U.S. patent application number 11/893481 was filed with the patent office on 2008-10-09 for process for phenylacetic acid derivatives.
Invention is credited to Murat Acemoglu, Thomas Allmendinger, John Vincent Calienni, Jacques Cercus, Olivier Loiseleur, Gottfried Sedelmeier, David Xu.
Application Number | 20080249318 11/893481 |
Document ID | / |
Family ID | 10861676 |
Filed Date | 2008-10-09 |
United States Patent
Application |
20080249318 |
Kind Code |
A1 |
Acemoglu; Murat ; et
al. |
October 9, 2008 |
Process for phenylacetic acid derivatives
Abstract
A process for the production of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable prodrug ester thereof, ##STR00001## comprising cleaving
a lactam of formula II ##STR00002## wherein the symbols are as
defined, with a base; and precursors therefor and processes for the
preparation of the precursors. The compounds of Formula I are
pharmaceutically active compounds which are selective inhibitors of
Cyclooxygenase II.
Inventors: |
Acemoglu; Murat; (Basel,
CH) ; Allmendinger; Thomas; (Lorrach, DE) ;
Calienni; John Vincent; (Cranford, NJ) ; Cercus;
Jacques; (Rixheim, FR) ; Loiseleur; Olivier;
(Saint-Louis, FR) ; Sedelmeier; Gottfried;
(Schallstadt, DE) ; Xu; David; (Whippany,
NJ) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
10861676 |
Appl. No.: |
11/893481 |
Filed: |
August 16, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10089038 |
Mar 25, 2002 |
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PCT/EP00/09346 |
Sep 25, 2000 |
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11893481 |
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Current U.S.
Class: |
548/486 ;
562/456; 564/202; 564/305 |
Current CPC
Class: |
A61P 29/00 20180101;
C07C 233/15 20130101; C07C 229/42 20130101; C07D 209/34 20130101;
C07C 2601/16 20170501; C07C 211/52 20130101; C07C 235/24 20130101;
C07C 235/16 20130101; C07C 211/56 20130101; C07C 227/22
20130101 |
Class at
Publication: |
548/486 ;
562/456; 564/305; 564/202 |
International
Class: |
C07D 209/34 20060101
C07D209/34; C07C 227/22 20060101 C07C227/22; C07C 211/55 20060101
C07C211/55; C07C 233/01 20060101 C07C233/01 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 27, 1999 |
GB |
9922830.6 |
Claims
1. process for the production of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable prodrug ester thereof, ##STR00073## wherein R is methyl
or ethyl; R.sub.1 is chloro or fluoro; R.sub.2 is hydrogen or
fluoro; R.sub.3 is hydrogen, fluoro, chloro, methyl, ethyl,
methoxy, ethoxy or hydroxy; R.sub.4 is hydrogen or fluoro; and
R.sub.5 is chloro, fluoro, trifluoromethyl or methyl, provided that
R.sub.1, R.sub.2, R.sub.4 and R.sub.5 are not all fluoro when R is
ethyl and R.sub.3 is H; comprising cleaving a lactam of formula II
##STR00074## wherein the symbols are as defiled above with a base;
and in the above process, if desired, temporarily protecting any
interfering reactive groups and then isolating the r in compound of
the invent; and, if desired, converting the free carboxylic acid of
the compound of formula I into a pharmaceutically acceptable ester
derivative thereof; and/or if desired, converting the free acid of
formula I into a salt or a resulting salt into the free acid or
into another salt.
2. A process selected from a) a process for the production of a
lactam of formula II ##STR00075## which comprises oxidizing of a
lactam of formula II ##STR00076## b) a process for the production
of the lactam of formula II as defined in a) above, which comprises
cyclisation of a compound of formula VII ##STR00077## c) a process
for the preparation of a compound of formula III as defined above
comprising coupling as aniline derivative of formula IV
##STR00078## with a cyclohexanone derivative of formula Va or an
amino substituted cyclohexene derivative of formula Vb ##STR00079##
wherein R is ethyl or methyl and R' is lower alkyl or similar or
NR'.sub.2 forms a ring as in piperidine or morpholine. d) a process
for the production of a compound of formula VII which comprises
N-acylation of a diphenylamine of formula VIII ##STR00080## with a
haloacetyl chloride e) a process for the preparation of a compound
of formula VIII which comprises rearrangement and hydrolysis of a
compound of formula IX. ##STR00081## f) a process for the
production of a compound of formula VIII which comprises coupling
of a halobenzene derivative of formula XI with p-toluidine or
4-ethyl-aniline ##STR00082## where X is a halogen g) a process for
the production of a compound of formula VIII as defined in d) above
which comprises coupling an aniline derivative of formula IV as
defined in c) above with 4-bromotoluene or 1-ethyl-bromobenzene h)
a process for the production of a compound of formula VIII as
defined in d) above which comprises cleavage of a compound of
formula X ##STR00083## i) a process for the formation of a compound
of formula X as defined in h) above which comprises rearrangement
of a compound of formula IX as defined in e) above j) a process for
the product of a compound of formula IX as defined in e) above with
comprises alkylation of a compound of formula XII ##STR00084## with
2-chloro-N-(4-methylphenyl)acetamide or 2
chloro-N-(4-ethylphenyl)acetamide k) a process for the production
of a compound of formula VIII as defined in d) above which
comprises alkylation of a compound of formula XII as defined in j)
above with 2-chloro-N-(4-methylphenyl)acetamide or 2 chloro-N-(4
ethylphenyl)acetamide followed by rearrangement and cleavage l) a
process for the production of a compound of formula VIII as defined
in d) above comprising oxidation of the corresponding compound of
formula XIII (or a tautomer thereof) ##STR00085## m) a process for
the production of a compound of formula XIII as defined in l) above
which comprises coupling 1-methoxy-4-methylcyclohexa-1,4-diene or
1-methoxy-4-ethylcyclohexa-1,4-diene with an aniline derivative of
formula IV as defined in c) above, and n) a process for the
production of a compound of formula VIII as defined in d) above
con-sing coupling 1-methoxy-4-methylcyclohexa-1,4-diene or
1-methoxy-4-ethylcyclohexa-1,4-diene with an aniline derivative or
formula IV as defined in c) above, followed by oxidation, wherein
the symbols are as defined in claim 1.
3. A process for the preparation of a compound of formula I as
defined in claim 1. ##STR00086## which comprises one or more of
processes a) to n) as defined in claim 2 and optionally a process
according to claim 1.
4. A process according to claim 3 for the preparation of a compound
selected from:
5-methyl-2-(2',4'-dichloro-6'-methylanilino)phenylacetic acid;
5-methyl-2-(2', 3', 5',6'-tetrafluoroanilino)phenylacetic acid;
5-methyl-2-(2', 3', 4',6'-tetrafluoroanilino)phenylacetic acid;
5-methyl-2-(2',6'-dichloroanilino)phenylacetic acid;
5-methyl-2-(2',6'-dichloroanilino)phenylacetic acid, potassium
salt; 5-methyl-2-(2',6'-dichloroanilino)phenylacetic acid, sodium
salt; 5-methyl-2-(2'-chloro-6'fluoroanilino)phenylacetic acid;
5-methyl-2-(2',6'-dichloro-4'-methylanilino)phenylacetic acid;
5-methyl-2-(2'-chloro-6'-methylanilino)phenylacetic acid;
5-methyl-2-(2',4'-difluoro-6'-chloroanilino)phenylacetic acid;
5-methyl-2-(2'-fluoro-4',6'-dichloroanilino)phenylacetic acid;
5-methyl-2-(2'-chloro-4'-fluoro-6'-methylanilino)phenylacetic acid;
5-methyl-2-(2'-fluoro-6'-chloroanilino)phenylacetic acid;
5-ethyl-2-(2'-chloro-6'-methylamino)phenylacetic acid;
5-ethyl-2-(2',3',6'-trifluroanilino)phenylacetic acid;
5-ethyl-2-(2',3',5',6'-tetrafluoro-4'-ethoxyanilino)phenylacetic
acid;
5-ethyl-2-(2',3',5',6'-tetrafluoro-4'-ethoxyanilino)phenylacetic
acid; 5-ethyl-2-(2'-chloro-4',6-difluoroanilino)phenylacetic acid;
5-ethyl-2-(2',4'-dichloro-6'-fluoroanilino)phenylacetic acid;
5-ethyl-2-(2',4'-dichloro-6'-methylamino)phenylacetic acid;
5-ethyl-2-(2'-fluoro-4'-chloro-6'-methylanilino) phenylacetic acid;
5-ethyl-2-(2',4'-difluoro-6'-methylanilino)phenylacetic acid
5-ethyl-2-(2'-chloro-4'-fluoro-6'-methylanilino)phenylacetic acid;
5-methyl-2-(2'-chloro-4'-hydroxy-6'-fluoroanilino)phenylacetic
acid; 5-methyl-2-(2'-fluoro-6'-trifluoromethylanilino)phenylacetic
acid, and
5-methyl-2-2',4'-dichloro-6'-trifluoromethylanilino)phenylacetic
acid, and pharmaceutically acceptable salts thereof; and
pharmaceutically acceptable prodrug esters thereof.
5. A process according to claim 3 for the preparation of a compound
selected from: 5-methyl-2-(2', 3',
4',6'-tetrafluoroanilino)phenylacetic acid;
5-methyl-2-(2',6'-dichloroanilino)phenylacetic acid;
5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid;
5-methyl-2-(2',6'-dichloro-4'-methylanilino)phenylacetic acid;
5-methyl-2-(2'-chloro-6'-methylanilino)phenylacetic acid;
5-methyl-2-(2'-chloro-4'-fluoro-6'-methylanilino)phenylacetic acid;
5-ethyl-2-(2'-fluoro-6'-chloroanilino)phenylacetic acid;
5-ethyl-2-(2'-chloro-6'-methylanilino)phenylacetic acid;
5-ethyl-2-(2',3',6'-trifluroanilino)phenylacetic acid, and
5-ethyl-2-(2',4'-dichloro-6'-methylanilino)phenylacetic acid, and
pharmaceutically acceptable salts thereof; and pharmaceutically
acceptable prodrug esters thereof.
6. A compound of formula I, as defined in claim 1 ##STR00087## or a
pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable prodrug ester thereof, when prepared by a process as
defined in claim 3.
