Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR PREPARING 4-HYDROXY INDOLE, INDAZOLE AND
C:ARBAZOLE COMPOUNDS
This invention relates to a process for preparing
certain 4-hydroxy indole, indazole and 4-hydroxy carbozole
compounds useful as intermediates for preparing compounds
useful for inhibiting sPLA2 mediated release of fatty acids
for conditions such as septic shock.
Certain 1H-:indole-3-glyoxamides are known to be
potent and selective .inhibitors of mammalian sPLA2 useful
for treating diseases,. such as septic shock, adult
respiratory distress syndrome, pancreatitis, trauma,
bronchial asthma, allf~rgic rhinitis, rheumatoid arthritis
and related sPLA2 induced diseases. EPO publication No.
0675110, far example, discloses such compounds.
Various patE~nts and publications describe
processes for making l.hese compounds using 4-hydroxy indole
intermediates.
The article,, "Recherches en serie indolique. VI
sur tryptamines substituees", by Marc Julia, Jean Igolen and
Hanne Igolen, Bull. Sor_. Chim. France, 1962, pp. 1060-1068,
describes certain indole-3-glyoxylamides and their
conversion to tryptamine derivatives.
The article,. "2-Aryl-3-Indoleglyoxylamides
(FGIN-1): A New Class of Potent and Specific Ligands for
the Mitochondrial DBI Receptor (MDR)" by E. Romeo, et al.,
The Journal of Pharmacology and Experimental Therapeutics,
Vol. 262, No. 3, (pp. 971-978) describes certain 2-aryl-3-
indolglyoxylamides having research applications in mammalian
central nervous systems.
The abstraci~, "Fragmentation of N-benzylindoles in
Mass Spectrometry"; Chemical Abstracts, Vol. 67, 1967,
73028h, reports various benzyl substituted phenols including
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those having glyoxy:Lamide groups at the 3 position of the
indole nucleus.
U.S. Patent No. 3,449,363 describes
trifluoromethylindo:Les having glyoxylamide groups at the 3
position of the indole nucleus.
U.S. Patent No. 3,351,630 describes alpha-
substituted 3-indolyl acetic acid compounds and their
preparation inclusive of glyoxylamide intermediates.
U.S. Patent No. 2,825,734 describes the
preparation of 3-(2--amino-1-hydroxyethyl)indoles using 3-
indoieglyoxylamide :intermediates such as 1-phenethyl-2-
ethyl-6-carboxy-N-propyl-3-indoleglyoxylamide (see, Example
30) .
U.S. Patent No. 4,397,850 prepares isoxazolyl
indolamines using g:Lyoxylamide indoles as intermediates.
U.S. Patent No. 3,801,594 describes analgesics
prepared using 3-indoleglyoxylamide intermediates.
The artic:Le, "No. 565. - Inhibiteurs d'enzymes.
XII. - Preparation de (propargylamino-2 ethyl)-3 indoles" by
A. Alemanhy, E. Fernandez Alvarez, 0. Nieto Lopey and M.E.
Rubio Herraez; Bulletin De La Societe Chimique De France,
1974, No. 12, pp. 2883-2888, describes various indolyl-3
glyoxamides which a:re hydrogen substituted on the 6-membered
ring of the indole nucleus.
The article "Indol-Umlagerung von 1-Diphenylamino-
2,3-dihydro-2,3-pyr:rolidonen" by Gert Kollenz and Christa
Labes; Liebigs Ann. Chem., 1975, pp. 1979-1983, describes
phenyl substituted :3-glyoxylamides.
Many of these processes employ a 4-hydroxy indole
intermediate. For example U.S. Patent No. 5,654,326 U.S.,
herein incorporated by reference in its entirety, discloses
a process for preparing 4-substituted-1H-indole-3-glyoxamide
derivatives comprising reacting an appropriately substituted
4-methoxyindole (prepared as described by Clark, R.D. et
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al., Synthesis, 199:1, pp 871-878, the disclosures of which
are herein incorporated by reference) with sodium hydride in
dimethylformamide at~ room temperature (20-25°C) then
treating with arylmethyl halide at ambient temperatures to
give the 1-arylmethylindole which is 0-demethylated using
boron tribromide in methylene chloride (Tsung-Ying Shem and
Charles A. Winter, Adv. Drug Res., 1977, 12, 176, the
disclosure of which is incorporated by reference) to give
the 4-hydroxyindole. Alkylation of the hydroxy indole is
achieved with an alpha bromoalkanoic acid ester in
dimethylformamide uaing sodium hydride as a base.
Conversion to the g:Lyoxamide is achieved by reacting the oc-
[(indol-9-yl)oxy]allcanoic acid ester first with oxalyl
chloride, then with ammonia, followed by hydrolysis with
sodium hydroxide in methanol.
