U.S. patent application number 10/934031 was filed with the patent office on 2005-06-30 for process for the preparation of pyrazolo[4,3-d]pyrimidin-7-one compounds and intermediates thereof.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Allerton, Charlotte Moira Norfor, Barber, Christopher Gordon, Devries, Keith Michael, Harris, Laurence James, Levett, Philip Charles, Negri, Joanna Teresa, Rawson, David James, Wood, Albert Shaw.
Application Number | 20050143367 10/934031 |
Document ID | / |
Family ID | 27546604 |
Filed Date | 2005-06-30 |
United States Patent
Application |
20050143367 |
Kind Code |
A1 |
Allerton, Charlotte Moira Norfor ;
et al. |
June 30, 2005 |
Process for the preparation of pyrazolo[4,3-d]pyrimidin-7-one
compounds and intermediates thereof
Abstract
A process is provided for the preparation of compounds of
formula (I) herein comprising reacting a compound of formula (II),
(III), (IV) or (V) in the presence of .sup.-OR.sup.3 and a
hydroxide trapping agent or in the case of compounds of formula
(IV) reacting in the presence of an auxiliary base and a hydroxide
trapping agent ( i.e. .sup.-OR.sup.3 is substituted by the
auxiliary base), wherein X is a leaving group and R.sup.1 to
R.sup.4 are as defined.
Inventors: |
Allerton, Charlotte Moira
Norfor; (Kent, GB) ; Barber, Christopher Gordon;
(Kent, GB) ; Devries, Keith Michael; (Carmel,
IN) ; Harris, Laurence James; (Kent, GB) ;
Levett, Philip Charles; (Kent, GB) ; Negri, Joanna
Teresa; (Mystic, CT) ; Rawson, David James;
(Kent, GB) ; Wood, Albert Shaw; (Kent,
GB) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
27546604 |
Appl. No.: |
10/934031 |
Filed: |
September 3, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10934031 |
Sep 3, 2004 |
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09916099 |
Jul 26, 2001 |
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6809200 |
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60276532 |
Mar 16, 2001 |
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60292378 |
May 21, 2001 |
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Current U.S.
Class: |
514/210.21 ;
514/262.1; 544/255 |
Current CPC
Class: |
C07D 487/04
20130101 |
Class at
Publication: |
514/210.21 ;
514/262.1; 544/255 |
International
Class: |
A61K 031/519; C07D
487/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 28, 2000 |
GB |
0018660.1 |
Mar 26, 2001 |
GB |
0107526.6 |
Apr 26, 2001 |
GB |
0110251.6 |
Claims
1. A process for the preparation of a compound of general formula
(I): 33or a pharmaceutically or veterinarily acceptable salt,
pro-drug, polymorph and/or solvate thereof, wherein Q represents O
or NR.sup.5 R.sup.1 represents H, lower alkyl, Het, alkylHet, aryl
or alkylaryl (which latter five groups are all optionally
substituted and/or terminated with one or more substituents
selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl),
OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9,
C(O)NR.sup.10OR.sup.11, NR.sup.12R.sup.13 and
SO.sub.2NR.sup.14R.sup.15) R.sup.2 represents H, halo, cyano,
nitro, OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9,
C(O)NR.sup.10OR.sup.11, NR.sup.12R.sup.13,
SO.sub.2NR.sup.14R.sup.15, lower alkyl, Het, alkylHet, aryl or
alkylaryl (which latter five groups are all optionally substituted
and/or terminated with one or more substituents selected from halo,
cyano, nitro, lower alkyl, halo(loweralkyl), OR.sup.6,
OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9, C(O)NR.sup.10R.sup.11,
NR.sup.12R.sup.13 and SO.sub.2NR.sup.14R.sup.15) R.sup.3 represents
H, lower alkyl, alkylHet or alkylaryl (which latter three groups
are all optionally substituted and/or terminated with one or more
substituents selected from halo, cyano, nitro, lower alkyl,
halo(loweralkyl), OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8,
C(O)OR.sup.9, C(O)NR.sup.10OR.sup.11, NR.sup.12R.sup.13 and
SO.sub.2NR.sup.14R.sup.15) R.sup.4 represents H, halo, cyano,
nitro, halo(loweralkyl), OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8,
C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13,
NR.sup.16Y(O)R.sup.17, N[Y(O)R.sup.17].sub.2, SOR.sup.18,
SO.sub.2R.sup.19, C(O)AZ, lower alkyl, lower alkenyl, lower
alkynyl, Het, alkylHet, aryl, alkylaryl (which latter seven groups
are all optionally substituted and/or terminated with one or more
substituents selected from halo, cyano, nitro, lower alkyl,
halo(loweralkyl), OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8,
C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13 and
SO.sub.2NR.sup.14R.sup.15) Y represents C or S(O) A represents
lower alkylene Z represents OR.sup.6, halo, Het or aryl (which
latter two groups are both optionally substituted with one or more
substituents selected from halo, cyano, nitro, lower alkyl,
halo(loweralkyl), OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8,
C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13 and
SO.sub.2NR.sup.14R.sup.15) R.sup.10 and R.sup.11 independently
represent H or lower alkyl (which latter group is optionally
substituted and/or terminated with one or more substituents
selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl),
OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9,
C(O)NR.sup.10aR.sup.11a, NR.sup.12R.sup.13,
SO.sub.2NR.sup.14R.sup.15 and NR.sup.20S(O).sub.2R.sup.21 or Het or
aryl optionally substituted with one or more of said latter
thirteen groups) or one of R.sup.10 and R.sup.11 may be lower
alkoxy, amino or Het, which latter two groups are both optionally
substituted with lower alkyl R.sup.10a and R.sup.11a independently
represent R.sup.10 and R.sup.11 as defined above, except that they
do not represent groups that include lower alkyl, Het or aryl, when
these three groups are substituted and/or terminated (as
appropriate) by one or more substituents that include one or more
C(O)NR.sup.10aR.sup.11a and/or NR.sup.12R.sup.13 groups R.sup.12
and R.sup.13 independently represent H or lower alkyl (which latter
group is optionally substituted and/or terminated with one or more
substituents selected from OR.sup.6, C(O)OR.sup.9,
C(O)NR.sup.22R.sup.23 and NR.sup.24R.sup.25), one of R.sup.12 or
R.sup.13 may be C(O)-lower alkyl or C(O)Het (in which Het is
optionally substituted with lower alkyl), or R.sup.12 and R.sup.13
together represent C.sub.3-7 alkylene (which alkylene group is
optionally unsaturated, optionally substituted by one or more lower
alkyl groups and/or optionally interrupted by O or NR.sup.26)
R.sup.14 and R.sup.15 independently represent H or lower alkyl or
R.sup.14 and R.sup.15, together with the nitrogen atom to which
they are bound, form a heterocyclic ring R.sup.16 and R.sup.17
independently represent H or lower alkyl (which latter group is
optionally substituted and/or terminated with one or more
substituents selected from OR.sup.6, C(O)OR.sup.9,
C(O)NR.sup.22R.sup.23 and NR.sup.24R.sup.25) or one of R.sup.16 and
R.sup.17 may be Het or aryl, which latter two groups are both
optionally substituted with lower alkyl R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.18, R.sup.19, R.sup.20, R.sup.22, R.sup.23,
R.sup.24 and R.sup.25 independently represent H or lower alkyl
R.sup.18 and R.sup.19 independently represent lower alkyl R.sup.21
represents lower alkyl or aryl R.sup.26 represents H, lower alkyl,
aryl, C(O)R.sup.27 or S(O).sub.2R.sup.28 R.sup.27 represents H,
lower alkyl or aryl R.sup.28 represents lower alkyl or aryl Het
represents an optionally substituted four- to twelve-membered
heterocyclic group, which group contains one or more heteroatoms
selected from nitrogen, oxygen, sulphur and mixtures thereof said
process comprising reacting a compound of formula (II), (III), (IV)
or (V) in the presence of .sup.-OR.sup.3 and a hydroxide trapping
agent or, alternatively, in the case of compounds of formulae (IV)
or (V) reacting in the presence of an auxiliary base and a
hydroxide trapping agent (i.e. .sup.-OR.sup.3 is substituted by the
auxiliary base) 34wherein X is a leaving group and Q and R.sup.1 to
R.sup.4 are as defined above.
2. A process for the preparation of a compound of formula (IA):
35said process comprising reacting a compound of formula (IIA),
(IIIA) or (IVA) respectively 36in the presence of .sup.-OR.sup.3
and a hydroxide trapping agent, or alternatively in the case of
compounds of formula (IVA) reacting in the presence of a hydroxide
trapping agent and an auxiliary base, wherein OR.sup.3 in the case
of formation of compound (IA) and (IVA) is
CH.sub.3(CH.sub.2).sub.3O-- and wherein X in formulae (IIA) and
(IIIA) is a leaving group.
Description
[0001] This invention relates to a series of
pyrazolo[4,3-d]pyrimidin-7-on- e compounds of formula I (as defined
below) and intermediates thereof. More notably, most of the
compounds of interest are inhibitors of type 5 cyclic guanosine
3',5'-monophosphate phosphodiesterase (cGMP PDE5) and have utility
in a variety of therapeutic areas (such as male erectile
dysfunction). A compound of particular interest is
5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-di-
hydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (hereinafter compound of
formula IA).
[0002] Processes for the preparation of compounds of formula I are
disclosed in WO 01/27112. In particular, example 132 of WO 01/27112
discloses a cyclisation reaction for preparing compound IA.
[0003] According to a first aspect of the invention there is
provided a process for the preparation of a compound of formula
(I): 1
[0004] or a pharmaceutically or veterinarily acceptable salt,
pro-drug, polymorph and/or solvate thereof, wherein
[0005] Q represents O or NR.sup.5
[0006] R.sup.1 represents H, lower alkyl, Het, alkylHet, aryl or
alkylaryl (which latter five groups are all optionally substituted
and/or terminated with one or more substituents selected from halo,
cyano, nitro, lower alkyl, halo(loweralkyl), OR.sup.6,
OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9, C(O)NR.sup.10R.sup.11,
NR.sup.12R.sup.13 and SO.sub.2NR.sup.14R.sup.15)
[0007] R.sup.2 represents H, halo, cyano, nitro, OR.sup.6,
OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9, C(O)NR.sup.10R.sup.1, NR
R.sup.13, SO.sub.2NR.sup.14R.sup.15, lower alkyl, Het, alkylHet,
aryl or alkylaryl (which latter five groups are all optionally
substituted and/or terminated with one or more substituents
selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl),
OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9,
C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13 and
SO.sub.2NR.sup.14R.sup.15)
[0008] R.sup.3 represents H, lower alkyl, alkylHet or alkylaryl
(which latter three groups are all optionally substituted and/or
terminated with one or more substituents selected from halo, cyano,
nitro, lower alkyl, halo(loweralkyl), OR.sup.6, OC(O)R.sup.7,
C(O)R.sup.8, C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13
and SO.sub.2NR.sup.14R.sup.15)
[0009] R.sup.4 represents H, halo, cyano, nitro, halo(loweralkyl),
OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9,
C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13, NR.sup.16Y(O)R.sup.17,
N[Y(O)R.sup.17].sub.2, SOR.sup.18, SO.sub.2R.sup.19, C(O)AZ, lower
alkyl, lower alkenyl, lower alkynyl, Het, alkylHet, aryl, alkylaryl
(which latter seven groups are all optionally substituted and/or
terminated with one or more substituents selected from halo, cyano,
nitro, lower alkyl, halo(loweralkyl), OR.sup.6, OC(O)R .sup.7,
C(O)R.sup.8, C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13
and SO.sub.2NR.sup.14R.sup.15)
[0010] Y represents C or S(O)
[0011] A represents lower alkylene
[0012] Z represents OR.sup.6, halo, Het or aryl (which latter two
groups are both optionally substituted with one or more
substituents selected from halo, cyano, nitro, lower alkyl,
halo(loweralkyl), OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8,
C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13 and
SO.sub.2NR.sup.14R.sup.15)
[0013] R.sup.10 and R.sup.11 independently represent H or lower
alkyl (which latter group is optionally substituted and/or
terminated with one or more substituents selected from halo, cyano,
nitro, lower alkyl, halo(loweralkyl), OR.sup.6, OC(O)R.sup.7,
C(O)R.sup.8, C(O)OR.sup.9, C(O)NR.sup.10aR.sup.11a,
NR.sup.12R.sup.13, SO.sub.2NR.sup.14R.sup.15 and
NR.sup.20S(O).sub.2R.sup.21 or Het or aryl optional substituted
with one or more of said latter thirteen groups) or one of R.sup.10
and R.sup.11 may be lower alkoxy, amino or Het, which latter two
groups are both optionally substituted with lower alkyl
[0014] R.sup.10a and R.sup.11a independently represent R.sup.10 and
R.sup.11 as defined above, except that they do not represent groups
that include lower alkyl, Het or aryl, when these three groups are
substituted and/or terminated (as appropriate) by one or more
substituents that include one or more C(O)NR.sup.10aR.sup.11a
and/or NR.sup.12R.sup.13 groups
[0015] R.sup.12 and R.sup.13 independently represent H or lower
alkyl (which latter group is optionally substituted and/or
terminated with one or more substituents selected from OR.sup.6,
C(O)OR.sup.9, C(O)NR.sup.22R.sup.23 and NR.sup.24R.sup.25), one of
R.sup.12 or R.sup.13 may be C(O)-lower alkyl or C(O)Het (in which
Het is optionally substituted with lower alkyl), or R.sup.12 and
R.sup.13 together represent C.sub.3-7 alkylene (which alkylene
group is optionally unsaturated, optionally substituted by one or
more lower alkyl groups and/or optionally interrupted by O or
NR.sup.26)
[0016] R.sup.14 and R.sup.15 independently represent H or lower
alkyl or R.sup.14 and R.sup.15, together with the nitrogen atom to
which they are bound, form a heterocyclic ring
[0017] R.sup.16 and R.sup.17 independently represent H or lower
alkyl (which latter group is optionally substituted and/or
terminated with one or more substituents selected from OR.sup.6,
C(O)OR.sup.9, C(O)NR.sup.22R.sup.23 and NR.sup.24R.sup.25) or one
of R.sup.16 and R.sup.17 may be Het or aryl, which latter two
groups are both optionally substituted with lower alkyl
[0018] R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.18,
R.sup.19, R.sup.20, R.sup.22, R.sup.23, R.sup.24 and R.sup.25
independently represent H or lower alkyl
[0019] R.sup.18 and R.sup.19 independently represent lower
alkyl
[0020] R.sup.21 represents lower alkyl or aryl
[0021] R.sup.26 represents H, lower alkyl, aryl, C(O)R.sup.27 or
S(O).sub.2R.sup.28
[0022] R.sup.27 represents H, lower alkyl or aryl
[0023] R.sup.28 represents lower alkyl or aryl
[0024] Het represents an optionally substituted four- to
twelve-membered heterocyclic group, which group contains one or
more heteroatoms selected from nitrogen, oxygen, sulphur and
mixtures thereof
[0025] said process comprising reacting a compound of formula (II),
(III), (IV) or (V) in the presence of .sup.-OR.sup.3 and a
hydroxide trapping agent or, alternatively, in the case of
compounds of formulae (IV) or (V) reacting in the presence of an
auxiliary base and a hydroxide trapping agent. An auxiliary base as
defined herein means a base other than .sup.-OR.sup.3 which is used
in place of .sup.-OR.sup.3. 2
[0026] wherein X is a leaving group and Q and R.sup.1 to R.sup.4
are as defined above.
[0027] The term "aryl", when used herein, includes six- to
ten-membered carbocyclic aromatic groups, such as phenyl and
naphthyl, which groups are optionally substituted with one or more
substituents selected from aryl (which group may not be substituted
by any further aryl groups), lower alkyl, Het, halo, cyano, nitro,
OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9,
C(O)NR.sup.10aR.sup.11a, NR.sup.12aR.sup.13a (wherein R.sup.12a and
R.sup.13a independently represent R.sup.12 and R.sup.13 as
hereinbefore defined, except that: (i) they do not represent
C(O)Het in which Het is substituted by one or more substituents
that include one or more C(O)NR.sup.10aR.sup.11a and/or
NR.sup.12aR.sup.13a groups; or (ii) they do not together represent
C.sub.3-7 alkylene interrupted by NR.sup.26) and
SO.sub.2NR.sup.14R.sup.15.