7. A compound selected from a) a compound of formula II
##STR00088## b) a compound of formula III ##STR00089## c) a
compound of formula VII ##STR00090## d) a compound of formula VIII
##STR00091## e) a compound of formula IX ##STR00092## f) a compound
of formula X ##STR00093## or g) a compound of formula XIII
##STR00094## wherein the symbols are as defined in claim 1.
Description
[0001] The present invention relates to processes for the
production of 2-phenylamino-5-alkylphenyl acetic acids (the
compounds of formula I given below), intermediates therefor and
pharmaceutically acceptable salts thereof and pharmaceutically
acceptable prodrug esters thereof;
##STR00003##
wherein [0002] R is methyl or ethyl; [0003] R.sub.1 is chloro or
fluoro; [0004] R.sub.2 is hydrogen or fluoro; [0005] R.sub.3 is
hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or
hydroxy; [0006] R.sub.4 is hydrogen or fluoro; and [0007] R.sub.5
is chloro, fluoro, trifluoromethyl or methyl, provided that
R.sub.1, R.sub.2, R.sub.4 and R.sub.5 are not all fluoro when R is
ethyl and R.sub.3 is H.
[0008] Accordingly in a first aspect the invention provides a
process for the production of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable and physiology cleavable prodrug ester thereof,
comprising cleaving a lactam of formula II
##STR00004##
wherein the symbols are as defined above with a base.
[0009] The above processes may include, if desired, temporarily
protecting any interfering reactive groups and then isolating the
resulting compound of the invention; and, if desired, converting
the free carboxylic acid of the compound of formula I into a
pharmaceutically acceptable ester derivative thereof; and/or if
desired, converting the free acid of formula I into a salt or a
resulting salt into the free acid or into another salt.
[0010] The above processes may be carried out under conditions
known in the art for the hydrolytic cleavage of lactams, preferably
with a strong base, such as aqueous sodium hydroxide (e.g. a 30%
aqueous solution of NaOH), optionally in the presence of a water
miscible organic solvent such as ethanol or methanol, preferably at
elevated temperature, e.g. at a temperature in the range from about
50.degree. to 100.degree. C., (for instance as generally described
in U.S. Pat. No. 3,558,690). The resultant reaction mixture is
conveniently neutralised with an acid, e.g. a mineral acid such as
hydrochloric acid to give the free acid product of formula I, which
may be recovered by crystallisation, e.g. on cooling of the
reaction mixture to ambient temperature, and filtration.
[0011] Pharmaceutically acceptable prodrug esters are ester
derivatives which are convertible by solvolysis or under
physiological conditions to the free carboxylic acids of formula I.
Such esters are e.g. lower alkyl esters (such as the methyl or
ethyl ester), carboxy-lower alkyl esters such as the carboxymethyl
ester, nitrooxy-lower alkyl esters (such as the 4-nitrooxybutyl
ester), and the like.
[0012] Pharmaceutically acceptable salts represent metal salts,
such as alkaline metal salts, e.g. sodium, potassium magnesium or
calcium salts, as well as ammonium salts, which are formed e.g.
with ammonia and mono- or di-alkylamines, such as diethylammonium
salts, and with amino acids such as arginine and histidine
salts.
[0013] Preferred compounds of formula I which may be prepared
according to the present invention include: [0014]
5-methyl-2-(2',4'-dichloro-6'-methylanilino)phenylacetic acid;
[0015] 5-methyl-2-(2', 3', 5',6'-tetrafluoroanilino)phenylacetic
acid; [0016] 5-methyl-2-(2', 3',
4',6'-tetrafluoroanilino)phenylacetic acid; [0017]
5-methyl-2-(2',6'-dichloroanilino)phenylacetic acid; [0018]
5-methyl-2-(2',6'-dichloroanilino)phenylacetic acid, potassium
salt; [0019] 5-methyl-2-(2',6'-dichloroanilino)phenylacetic acid,
sodium salt; [0020]
5-methyl-2-(2'-chloro-6'fluoroanilino)phenylacetic acid; [0021]
5-methyl-2-(2',6'-dichloro-4'-methylanilino)phenylacetic acid;
[0022] 5-methyl-2-(2'-chloro-6'-methylanilino)phenylacetic acid;
[0023] 5-methyl-2-(2',4'-difluoro-6'-chloroanilino)phenylacetic
acid; [0024]
5-methyl-2-(2'-fluoro-4',6'-dichloroanilino)phenylacetic acid;
[0025]
5-methyl-2-(2'-chloro-4'-fluoro-6'-methylanilino)phenylacetic acid;
[0026] 5-methyl-2-(2'-fluoro-6'-chloroanilino)phenylacetic acid;
[0027] 5-ethyl-2-(2'-chloro-6'-methylamino)phenylacetic acid;
[0028] 5-ethyl-2-(2',3',6'-trifluroanilino)phenylacetic acid;
[0029]
5-ethyl-2-(2',3',5',6'-tetrafluoro-4'-ethoxyanilino)phenylacetic
acid; [0030] 5-ethyl-2-(2'-chloro-4',6-difluoroanilino)phenylacetic
acid; [0031]
5-ethyl-2-(2',4'-dichloro-6'-fluoroanilino)phenylacetic acid;
[0032] 5-ethyl-2-(2',4'-dichloro-6'-methylamino)phenylacetic acid;
[0033] 5-ethyl-2-(2'-fluoro-4'-chloro-6'-methylanilino)
phenylacetic acid; [0034]
5-ethyl-2-(2',4'-difluoro-6'-methylanilino)phenylacetic acid [0035]
5-ethyl-2-(2'-chloro-4'-fluoro-6'-methylanilino)phenylacetic acid;
[0036]
5-methyl-2-(2'-chloro-4'-hydroxy-6'-fluoroanilino)phenylacetic
acid; [0037]
5-methyl-2-(2'-fluoro-6'-trifluoromethylanilino)phenylacetic acid,
and [0038]
5-methyl-2-2',4'-dichloro-6'-trifluoromethylanilino)phenylacetic
acid, and pharmaceutically acceptable salts thereof, and
pharmaceutically acceptable prodrug esters thereof.
[0039] Particularly preferred compounds of formula I which may be
prepared according to the present invention include: [0040]
5-methyl-2-(2', 3', 4',6'-tetrafluoroanilino)phenylacetic acid;
[0041] 5-methyl-2-(2',6'-dichloroanilino)phenylacetic acid; [0042]
5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid; [0043]
5-methyl-2-(2',6'-dichloro-4'-methylanilino)phenylacetic acid;
[0044] 5-methyl-2-(2'-chloro-6'-methylanilino)phenylacetic acid;
[0045]
5-methyl-2-(2'-chloro-4'-fluoro-6'-methylanilino)phenylacetic acid;
[0046] 5-ethyl-2-(2'-fluoro-6'-chloroanilino)phenylacetic acid;
[0047] 5-ethyl-2-(2'-chloro-6'-methylanilino)phenylacetic acid;
[0048] 5-ethyl-2-(2',3',6'-trifluroanilino)phenylacetic acid, and
[0049] 5-ethyl-2-(2',4'-dichloro-6'-methylanilino)phenylacetic
acid, [0050] and pharmaceutically acceptable salts thereof; and
pharmaceutically acceptable prodrug esters thereof.
[0051] Thus, preferably also the processes of the invention may be
used to prepare compounds of formula I in which R is methyl or
ethyl; R.sub.1, is chloro or fluoro; R.sub.2 is hydrogen; R.sub.3
is hydrogen, fluoro, chloro, methyl or hydroxy, R.sub.4 is
hydrogen; R.sub.5 is chloro, fluoro or methyl; or a
pharmaceutically acceptable salt or a pharmaceutically acceptable
prodrug ester thereof.
[0052] The lactam of formula I may be prepared by oxidation of a
lactam of formula III
##STR00005##
[0053] wherein the symbols are as defined above.
[0054] Standard mild oxidation conditions may be used, such as
heating with catalytical amounts of palladium on charcoal in a
proper solvent, e.g. xylene.
[0055] The lactam of formula III may be prepared by coupling an
aniline derivative of formula IV
##STR00006##
wherein the symbols are as defined above, with a cyclohexanone
derivative of formula Va or an amino substituted cyclohexene
derivative of formula Vb
##STR00007##
[0056] wherein R is ethyl or methyl and R' is lower alkyl or
similar.
[0057] Coupling of IV with Va and Vb typically involves elimination
of water or the secondary amine, HNR'.sub.2, e.g. under acidic
conditions.
[0058] Vb may be prepared by reaction of the amino substitutes
cyclohexene derivative of formula Vb'
##STR00008##
[0059] wherein R and R' are as defined above, with methyl or ethyl
glyoxylate. Vb may be converted to Va by hydrolysis, for instance
as hereinafter described in the Examples.
[0060] Alternatively the lactam of formula I is obtained by
cyclisation of a compound of formula VII
##STR00009##
[0061] wherein the symbols are as defined above.
[0062] The cyclisation process is conveniently carried out under
Friedel-Crafts alkylation conditions, e.g. in the presence of a
Friedel-Crafts catalyst such as aluminium chloride or ethyl
aluminium dichloride, preferably at elevated temperature, e.g. a
temperature in the range from about 100.degree. to about
180.degree. C. The cyclisation reaction may be carried out in the
presence of an inert solvent such as dichlorobenzene, or preferably
a melt of the compound of formula VII is heated with the
Friedel-Crafts catalyst.
[0063] The compound of formula VII is prepared by N-acylation of a
diphenylamine of formula VII
##STR00010##
[0064] wherein the symbols are as defined above with a haloacetyl
chloride.
[0065] For instance, the compound of formula VIII is heated e.g. to
about 80.degree. C., with chloroacetylchloride. The product may be
recovered by diluting the reaction mixture with solvent, e.g.
2-propanol, and crystallisation.
[0066] The compound of formula VIII may be obtained by
rearrangement and hydrolysis of a compound of formula IX.
##STR00011##
[0067] wherein the symbols are as defined above.
[0068] Conveniently the compound of formula IX is treated with an
organic base, e.g. an alkali metal alkoxide such as sodium
methoxide, preferably with beating, e.g. to a temperature of at
least about 75.degree. C. During this procedure an intermediate
product of formula X,
##STR00012##
wherein the symbols are as defined above, forms as a result of the
initial rearrangement ion, but undergoes direct cleavage under the
prevailing reaction conditions to give the diphenylamine compound
of formula VIII.
