NZ711026B2 - Processes and intermediates for preparing a medicament - Google Patents

Abstract

Disclosed is a process for the preparation of the following compounds: (I), (II) where R1, R1a and R2a have the definitions in the description, as well as a process to prepare other intermediates that may be useful to synthesise downstream products, especially compounds that are useful as medicaments, for instance Bruton's tyrosine kinase (Btk) inhibitors such as ibrutinib. Also disclosed are other processes, other intermediates and compounds per se. s, for instance Bruton's tyrosine kinase (Btk) inhibitors such as ibrutinib. Also disclosed are other processes, other intermediates and compounds per se.

Description

PROCESSES AND INTERMEDIATES FOR ING A MEDICAMENT Field of the ion The present invention relates to sis procedures and synthesis intermediates of substituted bicyclic compounds, especially compounds that are usefial as medicaments, for instance Bruton’s tyrosine kinase (Btk) inhibitors such as ibrutinib.

Background of the Invention Ibrutinib is an organic small molecule having IUPAC name 1-[(3R)[4-amino (4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidinyl]piperidinyl]propenone. It is described in a number of published documents, including international patent application WO2008/039218 le lb), and is described as an irreversible inhibitor of Btk.

Btk plays an essential role in the B-cell ing pathway g cell surface B-cell receptor stimulation to downstream ellular ses. Btk is a key regulator of B-cell development, activation, signaling, and al (Kurosaki, Curr 0p Imm, 2000, 1; Schaeffer and Schwartzberg, Curr 0p [mm 2000, 282-288). In addition, Btk plays a role in a number of other hematopoetic cell signaling pathways, e.g. Toll like receptor (TLR) and cytokine receptor-mediated TNF-(x production in macrophages, IgE receptor (FcepsilonRI) signaling in Mast cells, inhibition of Fas/APO-l apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation.

See e.g., C. A. Jeffries, et al., (2003), Journal ofBiological Chemistry 27826258- 26264; N. J. Horwood, et al., (2003), The Journal ofExperimental Medicine 197: 1603- 1611; Iwaki et al. (2005), Journal ofBiological try 280(48):40261-40270; VassileV et al. (1999), Journal ofBiological Chemistry 274(3): 1646-1656, and Quek et al (1998), Current Biology 8(20):1137-1140.

Ibrutinib is therefore being studied in Phase II and III clinical trials for various logical malignancies such as chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma and multiple myeloma.

There are various processes for preparing functionalised bicyclic heterocycles, for example as described in US patent document US 082137, which includes syntheses to filSGd es from pyrazoles and substituted hydrazines.

W0 2014/139970 Ibrutinib may be prepared in W02008/039218 (Example lb) in accordance with the following scheme: CN\boc 6M5 First, 4-amino(4-phenoxyphenyl)-lH-pyrazole[3,4-d]pyrimidine may be prepared in accordance with procedures described in W02008/039218, for instance by converting 4-phenoxybenzoic acid to the corresponding acyl chloride (by using l chloride), which latter product may be d with malononitrile to prepare l,l-dicyano hydroxy(4-phenoxyphenyl)ethene. The methoxy moiety is then methylated using trimethylsilyldiazomethane, and that methylated product is the treated with ine hydrate to e 3-aminocyano(4-phenoxyphenyl)pyrazole, which is reacted with formamide to e 4-amino(4-phenoxyphenyl)-lH-pyrazole[3,4-d]— pyrimidine, as illustrated in the following scheme: 0’Ph O/Ph O HOi O/Ph O/Ph NC. l _’ NC, i —’ NC / / OH 0 CN CN / HZN Thereafter, the 4-amino(4-phenoxyphenyl)-lH-pyrazole[3,4-d]pyrimidine may have the requisite piperidinyl moiety introduced at the lH-position (i.e. on the -NH of the pyrazole moiety). As indicated in the above scheme, this is done by means of a Mitsunobu reaction — more specifically by converting the y moiety of the Boc- protected 3-hydroxypiperidine-l-carboxylate to a better leaving group, y allowing a substitution reaction with the -NH moiety of the pyrazole (with inversion).

Hence, the chirality of the hydroxypiperidine is translated into the product, which is then converted to the single enantiomer ibrutinib by Boc-deprotection and acylation with acryl chloride.

This process has a number of disadvantages, such as those associated with cost, efficiency and environmental disadvantages. For instance the Mitsunobu step may be wasteful, costly and cumbersome. It is therefore desired to find a new process that overcomes these disadvantages.

There is now provided a process for the ation of a nd of formula I, I \N HN N (I) or a derivative thereof, wherein R1 represents hydrogen or, more preferably, a nitrogen protecting group; R181 represents -CN, R1b or -C(O)N(R1°)(R1d); Rlb, R10 and R1d each independently represent C1_6 alkyl, aryl or heteroaryl; R2a represents: (i) phenyl substituted at the 4-position with halo or -O-R2b; or (ii) hydrogen; R2b represents hydrogen or ; which process ses reaction of a compound of formula 11, R18WAX, (II) or a derivative thereof, wherein R181 and R2a are as defined above; X1 represents a suitable g group, with a compound of formula III, (III) . . . 1 . or a derivative thereof, where1n R 1s as defined above, which process is hereinafter referred to as a "process of the invention".

In the embodiment of the invention bed above, it is indicated that R1 may represent hydrogen or a nitrogen-protecting group. The ion itself represents the process, i.e. the formation of the pyrazole as ed above. However, this inventive concept may be further divided into two: i.e. there may be two sub-embodiments of the invention in which: (i) R1 ents hydrogen; and (ii) R1 ents a nitrogen-protecting group, and the invention may be directed to either one of these two aspects (or sub- embodiments). For instance, in aspect (ii), R1 is a nitrogen-protecting group, and the process of the invention may be performed on a compound of formula (III) in which R1 is a protecting group to e a compound of formula (I) also containing that R1 protecting group. That R1 protecting group may be removed at any ient stage (e.g. in downstream steps) as described herein. This aspect (ii) is discussed , and is also described in the examples (see Example 1). In the other aspect (i), R1 is hydrogen, and hence the compound of formula (III) represents a piperidine unsubstituted at the nitrogen atom, and this has the advantage that the compound of formula (III) need not be protected, i.e. in which R1 is hydrogen, in order to form a compound of formula (I) which is also not protected at the piperidine nitrogen atom.

This may therefore have the advantage that this aspect avoids the need for additional protection and de-protection steps. This aspect (i) is also discussed herein, and is also described in the examples (see Example 2).

In the processes of the invention described , it is indicated that "derivatives" may be employed, which includes salts and solvates. Hence, for instance the compound of formula (III), i.e. the hydrazine, may be in the form of the free base or in the form of a salt (e. g. a di-hydrogen de salt, although the hydrazine may be in another salt form). Where riate, "derivative" may also encompass a relevant protecting group (which may be removed later in the synthesis scheme). It should also be noted that compounds mentioned herein may exhibit isomerism, e.g. tautomerism.