The proceas for preparing 4-substituted-1H-indole-
3-glyoxamide derivatives, as set forth above, has utility.
However, this proceas uses expensive reagents and
environmentally hazardous organic solvents, produces furan
containing by-products and results in a relatively low yield
of desired product.
In an alt~arnate preparation an appropriately
substituted propronylacetate is halogenated with sulfuryl
chloride. The halogenated intermediate is hydrolyzed and
decarboxylated by treatment with hydrochloric acid then
reacted with an appropriately substituted cyclohexane dione.
Treatment of the alkylated dione with an appropriate amine
affords a 4-keto-indole which is oxidized by refluxing in a
high-boiling polar :hydrocarbon solvent such as carbitol in
the presence of a catalyst, such as palladium on carbon, to
prepare the 4-hydro:xyindole which may then be alkylated and
converted to the desired glyoxamide as described above.
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This process however is limited by the required
high temperature oxidation and requires recovery of a
precious metal catalyst.
While the methods described above for preparing
the 4-hydroxy indole intermediate are satisfactory, a more
efficient transformation is desirable.
The present invention provides an improved process
for preparing 4-hydroxy-indole intermediates. The process
of the present invention can be performed with inexpensive,
readily available, reagents under milder conditions. In
addition, the present process allows for transformation with
a wider variety of substituents on the indole platform.
Other objects, features and advantages of the present
invention will become apparent from the subsequent
description and the appended claims.
The present invention provides a process for
preparing a compound of the formula I
R~
(Ray / ~ /y
N I
i
R
wherein:
Y is -CRQ or -N-;
R9 is H, - (C,-C6) alkyl or when taken together with RZ forms a
cyclohexeny ring
R2 is non-interfering substituent;
R3 is a non-interfering substituent;
m is 1-3 both inclusive; and
R' is selected from groups (a) , (b) and (c) where;
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(a) is - (C1-CZ°) alkyl, - (CZ-C2°) alkenyl, - (CZ-Cz°)
alkynyl,
carbocyclic radicals, or heterocyclic radicals, or
(b) is a memeber of (a) substituted with one or more
independently selected non-interfering
substituents; or
(c) is the group - (L) -Rg°; where, (L) -is a divalent
linking group of 1 to 12 atoms selected from
carbon, hydrogen, oxygen, nitrogen, and sulfur;
wherein the combination of atoms in -(L)- are
selected from the group consisting of (i) carbon
and hydrogen only, (ii) one sulfur only, (iii) one
oxygen only, (iv) one or two nitrogen and hydrogen
only, (v) carbon, hydrogen, and one sulfur only,
and (vi) an carbon, hydrogen, and oxygen only; and
where RR° is a group selected from (a) or (b) ;
which process comprises oxidizing a compound of formula III
R
(Rs)m
m
R III
O
by heating with a base and a compound of the formula RJX
where R is - (C1-C6) alkyl or aryl and X is - (C,-C6) alkoxy,
halo or -OCOZ (C1-C6) alkyl .
The invention provides in addition novel
2 R~X
5 reagents of the formula
where R is -(C1-C6)alkyl, aryl or substituted aryl; and
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X is -OCO, (C1-C6) alkyl provided that when X is -OCOZCH3, R .
cannot be tolulyl.
The present invention provides, in addition novel
intermediates of the formula
C
R~ R2
(:R3)m
R1
wherein:
R is -(Cl-C6)alkyl, aryl or substituted aryl,
Y is -CR9 or -N-;
R" is H, - (C,-C6) alkyl or when taken together with RZ forms a
cyclohexeny ring
Rz is non-interfering substituent;
R3 is a non-interfering substituent;
m is 1-3; and
R' is selected from groups (a} , (b) and (c) where;
(a) is - (C,-CZ°) alkyl, - (C2-C2°) alkenyl, - (Cz-CZ°)
alkynyl,
carbocyclic radicals, or heterocyclic radicals, or
(b) is a memeb~er of (a) substituted with one or more
independently selected non-interfering
substituents; or
(c) is the group -(L)-Re°; where, (L)-is a divalent
linking o~roup of 1 to 12 atoms selected from
carbon, hydrogen, oxygen, nitrogen, and sulfur;
wherein t:he combination of atoms in -(L)- are
selected from the group consisting of (i) carbon
and hydrogen only, (ii) one sulfur only, (iii) one
oxygen only, (iv) one or two nitrogen and hydrogen
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only, (v) carbon, hydrogen, and one sulfur only,
and (vi) an carbon, hydrogen, and oxygen only; and
where R~° is a group selected from (a) or (b) .
Such intermediates are useful for preparing compounds
useful for inhibiting sPLAz mediated release of fatty acids
for conditions sur_h. as septic shock.
Other objects, features and advantages of the
present invention will become apparent from the subsequent
description and the appended claims.
