U.S. patent application number 14/849015 was filed with the patent office on 2015-12-31 for processes and intermediates for preparing a medicament.
The applicant listed for this patent is Janssen Pharmaceutica NV. Invention is credited to Cyril BEN HAIM, Matteo CONZA, Ioannis Nicolaos HOUPIS, Philip PYE.
Application Number | 20150376193 14/849015 |
Document ID | / |
Family ID | 51529964 |
Filed Date | 2015-12-31 |
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United States Patent
Application |
20150376193 |
Kind Code |
A1 |
PYE; Philip ; et
al. |
December 31, 2015 |
PROCESSES AND INTERMEDIATES FOR PREPARING A MEDICAMENT
Abstract
Disclosed is a process for the preparation of the following
compounds: ##STR00001## where R.sup.1, R.sup.1a and R.sup.2a 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.
Inventors: |
PYE; Philip; (Beerse,
BE) ; BEN HAIM; Cyril; (Beerse, BE) ; CONZA;
Matteo; (Schaffhausen, CH) ; HOUPIS; Ioannis
Nicolaos; (Antwerp, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceutica NV |
Beerse |
|
BE |
|
|
Family ID: |
51529964 |
Appl. No.: |
14/849015 |
Filed: |
September 9, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14203622 |
Mar 11, 2014 |
9156847 |
|
|
14849015 |
|
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|
61786842 |
Mar 15, 2013 |
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Current U.S.
Class: |
514/262.1 ;
544/262; 546/211; 546/223 |
Current CPC
Class: |
C07D 211/56 20130101;
C07D 487/04 20130101; C07D 401/04 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 211/56 20060101 C07D211/56; C07D 401/04 20060101
C07D401/04 |
Claims
1. A process for the preparation of a compound of formula I,
##STR00034## or a derivative thereof, wherein R.sup.1 represents a
nitrogen protecting group; R.sup.1a represents --CN,
--C(O)OR.sup.1b or --C(O)N(R.sup.1c)(R.sup.1d); R.sup.1b, R.sup.1c
and R.sup.1d each independently represent C.sub.1-6 alkyl, aryl or
heteroaryl; R.sup.2a represents: (i) phenyl substituted at the
4-position with halo or --O--R.sup.2b; or (ii) hydrogen; R.sup.2b
represents hydrogen or phenyl; which process comprises reaction of
a compound of formula II, ##STR00035## or a derivative thereof,
wherein R.sup.1a and R.sup.2a are as defined above; X.sup.1
represents a suitable leaving group, with a compound of formula
III, ##STR00036## or a derivative thereof, wherein R.sup.1 is as
defined above.
2. A process for the preparation of a compound of formula I as
claimed in claim 1 wherein the process comprises preparation of the
following compound of formula (I): ##STR00037## or a derivative
thereof, wherein R.sup.1 is as defined in claim 1, which process
comprises reaction of the following compound of formula (II),
##STR00038## or a derivative thereof, with the following compound
of formula III, ##STR00039## or a derivative thereof.
3. A process for the preparation of a compound of formula (IVA),
which process comprises conversion of a compound of formula (I) as
defined in claim 1 to a compound of formula (IVA) (and, in
particular, 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), ##STR00040## or a derivative (including
isomer), wherein X.sup.2 represent --OH or --NH.sub.2, and R.sup.1
and R.sup.2a are as defined in claim 1.
4. A process for the preparation of a compound of formula (IV),
##STR00041## or a derivative thereof, wherein R.sup.1 is as
hereinbefore defined, which process comprises conversion of a
compound of formula (I) as defined in claim 2 by (and, in
particular, comprises a process for the preparation of a compound
of formula (I) as claimed in claim 1 followed by) reaction with
either: (i) formamide (HCONH.sub.2); (ii) formamidine or a
formamidine salt H--C(.dbd.NH)--NH.sub.3.sup.+X.sup.-, wherein
X.sup.- represents a suitable counterion, such as a halide (e.g.
Cl.sup.-) or an oxy anion (e.g. acyl-O.sup.-), 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.
5. A process as claimed in claim 3, wherein 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 5, wherein the reaction
is performed at a temperature of below 160.degree. C., for instance
between 100.degree. C. and 140.degree. C.
7. A compound of formula (III), characterised in that it has an ee
of greater than 50%.
8. A compound of formula (I), (II) or (IVA) (or derivatives
thereof) as defined in claim 1.
9. A process for the preparation of ibrutinib: ##STR00042## which
process comprises either: a process for the preparation of a
compound 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 formula (IVA) or (IV) as defined in any one of claims 2
to 6, followed by conversion to ibrutinib, for example by
deprotection (i.e. removal of the R.sup.1 group) followed by
acylation with acryl chloride; and/or a resolution process for the
preparation of a compound of formula (III) as defined in claim 1,
followed by conversion to ibrutinib.
10. A use of a compound of formula (I), (IVA), (IV) and/or (III)
(or derivatives thereof) as defined in claim 1 as intermediates in
the preparation of ibrutinib.
11. A process for the preparation of a pharmaceutical formulation
comprising ibrutinib, which process comprises bringing into
association ibrutinib (or a pharmaceutically acceptable salt
thereof), which is prepared as claimed in claim 9, with (a)
pharmaceutically acceptable excipient(s), adjuvant(s), diluents(s)
and/or carrier(s).
