U.S. patent application number 15/958645 was filed with the patent office on 2018-11-01 for processes for making alkylated arylpiperazine and alkylated arylpiperidine compounds including novel intermediates.
The applicant listed for this patent is Johnson Matthey Public Limited Company. Invention is credited to Steven COLLIER, Daniel J. COUGHLIN, Da-Ming GOU, Jeremy C. WILT.
Application Number | 20180312530 15/958645 |
Document ID | / |
Family ID | 54835598 |
Filed Date | 2018-11-01 |
United States Patent
Application |
20180312530 |
Kind Code |
A1 |
COUGHLIN; Daniel J. ; et
al. |
November 1, 2018 |
PROCESSES FOR MAKING ALKYLATED ARYLPIPERAZINE AND ALKYLATED
ARYLPIPERIDINE COMPOUNDS INCLUDING NOVEL INTERMEDIATES
Abstract
Novel processes, and intermediates, for making alkylated
arylpiperazine and alkylated arylpiperidine compounds of the
general formulas (I) and (VII), respectively ##STR00001## wherein,
R.sub.1 and R.sub.2 are individually selected from hydrogen, alkyl,
substituted or alkyl; n=0, 1, or 2; Y=NR.sub.3R.sub.4, OR.sub.5, or
SR.sub.5, where R.sub.3 and R.sub.4 are individually selected from
acyl or sulfonyl, and where R.sub.5 is aryl or heteroaryl, or
heterocyclic; and Ar is an aryl, heteroaryl, or heterocyclic
compound.
Inventors: |
COUGHLIN; Daniel J.;
(Paulsboro, NJ) ; WILT; Jeremy C.; (Devens,
MA) ; GOU; Da-Ming; (Burlington, MA) ;
COLLIER; Steven; (Devens, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Johnson Matthey Public Limited Company |
London |
|
GB |
|
|
Family ID: |
54835598 |
Appl. No.: |
15/958645 |
Filed: |
April 20, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15784585 |
Oct 16, 2017 |
9957283 |
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15958645 |
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14737599 |
Jun 12, 2015 |
9790237 |
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15784585 |
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62012701 |
Jun 16, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 215/227 20130101;
C07D 417/12 20130101; C07D 417/08 20130101; C07D 519/00 20130101;
C07C 39/00 20130101; C07D 413/14 20130101; C07D 275/06 20130101;
C07D 311/06 20130101; C07D 413/04 20130101; C07D 209/52 20130101;
C07D 413/12 20130101; C07D 471/12 20130101; C07D 215/22 20130101;
C07D 403/12 20130101; C07D 209/56 20130101; C07D 311/20 20130101;
C07D 239/88 20130101; C07D 241/04 20130101; C07D 487/12 20130101;
C07D 401/12 20130101; C07D 261/20 20130101 |
International
Class: |
C07D 519/00 20060101
C07D519/00; C07D 241/04 20060101 C07D241/04; C07D 209/56 20060101
C07D209/56; C07D 401/12 20060101 C07D401/12; C07D 275/06 20060101
C07D275/06; C07D 215/227 20060101 C07D215/227; C07D 417/08 20060101
C07D417/08; C07D 417/12 20060101 C07D417/12; C07D 261/20 20060101
C07D261/20; C07D 413/12 20060101 C07D413/12; C07D 403/12 20060101
C07D403/12; C07D 311/06 20060101 C07D311/06; C07D 215/22 20060101
C07D215/22; C07D 471/12 20060101 C07D471/12; C07D 413/04 20060101
C07D413/04; C07D 487/12 20060101 C07D487/12; C07C 39/00 20060101
C07C039/00; C07D 209/52 20060101 C07D209/52; C07D 239/88 20060101
C07D239/88; C07D 311/20 20060101 C07D311/20 |
Claims
1-14. (canceled)
15. A method of preparing a 6-fluoro-3-[1-(3-substituted
propyl)piperidin-4-yl]-1,2-benzoxazole of the following formula
##STR00080## comprising (i) alkylating 1,3,2-dioxathiane
2,2-dioxide having the formula ##STR00081## with a phenolic
compound of the formula ##STR00082## in the presence of base
selected from potassium carbonate, sodium carbonate, magnesium
carbonate, calcium carbonate, potassium hydroxide, sodium
hydroxide, magnesium hydroxide or calcium hydroxide, to form the
corresponding alkylation compound of the formula ##STR00083##
wherein Q is potassium, sodium, magnesium or calcium; (ii)
hydrolyzing the alkylation compound of step (i) with aqueous acid
to obtain the corresponding hydroxyl compound of formula
##STR00084## (iii) converting the compound of formula ##STR00085##
of step (ii) to the corresponding alkylating agent compound of
formula ##STR00086## wherein LG is selected from the group
consisting of aryl sulfonate or alkyl sulfonate; and (iv)
alkylating the compound of formula ##STR00087## of step (iii) with
the compound of formula ##STR00088## in the presence of a base
selected from potassium carbonate, sodium carbonate, magnesium
carbonate, calcium carbonate, potassium hydroxide, sodium
hydroxide, magnesium hydroxide or calcium hydroxide.
16. The process of claim 1 wherein the base of steps (i) and (iv)
is potassium carbonate.
17. The process of claim 1 wherein LG is methylsulfonate.
18. The process of claim 1 wherein Y is ##STR00089##
19. The process of claim 1 wherein Y is ##STR00090##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority of U.S. Provisional Patent
Application No. 62/012,701, filed Jun. 16, 2014, the disclosures of
which are incorporated herein by reference in their entireties for
all purposes.
FIELD OF THE INVENTION
[0002] The present disclosure provides processes for making
alkylated arylpiperazine and alkylated arylpiperidine compounds as
well as novel intermediate compounds formed during those
processes.
BACKGROUND OF THE INVENTION
[0003] The piperazines are a broad class of chemical compounds,
many with important pharmacological properties, which contain a
core piperazine functional group. Many currently notable
pharmaceutical drugs contain a piperazine ring as part of their
molecular structure. Examples include: antianginals (ranolazine,
trimetazidine); antidepressants (amoxapine, befuraline, buspirone,
flesinoxan, gepirone, ipsapirone, nefazodone, piberaline,
tandospirone, trazodone, vilazodone, zalospirone); antihistamines
(buclizine, meclozine, cinnarizine, cyclizine, hydroxyzine,
cetirizine, levocetirizine, niaprazine); antipsychotics
(fluphenazine, perphenazine, trifluoperazine, prochlorperazine,
thiothixene, flupentixol, zuclopenthixol, amperozide, aripiprazole,
lurasidone, clozapine, olanzapine, perospirone, ziprasidone);
urologicals (sildenafil, vardenafil).