It is further indicated above that R1 is a en ting group. Such groups include those that result in the formation of: - an 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) - a carbamate - a urea - trityl (triphenylmethyl), diphenylmethyl, or the like Hence, R1 may, amongst other groups, represent: -C(O)Rt1 (in which Rt1 may represent hydrogen, so g -C(O)H, but preferably represents C1_6 alkyl or optionally substituted aryl); C1_6alkyl, which alkyl group is optionally substituted by one or more substituents selected from optionally substituted aryl (e.g. preferably forming a benzyl moiety); -S(O)2Rt2 (in which Rt2 preferably represents optionally substituted aryl); or, preferably, -C(O)ORt3 (in which Rt3 preferably represents ally substituted aryl or, more preferably, optionally substituted C1_6 (e.g. C1_4) alkyl, e. g. tert—butyl (so forming, for example, a utoxycarbonyl protecting group, i.e. when taken together with the amino , a tert-butylcarbamate group) or a -CH2phenyl group (so g a carboxybenzyl protecting group); -C(O)N(Rt4)Rt5 (in which, preferably, Rt4 and R6 ndently represent hydrogen, C1_6 alkyl, optionally substituted aryl or t6, and Rt6 represents C1_6 alkyl or optionally substituted aryl).

Unless otherwise specified, alkyl groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms be branched-chain, and/or cyclic. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such alkyl groups may also be part cyclic/acyclic.

Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be unsaturated.

The term , when used herein, es €6-10 groups. Such groups may be monocyclic, bicyclic or tricyclic and, when polycyclic, be either wholly or partly aromatic. C640 aryl groups that may be mentioned include phenyl, naphthyl, and the like. For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any carbon atom of the ring system.

The term "heteroaryl", when used herein, includes 5- to 14-membered heteroaryl groups containing one or more heteroatoms ed from oxygen, nitrogen and/or sulfur. Such heteroaryl group may comprise one, two or three rings, of which at least one is aromatic.

Preferably, such groups are 5- to 12-membered, e.g. 5- to 10-membered.

Where mentioned herein, C1-6 alkyl, aryl and heteroaryl may be optionally substituted. Such substitution is le if it does not affect the concept of the invention, i.e. the process(es) defined herein (which may be performed on certain compounds irrespective of the substitution pattern thereon). Such substituents include aryl (e.g. phenyl, itself optionally tuted by substituents selected from halo, alkyl and the like), alkyl, halo, -CN and the like.

It is indicated that X1 represents a le leaving group, and in particular may represent chloro, bromo, iodo, -OR3a (in which R3a ents optionally substituted alkyl, e.g. in which the optional substituent(s) include aryl such as , so forming e.g. -OCH3, -OCH2-phenyl or the like) or a sulfonate group (e.g. -O-S(O)2R4a, in which R4a represents optionally substituted alkyl or aryl, so forming e.g. 2CF3, -OS(O)2CH3 or –S(O)2PhMe or the like, i.e. tosyl, mesyl or the like).

In a particular aspect, the present invention provides a process for the preparation of a nd of formula I, NC (I) N R1 or a salt or solvate thereof, wherein R1 represents hydrogen or a nitrogen protecting group; [FOLLOWED BY 6a] -6awhich process comprises reaction of a compound of formula II, O Ph (II) or a salt or e thereof, wherein X1 represents a suitable leaving group, with a compound of formula III, (III) N R1 or a salt or e thereof, wherein R1 is as defined above.

Preferred compounds of formula (I) that may be prepared by a process of the invention described herein include those in which: R1a represents –CN; R2a represents phenyl substituted at the 4-position by –O-R2b; and/or R2b represents phenyl; hence the compound of formula (I) is preferably: NC (I) N R1 [FOLLOWED BY PAGE 7] the compound of formula (II) is preferably: O/Ph (ll) wherein, preferably, X1 represents —OR3a, in which R381 is preferably alkyl, more preferably unsubstituted alkyl and, most preferably, methyl, so forming a -OCH3 group; and hence, most preferably, the compound of formula (11) represents: O/Ph (ll) For the avoidance of doubt, the compound of formula (III) is a single enantiomer containing a chiral centre that has an (R)-conf1guration. By single omer, we mean that the compound is present in some enantiomeric excess (in this case, that there is more (R)-enantiomer present than the (S)-enantiomer), for instance in r than 50% ee, e.g. greater than 60%ee. The chirality is retained in the process of the reaction, i.e. the on is stereospecif1c, and the compound of formula (1) thereby produced is also a single enantiomer with the same uration at the relevant chiral centre.

Downstream synthetic steps will also proceed with retention of the stereochemistry (unless specified otherwise).

Particularly preferred protecting groups that R1 may represent include those forming carbamates (especially the tert—butoxycarbonyl or t-Boc group and the ybenzyl or Cbz group) and substituted alkyl es (especially the benzyl group). Such protecting groups may be more easily introduced onto the compound of formula (111) and/or ultimately more easily d from the relevant nitrogen atom in a downstream step.

Such a process of the invention may be conducted using the free base of a compound of formula (III) or salt thereof, e.g. a di-hydrogen chloride salt of the compound of formula (111). Further the ting group R1 is preferably a non acid-labile protecting group (e.g. a group labile to base or ble though hydrogenation or the like) such as a carboxybenzyl (Cbz) protecting group. However, the choice of this protecting group is influenced by the choice of the protecting group R2 (e.g. the two are preferably mutually compatible) as indicated hereinafter.

In this aspect of the s of the invention, the compound of formula (III) (or derivative thereof, e.g. di-HCl salt) may be added to the compounds of formula (11). ably less than two equivalents of the compound of a (III) is employed compared to the compound of formula (II), more preferably less than 1.5 equivalents.

However, the equivalents ratio of compound of formula (III) to nd of formula (11) may be between 1.5 : 1 to 1: 1.5, preferably between 1.2 : 1 to 1 : 1.2 and in particular, the ratio is about 1 : 1.

Preferably, this aspect of the process of the invention may be performed in a suitable solvent, such as in the presence of a polar solvent, such as an lic t (e. g. ethanol) and/or water, or mixtures thereof. It is preferred that a mixture of an alcohol (e. g. ethanol) and water is employed. ed to the weight of the compound of formula (II) employed, at least one (e.g. at least five, but preferably less than 20) volume equivalent(s) of the solvent/alcohol and at least one (e.g. at least five, but preferably less than 20) volume equivalents of water are employed. Preferably about 13 volume equivalents of the alcohol and about 10 volume equivalents of water are employed.

Preferably, the compound of formula (II) in the ce of a suitable solvent (as described above) is cooled to below room temperature, for example to below 10°C, e. g. to about 5°C. The compound of formula (III) (or derivative thereof) is then added to the e of compound of formula (II) and solvent. Preferably this is done so as to in the temperature of the on mixture below room temperature (e.g. at below about 10°C, preferably between 5 and 10°C). For instance, this addition may be drop- wise.

