U.S. patent application number 12/104960 was filed with the patent office on 2008-08-28 for processes for the preparation of aminoethoxybenzyl alcohols.
This patent application is currently assigned to WYETH. Invention is credited to Pietro ALLEGRINI, Giuseppe BARRECA, Giorgio SORIATO.
Application Number | 20080207898 12/104960 |
Document ID | / |
Family ID | 36570630 |
Filed Date | 2008-08-28 |
United States Patent
Application |
20080207898 |
Kind Code |
A1 |
ALLEGRINI; Pietro ; et
al. |
August 28, 2008 |
PROCESSES FOR THE PREPARATION OF AMINOETHOXYBENZYL ALCOHOLS
Abstract
The present invention provides processes and intermediates for
the preparation of aminoethoxybenzyl alcohols of Formula I useful
in the production of pharmaceutically useful compounds.
##STR00001##
Inventors: |
ALLEGRINI; Pietro; (Milan,
IT) ; BARRECA; Giuseppe; (Lecco, IT) ;
SORIATO; Giorgio; (Verona, IT) |
Correspondence
Address: |
WilmerHale/Wyeth
60 STATE STREET
BOSTON
MA
02109
US
|
Assignee: |
WYETH
Madison
NJ
|
Family ID: |
36570630 |
Appl. No.: |
12/104960 |
Filed: |
April 17, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11329503 |
Jan 11, 2006 |
7375251 |
|
|
12104960 |
|
|
|
|
60643505 |
Jan 13, 2005 |
|
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|
Current U.S.
Class: |
540/607 ;
564/336 |
Current CPC
Class: |
C07D 295/088 20130101;
C07C 213/02 20130101 |
Class at
Publication: |
540/607 ;
564/336 |
International
Class: |
C07D 223/04 20060101
C07D223/04; C07C 215/28 20060101 C07C215/28 |
Claims
1. A compound of Formula VI: ##STR00030## wherein: R.sub.1 and
R.sub.2 are each independently selected from the group consisting
of C.sub.1-C.sub.12 alkyl, heteroaryl and aryl; or R.sub.1 and
R.sub.2 together form a group of formula --(CH.sub.2).sub.n-- that
is optionally substituted with from 1-3 substituents selected from
the group consisting of CN, NO.sub.2, C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, aryl, heteroaryl, halogen, OH, NR.sub.5R.sub.5', CHO,
COOR.sub.5, CONR.sub.5R.sub.5', SR.sub.5, --O-aryl and
--O-heteroaryl; R.sub.3 is selected from the group consisting of H,
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl, heteroaryl, CN,
NO.sub.2 and halogen; R.sub.4 is H or C.sub.1-6 alkoxy; R.sub.5 and
R.sub.5' are each, independently, H or C.sub.1-6 alkyl; and n is 2,
3, 4, 5, 6 or 7.
2. The compound of claim 1 wherein: R.sub.1 and R.sub.2 together
form a group of formula --(CH.sub.2).sub.n-- that is optionally
substituted with from 1-3 substituents selected from the group
consisting of CN, NO.sub.2, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
aryl, heteroaryl, halogen, OH, NR.sub.5R.sub.5', CHO, COOR.sub.5,
CONR.sub.5R.sub.5', SR.sub.5, --O-aryl and --O-heteroaryl; and
R.sub.4 is H.
3. The compound of claim 1 wherein: R.sub.1 and R.sub.2 together
form --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5-- or
--(CH.sub.2).sub.6--; and R.sub.3 is H, C.sub.1-6 alkyl or
halogen.
4. The compound of claim 3 wherein R.sub.3 is H.
5. The compound of claim 4 wherein R.sub.4 is H.
6. The compound of claim 1 wherein: R.sub.1 and R.sub.2 together
form --(CH.sub.2).sub.6--; and R.sub.3 is H, C.sub.1-6 alkyl or
halogen.
7. The compound of claim 6 wherein R.sub.3 is H.
8. The compound of claim 7 wherein R.sub.4 is H.
9. The compound of claim 1 wherein the group represented by
COR.sub.4 is in the para position relative to
OCH.sub.2CONR.sub.1R.sub.2.
10. The compound of claim 9 wherein: R.sub.1 and R.sub.2 together
form --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5-- or
--(CH.sub.2).sub.6--; and R.sub.3 is H, C.sub.1-6 alkyl or
halogen.
11. The compound of claim 10 wherein R.sub.3 is H.
12. The compound of claim 11 wherein R.sub.4 is H.
13. The compound of claim 9 wherein: R.sub.1 and R.sub.2 together
form --(CH.sub.2).sub.6--; and R.sub.3 is H, C.sub.1-6 alkyl or
halogen.
