Processes and intermediates for preparation of btk inhibitors

Abstract

The present invention relates to processes and intermediates for the preparation of BTK inhibitors. Disclosed is a process for the preparation of certain intermediates, such as a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof in enantiomeric enriched form, which intermediates and processes are useful in the preparation of BTK inhibitors, such as ibrutinib. # imgabs0 #

Description

[0001] This application is a divisional application of the patent application for invention with the application date of May 20, 2020, the application number of 202080037848.5, and the invention title of "Methods and Intermediates for the Preparation of BTK Inhibitors". Technical Field

[0002] The present invention relates to synthetic procedures and synthetic intermediates of substituted bicyclic compounds, particularly compounds used as pharmaceuticals, such as Bruton's tyrosine kinase (Btk) inhibitors like ibrutinib. Background Art

[0003] Ibrutinib is an organic small 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 a number of published documents, including International Patent Application WO 2008 / 039218 (Example 1b), and it is described as an irreversible inhibitor of Btk.

[0004] Btk plays an important role in linking the activation of the cell surface B cell receptor to downstream intracellular responses in the B cell signaling pathway. Btk is a key regulator of B cell development, activation, signaling, and survival (Kurosaki, Curr Op Imm [Current Opinion in Immunology], 2000, 276 - 281; Schaeffer and Schwartzberg, Curr Op Imm [Current Opinion in Immunology] 2000, 282 - 288). In addition, Btk plays a role in several other hematopoietic cell signaling pathways, such as Toll-like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (FcepsilonRI) signal transduction in mast cells, inhibition of Fas / APO-1 apoptosis signaling in B lineage lymphocytes, and collagen-stimulated platelet aggregation. See, for example, C.A. Jeffries, et al., (2003), Journal of Biological Chemistry 278:26258 - 26264; N.J. 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.

[0005] Ibrutinib has been approved for use in certain hematological malignancies in several countries including the United States and the European Union, and is also being investigated in clinical trials for other hematological malignancies. Such malignancies include chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B cell lymphoma, and multiple myeloma.

[0006] There are multiple ways to prepare functionalized bicyclic heterocycles and ibrutinib, which have been described particularly in U.S. Patent Document US2011 / 0082137 and International Patent Application WO 2008 / 039218 (Example 1b). The later steps of the synthesis of ibrutinib are shown in the following scheme:

[0007]

[0008] The above synthesis also enabled several synthetic strategies for preparing chiral hydroxypiperidine intermediates, including those in the unpublished PCT application PCT / EP2017 / 075289.

[0009] Other methods for synthesizing ibrutinib have been disclosed in International Patent Application WO 2014 / 139970, including the following scheme:

[0010]

[0011] The final step of introducing a substituent on the nitrogen atom of the piperidinyl ring can also be carried out according to the procedure described in International Patent Application WO2016 / 115356, by reaction with 3-chloropropionyl chloride (e.g., in the presence of an aqueous solution of NaHCO 3 ), thereby introducing a -C(O)-CH 2 CH 2 -Cl group at the nitrogen atom of the piperidinyl. Then such an intermediate undergoes an elimination reaction in the presence of DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) to provide ibrutinib.

[0012] The above synthesis utilizes an asymmetric chiral hydrazine, which is a key element of the synthetic route. Such chiral hydrazine is prepared by resolution, and chiral chromatography, such as chiral SFC, is mentioned herein. Such methods can be cumbersome and / or inefficient. The object of the present invention is to find an alternative / improved method for such chiral hydrazine (which can be used as a structural unit in the further synthesis of functionalized heterocycles such as ibrutinib). SUMMARY OF THE INVENTION

[0013] There is now provided a method for preparing a compound of formula (I)

[0014]

[0015] or a pharmaceutically acceptable salt thereof, in an enantiomerically enriched form,

[0016] wherein

[0017] R 1 represents hydrogen or a nitrogen protecting group;

[0018] * represents a chiral center having the (R) configuration;

[0019] The method comprises reacting a compound of formula (II)

[0020]

[0021] i.e., 3-hydroxypyridine, or a salt thereof, with a compound of formula (III)

[0022] H 2 N-N(H)-R 2 (III)

[0023] or its salt by reductive hydrazination, where R 2 represents hydrogen or a nitrogen protecting group, thereby forming a compound having formula (IV),

[0024]

[0025] or its salt, where R 2 is as defined above, and then, in any order, optionally deprotecting at R 2 (when R 2 represents a nitrogen protecting group), optionally introducing R 1 at the NH moiety of the piperidinyl ring (when R 1 represents a nitrogen protecting group), and then (if desired) resolving,

[0026] This method may be referred to herein as the method of the present invention (which consists of one or more embodiments).

[0027] The method of the present invention produces an enantiomerically enriched compound having formula (I) and may alternatively be described as a method for preparing a composition comprising a compound having formula (I), wherein the (R)-enantiomer is the predominantly formed enantiomer, thus providing an ee greater than 20% (and in the embodiments described herein, the ee is still greater).

[0028] In this document, the method of the present invention (and the embodiments described herein) indicate that salts of the compounds may be used and / or produced. Alternatively (and in preferred embodiments), the free bases of the compounds may be used and / or produced. Additionally, if the salt form is used and / or produced, it may be liberated to form the free base form (e.g., for further reactions, e.g., for use in further method steps as described herein). It should also be noted that the compounds mentioned herein may exhibit isomerism, such as tautomerism.

[0029] As mentioned above, the compound having formula (II) may be in the form of a salt and may thus be a compound that results in the formation of a quaternary salt (e.g., a benzyl group may be present on the nitrogen of the pyridyl moiety, thereby forming a benzyl quaternary salt).

[0030] An advantage of the method of the present invention is the reduction of the compound having formula (II) in a single step, which involves effectively reducing the keto group (the tautomer of the depicted enol moiety) to a hydrazone and then to a hydrazine. This has the advantage of not requiring the separation and / or isolation of intermediates (such as possibly unstable intermediates).

