HK40048820A - Processes and intermediates for preparing a medicament - Google Patents

Description

Process and intermediates for the preparation of a medicament

The application is a divisional application of an invention patent application with the application date of 2014, 3, and 11, the application number of 201480015131.5, and the invention name of the invention is 'a method and an intermediate for preparing a medicine'.

Technical Field

The present invention relates to synthetic processes and synthetic intermediates for substituted bicyclic compounds, particularly compounds useful as pharmaceuticals, for example bruton's tyrosine kinase (Btk) inhibitors such as ibrutinib.

Background

Ibrutinib is a small organic molecule with the IUPAC name 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] prop-2-en-1-one. It is described in a number of publications, including international patent application WO2008/039218 (example 1b), and is described as an irreversible inhibitor of Btk.

Btk plays an important role in the activation of cell surface B cell receptors by B cell signaling pathways coupled to responses within downstream cells. Btk is a key regulator of B-cell development, initiation, signaling, and survival (Nagasaki (Kurosaki), an immunological novelties (Curr Op Imm), 2000, 276-. In addition, Btk plays a role in a number of 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 apoptosis signaling in B-lineage lymphocytes, and collagen-stimulated platelet aggregation. See, e.g., c.a. jeffels (Jeffries) et al, (2003), Journal of biochemistry (Journal of Biological Chemistry) 278: 26258-26264; n.j. royal wood (Horwood), et al, (2003), Journal of Experimental Medicine (The Journal of Experimental Medicine) 197: 1603-1611; yiweiqi (Iwaki) et al, (2005), Journal of biochemistry (Journal of Biological Chemistry)280 (48): 40261-40270; wasselff (Vassilev) et al, (1999), Journal of biochemistry (Journal of Biological Chemistry)274 (3): 1646-1656, and Guo (Quek) et al (1998), Current Biology (Current Biology)8 (20): 1137-1140.

Ibrutinib has therefore been studied in second and third phase clinical trials for various hematological malignancies, such as chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma and multiple myeloma.

There are various methods for preparing functionalized bicyclic heterocycles, for example, as described in US patent document US 2011/0082137 (including the synthesis of fused bicyclic rings from pyrazoles and substituted hydrazines).

Ibrutinib can be prepared in WO2008/039218 (example 1b) according to the following scheme:

first, 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidine may be prepared according to the procedure described in WO2008/039218, for example by converting 4-phenoxybenzoic acid to the corresponding acid chloride (by using thionyl chloride), which latter product may be reacted with malononitrile to prepare 1, 1-dicyano-2-hydroxy-2- (4-phenoxyphenyl) ethylene. The methoxy moiety is then methylated using trimethylsilyldiazomethane and the methylated product is treated with hydrazine hydrate to provide 3-amino-4-cyano-5- (4-phenoxyphenyl) pyrazole, which is reacted with formamide to provide 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] -pyrimidine as illustrated in the following scheme:

thereafter, the 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidine may have the necessary piperidinyl moiety introduced at the 1H-position (i.e., on the-NH of the pyrazole moiety). As indicated in the above scheme, this is accomplished by a mitsunobu reaction-more specifically by converting the hydroxyl moiety of the Boc-protected 3-hydroxypiperidine-1-carboxylate to a better leaving group, allowing for substitution reactions (inversions) with the-NH moiety of the pyrazole. Thus, the chiral hydroxypiperidine is converted into the product which is then converted into the single enantiomer ibrutinib by Boc deprotection and acylation with acryloyl chloride.

This approach has a number of disadvantages, such as those associated with cost, efficiency and environmental disadvantages. For example, the three signal steps can be wasteful, expensive, and cumbersome. It is therefore desirable to find a new way to overcome these disadvantages.

There is now provided a process for the preparation of a compound of formula I

Or a derivative thereof, wherein

R¹Represents hydrogen or, more preferably, a nitrogen protecting group;

R^1arepresents-CN, -C (O) OR^1bor-C (O) N (R)^1c)(R^1d)；

R^1b、R^1cAnd R^1dEach independently represents C_1-6Alkyl, aryl or heteroaryl;

R^2arepresents:

(i) at the 4-position via halogen or-O-R^2bSubstituted phenyl; or

(ii) Hydrogen;

R^2brepresents hydrogen or phenyl;

the method comprises a compound of formula II,

or a derivative thereof, wherein

R^1aAnd R^2aAs defined above;

X¹represents a suitable leaving group which is, in turn,

with a compound of formula III,

or derivatives thereof, wherein R¹As defined above, the above-mentioned,

this method is hereinafter referred to as "the method of the invention".

In the above-described embodiments of the present invention, R is shown¹May represent a hydrogen or nitrogen protecting group. The invention itself represents a process, i.e. the formation of pyrazoles as indicated above. However, the concept of the invention can be further divided into two, namely, there are two following sub-embodiments of the invention, wherein:

(i)R¹represents hydrogen; and is

(ii)R¹Represents a nitrogen-protecting group, and is,

and the present invention may be directed to one of these two aspects (or sub-embodiments). For example, in the aspect (ii), R¹Is a nitrogen protecting group, and the present inventionCan be carried out on a compound of formula (III) (wherein R is¹Is a protecting group) to provide a compound also containing the R¹A compound of formula (I) for a protecting group. The R is¹The protecting group may be removed at any convenient stage (e.g., in a downstream step) as described herein. Aspect (ii) is discussed herein and is also described in the examples (see example 1). In another aspect (i), R¹Is hydrogen and therefore the compound of formula (III) represents a piperidine unsubstituted at the nitrogen atom and this has the following advantages: to form a compound of formula (I) which does not require protection at the piperidine nitrogen atom, a compound of formula (III) is also not required to be protected, i.e. wherein R is¹Is hydrogen. This may therefore have the following advantages: this aspect avoids the need for additional protection and deprotection steps. Aspect (i) is also discussed herein and is also described in the examples (see example 2).

In the methods of the invention described herein, it is indicated that "derivatives" may be used, including salts and solvates. Thus, for example, a compound of formula (III), i.e. hydrazine, may be in the form of the free base or in the form of a salt (e.g. the dihydrogen chloride salt, although hydrazine may be in another salt form). Where appropriate, "derivatives" may also include related protecting groups (which may be removed later in the synthetic scheme). It should also be noted that the compounds mentioned herein may exhibit isomerism, such as tautomerism.

