Processes and intermediates for preparing BTK inhibitors

Abstract

Processes for preparing certain intermediates, e.g., enantioenriched forms of compounds of formula (I) [Formula 1] TIFF2022533219000031.tif40170 or a pharmaceutically acceptable salt thereof, are disclosed, and the intermediates and processes are useful in the preparation of BTK inhibitors such as ibrutinib.

Description

[Technical Field]

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

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

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

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

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

[0006] The above synthesis also led to several synthetic strategies for preparing chiral hydroxypiperidine intermediates, including those in unpublished PCT application PCT / EP2017 / 075289.

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

[0008] The final step for introducing a substituent onto the nitrogen atom of the piperidinyl ring can also be carried out by reaction with 3-chloropropionyl chloride (e.g., in the presence of aqueous NaHCO in Me-THF), thereby introducing a -C(O)-CHCH-Cl group onto the piperidinyl nitrogen atom, according to the procedure described in International Patent Application WO 2016 / 115356. Such intermediates are subsequently subjected to an elimination reaction in the presence of DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) to afford ibrutinib.

[0009] The above synthesis uses unsymmetrical chiral hydrazines, which are key components of the synthetic pathway. These chiral hydrazines are prepared by resolution, which is referred to herein as chiral chromatography, e.g., chiral SFC. These processes can be cumbersome and / or inefficient. The objective of the present invention is to discover alternative / improved processes for these chiral hydrazines, which may be useful as building blocks in the further synthesis of functionalized heterocycles, e.g., ibrutinib. Summary of the Invention

[0010] Enantioenriched forms of compounds of formula (I) [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 represents a hydrogen or nitrogen protecting group; * denotes a chiral center in the (R) configuration; The process comprises reacting a compound of formula (II) [ka] , i.e., 3-hydroxypyridine, or a salt thereof, and a compound of formula (III) H2N-N(H)-R 2 (III) or a salt thereof, wherein R 2 represents a hydrogen or nitrogen protecting group, and thus compounds of formula (IV) [ka] or a salt thereof, wherein R 2 is as defined above, and then, in any order, R 2 Optional deprotection (R 2represents a nitrogen protecting group), the optional R 1 Introduction of R 1 represents a nitrogen protecting group), followed (if necessary) by cleavage, This process may be referred to herein as the process of the present invention (consisting of one or more embodiments).

[0011] The process of the present invention may also be described as a process for producing an enantiomerically enriched compound of formula (I), or 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 embodiments described herein, an ee of even greater).

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

[0013] As noted above, the compound of formula (II) may be in the form of a salt, and thus may 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).

[0014] An advantage of the process of the present invention is that the compound of formula (II) is reduced in a single step which effectively involves reducing what is a keto group (a tautomer of the enol moiety shown) to a hydrazone and subsequently to a hydrazine, which has the advantage that separation and / or isolation of intermediates (which may, for example, be unstable) is not required.

[0015] The reductive hydrazination of the process of the present invention to produce a compound of formula (IV), and optionally R 2 (if this is a nitrogen protecting group) and deprotection / removal of R 1 For the avoidance of doubt, after the introduction of (if this is a nitrogen protecting group), a compound of formula (V) below can be converted to a compound of formula (VA) 1 and R 2 independently represent a nitrogen protecting group) (and in one embodiment, R 1 represents a nitrogen protecting group). [ka] DETAILED DESCRIPTION OF THE INVENTION

[0016] In one embodiment of the present invention, there is also provided a process (e.g., under conditions described herein) for preparing a compound of formula (I), comprising the resolution of a compound of formula (V). In such an embodiment, the compound of formula (V) need not be prepared as described in the process of the present invention set forth above, although in a further embodiment, the compound of formula (V) can be prepared as described above (i.e., reductive hydrazination of a compound of formula (II) with a compound of formula (III), followed by optional ... 2 (if this is a nitrogen protecting group) and deprotection / removal of R 1 (if this is a nitrogen protecting group). Preferred compounds of formula (V) for use in resolution to provide the desired compounds of formula (I) are those 1 represents a nitrogen protecting group (such as those described herein).

[0017] In the process of the present invention, the advantage of using a compound of formula (II) that is a quaternary salt, for example a quaternary salt having a nitrogen protecting group such as benzyl on the nitrogen atom, is that R 1represents such a protecting group (e.g., benzyl), such a group need not be introduced after the reductive hydrazination step of the process of the present invention.

[0018] Any individual feature (e.g., a preferred feature) mentioned in this specification may be interpreted alone or in combination with any other feature (including a preferred feature) mentioned in this specification (and thus a preferred feature may be interpreted in conjunction with or independently of other preferred features).

[0019] Those skilled in the art will understand that the compounds referred to in the context of the processes of the present invention are stable, i.e., the compounds included herein are robust enough to withstand isolation to a useful degree of purity, for example, from a reaction mixture.

[0020] For the avoidance of doubt, compounds of formula (V) are racemic (or have low enantiopurity, e.g., exhibit an enantiomeric excess "ee" of less than 20%), i.e., the chiral center at the point of attachment of the -N(H)NH group contains an equimolar mixture of the (R)- and (S)-configurations (or have a substantially lower preference for one configuration compared to the other, e.g., less than 60% of the predominant enantiomer), whereas the corresponding chiral center in compounds of formula (I) is predominantly in the (R)-configuration (this is referred to as the "enantiomerically enriched product").

