U.S. patent application number 12/505087 was filed with the patent office on 2009-11-12 for process for the preparation of n-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo- [b,d]furan-1-carboxamide.
This patent application is currently assigned to Glenmark Pharmaceuticals, S.A.. Invention is credited to Batchu Chandrasekhar, Laxmikant A. Gharat, Balasubramanian Gopalan, Bijukumar Gopinathan Pillai.
Application Number | 20090281146 12/505087 |
Document ID | / |
Family ID | 35911095 |
Filed Date | 2009-11-12 |
United States Patent
Application |
20090281146 |
Kind Code |
A1 |
Gopalan; Balasubramanian ;
et al. |
November 12, 2009 |
PROCESS FOR THE PREPARATION OF
N-(3,5-DICHLOROPYRID-4-YL)-4-DIFLUOROMETHOXY-8-METHANESULFONAMIDO-DIBENZO-
[B,D]FURAN-1-CARBOXAMIDE
Abstract
The present invention relates to a method of preparing
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide and pharmaceutically acceptable salts
thereof, such as its sodium salt, and novel intermediate compounds
useful in the synthesis of the aforementioned compound.
Inventors: |
Gopalan; Balasubramanian;
(Secunderabad, IN) ; Gharat; Laxmikant A.; (Thane
(w), IN) ; Chandrasekhar; Batchu; (Mumbia, IN)
; Pillai; Bijukumar Gopinathan; (Navi Mumbai,
IN) |
Correspondence
Address: |
Glenmark Pharmaceuticals S.A.;c/o Darby & Darby P.C.
P.O Box 770, Church Street Station
New York
NY
10008-0770
US
|
Assignee: |
Glenmark Pharmaceuticals,
S.A.
La Chaux-de-Fonds
CH
|
Family ID: |
35911095 |
Appl. No.: |
12/505087 |
Filed: |
July 17, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11251567 |
Oct 13, 2005 |
7563900 |
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12505087 |
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60618474 |
Oct 13, 2004 |
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60621981 |
Oct 21, 2004 |
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Current U.S.
Class: |
514/337 |
Current CPC
Class: |
C07D 307/91 20130101;
A61P 11/00 20180101; C07C 47/575 20130101; C07C 201/12 20130101;
C07C 205/38 20130101; A61P 11/06 20180101; C07C 47/575 20130101;
C07C 201/12 20130101; C07C 45/71 20130101; C07C 2601/08 20170501;
C07D 405/12 20130101; C07C 45/71 20130101 |
Class at
Publication: |
514/337 |
International
Class: |
A61K 31/443 20060101
A61K031/443 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 14, 2004 |
IN |
1099/MUM2004 |
Claims
1-56. (canceled)
57.
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dib-
enzo[b,d]furan-1-carboxamide or a pharmaceutically acceptable salt
thereof containing: (a)
4-cyclopentyloxy-3-(4'-nitro-2'-bromophenoxy)benzaldehyde (C); (b)
a compound of the formula ##STR00034## where R.sup.1 is hydrogen or
a substituted or unsubstituted C.sub.1-6 alkyl, and PG is an
aldehyde protecting group; or (c)
p-nitrophenyl-4-difluoromethoxy-8-nitro
dibenzo[b,d]furan-1-carboxylic acid ester (H), in an amount greater
than 0% but less than 0.15%.
58.
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dib-
enzo[b,d]furan-1-carboxamide of claim 49, wherein the compound of
formula E-I is 1-{[(4-methylphenyl)imino]methyl}-8-nitro-dibenzo
[b,d] furan-4-ol (E.sup.1) or
1-{[(4-methylphenyl)imino]methyl}-4-difluoromethoxy-8-nitro-dibenzo
[b,d] furan (E.sup.2).
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/618,474, filed Oct. 13, 2004, Indian Provisional
Application No. 1099/Mum/2004, filed Oct. 14, 2004, and U.S.
Provisional Application No. 60/621,981, filed Oct. 21, 2004, both
of which are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a method of preparing
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide and pharmaceutically acceptable salts
thereof, such as its sodium salt, and novel intermediate compounds
useful in the synthesis of the aforementioned compound.
BACKGROUND OF THE INVENTION
[0003] Although several research groups all over the world are
working to find highly selective PDE-4 isozyme inhibitors, so far
success has been limited. Various compounds have shown PDE-4
inhibition. SmithKline Beecham's "Ariflo", Byk Gulden's Roflumilast
and Bayer's Bay-19-8004 have reached advanced stage of human
clinical trials. Other compounds which have shown potent PDE-4
inhibitory activity include Celltech's CDP-840, Schering Plough's
D-4418, Pfizer's 5CP-220,629, Parke Davis's PD-168787 and Wyeth's
Filaminast. However, recently due to efficacy and side effects
problems, Ariflo, CDP-840 and Bay-19-8004 were discontinued from
clinical trials as a treatment for asthma. D-4418 and 5CP-220,629
are presently undergoing phase-1 clinical trials.
[0004] International Publication No. WO 2004/089940 discloses
heterocyclic PDE-4 inhibitors,
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
-[b,d]furan-1-carboxamide and pharmaceutically acceptable salts
thereof, useful in the treatment of certain allergic and
inflammatory diseases, such as asthma and chronic obstructive
pulmonary disease (COPD).
[0005] There remains a need for alternative methods for preparing
N-(3,5-dichloropyridnyl-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibe-
nzo[b,d]furan-1-carboxamide and pharmaceutically acceptable salts
thereof.
BRIEF SUMMARY OF THE INVENTION
[0006] The present invention provides new methods for the
preparation of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide or a pharmaceutically acceptable salt
thereof, such as its sodium salt.
[0007] One aspect of the invention is a method for the preparation
of 4-cyclopentoxy-3-(4'-nitro-3'-bromo phenoxy)-benzaldehyde (C) by
reacting 4-cyclopentyloxy-3-hydroxy-benzaldehyde (B) with
3-bromo-4-fluoro nitrobenzene (B.sup.1)
##STR00001##
The reaction is preferably performed in the presence of an alkali
halide, such as potassium fluoride. The reaction is also preferably
performed in a polar aprotic solvent.
[0008] Another aspect of the invention is a method for the
preparation of 4-cyclopentyloxy-8-nitro-1-formyl dibenzo-furan (D)
by cyclizing
4-cyclopentoxy-3-(4'-nitro-3'-bromo-phenoxy)-benzaldehyde (C)
##STR00002##
The benzaldehyde (C) may be prepared by reacting compounds (B) and
(B.sup.1) as discussed herein. The cyclization is preferably
performed in the presence of palladium acetate. A suitable solvent
for the reaction is dimethyl formamide.
[0009] Yet another aspect of the invention is a method for the
preparation of a compound of formula (E-I)
##STR00003##
wherein R.sup.1 is a hydrogen atom and PG is an aldehyde protecting
group, by protecting 4-hydroxy-8-nitro-1-formyl dibenzofuran
(E)
##STR00004##
with an aldehyde protecting group. The dibenzofuran (E) may be
prepared by any method described herein.
[0010] Yet another aspect of the invention is a method for the
preparation of a compound of formula (E-Ib)
##STR00005##
where R.sup.1 is a substituted or unsubstituted C.sub.1-C.sub.6
alkyl and PG is an aldehyde protecting group, by alkylation of a
compound of formula (E-I)
##STR00006##
where R.sup.1 is hydrogen and PG is as defined above. The
dibenzofiran (E-I) may be prepared by any method described
herein.
[0011] Yet another aspect of the invention is method for the
preparation of a compound of formula (E-Ia)
##STR00007##
where
[0012] R is a substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylakyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, or substituted or unsubstituted
heterocyclylalkyl, and
[0013] R.sup.1 is hydrogen,
by reacting 4-hydroxy-8-nitro-1-formyl dibenzofuran (E)
##STR00008##
with an amine of the formula R-NH.sub.2, where R is as defined
above. The dibenzofiran (E) may be prepared by any method described
herein.
[0014] Yet another aspect of the invention is a method for the
preparation of a compound of formula (E-Ic)
##STR00009##
where
[0015] R is substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylakyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, or substituted Or unsubstituted
heterocyclylalkyl, and
[0016] R.sup.1 is a substituted or unsubstituted C.sub.1-6
alkyl,
by alkylation of a compound of general formula (E-Ia)
##STR00010##
where R.sup.1 is hydrogen and R is as defined above. The
dibenzofuran (E-Ia) may be prepared by any method described
herein.
[0017] Yet another aspect of the invention is a method for the
preparation of 1-{[(4-methylphenyl)imino]methyl}-8-nitro-dibenzo
[b,d]furan-4-ol (E.sup.1)
##STR00011##
by reacting 4-hydroxy -8-nitro-1-formyl dibenzofuran (E)
##STR00012##
with 4-methyl aniline (p-toludine).