14. The compound of claim 13 wherein R.sub.3 is H.
15. The compound of claim 14 wherein R.sub.4 is H.
16. A compound of Formula I: ##STR00031## wherein: R.sub.1 and
R.sub.2 are each, independently, selected from the group consisting
of C.sub.1-C.sub.12 alkyl, heteroaryl and aryl; or R.sub.1 and
R.sub.2 together form a group of formula --(CH.sub.2).sub.n-- that
is optionally substituted with from 1-3 substituents selected from
the group consisting of CN, NO.sub.2, C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, aryl, heteroaryl, halogen, OH, NR.sub.5R.sub.5', CHO,
COOR.sub.5, CONR.sub.5R.sub.5', SR.sub.5--O-aryl and
--O-heteroaryl; R.sub.3 is selected from the group consisting of H,
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl, heteroaryl, CN,
NO.sub.2 and halogen; R.sub.5 and R.sub.5' are each, independently,
H or C.sub.1-6 alkyl; and n is 2, 3, 4, 5, 6 or 7; prepared by the
process comprising: a) reacting an .alpha.-haloacetamide of Formula
IV: ##STR00032## wherein X.sub.1 is Cl or Br, and R.sub.1 and
R.sub.2 are defined as hereinabove; with a compound of Formula V:
##STR00033## wherein R.sub.4 is H or C.sub.1-6 alkoxy, and R.sub.3
is defined as hereinabove; in the presence of base and optionally
in the presence of a phase transfer catalyst for a time and under
conditions effective to form a phenoxyacetamide of Formula VI:
##STR00034## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are
defined as hereinabove; and b) reacting the phenoxyacetamide of
Formula VI with a reducing agent for a time and under conditions
effective to form said compound of Formula I.
17. The compound of claim 16, wherein the reducing agent comprises
lithium aluminum hydride or sodium bis(2-methoxyethoxy)-aluminum
hydride.
18. A compound of Formula I: ##STR00035## wherein: R.sub.1 and
R.sub.2 are each, independently, selected from the group consisting
of C.sub.1-C.sub.12 alkyl, heteroaryl and aryl; or R.sub.1 and
R.sub.2 together form a group of formula --(CH.sub.2).sub.n-- that
is optionally substituted with from 1-3 substituents selected from
the group consisting of CN, NO.sub.2, C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, aryl, heteroaryl, halogen, OH, NR.sub.5R.sub.5', CHO,
COOR.sub.5, CONR.sub.5R.sub.5', SR.sub.5--O-aryl and
--O-heteroaryl; R.sub.3 is selected from the group consisting of H,
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl, heteroaryl, CN,
NO.sub.2 and halogen; R.sub.5 and R.sub.5' are each, independently,
H or C.sub.1-6 alkyl; and n is 2, 3, 4, 5, 6 or 7; prepared by the
process comprising: a) reacting an acid halide of Formula II:
##STR00036## wherein X.sub.1 and X.sub.2 are each, independently,
Cl or Br; with an amine of Formula III: ##STR00037## wherein
R.sub.1 and R.sub.2 are defined as hereinabove; for a time and
under conditions effective to form an .alpha.-haloacetamide of
Formula IV: ##STR00038## wherein X.sub.1, R.sub.1 and R.sub.2 are
defined as hereinabove; b) reacting the .alpha.-haloacetamide of
Formula IV with a compound of Formula V: ##STR00039## wherein
R.sub.4 is H or C.sub.1-6 alkoxy; in the presence of base and
optionally in the presence of a phase transfer catalyst for a time
and under conditions effective to form a phenoxyacetamide of
Formula VI ##STR00040## wherein R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are defined as hereinabove; and c) reacting the
phenoxyacetamide of Formula VI with a reducing agent for a time and
under conditions effective to form said compound of Formula I.
19. The compound of claim 18, wherein the reducing agent comprises
lithium aluminum hydride or sodium bis(2-methoxyethoxy)-aluminum
hydride.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of U.S. patent application
Ser. No. 11/329,503 filed Jan. 11, 2006, which claims the benefit
of priority from provisional U.S. Patent Application Ser. No.
60/643,505 filed Jan. 13, 2005, each of the aforementioned
applications is incorporated herein in its entirety.
FIELD OF THE INVENTION
[0002] This present invention relates to processes and
intermediates for the preparation of aminoethoxybenzyl alcohols
that can be used in the preparation of pharmaceuticals.
BACKGROUND OF THE INVENTION
[0003] Aminoethoxybenzyl alcohols are widely useful as
intermediates for the preparation of various pharmaceuticals. For
example, conversion of the benzylic alcohol to a halogen results in
the appropriate intermediate for the preparation of indole based
estrogen receptor modulators as described in, for example, U.S.
Pat. No. 5,998,402. Additionally, similar benzylic halides that can
be derived from their corresponding benzylic alcohols have been
described as intermediates used in the preparation of compounds
known to have inhibitory activity against various matrix
metalloproteinase enzymes as well as against tumor necrosis factor
.alpha. converting enzyme (TACE) (see, e.g., U.S. Pat. No.
5,929,097).