This process aspect of the invention is preferably conducted in the presence of a base, such as an organic base, ably an amine base such as a tertiary amine base (e. g. triethylamine). Preferably between one and four molar equivalents of base are employed in the process of the invention (compared to the molar equivalents of the compound of formula (II) or (111)), and more preferably between 1.5 and 2.5 equivalents are employed (e. g. about two lents). Preferably the base is added dropwise, and preferably the temperature is maintained at below room temperature (e.g. at below about 10°C, preferably between 5 and 10°C).

After the addition of the base, the reaction mixture is the preferably allowed to warm to about room temperature, after which it is allowed to stir at that temperature for a period of time g which the conversion to desired product compound (I) may be monitored), which may depend on the conversion rate to product. Typically, the reaction mixture is d to stir for at least 20 minutes, for example for about one hour, after which r water may be added (e.g. between about 10 and 20 volume equivalents), the reaction mixture may be cooled (again) to below room temperature (e.g. to below about 10°C, preferably about 5°C or below, e. g. about 0°C). The desired product may then solidify, and may therefore be separated/isolated by filtration. It may be further purified if required.

Such an aspect of the process of the invention has several ages. For instance, the fact that the substituted hydrazine of formula (III) (that may be employed in e.g. the free base form, or in the salt form which may be formed in situ) is employed in the reaction has at least the following advantages: (i) the use of hydrazine hydrate is avoided, which is a hazardous reagent to handle, especially at high temperatures (for instance hydrazine is combustible even in the absence of oxygen); (ii) the reaction leads to a lN-substituted pyrazole and hence downstream substitution at the lN—position is circumvented (when substitution is required at that position), for instance a downstream obu on to introduce a substituent is circumvented, the latter reaction generating enormous amounts of waste (e.g. the Mitsunobu reaction may require two equivalents of the 3-hydroxy-N—Boc piperidine, due to a competing elimination on); (iii) the use of the expensive chiral 3-hydroxy-N—Boc piperidine is circumvented; (iv) the reaction of compound (II) with a non-symmetrical hydrazine may be expected to result in a variety of products (as opposed to reaction with the symmetrical ine itself) but however, advantageously and unexpectedly, the on proceeds in a regioselective . That is the process of the invention predominantly s in the formation of a pyrazole with a substitution pattern as depicted by the compound of a (I), i.e. in the l(N)-position the piperidine, R2a group (e.g. 4-phenoxy-phenyl) in the tion, etc, as opposed to a le with the piperidine at the 2-position adjacent the R281 group. Advantageously, the desired regioisomer is present in higher quantity than the red regioisomer, and for instance is present in a ratio of greater than 75 :25 compared to the undesired regioisomer, more 2014/054621 particularly, this ratio is r than 90:10, and most advantageously there may be a negligible or undetectable amount of the undesired regioisomer.

Hence, this aspect of the process of the invention may be ageous in terms of economy (e. g. cost of goods), efficiency and environmental considerations (e. g. less waste).

After the first process of the ion, the compound of formula (I) that is prepared may be converted to a compound of formula (IV), (IV) or a derivative (including isomer) thereof, wherein R1 is as before defined. In particular, the preparation routes are particularly suitable for corresponding compounds in which R1 represents a protecting group (as defined herein) or may also be suitable for corresponding compounds in which R1 represents hydrogen (such embodiments may be specifically referred to below).

In the conversion to the compound of formula (IV), the compound of formula (I) may first be converted to a compound of formula (IVA), be (IVA) or a derivative (including isomer), wherein X2 represent -OH or -NH2, and R1 and R2&1 are as before defined.

For instance, for compounds of formula (I) in which R1&1 represents -CN, a corresponding product of formula (IVA) in which X2 ents -NH2 may be produced by reaction with either: (i) ide (HCONH2); (ii) formamidine or a formamidine salt H-C(=NH)-NH3+X', wherein X" represents a suitable counterion, such as a halide (e.g. C1") or an oxy anion (e.g. acyl-O'), so forming for example formamidine HCl or formamidine acetate or the like; (iii) alkyl (e.g. ethyl) formimidate, or a salt thereof, such as ethyl formimidate HCl; (iv) ethylorthoformate followed by ammonium acetate.

For the aspect of the invention where compounds of formula (I) in which R1 represents hydrogen are concerned, such compounds may also be converted to a compound of formula (IV) or a compound of a (IVA), and in this instance, such a reaction may result in the replacement of the hydrogen at R1, for example by on with formamide (HCONHZ), this may result in rent substitution (along with the desired cyclisation) at the R1 position to a compound of formula (IV) or (IVA) in which R1 represents . In such an instance, an additional step of deprotection (or removal of the -C(O)H moiety) may be required at an appropriate stage in the sequence (for example as described in Example 2 hereinafter). Such an intermediate may also be used to tely prepare Ibrutinib as defined hereinafter.

For compounds of formula (I) in which R181 represents -C(O)OR1b or -C(O)N(R1°)(R1d), a corresponding product of formula (IVA) in which X2 represents -OH (or a tautomer thereof, as depicted by formula (IVB) below) may be produced by reaction with for example, CH(OEt)3 optionally in the presence of a catalyst (e.g. ZnClz, 0.1 equiv), followed by the addition of e.g. NH4OAc, which reaction may be performed in the ce of a suitable solvent (e.g. an aromatic solvent such as toluene): "65:4" (IVB) Thereafter, compounds of formula (IVA) in which X2 represents -OH (or the tautomer, i.e. compound (IVB) depicted above) may be converted to corresponding nds of formula (IVA) in which X2 ents -NH2, by first ting to the corresponding chlorinated derivative (which need not be isolated) followed by a nucelophilic aromatic tution to e the desired compound, conditions including the use of POC13 (or another suitable chlorinating reagent) followed by on with NH4OAc (or another suitable source of ammonia).

For compounds of formula (IVA) in which R281 represents hydrogen, such a compound may be ted to a compound of formula (IVC): (IVC) wherein X2 is as hereinbefore , and X3 is a le group such as halo (e.g. bromo, chloro or ably, iodo), which reaction may take place in the presence of a source of halide, for instance an ophile that provides a source of iodine es iodine, diiodoethane, or preferably, N—iodosuccinimide, and sources of bromide and chloride e N—bromosuccinimide and N—chlorosuccinimide, and which reaction may be performed in the presence of a suitable solvent such as an alcohol (e. g. methanol) or preferably a halogenated solvent (e.g. chloroform) or a polar aprotic solvent (such as DMF).