[0004] Piperidine is also widely used building block and chemical
reagent in the synthesis of organic compounds, including
pharmaceuticals. Similar to piperazine, piperidine and its
derivatives are ubiquitous building blocks in the synthesis of
pharmaceuticals and fine chemicals. For example, the piperidine
structure is found in the following classes of pharmaceuticals:
SSRI (selective serotonin reuptake inhibitors) (paroxetine);
analeptics/nootropics (stimulants) (methylphenidate,
ethylphenidate, pipradrol, desoxypipradrol); SERM (selective
estrogen receptor modulators) (raloxifene); vasodilators
(minoxidil); neuroleptics (antipsychotics) (risperidone,
thioridazine, haloperidol, droperidol, mesoridazine); opioids
(pethidine, meperidine, loperamide).
[0005] Considering their prevalence in the formation of a variety
of important pharmaceutical compounds, there is a need for new and
improved processes for making both piperazine and piperidine
compounds, including intermediates and derivatives thereof, that
minimizes the formation of unwanted by-products and eliminates the
need for additional purification steps where product is lost.
SUMMARY OF THE INVENTION
[0006] The present disclosure provides processes for making
alkylated arylpiperazine and alkylated arylpiperidine compounds,
including intermediates and derivatives thereof. More specifically,
the present invention provides processes for making a variety of
alkylated arylpiperazine and alkylated arylpiperidine compounds of
the general formulas (I) and (VII), respectively,
##STR00002##
wherein, R.sub.1 and R.sub.2 are individually selected from
hydrogen, unsubstituted alkyl, and substituted alkyl, or R.sub.1
and R.sub.2 are connected to form a 5 to 8 carbon cyclic ring; n is
0, 1, or 2; Y is NR.sub.3R.sub.4, OR.sub.5, or SR.sub.5, where
R.sub.3 and R.sub.4 are individually selected from acyl or
sulfonyl, wherein R.sub.3 and R.sub.4 may be connected to form a
substituted or unsubstituted cyclic or bicyclic ring, and wherein
R.sub.5 is aryl or heteroaryl, or heterocyclic; and Ar is an aryl
or heteroaryl group.
[0007] Novel intermediate compounds, made during the processes
described and claimed herein, are also disclosed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] No drawings.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0009] Unless otherwise stated, the following terms used in this
Application, including the specification and claims, have the
definitions given below. It must be noted that, as used in the
specification and the appended claims, the singular forms "a",
"an," and "the" include plural referents unless the context clearly
dictates otherwise.
[0010] All numerical designations, such as, weight, pH,
temperature, time, concentration, and molecular weight, including
ranges, are approximations which are varied by 10%. It is to be
understood, although not always explicitly stated, that all
numerical designations are preceded by the term "about." It also is
to be understood, although not always explicitly stated, that the
reagents described herein are merely exemplary and that equivalents
of such are known in the art.
[0011] In reference to the present disclosure, the technical and
scientific terms used in the descriptions herein will have the
meanings commonly understood by one of ordinary skill in the art,
unless specifically defined otherwise. Accordingly, the following
terms are intended to have the following meanings.
[0012] Compounds described herein can comprise one or more
asymmetric centers, and thus can exist in various isomeric forms,
e.g., enantiomers and/or diastereomers. For example, the compounds
described herein can be in the form of an individual enantiomer,
diastereomer or geometric isomer, or can be in the form of a
mixture of stereoisomers, including racemic mixtures and mixtures
enriched in one or more stereoisomer. Isomers can be isolated from
mixtures by methods known to those skilled in the art, including
chiral high pressure liquid chromatography (HPLC) and the formation
and crystallization of chiral salts; or preferred isomers can be
prepared by asymmetric syntheses. The invention additionally
encompasses compounds described herein as individual isomers
substantially free of other isomers, and alternatively, as mixtures
of various isomers.
[0013] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5,
C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4,
C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5,
and C.sub.5-6 alkyl.
[0014] As used herein, the term "alkyl" means the monovalent linear
or branched saturated hydrocarbon moiety, consisting solely of
carbon and hydrogen atoms, having from one to twelve carbon atoms.
"Lower alkyl" refers to an alkyl group of one to six carbon atoms,
i.e., C.sub.1-C.sub.6 alkyl. Examples of alkyl groups include, but
are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the
like. "Branched alkyl" means, for example, isopropyl, isobutyl, and
tert-butyl. Specifically included within the definition of "alkyl"
are those aliphatic hydrocarbon chains that are optionally
substituted.
[0015] As used herein, the term "alkylene" means a linear saturated
divalent hydrocarbon radical of one to six carbon atoms or a
branched saturated divalent hydrocarbon radical of three to six
carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene,
propylene, 2-methylpropylene, butylene, pentylene, and the
like.
[0016] As used herein, the term "aryl" refers to a radical of a
monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2
aromatic ring system (e.g., having 6, 10, or 14 .pi. electrons
shared in a cyclic array) having 6-14 ring carbon atoms and zero
heteroatoms provided in the aromatic ring system ("C.sub.6-14
aryl"). In some embodiments, an aryl group has six ring carbon
atoms ("C.sub.6 aryl"; e.g., phenyl). In some embodiments, an aryl
group has ten ring carbon atoms ("C.sub.10 aryl"; e.g., naphthyl
such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl
group has fourteen ring carbon atoms ("C.sub.14 aryl"; e.g.,
anthracyl). "Aryl" also includes ring systems wherein the aryl
ring, as defined above, is fused with one or more carbocyclic or
heterocyclic groups wherein the radical or point of attachment is
on the aryl ring, and in such instances, the number of carbon atoms
continue to designate the number of carbon atoms in the aryl ring
system. Typical aryl groups include, but are not limited to, groups
derived from aceanthrylene, acenaphthylene, acephenanthrylene,
anthracene, azulene, benzene, chrysene, coronene, fluoranthene,
fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,
indane, indene, naphthalene, octacene, octaphene, octalene,
ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene,
perylene, phenalene, phenanthrene, picene, pleiadene, pyrene,
pyranthrene, rubicene, triphenylene, and trinaphthalene.
Particularly aryl groups include phenyl, naphthyl, indenyl, and
tetrahydronaphthyl. Unless otherwise specified, each instance of an
aryl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted aryl") or substituted (a
"substituted aryl") with one or more substituents. In certain
embodiments, the aryl group is unsubstituted C.sub.6-14 aryl. In
certain embodiments, the aryl group is substituted C.sub.6-14
aryl.
[0017] As used herein, the term "heteroaryl" refers to a radical of
a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system
(e.g., having 6 or 10 .pi. electrons shared in a cyclic array)
having ring carbon atoms and 1-4 ring heteroatoms provided in the
aromatic ring system, wherein each heteroatom is independently
selected from nitrogen, oxygen and sulfur ("5-10 membered
heteroaryl"). In heteroaryl groups that contain one or more
nitrogen atoms, the point of attachment can be a carbon or nitrogen
atom, as valency permits. Heteroaryl bicyclic ring systems can
include one or more heteroatoms in one or both rings. "Heteroaryl"
includes ring systems wherein the heteroaryl ring, as defined
above, is fused with one or more carbocyclic or heterocyclic groups
wherein the point of attachment is on the heteroaryl ring, and in
such instances, the number of ring members continue to designate
the number of ring members in the heteroaryl ring system.