[0028] The term "Het", when used herein, includes four- to
twelve-membered, preferably four- to ten-membered, ring systems,
which rings contain one or more heteroatoms selected from nitrogen,
oxygen, sulfur and mixtures thereof, and which rings may contain
one or more double bonds or be non-aromatic, partly aromatic or
wholly aromatic in character. The ring systems may be monocyclic,
bicyclic or fused. Each "Het" group identified herein is optionally
substituted by one or more substituents selected from halo, cyano,
nitro, oxo, lower alkyl (which alkyl group may itself be optionally
substituted or terminated as defined below), OR.sup.6,
OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9, C(O)NR.sup.10aR.sup.11a,
NR.sup.12aR.sup.13a and SO.sub.2NR.sup.14R.sup.1- 5. The term thus
includes groups such as optionally substituted azetidinyl,
pyrrolidinyl, imidazolyl, indolyl, furanyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,
oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl,
pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl,
pyrazolyl imidazopyridinyl and piperazinyl. Substitution at Het may
be at a carbon atom of the Het ring or, where appropriate, at one
or more of the heteroatoms.
[0029] "Het" groups may also be in the form of an N-oxide.
[0030] The heterocyclic ring that R.sup.14 and R.sup.15 (together
with the nitrogen atom to which they are bound) may represent may
be any heterocyclic ring that contains at least one nitrogen atom,
and which ring forms a stable structure when attached to the
remainder of the molecule via the essential nitrogen atom (which,
for the avoidance of doubt, is the atom to which R.sup.14 and
R.sup.15 are attached). In this respect, heterocyclic rings that
R.sup.14 and R.sup.15 (together with the nitrogen atom to which
they are bound) may represent include four- to twelve-membered,
preferably four- to ten-membered, ring systems, which rings contain
at least one nitrogen atom and optionally contain one or more
further heteroatoms selected from nitrogen, oxygen and/or sulfur,
and which rings may contain one or more double bonds or be
non-aromatic, partly aromatic or wholly aromatic in character. The
term thus includes groups such as azetidinyl, pyrrolidinyl,
imidazolyl, indolyl, isoazoyl, oxazoyl, triazolyl, tetrazolyl,
morpholinyl, piperidinyl, pyrazolyl and piperazinyl.
[0031] The term "lower alkyl" (which includes the alkyl part of
alkylHet and alkylaryl groups), when used herein, means C.sub.1-6
alkyl and includes methyl, ethyl, propyl, butyl, pentyl and hexyl
groups. Unless otherwise specified, alkyl groups may, when there is
a sufficient number of carbon atoms, be linear or branched, be
saturated or unsaturated, be cyclic, acyclic or part
cyclic/acyclic, and/or be substituted by one or more halo atoms.
Preferred lower alkyl groups for use herein are C.sub.1-3 alkyl
groups. Alkyl groups which R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17,
R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23,
R.sup.24, R.sup.25, R.sup.26, R.sup.27 and R.sup.28 may prepresent,
and with which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.16, R.sup.17, aryl, alkylaryl,
alkyHet and Het may be substituted, may, when there is a sufficient
number of carbon atoms, be linear or branched, be saturated or
unsaturated, be cyclic, acyclic or part cyclic/acyclic, be
interrupted by one or more of oxygen; sulfur and optionally
alkylated or optionally acylated nitrogen and/or be substituted by
one or more halo atom. The terms "lower alkenyl" and "lower
alkynyl", when used herein, include C.sub.2-6 groups having one or
more double or triple carbon-carbon bonds, respectively. Otherwise,
the terms "lower alkenyl" and "lower alkynyl" are defined in the
same way as the term "lower alkyl". Similarly, the term "lower
alkylene", when used herein, includes C.sub.1-6 groups which can be
bonded at two places on the group and is otherwise defined in the
same way as "lower alkyl". The term "acyl" includes C(O)-lower
alkyl.
[0032] In the above definition, unless otherwise indicated, alkyl,
alkoxy and alkenyl groups having three or more carbon atoms, and
alkanoyl groups having four or more carbon atoms, may be straight
chain or branched chain.
[0033] The terms "alkylHet" and "alkylaryl" include C.sub.1-6
alkylHet and C.sub.1-6 alkylaryl. The alkyl groups (e.g. the
C.sub.1-6 alkyl groups) of alkylHet and alkylaryl may, when there
is a sufficient number of carbon atoms, be linear or branched, be
saturated or unsaturated, and/or be interrupted by oxygen. When
used in this context, the terms "Het" and "aryl" are as defined
hereinbefore. Substituted alkylHet and alkylaryl may have
substituents on the ring and/or on the alkyl chain.
[0034] Halo groups with which the above-mentioned groups may be
substituted or terminated include fluoro, chloro, bromo and iodo
and the terms haloalkyl and haloalkoxy include CF.sub.3 and
OCF.sub.3 respectively.
[0035] Compounds of general formula (I) can be represented by
formulae I' and I": 3
[0036] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Q are as
defined hereinbefore.
[0037] The compounds of formulae (I) may contain one or more chiral
centres and therefore can exist as stereoisomers, i.e. as
enantiomers or diastereoisomers, as well as mixtures thereof. The
invention relates to formation of both the individual stereoisomers
of the compounds of formulae (I) and any mixture thereof.
[0038] In a first preferred embodiment of the invention a compound
of formulae (IA) is prepared. 4
[0039] Accordingly, in a preferred aspect of the invention there is
provided a process for the preparation of a compound of formula
(IA). 5
[0040] comprising reacting a compound of formula (IIA), (IIIA) or
(IVA) respectively 6
[0041] in the presence of .sup.-OR.sup.3 and a hydroxide trapping
agent, or alternatively in the case of compounds of formula (IVA)
reacting in the presence of a hydroxide trapping agent and an
auxiliary base, wherein OR.sup.3 in the case of formation of
compound (IA) and (IVA) is CH.sub.3(CH.sub.2).sub.3O-- and wherein
X in formulae (IIA) and (IIIA) is a leaving group.
[0042] Intermediates of the general formula (IIA), (IIIA) and
(IVA), where novel, form further aspects of the invention.
[0043] As a result of use of the hydroxide trapping agent, a
particular advantage of the present process is that a high yield of
final product (compounds of formula (I, IA) and intermediate
compounds (II, IIA) can be obtained.
[0044] In a preferred embodiment compounds of formula (I) can be
obtained in good yield without intermediate isolation.
[0045] It is most advantageous to form the compounds of formula (I)
from intermediates of formula (III) since the cyclisation step (III
to II) and the nucleophilic displacement of X by .sup.-OR.sup.3 (II
to I) can be carried out in a one-pot reaction. Furthermore this
process can be run at ambient pressure whereas the cyclisation step
of the 2 step process can require higher pressures where XH is a
lower alkanol, such as methanol, ethanol or isomers of
propanol.
[0046] In a further aspect of the invention, there is provided a
process for the formation of compounds of formula (II) (more
particularly IIA wherein X in II/IIA=.sup.-OR.sup.3) comprising the
cyclisation of compounds of formula (III) (more particularly IIIA)
wherein X is a leaving group as defined hereinbefore, in the
presence of said hydroxide trapping agent. Again, this step
benefits from the higher yield provided by using the hydroxide
trapping agent.
[0047] Of course, the trapping agent technology could be used to
form compounds of formula (IV) (more particularly IVA) from
compounds of formula (III) (more particularly IIIA) in the presence
of .sup.-OR.sup.3, advantageously up to about 1 molar equivalent of
.sup.-OR.sup.3 (to compounds (III)). If substantially more than 1
equivalent of .sup.-OR.sup.3 was used, the reaction would proceed
through to compounds (I) (more particularly IA).
[0048] Preferably the hydroxide trapping agent is an ester.
[0049] More preferably said hydroxide trapping agent is an ester of
the formula:
[0050] wherein OT is OR.sup.3 as defined hereinbefore or, OT is the
residue of a bulky alcohol or a non-nucleophilic alcohol, or TOH is
an alcohol which can be azeotropically removed during the
reaction;
[0051] and C(O)W is the residue of a carboxylic acid.
[0052] For example, where X is OEt in compound (IIA) and (IIIA) the
ester trapping agent can be n-butyl acetate (i.e. OT=X and C(O)W is
a residue of acetic acid), or ethyl acetate or ethyl pivalate, more
preferably butyl pivalate (OT=X and C(O)W is the residue of pivalic
acid- i.e. a carboxylic acid with no enolisable proton).
[0053] In a most preferred process, wherein X is OEt in compound
(IIA) or (IIIA) the ester trapping agent is butyl actetate.
[0054] Preferably X is selected from the group consisting of
optionally substituted arylsulphonyloxy, preferably
phenylsulphonyloxy, more preferably a para substituted aryl
(phenyl) such as by a C.sub.1-C.sub.4 alkyl group e.g.
p-toluenesulphonyloxy; C.sub.1-C.sub.4 alkylsulphonyloxy e.g.
methanesulphonyloxy; nitro or halo substituted benzenesulphonyloxy
preferably para substituted e.g. p-bromobenzenesulfonyloxy or
p-nitrobenzenesulphonyloxy; C.sub.1-C.sub.4
perfluoroalkylsulphonyloxy e.g. trifluoromethylsulphonyloxy;
optionally substituted aroyloxy such as benzoyloxy; C.sub.1-C.sub.4
perfluoroalkanoyloxy such as trifluoroacetyloxy; C.sub.1-C.sub.4
alkanoyloxy such as acetyloxy; halo; diazonium; C.sub.1-C.sub.6
primary and secondary alkoxy such as methoxy; quatenaryammonium
C.sub.1-C.sub.4 alkylsulphonyloxy; halosulphonyloxy e.g.
fluorosulphonyloxy and other fluorinated leaving groups; and
diarylsulphonylamino e.g. ditosyl (NTs.sub.2).
[0055] Most preferably, for formation of compounds of formula (I)
more particularly (IA), X is a C.sub.1-C.sub.4 alkoxy
(advantageously ethoxy or methoxy) or halogen since this lends
itself to simpler and cheaper formation of compounds--for example
see Schemes 1 and 3 hereinafter.
[0056] An advantage of using labile leaving groups such as chloro
or fluoro may be that an inert solvent could then be used rather
than R.sup.3OH (which will often be more expensive). Thus only a
sufficient amount of .sup.-OR.sup.3 (such as from R.sup.3OH) as
reactant would be required.
[0057] --.sup.-OR.sup.3 can act both as a nucleophile (to displace
the leaving group by nucleophilic substitution) and as a base (to
bring about the cyclisation).
[0058] --.sup.-OR.sup.3 can be generated in solution from, for
example, a salt ZOR.sup.3 (wherein Z is a cation) such as a metal
salt. More particularly an alkali (such as sodium or potassium) or
alkaline earth metal salt of --.sup.-OR.sup.3 in a suitable solvent
would give rise to --.sup.-OR.sup.3 in solution. For example,
potassium butoxide, potassium amylate, KHMDS or NaHMDS in a
suitable solvent, under suitable temperature conditions, such as
1-butanol, with intermediate (IIA) or (IIIA) would form compound
(IA). In another embodiment, --.sup.-OR.sup.3 can be formed in situ
from R.sup.3OH plus an auxiliary base (i.e. a base other than
.sup.-OR.sup.3). However, in another system, ZOR.sup.3 could be
used in the reaction system with an auxiliary base.
[0059] As will be appreciated the solvent in which the reaction
takes place can be R.sup.3OH or an inert solvent (or a mixture of
both). By inert solvent we mean a solvent which will not form a
nucleophile under the reaction conditions, or, if a nucleophile is
formed it is sufficiently hindered or un-reactive such that it does
not substantially compete in the displacement reaction. When
R.sup.3OH is used as a source of .sup.-OR.sup.3, then a separate
solvent is not essentially required but an (auxiliary) inert
solvent (i.e. a solvent other than R.sup.3OH) may be used as a
co-solvent in the reaction.
[0060] Suitable solvents are as follows:
[0061] R.sup.3OH, a secondary or tertiary C.sub.4-C.sub.12 alkanol,
a C.sub.3-C.sub.12 cycloalkanol, a tertiary C.sub.4-C.sub.12
cycloalkanol, a secondary or tertiary (C.sub.3-C.sub.7
cycloalkyl)C.sub.2-C.sub.6 alkanol, a C.sub.3-C.sub.9 alkanone,
1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran,
1,4-dioxan, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene,
acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide,
N-methylpyrrolidin-2-one, pyridine, and mixtures thereof.
[0062] More preferably, the solvent is R.sup.3OH, a tertiary
C.sub.4-C.sub.12 alkanol, a tertiary C.sub.4-C.sub.12 cycloalkanol,
a tertiary (C.sub.3-C.sub.7 cycloalkyl)C.sub.2-C.sub.6 alkanol, a
C.sub.3-C.sub.9 alkanone, 1,2-dimethoxyethane, 1,2-diethoxyethane,
diglyme, tetrahydrofuran, 1,4-dioxan, toluene, xylene,
chlorobenzene, 1,2-dichlorobenzene, acetonitrile, dimethyl
sulphoxide, sulpholane, dimethylformamide,
N-methylpyrrolidin-2-one, pyridine, and mixtures thereof.
[0063] Most preferably the solvent is R.sup.3OH, which means that
.sup.-OR.sup.3 is formed in situ, such as, in the presence of an
auxiliary base. For compound (IA) the solvent is preferably
CH.sub.3(CH.sub.2).sub.3OH (1-butanol).
[0064] A wide range of auxiliary bases can be used in the process
of the invention. Typically the bases would not substantially
compete with .sup.-OR.sup.3 in the nucleophilic substitution of X
(i.e. they would be non nucleophilic) such as by being suitably
sterically hindered.
[0065] Preferably the auxiliary base is selected from the group
consisting of a sterically hindered metal alkoxide base, a metal
amide, a metal hydride, metal oxide, metal carbonate and metal
bicarbonate.
[0066] Examples of suitable alcohol and amine metal salts include
metal salts of: a secondary or tertiary C.sub.4-C.sub.12 alkanol; a
C.sub.3-C.sub.12 cycloalkanol and a secondary or teritary
(C.sub.3-C.sub.8 cycloalkyl)C.sub.1-C.sub.6 alkanol; a N-(secondary
or tertiary C.sub.3-C.sub.6 alkyl)-N-- (primary, secondary or
tertiary C.sub.3-C.sub.6 alkyl)amine; a N-(C.sub.3-C.sub.8
cycloalkyl)-N-(primary, secondary or tertiary C.sub.3-C.sub.6
alkyl)amine; a di(C.sub.3-C.sub.8 cycloalkyl)amine or
hexamethyldisilazane; or 1,5-diazabicyclo[4,3,O]non-5- -ene and
1,8-diazabicyclo[5,4,0]undec-7-ene.
[0067] Examples of suitable metal salts of a tertiary
C.sub.4-C.sub.6 alcohol such as the alkali or alkaline earth metal
salts (e.g. Na/K) of t-butanol or t-amyl alcohol, or the base are:
potassium t-butoxide, potassium hexamethyldisilazone (KHMDS) or
NaHMDS.
[0068] More preferably the auxiliary base is a sterically hindered
base selected from: metal salts of sterically hindered alcohols or
amines; or metal carbonates. Preferred herein are metal carbonates,
and advantageously potassium carbonate for the delivery of higher
yield, improved impurity profile.
[0069] Further examples of suitable carbonate bases for use herein
include sodium carbonate, caesium carbonate, lithium carbonate,
rubidium carbonate, strontium carbonate, barium carbonate,
beryllium carbonate and magnesium carbonate. Preferred for use
herein are non-toxic carbonate bases with reasonably rapid reaction
rate, in the cyclisation reaction according to the present
invention. Potassium carbonate is especially preferred as defined
hereinbefore.