[0031] The reductive hydrazination of the method of the present invention to produce a compound having formula (IV) and optionally deprotect / remove R 2 (when it is a nitrogen protecting group) and introduce R 1 (when it is a nitrogen protecting group), for the sake of clarity, via a compound having formula (VA) wherein R 1 and R 2 independently represent a nitrogen protecting group) to obtain the following compound having formula (V) (and in one embodiment R 1 represents a nitrogen protecting group)

[0032]

[0033] In one embodiment of the present invention, there is also provided a method for preparing a compound having formula (I), the method comprising resolving a compound having formula (V) (e.g., under the conditions described herein). In such an embodiment, the compound having formula (V) prepared as described above is not required in the method of the present invention, but in another embodiment, the compound having formula (V) is prepared as described above (i.e., by reductive hydrazination of a compound having formula (II) with a compound having formula (III), followed by optionally deprotecting / removing R 2 (when it is a nitrogen protecting group) and introducing R 1 (when it is a nitrogen protecting group)). The preferred compound having formula (V) used in the resolution to provide the desired compound having formula (I) is one wherein R 1 represents a nitrogen protecting group (such as those described herein).

[0034] In the method of the present invention, the advantage of using a compound having formula (II) (which is a quaternary salt, such as a quaternary salt having a nitrogen protecting group (such as benzyl on the nitrogen atom)) is that if it is desired to prepare a compound having formula (VA) (and / or a compound having formula (V)) wherein R 1 represents such a protecting group (such as benzyl), then such a group does not need to be introduced after the reductive hydrazination of the method of the present invention.

[0035] All individual properties mentioned herein (e.g., preferred features) can be employed independently or in combination with any other feature mentioned herein (including preferred features) (thus, preferred features can be combined with other preferred features or employed independently of them).

[0036] Those skilled in the art will understand that the compounds mentioned in the context of the method of the present invention are those that are stable. That is, the compounds included herein are robust enough to withstand separation from, for example, a reaction mixture to a useful purity.

[0037] To avoid ambiguity, the compounds of formula (V) are racemic (or have low enantiomeric purity, e.g., showing an enantiomeric excess "ee" of less than 20%), i.e., the chiral center at the point of attachment of the -N(H)NH 2 group contains an equimolar mixture of (R)- and (S)-configurations (or a substantially lower preference for one configuration compared to the other, e.g., less than 60% of the major enantiomer). However, the corresponding chiral center of the compounds of formula (I) predominantly has the (R)-configuration (and is described as an "enantiomerically enriched product").

[0038] As described above, the method of the present invention includes "reductive hydrazination", by which we mean the introduction of a hydrazine group (or a protected form thereof, as defined for the compounds of formula (III) and R 2 as defined) while performing a reduction (reduction of the aromatic ring of the pyridine of formula (II)).

[0039] In the method of the present invention, in one embodiment, the compound of formula (III) is a compound in which R 2 is a nitrogen protecting group. For example, a nitrogen protecting group is a group that leads to the formation of the following substances:

[0040] - amide (e.g., N-acetyl)

[0041] - optionally substituted N-alkyl (e.g., N-alkyl or optionally substituted N-benzyl)

[0042] - N-sulfonyl (e.g., optionally substituted N-phenylsulfonyl)

[0043] - carbamate

[0044] - urea

[0045] - trityl (triphenylmethyl), dibenzyl, etc.

[0046] Thus, among other groups, R 2 can represent:

[0047] - C(O)R t1 (wherein R t1 preferably represents C 1-6 alkyl or optionally substituted aryl);

[0048] C 1-6 alkyl, the alkyl group of which is optionally substituted by one or more selected from optionally substituted aryl (e.g., preferably forming a benzyl group);

[0049] - S(O) 2 R t2 (wherein R t2preferably represents an optionally substituted aryl); or, preferably -C(O)OR t3 (wherein R t3 preferably represents an optionally substituted aryl) or, more preferably, optionally substituted C 1-6 (e.g., C 1-4 )alkyl, such as tert-butyl (thus forming, for example, a tert-butoxycarbonyl protecting group, i.e., when together with an amino moiety (tert-butyl carbamate group)) or -CH 2 phenyl group (thus forming a carboxybenzyl protecting group);

[0050] -C(O)N(R t4 )R t5 (wherein, preferably, R t4 and R t5 independently represent hydrogen, C 1-6 alkyl, optionally substituted aryl or -C(O)R t6 , and R t6 represents C 1-6 alkyl or optionally substituted aryl).

[0051] In one embodiment, the most preferred R 2 group is tert-butoxycarbonyl (i.e., -C(O)-O-tert-butyl or t-BOC), such that the compound of formula (III) represents H 2 N-N(H)-C(O)-O-tert-butyl. It is particularly advantageous in view of the fact that hydrazine (or its suitable form) can be difficult to handle and further may facilitate the production of a compound of formula (IV) (wherein R 2 represents a nitrogen protecting group (e.g., t-Boc)), so that subsequent steps, such as protecting the nitrogen of the piperidyl ring, i.e., introducing an R 1 protecting group, and / or deprotecting the hydrazine protecting group, i.e., removing the R 2 protecting group (to form a compound of formula (V) (wherein R 1 represents a nitrogen protecting group)), can occur in a manageable process step, such that the compound of formula (V) can be resolved according to the methods described herein. Compounds of formula (VA) or (V) (wherein R 1 is certain leaving groups (especially when it is benzyl)) can give improved or better ee in the resolution step (in particular, this applies to compounds of formula (V), in view of the fact that in one embodiment, the compound of formula (VA) is deprotected before the resolution step to give a compound of formula (V)). In addition to such compounds (wherein R 1Apart from certain protecting groups that result in an advantage or improvement with respect to ee in the splitting step, such protecting groups may also have other advantages, for example, they are most effective during other reaction steps (such as reduction in the main method of the present invention) in terms of ease of protection / deprotection.

