U.S. patent application number 12/343571 was filed with the patent office on 2009-07-30 for synthesis of heterocyclic compounds.
This patent application is currently assigned to FOREST LABORATORIES HOLDINGS LIMITED. Invention is credited to Gian-Luca Araldi, Nhut Diep, Melanie Ronsheim, Shao Hong Zhou.
Application Number | 20090192315 12/343571 |
Document ID | / |
Family ID | 38895431 |
Filed Date | 2009-07-30 |
United States Patent
Application |
20090192315 |
Kind Code |
A1 |
Araldi; Gian-Luca ; et
al. |
July 30, 2009 |
SYNTHESIS OF HETEROCYCLIC COMPOUNDS
Abstract
Methods for the synthesis of heterocyclic compounds including
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide and pharmaceutically acceptable salts
thereof.
Inventors: |
Araldi; Gian-Luca; (East
Setauket, NY) ; Ronsheim; Melanie; (Port Jefferson,
NY) ; Diep; Nhut; (Hauppauge, NY) ; Zhou; Shao
Hong; (Commack, NY) |
Correspondence
Address: |
Forest Laboratories, Inc.;Attn: Charles S. Ryan
909 3rd Avenue
New York
NY
10022
US
|
Assignee: |
FOREST LABORATORIES HOLDINGS
LIMITED
Hamilton
BM
|
Family ID: |
38895431 |
Appl. No.: |
12/343571 |
Filed: |
December 24, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11772863 |
Jul 3, 2007 |
7511150 |
|
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12343571 |
|
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60806649 |
Jul 6, 2006 |
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Current U.S.
Class: |
546/284.1 ;
549/461; 568/424 |
Current CPC
Class: |
C07D 405/12 20130101;
C07D 307/91 20130101; C07C 201/12 20130101; C07C 201/12 20130101;
C07C 205/38 20130101 |
Class at
Publication: |
546/284.1 ;
568/424; 549/461 |
International
Class: |
C07D 405/12 20060101
C07D405/12; C07C 201/12 20060101 C07C201/12; C07D 307/91 20060101
C07D307/91 |
Claims
1. A method for preparing a compound of formula (c) comprising
reacting a compound of formula (a) with a compound of formula (b):
##STR00013## wherein R.sup.1 is selected from the group consisting
of OH and OR.sup.2, where R.sup.2 is a substituted or unsubstituted
alkyl; R.sup.3 is selected from the group consisting of H, OH,
halogen, and --OCHR.sup.4R.sup.5, wherein R.sup.4 and R.sup.5 are
each independently selected from the group consisting of H and
halogen; and R.sup.6 and R.sup.7 are each independently selected
from the group consisting of OH and halogen.
2. (canceled)
3. The method of claim 1, wherein the reaction is performed in the
presence of a solvent selected from the group consisting of
dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane and
combinations thereof.
4. The method of claim 1, wherein the reaction is performed in the
presence of a halide salt.
5. The method of claim 4, wherein the halide salt is potassium
fluoride.
6. The method of claim 1, wherein the reaction is performed in the
presence of an inorganic base.
7. The method of claim 6, wherein the inorganic base is sodium
carbonate.
8-10. (canceled)
11. A compound of formula (c): ##STR00014## or a pharmaceutically
acceptable salt thereof, wherein R.sup.3 is selected from the group
consisting of H, OH, halogen and --OCHR.sup.4R.sup.5, wherein
R.sup.4 and R.sup.5 are each independently selected from the group
consisting of H and halogen; and R.sup.6 is selected from the group
consisting of OH and halogen.
12-53. (canceled)
54. A compound according to claim 11, wherein R.sup.3 is
--OCHR.sup.4R.sup.5.
55. A compound according to claim 54, wherein R.sup.3 is
--OCHF.sub.2.
56. A compound according to claim 11, wherein R.sup.6 is
halogen
57. A compound according to claim 11, wherein R.sup.3 is
--OCHF.sub.2 and R.sup.6 is Br.
58. The method of claim 1, wherein R.sup.3 is
--OCHR.sup.4R.sup.5.
59. The method of claim 58, wherein R.sup.3 is --OCHF.sub.2.
60. The method of claim 1, wherein R.sup.1 is OH.
61. The method of claim 1, wherein R.sup.6 and R.sup.7 are each,
independently, halogen.
62. The method of claim 61, wherein R.sup.6 is Br and R.sup.7 is
F.
63. The method of claim 1, wherein R.sup.1 is OH, R.sup.3 is
--OCHF.sub.2, R.sup.6 is Br and R.sup.7 is F.
64. The method of claim 1, wherein compound (a) is
4-difluoromethoxy-3-hydroxybenzaldehyde.
65. The method of claim 1, wherein compound (a) is
4-difluoromethoxy-3-hydroxybenzaldehyde and compound (b) is
2-bromo-1-fluoro-4-nitrobenzene.
66. The method of claim 1, further comprising the step of cyclizing
a compound of formula (c) to form a compound of formula (d):
##STR00015##
67. The method of claim 66, wherein R.sup.3 is --OCHF.sub.2.
68. The method of claim 66, wherein the reaction is performed in
the presence of a catalyst.
69. The method of claim 66, wherein the catalyst is a transition
metal complex.
70. The method of claim 69, wherein the transition metal complex is
palladium acetate.
71. The method of claim 66, wherein the cyclization step is
performed in the presence of a solvent selected from the group
consisting of dimethylformamide, dimethyl sulfoxide,
tetrahydrofuran, dioxane and combinations thereof.
