AMINOALKYLBENZOFURANS AS SEROTONIN (5-HT(2C)) AGONISTS

AMINOALKYLBENZOFURANNES FAISANT OFFICE D'AGONISTES DE LA SEROTONINE (5-HT(2C))

English Abstract

The present invention provides serotonergic aminoalkylbenzofurans of Formula
(I): where R, R1, R2, R3, R4, R4', R5, R5', and R12 are as described in the
specification.

French Abstract

La présente invention concerne des aminoalkylbenzofurannes sérotoninergiques de formule (I), dans laquelle R, R?1¿, R?2¿, R?3¿, R?4¿, R?4'¿, R?5¿, R?5'¿ et R?12¿ sont tels que définis dans le mémoire descriptif.

Claims

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WE CLAIM:

1. The compounds of Formula I:
Image
where:
A is -CHR13- or a bond;
R is hydrogen, halo, cyano, -C(O)NR6R7, C1-C6 alkyl,
C1-C4 alkoxycarbonyl, carboxy, or phenyl optionally
substituted with one or two substituents selected from the
group consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;
R1 is hydrogen, halo, cyano, carboxamido, formyl,
trimethylsilyl, trifluoromethyl, pentafluoroethyl, or C1-C6
alkyl;
R2 and R3 are independently hydrogen, halo, amino,
nitro, C1-C4 alkoxy, cyano, carboxamido, -C(O)NR8R9,
-NR10R11, -NHC(O)NHR14, C1-C4 alkoxycarbonyl, carboxyl,
trifluoromethyl, or C1-C6 alkyl optionally substituted with
a substituent selected from the group consisting of C1-C4
alkoxy, hydroxy, phenoxy, and phenyl;
R4 and R4' are independently hydrogen, C1-C4 alkyl, or
benzyl; or R4 and R4' together with the carbon atom to which
they are attached form a cyclopropyl moiety;
R5 is hydrogen, C1-C4 alkyl, or benzyl;
R5' is hydrogen, or R5 and R5' together with the carbon
atom to which they are attached form a cyclopropyl moiety;
R6 and R7 are independently hydrogen or C1-C4 alkyl;


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R8 is hydrogen or C1-C4 alkyl;
R9 is C1-C8 alkyl where the alkyl chain is optionally
substituted with a substituent selected from the group
consisting of carboxy, phenyl, or pyridyl, said phenyl or
pyridyl substituent optionally substituted with one or two
substituents selected from the group consisting of halo, C1-
C4 alkyl, or C1-C4 alkoxy;
R10 is hydrogen or C1-C4 alkyl;
R11 is C1-C4 alkyl or C1-C4 acyl;
R12 is hydrogen, halo, or C1-C4 alkyl;
R13 is hydrogen, C1-C4 alkyl, or benzyl;
R14 is hydrogen, C1-C4 alkyl, or phenyl optionally
substituted with a substituent selected from the group
consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;
or pharmaceutically acceptable acid addition salts thereof.
2. A pharmaceutical formulation which comprises, in
association with a pharmaceutically acceptable carrier,
diluent or excipient, a compound of Formula I:
Image
where:
A is -CHR13- or a bond;
R is hydrogen, halo, cyano, -C(O)NR6R7, C1-C6 alkyl,
C1-C4 alkoxycarbonyl, carboxy, or phenyl optionally
substituted with one or two substituents selected from the
group consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;




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R1 is hydrogen, halo, cyano, carboxamido, formyl,
trimethylsilyl, trifluoromethyl, pentafluoroethyl, or C1-C6
alkyl;
R2 and R3 are independently hydrogen, halo, amino,
nitro, C1-C4 alkoxy, cyano, carboxamido, -C(O)NR8R9,
-NR10R11, -NHC(O)NHR14, C1-C4 alkoxycarbonyl, carboxyl,
trifluoromethyl, or C1-C6 alkyl optionally substituted with
a substituent selected from the group consisting of C1-C4
alkoxy, hydroxy, phenoxy, and phenyl;
R4 and R4' are independently hydrogen, C1-C4 alkyl, or
benzyl; or R4 and R4' together with the carbon atom to which
they are attached form a cyclopropyl moiety;
R5 is hydrogen, C1-C4 alkyl, or benzyl;
R5' is hydrogen, or R5 and R5' together with the carbon
atom to which they are attached form a cyclopropyl moiety;
R6 and R7 are independently hydrogen or C1-C4 alkyl;
R8 is hydrogen or C1-C4 alkyl;
R9 is C1-C8 alkyl where the alkyl chain is optionally
substituted with a substituent selected from the group
consisting of carboxy, phenyl, or pyridyl, said phenyl or
pyridyl substituent optionally substituted with one or two
substituents selected from the group consisting of halo, C1-
C4 alkyl, or C1-C4 alkoxy;
R10 is hydrogen or C1-C4 alkyl;
R11 is C1-C4 alkyl or C1-C4 acyl;
R12 is hydrogen, halo, or C1-C4 alkyl;
R13 is hydrogen, C1-C4 alkyl, or benzyl;
R14 is hydrogen, C1-C4 alkyl, or phenyl optionally
substituted with a substituent selected from the group
consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;
or pharmaceutically acceptable acid addition salts thereof.

3. A method for increasing activation of the 5-HT2C
receptor in mammals, comprising administering to a mammal in


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need of such activation a pharmaceutically effective amount
of a compound of Formula I:
Image
where:
A is -CHR13- or a bond;
R is hydrogen, halo, cyano, -C(O)NR6R7, C1-C6 alkyl,
C1-C4 alkoxycarbonyl, carboxy, or phenyl optionally
substituted with one or two substituents selected from the
group consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;
R1 is hydrogen, halo, cyano, carboxamido, formyl,
trimethylsilyl, trifluoromethyl, pentafluoroethyl, or C1-C6
alkyl;
R2 and R3 are independently hydrogen, halo, amino,
nitro, C1-C4 alkoxy, cyano, carboxamido, -C(O)NR8R9,
-NR10R11, -NHC(O)NHR14, C1-C4 alkoxycarbonyl, carboxyl,
trifluoromethyl, or C1-C6 alkyl optionally substituted with
a substituent selected from the group consisting of C1-C4
alkoxy, hydroxy, phenoxy, and phenyl;
R4 and R4' are independently hydrogen, C1-C4 alkyl, or
benzyl; or R4 and R4' together with the carbon atom to which
they are attached form a cyclopropyl moiety;
R5 is hydrogen, C1-C4 alkyl, or benzyl;
R5' is hydrogen, or R5 and R5' together with the carbon
atom to which they are attached form a cyclopropyl moiety;
R6 and R7 are independently hydrogen or C1-C4 alkyl;
R8 is hydrogen or C1-C4 alkyl;