[0018] Yet another aspect of the invention is a method for the
preparation of
1-{[(4-methylphenyl)imino]methyl}-4-difluoromethoxy-8-nitro-dibenzo
[b,d]furan (E.sup.2)
##STR00013##
by reacting 4-hydroxy-8-nitro-1-formyl dibenzofuran (E.sup.1)
##STR00014##
with CHClF.sub.2.
[0019] Yet another aspect of the invention is a method for the
preparation of p-nitrophenyl-4-difluoromethoxy-8-nitro dibenzofuran
carboxylic acid ester (H) by reacting
4-difluoro-methoxy-8-nitro-dibenzofuran carboxylic acid (G) with
para-nitro phenol (G.sup.1)
##STR00015##
Preferably, the reaction is performed in the presence of thionyl
chloride, and/or a suitable solvent.
[0020] Yet another aspect of the invention is a method for the
preparation of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitrodibenzo[b,d]furan--
1-carboxamide (I) by reacting p-nitrophenyl
4-difluoromethoxy-8-nitro-dibenzofuran carboxylic acid ester (H)
with 4-amino-3,5-dichloropyridyl (H.sup.1)
##STR00016##
Preferably, the reaction is performed in the presence of a base,
such as sodium hydride, and/or in a suitable solvent.
[0021] The intermediates formed in any of the aforementioned
methods may be converted to
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide or a pharmaceutically acceptable salt
thereof, such as its sodium salt, for example, by the methods
described herein.
[0022] Yet another aspect of the invention is
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide or a pharmaceutically acceptable salt
thereof prepared by any of the methods of the present
invention.
[0023] Yet another aspect of the invention are the following novel
intermediate compounds and salts thereof:
[0024] (i) 4-cyclopentoxy-3-(4'-nitro-2'-bromophenoxy)-benzaldehyde
(C),
[0025] (ii) a compound of the formula
##STR00017##
where [0026] R.sup.1 is hydrogen, and [0027] PG is an aldehyde
protecting group,
[0028] (iii) a compound of the formula
##STR00018##
where [0029] R.sup.1 is a substituted or unsubstituted C.sub.1-6
alkyl, and [0030] PG is an aldehyde protecting group,
[0031] (iv) a compound of the formula
##STR00019##
where [0032] R is a substituted or unsubstituted alkyl, substituted
or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylakyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, substituted or unsubstituted heterocyclylalkyl,
and [0033] R.sup.1 is hydrogen,
[0034] (v) a compound of the formula
##STR00020##
where [0035] R is a substituted or unsubstituted alkyl, substituted
or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylakyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, substituted or unsubstituted heterocyclylalkyl,
and [0036] R.sup.1 is substituted or unsubstituted C.sub.1-6
alkyl,
[0037] (vi) 1-{[(4-methylphenyl)imino]methyl}-8-nitro-dibenzo[b,d]
furan-4-ol (E.sup.1),
##STR00021##
[0038] (vii)
1-{[(4-rnethylphenyl)imino]methyl}-4-difluoromethoxy-8-nitro-dibenzo
[b,d]furan (E.sup.2),
##STR00022##
[0039] (viii) p-nitrophenyl 4-difluoro methoxy-8-nitro dibenzofuran
carboxylic acid ester (H)
##STR00023##
[0040] Preferred intermediate compounds, include intermediate (iii)
(compounds E-Ia), where R is a substituted or unsubstituted aryl.
Further preferred are compounds where R is 4-methylphenyl. Further
preferred are compounds where R.sup.1 is hydrogen. Further
preferred are compounds where R.sup.1 is a substituted or
unsubstituted C.sub.1-6 alkyl. Further preferred are compounds
where R.sup.1 is CHF.sub.2.
[0041] Yet another aspect of the invention is a compound having the
formula:
##STR00024##
or a salt thereof.
[0042] Yet another aspect of the invention is a compound having the
formula:
##STR00025##
where R is cycloalkyl, or a salt thereof.
[0043] Yet another aspect of the invention is
N-(3,5-dichloropyrid-4-yl)4-difluoromethoxy-8-methanesulfonamido-dibenzo[-
b,d]furan-1-carboxamide or a pharmaceutically acceptable salt
thereof having any one of the aforementioned intermediates,
compound L, or compound L2 in an amount less than 0.2%, 0.15%,
0.1%, or 0.05% (based upon 100% total weight of
N-(3,5-dichloropyrid-4-yl)-4difluoromethoxy-8-methanesulfonamido-dibenzo[-
b,d]furan-1-carboxamide or its pharmaceutically acceptable salt
thereof and the intermediate). According to one embodiment, the
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide or a pharmaceutically acceptable salt
thereof has intermediate compound F, G, H, I, or J, compound L or
compound L2 in an amount less than 0.2%, 0.15%, 0.1%, or 0.05%.
[0044] Yet another aspect of the invention is a pharmaceutical
composition comprising
N-(3,5-dichloropyrid-4-yl)4-difluoromethoxy-8-methanesulfonamido-dibenzo[-
b,d]furan-1-carboxamide or a pharmaceutically acceptable salt
thereof containing any one of the aforementioned intermediates,
compound L, or compound L2 in an amount less than 0.2%, 0.15%,
0.1%, or 0.05% (based upon 100% total weight of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide or its pharmaceutically acceptable salt
thereof and the intermediate, compound L, or compound L2).
Preferably, the pharmaceutical composition includes a
pharmaceutically acceptable excipient such as a carrier or
diluent.
[0045] Yet another aspect of the invention is
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide or a pharmaceutically acceptable salt
thereof (such as its sodium salt) having a purity of at least 98,
99, or 99.5%.
[0046] Yet another aspect of the invention is a pharmaceutical
composition comprising
N-(3,5-dichloropyrid-4-yl)4difluoromethoxy-8-methanesulfonamido-dibenzo[b-
,d]furan-1-carboxamide or a pharmaceutically acceptable salt
thereof having a purity of at least 98, 99, or 99.5%.
[0047] Yet another aspect of the invention is a method of treating
an allergic or inflammatory disease (including those disclosed in
International Publication No. WO 2004/089940 and U.S. Patent
Publication No. 2005-0027129, both of which are hereby incorporated
by reference), such as asthma or COPD, by administering (i)
N-(3,5-dichloropyrid-4yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[-
b,d]furan-1-carboxamide or a pharmaceutically acceptable salt
thereof containing any one of the aforementioned intermediates in
an amount less than 0.2%, 0.15%, 0.1%, or 0.05%, (ii)
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-3-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide or a pharmaceutically acceptable salt
thereof having a purity of at least 98, 99, or 99.5%, or (iii) a
pharmaceutical composition of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0048] An "aldehyde-protecting group" is a substituent attached to
an aldehyde group that blocks or protects the carbonyl group of the
aldehyde functionality in the compound. Suitable carbonyl
protecting groups of the aldehyde functionality include, but are
not limited to (a) cyclic acetals and ketals, (b) cyclic mono or
di-thio acetals or ketals or other derivatives such as imines,
hydrazones, cyanohydrin, oximes or semicarbazones, for example,
dialkyl or diaryl acetals or 1,3 dithiane, (c) cyclic imines such
as substituted methylene derivatives or N,N'-dimethylimidazolidine.
For a general description of protecting groups and their use, see,
T. W. Greene, Protective Groups in Organic Synthesis, John Wiley
& Sons, New York, 1991 and T. W. Greene P. G. M. Wuts,
Protective Groups in Organic Synthesis, 3rd edition John Wiley
& Sons, Inc., 1999.
[0049] The term "alkyl" refers to a straight or branched
hydrocarbon chain radical consisting solely of carbon and hydrogen
atoms, containing no unsaturation, having from one to eight carbon
atoms, and which is attached to the rest of the molecule by a
single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl
(isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl
(t-butyl).
[0050] The term "cycloalkyl" denotes a non-aromatic mono or
multicyclic ring system of about 3 to 12 carbon atoms such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and examples of
multicyclic cycloalkyl groups include perhydronapththyl, adamantyl
and norbornyl groups bridged cyclic group or sprirobicyclic groups
e.g., sprio (4,4) non-2-yl.
[0051] The term "aryl" refers to aromatic radicals having in the
range of 6 up to 14 carbon atoms such as phenyl, naphthyl,
tetrahydronapthyl, indanyl, and biphenyl.