72. The method of claim 66, further comprising the step of
oxidizing a compound of formula (d) to produce a compound of
formula (e): ##STR00016##
73. The method of claim 72, wherein R.sup.3 is --OCHF.sub.2.
74. The method of claim 72, wherein the reaction is performed in
the presence of an oxidizing agent selected from the group
consisting of potassium permanganate, sulfamic acid, sodium
chlorite, hydrogen peroxide, silver oxide, ruthenium chloride and
combinations thereof.
75. The method of claim 74, wherein the oxidizing agent comprises a
combination of sulfamic acid and sodium chlorite.
76. The method of claim 75, wherein the sulfamic acid to sodium
chlorite ratio is between approximately 1:2 and approximately
2:1.
77. The method of claim 75, wherein the sulfamic acid to sodium
chlorite ratio is between approximately 2:3 and approximately
3:2.
78. The method of claim 72, wherein the reaction is performed in
the presence of glacial acetic acid.
79. The method of claim 72, further comprising the step of reacting
a compound of formula (e) with a compound of formula (f) to produce
a compound of formula (g): ##STR00017## wherein R.sup.8 is selected
from the group consisting of H and alkyl; and R.sup.9 and R.sup.10
are each, independently, selected from the group consisting of H,
OH and halogen.
80. The method of claim 79, wherein R.sup.3 is --OCHF.sub.2.
81. The method of claim 79, wherein R.sup.9 and R.sup.10 are each,
independently, halogen.
82. The method of claim 79, wherein the reaction is performed in
the presence of an inorganic acid halide.
83. The method of claim 82, wherein the inorganic acid halide is
selected from the group consisting of thionyl chloride, phosphorus
trichloride, phosphorus pentachloride and pyridine.
84. The method of claim 83, wherein the inorganic acid halide is
thionyl chloride.
85. The method of claim 84, wherein the thionyl chloride is added
in the presence of a catalytic amount of dimethylformamide.
86. The method of claim 79, wherein the reaction is performed in
the presence of a base.
87. The method of claim 86, wherein the base is selected from the
group consisting of potassium tertiary butoxide, sodium tertiary
butoxide and lithium tertiary butoxide.
88. The method of claim 79, wherein compound (g) is
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide.
89. The method of claim 88, further comprising the step of reducing
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide in the presence of a reducing agent to produce
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-c-
arboxamide.
90. The method of claim 89, wherein the reducing agent is selected
from the group consisting of zinc, indium, iron, tin, Raney-nickel
and sodium borohydride.
91. The method of claim 89, further comprising the step of reacting
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-c-
arboxamide with methanesulfonyl chloride in a solvent in the
presence of a base to produce
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)
dibenzo[b,d]furan-1-carboxamide.
92. The method of claim 91, wherein the solvent is selected from
the group consisting of tetrahyrdofuran, dioxane and toluene.
93. The method of claim 91, wherein the base is selected from the
group consisting of pyridine, 2,6-lutidine and triethylamine.
94. The method of claim 91, further comprising the step of
converting the
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)
dibenzo[b,d]furan-1-carboxamide to a sodium salt thereof.
95. The method of claim 94, wherein the
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)
dibenzo[b,d]furan-1-carboxamide is reacted with sodium hydride in
the presence of a solvent.
96. The method of claim 95, wherein the solvent is
tetrahydrofuran.
97.
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)
dibenzo[b,d]furan-1-carboxamide prepared by a process according to
claim 91.
98.
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)
dibenzo[b,d]furan-1-carboxamide sodium salt prepared by a process
according to claim 94.
Description
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/806,649, filed Jul. 6, 2006, the entire
disclosure of which is hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to methods for the synthesis
of heterocyclic compounds including
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide and pharmaceutically acceptable salts
thereof.
BACKGROUND OF THE INVENTION
[0003] Phosphodiesterases ("PDEs") are a family of enzymes involved
in regulating intracellular signalling. PDEs act by cleaving the
intracellular second messengers cyclic AMP ("cAMP") and cyclic GMP
("cGMP"). Among the PDEs, PDE IV is the major cAMP metabolizing
enzyme found in inflammatory and immune cells. PDE IV inhibitors
have been investigated as anti-inflammatory treatments in airway
diseases, including the treatment of asthma and chronic obstructive
pulmonary disease (COPD).
[0004] U.S. patent application Ser. No. 10/821,642 (the '642
application), published as Publication No. 2005/0027129, discloses
novel heterocyclic compounds for use as PDE IV inhibitors, the
disclosure of which is incorporated by reference in its entirety.
In addition, the '642 application discloses a multi-step synthesis
of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide and the corresponding sodium salt. One
such compound is
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide sodium salt, represented by the following
formula:
##STR00001##
[0005] International Publication No. WO 2006/040652 also discloses
methods for preparing N-(3,5
dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]fu-
ran-1-carboxamide and its sodium salt, the disclosure of which is
incorporated by reference in its entirety.
[0006] However, there remains a need in the art to provide methods
for the synthesis of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide and pharmaceutically acceptable salts
thereof.
SUMMARY OF THE INVENTION
[0007] The present invention relates to methods for the synthesis
of heterocyclic compounds including
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide and pharmaceutically acceptable salts
thereof.
[0008] According to some embodiments, the present invention
provides methods for preparing a substituted nitrophenoxy
benzaldehyde of formula (c) comprising reacting a substituted
benzaldehyde of formula (a) with a substituted nitrobenzene of
formula (b):
##STR00002##
wherein R1 is selected from the group consisting of O, OH, and OR2;
R2 is a substituted or unsubstituted alkyl; R3 is selected from the
group consisting of H, OH, halogen, and O--CHR4R5, wherein R4 and
R5 are each independently selected from the group consisting of H,
OH, and halogen; and R6 and R7 are each independently selected from
the group consisting of H, OH, and halogen.