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R9 is C1-C8 alkyl where the alkyl chain is optionally
substituted with a substituent selected from the group
consisting of carboxy, phenyl, or pyridyl, said phenyl or
pyridyl substituent optionally substituted with one or two
substituents selected from the group consisting of halo, C1-
C4 alkyl, or C1-C4 alkoxy;
R10 is hydrogen or C1-C4 alkyl;
R11 is C1-C4 alkyl or C1-C4 acyl;
R12 is hydrogen, halo, or C1-C4 alkyl;
R13 is hydrogen, C1-C4 alkyl, or benzyl;
R14 is hydrogen, C1-C4 alkyl, or phenyl optionally
substituted with a substituent selected from the group
consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;
or pharmaceutically acceptable acid addition salts thereof.
4. A method for the treatment of obesity in mammals,
comprising administering to a mammal in need of such
treatment an effective amount of a compound of Formula I:
Image
where:
A is -CHR13- or a bond;
R is hydrogen, halo, cyano, -C(O)NR6R7, C1-C6 alkyl,
C1-C4 alkoxycarbonyl, carboxy, or phenyl optionally
substituted with one or two substituents selected from the
group consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;


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R1 is hydrogen, halo, cyano, carboxamido, formyl,
trimethylsilyl, trifluoromethyl, pentafluoroethyl, or C1-C6
alkyl;
R2 and R3 are independently hydrogen, halo, amino,
nitro, C1-C4 alkoxy, cyano, carboxamido, -C(O)NR8R9,
-NR10R11, -NHC(O)NHR14, C1-C4 alkoxycarbonyl, carboxyl,
trifluoromethyl, or C1-C6 alkyl optionally substituted with
a substituent selected from the group consisting of C1-C4
alkoxy, hydroxy, phenoxy, and phenyl;
R4 and R4' are independently hydrogen, C1-C4 alkyl, or
benzyl; or R4 and R4' together with the carbon atom to which
they are attached form a cyclopropyl moiety;
R5 is hydrogen, C1-C4 alkyl, or benzyl;
R5' is hydrogen, or R5 and R5' together with the carbon
atom to which they are attached form a cyclopropyl moiety;
R6 and R7 are independently hydrogen or C1-C4 alkyl;
R8 is hydrogen or C1-C4 alkyl;
R9 is C1-C8 alkyl where the alkyl chain is optionally
substituted with a substituent selected from the group
consisting of carboxy, phenyl, or pyridyl, said phenyl or
pyridyl substituent optionally substituted with one or two
substituents selected from the group consisting of halo, C1-
C4 alkyl, or C1-C4 alkoxy;
R10 is hydrogen or C1-C4 alkyl;
R11 is C1-C4 alkyl or C1-C4 acyl;
R12 is hydrogen, halo, or C1-C4 alkyl;
R13 is hydrogen, C1-C4 alkyl, or benzyl;
R14 is hydrogen, C1-C4 alkyl, or phenyl optionally
substituted with a substituent selected from the group
consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;
or pharmaceutically acceptable acid addition salts thereof.
5. A method for the treatment of depression in
mammals, comprising administering to a mammal in need of


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such treatment an effective amount of a compound of Formula
I:
Image
where:
A is -CHR13- or a bond;
R is hydrogen, halo, cyano, -C(O)NR6R7, C1-C6 alkyl,
C1-C4 alkoxycarbonyl, carboxy, or phenyl optionally
substituted with one or two substituents selected from the
group consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;
R1 is hydrogen, halo, cyano, carboxamido, formyl,
trimethylsilyl, trifluoromethyl, pentafluoroethyl, or C1-C6
alkyl;
R2 and R3 are independently hydrogen, halo, amino,
nitro, C1-C4 alkoxy, cyano, carboxamido, -C(O)NR8R9,
-NR10R11, -NHC(O)NHR14, C1-C4 alkoxycarbonyl, carboxyl,
trifluoromethyl, or C1-C6 alkyl optionally substituted with
a substituent selected from the group consisting of C1-C4
alkoxy, hydroxy, phenoxy, and phenyl;
R4 and R4' are independently hydrogen, C1-C4 alkyl, or
benzyl; or R4 and R4' together with the carbon atom to which
they are attached form a cyclopropyl moiety;
R5 is hydrogen, C1-C4 alkyl, or benzyl;
R5' is hydrogen, or R5 and R5' together with the carbon
atom to which they are attached form a cyclopropyl moiety;
R6 and R7 are independently hydrogen or C1-C4 alkyl;
R8 is hydrogen or C1-C4 alkyl;


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R9 is C1-C8 alkyl where the alkyl chain is optionally
substituted with a substituent selected from the group
consisting of carboxy, phenyl, or pyridyl, said phenyl or
pyridyl substituent optionally substituted with one or two
substituents selected from the group consisting of halo, C1-
C4 alkyl, or C1-C4 alkoxy;
R10 is hydrogen or C1-C4 alkyl;
R11 is C1-C4 alkyl or C1-C4 aryl;
R12 is hydrogen, halo, or C1-C4 alkyl;
R13 is hydrogen, C1-C4 alkyl, or benzyl;
R14 is hydrogen, C1-C4 alkyl, or phenyl optionally
substituted with a substituent selected from the group
consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;
or pharmaceutically acceptable acid addition salts thereof.
6. A method of any of Claims 3, 4, or 5 where the
mammal is human.