"Heteroaryl" also includes ring systems wherein the heteroaryl
ring, as defined above, is fused with one or more aryl groups
wherein the point of attachment is either on the aryl or heteroaryl
ring, and in such instances, the number of ring members designates
the number of ring members in the fused (aryl/heteroaryl) ring
system. Bicyclic heteroaryl groups wherein one ring does not
contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and
the like) the point of attachment can be on either ring, i.e.,
either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring
that does not contain a heteroatom (e.g., 5-indolyl).
[0018] In some embodiments, a heteroaryl group is a 5-10 membered
aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from nitrogen, oxygen, and
sulfur ("5-10 membered heteroaryl"). In some embodiments, a
heteroaryl group is a 5-8 membered aromatic ring system having ring
carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring
system, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-6 membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur ("5-6
membered heteroaryl"). In some embodiments, the 5-6 membered
heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen,
and sulfur. In some embodiments, the 5-6 membered heteroaryl has
1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In
some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom
selected from nitrogen, oxygen, and sulfur. Unless otherwise
specified, each instance of a heteroaryl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
heteroaryl") or substituted (a "substituted heteroaryl") with one
or more substituents. In certain embodiments, the heteroaryl group
is unsubstituted 5-14 membered heteroaryl. In certain embodiments,
the heteroaryl group is substituted 5-14 membered heteroaryl.
[0019] Exemplary 5-membered heteroaryl groups containing one
heteroatom include, without limitation, pyrrolyl, furanyl and
thiophenyl. Exemplary 5-membered heteroaryl groups containing two
heteroatoms include, without limitation, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary
5-membered heteroaryl groups containing three heteroatoms include,
without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
Exemplary 5-membered heteroaryl groups containing four heteroatoms
include, without limitation, tetrazolyl. Exemplary 6-membered
heteroaryl groups containing one heteroatom include, without
limitation, pyridinyl. Exemplary 6-membered heteroaryl groups
containing two heteroatoms include, without limitation,
pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered
heteroaryl groups containing three or four heteroatoms include,
without limitation, triazinyl and tetrazinyl, respectively.
Exemplary 7-membered heteroaryl groups containing one heteroatom
include, without limitation, azepinyl, oxepinyl, and thiepinyl.
Exemplary 5,6-bicyclic heteroaryl groups include, without
limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,
benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and
purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without
limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
[0020] As used herein, the term "heterocyclic" refers to a radical
of a 3 to 10 membered non-aromatic ring system having ring carbon
atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is
independently selected from nitrogen, oxygen, sulfur, boron,
phosphorus, and silicon ("3-10 membered heterocyclic"). In
heterocyclic groups that contain one or more nitrogen atoms, the
point of attachment can be a carbon or nitrogen atom, as valency
permits. A heterocyclic group can either be monocyclic ("monocyclic
heterocyclic") or a fused, bridged or spiro ring system such as a
bicyclic system ("bicyclic heterocyclic"), and can be saturated or
can be partially unsaturated. Heterocyclic bicyclic ring systems
can include one or more heteroatoms in one or both rings.
"Heterocyclic" also includes ring systems wherein the heterocyclic
ring, as defined above, is fused with one or more carbocyclic
groups wherein the point of attachment is either on the carbocyclic
or heterocyclic ring, or ring systems wherein the heterocyclic
ring, as defined above, is fused with one or more aryl or
heteroaryl groups, wherein the point of attachment is on the
heterocyclic ring, and in such instances, the number of ring
members continue to designate the number of ring members in the
heterocyclic ring system. Unless otherwise specified, each instance
of heterocyclic is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted heterocyclic") or substituted (a
"substituted heterocyclic") with one or more substituents. In
certain embodiments, the heterocyclic group is unsubstituted 3-10
membered heterocyclic. In certain embodiments, the heterocyclic
group is substituted 3-10 membered heterocyclic.
[0021] In some embodiments, a heterocyclic group is a 5-10 membered
non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10
membered heterocyclic"). In some embodiments, a heterocyclic group
is a 5-8 membered non-aromatic ring system having ring carbon atoms
and 1-4 ring heteroatoms, wherein each heteroatom is independently
selected from nitrogen, oxygen, and sulfur ("5-8 membered
heterocyclic"). In some embodiments, a heterocyclic group is a 5-6
membered non-aromatic ring system having ring carbon atoms and 1-4
ring heteroatoms, wherein each heteroatom is independently selected
from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclic"). In
some embodiments, the 5-6 membered heterocyclic has 1-3 ring
heteroatoms selected from nitrogen, oxygen, and sulfur. In some
embodiments, the 5-6 membered heterocyclic has 1-2 ring heteroatoms
selected from nitrogen, oxygen, and sulfur. In some embodiments,
the 5-6 membered heterocyclic has one ring heteroatom selected from
nitrogen, oxygen, and sulfur.
[0022] Exemplary 3-membered heterocyclic groups containing one
heteroatom include, without limitation, azirdinyl, oxiranyl, and
thiiranyl. Exemplary 4-membered heterocyclic groups containing one
heteroatom include, without limitation, azetidinyl, oxetanyl and
thietanyl. Exemplary 5-membered heterocyclic groups containing one
heteroatom include, without limitation, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,
pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary
5-membered heterocyclic groups containing two heteroatoms include,
without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and
oxazolidin-2-one. Exemplary 5-membered heterocyclic groups
containing three heteroatoms include, without limitation,
triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary
6-membered heterocyclic groups containing one heteroatom include,
without limitation, piperidinyl, tetrahydropyranyl,
dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic
groups containing two heteroatoms include, without limitation,
piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered
heterocyclic groups containing two heteroatoms include, without
limitation, triazinanyl. Exemplary 7-membered heterocyclic groups
containing one heteroatom include, without limitation, azepanyl,
oxepanyl and thiepanyl. Exemplary 8 membered heterocyclic groups
containing one heteroatom include, without limitation, azocanyl,
oxecanyl and thiocanyl. Exemplary 5-membered heterocyclic groups
fused to a C.sub.6 aryl ring (also referred to herein as a
5,6-bicyclic heterocyclic ring) include, without limitation,
indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclic
groups fused to an aryl ring (also referred to herein as a
6,6-bicyclic heterocyclic ring) include, without limitation,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
[0023] As used herein, the term "acyl" refers to a radical
--C(O)R.sup.a, where R.sup.a is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclic, substituted or unsubstituted heterocyclic, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
as defined herein. Representative acyl groups include, but are not
limited to, formyl (--CHO), acetyl (--C(.dbd.O)CH.sub.3),
cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl
(--C(.dbd.O)Ph), benzylcarbonyl (--C(.dbd.O)CH.sub.2Ph),
--C(O)--C.sub.1-C.sub.8 alkyl,
--C(O)--(CH.sub.2).sub.tC.sub.6-C.sub.10 aryl),
--C(O)--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--C(O)--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--C(O)--(CH.sub.2).sub.t(4-10 membered heterocyclic), wherein t is
an integer from 0 to 4.