[0052] In a further embodiment of the present invention, certain compounds per se are provided, such as: compounds having formula (IV), compounds having formula (VA), and / or compounds having formula (V).

[0053] The method of the present invention involves reductive hydrazination, which converts a compound having formula (II) into a compound having formula (IV) in the presence of a hydrazine compound having formula (III). It will be understood that such a "reductive" step will necessarily be carried out in the presence of a hydrogen source. For example, it can be carried out in the presence of a suitable catalyst (such as a metal catalyst, such as palladium, nickel, platinum, ruthenium, rhodium, and / or iridium) (in one embodiment, palladium is used, such as palladium on carbon, i.e., Pd / C, which can be Pd / C between 5% and 10%). Any suitable hydrogen source can be used for reduction (or reductive hydrazination), such as H 2 gas (this gas can be introduced, for example, at a pressure of about 20 bar; generally, H 2 gas will be stored in a pressurized cylinder and the method uses H greater than 1 atmosphere 2 ). Another suitable hydrogen source can also be used (in addition to H 2 gas or as an alternative to using this hydrogen source), such as a suitable donor molecule like a protonic acid, such as acetic acid, formic acid, etc. (such as sodium formate in water). This aspect of the method of the present invention can also be carried out in the presence of a suitable solvent. In one embodiment of the present invention, for example, any suitable solvent such as an alcoholic solvent (such as methanol). In one embodiment, the container or autoclave in which the reduction (or reductive hydrazination) is carried out is heated, for example, to a temperature above room temperature (such as above 40 °C, such as above 55 °C, such as between 55 °C and 70 °C, but the maximum temperature will depend on the boiling point of any solvent used; for example, if the reaction is carried out in the presence of methanol, then the temperature is about 62 °C). The reaction can be carried out for several hours until completion, for example, overnight (such as about 12 hours), however, the progress / completion of the reaction can be monitored and the duration adjusted accordingly. If the catalyst used in this reaction contains water, then if desired, the water can be partially removed by stirring in the solvent (such as an alcoholic solvent, methanol) used in this method step. After the reaction has progressed, the reaction mixture can be post-treated and the desired product (the compound having formula (IV)) can be extracted, separated, and / or isolated.

[0054] Then it is pointed out that by (i) in R 2 (when R 2Optionally deprotect at the position representing the nitrogen protecting group) and (ii) optionally introduce R at the NH moiety of the piperidine ring 1 (when R 1 represents a nitrogen protecting group) to convert the compound of formula (IV). In one embodiment, it is preferred that the compound of formula (III) is one in which R 2 represents a nitrogen protecting group (in one embodiment, it represents a BOC - protecting group), and thus the resulting compound of formula (IV) is also one in which R 2 represents such a protecting group. In one embodiment, it is also preferred that the compound of formula (I) is one in which R 1 represents a nitrogen protecting group, and thus, in one embodiment, to the compound of formula (IV) produced by reductive hydrazination, step (ii) (i.e., introducing R 1 protecting group) is preferably carried out first, thus forming a compound of formula (VA) (or a compound of formula (V)).

[0055] When producing the compounds of formula (VA) and (V), it is particularly preferred that R 1 represents a nitrogen protecting group to be resolved (especially for the compound of formula (V)). In this regard, R 1 can represent a group that leads to the formation of the following substances:

[0056] - amide (e.g., N - acetyl)

[0057] - optionally substituted N - alkyl (e.g., N - alkyl or optionally substituted N - benzyl)

[0058] - N - sulfonyl (e.g., optionally substituted N - benzenesulfonyl)

[0059] - carbamate

[0060] - urea

[0061] - trityl (triphenylmethyl), dibenzyl, etc.

[0062] Thus, among other groups, R 1 can represent:

[0063] - C(O)R t1 (wherein R t1 preferably represents C 1-6 alkyl or optionally substituted aryl);

[0064] C 1-6 alkyl, the alkyl group of which is optionally substituted by one or more selected from optionally substituted aryl (e.g., preferably forming a benzyl group);

[0065] -S(O) 2 R t2 (wherein R t2 preferably represents an optionally substituted aryl); or, preferably -C(O)OR t3 (wherein R t3 preferably represents an optionally substituted aryl) or, more preferably, an optionally substituted C 1-6 (such as C 1-4 ) alkyl, such as tert-butyl (thus forming, for example, a tert-butoxycarbonyl protecting group, i.e., when together with an amino moiety (tert-butyl carbamate group)) or -CH 2 phenyl group (thus forming a carboxybenzyl protecting group);

[0066] -C(O)N(R t4 )R t5 (wherein, preferably, R t4 and R t5 independently represent hydrogen, C 1-6 alkyl, an optionally substituted aryl or -C(O)R t6 , and R t6 represents C 1-6 alkyl or an optionally substituted aryl).

[0067] In one embodiment, the most preferred R 1 group is a C 1-6 alkyl (such as -CH 3 ) substituted by an aryl (such as by a phenyl ring), thus forming, for example, a benzyl group.

[0068] Converting a compound of formula (IV) (such as wherein R 2 represents a protecting group, as defined above) to a compound of formula (VA) (wherein R 1 represents a nitrogen protecting group) can occur under suitable conditions, for example when R 1 represents a C 1-6 alkyl substituted by an aryl (such as a benzyl group), then the compound of formula (IV) can be reacted with a compound of formula R x -L x , wherein L x represents a suitable leaving group (such as bromine, chlorine, iodine, sulfonate (mesylate, tosylate, triflate), etc.) and R x represents a C 1-6 alkyl substituted by an aryl (such as benzyl); thus for the introduction of a benzyl group, the reaction can be carried out in the presence of benzyl bromide optionally in a suitable solvent (such as dichloromethane) and a suitable base (such as an organic base, such as an amine base (such as triethylamine), etc.).