The above further shows that R¹Is a nitrogen protecting group. Such groups include those that result in the formation of:

an amide (e.g. N-acetyl)

Optionally substituted N-alkyl (e.g. N-alkyl or optionally substituted N-benzyl)

-N-sulfonyl (e.g. optionally substituted N-phenylsulfonyl)

A carbamate

-a urea

Trityl (triphenylmethyl), benzhydryl, and the like

Thus, R is, among other groups¹Can represent that:

-C(O)R^t1(wherein R is^t1May represent hydrogen, thus forming-C (O) H, but preferably represents C_1-6Alkyl or optionally substituted aryl);

C_1-6an alkyl group, the alkyl group of which is optionally substituted with one or more groups selected from optionally substituted aryl (e.g., preferably forming a benzyl group);

-S(O)₂R^t2(wherein R is^t2Preferably represents an optionally substituted aryl group); OR preferably-C (O) OR^t3(wherein R is^t3Preferably represents an optionally substituted aryl group, or more preferably an optionally substituted C_1-6(e.g. C)_1-4) Alkyl, e.g. tert-butyl (formed, e.g. with a tert-butoxycarbonyl protecting group, i.e. when taken together with an amino moiety, tert-butylcarbamate group) or a-CH₂Phenyl group (thus forming a carboxybenzyl protecting group);

-C(O)N(R^t4)R^t5(wherein, R is preferred^t4And R^t5Independently represent hydrogen, C_1-6Alkyl, optionally substituted aryl or-C (O) R^t6And R is^t6Represents C_1-6Alkyl 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, branched and/or cyclic. Furthermore, such alkyl groups may also be partially cyclic/acyclic when there is a sufficient number (i.e., a minimum of four) of carbon atoms. Such alkyl groups may also be saturated or, when a sufficient number (i.e., a minimum of two) of carbon atoms are present, unsaturated.

The term "aryl", as used herein, includes C_6-10A group. Such groups may be monocyclic, bicyclic or tricyclic and, when polycyclic, may be fully or partially aromatic. There may be mentioned C_6-10Aryl radicals including phenyl, naphthylAnd the like. For the avoidance of doubt, the point of attachment of a substituent on an aryl group may be via any carbon atom of the ring system.

The term "heteroaryl", as used herein, includes 5-to 14-membered heteroaryl groups containing one or more heteroatoms selected from: oxygen, nitrogen and/or sulfur. Such heteroaryl groups may include one, two or three rings, at least one of which is aromatic. Preferably, such groups are 5 to 12 membered, for example 5 to 10 membered.

When referred to herein, C_1-6The alkyl, aryl and heteroaryl groups may be optionally substituted. Such substitutions are possible if they do not affect the concept of the invention, i.e. one or more of the methods defined herein (which may be performed on certain compounds irrespective of the substitution pattern thereon). Such substituents include aryl (e.g., phenyl which may itself be optionally substituted with a substituent selected from the group consisting of halogen, alkyl, and the like), alkyl, halogen, -CN, and the like.

Shows X¹Represents a suitable leaving group and may in particular represent chlorine, bromine, iodine, -OR^3a(wherein R is^3aRepresents optionally substituted alkyl, for example wherein the optional substituent or substituents comprise aryl, such as phenyl, thus forming, for example, -OCH₃、-OCH₂Phenyl, etc.) or a sulfonate group (e.g., -O-S (O)₂R^4aWherein R is^4aRepresents optionally substituted alkyl or aryl, thus forming, for example, -OS (O)₂CF₃、-OS(O)₂CH₃or-S (O)₂PhMe, etc., i.e., tosyl, mesyl, etc.).

Preferred compounds of formula (I) that can be prepared by the process of the invention described herein include those wherein:

R^1arepresents-CN;

R^2arepresents a 4-position via-O-R^2bSubstituted phenyl; and/or

R^2bRepresents phenyl;

thus, the compounds of formula (I) are preferably:

the compounds of formula (II) are preferably:

among them, X is preferable¹represents-OR^3aWherein R is^3aPreferred is alkyl, more preferred is unsubstituted alkyl, and most preferred is methyl, such that-OCH is formed₃A group;

and therefore, most preferably, the compound of formula (II):

for the avoidance of doubt, the compound of formula (III) is a single enantiomer comprising a chiral centre having the (R) -configuration. By a single enantiomer is meant that the compound is present in an enantiomeric excess (in this case, more of the (R) -enantiomer is present than the (S) -enantiomer), for example in an ee of greater than 50%, for example greater than 60%. The chirality is retained during the reaction, i.e. the reaction is stereospecific, and the resulting compound of formula (I) is also a single enantiomer with the same configuration at the relevant chiral centre. The downstream synthesis steps will also be performed with retention of stereochemistry (unless otherwise indicated).

R¹Particularly preferred protecting groups which may be represented include those which form carbamates, particularly t-butoxycarbonyl or t-Boc groups and carboxybenzyl or Cbz groups, and substituted alkyl moieties, particularly benzyl groups. Such protecting groups can be more easily introduced intoThe compounds of formula (III) are more easily removed from the relevant nitrogen atom in downstream steps and/or finally.

Such processes of the invention may be carried out using the free base of a compound of formula (III) or a salt thereof, for example the dihydrogen chloride salt of a compound of formula (III). Furthermore, a protecting group R¹Preferred is a non-acid labile protecting group (e.g., a base labile or removable by hydrogenation group, etc.) such as a carboxybenzyl (Cbz) protecting group. However, as indicated below, the choice of protecting group is protected by the protecting group R²E.g., the two are preferably compatible with each other.

In this aspect of the process of the invention, the compound of formula (III) (or a derivative thereof, such as a di-HCl salt) may be added to the compound of formula (II). Preferably, less than two equivalents of compound of formula (III) are used compared to compound of formula (II), more preferably less than 1.5 equivalents. However, the equivalent ratio of compound of formula (III) to compound of formula (II) may be between 1.5: 1 and 1: 1.5, preferably between 1.2: 1 and 1: 1.2 and in particular the ratio is about 1: 1.

Preferably, this aspect of the process of the invention may be carried out in a suitable solvent, for example in the presence of a polar solvent, such as an alcoholic solvent (e.g. ethanol) and/or water, or a mixture thereof. Preferably, a mixture of an alcohol (e.g., ethanol) and water is used. At least one (e.g. at least five, but preferably less than 20) volume equivalents of solvent per alcohol and at least one (e.g. at least five, but preferably less than 20) volume equivalents of water are used compared to the weight of the compound of formula (II) used. Preferably, about 13 volume equivalents of alcohol and about 10 volume equivalents of water are used.