[0052] The term "heterocyclic ring" refers to a stable 3- to 15
membered ring radical which consists of carbon atoms and from one
to five heteroatoms selected from the group consisting of nitrogen,
phosphorus, oxygen and sulfur. For purposes of this invention, the
heterocyclic ring radical may be a monocyclic, bicyclic or
tricyclic ring system, which may include fused, bridged or spiro
ring systems, and the nitrogen, phosphorus, carbon, oxygen or
sulfur atoms in the heterocyclic ring radical may be optionally
oxidized to various oxidation states. In addition, the nitrogen
atom may be optionally quaternized; and the ring radical may be
partially or fully saturated (i.e., heteroaromatic or heteroaryl
aromatic). Examples of such heterocyclic ring radicals include, but
are not limited to, azetidinyl, acridinyl, benzodioxolyl,
benzodioxanyl, benzofinyl, carbazolyl, cinnolinyl, dioxolanyl,
indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,
phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl,
purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,
tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,
2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,
pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,
oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl,
morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl,
quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl,
isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl,
isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl,
benzopyranyl, benzothiazolyl, benzooxazolyl, furyl,
tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl,
thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinyl sulfone,
dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The
above includes substituted or unsubstituted pyridyl N-oxides.
[0053] The term "heteroaryl" refers to heterocyclic ring radical as
defined above. The heteroaryl ring radical may be attached to the
main structure at any heteroatom or carbon atom that results in the
creation of a stable structure.
[0054] The term "halogen" includes radicals of fluorine, chlorine,
bromine and iodine.
[0055] The terms "alkali halide salt" and "alkali halide" include,
but are not limited, to, KF, KBr, KCL, KI, NaF, NaBr, NaCl, Nal,
LiF, Cl, LiBr, and LiI.
[0056] The term "organic acid" includes, but is not limited to,
carboxylic acids such as acetic acid, propionic acid, formic,
trifluoroacetic, and paratoluene sulfonic.
[0057] The term "inorganic acid" includes, but is not limited to,
mineral acids, HBr, phosphoric acid, HCl, HI, H.sub.2SO.sub.4 and
Lewis Acids, such as BF.sub.3, BCl.sub.3, and AlCl.sub.3.
[0058] The term "organic base" includes, but is not limited to,
trialkyl amines, such as triethylamine and diisopropylamines, and
heterocylic amines, such as imidazole, pyridine, pyridazine,
pyrimidine, and pyrazine; anionic nitrogen bases, such as lithium
diisopropylamide, and potassium bis(trimethylsilyamide), and
bicyclic amines, such as DBN, and DBU.
[0059] The term "inorganic base" includes, but is not limited to,
carbonates such as lithium carbonate sodium carbonate, sodium
bicarbonate and cesium carbonate.
[0060] Suitable oxidants includes, but is not limited to, reagents
such as potassium permanganate and chromium based oxidants such as
the Jones Reagent (CrO.sub.3 in sulfuric acid).
[0061] Suitable catalysts for the reduction step include, but are
not limited to, suitable hydrogenation catalysts such as
reactivated Raney Nickel, Pearlmans catalyst (palladium hydroxide),
and Pd/C.
[0062] The term "palladium catalyst" includes, but is not limited
to, Pd(II) complexes such as Pd(OAc).sub.3.
[0063] Pharmaceutically acceptable salts forming part of this
invention include salts derived from inorganic bases such as Li,
Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as
N,N'-diacetylethylenediamine, glucamine, triethylamine, choline,
hydroxide, dicyclohexylamine, metformin, benzylamine,
trialkylamine, thiamine, and the like; chiral bases like
alkylphenylamine, glycinol, phenyl glycinol and the like, salts of
natural amino acids such as glycine, alanine, valine, leucine,
isoleucine, norleucine, tyrosine, cystine, cysteine, methionine,
proline, hydroxy proline, histidine, omithine, lysine, arginine,
serine, and the like; quaternary ammonium salts of the compounds of
invention with alkyl halides, alkyl sulphats like MeI,
(Me).sub.2SO.sub.4 and the like. Non-natural amino acids such as
D-isomers or substituted amino acids; guanidine, substituted
guanidine wherein the substituents are selected from nitro, amino,
alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and
aluminum salts. Salts may include acid addition salts where
appropriate which are, sulphates, nitrates, phosphates,
perchlorates, borates, hydrohalides, acetates, tartrates, maleates,
citrates, fumarates, succinates, palmoates, methanesulphonates,
benzoates, salicylates, benzenesulfonates, ascorbates,
glycerophosphates, ketoglutarates and the like. Pharmaceutically
acceptable solvates may be hydrates or comprise other solvents of
crystallization such as alcohols.
[0064] Salts can be obtained by dissolving the free compound in a
suitable solvent, e.g., in a chlorinated hydrocarbon, such as
methylene chloride or chloroform, or a low molecular weight
aliphatic alcohol (e.g., ethanol and isopropanol) which contains
the desired acid or base, or to which the desired acid or base is
then added. The salts are obtained by filtering, re-precipitating,
precipitating with a non-solvent for the addition salt or by
evaporating the solvent. Salts obtained can be converted by
basification or by acidifying into the free compounds which, in
turn can be converted into salts.
[0065] The substances according to the invention are isolated and
purified in a manner known per se, e.g. by distilling off the
solvent in vacuum and recrystallizing the residue obtained from a
suitable solvent or subjecting it to one of the customary
purification methods, such as column chromatography on a suitable
support material.
[0066] In general, organic solvents include, but are not limited
to, the ethereal solvents described herein as well as 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 alchoholic solvents
include, but are not limited to, methanol, ethanol, n-propanol,
isopropanol, and tert-butanol. Sutiable polar aprotic solvents
include, but are not limited to, N, N-dimethylformamide and
dimethyl sulfoxide.
[0067] In general, the compounds prepared in the above described
processes are obtained in pure form by using well known techniques
such as crystallization using solvents such as pentane, diethyl
ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate,
acetone, methanol, ethanol, isopropanol, water or their
combinations, or column chromatography using alumina or silica gel
and eluting the column with solvents such as hexane, petroleum
ether (pet.ether), chloroform, ethyl acetate, acetone, methanol or
their combinations.
Synthesis
[0068] In one embodiment
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfon
amido-dibenzo[b,d]furan-1-carboxamide or a pharmaceutically
acceptable salt thereof is synthesized by the method shown in
scheme I below. In the scheme, Intermediate E can be converted to
Intermediate F either directly by alkylation in the presence of
CHClF.sub.2 and K.sub.2CO.sub.3-DMF, or by protection of the
aldehyde functionality by forming a Schiff base to provide
(E.sup.1) followed by alkylation of (E.sup.1) in the presence of
CHClF.sub.2 and K2CO3-DMF to provide (E.sup.2) which can then be
subjected to deprotection (with or without isolation) using dilute
HCl to give Intermediate F. This indirect conversion of
Intermediate E to Intermediate F via E.sup.1 and E.sup.2 provides a
significant improvement in the percentage yield of Intermediate F
which in turn results in increased overall yield of
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-
[b,d]furan-1-carboxamide (or a pharmaceutically acceptable salt
thereof) Intermediate F is then converted to the desired compound
N-(3,5-dichloropyrid-4-yl)4-difluoromethoxy-8-methanesulfonamido-dibenzo[-
b,d]furan-1-carboxamide or a pharmaceutically acceptable salt.
##STR00026## ##STR00027##
[0069] Compound L may be prepared by skipping the step of
converting compound D to compound F, i.e., compound D is converted
to an analog of compound G, where the --OCHF.sub.2 substituent is
replaced by a cyclopentyl group.
[0070] An alternative synthesis, Scheme IA, is provided below.
##STR00028## ##STR00029##
[0071] In Scheme IA, the hydroxyl group in the carboxylic acid
moiety of compound G is converted to a halogen, such as Cl
(Compound H.sup.2). This conversion may be performed by reacting
compound G with an acid halide, such as an acid chloride.
Alternatively, the carboxylic acid group of compound G may be
converted to an carboxyl activating group of the formula --C(O)L.
The phrase "carboxyl activating group" is defined below.
[0072] Compound H.sup.2 (and any compound prepared by converting
the carboxylic acid group of compound G to a carboxyl activating
group as discussed above) may be converted with compound H.sup.1 to
compound I as discussed in Scheme I above.
[0073] Compound L may be prepared by skipping the step of
converting compound D to compound F, i.e., compound D is converted
to an analog of compound G, where the --OCHF.sub.2 substituent is
replaced by a cyclopentyl group.
[0074]
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-d-
ibenzo [b,d]furan-1-carboxamide or a pharmaceutically acceptable
salt thereof can also be synthesized using the general method shown
in scheme II below.
##STR00030## ##STR00031##
[0075] In the scheme II, 3,4-hydroxy benzaldehyde (1) is reacted
with an alkyl or cycloalkyl halide to form an aryl ether of Formula
2. Preferably, 3,4-hydroxy benzaldehyde (1) is reacted with a
cycloalkyl halide, such as a cyclopentyl halide. Preferably, the
halide is bromo. The reaction is preferably performed in the
presence of an inorganic or organic base, preferably
K.sub.2CO.sub.3. The reaction is also preferably performed in a
polar aprotic solvent (e.g., DMF).