[0024] As used herein, the term "alkoxy" refers to the group
--OR.sup.b where R.sup.b is substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclic, substituted or
unsubstituted heterocyclic, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl. Particular alkoxy groups
are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy,
sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular
alkoxy groups are lower alkoxy, i.e., with between 1 and 6 carbon
atoms. Further particular alkoxy groups have between 1 and 4 carbon
atoms.
[0025] As used herein, the term "halo" or "halogen" refers to
fluoro (F), chloro (Cl), bromo (Br), and iodo (I).
[0026] Alkyl, heterocyclic, aryl, and heteroaryl groups, as defined
herein, are optionally substituted (e.g., "substituted" or
"unsubstituted" alkyl, "substituted" or "unsubstituted"
heterocyclic, "substituted" or "unsubstituted" aryl or
"substituted" or "unsubstituted" heteroaryl group). In general, the
term "substituted", whether preceded by the term "optionally" or
not, means that at least one hydrogen present on a group (e.g., a
carbon or nitrogen atom) is replaced with a permissible
substituent, e.g., a substituent which upon substitution results in
a stable compound, e.g., a compound which does not spontaneously
undergo transformation such as by rearrangement, cyclization,
elimination, or other reaction. Unless otherwise indicated, a
"substituted" group has a substituent at one or more substitutable
positions of the group, and when more than one position in any
given structure is substituted, the substituent is either the same
or different at each position. The term "substituted" is
contemplated to include substitution with all permissible
substituents of organic compounds, any of the substituents
described herein that results in the formation of a stable
compound. The present invention contemplates any and all such
combinations in order to arrive at a stable compound. For purposes
of this invention, heteroatoms such as nitrogen may have hydrogen
substituents and/or any suitable substituent as described herein
which satisfy the valencies of the heteroatoms and results in the
formation of a stable moiety.
[0027] Optional substituents for alkyl, alkenyl, aryl, heteroaryl,
or heterocycle groups are well known to those skilled in the art.
These substituents include alkyl, alkoxy, aryloxy, hydroxy, acetyl,
cyano, nitro, glyceryl, and carbohydrate, or two substituents taken
together may be linked as an -alkylene-group to form a ring.
[0028] As used herein, the term "leaving group" or "LG" means the
group with the meaning conventionally associated with it in
synthetic organic chemistry, i.e., an atom or group displaceable
under substitution reaction conditions. Examples of leaving groups
include, but are not limited to, halogen, alkane- or
arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,
thiomethyl, benzenesulfonyloxy, tosyloxy, mesylate, and thienyloxy,
dihalophosphinoyloxy, optionally substituted benzyloxy,
isopropyloxy, acyloxy, and the like.
Preferred Embodiments of the Process of the Invention
[0029] The present invention provides processes for making
arylpiperazine and arylpiperidine compounds, including
intermediates and derivatives thereof. More specifically, the
present invention provides processes or methods for making a
variety of alkylated arylpiperazine and alkylated arylpiperidine
compounds of the general formulas (I) and (VII), respectively.
##STR00003##
wherein, R.sub.1 and R.sub.2 are individually selected from
hydrogen, unsubstituted alkyl, and substituted alkyl, or R.sub.1
and R.sub.2 are connected to form a 5 to 8 carbon cyclic ring; n is
0, 1, or 2; Y is NR.sub.3R.sub.4, OR.sub.5, or SR.sub.5, where
R.sub.3 and R.sub.4 are individually selected from acyl or
sulfonyl, wherein R.sub.3 and R.sub.4 may be connected to form a
substituted or unsubstituted cyclic or bicyclic ring, and wherein
R.sub.5 is aryl or heteroaryl, or heterocyclic; and Ar is an aryl
or heteroaryl group.
[0030] Arylpiperazine compounds of formula (I) include, for
example, lurasidone, tiospirone, revospirone, perospirone,
brexipirazole, aripiprazole, buspirone, gepirone, ipsapirone,
eptapirone, umespirone, tandospirone, and zalospirone.
[0031] Arylpiperidine compounds of formula (VII) include, for
example, iloperidone and abaperidone.
[0032] The processes for making the alkylated arylpiperazine and
alkylated arylpiperidine compounds disclosed herein have certain
common features and process steps. For example, as shown, the
processes for making the alkylated arylpiperazine and alkylated
arylpiperidine compounds both comprise the step of alkylating the
compound YH with a cyclic sulfate of formula (II) in the presence
of a base to form a compound of formula (III) wherein Q is
hydrogen, a metal, or an ammonium salt.
##STR00004##
[0033] In preferred embodiments, R.sub.1 and R.sub.2 in formulas
(II) and (III) are connected to form a 5 to 8 carbon cyclic ring.
Preferably, R.sub.1 and R.sub.2 are connected to form a 5 or 6
carbon cyclic ring and, most preferably a 6 carbon cyclic aliphatic
ring.
[0034] In preferred embodiments, the compound YH is a cyclic imide
or cyclic amide such that Y is NR.sub.3R.sub.4, where R.sub.3
and/or R.sub.4 are acyl, and wherein R.sub.3 and R.sub.4 are
connected to form a cyclic or bicyclic ring. Preferred compounds
that meet the requirements for YH include, for example:
TABLE-US-00001 TABLE 1 Representative Compounds of Formula YH Entry
YH 1 ##STR00005## 2 ##STR00006## 3 ##STR00007## 4 ##STR00008## 5
##STR00009## 6 ##STR00010## 7 ##STR00011## 8 ##STR00012## 9
##STR00013## 10 ##STR00014## 11 ##STR00015## 12 ##STR00016## 13
##STR00017## 14 ##STR00018## 15 ##STR00019## 16 ##STR00020##
[0035] In a preferred embodiment of the present invention, YH
is:
##STR00021##
[0036] In the reaction between compound YH and the cyclic sulfate
of formula (II) in the present invention, compound YH is preferably
present in the reaction mixture in an amount of from about 1.0 to
2.0 equivalents and, more preferably, from about 1.1 to 1.2
equivalents based on the amount of the cyclic sulfate of formula
(II).
[0037] The alkylation reaction according to the present invention
is preferably carried out in a suitable solvent at a temperature of
from about 20.degree. C. to about 120.degree. C. in the presence of
a base.