[0069] Alternatively the diphenylamine compound of formula VIII may
be obtained by coupling of the corresponding halobenzene derivative
of formula XI
##STR00013##
where X is a halogen, e.g. I or Br, and the other symbols are as
defined above with p-toluidine or 4-ethyl aniline.
[0070] Such a coupling reaction may be carded out by use of
Buchwald chemistry. For example, the compound of formula XI and the
p-toluidine or 4-ethyl aniline are mixed with an organic base, e.g.
sodium tertiary butylate, and an appropriate ligand, e.g. BINAP, in
an organic solvent such as toluene; a palladium compound or
catalyst precursor such as Pd(dba).sub.2 is added and the reaction
mixture is heated. After cooling and treatment with acid, e.g. HCl,
the diphenylamine product of formula VIII may be recovered from the
organic phase of the reaction mixture.
[0071] In a further alternative, the diphenylamine compound of
formula VIII may be obtained by coupling of the corresponding
aniline derivative of formula IV
##STR00014##
as defined above with 4-bromotoluene or 1-ethyl-4-bromobenzene.
Such a coupling reaction may be carried out similarly by use of
Buchwald chemistry. For example, the compound of formula IV and the
4-bromotoluene or 1-ethyl-4-bromobenzene are mixed with an organic
base, e.g. sodium tertiary butylate in an organic solvent such as
toluene; a palladium compound or catalyst precursor e.g.
Pd(dba).sub.2, and a ligand, e.g. P(tBu).sub.3, or BINAP, are added
to this reaction mixture which is then stirred at elevated
temperature, e.g. 110.degree. C., until completion of the reaction,
e.g. overnight. Similarly the diphenylamine product of formula VIII
may be recovered from the organic phase of the reaction mixture,
for instance after cooling and treatment with acid, e.g. HCl.
[0072] The compound of formula IX may be prepared by alkylation of
the corresponding phenol derivative of formula XII
##STR00015##
wherein the symbols are as defined above, with
2-chloro-N-(methylphenyl)acetamide or 2
chloro-N-(4-ethylphenyl)acetamide. For instance, the compound of
formula XII and 2-chloro-N-(4-methylphenyl)acetamide or
2-chloro-N-(4-ethylphenyl)acetamide are mixed in an organic solvent
such as 2-propanol in the presence of a base, e.g. K.sub.2CO.sub.3.
and the reaction mixture boiled until completion of the reaction,
e.g. for about 4 hours. 2-chloro-N-(4-methylphenyl)acetamide and
2-chloro-N-(4-ethylphenyl)acetamide may be prepared, e.g. in situ,
by reaction of 4-methyl- or 4-ethylaniline with chloroacetyl
chloride. The compound of formula IX may be recovered from the
reaction mixture if desired. Preferably, however, the compound of
formula IX is not isolated but is converted to the compound of
formula VIII, by rearrangement and hydrolysis as described above
carried out on the product reaction mixture resulting from the
alkylation of the compound of formula XII.
[0073] Alternatively the diphenylamine of formula VIII may be
prepared by oxidation of the corresponding compound of formula XIII
(or tautomer thereof)
##STR00016##
wherein the symbols are as defined above.
[0074] The dehydrogenation reaction may be carried out by classical
methods, for instance by treatment with iodine, e.g. 12 in
THF/AcOH.
[0075] The compound of formula XII may be prepared by coupling of
1-methoxy-4-methylcyclohexa-1,4-diene or
1-methoxy-4-ethylcyclohexa-1,4-diene with an aniline derivative of
formula IV as defined above.
[0076] This coupling reaction may be carried out in the presence of
a catalyst such as TiCl.sub.4 in organic solvents e.g. THF and
chlorobenzene, preferably with cooling, e.g. at about -40.degree.
C.
[0077] 1-methoxy-4-methylcyclohexa-1,4-diene or
1-methoxy-4-1,4-diene may be prepared by partial reduction of
4-methylanisole or 4-ethylanisole by Birch reduction, e.g. by
treatment with Na in liquid ammonia, for instance as described by
Subba Rao et al., Australian Journal of Chemistry 1992, 45, p.
187-203.
[0078] Conveniently the compound of formula XIII is not isolated,
but the coupling reaction between the compound of formula IV and
the 1-methoxy-4-methylcyclohexa-1,4-diene or
1-methoxy-4-ethylcyclohexa-1,4-diene, is followed by oxidation to
give the diphenylamine derivative of formula VIII.
[0079] In starting compounds and intermediates, which are converted
to the compounds of formulae I to XIII in a manner as hereinbefore
described, functional groups present such as amino, hydroxy and
carboxyl groups, are optionally protected by conventional
protecting groups that are common in preparative organic chemistry.
Protected hydroxy, amino and carboxyl groups are those that can be
converted under mild conditions into free amino, hydroxy and
carboxyl groups without other undesirable side reactions taking
place. For example, hydroxy protecting groups are preferably benzyl
or substituted benzyl groups.
[0080] Processes for the preparation of the
2-phenylamino-5-alkylphenylacetic acid derivatives as described
above are shown schematically on the following page.
Preparation of 2-Arylamino-arylacetic acids (COX-2 inhibitors)
Overview Synthetic Methodologies
##STR00017##
[0082] The processes for the production of the compounds of
formulae II, III, VII, VIII, IX, X and XIII as described above are
included within the scope of the present invention.
[0083] Thus in further aspects the invention includes a process
selected from
a) A process for the production of the lactam of formula II
##STR00018##
which comprises oxidizing of a lactam of formula III
##STR00019##
b) A process for the production of the lactam of formula II as
defined above, which comprises cyclisation of a compound of formula
VII
##STR00020##
c) A process for the preparation of a compound of formula III as
defined above comprising coupling an aniline derivative of formula
IV
##STR00021##
with a cyclohexanone derivative of formula Va or an amino
substituted cyclohexene derivative of formula Vb
##STR00022##
wherein R is ethyl or methyl and R' is lower alkyl or similar d) A
process for the production of a compound of formula VI which
comprises N-acylation of a diphenylamine of formula VIII
##STR00023##
with a haloacetyl chloride e) A process for the preparation of a
compound of formula VIII which comprises rearrangement and
hydrolysis of a compound of formula IX.
##STR00024##
f) A process for the production of a compound of formula VIII which
comprises coupling of a halobenzene derivative of formula XI
##STR00025##
in which X is halo, with p-toluidine or 4-ethyl-anine; g) A process
for the production of a compound of formula VIII which comprises
coupling an aniline derivative of formula IV with 4-bromotoluene or
1-ethyl-4-bromobenzene; h) A process for the production of a
compound of formula VIII which comprises cleavage of a compound of
formula X
##STR00026##
i) A process for the formation of a compound of formula X which
comprises rearrangement of a compound of formula IX j) A process
for the production of a compound of formula IX which comprises
alkylation of a compound of formula XII with
2-chloro-N-(4-methylphenyl)acetamide or 2
chloro-N-(4-ethylphenyl)acetamide k) A process for the production
of a compound of formula VIII which comprises alkylation of a
compound of formula XII with 2-chloro-N-(4-methylphenyl)acetamide
or 2 chloro-N-(4-ethylphenyl)acetamide followed by rearrangement
and cleavage of the intermediate compound of formula IX; l) A
process for the production of a compound of formula VIE coming
oxidation of the corresponding compound of formula MM (or tautomer
thereof)
##STR00027##
m) A process for the production of a compound of formula XIII which
comes coupling 1-methoxy-4-methylcyclohexa-1,4-diene or
1-methoxy-4-ethylcyclohexa-1,4-diene with an aniline derivative of
formula IV as defined above, and n) A process for the production of
a compound of formula VIII comprising coupling
1-methoxy-4-methylcyclohexa-1,4-diene or
1-methoxy-4-ethylcyclohexa-1,4-diene with an aniline derivative or
formula IV, followed by dehydrogenation
[0084] wherein all symbols used are as defined above.
[0085] One or more of the processes a) to n) above may be used in
appropriate sequence (see the scheme given above) in the
preparation of the compound of formula I.
[0086] Thus the invention further provides a process for the
preparation of a compound of formula I
##STR00028##
wherein the symbols are as defined above, which comprises one or
more of processes selected from processes a) to n) as defined
above, optionally in combination with a process according to the
first aspect of the invention.
[0087] Still yet further the invention provides a compound of
formula I, or a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable prodrug ester thereof, when prepared by
a process which comprises one or more of processes a) to n) as
defined above, preferably with a process according to the first
aspect of the invention.
[0088] The compounds of formulae II, III, VII, VIII, IX, X and XIII
are included per se within the scope of the present invention.
[0089] Thus in yet further aspects the invention provides a
compound selected from:
a) A compound of formula II
##STR00029##
b) A compound of formula III
##STR00030##
c) A compound of formula VII
##STR00031##
d) A compound of formula VIII
##STR00032##
e) A compound of formula IX
##STR00033##
f) A compound of formula X
##STR00034##
g) A compound of formula XIII, or a tautomer thereof
##STR00035##
[0090] wherein the symbols are as defined above.
[0091] Compounds of formula XII in which at one of R.sub.1 or
R.sub.6 is chlorine and the other is fluorine may be prepared by
methods known in the art of chlorination of phenols, preferably in
the presence of catalytic amounts of a secondary amine, e.g.
diisopropylamine. In a preferred embodiment according to the
present invention, the chlorination reaction comprises simultaneous
addition of chlorine and phenol to the reaction mixture, preferably
using hexane fraction as the solvent. It has been found that
simultaneous addition of at least part, preferably the majority, of
the chlorine and the phenol to the reaction mixture gives rise to
high productivity and selectivity in production of the desired
product as compared with the unwanted side products. Furthermore
use of hexane fractions permits isolation of the desired phenol
product in high purity (e.g. 99%) by crystallisation.
[0092] The invention is further described by way of illustration
only in the following Examples.
EXAMPLES
[0093] The diphenylamine compounds of Formula VIII
##STR00036##
are prepared by Buchwald chemistry as described below in Examples 1
and 2, either by coupling of an aniline derivative of Formula
IV
##STR00037##
with 4-bromotoluene or 1-ethyl-4-bromobenzene as described in
Example 1, or by coupling of a halobenzene derivative of Formula
XI
##STR00038##
with p-toluidine or 4-ethylaniline as described in Examples 2. The
compounds of Formula VIII thus obtained may be converted into the
corresponding compounds of Formula I by procedures as described
below.