[0069] In the resulting compound of formula (VA), in one embodiment, the nitrogen protecting group of R 1 is different from the nitrogen protecting group of R 2 By different, we mean that under certain conditions, either nitrogen protecting group (e.g., the nitrogen protecting group of R 2 ) can be removed while the other nitrogen protecting group (e.g., the nitrogen protecting group of R 1 ) remains substantially intact. Thus, as described above (when R 2 represents a nitrogen protecting group), in one embodiment, such an R 2 protecting group is removed (while the R 1 protecting group, e.g., the one that has just been introduced, remains intact) and the compound of formula (VA) is converted into a compound of formula (V). Such a conversion illustrates why the R 1 and R 2 protecting groups are different and are cleavable under different conditions. For example, when R 1 represents a C 1-6 alkyl substituted by an aryl (e.g., a phenyl ring; thus forming, for example, a benzyl group), the R 2 protecting group is preferably a protecting group that can be removed / cleaved under conditions that do not result in the removal of the R 1 protecting group. For example, when R 2 represents a BOC - protecting group, suitable conditions can be used to remove this group while keeping the R 1 protecting group (e.g., when it is benzyl) intact. Such conditions that can be used include acidic conditions (e.g., in the presence of water and HCl), where the temperature can also be controlled such that the temperature does not exceed room temperature (e.g., about 25 °C), for example, by using a water bath. Although the progress of the reaction can be monitored and the time adjusted accordingly, the reaction can be allowed to proceed at about room temperature (e.g., about 20 °C - 25 °C) for several hours (e.g., overnight, about 12 hours). After the reaction has proceeded / been completed, the reaction can be worked up, for example, by cooling in an ice bath and adding an alkaline solution (e.g., NaOH solution, which can be 32 m%) to neutralize any remaining acid, and the desired product (the compound of formula (V)) can be extracted, separated, and / or isolated.

[0070] In one embodiment, the compound of formula (V) (where R 1 represents benzyl) is the compound used in the resolution step to provide the compound of formula (I).

[0071] In an embodiment of the method of the present invention, where a compound of formula (V) is resolved to provide a compound of formula (I) (either prior to the method for preparing a compound of formula (V) as described above, i.e., reductive hydrazination, or otherwise), certain resolution methods are preferred. For example, in one embodiment of the present invention, the resolution is carried out in the presence of D-(-)-tartaric acid to produce the D-(-)-tartrate salt of the (R)-enantiomer as defined herein, i.e., an ee greater than 20% (and in the embodiments described herein, the ee is still greater). For example, an enantiomerically enriched product (e.g., a compound of formula (I)) can be produced with an enantiomeric excess greater than 40% (e.g., greater than 60%, and in one embodiment, greater than 80% enantiomeric excess). These enantiomerically enriched products can even be above 90% (e.g., they can consist essentially of a single enantiomer, by which we mean the ee can be 95% or higher, e.g., above 98% or about 100%). Such enantiomeric abundance (or ee) can be obtained directly or by additional purification techniques well known to those skilled in the art. For example, the method of this embodiment of the present invention can produce a compound of formula (I), where R 1 represents a nitrogen protecting group (e.g., benzyl), and where such a product is enantiomerically enriched.

[0072] In this regard, and in a further embodiment, a compound of formula (IA) is provided,

[0073]

[0074] which compound is a compound of formula (I) especially in the form of the D-(-)-tartrate salt, and where R 1 is as defined herein (e.g., represents a nitrogen protecting group such as benzyl). As described above (e.g., in the context of a compound of formula (I)), such a product is enantiomerically enriched, e.g., with an enantiomeric excess above 40%, 60%, 80% or above 90% (e.g., the ee can be 95% or higher, e.g., above 98% or about 100%).

[0075] In one embodiment, a compound of formula (I) (e.g., a compound of formula (IA), where R 1 is a nitrogen protecting group (e.g., a C 1-6 alkyl group substituted by an aryl (e.g., benzyl))) is a compound that can be used in downstream steps to provide (ultimately) ibrutinib. For example, it is precisely such a compound of formula (I) or (IA) that can be used in a reaction with a compound of formula (VI) (see below) to produce a compound of formula (VII), where R 1 represents such a protecting group.

[0076] The splitting step described herein can be carried out in multiple embodiments, for example by using a chiral salt, and in particular by crystallization using the D-(−)-tartrate as described herein. In the presence of a suitable solvent system, such a salt (e.g., the D-(−)-tartrate of formula (IA)) can be prepared by mixing the D-(−)-tartrate with the non-salt form of the compound of formula (I). For example, the solvent system can comprise an alcohol (e.g., methanol or ethanol and aqueous alcohols such as aqueous methanol or aqueous ethanol), for example, the ratio of alcohol:water is between 1:1 and 20:1 (wherein the alcohol is preferably methanol), and in one embodiment, the ratio is between 2:1 and 8:1 (e.g., about 4:1). An interesting solvent system is a mixture of mainly alcohol (e.g., methanol) and alcohol / water containing a small amount of water (e.g., the water content is in the range of about 2% to about 20%, or about 5% to about 10% (w / w)). In particular, a water / methanol mixture with a water content in the range of about 5% to about 10%, such as about 5% (w / w), can be used. Crystallization is carried out at a certain temperature. For example, in one embodiment of the present invention, it can be carried out at a temperature between about 0 °C and 80 °C, for example, between about room temperature and 65 °C (e.g., between about 40 °C and 60 °C, and in one embodiment about 50 °C). Crystallization can involve stirring for a period of time (e.g., between 30 min and 2 hours; this time can initiate crystallization) at an elevated temperature (such as those temperatures mentioned above, e.g., 50 °C), followed by cooling for another period of time (e.g., between 30 min and 8 hours, such as about 4 hours) back to room temperature. Recrystallization can also be carried out to enhance the ee. For example, recrystallization can be carried out in the presence of the solvent system mentioned above, for example, under reflux, followed by cooling (and optionally seeding).

