Methods and intermediates for preparing BTK inhibitors

Abstract

Disclosed is a process for preparing certain intermediates, such as a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof in an enantiomerically enriched form, which can be used to prepare BTK inhibitors, such as ibrutinib.

Description

Technical Field

[0001] The present invention relates to synthetic procedures and synthetic intermediates of substituted bicyclic compounds, in particular compounds useful as pharmaceuticals, for example Bruton's tyrosine kinase (Btk) inhibitors such as ibrutinib. Background Art

[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 is described in several publications, including International Patent Application WO 2008 / 039218 (Example 1b), and is described as an irreversible inhibitor of Btk.

[0003] Btk plays an important role in the B cell signaling pathway connecting cell surface B cell receptor activation to downstream intracellular responses. Btk is a key regulator of B cell development, activation, signaling and survival (Kurosaki, Curr Op Imm [New Immunology], 2000, 276-281; ​​Schaeffer and Schwartzberg, Curr Op Imm [New Immunology] 2000, 282-288). In addition, Btk plays a role in multiple other hematopoietic cell signaling pathways, such as Toll-like receptors (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 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 has been approved for use in certain hematological malignancies in several countries, including the United States and the European Union, and is also being studied in clinical trials for other hematological malignancies, including chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and multiple myeloma.

[0005] There are various ways to prepare functionalized bicyclic heterocycles and ibrutinib, which have been described in particular in US patent document US 2011 / 0082137 and international patent application WO 2008 / 039218 (Example 1b). With respect to the latter, the later steps of the synthesis of ibrutinib are shown in the following scheme:

[0006]

[0007] The above synthesis also led to several synthetic strategies for preparing chiral hydroxypiperidine intermediates, including in the unpublished PCT application PCT / EP2017 / 075289.

[0008] Other methods for synthesizing ibrutinib have been disclosed in international patent application WO2014 / 139970, including by the following scheme:

[0009]

[0010] 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 aqueous NaHCO3 in Me-THF), thereby introducing a -C(O)-CH2CH2-Cl group at the nitrogen atom of the piperidinyl group. Such an intermediate then undergoes an elimination reaction in the presence of DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) to provide ibrutinib.

[0011] The above synthesis utilizes asymmetric chiral hydrazines, which are key elements of the synthetic route. Such chiral hydrazines are prepared by splitting, and what is referred to herein is chiral chromatography, such as chiral SFC. Such methods may be cumbersome and / or inefficient. The object of the present invention is to find alternative / improved methods for such chiral hydrazines, which can be used as structural units in further synthesis of functionalized heterocycles (e.g., ibrutinib). Summary of the invention

[0012] There is now provided a method for preparing a compound of formula (I) in enantiomerically enriched form

[0013]

[0014] or a pharmaceutically acceptable salt thereof,

[0015] in

[0016] R 1 represents a hydrogen or nitrogen protecting group;

[0017] * represents a chiral center with (R) configuration;

[0018] The method comprises subjecting a compound having formula (II) to

[0019]

[0020] That is, 3-hydroxypyridine, or a salt thereof, and a compound having formula (III)

[0021] H2N-N(H)-R 2 (III)

[0022] or its salt reductive hydrazine, wherein R 2 represents a hydrogen or nitrogen protecting group, thus forming a compound having the formula (IV),

[0023]

[0024] or a salt thereof, wherein R 2 As defined above, followed in any order, in R 2 Optional deprotection (when R 2 represents a nitrogen protecting group), optionally introducing R 1 (When R 1 represents a nitrogen protecting group), followed by resolution (if necessary),

[0025] This method may be referred to herein as the method of the present invention (which consists of one or more embodiments).

[0026] The process of the invention produces an enantiomerically enriched compound of formula (I), and may alternatively be described as a process for preparing a composition comprising a compound of formula (I), wherein the (R)-enantiomer is the predominant enantiomer formed, thus providing an ee of greater than 20% (and in the embodiments described herein, the ee is still greater).

[0027] In this article, the method of the present invention (and the embodiments described herein) indicates that the salt of the compound can be used and / or produced. Alternatively (and in a preferred embodiment), the free base of the compound can be used and / or produced. In addition, if a salt form is used and / or produced, it can be released to form a free base form (e.g., for other reactions, such as for use in those other method steps as described herein). It should also be noted that the compounds mentioned herein can exhibit isomerism, such as tautomerism.

[0028] As mentioned above, the compound of formula (II) may be in the form of a salt and thus it may be a compound that results in the formation of a quaternary salt (eg a benzyl group may be present on the nitrogen of the pyridyl moiety, thereby forming a benzyl quaternary salt).

[0029] The advantage of the process of the present invention is that the compound of formula (II) is reduced in a single step, which includes effectively reducing the keto group (the tautomer of the enol moiety depicted) to a hydrazone and then to a hydrazine. This has the advantage that there is no need to separate and / or isolate intermediates (e.g., potentially unstable intermediates).

[0030] The reductive hydrazine reaction of the present invention to produce a compound of formula (IV) and optionally deprotecting / removing R 2 (when it is a nitrogen protecting group) and introduce R 1 (when it is a nitrogen protecting group), then, for the avoidance of doubt, via a compound of formula (VA) (wherein R 1 and R 2 independently represents a nitrogen protecting group) to obtain the following compound having formula (V) (and in one embodiment R 1 represents a nitrogen protecting group)

[0031]

[0032] In one embodiment of the invention, a method for preparing a compound of formula (I) is also provided, the method comprising resolving a compound of formula (V) (e.g., under conditions described herein). In such an embodiment, a compound of formula (V) prepared as described above is not required in the method of the invention, but in another embodiment, a compound of formula (V) is prepared as described above (i.e., by reductive hydrazine hydration of a compound of formula (II) with a compound of formula (III), followed by optional deprotection / removal of R 2 (when it is a nitrogen protecting group) and introduce R 1 (when it is a nitrogen protecting group). Preferred compounds of formula (V) used in the resolution to provide the desired compounds of formula (I) are those wherein R 1 Compounds representing nitrogen protecting groups (eg, as described herein).