Description

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AMINOALKYLBENZOFURANS AS SEROTONIN (5-HT(2C)) AGONISTS
The neurotransmitter serotonin (5-hydroxytryptamine,
5-HT) has a rich pharmacology arising from a heterogeneous
population of at least seven receptor classes. The
serotonin 5-HT2 class is further subdivided into at least
three subtypes, designated 5-HT2a, 5-HT2b, and 5-HT2c. The
5-HT2c receptor has been isolated and characterized (Julius,
et al., U.S. Patent No. 4,985,352), and transgenic mice
lacking the 5-HT2c receptor have been reported to exhibit
seizures and an eating disorder resulting in increased
consumption of food (Julius, et al., U.S. Patent No.
5,698,766). Compounds selective for the 5-HT2c receptor
would provide useful therapies for the treatment of seizure
and eating disorders without the side effects associated
with current therapies.
The present invention provides aminoalkylbenzofurans of
Formula I:
Rs, NH2
RS R4,
~ Ra
A
2
R3 R
R'2
O R
R
where:
I
A is -CHR13- or a bond;
R is hydrogen, halo, cyano, -C(O)NR6R7, C1-C6 alkyl,
C1-C4 alkoxycarbonyl, carboxy, or phenyl optionally
substituted with one or two substituents selected from the
group consisting of halo, C1-C4 alkyl, and C1-Cg alkoxy;



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R1 is hydrogen, halo, cyano, carboxamido, formyl,
trimethylsilyl, trifluoromethyl, pentafluoroethyl, or C1-C6
alkyl;
R2 and R3 are independently hydrogen, halo, amino,
nitro, C1-C4 alkoxy, cyano, carboxamido, -C(O)NRgR9,
-NR10R11, -NHC(0)NHR14, C1-C4 alkoxycarbonyl, carboxyl,
trifluoromethyl, or C1-C6 alkyl optionally substituted with
a substituent selected from the group consisting of C1-C4
alkoxy, hydroxy, phenoxy, and phenyl;
R4 and R4' are independently hydrogen, C1-C4 alkyl, or
benzyl; or R4 and R4' together with the carbon atom to which
they are attached form a cyclopropyl moiety;
R5 is hydrogen, C1-C4 alkyl, or benzyl;
R5' is hydrogen, or R5 and R5' together with the carbon
atom to which they are attached form a cyclopropyl moiety;
R6 and R~ are independently hydrogen or C1-C4 alkyl;
R8 is hydrogen or C1-C4 alkyl;
R9 is C1-Cg alkyl where the alkyl chain is optionally
substituted with a substituent selected from the group
consisting of carboxy, phenyl, or pyridyl, said phenyl or
pyridyl substituent optionally substituted with one or two
substituents selected from the group consisting of halo, C1-
C4 alkyl, or C1-C4 alkoxy;
R10 is hydrogen or C1-C4 alkyl;
R11 is C1-C4 alkyl or C1-C4 acyl;
R12 is hydrogen, halo, or C1-C4 alkyl;
R13 is hydrogen, C1-C4 alkyl, or benzyl;
R14 is hydrogen, C1-C4 alkyl, or phenyl optionally
substituted with a substituent selected from the group
consisting of halo, C1-C~ alkyl, and C1-C4 alkoxy;
or pharmaceutically acceptable acid addition salts
thereof.
This invention also provides a pharmaceutical
formulation which comprises, in association with a



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pharmaceutically acceptable carrier, diluent or excipient, a
compound of Formula I.
The present invention provides a method for increasing
activation of the 5-HT2-C receptor-in mammals by
administering to a mammal in need of such activation a
pharmaceutically effective amount of a compound of Formula
I.
A further embodiment of this invention is a method
for increasing activation of the 5-HT2C receptor for
treating a variety of disorders which have been linked to
decreased neurotransmission of serotonin in mammals.
Included among these disorders are depression, obesity,
bulimia, premenstrual syndrome or late luteal phase
syndrome, alcoholism, tobacco abuse, panic disorder,
anxiety, post-traumatic syndrome, memory loss, dementia
of aging, social phobia, attention deficit hyperactivity
disorder, disruptive behavior disorders, impulse control
disorders, borderline personality disorder, obsessive
compulsive disorder, chronic fatigue syndrome, premature
ejaculation, erectile difficulty, anorexia nervosa,
disorders of sleep, autism, anxiety, seizure disorders,
and mutism. Any of these methods employ a compound of
Formula I.
This invention also provides the use of a compound of
Formula I for the manufacture of a medicament for the
treatment of obesity. Additionally, this invention provides
a pharmaceutical formulation adapted for the treatment of
obesity containing a compound of Formula I. Furthermore,
this invention includes a method for the treatment of
obesity which comprises administering an effective amount of
a compound of Formula I.
The general chemical terms used in the formulae above
have their usual meanings. For example, the term "alkyl"
includes such groups as methyl, ethyl, n-propyl, isopropyl, n-



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butyl, isobutyl, sec-butyl, tert-butyl, and the like. The
term "alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy,
butoxy and the like. The term "acyl" includes such groups as
formyl, acetyl, propionyl, butyryl, 2-methylpropionyl, and the
like. The term "halo" includes fluoro, chloro, bromo and
iodo.
Since the compounds of this invention are amines, they
are basic in nature and accordingly react with any of a
number of inorganic and organic acids to form
pharmaceutically acceptable acid addition salts. Since some
of the free amines of the compounds of this invention are
typically oils at room temperature, it is preferable to
convert the free amines to their pharmaceutically acceptable
acid addition salts for ease of handling and administration,
since the latter are routinely solid at room temperature.
Acids commonly employed to form such salts are inorganic
acids such as hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, and the
like, and organic acids, such as p-toluenesulfonic acid,
methanesulfonic acid, oxalic acid, p-bromophenylsulfonic
acid, carbonic acid, succinic acid, citric acid, benzoic
acid, acetic acid and the like. Examples of such
pharmaceutically acceptable salts thus are the sulfate,
pyrosulfate, bisulfate, sulfite, bisulfate, phosphate,,
monohydrogen-phosphate, dihydrogenphosphate, metaphosphate,
pyro-phosphate, chloride, bromide, iodide, acetate,
propionate, decanoate, caprylate, acrylate, formate,
isobutyrate, caproate, heptanoate, propiolate, oxalate,
malonate, succinate, suberate, sebacate, fumarate, maleate,
butyne-1,4-dioate, hexyne-1,6-dioate, benzoate,
chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxy-
benzoate, methoxybenzoate, phthalate, sulfonate,
xylenesulfonate, phenylacetate, phenylpropionate,
phenylbutyrate, citrate, lactate, (3-hydroxybutyrate,