[0009] According to other embodiments, the present invention
provides compounds of formula I:
##STR00003##
and physiologically acceptable salts thereof wherein R3 is selected
from the group consisting of H, OH, halogen, and O--CHR4R5, wherein
R4 and R5 are each independently selected from the group consisting
of H and halogen; and R6 is selected from the group consisting of
H, OH, and halogen.
[0010] According to other embodiments, the present invention
provides methods of preparing a substituted dibenzofuran of formula
(d) comprising cyclization of a substituted nitrophenoxy
benzaldehyde of formula (c):
##STR00004##
wherein R3 is selected from the group consisting of H, OH, halogen,
and O--CHR4R5, wherein R4 and R5 are each independently selected
from the group consisting of H, OH and halogen; and R6 is selected
from the group consisting of H, OH, and halogen.
[0011] According to other embodiments, the present invention
provides methods for preparing a substituted carboxylic acid of
formula (e) comprising oxidizing a substituted dibenzofuran of
formula (d):
##STR00005##
wherein R3 is selected from the group consisting of H, OH, halogen,
and O--CHR4R5, wherein R4 and R5 are each independently selected
from the group consisting of H, OH and halogen.
[0012] According to other embodiments, the present invention
provides methods for preparing a substituted carboxylic acid of
formula (e) comprising oxidizing a substituted dibenzofuran of
formula (d):
##STR00006##
wherein R3 is selected from the group consisting of H, OH, halogen,
and O--CHR4R5, wherein R4 and R5 are each independently selected
from the group consisting of H, OH and halogen.
[0013] According to other embodiments, the present invention
provides methods of preparing a substituted carboxamide of formula
(g) comprising reacting a substituted carboxylic acid of formula
(e) with a substituted aminopyridine of formula (f):
##STR00007##
wherein R3 is selected from the group consisting of H, OH, halogen,
and O--CHR4R5, wherein R4 and R5 are each independently selected
from the group consisting of H, OH and halogen; R8 is selected from
the group consisting of H and alkyl; and R9 and R10 are each
independently selected from the group consisting of H, OH and
halogen.
[0014] According to other embodiments, the present invention
provides methods of preparing
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamide-dibenzo-
[b,d]furan-1-carboxamide comprising the steps of: (a) reacting
4-difluoromethoxy-3-hydroxybenzaldehyde with
2-bromo-1-fluoro-4-nitrobenzene in a first solvent comprising
potassium fluoride to produce
4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde; (b)
cyclizing 4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde
in a second solvent comprising a catalyst to produce
4-difluoromethoxy-8-nitro-1-formyl dibenzofuran; (c) oxidizing
4-difluoromethoxy-8-nitro-1-formyl dibenzofuran in a third solvent
comprising an oxidizing agent to produce
4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid; (d)
reacting 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid
in a fourth solvent comprising an inorganic acid halide,
4-amino-3,5-dichloropyridine and a first base, wherein
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide is produced; (e) reducing
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide in the presence of a reducing agent to produce
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-c-
arboxamide; and (f) reacting
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-c-
arboxamide in a fifth solvent comprising methanesulfonyl chloride
and a second base to produce
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)
dibenzo[b,d]furan-1-carboxamide.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 shows an exemplary method for the synthesis of
heterocyclic compounds according to the present invention.
DETAILED DESCRIPTION
[0016] The present invention relates to methods for the synthesis
of heterocyclic compounds including
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide and pharmaceutically acceptable salts
thereof.
[0017] As used herein the term "alkyl" means a substituted or
unsubstituted aliphatic hydrocarbon which may be straight or
branched and may comprise 1 to 20 carbon atoms. Preferably the
alkyl group contains 1 to 12 carbon atoms. More preferably the
alkyl group contains 1 to 6 carbon atoms. Exemplary substituted
alkyls include, but are not limited to, haloalkyl, heteroalkly and
arylalkyl groups.
[0018] The term "halogen" means either Cl, Br, I or F.
[0019] The term "substituted" means that one or more of the atoms
have been replaced by one or more substituents.
[0020] In one embodiment, a substituted nitrophenoxy benzaldehyde
of formula (c) is formed by reacting a substituted benzaldehyde of
formula (a) with a substituted nitrobenzene of formula (b) as shown
in scheme I:
##STR00008##
wherein R1 is selected from the group consisting of O, OH, and OR2;
R2 is a substituted or unsubstituted alkyl; R3 is selected from the
group consisting of H, OH, halogen, and O--CHR4R5, wherein R4 and
R5 are each independently selected from the group consisting of H,
OH, and halogen; and R6 and R7 are each independently selected from
the group consisting of H, OH, and halogen.
[0021] In exemplary embodiments, the substituted benzaldehyde of
formula (a) is 4-difluoromethoxy-3-hydroxybenzaldehyde. In other
exemplary embodiments, the substituted nitrobenzene of formula (b)
is 2-bromo-1-fluoro-4-nitrobenzene. In further embodiments, the
substituted nitrophenoxy benzaldehyde of formula (c) produced using
scheme I is
4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde.
[0022] The reactions of scheme I may be performed in the presence
of an organic solvent. Exemplary organic solvents include, but are
not limited to, chlorinated solvents, aromatic solvents, alcoholic
solvents, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran,
diisopropyl ether, and 1,4-dioxane. Suitable chlorinated solvents
include, but are not limited to, dichloromethane,
1,2-dichloroethane, chloroform, and carbon tetrachloride. Suitable
aromatic solvents include, but are not limited to, benzene and
toluene. Suitable alcoholic solvents include, but are not limited
to, methanol, ethanol, n-propanol, isopropanol, and tert-butanol.
Suitable polar aprotic solvents include, but are not limited to,
N,N-dimethylformamide and dimethyl sulfoxide. In preferred
embodiments, the reaction may be performed using dimethylformamide,
dimethyl sulfoxide, tetrahydrofuran or dioxane.