The compounds of the invention employ certain
defining terms as follows:
As used herein, the term, "alkyl" by itself or as
part of another substituent means, unless otherwise defined,
a straight or branched chain monovalent hydrocarbon radical
such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
tertiary butyl, isobutyl, sec-butyl tert butyl, n-pentyl,
isopentyl, neopenty~., heptyl, hexyl, octyl, nonyl, decyl,
undecyl, dodecyl, t:ridecyl, tetradecyl and the like. The
term "alkyl" includes
- (C1-C2) alkyl, - (-C:4) alkyl, - (Cl-C6) alkyl, - (C5-C14) alkyl,
and -(C1-C10)alkyl.
The term "alkenyl" as used herein represents an
olefinically unsaturated branched or linear group having at
least one double bond. Examples of such groups include
radicals such as vinyl, allyl, 2-butenyl, 3-butenyl,
2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-
hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-
heptenyl, 6-heptenyl as well as dimes and trienes of
straight and branched chains.
The term "alkynyl" denotes such radicals as
ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl as
well as di- and tri-ynes.
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The term "(Cl-C10) alkoxy", as used herein,
denotes a group such as methoxy, ethoxy, n-propoxy,
isopropoxy, n-butox:y, t-butoxy, n-pentoxy, isopentoxy,
neopentoxyl, heptox:y, hexoxy, octoxy, nonoxy, decoxy and
like groups, attached to the remainder of the molecule by
the oxygen atom. The term (C,-Clo) alkoxy includes (C1
C6) alkoxy.
The term "halo" means fluoro, chloro, bromo or
iodo.
The term "aryl" means a group having the ring
structure characteristic of benzene, pentalene, indene,
naphthalene, azulene, heptalene, phenanthrene,
anthracene,etc. 'The aryl group may be optionally
substituted with 1 too 3 substituents selected from the group
consisting of (C1-C;~) alkyl (preferably methyl) ,
(C1-C6)alkoxy or halo (preferable fluorine or chlorine).
The term, "heterocyclic radical", refers to
radicals derived from monocyclic or polycyclic, saturated or
unsaturated, substituted or unsubstituted heterocyclic
nuclei having 5 to 14 ring atoms and containing from 1 to 3
hetero atoms selected from the group consisting of nitrogen,
oxygen or sulfur. Typical heterocyclic radicals are
pyridyl, thienyl, i=luorenyl, pyrrolyl, furanyl, thiophenyl,
pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl,
isoxazolyl, oxazolvl, thiazolyl, thiadiazolyl, indolyl,
carbazolyl, norharrnanyl, azaindolyl, benzofuranyl,
dibenzofuranyl, th_Lanaphtheneyl, dibenzothiophenyl,
indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl,
anthranilyl, 1,2-bf~nzisoxazolyl, benzoxazolyl,
benzothiazolyl, purinyl, pryidinyl, dipyridylyl,
phenylpyridinyl, bc~nzylpyridinyl, pyrimidinyl,
phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl,
phthalazinyl, quinazolinyl, and quinoxalinyl.
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The term "carbocyclic radical" refers to radicals
derived from a saturated or unsaturated, substituted or
unsubstituted 5 to 14 membered organic nucleus whose ring
forming atoms (other than hydrogen) are solely carbon atoms.
Typical carbocyclic radicals are cycloalkyl, cycloalkenyl,
phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl,
xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl,
phenylcyclohexeyl, acenaphthylenyl, and anthracenyl,
biphenyl, bibenzylyl and related bibenzylyl homologues
represented by the formula (bb),
(CHI) '~ ~ ~ (bb)
where n is an integ~=_r from 1 to 8.