[0038] Suitable solvents for this step include, but are not limited
to, hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons,
esters, ethers, nitriles, ketones, and mixtures thereof. In
preferred embodiments, the solvent is acetonitrile.
[0039] Suitable bases for this step include alkali metal carbonates
such as potassium carbonate, sodium carbonate, calcium carbonate,
and magnesium carbonate; alkali metal bicarbonates such as sodium
bicarbonate, and potassium bicarbonate; preferably an alkali metal
carbonate, in particular, potassium carbonate; alkali metal
hydroxides such as sodium hydroxide, potassium hydroxide, magnesium
hydroxide, or calcium hydroxide; alkali metal phosphates such as
sodium phosphate or potassium phosphate; and organic amine bases
such as triethylamine, diisopropylethylamine and pyridine. Ammonium
salts of the above bases are also suitable. Solid inorganic bases
may be used alone or as a mixture of two or more kinds of bases,
and may be an anhydrous form or a hydrate thereof. In preferred
embodiments, the base employed for this step is potassium
carbonate, K.sub.2CO.sub.3.
[0040] The amount of the base used herein is generally about 0.7
mole or more, preferably 1.0 mole or more, per one mole of the
total amount of compound YH. The upper limit amount of the solid
inorganic base used herein is not limited but an excess amount of
base can increase process costs. Accordingly, a practical amount of
solid inorganic base is 10 mole or less, preferably 2.0 mole or
less, per one mole of the total amount of compound YH.
[0041] The progress of the alkylation reaction in the present
invention can be monitored by any means known to those skilled in
the art such as, for example, gas chromatography (GC) or high
performance liquid chromatography (HPLC).
[0042] The compound of formula (III) may be isolated by any method
known to those skilled in the art. In preferred embodiments,
however, the compound of formula (III) is not isolated from the
reaction mixture in which it was formed, but rather is telescoped.
In this regard, the compound of formula (III) may be readied for a
hydrolysis step by the addition of water, which generates a clean
phase split with, for example, acetonitrile due to the solubilized
base such as, for example, potassium carbonate, without significant
product loss. The organic solvent layer is then preferably washed
further with aqueous NaCl in a conventional extraction process to
remove any residual carbonate prior to a hydrolysis reaction.
[0043] An unexpected benefit of employing a cyclic sulfate of
formula (II) in the process of the present invention is that it
leads to the advantageous selective monoalkylation of the cyclic
sulfate without the possibility of double alkylation. The anionic
ring-opened sulfate (after initial alkylation) is not prone to
further displacement by nucleophiles. Thus, after conversion of the
alcohol to a suitable leaving group, simple displacement chemistry
is employed to provide the final product. In other words, the
process of the present invention produces alkylated arylpiperazine
and alkylated arylpiperidine compounds wherein no bis-imide product
is detected in the alkylation of the cyclic sulfate.
[0044] The process for making the alkylated arylpiperazine and
arylpiperidine derivative compounds according to the present
invention also comprises the step of hydrolyzing a compound of
formula (III) to form an alcohol of formula (IV) as shown here.
##STR00022##
[0045] In this reaction step, aqueous acid is added to a washed
organic solvent layer containing the compound of formula (III) and
the mixture is agitated at a temperature of from about 20.degree.
C. to about 100.degree. C. During this step, the sulfate ester
moiety of the compound of formula (III) is hydrolyzed to an alcohol
group (--OH). In some embodiments, an additional solvent such as,
for example, toluene, may be added to the mixture prior to the
aqueous acid.
[0046] The progress of the hydrolysis reaction in the present
invention can be monitored by any means known to those skilled in
the art such as, for example, high performance liquid
chromatography (HPLC).
[0047] Preferably, once the reaction is complete, the organic phase
is cooled and the organic phase is prepared for another step in the
process of the present invention. This preparation typically
involves washing several times with water employing a conventional
extraction process. The organic phase may also be distilled under
vacuum followed by addition of the desired solvent for the next
step of the process. An example of such solvent is toluene.
[0048] The process of the present invention for making alkylated
arylpiperazine and alkylated arylpiperidine compounds also
comprises a step of converting the compound of formula (IV) to an
alkylating agent of formula (V) wherein LG is a leaving group.
##STR00023##
[0049] In the compound of formula (V), preferably LG is selected
from the group consisting of an aryl sulfonate, alkyl sulfonate,
phosphate, phosphonate, proazaphosphatrane and a halogen. In
preferred embodiments, LG is a mesylate.
[0050] The conversion of the hydroxyl group to one of the recited
leaving groups can be effected by any means known to one skilled in
the art. In preferred embodiments where LG is a mesylate, for
example, it was found that the conversion can occur quickly and
effectively in a mixture of toluene and a base such as, for
example, triethylamine. In this embodiment, about 1.2 equivalents
of methanesulfonyl chloride relative to the alcohol is added to the
mixture to initiate the reaction. Other suitable solvents for this
step include, for example, hydrocarbons, halogenated hydrocarbons,
aromatic hydrocarbons, esters, ethers, nitriles, ketones, and
mixtures thereof.
[0051] The progress of the conversion reaction in the present
invention can be monitored by any means known to those skilled in
the art such as, for example, HPLC. Such a reaction typically
requires from about 0.5 hours to about 12 hours for completion,
depending on variables such as, for example, temperature,
equivalents of activating agent, and concentration of the
reactants. For example, the less solvent employed the faster the
reaction is likely to proceed.
[0052] Once the reaction is complete, the mixture is preferably
washed with water. The aqueous layer can then be separated and
removed following the wash. Preparation of the organic phase for
the next step in the process of the present invention can be
accomplished by vacuum distillation until the desired volume is
reached.
[0053] The process of making alkylated arylpiperazine compounds
according to the present invention comprises a step of alkylating a
piperazine compound of formula (VI) with an alkylating agent of
formula (V) to provide the alkylated arylpiperazine of formula
(I).
##STR00024##
[0054] In the reaction between the compounds of formula (V) and
(VI) in the present invention, the compound of formula (VI) is
preferably present in the reaction mixture in an amount of from 1.0
to 10.0 equivalents and, more preferably, from 1.1 to 1.2
equivalents based on the amount of the compound of formula (V).
Also present in the reaction is about 1.5 equivalents of a base.