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glycollate, tartrate, methanesulfonate, propanesulfonate,
naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate
and the like. Preferred pharmaceutically acceptable salts
are those formed with hydrochloric acid.
The skilled artisan will appreciate that.certain of the
compounds of the present invention have at least one chiral
carbon, and may therefore exist as a racemate, as individual
enantiomers or diastereomers, and as mixtures of individual
enantiomers or diastereomers. For example, individual
enantiomers of compounds of the invention where R4' and R5'
are hydrogen and one of R4 and R5 are hydrogen, are
illustrated by the following structures:
NHz NHz NHz NHz
H H R5 RS,...
R4 .~~ R4 H~ H
A A A A
Rs \ Rz Rs \ Rz Rs \ Rz R3 \ Rz
/ / / /
R'z O~R~ R'z O~R~ R'z O~R~ R'z O~Ri
R -R~J -R~~/ R
Individual diastereomers, for example those compounds of the
present invention where R4' and R5' are hydrogen and both R4
and R5 are other than hydrogen, are illustrated by the
following structures:
NHz NHz NHz NHz
R H R ~, H RS.,.. ' H RS".. H
H' R4 H ..~ R4 H ~R4 H ~~ R4
A A A A
\ R2 R3 \ R2 R3 \ R2 Rg \ R2
R
/ / / /
Riz ~ R,z ~ R~z ~ R~z
't-' R O t-' R O't-' R O't-' R
R R R R



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The skilled artisan will appreciate that those compounds of
the invention where variable A is -CHR13- and R13 is other
than hydrogen, and those compounds of the invention where
R4' and R4 are not the same, introduce additional asymmetric
centers into the molecule which create additional optical
isomers as described above.
While it is a preferred embodiment of the invention
that the compounds of the invention exist, are formulated,
and are used as single enantiomers or diastereomers, the
present invention also contemplates the compounds of the
invention existing in racemic form and as mixtures of the
individual enantiomers and diastereomers. The methods and
formulations of the invention also contemplate the use and
formulation of the compounds of the invention in their
racemic form and as mixtures of the individual enantiomers
and diastereomers.
The individual enantiomers and diastereomers may be
prepared by chiral chromatography of the racemic or
enantiomerically or diastereomerically enriched free amine,
or fractional crystallization of salts prepared from racemic
or enantiomerically or diastereomerically enriched free
amine and a chiral acid. Alternatively, the free amine may
be reacted with a chiral auxiliary and the enantiomers or
diastereomers separated by chromatography followed by
removal of the chiral auxiliary to regenerate the free
amine. Furthermore, separation of enantiomers or
diastereomers may be performed at any convenient point in
the synthesis of the compounds of the invention. The
compounds of the invention may also be prepared by the use
of chiral syntheses.
While all of the aminoalkylbenzofurans of Formula I are
useful 5-HT2c agonists, certain classes of the compounds are
preferred. The following paragraphs describe such preferred
classes.



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aa) A is a bond;


ab) A is attached at the 4-position of the benzofuran


ring;


ac) A is attached at the 5-position of the benzofuran


ring;


ad) A is attached at the 6-position of the benzofuran


ring;


ae) A is attached at the 7-position of the benzofuran


ring;


af) R is hydrogen;


ag) R is halo;


ah) R is cyano;


ai) R is -C(O)NR6R~;


aj) R is C1-C6 alkyl;


ak) R is C1-C4 alkoxycarbonyl;


al) R is carboxy;


am) R is phenyl optionally substituted with one or two


substituents selected from the group consisting of halo, C1-C4


alkyl, 1-Cg alkoxy;
and C


an) R1 is hydrogen;


ao) R1 is halo;


ap) R1 is cyano;


aq) R1 is carboxamido;


ar) R1 is trifluoromethyl;


as) R1 is C1-C4 alkyl;


at) R2 is hydrogen;


au) R2 is halo;


av) R2 is fluoro;


aw) R2 is amino;


ax) R2 is C1-C4 alkoxy;


ay) R2 is C1-C4 alkyl optionally substituted with a


substituent selected from the group consisting of C1-Cg


alkoxy, hydroxy, phenoxy, and phenyl;


az) R2 is -C(0)NR8R9;





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ba) R2 is -NR10R11;
bb) R2 is trifluoromethyl;
bc) R3 is hydrogen;
bd) R3 is halo;
be) R3 is fluoro;
bf) R3 is trifluoromethyl;
bg) R3 is C1-C4 alkyl optionally substituted with a
substituent selected from the group consisting of C1-C4
alkoxy, hydroxy, phenoxy, phenyl;
bh) R3 is -NR10R11;
bi) R4 is hydrogen;
bj) R4 is C1-C4 alkyl;
bk) R4 is methyl;
bl) R4~ is hydrogen;
bm) R4' is C1-C4 alkyl;
bn) R4' is methyl;
bo) R4 and R4' taken together with the carbon to which
they are attached form a cyclopropyl moiety;
bp) R5 is hydrogen;


bq) R5 is C1-C4 alkyl;


br) R5 is methyl;


bs) R5' is hydrogen;


bt) R6 is hydrogen;


bu) R6 is C1-C4 alkyl;


bv) R6 is methyl;


bw) R~ is hydrogen;


bx) R~ is C1-Cg alkyl;


by) R~ is methyl;


bz) R8 is hydrogen;


ca) R8 is C1-Cg alkyl;


cb) Rg is methyl;


cc) R10 is hydrogen;


cd) R10 is C1-C4 alkyl;


ce) R10 is methyl;