The term, "non-interfering substituent", refers to
hydrogen, - (Cl-C14 ) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl,
-(C~-C12)aralkyl, -(C~-C12)alkaryl, -(C3-Cg)cycloalkyl,
-(C3-Cg)cycloalkeny:l, phenyl, tolulyl, xylenyl, biphenyl,
- (Cl-C6) alkoxy, - (C2-C6) alkenyloxy, - (C2-C6) alkynyloxy,
-(C1-C12}alkoxyalky:l, -(Cl-C12)alkoxyalkyloxy,
-(C1-C12)alkylcarbonyl, -(C1-C12)alkylcarbonylamino,
-(C1-C12)alkoxyamino, -(Cl-C12)alkoxyaminocarbonyl,
-(C1-C12)alkylamino, -(C1-C6)alkylthio,
- (C1-C12) alkylthiocarbonyl, - (C1-C6) alkylsulfinyl,
- (Cl-C6) alkyl.sulfon:yl, - (C1-C6) haloalkoxy,
- (C1-C6) haloalkylsu:lfonyl, - (Cl-C6) haloalkyl,
- (C1-Cg) hydroxyalky:l, - (CH2 ) nCN, - (CH2) nNR9R10,
-C (0) 0 (Cl-C6alkyl) , - (CH2) n0 (C1-C6 alkyl) , benzyloxy,
phenoxy, phenylthio; - (CONHS02) R'S, where R'S is - (C1-
C6) alkyl; -CFA , naphthyl or - (CHz) t;phenyl where s is 0-5;
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-CHO, -CF;, -OCF3, ~>yridyl, amino, amidino, halo, carbamyl,
carboxyl, carbalkoxy, -(CH2)nC02H, cyano, cyanoguanidinyl,
guanidino, hydrazide, hydrazino, hydrazido, hydroxy,
hydroxyamino, vitro, phosphono, -S03H, thioacetal,
thiocarbonyl, furyl, thiophenyl -COR9, -CONR9R1°, -NR9R"', -
NCHCOR9, -SOZR9, -UR9, -SR9, CH?50~R'3, tetrazolyl or tetrazolyl
subs tituted with - (C1-C6) alkyl, phenyl or - (C1-
Cq) alkylphenyl, - (C13~) "OSi (C1-C°) alkyl and (Cl-
C6)alkylcarbonyl; where n is from 1 to 8 and R9 and R'' are
independently hydrogen, -CF3, phenyl, - (C1-C9) alkyl, - (CI-
CQ) al kylphenyl or -phenyl (C,-C~) alkyl.
A preferred group of compounds of formula I
prepared by the process of the instant invention are those
wherein:
Y is CR' where RQ :i~; H or when taken together with R' forms a
cyclohexenyl ring;
R3 is H, -0 (C1-C4) alkyl, halo, - (C1-C6) alkyl, phenyl, - (C,-
Cg) alkylphenyl; phenyl substituted with - (C;-C6) alkyl,
halo, or -CF3; -CHZOSi (C1-C6) alkyl, furyl, thiophenyl, -
(C1-C6) hydroxyalkyl, - (C1-Cs) alkoxy (C,-C6) alkyl, - (C;-
C6) alkoxy (C1-C5) alkenyl; or - (CHZ) "RB where R8 is H, -
CONH~, -NR9R'°, -CN or phenyl where R9 and R'° are
independently hydrogen, -CF;, phenyl, - (C,-CQ) alkyl,
(C1-CQ) alkylphenyl or -phenyl (C1-CQ) alkyl and n is 1 to
8 ; and
Rl is H, - (C5-C14) alkyl, - (C3-C14) cycloalkyl, pyridyl, phenyl
or phenyl substituted with from 1-5 substituents
selected from the group consisting of -(C,-C6)alkyl,
halo, -CF3, -OCF3 , - (C1-Cq) alkoxy, -CN, - (C1-
Cq) alkylthio, phenyl (C1-CQ) alkyl, - (C1-Cg) alkylphenyl,
phenyl, phenox:y, -OR9; where R9 and Rl° are
independently hydrogen, -CF3, phenyl, - (C1-C4) alkyl, -
(C,-C~) alkylphenyl or -phenyl (C,-CQ) alkyl; tetrazole;
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tetrazole substituted with - (C,-C9) alkyl or - (C,-
Cq ) alkylphenyl;~ or naphthyl .
The process of the present invention provides an
improved method for synthesizing the compounds of formula I
using inexpensive, readily available reagents as shown in
Scheme I as follows.
Scheme I
RS
1 ) base
(Rs)~ 2)RII (R.
R1
R
(III) (II)
Rz
(R3)
R1
(I)
Ketone (III) is dissolved in a suitable solvent preferably
an aprotic solvent such as THF. Other suitable solvents
include but are not limited to DMF, dioxane, or toluene.
The substrate/solvent solution may be sonicated or heated
slightly, if necessary to facilitate dissolution.
The amount of solvent used should be sufficient to
ensure that all compounds stay in solution until the desired
reaction is complete.
The solution is treated with a base, preferably a
strong base such as sodium hydride, then with a sulfinating
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R~X
agent of the formula where R is -(C,-C6)alkyl, aryl or
substituted aryl and X is (C1-C6) alkoxy, halo or -OCOZ (C~-
C6)alkyl. The sulf:inating reagent may be prepared according
to the procedure of J.W. Wilt et al., J. Org. Chem, 1967,
32, 2097. Preferred sulfinating agents include methyl p-
tolyl sulfinate, methylbenzene sulfinate or p-toluylsulfinic
isobutyric anhydride. Other suitable bases include but are
not limited to LDA, sodium methoxide, or potassium
methoxide. Preferably two equivalents of base are used.
Preferably, when sodium hydride is employed, the base is
added before the sulfinating reagent. The order of addition
of reagents is not important when sodium methoxide is used.
The reaction may be conducted at temperatures from
about 25°C to reflu:~, preferably at reflux and is
substantially complete in from one to 24 hours.