Compounds of formula (IVC), in particular those in which X2 represents -NH2, may be converted to compounds of formula (IVA) in which R281 represents phenyl substituted at the 4-position with halo or -OR2b, by reaction of the compound of formula (IVC) with a compound of formula (IVD): X4_R2aa (IVD) wherein R28181 represents phenyl substituted at the 4-position with halo or -OR2b (with R2b as before defined), and wherein X4 represents a suitable group such as -B(OH)2, -B(ORW)2 or -Sn(RW)3, in which each RW ndently represents a C1_6 alkyl group, or, in the case of -B(ORW)2, the respective RW groups may be linked together to form a 4- to 6-membered cyclic group (such as a 4,4,5,5-tetramethyl-l,3,2-dioxa- borolanyl group, thereby forming e.g. a pinacolato boronate group), and wherein the coupling reaction may be med in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, CuI, Pd/C, Pd(OAc)2, Pd(Ph3P)2C12, Pd(Ph3P)4, Pd2(dba)3 and/or NiC12 (preferred catalysts include palladium) and a ligand such as PdC12(dppf).DCM, t-BU3P or the like, optionally in the presence of a suitable base (e. g. a carbonate base, hydroxide base, etc) and a suitable solvent.

Where, e. g. for compounds of formula (IVA) as defined above in which X2 represents -NH2 (or a ted derivative thereof) and R281 ents phenyl substituted at the 4-positon by halo or -OH, then conversion to the compound of formula (IV) may be possible by a coupling reaction with X4-phenyl-O-phenyl or X4-phenyl, for instance using similar catalytic ng reactions to those mentioned above.

Hence, ultimately compounds of formula (IV) may be prepared according to the processes ned above.

The ses discussed above (including those to prepare compounds of a (IV) and (IVA)) are also embraced by the concept of the invention, and are also processes that may be referred to herein as a "process of the invention".

There is therefore provided a process for the preparation of a compound of formula (IV) which process comprises a process for the preparation of a compound of formula (I) as hereinbefore defined ed by a process for the conversion of (I) to (IV) as hereinbefore described.

There is also provided a process for the preparation of a compound (IV) or (IVA), which process comprises reaction of a compound of formula (I) (as hereinbefore defined) with a formamidine salt d at (ii) above. Such a process is also an aspect of the invention and has associated advantages compared with reaction with formamide. For instance, the use of the formamidine salt may be advantageous as it circumvents the use of ide, the latter being using in prior processes at high temperatures (e.g. at about 165°C, which represents a thermal hazard), whereas the use of the formamidine salt allows lower temperatures to be employed.

This aspect of the invention (conversion of compound (I) to compound (IV) or (IVA)) is preferably performed by reaction of the compound (I) with a formamidine salt (as defined hereinbefore). The formamidine salt is preferably an acetate salt and is preferably employed in excess compared with the molar equivalents of compound of a (I) ed (e.g. in greater than two equivalents compared to compound of formula (I), e.g. greater than five equivalents, such as greater than 10 equivalents and preferably about fifteen lents).

This aspect of the s of the invention may be performed in the presence of a suitable solvent, which may be selected from aromatic solvents (e.g. toluene), alcohols, ethers and N-methylpyrrolidone, or the like. Glycols ethers may be particularly preferred (e.g. due to high boiling points), and a particularly preferred solvent is ore ethylene glycol monoethyl ether. The solvent is ably de-gassed and the reaction is preferably carried out under an inert here. More than five volume equivalents of solvent is employed (e.g. more than ten, and preferably around 13).

The resultant reaction mixture is then preferably heated to above room temperature, e.g. to above 40°C, e.g. above 60°C such as above 80°C. Most preferably it is heated to above 100°C. However, the temperature of the reaction mixture is preferably below 160°C, for instance the preferred temperature range is between 100°C and 140°C, most preferably between about 110°C and 130°C (e.g. about .

The reaction mixture may be monitored for progress, consequently affecting the time period of the reaction. After adequate completion of the reaction, mixture may be allowed to cool down and the reaction mixture worked up to provided the desired There is further provided a process for the preparation of a compound of formula (III) as hereinbefore defined, which process comprises resolution of a corresponding racemic mixture (or derivative, e.g. ted derivative, f), which may be performed by means of chiral chromatography (e.g. using chiral SFC), thereby advantageously obtaining a nd of formula (III) in greater than 50%ee, for example greater than 60%ee. Given that the process of the invention is stereoselective, it is le to purify downstream so as to provide an enantiomerically pure downstream compound.

Advantageously, this may produce product (compound (111)) in greater than 50% ee, for instance greater than 60% ee. Introducing the ity at this stage allows the processes hereinbefore described to be effected, thereby circumventing other methods for introducing the chirality (e.g. using chiral 3-hydroxy-piperidine) and venting the undesired Mitsunobu reaction prior disclosed in a process for preparing ibrutinib.

Compounds of formula (III), or protected derivatives thereofmay be ed by reaction of a nd of formula (VI), (VI) N\R1 2014/054621 or a derivative thereof, wherein R1 is as hereinbefore , with a compound of formula (VII), RZ-N(H)-NH2 (v11) wherein R2 is hydrogen or a suitable nitrogen protecting group (which may be subsequently removed), which may also be referred to as an aspect of the invention. This aspect of the invention may be conducted under standard dehydration reaction conditions optionally in the ce of a suitable solvent.

In general, the protection and ection of fianctional groups may take place before or after any of the reaction steps described hereinbefore.

Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as bed hereinafter.

The use of protecting groups is described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999).

The following scheme (which may have its individual numbering, as may the experimental section) provides a non-limiting example of various processes of the invention: O’Ph X = CI O’Ph o’Ph O’Ph o’Ph OH 0 V' O OH \ NC NC \ EWG = -C02Et, CONH2 ,NHZ ,NH2 2HCI 2HCI STEP-4a STEP-4 N\ N\ R1 R1 X-Boc :R1= Boc X-Boc :R1= Boc X-Bn :R1= Bn X-Bn :R1= Bn X-Cbz :R1= Cbz X-Cbz :R1= Cbz EWG NC NH2 NH2 O 0 \ \ / / , Ph N N031 Ph N N031 STEP-5 STEP-5a Xl-Boc :R1= Boc Xla-Boc :R1= Boc ZnCI2 Xl-Bn :R1= Bn NH Xla-Bn :R1= Bn AGOH CH(OEt)3 Xl-Cbz z JL Xla-Cbz :R1= Cbz NH4OAc 0 T\ 1)POC|3 /O \ —> / N R Ph Ph N U 1 2) NH4OAC STEP-6a STEP-6 XIIIa-Boc :R1= Boc XIII-Boc :R1= Boc XIIIa-Bn :R1= Bn :R1= Bn XIIIa-Cbz :R1= Cbz XIII-Cbz :R1= Cbz O H2N /N\\\ For instance, for compounds of formula (II) in which X1 represents an alkoxy leaving group -OR381 (or sulfonate), then such a compound may be prepared by alkylation (e.g.

W0 2014/139970 2014/054621 methylation) (or appropriate sulfonylation) of a compound corresponding to a compound of formula (II) but in which -OR3a represents -OH. Conversion of the —OH to other suitable leaving groups (e.g. to halo) may also be effected.