[0021] As indicated above, the process of the present invention involves "reductive hydrazination", which is the process of reductive hydrazination of a hydrazine group (or a compound of formula (III) and R 2 means reduction (of the aromatic ring of the pyridine of formula (II)) with introduction of a protected variant thereof according to the definition of

[0022] In the process of the present invention, in one embodiment, the compound of formula (III) is R 2is a nitrogen protecting group. For example, the nitrogen protecting group is -amide (e.g., N-acetyl) -optionally substituted N-alkyl (e.g., N-allyl or optionally substituted N-benzyl) -N-sulfonyl (e.g., optionally substituted N-benzenesulfonyl) -Carbamate -urea -A group that leads to the formation of trityl (triphenylmethyl), diphenylmethyl, etc.

[0023] Therefore, R 2 may represent, among other groups: -C(O)R t1 (In the formula, R t1 is preferably C 1~6 alkyl, or optionally substituted aryl; C 1~6 alkyl (wherein the alkyl group is optionally substituted with one or more substituents selected from optionally substituted aryl (e.g., preferably forming a benzyl moiety); -S(O)2R t2 (In the formula, R t2 preferably represents optionally substituted aryl; or preferably -C(O)OR t3 (In the formula, R t3 is preferably an optionally substituted aryl or, more preferably, an optionally substituted C 1~6 (For example, C 1~4 ) alkyl, such as tert-butyl (thus forming, for example, a tert-butoxycarbonyl protecting group, i.e., a tert-butyl carbamate group when combined with an amino moiety), or a —CH phenyl group (thus forming a carboxybenzyl protecting group); -C(O)N(R t4 )R t5 (wherein, preferably, R t4 and R t5 are independently hydrogen, C 1~6alkyl, optionally substituted aryl, or —C(O)R t6 represents R t6 C 1~6 represents alkyl or optionally substituted aryl).

[0024] In one embodiment, most preferably R 2 The group is tert-butoxycarbonyl (i.e., —C(O)—O-tert-butyl or t-Boc), i.e., so that the compound of formula (III) represents HN—N(H)—C(O)—O-tert-butyl. This is particularly advantageous given that handling of hydrazine (or a suitable form thereof) can be difficult, and furthermore, 2 represents a nitrogen protecting group (e.g., t-Boc), so that subsequent steps, such as protection of the nitrogen of the piperidinyl ring, i.e., R 1 Introduction of a protecting group and / or deprotection of a hydrazine protecting group, i.e., R 2 Removal of the protecting group (where R 1 It may be advantageous that the reaction (to form a compound of formula (V) where R represents a nitrogen protecting group) can occur in a convenient process step, for example so that a compound of formula (V) can be resolved according to the processes described herein. 1 Compounds of formula (VA) or (V) in which R is a particular leaving group (particularly when it is benzyl) may result in improved or better ee in the resolution step (this is particularly true for compounds of formula (V) given that in one embodiment, compounds of formula (VA) are deprotected to give compounds of formula (V) prior to the resolution step). 1 are particular protecting groups, and in addition to compounds that provide advantages or improvements in terms of ee in the resolution step, such protecting groups may also have other advantages, for example, in terms of ease of protection / deprotection that will be most efficient in other reaction steps (e.g., reduction in the main process of the present invention).

[0025] In further embodiments of the present invention, there are provided certain compounds per se, for example compounds of formula (IV), compounds of formula (VA), and / or compounds of formula (V).

[0026] The process of the present invention involves reductive hydrazination, which is the conversion of a compound of formula (II) to a compound of formula (IV) in the presence of a hydrazine compound of formula (III). It will be understood that such a "reductive" step is necessarily 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, e.g., palladium on carbon, i.e., Pd / C, which can be 5-10% Pd / C). Any suitable hydrogen source for the reduction (or reductive hydrazination) can be present, such as H2 gas (which can be introduced under pressure, e.g., about 20 bar; typically, H2 gas is stored in a pressurized cylinder, and the process employs H2 at pressures above 1 atmosphere). Another suitable hydrogen source can be used (in addition to, or as an alternative to, H2 gas), such as a suitable donor molecule (e.g., aqueous sodium formate), e.g., a protic acid, e.g., acetic acid, formic acid, or the like. This aspect of the process of the present invention can be carried out in the presence of, for example, any suitable solvent, such as, in one embodiment of the present invention, an alcoholic solvent (e.g., methanol). In one embodiment, the vessel or autoclave in which the reduction (or reductive hydrazination) is carried out is heated, for example, to a temperature above room temperature (e.g., above 40°C, e.g., above 55°C, e.g., 55-70°C, although 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 a number of hours, for example, overnight (e.g., about 12 hours), until completion, although the reaction can be monitored for progress / completion and the duration adjusted accordingly. If the catalyst used in this reaction contains water, it can be partially removed, if necessary, by stirring the solvent (e.g., alcoholic solvent, methanol) used in this process step. After the reaction has proceeded, the reaction mixture can be worked up to extract, separate, and / or isolate the desired product (compound of formula (IV)).