Preferably, the compound of formula (II) is cooled to below room temperature, for example to below 10 ℃, such as to about 5 ℃, in the presence of a suitable solvent (as described above). The compound of formula (III) (or derivative thereof) is then added to the mixture of the compound of formula (II) and the solvent. Preferably, this is done so as to maintain the temperature of the reaction mixture below room temperature (e.g., below about 10 ℃, preferably between 5 and 10 ℃). For example, such addition may be dropwise.

The process aspect of the invention is preferably carried out in the presence of a base, for example an organic base, preferably an amine base such as a tertiary amine base (e.g. triethylamine). In the process of the invention, preferably between one and four molar equivalents of base (compared to the molar equivalents of the compound of formula (II) or (III)) are used, and more preferably between 1.5 and 2.5 equivalents of base (e.g. about 2 equivalents) are used. Preferably, the base is added dropwise, and preferably the temperature is maintained below room temperature (e.g., below about 10 ℃, preferably between 5 ℃ and 10 ℃).

After addition of the base, the reaction mixture is preferably allowed to warm to about room temperature, after which it is allowed to stir at room temperature for a period of time (during the conversion to the desired product, compound (I) can be monitored), which period of time depends on the rate of conversion to product. Typically, the reaction mixture is allowed to stir for at least 20 minutes, for example for about one hour, after which more water is added (e.g., between about 10 and 20 volume equivalents), the reaction mixture may be (again) cooled to below room temperature (e.g., to below about 10 ℃, preferably about 5 ℃ or below, for example about 0 ℃). The desired product may then be cured and may thus be separated/isolated by filtration. It may be subjected to further purification if desired.

This aspect of the method of the invention has several advantages. For example, the fact that a substituted hydrazine of formula (III) is used in the reaction (e.g. it can be used in the free base form, or in the form of a salt that can be formed in situ) has at least the following advantages:

(i) avoiding the use of hydrazine hydrate, which is a very dangerous reagent to handle, especially at high temperatures (for example hydrazine is flammable, even in the absence of oxygen);

(ii) the reaction results in a 1N substituted pyrazole and thus circumvents downstream substitution at the 1N position (when substitution is required at that position), for example circumvents downstream mitsunobu reactions introducing substituents, the latter reaction resulting in substantial waste (e.g., mitsunobu reactions may require two equivalents of 3-hydroxy-N-Boc piperidine due to competition-elimination reactions);

(iii) circumventing the use of expensive chiral 3-hydroxy-N-Boc piperidine;

(iv) the reaction of compound (II) with an asymmetric hydrazine can be expected to yield a variety of products (in contrast to the reaction with the symmetric hydrazine itself), but this reaction proceeds regioselectively, whether advantageously or unexpectedly. That is, the process of the invention results primarily in the formation of pyrazoles having a substitution pattern as described by the compounds of formula (I), i.e. piperidine in the 1(N) -position, R in the 3-position^2aRadicals (e.g. 4-phenoxy-phenyl) or the like, as in R^2aPyrazoles with piperidines in the 2-position adjacent to the group are diametrically opposed. Advantageously, the desired regioisomer is present in a higher amount than the undesired regioisomer, and for example, in a ratio of greater than 75: 25 compared to the undesired regioisomer, more specifically, such a ratio is greater than 90: 10, and most advantageously, a negligible or undetectable amount of the undesired regioisomer is present.

Thus, this aspect of the inventive process may be advantageous in terms of economics (e.g., cost of goods), efficiency, and environmental conditions (e.g., less waste).

After the first process of the present invention, the prepared compound of formula (I) may be converted into a compound of formula (IV),

or derivatives (including isomers) thereof, wherein R¹As defined above. In particular, the preparation route is particularly suitable for the corresponding compounds, where R¹Represents a protecting group (as defined herein) or may also be applied to the corresponding compound, wherein R is¹Represents hydrogen (such examples)Specific reference may be made to the following).

In the conversion to the compound of formula (IV), the compound of formula (I) may be first converted to the compound of formula (IVA),

or derivatives (including isomers) thereof, wherein X²represents-OH or-NH₂And R is¹And R^2aAs defined above.

For example, to compounds of formula (I) (wherein R is^1arepresents-CN), a corresponding product of formula (IVA) (wherein X²represents-NH₂) It may be produced by reaction with one of the following:

(i) formamide (HCONH)₂)；

(ii) Formamidine or formamidine salt H-C (═ NH) -NH₃ ⁺X^-Wherein X is^-Represents a suitable counterion, for example a halide (e.g. Cl)^-) Or an oxyanion, for example, of acyl-O^-) Thus, for example, formamidine HCl or formamidine acetate, etc. are formed;

(iii) alkyl (e.g., ethyl) amidine ethers, or salts thereof, such as ethyl amidine ether HCl;

(iv) the ethyl orthoformate is followed by ammonium acetate.

With respect to aspects of the invention, when considering a compound of formula (I) (wherein R is¹Representing hydrogen), such compounds may also be converted into compounds of formula (IV) or compounds of formula (IVA), and in such a case, such a reaction may result in the presence of a compound of formula (IV) or (IVA)¹Replacement of hydrogen by, for example, formamide (HCONH)₂) Reaction, which may result in the formation of a metal complex at R¹The concurrent substitution of positions (together with the desired cyclization reaction) produces a compound of formula (IV) or a compound of formula (IVA), wherein R¹represents-C (O) H. In this case, at appropriate stages in order, mayAn additional deprotection step (or removal of the-c (o) H moiety) can be required (e.g., as described in example 2 below). Such intermediates may also be used to finally prepare ibrutinib as defined below.

To compounds of formula (I) (wherein R is^1arepresents-C (O) OR^1bor-C (O) N (R)^1c)(R^1d) Of the formula (IVA) (wherein X)²represents-OH (or a tautomer thereof, as described by formula (IVB) below)) by reaction with, for example, CH (OEt)₃Optionally in a catalyst (e.g., ZnCl)₂0.1 equivalent) followed by addition of, for example, NH₄OAc, which may be carried out in the presence of a suitable solvent (e.g., an aromatic solvent such as toluene):

thereafter, a compound of formula (IVA) (wherein X is²represents-OH (or a tautomer, i.e. the above-mentioned compound (IVB))) into the corresponding compound of formula (IVA) (wherein X is²represents-NH₂) By first conversion to the corresponding chlorinated derivative (which does not require isolation) followed by nucleophilic aromatic substitution to provide the desired compound, provided that the use of POCl is included₃(or another suitable chlorinating agent) followed by reaction with NH₄OAc (or another suitable source of ammonia) is reacted.