[0077] It can be advantageous to use tartaric acid (e.g., D-(−)-tartaric acid) for splitting for various reasons. For example, it provides the compound of formula (IA) as defined herein with sufficient ee, and in one embodiment it provides such a compound with higher ee (e.g., compared to other enantiomeric salts and / or other splitting methods) and / or it provides such a compound, the enantiomeric excess of which can be further improved (e.g., by recrystallization). Alternatively, or in addition, the compound of formula (IA) can be provided in a sufficiently high purity (e.g., compared to other methods) and / or in a form that can further enhance the purity of the compound of formula (IA) (e.g., by recrystallization). Therefore, in additional embodiments, an additional recrystallization step as described above (which enables the method to proceed to prepare the compound of formula (I) (or the compound of formula (IA))) can be provided.

[0078] As noted herein, the resolution can be carried out in a suitable solvent system (e.g., methanol / water), and likewise the product / salt of the compound of formula (I) thus formed can also be recrystallized in a suitable solvent system, e.g., the same solvent system used in the first crystallization. However, in one embodiment, the salt form of the compound of formula (I) (e.g., the compound of formula (IA)) does not need to undergo additional recrystallization, as it is possible that the first product has sufficient ee and / or purity (e.g., for use in additional method steps).

[0079] The salt form of the compound of formula (I) (e.g., the compound of formula (IA)) can be used directly in the additional method steps described herein. Alternatively, if the salt form of the compound of formula (I) is produced for the first time, the non-salt form can also be released prior to the additional reaction as described herein.

[0080] Unless otherwise specified, the alkyl groups defined herein can be straight-chain, or, when there are a sufficient number (i.e., at least three) of carbon atoms, can be branched and / or cyclic. In addition, when there are a sufficient number (i.e., at least four) of carbon atoms, such alkyl can also be partially cyclic / acyclic. Such alkyl can also be saturated, or when there are a sufficient number (i.e., at least two) of carbon atoms, can be unsaturated (thus including, for example, "vinyl" moieties).

[0081] In a further embodiment of the present invention, in the preparation of ibrutinib, the use of a compound of formula (I) (especially a compound of formula (IA)) is provided, e.g., prepared according to the method of the present invention described herein (including all its embodiments). For example, a compound of formula (I) prepared according to the method described herein can precede and proceed through known method steps (e.g., disclosed in International Patent Applications WO 2014 / 139970 and WO 2016 / 115356) to provide ibrutinib. In this regard, a method for preparing ibrutinib is provided, which method includes a method for preparing a compound of formula (I) as described herein, followed by conversion to ibrutinib - such additional steps can include the following:

[0082] (a) reacting a compound of formula (I) (especially a compound of formula (IA)) with a compound of formula (VI),

[0083]

[0084] or a derivative thereof, thereby forming a compound of formula (VII),

[0085]

[0086] or a derivative thereof, wherein R 1 is as defined herein (and in one embodiment is benzyl), and the reaction can be carried out under the conditions described in International Patent Application WO 2014 / 139970; the reaction can be carried out, for example, as follows: dissolving a compound having formula (I) (e.g., a compound having formula (IA)) in a suitable solvent (e.g., ethanol), adding a compound having formula (VI) (e.g., adding in excess, in solution), and stirring at a low temperature (e.g., at about 5 °C) for a period of time (e.g., 30 min), then adding a base (triethylamine, adding in excess) and stirring at a low temperature for a period of time (e.g., stirring at 5 °C - 10 °C for 1 hour), and then stirring at a higher temperature (e.g., about room temperature 25 °C) for another period of time (e.g., 14 hours), after work-up, a compound having formula (VII) can be obtained (e.g., wherein R 1 represents benzyl);

[0087] (b) Reacting a compound having formula (VII) or a derivative thereof to produce a compound having formula (VIII),

[0088]

[0089] or a derivative thereof, wherein R 1 is as defined above (e.g., benzyl), and the reaction is carried out with reagents and under the conditions described in WO 2014 / 139970; for example, a compound having formula (VII) or a derivative can be reacted with: (i) formamide (HCONH 2 ); (ii) formamidine or a formamidine salt H-C(=NH)-NH 3 + X - , wherein X - represents a suitable counterion, such as a halide (e.g., Cl - ) or an oxyanion (e.g., acyl-O - ), thus forming, for example, formamidine HCl or formamidine acetate, etc.; (iii) an alkyl (e.g., ethyl) formamidine ether, or a salt thereof, such as ethyl formamidine ether HCl; (iv) ethyl orthoformate followed by ammonium acetate. Deprotection can be carried out, for example, under standard conditions that allow removal of R 1 (e.g., when R 1 is benzyl) (under hydrogenation reaction conditions, e.g., in the presence of a palladium-based catalyst (e.g., Pd(OAc) 2 ), optionally in a suitable solvent (e.g., methanol) and an acid / proton source (e.g., 35% HCl), and in the presence of a hydrogen source (e.g., H 2, in the presence of (e.g., at 10 Psi) and with stirring for a suitable length of time (e.g., 2 hours, at 50 °C), a compound of formula (VIII) wherein R 1 is a nitrogen protecting group is converted to a compound of formula (VIII) wherein R 1 is hydrogen, and after appropriate work-up, a compound of formula (VIII) wherein R 1 represents hydrogen can be provided (e.g., separated or isolated);

[0090] (c) React a compound of formula (VIII) wherein R 1 represents hydrogen (or a derivative of such a compound) to provide ibrutinib, e.g., under the conditions described in WO 2014 / 139970 or WO 2016 / 115356; e.g., such a compound can react with Cl-C(O)-C(H)=CH 2 or can undergo a two-step process by reaction with 3-chloropropionyl chloride (e.g., in the presence of an aqueous solution of NaHCO 3 in Me-THF), thereby forming a compound of formula (IX),

[0091]

[0092] or a derivative thereof, wherein such an intermediate can undergo an elimination reaction, e.g., in the presence of DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) to provide ibrutinib.