[0076] Compound (2) is reacted with 2-bromo-1-fluoro-4-nitro
benzene to yield the coupled product of Formula 3. Preferably, this
reaction in performed in the presence of an alkali halide, such as
KF. This reaction is also preferably performed in a polar aprotic
solvent such as DMSO.
[0077] Compound (3) is cyclized to form compound (4). For example,
intramolecular cyclization of compound (3) can be performed using a
palladium reagent, such as Pd(OAc).sub.3. Preferably, the
cyclization is performed in the presence of an inorganic base, such
as Na.sub.2CO.sub.3. This reaction is also preferably performed in
a polar aprotic solvent, such as DMF.
[0078] The R group is then cleaved off compound (4) to form
compound (5). For example, the ether linkage can be cleaved by
treating compound (4) with an acid. Suitable acids include, but are
not limited to, inorganic acids, organic acids, and mixtures
thereof. A preferred acid mixture is HBr/AcOH.
[0079] Compound (5) is converted to compound (6), such as by
reaction with CHClF.sub.2. Preferably, this reaction is performed
in the presence of an inorganic or organic base, such as
K.sub.2CO.sub.3. This reaction is also preferably performed in a
polar aprotic solvent, such as DMF.
[0080] Alternatively, compound (5) may be converted to compound (6)
by (i) protecting the aldehyde group of compound (5), (ii)
converting the hydroxyl group of the compound to --OCHF.sub.2, such
as by reaction with CHlF.sub.2, and (iii) deprotecting the aldehyde
group. Step (ii) is preferably performed in the presence of an
inorganic or organic base, such as K.sub.2CO.sub.3. Step (ii) is
also preferably performed in a polar aprotic solvent, such as
DMF.
[0081] Compound (6) is oxidized, converting the aldehyde group to a
carboxylic acid group, to form compound (7). The oxidation may be
performed by treating compound (6) with an oxidizing reagent, such
as KMnO.sub.4. The oxidation may be performed in an aqueous organic
solvent, such as acetone.
[0082] The carboxylic acid functionality of compound (7) is
converted into an activated carboxyl group of the formula --C(O)L.
This step yields the compound (8). The phrase "carboxyl activating
group" refers to a moiety that replaces the hydrogen or hydroxyl of
a carboxylic acid thereby altering the chemical and electronic
properties of the carboxyl group such that the carboxyl group is
more susceptible to nucleophilic attack or substitution. In
embodiments in which the hydroxyl is replaced, exemplary carboxyl
activating groups include chloro. In embodiments in which the
hydrogen is replaced, exemplary carboxyl activating groups include
electron deficient alkyl, aryl or heteroaryl groups, and phenyl
group substituted with one or more electron withdrawing groups,
such as halogen or nitro.
[0083] A non-limiting example of a suitable leaving group is
chloro. Compound (8), where L is chloro, can be prepared by
reacting a compound (7) with SOCl.sub.2 in the presence of an
organic base.
[0084] The group --C(O)--L can also be an ester derived from an
electron deficient alcohol. For example, L can be an alkyl or aryl
with one or more electron withdrawing groups. Compound (8), where L
is alkyl or aryl with one or more election withdrawing groups, can
be prepared by reacting compound 8 where L is chloro with an
electron deficient alcohol to form compound (9). A suitable
electron deficient alcohol is p-nitro-phenol.
[0085] Compound (8) is coupled with 3,5 dichloro-4-amino pyridine
to form compound, (9). Preferably, compound (8) is reacted with 3,5
dichloro-4-amino pyridine in the presence of an organic or
inorganic base, such as NaH. Preferably, the coupling reaction is
performed in a polar aprotic solvent, such as DMF.
[0086] Alternatively, compound (9) may be prepared by directly
coupling the carboxylic acid group of compound (7) to
3,5-dichloro-amino pyridine. For example, compound (7) and 3,5
dichloro-4-amino-pyridine may be reacted in the presence of a
carbodimide and a catalyst to form compound (9). A non-limiting
example of a suitable carbodimide is dicyclohexyl carbodimide. A
non-limiting example of a suitable catalyst is dimethyl amino
pyridine (DMAP).
[0087] Compound (9) is reduced to form compound (10). Preferably,
the reduction reaction is performed with a catalyst, such as a
reactivated Raney Nickel. The reduction can be performed in an
alcoholic or polar aprotic solvent, such as DMF. According to one
embodiment, the reaction is performed in the presence of hydrogen.
The reduction can also be performed under phase transfer
hydrogenation conditions.
[0088] Compound (10) is reacted with methane sulfonyl chloride to
form compound (11). This reaction can be performed in the presence
of an inorganic or organic base, such as pyridine. This reaction
can also be performed in an organic solvent, such as THF.
[0089] The sulfonamide of Formula II is optionally converted to a
pharmaceutically acceptable salt thereof. For example, the
sulfonamide can be converted to its sodium salt by the action of
NaH in an organic solvent.
[0090] Compounds L and L2 may be prepared by skipping the step of
converting compound 4 to compound 6, i.e., compound 4 is converted
to an analog of compound 7, where the --OCHF.sub.2 substituent is
replaced by a cyclopentyl group. Compound 4 may be oxidized,
converting the aldehyde group to a carboxylic acid group, to form
the analog of compound (7). The oxidation may be performed by
treating compound (4) with an oxidizing reagent, such as
KMnO.sub.4. The oxidation may be performed in an aqueous organic
solvent, such as acetone.
[0091] Specifically, the synthesis of
N-(3,5-dichoropyrid-4-yl)-4-difluoromethoxy-8-methane
sulfonamido-dibenzo [b,d]furan-1-carboxamide and its corresponding
sodium salt can be synthesized using the method in Scheme III
below.
##STR00032## ##STR00033##
[0092] In the above mentioned scheme a dihydroxybenzaldehyde
compound 1, is 3,4 dihydroxy benzaldehyde 1 is reacted with
cyclopentyl bromide in the presence of K.sub.2CO.sub.3 in DMF to
afford a compound of the Formula 2. The cyclopentyl derivative is
then reacted with 2-bromo-1-fluoro-4-nitro benzene in the presence
of KF in DMSO to afford the compound of Formula 3. Intramolecular
cyclization of Formula 3 is accomplished using Pd(OAc).sub.3 in the
presence of Na.sub.2CO3 in DMF to afford the cyclized produce of
Formula 4. Formula 4 is then subjected to 30% HBr in AcOH to afford
Formula 5. Formula 5 is then reacted with chlorodifluoromethane in
the presence of K.sub.2CO.sub.3 in DMF to afford the product of the
Formula 6. Formula 6 is then oxidized using potassium permanganate
in acetone water to afford a compound of Formula 7. Formula 7 is
then reacted with thionyl chloride in the presence of triethylamine
in THF to form the corresponding acid chloride which is then
reacted in situ with p-nitrophenol to afford the compound of
Formula 8. Formula 8 is then reacted with
4-amino-3,5-dichloropyridine in the presence of sodium hydride in
DMF to afford the compound of Formula 9. Formula 9 is then reduced
using Reactivated Raney Nickel in the presence of hydrogen in DMF
to afford the compound of Formula 10. Formula 10 is then reacted
with methane sulfonyl chloride in the presence of pyridine in THF
to afford the title compound which is converted into its
corresponding sodium salt by the action of sodium hydride in
THF/isopropanol.
[0093] Compounds L and L2 may be prepared by scheme III by skipping
the step of converting compound 4 to compound 6, i.e., compound 4
is converted to an analog of compound 7, where the --OCHF.sub.2
substituent is replaced by a cyclopentyl group. Compound 4 may be
oxidized, converting the aldehyde group to a carboxylic acid group,
to form the analog of compound (7). The oxidation may be performed
by treating compound (4) with an oxidizing reagent, such as
KMnO.sub.4. The oxidation may be performed in an aqueous organic
solvent, such as acetone.
[0094] Other alternative reagents to those disclosed in Schemes
I-III are described in International Publication No. WO 2004/089940
and U.S. Patent Publication No. 2005-0027129, both of which are
hereby incorporated by reference.
[0095] It will be appreciated that some of the compounds of the
invention defined above according to the invention can contain one
or more asymmetrically substituted carbon atoms. The presence of
one or more of these asymmetric centers in the compounds of the
invention can give rise to stereoisomers and in each case the
invention is to be understood to extend to all such stereoisomers,
including enantiomers and diastereomers and their mixtures,
including racemic mixtures. The invention may also contain E and Z
geometrical isomers wherever possible in the compounds of the
invention which includes the single isomer or mixture of both the
isomers
[0096] The pharmaceutical compositions may be in the forms normally
employed, such as tablets, capsules, powders, syrups, solutions,
and suspensions, and may contain flavorants and sweeteners in
suitable solid or liquid carriers or diluents, or in suitable
sterile media to form injectable solutions or suspensions. The
active compounds of the invention will be present in such
pharmaceutical compositions in the amounts sufficient to provide
the desired dosage in the range as described above. Thus, for oral
administration, the compounds of the invention can be combined with
a suitable solid, liquid carrier or diluent to form capsules,
tablets, powders, syrups, solutions, suspensions and the like. The
pharmaceutical compositions, may, if desired, contain additional
components such as flavorants, sweeteners, excipients and the like.