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cf) R11 is C1-C4 alkyl;


cg) R11 is methyl;


ch) R11 is C1-C4 acyl;


ci) R12 is hydrogen;


cj) R12 is C1-C4 alkyl;


ck) R12 is methyl;


cl) R12 is halo;


cm) R12 is chloro;


cn) R12 is fluoro;


co) The compound is a free base;


cp) The compound is a salt;


cq) The compound is the hydrochloride salt;


cr) The compound is a racemate;


cs) The compound is a single enantiomer;


ct) The compound has one chiral center and is in the (R)


configuration;


cu) The compound has one chiral center and is in the (S)


configuration;
cv) The compound is a single diastereomer;
cw) The compound has two chiral centers which are both
in the (R) configuration;
cx) The compound has two chiral centers one of which is
in the (R) configuration and the other is in the (S)
configuration;
cy) The compound has two chiral centers which are both
in the (S) configuration;
cz) A is attached at the 7-position of the benzofuryl
moiety and only one of R2, R3, or R12 are other than hydrogen;
da) A is attached at the 7-position of the benzofuryl
moiety and only two of R2, R3, and R12 are other than
hydrogen;
db) A is attached at the 7-position of the benzofuryl
moiety and all three of R2, R3, and R12 are other than
hydrogen.



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It will be understood that the above classes may be combined
to form additional preferred classes.
The present invention also provides a method for
increasing activation of the 5-HT2C receptor in mammals by
administering to a mammal in need of such activation a
pharmaceutically effective amount of a compound of Formula
I. The preferred mammal is human.
The following group is illustrative of aminoalkylbenzo-
furans contemplated within the scope of the invention:
1-(2-pentafluoroethyl-5-fluorobenzofur-7-yl)-2-
aminopropane;
1-(2-(3-fluorophenyl)-5-chlorobenzofur-7-yl)-2-
aminopropane;
1-(3-(4-isopropylphenyl)benzofur-5-yl)-2-aminopropane
methanesulfonate;
(R)-1-(3-(2-methoxyphenyl)-7-trifluoromethylbenzofur-6-
yl)-2-aminopropane;
1-(4-(1-phenyleth-2-yl)benzofur-7-yl)-2-aminopropane 2-
naphthalenesulfonate;
1-(5-(4-phenoxypent-1-yl)benzofur-4-yl)-2-aminopropane
benzoate;
3-(5-fluorobenzofur-7-yl)-1-aminobutane hydrochloride;
3-(4-trifluoromethylbenzofur-6-yl)-1-aminobutane
hydrobromide;
3-(7-methylbenzofur-4-yl)-1-aminobutane maleate;
(S)-1-(5-([N'-methyl-N'-(1-(2-chlorophenyl)eth-2-yl)]-
carboxamido)benzofur-7-yl)-2-aminopropane;
1-(5-([N'-(5-(2,4-dimethoxyphenyl)pent-1-yl)]-
carboxamido)benzofur-7-yl)-2-aminopropane;
1-(5-([N'-(5-(3-chloro-4-methylphenyl)hex-2-yl)]-
carboxamido)benzofur-7-yl)-2-aminopropane fumarate;
1-(5-([N'-isopropyl-N'-(4-(3-bromopyridin-2-yl)but-1-
yl)]carboxamido)benzofur-7-yl)-2-aminopropane propionate;



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1-(4-([N'-(3-(4-methoxypyridin-3-yl)hept-2-yl)]-
carboxamido)benzofur-7-yl)-2-aminopropane succinate;
1-(5-([N'-(3-(2-chloro-6-methoxypyridin-4-yl)prop-1-
yl)]carboxamido)benzofur-7-yl)-2-aminopropane 4-
chlorobenzoate;
1-(2-aminoethyl)-1-(5-fluorobenzofur-7-yl)cyclopropane;
1-amino-1-(5-chloro-6-trifluoromethylbenzofur-4-yl)-
cyclopropane benzoate.
The compounds of the invention where variable A is a
bond are prepared beginning with an appropriately
substituted benzofuran as illustrated in the following
scheme where variables R, R1, R2, R3, R4, R4', and R5 are as
previously defined:



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Synthetic Scheme I
Ra Ra,
2
R i a RZ
R R5 O~ Ra,R \ Ri
Br ~ / \ _ 5
O R PdCh/CH30Sn(n_-butyl)3 R 3 ~ O R
R3
P(o-tolyl)3 O R
1. Mg/CuBr
Ra
Ra~ Reductive amination
2.
R
N~O
O
a Rz ~ Ra RZ i
Ra,R ~ R Deprotection a, ~ R
R '~
5 R5
R / ~ 3 / OXR
3'
NHR NHR
O
The bromobenzofuran is coupled with an appropriate enol
acetate in the presence of palladium(II) chloride, tri(o-
5 tolyl)phosphine, and tributyl tin methoxide to provide the
corresponding ketone. This ketone is then reductively
aminated under standard conditions, such as treatment of the
ketone with ammonium acetate and sodium cyanoborohydride in
the presence of acid, to provide the primary amines of the
present invention.
Alternatively, the bromobenzofuran may be treated with
magnesium to prepare the corresponding Grignard reagent. This
compound is then reacted with copper(I) bromide followed by an
appropriate N-protected aziridine to provide the corresponding
N-protected amine. Deprotection of the amine then provides
the compounds of the present invention. The skilled artisan
will appreciate that the nature of the substituents on the
benzofuran ring dictate those protecting groups which may be
conveniently removed. Commonly the protecting group employed



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is the tert-butoxycarbonyl group, which is then removed by
treatment with acid, typically hydrochloric acid.
Compounds of the invention where variable A is -CHR13_
are prepared as described in the following scheme where.y.
variables R, R1, R2, R3, R4, R5 R12, and R13 are as previously
defined:
Synthetic Scheme II
Ra
R'3 / RS
R2 ~ R'a R2
R OH O ~ R
Br '
Pd(acetate)z/P(o-tolyl)3 5 a s R'z O R
R R R R R
2
R~3 R '
R
NHZ
R5 RQ R3 R'z O R
The bromobenzofuran is coupled with an appropriate allylic
alcohol in the presence of palladium(II) acetate and an
appropriate triarylphosphine such as triphenylphosphine or
trio-tolyl)phosphine to provide the corresponding ketone.
This ketone is then reductively aminated under standard
conditions to provide the compounds of the present
invention. The skilled artisan will appreciate that the R4~
moiety may be introduced by reacting the ketone prepared
above with an appropriate alkylating agent under standard
conditions.