[0093] For the avoidance of doubt, ibrutinib has the following formula:

[0094]

[0095] In a further embodiment of the invention, the methods of the invention described herein (and all of its embodiments) can be preceded by one or more method steps to produce a compound of formula (VI) (or a derivative thereof) as described herein, e.g., the procedures described in WO 2014 / 139970 can be used; e.g., according to the following scheme:

[0096]

[0097] For example: in the presence of a suitable reagent (e.g., (COCl) in DMF, THF 2) The conversion from (VIA) to (VIB) can be carried out in the presence of; the conversion from (VIB) to (VIC) can be carried out by adding (e.g., dropwise) a suitable base (e.g., an organic base such as DIPEA - diisopropylethylamine) in the presence of malononitrile (e.g., in THF), for example, the reaction is carried out at a low temperature (e.g., between -60 °C and -30 °C for about 2 hours and then subsequently heated to about 20 °C - 25 °C); the conversion from (VIC) to (VI) can be carried out by directly adding (e.g., in situ) (e.g., in excess) dimethyl sulfate to the compound having the formula (VIC) after the formation of (VIC) from (VIB), wherein such a reaction can be carried out by adding dimethyl sulfate at a temperature of about 25 °C or below and then stirring at 60 °C - 65 °C for, e.g., 5 hours.

[0098] These starting materials and certain intermediates are commercially available or can be prepared according to conventional reaction procedures commonly known in the art.

[0099] In the case of referring to equivalents, for the sake of clarity, this is intended to mean molar equivalents.

[0100] In another aspect of the present invention, there is provided a method for separating the obtained product (the compound having the formula (I)) (which can be referred to herein as "the compound of the present invention") from the method of the present invention. Thus, the compound of the present invention (or the product obtained by the method of the present invention) can be separated. This can be achieved in several ways:

[0101] - Flash column chromatography

[0102] - Precipitation / crystallization

[0103] - Derivatization, optionally followed by precipitation / crystallization

[0104] - Extraction (e.g., derivatization, followed by extraction)

[0105] - Distillation

[0106] In one aspect, the method is derivatization, for example, wherein the unwanted products (e.g., unreacted starting materials) are derivatized (e.g., by reaction with succinic anhydride, thus forming a group having a terminal carboxylic acid moiety), which can allow for possible separation, extraction, or isolation (e.g., the carboxylic acid can be removed in a work-up procedure).

[0107] In further embodiments of the present invention, there is provided the method of the present invention as described herein, followed by additional method steps.

[0108] A compound having the formula (I) (in an enantiomer-enriched form) can be used to prepare additional compounds, such as additional pharmaceutical products (or intermediates thereof), such as pharmaceutical products useful for the treatment of cancer (e.g., hematological malignancies), and in particular, the pharmaceutical product can be ibrutinib.

[0109] Other transformations (of products directly obtained by the methods of the present invention or of additional products resulting from downstream steps as may be described herein) can be carried out according to standard techniques and procedures in the prior art, such as amide formation reactions (in which case the possible conditions and coupling reagents will be known to those skilled in the art), esterifications, nucleophilic substitution reactions, and aliphatic nucleophilic substitution reactions.

[0110] The present invention then further provides a method for preparing a pharmaceutical formulation comprising ibrutinib, the method comprising introducing the relevant ibrutinib (or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable excipients, adjuvants, diluents, and / or carriers, the relevant ibrutinib (or a pharmaceutically acceptable salt thereof) being prepared according to the method described above.

[0111] Generally speaking, the methods described herein can have the following advantages: compared to the methods disclosed in the prior art, the compounds prepared can be prepared in the following manner: using fewer reagents and / or solvents, and / or requiring fewer reaction steps (e.g., different / separate reaction steps).

[0112] Compared to the procedures disclosed in the prior art, the methods of the present invention can also have the following advantages: one or more of the compounds prepared are produced in higher yield, higher purity, higher selectivity (e.g., higher regioselectivity), less 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 use and / or waste of accompanying materials (including reagents and solvents). In addition, there may be several environmental benefits of the methods of the present invention.

[0113] Example

[0114] The following examples are intended to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0115] Example 1 - Preparation of the compound having the formula (I)

[0116] 1a. Reductive hydrazination

[0117]

[0118] The autoclave was charged with: compound (II) (76 g, 0.799 mol), Boc-N(H)NH 2(106 g, 0.799 mol), acetic acid (48 g, 0.799 mol), 100 ml of methanol and 15 g of 5% Pd / C. The catalyst contains 56% water which is partially removed by stirring in methanol (75 mL). The solution is then decanted and the remaining catalyst (in 30 ml of methanol by volume) and an additional 70 ml of methanol are charged to the reactor. So there is a total of 200 ml of methanol in the reactor. It takes 1 hour to heat the autoclave to 62 °C (set point: 65 °C).

[0119] Hydrogenation is carried out overnight at 62 °C and 20 bar.

[0120] Work-up: After filtering the catalyst (vacuum, paper), the filtrate is analyzed by GC. Complete conversion of pyridine is observed. Then MeOH is evaporated by a rotary evaporator. There remains approximately 258 g of a viscous oil. The oil is poured into 1800 mL of cold water (in an ice bath), and then 180 g of 8N NaOH is added with stirring by a propeller stirrer. The resulting clear solution is extracted with CH 2 CI 2 Extraction: 4 times 200 ml, then once 100 ml.

[0121] The combined organic layers are dried over sodium sulfate. To prevent crystallization of the product, the mixture is kept warm in a warm water bath and then filtered to remove sodium sulfate. One day later, some of the product (the compound of formula (IVA), i.e., the compound of formula (IV) as defined above, but wherein R 2 represents a Boc-protecting group) crystallizes out - filtered, without washing and drying.