To compounds of formula (IVA) wherein R^2aRepresents hydrogen, such compounds may be converted into compounds of formula (IVC):

wherein X²As defined above, and X³Is a suitable group such as halogen (e.g. bromine, chlorine or preferably iodine) and this reaction may beOccurs in the presence of a halide source, such as an electrophilic species which provides an iodine source, including iodine, diiodoethane, or preferably N-iodosuccinimide, as well as bromine and chlorine sources, including N-bromosuccinimide and N-chlorosuccinimide, and this reaction may be carried out 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 (e.g. DMF).

The compound of formula (IVC) may be prepared by reaction of a compound of formula (IVC) with a compound of formula (IVD), in particular wherein X²represents-NH₂Into a compound of formula (IVA), wherein R^2aRepresents halogen OR-OR in the 4-position^2bSubstituted phenyl group:

X⁴-R^2aa (IVD)

wherein R is^2aaRepresents halogen OR-OR in the 4-position^2bSubstituted phenyl (having R as defined above)^2b) And wherein X⁴Represents a suitable radical, e.g. -B (OH)₂、-B(OR^w)₂or-Sn (R)^w)₃Wherein R is^wIndependently represent C_1-6An alkyl group, OR-B (OR)^w)₂In particular, each R^wThe groups may be joined together to form a 4 to 6 membered ring group (e.g. a 4, 4, 5, 5-tetramethyl-1, 3, 2-dioxa-borolan-2-yl group, forming for example a pinacolato borate group) and wherein the coupling reaction may be carried out in the presence of a suitable catalyst system, for example a metal (or salt or complex thereof) such as Pd, CuI, Pd/C, Pd (OAc)₂、Pd(Ph₃P)₂Cl₂、Pd(Ph₃P)₄、Pd₂(dba)₃And/or NiCl₂(preferred catalysts include palladium) and ligands such as PdCl₂(dppf).DCM、t-Bu₃P, etc., optionally in the presence of a suitable base (e.g., carbonate base, hydroxide base, etc.) and a suitable solvent.

When for example directed to a compound of formula (IVA) as defined above, wherein X²represents-NH₂(or a protected derivative thereof) and R^2aRepresents phenyl substituted in the 4-position by halogen or-OH, then by reaction with X⁴-phenyl-O-phenyl or X⁴The coupling reaction of the phenyl group may possibly be converted into a compound of formula (IV), for example using a catalytic coupling reaction similar to those described above.

Thus, the compound of formula (IV) may be finally prepared according to the above-mentioned process.

The methods discussed above, including those for preparing compounds of formula (IV) and formula (IVA), are also encompassed within the concept of the present invention, and are also methods that may be referred to herein as "methods of the invention".

Accordingly, the present invention provides a process for the preparation of a compound of formula (IV), such process comprising a process for the preparation of a compound of formula (I) as defined above, followed by a process for the conversion of (I) to (IV) as described above.

The present invention also provides a process for the preparation of a compound of formula (IV) or (IVA), which process comprises the reaction of a compound of formula (I) (as hereinbefore defined) with a formamidine salt as hereinbefore defined in (ii). Such processes are also an aspect of the present invention and have related advantages over reactions with formamide. For example, the use of formamidine salts may be advantageous because it avoids the use of formamide, which was used at high temperatures in previous processes (e.g., at about 165 ℃, which represents a thermal hazard), whereas the use of formamidine salts allows use at lower temperatures.

This aspect of the invention (conversion of compound (I) to compound (IV) or (IVA)) is preferably carried out by reacting compound (I) with a formamidine salt (as defined above). The formamidine salt is preferably an acetate salt and is preferably used in excess of molar equivalents compared to the compound of formula (I) used (e.g. in greater than two equivalents compared to the compound of formula (I), for example greater than five equivalents, such as greater than 10 equivalents and preferably about fifteen equivalents).

This aspect of the process of the invention may be carried out in the presence of a suitable solvent which may be selected from aromatic solvents (e.g. toluene), alcohols, ethers and N-methyl-2-pyrrolidone, and the like. Glycol ethers are particularly preferred (e.g. due to high boiling point), and a particularly preferred solvent is ethylene glycol monoethyl ether. The solvent is preferably degassed and the reaction is preferably carried out under an inert atmosphere. More than five volume equivalents of solvent are used (e.g., more than ten, and preferably about 13).

The resulting reaction mixture is then preferably heated to above room temperature, e.g. to above 40 ℃, e.g. above 60 ℃ such as above 80 ℃. Most preferably, it is heated to above 100 ℃. However, the temperature of the reaction mixture is preferably below 160 ℃, for example a suitable temperature range is between 100 ℃ and 140 ℃, most preferably between about 110 ℃ and 130 ℃ (e.g. about 120 ℃).

The reaction mixture can be tested for progress, thereby affecting the time period of the reaction. After the reaction is sufficiently complete, the mixture may be allowed to cool and the reaction mixture provides the desired compound.

The present invention further provides a process for the preparation of a compound of formula (III) as defined above, which process comprises resolution of the corresponding racemic mixture (or a derivative thereof, e.g. a protected derivative), which resolution can be carried out by chiral chromatography (e.g. using chiral SFC), thereby advantageously obtaining a compound of formula (III) in excess of 50% ee, for example in excess of 60% ee. Assuming that the process of the invention is stereoselective, it is possible to purify the downstream to provide an enantiomerically pure downstream compound.

Advantageously, this may result in a product (compound (III)) of more than 50% ee, for example more than 60% ee. Introducing chirality at this stage allows the process described above to be influenced, thereby circumventing its other methods for introducing chirality (e.g. using chiral 3-hydroxy-piperidine) and circumventing the previously disclosed undesirable mitsunobu reactions in the process of preparing ibrutinib.

A compound of formula (VI),

or a derivative thereof, wherein R¹As defined above, with a compound of formula (VII) to produce a compound of formula (III), or a protected derivative thereof,

R²-N(H)-NH₂ (VII)

wherein R is²Hydrogen or a suitable nitrogen protecting group (which may be subsequently removed),

such a method may also be referred to as an aspect of the invention. This aspect of the invention may be carried out under standard dehydration reaction conditions, optionally in the presence of a suitable solvent.