[0027] Next, (i) R 2Optional deprotection (R 2 represents a nitrogen protecting group), and (ii) an optional R at the NH portion of the piperidinyl ring. 1 Introduction of R 1 where R represents a nitrogen protecting group) is shown to transform the compound of formula (IV). In one embodiment, the compound of formula (III) is 2 represents a nitrogen protecting group (in one embodiment represents a BOC-protecting group), and therefore the compound of formula (IV) thus formed also has R 2 represents such a nitrogen protecting group. In one embodiment, compounds of formula (I) include 1 represents a nitrogen protecting group, and therefore, in one embodiment, the compound of formula (IV) produced by reductive hydrazination is subjected to step (ii), i.e., R 1 It is also preferred that the introduction of a protecting group is preferably carried out first, thus forming a compound of formula (VA) (or a compound of formula (V)).

[0028] When compounds of formula (VA) and (V) are produced, R 1 It is particularly preferred that R represents a nitrogen protecting group (especially for compounds of formula (V) to be resolved). In this regard, R 1 teeth, -amide (e.g., N-acetyl) -optionally substituted N-alkyl (e.g., N-allyl or optionally substituted N-benzyl) -N-sulfonyl (e.g., optionally substituted N-benzenesulfonyl) -Carbamate -urea -may represent groups which result in the formation of trityl (triphenylmethyl), diphenylmethyl, and the like.

[0029] Therefore, R 1 may represent, among other groups: -C(O)R t1 (In the formula, R t1 is preferably C 1~6 alkyl, or optionally substituted aryl; C 1~6 alkyl (wherein the alkyl group is optionally substituted with one or more substituents selected from optionally substituted aryl (e.g., preferably forming a benzyl moiety); -S(O)2R t2 (In the formula, R t2 preferably represents optionally substituted aryl; or preferably -C(O)OR t3 (In the formula, R t3 is preferably an optionally substituted aryl or, more preferably, an optionally substituted C 1~6 (For example, C 1~4 ) alkyl, such as tert-butyl (thus forming, for example, a tert-butoxycarbonyl protecting group, i.e., a tert-butyl carbamate group when combined with an amino moiety), or a —CH phenyl group (thus forming a carboxybenzyl protecting group); -C(O)N(R t4 )R t5 (wherein, preferably, R t4 and R t5 are independently hydrogen, C 1~6 alkyl, optionally substituted aryl, or —C(O)R t6 represents R t6 C 1~6 represents alkyl or optionally substituted aryl).

[0030] In one embodiment, the most preferred R 1 The group may be substituted by an aryl (e.g., by one phenyl ring), thus forming, for example, a benzyl group. 1~6 It is alkyl (e.g., -CH3).

[0031] A compound of formula (IV) (e.g., where R 2 represents a protecting group such as those defined above, 1 Conversion to a compound of formula (VA), wherein R represents a nitrogen protecting group, can occur under suitable conditions, for example 1 is substituted by an aryl (e.g., a benzyl group) 1~6When alkyl is represented, the compound of formula (IV) has the formula R x -L x wherein L x represents a suitable leaving group (such as bromo, chloro, iodo, sulfonate (mesylate, tosylate, triflate) or the like), and R x is C substituted by aryl (e.g., benzyl) 1~6 Representing an alkyl group), thus introducing a benzyl group, the reaction can be carried out in the presence of benzyl bromide, optionally in the presence of a suitable solvent (e.g. dichloromethane) and a suitable base (e.g. an organic base, e.g. an amine base, such as triethylamine).

[0032] In the compound of formula (VA) thus produced, R 1 In one embodiment, the nitrogen protecting group is R 2 It is different from the nitrogen protecting group because one can be replaced by any one of them (e.g., R 2 nitrogen protecting group) can be removed, but another one (e.g., R 1 The nitrogen protecting group) is meant to remain substantially intact. 2 represents a nitrogen protecting group), in one embodiment, such R 2 The nitrogen protecting group is removed (while, for example, the just-introduced R 1 (with the nitrogen protecting group remaining intact), a compound of formula (VA) is converted to a compound of formula (V). 1 and R 2 Illustrate why different protecting groups are susceptible to cleavage under different conditions. For example, R 1 is substituted by an aryl (e.g., one phenyl ring forming a benzyl group) 1~6 When representing alkyl, R 2 The protecting group is preferably R 1 It can be removed / cleaved under conditions that do not allow the removal of the protecting group. For example, R 2 When represents a BOC-protecting group, suitable conditions can be used to 1The protecting group (e.g., when it is benzyl) can be removed while keeping the protecting group intact. Conditions that can be used include, for example, acidic conditions in the presence of water and HCl, and the temperature can be controlled, for example, by using a water bath, so as not to exceed room temperature (e.g., about 25°C). The reaction can be allowed to proceed at about room temperature (e.g., around 20-25°C) for a number of hours (e.g., overnight, about 12 hours), although the progress of the reaction can be monitored and the time adjusted accordingly. After the reaction has proceeded / completed, it can be worked up, for example, by cooling in an ice bath and adding an alkaline solution (e.g., NaOH solution, which can be 32m% NaOH) to neutralize any remaining acid, followed by extraction, separation, and / or isolation of the desired product (compound of formula (V)).

[0033] In one embodiment, R 1 The compound of formula (V) where represents benzyl is the compound used in the resolution step to provide the compound of formula (I).