Suitable bases for this step include alkali metal carbonates such
as potassium carbonate, sodium carbonate, calcium carbonate, and
magnesium carbonate; alkali metal bicarbonates such as sodium
bicarbonate, and potassium bicarbonate; preferably an alkali metal
carbonate, in particular, potassium carbonate; alkali metal
hydroxides such as sodium hydroxide, potassium hydroxide, magnesium
hydroxide, or calcium hydroxide; alkali metal phosphates such as
sodium phosphate or potassium phosphate; and organic amine bases
such as triethylamine, diisopropylethylamine and pyridine. Ammonium
salts of the above bases are also suitable. Solid inorganic bases
may be used alone or as a mixture of two or more kinds of bases,
and may be an anhydrous form or a hydrate thereof. In preferred
embodiments, the base employed for this step is potassium
carbonate, K.sub.2CO.sub.3. The amount of the base used herein is
generally about 0.7 mole or more, preferably 1.0 mole or more, per
one mole of the total amount of compound of formula (VI). The upper
limit amount of the solid inorganic base used herein is not
limited, but, in case that the amount is too much, the process cost
increases. Accordingly, a practical amount of the base is 3 mole or
less, preferably 2.0 mole or less, per one mole of the total amount
of compound of formula (VI).
[0055] The progress of the reaction can be monitored by any means
known to those skilled in the art such as, for example, HPLC.
[0056] Once complete, the reaction mixture is preferably cooled
followed by addition of solvent. The aqueous layer is removed
followed by additional washes of the organic phase with water. Once
the aqueous layer is separated, the organic layer is preferably
distilled under vacuum and an antisolvent is added. Suitable
antisolvents for this step include, but are not limited to,
hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons,
esters, ethers, nitriles, ketones, and mixtures thereof. To effect
crystallization of the arylpiperazine of formula (I), the mixture
is preferably successively heated and cooled in the mixture of
solvent and antisolvent.
[0057] The process of making alkylated arylpiperidine compounds
according to the present invention comprises a step of alkylating
an arylpiperidine compound of formula (VIII) with an alkylating
agent of formula (V) to provide the alkylated arylpiperidine of
formula (VII).
##STR00025##
[0058] The reaction conditions and product separation are about the
same as those described above regarding the alkylated
arylpiperazine compounds.
[0059] As will be understood by those of ordinary skill in the art,
the processes described above and herein can be employed to produce
a variety of compounds. For example, as shown in Table 2 below, the
following compounds can be made by the process described herein for
making the alkylated arylpiperazine compound of formula (I).
TABLE-US-00002 TABLE 2 Compounds of Formula (I) Compound Name
Structure R1 R2 n Lurasidone ##STR00026## --((CH.sub.2).sub.4)-- NA
2 Tiospirone ##STR00027## H H 2 Revospirone ##STR00028## H H 1
Aripiprazole Lauroxil ##STR00029## H H 2 Buspirone ##STR00030## H H
2 Gepirone ##STR00031## H H 2 Ipsapirone ##STR00032## H H 2
Eptapirone ##STR00033## H H 2 Umepirone ##STR00034## H H 2
Zalospirone ##STR00035## H H 2 Pelanserin ##STR00036## H H 1
Fananserin ##STR00037## H H 1 Piricapiron ##STR00038## H H 2
OPC-4392 ##STR00039## H H 1 Mafoprazine ##STR00040## H H 1
Enasculin ##STR00041## H H 1 Compound Name YH Ar Lurasidone
##STR00042## ##STR00043## Tiospirone ##STR00044## ##STR00045##
Revospirone ##STR00046## ##STR00047## Aripiprazole Lauroxil
##STR00048## ##STR00049## Buspirone ##STR00050## ##STR00051##
Gepirone ##STR00052## ##STR00053## Ipsapirone ##STR00054##
##STR00055## Eptapirone ##STR00056## ##STR00057## Umepirone
##STR00058## ##STR00059## Zalospirone ##STR00060## ##STR00061##
Pelanserin ##STR00062## ##STR00063## Fananserin ##STR00064##
##STR00065## Piricapiron ##STR00066## ##STR00067## OPC-4392
##STR00068## ##STR00069## Mafoprazine ##STR00070## ##STR00071##
Enasculin ##STR00072## ##STR00073##
[0060] Similarly, as shown in Table 3 below, the following
compounds can be made by the process described herein for making
the alkylated arylpiperidine compounds of formula (VII).
TABLE-US-00003 TABLE 3 Compounds of Formula (VII) Compound Name
Structure R1 R2 n YH Ar Iloperidone ##STR00074## H H 1 ##STR00075##
##STR00076## Abaperidone ##STR00077## H H 1 ##STR00078##
##STR00079##
[0061] In the process of making the alkylated arylpiperazine and
alkylated arylpiperidine compounds disclosed herein, numerous
intermediate compounds are produced.
[0062] The following examples illustrate various aspects of the
present invention.
Examples
Example 1: Telescoped Preparation of
(5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine 3,3-dioxide
[0063] [(1R,2R)-cyclohexane-1,2-diyl]dimethanol (mol. wt. 144.21)
is added to acetonitrile providing a reaction mixture in the form
of a suspension. The mixture is stirred and cooled to 0-5.degree.
C. Thionyl choride is added to the mixture at a temperature of
0-10.degree. C. which results in a clear solution. The solution is
stirred at 0-5.degree. C. and assayed periodically to confirm
completion of the reaction.
[0064] In a separate vessel, an aqueous solution of potassium
bicarbonate (2.5 eq) is added prepared and then cooled to
0-5.degree. C. The completed reaction solution above is then
quenched into the aqueous potassium bicarbonate solution. The batch
is then warmed to 20-25.degree. C. and the upper acetonitrile layer
is separated and collected. The aqueous layer is extracted with
acetonitrile and the organic layers are combined resulting in a
solution of (5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine 3-oxide
(mol. wt. 190.26).
[0065] In a separate vessel, 50% ruthenium oxide hydrate (0.1 wt.
%) and sodium periodate (1.1 eq.) are slurried in water (and EtOAc
at 20-25.degree. C. The
(5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine 3-oxide solution
above is then added to the sodium periodate/ruthenium oxide slurry
while maintaining the temperature at .ltoreq.30.degree. C. After
the reaction is complete, the batch is then filtered, after which
the filter cake is washed with EtOAc. The upper organic layer is
collected and washed with 20% aqueous sodium chloride. The organic
layer is distilled to a minimum volume after which isopropanol is
added to the distillate. The resulting slurry is heated to
40-45.degree. C. after which it is cooled to 0-5.degree. C., and
then filtered. The solids are washed with isopropanol and dried in
a vacuum oven resulting in (5aR,9aR)-octahydrobenzo[e][1,3,2]
dioxathiepine 3,3-dioxide (mol. wt. 206.26).
Example 2: Telescoped Preparation of Lurasidone Free Base
[0066] Acetonitrile is added to a mixture of
(5aR,9aR)-octahydrobenzo[e][1,3,2] dioxathiepine 3,3-dioxide (mol.
wt. 206.26, 1 eq.),
(3aR,4s,7R,7aS-hexahydro-1H-7,4-methanoisoindole-1,3(2H)-dione
(mol. wt. 165.19, 1.2 eq.) and potassium carbonate (2 eq.) and the
mixture is heated to about 75.degree. C.