[0070] Preferably the metal of the salt of ZOR.sup.3 and the
auxiliary base are independently selected from alkali metals
(lithium, sodium, potassium, rubidium, caesium) or alkaline earth
metals (beryllium, magnesium, calcium, strontium, barium). More
preferably the metal is sodium or potassium and potassium is
especially preferred.
[0071] To maximise yields, it is further preferred that at least
about 1 molecular equivalent of auxiliary base and .sup.-OR.sup.3
are used in accordance with the invention. If .sup.-OR.sup.3 also
functions as a base (i.e. there is no auxiliary base present) then
preferably at least about 2 equivalents of .sup.-OR.sup.3 are
present. Suitably, at least about 1 equivalent of trapping agent
(preferably at least about 2 equivalents) is present. Especially
preferred for use herein is about 3 equivalents of auxiliary base
(preferably potassium carbonate) and at least about 1, preferably
at least about 2 and especially about 3 equivalents of trapping
agent (preferably butyl acetate).
[0072] The temperature of the cyclisation reaction of compounds
(III) and (IV) to (I) (such as for the corresponding formation of
compound (IA)) is preferably at least about 80.degree. C., more
preferably about 80 to about 130.degree. C., more preferably still
about 100 to about 130.degree. C. and most preferably about
112.degree. C. to about 122.degree. C. These temperatures are also
applicable for the conversion of compounds (II) to (I), although
the temperature in this case could also probably be lower (e.g.
about 60.degree. C.) since there is no cyclisation taking
place.
[0073] The reaction temperature attainable to effect the conversion
of compounds of formulae (II) and (III) to compounds of formula (I)
depends on the solvent, the nature of .sup.-OR.sup.3 and X. When X
is an alkoxy and R.sup.3OH is the solvent, preferably XH (such as
C.sub.1-.sub.6 alkoxy) is removed azeotropically (of course the
reaction vessel must be configured to distil over the azeotrope
mixture) with R.sup.3OH by running the reaction at the azeotrope
temperature of XH and R.sup.3OH. In this way the yield and quality
of the final product can be further improved. For example, (where X
is an alkoxy) the conversion of compound (IIA), (IIIA) or (IVA) to
(IA) is preferably carried out at the azeotrope temperature of the
alcohol i.e. XH (preferably methanol or ethanol, most preferably
ethanol) and 1-butanol.
[0074] Thus according to further preferred embodiments the
invention provides
[0075] A process for the synthesis of compound (IA) by reaction of
compound (IIA) or (IIIA):
[0076] a) with 1-butanol and auxiliary base, preferably potassium
butoxide, optionally in an inert solvent such as toluene and in the
presence of said trapping agent TOC(O)W; or
[0077] b) with ZO(CH.sub.2).sub.3CH.sub.3 and an auxiliary base in
n-butanol or an inert solvent or both, in the presence of said
trapping agent; or
[0078] c) with ZO(CH.sub.2).sub.3CH.sub.3 and n-butanol or an inert
solvent or both, in the presence of said trapping agent.
[0079] Preferably, the trapping agent is BuOC(O)W or CH.sub.30C(O)W
wherein C(O)W is a residue of a carboxylic acid (preferably
sterically hindered) such as CH.sub.3(CH.sub.2).sub.3OC(O)CH.sub.3
or CH.sub.3(CH.sub.2).sub.3OC(O)(CH.sub.3).sub.3.
[0080] To maximise yields, it is further preferred that at least
about 1 molecular equivalent of auxiliary base and .sup.-OR.sup.3
are used in accordance with the invention. If .sup.-OR.sup.3 also
functions as a base (i.e. there is no auxiliary base present) then
preferably at least about 2 equivalents of .sup.-OR.sup.3 are
present. Thus to maximise yields of compounds (IA), suitably at
least about 1 equivalent of trapping agent (preferably at least
about 2 equivalents) is present. With respect to (a) above,
preferably there is at least about 2 molecular equivalents of base
and at least about 1 molecular equivalent of trapping agent
relative to the substrate (more preferably at least about 2.2 and
2.5 respectively). For (b) above, preferably there is at least
about 1 molecular equivalent of auxiliary base, trapping agent and
ZO(CH.sub.2).sub.3CH.sub.3 relative to the substrate (more
preferably at least about 1.2 equivalents of auxiliary base and at
least about 2.5 equivalents of trapping agent). For (c) above,
preferably there is at least about 2 molecular equivalents of
ZO(CH.sub.2).sub.3CH.sub.3 and at least about I equivalent of
trapping agent relative to the substrate (more preferably at least
about 2 and 2.5 equivalents respectively).
[0081] To further improve yields of final product and reduce
impurities, preferably C(O)W is the residue of a sterically
hindered carboxylic acid and/or a carboxylic acid which does not
contain an enolisable proton (e.g. pivalic acid).
[0082] The compounds of general formula (III) and (IIIA) may be
obtained from readily available starting materials for example, by
the routes depicted in the following reaction schemes. Reaction
Scheme 1 illustrates for preparation of compounds of compounds of
general formula (I) from compounds of formulae (IX) and (XII).
[0083] Compound (III) is formed by reaction of intermediate (IX)
and compound (XII) in the presence of a coupling agent, such as
N,N'-carbonyldiimidazole and a suitable solvent, such as ethyl
acetate. 7
[0084] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, X and Q are as
defined hereinbefore.
[0085] Further suitable conditions for the coupling of compounds of
formulae (XII) and (IX) to provide compounds of formula (III)
include: conventional amide bond-forming techniques, e.g. via the
acyl chloride derivative of (IX) in the presence of up to about a
five-fold excess of a tertiary amine such as triethylamine or
pyridine to act as scavenger for the acid by-product (e.g. HCl ),
optionally in the presence of a catalyst such as
4-dimethylaminopyridine, in a suitable solvent such as
dichloromethane, at from about 0.degree. C. to about room
temperature. For convenience pyridine may also be used as the
solvent.
[0086] In particular, any one of a host of amino acid coupling
variations may be used. For example, the acid of formula (IX) or a
suitable salt (e.g. sodium salt) thereof may be activated using a
carbodiimide such as 1,3-dicyclohexylcarbodiimide or
1-ethyl-3-(3-dimethylaminoprop-1-yl)carbo- diimide optionally in
the presence of 1-hydroxybenzotriazole hydrate and/or a catalyst
such as 4-dimethylaminopyridine, or by using a
halotrisaminophosphonium salt such as for example
bromotris(pyrrolidino)p- hosphonium hexafluorophosphate or by using
a suitable pyridinium salt such as 2-chloro-1-methylpyridinium
iodide. Either type of coupling is conducted in a suitable solvent
such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide,
optionally in the presence of a tertiary amine such as
triethylamine or N-ethyidiisopropylamine (for example when either
the compound of formula (XII), or the activating reagent--for the
acid of formula (IX), is presented in the form of an acid addition
salt), at from about 0.degree. C. to about room temperature.
Preferably, from 1 to 2 molecular equivalents of the activating
reagent and from 1 to 3 molecular equivalents of any tertiary amine
present are employed.
[0087] In a further variation, the carboxylic acid function of acid
(IX) may first of all be activated using up to about a 5% excess of
a reagent such as N,N-carbonyldiimidazole in a suitable solvent,
e.g. ethyl acetate or butan-2-one, at from about room temperature
to about 80.degree. C., followed by reaction of the intermediate
imidazolide with (XII) at from about 20.degree. C. to about
90.degree. C.
[0088] It will be appreciated that the general formula (XII) can
also be represented by the regioisomeric formulae (XII') and
(XII"): 8
[0089] wherein R.sup.1 and R.sup.2 are as previously defined
herein.
[0090] In Scheme 1 the compounds of general formula (I) can be
prepared from compounds of general formula (III) by: cyclisation
directly to a compound of formula (I), route A; exchange of "X" for
"QR.sup.3 followed by cyclisation of compound (IV) to a compound of
formula (I), route B; or by cyclisation to form a compound (II)
followed by exchange of "X" for "OR.sup.3", route C. The
cyclisation of route A includes both cyclisation where
X.dbd.OR.sup.3 as well as cyclisation with alkoxide exchange where
X is exchanged for OR.sup.3. Routes A, B and C are in a preferred
process according to the present invention carried out in a one-pot
process without isolation of intermediate compounds, such as for
example compounds (II) or (IV).
[0091] Reaction Scheme 2 illustrates the preparation of compounds
of general formula (IX) starting from the commercially available
material, 2-hydroxynicotinic acid. 9
[0092] In the compounds of Scheme 2, X and R.sup.4 are as
hereinbefore defined. P is a group which can undergo an oxidative
addition reaction with Palladium (0), such as for example halogen,
trifluoromethanesulfonat- e, perfluoroethane sulfonate, diazonium
salts and is preferably F, Cl, Br or I, more preferably Br or I. V
is any suitable carboxylic acid protecting group such as:
C.sub.1-C.sub.4 alkyl esters, preferably ethyl or methyl esters;
aryl groups such as benzyl; or a silicon protecting group such as a
trimethylsilyl (TMS) group. As illustrated in Scheme 2, where not
commercially available, the intermediate of formula (V) can be
formed from commercially available starting materials such as
2-chloronicotinic acid or 2-hydroxynicotinic acid or a salt thereof
by routine synthetic methods such as are exemplified hereinafter in
the preparations section.
[0093] Intermediate compounds of formula (IX) wherein
X.dbd.OR.sup.3a wherein OR.sup.3a is a different alkoxy group from
OR.sup.3 wherein R.sup.3a is a C.sub.1-C.sub.6 alkyl group,
preferably a C.sub.1-C.sub.4 alkyl group and R.sup.4 is as defined
hereinbefore can be formed from compounds of formula (VII) (wherein
X.dbd.OR.sup.3a and R.sup.4 are as defined for (IX) and V is as
defined hereinbefore) by hydrolysis, when V is an alkyl or aryl
group, (IX) is preferably formed via base hydrolysis with metal
hydroxide, more preferably with sodium hydroxide. Where V is a
benzyl or silyl group, (IX) is formed via hydrogenation.
[0094] Compounds of formula (VIII) wherein X.dbd.OR.sup.3a and
R.sup.4 and V are as defined herein before, can be formed from
compounds of formula (VII) (wherein X.dbd.OR.sup.3a and V are as
defined for (VII) and P is as defined hereinbefore) via a
substitution reaction (wherein group P is exchanged for the desired
R.sup.4 moiety), and preferably wherein such substitution reaction
is a metal-mediated reaction. According to a preferred process said
conversion is affected via acylation under Heck conditions as
exemplified hereinafter.
[0095] Accordingly the present invention provides a process for the
conversion of compound (VII) (wherein P.dbd.Br or I, wherein
X.dbd.OEt and wherein V is as defined hereinbefore) to compound
(VIII) (wherein R.sup.4.dbd.C(O)CH.sub.3 and X.dbd.OEt and V is as
defined hereinbefore) such as via reaction with butylvinyl ether
and triethylamine in a suitable solvent, such as for example
acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMAC),
N-methyl pyrrolidone (NMP) or water, under reflux conditions and at
atmospheric pressure wherein said reaction is carried out in the
presence of a suitable catalyst such as palladium acetate and a
ligand such as tri-o-tolyl phosphine wherein the ratio of compound
(VII) to acylating agent is about 1:15, preferably about 1:8, more
preferably about 1:10 molecular equivalents and wherein the ratio
of compound (VII) to base is about 1:2.0, preferably about 1:1.5
molecular equivalents and wherein the ratio of compound (VII) to
catalyst in about 1:0.25, preferably about 1:0.16 molecular
equivalents. To ensure appropriate conversion of the non-isolated
intermediate enol-ether compound VIII' to the desired ester VIII
the reaction should have an aqueous acidic work-up. 10
[0096] wherein X and V are as defined hereinbefore and wherein
R.sup.5 is a C.sub.1-C.sub.5 alkyl group, preferably
C.sub.1-C.sub.4 alkyl and especially butyl.
[0097] Compounds of formula (VII) wherein X.dbd.OR.sup.3a and V and
P are as defined hereinbefore, and preferably wherein
X.dbd.(C.sub.1-C.sub.4) primary or secondary alkoxy and P is a
halogen, can be formed from compounds of formula (VI) (wherein X
and P are as defined for (VII)) in an esterification/protection
reaction via treatment with a suitable acid catalyst and an alcohol
of formula V--OH, or treatment with a suitable base and an
alkylating agent wherein V is as defined hereinbefore, and wherein
V is preferably C.sub.1-C.sub.4 alkyl. Preferred conditions wherein
X.dbd.OEt; V--OH.dbd.CH.sub.3--OH include: treatment with an
HCl/H.sub.2SO.sub.4 mixture; or treatment with H.sub.2SO.sub.4; or
treatment with ethyl iodide and cesium cabonate.
[0098] Compounds of formula (VI) (wherein X.dbd.OR.sup.3a and P is
as previously defined) can be formed from compounds of formula (V)
wherein X.dbd.OR.sup.3a via a halogenation reaction such as
bromination with a suitable electrophilic halogenation agent i.e.
N-bromosuccinamide.
[0099] It is possible to undertake the three step conversion of
(VI) to (IX) (more particularly (VIA) to (IXA), see Scheme 5
hereinafter) in a single step.
[0100] Thus according to a highly preferred process of the
invention and as illustrated in Scheme 2, compounds of general
formula (VI) can be transformed directly into compounds of general
formula (IX). Such direct transformation reactions proceed via a
non isolated intermediate compound of general formula VI' as
illustrated below: 11
[0101] wherein X is as defined herein before.
[0102] In such a highly preferred process compounds of formula (IX)
can be prepared directly from compounds of formula (VI) in a
one-step reaction. Suitable reagents for such direct conversion of
compounds of formula (VI) to compounds of formula (IX) wherein
X.dbd.OR.sup.3a, preferably wherein X.dbd.OEt, and wherein P=a
halogen, preferably Br, include using butyl vinyl ether and
triethylamine in acetonitrile solvent at reflux temperature and at
ambient/atmospheric pressure in the presence of catalyst such as
palladium acetate and ligand such as tri-o-tolyl phosphine. For
such reactions suitable reagent amount are (i) the ratio of base to
compound (VI) is more than about 1.5:1, preferably more than about
2.0:1 and more preferably about 2.5:1 molecular equivalents and/or
; (ii) the ratio of acylating agent to compound (VI) is about 2.5:1
to about 5:1, preferably about 2.5:1 to about 3.5:1 and especially
about 3:1 molecular equivalents. Especially preferred herein for
the provision of high yield of (XI) are such reactions wherein in
addition to the aforementioned preferred ratios of acid (VI) to
base and/or acylating agent, the ratio of acid (VI) to catalyst is
about 1:0.04 molecular equivalents.
[0103] It is especially surprising that the above highly preferred
conditions furnished higher yields of (IX) versus similar reactions
where a higher catalyst level was utilised.
[0104] Following the initial reaction of compound (VI) with the
base, acylating agent and catalyst in an appropriate solvent it is
necessary that the reaction mixture is subjected to an aqueous
acidic work-up in order to furnish the desired compound of formula
(IX) rather than the intermediate enol-ether (VI') as detailed
hereinbefore.
[0105] Reaction Scheme 3 illustrates the preparation of compounds
of general formula (XI). 12
[0106] wherein R.sup.1 and R.sup.2 are as defined hereinbefore.
[0107] With reference to Scheme 3 compounds of formula (XII) can be
formed from compounds of formula (XI) via a suitable reduction
reaction such as with palladium on charcoal and hydrogen, under
pressure where necessary. Compounds of formula (XI) can be formed
from compounds of formula (X) via a suitable alkylation, arylation
or acylation reaction.
[0108] Reaction Schemes 4 to 6 provide the corresponding
intermediate compounds and transformations for the preparation of
highly preferred compound (IA).