Example 1a
N-(2',3',4',6'-Tetrafluorophenyl)-4-methylaniline
##STR00039##
[0094] A mixture of 2,3,4,6-tetrafluoroaniline (0.72 g, 4.4 mmol),
4-bromotoluene (0.8 g, 4.7 mmol), toluene (55 ml), sodium
tert-butoxide (0.8 g, 8.3 mmol), tri-tert-butylphosphine (130 mg,
0.64 mmol) and bis-dibenzylideneacetone-palladiun(0) (125 mg, 0.2
mmol) is heated under nitrogen to 85.degree. C. for 3 h. After
cooling, water (50 ml), concentrated aqu. HCl (10 ml) and hyflo (1
g) is added and stirring is continued for about one hour followed
by filtration. The organic phase is washed with water twice,
evaporated and the residue is subjected to flash chromatography on
silica (45 g) using heptane/toluene (2:1) as the eluent to afford
N-(2',3',4',6'-Tetrafluorophenyl).sub.4-methylaniline (0.92 g, 3.6
mmol) as an oil which crystallises (mp. 64-65.degree. C.).
[0095] .sup.1H-NMR (400 MHz, DMSO-d6): 2.20 (s, 3H, CH.sub.3); 6.63
[d, 8.2 Hz, 2H, HC (2), HC (6)]; 6.99 [d, 8.2 Hz, 2H, HC (3), HC
(5)]; 7.56 [symmetrical m, 1H, HC (5')]; 7.84 (s, 1H, NH).
[0096] N,N-Bis-p-tolyl-2,3,4,6-tetrafluoroaniline is isolated as a
byproduct, nip: 94.96.degree. C.
Example 1b
N-2',3',5',6'-Tetrafluorophenyl)-ethylaniline
##STR00040##
[0097] A mixture of 2,3,5,6-tetrafluoroaniline (4.5 g, 27.3 mmol),
4-ethylbromobenzene (5.0 g, 27 mmol), toluene (50 ml), sodium
tert-butoxide (4.67 g, 48 mmol), tri-tert-butylphosphin (217 mg,
1.07 mmol) and bis-dibenzylideneacetone-palladium(0) (260 mg, 0.45
mmol is heated under nitrogen to 85.degree. C. for 15.5 h The
mixture is cooled to room temperature and water (30 ml),
concentrated hydrochloric acid (20 ml) and hyflo are added. After
stirring for 45 minutes, the mixture is filtered and the organic
phase is washed with water three tires. The solvent is evaporated
in vacuo and the residue is chromatographed on silica using
hexane/toluene (9:1 to 3:1) affording
N-(2',3',5',6'-tetrafluorophenyl)-4-ethylanilin as a liquid.
[0098] .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.26 (t, 3H, CH.sub.3);
2.65 (q, 2H, CH.sub.2); 5.65 (s, 1H, NH); 6.73 [tt, 1H, H--C (4')];
6.88 [d, 2H, H--C (2, 6)]; 7.15 [d, 2H, H--C (3, 5)].
[0099] MS, m/z: 268 (M-H), 248 (M-HP).
Example 1c
N-(2'-Chloro-4'-fluoro-6'-methylphenyl)-4-methylaniline
##STR00041##
[0100] 3.08 g (19.3 mmol) of 2-chlor-4-fluoro-6-methyl-aniline
(prepared from N-acetyl-4-fluoro-2-methylaniline by chlorination
followed by hydrolyses), 3.48 g (20.3 mmol) of 4-bromotoluene are
dissolved in 55 ml of toluene and after the addition of 3.43 g (36
mmol) of sodium tert-butoxide, 166 mg (0.82 mmol) of
tri-tert-butylphosphin and 460 mg (0.8 mmol) of
bis-dibenzylideneacetone-palladium(0), the mixture is heated with
stirring under nitrogen to 90.degree. C. for 40 minutes. The usual
aqueous acidic workup (50 ml water, 10 ml conc. HC, 1 g hyflo,
filtration, washing the organic phase with water, drying,
evaporation) gave 5.5 g of the crude product which may be purified
by flash-chromatography using silica and heptane as the eluent
affording 3.52 g of
N2'-chloro-4'-fluoro-6'-methylphenyl)-4-methylaniline as an oily
substance.
[0101] .sup.1H-NMR (400 MHz, DMSO-d6): 2.18 (s, 3H, CH3); 6.37 (d,
2H, H--C (2, 6)]; 6.92 [d, 2H, H--C (3, 5)]; 7.19 (dd, 1H, H--C
(5')]; 7.32 (s, 1H, NH); 7.35 (dd, 1H, HC (3')].
Example 1d
N-(2'-Chloro-6'-methylphenyl)-4-methylaniline
##STR00042##
[0102] 1.02 g (7.2 mmol) of 2-chloro-6-methylaniline, 1.23 g (7.2
mmol) 4-bromotoluene, 1.15 g (12 mmol) sodium tert-butoxide, 160 mg
(0.7 mmol) tri-tert-butylphosphine and 130 mg (0.23 mmol)
bis-dibenzylideneacetone-paladium(0) are reacted in 50 ml toluene
under nitrogen at 90.degree. C. for 20 minutes and at 60.degree. C.
over night. Aqueous workup (3N HCl, with hyflo, washing the organic
phase with water) and flash-chromatography on silica using
heptan/toluene (4:1) as the eluent affords 1.49 g of
N-(2'-chloro-6'-methylphenyl)-4-methylaniline.
[0103] .sup.1H-NMR (400 MHz, CDCl.sub.3): 2.21 (s, 3H,
C-6'-CH.sub.3); 2.29 (s, 3H, C4-CH.sub.3); 5.61 (s, br, 1H, NH);
6.57 [d, 2H, HC (2, 6)]; 7.04 [d, 2H, HC (3, 5)]; 7.07 [t under
signal at 7.04, 1H, HC (4')]; 7.16 [d, 2H, H (C5')]; 7.33 [d, 1H,
H(C3')]. N,N-Bis-p-tolyl-2-chloro-6-methylaniline (9 mg) is
isolated as a byproduct.
Example 1e
N-(2'-Chloro-6'-methylphenyl)-4-ethylaniline
##STR00043##
[0104] To a solution of 5.2 g (37 mmol) of 2-chloro-6-methylaniline
and 6.95 g (37.6 mmol) of 4-ethyl bromobenzene in 50 ml of toluene
is added 6.5 g (68 mmol) sodium tert-butoxide, 180 mg (0.89 mmol)
tri-tert-butylphosphine (dissolved in 2 ml of toluene) and 300 mg
(0.52 mmol) of bis-dibenzylideneacetone palladium(0). The mixture
is heated under nitrogen to 90.degree. C. for 3 hours and then
cooled to room temperature. Hyflo (1 g), water (30 ml) and conc.
hydrochloric acid (10 ml) are added and after stirring for 30
minutes the mixture is filtered. The organic phase washed with
water (30 ml) twice and evaporated. The is subjected to
flash-chromatography on silica (75 g) eluting with hept to afford
5.3 g (21.6 mmol. 58%) of
N-2'-chloro-6'-methylphenyl)-4-ethylaniline as an almost colourless
liquid.
[0105] .sup.1H-NMR (300 MHz, CDCl.sub.3): 1.10 (t, 3H,
CH.sub.3--CH.sub.2--); 2.10 [s, 3H, CH3-C (6')]; 2.50 (q, 2H,
CH.sub.3--CH.sub.2--); 5.54 (s, br, 1H, NH); 6.48 [d, 2H, HC (2,
6)]; 6.93 [t, 1H, H (C4')]; 6.95 [d, 2H, HC (3, 5)]; 7.05 [d, 1H,
HC (5')]; 7.22 [d, 1H, HC (3')].
Example 1f
N-(2',4'-Dichloro-6'-methylphenyl)-4-ethylaniline
##STR00044##
[0106] The mixture of 2,4-dichloro-6-methylaniline (3.313 g, 18.8
mmol), 4-ethyl bromobenzene (3.64 g, 20 mmol), sodium tert-butoxide
(3.41 g, 35 mmol), racemic BINAP (0.274 g, 0.44 mmol),
bis-dibenzylideneacetone-palladium(0) (250 mg, 0.43 mmol) and
toluene (50 ml) is refluxed under nitrogen for 22 h The mixture is
cooled, treated with water (40 ml, conc. HCl (10 ml), hyflo (1.7 g)
stirred for additional 30 minutes and filtered. The organic phase
is washed with water twice and evaporated. The crude product (6.88
g) is purified by flash-chromatography (silica, toluene) to afford
2.93 g of N-(2',4'-dichloro-6'-methylphenyl)-4-ethylaniline.
[0107] .sup.1H-NMR (300 MHz, CDCl.sub.3): 1.15 (t, 3H,
CH.sub.3--CH.sub.2--Ar); 2.08 (s, 3H, C-6'-CH3); 2.50 (q, 2H,
CH.sub.3--CH.sub.2--Ar); 5.42 (s, br., 1H, NH); 6.50 [d, 2H, HC (2,
6)]; 6.96 [d, 2H, HC (3, 5)]; 7.10 [s, 1H, HC (5')]; 7.25 [s, 1H,
HC (3')].
The reaction proceeds much faster even at 85.degree. C. when BINAP
is replaced by tri-tert-butylphosphine; however
N,N-di-(4-ethylphenyl)-2',4'-dichloro-6'-methylaniline is formed as
a byproduct in considerable amounts when excess of 4-ethyl
bromobenzene is used. This byproduct can be isolated as a solid,
mp: 74-75.degree. C.; .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.24 (t,
6H CH.sub.2--CH.sub.3); 2.09 (s, 3H, C-6'-CH.sub.3); 2.61 (q, 4H,
CH.sub.2--CH.sub.3); 6.89 [d, 4H, HC (2, 6)]; 7.06 [d, 4H, HC (3,
5)]; 7.20 [s, 1H, HC (5')]; 7.36 [s, 1H, HC (3')]; MS: 383 (M+),
368 (M-CH.sub.3), 354 (M-CH.sub.2--CH.sub.3).
Example 2
N-(2',3',6'-Trifluorophenyl)-4-ethylaniline
##STR00045##
[0108] To a solution of 1.21 g of 4-ethylaniline, 1.10 g of
2,3,6-trifluoro-bromobenzene in 10 g of toluene is added
consecutively 350 mg BINAP and 300 mg of
bis-dibenzylideneaceton-paladium (0) [Pd(dba).sub.2) in 3 ml of
toluene and 0.9 g of sodium tert.-butoxide in 3 ml toluene. The
mixture is flushed with nitrogen and heated for 6 h under reflux.