[0034] In embodiments of the process of the present invention in which a compound of Formula (V) is resolved to provide a compound of Formula (I) (preceded by the process described above, i.e., the process for preparing a compound of Formula (V) by reductive hydrazination, or other processes), certain resolution processes 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., greater than 20% ee (and in embodiments described herein, greater ee). For example, enantiomerically enriched products (e.g., compounds of Formula (I)) can be produced with an enantiomeric excess of greater than 40%, e.g., greater than 60%, and in one embodiment, greater than 80%. Enantiomerically enriched products can even be greater than 90% (e.g., they can consist essentially of a single enantiomer, meaning that the ee can be 95% or greater, e.g., greater than 98% or about 100%). Such enantioenriched products (or ees) can be obtained directly or by further purification techniques known to those skilled in the art. For example, the process of this embodiment of the invention can be carried out by1 represents a nitrogen protecting group (e.g., benzyl), such that the product is enantioenriched.

[0035] In this regard, in a still further embodiment, there is provided a compound of formula (IA), specifically a compound of formula (I) in the D-(-)-tartrate salt form: [ka] In the formula, R 1 is as defined herein (e.g., represents a nitrogen protecting group such as benzyl). Such products are enantiomerically enriched as described above (e.g., in the context of compounds of formula (I)), e.g., in enantiomeric excess of greater than 40%, 60%, 80%, or 90% (e.g., the ee may be 95% or greater, e.g., greater than 98%, or about 100%).

[0036] In one embodiment, a compound of formula (I), e.g., where R 1 is substituted by a nitrogen protecting group (e.g., aryl, e.g., benzyl) 1~6 The compound of formula (IA) where R is an alkyl group can be used in downstream processing to (ultimately) provide ibrutinib. For example, this can be a compound of formula (IA) where R is an alkyl group 1 represents such a protecting group.

[0037] The resolution process described herein can be carried out in many embodiments, for example, by crystallization using a chiral salt, specifically the D-(-)-tartrate salt described herein. Such a salt (e.g., the D-(-)-tartrate salt of Formula (IA)) can be prepared by mixing the D-(-)-tartrate salt with a non-salt form of the compound of Formula (I) in the presence of a suitable solvent system. For example, the solvent system can include an alcohol (e.g., methanol or ethanol) and an aqueous alcohol, e.g., aqueous methanol or ethanol), in a ratio of, for example, 1:1 to 20:1 alcohol:water (where the alcohol is preferably methanol), and in one embodiment, the ratio is 2:1 to 8:1, e.g., about 4:1. Of interest are solvent systems that primarily contain alcohol (e.g., methanol) and a small amount of water, e.g., an alcohol / water mixture with a water content ranging from about 2% to about 20%, or from about 5% to about 10% (w / w). In particular, a water / methanol mixture having a water content in the range of about 5% to about 10%, e.g., about 5% (w / w), can be used. Crystallization is carried out at a specific temperature; for example, in one embodiment of the present invention, this can be carried out at a temperature of about 0°C to 80°C, e.g., about room temperature to 65°C (e.g., about 40-60°C, and in one embodiment, about 50°C). Crystallization can involve stirring at an elevated temperature (such as the temperatures mentioned above, e.g., 50°C) for a period of time (e.g., 30 minutes to 2 hours, which may initiate crystallization), followed by cooling back to room temperature for a further period of time (e.g., 30 minutes to 8 hours, e.g., about 4 hours). Recrystallization can also be carried out to improve the ee; for example, recrystallization can be carried out in the presence of the solvent system mentioned above, e.g., at reflux, followed by cooling (and optionally seeding).

[0038] Resolution using tartaric acid (e.g., D-(-)-tartaric acid) can be advantageous for a number of reasons, for example, it provides a compound of formula (IA) as defined herein in sufficient ee; in one embodiment, it provides such a compound in a higher ee (e.g., compared to other enantiomeric salts and / or other resolution methods); and / or it provides such a compound whose enantiomeric excess has been further improved, for example, through 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 in which its purity can be further improved (e.g., by recrystallization). Thus, in a further embodiment, a further recrystallization step (which advances the process for preparing a compound of formula (I) (or a compound of formula (IA))) may be provided, as described above.

[0039] As provided herein, the resolution may occur in a suitable solvent system (e.g., methanol / water), and the product / salt of the compound of formula (I) thus formed may also undergo recrystallization in a suitable solvent system, such as 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)) need not undergo further recrystallization because the first product may be of sufficient ee and / or purity (e.g., for use in further process steps).

[0040] The salt form of the compound of formula (I) (e.g., the compound of formula (IA)) may be used directly in further process steps described herein, or, if a salt form of the compound of formula (I) is first produced, the non-salt form may also be liberated prior to further reactions described herein.

[0041] Unless otherwise specified, alkyl groups as defined herein may be straight chain, or, if there is a sufficient number (i.e., at least three) of carbon atoms, they may be branched chain and / or cyclic. Furthermore, if there is a sufficient number (i.e., at least four) of carbon atoms, they may also be partially cyclic / acyclic. Furthermore, they may be saturated, or, if there is a sufficient number (i.e., at least two) of carbon atoms, they may be unsaturated (thus containing, for example, a "vinyl" moiety).