[0122] 1b. Benzylation

[0123]

[0124] A 250 mL round-bottom flask is charged with 8 g of the crystalline material obtained from Experiment 1a above (the crystalline material of the compound of formula (IVA) wherein R 2 is a Boc-protecting group). It is dissolved in 100 mL of DCM, 5.2 mL of Et 3 N (2 equivalents) and BnBr (benzyl bromide) (4.6 mL, 1.05 equivalents) are added, and then the mixture is stirred at R.T. for 3.5 hours.

[0125] Workup: The reaction mixture was washed three times with 25 ml of water. The resulting organic layer was dried and the solvent was evaporated. A colorless syrup (5.8 g) remained. To remove other impurities, the syrup was dissolved in 25 ml of MTBE + 25 ml of water. The layers were separated and the aqueous layer was extracted once with 25 ml of MTBE. The organic layers were combined, dried and the MTBE was evaporated. The remaining colorless syrup was dried by an oil pump to give 5.7 g (yield: 50%).

[0126] 1c. de-Boc acylation

[0127]

[0128] Under N 2 2, 150 ml of water was added to a round-bottom flask containing more than 50 g of the purified compound of formula (VA) wherein R 2 is a Boc-protecting group (as a hard crust on the flask wall). The solid material did not dissolve. Over 30 minutes, 100 ml of concentrated aqueous HCl was added quantitatively under nitrogen. The temperature was controlled by using a water bath (maximum 24 °C). When the addition of HCl was complete, a clear solution was obtained. The solution was left overnight at 22 °C.

[0129] Workup: The reaction mixture was cooled in an ice bath and 32 m% NaOH solution (144 g) was added until pH 12 was reached. The yellow solution was transferred to a separatory funnel under nitrogen and extracted with 100 ml of DCM. The layers were separated quickly. Under N 2 atmosphere, the aqueous layer was extracted twice with 100 ml of DCM. The combined organic layers were dried with sodium sulfate and the DCM was evaporated. The remaining light yellow oil was dried by an oil pump to give 33 g of an oil (yield = 84%). The product (compound of formula (V) wherein R 1 is benzyl) was stored under nitrogen.

[0130] 1d. Resolution:

[0131] Under a nitrogen atmosphere, a stirred yellow solution of 142 g (692 mmol) of racemic Y10-Bn free base in 1000 mL of MeOH was warmed to 50 °C and a warm solution of 58.0 g (386 mmol, 0.56 eq) of D-(-)-tartaric acid dissolved in 250 mL of MeOH was added slowly over 30 minutes. During the last part of the addition, the reaction mixture became turbid and began to crystallize slowly. Some seed crystals were added and the reaction mixture was stirred at 50 °C for 1 hour. During this time, slow crystallization occurred. Then the stirred reaction mixture was allowed to cool to room temperature over about 4 hours and further stirred overnight. After 20 h, the solid was filtered and washed with 120 mL of MeOH. After drying in a vacuum oven: 106.3 g (299 mmol, 43%) of a white solid was obtained. 1 1H NMR: 1:1 salt, containing 3 mol% of MeOH; HPLC: e.e. 86.6% (R).

[0132] 1e. Recrystallization

[0133] 176.8 g of (R)-Y10-Bn.D-(-)-TA salt (e.e. 84% (R)) was added to a conical flask equipped with a magnetic stirrer. The solid was suspended in 1500 ml of MeOH / H 2 2O 2:1 v / v and heated to reflux with stirring. At the reflux temperature of 75 °C, an additional 200 ml of MeOH / H2O 2:1 v / v was added in portions until the pale yellow solution became clear at reflux (total: 1700 ml of MeOH / H 2 2O 2:1 v / v). The heating was removed and the solution was allowed to cool with stirring. Seed crystals (50 mg) were added at 70 °C. Over 4 hours, the slowly crystallizing suspension was allowed to cool to room temperature with stirring. After stirring at room temperature for 20 h, the white solid was filtered off (vacuum filtered through a P2 glass filter), washed with 100 ml of MeOH / H 2 2O 2:1 and 100 ml of MeOH, and dried in the filter for 30 min. The solid was transferred to a 500 ml container (148.5 g) and dried in a vacuum oven at 20 °C for 24 hours.

[0134] Yield: 142.8 g of a white solid (81% crystallization yield); quantitative NMR with maleic acid: purity 97 ± 2 wt%; HPLC: e.e. ≥ 99% (R); specific rotation: [α]20 / D -16.7 (c = 1, H 2 2O).

[0135] Example 2 - Preparation of Ibrutinib (using the compound of formula (I) prepared according to Example 1)

[0136] Compounds 1 to 6

[0137]

[0138] Compound 1 (25.06 g, 117 mmol) was dissolved in dry THF (200 mL, 8 V) mixed with DMF (0.33 mL, 0.013 V). Under N 2 at 20 °C - 30 °C, oxalyl chloride (17.8 g, 0.14 mol, 1.2 equiv) was added dropwise to the THF solution and Compound 2 was obtained after 1 h of reaction. The mixture containing Compound 2 was charged into malononitrile (8.5 g, 128.7 mmol, 1.1 equiv) in THF (25 mL, 1 V). Subsequently, DIPEA (37.8 g, 292.5 mmol, 2.5 equiv) was added dropwise to the mixture over 2 h at -60 to -30 °C, then the temperature was raised to 20 °C to 25 °C, and Compound 3 was obtained. Subsequently, dimethyl sulfate (44.3 g, 351 mmol, 3.0 equiv) was added dropwise to the mixture at 25 °C, then the mixture was stirred at 60 °C - 65 °C for 5 h to obtain Compound 4. Compound 5 (29 g, 81.5 mmol, 0.7 equiv) was dissolved in EtOH (100 mL), and the mixture containing it was subsequently charged into the Compound 4 solution and stirred at 5 °C for 0.5 h, then 29.5 g of Et 3 N was added dropwise to the mixture over 1 h at 5 °C - 10 °C, then the mixture was stirred at 25 °C for 14 h to obtain Compound 6. 100 ml of EA (ethyl acetate) was charged into the mixture, then it was washed twice with water (100 ml). The aqueous phase was extracted with EA (200 ml), the organic phases were combined, then EA was exchanged with EtOH (90 ml) and a solid appeared. The solid was filtered and dried under vacuum at 40 °C for 7 h to obtain 22.47 g of Compound 6 with 99.18 a% HPLC purity. The overall yield of the four steps (S-1 to S-4) was 42.8%. It will be seen that Compound 5 is also referred to herein as a compound having the formula (IA) (where R 1 is benzyl) (which itself is a compound having the formula (I)).