[0033] In the process of the present invention, the advantage of using a compound of formula (II) which is a quaternary salt, for example a quaternary salt having a nitrogen protecting group (such as a benzyl group on the nitrogen atom) is that if one wishes to prepare a compound of formula (VA) (and / or a compound of formula (V)) wherein R 1 If the alkylene group represents such a protecting group (eg benzyl)), then it is not necessary to introduce such a group after the reductive hydrazine reaction in the process of the present invention.

[0034] All individual features (eg preferred features) mentioned herein may be taken independently or in combination with any other features (including preferred features) mentioned herein (thus preferred features may be taken in combination with other preferred features or independently of them).

[0035] The skilled artisan will appreciate that the compounds referred to in the context of the methods of the present invention are those that are stable. That is, the compounds included herein are those that are sufficiently robust to withstand isolation to a useful degree of purity from, for example, a reaction mixture.

[0036] For the avoidance of doubt, 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 centre at the point of attachment of the -N(H)NH2 group contains an equimolar mixture of (R)- and (S)-configurations (or a substantially lower preference for one configuration over the other, e.g. less than 60% of the major enantiomer). However, the corresponding chiral centre of compounds of formula (I) has predominantly the (R)-configuration (and is described as an "enantiomerically enriched product").

[0037] As mentioned above, the process of the present invention involves "reductive hydrazine", by which we mean the introduction of a hydrazine group (or a protected form thereof, as defined for compounds of formula (III) and R 2 ) is simultaneously reduced (reduction of the aromatic ring of the pyridine having the formula (II)).

[0038] In the method of the present invention, in one embodiment, the compound having formula (III) is wherein R 2 A compound that is a nitrogen protecting group. For example, a nitrogen protecting group is a group that results in the formation of:

[0039] -amides (e.g. N-acetyl)

[0040] - optionally substituted N-alkyl (eg N-alkyl or optionally substituted N-benzyl)

[0041] -N-sulfonyl (eg, optionally substituted N-phenylsulfonyl)

[0042] -Carbamate

[0043] -Urea

[0044] -trityl (triphenylmethyl), diphenylmethyl, etc.

[0045] Therefore, among other groups, R 2 Can represent:

[0046] -C(O)R t1 (where Rt1 Preferably represents C 1-6 alkyl or optionally substituted aryl);

[0047] C 1-6 Alkyl, whose alkyl group is optionally substituted by one or more selected from optionally substituted aryl groups (eg, preferably forming a benzyl group);

[0048] -S(O)2R t2 (where R t2 preferably represents optionally substituted aryl); or, preferably -C(O)OR t3 (where R t3 preferably represents optionally substituted aryl) or, more preferably, optionally substituted C 1-6 (For example, C 1-4 )alkyl, for example tert-butyl (thus forming, for example, a tert-butoxycarbonyl protecting group, ie when taken together with an amino moiety (tert-butylcarbamate group)) or a -CH2phenyl group (thus forming a carboxybenzyl protecting group);

[0049] -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).

[0050] In one embodiment, the most preferred R 2 The group is tert-butyloxycarbonyl (i.e., -C(O)-O-tert-butyl or t-BOC), so that the compound of formula (III) represents H2N-N(H)-C(O)-O-tert-butyl. This is particularly advantageous in view of the fact that hydrazine (or a suitable form thereof) may be difficult to handle, and further may be advantageous in producing a compound of formula (IV) (wherein R 2 represents a nitrogen protecting group (e.g., t-Boc), so the subsequent steps, such as protecting the nitrogen of the piperidinyl ring, are to introduce R 1 Protecting groups, and / or deprotecting hydrazine protecting groups, i.e. removing R 2 Protecting group (to form a compound having formula (V) (wherein R 1 represents a nitrogen protecting group)), can occur in a manageable process step, for example allowing the compound of formula (V) to be resolved according to the methods described herein. Compounds of formula (VA) or (V) wherein R 1Certain leaving groups (especially when they are benzyl) may give improved or better ee in the resolution step (particularly this applies to compounds of formula (V), since in one embodiment, the compound of formula (VA) is deprotected prior to the resolution step to give a compound of formula (V)). In addition to such compounds (where R 1 In addition to certain protecting groups that result in advantages or improvements with respect to ee in the resolution step, such protecting groups may also have other advantages, such as being most efficient during other reaction steps (e.g., reduction in the main method of the invention) with respect to ease of protection / deprotection.

[0051] In further embodiments of the present invention, certain compounds themselves are provided, for example, compounds of formula (IV), compounds of formula (VA), and / or compounds of formula (V).