[0109] Scheme 4 illustrates a preferred process for the coupling of
preferred compounds (IXA) and (XIIA) to provide compound of formula
(IIIA) which are then cyclised to provide the compound of formula
(IA) according to the process of the present invention. 13
[0110] Reaction Scheme 5 illustrates a preferred process for the
preparation of compounds of formula (IXA). 14
[0111] Scheme 5 illustrates a preferred embodiment for the
formation of compound (IX) as generally described in Scheme 2,
wherein X is an alkoxy (and so X in compound VA represents
OR.sup.3a), more preferably a C.sub.1-6 primary or secondary
alkoxy, such as ethoxy.
[0112] Compounds of the general formula (IXA) are prepared
according to methods shown in Examples section hereinafter.
[0113] According to a highly preferred process herein compound
(IXA) is prepared directly from compound (VIA) by reaction with
acylating agent, base and catalyst wherein the ratio of compound
(VIA):acylating agent:base:catalyst is about 1:3:2.5:0.04 molecular
equivalents. In an especially preferred process the acylating agent
is butyl vinyl ether, the base is triethylamine, the catalyst is
Pd(OAc).sub.2, the solvent is acetonitrile and the ligand is
tri-o-tolyl phosphine and the reaction is carried out under reflux
conditions at atmospheric pressure. Such preferred process is
illustrated at preparation 1(b) hereinafter.
[0114] Reaction Scheme 6 illustrates the preparation of compounds
of general formula (XIIA) as generally detailed in Scheme 3. 15
[0115] Compounds of formula (XIIA) can be formed from compounds of
formula (XIA) via hydrogenation such as via treatment with
palladium/charcoal and hydrogen and as exemplified herein at
preparation 9 hereinafter.
[0116] Compounds of formula (XIA) can be formed from compounds of
formula (XIDP) via a two stage process of: (i) amination (to
prepare an intermediate imine of general formula (XIDP') as
illustrated below: 16
[0117] such as via treatment with acetaldehyde or a synthetic
equivalent followed by; (ii) reduction such as with Na(OAc).sub.3
BH to furnish the desired compound of formula (XIA) and as
exemplified herein at preparation 8 hereinafter.
[0118] Compounds of formula (XIDP) can be formed from compounds of
formula (XIP) via de-protection of the N-protecting benzhydryl
group using suitable de-protection conditions such as exemplified
at preparation 7 hereinafter.
[0119] Compounds of formula (XIP) can be formed from compounds of
formula (XA) according to the processes at preparations 6(a) and
6(b) hereinafter. The process of preparation 6(b) is particularly
preferred herein as it provides higher yields.
[0120] According to a further aspect of the process hereinbefore
described for the preparation of compounds of the general formula
(XIA), such compounds can be prepared from compounds (XA) via a
"one-step" process via reaction with the compound: 17
[0121] wherein such reaction takes place in a suitable non
nucleophilic solvent, such as for example THF.
[0122] According to a particularly preferred process herein
compounds of the general formula (XIA) can be prepared directly
from compounds of the formula (XA). An advantage of such direct
transformation is process efficiency.
[0123] Compound (IIIA) is formed by reaction of intermediate (IX)
and
4-Amino-5-ethyl-1-(2-ethyl-azetidinyl)-1H-pyrazole-3-carboxamide
(compound XII) in the presence of a coupling agent, such as
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and
where desirable also in the presence of a base and/or an
accelerator. In one example of a coupling system, the carboxylic
acid function of (VIA) is first of all activated using molar
equivalent of a reagent such as N,N-carbonyldimidazole (as coupling
agent) in a suitable solvent, e.g. ethyl acetate, at from about
room temperature to about 80.degree. C., followed by reaction of
the intermediate imidazolide with (XIIA) at from about 35 to about
80.degree. C. In another example, intermediate (IXA) could be
coupled to the pyrazole (XIIA) in the presence of
1-hydroxybenzotriazole, triethylamine and
1-(3-dimethylaminopropyl)-3-eth- yl-carbodiimide hydrochloride.
[0124] It will be appreciated that salts of compounds (I) and (IA)
of Schemes 1 and 4 can be formed in accordance with the invention
by converting the relevant compound to a salt thereof (either in
situ or as a separate step). For example base addition salts of the
compounds of formulae (VI) and (XI) can be formed and can be
utilised in accordance with the process of the present invention.
Also the acid addition salts of the compounds of formulae (I) and
(IA) can be formed in accordance with the invention.
[0125] By way of illustration, acid addition salts of compounds of
formula (I) (more particularly (IA)) can be formed by reacting a
compound of formula (I) with an equimolar or excess amount of acid.
The salt may then be precipitated out of solution and isolated by
filtration or the solvent can be stripped off by conventional
means.
[0126] The pharmaceutically or veterinarily acceptable salts of the
compounds of formulae (I) and (IA) which contain a basic centre
are, for example, non-toxic acid addition salts formed with
inorganic acids such as hydrochloric, hydrobromic, hydroiodic,
sulphuric and phosphoric acid, with carboxylic acids or with
organo-sulphonic acids. Examples include the HCl, HBr, HI, sulphate
or bisulphate, nitrate, phosphate or hydrogen phosphate, acetate,
benzoate, succinate, saccarate, fumarate, maleate, lactate,
citrate, tartrate, gluconate, camsylate, methanesulphonate,
ethanesulphonate, benzenesulphonate, p-toluenesulphonate and
pamoate salts. Compounds (I) and (IA) can also provide
pharmaceutically or veterinarily acceptable metal salts, in
particular non-toxic alkali and alkaline earth metal salts, with
bases. Examples include the sodium, potassium, aluminium, calcium,
magnesium, zinc and diethanolamine salts. For a review on suitable
pharmaceutical salts see Berge et al, J. Pharm, Sci., 66,1-19,
1977.
[0127] The pharmaceutically acceptable solvates of compounds (I)
and (IA) include the hydrates thereof.
[0128] Suitable protecting groups for use in accordance with the
invention can be found in "Protecting Groups" edited by P. J.
Kocienski, Thieme, New York, 1994--see particularly chapter 4, page
118-154 for carboxy protecting groups; and "Protective Groups in
Organic Synthesis" 2.sup.nd edition, T. W. Greeene & P. G. M.
Wutz, Wiley--Interscience (1991)--see particularly chapter 5 for
carboxy protecting groups.
[0129] The process according to the present invention will now be
described by way of example only with reference to the following
examples.
Preparation 1--5-Acetyl-2-ethoxynicotinic acid
Preparation 1(a) Starting Material--5-Bromo-2-ethoxvnicotinic acid
(Preparation of VIA from VA)
[0130] 18
[0131] A solution of potassium t-butoxide (183.6 g, 1.60 mol) in
absolute ethanol (1200 mL) was added slowly to a solution of
2-chloronicotinic acid (120 g, 0.76 mol) in ethanol (400 mL), and
the reaction heated in a sealed vessel at 170.degree. C. for 20 h.
On cooling, the reaction mixture was concentrated under reduced
pressure, the residue dissolved in water (800 mL) and acidified to
pH 3 with aqueous hydrochloric acid. The aqueous solution was
extracted with dichloromethane (4.times.800 mL), the organic phases
combined, dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure to afford the 2-ethoxy nicotinic acid (109.6 g, 41%) as a
white solid [.sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.53 (t,
3H), 4.69 (q, 2H), 7.13 (m, 1H), 8.37 (d, 1H), 8.48 (d, 1 H)].
2-acid (83.6 g, 0.5 mol) was added portionwise to a mixture of
trifluoroacetic acid/trifluoroacetic anhydride (TFA/TFAA) (350 mL
of each) at room temperature with constant stirring.
N-Bromo-succinamide (NBS) (89.0 g, 0.5 mol) was then added
portionwise over 20 minutes before the reaction mixture was heated
to reflux for 5 hours. The reaction was cooled to room temperature
and allowed to stir overnight. The reaction was then poured into a
1:1 mixture of cooled brine/water (2 L). The resultant white solid
was filtered, washed with water and dissolved in EtOAc (300 mL).
The solution was dried over MgSO.sub.4 and filtered. The filtrate
was treated with hexane (1.2 L) and the resultant pale yellow
precipitate was filtered and washed with 40-60 petroleum ether. The
title compound was dried at 50.degree. C. under vacuum:
m.p.=122-124.degree. C.; 1H NMR (300 MHz, CDCl.sub.3): .delta.=1.53
(t, 3H), 2.64 (s, 3H), 4.67 (q, 2H), 8.42 (d, 1H), 8.57 (d,
1H).
Preparation 1(b)--5-Acetyl-2-ethoxynicotinic acid (Preparation of
IXA from VIA)
[0132] 19
[0133] Triethylamine (354 mL, 2.54 M), was added to a slurry of
5-bromo-2-ethoxynicotinic acid (250 g, 1.02 M) in acetonitrile (1
L). To this reaction mixture was added palladium (II) acetate (4.56
g, 20.3 mmol), butyl vinyl ether (305 g, 3.05 M) and tri-o-tolyl
phosphine (12.4 g, 40.6 mmol), each addition being washed in with
acetonitrile. Further acetonitrile (1 L) was then added and the
reaction mixture heated to reflux under nitrogen for 22 hours. The
reaction mixture was left at room temperature for 16 hours, and
then the precipitate removed by filtration. The filtrate was
concentrated in vacuo to give a brown gum, which was then stirred
for 1 hour in water (1L) and concentrated HCl (1L). The reaction
mixture was diluted with water (6.25 L), and extracted with
dichloromethane (6.times.500 mL). The combined organic layers were
extracted with 5% sodium bicarbonate solution (1.2 L, 2.times.400
mL). The basic aqueous extracts were washed with dichloromethane
(250 mL), and then acidified to pH 3. After stirring for 30 minutes
the precipitated product was removed by filtration, washed with
water (250 mL) and dried at 50.degree. C. in vacuo to yield the
target compound as a white solid (134 g, 64.1 mmol, 63%): 1H NMR
(400 MHz, CDCl.sub.3): .delta.=1.56 (t, 3H, J=7.1 Hz), 2.64 (s,
3H), 4.78 (q, 2H, J=6.7 Hz), 8.96 (d, 1H, J=2.6 Hz), 8.98 (d, 1H,
J=2.6 Hz); LRMS (m/z) (ES.sup.-) 208 (MH.sup.-)
Preparation 2
5-Acetyl-N-[3-(aminocarbonyl)-5-ethyl-1-(1-ethyl-3-azetidiny-
l)-1H-pyrazol-4-yl]-2-ethoxynicotinamide
Preparation 2(a)
1-(1-Benzhydryl-3-azetidinyl)-5-ethyl-4-nitro-1H-pyrazole-
-3-carboxamide
[0134] 20
[0135] The title compound was prepared by either of the following
methods;
[0136] a) 5-Ethyl-4-nitro-1H-pyrazole-3-carboxamide (WO 98/49166)
(25.0g, 136 mmol), sodium carbonate (57.6 g, 543 mmol), sodium
iodide (40.7 g, 272 mmol) and 1-benzhydryl-3-azetidinyl
methanesulfonate (86.2 g, 272 mmol) were suspended in
tetrahydrofuran (338 mL) and water (38 mL) and heated under reflux
for 5 days. The reaction mixture was then concentrated in vacuo and
taken up in ethyl acetate (500 mL) and water (300 mL). The
resulting precipitate was filtered, washed with ethyl acetate and
water to yield the title compound as a white solid (17g, 41.9 mmol,
31%): mp 257-260.degree. C.; 1H NMR (400 MHz, DMSO-d.sub.6):
.delta.=1.09 (t, 3H, J=7.6 Hz), 2.95 (q, 2H, J=7.3 Hz), 3.43 (t,
2H, J=7.6 Hz), 3.61 (t, 2H, J=7.6 Hz), 4.59 (s, 1H), 5.23 (quintet,
1H, J=7.3 Hz), 7.15-7.20 (m, 2H), 7.24-7.31 (m, 4H), 7.43-7.48 (m,
4H), 7.70 (br s, 1H), 7.95 (br s, 1H); LRMS (m/z) (TSP.sup.+) 406.2
(MH.sup.+).
[0137] b) 5-Ethyl-4-nitro-1H-pyrazole-3-carboxamide.sup.1 (800.0 g,
4.34 mol), sodium carbonate (1845 g, 17.4 mol), sodium iodide (965
g, 6.44 mol) and 1-benzhydryl-3-azetidinyl methanesulfonate (1837
g, 5.8 mol) were suspended in tetrahydrofuran (10.8 L) and water
(1.2 L) and heated under reflux for 5 days with constant stirring.
The reaction mixture was then distilled at atmospheric pressure so
that 7.5 L of solvent was distilled. The reaction was cooled to
40.degree. C. and water (8 L) was added to the reaction mixture.
The reaction mixture was again heated while solvent was distilled
at atmospheric pressure. In this distillation the internal
temperature rose to 96.degree. C. and 900 mL of solvent was
collected. The reaction was cooled to 80.degree. C. and MIBK (2.4
L) was added the reaction mixture was then heated to reflux for 1 h
and allowed to cool to room temperature overnight. The resulting
precipitate was cooled to 12.degree. C. and granulated for 2 hours
before filtering. The filter cake was washed with water (2 L) and
MIBK (2 L). The solid product was oven dried at 50.degree. C. under
vacuum. The resultant yellow solid was reslurried in water (9 L) at
room temperature for 3 hours before being filtered under vacuum.
The filter cake was washed with MIBK (1 L) with gentle agitation
using a spatula. The pale cream solid was oven dried at 50.degree.
C. under vacuum to afford the title compound (758 g, 43%): Data as
reported above.
Preparation 2(b)
1-(3-Azetidinyl)-5-ethyl-4-nitro-1H-pyrazole-3-carboxamid- e
[0138] 21
[0139] To a suspension of the title compound of Preparation 2(a)
(35.3 g, 87.1 mmol) in dichloromethane (700 mL) at 0.degree. C.
under nitrogen was added 1-chloroethyl chloroformate (10.4 mL, 95.8
mmol) dropwise. The reaction mixture was stirred at 0.degree. C.
for 30 minutes, and at room temperature for 18 hours. The reaction
mixture was then concentrated in vacuo, and the oily residue
dissolved in methanol (700 mL) and refluxed for 1 hour. The solvent
was then removed in vacuo, and the crude product triturated from
ethyl acetate (200 mL) and acetone (200 mL) to yield the
dihydrochloride salt of the title compound as a beige solid (21.3
g, 77.3 mmol, 89%): mp 164-167.degree. C.; 1H NMR (400 MHz,
DMSO-d.sub.6): .delta.=1.09 (t, 3H, J=7.6 Hz), 2.92 (q, 2H, J=7.3
Hz), 4.26-4.40 (m, 4H), 4.44-4.51 (m, 1H), 7.75 (br s, 1H), 8.01
(br s, 1H), 9.39 (br s, 2H); LRMS (m/z) (TSP.sup.+) 240.3
(MH.sup.+).
Preparation 2(c)
5-Ethyl-1-(1-ethyl-3-azetidinyl)-4-nitro-1H-pyrazole-3-ca-
rboxamide
[0140] 22
[0141] To a stirring solution of the title compound of Preparation
2(b) (31.1 g, 113 mmol) and triethylamine (14.1 mL, 102 mmol) in
dichloromethane (400 mL) and methanol (400 mL) at 0.degree. C., was
added sodium triacetoxyborohydride (60 g, 282 mmol) in one portion.
Acetaldehyde (19 mL, 339 mmol) was then added dropwise over 2
minutes. The reaction mixture was then allowed to warm up to room
temperature over 30 minutes. The solvent was then removed in vacuo,
and the residue partitioned between dichloromethane (500 mL) and
water (300 mL). The organic layer was separated, and the aqueous
layer basified with solid sodium bicarbonate and extracted with
dichloromethane (500 mL) and dichloromethane:methanol (95:5, 500
mL; 90:10, 500 mL). The combined organic layers were dried
(MgSO.sub.4), and concentrated in vacuo. The residue was triturated
from hot ethyl acetate, and a white solid separated by filtration.