The amount of sulfinating reagent is not critical,
however, the reaction is best accomplished using a molar
equivalent or excess relative to the starting material
(III) .
The above reactions may be run as a "one pot"
process with the reactants added to the reaction vessel in
the order given above, preferably with an acid quench of the
base prior to reflux.
Dioxane is a preferred solvent in a "one part"
process. THF and toluene, respectively, are preferred
solvents if a "two pot" process is employed.
The intermediate (II) can be isolated and purified
using standard crystalization or chromatographic procedures.
Standard analytical techniques such as TLC or HPLC
can be used to monitor the reactions in order to determine
when the starting materials and intermediates are converted
to product.
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In an alternate preparation, the sulfinating
reagent can be replaced with a disulfide compound of the
formula RZ°SSRZ°~wherEa RZ° is alkyl or aryl. Oxidation
of the
sulfide intermediate can then be readily achieved using an
appropriate oxidizing reagent such as hydrogen peroxide or
m-chloroperbenzoic acid.
It will be readily appreciated by the skilled
artisan that the starting materials for all of the above
procedures are either commercially available or can be
readily prepared by known techniques from commercially
available starting materials. For example, when X is N,
starting material (1) can be prepared according to the
procedure of Peet, N~.P., et al,. Heterocycles, Vol. 32, No.
1, 1991, 41.
When Y is -CHZR", starting material V, is prepared
according to the following procedure.
C r. l., r"n r. T T
0 0 0 0
$ $
R ~O~~Rv o ----~ R ~0 R3 0
X Cl IX
O 0
O Rso
Cl~R3 0
O
R3 O R3 0
VIII VII VI
0
~R3 0
R 3 //~~''N
R1
V
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R$ is - (C1-C6) alkyl or aryl
R~° is H or - (C,-C6) alkyl
An appropriately substituted propionyl acetate X
is first halogenated by treatment with sulfuryl chloride,
preferably at equimolar concentrations relative to the
starting material, a t temperatures of from about 0°C to
25°C, preferably less than 15°C, to prepare IX.
Hydrolysis and decarboxylation of IX is achieved
by refluxing with an aqueous acid, such as hydrochloric
acid, for from about= 1 to 24 hours. The solution containing
the decarboxylated product VIII is neutralized to adjust the
pH to about 7.0-7.5,, then reacted with cyclohexanedione VII
(preferably at equimolar concentrations) and a base,
preferably sodium hydroxide, to yield the triketone
monohydrate VI as a precipitate which may be purified and
isolated, if desired. The reaction is preferably conducted
at temperatures of :From -20°C to ambient temperatures and is
substantially complete in about 1 to 24 hours.
The above .reactions are preferably run as a "one
pot" process with the reactants added to the reaction vessel
in the order given above. Preferably, the reaction is
allowed to proceed without isolating compounds of formula IX
or VIII, thus avoiding exposure to these volatile
lachrymators.
Preparation of V is achieved by refluxing VI in a
high boiling non-polar solvent which forms an azeotrope with
water, preferably toluene, with an equimolar quantity of an
amine of the formula R1NH2, where R1 is as defined above.
When R1 is hydrogen, hexamethyldisilazane or ammonia may be
used.
Solvents with a boiling point of at least 100°C
are preferred, such as toluene, xylene, cymene, benzene,
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1,2-dichloroethane o:r mesitylene, thus eliminating the need
for a pressure reaci~or. Sufficient solvent should be
employed to ensure i~hat all compounds stay in solution until
the reaction is substantially complete in about 1 to 24
hours.
The following examples further illustrate the
process of the present invention. The examples also
illustrate the prepa ration of the intermediate compounds of
this invention. The=_ examples are illustrative only and not
intended to limit the scope of the invention in any way.
Preparation 1
1-Benzyl-2-et:hyl-4-oxo-4,5,6,7-tetrahydroindole
0 0
benzylam
o toluene
A. Preparation of 2-(2-oxobutyl)-1,3-cyclohexanedione
Methyl propionylacetate (130.158, 1.0 mol) is
placed into a 2L Morton flask equipped with a mechanical
stirrer, nitrogen inlet and thermocouple. External cooling
is applied until the internal temperature is 10°C. Sulfuryl
chloride (1358, 1.0 mol) is added dropwise at a rate to
maintain the temperature <15°C. When chromatographic
analysis indicaets the total conversion to the desired
chloro-compound 1M HCl (205 mL) is then added, and the
reaction mixture is stirred at reflux for 18 hours. After
cooling to room temperature, 4N NaOH is added to adjust the
pH tc 7.0 to 7.5. Cyclohexanedione (112.138, 1.0 mol) is
added and the mixture is cooled in an ice bath. Then, 5N
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NaOH (200mL, 1.0 mol) is added dropwise and the reaction is
stirred for 18 hours at room temperature. The resulting
thick precipitate is filtered, rinsed with water), and dried
in vacuo to yield the subtitled triketone monohydrate.