[0067] After the reaction is complete, the mixture is cooled to
20-25.degree. C. and water is added to the mixture. A lower,
aqueous phase is then removed and an upper, organic phase is washed
with aqueous sodium chloride.
[0068] The aqueous phases are combined and extracted with
acetonitrile. The organic phases are combined to form a solution of
potassium ((1R,2R)-2
(((3aR,4S,7R,7aS)-1,3-dioxooctahydro-2H-4,7-methanoisoindol-2-yl)methyl)
cyclohexyl)methyl sulfate (mol. wt. 409.54) in acetonitrile which
is then distilled to approximately 5 volumes. Toluene is added to
the batch and, separately a solution of sulfuric acid (0.5 eq.) and
water (0.6 volumes) is prepared. The sulfuric acid solution is
added to the batch. This mixture is then heated to approximately
75.degree. C. and the reaction is monitored by HPLC.
[0069] Once the reaction is complete, it is cooled to approximately
45.degree. C. and washed twice with water (4 volumes). The aqueous
layer is then removed and the organic layer is washed with 5%
aqueous KHCO.sub.3 (4 volumes) followed by two additional water
washes (4 volumes). The organic solution comprising
(3aR,4S,7R,7aS)-2-(((1R,2R)-2-(Hydroxymethyl)cyclohexyl)methyl)hexahydro--
1H-4,7methanoisoindole-1,3(2H)-dione (mol. wt. 291.39) is distilled
under vacuum to approximately 4 volumes and toluene is added to the
batch. This solution is distilled to approximately 4 volumes and
toluene is added. This batch is cooled to about 0-5.degree. C., and
triethylamine (1.5 eq.) is added after which methanesulfonyl
chloride (1.2 eq.) is added. The progress of this reaction is
monitored by HPLC.
[0070] Once the reaction is complete, water (3 volumes) is added.
The aqueous layer is removed and the organic layer is washed with
water (2.times.3 volumes).
[0071] The toluene solution of
((1R,2R)-2-(((3aR,4S,7R,7aS)-1,3-dioxooctahydro-2H-4,7-methanoisoindol-2--
yl)methyl)cyclohexyl)methyl methanesulfonate is distilled to about
4 volumes under vacuum, and this solution is added to a mixture of
3-(piperazin-1-yl)benzold]isothiazole (1.1 eq.) and KHCO.sub.3 (1.5
eq.). Water (1.8 volumes) is added and the mixture is heated to
approximately 90.degree. C. The progress of the reaction is
monitored by HPLC.
[0072] Once the reaction is complete, the batch is cooled to
45.+-.5.degree. C. and toluene (4.5 volumes), water (3.25 volumes),
and IPA (1.75 volumes) are added. The aqueous layer is removed and
the organic layer is washed with water (2.times.2.5 volumes) at
40.+-.5.degree. C. The organic layer is distilled under reduced
pressure to 3.5 volumes at 50-60.degree. C., then isopropanol (8
volumes) is added. The batch is distilled to 3.5 volumes, then IPA
(2.5 volumes) is added. The slurry is heated to 80.+-.5.degree. C.
for 1-2 hours, then cooled to 0-5.degree. C. and filtered. The
solids are washed with IPA and dried to isolate
(3aR,4S,7R,7aS)-2-(((1R,2R)-2-((4-(benzol[d]isothiazol-3-yl)piperazin-1-y-
l)methylcyclohexyl)methyl)
hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione (lurasidone free
base, mol. wt. 492.68).
Example 3: Crystallization of Lurasidone Free Base
[0073] The crude lurasidone free base of Example 2 is slurried in
ethyl acetate (10 volumes) and heated until a clear solution is
obtained. The solution is cooled to 50-55.degree. C. and filtered
to remove any particulates in the solution. The solution is further
distilled to approximately 4-5 volumes and then cooled to
approximately 0-5.degree. C. The resulting solid precipitate is
filtered, rinsed with ethyl acetate and then dried under vacuum to
provide crystalline lurasidone free base.
Example 4: Preparation of Lurasidone Hydrochloride
[0074] The lurasidone free base of Example 3 is slurried in
isopropanol (1 eq. base to 15 volumes of isopropanol). The slurry
is then heated until a clear solution results. The solution is
filtered to remove any particulates in the solution. A pre-filtered
solution of 10% aqueous HCl is then added, and the batch is slowly
cooled to approximately 45-70.degree. C. until crystals begin to
precipitate. The batch is held at this point for several hours,
then further cooled to approximately 0.degree. C. The resulting
solid precipitate is filtered and then washed with isopropanol
(3.times.2 volumes). The precipitate is dried to provide lurasidone
hydrochloride.
Example 5: Telescoped Preparation of
(3-(5-acetyl-2-methoxyphenoxy)propyl methanesulfonate Towards
Iloperidone
[0075] A mixture of 1,3,2-dioxathiane 2,2-dioxide (22.4 g, 160
mmol, 1 eq.), 1-(3-hydroxy-4-methoxyphenyl)ethan-1-one (26.9 g, 160
mmol, 1 eq.) and potassium carbonate (44.8 g, 320 mmol, 2 eq.) in
acetonitrile (220 mL) is heated at about reflux temperature. The
reaction is monitored by HPLC. Upon completion, the batch is cooled
to about 20-25.degree. C. The reaction mixture is filtered through
a Celite pad and the pad is washed with acetonitrile (180 mL) to
give a solution of potassium 3-(5-acetyl-2-methoxyphenoxy)propyl
sulfate in acetonitrile, which is used in the next step.
[0076] A solution of H.sub.2SO.sub.4 (10 mL H.sub.2SO.sub.4 in 90
mL water) is added slowly to the above acetonitrile solution. The
batch is then heated to about reflux; the reaction is monitored by
HPLC. Upon completion, the reaction mixture is cooled to about
20-25.degree. C., and the resulting phases separated. The organic
phase is washed with brine (100 mL.times.2) and divided into 2
portions (80 mL and 320 mL).
[0077] The 80 mL portion from the above reaction is worked up to
provide a reference marker of
1-(3-(3-hydroxypropoxy)-4-methoxyphenyl)ethan-1-one as follows. The
solvent is removed under reduced pressure to give the crude
product, which is purified by column chromatography on silica gel
(10.times. silica gel relative to crude product, petroleum
ether:ethyl acetate [2:1] to petroleum ether:ethyl acetate [1:1])
to give 1-(3-(3-hydroxypropoxy)-4-methoxyphenyl)ethan-1-one in 99%
purity (2.3 g, white solid).
[0078] A large portion of the acetonitrile solution of potassium
3-(5-acetyl-2-methoxyphenoxy)propyl sulfate (320 mL) is progressed
forward as follows. Approximately 80% of the solvent is removed,
and then ethyl acetate (200 mL) is added. About 80% of the solvent
is removed again to give a concentrated solution of
1-(3-(3-hydroxypropoxy)-4-methoxyphenyl)ethan-1-one in ethyl
acetate for the next step.