12. A compound of formula I, ##STR00043## or a derivative thereof,
wherein R.sup.1 represents a nitrogen protecting group; R.sup.1a
represents --CN, --C(O)OR.sup.1b or --C(O)N(R.sup.1c)(R.sup.1d);
R.sup.1b, R.sup.1c and R.sup.1d each independently represent
C.sub.1-6 alkyl, aryl or heteroaryl; R.sup.2a represents: (iii)
phenyl substituted at the 4-position with halo or --O--R.sup.2b; or
(iv) hydrogen; R.sup.2b represents hydrogen or phenyl.
13. A compound as claimed in claim 12 which is represented by the
following compound of formula (I): ##STR00044## or a derivative
thereof.
14. A compound as claimed in claim 13 where R.sup.1 represents Boc,
Bn or CBz.
15. A compound as claimed in claim 14 where R.sup.1 represents Bn
(i.e. "benzyl").
16. A compound of formula III, ##STR00045## or a derivative
thereof, characterised in that it has an ee of greater than 50%;
and wherein R.sup.1 represents a nitrogen protecting group.
17. A compound as claimed in claim 16 wherein R.sup.1 represents
Boc, Bn or Cbz.
18. A compound as claimed in claim 17 wherein R.sup.1 represents Bn
(i.e. "benzyl").
Description
FIELD OF THE INVENTION
[0001] The present invention relates to synthesis procedures and
synthesis intermediates of substituted bicyclic compounds,
especially compounds that are useful as medicaments, for instance
Bruton's tyrosine kinase (Btk) inhibitors such as ibrutinib.
BACKGROUND OF THE INVENTION
[0002] Ibrutinib is an organic small molecule having IUPAC name
1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piper-
idin-1-yl]prop-2-en-1-one. It is described in a number of published
documents, including international patent application WO
2008/039218 (Example 1b), and is described as an irreversible
inhibitor of Btk.
[0003] Btk plays an essential role in the B-cell signaling pathway
linking cell surface B-cell receptor stimulation to downstream
intracellular responses. Btk is a key regulator of B-cell
development, activation, signaling, and survival (Kurosaki, Curr Op
Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm 2000,
282-288). 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-.alpha. production in
macrophages, IgE receptor (FcepsilonRI) signaling in Mast cells,
inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid
cells, and collagen-stimulated platelet aggregation. See e.g., C.
A. Jeffries, et al., (2003), Journal of Biological Chemistry
278:26258-26264; N. J. Horwood, et al., (2003), The Journal of
Experimental Medicine 197:1603-1611; Iwaki et al. (2005), Journal
of Biological Chemistry 280(48):40261-40270; Vassilev et al.
(1999), Journal of Biological Chemistry 274(3):1646-1656, and Quek
et al (1998), Current Biology 8(20):1137-1140.
[0004] Ibrutinib is therefore being studied in Phase II and III
clinical trials for various hematological malignancies such as
chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large
B-cell lymphoma and multiple myeloma.
[0005] There are various processes for preparing functionalised
bicyclic heterocycles, for example as described in US patent
document US 2011/0082137, which includes syntheses to fused
bicycles from pyrazoles and substituted hydrazines.
[0006] Ibrutinib may be prepared in WO 2008/039218 (Example 1b) in
accordance with the following scheme:
##STR00002##
[0007] First,
4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4-d]pyrimidine may be
prepared in accordance with procedures described in WO 2008/039218,
for instance by converting 4-phenoxybenzoic acid to the
corresponding acyl chloride (by using thionyl chloride), which
latter product may be reacted with malononitrile to prepare
1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene. The methoxy moiety
is then methylated using trimethylsilyldiazomethane, and that
methylated product is the 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-pyrazole[3,4-d]pyrimidine, as
illustrated in the following scheme:
##STR00003##
[0008] Thereafter, the
4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4-d]pyrimidine may have
the requisite piperidinyl moiety introduced at the 1H-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 hydroxy moiety of the Boc-protected
3-hydroxypiperidine-1-carboxylate to a better leaving group,
thereby 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.
[0009] 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.
[0010] There is now provided a process for the preparation of a
compound of formula I,
##STR00004##
or a derivative thereof, wherein R.sup.1 represents a nitrogen
protecting group; R.sup.1a represents --CN, --C(O)OR.sup.1b or
--C(O)N(R.sup.1c)(R.sup.1d); R.sup.1b, R.sup.1c and R.sup.1d each
independently represent C.sub.1-6 alkyl, aryl or heteroaryl;
R.sup.2a represents: [0011] (i) phenyl substituted at the
4-position with halo or --O--R.sup.2b; or [0012] (ii) hydrogen;
R.sup.2b represents hydrogen or phenyl; which process comprises
reaction of a compound of formula II,
##STR00005##
[0012] or a derivative thereof, wherein R.sup.1a and R.sup.2a are
as defined above; X.sup.1 represents a suitable leaving group, with
a compound of formula III,
##STR00006##
or a derivative thereof, wherein R.sup.1 is as defined above, which
process is hereinafter referred to as a "process of the
invention".