[0023] The reactions of scheme I may also be performed in the
presence of an alkali halide salt. For example, the alkali halide
salts include, but are not limited to, KF, KBr, KCL, KI, NaF, NaBr,
NaCl, NaI, LiF, Cl, LiBr, and LiI. In preferred embodiments, the
alkali halide salt is potassium fluoride.
[0024] The reactions of scheme I may also be performed in the
presence of an inorganic base, such as, but not limited to, sodium
carbonate.
[0025] The present invention also includes compounds of formula I
and physiologically acceptable salts thereof
##STR00009##
wherein R3 is selected from the group consisting of H, OH, halogen,
and O--CHR4R5, wherein R4 and R5 are each independently selected
from the group consisting of H and halogen; and R6 is selected from
the group consisting of H, OH, and halogen. In preferred
embodiments, the compound of formula I is
4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde.
[0026] In other exemplary embodiments, a substituted dibenzofuran
of formula (d) is prepared by cyclization of a substituted
nitrophenoxy benzaldehyde of formula (c) as shown in scheme II:
##STR00010##
wherein R3 is selected from the group consisting of H, OH, halogen,
and O--CHR4R5, wherein R4 and R5 are each independently selected
from the group consisting of H, OH and halogen; and R6 is selected
from the group consisting of H, OH, and halogen.
[0027] In exemplary embodiments, the substituted nitrophenoxy
benzaldehyde of formula (c) is
4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde. In
further exemplary embodiments, the substituted dibenzofuran of
formula (d) is 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran.
[0028] The reaction of scheme II may be performed in the presence
of a catalyst. Suitable catalysts include, but are not limited to,
hydrogenation catalysts such as reactivated Raney Nickel, Pearlmans
catalyst (palladium hydroxide), and Pd/C. In exemplary embodiments,
the catalyst is a transition metal complex, such as a palladium
complex. For example, palladium catalysts include, but are not
limited to, Pd(II) complexes such as palladium acetate.
[0029] The reactions of scheme II may be performed in the presence
of an organic solvent. Exemplary organic solvents include, but are
not limited to, chlorinated solvents, aromatic solvents, alcoholic
solvents, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran,
diisopropyl ether, and 1,4-dioxane. Suitable chlorinated solvents
include, but are not limited to, dichloromethane,
1,2-dichloroethane, chloroform, and carbon tetrachloride. Suitable
aromatic solvents include, but are not limited to, benzene and
toluene. Suitable alcoholic solvents include, but are not limited
to, methanol, ethanol, n-propanol, isopropanol, and tert-butanol.
Suitable polar aprotic solvents include, but are not limited to,
N,N-dimethylformamide and dimethyl sulfoxide. In preferred
embodiments, the reaction may be performed using dimethylformamide,
dimethyl sulfoxide, tetrahydrofuran or dioxane.
[0030] In one embodiment, the substituted dibenzofuran of formula
(d) may be prepared according to schemes I and II without isolating
the substituted nitrophenoxy benzaldehyde of formula (c).
[0031] In another embodiment, a substituted carboxylic acid of
formula (e) is formed by oxidizing a substituted dibenzofuran of
formula (d) as shown in scheme III:
##STR00011##
wherein R3 is selected from the group consisting of H, OH, halogen,
and O--CHR4R5, wherein R4 and R5 are each independently selected
from the group consisting of H, OH and halogen.
[0032] In exemplary embodiments, the substituted dibenzofuran of
formula (d) is 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran. In
further exemplary embodiments, the substituted carboxylic acid of
formula (e) is
4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid.
[0033] The reaction of scheme III may be performed in the presence
of an oxidizing agent. For example, oxidizing agents may include,
but are not limited to, potassium permanganate, sulfamic acid,
sodium chlorite, hydrogen peroxide, silver oxide, rutenium chloride
and combinations thereof. In some embodiments, the oxidizing agent
may be a combination of sulfamic acid and sodium chlorite. In
further embodiments the sulfamic acid to sodium chlorite is in a
ratio between approximately 1:2 and approximately 2:1, preferably,
a ratio between approximately 2:3 and approximately 3:2.
[0034] The reactions of scheme III may be performed in the presence
of an organic solvent. Exemplary organic solvents include, but are
not limited to, chlorinated solvents, aromatic solvents, alcoholic
solvents, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran,
diisopropyl ether, and 1,4-dioxane. Suitable chlorinated solvents
include, but are not limited to, dichloromethane,
1,2-dichloroethane, chloroform, and carbon tetrachloride. Suitable
aromatic solvents include, but are not limited to, benzene and
toluene. Suitable alcoholic solvents include, but are not limited
to, methanol, ethanol, n-propanol, isopropanol, and tert-butanol.
Suitable polar aprotic solvents include, but are not limited to,
N,N-dimethylformamide and dimethyl sulfoxide. In preferred
embodiments, the reaction may be performed the presence of a polar
solvent. For example, the polar solvent may be glacial acetic
acid.
[0035] In other embodiments, a substituted carboxamide of formula
(g) may be prepared by reacting a substituted carboxylic acid of
formula (e) with a substituted aminopyridine of formula (f) as
shown in scheme IV:
##STR00012##
wherein R3 is selected from the group consisting of H, OH, halogen,
and O--CHR4R5, wherein R4 and R5 are each independently selected
from the group consisting of H, OH and halogen; R8 is selected from
the group consisting of H and alkyl; and R9 and R10 are each
independently selected from the group consisting of H, OH and
halogen.
[0036] In exemplary embodiments, the substituted carboxylic acid of
formula (e) is
4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid. In
other exemplary embodiments, the substituted aminopyridine of the
formula (f) is 4-amino-3,5-dichloropyridine. In further exemplary
embodiments, the substituted carboxamide of formula (g) is
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide.