The filtrate was concentrated in vacuo, and purified by flash
column chromatography (eluting with
CH.sub.2Cl.sub.2:MeOH:0.88NH.sub.3 95:5:0.5) to give a white solid
which was combined with the previous batch to yield the title
compound (23.3 g, 86.8 mmol, 77%): mp 177-179.degree. C.; 1H NMR
(400 MHz, CDCl.sub.3): .delta.=1.01 (t, 3H, J=7.3 Hz), 1.25 (t, 3H,
J=7.6 Hz), 2.62 (q, 2H, J=7.3 Hz), 2.95 (q, 2H, J=7.8 Hz), 3.55
(dt, 2H, J=2.0, 6.4 Hz), 3.83 (dt, 2H, J=2.0, 6.8 Hz), 4.96
(quintet, 1H, J=7.3 Hz), 6.13 (br s, 1H), 6.92 (br s, 1H); LRMS
(m/z) (TSP.sup.+) 268.3 (MH.sup.+).
Preparation 2(d)
4-Amino-5-ethyl-1-(1-ethyl-3-azetidinyl)-1H-pyrazole-3-ca-
rboxamide
[0142] 23
[0143] A mixture of the title compound from Preparation 2(c) (22.0
g, 82.3 mmol) and 10% palladium on charcoal (2.0 g) in ethanol (500
mL) was hydrogenated at 60 p.s.i. and room temperature for 4 hours.
The reaction mixture was then filtered through Arbocel.RTM. under
nitrogen, and the filtrate was concentrated in vacuo to yield the
title compound as a cream solid (19.6 g, 82.6 mmol, 100%): mp
155-157.degree. C.; 1H NMR (400 MHz, CDCl.sub.3): .delta.=1.01 (t,
3H, J=7.2 Hz), 1.13 (t, 3H, J=7.6 Hz), 2.54 (q, 2H, J=7.8 Hz), 2.59
(q, 2H, J=7.3 Hz), 3.46 (t, 2H, J=7.8 Hz), 3.77 (t, 2H, J=7.6 Hz),
3.93 (br s, 2H), 4.83 (quintet, 1H, J=7.3 Hz), 5.25 (br s, 1H),
6.64 (br s, 1H); LRMS (m/z) (TSP.sup.+) 238.2 (MH.sup.+).
Preparation 2(e)
5-Acetyl-N-[3-(aminocarbonyl)-5-ethyl-1-(1-ethyl-3-azetid- inyl)-1
H-pyrazol-4-yl]-2-ethoxynicotinamide
[0144] 24
[0145] 1,1-Carbonyldiimidazole (13.9 g, 85.8 mmol) was added to a
suspension of the title compound from Preparation 1(b) (17.1 g,
81.8 mmol) in ethyl acetate (140 mL) under nitrogen, and the
reaction mixture was stirred at 45.degree. C. for 45 minutes and
heated under reflux for 90 minutes. The reaction mixture was then
cooled to room temperature and a slurry of the title compound from
Preparation 9 (19.4 g, 81.8 mmol) in ethyl acetate (70 mL) was
added. The reaction mixture was then heated under reflux for 16
hours, after which a precipitate had formed. The suspension was
cooled to room temperature and the solid removed by filtration. The
solid was washed with water:ethanol 90:10 and then dried in vacuo
to yield the title compound as a white solid (24.0 g, 56.0 mmol,
69%): mp 230-233.degree. C.; 1H NMR (400 MHz, CDCl.sub.3):
.delta.=1.03 (t, 3H, J=7.3 Hz), 1.20 (t, 3H, J=7.8 Hz), 1.57 (t,
3H, J=7.3 Hz), 2.60 (s, 3H), 2.62 (q, 2H, J=6.8 Hz), 2.86 (q, 2H,
J=7.3 Hz), 3.53 (t, 2H, J=7.8 Hz), 3.83 (t, 2H, J=7.3 Hz), 4.77 (q,
2H, J=6.8 Hz), 4.99 (quintet, 1H, J=7.3 Hz), 5.30 (br s, 1H), 6.74
(br s, 1H), 8.89 (d, 1H, J=2.4 Hz), 9.02 (d, 1H, J=2.4 Hz), 10.48
(br s, 1H); LRMS (m/z) (TSP.sup.+) 429.2 (MH.sup.+).
Preparation 3 2-Propoxynicotinic acid
[0146] Sodium metal (9.2 g, 0.4 mol), washed free of oil (with
hexane), was added in small pieces, over 2 h, to anhydrous
n-propanol (350 mL) whilst maintaining a temperature between
50.degree. C. and 100.degree. C. To the resultant clear, yellow
solution was added a slurry of 2-chloronicotinic acid (31.5 g, 0.2
mol) in anhydrous propanol (100 mL), and the suspension heated to
reflux for 6 h. The bulk of the solvent was distilled off, and
replaced, after cooling, with diethyl ether (200 mL) to afford a
thick white solid which was removed by filtration and washed with
diethyl ether (500 mL). The solid was taken up in water (300 mL),
washed with dichloromethane (200 mL), and the aqueous phase
acidified with concentrated hydrochloric acid to pH 4.5 and
extracted with dichloromethane (3.times.200 mL). The combined
extracts were washed with brine, dried over MgSO.sub.4, and
concentrated to an oil (40 g). The oil was taken up in pentane (150
mL) and stood in ice for 30 mins to deliver a white crystalline
solid which was collected by filtration, washed with fresh pentane
(3.times.200 mL) and dried under vacuum to afford
2-propoxynicotinic acid (26.5 g, 146 mmol).
[0147] .sup.1H NMR (300 MHz, d.sub.6-DMSO+1 drop
d.sub.1-trifluoroacetic acid) .delta.=0.95 (t, 3H), 1.65-1.8 (m,
2H), 4.25 (t, 2H), 7.0 (m, 1H), 8.1 (d, 1H), 8.25 (d, 1 H).
Preparation 4 2-Propoxy-5-iodonicotinic acid
[0148] The title compound from Preparation 3 (9.30 g, 51.3 mmol)
was dissolved slowly in trifluoroacetic acid (75 mL) and
trifluoroacetic anhydride (19 mL). N-iodosuccinimide (18.6 g, 82.7
mmol) was then added portionwise, and the red/brown solution heated
at reflux for 6 h followed by 16 h at room temperature. The
reaction mixture was then concentrated in vacuo and water (150 mL)
added. The aqueous mixture was extracted with dichloromethane
(3.times.150 mL). The combined organic layers were extracted with
aqueous sodium hydroxide solution (1 N, 200 mL), and then the
aqueous acidified with concentrated hydrochloric acid. The acidic
aqueous layer was then extracted with dichloromethane (4.times.150
mL), the combined organic layers washed with brine (150 mL), dried
(MgSO.sub.4) and concentrated in vacuo. Trituration from pentane
yielded the target compound as an off-white solid (11.3 g, 36.8
mmol):
[0149] 1H NMR (300 MHz, CDCl.sub.3): .delta. 1.05 (t, 3H, J=7.6
Hz), 1.86-1.95 (m, 2H), 4.60 (t, 2H, J=7.0 Hz), 8.55 (d, 1H, J=2.4
Hz), 8.70 (d, 1H, J=2.7 Hz);
[0150] LRMS (m/z) (ES.sup.-): 306 (MH.sup.-).
Preparation 5
N-[3-(Aminocarbonyl)-5-ethyl-1H-pyrazol-4-yl]-5-iodo-2-propo-
xy-nicotinamide
[0151] The title compound from Preparation 4 (16 g, 52.1 mmol) was
suspended in dichloromethane (160 mL) and cooled to 0.degree. C.
Oxalyl chloride (13 mL, 1.49 mol) was then added followed by a drop
of N,N-dimethylformamide, and the reaction mixture allowed to warm
up to room temperature. After 2 h the reaction mixture was
concentrated in vacuo, and azeotroped with dichloromethane
(.times.2). The residue was then dissolved in dichloromethane (160
mL) and 4-amino-3-ethyl-1H-pyrazol- e-5-carboxamide (prepared as
described in WO 98/49166) (8.5 g, 55.1 mmol) and triethylamine
(20.8 mL, 1.49 mol) were added at 0.degree. C. The reaction mixture
was allowed to warm up to room temperature and stirred for 16 h
under nitrogen. The reaction mixture was then diluted with water
(150 mL) and dichloromethane (150 mL), and the precipitate removed
by filtration. The precipitate was washed well with dichloromethane
and water to yield the title compound. The combined organic
filtrates were then washed with aqueous hydrochloric acid (2M, 75
mL), saturated aqueous sodium bicarbonate solution (75 mL), brine
(100 mL), dried (MgSO.sub.4) and concentrated in vacuo. The
resulting crude product was triturated from ethyl acetate to give a
white solid. This solid was combined with the previous residue to
yield the title compound as a white solid (17.1 g, 38.6 mmol).
[0152] .sup.1H NMR (300 MHz, d.sub.4-methanol): .delta. 1.0 (t,
3H), 1.25 (t, 3H), 1.85-2.0 (m, 2H), 2.8 (q, 2H), 4.5 (t, 2H), 8.5
(s, 1H), 8.6 (s, 1H).
[0153] LRMS (TSP) 444 (MH.sup.+).
Preparation 6 2-Ethoxynicotinic acid
[0154] A solution of potassium t-butoxide (44.9 g, 0.40 mol) in
absolute ethanol (300 mL) was added slowly to a solution of
2-chloronicotinic acid (30 g, 0.19 mol) in ethanol (100 mL), and
the reaction heated in a sealed vessel at 170.degree. C. for 20 h.
On cooling, the reaction mixture was concentrated under reduced
pressure, the residue dissolved in water (200 mL) and acidified to
pH 3 with aqueous hydrochloric acid. The aqueous solution was
extracted with dichloromethane (4.times.200 mL), the organic phases
combined, dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure to afford the title compound (27.4 g, 16.4 mmol) as a
white solid.
[0155] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.53 (t, 3H),
4.69 (q, 2H), 7.13 (m, 1H), 8.37 (d, 1H), 8.48 (d, 1H).
Preparation 7 2-Ethoxynicotinic acid ethyl ester
[0156] A suspension of the title compound of Preparation 6 (16.4 g,
98 mmol), and cesium carbonate (32 g, 98 mmol) in
N,N-dimethylformamide (240 mL) was stirred at room temperature for
2 h. Ethyl iodide (7.85 mL, 98 mmol) was added and the reaction
stirred for a further 24 h. The reaction mixture was concentrated
under reduced pressure and the residue partitioned between aqueous
sodium carbonate solution (100 mL) and ethyl acetate (100 mL). The
phases were separated and the aqueous phase extracted with ethyl
acetate (2.times.100 mL). The combined organic solutions were
washed with brine, dried (Na.sub.2SO.sub.4) and evaporated under
reduced pressure to afford the title compound (18.0 g, 92.2 mmol)
as a pale yellow oil.
[0157] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.41 (m, 6H),
4.36, (q, 2H), 4.48 (q, 2H), 6.90 (m, 1H), 8.12 (d, 1H), 8.28 (d,
1H).
Preparation 8 Pyridine-2-ethoxy-5-nitro-3-carboxylic acid ethyl
ester
[0158] Ammonium nitrate (5.36 g, 66 mmol) was added portionwise to
an ice-cooled solution of the title compound of Preparation 7 (4.66
g, 22.3 mmol) in trifluoroacetic anhydride (50 mL) and the reaction
stirred for 18 h at room temperature. The reaction mixture was
carefully poured into ice water (200 mL) and the resulting
suspension stirred for an hour. The precipitate was filtered off,
washed with water and dried under suction to afford the title
compound (3.29 g, 13.7 mmol).
[0159] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.:1.41 (t, 3H),
1.48 (t, 3H), 4.41 (q, 2H), 4.62 (q, 2H), 8.89 (s, 1H), 9.16 (s,
1H).
Preparation 9 Pyridine-2-ethoxy-5-nitro-3-carboxylic acid
[0160] Aqueous sodium hydroxide solution (4 mL, 5N, 20 mmol) was
added dropwise to a solution of the title compound of Preparation 8
(5.1 g, 20 mmol) in ethanol (100 mL) and the reaction stirred at
room temperature for 18 h. The reaction mixture was concentrated in
vacuo, the residue suspended in water (50 mL) and acidified to pH 3
with hydrochloric acid. This aqueous solution was extracted with
ethyl acetate (3.times.100 mL), the combined organic layers washed
with brine (100 mL), dried (Na.sub.2SO.sub.4) and evaporated under
reduced pressure to give a beige solid. The crude product was
recrystallised from ethyl acetate/hexane to afford the title
compound (3.32 g, 15.6 mmol) as beige crystals.
[0161] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.:1.55 (t, 3H),
4.78 (q, 2H), 9.17 (s, 1H), 9.23 (s, 1H).
Preparation 10
N-[5-(Aminocarbonyl)-1-methyl-3-propyl-1H-pyrazol-4-yl]-2-e-
thoxy-5-nitronicotinamide
[0162] The product of Preparation 9 and
4-amino-1-methyl-3-propyl-1H-pyraz- ole-5-carboxamide (prepared as
described in EP 526 004) were combined using the method of
Preparation 5.
[0163] m.p. 251-3.degree. C.
[0164] 1H NMR (300 MHz, d.sub.6-DMSO): .delta. 0.9 (t, 3H), 1.38
(t, 3H), 1.5-1.7 (m, 2H), 2.5-2.55 (m, partially obscured by DMSO
peak, 2H), 3.9 (s, 3H), 4.5-4.65 (m, 2H), 7.3 (br s, 1H), 7.7 (br
s, 1H), 8.7 (s, 1H), 9.2 (s, 1 H), 9.7 (s, 1H).
[0165] LRMS (ES negative ion) 375 (M-H).sup.-.
[0166] Analysis: Found C, 50.99; H, 5.36; N, 22.33. Calcd for
C.sub.16H.sub.20N.sub.6O.sub.5 : C, 51.06; H, 5.36; N, 22.33%
Preparation 11a
3-Ethyl-1-[2-(4-morpholinyl)ethyl]-4-nitro-1H-pyrazole-5-c-
arboxamide and
Preparation 11b
5-Ethyl-1-[2-(4-morpholinyl)ethyl]-4-nitro-1H-pyrazole-3-c-
arboxamide
[0167] A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide
(prepared as in WO 98/49166) (20.0 g, 0.11 mol), potassium
carbonate (29.9 g, 0.22 mmol) and cesium carbonate (7.08 g, 21.7
mmol) were stirred together at room temperature. After 15 minutes
4(2-chloroethyl)morpholine. HCl (22.2 g, 0.12 mol) was added and
the reaction mixture was heated at 55.degree. C. for 16 h. The
reaction mixture was concentrated in vacuo, and then partitioned
between water (500 mL) and ethyl acetate (350 mL). Solid sodium
carbonate was added until the pH reached 10, and then the organic
layer was separated. The aqueous layer was extracted with further
ethyl acetate (150 mL). The combined organic layers were
concentrated in vacuo, combined with 1.6 g of a previous identical
batch and purified by flash column chromatography (eluting with
methanol:ethyl acetate:NH.sub.3 0:100:0 to 20:80:1). Two products
were separated. The first product was triturated from diethyl ether
to yield 3-ethyl-1-[2-(4-morpholinyl)ethyl]-
-4-nitro-1H-pyrazole-5-carboxamide as cream coloured crystals (16.2
g, 54.5 mmol).
[0168] m.p. 133.degree. C.
[0169] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.25 (t, 3H),
2.43 (t, 4H), 2.79 (t, 2H), 2.90 (q, 2H), 3.60 (t, 4H), 4.45 (t,
2H), 6.40 (br s, 1H), 7.63 (br s, 1H).
[0170] LRMS (TSP) 297.9 (MH.sup.+).
[0171] Analysis: Found C, 48.47; H, 6.47; N, 23.49. Calcd for
C.sub.12H.sub.19N.sub.5O.sub.4: C, 48.48; H, 6.44; N, 23.56%
[0172] The second product was triturated from ethyl acetate to
yield
5-ethyl-1-[2-(4-morpholinyl)ethyl]-4-nitro-1H-pyrazole-3-carboxamide
as white crystals (7.83 g, 26.3 mmol).