In general, the protection and deprotection of the functional groups may be performed before or after any of the reaction steps described above.

The protecting groups may be removed according to techniques well known to those skilled in the art and as described hereinafter.

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

The following schemes (which may have their respective numbers as in the experimental section) provide non-limiting examples of the various methods of the present invention:

for example, to compounds of formula (II) wherein X¹Represents an alkoxy leaving group-OR^3a(or sulfonate ester), such a compound may be usedThe compounds are prepared by reaction with a compound of formula (II) (but wherein OR^3arepresents-OH) corresponding compounds. Conversion of-OH to other suitable leaving groups (e.g., halogen) may also be performed.

A compound corresponding to formula (II) (but wherein-OR^3arepresents-OH) may be reacted under suitable reaction conditions by a compound of formula (VIII),

R^2a-C(O)X^1a (VIII)

wherein X^1aRepresents a suitable leaving group (e.g. chloro) and R^2aAs defined above, with a compound of formula (IX),

NC-CH₂-R^1a (IX)

wherein R is^1aAs defined above.

Some of the compounds described herein may be novel in their own right, and thus in another aspect of the invention there is provided:

-a compound of formula (I) or a derivative thereof

A compound of formula (III) or a derivative thereof, e.g. in at least more than 50% ee

-a compound of formula (II), (IV) or (IVA) or a derivative thereof

In one embodiment of the present invention, there is provided a process for preparing ibrutinib:

such methods include a method as defined herein, followed by conversion to ibrutinib, for example:

-a process for the preparation of a compound of formula (I) as described herein, followed by conversion to ibrutinib

-a process for the preparation of a compound of formula (IV) or (IVA) as described herein, followed by conversion to ibrutinib, for example by deprotection (i.e.,removal of R¹Group) followed by acylation with acryloyl chloride

A process for the preparation of a compound of formula (III) as described above, followed by conversion into ibrutinib, for example according to the process described herein

Accordingly, there is also provided the use of certain compounds (e.g. the use of compounds of formula (I), (IV), (IVA) and/or (III)) as intermediates in the preparation of ibrutinib.

The present invention then further provides a process for the preparation of a pharmaceutical formulation comprising ibrutinib, which process comprises introducing relevant ibrutinib (or a pharmaceutically acceptable salt thereof), which is prepared according to the process as described above, together with one or more pharmaceutically acceptable excipients, adjuvants, diluents and/or carriers.

In general, the methods described herein may have the following advantages: in contrast to the methods disclosed in the prior art, the compounds prepared can be prepared in the following manner: fewer reagents and/or solvents are used, and/or fewer reaction steps (e.g., different/separate reaction steps) are required.

The method of the invention may also have the following advantages over the processes disclosed in the prior art: the one or more compounds prepared are produced in higher yield, higher purity, higher selectivity (e.g., higher regioselectivity), less time, in a more convenient (i.e., easier to handle) form, from more convenient (i.e., easier to handle) precursors, at lower cost, and/or with less use and/or waste (including reagents and solvents) of materials. Furthermore, there may be several environmental benefits of the method of the present invention.

Examples of the invention

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

Experimental part

Example 1

Preparation of I from XI with Cbz protecting group

In the laboratory, the synthetic route from XIV-Cbz to I has been carried out with an overall yield of about 50%. The structure of I from this route has been confirmed by comparing HPLC, HNMR and CNMR with reference standard I.

100g (1.0 eq) of XIV-Cbz and 56.66g (1.0 eq) of Boc-NHNH were added₂Dissolved in 500mL of a solvent (methanol, 5.0V), and Na was added₂SO₄And the mixture was stirred at 28 ℃ for 4 h. The solvent was evaporated under reduced pressure to give 148g of XV-Cbz as a yellow oil. Ms (esi): m/z 370(M +23(Na))

45.8g (1.0 eq) of XIV-Boc and 38.2g (1.0 eq) of Cbz-NHNH₂Dissolved in 230mL of solvent (methanol, 5.0V) and the mixture stirred at 28 ℃ for 2 h. The solvent was evaporated under reduced pressure to give 78g of XV-Boc as a yellow oil. Ms (esi): m/z 370(M +23(Na))

100g (1.0 eq) of XIV-Bn. HCl. H₂O/Bn and 54.22g (1.0 eq.) Boc-NHNH₂Dissolved in 500mL of a solvent (methanol, 5.0V), and Na was added₂SO₄And the mixture was stirred at 25 ℃ for 2 h. The solvent was evaporated under reduced pressure to give 122g of XV-Bn as an orange foam. Ms (esi): m/z 304(M +1)

33.11g (1.0 eq) of XV-Cbz were dissolved in 160ml MeOH and cooled to 5deg.C and stirred under nitrogen. Then 2.0 equivalents of NaBH₃CN was added to the reaction mixture. Then, 1.0 equivalent of AcOH was added dropwise and stirred at 5 ℃ under nitrogen for 3 h. The reaction mixture was stirred at 25 ℃ for a further 3.5h, cooled to 10 ℃ and then saturated aqueous NH4Cl was added dropwise to a pH of about 6 (a large amount of white solid precipitated). The mixture was filtered and washed with H₂O washing the solid. The filter cake was dried under vacuum at 45-50 ℃ for 16h and isolated in 81.1% yield. Ms (esi): m/z 372(M +23(Na))

28.4g (1.0 eq) of XV-BOC were dissolved in 145mL THF and 30mL MeOH, cooled to 5 ℃ and stirred under nitrogen. Then 6.18g (2.0 equivalents) of NaBH was added₄Added to the reaction mixture and stirred at 5 ℃ under nitrogen for 3 h. It was allowed to stir at 20 ℃ for a further 15 h. Dropwise adding 15% aqueous NH₄Cl to a pH of about 6-7. 10V of ethyl acetate was then charged/added to the mixture. The phases were separated and the aqueous phase was extracted twice with 8V of ethyl acetate. The organic layers were combined and washed twice with 10V water. The organic solution was concentrated to 3-4V and then cooled to 0-5 ℃. PE was added dropwise to clean XVI-Boc as a white solid. The mixture was filtered and the filter cake was dried under vacuum at 40-45 ℃. 25g of XVI-Boc was obtained in 87.7% yield with 97.54% HPLC purity.