After cooling to room temperature, water (30 ml), concentrated
hydrochloric acid (10 ml) and hyflo (1 g) are added and stirring is
continued for 1 h. The mixture is filtered and the filtrate is
separated into its phases. The organic phase is washed three times
with water, dried using magnesium sulfate and evaporated to
dryness. The residue can be used as such in the following step or
purified by flash chromatography on silica using toluene as the
eluent affording 1.13 g of
N-(2',3',6'-trifluorophenyl)-4-ethylanilin.
[0109] .sup.1H-NMR (300 MHz, CDCl.sub.3): 1.14 (t, 7.7 Hz, 3H,
CH.sub.3--CH.sub.2--Ar); 2.53 (q, 7.7 Hz, 2H,
CH.sub.3--CH.sub.2--Ar); 5.29 (br. s, 1H, NH); 6.7-6.81 [m, 2H,
C-4'-H, HC (5')]; 6.75 [d, 2H, HC (2, 6)]; 7.02 [d, 8.5 Hz, 2H, HC
(3, 5)].
[0110] Diphenylamine compounds of Formula VIII, for instance as
prepared above in Examples 1 and 2, are converted to the
corresponding compounds of Formula VII
##STR00046##
as addressed in Example 3
Example 3a
N-(2',3',4',6'-Tetrafluorophenyl)-N-chloroacetyl-4-methylaniline
##STR00047##
[0111] The mixture of
N-(2',3',4',6'-tetrafluorophenyl)-4-methylanilin (0.82 g, 3.2 mmol)
and chloro acetylchloride (1.6 g) is heated with string to
90.degree. C. under nitrogen for 1.3 h. To destroy excess of the
acid chloride, 2-propanol and water (2 ml each) is added and
stirring is continued over night at room temperature. After adding
toluene (20 ml), the mixture is extracted with sodium bicarbonate
and the organic phase is dried with magnesium sulfate and
evaporated to dryness. The residue is purified by flash
chromatography (silica, toulene) to obtain
N-(2',3',4',6'-tetrafluorophenyl)-N-chloroacetyl-4-methylaniline
(0.98 g, 2.95 mmol) as an oil.
Example 3b
N-(2',3',5',6'-Tetrafluorophenyl)-N-chloroacetyl-4-ethylaniline
##STR00048##
[0112] N-2',3',5',6'-tetrafluorophenyl)-4-ethylanilin (2.05 g) and
chloro acetylchloride (1.99 g) is mixed without solvent and heated
with stirring to 90.degree. C. under nitrogen for 20 h.
Tetrahydrofurane (10 ml) and aqueous sodium bicarbonate are added
after cooling and stirring is continued for about 1 hour. The
organic phase is diluted with toluene and washed with water three
times and dried over magnesium sulfate. Evaporation and
chromatography of the residue (silica, toluene) gave
N-2',3',5',6'-tetrafluorophenyl)-N-chloroacetyl-4-ethylaniline
(1.84 g) as a solid which is recrystallised from heptane, mp.:
72.degree. C.
[0113] .sup.1H-NMR (400 MHz, DMF-d7, 140.degree. C.): 1.25 (t, 3H,
CH.sub.3); 2.70 (q, 2H, CH.sub.2); 4.28 (s, 2H, CH.sub.2--CO); 7.35
[(d, 2H, HC (3, 5)]; 7.43 [d, 2H, HC (2, 6)]; 7.65 [tt, 1H, HC
(4')].
Example 3c
N-(2'-Chloro-4'-fluoro-6'-methylphenyl)-N-chloroacetyl-4-methylamine
##STR00049##
[0114] 1.32 g of
N-(2'-Chloro-4'-fluoro-6'-methylphenyl)-4-methylaniline is reacted
with chloracetylchloride (1.76 g) at 90.degree. C. for 30 minutes.
The cooled mixture is stirred with toluene (20 ml) and aqu. sodium
carbonate for 30 minutes and the organic phase is evaporated. The
residue is purified flash-chromatography on silica using toluene
affording 1.04 g of
N-(2'-chloro-4'-fluoro-6'-methylphenyl)-N-chloroacetyl-4-methylaniline
as a solid which is recrystallised from heptane/2-propanol (9:1),
mp.: 96-97.degree. C.
[0115] .sup.1H-NMR (400 MHz, DMF-d7, 120.degree. C., all peaks
appear broadend or split): 2.43 (s, 3H, CH.sub.3); 4.31 (s, 2H,
Cl--CH.sub.2--CO); 7.31 [d, 1H, HC (5')]; 7.32 and 7.40 [AB, 4H,
C--HC (2, 6) and HC (3, 5)]; 7.45 [s, 1H, HC (3')].
Example 3d
N-(2'-Chloro-6'-methylphenyl)-N-chloroacetyl methylaniline
##STR00050##
[0116] The solution of N-(2'-chloro-6'-methylphenyl)-methylaniline
(1.4 g) in 2.21 g chloroacetylchloride is heated to 90.degree. C.
for 4 h. The mixture is diluted with toluene (25 ml), cooled to
room temperature and washed with aqu. sodium carbonate. The organic
phase dried, evaporated and the residue is subjected to flash
chromatography [57 g silica toluene and toluene/ethylacetate
(98:2)] to afford 1.45 g of
N-(2'-Chloro-6'-methylphenyl)-N-chloroacetyl-4-methylaniline which
is crystallised from heptane, mp: 113-114.degree. C.
Example 3e
N-(2'-Chloro-6'-methylphenyl)-N-chloroacetyl-4-ethylaniline
##STR00051##
[0117] N-(2'-Chloro-6'-methylphenyl)-N-4-ethylaniline (4.95 g, 20
mmol) is treated with chloro acetylchloride (3.23 g, 28.5 mmol) and
the mixture is heated with stirring under nitrogen at 95.degree. C.
for 40 minutes. After adding 2-propanol (5 ml) and cooling to room
temperature, the mixture is diluted with toluene and extracted with
aqu. sodium bicarbonate. The organic phase is washed with water and
evaporated to dryness. Flash chromatography on silica (55 g) using
toluene as the eluent affords 5.66 g (17.6 mmol. 88%) of
N-(2'-chloro-6'-methylphenyl)-N-chloroacetyl-4-ethylaniline as a
viscous liquid.
[0118] .sup.1H-NMR (400 MHz, DMF-d7, 140.degree. C.): 1.22 (t, 3H,
CH.sub.3--CH.sub.2), 2.32 (s, 3H, CH3-C6'); 2.65 (q, 2H,
CH.sub.3--CH.sub.2--); 4.12, 4.18 (AB, 2H, CH.sub.2--Cl); 7.22 and
7.31 [each d, each 2H, HC (2, 6) and HC (3, 5)]; 7.3-7.5 [m, 3H, HC
(3', 4', 5')].
Example 3f
N-(2',4'Dichloro-6'-methylphenyl)-N-chloroacetyl-4-ethylaniline
##STR00052##
[0119] N-(2',4'Dichloro-6'-methylphenyl)-4-ethylaniline (4.83 g as
a mixture with the byproduct
N,N-di-(4-ethylphenyl)-2',4'-dichloro-6'-methylaniline) is
dissolved in 4.18 g of chloro acetylchloride and heated to
100.degree. C. for 1.5 h. The mixture is cooled, diluted with
toluene (50 ml) and extracted with aqu. sodium bicarbonate. The
organic phase is evaporated to dryness and chromatographed on
silica (75 g) eluting with toluene to afford unreacted
N,N-di-(4-ethylphenyl)-2',4'-dichloro-6'-methylaniline and
N-(2',4'-dichloro-6'-methylphenyl)-N-chloroacetyl-4-ethylaniline
(2.95 g). A crystallised sample melts at 83-84.degree. C.
[0120] .sup.1H-NMR (400 MHz, DMF-d7, 140.degree. C.): 1.22 (t, 3H,
CH.sub.3--CH.sub.2); 2.31 (s, 3H, C-6'-CH3); 2.56 (q, 2H,
CH.sub.3--CH.sub.2); 4.20 (s, split, 2H, Cl--CH.sub.2--CO); 7.35,
7.42 [AB, 4H, HC (2, 6) and HC (3, 5) respectively]; 7.40 [s, br.
1H, HC (5')], 7.53 [s, br, 1H, HC (3')].
[0121] Alternatively compounds of Formula VIII may be prepared by a
procedure involving coupling of
1-methoxy-4-methylcyclohexa-1,4-diene or
1-methoxy-4-ethylcyclohexa-1,4-diene with an anile derivative of
formula IV as defined above to give an intermediate compound of
Formula XIII (or tautomer thereof)
##STR00053##
which is oxidised without isolation to give the compound of Formula
VIII, as described below in Example 4.
Example 4a
N-(2',6'-Dichlorophenyl)-4-methylaniline
##STR00054##
[0122] a) A solution of 4.35 g 2,6-dichloro-aniline in 4 ml of
tetrahydrofuran and 35 ml of chlorobenzene is cooled down to 40 to
45.degree. C. At this temperature, 5.09 g of titanium tetrachloride
is added to the solution, followed by the addition of 5.0 g of
1-Methoxy 4-methylcyclohexa-1,4-diene. The reaction mixture is
allowed to warn up to approximately -35.degree. C. and stirred for
2 hours at this temperature. A solution of 10.18 g of iodine in 20
ml of tetrahydrofuran and 2.3 ml of acetic acid is then added
dropwise to the reaction mixture and the temperature was allowed to
warn up to 0.degree. C. The mature was stirred for 1 hour at
0.degree. C. and 16 hours at 25.degree. C. Then 3.4 g of iodine is
added to the reaction mixture and stirring is continued for
additional 24 hours at 25.degree. C. The reaction is finally
quenched by pouring the reaction mixture onto a mixture of 250 ml
of aqueous Sodium bisulfite (38-40%) and 400 ml of saturated
aqueous sodium carbonate. The water phase is extracted with ethyl
acetate (1.times.200 ml and 2.times.100 ml), the ethyl acetate
phases are unified and washed with 100 ml of water. The organic
phase was dried over anhydrous sodium sulfate and evaporated in
vacuo to yield 11.44 g of a dark slurry. The slurry was dissolved
in hexane/t-butyl-methylether and the solution was filtered over
silica gel to obtain, after evaporation of the solvent, 5.75 g of
crude product. The product can be used directly in the next step.