[0013] In the processes of the invention described herein, 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 chloride salt, although the
hydrazine may be in another salt form). Where appropriate,
"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.
[0014] It is further indicated above that R.sup.1 is a nitrogen
protecting group. Such groups include those that result in the
formation of: [0015] an amide (e.g. N-acetyl) [0016] optionally
substituted N-alkyl (e.g. N-allyl or optionally substituted
N-benzyl) [0017] N-sulfonyl (e.g. optionally substituted
N-benzenesulfonyl) [0018] a carbamate [0019] a urea [0020] trityl
(triphenylmethyl), diphenylmethyl, or the like
[0021] Hence, R.sup.1 may, amongst other groups, represent:
--C(O)R.sup.t1 (in which R.sup.t1 preferably represents C.sub.1-6
alkyl or optionally substituted aryl); C.sub.1-6 alkyl, 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).sub.2.sup.t2 (in which R.sup.t2 preferably
represents optionally substituted aryl); or, preferably,
--C(O)OR.sup.t3 (in which R.sup.t3 preferably represents optionally
substituted aryl or, more preferably, optionally substituted
C.sub.1-6 (e.g. C.sub.1-4 alkyl, e.g. tert-butyl (so forming, for
example, a tert-butoxycarbonyl protecting group, i.e. when taken
together with the amino moiety, a tert-butylcarbamate group) or a
--CH.sub.2phenyl group (so forming a carboxybenzyl protecting
group); --C(O)N(R.sup.t4)R.sup.t5 (in which, preferably, R.sup.t4
and R.sup.t5 independently represent hydrogen, C.sub.1-6 alkyl,
optionally substituted aryl or --C(O)R.sup.t6, and R.sup.t6
represents C.sub.1-6 alkyl or optionally substituted aryl).
[0022] 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 of two) of carbon atoms, be
unsaturated.
[0023] The term "aryl", when used herein, includes C.sub.6-10
groups. Such groups may be monocyclic, bicyclic or tricyclic and,
when polycyclic, be either wholly or partly aromatic. C.sub.6-10
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.
[0024] The term "heteroaryl", when used herein, includes 5- to
14-membered heteroaryl groups containing one or more heteroatoms
selected 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.
[0025] Where mentioned herein, C.sub.1-6 alkyl, aryl and heteroaryl
may be optionally substituted. Such substitution is possible 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
substituted by substituents selected from halo, alkyl and the
like), alkyl, halo, --CN and the like.
[0026] It is indicated that X.sup.1 represents a suitable leaving
group, and in particular may represent chloro, bromo, iodo,
--OR.sup.3a (in which R.sup.3' represents optionally substituted
alkyl, e.g. in which the optional substituent(s) include aryl such
as phenyl, so forming e.g. --OCH.sub.3, --OCH.sub.2-phenyl or the
like) or a sulfonate group (e.g. --O--S(O).sub.2R.sup.4a, in which
R.sup.4a represents optionally substituted alkyl or aryl, so
forming e.g. --OS(O).sub.2CF.sub.3, --OS(O).sub.2CH.sub.3 or
--S(O).sub.2PhMe or the like, i.e. tosyl, mesyl or the like).
[0027] Preferred compounds of formula (I) that may be prepared by a
process of the invention described herein include those in
which:
R.sup.1a represents --CN; R.sup.2a represents phenyl substituted at
the 4-position by --O--R.sup.2b; and/or R.sup.2b represents phenyl;
hence the compound of formula (I) is preferably:
##STR00007##
the compound of formula (II) is preferably:
##STR00008##
wherein, preferably, X.sup.1 represents --OR.sup.3a, in which
R.sup.3a is preferably alkyl, more preferably unsubstituted alkyl
and, most preferably, methyl, so forming a --OCH.sub.3 group; and
hence, most preferably, the compound of formula (II)
represents:
##STR00009##
[0028] For the avoidance of doubt, the compound of formula (III) is
a single enantiomer containing a chiral centre that has an
(R)-configuration. By single enantiomer, 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 greater than 50% ee, e.g. greater than 60% ee. The chirality is
retained in the process of the reaction, i.e. the reaction is
stereospecific, and the compound of formula (I) thereby produced is
also a single enantiomer with the same configuration at the
relevant chiral centre. Downstream synthetic steps will also
proceed with retention of the stereochemistry (unless specified
otherwise).
[0029] Particularly preferred protecting groups that R.sup.1 may
represent include those forming carbamates (especially the
tert-butoxycarbonyl or t-Boc group and the carboxybenzyl or Cbz
group) and substituted alkyl moieties (especially the benzyl
group). Such protecting groups may be more easily introduced onto
the compound of formula (III) and/or ultimately more easily removed
from the relevant nitrogen atom in a downstream step.
[0030] 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 (III). Further
the protecting group R.sup.1 is preferably a non acid-labile
protecting group (e.g. a group labile to base or removable 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 R.sup.2 (e.g. the two are
preferably mutually compatible) as indicated hereinafter.
[0031] In this aspect of the process of the invention, the compound
of formula (III) (or derivative thereof, e.g. di-HCl salt) may be
added to the compounds of formula (II). Preferably less than two
equivalents of the compound of formula (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 compound of formula (II) 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.