[0037] The reaction of scheme IV may be performed in the presence
of an inorganic acid halide. For example, inorganic acid halides
that may be used include, but are no limited to, thionyl chloride,
phosphorus trichloride, phosphorus pentachloride, thionyl chloride
in presence of a catalytic amount of dimethylformamide, and
pyridine. In some embodiments, the inorganic acid halide is thionyl
chloride in the presence of a catalytic amount of
dimethylformamide. In some embodiments, the reaction of scheme IV
may be performed in the presence of a base. For example, the base
may include, but is not limited to, potassium tertiary butoxide,
sodium tertiary butoxide, and lithium tertiary butoxide.
[0038] In other embodiments, the present invention provides methods
of preparing
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonami-
de-dibenzo[b,d]furan-1-carboxamide, as shown in FIG. 1. For
example, 4-difluoromethoxy-3-hydroxybenzaldehyde may be reacted
with 2-bromo-1-fluoro-4-nitrobenzene in a first solvent comprising
potassium fluoride to produce
4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde (scheme
I). In a second step, the
4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde may be
cyclized in a second solvent comprising a catalyst to produce
4-difluoromethoxy-8-nitro-1-formyl dibenzofuran (scheme II). In a
third step, the 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran may
be oxidized in a third solvent comprising an oxidizing agent to
produce 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid
(scheme III). In a fourth step,
4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid may be
reacted in a fourth solvent comprising an inorganic acid halide,
4-amino-3,5-dichloropyridine and a first base to produce
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide (scheme IV). In a fifth step,
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide may be reduced in the presence of a reducing agent to
produce
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-c-
arboxamide. Suitable reducing agents include, but are not limited
to, zinc, indium, iron, tin, Raney-nickel and sodium borohydride.
In a sixth step, the
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d-
]furan-1-carboxamide may be reacted in a fifth solvent comprising
methanesulfonyl chloride and a second base to produce
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)
dibenzo[b,d]furan-1-carboxamide.
[0039] The solvent used in the fifth step may include organic
solvents such as, but not limited to, chlorinated solvents,
aromatic solvents, alcoholic solvents, diethyl ether,
1,2-dimethoxyethane, tetrahydrofuran, diisopropyl ether, and
1,4-dioxane. Suitable chlorinated solvents include, but are not
limited to, dichloromethane, 1,2-dichloroethane, chloroform, and
carbon tetrachloride. Suitable aromatic solvents include, but are
not limited to, benzene and toluene. Suitable alcoholic solvents
include, but are not limited to, methanol, ethanol, n-propanol,
isopropanol, and tert-butanol. Suitable polar aprotic solvents
include, but are not limited to, N,N-dimethylformamide and dimethyl
sulfoxide. In some embodiments, the reaction may be performed the
presence of tetrahyrdofuran, dioxane and toluene. In preferred
embodiments, the solvent is tetrahydrofuran. The base used in the
fifth step may include, but is not limited to, potassium tertiary
butoxide, sodium tertiary butoxide, lithium tertiary butoxide,
pyridine, 2,6-lutidine and triethylamine. In preferred embodiments,
the base is pryridine.
[0040] In yet other embodiments, the
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)
dibenzo[b,d]furan-1 is reacted in a sixth solvent comprising sodium
hydride to produce
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)
dibenzo[b,d]furan-1-carboxamide sodium salt, as shown in FIG. 1.
The solvent used to form the sodium salt may include organic
solvents such as, but are not limited to, chlorinated solvents,
aromatic solvents, alcoholic solvents, diethyl ether,
1,2-dimethoxyethane, tetrahydrofuran, diisopropyl ether, and
1,4-dioxane. Suitable chlorinated solvents include, but are not
limited to, dichloromethane, 1,2-dichloroethane, chloroform, and
carbon tetrachloride. Suitable aromatic solvents include, but are
not limited to, benzene and toluene. Suitable alcoholic solvents
include, but are not limited to, methanol, ethanol, n-propanol,
isopropanol, and tert-butanol. Suitable polar aprotic solvents
include, but are not limited to, N,N-dimethylformamide and dimethyl
sulfoxide. In some embodiments, the reaction may be performed the
presence of tetrahyrdofuran, dioxane and toluene. In preferred
embodiments, the solvent is tetrahydrofuran.
[0041] The present invention provides enhanced synthetic routes to
produce heterocyclic compounds with high quality and in high yield.
For example, the present invention provides novel methods for the
synthesis of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide and
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide sodium salt. In some embodiments, the
invention may be used to produce heterocyclic compounds with a
purity of at least 95%, preferably 98% and more preferably 99%.
Thus, the present invention provides methods to produce
pharmaceutical grade products that are suitable for being
formulated into pharmaceutical compositions.
[0042] The following examples are merely illustrative of the
present invention and should not be construed as limiting the scope
of the invention in any way as many variations and equivalents that
are encompassed by the present invention will become apparent to
those skilled in the art upon reading the present disclosure.
EXAMPLES
Example 1
Preparation of
4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde
[0043] 4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde was
produced by reacting 4-difluoromethoxy-3-hydroxybenzaldehyde with
2-bromo-1-fluoro-4-nitrobenzene in DMSO in the presence of
potassium fluoride. To a 1 L 3-neck round bottom flask, fitted with
a mechanical stirrer and reflux condenser was added
4-difluoromethoxy-3-hydroxybenzaldehyde (48.05 g, 255.41 mmol),
potassium fluoride (29.68 g, 510.82 mmol),
2-bromo-1-fluoro-4-nitrobenzene (56.75 g, 257.96 mmol) and dimethyl
sulfoxide (384 mL). The reaction mixture was heated to 90.degree.