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The requisite benzofuran intermediates are either
commercially available or may be prepared from an
appropriately substituted phenol by methods well known in
the art as illustrated in the following scheme where
variables R2, R3, and R12 are as previously defined:
Synthetic Scheme III
O(alkyl)
OH O(aikyi) R~z O~ Rz Riz
R~z Br~ O(alkyl)
Rz \ O(alkyl) _ Rz \ acid Br
base s Br R3 O
R3 Br R
~Br
acid
base
OH
Riz
O~ OH Rz \ ~CHC
R~z R~z '
Rz \ ~ Rz \ / 03 R3 Br
Br heat s Br reductive workup Rz
R R
Br OI
Rs R~z O
A solution of an appropriately substituted phenol in a
suitable solvent, typically dimethylformamide, is treated
with a base, to generate the corresponding phenoxide. Bases
useful for this reaction include hydride sources, such as
sodium or potassium hydride, or carbonates, such as sodium
or potassium carbonate. The phenoxide solution is then
reacted with a chloro- or bromoacetaldehyde which is
protected as a cyclic or dialkyl acetal. Bromoacetaldehyde
diethyl acetal is particularly useful for this reaction.



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The phenoxyacetaldehyde acetal prepared by this procedure is
reacted with a source of acid in a suitable solvent to
provide the desired benzofuran. Suitable solvents include
aromatic solvents such as toluene, xylene, benzene, and
halobenzenes such as chlorobenzene. Suitable acids include
concentrated sulfuric acid, polyphosphoric acid, and acidic
resins such as Amberlyst 15'x''.
Alternatively, the phenoxide solution is treated with
an allyl bromide or allyl chloride to provide, after
standard isolation and purification procedures, the
corresponding allyl ether. This purified ether is heated at
a temperature sufficient to effect an ortho-Claisen
rearrangement to provide the corresponding o-allylphenol.
It is critical that the allyl ether employed in this
rearrangement is substantially free of residual dimethyl-
formamide. The skilled artisan will appreciate that,
depending upon the location and nature of the R2 and R3
substituents, the rearrangement can provide a mixture of two
isomeric products. These isomers may be separated at this
stage or later in the synthetic sequence as is convenient or
desired. The separation may be effected by chromatography,
distilla-tion, or crystallization. The o-allylphenol is
then treated with an excess of ozone in an appropriate
solvent, dichloromethane and methanol are useful solvents
for this step. The reaction mixture is then purged of ozone
and the ozonide is treated under reducing conditions,
typically by treatment with triphenylphosphine or dimethyl-
sulfide, to provide the corresponding phenylacetaldehyde.
The skilled artisan will appreciate that the orientation of
the aldehyde with the respect to the phenolic hydroxyl group
gives rise to the formation of a cyclic hemiacetal which
exists in some equilibrium mixture with the free
hydroxyaldehyde. A solution of this equilibrium mixture in
a suitable solvent, such as toluene, is treated with a



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catalytic amount of an appropriate acid, such as sulfuric
acid, to provide the desired benzofuran.
The skilled artisan will appreciate that benzofurans
substituted in the 2- and/or 3-position may be prepared by
modification of the chemistry described in Synthetic Scheme
III. For example, the phenol may be alkylated with a
suitable haloketone and then cyclized to provide a
substituted benzofuran. Alternatively, the benzofuran
moiety may be substituted in the 2- or 3-position at any
convenient point in the synthesis of the compounds of the
present invention by methods known to those skilled in the
art.
The requisite benzofurans may also be prepared from an
appropriately.substituted phenol as illustrated in the
following scheme where variables R2, R3, and R12 are as
previously defined:
Synthetic Scheme IV
/N\
RZ G ~N RZ
R3 ~ gr R3 ~ ' Br
R~2 / OH acid R~z / OH
CHO
1. (Ph3PCH2Br)Br
2. ~ base
R2
R3 ~ ' Br
R~2
O



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A mixture of an appropriate phenol and hexamethylenetetra-
mine are treated with an appropriate acid, such as
trifluoroacetic acid, to provide upon aqueous workup the
corresponding o-formylphenol. This o-formylphenol is then
treated with (bromomethyl)triphenylphosphonium bromide
followed by an appropriate base such as potassium tert-
butoxide to provide the desired benzofuran.
Compounds of the invention where R4, R4' and R5 are
other than hydrogen may also be prepared as described in
Synthetic Scheme V where variables R2, R3, and R12 are as
previously defined:
Synthetic Scheme V
Rz R~z R~ R~z R~ Riz
R~ 1. Mg(0) 3 R~ 1. NaBH4 3 R~
R3 ~ _ R '~~ R
/ O''R 2. diethyl carbonate O / O-'R 2. AczO O / O~R
Br v v
O
Rz Riz Rz Riz Rz R~z
R' R3 R' 1. base R3 R
I /
O 3 / O~R O / O~R 2. R4-LG O O~R
Ra Ra
Hz~ Et0 Et0
Rz R~z
R'
R3 _
/ O~R
4
R
HzN



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An appropriate bromobenzofuran is treated with
elemental magnesium to prepare the corresponding Grignard
reagent. The Grignard reagent is quenched with diethyl
carbonate and the resulting adduct is treated sequentially
with sodium borohydride and acetic anhydride. The oc-
acetoxyester is then treated with samarium iodide to provide
the ethyl a-benzofurylacetate. The anion is generated and
then quenched with an appropriate alkylating agent (R4-LG?.
The resulting a,-alkylester is converted to the oc-alkylamine
by standard methods for such functional group
transformations. The skilled artisan will appreciate that a
second substituent could be added to the molecule by
generating the anion of the a-alkylester and quenching with
the same or a different alkylating agent prior to converting
the ester to the corresponding amine.
Compounds of the invention where R4 and R4~ taken
together with the carbon atom to which they are attached
form a cyclopropyl moiety may be prepared as illustrated in
Synthetic Scheme VI, where R. R1, R2. R3, and R12 are as
previously described.