[0042] In a further embodiment of the present invention, there is provided the use of a compound of formula (I) (particularly a compound of formula (IA)) prepared according to the process of the present invention described herein, including all embodiments thereof, for example, in the preparation of ibrutinib. For example, a compound of formula (I) prepared according to the process described herein may be preceded and followed by known process steps to provide ibrutinib (e.g., as disclosed in International Patent Applications WO 2014 / 139970 and WO 2016 / 115356). In this regard, there is provided a process for preparing ibrutinib, comprising a process for preparing a compound of formula (I) described herein, followed by conversion to ibrutinib, wherein such further steps may include: (a) a compound of formula (I) (particularly a compound of formula (IA)) and a compound of formula (VI), [ka] or a derivative thereof to give a compound of formula (VII), [ka] or a derivative thereof, wherein R 1is as defined herein (and in one embodiment is benzyl), and the reaction may be carried out under the conditions described in International Patent Application WO 2014 / 139970, 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. in excess, in solution form), stirring for a period of time (e.g. 30 minutes) at low temperature (e.g. about 5°C), followed by adding a base (e.g. triethylamine, in excess) and stirring at low temperature for a period of time (e.g. 1 hour at 5-10°C), followed by stirring at high temperature (e.g. about room temperature, 25°C) for a further period of time (e.g. 14 hours), and after work-up, producing a compound of formula (VII) (e.g. a compound of formula (IA) 1 represents benzyl) can be obtained by the reaction; (b) a compound of formula (VIII) [ka] or a derivative thereof, wherein R 1 is as defined above (e.g., benzyl), and the reaction is carried out using reagents and under conditions such as those described in WO 2014 / 139970, for example, when a compound of formula (VII) or a derivative thereof is prepared by reacting it with (i) formamide (HCONH2); (ii) formamidine or a formamidine salt HC(=NH)-NH3 + X - (In the formula, X - is a suitable counterion, such as a halide (e.g., Cl - ) or oxyanions (e.g., acyl-O - ), thus forming, for example, formamidine HCl or formamidine acetate, etc.), (iii) alkyl (e.g., ethyl) formimidate, or a salt thereof, such as ethyl formimidate HCl; (iv) ethyl orthoformate, which may be subsequently reacted with ammonium acetate. 1 is a nitrogen protecting group, the compound of formula (VIII) can be obtained by, for example, hydrogenation reaction conditions under R1 When R is benzyl, 1 Deprotection can be carried out under standard conditions that allow for such removal of R, for example, in the presence of a palladium-based catalyst (e.g., Pd(OAc)), optionally in a suitable solvent (e.g., methanol) and acid / proton source (e.g., 35% HCl), and in the presence of a hydrogen source (e.g., 10 Psi of H), with stirring for a suitable period of time (e.g., 2 hours at 50°C), to give a compound of formula R 1 is hydrogen, which, after appropriate work-up, can be converted to a compound of formula (VIII) in which R 1 represents hydrogen; (c) a compound of formula (VIII) for providing ibrutinib under conditions such as those described in either WO 2014 / 139970 or WO 2016 / 115356, wherein R 1 represents hydrogen, for example, such compounds may be reacted with Cl-C(O)-C(H)=CH2, or a two-step process may be carried out by reacting with 3-chloropropionyl chloride (e.g., in the presence of aqueous NaHCO3 in Me-THF), thereby producing a compound of formula (IX) [ka] or a derivative thereof, and such intermediate may be subjected to an elimination reaction in the presence of, for example, DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) to afford ibrutinib.

[0043] For the avoidance of doubt, ibrutinib has the following formula: [ka]

[0044] In a further embodiment of the present invention, the process of the present invention as 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 WO 2014 / 139970, for example according to the following scheme: [ka]

[0045] For example, the conversion of (VIA) to (VIB) can occur in the presence of a suitable reagent (e.g., DMF, (COCl) in THF), the conversion of (VIB) to (VIC) can occur in the presence of malononitrile (e.g., in THF) with the addition (e.g., dropwise addition) of a suitable base (e.g., an organic base, such as DIPEA (diisopropylethylamine)), for example, by reaction at low temperature (e.g., at -60 to -30°C for about 2 hours, followed by subsequent heating to about 20 to 25°C), and the conversion of (VIC) to (VI) can occur by adding dimethyl sulfate (e.g., in excess) directly to a compound of formula (VIC) (e.g., in situ) to promote the formation of (VIC) from (VIB), such a reaction may be such that dimethyl sulfate is added at about 25°C or below, followed by stirring, for example, at 60 to 65°C for 5 hours.

[0046] The starting materials and certain intermediates may either be commercially available or may be prepared according to conventional reaction procedures generally known in the art.

[0047] For the avoidance of doubt, when reference is made to equivalents, it is intended that this means molar equivalents.

[0048] In a further aspect of the present invention, there is provided a process for separating the product (compound of formula (I)) obtained from the process of the present invention (which may be referred to herein as the "compound of the present invention"). Thus, the compound of the present invention (or the product obtained by the process of the present invention) can be separated / isolated. This can be achieved in several ways: -Flash column chromatography -Precipitation / crystallization -Derivatization, optionally followed by precipitation / crystallization - extraction (e.g., derivatization followed by extraction) -distillation

[0049] In one aspect, the method can be, for example, a derivatization in which the undesired product (e.g., unreacted starting material) is derivatized (e.g., by reacting with succinic anhydride to form a group having a terminal carboxylic acid moiety), thereby allowing for possible separation, extraction, or isolation (e.g., the carboxylic acid can be removed in a workup procedure).

[0050] In a further embodiment of the present invention, there is provided the process of the present invention as described herein, followed by yet further process steps.