[0032] 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 alcoholic solvent (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. Compared 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.
[0033] Preferably, the compound of formula (II) in the presence of
a suitable solvent (as described above) is cooled to below room
temperature, for example to below 10.degree. C., e.g. to about
5.degree. C. The compound of formula (III) (or derivative thereof)
is then added to the mixture of compound of formula (II) and
solvent. Preferably this is done so as to maintain the temperature
of the reaction mixture below room temperature (e.g. at below about
10.degree. C., preferably between 5 and 10.degree. C.). For
instance, this addition may be drop-wise.
[0034] This process aspect of the invention is preferably conducted
in the presence of a base, such as an organic base, preferably 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 (III)), and more
preferably between 1.5 and 2.5 equivalents are employed (e.g. about
two equivalents). Preferably the base is added dropwise, and
preferably the temperature is maintained at below room temperature
(e.g. at below about 10.degree. C., preferably between 5 and
10.degree. C.).
[0035] 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
(during 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 allowed to stir for at least 20
minutes, for example for about one hour, after which further 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.degree. C., preferably about 5.degree. C.
or below, e.g. about 0.degree. C.). The desired product may then
solidify, and may therefore be separated/isolated by filtration. It
may be further purified if required.
[0036] Such an aspect of the process of the invention has several
advantages. 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: [0037] (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); [0038] (ii) the
reaction leads to a 1N-substituted pyrazole and hence downstream
substitution at the 1N-position is circumvented (when substitution
is required at that position), for instance a downstream Mitsunobu
reaction 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 reaction); [0039] (iii)
the use of the expensive chiral 3-hydroxy-N-Boc piperidine is
circumvented; [0040] (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 hydrazine
itself) but however, advantageously and unexpectedly, the reaction
proceeds in a regioselective manner. That is the process of the
invention predominantly results in the formation of a pyrazole with
a substitution pattern as depicted by the compound of formula (I),
i.e. in the 1(N)-position the piperidine, R.sup.2a group (e.g.
4-phenoxy-phenyl) in the 3-position, etc, as opposed to a pyrazole
with the piperidine at the 2-position adjacent the R.sup.2a group.
Advantageously, the desired regioisomer is present in higher
quantity than the undesired regioisomer, and for instance is
present in a ratio of greater than 75:25 compared to the undesired
regioisomer, more particularly, this ratio is greater than 90:10,
and most advantageously there may be a negligible or undetectable
amount of the undesired regioisomer.
[0041] Hence, this aspect of the process of the invention may be
advantageous in terms of economy (e.g. cost of goods), efficiency
and environmental considerations (e.g. less waste).
[0042] After the first process of the invention, the compound of
formula (I) that is prepared may be converted to a compound of
formula (IV),
##STR00010##
or a derivative (including isomer) thereof, wherein R.sup.1 is as
hereinbefore defined.
[0043] In the conversion to the compound of formula (IV), the
compound of formula (I) may first be converted to a compound of
formula (IVA),
##STR00011##
or a derivative (including isomer), wherein X.sup.2 represent --OH
or --NH.sub.2, and R.sup.1 and R.sup.2a are as hereinbefore
defined.
[0044] For instance, for compounds of formula (I) in which R.sup.1a
represents --CN, a corresponding product of formula (IVA) in which
X.sup.2 represents --NH.sub.2 may be produced by reaction with
either: [0045] (i) formamide (HCONH.sub.2); [0046] (ii) formamidine
or a formamidine salt H--C(.dbd.NH)--NH.sub.3.sup.+X.sup.-, wherein
X.sup.- represents a suitable counterion, such as a halide (e.g.
Cl.sup.-) or an oxy anion (e.g. acyl-O.sup.-), so forming for
example formamidine HCl or formamidine acetate or the like; [0047]
(iii) alkyl (e.g. ethyl) formimidate, or a salt thereof, such as
ethyl formimidate HCl; [0048] (iv) ethylorthoformate followed by
ammonium acetate.
[0049] For compounds of formula (I) in which R.sup.1a represents
--C(O)OR.sup.1b or --C(O)N(R.sup.1c)(R.sup.1d), a corresponding
product of formula (IVA) in which X.sup.2 represents --OH (or a
tautomer thereof, as depicted by formula (IVB) below) may be
produced by reaction with for example, CH(OEt).sub.3 optionally in
the presence of a catalyst (e.g. ZnCl.sub.2, 0.1 equiv), followed
by the addition of e.g. NH.sub.4OAc, which reaction may be
performed in the presence of a suitable solvent (e.g. an aromatic
solvent such as toluene):
##STR00012##
[0050] Thereafter, compounds of formula (IVA) in which X.sup.2
represents --OH (or the tautomer, i.e. compound (IVB) depicted
above) may be converted to corresponding compounds of formula (IVA)
in which X.sup.2 represents --NH.sub.2, by first converting to the
corresponding chlorinated derivative (which need not be isolated)
followed by a nucelophilic aromatic substitution to provide the
desired compound, conditions including the use of POCl.sub.3 (or
another suitable chlorinating reagent) followed by reaction with
NH.sub.4OAc (or another suitable source of ammonia).