[0079] Triethylamine (75 g) and ethyl acetate (200 mL) are added to
the above solution, then a solution of Ms.sub.2O (40 g) in ethyl
acetate (200 mL) is added dropwise at less than 15.degree. C. The
mixture is stirred at about 10.degree. C. overnight. The reaction
is monitored by HPLC. Aqueous sodium hydroxide (15%, 250 mL) is
added when the reaction is completed, and the mixture is stirred at
about 20-25.degree. C. for 15 min. The separated organic layer is
then washed with 2 M HCl (200 mL) and brine (200 mL). The solvent
is removed under reduced pressure to give the crude product
(3-(5-acetyl-2-methoxyphenoxy)propyl methanesulfonate as an
off-white solid (15 g, 90% AUC by HPLC).
Example 6: Preparation of Iloperidone Free Base
[0080] A mixture of 3-(5-acetyl-2-methoxyphenoxy)propyl
methanesulfonate (3 g, 10 mmol, 1 equiv),
6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (2.42 g, 11 mmol, 1.1
equiv), KHCO.sub.3 (1.5 g, 15 mmol, 1.5 equiv), H.sub.2O (6 g) and
toluene (15 mL) is heated at reflux temperature for 12-16 h. Once
the reaction is complete, the batch is cooled to about
20-25.degree. C., and then toluene (15 mL), IPA (10 mL) and water
(10 mL) are added. The biphasic solution is stirred for about 15
min at about 20-25.degree. C. The organic layer is separated and
washed with water (2.times.10 mL). The batch is concentrated to
about 3-4 volumes under vacuum at <50.degree. C. to precipitate
an off-white solid. Isopropanol (20 mL) is added, the batch is
concentrated to 3-4 volumes under vacuum at <50.degree. C.
Isopropanol (20 mL) is added again, and the batch is concentrated
to 3-4 volumes under vacuum at <50.degree. C. Isopropanol (10
mL) is added once again and the batch is heated at reflux
temperature for 1 h, and then the mixture is cooled to 5-8.degree.
C. over 4 h. The mixture is filtered; the cake is washed with
isopropanol (2.times.5 mL) and dried to give Iloperidone free base
(3.1 g, 74% yield, 98% AUC by HPLC).
Example 7: Preparation of Potassium
4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butyl sulfate
Towards Ipsapirone
[0081] A mixture of benzo[d]isothiazol-3(2H)-one 1,1-dioxide (16.0
g, 87.3 mmol, 1.0 eq.), 1,3,2-dioxathiepane 2,2-dioxide (15.3 g,
100.5 mmol, 1.2 eq.), K.sub.2CO.sub.3 (24.1 g, 174.6 mmol, 2.0 eq.)
and ACN (240 mL) is heated at reflux temperature for 20 h. After
the reaction is complete, the mixture is filtered and concentrated
under vacuum to give an oily product. To the residue is added ACN
(200 mL), and a solid is precipitated immediately. The mixture is
stirred for 1 h at 20-25.degree. C., then filtered. Potassium
4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butyl sulfate is
collected as a white solid (11.4 g, 35% yield, 98.5% AUC by HPLC);
LC-MS, M.sup.+: 335.6 (sulfonic acid).
Example 8: Preparation of
2-(4-hydroxybutyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide Towards
Ipsapirone
[0082] A solution of H.sub.2SO.sub.4 (0.8 g, 8.2 mmol, 0.5 eq.) in
H.sub.2O (2 mL) is added to a mixture of potassium
4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butyl sulfate (6.1
g, 16.3 mmol, 1.0 eq.) in ACN (90 mL) and H.sub.2O (5 mL) dropwise.
The resulting mixture is heated at 75-80.degree. C. until the
reaction is deemed complete by HPLC analysis. The mixture is
filtered, and filtrate is concentrated to approximately to 10 mL.
To the residue, dichloromethane and DI water are added. The layers
are separated and the organic layer is washed with saturated
NaHCO.sub.3 solution, dried over sodium sulfate and then
concentrated to give the crude product in 94% purity by HPLC. The
crude material is further purified by silica gel column
chromatography (petroleum ether:ethyl acetate 4:1 to 3:1) to
provide 2-(4-hydroxybutyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide
as a light yellow oil in (2.3 g, 55% yield, 99% AUC by HPLC);
LC-MS, M.sup.+: 255.8.
Example 9: Preparation of
4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butyl
methanesulfonate Towards Ipsapirone
[0083] To a mixture of
2-(4-hydroxybutyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (17.2 g,
67.4 mmol, 1.0 eq.) in ethyl acetate (172 mL, 10 vol), is added
triethylamine (13.6 g, 134.7 mmol, 2.0 eq.) at <5.degree. C.,
followed by dropwise addition of Ms.sub.2O (12.9 g, 74.1 mmol, 1.1
eq.) in ethyl acetate (20 mL) at 5-15.degree. C. The mixture is
stirred at 20-25.degree. C. for 20 h and the reaction is deemed
complete by HPLC. The mixture is washed with H.sub.2O twice, then
dried over Na.sub.2SO.sub.4. The solvent is removed under reduced
pressure to obtain crude material. The crude product is purified by
column chromatography on silica gel (30.times.silica gel, petroleum
ether:ethyl acetate [10:1] to petroleum ether:ethyl acetate [4:1])
which gives 4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butyl
methanesulfonate as a white solid (8.5 g, 38% yield, 96% AUC by
HPLC); LC-MS, Mt 355.6.
Example 10: Preparation of Ipsapirone Free Base
[0084] A suspension of
(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butyl
methanesulfonate (4.6 g, 13.8 mmol, 1.0 eq),
2-(piperazin-1-yl)pyrimidine (2.9 g, 17.9 mmol, 1.3 eq.),
KHCO.sub.3 (2.1 g, 20.7 mmol, 1.5 eq.) and toluene (46 mL) is
heated at 95-100.degree. C. for 22 h. Deionized water (35 mL) is
added, and the organic phase is separated. The aqueous phase is
extracted with ethyl acetate (2.times.30 mL). The organic phases
are combined and dried over Na.sub.2SO.sub.4. The solvent is
removed under reduced pressure to give the crude product, which is
purified by column chromatography on silica gel by elution with
17-33% EtOAc/petroleum ether to offer ipsapirone free base as an
off-white solid (2 g, 27% yield, 96% AUC by HPLC).
[0085] The foregoing examples and description of the preferred
embodiments should be taken as illustrating, rather than as
limiting the present invention as defined by the claims. As will be
readily appreciated, numerous variations and combinations of the
features set forth above can be utilized without departing from the
present invention as set forth in the claims. Such variations are
not regarded as a departure from the spirit and scope of the
invention, and all such variations are intended to be included
within the scope of the following claims.
* * * * *