B. Preparation of 1-Benzyl-2-ethyl-4-oxo-4,5,6,7-
tetrahydroindole
The compound of Part A, above (1000gms,
4.995moles) was suspended in toluene (6000m1, 6vo1). The
mixture was warmed to 85°C and stirred for 5 minutes.
Benzylamine (562.6gms, 5.25moles, 1.05eq) was added dropwise
over about 30-45 minutes. Following the addition, the
mixture turned to an amber colored solution. Heat was
applied to the solution and water was azeotroped off until
the reaction temperature reached 110°C. The reaction was
allowed to stir ate 110°C for 2 hours at which time about
4000 mls of solvent was distilled off at atmospheric
pressure. The so=Lution was transferred to a Buchi flask and
further evaporated to an amber viscous oil.
Example 1
Preparation of 1-Benzyl-2-ethyl-4-hydroxyindole
The compound of Preparation 1 (0.5 g, 2 mmol) was
dissolved in dioxane (2.5 mL). Sodium hydride (0.18 g, 4.5
mmol) was added. After 5 minutes, methyl benzenesulfinate
(0.49 g, 3.2 mmol) was added. The mixture was warmed until
the color changed to pink. The heat source was removed and
the color of the mixture darkened from pink to red as gas
evolution was observed. Thin layer chromotography indicated
complete consumption of starting material (diastereomeric
sulfoxides, Rf 0.13, 0.19; 1/1 hexane/ethyl acetate).
After 1 hour, dioxame (2.5 mL) was added, followed by acetic
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acid (0.26 mL, 4.5 mmol). The purple slurry was refluxed
for 2 hours at which time the sulfoxides were no longer
observed by thin 7_ayer chromotography . The reaction
mixture was cooled to room temperature and diluted with
chloroform. The solution was washed with saturated sodium
bicarbonate solution, dried over anhydrous sodium sulfate
and evaporated to give a red oil. Column chromatography
with loo ethyl acetate in hexane provided 0.39 g of a yellow
solid. (79% yield)
Elemental Analysis for CI~H1-,NO
Theory: C, 81.24, H, 6.82, N, 5.57
Found: C, 81.13, H, 6.80, N, 5.81.
Example 2
Preparation of 1-Benzyl-2-ethyl-4-hydroxyindole
A. The compound of Preparation 1 (0.5 g, 2 mmol) was
dissolved in tetrahydrofuran (2.5 mL). Sodium hydride (0.18
g, 4.5 mmol) was added. After 5 minutes, methyl
benzenesulfinate (0.49 g, 3.2 mmol) was added. After 15
minutes, the color of the mixture darkened to red as gas
evolution was observed. The mixture was stirred for 1 hour.
Thin Layer Chromotography indicated complete consumption of
starting material (diastereomeric sulfoxides, Rf 0.13,
0.19; 1/1 hexane/ethyl acetate). The reaction mixture was
quenched with water, stirred for 5 minutes, and diluted with
chloroform. The solution was washed with saturated sodium
bicarbonate solution, dried over anhydrous sodium sulfate
and evaporated to give a brown oil. The oil was dissolved
in dioxane (5 mL) and refluxed for 2 hours at which time the
sulfoxides were na longer observed by thin layer
chromatography. The reaction mixture was cooled to room
temperature and diluted with chloroform. The solution was
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washed with saturated sodium bicarbonate solution, dried
over anhydrous sodium sulfate and evaporated to give a red
oil. Column chromatography with lOg ethyl acetate in hexane
provided 0.40 g of a yellow solid. (80o yield)
Example 3
Preparation of 9-benzyl-4-hydroxy-6-methoxy carbazole
A. Preparation of 9-benzyl-4-hydroxy-6-oxy carbazole
A solution of N-benzyl anisidine (2.1 g, 11 mmol),
1,3-cyclohexadione (1.23 g, 11. mmol) and catalytic p-
toluenesulfonic acid in 250 mL toluene was heated to reflux
for 2 h with removal of water by codistillation. The
resulting mixture was cooled to room temperature and
concentrated. A dichloromethane solution of the residue was
loaded on florisil. and the product was eluted with a 1-30
methanol in dichloromethane. The eluent was concentrated
and the resulting material (3.10 g) was dissolved in 250 mL
acetonitrile. Palladium (II) acetate (2.7 g) was added and
the mixture was heated to reflux for 2 h. The mixture was
cooled and concentrated. A dichloromethane suspension of
the mixture was loaded on florisil and the product was
eluted with a 1-3°s methanol in dichloromethane. Additional
purification of the product was accomplished by silica gel
chromatography (1-3o methanol in dichloromethane) to give
800 mg of the desired product. Recrystallization from
dichloromethane/ethanol provided an analytically pure
sample.