[0052] The method of the present invention relates to a reductive hydrazine reaction, which converts a compound of formula (II) into a compound of formula (IV) in the presence of a hydrazine compound of formula (III). It will be understood that such a "reduction" 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 (e.g., a metal catalyst such as palladium, nickel, platinum, ruthenium, rhodium and / or iridium) (in one embodiment, palladium is used, such as palladium carbon, i.e., Pd / C, which can be between 5% and 10% Pd / C). Any suitable hydrogen source can be used for reduction (or reductive hydrazine reaction), such as H2 gas (which can be introduced at a pressure of, for example, about 20 bar; typically, H2 gas will be stored in a pressurized cylinder and the method uses H2 at a pressure greater than 1 atmosphere). Another suitable hydrogen source (which can be used in addition to or as an alternative to H2 gas) can also be used, such as a suitable donor molecule such as a protonic acid, such as acetic acid, formic acid, etc. (e.g., 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 alcohol solvent (e.g., methanol). In one embodiment, the container or autoclave (wherein the reduction (or reductive hydrazine) is heated, for example, to a temperature above room temperature (e.g., above 40°C, for example, above 55°C, such as between 55°C-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, the temperature is about 62°C). The reaction can be carried out for several hours to completion, for example, overnight (e.g., about 12 hours), but the reaction progress / completion can be monitored and the duration can be adjusted accordingly. If the catalyst used in the reaction contains water, then if desired, the water can be partially removed by stirring in the solvent (e.g., alcohol solvent, methanol) used in this method step. After the reaction has progressed, the reaction mixture can be post-treated and the desired product (compound with formula (IV)) can be extracted, separated and / or isolated.

[0053] Then point out that by (i) in R 2 (When R 2 represents a nitrogen protecting group) and (ii) optionally introducing R 1 (When R 1 represents a nitrogen protecting group) to convert the compound having formula (IV). In one embodiment, it is preferred that the compound having formula (III) is wherein R 2 represents a nitrogen protecting group (in one embodiment, it represents a BOC-protecting group), so the compound of formula (IV) formed thereby is also one in which R 2 In one embodiment, it is also preferred that the compound of formula (I) is wherein R 1 represents a nitrogen protecting group, and thus, in one embodiment, to a compound of formula (IV) produced by reductive hydrazine, step (ii) (i.e., introducing R 1 Protecting groups) are preferably carried out first, thereby forming a compound of formula (VA) (or a compound of formula (V)).

[0054] When producing compounds of formula (VA) and (V), it is particularly preferred that R 1 represents the nitrogen protecting group to be cleaved (especially the compound of formula (V)). In this regard, R 1 Can represent groups that lead to the formation of:

[0055] -amides (e.g. N-acetyl)

[0056] - optionally substituted N-alkyl (eg N-alkyl or optionally substituted N-benzyl)

[0057] -N-sulfonyl (eg, optionally substituted N-phenylsulfonyl)

[0058] -Carbamate

[0059] -Urea

[0060] -trityl (triphenylmethyl), diphenylmethyl, etc.

[0061] Therefore, among other groups, R 1 Can represent:

[0062] -C(O)R t1 (where R t1 Preferably represents C 1-6 alkyl or optionally substituted aryl);

[0063] C 1-6Alkyl, whose alkyl group is optionally substituted by one or more selected from optionally substituted aryl groups (eg, preferably forming a benzyl group);

[0064] -S(O)2R t2 (where R t2 preferably represents optionally substituted aryl); or, preferably -C(O)OR t3 (where R t3 preferably represents optionally substituted aryl) or, more preferably, optionally substituted C 1-6 (For example, C 1-4 )alkyl, for example tert-butyl (thus forming, for example, a tert-butoxycarbonyl protecting group, ie when taken together with an amino moiety (tert-butylcarbamate group)) or a -CH2phenyl group (thus forming a carboxybenzyl protecting group);

[0065] -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).

[0066] In one embodiment, the most preferred R 1 The group is a C substituted by an aromatic group (e.g., by a phenyl ring). 1-6 Alkyl (eg -CH3), thus forming, for example, a benzyl group.

[0067] A compound having the formula (IV) (eg, wherein R 2 represents a protecting group, such as the protecting group defined above) is converted into a compound of formula (VA) (wherein R 1 represents a nitrogen protecting group) can occur under appropriate conditions, for example when R 1 represents a C substituted by an aryl group (e.g. a benzyl group) 1-6 When the alkyl group is present, then the compound of formula (IV) can be reacted with a compound of formula R x -L x The compound reaction, where L x represents a suitable leaving group (such as bromine, chloride, iodine, sulfonate (mesylate, tosylate, triflate), etc.) and R x represents a C substituted by an aryl group (e.g. benzyl) 1-6Alkyl; thus for the introduction of a benzyl group, the reaction can be carried out in the presence of benzyl bromide, optionally in the presence of a suitable solvent (eg dichloromethane) and a suitable base (eg an organic base such as an amine base (eg triethylamine) and the like).

[0068] In the resulting compound of formula (VA), in one embodiment, R 1 The nitrogen protecting group is different from R 2 By nitrogen protecting group, we mean any nitrogen protecting group (e.g., R 2 A nitrogen protecting group) and another nitrogen protecting group (e.g. R 1 The nitrogen protecting group) remains substantially intact. 2 represents a nitrogen protecting group), in one embodiment, removing such R 2 Protecting group (while R 1 The protecting group, such as that which has just been introduced, remains intact) and the compound of formula (VA) is converted into the compound of formula (V). Such a conversion explains why R 1 and R 2 Protecting groups are different and are susceptible to cleavage under different conditions. 1 represents a C substituted by an aryl group (e.g. a phenyl ring; thus forming, for example, a benzyl group) 1-6 When alkyl, R 2 The protecting group is preferably a group that can be used without causing R 1 A protecting group that is removed / cleaved under conditions where the protecting group is removed. For example, when R 2 When it represents a BOC-protecting group, suitable conditions can be used to remove the group while maintaining R 1 The protecting group (for example, when it is benzyl) is complete. Such conditions that can be used include acidic conditions (for example, in the presence of water and HCl), wherein the temperature can also be controlled so that the temperature does not exceed room temperature (for example, about 25 ° C), for example, by using a water bath. Although the progress of the reaction can be monitored and the time can be adjusted accordingly, the reaction can be allowed to progress for several hours (for example, overnight, about 12 hours) at about room temperature (for example, about 20 ° C-25 ° C). After the reaction has progressed / completed, the reaction can be post-processed, for example, by cooling in an ice bath and adding an alkaline solution (for example, NaOH solution, which can be 32m%) to neutralize any remaining acid, and the product (compound with formula (V)) desired can be extracted, separated and / or separated.