For parenteral administration, the compounds of the invention can
be combined with sterile aqueous or organic media to form
injectable solutions or suspensions. For example, solutions in
sesame or peanut oil, aqueous propylene glycol and the like can be
used as well as aqueous solutions of water-soluble
pharmaceutically-acceptable acid addition salts or salts with base
of the compounds of the invention The injectable solutions prepared
in this manner can then be administered intravenously,
intraperitoneally, subcutaneously, or intramuscularly, with
intramuscular administration being preferred in humans.
[0097] The compounds can also be administered by inhalation when
application within the respiratory tract is intended. Formulation
of the present compounds is especially significant for respiratory
inhalation, wherein the compound of the invention is to be
delivered in the form of an aerosol under pressure. It is preferred
to micronize the compound of the invention after it has been
homogenized, e.g., in lactose, glucose, higher fatty acids, sodium
salt of dioctylsulfosuccinic acid or, most preferably, in
carboxymethyl cellulose, in order to achieve a microparticle size
of 5 .mu.m or less for the majority of particles. For the
inhalation formulation, the aerosol can be mixed with a gas or a
liquid propellant for dispensing the active substance. An inhaler
or atomizer or nebulizer may be used. Such devices are known. See,
e.g., Newman et al., Thorax, 1985, 40:61-676; Berenberg, M., J.
Asthma USA, 1985, 22:87-92; incorporated herein by reference in
their entirety. A Bird nebulizer can also be used. See also U.S.
Pat. Nos. 6,402,733; 6,273,086; and 6,228,346, incorporated herein
by reference in their entirety. The compound of the invention for
inhalation is preferably formulated in the form of a dry powder
with micronized particles. The compounds of the invention may also
be used in a metered dose inhaler using methods disclosed in U.S.
Pat. No. 6, 131,566, incorporated herein by reference in its
entirety.
[0098] In addition to the compounds of the invention, the
pharmaceutical compositions of the present invention may also
contain or be co-administered with one or more known drugs selected
from other clinically useful therapeutic agents.
[0099] The invention is explained in detail in the examples given
below which are provided by way of illustration only and therefore
should not be construed to limit the scope of the invention.
EXAMPLE 1
4-Cyclopentyloxy-3-hydroxybenzaldehyde
[0100] In a 10 L 4 necked RB flask fitted with a mechanical
stirrer, reflux condenser, was added DMF (3.5 L),
3,4-Dihydroxybenzaldebyde (1.15 Kg, 8.3 M), cyclopentyl bromide
(3.1 kg, 20.3 M) and powdered anhydrous potassium carbonate (1.15
kg, 20.3 M) at temperature in the range of 25-35.degree. C. under
stirring. The reaction mixture was heated to temperature of
75-80.degree. C. under stirring and maintained under stirring for 1
hr. To the reaction mixture, powdered potassium carbonate (140 g, 1
M) was added at temperature of 75-80.degree. C. under stirring.
After addition, the reaction mixture was maintained at
75-80.degree. C. for 1 hr. The progress of the reaction was
monitored by TLC and HPLC. After ascertaining the completion of the
reaction, the reaction mixture was brought to 25-35.degree. C. and
filtered. The inorganic salt cake was washed with DMF (300
ml.times.2) and combine the washings with filtrate. The organic
layer was concentrated at temperature below 75.degree. C. under
high vaccum. Add toluene (2 L) to the residue of distil of the
residual DMF. Add toluene (2 L) to the resulting mass and distill
off the traces of DMF. To the resulting mass, add toluene (5.7 L),
celite (300 g), activated charcoal (100 g), 5% sodium hydroxide
solution(1.2 L) and cool to 10-15.degree. C. under stirring.
Separate the organic and aqueous layer. The organic layer was
repeatedly extracted with 5% sodium hydroxide solution (1.2
L.times.5) and combine the aqueous sodium hydroxide layers. The
aqueous layer was washed with toluene (2 L.times.2) and separate
the aqueous layer. The pH of the aqueous layer was adjusted to
acidic 2-3 with conc. HCl (1.1 L) at 10-15.degree. C. under
stirring. The precipitated solid was filtered, washed with
water(2L.times.3) filtered and dried in the hot air oven below
60.degree. C. temp. The product appear as cream color solid,
weighing about 920-950 g, yield 54%-56% purity 98-99%, m.p
87-89.degree. C. The IR (KBr) spectrum shows 3300 (OH str), 3150
(CH str), 1670 (CHO str), 1620 (C.dbd.C str). The 1H-NMR (DMSO-d6)
shows .delta. 9.8 (s, 1H), 9.2(s, 1H), 7.1 (d, 1H), 7.2-7.4 (m,
2H), 4.9 (m, 1H), 1.4-2.0 (m, 8H). The CI mass shows m/z 206 (M+).
The elemental analysis shows calculated % C 69.88, % H 6.84, % O
23.27; observed % C 69.70, % H 6.65,% O23.15.
EXAMPLE 2
2-bromo-1-fluoro4-nitro benzene
[0101] In a 20 L 4- necked RB flask, fitted with a mechanical
stirrer, reflux condenser, add DM water (550 ml), conc. Sulphuric
acid (6.2 L, 113 M), 4-fluronitrobenzene (1.0 kg, 7.09 M) at
25-35.degree. C. under stirring. The reaction mixture was cooled to
10.degree. C. and bromine (1.13 kg, 7.06 M) was added to reaction
mixture under stirring. The reaction mixture was brought to
temp.25-35.degree. C., silver sulfate (1.1 kg, .about.3.53 M) was
added in one portion to the reaction mixture at 25-35.degree. C.
and maintained for 30-32 h under stirring. Monitor the progress of
the reaction by GC and after ascertaining completion, the reaction
mixture was poured slowly into ice cold water (12 L) and
dichloromethane (12 L) mixture. Filter the insoluble and wash the
inorganic with dichloromethane (2 L). Combine the organic layer,
wash with 10% sodium bicarbonate (3 L), water (5 L). The
dichloromethane layer was distilled below 40.degree. C. under
vacuum and add n-Hexane (4.5 L) to the residue. The resulting mass
was stirred at 25-35.degree. C. for 4-5 hr, filter the product and
dried in vacuum oven below 35.degree. C. till LOD reaches <1%.
The dried product appears as white lustrous crystalline solid,
weighs about 1.1-1.2 kg, yield 70-77%, purity 97-98% by HPLC, m.p.
56-58.degree. C. The structure assigned to the product is in
agreement with spectral data.
EXAMPLE 3
4-Cyclopentyloxy-3-(4'-nitro-2'-bromophenoxy) benzaldehyde
[0102] In a 20 L 4- necked RB flask, fitted with a mechanical
stirrer, reflux condenser, add dimethyl sulfoxide (4.5 L)
4-cyclopentyloxy-3-hydroxybenzaldehyde (900 g, 4.36 M) potassium
fluoride (510 g, 8.5 M), 2-bromo-1-fluoro-4-nitro benzene (970 g,
4.38 M) at temperature 25-35.degree. C. under stirring. The
reaction mixture was heated to 95-100.degree. C. and maintained for
18-20 h under stirring. The reaction mixture was cooled to
temperature of 25-35.degree. C. and water (4.5 L) was added to the
reaction mixture and maintained for 2 h under stirring. The
precipitated product was filtered, washed with water(3L.times.3),
5% sodium hydroxide solution (2L.times.2), water (5L.times.4),
finally with n-Hexane (4.5L.times.2). The product was dried in
vacuum. Oven at 55-60.degree. C. till MC reaches <1%. The dried
product appears as pale yellow solid, weight 1.689 kg-1.7 kg, yield
70-77%, m.p 95-96.degree. C., purity 97-98% by HPLC, m.p.
92-94.degree. C. The IR (KBr) spectrum shows 3150 (CH str), 2960
(CH str), 1682 (CHO str), 1340 (NO2 str). The 1H-NMR (DMSO-d6)
shows .delta. 9.8 (s, 1H), 8.8(s, 1H), 8.2 (d, 1H), 7.8-8.0 (m,
2H), 7.4 (d, 1H) 6.8 (d, 1H) 5.0 (m, 1H), 1.2-1.8 (m, 8H). The CI
mass shows m/z 406 (M+). The elemental analysis shows calculated %
C 53.22, % H 3.97, % N 3.46; observed % C 53.10, % H 3.86, % N
3.35.