[0051] For compounds of formula (IVA) in which R.sup.2a represents
hydrogen, such a compound may be converted to a compound of formula
(IVC):
##STR00013##
wherein X.sup.2 is as hereinbefore defined, and X.sup.3 is a
suitable group such as halo (e.g. bromo, chloro or preferably,
iodo), which reaction may take place in the presence of a source of
halide, for instance an electrophile that provides a source of
iodine includes iodine, diiodoethane, or preferably,
N-iodosuccinimide, and sources of bromide and chloride include
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).
[0052] Compounds of formula (IVC), in particular those in which
X.sup.2 represents --NH.sub.2, may be converted to compounds of
formula (IVA) in which R.sup.2a represents phenyl substituted at
the 4-position with halo or --OR.sup.2b, by reaction of the
compound of formula (IVC) with a compound of formula (IVD):
X.sup.4--R.sup.2aa (IVD)
wherein R.sup.2aa represents phenyl substituted at the 4-position
with halo or --OR.sup.2b (with R.sup.2b as hereinbefore defined),
and wherein X.sup.4 represents a suitable group such as
--B(OH).sub.2, --B(OR.sup.w).sub.2 or --Sn(R.sup.w).sub.3, in which
each R.sup.w independently represents a C.sub.1-6 alkyl group, or,
in the case of --B(OR.sup.w).sub.2, the respective R.sup.w groups
may be linked together to form a 4- to 6-membered cyclic group
(such as a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group,
thereby forming e.g. a pinacolato boronate group), and wherein the
coupling reaction may be performed 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).sub.2, Pd(Ph.sub.3P).sub.2Cl.sub.2,
Pd(Ph.sub.3P).sub.4, Pd.sub.2(dba).sub.3 and/or NiCl.sub.2
(preferred catalysts include palladium) and a ligand such as
PdCl.sub.2(dppf).DCM, t-Bu.sub.3P or the like, optionally in the
presence of a suitable base (e.g. a carbonate base, hydroxide base,
etc) and a suitable solvent.
[0053] Where, e.g. for compounds of formula (IVA) as defined above
in which X.sup.2 represents --NH.sub.2 (or a protected derivative
thereof) and R.sup.2a represents phenyl substituted at the
4-position by halo or --OH, then conversion to the compound of
formula (IV) may be possible by a coupling reaction with
X.sup.4-phenyl-O-phenyl or X.sup.4-phenyl, for instance using
similar catalytic coupling reactions to those mentioned above.
[0054] Hence, ultimately compounds of formula (IV) may be prepared
according to the processes mentioned above.
[0055] The processes discussed above (including those to prepare
compounds of formula (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".
[0056] 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 followed by a process for the conversion of (I) to (IV) as
hereinbefore described.
[0057] 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 defined 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 formamide,
the latter being using in prior processes at high temperatures
(e.g. at about 165.degree. C., which represents a thermal hazard),
whereas the use of the formamidine salt allows lower temperatures
to be employed.
[0058] 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 formula (I) employed (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 equivalents).
[0059] This aspect of the process 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-methyl-2-pyrrolidone, or the like. Glycols ethers may be
particularly preferred (e.g. due to high boiling points), and a
particularly preferred solvent is therefore ethylene glycol
monoethyl ether. The solvent is preferably de-gassed and the
reaction is preferably carried out under an inert atmosphere. More
than five volume equivalents of solvent is employed (e.g. more than
ten, and preferably around 13).
[0060] The resultant reaction mixture is then preferably heated to
above room temperature, e.g. to above 40.degree. C., e.g. above
60.degree. C. such as above 80.degree. C. Most preferably it is
heated to above 100.degree. C. However, the temperature of the
reaction mixture is preferably below 160.degree. C., for instance
the preferred temperature range is between 100.degree. C. and
140.degree. C., most preferably between about 110.degree. C. and
130.degree. C. (e.g. about 120.degree. C.).
[0061] 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
compound.
[0062] 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. protected derivative, thereof), which may be
performed by means of chiral chromatography (e.g. using chiral
SFC), thereby advantageously obtaining a compound 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 possible to
purify downstream so as to provide an enantiomerically pure
downstream compound.
[0063] Advantageously, this may produce product (compound (III)) in
greater than 50% ee, for instance greater than 60% ee. Introducing
the chirality 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 circumventing the undesired Mitsunobu reaction prior disclosed
in a process for preparing ibrutinib.
[0064] Compounds of formula (III), or protected derivatives thereof
may be prepared by reaction of a compound of formula (VI),
##STR00014##
or a derivative thereof, wherein R.sup.1 is as hereinbefore
defined, with a compound of formula (VII),
R.sup.2--N(H)--NH.sub.2 (VII)
wherein R.sup.2 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 presence of a suitable solvent.
[0065] In general, the protection and deprotection of functional
groups may take place before or after any of the reaction steps
described hereinbefore.
[0066] Protecting groups may be removed in accordance with
techniques which are well known to those skilled in the art and as
described hereinafter.
[0067] 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",
3.sup.rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience
(1999).
[0068] 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:
##STR00015##
[0069] For instance, for compounds of formula (II) in which X.sup.1
represents an alkoxy leaving group --OR.sup.3a (or sulfonate), then
such a compound may be prepared by alkylation (e.g. methylation)
(or appropriate sulfonylation) of a compound corresponding to a
compound of formula (II) but in which --OR.sup.3a represents --OH.