In N₂Next, a solution of XV-Bn (37.6g in 130mL MeOH) in MeOH was cooled to 5 ℃. In N₂Then, the temperature is kept between 5 ℃ and 10 ℃, and 2.0 equivalent of NaBH is charged₃And (C) CN. 1.0 equivalent of AcOH is added dropwise at 5-10 ℃. Heating the mixture to 25 ℃ and under N₂Stirring for 16 h. The reaction mixture was cooled to 10 ℃. Saturated aqueous NH4Cl to R1 was added dropwise until pH about 6. The mixture was concentrated under vacuum and then with EA(100ml x 3) the aqueous phase was extracted. The organic phase was concentrated. The mixture was filtered and the filter cake was washed with MTBE. The filter cake was dried under vacuum at 45 deg.C-50 deg.C for 16h to give 23g of XVI-Bn in 97.9% purity as a white solid. Ms (esi): 306(M +1)

80mL of methanol was charged to 16.12g (1.0 equivalent) of XVI-Cbz. 92.2mL of HCl (4M) in MeOH were charged and stirred at 28 ℃ for 3 h. MeOH was converted to EtOAc (large amount of white solid precipitated). In N₂The solid was filtered under protection. The filter cake was dried at 35-40 ℃ for 16h under vacuum to yield 11.9g of 94.97% purity (80.2% yield). (ESI): m/z 249.9(M +1)

Pd (OH)₂the/C was used as a catalyst and 2.0 equivalents of HCl (2M MeOH in) were added to suppress the production of dimer by-product. From LCMS, a strong MS signal for X-Boc was found. After work-up, 3.9g of X-Boc were obtained in 79.6% yield as foam. The process is as follows: 90mL (15.0V.) of methanol was charged to 6.0g (1.0 eq.) of XVI-Boc, then 34.36mL (2.0 eq.) of HCl (1M) in MeOH was charged to 3.61g (0.30 eq.) of Pd (OH)2/C in N₂Stirring was continued for 1h at 28 ℃. The solvent was switched to EtOAc to precipitate the product. The mother liquor was transferred out and the residue was dried under vacuum to give 3.9g of X-Boc as a white foam (79.6% yield). (ESI): m/z 216.0(M +1)

In N₂20g (1.0 eq.) of XVI-Bn are charged in N₂Next, 11 equivalents of HCl MeOH solution (4M) were added to R1 at 20 deg.C-25 deg.C and stirred at 50 deg.C for 2 h. The solvent was switched to EtOAc and then a large amount of white precipitate precipitatedAnd (3) a solid. In N₂The mixture was filtered under protection. The solid was dried under vacuum at 45 deg.C-50 deg.C to yield 14g of X-Bn (76.9% yield).

In N₂Next, 60mL (13V.) of ethanol and 43mL (10V) of water were charged to 4.29g (1.0 eq.) of VI. The mixture was cooled to 5 ℃. In N₂X-Cbz is added in three batches at 5-10 ℃. 3.15g (2.0. eq.) of NEt are added dropwise at 5 ℃ to 10 ℃₃. Heat to 25 ℃ under N2 and stir at 25 ℃ for 1h (solid precipitated). 17V H was added dropwise at 25 deg.C₂O into the reaction mixture. The reaction mixture was cooled to 0-5 ℃ and stirred for 1 h. The mixture was filtered. The filter cake was dried at 40-45 ℃ under vacuum to yield 7.79g of 99.81% purity (100% yield). (ESI): m/z 494.1(M +1)

3g (1.0 equiv.) of XI-Cbz were combined with 9.5g (15.0 equiv.) of formamidine acetate and 40mL (13V) of C₂H₅OC₂H₄OH (degassed) was mixed and the reaction mixture was stirred at 120 ℃ for 6h and cooled to room temperature. H2O (13V) and EA (15V) were added dropwise. The mixture was partitioned and the aqueous phase was extracted twice with EA. The organic phases are combined and washed with H₂O wash it twice. The solvent was evaporated in vacuo to give crude XIII-Cbz as a yellow oil of 97.9% purity. (ESI): m/z 521.4(M +1)

Set I (telescope prepnration) was performed from VI. In step 4, the conversion of VI was 100% and XI-Cbz was produced at 99.8% area percent. In step 5, the conversion of XI-Cbz was 97.7% and XIII-Cbz was produced at 94.2% area. In step 6, the conversion of XIII-Cbz was 100% and I was obtained as 92.5% HPLC area percentage.

The process is as follows: 10mL (16.6V.) of ethanol and 6mL (10V.) were charged to 4.29g (1.0 eq.) of VI under N2. Cooling R1 to 5-10 ℃. A solution of 0.7g (1.0 eq) of X-Cbz in water is added dropwise over 15min at 5 ℃ to 10 ℃. 0.45g (2.0 equivalents) of NEt is added dropwise at 5 ℃ to 10 ℃ over 5min₃. In N₂Heat to 20 ℃ about 30 ℃ and stir R1 at 20 ℃ to 30 ℃ for 1 h. 10V EA was added and then 10V H2O was added to the reaction mixture. The mixture was partitioned and the aqueous phase was extracted twice with 10V EA. The organic phases were combined and washed with 10V H2O. The solvent was switched to 13V etoetoeooh. To the mixture was added 15 equivalents of formamidine acetate. Heated to 120 ℃ and stirred at 120 ℃ for 5 h. The mixture was cooled to room temperature and 15V EA and 15V H2O were added to the mixture. The mixture was partitioned and the aqueous phase was extracted twice with 10V EA. The organic phases were combined and washed twice with 10V H2O. The solvent was switched to 10V MeOH. Pd (OH2)/C (0.3 equiv.) was added and the mixture was heated at 3 bar H₂The mixture is then stirred at 55 ℃ to 60 ℃. The reaction mixture was filtered and the filter cake was washed with MeOH. The crude I MeOH solution was combined and concentrated to 2-3V. H2O (5-6V) was added dropwise to the MeOH solution (a large amount of off-white solid precipitated). The mixture was filtered and the filter cake was washed with MeOH/H2O (1V/1V). The solid was dried under vacuum at 40-45 ℃ to obtain I in 80% yield (over 3 steps) of 92.5% purity.