[0173] m.p. 144.9-147.1.degree. C.
[0174] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.30 (t, 3H),
2.43 (t, 4H), 2.82 (t, 2H), 3.00 (q, 2H), 3.62 (t, 4H), 4.20 (t,
2H), 6.00 (br s, 1H), 7.22 (br s, 1H).
[0175] LRMS (TSP) 297.7 (MH.sup.+).
[0176] Analysis: Found C, 48.2; H, 6.43; N, 23.30. Calcd for
C.sub.12H.sub.19N.sub.5O.sub.4: C, 48.48; H, 6.44; N, 23.56%
[0177] The regiochemistry was determined by nOe studies.
Preparation 12
4-Amino-3-ethyl-1-[2-(4-mornholinyl)ethyl]-1H-pyrazole-5-ca-
rboxamide
[0178] The title compound of Preparation 11a (16 g, 54 mmol) was
dissolved in ethanol (320 mL) and treated with 10% Pd on C (1.5 g)
before stirring at room temperature under 60 psi of hydrogen for 6
h. The catalyst was removed by filtration through Arbocel.RTM., the
filtrate concentrated in vacuo to an oil which afforded the title
compound as a pink solid after trituration with diisopropyl ether
(13.18 g, 49.3 mmol).
[0179] m.p. 115-7.degree. C.
[0180] 1H NMR (300 MHz, CDCl.sub.3): .delta.=1.2 (t, 3H), 2.4-2.5
(m, 4H), 2.55 (q, 2H), 2.8 (t, 2H), 3.4 (s, 2H), 3.6-3.65 (m, 4H),
4.45 (t, 2H).
[0181] LRMS (TSP) 268 (MH.sup.+).
[0182] Analysis: Found C, 53.89; H, 8.04; N, 25.86. Calcd for
C.sub.12H.sub.21N.sub.5O.sub.2: C, 53.92; H, 7.92; N, 26.20%
Preparation 13
N-{5-(Aminocarbonyl)-3-ethyl-1-[2-(4-morpholinyl)ethyl]-1H--
pyrazol-4-yl}-5-iodo-2-propoxynicotinamide
[0183] The title compound was prepared by the method of Preparation
5 using the title compounds of Preparations 4 and 12.
[0184] m.p. 180-180.5.degree. C.
[0185] 1H NMR (300 MHz, CDCl.sub.3): .delta.=1.05 (t, 3H), 1.25 (t,
3H), 1.85-1.95 (m, 2H), 2.4-2.55 (m, 4H), 2.6 (q, 2H), 2.8 (t, 2H),
3.55-3.7 (m, 4H), 4.5 (t, 2H), 4.55 (t, 2H), 5.6 (br s, 1H), 8.25
(br s 1H), 8.5 (s, 1H), 8.75 (s, 1H), 9.5 (s, 1H).
[0186] LRMS (TSP) 558 (MH.sup.+).
[0187] Analysis: Found C, 45.05; H, 5.23; N, 14.59. Calcd for
C.sub.21H.sub.29N.sub.6O.sub.4I. 0.2H.sub.2O: C, 45.04; H, 5.29; N,
15.01%
Preparation 14 2-Ethoxy-5-iodonicotinic acid
[0188] The title compound was prepared from 2-ethoxynicotinic acid
using the method of Preparation 4.
[0189] .sup.1H NMR (400 MHz, d.sub.6-DMSO): .delta.=1.3 (t, 3H),
4.35 (q, 2H), 8.3 (d, 1H), 8.5 (d, 1H), 13.2 (br s, 1H)
Preparation 15
N-[5-(Aminocarbonyl)-3-ethyl-1H-pyrazol-4-yl]-2-ethoxy-5-io-
donicotinamide
[0190] The title compound of Preparation 14 (8 g, 27.3 mmol) in
dichloromethane (200 mL) was treated with 1-hydroxybenzotriazole
hydrate (4.43 g, 32.8 mmol), N,N-diisopropylethylamine (14.3 mL,
77.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (6.27 g, 31.7 mmol) and
4-amino-3-ethyl-1H-pyrazole-5-carboxamide (prepared as described in
WO 98/49166; 3.78 g, 24 mmol), and the resultant mixture stirred at
room temperature for 14 h. After washing with water (100 mL), a
portion of the title compound was isolated by filtration of the
precipitate as a pale brown solid (6.55 g, 15.3 mmol). The organic
phase was dried over MgSO.sub.4, concentrated, and the residue
treated with diethyl ether to give further title compound as a pale
brown solid (1.65 g, 3.84 mmol).
[0191] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.25 (t, 3H),
1.55 (t, 3H), 2.9 (2H, q), 2.65 (2H, q), 5.4 (br s, 1H), 6.75 (br
s, 1H), 8.4 (d, 1H), 8.8 (d, 1H), 10.65 (br s, 1H).
[0192] LRMS (ES.sup.- positive ion) 430 (MH.sup.+).
Preparation 16
N-[3-(Aminocarbonyl)-1-(4-cyanobenzyl)-5-ethyl-1H-pyrazol-4-
-yl]-2-ethoxy-5-iodonicotinamide
[0193] The title compound from Preparation 15 (1.00 g, 2.33 mmol)
was dissolved in tetrahydrofuran (25 mL) and cooled to 0.degree. C.
Sodium hydride (112 mg, 60% in mineral oil, 2.80 mmol) was then
added, followed by 4-cyanobenzylbromide (548 mg, 2.8 mmol) after 30
minutes. The reaction mixture was heated at 60.degree. C. for 16 h.
The solvent was then removed in vacuo, and the residue partitioned
between water (50 mL) and dichloromethane (50 mL). The organic
phase was separated, dried (MgSO.sub.4), and concentrated in vacuo.
The crude product was purified by flash column chromatography
(eluting with dichloromethane:methanol 100:1 to 95:5) to give the
title compound (1.06 g, contaminated with low level of impurity).
Taken on to next stage crude.
[0194] 1H NMR (300 MHz, CDCl.sub.3): .delta.=1.2 (t, 3H), 1.55 (t,
3H), 2.8 (q, 2H), 3.0 (s, 3H), 3.1 (s, 3H), 4.65 (q, 2H), 4.95 (s,
2H), 5.2 (br s, 1 H), 6.6 (br s, 1 H), 8.40 (d, 1H), 8.80 (d, 1H),
10.45 (br s, 1H).
[0195] LRMS (TSP) 514 (MH.sup.+), 537 (MNa.sup.+).
Preparation 17
N-[3-(Aminocarboyl)-5-ethyl-1-(2-pyridinylmethyl)-1H-pyrazo-
l-4-yl]-5-iodo-2-propoxynicotinamide
[0196] The title compound was prepared using the method of
Preparation 5 and the title compounds of Preparations 4 and
4-amino-5-ethyl-1-(2-pyridi- nylmethyl)-1H-pyrazole-3-carboxamide
(WO 9849166).
[0197] 1H NMR (400 MHz, CDCl.sub.3): .delta.=1.00 (m, 6H), 1.90 (m,
2H), 2.80 (q, 2H), 4.50 (t, 2H), 5.20 (s, 1H), 5.40 (s, 2H), 6.60
(s, 1H), 6.90 (d, 1H), 7.20 (m, 1H), 7.60 (app. t, 1H), 8.40 (d,
1H), 8.60 (m, 1H), 8.75 (s, 1H), 10.40 (s, 1H)
[0198] LRMS (ES--positive ion) 535 (MH.sup.+), (ES--negative ion)
533 (M-H)
[0199] Anal. Found C, 47.53; H, 4.41; N, 15.69. Calcd for
C.sub.21H.sub.23O.sub.3N.sub.6I: C, 47.20; H, 4.34; N, 15.73.
Preparation 18 tert-Butyl 3-iodo-1-azetidinecarboxylate
[0200] A mixture of tert-butyl
3-[(methylsulfonyl)oxy]-1-azetidinecarboxyl- ate (prepared as
described in Synlett 1998, 379; 5.0 g, 19.9 mmol), and potassium
iodide (16.5 g, 99.4 mmol) in N,N-dimethylformamide (25 mL), was
heated at 100.degree. C. for 42 h. The cooled mixture was
partitioned between water and ethyl acetate, and the layers
separated. The organic phase was dried over MgSO.sub.4,
concentrated under reduced pressure and the residue azeotroped with
xylene. The crude product was purified by flash column
chromatography (dichloromethane as eluant) to give the title
compound (3.26 g, 11.5 mmol).
[0201] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.=1.43 (s, 9H), 4.28
(m, 2H), 4.46 (m,1H), 4.62 (m, 2H).
[0202] LRMS (TSP) 284 (MH).sup.+
Preparation 19 tert-Butyl
3-(3-(aminocarbonyl)-5-ethyl-4-{[(5-iodo-2-propo-
xy-3-pyridinyl)carbonyl]amino}-1H-pyrazol-1-yl)-1-azetidinecarboxylate
[0203] The title compounds from Preparation 5 (5.00 g, 11.3 mmol)
and Preparation 18 (3.84 g, 13.5 mmol) were stirred together in dry
N,N-dimethylformamide (40 mL) at room temperature under nitrogen,
and then cesium carbonate (4.41 g, 13.5 mmol) was added. The
reaction mixture was stirred at room temperature for 2 h and then
heated at 60.degree. C. for 16 h. Further aliquots of the title
compound from Preparation 18 (959 mg, 3.39 mmol) and cesium
carbonate (1.10 g, 3.39 mmol) were then added and stirring
continued for 24 h at 60.degree. C. and 36 h at room temperature.
The reaction mixture was then filtered to yield the title compound
as a white solid (3.47 g). The filtrate was diluted with
dichloromethane (100 mL), and washed with citric acid (10% aq.,
2.times.30 mL), water (30 mL), then dried (MgSO.sub.4) and
concentrated in vacuo to yield an oil. The crude oil was purified
by flash column chromatography (eluting with 99:1 to 97:3
dichloromethane:methanol) and trituration from hot ethyl acetate to
yield the title compound as a white solid (900 mg). The two batches
of title compound were combined (4.37 g, 7.30 mmol).
[0204] 1H NMR (400 MHz, DMSO): .delta.=0.95 (t, 3H), 1.05 (t, 3H),
1.40 (s, 9H), 1.78-1.88 (m, 2H), 2.68 (q, 2H), 4.22-4.35 (m, 4H),
4.40 (t, 2H), 5.33 (t, 1 H), 7.35 (bs, 1H), 7.52 (bs, 1H), 8.40 (s,
1H), 8.55 (s, 1H), 10.10 (s, 1H)
[0205] LRMS (TSP--positive ion) 373.2 (MH.sup.+--BOC and I)
[0206] Anal. Found C, 45.1 1; H, 5.07; N, 13.56 Calcd for
C.sub.23H.sub.31O.sub.5N.sub.6I. 0.2 dichloromethane: C, 45.28; H,
5.14; N, 13.66.
Preparation 20 tert-Butyl
4-(3-(aminocarbonyl)-5-ethyl-4-{[(5-iodo-2-propo-
xy-3-pyridinyl)carbonyl]amino}-1H-pyrazol-1-yl)-1-piperidinecarboxylate
[0207] The title compound was prepared from the product of
Preparation 5 with tert-butyl
4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate (WO 93/19059) as
alkylating agent, using the method of Preparation 19.
[0208] 1H NMR (400 MHz, CDCl.sub.3): .delta.=1.00 (t, 3H), 1.10 (t,
3H), 1.45 (s, 9H), 1.85-1.95 (m, 4H), 2.10 (m, 2H), 2.84 (m, 4H),
4.10-4.30 (m, 3H), 4.50 (t, 2H), 5.10 (s, 1H), 6.60 (s, 1H), 8.40
(s, 1H), 8.72 (s, 1H), 10.30 (s, 1H)
[0209] LRMS (TSP--positive ion) 628 (MH.sup.+)
[0210] Anal. Found C, 47.55; H, 5.71; N, 13.07 Calcd for
C.sub.25H.sub.35O.sub.5N.sub.6I.0.3H.sub.2O, C, 47.52; H, 5.68; N,
13.30
COMPARATIVE EXAMPLE A
Preparation of Compound 1A
5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1--
ethyl-3-azetidinyl)-2,6-dihydro-7H-Pyrazolo[4,3-d]pyrimidin-7-one
[0211] 25
Preparation
A(c)--5-Acetyl-N-[3-(aminocarbonyl)-5-ethyl-1H-pyrazol-4-yl]-2-
-ethoxynicotinamide
[0212] 26
[0213] A solution of the title compound from Preparation 1(b) (5.70
g, 27.3 mmol) and
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluor-phosphate (10.9 g, 28.6 mmol) in dichloromethane (100 mL)
was added to a solution of
4-amino-3-ethyl-1H-pyrazole-5-carboxamide.sup.i (4.20 g, 27.3 mmol)
and diisopropylethylamine (23.7 mL, 136.2 mmol) in dichloromethane
(115 mL) under nitrogen. After 1 h the mixture was diluted with
brine (100 mL) and washed with a saturated aqueous sodium
bicarbonate solution (100 mL) and 2N HCl (100 mL). Each aqueous
layer was extracted with dichloromethane (100 mL), and the combined
organics washed with brine (100 mL), dried (MgSO.sub.4) and
concentrated in vacuo. An analytical sample of the title compound
was obtained by trituration with ethyl acetate, followed by
recrystallisation from ethanol, while the remainder was purified by
column chromatography on silica gel (eluting with 95:5
CH.sub.2Cl.sub.2:MeOH) to yield the title compound as a white solid
(total weight=7.8 g, 22.5 mmol, 83%): mp 217-219.degree. C.; 1H NMR
(400 MHz, DMSO-d.sub.6): .delta.=1.10 (t, 3H, J=7.6 Hz), 1.42 (t,
3H, J=7.1 Hz), 2.56 (s, 3H), 2.73 (q, 2H, J=7.6 Hz), 4.62 (q, 2H,
J=6.9 Hz), 7.26 (br s, 1H), 7.48 (br s, 1H), 8.71 (d, 1H, J=1.8
Hz), 8.91 (d, 1H, J=2.4 Hz), 10.52 (br s, 1H), 12.93 (br s, 1H);
LRMS (m/z) (TSP.sup.+) 346.2 (MH.sup.+).
Preparation A(d) tert-Butyl
3-[4-{[(5-acetyl-2-ethoxy-3-pyridinyl)carbonyl-
]amino}-3-(aminocarbonyl)-5-ethyl-1H-pyrazol-1-yl]-1-azetidinecarboxylate
[0214] 27
[0215] Cesium carbonate (46.4 g, 142 mmol) was added to a stirring
solution of the title compound of Preparation A(c) (32.8 g, 95.0
mmol) and tert-butyl-3-iodo-1-azetidinecarboxylate (40.4 g, 143
mmol) in N,N-dimethylformamide (400 mL), and the reaction mixture
was heated at 50.degree. C. for 16 hours. The solvent was then
removed in vacuo, and the residue triturated from ethyl acetate
(100 mL). The resulting solid was filtered off, washed with ethyl
acetate and partitioned between dichloromethane (500 mL) and water
(300 mL) in the presence of concentrated hydrochloric acid (5 mL).
The organic layer was separated, and the aqueous layer was
extracted further with dichloromethane (2.times.100 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. The resulting crude product was triturated
from acetonitrile, filtered and washed with acetonitrile and ether
to yield the title compound as a white solid (30.3 g, 60.0 mmol,
63%): mp 220-223.degree. C.; 1H NMR (400 MHz, CDCl.sub.3):
.delta.=1.15 (t, 3H, J=7.6 Hz), 1.44 (s, 9H), 1.54 (t, 3H, J=7.1
Hz), 2.57 (s, 3H), 2.83 (q, 2H, J=7.3), 4.32 (t, 2H, J=8.1 Hz),
4.37-4.46 (m, 2H), 4.74 (q, 2H, J=7.1 Hz), 5.02-5.10 (m, 1H), 5.33
(br s, 1H), 6.72 (br s, 1H), 8.85 (d, 1H, J=2.5 Hz), 8.98 (d, 1H,
J=2.4 Hz), 10.49 (br s, 1H); LRMS (m/z) (ES.sup.+) 523.0
(MNa.sup.+), (ES.sup.-) 499.0 (MH.sup.-).