Conversion of the --OH to other suitable leaving groups (e.g. to
halo) may also be effected.
[0070] Compounds corresponding to formula (II) but in which
--OR.sup.3a represents --OH may be prepared by reaction of a
compound of formula (VIII),
R.sup.2a--C(O)X.sup.1a (VIII)
wherein X.sup.1a represents a suitable leaving group (e.g. chloro)
and R.sup.2a is as hereinbefore defined, with a compound of formula
(IX),
NC--CH.sub.2--R.sup.1a (IX)
wherein R.sup.1a is as hereinbefore defined, under suitable
reaction conditions.
[0071] Some compounds described herein may be novel themselves, and
hence in a further aspect of the invention, there is provided:
[0072] a compound of formula (I) or a derivative thereof [0073] a
compound of formula (III) or a derivative thereof, for instance in
at least greater than 50% ee [0074] a compound of formula (II),
(IV) or (IVA) or a derivative thereof
[0075] In an embodiment of the invention, there is provided a
process for the preparation of ibrutinib:
##STR00016##
which process comprises a process as defined herein, followed by
conversion to ibrutinib, for example: [0076] a process for the
preparation of a compound of formula (I) as herein described,
followed by conversion to ibrutinib [0077] a process for the
preparation of a compound of formula (IV) or (IVA) as herein
described, followed by conversion to ibrutinib, for example by
deprotection (i.e. removal of the R.sup.1 group) followed by
acylation with acryl chloride [0078] a process for the preparation
of a compound of formula (III) as hereinbefore described, followed
by conversion to ibrutinib, for example in accordance with the
procedures described herein
[0079] Hence, there is also provided the use of certain compounds
(e.g. the use of a compound of formula (I), (IV), (IVA) and/or
(III)) as intermediates in the preparation of ibrutinib.
[0080] There is then further provided a process for the preparation
of a pharmaceutical formulation comprising ibrutinib, which process
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 excipient(s), adjuvant(s), diluents(s)
and/or carrier(s).
[0081] 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.
[0082] The process 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 disclosed in the prior art. Furthermore, there may be
several environmental benefits of the process of the invention.
EXAMPLES
[0083] The following examples are intended to illustrate the
present invention and should not be construed as a limitation of
the scope of the present invention.
Experimental Section
[0084] 1 Prepare I from XI with Cbz protecting group
[0085] The synthesis route from XIV-Cbz to I has been performed in
the laboratory with the total yield of .about.50%. Structure of I
from this route has been confirmed by comparing HPLC, HNMR and CNMR
with reference standard I.
##STR00017## ##STR00018##
[0086] 100 g (1.0 eq.) of XIV-Cbz and 56.66 g (1.0 eq.)
Boc-NHNH.sub.2 was dissolved in 500 mL solvent (methanol, 5.0 V),
Na.sub.2SO.sub.4 was added and the mixture was stirred for 4 h at
28.degree. C. The solvent was evaporated by reduce pressure to get
148 g of XV-Cbz as a yellow oil. MS (ESI): m/z=370 (M+23(Na))
##STR00019##
[0087] 45.8 g (1.0 eq.) of XIV-Boc and 38.2 g (1.0 eq.)
Cbz-NHNH.sub.2 was dissolved in 230 mL solvent (methanol, 5.0 V),
the mixture was stirred for 2 h at 28.degree. C. The solvent was
evaporated by reduce pressure to get 78 g of XV-Boc as a yellow
oil. MS (ESI): m/z=370 (M+23 (Na))
##STR00020##
[0088] 100 g (1.0 eq.) of XIV-Bn.HCl.H.sub.2O/Bn and 54.22 g (1.0
eq.) Boc-NHNH.sub.2 was dissolved in 500 mL solvent (methanol, 5.0
V), Na.sub.2SO.sub.4 was added and the mixture was stirred for 2 h
at 25.degree. C. The solvent was evaporated by reduce pressure to
get 122 g of XV-Bn as orange foam. MS (ESI): m/z=304 (M+1)
##STR00021##
[0089] 33.11 g (1.0 eq) of XV-Cbz was dissolved in 160 mL of MeOH,
cool 5.degree. C. and stirred under nitrogen. 2.0 eq. NaBH.sub.3CN
was then added to the reaction mixture. Then, 1.0 eq of AcOH was
added dropwise and stirred at 5.degree. C. under nitrogen for 3 h.
The reaction mixture was stirred for another 3.5 h at 25.degree.
C., cooled to 10.degree. C., and then saturated aq.NH4Cl was added
dropwise until pH.about.6. (A lot of white solid separated out).