By comparing the HPLC, HNMR and CNMR of I with a reference of, for example, a compound (or derivative thereof) known from the prior art, it can be concluded that I prepared by such a synthesis has the same HPLC retention time, the same HNMR and CNMR. Thus, this synthetic route from SM-Cbz to I is one useful processing route.

0.41g (1.0 eq) of VI in THF was charged. 0.32g (1.0 equiv) of X-Boc was dissolved in EtOH (2V)/H2O (0.5mL, 1.5V)/Et3N (3.0 equiv). X-Boc was added dropwise to R1 at 5 deg.C-10 deg.C. Heat to 25 ℃ under N2 and stir R1 at 25 ℃ for 1 h. Water (10V) was added dropwise at 5-10 ℃. The mixture was concentrated in vacuo and extracted with ethyl acetate (20ml x 3). The organic phase was washed with H2O. The solvent was evaporated in vacuo to give crude XI-Boc as a yellow oil. The de-Boc compound, Imp-A, was produced as the main product. XI-Boc was obtained in 29% yield with 96% purity by column chromatography

XI-Boc (0.3g, 1.0 eq.) was charged at room temperature under N2. Formamidine acetate (15 eq) was charged to R1 under N2. Under N2, C₂H₅OC₂H₄OH (13V) was charged to R1. Heat to 120 ℃ (internal temperature) and stir the mixture at 120 ℃ for 8 h. In this reaction mixture, 4.3% Imp-B was also observed. The reaction mixture was cooled to room temperature. Dropwise addition of H₂O (40mL, 13V) and EA (15V). The mixture was partitioned and the aqueous phase was extracted twice with EA. The organic phases were combined and the solvent was switched to MeOH. HCl (10 eq, MeOH solution) was added to the mixture. Heat to 50 ℃ and stir for 3 h. Cool to room temperature and concentrate the reaction mixture to 2-3 mL. 3mL of H2O was added and then 30% aqueous NaOH was added dropwise to adjust the pH to 10. The mixture was filtered and the filter cake was dried under vacuum at 45 ℃. Can be prepared by crystallization of MeOH/H₂O I was isolated in 95.6% purity in 87.3% overall yield.

By comparing the HPLC, HNMR and CNMR of I with a reference of, for example, a compound (or derivative thereof) known from the prior art, it can be concluded that I prepared by such a synthesis has the same HPLC retention time, the same HNMR and CNMR. Thus, this synthetic route from SM-Boc to I is a useful processing route.

4mL (8V.) of ethanol was charged to 0.496g (1.0 eq) of VI under N2. The mixture was cooled to 5 ℃. X-Bn (dissolved in 5V EtOH and 10V H) was added in three portions at 5 ℃ -10 ℃ under N2₂O). 0.51g (2.0. eq.) of NEt is added dropwise at 5 ℃ to 10 ℃₃. Heat to 25-30 ℃ under N2 and stir at 25-30 ℃ for 1h (solids precipitated). 17V H was added dropwise at 25 deg.C₂O into the reaction mixture. The reaction mixture was cooled to 0-5 ℃ and stirred for 1 h. The mixture was filtered. The filter cake was dried under vacuum at 40 deg.C-45 deg.C to yield 0.65g of XI-Bn (80% yield) of 94.03% purity. (ESI): m/z 450(M +1)

A batch of XIII-Bn preparations was made from 1.72g of XI-Bn. In the first ring closure step, the conversion of XI-Bn was 100% and XIII-Bn was produced with 99.12% LCMS purity. Even after stirring at 120 ℃ for 21h, no decomposition was observed. In the second step, we try two conditions. One with 2 equivalents of HCl (4M MeOH solution) added and the other without HCl. This batch with HCl added was faster than the other batch. However, the conversion of XIII-Bn is only 20%. The process is as follows: at room temperature under N₂Next, formamidine acetate (15 equivalents) and C were added₂H₅OC₂H₄OH (13V) was charged to XI-Bn. Heat to 120 ℃ and stir the mixture at 120 ℃ for 8 h. The reaction mixture was cooled to room temperature. Dropwise addition of H₂O (13V) and EA (10V). The mixture was partitioned and the aqueous phase was extracted twice with 10V EA. The organic phases were combined and washed with 10V H₂O wash it three times. The solvent was switched from EA to MeOH. Charged with 0.1 equivalent of Pd (OH)₂C and 2 equivalents of HCl (4M in MeOH). Heating to 45-50 deg.C. The mixture was stirred in R2 at 40 ℃ to 50 ℃. The desired product is obtained from this process. (ESI): m/z 387.0(M +1)

Example 2

Preparation of Y6 Compound (also referred to above as Compound I) from unprotected piperidine-hydrazine (hereinafter Y20)

This example represents a further example of the present invention. Compound Y20 (piperidine-hydrazine; also referred to herein as a compound of formula (III)), compound Y20 corresponds to the general compound X in the 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 admixed with compound Y3 (also referred to in example 1 as compound VI, also a compound of formula (II) as defined herein). The reaction is similar to step 4 in example 1, but unlike in example 1, this example shows that piperidine-hydrazine does not require protection because of the reaction with Y3 (see procedure S-1 below). Indeed, the final product Y4 (also referred to herein as a compound of formula (I) as described above) can be advantageously produced without the need to protect the piperidine-hydrazine (and then subsequently deprotect it). Compound Y4 (which compound Y4 remains unsubstituted at the piperidine N atom) may then be used directly in the next reaction step (i.e., without the addition of a protecting group) in which a mixture comprising Y4 and formamide (or another suitable reagent that achieves the same result as described herein) is allowed to react (see process S-2 below) to form compound Y16 (which compound Y16 is a protected form of the compound of formula (IV) as described herein (or a protected form of compound I as illustrated in example 1, i.e., XIII, but where R is₁represents-C (O) H). With acylation of the N atom of the piperidine (via the-C (O) H group) during the cyclization reaction to give the bicyclic pyrimidine moiety (pyrazolo [3, 4-d)]Pyrimidine), and such groups can be removed by deprotectionDivide (e.g., as shown by process S-3 below).