[0051] The compounds of formula (I) (enantiomerically enriched form) may be used to prepare further compounds, for example further pharmaceutical agents (or intermediates thereof), such as pharmaceutical agents useful in the treatment of cancer (such as hematological malignancies), in particular the pharmaceutical agent may be ibrutinib.

[0052] Other transformations (of the products obtained directly by the process of the present invention or of further products obtained from downstream processes, e.g. as may be described herein) can be carried out according to standard techniques and processes of the prior art, e.g. amide formation reactions (in which case possible conditions and coupling reagents will be known to the skilled person), esterifications, nucleophilic substitution reactions, and aromatic nucleophilic substitution reactions.

[0053] Subsequently, there is further provided a process for preparing a pharmaceutical formulation comprising ibrutinib, which process comprises bringing ibrutinib (or a pharmaceutically acceptable salt thereof) prepared according to the process described above into association with (a) a pharmaceutically acceptable excipient, adjuvant, diluent, and / or carrier.

[0054] In general, the methods described herein may have the advantage that the compounds prepared may be produced in a manner that utilizes fewer reagents and / or solvents and / or requires fewer reaction steps (e.g., different / separate reaction steps) compared to processes disclosed in the prior art.

[0055] The processes of the present invention may also have the advantage that the compounds prepared are produced in higher yield, higher purity, with higher selectivity (e.g., higher regioselectivity), in shorter time, in a more convenient (i.e., easier to handle) form, from more convenient (i.e., easier to handle) precursors, at lower cost, and / or with less usage and / or loss of materials (including reagents and solvents) compared to procedures disclosed in the prior art. Additionally, there may be several environmental advantages of the processes of the present invention. [Example]

[0056] The following examples are intended to illustrate the present invention and should not be construed as limiting the scope of the invention.

[0057] Example 1: Preparation of compounds of formula (I) 1a. Reductive hydrazination [ka] An autoclave was charged with Compound (II) (76 g, 0.799 mol), Boc-N(H)NH (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 contained 56% water, which was partially removed by stirring in methanol (75 mL). The solution was then decanted, and the remaining catalyst (in a volume of 30 ml of methanol) was charged to the reactor along with an additional 70 ml of methanol, bringing the total to 200 ml of methanol in the reactor. The autoclave was heated to 62 °C (set point: 65 °C) over 1 hour.

[0058] The hydrogenation was carried out at 62° C. and 20 bar overnight.

[0059] Workup: After filtering the catalyst (vacuum, paper), the filtrate was analyzed by GC. Complete conversion of pyridine was observed. MeOH was then evaporated on a rotary evaporator. Approximately 258 g of a viscous oil remained. This oil was poured into 1800 mL of cold water (in an ice bath), followed by the addition of 180 g of 8N NaOH while stirring with a propellor stir bar. The resulting clear solution was extracted with CH2CI2 (4 x 200 ml, followed by 1 x 100 ml).

[0060] The combined organic layers were dried over sodium sulfate. To prevent crystallization of the product, the mixture was kept warm in a hot water bath and subsequently filtered to remove the sodium sulfate. After 1 day, a portion of the product (a compound of formula (IVA), i.e., a compound of formula (IV) defined above, except that R 2 represents a BOC protecting group) crystallized, which was filtered and dried without washing.

[0061] 1b. Benzylation [ka] In a 250 mL round bottom flask, 8 g of the compound of formula (IVA, where R 2The crystallized material of compound (wherein is a BOC-protecting group) was dissolved in 100 mL of DCM, and 5.2 mL of EtN (2 eq) and BnBr (benzyl bromide) (4.6 mL, 1.05 eq) were added, followed by stirring at room temperature for 3.5 h.

[0062] 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, this syrup was dissolved in 25 ml of MTBE and 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 in an oil pump to give 5.7 g (yield: 50%).

[0063] 1c. De-Bocylation [ka] Under N2, 150 ml of water was added to a round bottom flask containing over 50 g of purified compound of formula (VA), where R 2 is the BOC-protecting group (as a hard crust on the flask wall). The solid material did not dissolve. 100 ml of concentrated aqueous HCl was dosed / added under nitrogen over 30 minutes. The temperature was controlled (maximum 24°C) by using a water bath. Once the addition of HCl was complete, a clear solution was obtained. The solution was left at 22°C overnight.

[0064] Work-up: The reaction mixture was cooled in an ice bath and 32 m% NaOH solution (144 g) was added until a pH of 12 was reached. The yellow solution was transferred to a separatory funnel under nitrogen and extracted with 100 ml of DCM. The layers were quickly separated. The aqueous layer was extracted twice with 100 ml of DCM under a N2 atmosphere. The combined organic layers were dried over sodium sulfate and the DCM was evaporated. The remaining pale yellow oil was dried on an oil pump to give 33 g of oil (yield=84%). This product (R 1 Compounds of formula (V) where is benzyl were stored under nitrogen.

[0065] 1d. Division A stirred yellow solution of 142 g (692 mmol) of racemic Y10-Bn free base in 1000 mL of MeOH under a nitrogen atmosphere was heated to 50 °C, and a warm solution of 58.0 g (386 mmol, 0.56 equiv.) of D-(-)-tartaric acid dissolved in 250 mL of MeOH was added slowly over 30 min. During the final portion of the addition, the reaction mixture became opaque and gradually began to crystallize. Several seed crystals were added, and the reaction mixture was stirred at 50 °C for 1 h. During this time, slow crystallization proceeded. The stirred reaction mixture was then cooled to room temperature over approximately 4 h 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 H NMR: 1:1 salt, containing 3 mol% MeOH, HPLC: ee 86.6% (R).