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Synthetic Scheme VI
R~z Rs R~z R3 R~z Rs
z forrnylation ~ z reduction z
Br / R ~ OHC / R ~ HOCHz / R
O~Ri O~Ri O~R~
R~ Rte' R
cyanation
R~z R3 R~z R3 Riz Ra
Rz formamiy ~ / Rz dehy~ NCCHz ' / Rz
O base O
OEt O-~-~R~ NHz O-~R~ O-~Ri
R R R
1. base 1. base/catalyst
2. 1,2-dibromoethane 2. 1,2-dibromoethane
R~z Rs Riz R3 R~z R3
NC
Rz HzN ~ ~ Rz reduction . Rz
/ / ~ /
O
OEt O-~-~R1 O-~R~ O-~R'
R >/ R R
formamide/
base
reduction
R~z
Rz
H O-~.-~R~
2
An appropriately substituted bromobenzofuran is treated
with either magnesium metal to provide the corresponding
Grignard reagent, or with an alkyllithium at low temperature
to effect halogen metal exchange. Either of these reagents
is then reacted with an appropriate reagent, for example



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dimethylformamide, to provide the corresponding
formylbenzofuran. This formylbenzofuran is reduced under
standard hydride reducing conditions, for example sodium
borohydride in ethanol, to provide the corresponding
alcohol. The alcohol is then converted to the corresponding
nitrile by either converting first to the corresponding
halide and displacing with a source of cyanide anion, or by
directly converting the alcohol to the nitrile by reaction
with trimethylsilylchloride and sodium cyanide in a mixture
of dimethylformamide and acetonitrile in the presence of
catalytic sodium iodide as described by Dans et al. (Journal
of Organic Chemistry, 46, 2985 (1981)).
The requisite nitrile may also be prepared beginning
with an appropriate benzofurylacetate ester, such as ethyl
benzofurylacetate. The benzofurylacetate ester is reacted
with formamide in the presence of an appropriate base, such
as sodium methoxide, to prepare the corresponding benzofur-
ylacetamide. This acetamide is then dehydrated to provide
the desired nitrite by reaction with an appropriate
dehydrating agent, such as trifluoroacetic anhydride in the
presence of pyridine as described by Campagna, et al.
(Tetrahedron Letters, 1813 (1977)).
The cyclopropyl moiety is introduced by reacting this
nitrite with 1,2-dibromoethane and aqueous sodium hydroxide
in the presence of a phase-transfer catalyst such as
benzyltriethylammonium chloride under the conditions
described by Sychkova and Shabarov (Zh. Org. Khim., 16, 2086
(1980)). Reduction of the corresponding cyclopropylamide
with an appropriate hydride reducing agent, for example
lithium aluminum hydride or borane dimethylsulfide complex,
provides the compound of the present invention.
Alternatively, the benzofurylacetate ester may be
reacted with 1,2-dibromoethane in the presence of an excess
of an appropriate base, such as lithium diisopropylamide, to



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provide the corresponding ester of 1-benzofuryl-1-carboxycy-
clopropane. The ester moiety is then converted to the
requisite aminomethyl moiety by the functional group
transformations previously described.
Compounds of the invention where R5 and R5' taken
together with the carbon atom to which they are attached
form a cyclopropyl moiety may be prepared as illustrated in
Synthetic Scheme VII, where R. R1, R2. R3, and R12 are as
previously described and BOC is tert-butoxycarbonyl.



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Synthetic Scheme VII
R~z R3 R~z R3 R~z R3
formylation ~ 2 1. reduction ~ R2
Br R --~ OHC R -~ BrCHz
2. bromide
O-~R~ O~R' displacement O~l'R'
R R R
O O
Mg tBuO ~~ tBuO
R~z Rs R~z R3
HO reduce
Rz - Rz z
BrMg
O~R~ ~ O~Ri R~
O ~'R
R ~ tBuO
O ~ Curtius
~ ' ~' rearrangement
BOCNH~N~ BOCNH~H
IO' I'O
R~z Rs Riz Rs
'- reduce HO Rz reduce Rz
~ BOCNH
R' BOCNH O~R' O~'R'
IR- R
acid
R'
An appropriately substituted bromobenzofuran is
converted to the corresponding aldehyde as described supra.
This aldehyde is then reacted with 1-tert-butoxycarbon-
ylcyclopropyllithium essentially as described by Haener et
al. (Helvetica Chimica Acta, 69, 1655-65 (1986)) to provide
the corresponding l-tert-butoxycarbonyl-1-(benzofuryl)hy-
droxymethylcyclopropane. The alcohol is reduced to



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methylene by treating the corresponding acetate with
samarium(II) iodide as described supra. The resulting tert-
butyl ester is subjected to standard Curtius rearrangement
conditions to provide the corresponding N-tert-
butoxycarbonyl 1-amino-1-(benzofuryl)methylcyclopropane.
This compound is deprotected by treatment with acid to
provide the compounds of the present invention. If
necessary or desired, the starting aldehyde may be reduced
to the corresponding alcohol and then converted to the
corresponding bromomethylbenzofuran. This reagent is then
reacted with 1-tert-butoxycarbonylcyclopropyllithium
essentially as described by Haener, to provide 1-tert-
butoxycarbonyl-1-(benzofuryl)methylcyclopropane which is
then subjected to the Curtius rearrangement/deprotection
sequence described supra to provide the compounds of the
present invention.
Alternatively, the starting bromobenzofuran may be
reacted with magnesium metal under standard conditions to
prepare the corresponding Grignard reagent, benzofurylmag-
nesium bromide. This Grignard reagent is then reacted with
the Weinreb amide, N-methyl N-methoxy 1-(tert-butoxycarbon-
ylamino)cyclopropane-1-carboxamide, to provide 1-(tert-
butoxycarbonylamino)-1-(benzofurylcarbonyl)cyclopropane.
This ketone is then reduced under standard conditions,
typically with sodium borohydride in methanol or ethanol, to
provide 1-(tert-butoxycarbonylamino)-1-(benzofuryl(hydroxy-
methyl))cyclopropane. This alcohol is then converted to the
corresponding acetate and reduced to the corresponding
methylene by treatment with samarium iodide as previously
described. The resulting 1-(tert-butoxycarbon-yl)-1-
(benzofurylmethyl)cyclopropane i.s treated with acid under
standard conditions to provide the compounds of the present
invention. If necessary or desired, the Weinreb amide may
be reduced by reaction with lithium aluminum hydride to