[0069] In one embodiment, the compound of formula (V) (wherein R 1 represents benzyl) is the compound used in the resolution step to provide the compound of formula (I).

[0070] In embodiments of the methods of the invention, where a compound of formula (V) is split to provide a compound of formula (I) (or prior to a method for preparing a compound of formula (V) as described above, i.e., reductive hydrazination, or otherwise), certain splitting methods are preferred. For example, in one embodiment of the invention, the splitting is carried out in the presence of D-(-) tartaric acid to produce a D-(-)-tartrate of the (R)-enantiomer as defined herein, i.e., an ee of greater than 20% (and in embodiments described herein, the ee is still greater). For example, an enantiomeric excess of greater than 40% (e.g., greater than 60%, and in one embodiment, greater than 80%) may be produced for an enantiomeric excess of ... Such enantiomeric abundance (or ee) can be obtained directly or by additional purification techniques, which are well known to those skilled in the art. For example, the method of this embodiment of the invention can produce a compound of formula (I) wherein R 1 represents a nitrogen protecting group (eg benzyl), wherein such a product is enantiomerically enriched.

[0071] In this regard, and in further embodiments, provided are compounds having formula (IA)

[0072]

[0073] The compound is a compound of formula (I), particularly in the form of a D-(-)-tartrate salt, and wherein R 1 As defined herein (e.g. representing 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 of greater than 40%, 60%, 80% or greater than 90% (e.g., the ee may be 95% or more, e.g. greater than 98% or about 100%).

[0074] In one embodiment, a compound of formula (I) (eg, a compound of formula (IA) wherein R 1 is a nitrogen protecting group (e.g., a C substituted with an aryl group (e.g., benzyl) 1-6 alkyl)) is a compound that can be used in a downstream step to provide (final) ibrutinib. For example, just such a compound of formula (I) or (IA) can be used in a reaction with a compound of formula (VI) (see below) to produce a compound of formula (VII), wherein R 1 represents such a protecting group.

[0075] The separation step described herein can be carried out in a plurality of embodiments, for example by using a chiral salt, and in particular using D-(-)-tartrate as described herein for crystallization. In the presence of a suitable solvent system, such salt (e.g., D-(-)-tartrate with a non-salt form of a compound of formula (I)) can be prepared by mixing D-(-)-tartrate. For example, the solvent system can include alcohol (e.g., methanol or ethanol and aqueous alcohol, 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 alcohol (e.g., methanol) and alcohol / water containing a small amount of water (e.g., water content in the range of about 2% to about 20%, or about 5% to about 10% (w / w)). In particular, a mixture of water / methanol in the range of about 5% to about 10%, for example, about 5% (w / w) can be used. Crystallization is performed at a certain temperature, for example, in one embodiment of the present invention, it can be performed at a temperature between about 0°C and 80°C, for example, between about room temperature and 65°C (for example, between about 40°C and 60°C, and in one embodiment about 50°C). Crystallization can involve stirring at an elevated temperature (such as those mentioned above, such as 50°C) for a period of time (for example, between 30 min and 2 hours; this time can initiate crystallization), followed by cooling for another period of time (for example, between 30 min and 8 hours, such as about 4 hours) back to room temperature. Recrystallization can also be performed to enhance ee, for example, recrystallization can be performed in the presence of the solvent system mentioned above, such as under reflux, followed by cooling (and optionally seeding).

[0076] The use of tartaric acid (e.g. D-(-)-tartaric acid) for resolution may be advantageous for a variety of reasons, for example it provides a compound of formula (IA) as defined herein with sufficient ee, and in one embodiment it provides such a compound with a higher ee (e.g. compared to other enantiomeric salts and / or other resolution methods) and / or it provides such a compound, the enantiomeric excess of which may be further improved (e.g. by recrystallization). Alternatively, or in addition, the compound of formula (IA) may be provided in a sufficiently high purity (e.g. compared to other methods) and / or in a form that may further enhance the purity of the compound of formula (IA) (e.g. by recrystallization). Thus, in further embodiments, a further recrystallization step as described above may be provided (which allows the method to be carried out to prepare a compound of formula (I) (or a compound of formula (IA))).

[0077] As noted herein, the resolution can be performed in a suitable solvent system (e.g., methanol / water), and likewise the product / salt of the compound of formula (I) formed therefrom can also be subjected to recrystallization in a suitable solvent system, such as in the same solvent system used for the first crystallization. However, in one embodiment, the salt form of the compound of formula (I) (e.g., a compound of formula (IA)) does not need to be subjected to additional recrystallization, as it may be the case that the first product has sufficient ee and / or purity (e.g., for use in additional process steps).