[0066] 1e. Recrystallization Into an Erlenmeyer flask equipped with a magnetic stirrer, 176.8 g of (R)-Y10-Bn.D-(-)-TA salt (ee 84% (R)) was added. The solid was suspended in 1500 ml of MeOH / HO (2:1 v / v) and heated to reflux with stirring. At a reflux temperature of 75 °C, an additional 200 ml of MeOH / HO (2:1 v / v) was added in portions until the slightly yellow solution became clear at reflux (total: 1700 ml of MeOH / HO (2:1 v / v)). The heat was removed, and the solution was maintained in a cooled state with stirring. At 70 °C, seed crystals (50 mg) were added. The slowly crystallizing suspension was allowed to cool to room temperature with stirring for 4 h. After stirring at room temperature for 20 hours, the white solid was filtered off (vacuum filtration on a P2 glass filter), washed with 100 ml of MeOH / HO (2:1) and 100 ml of MeOH, and dried on the filter for 30 minutes. The solid was transferred to a 500 ml container (148.5 g) and dried in a vacuum oven at 20 °C for 24 hours. Yield: 142.8 g of white solid (81% crystallization yield); quantitative NMR using maleic acid: purity 97 ± 2 wt%; HPLC: ee ≥ 99% (R); optical rotation: [α] / D -16.7 (c = 1, HO).

[0067] Example 2: Preparation of Ibrutinib (using the compound of formula (I) prepared according to Example 1) Compound 1 to Compound 6 [ka] 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 at 20-30 °C under N2, and compound 2 was obtained after 1 h of reaction. The mixture containing compound 2 was then poured into malononitrile (8.5 g, 128.7 mmol, 1.1 eq) in THF (25 mL, 1 V). DIPEA (37.8 g, 292.5 mmol, 2.5 eq) was then added dropwise to the mixture over 2 h at -60 to -30 °C, followed by warming to 20-25 °C to obtain compound 3. Dimethyl sulfate (44.3 g, 351 mmol, 3.0 eq) was then added dropwise to the mixture below 25 °C, followed by stirring at 60–65 °C for 5 h to give compound 4. Compound 5 (29 g, 81.5 mmol, 0.7 eq) was dissolved in EtOH (100 mL), and the resulting mixture was then poured into the compound 4 solution and stirred at 5 °C for 0.5 h. 29.5 g of EtN was then added dropwise to the mixture over 1 h at 5–10 °C, followed by stirring at 25 °C for 14 h to give compound 6. 100 mL of EA (ethyl acetate) was added to the mixture, followed by washing twice with water (100 mL). The aqueous phase was extracted with EA (200 mL), and the organic phases were combined. EA was then replaced with EtOH (90 mL), resulting in the appearance of a solid. The solid was filtered and dried under reduced pressure at 40°C for 7 hours to give 22.47g of compound 6 (HPLC purity 99.18a%). The overall yield of the four steps (S-1 to S-4) was 42.8%. Compound 5 is herein defined as 1It will be appreciated that this may also be referred to as a compound of formula (IA) where is benzyl (which is itself a compound of formula (I)).

[0068] result: 1) From a three-step telescope reaction, compound 4 was produced from IPC in 81.64% yield. After reacting with a total of 0.7 eq of compound 5, compound 6 was produced in 75.5% yield. After workup of this reaction, 22.47 g of compound 6 was isolated (HPLC purity 99.18%). 2) A reaction was carried out to prepare compound 6 with an HPLC purity of 66.04% from crude compound 4 (THF reaction mixture, containing 19.15 g of pure Y3). After workup and three EtOH / HO crystallizations, 10.28 g of compound 6 was obtained (HPLC purity 98.88%). The mother liquor was recovered by column chromatography and slurried in EtOH to give 1.86 g of compound 6 (HPLC purity 99.47%). This gives a total isolate yield of 39.0% for the four steps.

[0069] Compound 6 to Compound 7 [ka] 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, 15V), and the mixture was stirred at 120°C for 19 h, then cooled to 20-25°C. EA (150 mL, 10V) was added to the mixture, followed by washing twice with water (125 mL). The aqueous phase was extracted twice with EA (125 mL), and the organic layers were combined and evaporated to 100 mL, after which a solid appeared (or crashed out). 150 mL of MeOH was added, followed by evaporation to 100 mL, after which a further solid appeared. The mixture was cooled to 10-15°C, and the precipitate was filtered and washed with MeOH (20 mL). After drying under vacuum at 35°C for 16 hours, 7.16 g of compound 7 was obtained (HPLC purity 99.21%). The isolated yield was 67.55%.

[0070] Compound 7 to Compound 8 [ka] Compound 7 (9.98 g, 20.9 mmol) was dissolved in MeOH (150 mL, 15 V), and Pd(OAc) (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. 5% KOH (200 mL) was then added dropwise to the mixture, and the precipitate was filtered. After drying under vacuum, 5.46 g of compound 8 was obtained (HPLC purity 98.80%, yield 67.4%).