EXAMPLE 4
4-Cyclopentyloxy-8-nitro-1-formyl dibenzofuran
[0103] In a 20 L 4 necked RB Flask, fitted with a mechanical
stirrer, reflux condenser, add
4-cyclopentyloxy-3(4'-nitro-2'-bromophenoxy)benzaldehyde (1.3 kg,
3.20 M), dimethyl formamide (7.8 L), sodium carbonate (0.51 kg, 4.8
M) at temperature in the range of 25-35.degree. C. under stirring.
Heat the reaction mixture to temperature of 130-140.degree. C. and
add palladium acetate. Trimer (75 g, 0.11 M) and maintain at
temperature of 130-140.degree. C. for 1 h under stirring. After 1
hr maintenance, the second lot of palladium acetate trimer (75 g,
0.11 M) was added at temperature of 130-140.degree. C. under
stirring and maintained for 1 hr. After 2 hr maintenance the third
lot of palladium acetate trimer (75 g, 0.11 M) was added at
temperature of 130-140.degree. C. under stirring and maintained for
1 hr. The progress of the reaction mixture was monitored by HPLC.
The reaction mixture was cooled to 70.degree. C. and 4.7 L of THF
was added to the reaction mixture and stirred for 30 min. The
inorganic insolubles were filtered and washed with THF (1
L.times.2). Collect the THF MLS and add to DM water (15 L) under
stirring. The precipitated product was filtered, washed with water
(5 L) and dried in the vacuum oven at temp. below 60.degree. C. The
dried product was subjected to reflux in a mixture of THF (1.3 L)
and Ethyl acetate (2.6 L) for 2h and brought to room temperature.
The precipitated product was filtered, dried in oven at temp.below
60.degree. C. under vaccum till MC reaches <1%. The dried
product appears as pale yello solid, weighs about 650-700 g, yield
60-65%, purity 97-98% by HPLC, m.p.230-232 .degree. C. The IR (KBr)
spectrum shows 3120 (CH str), 2960 (CH str), 1682 (CHO str), 1340
(NO2 str)
[0104] The 1H-NMR (DMSO-d6) shows .delta. 10.2 (s, 1H), 9.8 (s,
1H), 8.4 (d, 1H), 8.2-7.8-(dd, 2H), 7.4 (d, 1H), 5.2 (m, 1H),
1.6-2.2 (m, 8H). The Cl mass shows m/z 325 (M+). The elemental
analysis shows calculated % C 66.46, % H 4.65, % N 4.31; observed %
C 66.35, % H 4.51, % N 4.25.
EXAMPLE 5
4-hydroxy-8-nitro-1-formyldibenzofuran
[0105] In a 20 L 4 necked RB flask fitted with a mechanical
stirrer, reflux condenser, add 4- cyclopentyloxy
-8-nitro-1-formyldibenzofuran ( 1.2 kg, 3.75 M), 30% Hydrobromic
acid in acetic acid (6 L) under stirring. Heat the reaction mixture
to 80-90.degree. C. and maintain for 30 min under stirring.
Additional quantity of 30% Hydrobromic acid in acetic acid (4.2
L.times.3 times) was added lot wise in the interval of every 45
minutes at temp. 80-90.degree. C. The progress of the reaction was
monitored by HPLC. It was observed that that 2-3% of the starting
material was left un reacted, even after prolonging the maintenance
for additional 1 hr. After this, the reaction mixture was cooled to
10-15.degree. C. and water (24 L) was added at 10-15.degree. C.
under stirring. The diluted reaction mixture was brought to
25-35.degree. C. and maintained for 30 min under stirring. The
precipitated product was filtered, washed with water (8 L.times.5)
till pH becomes neutral. The wet cake was charged with toluene (12
L) and subjected to azeotropic distillation of water by refluxing
to temperature of 110.degree. C. After complete removal of water,
the reaction mixture was brought to 25-35.degree. C. filtered and
dried in vaccum oven below 60.degree. C. till MC/LOD reaches
<1%. The dried product appears as pale yellow solid, weighs
about 896-915 g, yield 93-95%, purity 97% by HPLC, m
p>270.degree. C. The product was further purified as follows. In
a 10 L four necked RB flask, fitted with a mechanical stirrer,
reflux condenser add 4-hydroxy-8-nitro-1-formyldibenzofuran
obtained in the above step (1.0 kg, 3.89 M), dimethyl foramide (2
L) at 25-35.degree. C. under stirring. The RM was heated to
80.degree. C. and maintained for 30 min under stirring for complete
dissolution. After dissolution, potassium carbonate (850 g, 6.11 M)
was added at 80.degree. C. and maintained for 2h under stirring.
The reaction mixture was cooled to 10.degree. C. and filtered. The
wet cake was washed with acetone (1 L) and the solid after washing
was dissolved in DM water (9 L) and the solution was cooled to
5-10.degree. C. under stirring. The pH of the aqueous solution was
adjusted from 10 to 4.5 by neutralizing with conc. HCl (1.5 L). The
precipitated product was filtered washed with water (10 L.times.5)
till pH becomes neutral, dried in vacuum. Oven at 60-65.degree. C.
till MC<1%. The dried product appears as cream solid, weighs
about 800-820 g, yield 83%-85%, m.p.>270; purity>99% by HPLC.
The IR (KBr) spectrum shows 3130 (CH str), 1657 (CO str), 1333 (NO2
str) The 1H-NMR (DMSO-d6) shows .delta. 12.0 (broad, 1H), 10.2 (s,
1H), 9.8 (s, 1H), 8.6 (d, 1H), 8.0 (m, 2H), 7.2 (d, 1H). The CI
mass shows m/z 257 (M+). The elemental analysis shows calculated %
C 60.71, % H 2.74, % N 5.45; observed % C 60.59, % H.
EXAMPLE 6
4-difluoro methoxy-8-nitrol-formyl dibenzo(b,d) furan
[0106] Method A
[0107] In a 10 L 4 necked RB flask fitted with a mechanical
stirrer, reflux condenser, add 4-
hydroxyl-8-nitro-1-formyl-dibenzo(b,d)furan (700 g, 2.72 M),
dimethyl formamide (4.2 L) at temp. 25-35.degree. C. under
stirring. The reaction mixture was heated to 80-90.degree. C. under
stirring and potassium carbonate (1.126 kg, 8.1 M) was added at
80-90.degree. C. under stirring. Chlorodifluoromethane gas was
bubbled into the reaction mixture at 80-90.degree. C. for 34 hr
while monitoring the HPLC at every 1 hr interval of time. After
ascertaining the completion of the reaction by HPLC, bring the RM
to 25-35.degree. C. and filter the inorganic salts. The inorganic
salts cake was washed with DMF(600 ml.times.2) and collect, combine
all the washings. The combined DMF layer was distilled below
90.degree. C. under high vacuum. DM water (1.6 L) was added to the
residue and the pH of the aqueous solution was adjusted to pH 4-5
with conc. HCl (40 ml. The precipitated product was filtered,
washed with DM water (400ml.times.2) and suck dried. The wet cake
was subjected to azeotropic removal of water by refluxing in
toluene (7 L) at temperature of 100-110.degree. C. After complete
removal of water, the reaction mixture was brought to 25-35.degree.
C. under stirring and the insoluble solid was filtered. The
insoluble cake was washed with toluene (400 ml.times.2). Collect
all the washings and combine for distillation. The combined toluene
layer was concentrated below, 70.degree. C. under vacuum. The
precipitated product was filtered washed with toluene (1 L) and
dried in vaccum oven at temp. below 60.degree. C. The dried product
appears as cream color solid, weighs about 393-410 g, yield 50-52%,
purity .about.95% by HPLC, m.p. 245-248.degree. C. The IR(KBr)
spectrum shows 3120 (CH str), 2950 (CH str), 1690 (CHO str), 1340
(NO2 str) cm-1. The 1H-NMR (DMSO-d6) shows .delta. 10.2 (s, 1H),
9.8 (s, 1H), 8.6 (d, 1H), 8.2 (d, 1H), 8.2 (d, 1H), 7.4-7.8 (m, 3H)
The CI mass shows m/z 307 (M+). The elemental analysis shows
calculated % C 54.7, % H 2.30, % N 4.56; observed % C 54.5, % H
2.15% N 4.40.
[0108] Method B
[0109] Step I: Synthesis of 1-{(4
Methylphenyl)imino]methyl-}8-nitrodibenzo-[b,d]furan-4-ol: The
reactor (capacity?) was charged with 4-
hydroxyl-8-nitro-1-formyl-dibenzo(b,d)furan (10 Kg, 0.52 M ) and
Methanol (200 L) and strried for 15 min. Then p-toluidine (12.5 Kg.