Process S-1

The reaction process was carried out according to the following procedure

1. In the first reactor, Y20(0.058g, 1.5 equiv.) was dissolved in 0.5mL MeOH

2. NaOMe in MeOH was added dropwise to Y20 to adjust the pH to about 9

3. Y3(1.0 eq.) and 0.45mL MeOH were added to the second reactor

4. Cooling the reaction mixture in the second reactor to 0-10 deg.C

5. A solution of Y20 in MeOH in the first reactor was added dropwise to the reaction mixture in the second reactor at 0-10 deg.C

6. The subsequent reaction mixture was stirred at 20 ℃ to 25 ℃ for 2h

7. Cooling the reaction mixture to 0-10 deg.C

8.2 mL of H2O was added dropwise to the reaction mixture (an off-white solid precipitated)

9. The mixture was filtered and the product was dried under vacuum

Process S-2

1. In N₂The charge Y4 was taken down into the first reactor.

2. Charge 9.6X formamide into the reactor.

3. The mixture was heated to 165-175 ℃.

4. The reaction mixture was stirred at 165-175 ℃ for 2 h.

5. Calculation of ion impact on reagents (IPC) based on LCMS analysis

6. The reaction mixture was cooled to 40 ℃ (solids precipitated).

7. 6V water is added into the reactor

8. The reaction mixture was stirred at 40 ℃ for 0.5 h.

9. The reaction mixture was cooled to 20 ℃ (or around room temperature).

10. The mixture was filtered.

11. The filter cake was dried in vacuo at 40-45 ℃ for 16h

12. Crude yield: 92 percent of

Process S-3

1. In N₂Next, 0.5g of Y16 (material directly obtained from S-2 above) was charged into the first reactor.

2. 0.5mL of 35% HCl (5.0 equiv.) was charged to the first reactor.

3. The mixture was heated to 55-65 ℃.

4. The mixture was stirred in the reactor at 55 ℃ to 65 ℃ (see table below).

5. The effect of the ions on the reagent (IPC) was calculated based on LCMS analysis (see Table below)

6. The reaction mixture was cooled to 20 ℃ (or around room temperature).

7. KOH was added dropwise to the reactor to adjust the pH to 11-13 (solid evolution).

8. The mixture was stirred in the reactor at 20 ℃ for 0.5h

9. The mixture was filtered.

10. The solid was dried in vacuo at 40-45 ℃ for 16 h.

11. Crude yield: 63 percent of

Example-pharmaceutical formulation

Ibrutinib can be formulated into pharmaceutically acceptable formulations using standard procedures.

For example, the present invention provides a process for the preparation of a pharmaceutical formulation comprising ibrutinib or a derivative thereof, such process being characterized in that it comprises as one process step a process as defined above. The skilled person will know that such pharmaceutical formulations will comprise/consist of (e.g. a mixture of active ingredients (i.e. ibrutinib or a derivative thereof) and pharmaceutically acceptable excipients, adjuvants, diluents and/or carriers).

The present invention further provides a process for the preparation of a pharmaceutical formulation comprising ibrutinib (or a derivative thereof), such process comprising the introduction of the relevant ibrutinib, or a pharmaceutically acceptable salt thereof, which may be formed by the process as described above, together with one or more pharmaceutically acceptable excipients, adjuvants, diluents and/or carriers.

Claims (15)

1. A process for the preparation of a compound of formula I,

or a salt thereof, wherein

R¹Represents H, Cbz or Bn;

the method comprises providing a compound of formula II,

or a salt thereof, wherein

X¹Represents a suitable leaving group which is, for example,

with a compound of the formula III,

or a salt thereof, wherein R¹As defined above.

2. A process as claimed in claim 1 for the preparation of a compound of formula I wherein:

in the compounds of formulae I and III, R¹Represents Cbz or Bn;

and/or

In the compound of formula II, X¹represents-OR^3aWherein R is^3aRepresents an alkyl group, such as methyl.

3. A process for the preparation of a compound of formula (IVA), which process comprises a process for the preparation of a compound of formula (I) as defined in claim 1, followed by conversion to a compound of formula (IVA),

or a salt thereof, wherein X²represents-OH or-NH₂And R is¹As defined in claim 1.

4. A process for the preparation of a compound of formula (IV),

or a salt thereof, wherein R¹As defined in claim 1 or claim 2, which comprises a process for the preparation of a compound of formula (I) as claimed in claim 1, followed by reaction with any one of:

(i) carboxamides, i.e. HCONH₂；

(ii) Formamidine or formamidine salt H-C (= NH) -NH₃ ⁺X^-Wherein X is^-Represents a suitable counterion;

(iii) alkyl formimidates, or salts thereof;

(iv) the ethyl orthoformate is followed by ammonium acetate.

5. The method as claimed in claim 4, wherein X in "(ii)"^-Represents halogen or an oxyanion, the alkyl group in "(iii)" being ethyl, the salt in "(iii)" being ethyl formimidate HCl.

6. The method as claimed in claim 5, wherein halogen is Cl^-The oxyanion being acyl-O^-。

7. A process as claimed in claim 4 wherein the formamidine salt is formamidine HCl or formamidine acetate.

8. A process as claimed in claim 3 or claim 4, wherein the reaction is carried out with (ii) a formamidine salt, wherein the counterion is a halogen or oxyanion.

9. The process of any one of claims 3 to 8, wherein the reaction is carried out at a temperature of less than 160 ℃.

10. The method as claimed in claim 9, wherein the reaction is carried out at a temperature between 100 ℃ and 140 ℃.

11. A compound of formula (III) characterized in that it has an ee of greater than 50%

，

Wherein R is¹As defined in claim 1.

12. A process for preparing ibrutinib:

the method comprises any one of the following:

-a process as defined in claim 1 or claim 2 for the preparation of a compound of formula (I), followed by conversion to ibrutinib;

-a process as defined in any one of claims 3 to 10 for the preparation of a compound of formula (IVA) or (IV), followed by conversion into ibrutinib; and/or

-a resolution process for the preparation of a compound of formula (III) as defined in claim 1 or claim 11, followed by conversion to ibrutinib.

13. The process of claim 12, wherein the process for preparing a compound of formula (IVA) or (IV), as defined in any one of claims 3 to 10, is followed by deprotection, i.e. removal of R¹The group, which is subsequently acylated with acryloyl chloride, is converted to ibrutinib.

14. Use of a compound of formula (I), (IVA), (IV) and/or (III) as defined in any one of claims 1, 2, 3 or 11, or a salt thereof, as an intermediate in the preparation of ibrutinib in the process of claim 12.

15. A process for the preparation of a pharmaceutical formulation comprising ibrutinib, the process comprising preparing ibrutinib or a pharmaceutically acceptable salt thereof according to the process of claim 12, combining ibrutinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients, adjuvants, diluents and/or carriers.