[0071] Compound 8 to pure PCI-32765 (ibrutinib) [ka] The final step for introducing a substituent onto the nitrogen atom of the piperidinyl ring can be carried out by reaction with 3-chloropropionyl chloride (e.g., in the presence of aqueous NaHCO in Me-THF), thereby introducing a -C(O)-CHCH-Cl group onto the piperidinyl nitrogen atom, according to the procedure described in International Patent Application WO 2016 / 115356. Such intermediates are subsequently subjected to an elimination reaction in the presence of DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) to afford ibrutinib.

[0072] Example 3: Ibrutinib (or a salt thereof) is prepared by preparing an intermediate using any of the process steps described in Example 1, and then converting it to ibrutinib (or a salt thereof).

[0073] Further Example 4: First, ibrutinib (or a salt thereof) is prepared according to Example 2, and then a pharmaceutical composition is prepared by contacting the ibrutinib (or a salt thereof) thus obtained with a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0074] Pharmaceutical preparations Ibrutinib can be formulated into pharmaceutically acceptable formulations using standard procedures.

[0075] For example, there is provided a process for preparing a pharmaceutical formulation comprising ibrutinib or a derivative thereof, characterized in that the process comprises the above-defined process as a process step. Those skilled in the art will know that such a pharmaceutical formulation comprises / consists of (e.g., a mixture of an active ingredient (i.e., ibrutinib or a derivative thereof) with pharmaceutically acceptable excipients, adjuvants, diluents, and / or carriers).

[0076] Further provided is a process for preparing a pharmaceutical formulation comprising ibrutinib (or a derivative thereof), the process comprising bringing ibrutinib, or a pharmaceutically acceptable salt thereof (which may be formed by the process described above), into association with (a) a pharmaceutically acceptable excipient, adjuvant, diluent, and / or carrier. The present invention includes the following embodiments. [Claim 1] a compound of formula (I) in enantioenriched form, [ka] or a pharmaceutically acceptable salt thereof, comprising: During the ceremony, R 1 represents a hydrogen or nitrogen protecting group; * denotes a chiral center in the (R) configuration; The process comprises reacting a compound of formula (II) [ka] , i.e., 3-hydroxypyridine, or a salt thereof, and a compound of formula (III) H 2 NN(H)-R 2 (III) or a salt thereof, wherein R 2 represents a hydrogen or nitrogen protecting group, and thus compounds of formula (IV)

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Claims

1. a compound of formula (I) in enantioenriched form, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, comprising: During the ceremony, R １ represents a hydrogen or nitrogen protecting group; * represents a chiral center in the (R) configuration; The process comprises reacting a compound of formula (II) 【Chemistry 2】 , i.e., 3-hydroxypyridine, or a salt thereof, and a compound of formula (III) H ２ !!!!R ２ (_=) or a salt thereof, wherein R ２ represents a hydrogen or nitrogen protecting group, and thus compounds of formula (IV) 【Transformation 3】 or a salt thereof, wherein R ２ is as defined above, and then, in any order, R ２ Optional deprotection in (R ２ represents a nitrogen protecting group), the optional R １ Introduction of (R １ represents a nitrogen protecting group), followed by optical resolution.

2. The compound of formula (IV) can be prepared by reacting a compound of formula (VA) １ and R ２ and R independently represent a nitrogen protecting group), to form a compound of formula (V) １ represents a nitrogen protecting group). 【Chemistry 4】

3. 3. The process of claim 2, wherein the compound of formula (V) is resolved to provide a compound of formula (I).

4. 4. The process of claim 1, wherein the reductive hydrazination is carried out in the presence of a hydrogen source and in the presence of a metal catalyst.

5. 5. The process of claim 4, wherein the metal catalyst is palladium on carbon.

6. A compound of formula (IA) 【Transformation 5】 In the formula, R １ represents a hydrogen or nitrogen protecting group.

7. 6. The process of any one of claims 1 to 5, wherein said process step is used for the preparation of ibrutinib.

8. 10. A process for manufacturing ibrutinib, wherein the compound of formula (I) is prepared by a process according to any one of claims 1 to 5, comprising the following process steps to provide ibrutinib: (a) a compound of formula (I) and a compound of formula (VI); 【Transformation 6】 with, thus producing a compound of formula (VII), 【Transformation 7】 wherein R １ represents a hydrogen or nitrogen protecting group; (b) a compound of formula (VIII) 【Transformation 8】 Reaction of a compound of formula (VII) to produce １ is as defined above, reaction; (c) A compound of formula (VIII) to provide ibrutinib, wherein R １ represents hydrogen, the reaction of the compound, The process of claim 7, which is carried out by:

9. The reaction (b) is carried out by reacting a compound of formula (VII) with (i) formamide (HCONH ２ ); (ii) formamidine or formamidine salt H—C(═NH)—NH ３ ＋ X － (In the formula, X － represents a halide or oxyanion); (iii) ethyl formimidate, or a salt thereof; or (iv) ethyl orthoformate followed by ammonium acetate; The reaction (c) is carried out by reacting a compound of formula (VIII) with Cl-C(O)-C(H)=CH ２ or by reacting a compound of formula (VIII) with 3-chloropropionyl chloride to give a compound of formula (IX) 【Chemistry 9】 and the compound of formula (IX) is subjected to an elimination reaction to provide ibrutinib.

10. 10. A process for preparing a pharmaceutical composition comprising ibrutinib or a salt thereof, comprising contacting ibrutinib or a salt thereof after preparing it as described in claim 8 or 9 with a pharmaceutically acceptable carrier, diluent, and / or excipient.

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