[0004] Previous processes for preparing aminoethoxybenzyl alcohols
are reported in U.S. Pat. Nos. 6,005,102, 6,242,605 and 6,268,504,
as well as PCT Pat. Appln. No. WO 99/19293. Reports of preparation
of related compounds can also be found in German patent document,
DE 4438028. A summary of such a method is shown in Scheme I:
##STR00002##
[0005] The reported synthetic methods employ unstable materials
such as haloethylamines, which are well known to be difficult to
handle (see, e.g., Ludwig Knorr, Berichte, (1904) 37: 3507). The
multi-step procedures also reportedly employ dimethylformamide
(DMF) as solvent, an expensive and difficult solvent to handle,
especially in large scale preparations. Accordingly, more efficient
methods for preparing aminoethoxybenzyl alcohols are needed. The
processes and intermediates described herein help meet these and
other needs.
SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention provides processes for
preparing a compound of Formula I:
##STR00003##
wherein:
[0007] R.sub.1 and R.sub.2 are, each, independently, selected from
C.sub.1-C.sub.12 alkyl, heteroaryl, or aryl; or
[0008] R.sub.1 and R.sub.2 together form (CH.sub.2).sub.n
optionally substituted with from 1-3 substituents selected from CN,
NO.sub.2, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl, heteroaryl,
halogen, OH, NR.sub.5R.sub.5', CHO, COOR.sub.5, CONR.sub.5R.sub.5',
SR.sub.5, --O-aryl or --O-heteroaryl;
[0009] R.sub.3 is H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl,
heteroaryl, CN, NO.sub.2 or halogen;
[0010] R.sub.5 and R.sub.5' are each, independently, H or C.sub.1-6
alkyl; and
[0011] n is 2, 3, 4, 5, 6 or 7;
comprising reducing a phenoxyacetamide of Formula VI:
##STR00004##
wherein R.sub.4 is H or C.sub.1-6 alkoxy; with a reducing agent for
a time and under conditions effective to form the compound of
Formula I.
[0012] In a further aspect, the present invention provides
processes for preparing a compound of Formula I:
##STR00005##
wherein the constituent variables are as define above,
comprising:
[0013] a) reacting an .alpha.-haloacetamide of Formula IV:
##STR00006##
wherein X.sub.1 is Cl or Br; with a compound of Formula V:
##STR00007##
wherein R.sub.4 is H or C.sub.1-6 alkoxy; in the presence of base
and optionally in the presence of a phase transfer catalyst for a
time and under conditions effective to form a phenoxyacetamide of
Formula VI:
##STR00008##
and
[0014] b) reducing the phenoxyacetamide of Formula VI with a
reducing agent for a time and under conditions effective to form
the compound of Formula I.
[0015] In a further aspect, the present invention provides a
process for preparing a compound of Formula I:
##STR00009##
wherein the constituent variables are as defined above;
comprising:
[0016] a) reacting an acid halide of Formula II:
##STR00010##
wherein X.sub.1 and X.sub.2 are each, independently, Cl or Br with
an amine of Formula III:
##STR00011##
for a time and under conditions effective to form an
.alpha.-haloacetamide of Formula IV:
##STR00012##
[0017] b) reacting the .alpha.-haloacetamide of Formula IV with a
compound of Formula V:
##STR00013##
wherein R.sub.4 is H or C.sub.1-6 alkoxy; in the presence of base
and optionally in the presence of a phase transfer catalyst for a
time and under conditions effective to form a phenoxyacetamide of
Formula VI:
##STR00014##
and
[0018] c) reducing the phenoxyacetamide of Formula VI with a
reducing agent for a time and under conditions suitable for forming
the compound Formula I.
[0019] In some embodiments, the base comprises an inorganic
carbonate such as Na.sub.2CO.sub.3 or K.sub.2CO.sub.3.
[0020] In some embodiments, the reducing agent comprises lithium
aluminum hydride or sodium bis(2-methoxyethoxy)-aluminum hydride,
preferably, sodium bis(2-methoxyethoxy)-aluminum hydride.
[0021] In some embodiments, one or more steps of the processes of
the invention are carried out in the presence of solvent. In some
embodiments, the solvent comprises an aromatic hydrocarbon solvent,
a halogenated hydrocarbon solvent or an ether solvent. In some
embodiments, the solvent comprises an aromatic hydrocarbon solvent,
preferably, toluene.
[0022] In some embodiments, a phase transfer catalyst is present in
the reaction of compounds IV and V. In some embodiments, the phase
transfer catalyst is a quaternary amine, for example,
tricaprylmethylammonium chloride.
[0023] In some embodiments, the invention provides compounds
prepared by the processes described herein.