[0078] The salt form of the compound of formula (I) (e.g., the compound of formula (IA)) can be used directly in the further process steps described herein. Alternatively, if the salt form of the compound of formula (I) is generated for the first time, the non-salt form can also be released before the further reactions as described herein.

[0079] Unless otherwise indicated, alkyl groups as defined herein may be linear, or, when there are a sufficient number (i.e., a minimum of three) of carbon atoms, may be branched and / or cyclic. In addition, such alkyl groups may also be partially cyclic / acyclic when there are a sufficient number (i.e., a minimum of four) of carbon atoms. Such alkyl groups may also be saturated, or, when there are a sufficient number (i.e., a minimum of two) of carbon atoms, may be unsaturated (thus including, for example, "vinyl" moieties).

[0080] In a further embodiment of the invention, in the preparation of ibrutinib, there is provided the use of a compound of formula (I), in particular a compound of formula (IA), for example as prepared according to the methods of the invention as described herein (including all embodiments thereof). For example, a compound of formula (I) prepared according to the methods described herein may be preceded by and carried out by known method steps (e.g. disclosed in international patent applications WO 2014 / 139970 and WO 2016 / 115356) to provide ibrutinib. In this regard, there is provided a method for preparing ibrutinib, comprising a method for preparing a compound of formula (I) as described herein, followed by conversion to ibrutinib - such further steps may include the following:

[0081] (a) reacting a compound of formula (I) (particularly a compound of formula (IA)) with a compound of formula (VI),

[0082]

[0083] or a derivative thereof, thereby forming a compound having formula (VII),

[0084]

[0085] or its derivatives, wherein R 1 is as defined herein (and in one embodiment is benzyl), 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, by dissolving a compound of formula (I) (e.g. a compound of formula (IA)) in a suitable solvent (e.g. ethanol), adding a compound of formula (VI) (e.g. an excess amount, in solution) and stirring at low temperature (e.g. at about 5°C) for a period of time (e.g. 30 min), then adding a base (triethylamine, added in excess) and stirring at 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 of formula (VII) (e.g. wherein R 1 represents benzyl);

[0086] (b) reacting a compound of formula (VII) or a derivative thereof to produce a compound of formula (VIII),

[0087]

[0088] or its derivatives, wherein R 1 is as defined above (e.g. benzyl), and the reaction is carried out with reagents and under conditions described in WO 2014 / 139970; for example, a compound or derivative of formula (VII) may be reacted with: (i) formamide (HCONH2); (ii) formamidine or a formamidine salt HC(=NH)-NH3 + X - , where X - represents a suitable counterion, such as a halide (e.g. Cl - ) or oxygen anions (e.g. acyl-O - ), thus forming, for example, formamidine HCl or formamidine acetate, etc.; (iii) an alkyl (e.g., ethyl) amidine ether, or a salt thereof, such as ethyl amidine ether HCl; (iv) ethyl orthoformate followed by ammonium acetate. The deprotection may be performed, for example, in a manner that allows removal of R 1 (For example, when R 1 is benzyl) under standard conditions (under hydrogenation reaction conditions, for example 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. H2 at 10 Psi), and with stirring for an appropriate length of time (e.g. 2 hours at 50°C)), a compound of formula (VIII) (wherein R 1is a nitrogen protecting group) into a compound having the formula (VIII) (wherein R 1 is hydrogen), and after appropriate post-treatment, can provide (eg, separate or isolate) a compound of formula (VIII) (wherein R 1 represents hydrogen);

[0089] (c) reacting a compound having the formula (VIII) wherein R 1 represents hydrogen (or a derivative of such a compound) to provide ibrutinib, for example under the conditions described in WO 2014 / 139970 or WO 2016 / 115356; for example such a compound can be reacted with Cl-C(O)-C(H)=CH2, or can be reacted in a two-step process with 3-chloropropionyl chloride (for example in the presence of aqueous NaHCO3 in Me-THF) to form a compound of formula (IX),

[0090]

[0091] or a derivative thereof, wherein such intermediate can undergo an elimination reaction, for example in the presence of DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) to provide ibrutinib.

[0092] For the avoidance of doubt, ibrutinib has the following formula:

[0093]

[0094] In further embodiments of the invention, the methods of the invention described herein (and all embodiments thereof) may be preceded by one or more process steps to produce a compound of formula (VI) as described herein (or a derivative thereof), for example using the procedure described in WO2014 / 139970; for example according to the following scheme:

[0095]

[0096] For example: the conversion from (VIA) to (VIB) can be carried out in the presence of a suitable reagent (e.g., (COCl)2 in DMF, THF); the conversion from (VIB) to (VIC) can be carried out by adding (e.g., dropwise addition) of a suitable base (e.g., an organic base such as DIPEA-diisopropylethylamine) in the presence of malononitrile (e.g., in THF), for example, at low temperature (e.g., between -60°C and -30°C for about 2 hours, followed by subsequent warming to about 20°C-25°C); the conversion from (VIC) to (VI) can be carried out by adding dimethyl sulfate directly (e.g., in situ) (e.g., in excess) to a compound having formula (VIC) after the formation of (VIC) from (VIB), wherein such a reaction can result in the addition of dimethyl sulfate at a temperature of about 25°C or below, followed by stirring at 60°C-65°C for, for example, 5 hours.

[0097] These starting materials and certain intermediates are either commercially available or can be prepared according to conventional reaction procedures generally known in the art.

[0098] Where reference is made to equivalents, for the avoidance of doubt this is intended to refer to molar equivalents.