C. for 2 h (or until HPLC showed completion). The reaction was
cooled to room temperature then added drop wise to ice-cold water
(15 L) while stirring. Stirring was maintained for 1 h at room
temperature. The precipitated product was filtered, washed with
water (15 L). The product was dried in a vacuum oven at 65.degree.
C. overnight to yield a yellow solid (97.0 g, 97.9%). Purity 99.54%
by HPLC. CHN calculated % C 43.33, % H 2.08, % N 3.61; observed % C
43.18, % H 1.76, % N 3.57.
Example 2
Preparation of 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran
[0044] 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran was produced
by reacting
4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde (prepared
using the procedure of Example 1) with catalytic palladium acetate
in DMF in the presence of sodium acetate. To a 1 L 3-neck round
bottom flask, fitted with a mechanical stirrer and reflux condenser
was added 4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde
(92.50 g, 238.33 mmol), sodium acetate (29.33 g, 357.50 mmol) and
dimethyl formamide (555.0 mL) with stirring. The reaction mixture
was heated to 110-115.degree. C. after which palladium acetate
(1.34 g, 5.96 mmol) was added and the temperature maintained at
110-115.degree. C. for 1 h. After this time, a second portion of
palladium acetate (1.34 g, 5.96 mmol) was added and stirred for an
additional 1 h. An additional six portions of palladium acetate
(each 1.34 g, 5.96 mmol) were added to the reaction mixture every
hour while monitoring the reaction by HPLC. The reaction mixture
was cooled to 60.degree. C., filtered through celite and washed
with DMF. The filtrate was added drop wise to a stirred vessel of
water over 30-60 minutes. The precipitates were filtered, washed
with water (500 mL) and dried in a vacuum oven (70.degree. C.). The
crude aldehyde was recrystallized with acetic acid (800 mL), the
solid was filtered and washed with acetic acid (70 mL), heptane
(500 mL) and dried in a vacuum oven (65-70.degree. C.). The dried
product appeared as a tan solid (51.07 g, 71.1%). Purity 93.46% by
HPLC. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 7.68 (t, J=72.3 Hz, 1H),
7.78 (d, J=8.5 Hz, 1H), 8.11 (d, J=9.5 Hz, 1H), 8.26 (d, J=8.0 Hz,
1H), 8.55 (dd, J=2.5, 9.0 Hz, 1H), 9.78 (d, J=2.5 Hz, 1H), 10.28
(s, 1H) ppm.
Example 2A
Preparation of 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran
[0045] 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran was produced
by reacting 4-difluoromethoxy-3-hydroxybenzaldehyde with
2-bromo-1-fluoro-4-nitrobenzene in DMF in the presence of sodium
carbonate, followed by the reaction with catalytic palladium
acetate in the presence of sodium acetate. To a 100 mL 3-neck round
bottom flask, fitted with a mechanical stirrer and reflux condenser
was added 4-difluoromethoxy-3-hydroxybenzaldehyde (7.525 g, 40
mmol), sodium carbonate (2.544 g, 24 mmol),
2-bromo-1-fluoro-4-nitrobenzene (8.89 g, 40 mmol) and dimethyl
formamide (DMF, 60 mL). The reaction mixture was heated to
90.degree. C. for 2 h. To this were added sodium acetate (4.92 g,
60 mmol) and palladium acetate (0.898 g, 4 mmol) with stirring. The
reaction mixture was heated to 130.degree. C. and the temperature
maintained at 125-130.degree. C. for 1 h. After this time, a second
portion of palladium acetate (0.45 g, 2 mmol) was added and stirred
for an additional 1 h. The reaction mixture was cooled to room
temperature, filtered through celite and washed with DMF. The
filtrate was added drop wise to a stirred vessel of water over
30-60 minutes. The precipitates were filtered, washed with water
(50 mL) and dried in a vacuum oven (70.degree. C.). The crude
aldehyde was recrystallized with acetic acid (800 mL), the solid
was filtered and washed with acetic acid (20 mL) and dried in a
vacuum oven (65-70.degree. C.). The dried product appeared as a tan
solid (8.24 g, 67%).
Example 3
Preparation of
4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid
[0046] 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid
was prepared by oxidizing 4-difluoromethoxy-8-nitro-1-formyl
dibenzofuran (prepared using the procedure of Example 2) in
sulfamic acid, glacial acetic acid and sodium chlorite. To a 2 L
3-neck round bottom flask, fitted with a mechanical stirrer was
added 4-difluoromethoxy-8-nitro-1-formyl dibenzo[b,d]furan (51.00
g, 166.01 mmol), sulfamic acid (48.35 g, 498.03 mmol), glacial
acetic acid (510.0 mL) and stirred at room temperature. To this
mixture was added sodium chlorite (45.05 g, 498.03 mmol) in
portions (slight exotherm). The reaction was stirred at room
temperature for 50 minutes (reaction monitored by HPLC). Additional
sodium chlorite (16.12 g, 178.24 mmol) was added to the reaction
and stirred at room temperature until HPLC indicated completion of
the reaction. Water (1.53 L) was added to the reaction mixture and
stirred for 30-60 minutes. The precipitated solid was filtered,
washed with water (350 mL), heptane (350 mL) and dried in vacuum
oven (65.degree. C.) overnight. The dried product appeared as a
yellow solid (51.27 g, 97.8%). Purity 95.61% by HPLC; .sup.1H NMR
(500 MHz, DMSO-d.sub.6): 7.61 (t, J=72.5 Hz, 1H), 7.62 (d, J=8.5
Hz, 1H), 8.07 (d, J=9.0 Hz, 1H), 8.12 (d, J=8.5 Hz, 1H), 8.52 (dd,
J=2.5, 9.0 Hz, 1H), 9.77 (d, J=2.5 Hz, 1H), 13.73 (bs, 1H) ppm.