[0024] The present invention further provides compounds of Formula
VI:
##STR00015##
wherein:
[0025] R.sub.1 and R.sub.2 are, each, independently, selected from
C.sub.1-C.sub.12 alkyl, heteroaryl or aryl; or
[0026] R.sub.1 and R.sub.2 together form (CH.sub.2).sub.n
optionally substituted with from 1-3 substituents selected from CN,
NO.sub.2, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl, heteroaryl,
halogen, OH, NR.sub.5R.sub.5', CHO, COOR.sub.5, CONR.sub.5R.sub.5',
SR.sub.5, --O-aryl or --O-heteroaryl;
[0027] R.sub.3 is H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl,
heteroaryl, CN, NO.sub.2 or halogen;
[0028] R.sub.4 is H or C.sub.1-6 alkoxy;
[0029] R.sub.5 and R.sub.5' are each, independently, H or C.sub.1-6
alkyl; and
[0030] n is 2, 3, 4, 5, 6 or 7.
[0031] In some embodiments of the present compounds and processes,
R.sub.1 and R.sub.2 together form a group of formula
--(CH.sub.2).sub.n-- that is optionally substituted with from 1-3
substituents selected from CN, NO.sub.2, C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, aryl, heteroaryl, halogen, OH, NR.sub.5R.sub.5', CHO,
COOR.sub.5, CONR.sub.5R.sub.5', SR.sub.5, --O-aryl or
--O-heteroaryl.
[0032] In some embodiments of the present compounds and processes,
R.sub.1 and R.sub.2 together form --(CH.sub.2).sub.4--,
--(CH.sub.2).sub.5-- or --(CH.sub.2).sub.6--, preferably,
--(CH.sub.2).sub.6--.
[0033] In some embodiments of the present compounds and processes,
R.sub.3 is H, C.sub.1-6 alkyl or halogen, preferably, H.
[0034] In further embodiments of the present compounds and
processes, R.sub.1 and R.sub.2 together form --(CH.sub.2).sub.n--
optionally substituted with from 1-3 substituents selected from CN,
NO.sub.2, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl, heteroaryl,
halogen, OH, NR.sub.5R.sub.5', CHO, COOR.sub.5, CONR.sub.5R.sub.5',
SR.sub.5, --O-aryl or --O-heteroaryl; R.sub.3 is H, C.sub.1-6 alkyl
or halogen; and n is 4, 5 or 6. Preferably, R.sub.3 is H and n is
6. More preferably, R.sub.1 and R.sub.2 together form
--(CH.sub.2).sub.6-- and R.sub.3 is H.
[0035] In some embodiments of the present compounds and processes,
X.sub.1 is Cl, or X.sub.2 is Cl, or both X.sub.1 and X.sub.2 are
Cl.
[0036] In some further embodiments of the present compounds and
processes, R.sub.4 is H.
[0037] In some embodiments of the present compounds and processes,
the group of formula COR.sub.4 is in the para position relative to
the phenolic hydroxyl group of formula V. In further embodiments of
the present compounds and processes, the group of formula COR.sub.4
is in the para position relative to the OCH.sub.2CONR.sub.1R.sub.2
group of formula VI. In some such embodiments of the present
compounds and processes, X.sub.1 is Cl, or X.sub.2 is Cl, or both
X.sub.1 and X.sub.2 are Cl.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0038] The present invention is directed to, inter alia, processes
for the preparation of compounds of Formula I that can be employed
in the preparation of, for example, inhibitors of matrix
metalloproteinases and tumor necrosis factor .alpha. converting
enzyme (TACE) inhibitors, which are useful in the treatment of
various diseases including arthritis, tumor metastasis, tissue
ulceration, abnormal wound healing, periodontal disease, bone
disease, proteinuria, aneurysmal aortic disease, degenerative
cartilage loss following traumatic joint injury, demyelinating
diesases of the nervous system, HIV infection, osteoporosis,
prostatic hypertorphy, infertility, breast cancer, endometrial
hyperplasia and cancer, cardiovascular disease, contraception,
Alzheimer's disease, and melanoma (see, e.g., WO 99/19293).
[0039] In some embodiments, the present invention provides a
process for preparing a compound of Formula I:
##STR00016##
wherein:
[0040] R.sub.1 and R.sub.2 are each, independently, selected from
the group consisting of C.sub.1-C.sub.12 alkyl, heteroaryl and
aryl; or
[0041] R.sub.1 and R.sub.2 together form a group of formula
--(CH.sub.2).sub.n-- that is optionally substituted with from 1-3
substituents selected from the group consisting of CN, NO.sub.2,
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl, heteroaryl, halogen,
OH, NR.sub.5R.sub.5', CHO, COOR.sub.5, CONR.sub.5R.sub.5',
SR.sub.5, --O-aryl and --O-heteroaryl;
[0042] R.sub.3 is selected from the group consisting of H,
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl, heteroaryl, CN,
NO.sub.2 and halogen;
[0043] R.sub.5 and R.sub.5' are each, independently, H or C.sub.1-6
alkyl; and
[0044] n is 2, 3, 4, 5, 6 or 7; comprising reacting a
phenoxyacetamide of Formula VI:
##STR00017##
wherein R.sub.4 is H or C.sub.1-6 alkoxy; with a reducing agent for
a time and under conditions effective to form said compound of
Formula I; wherein optionally the phenoxyacetamide of Formula VI is
formed by a process comprising:
[0045] a) reacting an .alpha.-haloacetamide of Formula IV:
##STR00018## [0046] wherein X.sub.1 is Cl or Br; and [0047] wherein
optionally the .alpha.-haloacetamide of Formula IV is formed by a
process comprising: [0048] i) reacting an acid halide of Formula
II:
[0048] ##STR00019## [0049] wherein X.sub.1 and X.sub.2 are each,
independently, Cl or Br; [0050] with an amine of Formula III:
[0050] ##STR00020## [0051] for a time and under conditions
effective to form an .alpha.-haloacetamide of Formula IV:
[0052] b) with a compound of Formula V:
##STR00021##
[0053] wherein R.sub.4 is H or C.sub.1-6 alkoxy;
in the presence of base and optionally in the presence of a phase
transfer catalyst for a time and under conditions effective to form
the phenoxyacetamide of Formula VI.