[0099] In another aspect of the present invention, a method for isolating the product obtained from the process of the present invention (compound of formula (I)) (which may be referred to herein as "compound of the present invention") is provided. The compound of the present invention (or the product obtained by the process of the present invention) may thus be separated / isolated. This can be achieved in several ways:

[0100] - Flash column chromatography

[0101] -Precipitation / Crystallization

[0102] - Derivatization, optionally followed by precipitation / crystallization

[0103] - Extraction (e.g. derivatization followed by extraction)

[0104] - Distillation

[0105] In one aspect, the method is a derivatization, e.g., wherein undesired products (e.g., unreacted starting materials) are derivatized (e.g., by reaction with succinic anhydride, thereby 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).

[0106] In further embodiments of the present invention, there is provided a method of the present invention as described herein followed by yet further method steps.

[0107] The compound of formula (I) (in enantiomerically enriched form) can be used to prepare further compounds, such as further pharmaceutical products (or intermediates thereof), such as pharmaceutical products useful for treating cancer (e.g. hematological malignancies), and in particular the pharmaceutical product may be ibrutinib.

[0108] Other transformations (of the products obtained directly by the process of the invention or resulting from additional products in downstream steps as may be described herein) can be carried out according to standard techniques and procedures in the art, such as amide formation reactions (in this case, possible conditions and coupling reagents will be known to those skilled in the art), esterification, nucleophilic substitution reactions, and aliphatic nucleophilic substitution reactions.

[0109] The present invention further provides a method for preparing a pharmaceutical formulation comprising ibrutinib, which comprises introducing relevant ibrutinib (or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable excipients, adjuvants, diluents and / or carriers, wherein the relevant ibrutinib (or a pharmaceutically acceptable salt thereof) is prepared according to the method described above.

[0110] In general, the methods described herein can have the following advantages: compared to methods disclosed in the prior art, the prepared compounds can be prepared in a manner that uses fewer reagents and / or solvents, and / or requires fewer reaction steps (e.g., different / separate reaction steps).

[0111] Compared to the procedures disclosed in the prior art, the methods of the present invention may also have the following advantages: the one or more compounds prepared are produced in higher yield, higher purity, higher selectivity (e.g., higher regioselectivity), less time, in a more convenient (i.e., easy to handle) form, from more convenient (i.e., easy 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.

[0112] Examples

[0113] The following examples are intended to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0114] Example 1 - Preparation of compounds of formula (I)

[0115] 1a. Reductive hydrazine

[0116]

[0117] The autoclave was charged with: compound (II) (76 g, 0.799 mol), Boc-N(H)NH2 (106 g, 0.799 mol), acetic acid (48 g, 0.799 mol), 100 ml methanol and 15 g 5% Pd / C. The catalyst contained 56% water which was partially removed by stirring in methanol (75 mL). The solution was then decanted and the remaining catalyst (volume 30 ml methanol) and another 70 ml methanol were charged to the reactor. So there was a total of 200 ml methanol in the reactor. It took 1 hour to heat the autoclave to 62° C. (set point: 65° C.).

[0118] Hydrogenation was carried out at 62°C and 20 bar overnight.

[0119] Workup: After filtering the catalyst (vacuum, paper), the filtrate was analyzed by GC. It was observed that the pyridine was completely converted. The MeOH was then evaporated by rotary evaporator. About 258 g of thick oil remained. The oil was poured into 1800 mL of cold water (in an ice bath) and then 180 g of 8N NaOH was added while stirring by a propeller stirrer. The clear solution obtained was extracted with CH2CI2: 4 times 200 ml, then once 100 ml.

[0120] The combined organic layers were dried over sodium sulfate. To prevent crystallization of the product, the mixture was kept warm in a warm water bath and then filtered to remove the sodium sulfate. After one day, some of the product (a compound of formula (IVA), i.e., a compound of formula (IV) as defined above, but wherein R 2 represents the BOC protecting group) crystallized out - filtered without washing and drying.

[0121] 1b. Benzylation

[0122]

[0123] A 250 mL round bottom flask was charged with 8 g of crystalline material obtained from Experiment 1a above (crystalline material of a compound of formula (IVA) wherein R 2 is a Boc-protecting group). It was dissolved in 100 mL of DCM, 5.2 mL of Et3N (2 eq.) and BnBr (benzyl bromide) (4.6 mL, 1.05 eq.) were added, and then stirred at RT for 3.5 hours.

[0124] Workup: The reaction mixture was washed 3 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 oil pump, yielding 5.7 g (yield: 50%).

[0125] 1c. De-Boc acylation

[0126]

[0127] Under N2, 150 ml of water was added to a mixture containing more than 50 g of the purified compound of formula (VA) (wherein R 2 The solid material did not dissolve. Over 30 minutes, under nitrogen, 100 ml of concentrated aqueous HCl were dosed / added. 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 at 22° C. overnight.

[0128] Workup: The reaction mixture was cooled in an ice bath and 32m% 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 DCM. The layers were separated quickly. The aqueous layer was extracted twice with 100 ml DCM under N2 atmosphere. The combined organic layers were dried over sodium sulfate and the DCM was evaporated. The remaining light yellow oil was dried by an oil pump to produce 33 g of oil (yield = 84%). The product (compound of formula (V) wherein R 1 is benzyl) and stored under nitrogen.