Elemental Analysis for C2pHlgN O2:
Calculated: C, 78.66; H, 6.27; N 4.59.
Found: C, 78.90; H, 6.34; N, 4.55.
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B. Preparation of 9-benzyl-4-hydroxy-6-methoxy
carbazole
The compound of part A, above (0.2 g, 0.65 mmol),
was dissolved in tetrahydrofuran (2 mL). Sodium hydride
(0.06 g, 1.5 mmol) was added. After 5 minutes, methyl
benzenesulfinate (0.16 g, 1 mmol) was added. After 30
minutes, the brown mixture was warmed until gas evolution
was sustained. The mixture became a thick paste.
tetrahydrofuran (2 mL) was added and the resultant slurry
was refluxed for 20 minutes. TLC indicated consumption of
starting material (diastereomeric sulfoxides, Rf 0.1, 0.14;
1/1 hexane/ethyl acetate). The reaction mixture was quenched
with water, stirred for 5 minutes, and diluted with
chloroform. The solution was washed with saturated sodium
bicarbonate solution, dried over anhydrous sodium sulfate
and evaporated to give an orange oil. The oil was dissolved
in dioxane (5 mL) a:nd refluxed for 1 hour at which time the
sulfoxides were no longer observed by thin layer
chromatography. The reaction mixture was cooled to room
temperature and diluted with chloroform. The solution was
washed with saturated sodium bicarbonate solution, dried
over anhydrous sodium sulfate and evaporated. Column
chromatography with 80$ chloroform in hexane to 100%
chloroform provided 0.13 g of an amber solid. (65o yield)
Thin layer chromatography Rf 0.27 (20% EtOAc in hexane);
Elemental Analyses for C2oH1-,NOz
Calculated: C, 79.19; H, 5.65; N, 9.62;
Found: C, 79.43; H, 5.62; N, 4.67.
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Example 4
Preparation of 1-(3-chlorophenyl(methyl))-4-hydroxyindole
0 H
' 1. NaH
N _-.. .-.. N
c.
'' Reflux
ci ~ 2. ~..,.ocH, ci
/ 1 /
1-(3-chl.orobenzyl)-4-oxo-4,5,6,7-tetrahydroindole
was prepared from 1,5,6,7-tetrahydro-4H-indol-4-one and 3-
chlorobenzylbromide using methodology common to the art.
The pyrrole (0.5 g, 1.9 mmol) was dissolved in
tetrahydrofuran (2.5 mL). Sodium hydride (0.18 g, 4.4 mmol)
was added. After 5 minutes, methyl benzenesulfinate (0.48
g, 3.1 mmol) was added. The color of the mixture darkened
to red as gas evolution was observed. The mixture was
stirred for 1 hour. Thin layer chromatography indicated
complete consumption of starting material (sulfoxides, Rf
0.11; 1/1 hexane/ethyl acetate). The reaction mixture was
quenched with water, stirred for 10 minutes, and diluted
with chloroform. The solution was washed with saturated
sodium bicarbonate solution, dried over anhydrous sodium
sulfate and evapora.t:ed to give an orange oil. The oil was
dissolved in dioxan.e (5 mL) and refluxed for 3 hours at
which time the sulfoxides were no longer observed by thin
layer chromatography. The reaction mixture was cooled to
room temperature and a solution of lithium hydroxide (85 mg)
in water (2 mL) way; added. The solvent was evaporated and
the residue was di~;solved in chloroform. The solution was
washed with saturated sodium bicarbonate solution, dried
over anhydrous sodium sulfate and evaporated to give an
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orange oil. Column chromatography with 20o ethyl acetate in
hexane provided 0.41 g of a yellow solid. (81o yield) TLC
Rf 0.28 (20o EtOAc in hexane) ; 'H NMR (CDClj) : d 7.30 (d, J
- 8.2, 1 H) , 7.24 (1., J = 7. 8, 1 H) , 7. 18 (s, 1 H) , 7. 11 (t,
J = 7. 9, 1 H) , 7. 07 (d, J = 3.2, 1 H) , 6. 98 (d, J = 7. 6, 1
H) , 6. 92 (d, J = 8.3, 1 H) , 6.75 (d, J = 3. 3, 1 H) , 6. 63 (d,
J = 7. 6, 1 H) , 6.01 (s, 1 H) , 5.24 (s, 2 H) .
Elemental Analyses for C15H12NOC1:
Calculated: C,, 69.91; H, 4.69; N, 5.43; C1, 13.76
Found: C,. 69.75; H, 4.64; N, 5.30; Cl, 14.05.