Example 4
Preparation of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide
[0047]
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]fu-
ran-1-carboxamide was prepared by reacting
4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid
(prepared using the procedure of Example 3) with thionyl chloride
and dimethyl formamide in toluene. To a 1 L 3-neck round bottom
flask, fitted with a mechanical stirrer and reflux condenser was
added 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid
(34.00 g, 105.19 mmol), toluene (510.0 mL), thionyl chloride (38.3
mL, 525.95 mmol) and catalytic dimethyl formamide (2.6 mL). The
reaction mixture was heated to 80-90.degree. C. for 2-2.5 h. After
ascertaining completion of the reaction, the reaction mixture was
concentrated in vacuo at 55-60.degree. C. to give the acid chloride
as a yellow solid. Dimethyl formamide (140 mL) was added to the
acid chloride and used without further purification in the
following coupling step. A 1 L 3-neck round bottom flask, fitted
with a mechanical stirrer was added 4-amino-3,5-dichloropyridine
(34.30 g, 210.39 mmol) and dimethyl formamide (680.00 mL).
Potassium tert-butoxide (23.61 g, 210.39 mmol) was added to the
reaction mixture and stirred at room temperature for 0.5-1 h. The
acid chloride solution, prepared earlier, was added drop wise to
the potassium salt suspension whilst stirring vigorously,
maintaining the temperature below 30.degree. C. The reaction was
stirred at room temperature until HPLC indicated the reaction was
complete. Water (2.04 L) was added to the reaction mixture, the pH
adjusted to 2-3 with concentrated hydrochloric acid. The
precipitate was filtered, washed with water (200 mL) and
resuspended in a solution of water (2 L) and acetonitrile (170 mL).
The pH was adjusted to 10 with 2N NaOH (7.6 mL) solution followed
by heating to 63-67.degree. C. for 0.5-1 h. The mixture was cooled
to room temperature, the solid was filtered, washed with water (200
mL) and dried in a vacuum oven (65.degree. C.) overnight. The crude
amide was recrystallized from boiling acetic acid (2.42 L) and DMF
(33 mL). The product was filtered, washed with acetic acid (132.0
mL), heptane (264.0 mL) and dried in a vacuum oven (65.degree. C.)
overnight. The product appeared as an off-white solid (32.49 g,
74.28%). Purity 97.94% by HPLC; m/z 467.68 (M.sup.+).
Example 5
Reduction of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide
[0048]
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]fur-
an-1-carboxamide was prepared using four separate reduction
routes.
[0049] First,
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-c-
arboxamide was prepared by reacting
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide (prepared using the procedure of Example 4) with indium
in ethanol and saturated ammonium chloride. To a 1 L 3-neck round
bottom flask, fitted with a mechanical stirrer and reflux condenser
was added
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide (22.00 g, 46.99 mmol), ethanol (308.0 mL), sat. aq.
NH.sub.4Cl (132.0 mL) and indium (32.37 g, 281.93 mmol). The
reaction mixture was heated to 80.degree. C. for 4-5 h (reaction
monitored by HPLC). Additional indium (5.40 g, 47.03 mmol) was
added to the reaction and heated to 80.degree. C. until HPLC
indicated completion. After cooling to room temperature the
reaction was evaporated to dryness. DMF (200 mL) was added to the
solids and heated to 70-75.degree. C. The solution was filtered,
washed with DMF (100 mL) and concentrated to a volume of 50 mL in
vacuo. Water (3 L) was added to the reaction mixture, the solid was
filtered, washed with water (66 mL) and dried in a vacuum oven
(65.degree. C.) overnight. The dried product appeared as a yellow
solid (17.77 g, 77.4%). Purity 87.84% by HPLC; .sup.1H NMR (500
MHz, DMSO-d.sub.6): 5.11 (bs, 2H), 6.86 (dd, J=2.3, 8.8 Hz, 1H),
7.46-7.51 (m, 3H), 7.53 (t, J=73.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H),
8.80 (s, 2H), 10.93 (bs, 1H) ppm. m/z 437.1 (M.sup.+).
[0050] Second,
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-c-
arboxamide was prepared by reacting
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide (prepared using the procedure of Example 4) with Raney
Nickel. In particular, to a 500 mL pressure vessel was added
N'-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-
-carboxamide (2.00 g, 4.27 mmol), DMF (30.0 mL) and Raney Nickel
(1.79 g). The reaction mixture was hydrogenated (50 psi) for 23 h
(reaction monitored by HPLC). The reaction mixture was filtered,
washed with DMF (20 mL) and the filtrate concentrated to a 5 mL
volume (distilled below 70.degree. C. under vacuum). Water (33.0
mL) was added, the precipitate filtered, washed with water (20 mL)
and dried in a vacuum oven (65.degree. C.) to yield the amine as a
cream colored solid (1.67 g, 91.3%). Purity 98.67% by HPLC.
[0051] Third,
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-c-
arboxamide was prepared by reacting
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide (prepared using the procedure of Example 4) with zinc.
In particular, to a 250 mL 2-necked round bottom flask was added
N'-(3,5-dichloropyrid-4-yl)-4-difluoro
methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (1.00 g, 2.14
mmol), sat.aq. ammonium chloride (30.0 mL), ethanol (10.0 mL) and
zinc (0.84 g, 12.82 mmol). The reaction mixture was heated to
95.degree. C. over the weekend. The solvent was removed in vacuo,
DMF (14 mL) was added to the residue and heated to 50-55.degree. C.
until dissolution. The hot solution was filtered, washed with DMF
(4 mL) and poured onto water (100 mL). The precipitate was
filtered, washed with water (20 mL) and dried in a vacuum oven to
yield the amine as a pale yellow solid (0.73 g, 79.4%). Purity
86.31% by HPLC.
