuBr. Compound 10 was obtained in 92.5% yield. The second route uses Cu2O as a catalyst, NMP (N-methyl-2-pyrrolidine) as a solvent, and NH4OH as a reactant. Compound 10 was obtained in 67.2% yield. The third route involves first reacting with PMBNH2 (4-methoxybenzylamine) to form compound 12, and then using DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) to deprotect the PMB (4-methoxybenzyl) group. Compound 10 was obtained in 57.3% yield (89.1% x 64.2%). From compound 10 to compound 11, the yield was 73.1%. [ka]

[0049] Final synthetic route for compound 11 (a key intermediate in the synthesis of ibrutinib) This route uses a single (R)-enantiomer of starting material 2 (below), labeled "2R" (where downstream single enantiomers are produced, and these are subscripted with an "R" in comparison to the numbering used in the scheme above). [ka]

[0050] Compound 1 and Compound 2R to Compound 3R Experimental content Compound 1 (50.01 g, 289 mmol) and compound 2R (75.24 g, 376 mmol, 1.3 eq.) were dissolved in dry THF (550 mL, 11 V) mixed with sodium carbonate (30.6 g, 289 mmol, 1.00 eq). The mixture was stirred at 33° C. under N2 for 24 h, after which the reaction was quenched by addition of water (500 ml, 10 V) and the phases were subsequently separated. The organic layer was washed again with water (250 ml, 5 V) and the aqueous layer was extracted twice with EA (ethyl acetate) (250 ml, 5 V). The organic layers were combined and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 15:1 to 5:1) to obtain 55.56 g of compound 3R in an overall yield of 57.19% (35.03 with a purity of 99.20% and 20.53 g with a purity of 98.59%).

[0051] Compound 3R and Compound 4 to Compound 5R Experimental content Compound 4 (65.03 g, 262 mmol, 3 eq.) was dissolved in dry THF (300 mL, 10 V) and then cooled to -70 to -75 °C. A THF solution of n-BuLi (16.73 g, 261 mmol, 3 eq.) was then added dropwise to the THF solution of compound 4 under N2 at -70 to -75 °C. Compound 3R (29.45 g, 87.4 mmol, 1 eq.) was dissolved in dry THF (300 mL, 10 V) and then added dropwise to the above intermediate solution under N2 at -70 to -75 °C. After stirring for 1 h, saturated ammonium chloride (300 mL, 10 V) was added dropwise to the reaction mixture to quench the reaction. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (PE:EA = 10:1 to 3:1) (petroleum ether / ethyl acetate) to give 30.95 g of compound 5R in an overall yield of 69.88% (2.63 g with a purity of 98.21% and 28.32 g with a purity of 91.51%).

[0052] Compound 5R to Compound 6R Experimental content Compound 5R (1.05 g, 2.1 mmol), CuBr (148.3 mg, 0.5 eq), and dry DMA (10 ml, 10 V) were added to a dry flask, and the reaction mixture was then heated to 85° C. and stirred under a dry air stream for 10 h. EA (10 ml, 10 V) was added to the mixture, and the organic layer was washed twice with water (100 ml, 10 V). The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (PE:EA=10:1) to give 0.48 g of compound 6R (HPLC purity 98.61 a%) in 45.89% yield.

[0053] Compound 6R to Compound 10R Experimental content Compound 6R (1.72 g, 3.4 mmol) was dissolved in DMA (12 ml, 7 V) in an autoclave, followed by bubbling with NH3 for 25 min. CuBr (240 mg, 0.5 eq) was added to the reaction mixture, followed by heating the mixture to 85 °C. After stirring for 16 h, EA (26 ml, 15 V) was added and the organic layer was washed three times with water (17 ml, 10 V). The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (PE:EA = 5:1 to 2:1) to give 1.53 g of compound 10R (HPLC purity 99.15 a%) in 92.5% yield.

[0054] Compound 10R to Compound 11R Experimental content Compound 10R (1.03 g, 2.1 mmol) was dissolved in toluene (8 ml, 8 V), followed by the addition of water (7.5 ml, 7.5 V), followed by 35% HCl (2.21 g, 21 mmol, 10 eq.). The reaction mixture was heated to 65° C. and stirred for 2 h. The mixture was cooled to 20-25° C., followed by phase separation. MeOH (5 ml, 5 V) was added to the mixture, followed by pH adjustment to 10-13 with 30% KOH. The solids were filtered and the cake was washed with 50 wt% MeOH / H2O (1 g). The wet cake was dissolved in MeOH (17 ml, 17 V) at 45° C., followed by dropwise addition of 50 wt% KOH / H2O (14 g, 14X). The mixture was cooled to 20-25 °C, followed by filtering the solids and washing the cake with 50 wt% MeOH / HO (1 g). After drying under reduced pressure at 45 °C for 16 h, 0.69 g of compound 11R was obtained (HPLC purity 99.7a%, 100% chiral). The yield was 86.9%.

[0055] Compound 11R to Ibrutinib Ibrutinib was prepared according to the procedures disclosed in WO 2016 / 115356, WO 2008 / 039218 (Example 1b), and / or WO 2014 / 139970.

[0056] Further Example A: Ibrutinib (or a salt thereof) is prepared by preparing an intermediate using any of the process steps described in Example 1 and then converting it to ibrutinib (or a salt thereof).