Alternatively, it can be purified e.g. by column chromatography on
silica gel with hexane/t-butyl-methylether (9:1) as eluent to yield
pure N-(2',6'-Dichlorophenyl)-4-methylaniline.
[0123] .sup.1H-NMR (CDCl.sub.3, 400 MHz 300K) .delta. 2.31 (s, 3H,
CH.sub.3), 3.6-4.8 (broad signal, 1H, NH), 6.68 (d, J=8 Hz, 2H,
H--C (2) and H--C (6)), 7.02-7.12 (m, 3H, H--C (3), H--C (5) and
H--C (4')), 7.38 (d, J=8 Hz, 2H, HC (3') and H--C (5')).
[0124] MS (EI): m/z 251 (M.sup.+), 216 (M-Cl.sup.+), 181
(M-2Cl).sup.+
Example 4b
N-(2'-Chloro-6'-fluoro-phenyl)-4-methylaniline
##STR00055##
[0125] A solution of 3.91 g 2-chloro-6-fluoroaniline in 4 nm of
tetrahydrofuran and 35 ml of chlorobenzene is cooled down to -40 to
-45.degree. C. At this temperature, 5.09 g of titanium
tetrachloride is added to the solution, followed by the addition of
5.0 g of 1-Methoxy-4-methylcyclohexa-1,4-diene. The reaction
mixture is allowed to warm up to approx. -35.degree. C. and stirred
for 2 hours at this temperature. A solution of 10.18 g of iodine in
20 ml of tetrahydrofuran and 2.3 ml of acetic acid is then added
drop-wise to the reaction mixture and the temperature was allowed
to warm up to 0.degree. C. The mixture was stirred for 1 hour at
0.degree. C. and 16 hours at 25.degree. C. Then 3.4 g of iodine is
added to the reaction mixture and stirring is continued for
additional 24 hours at 25.degree. C. The reaction is finally
quenched by pouring the reaction mixture onto a mixture of 250 ml
of aeq. Sodium bisulfite (38-40%) and 400 ml of saturated aeq.
sodium carbonate. The aqueous phase is extracted with ethyl acetate
(1.times.200 ml and 2.times.100 ml), the ethyl acetate phases are
unified and washed with 100 ml of water. The organic phase was
dried over anhydrous sodium sulfate and evaporated in vacuo to give
a yellow viscous liquid. The liquid was dissolved in
hexane/t-butyl-methylether and the solution was filtered over
silica gel to obtain, after evaporation of the solvent, 4.33 g of
crude product. The product can be used directly in the next step.
Alternatively, it can be purified e.g. by column chromatography on
silica gel with hexane/t-butyl-methylether (9:1) as eluent to yield
pure N-(2-Chloro-6'-fluoro-phenyl)-4-methylaniline.
[0126] .sup.1H-NMR (DMSO-d.sup.6, 500 MS, 300K) .delta. 2.17 (s,
3H, CH.sub.3); 6.53 [dd, J=8.5 Hz, J.sub.H-F=1.5 Hz, 2H, HC (2) and
HC (6)], 6.94 [d, J=8.0 Hz, 2H HC (3) and HC (5)], 7.16 [ddd, J=8.0
Hz, J.sub.H-F=6.0 Hz, 1H, HC (4')], 7.25 [ddd, J=8.0, 1.5 Hz,
J.sub.H-F=8.0, 1H, HC (5')]; 7.34 [ddd, J=8.0, 1.5 Hz, J.sub.H-F,
1.5, 1H, HC (3')]; 7.63 (s, 1H, NH).
[0127] MS (EI) m/z 235 (100, M.sup.+), 200 (35, (M-Cl).sup.+), 185
(55)
Example 4c
N42'-Chloro-6'-methyl-phenyl)-4-ethylaniline
##STR00056##
[0128] A solution of 3.0 g 2-Chloromethyl-aniline in 3.5 ml of
tetrahydrofuran and 31 ml of chlorobenzene is cooled down to 40 to
-45.degree. C. At this temperature, 4.01 g of
titanium-tetrachloride is added to the solution, followed by the
addition of 6.18 g of 1-Methoxy-4-ethylcyclohexa-1,4-diene. The
reaction mixture is allowed to warm up to approx -35.degree. C. and
stirred for 3 hours at this temperature. A solution of 8.06 g of
iodine .+-.16.4 ml of tetrahydrofuran and 1.8 ml of acetic acid is
added to the reaction mixture and the temperature is allowed to
warm up to 0.degree. C. The mixture is stirred for 30 minutes at
0.degree. C. and 2 hours at 25.degree. C. Then 2.68 g of iodine is
added to the reaction mixture and stirring is continued for
additional 24 hours at 25.degree. C. Again, 2.68 g of iodine is
added and stirring is continued for additional 72 hours at
25.degree. C. The reaction is finally quench by pouring the
reaction mixture onto a mixture of 250 ml of aqueous sodium
bisulfite (38-40%) and 450 ml of saturated aqueous sodium
carbonate. The water phase is extracted with ethyl acetate
(1.times.200 ml and 2.times.100 ml, the ethyl acetate phases are
unified and washed with 100 ml of brine. The organic phase was
dried over anhydrous sodium sulfate and evaporated in vacuo to give
a dark viscous liquid. The liquid was dissolved in heptane/toluene
and the solution was filtered over silica gel to obtain, after
evaporation of the solvent, 2.0 g of crude product. The product can
be used directly in the next step. Alternatively, it can be
purified e.g. by column chromatography on silica gel with heptane I
toluene (7:3) as eluent to yield pure
N-(2'-Chloro-6'-methyl-phenyl)-4-ethylaniline.
[0129] .sup.1H-NMR (CDCl.sub.3, 400 MHz, 300K) .delta. 1.24 (t,
J=7.5 Hz, 3H, H.sub.3C (8)), 2.22 (s, 3H, H.sub.3C--C (2')), 2.61
(q, J=7.5 Hz, 2H, H.sub.2C (7)), 4.0-5.5 (broad signal, 1H, NH),
6.60 (d-like, J=8 Hz, 2H, H--C (2) and H--C (6)), 7.02-7.10 (m, 3H,
H--C (3), H--C (5) and H--C (4'), 7.10-7.20 (m, 1H, H--C (3)), 7.33
(d-like, J=9 Hz, 1H, H--C (5)).
[0130] MS: m/z 245 (M.sup.+), 230, 214, 194, 180.
The 1-Methoxy 4-methylcyclohexa-1,4-diene and
1-Methoxy-4-ethylcyclohexa-1,4-diene starting materials for Example
4 are prepared according to a known literature procedure.
1-Methoxy-4-methylcyclohexa-1,4-diene
##STR00057##
[0131] Preparation according to a known literature procedure:
G. S. R. Subba Rao, D. K Banerjee L. Uma Devi and Uma Sheriff,
Australian Journal of Chemistry 1992, 45, p. 187-203
1-Methoxy-4-ethylcyclohexa-1,4-diene
##STR00058##
[0132] Compound 4 was prepared according to the same literature
procedure given above for
1-methoxy-4-methylcyclohexa-1,4-diene.
[0133] The products of Examples 4 are converted into the
corresponding compounds of Formula VII for instance as described in
Examples 3 above and 5 below
Example 5
N-(2',6'-Dichlorophenyl)-N-chloroacetyl-4-methylaniline
##STR00059##
[0134] N-(2',6'-Dichlorophenyl methylaniline (4.86 g) is reacted
with chloroacetylchloride (3.92 g) at 90.degree. C. for 2 h. After
dilution with toluene, the mixture is washed with aqueous sodium
carbonate twice, 40% aqu. sodium bisulfite and water. The organic
phase is dried (MgSO4) and evaporated. The residue is
recrystallised from ethanol (12 g) to obtain
N-(2',6'-Dichlorophenyl)-N-chloroacetyl-4-methylaniline in (2.83
g), mp: 129.5-130.degree. C.
[0135] In a yet further alternative compounds of Formula VII may be
prepared by a procedure involving a Smiles type rearrangement of a
compound of Formula IX
##STR00060##
to give an intermediate product of Formula VIII as defined above
which is converted without being isolated to the compound of
Formula VII as described in Example below.
Example 6a
N-(2',6'-dichloro-4'-methylphenyl)-N-chloroacetyl-4-methylaniline
##STR00061##
[0136] 12 g (67 mmol) of 2,6-dichloro-4-methylphenol are dissolved
in 25 ml of 2-propanol followed by the addition of 10.5 g (76 mmol)
of potassium carbonate and 12.8 g (70 mmol) of
2-chloro-N-(4-methylphenyl)acetamide. The mixture is refluxed for 4
h. At this time, the formation of A:
2-(2',6'-dichloro-4'-methylphenoxy-N-(4-methylphenyl)acetamide is
completed. 13.6 ml of sodium methylate solution 30% in methanol are
slowly added and the t is i to about 85.degree. C. by distilling 25
ml of solvent. The mixture is stirred 2 h more to complete the
formation of B.
[0137] 25 ml of water are added at 70.degree. C. to obtain a 2
phases solution. The lower layer is discarded. The upper layer is
diluted with 20 ml of heptane-fraction and washed with 2.times.20
ml of water. The organic phase is separated and concentrated in
vacuo to obtain N-(2',6'-dichloro-4'-methylphenyl)-4-methylaniline
as a crude oil. GC/MS: 265 (100, M.sup.+), 195 (130).
This oil is heated to 90.degree. C. and treated with 6.5 ml of
chloroacetylchloride. After 2 h the mixture is diluted with 60 ml
of 2-propanol, cooled to about 20.degree. C. and seeded. The
precipitated suspension is cooled to 0.degree. C. The crystals are
isolated by filtration, washed with cold 2-propanol and dried to
obtain
N-(2',6'-dichloro-4'-methylphenyl)-N-chloroacetyl-4-methylamine.
Mp: 140-141.degree. C.
[0138] .sup.1H-NMR (DMF-d7, 413K, 400 Mz) 2.33 (s, 3H, CH.sub.3);
2.40 (s, 3H, CH.sub.3); 4.18 (s, 2H, CH.sub.2); 7.22 [d, 2H, HC (5)
and HC (3)]; 7.38 [d, 2H, HC (2) and HC (6)]; 7.42[s, 2H, HC (3')
and HC (5')].