[0052] Fourth,
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-c-
arboxamide was prepared by reacting
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide (prepared using the procedure of Example 4) with sodium
borohydride in methanol and palladium on carbon (50% wet with
water) catalyst. In particular, to a 100 mL 3-neck round bottom
flask were added
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1--
carboxamide (0.468 g, 1 mmol), methanol (15.0 mL), and 10% Pd--C
(50% wet, 0.012 g). The reaction mixture was cooled to 5-10.degree.
C. and treated with sodium borohydride (0.127 g, 4 mmol) in four
portions. The reaction mixture was acidified with conc. HCl to
pH-6, filtered and the Pd--C catalyst was washed with MeOH
(.about.10 ml). The combined filtrate was concentrated to a residue
and slurried in excess water. The solid was filtered, washed with
water (75 mL) and dried in a vacuum oven (65.degree. C.) overnight.
The dried product appeared as a yellow solid (0.310 g, 70.7%).
Purity 79.57% by HPLC.
Example 6
Preparation of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)
dibenzo[b,d]furan-1
[0053]
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)-
dibenzo[b,d]furan-1-carboxamide was prepared by reacting
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-c-
arboxamide (prepared using the procedure of Example 5) with
methanesulfonyl chloride in THF and pyridine. To a 1 L 4-neck round
bottom flask, fitted with a mechanical stirrer and reflux condenser
was added
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]fur-
an-1-carboxamide (17.00 g, 38.79 mmol) and THF (255 mL). Pyridine
(12.5 mL) was added slowly to the mixture and allowed to stir for
15 minutes. Methanesulfonyl chloride (18.1 mL, 232.74 mmol) was
added to the reaction mixture and stirred at room temperature until
reaction completion as indicated by HPLC. 2 N HCl (34.0 mL) was
added to the reaction mixture and stirred for 10-15 minutes. This
mixture was added drop wise to water (1.7 L), the solid was
filtered, washed with 2 N HCl (17.0 mL), water (51 mL) and methanol
(51 mL). The crude product was recrystallized from hot acetic acid
(700 mL) and the solids dried in a vacuum oven (65-70.degree. C.)
to yield the product as a cream colored solid (14.24 g, 81.1%).
Purity 98.04% by HPLC; .sup.1H NMR (500 MHz, DMSO-d.sub.6): 2.94
(s, 3H), 7.52 (dd, J=2.0, 9.0 Hz, 1H), 7.58 (t, J=73.0 Hz, 1H),
7.62 (d, J=8.5 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.93 (d, J=8.5 Hz,
1H), 8.31 (m, 1H), 8.82 (s, 2H), 9.76 (s, 1H), 11.04 (s, 1H) ppm;
m/z 515.79 (M.sup.+).
Example 7
Preparation of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)
dibenzo[b,d]furan-1-carboxamide sodium salt
[0054]
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)-
dibenzo[b,d]furan-1-carboxamide sodium salt was prepared by
reacting
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)dibenz-
o[b,d]furan-1-carboxamide (prepared using the procedure of Example
6) with sodium hydride in THF. To a 500 mL 3-neck round bottom
flask was added GRC-3845 (17.00 g, 32.93 mmol) and THF (170.0 mL)
and cooled to 0-5.degree. C. Sodium hydride (1.48 g, 36.88 mmol,
60% dispersed in mineral oil) was added slowly, maintaining the
temperature between 0-5.degree. C. The mixture was maintained at
this temperature for 10 minutes and then warmed to room
temperature. The mixture was diluted with THF (34.0 mL) and heated
to reflux for 1-2 h. The solvent was removed in vacuo (temperature
40.degree. C.). Isopropyl alcohol (102 mL) was added to the residue
and the mixture heated to reflux for 3-4 h. The reaction was cooled
to room temperature, filtered, washed with isopropyl alcohol (25
mL) and dried in a vacuum oven (70.degree. C.) to yield the sodium
salt as a pale yellow solid (16.33 g, 92.8%). Purity 99.6% by HPLC;
m/z 515.80 (M.sup.+).
[0055] Using the indium reduction described in example 5, 97.0
grams of starting material was converted to 44.9 grams of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)dibenz-
o[b,d]furan-1-carboxamide for a yield of 34.1% and 43.4 grams of
-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)dibenzo-
[b,d]furan-1-carboxamide sodium salt for a yield of 31.6%. Using
the Raney-nickel reduction described in example 5, 97.0 grams of
starting material was converted to 53.1 grams of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)dibenz-
o[b,d]furan-1-carboxamide for a yield of 39.9% and 51.3 grams of
-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)dibenzo-
[b,d]furan-1-carboxamide sodium salt for a yield of 37.0%. Using
the zinc reduction described in example 5, 97 grams of starting
material was converted to 36.8 grams of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)dibenz-
o[b,d]furan-1-carboxamide for a yield of 27.9% and 35.6 grams of
-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)dibenzo-
[b,d]furan-1-carboxamide sodium salt for a yield of 25.9%.
[0056] While the invention has been depicted and described by
reference to exemplary embodiments of the invention, such a
reference does not imply a limitation on the invention, and no such
limitation is to be inferred. The invention is capable of
considerable modification, alteration, and equivalents in form and
function, as will occur to those ordinarily skilled in the
pertinent arts having the benefit of this disclosure. The depicted
and described embodiments of the invention are exemplary only, and
are not exhaustive of the scope of the invention. Consequently, the
invention is intended to be limited only by the spirit and scope of
the appended claims, giving full cognizance to equivalence in all
respects. All references cited herein are hereby incorporated by
reference in their entirety.
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