116.82 M) and PTSA (0.1 Kg, 0.52 M) was added to the reactor at
temp. 25-35.degree. C. under stirring. The reaction mixture was
heated to 65-70.degree. C. Reaction was monitored by TLC and HPLC.
Reaction was complete in 4-5 h. Methanol was distilled out from
reaction mixture below 50.degree. C. under vacuum. Hexane was
charged to the reaction mass and stirred for 30 min at 35.degree.
C. Reaction mass was cooled to25-30.degree. C. and stirred for 1 h.
Reaction mass was filtered and solid was washed with hexane (10 L).
Solid was spin dried for 1 h and then at 50.degree. C. for 5 h.
Yield=12.0-13.0 Kg, Purity=98% by HPLC. The 1H-NMR (DMSO-d6) shows
.delta. 11.3 (s, 1H), 10.8 (s, 1H), 9.0 (s, 1H), 8.5 (d, 1H), 8.0
(d, 1H), 7:8 (d, 1H), 7.2-7.5 (m, 5H), 2.4)(s, 3H).
[0110] Step II: Preparation of 4-difluoro methoxy-8-nitro-1-formyl
dibenzo(b,d) furan: The reactor was charged with DMF (120 L) and
1-{(4-Methylphenyl)imino]methyl-}8-nitrodibenzo[b,d]furan-4-ol
(10.0 Kg) and strried for 15 min. Then Potassium carbonate (7.97
Kg, 57.66 M) was added to the reactor and stirred for 15min at
25-30.degree. C. Chlorodifluoromethane gas was bubbled into the
reaction mixture at 60.degree. C. for 3-4 hr while monitoring the
HPLC at every 1 hr interval of time. After ascertaining the
completion of the reaction by HPLC, bring the RM to 25-35.degree.
C. and filter the inorganic salts through hyflo-bed. The inorganic
salts cake was washed with DMF(600 ml.times.2) and collect, combine
all the washings. The combined DMF layer was distilled below
60.degree. C. under high vacuum (upto 15 L volume) to yield a crude
mass of 1-{(4-Methylphenyl)imino]methyl-}4-difluoro
methoxy-8-nitrodibenzo[b,d]furan.
[0111] Step III: The above crude residue of
1-{(4-Methylphenyl)imino]methyl-}4-difluoro
methoxy-8-nitrodibenzo[b,d]furan was cooled to 25-30.degree. C. and
add conc. HCl (50 ml) stir for 15 mins. Then add Methanol (10 L)
and water (50 L) to the reaction mass. Heat the reaction mass to
60.degree. C. and check the completion of hydrolysis by TLC and
HPLC. Reaction was complete in 2-3 h. After completion of reaction,
the reaction mass was cooled to 40.degree. C. The precipitated
product was filtered, washed with DM water till pH is 7.0. The wet
cake was subjected to spin dry for 1 h and dried at 60.degree. C.
for 8 h under vacuum. Yield 8 Kg, purity .about.98% by HPLC. NMR
(DMSO-d6) shows .delta. 10.2 (s, 1H), 9.8 (s, 1H), 8.6 (d, 1H), 8.2
(d, 1H), 7.4-7.8 (m, 3H).
EXAMPLE 6a
1-{(4-Methylphenyl)imino]methyl-}4-difluoro
methoxy-8-nitrodibenzo[b,d]furan
[0112] The compound was synthesized using the process as described
in Step I and Step-II of Method B followed by purification to
provide 1-{(4-Methylphenyl)imino]methyl-}4-difluoro
methoxy-8-nitrodibenzo[b,d]furan.
[0113] .sup.1H NMR (.delta. ppm): 2.4(3H, s), 7.3-8.1(8H), 8.4(1H,
dd), 9.0(1H, s), 10.3 (1H, d).
EXAMPLE 7
4-difluoromethoxy-8-nitrodibenzo[b,d]furan-1-carboxylic acid
[0114] In a 20 L 4 necked RB flask, fitted with a mechanical
stirrer, reflux condenser, add 4- difluoro methoxy-8-nitro-1-formyl
dibenzo[b,d] furan (1 kg, 3.25 M), acetone (7.2 L) and heat to
temp. 70-75.degree. C. under stirring. Add a slurry of potassium
permanganate (0.48 kg) in water (3 L) to the reaction mixture at
70-75.degree. C. under stirring and maintain for 1 hr. After 1 hr
maintenance, the second lot of potassium permanganate (0.120 kg) in
water (400 ml) was added at 70-75.degree. C. under stirring and
maintain for 1 hr. After 2 hr maintenance, the third lot of
potassium permanganate (0.120 kg) in water (400 ml) was added at
70-75.degree. C. under stirring and maintain for 1 hr. The progress
of the reaction was monitored by HPLC. After ascertaining the
completion of the reaction, acetone (7.2 L) was added at temp. of
70-75.degree. C. under stirring and maintained for 30 min. The
reaction mixture was brought to 25-35.degree. C., filtered. The
inorganic salt cake was washed with acetone (2 L) collect and
combine all the acetone washings. The acetone MLS were distilled at
temp. below 75.degree. C. under vacuum, cool the residue to
25-35.degree. C. and maintain under stirring for 30 min. The
precipitated product was filtered, dried and the wet cake was
subjected to reflux with a solvent mixture of (5 L acetone and 1.25
L water) and maintained for 3 h. Cool the reaction mass to
10-15.degree. C. maintain for 30 min under stirring, filter the
precipitated product, wash the product with water (1 L). The wet
cake was subjected to azeotropic removal of water by refluxing with
toluene (10 L) After complete removal of water, the reaction
mixture was brought to 25-35.degree. C., maintained for 30 min,
filtered and dried in vacuum oven below 70.degree. C. till
LOD<1%. The dried product appears as cream color, solid, weighs
about 840-850 g, yield 80-81%, purity .about.95% by HPLC,
m.p.>270.degree. C. The IR (KBr) spectrum shows 3100 (C--H str),
1695 (--COOH str), 1100 (C--F str) cm -1. The 1H-NMR spectrum shows
.delta. 9.8 (s, 1H), 8.6 (d, 1H), 8.2(m, 2H), 7.3 (m, 3H), 7.6 (m,
1H). The CI mass shows m/z 322 (M+) The elemental analysis shows
calculated % C 52.03, % H 2.18, % N 4.33; Observed % C 52.04; % H
2.03; % N 4.45%.
EXAMPLE 8
P-nitrophehyl 4-difluormethoxy-8-nitro dibenzofuran carboxylic acid
ester
[0115] In a 20 L 4-necked RB flask, filled with a mechanical
stirrer, reflux condenser, add
4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid (1.0 kg,
3.09 M), thionyl chloride (3.0 L, .about.4.86 kg, 40 M) at temp.
25-35.degree. C. under stirring. The reaction mixture was heated to
80-90.degree. C. and maintained for 3 h. The progress of the
reaction was monitored by TLC. After ascertaining completion of the
reaction, distil off thionyl chloride under vacuum below 70.degree.
C. The traces of thionyl chloride were removed completely by adding
toluene (5 L.times.3) and distill off. To the residue THF (13 L), a
suspension of p-nitrophenol (403 g in THF 2 L), triethyl amine (620
g, 6.13 M) were added under stirring at 25-35.degree. C. The
reaction mixture was maintained at 25-35.degree. C. for 5-6 hr
while monitoring the progress of the reaction by HPLC. After
ascertaining the completion of the reaction, ice cold water (15 L)
was added to the reaction mixture maintained for 30 min under
stirring at 25-35.degree. C. The precipitated product was filtered,
washed with water (10 L.times.5), methanol (1 L), suck dried. The
wet cake was subjected to leaching at 90-95.degree. C. with
ethylene glycol monoethyl ether (5.0 L) for 34 hr. The reaction
mixture was brought to 25-35.degree. C., cooled to 5-10.degree. C.
under stirring, filter and dried at below 70.degree. C. under
vaccum till LOD reaches <1%. The dried product appears as cream
color solid, weighs about 800-850 g, yield 58-62%,
m.p.>270.degree. C., purity 98% by HPLC. The IR (KBr) spectrum
shows 3140 (C--H str), 1740 (CO str), 1346 (NO2 str), 1103 (C--F
str) cm-1 The 1H-NMR spectrum shows ( DMSO-d6) shows 8 9.6(s, 1H),
8.4-8.6 (m, 4H), 8.1-8.2 (m, 2H), 7.6-7.8 (m, 4H) The CI Mass shows
m/z 444 (M+). The elemental analysis shows calculated % C 54.07, %
H 2.27, % N 6.31; observed % C 53.93, % H 2.20; % N 5.94.