The mixture was filtered and the solid washed with H.sub.2O. The
cake was dried under vacuum at 45-50.degree. C. for 16 hrs and
isolated in 81.1% yield. MS (ESI): m/z=372 (M+23(Na))
##STR00022##
[0090] 28.4 g (1.0 eq) of XV-BOC was dissolved in 145 mL of THF and
30 mL of MeOH, cool 5.degree. C. and stirred under nitrogen. 6.18 g
(2.0 eq) of NaBH.sub.4 was then added to the reaction mixture and
stir at 5.degree. C. under nitrogen for 3 h. It was allowed to stir
for another 15 h at 20.degree. C. 15% aq. NH.sub.4Cl was added
dropwise until pH-6-7. Then 10V of Ethyl acetate was charged/added
into the mixture. The phase was separated, and the aqueous was
extracted twice with 8V of ethyl acetate. 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.degree. 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.degree. C. 25
g of XVI-Boc was obtained with 97.54% HPLC purity in the yield of
87.7%.
##STR00023##
[0091] A MeOH solution of XV-Bn (37.6 g in 130 mL MeOH) was cooled
to 5.degree. C. under N.sub.2. 2.0 eq. NaBH.sub.3CN was charged
under N.sub.2 keeping the temperature at 5-10.degree. C. 1.0 eq of
AcOH was added dropwise at 5-10.degree. C. The mixture was warmed
to 25.degree. C. and stirred under N.sub.2 for 16 h. The reaction
mixture was cooled to 10.degree. C. Saturated aq.NH4Cl was added
dropwise into R1 to pH.about.6. The mixture was concentrated under
vacuum and then aqueous phase was extracted with EA (100 ml*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.degree. C. for 16 hrs to get 23 g XVI-Bn as white solid 97.9%
purity. MS (ESI): m/z=306 (M+1)
##STR00024##
[0092] 16.12 g (1.0 eq.) XVI-Cbz was charged with 80 mL of
methanol. 92.2 mL MeOH solution of HCl (4M) was charged and stirred
for 3 h at 28.degree. C. MeOH was switched to EtOAc (a lot of white
solid separated out). The solid was filtered under N.sub.2
protection. The filter cake was dried under vacuum at 35-40.degree.
C. for 16 hrs to result in 11.9 g (80.2% Yield) with a purity of
94.97%. (ESI): m/z=249.9 (M+1)
##STR00025##
[0093] Pd(OH).sub.2/C was used as catalyst and 2.0 eq 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, 3.9 g of X-Boc was obtained as foam in the yield
of 79.6%.
[0094] 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
34.36 mL (2.0 eq) of MeOH solution of HCl (1M), stir for 1 h at
28.degree. C. under N.sub.2. Switch the solvent to EtOAc to
separate the product out. Transfer the mother liquor out and dry
the residue under vacuum to get 3.9 g of X-Boc as white foam (79.6%
Yield). (ESI): m/z=216.0 (M+1)
##STR00026##
[0095] Charge 20 g (1.0 eq) of XVI-Bn under N.sub.2, add 11 eq. HCl
MeOH solution (4M) into R1 under N.sub.2 at 20-25.degree. C. and
stir at 50.degree. C. for 2 h. Switch the solvent to EtOAc and then
a lot of white solid separated out. Filter the mixture under
N.sub.2 protection. The solid was dried under vacuum at
45-50.degree. C. to yield 14 g of X-Bn (76.9% Yield).
##STR00027##
[0096] Charge 4.29 g (1.0 eq.) of VI under N.sub.2 with 60 mL (13
V.) ethanol and 43 ml (10V) of water. Cool the mixture to 5.degree.
C. Add X-Cbz in three portions at 5-10.degree. C. under N.sub.2.
Add dropwise 3.15 g (2.0. eq.) NEt.sub.3 at 5-10.degree. C. Warm to
25.degree. C. under N2 and stir for 1 h at 25.degree. C. (solid
separate out). Add dropwise 17V H.sub.2O into the reaction mixture
at 25.degree. C. Cool the reaction mixture 0-5.degree. C. and stir
for 1 h. Filter the mixture. The cake was dried under vacuum at
40-45.degree. C. to result in 7.79 g (100% Yield) with a purity of
99.81% (ESI): m/z=494.1 (M+1)
##STR00028##
[0097] 3 g (1.0 eq) of XI-Cbz was mixed with 9.5 g (15.0 eq) of
formamidine acetate and 40 mL (13V) C.sub.2H.sub.5OC.sub.2H.sub.4OH
(degassed), the reaction mixture was stirred at 120.degree. C. for
6 hrs, Cool the reaction mixture to r.t. Add dropwise H.sub.2O
(13V) and EA (15V). Separate the mixture and extract the aqueous
phase with EA fro twice. Combine the organic phase and wash it with
H.sub.2O twice. Evaporate solvent under vacuum to get crude
XIII-Cbz as yellow oil in 97.9% purity. (ESI): m/z=521.4 (M+1)
##STR00029##
[0098] 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.
[0099] Procedure: Charge 4.29 g (1.0 eq.) VI under N2 with 10 mL
(16.6 V.) ethanol and 6 ml (10V.) Cool R1 to 5-10.degree. C. Add
0.7 g (1.0. eq.) X-Cbz solution in water was added drop-wise over
15 min at 5-10.degree. C. Add 0.45 g (2.0. eq.) NEt.sub.3 drop-wise
over 5 min at 5-10.degree. C. Warm to 20.about.30.degree. C. under
N.sub.2 and stir R1 for 1 h at 20.about.30.degree. C. Add 10V EA
and then 10V H2O into the reaction mixture. Separate the mixture
and extract the aqueous phase with 10V EA twice. Combine the
organic phase and wash with 10V H2O. Switch the solvent to 13V
EtOEtOH. Add 15 eq formamidine acetate into the mixture. Heat to
120.degree. C. and stir for 5 hrs at 120.degree. C. Cool the
mixture to r.t. and add 15V EA and 15V H2O into the mixture.