Example 5
Preparation of l.-phenyl-3-methyl-4-hydroxy indazole
O C~ OH C
~N 1. NaH ~ I ~N
N 2. ~ reflux \ N
w S.OC~ /
Starting material 1-phenyl-3-methyl-4-oxo-9,5,6,7-
tetrahydroindazole (0.2 g, 0.9 mmol, prepared as described
by Peet, N. P.; LeTourneau, M. E. Heterocycles 1991, 32, 41,
was dissolved in tetrahydrofuran (2 mL). Sodium hydride
(0.07 g, 1.6 mmol) was added. After 5 minutes, methyl
benzenesulfinate (0.17 g, 1.1 mmol) was added. The color of
the mixture changed to pink as gas evolution was observed.
The mixture was stirred for 45 minutes. Thin layer
chromatograhy indicated complete consumption of starting
material (sulfoxides, Rf 0.27, 0.33; 1/1 hexane/ethyl
acetate). The reaction mixture was quenched with water,
stirred for 1 hour, arid diluted with dichloromethane. The
solution was washed with saturated sodium bicarbonate
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solution, dried over anhydrous sodium sulfate and evaporated
to give an orange oil. The oil was dissolved in dioxane (2
mL) and refluxed for 1 hour at which time the sulfoxides
were no longer observed by TLC. The reaction mixture was
cooled to room temperature and a solution of lithium
hydroxide (38 mg) in water (2 mL) was added. The solvent
was evaporated and the residue was dissolved in
dichloromethane. The solution was washed with saturated
sodium bicarbonate solution, dried over anhydrous sodium
sulfate and evaporated to give an orange solid. Column
chromatography with 20% ethyl acetate in hexane provided
0.14 g of a white solid. (70~ yield) TLC Rf 0.25 (200
EtOAc in hexane);
Elemental Analysis for C14H12N20:
Calculated: C, 74.98; H, 5.39; N, 12,48; O, 7.13;
Found: C, 75.17; H, 5.65; N, 12.28; O, 7.32.
Example 6
Preparation of 4-hydroxy-9-methyl carbazole
7_ . NaH heat
- --a
2. ArSO~Me Cj-
CH3
A suspension of 9-methyl-4-oxo-1,2,3,4-
tetrahydrocarbazole (prepared by the methods described by
Osuka, A.; Mori, Y.; Suzuki, H. Chem. Lett. 1982, 2031-2034;
and Elz, S.; Heil, W.. L. Biorg. Med. Chem. Lett. 1995, 5,
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667 ) . ( 0 . 20 g, 1 . 0 nu:nol ) in 3 mL tetrahydrofuran was
sonicated and heated to 50 C. Sodium hydride (60%
dispersion in mineral oil; 0.07 g, 1.8 mmol) was added in
one portion. Sonication and heating was continued for 1
hour and then methyl phenylsulfinate (0.2 g, 1.2 mmol) was
added in one portion. The mixture was diluted after 3 hours
with tetrahydrofuran and water to give a homogenous
solution. The solution was concentrated by rotary
evaporation and the residue was partitioned between
dichloromethane and water. The organic layer was washed
with sodium bicarbonate and brine and then dried over
magnesium sulfate, filtered and concentrated. The residue
was dissolved in dioxane and heated to reflux for 1 hour.
The mixture was concentrated and partitioned between
dichloromethane and water. The organic fraction was dried
over magnesium sulfate, filtered and concentrated. The
mixture was purified by silica gel chromatography (20%
EtOAc, hexanes) to 0.075 g of the desired product (38%).
TLC R.f = 0.49 (20% ethyl acetate, hexanes); 13C NMR (CDC13)
d 151.5, 142.6, 140.1, 126.0, 124.6, 122.4, 121.5, 118.8,
110.?, 107.7, 104.6, 101.0, 28.9; mass spectrum, m/z (FD,
M+1) 198.
Example 7
Preparation of 1--phenylmethyl-4-hydroxy-6-methyl indole
OH
1) NaH heat
2) ArS02Me H C ~ I N
3
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To a so_Lution of the 1-phenylmethyl-4-oxo-6-
methyl-4,5,6,7-tet=rahydroindole (l.Og, 3.5 mmol) in 5 mL
tetrahydrofuran was added NaH (0.3 g, 7.5 mmol) in portions.
The resulting mixture was stirred 10 min and methyl
phenylsulfinate (0.7 g, 4.5 mmol) was added in one portion.
The mixture was stirred for 45 minutes and then warmed (35 -
45 C) for 30 minutes. Water (5 mL) was added and the
resulting mixture was stirred for 10 minutes. The
intermediate sul_foxide was extracted with toluene. The
tolurene solution was dried over sodium sulfate, filtered
and concentrated to approximately 50 mL. The mixture was
heated to reflux :Eor 45 min. The solution was cooled to
room temperature and washed with sodium bicarbonate and
brine. The organic solution was dried over Na2S04, filtered
and concentrated to an oil. The residue was purified by
silica gel chromatography (10'-o ethyl acetate in hexanes) to
give 0.60 g of the desired product (600).