[0139] Results:

[0140] 1) According to the three-step telescoping reaction, 81.64% of Compound 4 was produced from IPC. After reacting with a total of 0.7 equiv of Compound 5, 75.5% of Compound 6 was produced. After the work-up of this reaction, 22.47 g of Compound 6 with 99.18% HPLC purity was isolated.

[0141] (2) A reaction was carried out to prepare Compound 6 with 66.04% HPLC purity from crude Compound 4 (THF reaction mixture, containing 19.15 g net Y3). After work-up and three recrystallizations from EtOH / H 2 O, 10.28 g of Compound 6 with 98.88% HPLC purity was obtained. The mother liquor was recovered by column chromatography and slurried in EtOH to obtain 1.86 g of Compound 6 with 99.47% HPLC purity. So the total isolation yield of the four steps was 39.0%.

[0142] Compounds 6 to 7

[0143]

[0144] Compound 6 (10.0 g, 22.2 mmol) and formamidine acetate (23.2 g, 222 mmol, 10 eq) were dissolved in n-BuOH (150 mL, 15 V). The mixture was stirred at 120 °C for 19 h and then cooled to 20 °C - 25 °C. EA (150 ml, 10 V) was charged to the mixture, and then it was washed twice with water (125 ml). The aqueous phase was extracted twice with EA (125 ml). The organic layers were combined and evaporated to 100 ml, and then a solid appeared (or precipitated). 150 ml of MeOH was charged and then evaporated to 100 ml, and more solid appeared. The mixture was cooled to 10 °C - 15 °C, the precipitate was filtered and washed with MeOH (20 ml). After drying in vacuo at 35 °C for 16 h, 7.16 g of Compound 7 with 99.21% HPLC purity was obtained. The isolated yield was 67.55%.

[0145] Compounds 7 to 8

[0146]

[0147] Compound 7 (9.98 g, 20.9 mmol) was dissolved in MeOH (150 mL, 15 V), and Pd(OAc) 2 (1.0 g, 10 wt%) and 35% HCl (2.2 g, 20.9 mmol, 1.0 eq) were added sequentially. The mixture was stirred at 50 °C under hydrogen (20 Psi) for 2 h, then filtered and washed with MeOH. Subsequently, 5% KOH (200 ml) was added dropwise to the mixture, and then the precipitate was filtered. After drying in vacuo, 5.46 g of Compound 8 with 98.80% HPLC purity was obtained, with a yield of 67.4%.

[0148] Compound 8 to pure PCI-32765 (Ibrutinib)

[0149]

[0150] The final step of introducing a substituent on the ring nitrogen atom of the piperidinyl group can be carried out according to the procedure described in International Patent Application WO 2016 / 115356 by reaction with 3-chloropropionyl chloride (e.g., in the presence of an aqueous solution of NaHCO 3 to introduce a -C(O)-CH 2 CH 2 -Cl group at the nitrogen atom of the piperidinyl group. Then such an intermediate undergoes an elimination reaction in the presence of DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) to provide ibrutinib.

[0151] Example 3 : Ibrutinib (or a salt thereof) is prepared by using any of the method steps described in Example 1 to prepare an intermediate, which is subsequently converted into ibrutinib (or a salt thereof).

[0152] Additional Example 4 : A pharmaceutical composition is prepared by first preparing ibrutinib (or a salt thereof) according to Example 2 and then contacting the ibrutinib (or a salt thereof) so obtained with a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0153] Drug formulation

[0154] Ibrutinib can be formulated into a pharmaceutically acceptable formulation using standard procedures.

[0155] For example, the present invention provides a method for preparing a pharmaceutical formulation comprising ibrutinib or a derivative thereof, the method being characterized in that it comprises the method as defined above as a method step. A person skilled in the art will know that such pharmaceutical formulations will contain, for example, a mixture of active ingredients (i.e., ibrutinib or a derivative thereof) and pharmaceutically acceptable excipients, adjuvants, diluents, and / or carriers or consist of them.

[0156] The present invention further provides a method for preparing a pharmaceutical formulation comprising ibrutinib (or a derivative thereof), the method comprising introducing the relevant ibrutinib, or a pharmaceutically acceptable salt thereof (which can be formed by the methods described above), and one or more pharmaceutically acceptable excipients, adjuvants, diluents, and / or carriers.

Claims

1. A compound having the formula (IA), The compound is a compound of formula (I) in the form of the D-(-)-tartrate salt, and wherein R 1 is benzyl, and the compound is enantiomerically enriched.

2. The compound according to claim 1, wherein the compound has an enantiomeric excess greater than 40%.

3. The compound according to claim 1, wherein the compound has an enantiomeric excess greater than 60%.

4. The compound according to claim 1, wherein the compound has an enantiomeric excess greater than 80%.

5. The compound according to claim 1, wherein the compound has an enantiomeric excess greater than 90%.

6. The compound according to claim 1, wherein the compound has an enantiomeric excess of 95% or higher.

7. The compound according to claim 1, wherein the compound has an enantiomeric excess greater than 98%.

8. The compound according to claim 1, wherein the compound has an enantiomeric excess of 100%.

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