[0054] A general outline of the processes of the present invention
is provided in Scheme II, where constituent members of the depicted
compounds of Formulas I, II, III, IV, V, and VI are defined
hereinbelow.
##STR00022##
[0055] Constituent members of compounds of Formulas I, II, III, IV,
V, and VI according to the compounds and processes provided herein
are as described supra.
[0056] According to some embodiments, R.sub.1 and R.sub.2 together
form (CH.sub.2).sub.n optionally substituted with from 1-3
substituents selected from CN, NO.sub.2, C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, aryl, heteroaryl, halogen, OH, NR.sub.5R.sub.5', CHO,
COOR.sub.5, CONR.sub.5R.sub.5', SR.sub.5, --O-aryl or
--O-heteroaryl; R.sub.3 is H, C.sub.1-6 alkyl or halogen; and n is
4, 5 or 6.
[0057] According to further embodiments, R.sub.1 and R.sub.2
together form (CH.sub.2).sub.n optionally substituted with from 1-3
substituents selected from CN, NO.sub.2, C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, aryl, heteroaryl, halogen, OH, NR.sub.5R.sub.5', CHO,
COOR.sub.5, CONR.sub.5R.sub.5', SR.sub.5, --O-aryl or
--O-heteroaryl; R.sub.3 is H; and n is 6.
[0058] In some further embodiments, R.sub.1 and R.sub.2 together
form (CH.sub.2).sub.6 and R.sub.3 is H.
[0059] The present invention provides, in part, a process for
preparing a compound Formula I:
##STR00023##
comprising reacting a phenoxyacetamide of Formula VI:
##STR00024##
with a reducing agent for a time and under conditions suitable for
forming the compound Formula I.
[0060] Suitable reducing agents include inorganic metal hydrides
such as aluminum hydride salts. Some examples of aluminum hydride
salts include lithium aluminum hydride (LAH), sodium
bis(2-methoxyethoxy)-aluminum hydride (commercially available as
VITRIDE.RTM.), and the like. Suitable reducing agents can, for
example, concomitantly reduce the amide and COR.sub.4 moieties to
their respective amine and alcohol. The reducing agent can be
provided in molar excess (more reducing equivalents than
theoretically needed to reduce the full amount of compound of
Formula VI to the compound of Formula I), and/or combined with the
compound of Formula VI in such a way that the reducing agent is
present in molar excess for the duration of the addition (e.g.,
compound of Formula VI in solution can be added to a vessel
containing at least enough reducing agent to fully reduce the
compound of Formula VI to a compound of Formula I).
[0061] The reduction can be conducted at any reasonable temperature
that does not lead to any substantial decomposition of reactants,
products or solvent (if present). The temperature at which the
reduction is carried out can be controlled by well known
techniques. For example, the reaction temperature can be maintained
between about 15 to about 35.degree. C., about 20 to about
30.degree. C. or about 20 to about 25.degree. C.
[0062] Compounds of Formula VI can be prepared by any method such
as an alkylation reaction involving the reacting of an
.alpha.-haloacetamide of Formula IV:
##STR00025##
with a compound of Formula V:
##STR00026##
in the presence of base and optionally in the presence of a phase
transfer catalyst for a time and under conditions suitable for
forming the phenoxyacetamide of Formula VI.
[0063] Suitable bases for the alkylation reaction can contain
inorganic carbonates such as alkaline earth carbonates and alkali
carbonates, inorganic hydroxides such as alkaline earth hydroxides
and alkali hydroxides, and inorganic hydrides such as alkali
hydrides, and the like. According to some embodiments, the base is
an alkali carbonate such as K.sub.2CO.sub.3 or Na.sub.2CO.sub.3.
Base can be present in the reaction in molar excess with respect to
the compound of Formula V. In some embodiments, the a molar ratio
(base:compound of Formula V) can be about 1.01 to about 1.5, about
1.01 to about 1.3 or about 1.01 to about 1.2.