[0129] 1d. Split:

[0130] Under nitrogen atmosphere, a stirred yellow solution of 142g (692mmol) of racemic Y10-Bn free base in 1000mL of MeOH was heated to 50°C and a warm solution of 58.0g (386mmol, 0.56 equivalent) of D-(-)-tartaric acid dissolved in 250mL of MeOH was slowly added over 30 minutes. During the last part of the addition, the reaction mixture became cloudy and began to slowly crystallize. Some seed crystals were added and the reaction mixture was stirred at 50°C for 1 hour. During this time, slow crystallization was carried out. The stirred reaction mixture was then placed to cool to room temperature in about 4 hours and further stirred overnight. After 20h, the solid was filtered and washed with 120mL of MeOH. After drying in a vacuum oven: 106.3g (299mmol, 43%) of white solid was obtained.1 H NMR: 1:1 salt containing 3 mol% MeOH; HPLC: ee 86.6% (R).

[0131] 1e. Recrystallization

[0132] 176.8 g of (R)-Y10-Bn.D-(-)-TA salt (ee84% (R)) was added to a conical flask with a magnetic stirrer. The solid was suspended in 1500 ml MeOH / H2O 2:1 v / v and heated to reflux under stirring. At a reflux temperature of 75°C, another 200 ml of MeOH / H2O 2:1 v / v was added in batches until the pale yellow solution became clear under reflux (total: 1700 ml MeOH / H2O 2:1 v / v). The heating was removed and the solution was placed under stirring to cool. Seed crystals (50 mg) were added at 70°C. Within 4 hours, the slowly crystallized suspension was placed under stirring to cool to room temperature. After stirring at room temperature for 20 h, the white solid was filtered off (vacuum filtration in a P2 glass filter), washed with 100 ml MeOH / H2O 2:1 and 100 ml 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.

[0133] Yield: 142.8 g of white solid (81% crystallization yield); quantitative NMR with maleic acid: purity 97±2 wt%; HPLC: ee≥99% (R); optical rotation: [α]20 / D-16.7 (c=1, H2O).

[0134] Example 2 - Preparation of Ibrutinib (using the compound of formula (I) prepared according to Example 1)

[0135] Compound 1 to Compound 6

[0136]

[0137] 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), oxalyl chloride (17.8 g, 0.14 mol, 1.2 eq) was added dropwise to the THF solution under N2 at 20° C.-30° C. and compound 2 was obtained after reaction for 1 h. The mixture containing compound 2 was charged into malononitrile (8.5 g, 128.7 mmol, 1.1 eq) in THF (25 ml, 1 V). Subsequently, DIPEA (37.8 g, 292.5 mmol, 2.5 eq) was added dropwise to the mixture at -60 to -30° C. over 2 h, then heated to 20° C. to 25° C., and compound 3 was obtained. Subsequently, dimethyl sulfate (44.3 g, 351 mmol, 3.0 equivalents) was added dropwise to the mixture at 25 ° C, and then stirred at 60 ° C-65 ° C for 5 h to obtain compound 4. Compound 5 (29 g, 81.5 mmol, 0.7 equivalents) was dissolved in EtOH (100 mL), and the mixture containing it was subsequently loaded into the compound 4 solution and stirred at 5 ° C for 0.5 h, and then 29.5 g Et3N was added dropwise to the mixture at 5 ° C-10 ° C for 1 h, and then stirred at 25 ° C for 14 h to obtain compound 6. 100 ml EA (ethyl acetate) was loaded into the mixture, and then washed twice with water (100 ml). The aqueous phase was extracted with EA (200 ml), the organic phases were combined, and then EA was exchanged with EtOH (90 ml) and solids appeared. The solid was filtered and dried under vacuum at 40 ° C for 7 h to obtain 22.47 g compound 6 with 99.18a% HPLC purity. The total yield of the four steps (S-1 to S-4) is 42.8%. It will be noted that compound 5 is also referred to herein as a compound having formula (IA) (wherein R 1 is benzyl) (which itself is a compound of formula (I)).

[0138] result:

[0139] 1) According to the three-step telescope reaction, 81.64% of compound 4 was produced from IPC. After reaction with a total of 0.7 equivalents of compound 5, 75.5% of compound 6 was produced. After work-up of the reaction, 22.47 g of compound 6 was isolated with a HPLC purity of 99.18%.

[0140] 2) The reaction was carried out to prepare compound 6 with 66.04% HPLC purity from crude compound 4 (THF reaction mixture, containing 19.15 g of neat Y3). After work-up and three EtOH / H2O crystallizations, 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 isolated yield of the four steps was 39.0%.

[0141] Compound 6 to Compound 7

[0142]

[0143] Compound 6 (10.0 g, 22.2 mmol) and acetic acid formamidine (23.2 g, 222 mmol, 10 equivalents) were dissolved in n-BuOH (150 mL, 15 V), and the mixture was stirred at 120 ° C for 19 h, then cooled to 20 ° C-25 ° C. EA (150 ml, 10 V) was charged into the mixture, then 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, after which a solid appeared (or precipitated). 150 ml of MeOH was charged, then evaporated to 100 ml, after which more solid appeared. The mixture was cooled to 10 ° C-15 ° C, the precipitate was filtered and washed with MeOH (20 ml). After vacuum drying 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%.

[0144] Compound 7 to Compound 8

[0145]

[0146] 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%), 35% HCl (2.2 g, 20.9 mmol, 1.0 eq.) were added in sequence. 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 the precipitate was filtered. After vacuum drying, 5.46 g of compound 8 with 98.80% HPLC purity was obtained, and the yield was 67.4%.

[0147] Compound 8 to pure PCI-32765 (ibrutinib)

[0148]

[0149] 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 the international patent application WO 2016 / 115356 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 at the nitrogen atom of the piperidinyl group. Such an intermediate then undergoes an elimination reaction in the presence of DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) to provide ibrutinib.