Compounds corresponding to formula (II) but in which -OR3a represents -OH may be ed by reaction of a compound of formula (VIII), R28‘-C(O)X1a (VIII) wherein X181 ents a suitable leaving group (e.g. chloro) and R2&1 is as hereinbefore defined, with a compound of formula (IX), NC-CHz-R1a (IX) n R181 is as hereinbefore defined, under suitable reaction conditions.

Some compounds described herein may be novel themselves, and hence in a further aspect of the ion, there is provided: - a compound of formula (I) or a derivative thereof - a compound of formula (III) or a derivative thereof for instance in at least greater than 50%ee - a compound of formula (11), (IV) or (IVA) or a derivative thereof In an embodiment of the invention, there is provided a process for the preparation of ibrutinib: O which process comprises a process as defined herein, followed by conversion to ibrutinib, for example: - a process for the ation of a compound of a (I) as herein described, followed by conversion to ibrutinib 2014/054621 - a process for the preparation of a compound of formula (IV) or (IVA) as herein described, ed by conversion to ibrutinib, for e by deprotection (i.e. removal of the R1 group) followed by acylation with acryl chloride - a process for the preparation of a compound of formula (III) as hereinbefore described, followed by conversion to nib, for e in accordance with the procedures bed herein Hence, there is also provided the use of certain compounds (e.g. the use of a compound of formula (1), (IV), (IVA) and/or (111)) as intermediates in the preparation of ibrutinib.

There is then further provided a process for the preparation of a ceutical formulation comprising ibrutinib, which s comprises bringing into association ibrutinib (or a pharmaceutically acceptable salt thereof), which is prepared in accordance with the processes described hereinbefore, with (a) pharmaceutically acceptable ent(s), adjuvant(s), diluents(s) and/or carrier(s).

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

The s of the invention may also have the advantage that the compound(s) prepared is/are produced in higher yield, in higher purity, in higher selectivity (e.g. higher regioselectivity), in less time, in a more convenient (i.e. easy to handle) form, from more convenient (i.e. easy to handle) precursors, at a lower cost and/or with less usage and/or wastage of materials (including reagents and solvents) compared to the procedures sed in the prior art. Furthermore, there may be several environmental benefits of the process of the invention.

Examples The following examples are intended to illustrate the t invention and should not be construed as a limitation of the scope of the present invention. 2014/054621 Experimental Section Example 1 Prepare I from XI with Cbz protecting group The synthesis route from z to I has been performed in the laboratory with the total yield of ~50%. Structure of I from this route has been confirmed by comparing lO HPLC, HNMR and CNMR with reference standard I.

STEP-7 STEP-8 STEP-9 STEP-4 Ph’ CN R2 H CN & Hl\ll HN’ R HN’NHZ VI 4—. 2 2HC| / NHZNHRZ GeIx] N R1 bN bN\ R1 R1 XIV-Boc :R1= Boc XV-Boc :R1= Boc, R2= Cbz XVI-Boc :R1= Boc, R2= Cbz X-Boc :R1= Boc XIV-Bn :R1= Bn XV-Bn :R1= Bn, R2: Boc XVI-Bn :R1= Bn, R2: Boc X-Bn :R1= Bn XIV-Cbz :R1= Cbz XV-Cbz :R1= Cbz, R2: Boc XVI-Cbz :R1= Cbz, R2: Boc X-Cbz :R1= Cbz STEP-5 STEP-6 NC N N NH H2N / \\\ HzN / NH ACOH \\\ \ XIIJL 5 N \ \ N O \ H NH I ’N ,R 2 01 '3th \ O Ph N \ , N —, N N’R1 / ’N Xl-Boc :R1= Boc XIII-Boc :R1= Boc Xl-Bn :R1= Bn n :R1= Bn Xl-Cbz :R1= Cbz XIII-Cbz :R1= Cbz XV-Cbz Exact Mass: 347.18 100 g (1.0 eq.) of XIV-Cbz and 56.66 g (1.0 eq.) Boc-NHNHZ was dissolved in 500 mL solvent (methanol, 5.0 V), NaZSO4 was added and the mixture was stirred for 4h at 28°C. The solvent was evaporated by reduce pressure to get 148g ofXV-Cbz as a yellow oil. MS (ESI):m/z =370 (M+23(Na)) CszN— NBoc XV-Boc Exact Mass: 347.18 45.8g (1.0 eq.) ofXIV-Boc and 38.2 g (1.0 eq.) Cbz-NHNHz was dissolved in 230 mL solvent (methanol, 5.0 V), the mixture was stirred for 2h at 28°C. The solvent was evaporated by reduce pressure to get 78g ofXV-Boc as a yellow oil. MS (ESI):m/z = 370 (M+23(Na)) XV-Bn Exact Mass: 303.19 100 g (1.0 eq.) of XIV-Bn.HCl.H20/Bn and 54.22 g (1.0 eq.) Boc-NHNHz was dissolved in 500 mL solvent nol, 5.0 V), Na2S04 was added and the mixture was stirred for 2h at 25°C. The solvent was ated by reduce pressure to get l22g of XV-Bn as orange foam. MS (ESI):m/z =304 (M+l) BocHN—NH NCbz XVI-Cbz Exact Mass: 349.20 33.1 lg (1.0 eq) of XV-Cbz was dissolved in l60mL of MeOH, cool 5°C and d under en. 2.0 eq. NaBHgCN was then added to the reaction mixture. Then, 1.0eq ofAcOH was added dropwise and stirred at 5 0C under nitrogen for 3h. The reaction e was stirred for another 3.5h at 25 OC, cooled to 10°C, and then saturated aq.NH4Cl was added dropwise until pH~6. (A lot of white solid separated out). The mixture was filtered and the solid washed with H20. The cake was dried under vacuum at 45-50°C for l6hrs and isolated in 81.1% yield. MS (ESI):m/z =372 (M+23(Na)) -2]- CszN NBoc XVI-Boc Exact Mass: 349.20 28.4g (1.0 eq) ofXV-BOC was ved in l45mL of THF and 30mL of MeOH, cool °C and stirred under nitrogen. 6. 18g (2.0 eq) ofNaBH4 was then added to the reaction mixture and stir at 5 °C under nitrogen for 3h. It was allowed to stir for another l5h at °C. 15% aq. NH4Cl was added dropwise until pH~6-7. Then 10V of Ethyl e was charged/added into the mixture. The phase was separated, and the aqueous was extracted twice with 8V of ethyl e. The organic layers were combined and washed twice with 10V of water. The organic solution was concentrated to 3-4V and then cooled to 0-5°C. PE was added dropwise to crystallize XVI-Boc as white solid.

The mixture was filtered and the cake dried under vacuum at 40-45°C. 25g of XVI-Boo was ed with 97.54% HPLC purity in the yield of 87.7%.