[0064] Suitable phase transfer catalysts include quaternary amine
salts such as tetralkylammonium halides (e.g., tetrabutylammonium
bromide, tricaprylmethylammonium chloride (ALIQUAT.RTM.), etc.) and
aralkyltrialkylammonium halides (e.g., benzyltrimethylammonium
chloride). Other suitable phase transfer catalysts include
phosphonium salts and crown ethers. The phase transfer catalyst can
be provided in a catalytic amount (e.g., amount sufficient to
accelerate the alkylation reaction rate), such as in a molar ratio
(phase transfer catalyst:compound of Formula V) of about 0.01,
about 0.05, about 0.1, about 0.2, about 0.5 or less than about
1.0.
[0065] The alkylation can be carried out at elevated temperature,
such as reflux temperature. In some embodiments, elevated
temperature is about 30 to about 150.degree. C., 50 to about
120.degree. C., or about 80 to about 120.degree. C. or about 110 to
about 115.degree. C. The reaction can be maintained at elevated
temperature for enough time to ensure substantial reaction
completion, such as for example, about 1 to about 24 hours, about 2
to about 12 hours or about 2 to about 5 hours.
[0066] In some preferred embodiments, the compound of Formula V is
a 4-hydroxybenzoate alkyl ester or 4-hydroxybenzaldehyde,
preferably, 4-hydroxybenzaldehyde.
[0067] Compounds of Formula IV can be prepared by any method such
as a reaction involving the reaction of an acid halide of Formula
II:
##STR00027##
with an amine of Formula III:
##STR00028##
for a time and under conditions suitable for forming the
.alpha.-haloacetamide of Formula IV.
[0068] The reaction can be carried out such that the amine of
Formula III is provided in molar excess relative to the amount of
compound of Formula II. For example, the molar ratio (compound of
Formula III:compound of Formula II) can be about 1.1, about 1.5,
about 2.0, about 2.5, about 3, about 5 or about 10. The
condensation reaction can be carried out at any suitable
temperature such as from about -10 to about 25.degree. C., about
-10 to about 10.degree. C. or about -5 to about 5.degree. C.
[0069] The reaction can further be conducted in the presence of a
tertiary amine such as a trialkylamine (e.g., trimethylamine,
triethylamine, etc). The tertiary amine can be present in a
catalytic amount.
[0070] In some embodiments, the compound of Formula II is
.alpha.-chloroacetyl chloride. In some further embodiments, the
compound of Formula III is pyrrolidine, piperidine or
hexamethyleneimine, preferably, hexamethyleneimine.
[0071] In some embodiments of the invention, multi-step processes
are carried out stepwise and each intermediate is isolated before
proceeding to the next step. In other embodiments of the invention,
some of the intermediates are isolated and others are not. In yet
other embodiments, none of the intermediates are completely
isolated and all of the reactions take place in a single reactor
vessel.
[0072] The processes described herein have numerous advantages
readily apparent to the skilled artisan. For example, the use of
unstable haloethylamines is avoided, and less costly solvents can
be used than for similar processes. Furthermore, the entire
reaction sequence can be typically accomplished in a one-pot
procedure leading to a more efficient preparation.
[0073] The processes of the invention can be performed on any
desired scale, for example, milligram scale or gram scale. In some
embodiments, the processes are performed on the larger scales,
i.e., kilogram scale or larger.
[0074] It is understood in the generic description above and for
other groups described herein that, in each instance, any variable
group may be independently substituted by their allowed groups.
Thus, for example, where a structure is described wherein two
R.sub.2 groups are simultaneously present on the same compound, the
two R.sub.2 groups can represent different groups.
[0075] The term "alkyl", employed alone, is defined herein as,
unless otherwise stated, either a straight-chain or branched
saturated hydrocarbon moiety. In some embodiments, the alkyl moiety
contains 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.
Examples of saturated hydrocarbon alkyl moieties include, but are
not limited to, chemical groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, higher
homologs such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the
like.
[0076] The term "cycloalkyl", employed alone or in combination with
other terms, is defined herein as, unless otherwise stated, a
monocyclic, bicyclic, tricyclic, fused, bridged, or spiro
monovalent saturated hydrocarbon moiety of 3-8 or 3-7 carbon atoms.
Any suitable ring position of the cycloalkyl moiety can be
covalently linked to the defined chemical structure. Examples of
cycloalkyl moieties include, but are not limited to, chemical
groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, norbornyl, adamantyl, spiro[4.5]decanyl, and homologs,
isomers, and the like.
[0077] The terms "halo" or "halogen", employed alone or in
combination with other terms, is defined herein as, unless
otherwise stated, fluoro, chloro, bromo or iodo.
[0078] The term "aryl", employed alone or in combination with other
terms, is defined herein as, unless otherwise stated, an aromatic
carbocyclic moiety of up to 14 carbon atoms, e.g., 6-14 carbon
atoms, which can be a single ring (monocyclic) or multiple rings
(bicyclic, up to three rings) fused together or linked covalently.