[0150] Example 3 : Ibrutinib (or its salt) is prepared by preparing an intermediate using any one of the process steps described in Example 1, followed by conversion into ibrutinib (or its salt).

[0151] Another example 4 : A pharmaceutical composition is prepared by first preparing ibrutinib (or its salt) according to Example 2, and then contacting the ibrutinib (or its salt) thus obtained with a pharmaceutically acceptable carrier, diluent and / or excipient.

[0152] Pharmaceutical preparations

[0153] Ibrutinib can be formulated into a pharmaceutically acceptable formulation using standard procedures.

[0154] For example, the present invention provides a method for preparing a pharmaceutical formulation comprising ibrutinib or a derivative thereof, characterized in that it comprises as a method step a method as defined above. A skilled person will know that such a pharmaceutical formulation will comprise, for example, a mixture of an active ingredient (i.e., ibrutinib or a derivative thereof) and a pharmaceutically acceptable excipient, adjuvant, diluent and / or carrier or consist thereof.

[0155] The present invention further provides a method for preparing a pharmaceutical formulation comprising ibrutinib (or its derivatives), which comprises introducing the relevant ibrutinib, or a pharmaceutically acceptable salt thereof (which can be formed by the method described above) and one or more pharmaceutically acceptable excipients, adjuvants, diluents and / or carriers.

Claims

1. A method for preparing a compound of formula (I) in an enantiomerically enriched form or a pharmaceutically acceptable salt thereof, in R 1 represents a hydrogen or nitrogen protecting group; * represents a chiral center with (R) configuration; The method comprises subjecting a compound having formula (II) to That is, 3-hydroxypyridine, or a salt thereof, and a compound having formula (III) H2N-N(H)-R 2 (III) or its salt reductive hydrazine, wherein R 2 represents a hydrogen or nitrogen protecting group, thus forming a compound having the formula (IV), or a salt thereof, wherein R 2 As defined above, then in any order, when R 2 When R represents a nitrogen protecting group 2 Deprotection is performed at 1 When it represents a nitrogen protecting group, R is introduced into the NH portion of the piperidinyl ring. 1 , then split.

2. The method of claim 1, wherein the compound of formula (IV) is obtained by 1 and R 2 The compound of formula (VA) independently representing a nitrogen protecting group is converted to the following wherein R 1 Compounds of formula (V) representing nitrogen protecting groups 3. The method of claim 2, wherein the compound of formula (V) is resolved to provide a compound of formula (I).

4. A process as claimed in any one of the preceding claims, wherein the reductive hydrazine is carried out in the presence of a hydrogen source and in the presence of a catalyst.

5. The method of claim 4, wherein the catalyst is a metal catalyst.

6. The process of claim 4, wherein the catalyst is palladium, nickel or platinum.

7. The process as claimed in claim 6, wherein palladium is used.

8. The method of claim 6, wherein palladium on carbon, i.e., Pd / C, is used.

9. The method of claim 6, wherein 5% to 10% Pd / C is used.

10. A method as claimed in any one of the preceding claims, wherein such method steps are used in the preparation of ibrutinib.

11. The method of claim 10, wherein the compound of formula (I) is prepared and carried out by the following method steps to provide ibrutinib: (a) reacting a compound having formula (I) or a compound having formula (IA) with a compound having formula (VI), or a derivative thereof, thereby forming a compound having formula (VII), or its derivatives, wherein R 1 As defined in claim 1; (b) reacting a compound of formula (VII) or a derivative thereof to produce a compound of formula (VIII), or its derivatives, wherein R 1 As defined in claim 1; (c) making a compound having the formula (VIII) wherein R 1 represents hydrogen, or a derivative of such a compound, to provide ibrutinib.

12. The method of claim 11, wherein R 1 It's benzyl.

13. The process of claim 11, wherein the compound or derivative of formula (VII) is reacted with: (i) formamide HCONH2; (ii) formamidine or formamidine salt HC(=NH)-NH3 + X - , where X - represents the counterion; (iii) an alkyl amidine ether, or a salt thereof; (iv) ethyl orthoformate followed by ammonium acetate.

14. The method of claim 13, wherein the counter ion is a halide ion or an oxyanion.

15. The method of claim 14, wherein the halide ion is Cl - , and the oxygen anion is acyl-O - .

16. The method of claim 13, wherein the alkyl group is ethyl.

17. The process of claim 13, wherein the compound of formula (VII) or derivative is reacted with ethyl amidine ether HCl.

18. The method of claim 11, wherein a compound having formula (VIII) is used, wherein R 1 represents hydrogen, and reacts with Cl-C(O)-C(H)=CH2 to provide ibrutinib.

19. The method of claim 11, wherein a compound having formula (VIII) is used, wherein R 1 represents hydrogen, reacts with 3-chloropropionyl chloride, thereby forming a compound having formula (IX), or a derivative thereof, wherein such intermediate undergoes an elimination reaction to provide ibrutinib.

20. The method of claim 11, wherein a compound having the formula (VIII) is used, wherein R 1 represents hydrogen, reacted with 3-chloropropionyl chloride in the presence of aqueous NaHCO3 in Me-THF, thereby forming a compound having formula (IX), or a derivative thereof, wherein such intermediate undergoes an elimination reaction in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene to provide ibrutinib.

21. A method for preparing a pharmaceutical composition, comprising the method for preparing ibrutinib or a salt thereof according to claim 10 or 11, followed by contacting it with a pharmaceutically acceptable carrier, diluent and / or excipient.

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