EXAMPLE 9
N'-(3,S dichloropyrid-4-yl)-4-difluoromethoxy-8-Nitro dibenzo [b,d]
furan-1-carboxamide
[0116] In a 20 L 4 necked RB flask, fitted with a mechanical
stirrer, reflux condenser, add p-ntrophenyl
4-difluoromethoxy-8-nitro dibenzofuran carboxylic acid ester (700
g, 1 .56 M) DMF(4 L), a suspension of 4-amino-3,5-dichloropyridine
(307 g, 1.88 M) in DMF (1L) at temp. 25-35.degree. C. under
stirring. The reaction mixture was maintained at 25-35.degree. C.
for 20-25 min. Cool the reaction mixture to 0-5.degree. C. under
stirring for 30 min, 60% sodium hydride (125 g, 3.26 M) was added
at 0-5.degree. C. After addition the reaction mixture was brought
to 25-35.degree. C. and maintained 1 h. The progress of the
reaction was monitored by HPLC. After ascertaining completion of
the reaction by HPLC, the reaction mixture was cooled to
10-15.degree. C. and 40% brine solution (500 ml), ice cold water (5
L) was added to the reaction mixture slowly and maintained for 10
min. 10% HCl (1.5 L) was added to the reaction mass till pH becomes
4.5-5.5 and maintained at pH 4.5-5.5 for 30 min. The precipitated
product was filtered, washed with water (5 L.times.4). The wet cake
was subjected to leaching at temp. 85-90.degree. C. with ethylene
glycol mono ethyl ether (3.5 L) for 8-10 hr under stirring. The
reaction mixture was brought to 25-35.degree. C., filter, wash the
cake with diethylene glycol monoethyl ether (700 ml) and dried in
vacuum. Oven below 70.degree. C. till MC<1%. The dried product
appears as cream color solid, weighs about 650-670g, yield 86-90%,
purity 98%, m.p.>270 .degree. C. The IR (KBr) spectrum shows
3146 cm-1 (CH, str) 1674 cm-1 (CONH str) 1340 (NO2 str) The 1H NMR
(DMSO d6) spectrum shows .delta. 8.0 (s, 1H), 7.6 (s, 1H), 8-9 (s,
1H), 8.2 (s, 2H), 8.0 (s, 1H), 7.6 (s, 1H), 7.3 (s, 1H). The CI
mass spectrum shows m/z 468(M+).The elemental analysis shows
calculated % C, 48.74%, % H 1.94; % N 8.97; observed % C, 48.64%, %
H 1.86; % N 8.76.
EXAMPLE 10
N1-(3,5-dichloro pyrid-4-yl)-4-difluoromethoxy-8-amino dibenzo[b,d]
furan-1-carboxamide
[0117] In a 10 Lt autoclave, add
N1-(3,5-dochloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]
furan-1-carboxarnide(600 g, 1.36 M), DMF (4.8 L) and reactivated
Rancy Nickel (250 g) at 25-35.degree. C. under stirring. The
reaction mixture was hydrogenated with Hydrogen gas at a pressure
of 5-6 kg/cm-2 for 5-6h. The progress of the reaction was monitored
by HPLC. After completion of the reaction, the reaction mixture was
filtered and the Nickel cake was washed with DMF (500 ml). The DMF
washings were collected, combined and distilled below 70.degree. C.
under vaccum. The residue was diluted with water (10 L), filter the
precipitated product, washed the product cake with DM water(5
L.times.2), dry the product. The dried product appears as cream
color solid, weighs about 540-550 g, yield 91-92%,
m.p.>270.degree. C., purity 98% by HPLC. The IR (KBr) spectrum
shows 3450 (NH str), 3180 (CH str), 1670 (CONH str) cm-1. The 1H
NMR (DMSO-d6) shows .delta. 11 (s, 1H), 9.0 (s, 1H), 8.2 (s, 2H),
7.6-7.7 (m, 1H), 7.3-7.4 (m, 3H).The CI mass show m/z 438 (M+). The
elemental analysis shows calculated % C 52.08%, % H 2.53; % N 9.59.
Observed % C 52.0%, % H 2.30; % N 9.86.
EXAMPLE 11
N1-(3,5dichloropyrid4-yl)-4-difluoromethoxy-8-(methanesulfonamide)-dibenzo-
[b,d] furan-1-carboxamide
[0118] In a 20 Lt 4 necked RB flask fitted with a mechanical
stirrer, reflux condenser, add N1-(3,5-dichloro pyrid-4-yl-
difluoromethoxy-8-amino dinebzo[b,d] furan-1-carboxamide (500 g,
1.14 M), THF (5 L), pyridine (1L) at temperature 25-35.degree. C.
under stirring in about 30 min. The reaction mixture was maintained
at 25-35.degree. C. for 6 h. Monitor the progress of the reaction
by HPLC. After ascertaining completion of the reaction, ice cold
water (10 L) was added to the reaction mixture and maintained under
stirring for 30 min. The precipitated product was filtered, washed
with 5% HCl (5 L), water (5 L.times.2) and suck dried. The wet cake
was subjected to leaching at 70-80.degree. C. by refluxing with
methanol (5 L) for 12 hrs. The reaction mixture was brought to
25-35.degree. C. maintained for 30 min and filtered. The wet cake
was washed with MeOH (500 ml) and dried in vacuum. Oven below temp.
70 .degree. C. The dried product appears as cream color solid,
weighs about 530-540 g, yield 90-92%, purity 98% by HPLC,
m.p.>270 .degree. C. The IR (KBr) 3320 (N--H str) 1698 (CONH
str) 1277 (SO2 str), 1100 (CH str ) cm-1. The 1H-NMR(DMSO-d6), 8
9-7 (s, 1H), 8-9-9.0 (s, 1H), 8.2 (s, 2H), 8.0 (d, 1H), 7.6-7.7
(2h, 1H), 7.3-7.4 (m, 3H) 2.8 (s, 3H).The CIMS shows m/z 516 (M+);
The elemental analysis shows calculated % C 46.53; % H 2.54, % N
8.14: observed % C 46.43, % H 2.45; % N 7.84.
EXAMPLE 12
N1-(3,5-dichloropyridine-4-yl)-4-(difluoromethoxy)-8-methane
sulfonamide] dibenzo[b,d] furan-1-carboxamide sodium salt
[0119] In a 10 Lt 4 necked RB flask fitted with a mechanical
stirrer, reflux condenser, add
N1-(3,5-dichloropyridine-4-yl)-(difluoromethoxy)-8-methanesulfonamido]
dibenzo[b,d]furan-1-carboxamide (225 g, 0.43 M), THF (2.2 L) under
nitrogen atmosphere and stirring. The reaction mixture was cooled
to 0-5.degree. C. and 60% sodium hydride (19.2 g, 0.48 M) was added
portion wise in about two hours. After the addition was completed
the reaction mixture was maintained for 10 min at 5-10.degree. C.
and brought to 25-30.degree. C. under stirring. THF (500 ml) was
added to the reaction mixture and heated to 40-45.degree. C.
maintained for 30 min. Filter the reaction mixture and collect the
THF MLS. To the THF MLS, charcoal (45 g) made as slurry in THF (250
ml) was added under stirring and maintained at 40-45.degree. C.
under stirring for 30 minutes. To the THF MLS, charcoal (45 g) made
as a slurry in THF (250 ml) was added under stirring and maintained
at 40-45.degree. C. under stirring for 30 minutes To the THF MLS,
charcoal (45 g) made as a slurry in THF (250 ml) was added under
stirring and maintained at 40-45.degree. C. under stirring for 30
minutes Filter the reaction mixture, separate the THF MLS, collect
and combined. The combined THF MLS were distilled below 70.degree.
C. Isopropanol (1.3 L) was added to the residue under stirring,
maintain under reflux for 8 h. The reaction mixture was cooled to
25-35.degree. C., filter, wash with isopropanol (200 ml) and dried
in the vacuum. Oven below 70.degree. C. The dried product as pale
yellow solid, weighs about 210-220 g, yield 90-95%, purity 98% by
HPLC. The IR (KBr) spectrum shows 3094 (NH str), 3100 (C--H str),
1674 (CONH str), 1277 (SO2). Cm-1. The 1H-NMR (DMSO-d6) shows
.delta. 9.7 (s, 1H), 8.9-9.0 ( s, 1H), 8.2 (s, 2H), 8.0 (1H, d),
7.6-7.7 (m, 1H) 7.3-7.4 (m, 3H) 2.8 (s, 3H,). The 13C NMR (DMSO-d6)
shows .delta.164.6, 155.9, 153, 146.8, 146.6, 135.7, 135.6, 134.6,
127.2, 125.2, 124.9, 122.3, 121.7, 120.3, 113.4, 116.7, 116.8,
111.5, 39.0. The CI mass spectrum shows m/z, 514 (M+). The
elemental analysis shows calculated % C, 44.63, % H 2.25, % N 7.81;
observed % C, 44.77, % H 2.28, % N 7.70.
[0120] All references, patents, and patent applications referred to
herein are incorporated by reference.
* * * * *