Preparation A(e) tert-Butyl
3-[5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-7-
-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-1-azetidinecarboxylate
[0216] 28
[0217] The title compound of Preparation A(d) (30.3 g, 60.0 mmol)
and cesium carbonate (40.0 g, 123 mmol) were dissolved in n-butanol
(500 mL) in the presence of 3 .ANG. molecular sieves (5.00 q)and
heated under reflux for 6 h. The first 90 mL of solvent were
removed via distillation. The reaction mixture was then left at
room temperature for 16 h, before being concentrated in vacuo. The
residue was partitioned between ethyl acetate (400 mL) and water
(400 mL), and solid carbon dioxide added until pH8. The organic
layer was then separated, and the aqueous extracted further with
ethyl acetate (400 mL). The combined organic layers were then dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. The crude product
was purified by column chromatography on silica gel (eluting with
CH.sub.2Cl.sub.2:MeOH:0.88NH.sub.3 98:2:0.2 to 96:4:0.4), followed
by crystallisation from diisopropylether. This yielded the title
compound, containing a 10% impurity, as white crystals (13.5 g,
26.4 mmol, 46%): mp 176-178.degree. C.; 1H NMR (400 MHz,
CDCl.sub.3): .delta.=0.98 (t, 3H, J=7.6 Hz), 1.33 (t, 3H, J=7.6
Hz), 1.44 (s, 9H), 1.48-1.54 (m, 2H), 1.85-1.95 (m, 2H), 2.62 (s,
3H), 3.00 (q, 2H, J=7.6 Hz), 4.34 (t, 2H, J=6.8 Hz), 5.19-5.27 (m,
1H), 8.82 (d, 1H, J=2.4 Hz), 9.21 (d, 1H, J=2.4 Hz), 10.64 (br s,
1H); LRMS (m/z) (ES.sup.+) 433 (MNa.sup.+), (ES.sup.-) 509
(MH.sup.-).
Preparation A(f)
5-(5-Acetyl-2-butoxy-3-pyridinyl)-2-(3-azetidinyl)-3-ethy-
l-2.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0218] 29
[0219] Trifluoroacetic acid (25 mL, 31 % vol) was added to a
solution of the title compound of Preparation A(e) (13.4 g, 262
mmol) in dichloromethane (80 mL) at 0.degree. C., and the mixture
was then stirred at room temperature for 1 hour. The reaction
mixture was poured into toluene (100 mL) and concentrated in vacuo
to yield an oil. The oil was azeotroped again with toluene (50 mL),
and the residue taken up in isopropylacetate. The resulting
precipitate was removed by filtration and dried in vacuo to yield
the trifluoacetate salt of the title compound as a white solid
(11.2 g, 17.5 mmol, 67%): 1H NMR (400 MHz, DMSO-d.sub.6):
.delta.=0.87 (dt, 3H, J=1.5, 7.3 Hz), 1.19 (t, 3H, J=7.3 Hz),
1.35-1.44 (m, 2H), 1.63-1.72 (m, 2H), 2.58 (s, 3H), 2.92 (q, 2H,
J=7.8 Hz), 3.78 (t, 2H, J=7.6 Hz), 4.05-4.11 (m, 2H), 4.34-4.43 (m,
2H), 5.45-5.53 (m, 1H), 8.39 (d, 1H, J=1.5 Hz), 8.90 (d, 1H, J=1.5
Hz); LRMS (m/z) (ES.sup.+) 411.0 (MH.sup.+), (ES.sup.-) 409.0
(MH.sup.-)
Preparation A(g)
5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-az-
etidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0220] Potassium carbonate (4.80 g, 34.7 mmol) and ethyl iodide
(1.4 mL, 17.5 mmol) were added to a cloudy solution of the title
compound from Preparation A(f) (11.1 g, 17.4 mmol) in acetonitrile
(600 mL), and then the reaction mixture was heated to 45-50.degree.
C. for 2.5 h. The solvent was then removed in vacuo, and the
residue dissolved in dichloromethane:methanol:ammonia 95:5:0.5 (50
mL). The resulting solution was filtered, and then purified by
column chromatography on silica gel (eluting with
CH.sub.2Cl.sub.2:MeOH:0.88NH.sub.3 95:5:0.5 to 92:8:1). The product
was crystallised from diisopropylether to yield the title compound
as white crystals (4.90 g, 11.2 mmol, 64%).
COMPARATIVE EXAMPLE B
Preparation of Compound 1A 5-(5-Acetyl
-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-
-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0221] 30
[0222] Cesium carbonate (38.6 g, 119 mmol) was added to a solution
of the title compound from Preparation 2(e) (25.4 g, 59.3 mmol) in
n-butanol (400 mL) in the presence of powdered 3A molecular sieves
(10 g). The reaction mixture was then heated to reflux, and 20 mL
of solvent removed via distillation into a splash trap. Refluxing
was then continued for 4 h, after which the reaction mixture was
cooled and filtered. The filtrate was concentrated in vacuo, and
then purified by column chromatography on silica gel (eluting with
CH.sub.2Cl.sub.2:MeOH:0.88NH.sub.3 95:5:0.5) to yield a green oil.
The crude product was then purified by crystallisation from ethyl
acetate, to yield the title compound as a white solid (9.00 g, 20.5
mmol, 35%): mp 143.0-144.0.degree. C.; 1H NMR (400 MHz,
DMSO-d.sub.6): .delta.=1.01 (t, 3H, J=7.3 Hz), 1.03 (t, 3H, J=7.3
Hz), 1.37 (t, 3H, J=7.8 Hz), 1.49-1.59 (m, 2H), 1.89-1.97 (m, 2H),
2.65 (s, 3H), 2.66 (q, 2H, J=7.3 Hz), 3.03 (q, 2H, J=7.3 Hz), 3.72
(t, 2H, J=7.8 Hz), 3.90 (t, 2H, J=7.8 Hz), 4.68 (t, 2H, J=6.8 Hz),
5.12-5.19 (m, 1H), 8.85 (d, 1H, J=2.4 Hz), 9.23 (d, 1H, J=2.4 Hz),
10.62 (br s, 1H); LRMS (m/z) (TSP.sup.+) 439.2 (MH.sup.+); Anal.
Found C, 63.00; H, 6.92; N, 19.14; Calcd for
C.sub.23H.sub.30N.sub.6O.sub.3 C, 63.00; H, 6.90; N, 19.16.
EXAMPLE 1
Preparation of Compound 1A 5-(5-Acetyl
-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-
-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0223] 31
[0224] To a stirred suspension of
5-Acetyl-N-[3-(aminocarbonyl)-5-ethyl-1--
(1-ethyl-3-azetidinyl)-1H-pyrazol-4-yl]-2-ethoxynicotinamide, the
title compound of Preparation 2(e), (0.41 g, 0.96 mMol) in
n-butanol (4 mL) under nitrogen atmosphere at room temperature was
added n-butyl acetate (1.92 mMol, 0.25 mL) followed by potassium
tert-butoxide (14.4 mMol, 162 mg) as a single solid portion. The
reaction was left to stir at room temperature for 5 minutes before
being heated to reflux overnight. The reaction was not complete so
further n-butyl acetate (1.92 mMol, 0.25 mL) and potassium
tert-butoxide (1.92 mMol, 215 mg) were added and the reaction was
heated to reflux for a further 2 h. The reaction was allowed to
cool to room temperature and then reduced to low volume (ca 1 mL)
at reduced pressure. The crude concentrate was then diluted with
DCM (50 mL) and washed with water (50 mL). The bi-phasic mixture
was then passed through a pad of celite and the cake was washed
with further DCM (50 mL). The two phases were then treated with
brine (20 mL) and separated. The aqueous phase was then extracted
with DCM (3.times.40 mL). The combined organics were then
evaporated at reduced pressure to afford a dark brown oil that
appeared to contain residual n-butanol. The crude residue was
triturated with hexane (10 mL) and the resultant tan solid isolated
by decanting the liquors to afford the title compound, 0.50 g,
yield by HPLC=50%. M/Z=439 (M+H).sup.+.
EXAMPLE 2
Preparation of Compound 1A 5-(5-Acetyl
-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-
-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0225] 32
[0226] To a stirred suspension of
5-Acetyl-N-[3-(aminocarbonyl)-5-ethyl-1--
(1-ethyl-3-azetidinyl)-1H-pyrazol-4-yl]-2-ethoxynicotinamide, the
title compound of Preparation 2(e), (1.07 g, 2.5 mMol) in n-butanol
(10 mL) under nitrogen atmosphere at room temperature was added
n-butyl acetate (7.5 mMol, 0.87 mL) followed by potassium carbonate
(7.5 mMol, 1.04 mg) as a single solid portion. The reaction was
left to stir at room temperature for 5 minutes before being heated
to reflux for 24 hours. The reaction was allowed to cool to room
temperature and then reduced to low volume (ca 2 to 3 mL) at
reduced pressure. The crude concentrate was then diluted with water
(20 mL), this aqueous mixture was then treated with dilute HCl
until pH 7 was attained at which point the remaining solvent was
azeotroped out under reduced pressure. The resulting precipitate
was cooled and filtered and the solid product dried to afford the
title compound, 1.09 g, yield by HPLC=81%. M/Z=439 (M+H).sup.+.
[0227] Thus the process according to the present invention (i.e.
using the hydroxide trapping agent), as illustrated hereinbefore by
Examples 1 and 2 is a more efficient (2-steps from the coupling
reaction) process for the preparation of compounds of general
formula I, and in particular compound 1A, compared to the process
of Comparative Example A which requires 5-steps from the coupling
reaction to furnish compounds of general formula I. Further, the
process of Examples 1 and 2 provides improved yields versus the
process of comparative example A.
[0228] The process of the present invention as illustrated by
Example 2 provides compound of general formula 1, in particular
compound 1A in of 81% from the compound of general formula II,
specifically compound IIIA using the process of the present
invention whilst Comparative Example B provides only 35% yield. In
particular the coupling of compounds IXA and XIIA followed by
cyclisation of compound IIIA to IA as exemplified herein in Example
2 provides the desired material in 56% yield whereas the
corresponding reaction sequence in WO 01/27112 provides a yield of
35%.
[0229] Additionally, in accordance with the invention, the
intermediate compounds (IX) (more particularly (IXA)) can be
prepared from commercially available starting materials (2-chloro
or 2-hydroxy nicotinic acid) in better yield than the corresponding
reaction sequence in WO 01/27112.
[0230] More particularly compounds of general formula (IA) can be
prepared in an overall yield of about 56% (from the corresponding
intermediate compounds (IXA) and (XIIA)) according to the process
of the present invention, as opposed to a yield of about 10% via
the process detailed in WO 01/27112 and yields of about 10% and
about 24% versus Comparative Examples A and B. Furthermore, the
reaction scheme of the present invention is safer and cheaper to
operate, and in the case of the process for the preparation of
intermediates (IX)/(IXA) also involves less steps (and processing
time).
[0231] In a preferred aspect compounds of formula (I) and (IA) are
prepared from 2-hydroxy nicotinic acid or 2-chloro nicotinic acid
in accordance with Schemes 1 and 2. In particular preparative
example 1(b) illustrates an improved process for the preparation of
compounds of general formula IXA from compounds of VIA in a yield
of 63%.
[0232] Thus, in a preferred aspect of the invention there is
provided a process for the preparation of a compound of formula (I)
and (IA) according to the Scheme 4 as hereinbefore detailed.
[0233] Preliminary analysis indicates that compound 1A is anhydrous
and non-hygroscopic which are desirable properties for compounds in
the formulation of certain pharmaceutical products, such as, for
example, tablets.
[0234] Differential Scanning Calorimetry (DSC) measurements were
made for the compound 1A (of Example A). The sample was scanned at
20.degree. C./minute, ambient to 300.degree. C. on a T. A.
Instruments Series 2910 machine and the flow gas was nitrogen. The
DSC trace showed a sharp endotherm at 141.degree. C. (.DELTA.H 87.2
J/g), due to the material melting. Following this event the sample
decomposed.
[0235] Powder X-Ray Diffraction (PXRD) Data was generated in
respect of the compound 1A (of Example A). The PXRD data for was
obtained from a sample of the solid mounted on a silicon wafer and
rotated to reduce the effects of particle size and orientation. The
solid sample was exposed to X-ray radiation using
CuK.sub..alpha.1(.lambda.=1.5406 .ANG.) and scanned through an
angular range of 2.degree. to 55.degree. 2-Theta (.theta.) on a
Siemens D5000 powder X-Ray diffractometer equipped with variable
slits and a graphite secondary monochromator.
[0236] The main peaks of the resulting PXRD pattern are illustrated
in Table 1.
1 TABLE 1 2-Theta Intensity (.degree.) (%) 7.93 100 8.14 11.1 12.21
0.8 12.96 0.8 13.39 1.4 14.06 9.8 15.36 2.3 15.89 28.0 16.20 3.4
16.90 0.8 17.68 3.7 18.59 2.6 20.36 2.3 20.64 4.8 21.08 2.4 21.54
5.3 22.17 2.4 23.57 21.4 23.90 12.9 24.33 3.2 24.56 3.5 25.29 1.0
26.51 1.2 27.79 2.8 28.40 4.0 29.26 1.3 29.83 4.9 30.20 4.8 32.31
0.9 32.77 3.6 35.65 1.2 37.30 0.9 40.38 1.2 41.04 1.3 43.50 1.1
44.45 0.9 46.11 0.8 46.78 1.2 47.81 1.2 54.60 1.1
[0237] Thus the present invention provides
5-(5-Acetyl-2-butoxy-3-pyridiny-
l)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidi-
n-7-one material having a PXRD pattern substantially as defined in
Table 1 when measured according to the method described
hereinbefore.
[0238] As will be appreciated by the skilled crystallographer,
whilst the relative intensities of the various peaks within Table 1
may vary due to a number of factors such as for example orientation
effects of crystals in the X-ray beam or the purity of the material
being analysed or the degree of crystallinity of the sample, the
peak positions will remain substantially as defined in Table 1 with
small variations being possible due to the height of the sample in
the X-ray beam as a result of the height of the powder bed for
example.
[0239] The skilled crystallographer will also appreciate that
measurements using a different wavelength will result in different
shifts according to the Bragg equation--n.lambda.=2d sin
.theta..
[0240] Such further PXRD patterns of
5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-e-
thyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on-
e generated by use of alternative wavelengths are considered to be
alternative representations of the PXRD pattern of the crystalline
material of the present invention and as such are within the scope
of the present invention.
[0241] The same compound, as defined by the XRD pattern described
in Table 1, when made via alternative routes (as detailed in
Examples section hereinbefore) can have a melting point in the
range of from 138.degree. C. to 149.degree. C. (measured using a
Perkin Elmer DSC7/TGA7 at a heating rate of 20.degree.
C./minute).
[0242] Preliminary analysis indicates that the crystalline compound
1A as defined herein tends to exist in one polymorphic form.
Monomorphic compounds are particularly desirable for pharmaceutical
purposes.
EXAMPLE 3
3-ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyr-
imidin-7-one
[0243] A solution of the title compound from Preparation 5 (1.0 g,
2.3 mmol) in n-propanol (10 mL) and ethyl acetate (0.5 mL) was
treated with potassium tert-butoxide (253 mg, 2.3 mmol) and heated
to reflux for 24 h. After evaporation to dryness, the reaction
mixture was partitioned between ethyl acetate and water whereupon a
white solid precipitated which was separated by filtration. The
organic phase was separated, dried over Na.sub.2SO.sub.4,
concentrated and combined with the above solid, and this was then
washed with ethyl acetate and recrystallised from hot
methanol-dichloromethane to afford the title compound as a white
solid (553 mg, 1.3 mmol).