[0057] Further Example B: A pharmaceutical composition is prepared by first preparing ibrutinib (or a salt thereof) according to Example 2 and subsequently contacting the ibrutinib (or a salt thereof) thus obtained with a pharma- ceutically acceptable carrier, diluent, and / or excipient. The present invention includes the following embodiments. [Claim 1] A process for preparing a compound of formula (I), comprising: [ka] During the ceremony, R 1 represents a nitrogen protecting group, R 2 represents hydrogen or aryl (e.g., phenyl); X 1 is a leaving group (e.g. halo, -OY 1 etc.) and -N(R 3 )R 4 represents a substituent selected from Y 1 is hydrogen or sulfone (e.g., -S(O) 2 -R x , where R x is optionally substituted by one or more fluoro atoms 1~3 Alkyl, or optionally halo and C 1~3 alkyl (which latter group may itself optionally be substituted by one or more fluoro atoms) substituted by one or more substituents selected from aryl (e.g. phenyl), and thus X 1 -OY 1 When X represents a sulfonate group may be formed, for example X 1 may represent tosylate, mesylate, or triflate; R 3 and R 4 at least one of represents a nitrogen protecting group and the other represents hydrogen or an independent nitrogen protecting group; The process is carried out in the presence of an oxidant (e.g., a source of oxygen, e.g., air, and specifically, O 2 ) in the presence of a copper based catalyst,

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Claims

1. A process for preparing a compound of formula (I), comprising: 【Chemistry 1】 During the ceremony, R １ represents a nitrogen protecting group, R ２ represents hydrogen or aryl; X １ is a leaving group and -N(R ３ ) R ４ represents a substituent selected from R ３ and R ４ at least one of represents a nitrogen protecting group and the other represents hydrogen or an independent nitrogen protecting group; The process comprises reacting a compound of formula (II) in the presence of an oxidizing agent and a copper-based catalyst, 【Chemistry 2】 In the formula, R １ , R ２ , and X １ is as defined above.

2. The process of claim 1, wherein the oxidant is an oxygen source.

3. The reaction is carried out in the presence of a copper-based catalyst and air (O ２ 3. The process according to claim 1 or 2, carried out in the presence of

4. The catalyst used is Cu(OAc) ２ or CuBr.

5. R 2 represents hydrogen or phenyl; X 1 is selected from halo, -O-Y 1 and -N(R 3 )R 4 ; 5. The process according to any one of claims 1 to 4, wherein Y 1 represents hydrogen or -S(O) 2 -R x , wherein R x represents C 1-3 alkyl optionally substituted by one or more fluoro atoms, or represents phenyl optionally substituted by one or more substituents selected from halo and C 1-3 alkyl optionally substituted by one or more fluoro atoms.

6. X １ is halo or -O-Y １ and / or Y １ represents hydrogen, and / or R ２ The process of any one of claims 1 to 5, wherein represents phenyl.

7. The process of claim 1, wherein X 1 is chloro or represents tosylate, mesylate, or triflate.

8. The compound of formula (II) is a compound of formula (III) 【Chemistry 3】 or a salt thereof (wherein, R １ and X １ is as defined above) and a compound of formula (IV) 【Chemistry 4】 or a salt thereof (wherein, R ２ is as defined, and X ２ The process according to any one of claims 1 to 7, wherein the compound is prepared by reaction with a halogen atom,

9. The compound of formula (III) is a compound of formula (V) 【Chemistry 5】 or a salt thereof (wherein X １ is as defined above, and X ３ is halo or -O-Y ２ represents a leaving group selected from ２ represents a sulfone), and Compound of formula (VI) 【Chemistry 6】 or a salt thereof (wherein R １ is as defined above) under nucleophilic aromatic substitution reaction conditions.

10. The process of claim 9, wherein X 3 is chloro, bromo or iodo, or represents -O-Y 2 , and Y 2 represents -S(O) 2 -R y , where R y represents C 1-3 alkyl optionally substituted by one or more fluoro atoms, or represents phenyl optionally substituted by one or more substituents selected from halo and C 1-3 alkyl optionally substituted by one or more fluoro atoms.

11. The process of claim 9 or 10, wherein X 3 represents tosylate, mesylate, or triflate.

12. A process for the preparation of Ibrutinib comprising the conversion of a compound of formula (I) 【Chemistry 1】 X in the formula １ Ha-NH ２ represents R ２ represents unsubstituted phenyl; R １ represents hydrogen or a nitrogen protecting group; The compound of formula (I) is prepared by the process according to any one of claims 1 to 11.

13. 13. The process of claim 12, wherein the compound of formula (I) is converted to ibrutinib.

14. The conversion of the compound of formula (I) comprises reacting said compound of formula (I) with Cl-C(O)-C(H)=CH 2 , or The compound of formula (I) is reacted with 3-chloropropionyl chloride to give a compound of formula (VII) 【Chemistry 7】 and said compound of formula (VII) is subjected to an elimination reaction to give ibrutinib.

14. The process of claim 12 or 13, comprising:

15. The two-step process, wherein the reaction of the compound of formula (I) with 3-chloropropionyl chloride is carried out in the presence of aqueous NaHCO 3 in Me-THF; 15. The process of claim 14, wherein the elimination reaction is carried out in the presence of DBU (1,8-diazabicyclo(5.4.0)undec-7-ene).

16. A process for preparing a pharmaceutical composition comprising ibrutinib or a salt thereof, comprising preparing ibrutinib or a salt thereof as described in any one of claims 12 to 15 and then contacting it with a pharma- ceutically acceptable carrier, diluent, and / or excipient.

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