HN,NHBoc XV-Bn Exact Mass: 305.21 A MeOH on ofXV-Bn (37.6g in l30mL MeOH) was cooled to 5°C under N2. 2.0 eq. NaBHgCN was charged under N2 keeping the temperature at 5-10 °C. l.0eq of AcOH was added dropwise at 5-10°C. The mixture was warmed to 25 °C and stirred under N2 for 16h. The reaction mixture was cooled to 10°C. Saturated aq.NH4Cl was added dropwise into Rl to pH~6. The mixture was trated under vacuum and then aqueous phase was extracted with EA (100ml*3). The organic phase was concentrated. The mixture was filtered and the filter cake washed with MTBE. The cake was dried under vacuum at 45-50°C for 16hrs to get 23g XVI-Bn as white solid 97.9% purity. MS (ESI):m/z =306 (M+l) 2HC| HZN GCbz Exact Mass: 249.15 X-Cbz 16.12 g (1.0 eq.) XVI-Cbz was charged with 80 mL of methanol. 92.2mL MeOH solution of HCl (4M) was charged and stirred for 3h at 28 0C. MeOH was switched to EtOAc (a lot of white solid separated out). The solid was filtered under N2 tion.

The filter cake was dried under vacuum at 35-40 0C for 16hrs to result in 1 1.9g (80.2% Yield) with a purity of 94.97%. (ESI):m/z =249.9 (M+l) 2HC| H2N_NH < N Boc Exact Mass: 215.16 X-Boc Pd(OH)2/C was used as catalyst and 2.0eq HCl (2M MeOH solution) was added to inhibit the generation of a dimmer by-product. Form LCMS, a strong MS signal of X-Boc could be found. After the workup, 3.9g of X-Boc was obtained as foam in the yield of 79.6%. Procedure: Charge 6.0 g (1.0 eq.) of XVI-Boc with 90 mL (15.0 V.) Methanol, then charge 3.61 g (0.30 eq.) Pd(OH)2/C with 34.36mL(2.0 eq) ofMeOH solution of HCl (1M), stir for 1h at 28 0C under N2. Swich the solvent to EtOAc to separate the product out. Transfer the mother liquor out and dry the residue under vacuum to get 3.9g of X-Boc as white foam (79.6% . (ESI):m/z =2l6.0 (M+l) 2HCI H2N X-Bn Exact Mass: 205.16 Charge 20g (1.0 eq) ofXVI-Bn under N2, add 11 eq. HCl MeOH on (4M) into Rl under N2 at 20-25°C and stir at 50 CC for 2h. Switch the solvent to EtOAc and then a lot of white solid separated out. Filter the mixture under N2 protection. The solid was dried under vacuum at 45-50°C to yield 14g of X-Bn (76.9% Yield).

O \ / , Ph N NUCbz Exact M ass: 493 .21 Xl-Cbz Charge 4.29 g (1.0 eq.) of VI under N2 with 60mL (13 V.) ethanol and 43ml (10V) of water. Cool the mixture to 5 0C. Add X-Cbz in three portions at 5-10 0C under N2. Add dropwise 3.15 g (2.0.eq.) NEt3 at 5-10 0C. Warm to 25°C under N2 and stir for 1 h at °C (solid separate out). Add dropwise 17V H20 into the reaction mixture at 25 0C.

Cool the reaction mixture 0 -5°C and stir for 1h. Filter the mixture. The cake was dried under vacuum at 40-45 0C to result in 7.79g ield) with a purity of 99.81% (ESI):m/z =494.1 (M+1) H2N / \ \\ N o \ Ph N NUCbZ, XHLCbz Exact Mass: 520.22 3g (1 .0eq) of XI-Cbz was mixed with 9.5g (15.0 eq) of formamidine acetate and 40mL (13V) 2H4OH (degassed), the reaction mixture was stirred at 120 0C for 6hrs, Cool the reaction mixture to r.t. Add se H2O (13V) and EA (15V). Separate the mixture and t the aqueous phase with EA fro twice. Combine the organic phase and wash it with H20 twice. Evaporate solvent under vacuum to get crude XIII-Cbz as yellow oil in 97.9% purity. (ESI):m/z = 521.4 (M+1) STEP-4 HZN‘NH STEP-5 Ph/o 2HC| CN N NH2 NH / ACOH \Cbz \ CN A /0 \ N Cb H NH2 /0 X-Cbz Ph N’ Z —’ 115°C EtOH C09051809-C EtOEtOH XI-Cbz Exact Mass: 493.21 H2N /NW\ STEP-6 H2N / \\\ N N \ \ O \ Pd(OH)2/C O \ Ph/ , N CbZ / _. , N Ph/ N XIII-Cbz Exact Mass: 386.19 Exact Mass: 520.22 Telescope preparation of I from VI was carried out. In step-4, conversion of VI was 100% and XI-Cbz was generated with 99.8% area percent. In step-5, conversion of XI-Cbz was 97.7% and XIII-Cbz was generated with 94.2% area percent. In step-6, conversion of XIII-Cbz was 100% and I was obtained with 92.5% HPLC area percent.

Procedure: Charge 4.29 g (1.0 eq.) VI under N2 with 10mL (16.6 V.) ethanol and 6ml (10V.) Cool R1 to 5-10 0C. Add 0.7g (1.0.eq.) X-Cbz solution in water was added drop- wise over 15 min at 5-10 0C. Add 0.45g (2.0.eq.) NEt3 drop-wise over 5min at 5-10 0C.

Warm to 20~30 0C under N2 and stir R1 for 1 h at 20~30 0C. Add 10V EA and then 10V H20 into the reaction mixture. Separate the mixture and extract the aqueous phase with 10V EA twice. Combine the organic phase and wash with 10V H20. Switch the solvent to 13V EtOEtOH. Add 15eq formamidine acetate into the mixture. Heat to 120°C and stir for 5hrs at 120°C. Cool the mixture to r.t. and add 15V EA and 15V H2O into the mixture. Separate the mixture and extract the s phase with 10V EA twice. Combine the organic phase and wash with 10V H2O twice. Switch the t to 10V MeOH. Add Pd(OH2)/C(0.3eq) and stir the mixture at 55-60 0C under 3Bar H2.

Filter the reaction mixture and wash the cake with MeOH. Combine the MeOH solution of crude I and concentrate to 2-3VAdd dropwise H2O (5-6V) into the MeOH solution (a lot of off-white solid separated out). Filter the mixture and wash the cake with MeOH/H2O (1V/1V). The solid was dried under vacuum at 40-45 0C to obtain I in 80% yield (over 3 steps) in 92.5% purity.

By comparing the HPLC, HNMR and CNMR of I with a reference of that compound e.g. known from the art (or derivatised therefrom), it could be concluded that I that is prepared by this synthesis had the same HPLC retention time, same HNMR and CNMR. Therefore, this synthesis route from SM-Cbz to I is an available working route.

STEP-4' H2N~ NH NC /o 2HCI NC Ph CN NH2 \ NH2 / N\ O \ O CN Boc Ph/ N’N N,Boc + / ,H Ph \N’N o X-Boc / \0 0 Exact Mass: 276.09 :8: Exact Mass: 45923 Exact Mass: 359.17 V| Xl-Boc Imp-A Charge 0.41 g (1.0 eq.) of VI (in THF solution). Dissolve 0.32g (1.0 eq.) of X-Boc in EtOH(2V) /H20(0.5mL, 1.5V)/ Et3N ). Add drop-wise X-Boc to R1 at 5-10°C.