[0244] .sup.1H NMR (300 MHz, d.sub.6-DMSO): .delta.=0.9 (t, 3H),
1.3 (t, 3H), 1.6-1.8 (m, 2H), 2.8-2.95 (br m, 2H), 4.25 (t, 2H),
8.25 (s, 1H), 8.5 (s, 1H).
[0245] LRMS (TSP) 426 (MH.sup.+), 443 (MNH.sub.4.sup.+).
[0246] Analysis: found C, 42.40; H, 3.69; N, 16.39. Calcd for
C.sub.15H.sub.16IN.sub.5O.sub.2: C, 42.37; H, 3.796; N, 16.47%
EXAMPLE 4
5-[2-(Cyclobutyloxy)-5-nitro-3-pyridinyl]-1-methyl-3-propyl-1,6-dihydro-7H-
-pyrazolo[4,3-d]pyrimidin-7-one
[0247] The title compound of Preparation 10 (1.0 g, 2.66 mmol), and
potassium hexamethyldisilazide (1.72 g, 10.63 mmol) suspended in
cyclobutanol (5 mL) and ethyl acetate (0.5 mL) was heated to reflux
for 14 h. After cooling, the solvent was removed in vacuo and the
residue taken up in water (20 mL) and extracted with
dichloromethane (3.times.50 mL). Combined organic extracts were
washed with brine (50 mL), dried over MgSO.sub.4 and concentrated
to a yellow solid (.about.800 mg). Purification by column
chromatography (elution with 30:70 ethyl acetate:pentane) gave the
title compound (295 mg, 0.76 mmol).
[0248] m.p. 212-4.degree. C.
[0249] 1H NMR (300 MHz, CDCl.sub.3): .delta.=1.05 (t, 3H), 1.75-2.1
(m, 4H), 2.3-2.4 (m, 2H), 2.5-2.7 (m, 2H), 2.95 (t, 2H), 4.3 (s,
3H), 5.5-5.6 (m, 1H), 9.1 (s, 1H), 9.5 (s, 1H), 10.8 (br s,
1H).
[0250] LRMS (TSP) 385 (MH.sup.+).
[0251] Analysis: Found C, 56.03; H, 5.28; N, 21.63. Calcd for
C.sub.18H.sub.20N.sub.6O.sub.4: C, 56.24; H, 5.24; N, 21.86%
EXAMPLE 5
3-Ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-1-[2-(4-morpholinyl)ethyl]-1,6-di-
hydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0252] The title compound of Preparation 13 (15.78 g, 28.4 mmol)
was dissolved in n-propanol (200 mL), ethyl acetate (6 mL) and
potassium t-butoxide (3.2 g, 28.4 mmol) were added and the
resultant mixture heated to reflux for 6h. Additional potassium
t-butoxide (1.6 g, 14.2 mmol) was added and the mixture heated for
a further 2 h, after which the solvent was removed in vacuo. The
residue was partitioned between water (50 mL) and dichloromethane
(100 mL) and the organic phase separated. The aqueous phase was
extracted with dichloromethane (2.times.100 mL) and the combined
organics dried over MgSO.sub.4 and reduced to a yellow solid
(.about.17 g). Purification by column chromatography (elution with
ethyl acetate) gave the title compound (13.3 g, 24.1 mmol).
[0253] m.p. 175-177.degree. C.
[0254] 1H NMR (300 MHz, CDCl.sub.3): .delta.=1.1 (t, 3H), 1.4 (t,
3H), 1.9-2.05 (m, 2H), 2.45-2.55 (m, 4H), 2.85 (t, 2H), 3.0 (q,
2H), 3.6-3.65 (m, 4H), 4.5 (t, 2H), 4.7 (t, 2H), 8.4 (s, 1H), 9.0
(s, 1H), 10.95 (br s, 1H).
[0255] LRMS (TSP) 540 (MH.sup.+).
[0256] Analysis: found C, 46.79; H, 5.01; N, 15.44. Calcd for
C.sub.21H.sub.27N.sub.6O.sub.3I: C, 46.85; H, 5.05; N, 15.61%
EXAMPLE 6
4-{[5-(2-Ethoxy-5-iodo-3-pyridinyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[-
4,3-d]pyrimidin-2-yl]methyl}benzonitrile
[0257] The title compound was prepared from the title compound of
Preparation 16 in ethanol using the method of example 3.
[0258] 1H NMR (400 MHz, CDCl.sub.3): .delta.=1.25 (t, 3H), 1.5 (t,
3H), 2.95 (q, 2H), 4.6 (q, 2H), 5.6 (s, 2H), 7.25 (d, 2H), 7.60 (d,
2H), 8.40 (d, 1H), 8.95 (d, 1H), 10.8 (br s, 1H).
[0259] LRMS 527 (MH.sup.+), 549 (MNa.sup.+).
EXAMPLE 7
5-(2-Propoxy-5-iodo-3-pyridinyl)-3-ethyl-2-(2-pyridinylmethyl)-2,6-dihydro-
-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0260] The title compound was prepared from the product of
Preparation 17 using the method of example 3.
[0261] m.p. 228.9-233.8.degree. C.
[0262] 1H NMR (400MHz, CDCl.sub.3): .delta.=1.05 (t, 3H), 1.25 (t,
3H), 1.90 (m, 2H), 3.00 (q, 2H), 4.50 (t, 2H), 5.65 (s, 2H), 7.05
(d, 1H), 7.20 (m, 1H), 7.60 (t, 1H), 8.40 (s, 1H), 8.55 (d, 1H),
8.95 (s, 1H), 10.70 (s, 1H)
[0263] LRMS (ES--positive ion) 517 (MH.sup.+)
[0264] Anal. Found C, 48.73; H, 3.89; N, 16.14. Calcd for
C.sub.21H.sub.21O.sub.2N.sub.6I: C, 48.85; H, 4.10; N, 16.28.
EXAMPLE 8
tert-Butyl
3-[3-ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-2-
H-pyrazolo[4,3-d]pyrimidin-2-yl]-1-azetidinecarboxylate
[0265] The title compound was prepared from the product of
Preparation 19 using the method of example 3.
[0266] 1H NMR (400 MHz, CDCl.sub.3): .delta.=1.05 (t, 3H), 1.30 (t,
3H), 1.43 (s, 9H), 1.87-1.96 (m, 2H), 3.00 (q, 2H), 4.34 (t, 2H),
4.49 (t, 2H), 4.60 (br s, 2H), 5.20 (t, 1H), 8.41 (d, 1H), 8.94 (s,
1H), 10.75 (br s, 1H)
[0267] LRMS (TSP--positive ion) 598.1 (MNH.sub.4.sup.+)
[0268] Anal. Found C, 47.54; H, 5.02; N, 14.09 Calcd for
C.sub.23H.sub.29O.sub.4N.sub.6I: C, 47.60; H, 5.04; N, 14.48.
EXAMPLE 9
tert-Butyl
4-[3-ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-2-
H-pyrazolo[4,3-d]pyrimidin-2-yl]-1-piperidinecarboxylate
[0269] The title compound was prepared from the product of
Preparation 20 using the method of example 3.
[0270] 1H NMR (400 MHz, CDCl.sub.3): .delta.=1.10 (t, 3H), 1.40 (t,
3H), 1.45 (s, 9H), 1.92 (m, 4H), 2.40 (m, 2H), 2.90 (m, 2H), 3.08
(q, 2H), 4.38 (m, 3H), 4.50 (t, 2H), 8.40 (s, 1H), 8.98 (s, 1H),
10.69 (s, 1H)
[0271] LRMS (TSP--positive ion) 609.7 (MH.sup.+), 509.0
(MH.sup.+-BOC)
EXAMPLE 10
3-Ethyl-1-[2-(4-morpholinyl)ethyl]-5-{2-propoxy-5-[(trimethylsilyl)ethynyl-
]-3-pyridinyl}-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0272] Trimethylsilylacetylene (0.39 mL, 2.79 mmol) was added to a
solution of the title compound of example 5 (1.0 g, 1.86 mmol) in
triethylamine (20 mL). Acetonitrile (1 mL),
bis(triphenylphosphine)pallad- ium (II) chloride (33 mg, 2.5 mol%),
and copper (I) iodide (9 mg, 2.5 mol%) were added and the resultant
mixture stirred at room temperatue for 1 h after which further
trimethylsilylacetylene (0.39 mL, 2.79 mmol) was added and the
mixture stirred for 10 h. After removal of the solvent in vacuo,
the residue was partitioned between ethyl acetate (25 mL) and water
(20 mL), the aqueous phase separated and extracted with further
ethyl acetate (3.times.25 mL). Combined organics were washed with
brine (25 mL), dried over MgSO.sub.4, and concentrated to an oil
which was crystallised from diisopropyl ether to afford the title
compound as a white solid (156 mg, 0.30 mmol). The addition of
pentane to the concentrated mother liquors afforded a second crop
(509 mg, 1.0 mmol).
[0273] m.p. 132-134.degree. C.
[0274] 1H NMR (300 MHz, CDCl.sub.3): .delta.=0.25 (s, 9H), 1.1 (t,
3H), 1.4 (t, 3H), 1.95-2.05 (m, 2H), 2.45-2.5 (m, 4H), 2.85 (t,
2H), 3.0 (q, 2H), 3.55-3.65 (m, 4H), 4.55 (t, 2H), 4.7 (t, 2H),
8.35 (s, 1H), 8.8 (s, 1H), 11 (br s, 1H).
[0275] LRMS (ES--negative ion) 507 (M-H).sup.-. (ES--positive ion)
509 (MH.sup.+).
[0276] Analysis: found C, 61.18; H, 7.12; N, 16.53. Calcd for
C.sub.26H.sub.36N.sub.6O.sub.3Si: C, 61.39; H, 7 13 N 16.52%
EXAMPLE 11
5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dih-
ydro-7H-pyrazolo[4,3-d]pyrimidin-7-one hydrochloride
[0277] A solution of 4M hydrochloric acid in dioxan (1 mL) was
added to ethyl acetate (3mL). An aliquot of this solution (0.3 mL),
was then added to a solution of
5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-a-
zetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (132 mg,
0.3 mmol) in ethyl acetate (5 mL) giving a precipitate. This
mixture was warmed to 50.degree. C. for 10 minutes, then allowed to
cool to 0.degree. C. The resulting powder was filtered, washed with
ethyl acetate and dried at 50.degree. C. in vacuo, to afford the
title compound, 118 mg (81%).
[0278] m.p. 153-159.degree. C.
[0279] .sup.1Hnmr (CDCl.sub.3, 300MHz) .delta.: 0.89 (t, 3H,
J=7.3Hz), 1.20 (m, 3H), 1.24 (t, 3H, J=7.7Hz), 1.41 (m, 2H), 1.71
(m, 2H), 2.61 (s, 3H), 2.97 (m, 2H), 3.40 (m, 2H), 4.44 (t, 2H,
J=6.2 Hz), 4.47 (m, 2H), 4.71 (m, 2H), 5.60 (m, 0.5H), 5.80 (m,
0.5H), 8.40 (d, 1H, J=2.3 Hz), 8.94 (d, 1H, J=2.3 Hz), 10.60 (bs,
1H), 11.20 (bs, 0.5H), 11.94 (s, 0.5H) (1:1 mixture of cis and
trans isomers)
[0280] Microanalysis found: C, 56.89; H, 6.65; N, 17.29
C.sub.23H.sub.30N.sub.6O.sub.3;HCl requires C, 57.08; H, 6.66; N,
17.36%.
[0281] Powder X-Ray Diffraction (PXRD) Data was generated in
respect of the compound of Example 11 in accordance with the method
detailed hereinbefore for the compound of Example 1. The main peaks
of the resulting PXRD pattern are illustrated in Table 2.
2 TABLE 2 2-Theta Intensity (.degree.) (%) 6.40 44.1 7.71 50.8
10.26 14.8 10.81 32.2 12.25 13.8 12.87 17.7 15.42 30.9 17.20 34.4
18.28 29.6 18.97 23.8 21.28 28.9 21.88 41.8 23.14 38.6 23.78 47.6
25.33 47.1 26.14 89.4 26.52 100 27.51 53.6 28.16 46.4 29.13 37.9
32.61 28.1 35.21 23.2 36.41 28.1 45.77 20.9
[0282] Thus the present invention provides
5-(5-Acetyl-2-butoxy-3-pyridiny-
l)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidi-
n-7-one hydrochloride material having a PXRD pattern substantially
as defined in Table 2 when measured according to the method
described hereinbefore.
EXAMPLE 12
5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dih-
ydro-7H-pyrazolo[4,3-d]pyrimidin-7-one benzenesulfonate
[0283]
5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)--
2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (88 mg, 0.2 mmol) was
dissolved in warm ethyl acetate (2 mL). A solution of
benzenesulfonic acid (32 mg, 0.2 mmol) in ethyl acetate (2 ml) was
then added, giving a precipitate. This mixture was warmed to
50.degree. C. for 15 minutes, then allowed to cool to 0.degree. C.
The resulting solid was filtered, washed with ethyl acetate and
dried in vacuo, to afford the title compound as a white solid 89 mg
(74%).
[0284] m.p. 228-229.degree. C.
[0285] .sup.1Hnmr (CDCl.sub.3, 300 MHz) .delta.:0.90 (t, 3H, J=7.3
Hz), 1.16-1.26 (m, 6H), 1.42 (m, 2H), 1.71 (m, 2H), 2.62 (s, 3H),
2.96 (m, 2H), 3.35 (m, 2H), 4.44 (t, 2H, J=6.6 Hz), 4.52 (m, 2H),
4.65 (m, 1H), 4.76 (m, 1H), 5.70 (m, 1H), 7.30 (m, 3H), 7.60 (m,
2H), 8.40 (d, 1H, J=2.2 Hz), 8.95 (d, 1H, J=2.2 Hz), 9.80 (bs,
0.5H), 10.25 (bs, 0.5H), 11.95 (S, 1H) (1:1 mixture of cis and
trans isomers)
[0286] Microanalysis found: C, 57.56; H, 5.98; N, 13.74.
C.sub.23H.sub.30N.sub.6O.sub.3;C.sub.6H.sub.6O.sub.3S;0.5H.sub.2O
requires C, 57.51; H, 6.16; N, 13.87%.
[0287] The compound of Example 12 was found to be non-hygroscopic
which is for compounds in the formulation of certain pharmaceutical
products, such as, for example, tablets.
[0288] Dvnamic VaDour SorDtion (DVS) measurements were made for the
compound of Example 12 by exposing a solid sample to controlled
relative humidity (% RH) and weight change recorded with time on an
automated water sorption analyser. The sorption/desorption isotherm
for the compound of Example 12 shows that on drying the material
lost a small amount of weight (0.9%) due to loss of residual
solvent or surface moisture.
[0289] Powder X-Ray Diffraction (PXRD) Data was generated in
respect of the compound of Example 13 in accordance with the method
detailed hereinbefore for the compound of Example 1. The main peaks
(those over 10% intensity) of the resulting PXRD pattern are
illustrated in Table 3.
3 TABLE 3 2-Theta Intensity (.degree.) (%) 3.80 81.8 7.79 90.6 8.66
14.4 10.83 14.6 11.36 11.9 13.72 11.1 15.16 23.1 16.03 19.7 16.67
13.2 17.26 18.7 17.56 11.1 18.46 10.6 18.77 45.4 20.66 16.8 20.91
36.7 21.70 37.7 21.97 52.8 22.21 21.5 22.82 31.5 23.28 16.0 23.60
100.0 24.05 35.5 24.48 35.3 24.88 15.6 25.92 22.6 26.64 20.7 27.00
12.4 27.33 15.1 27.56 14.9 27.95 11.1 31.62 15 33.06 10.9 41.56
11.6 48.20 11.4
[0290] Thus the present invention provides
5-(5-Acetyl-2-butoxy-3-pyridiny-
l)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidi-
n-7-one benzenesulfonate material having a PXRD pattern
substantially as defined in Table 3 when measured according to the
method described hereinbefore.
* * * * *