Separate the mixture and extract the aqueous phase with 10V EA
twice. Combine the organic phase and wash with 10V H2O twice.
Switch the solvent to 10V MeOH. Add Pd(OH2)/C (0.3 eq) and stir the
mixture at 55-60.degree. C. under 3 Bar H.sub.2. 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.degree. C. to obtain I in 80%
yield (over 3 steps) in 92.5% purity.
[0100] 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.
##STR00030##
[0101] Charge 0.41 g (1.0 eq.) of VI (in THF solution). Dissolve
0.32 g (1.0 eq.) of X-Boc in EtOH (2V)/H2O (0.5 mL, 1.5V)/Et3N (3.0
eq). Add drop-wise X-Boc to R1 at 5-10.degree. C. Warm to
25.degree. C. under N2 and stir R1 for 1 h at 25.degree. C. Add
water (10V) drop-wise at 5-10.degree. C. Concentrate the mixture
under vacuum and extract it with ethyl acetate (20 ml*3). Wash the
organic phase with H2O. Evaporate solvent under vacuum to get crude
XI-Boc as yellow oil. The de-Boc compound, Imp-A, was generated as
the main product. XI-Boc was obtained in 29% yield with 96% purity
by column chromatography
##STR00031##
[0102] Charge XI-Boc (0.3 g, 1.0 eq.) at r.t under N2. Charge
formamidine acetate (15 eq) into R1 under N2. Charge
C.sub.2H.sub.5OC.sub.2H.sub.4OH (13V) into R1 under N2. Heat to
120.degree. C. (inter temp) and stir the mixture at 120.degree. C.
for 8 hrs. In this reaction mixture, 4.3% of Imp-B also could be
observed. Cool the reaction mixture to r.t. Add dropwise H.sub.2O
(40 mL, 13V) and EA (15V). Separate the mixture and extract the
aqueous phase with EA twice. Combine the organic phase and switch
the solvent to MeOH. Add HCl (10 eq, MeOH solution) into the
mixture. Heat to 50.degree. C. and stir for 3 hrs. Cool to r.t,
concentrate the reaction mixture to 2-3 mL. Add 3 mL H2O and then
add dropwise 30% aq. NaOH to adjust pH to 10. Filter the mixture
and dry the cake under vacuum at 45.degree. C. I could be isolated
by crystallization form MeOH/H.sub.2O with 95.6% purity in the
total yield of 87.3%
[0103] 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-Boc to I is an available
working route.
##STR00032##
[0104] Charge 0.496 g (1.0 eq.) of VI under N2 with 4 mL (8V.)
ethanol. Cool the mixture to 5.degree. C. Add X-Bn (dissolve in 5V
EtOH and 10V H.sub.2O) in three portions at 5-10.degree. C. under
N2. Add dropwise 0.51 g (2.0. eq.) NEt.sub.3 at 5-10.degree. C.
Warm to 25-30.degree. C. under N2 and stir for 1 h at 25-30.degree.
C. (solid separate out). Add dropwise 17V H.sub.2O into the
reaction mixture at 25.degree. C. Cool the reaction mixture
0-5.degree. C. and stir for 1 h. Filter the mixture. The cake was
dried under vacuum at 40-45.degree. C. to yield 0.65 g of XI-Bn
(80% Yield) with 94.03% purity. (ESI): m/z=450 (M+1)
##STR00033##
[0105] One batch to prepare XIII-Bn was carried out from 1.72 g
XI-Bn. In the first ring closure step, Conversion of XI-Bn was 100%
and XIII-Bn was generated with 99.12% LCMS purity. Even been
stirred for 21 hrs at 120.degree. C., no decomposition could be
observed. In the second step, we tried two conditions. One added 2
eq 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%. Procedure: Charge XI-Bn at r.t with
formamidine acetate (15 eq) and C.sub.2H.sub.5OC.sub.2H.sub.4OH
(13V) under N2. Heat to 120.degree. C. and stir the mixture at
120.degree. C. for 8 hrs. Cool the reaction mixture 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 H.sub.2O for three times. Switch the solvent
to MeOH from EA. Charge 0.1 eq Pd(OH)2/C and 2 eq HCl (4M MeOH
solution). Heat to 45-50.degree. C. Stir the mixture in R2 at
40-50.degree. C. The desired product was obtained from this
procedure. (ESI): m/z=387.0 (M+1)
EXAMPLE
Pharmaceutical Formulation
[0106] Ibrutinib may be formulated into a pharmaceutically
acceptable formulation using standard procedures.
[0107] For example, there is provided a process for preparing a
pharmaceutical formulation comprising ibrutinib, or a derivative
thereof, which process 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).
[0108] There is further provided a process for the preparation of a
pharmaceutical formulation comprising ibrutinib (or a derivative
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), adjuvant(s), diluent(s)
and/or carrier(s).
* * * * *