Warm to 25 CC under N2 and stir R1 for 1h at 25 CC. Add water (10V) drop-wise at -10 C’C. trate the mixture under vacuum and extract it with ethyl acetate 3). Wash the organic phase with H20. Evaporate solvent under vacuum to get crude XI-Boc as yellow oil. The de-Boc compound, Imp-A, was generated as the main t. XI-Boc was obtained in 29% yield with 96% purity by column chromatography NC H H2N /N\\\ HZN /N\\\ \ N \ \ N ,0 \ H NH2 ACOH , Boc O \ O \ idine acetate / MBOH Ph N'N ,Boc ph/ N’N —, 0 —»HC' C2H5OC2H4OH UH Exact Mass: 459.23 Exact Mass: 486.24 Exact Mass: 386.19 120°C Xl-Boc XIII-Boc | H2N ,N\\\ p \ 5: Ph N’NU H ExactMass:414.18 Imp-B Charge XI-Boc (0.3g, l.0eq.) at r.t under N2. Charge idine acetate (15eq) into Rl under N2. Charge C2H50C2H4OH (13V) into R1 under N2. Heat to 120°C (inter temp) and stir the mixture at 120°C for 8hrs. In this reaction mixture,4.3% of Imp-B also could be observed. Cool the reaction mixture to r.t. Add dropwise H20 (40mL,l3V) and EA (15V). Separate the mixture and extract the s phase with EA twice. Combine the organic phase and switch the solvent to MeOH. Add HCl (10eq, MeOH solution) into the mixture. Heat to 50°C and stir for 3hrs. Cool to r.t, concentrate the reaction mixture to 2-3mL. Add 3mL H20 and then add dropwise 30% aq. NaOH to adjust pH to 10. Filter the mixture and dry the cake under vacuum at 45°C. I could be isolated by crystallization form MeOH/HZO with 95.6% purity in the total yield of 87.3% By ing the HPLC, HNMR and CNMR of I with a reference of that compound e.g. known from the art (or derivatised therefrom), it could be concluded that I that is prepared by this synthesis had the same HPLC retention time, same HNMR and CNMR. Therefore, this synthesis route from SM-Boc to I is an available working route. 0 \ / , Ph N NU,Bn XI-Bn Exact Mass: 449.22 Charge 0.496 g (1.0 eq.) of VI under N2 with 4mL (8V) ethanol. Cool the mixture to °C. Add X-Bn (dissolve in 5V EtOH and 10V H20) in three portions at 5-10 0C under N2. Add dropwise 0.5 lg (2.0.eq.) NEt3 at 5-10 0C. Warm to 25-300C under N2 and stir for l h at 25-30°C (solid separate out). Add dropwise 17V H20 into the reaction mixture at 25 0C. Cool the reaction e 0 -5°C and stir for 1h. Filter the mixture.

The cake was dried under vacuum at 40-45 0C to yield 0.65g of XI-Bn (80% Yield) with 94.03% purity. (ESI):m/z =450 (M+1) NC H2N NH 2 J’LH H2N /N\\\ /N\\\ N N \ \ /O \\N H NH2 AcOH r Bn o \ o \ Ph N U formamidine acetate Ph/ N’N /Bn Pd(OH)2/C ph/ N’N MeOH C2H50C2H4OH Exact Mass: 449.22 Exact Mass: 476-23 120°C Exact Mass: 386.19 XI-Bn XIII-Bn One batch to prepare XIII-Bn was carried out from 1.72g XI-Bn. In the first ring e step, Conversion of XI-Bn was 100% and XIII-Bn was generated with 99.12% LCMS purity. Even been stirred for 21hrs at 120°C, no decomposition could be observed. In the second step, we tried two conditions. One added 2eq of HCl (4M MeOH solution) and the other one was without HCl. The batch adding HCl was faster than the other one. However, conversion of XIII-Bn was only 20%. ure: Charge XI-Bn at r.t with formamidine acetate (15eq) and C2H50C2H4OH (13V) under N2. Heat to 120°C and stir the mixture at 120°C for 8hrs. Cool the reaction e to r.t. Add dropwise H2O (13V) and EA (10V). Separate the mixture and extract the aqueous phase with 10V EA for twice. Combine the organic phase and wash it with 10V H2O for three times. Switch the solvent to MeOH from EA. Charge 0.1eq Pd(OH)2/C and 2eq HCl(4M MeOH solution). Heat to 45-50°C Stir the mixture in R2 at 40-50°C. The desired product was obtained from this procedure. (ESI):m/z =3 87.0 (M+1) Example 2 ation of compound Y6 (also referred to as compound I above) from ected piperidine-hydrazine (referred to as Y20 below) H N2 ~ NC Ph’o NH nHCI GH NH2 CN \ i / 0—< >—<\ CN Ph/ N’NU’H H NH2 / Y20 165—17500 Exact Mass: 276.09 NaOMe, MeOH Exact Mass: 359.17 2h 309-c H2N N 3-3 H2N N / \\\ / \ N N \ O \ O \ O Ph’ N’NUJLH \ % HCI Ph’ 55—65°C N’NUH Exact Mass: 414.18 Exact Mass: 386.19 Y16 Y6 This example represents a further embodiment of the invention. The compound Y20 (the piperidine-hydrazine; also referred to herein as a compound of formula (111)), which corresponds to the general compound X in previous Example 1 (but wherein in that case the N atom of the piperidine is protected with -Boc, -Bn or -CBz), is unsubstituted at the piperidine N atom, and is directly mixed with the compound Y3 (also referred to in e 1 as compound V1, which is also a compound of formula (11) as defined herein). The reaction is similar to Step-4 in Example 1 but, unlike in Example 1, this example shows that the piperidine-hydrazine need not be protected for the reaction with Y3 to proceed (see Procedure S-l below). Indeed, the resultant product Y4 (also referred to herein as a compound of formula (1) as hereinbefore described) is advantageously produced without the need to protect the piperidine- hydrazine (and then subsequently deprotect it). The compound Y4 (which is still unsubstituted at the piperidine N atom) may then be ly used in the next reaction step (i.e. without the need to add a ting group), where a mixture containing Y4 and formamide (or another le reagent that achieves the same result, as described herein) are allowed to react (see Procedure S-2 below) thereby forming a compound Y16 (which is a ted version of a compound of formula (IV) as described herein (or a protected version of compound 1 as specified in Example 1, i.e. X111 but in which R1 represents -C(O)H). It is incidental that the N atom of the piperidine is acylated (by a -C(O)H group) during the cyclisation on to produce the pyrimidine moiety of the bicycle (pyrazole[3,4-d]pyrimidine), and this group may be removed by deprotection (for example as shown by the ure S-3 below).