Example 6b
N-(2'-chloro-6'-fluorophenyl)-N-chloroacetyl-4-methylaniline
[0139] Same procedure as example 6a, starting from
2-chloro-6-fluorophenol
[0140] Mp: 80-82.degree. C.
[0141] .sup.1H-NMR (DMF-d7, 393K, 400 Mz) 2.4 (s, 3H, CH.sub.3);
4.3 (s, 2H, CH.sub.2); 7.35 [d, 2H, HC (3) and HC (5)]; 7.43 [ddd,
1H, HC (5')]; 7.48 [d, 2H, HC (2) and HC (6)]; 7.55 [d, 1H, HC
(3')]; 7.6 [ddd, 1H, HC (4')].
Example 6c
N-2',3',6'-trifluorophenyl)-N-chloroacetyl-4-ethylaniline
[0142] Same procedure as example 6a, starting from
2,3,6-trifluorophenol and 2-chloro-N-(4 ethylphenyl)acetamide. The
crude intermediate N-(2',3',6'-trifluorophenyl)-4-ethylaniline was
roughly purified by filtration on silica using toluene as
eluent.
[0143] Mp: 49-50.degree. C. .sup.1H-NMR (DMF-d7, 413K, 400 MHz)
1.24 (t, 3H, CR.sub.3); 2.70 (q, 2H, CH.sub.2--CH.sub.3); 4.25 (s,
2H, CH.sub.2--Cl); 7.20 [m, 1H, HC (5')]; 7.34 [d, 2H, HC (3) and
HC (S)]; 7.42 [d, 2H, HC (2) and HC (6)]; 7.46 [m, 1H, HC
(4')].
Example 6d
N-(2'-chloro-6'-fluorophenyl)-N-chloroacetyl-4-ethylaniline
[0144] Same procedure as example 6a starting from
2-chloro-6-fluorophenol and
2-chloro-N-(4-ethylphenyl)acetamide.
[0145] Mp: 67-68.degree. C. .sup.1H-NMR (DMF-d7, 413K, 500 MHz)
1.23 (t, 3H, CH.sub.3); 2.68 (q, 2H, CH.sub.2--CH.sub.3); 4.20 (s,
2H, CH.sub.2--Cl); 7.29 [d, 2H, HC (3) and HC (5)]; 7.34 [m, 1H, HC
(5')]; 7.43 [d, 2H, HC (2) and HC (6)]; 7.48 [m, 2H, HC (3') and HC
(4')].
Example 6e
N-(2',6'-dichlorophenyl)-N-chloroacetyl-4-methylaniline
[0146] Same procedure as example 6a starting from
2,6-dichlorophenol and 2-chloro-N-(4-methylphenyl)acetamide. At the
end of the acetylation reaction the mixture was diluted with a
small amount of toluene (0.2 part) to prevent solidification.
[0147] Mp: 129-130.degree. C. .sup.1H-NMR (DMF-d7, 393K, 500 Mz)
2.40 (s, 3H, CH.sub.3); 4.28 (s, 2H, CH.sub.2--Cl); 7.30 [d, 2H, HC
(3) and HC (5)]; 7.46 [d, 2H, HC (2) and HC (6)]; 7.54 [m, 1H, HC
(4')]; 7.67 [d, 2H, HC (3') and HC (5')].
[0148] Compounds of Formula VII are cyclised to give lactams of
Formula II
##STR00062##
as described in Example 7
Example 7a
N-(2',6'-dichloro-4'-methylphenyl)-5-methyloxindole
##STR00063##
[0149] A mixture of 6.85 g (20 mmol) of
N-(2',6'-dichloro-4'-methylphenyl)-N-chloroacetyl-4-methylaniline
and 3.36 g (26 mmol) of aluminium chloride was heated slowly to
160-170.degree. C. and held at this temperature for 3-4 h. During
this time, nitrogen was continuously bubbled into the melt. The
mixture was diluted with 20 ml of toluene and added on 20 ml of
warm water. The organic layer was separated, washed with water and
evaporated. The residue was crystallised from 20 ml of 2-propanol
giving N-(2',6'-dichloro-4'-methylphenyl)-5-methyloxindole. Mp:
153-154.degree. C.
[0150] .sup.1H-NMR (DMSO-d6, 500 Mz, 300K) 2.29 [s, 3H, CH.sub.3--C
(5)]; 2.41 [s, 3H, CH.sub.3--C (4')]; 3.81 (s, 2H, CH.sub.2); 6.27
[d, 1H, HC (7)]; 7.00 [d, 1H, HC (6)]; 7.19 [s, 1H, HC (4)]; 7.58
[s, 2H, HC (3') and HC (5')].
Example 7b
N-(2'-chloro-6'-fluorophenyl)-5-methyloxindole
[0151] Same procedure as example 7a
[0152] Mp: 137-138.degree. C. .sup.1H-NMR (DMSO-d6, 500 MHz, 300K)
2.27 (s, 3H, CH.sub.3); 3.83 (s, 2H, CH.sub.2) 6.35 [d, 1H, HC
(7)]; 7.01 [d, 1H, HC (6)]; 7.19 [s, 1H, HC (4)]; 7.52 [d, 1H, HC
(5')]; 7.60 [d, 1H, HC (3')], 7.63 [d, 1H, HC (4')].
Example 7c
N-(2',3',6'-trifluorophenyl)-5-ethyloxindole
[0153] Same procedure as example 7a. After 4 h reaction, 10% more
aluminium chloride was added. Overall reaction time: 6 h.
[0154] Mp: 171-172.degree. C. .sup.1H-NMR (DMSO-d6, 500 Mz, 300K)
1.18 (t, 3H, CH.sub.3); 2.60 [q, 2H, CH.sub.2--CH3]; 3.89 [s, 2H
CH.sub.2--CO]; 6.62 [d, 1H, HC (7)]; 7.09 [d, 1H, HC (6)]; 7.25 [s,
1H, HC (4)]; 7.46 [m, 1H, HC (5')]; 7.76 [m, 1H, HC (4')].
Example 7d
N-(2'-chloro-6'-fluorophenyl)-5-ethyloxindole
[0155] Same procedure as example 7c.
[0156] Mp: 129-130.degree. C. .sup.1H-NMR (DMSO-d6, 300K, 500 Mz)
1.18 (t, 3H, CH.sub.3); 2.59 [q, 2H, CH.sub.2--CH.sub.3]; 3.86 (s,
2H, CH2-CO); 6.39 [d, 1H, HC (7)]; 7.05 [d, 1, HC (6)]; 7.24 [s,
1H, HC (4)], 7.59 [m, 1H, HC (5')]; 7.64 [m, 2H, HC (3') and HC
(4')].
Example 7e
N-(2',6'-dichlorophenyl)-5-methyloxindole
[0157] Same procedure as 7a
[0158] .sup.1H-NMR (DMSO-d6, 500 MHz, 300K) 2.30 (s, 3H, CH.sub.3);
3.85 (s, 2H, CH.sub.2); 6.29 [d, 1H, HC (7)]; 7.02 [d, 1H, HC (6)];
7.22 [s, 1H, HC (4)], 7.62 [t, 1H, HC (4')]; 7.761 [d, 2H, HC (3')
and HC (5')].
Example 7f
N-(2',3',4',6'-Tetrafluorophenyl)-5-methyloxindole
##STR00064##
[0159] The solution of
N-(2',3',4',6'-tetrafluorophenyl-N-chloroacetyl-4-methylaniline
(0.97 g, 2.97 mmol) in chlorobenzene (2.5 g) is treated with
aluminum trichloride (1.05 g, 7.8 mmol) and the mixture is heated
with stirring in an oil bath (155.degree. C.) for 5 h while
flushing the flask with nitrogen. Toluene (30 ml) and water (20 ml)
are added and stirring is continued for 30 minutes at room
temperature. The phases are separated and the organic phase is
washed with hydrochloric acid (2N) and water. Evaporation under
reduced pressure affords a solid (0.84 g, 2.85 mmol) which is
recrystallised from 2-propanol to afford pure
N-(2',3',4',6'-tetrafluorophenyl)-5-methyloxindole, mp.
172-173.degree. C.
[0160] .sup.1H-NMR (300 MHz, 300K, CDCl.sub.3): 2.28 (s, 3H,
CH.sub.3); 3.65 [s, 2H, H.sub.2C (3)]; 6.39 [d, 7.5 Hz, 1H, HC
(7)]; 6.85-7.0 [m, 1H, HC (5')]; 6.98 ud, 7.5 Hz 1H, HC (6)]; 7.09
[s, 1H, HC (4)].
Example 7g
N-(2'-Chloro-6'-methylphenyl)-5-ethyloxindole
##STR00065##
[0161] In a flask are mixed
N-(2'-chloro-6'-methylphenyl-N-chloroacetyl-4-ethylaniline (2.08 g)
are mixed with aluminium trichloride (1.16 g) and the mixture is
flushed with nitrogen. The flask is introduced into an oil bath
(155-160.degree. C.) and the mixture is stirred under a stream of
nitrogen for 4.5 hours. The mixture is slightly cooled to about
100.degree. C., treated with toluene (30 ml) and 1N HO (20 ml) and
stirred for 30 minutes while the temperature decreases gradually.
After phase separation, the organic phase is washed with 1N HCl and
water, dried (magnesium sulfate) and evaporated. The residue is
chromatographed on silica (86 g) using toluene containing 5-20%
isopropyl acetate as eluent affording the title product.
[0162] Mp: 125-126.degree. C.
[0163] In a yet further alternative lactams of Formula II are
prepared by oxidation of an unsaturated lactam of Formula III
##STR00066##
which may be prepared, for instance as described in Example 8.
Example 8
(5-Ethyl-2-morpholin-4-yl-cyclohex-2-enylidene)-acetic acid ethyl
ester
##STR00067##
[0164] 91.6 g of 4-Ethyl-cyclohexanone, 73.6 g of morpholine and 2
g of p-toluene-sulfonic acid monohydrate are dissolved in 400 ml of
toluene. The mixture is heated to reflux and the water formed is
removed by a water separator. After reacting for about 24 h, the
reaction mixture is cooled to 100.degree. C. and 2 g of
p-toluene-sulfonic acid arc added, followed by the addition of
157.22 g of glyoxylic acid ethyl ester during 30 minutes The
mixture is again heated to reflux for 5 hours and allowed to cool
down to 22.degree. C. The solvent is evaporated in vacuo and the
crude product is distilled in vacuo at 140-150.degree.