Any suitable ring position of the aryl moiety can be covalently
linked to the defined chemical structure. Examples of aryl moieties
include, but are not limited to, chemical groups such as phenyl,
1-naphthyl, 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl,
biphenyl, anthryl, phenanthryl, fluorenyl, indanyl, biphenylenyl,
acenaphthenyl, acenaphthylenyl, and the like. Aryl moieties can be
optionally substituted by one or more substituents selected from
halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN or
NO.sub.2.
[0079] The term "arylalkyl" or "aralkyl," employed alone or in
combination with other terms, is defined herein as, unless
otherwise stated, an alkyl, as herein before defined, suitably
substituted on any open ring position with an aryl moiety wherein
the alkyl chain is a saturated hydrocarbon moiety. In some
embodiments, the alkyl moiety has from 1 to 8, 1 to 6, or 1 to 4
carbon atoms. Examples of arylalkyl moieties include, but are not
limited to, chemical groups such as benzyl, 1-phenylethyl,
2-phenylethyl, diphenylmethyl, 3-phenylpropyl, 2-phenylpropyl,
fluorenylmethyl, and homologs, isomers, and the like.
[0080] As used herein, "heteroaryl" groups are aromatic
heterocarbocyclyl groups and include monocyclic and polycyclic
aromatic hydrocarbons that have at least one heteroatom ring member
(e.g., 1 to 4) such as sulfur, oxygen, or nitrogen and 5-20 ring
members. Heteroaryl groups include, without limitation, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl,
isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,
oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl,
pyrazolyl, triazolyl, tetrazolyl indazolyl, 1,2,4-thiadiazolyl,
isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-5-oxide, 2,3-dihydrobenzothienyl-5-dioxide,
benzoxazolin-2-on-yl, indolinyl, benzodioxolanyl, benzodioxane, and
the like. In some embodiments, heteroaryl groups can have from 1 to
about 20 carbon atoms, and in further embodiments from about 3 to
about 20 carbon atoms. In some embodiments, heteroaryl groups have
1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. Heteroaryl
groups can be optionally substituted by one or more substituents
selected from halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
CN or NO.sub.2 group.
[0081] The term "alkoxy", employed alone or in combination with
other terms, is defined herein as, unless otherwise stated,
--O-alkyl. Examples of alkoxy moieties include, but are not limited
to, chemical groups such as methoxy, ethoxy, isopropoxy,
sec-butoxy, tert-butoxy, and homologs, isomers, and the like.
[0082] The compounds of the present invention can contain an
asymmetric atom, and some of the compounds can contain one or more
asymmetric atoms or centers, which can thus give rise to optical
isomers (enantiomers) and diastereomers. While shown without
respect to the stereochemistry in Formula I, the present invention
includes such optical isomers (enantiomers) and diastereomers
(geometric isomers); as well as the racemic and resolved,
enantiomerically pure R and S stereoisomers; as well as other
mixtures of the R and S stereoisomers and pharmaceutically
acceptable salts thereof. Optical isomers can be obtained in pure
form by standard procedures known to those skilled in the art, and
include, but are not limited to, diastereomeric salt formation,
kinetic resolution and asymmetric synthesis. It is also understood
that this invention encompasses all possible regioisomers, and
mixtures thereof, which can be obtained in pure form by standard
separation procedures known to those skilled in the art, and
include, but are not limited to, column chromatography, thin-layer
chromatography and high-performance liquid chromatography.
[0083] The compounds provided herein can also include their salts
formed from, for example, mineral or organic acid salts of basic
residues such as amines, alkali or organic salts of acidic residues
such as carboxylic acids, and the like. The invention includes
acceptable salt forms formed from the addition reaction with either
inorganic or organic acids. Additionally, this invention includes
quaternary ammonium salts of the compounds herein, which can be
prepared by reacting the nucleophilic amines with a suitably
reactive alkylating agent such as an alkyl halide or benzyl halide.
Lists of suitable salts are found in Remington's Pharmaceutical
Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.
1418, the disclosure of which is hereby incorporated by
reference.
[0084] As used herein, the term "reacting" refers to the bringing
together of designated chemical reactants such that a chemical
transformation takes place generating a compound different from any
initially introduced into the system. Reacting can take place in
the presence or absence of solvent.
[0085] The processes described herein can be monitored according to
any suitable method known in the art. For example, product
formation can be monitored by spectroscopic means, such as nuclear
magnetic resonance spectroscopy (e.g., .sup.1H or .sup.13C),
infrared spectroscopy, spectrophotometry (e.g., UV-visible) or mass
spectrometry, or by chromatography such as high performance liquid
chromatograpy (HPLC) or thin layer chromatography.
[0086] The reactions of the processes described herein can be
carried out in suitable solvents that can be readily selected by
one of skill in the art of organic synthesis. Suitable solvents can
be substantially nonreactive with the starting materials
(reactants), the intermediates, or products at the temperatures at
which the reactions are carried out, e.g., temperatures which can
range from the solvent's freezing temperature to the solvent's
boiling temperature. A given reaction can be carried out in one
solvent or a mixture of more than one solvent. Depending on the
particular reaction step, suitable solvents for a particular
reaction step can be selected. In some embodiments, reactions can
be carried out in the absence of solvent, such as when at least one
of the reagents is a liquid or gas. Some example solvents suitable
for the processes described herein include halogenated hydrocarbons
(e.g., methylene chloride), aromatic hydrocarbons (e.g., benzene,
toluene, etc.), and ethers (e.g., diethyl ether, tetrahydrofuran).