Procedure 8-1 The reaction procedure was ed in ance with the following steps )? Dissolve Y20 g, 1.5eq) in 0.5mL MeOH in a first reaction vessel Add dropWise a MeOH solution ofNaOMe into Y20 to adjust pH value to N9 Add Y3 (1.0eq) and 0.45 mL MeOH into a second reaction vessel Cool the reaction mixture in the second on vessel to 0-10°C Add dropWise the MeOH solution of Y20 in the first reaction vessel to the reaction mixture in the second reaction vessel at 0-10°C Stir the uent reaction mixture at 20-25°C for 2hrs Cool the reaction mixture to 0-10°C Add se 2mL H20 into the reaction mixture (off-White solid separated out) .0908?" Filter the mixture and dry the product under vacuum Procedure S-2 Charge Y4 into a first reaction vessel under N2.

Charge 9.6X formamide into that reaction vessel.

FOWSQShthJNE Heat the mixture to 165-175 °C.

Stir the on mixture for 2 h at 165-175 °C.

Calculate Impact of Ion-Pair Reagents (IPC) on LCMS analysis Cool the reaction mixture 40°C (solid separate out).

Add drop Wise 6V water into the reaction vessel Stir the reaction mixture for 0.5 h at 40°C Cool the reaction mixture 20°C (or around room temperature) j—A .0 Filter the mixture.

HH NH . Dry the cake under vacuum at 40-45 °C for 16hrs Crude yield: 92% Procedure S-3 1. Charge 0.5g of Yl6 (the material obtained directly from S-2 above) into a first reaction vessel under N2.

Charge 0.5mL 35%HCl (5.0eq) into that first reaction vessel.

SQSherJN Heat the mixture to 55-65 °C.

Stir the mixture in the reaction vessel at 55-65°C (see table below). ate Impact of Ion-Pair Reagents (IPC) on LCMS analysis (see table below) Cool the reaction e to 20°C (or around room temperature).

Add, drop Wise, KOH into the reaction vessel to adjust pH to 11-13 (solid separate out). 8. Stir the mixture in the reaction vessel for 0.5 h at 20°C 9. Filter the mixture.

. Dry the solid under vacuum at 40-45°C for l6hrs. ll. Crude yield: 63% IPC (21%), as shown by Raw materials Condition Results LCMS Y16 HCl Time T. Purity (by Crude Conv Y6 Y16 Qty (g) eq. (h) (°C) LCMS) Yield 0.5g 4 55-65 90.64 88.9 9.36 Of Material S-3 5.0eq. 0.29g 63% from 8-2 98.9% 55-65 99.46 97.6 0.54 96.6% Example — Pharmaceutical Formulation Ibrutinib may be formulated into a pharmaceutically acceptable ation using standard procedures.

For example, there is provided a process for preparing a pharmaceutical formulation sing ibrutinib, or a derivative f, which s is characterised in that it includes as a process step a process as hereinbefore defined. The skilled person will know what such pharmaceutical formulations will comprise/consist of (e.g. a mixture of active ingredient (i.e. ibrutinib or derivative thereof) and pharmaceutically acceptable excipient, adjuvant, diluent and/or carrier).

There is filrther provided a process for the ation of a pharmaceutical formulation comprising ibrutinib (or a tive thereof), which process comprises bringing into association ibrutinib, or a pharmaceutically acceptable salt thereof (which may be formed by a process as hereinbefore described), with (a) pharmaceutically acceptable excipient(s), nt(s), diluent(s) and/or carrier(s).

Claims (13)

Claims

1. A process for the preparation of a compound of formula I, NC (I) N R1 or a salt or solvate thereof, wherein R1 represents hydrogen or a en protecting group; which process ses reaction of a compound of formula II, O Ph (II) or a salt or solvate f, wherein X1 represents a suitable leaving group, with a compound of formula III, (III) N R1 or a salt or solvate thereof, wherein R1 is as defined above.

2. A process for the preparation of a compound of formula I as claimed in Claim 1, wherein: - in the compound of formula (I) and (III) R1 represents a nitrogen-protecting group; and/or - in the nd of formula (II), X1 represents -OR3a, in which R3a represents alkyl such as methyl.

3. A process for the preparation of a compound of formula (IVA), which process comprises a process for the ation of a compound of formula (I) as defined in Claim 1 followed by conversion to a compound of formula (IVA), (IVA) N N N 1 or a salt or solvate, wherein X2 represent -OH or -NH2, and R1 is as defined in Claim 1.

4. A process for the ation of a nd of formula (IV), (IV) N N N R1 or a salt or solvate thereof, wherein R1 is as d in Claim 1 or Claim 2, which process comprises a process for the preparation of a compound of formula (I) as claimed in Claim 1 followed by reaction with either: (i) formamide (HCONH2); (ii) formamidine or a formamidine salt H-C(=NH)-NH3+X-, wherein X- represents a suitable counterion, such as a halide (e.g. Cl-) or an oxy anion (e.g. acyl-O-), so g for example formamidine HCl or formamidine acetate or the like; (iii) alkyl (e.g. ethyl) formimidate, or a salt thereof, such as ethyl formimidate HCl; (iv) ethylorthoformate followed by ammonium acetate.

5. A process as claimed in Claim 4, n the reaction is with (ii) a formamidine salt in which the counterion is a halide or oxygen-based anion.

6. A process as claimed in any one of Claim 3 to 5, wherein the reaction is performed at a temperature of below 160°C, for instance n 100°C and 140°C.

7. A compound of formula (III) as defined in Claim 1 or Claim 2, which has an ee of greater than 50%.

8. A compound of formula (I) as defined in any one of Claims 1, 2 or 3 and wherein R1 represents hydrogen or a en protecting group that results in the formation of a carboxybenzyl group.

9. A compound of formula (IVA) as d in claim 3 wherein R1 represents a carboxybenzyl protecting group.

10. A process for the preparation of ibrutinib: N N which process comprises either: - a process for the preparation of a nd of formula (I) as defined in Claim 1 or Claim 2, followed by conversion to ibrutinib; - a process for the preparation of a compound of a (IVA) or (IV) as defined in any one of Claims 3 to 6, followed by conversion to ibrutinib, for example by deprotection (i.e. removal of the R1 group) followed by acylation with acryl chloride; and/or - a resolution process for the ation of a compound of formula (III) as defined in Claim 1 or Claim 7, followed by conversion to ibrutinib.

11. A use of a compound of formula (I), (IVA) and/or (III) (or salts or solvates thereof) as defined in any one of Claims 1, 2, 7, 8 or 9 as intermediates in the preparation of ibrutinib.

12. A process for the preparation of a pharmaceutical formulation comprising ibrutinib, which s comprises bringing into association ibrutinib (or a pharmaceutically acceptable salt thereof), which is prepared as d in Claim 10, with (a) pharmaceutically able excipient(s), adjuvant(s), diluents(s) and/or carrier(s).

13. A process of claim 1, substantially as herein described with reference to any one of the Examples thereof.