C./9.5.sup.-2 mbar.
[0165] .sup.1H-NMR (CDCl.sub.3, 500 MHz, 277K) .delta. 0.896 ppm
(t, J=7 Hz, 3H, H.sub.3C (17)), 1.277 (t, J=7 Hz, 3H, H.sub.3C
(10)), 1.20-1.45 (m, 2H, H.sub.2C (16)), 1.50-1.62 (m, 1H, H--C
(4)), 1.876 (ddd, J.sub.1=18 Hz, J.sub.2=9 Hz, J.sub.3=3 Hz, 1H,
H--C (3)), 2.13 (m, 1H, H--C (5)), 2.35 (dt, J.sub.1=17 Hz,
J.sub.2=5 Hz, 1H, H--C (3)), 2.55-2.65 (m, 2H, H--C (12) and H--C
(15)), 2.72-2.80 (m, 2H, H--C (12) and H--C (15)), 3.55 (dm, J=15
Hz, 1H, H--C (5)), 3.74 (m, 4H, H.sub.2C (13) and H.sub.2C (14)),
4.152 (q, J=7 Hz, 2H, H.sub.2C (9)), 5.46 (dd, J.sub.1=5 Hz,
J.sub.2=3 Hz, 1H, H--C (2)), 6.17 (broad s, 1H, H--C (7)).
Assignments according to numbers given on the formula.
[0166] IR (film): strong absorptions at 2960, 1710, 1624, 1609,
1191, 1156 and 1120 cm.sup.-1.
[0167] MS (EI): m/z 279 (M.sup.+), 250 (M-C.sub.2H.sub.5).sup.+,
234, 206 (M-CO.sub.2C.sub.2H.sub.5).sup.+, 176, 164, 135, 84.
b). Synthesis of (5-Ethyl-2-oxo-cyclohexylidene)-acetic acid ethyl
ester
##STR00068##
[0168] 10 g of
[5-Ethyl-2-morpholin-4-yl-cyclohex-2-enylidene]-acetic acid ethyl
ester are dissolved in 20 ml of toluene. 12 ml of 6M HCl are added
dropwise under rigorous string and the reaction mixture is stirred
for additional 60 minutes at 22.degree. C. The organic layer is
separated and washed with 25 ml of water twice. The combined water
layers are extracted with 25 ml of toluene. The combined toluene
layers are dried over anhydrous sodium sulfate and the solvent is
evaporated in vacuo to yield 6.72 g of
[5-ethyl-2-oxo-cyclohexylidene]-acetic acid ethyl ester as an
oil.
[0169] .sup.1H-NMR (CDCl.sub.3, 500 MHz, 277K) .delta. 0.935 ppm
(t, J=7 Hz, 3H, H.sub.3C (12)), 1.259 (t, J=7 Hz, 3H, H.sub.3C
(10)), 1.31-1.45 (m, 2H, H.sub.2C (11)), 1.46-1.55 (m, 1H, HC (5)),
1.59-1.69 (m, 1H, H--C (4)), 1.97-2.04 (m, 1H, H--C (5)), 2.296
(ddd, J=17 Hz, 11 Hz and 3 Hz, 1H, H--C (3)), 2.383 (m, 1H, H--C
(6)), 2.615 (dt, J=17 and 4 Hz, 1H, H--C (6)), 3.57 (dm, J=17 Hz,
1H, H--C (3)), 4.17 (q, J=7 Hz, 2H, H.sub.2C (9)), 6.42 (m, 1H,
H--C (7)). Assignments according to numbers given on the
formula.
[0170] IR (film): strong absorptions at 1719, 1698 and 1200
cm.sup.-1.
[0171] MS (EI): m/z 210 (M.sup.+), 164 (M-C.sub.2H.sub.5OH).sup.+,
135.
c). Synthesis of
1-(2-Chloro-6-methyl-phenyl)-5-ethyl-1,4,5,6-tetrahydro-indol-2-one
##STR00069##
[0172] 3.45 g of 2-Chloro-6-methyl-aniline are dissolved in 26 ml
of toluene. 0.227 g of p-toluene-sulfonic acid (mono hydrate) are
added and the mixture is heated to reflux. A solution of 5.0 g of
(5-Ethyl-2-oxo-cyclohexylidene)acetic acid ethyl ester in 13 ml of
toluene is added drop-wise during 75 minutes and the water formed
is collected by the means of a water separator. The reaction
mixture is heated to reflex for 15 hours, during which time the
condensing solvent is frequently removed and replaced by fresh
toluene. For work-up, the mixture is cooled to 22.degree. C. and is
treated with 70 ml of saturated aqueous sodium bicarbonate solution
under rigorous stirring. The layers are separated and the toluene
phase is washed with a 5% aqueous solution of citric acid and f
with a 10% solution of sodium chloride in water. The aqueous phases
are extracted with 70 ml of toluene and the toluene phases are
combined. The solvent is evaporated in vacuo to yield 7.1 g of the
crude product as a highly viscous oil. An analytical sample of the
crude product can be purified by chromatography on silica gel using
toluene/ethyl acetate (9:1) as eluent to yield pure
1-(2-Chloro-6-methyl-phenyl)-5-ethyl-1,4,5,6-tetrahydro-indol-2-one.
[0173] .sup.1H-NMR (d.sub.6-DMSO, 400M 300K) .delta. 0.894 ppm (t,
J=7 Hz, 3H, H.sub.3C (11)), 1.34-1.43 (m, 2H, H.sub.2C (10)),
1.70-1.82 (m, 1H, H--C (5)), 1.90-2.02 (m, 1H, H--C (6)), 2.038 (s,
1H, H.sub.3C (6')), 2.28-2.40 (m, 2H, H--C (4) and H--C (6)), 2.87
(dd, J.sub.1=17 Hz and J.sub.3=4 Hz, 1H, H--C (4)), 5.14 (m, 1H,
H--C (5)), 5.96 (broad s, 1, H--C (3)), 7.3-7.5 (m, 3H, H--C (3'),
H--C (4'), H--C (5')). Assignments according to the numbers given
on the formula.
[0174] IR (film): strong absorptions at 1703, 1660 and 1476
cm.sup.-1.
[0175] MS (EI): m/z 287 (M.sup.+), 272 (M-CH.sub.3).sup.+, 258
(M-C.sub.2H.sub.5).sup.+, 252 (M-Cl).sup.+.
d): Synthesis of N-(2-Chloro-6-methyl-phenyl)-5-ethyl-oxindole
##STR00070##
[0177]
1-(2-Chloro-6-methyl-phenyl)-5-ethyl-1,4,5,6-tetrahydro-indol-2-one
can be oxidized by classical methods, e.g. with 10% Pd--C in
refluxing xylene to yield
N-(2-Chloro-6-methyl-phenyl)-5-ethyl-oxindole.
[0178] .sup.1H-NMR and MS spectra see example 7g.
[0179] Lactams of Formula II as defined above are converted to
compounds of Formula I as defined above, for instance as described
in Example 9 below.
Example 9a
5-Methyl-2 (2',6'-dichloro-4'-methylanilino)phenylacetic acid
##STR00071##
[0180] A mixture of 1.5 g of
N-(2',6'-dichloro-4'-methylphenyl)-5-methyloxindole, 18 ml of
ethanol and 1 ml of water is heated to reflux. 1.9 g of a 30%
sodium hydroxide solution is slowly added and reflux is continued
for 45 h. The solution is cooled to about 40.degree. C. and treated
slowly with a solution of 1.5 g of concentrated hydrochloric acid
in 12 nm of water up to a pH of 3-4. The obtained suspension is
cooled to 20.degree. C. The crystals are collected by filtration,
washed with water and dried giving
5-Methyl-2-(2',6'-dichloro-4'-methylanilino)phenylacetic acid.
[0181] Mp: 179-182.degree. C. .sup.1H-NMR (DMSO-d6, 300K, 500 Mz)
2.22 [s, 3H, CH.sub.3--C (5)]; 2.32[s, 3H, CH.sub.3C (4')]; 3.67
(s, 2H, CH.sub.2); 6.18 [d, 1H, HC (3)], 6.87 [s, d, 1H, HC (4)];
6.97 (s, 1H, NH); 7.02 [s, 1H, HC (6)]; 7.36 [s, 2H, HC (3') and HC
(5')]; 12.68 (br. s, 1H, COOH).
Example 9b
5-Methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid
[0182] Same procedure as 9a
[0183] Mp: 152-154.degree. C. .sup.1H-NMR (DMSO-d6, 500 MHz, 300K)
.delta. 2.21 (s, 3H, CH.sub.3), 3.64 (s, 2H, CH.sub.2); 6.42 [dd,
1H, HC (3)], 6.90 [dd, 1H, HC (4)], 7.01 [d, 1H, HC (6)], 7.09 (s,
1H, NH), 7.09 [ddd, 1H, HC (4')], 7.23 [ddd, 1H, HC (5')], 7.34
[ddd, 1H, HC (3')], 12.67 (s, 1H, COOH).
Example 9c
5-Methyl-2-(2',3',4',6'-tetrafluoroanilino)-phenylacetic acid
##STR00072##
[0184] The suspension of 350 mg of
N-(2',3',4',6'-tetrafluorophenyl)-5-methyloxindole in 20 ml of
ethanol and 5 ml of water is degassed by pang through nitrogen for
1.5 h. Then 26 mg of 30% aqueous sodium hydroxide added and the
mixture is heated to reflux for 6.5 hours. Most of the ethanol is
then removed by distillation the mixture is cooled to room
temperature followed by the slow addition of 1N hydrochloric acid
(1.05 g) to reach a pH of about 3. The precipitate is then
filtered, washed with ethanol/water (1:1) and dried in vacuo at
room temperature affording the title product.
[0185] Mp: 145-146.degree. C.
[0186] .sup.1H-NMR (300 MHz, DMSO-d6): 2.23 (s, 3H, CH3); 3.65 (s,
2H, CH2-COO); 6.55 [s, 1H, HC (3)]; 6.92 [d, 1H, HC (4)]; 7.00 [s,
1H, HC86)]; 7.20 (s, 1H, NH); 7.50 [m, 1H, HC (5')].
[0187] Similarly other lactams of formula II are converted to
compounds of Formula I substantially as described above.
* * * * *