In some embodiments, the solvent is an aromatic hydrocarbon such as
toluene.
[0087] The reactions of the processes described herein can be
carried out at appropriate temperatures that can be readily
determined by the skilled artisan. Reaction temperatures will
depend on, for example, the melting and boiling points of the
reagents and solvent, if present, the thermodynamics of the
reaction (e.g., vigorously exothermic reactions are typically
carried out at reduced temperatures) and the kinetics of the
reaction (e.g., a high activation energy barrier typically
necessitates elevated temperatures). "Elevated temperature" refers
to temperatures above room temperature (about 20.degree. C.) and
"reduced temperature" refers to temperatures below room
temperature.
[0088] The reactions of the processes described herein can be
carried out in air or under an inert atmosphere. Typically,
reactions containing reagents or products that are substantially
reactive with air can be carried out using air-sensitive synthetic
techniques that are well known to the skilled artisan.
[0089] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, can also be provided in combination in a single
embodiment. Conversely, various features of the invention which
are, for brevity, described in the context of a single embodiment,
can also be provided separately or in any suitable
subcombination.
[0090] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of noncritical parameters that can be changed or modified
to yield essentially the same results.
EXAMPLE
PREPARATION OF
[4-(2-HEXAMETHYLENEIMINO-1-YL-ETHOXY)-PHENYL]-METHANOL
##STR00029##
[0091] Preparation of
1-Hexamethyleneimin-1-Yl-2-Chloro-Ethanone
[0092] Hexamethyleneimine (76.4 kg) was added to a solution of
2-chloro-acetyl chloride (43.5 kg) and toluene (200 kg) maintaining
the temperature between 0.degree. C. and -3.degree. C. At the end
of the reaction, water (57.8 kg) was slowly added and the resultant
mixture was heated to 20-25.degree. C. The aqueous layer was
discharged and the organic layer containing
1-chloroacetyl-hexamethyleneimine was used in the subsequent step
without any further purification.
Preparation of
4-(2-Oxo-2-Hexamethyleneimino-Ethoxy)-Benzaldehyde
[0093] The phase transfer catalyst tricaprylmethylammonium
chloride, K.sub.2CO.sub.3 (58.5 Kg), 4-hydroxybenzaldehyde (50 kg)
and toluene (8.5 kg to rinse the lines) were added to the solution
of 1-chloroacetyl-hexamethyleneimine obtained from the previous
step. The resulting mixture was heated to reflux temperature and
water was removed by azeotropic distillation. In this way, the
suspension reached the internal temperature of 112.degree.
C.-113.degree. C. At the end of the reaction, the mixture was
cooled at 65.degree. C. Water (115.5 kg) was added to the reaction
and the resultant mixture was kept under stirring for 30 minutes.
The aqueous layer was separated and the organic solution was washed
with at 55-65.degree. C. with diluted sodium hydroxide (72.6 kg of
NaOH 4% w/w) and then with water (57.6 kg). Water was removed by
azeotropic distillation and the resultant solution was concentrated
by vacuum distillation until a residual volume of 240 liters was
reached. The resultant solution was kept at 60.degree. C. to
prevent spontaneous crystallization of
4-(2-oxo-2-hexamethyleneimino-ethoxy)-benzaldehyde.
Preparation of 4-(2-Hexamethyleneimino-Ethoxy)-Benzyl Alcohol
[0094] The solution from the previous step was added to sodium
bis(2-methoxyethoxy)-aluminum hydride (179.9 kg) diluted with
toluene (38.7 kg). During the addition, the temperature was kept
between 20.degree. C. and 30.degree. C. At the end of the reaction,
the mixture was poured into 15% w/w sodium hydroxide (176.2 kg).
During the quenching, the temperature was kept below 30.degree. C.
Toluene was then charged (56.8 kg) and the aqueous layer was
separated. After several washings with water (overall amount 265 kg
divided into 5 portions), the organic phase was submitted to
azeotropic distillation of the residual moisture. The resultant
toluene solution was cooled at 20-25.degree. C. According to the
HPLC assay of the mixture, 84.5 kg of
4-(2-hexamethyleneimino-ethoxy)-benzyl alcohol was obtained (88%
from 2-chloroacetyl chloride).
[0095] It is intended that each of the patents, applications, and
printed publications, including books, mentioned in this patent
document be hereby incorporated by reference in their entirety.
[0096] As those skilled in the art will appreciate, numerous
changes and modifications may be made to the embodiments of the
invention without departing from the spirit of the invention. It is
intended that all such variations fall within the scope of the
invention.
* * * * *