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provide the corresponding aldehyde essentially as described
by Fehrentz and Castro (Synthesis, 676 (1983)). This
aldehyde is then reacted with the Grignard reagent
previously described to prepare 1-(tert-
' butoxycarbonylamino)-1-(benzofuryl(hydroxy-
methyl))cyclopropane, which is then subjected to the
reaction conditions previously described to prepare the
compounds of the present invention. The requisite Weinreb
amide, N-methyl N-methoxy 1-(tert-butoxycarbonylamino)cyclo-
propane-1-carboxamide, may be prepared from the commercially
available 1-amino-1-carboxycyclopropane by standard methods
well known in the art.
The skilled artisan will appreciate that not all
substituents are compatible with the reaction conditions
employed to prepare the compounds of the invention. Those
substituents incompatible with these conditions may be
introduced at a more convenient point in the synthesis, or
may be prepared by functional group transformations well
known to one of ordinary skill in the art. Furthermore,
many of the compounds of the present invention, while useful
5-HT2C agonists in their own right, are useful intermediates
to prepare other compounds of the invention. Those
compounds of the invention bearing an ester functionality,
for example, may be hydrolyzed under standard conditions to
provide the corresponding carboxylic acids. These acids may
then be reacted with amines under standard peptide coupling
conditions to provide the corresponding amides.
Alternatively, the esters may be reduced to provide the
corresponding alcohols. Furthermore, alkoxy groups may be
cleaved to provide the corresponding phenols, and primary
amines may be diazotized and displaced to provide the
corresponding halogenated compounds.



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The following Preparations and Examples are
illustrative of methods useful for the synthesis of the
compounds of the present invention.
Preparation I
5-fluoro-7-bromobenzofuran
2-(2-bromo-4-fluorophenoxy)acetaldehyde diethyl acetal
To a solution of 20 gm (105 mMol) 2-bromo-4-
fluorophenol in 211 mL dimethylformamide were added 15.8 mL
(105 mMol) bromoacetaldehyde diethyl acetal followed by 14.5
gm (105 mMol) anhydrous potassium carbonate. This mixture
was then heated at reflux for about 18 hours under a
nitrogen atmosphere. The reaction mixture was then
concentrated under reduced pressure and the resulting
residue partitioned between 200 mL of ethyl acetate and 200
mL 1N sodium hydroxide. The phases were separated and the
ethyl acetate phase was washed with 200 mL of water, giving
rise to an emulsion. An additional 100 mL ethyl acetate and
mL of water were added to the emulsion. The separated
20 ethyl acetate phase and emulsion were removed and, saved.
The ethyl acetate phase was washed again with 200 mL of
water. This new emulsion was combined with the original
emulsion and aqueous phase. The mixture was partitioned
between 700 mL ethyl acetate and 780 mL of water. The
emulsion and aqueous layer (1600 mL) were removed. The
organic phase was dried over magnesium sulfate and
concentrated under reduced pressure to provide 26.4 gm (820)
of the desired material as an amber oil. The reserved
emulsion and aqueous phase was washed with 1L of toluene.
The phases were separated and organic phase was dried over
magnesium sulfate and concentrated under reduced pressure to
provide an additional 4.67 gm of the desired compound as an
amber oil. Total recovery of desired product was 31.1 gm
(96.7 0) .



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Cyclization
A mixture of 109.4 gm Amberlyst-15 in 707 mL
chlorobenzene was heated at reflux to remove water by
azeotropic distillation. Distillate was removed until the
volume remaining in the pot was about 500 mL. To this
mixture was then added dropwise over 2 hours a solution of
109.4 gm (356 mMol) 2-(2-bromo-4-fluorophenoxy)acetaldehyde
diethyl acetal in 4060 mL chlorobenzene. The mixture was
stirred at reflux with constant water removal. When no more
water was observed in the azeotrope distillate, the reaction
mixture was cooled to room temperature. The filter cake was
washed with 400 mL dichloromethane and the combined
filtrates were concentrated under reduced pressure to
provide 102 gm of a colorless oil. This oil was diluted
with 500 mL hexane and subjected to silica gel
chromatography, eluting with hexane. Fractions containing
the desired product were combined and concentrated under
reduced pressure to provide 39.6 gm (52%) of the title
compound.
1H-NMR(CDC13): 8 7.75 (d, J = 2.1 Hz, 1H), 7.27 (dd, JH,H =
2.5 Hz, JH,F = 8.8 Hz, 1H), 7.25 (dd, JH,H = 2.5 Hz, JH,F =
8.3 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H).
Preparation II
4-methoxy-7-bromobenzofuran
2-bromo-5-methoxyphenol and 4-bromo-5-methoxyphenol
A solution of 40.0 gm (322.2 mMol) 3-methoxyphenol in
1L acetonitrile was cooled to OoC under a nitrogen
atmosphere. To this cooled solution was added a solution of
57.35 gm (322.2 mMol) N-bromosuccinimide in 500 mL
acetonitrile dropwise at a rate to maintain the temperature
of the reaction mixture at 0°C (approximately 2 hours). The
reaction mixture was stirred at 0°C for about 1 hour after



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the addition was complete and was then concentrated under
reduced pressure. The residue was treated with carbon
tetrachloride and the solid which formed was removed by
filtration. The filtrate was concentrated under reduced
pressure to provide a mixture of bromination isomers as a
red oil.
This oil was subjected to silica gel chromatography,
eluting with a gradient system of hexane containing from 0-
300 ethyl acetate. Fractions containing the fastest eluting
compound were combined and concentrated under reduced
pressure to provide 18.1 gm (28%) of 2-bromo-5-methoxyphenol
as a clear liquid.
1H-NMR(CDC13): 8 7.31 (d, 1H), 6.6 (d, 1H), 6.41 (dd, 1H),
5.5 (s, 1H), 3.77 (s, 3H).
Fractions containing the later eluting components were
combined and concentrated under reduced pressure. This
residue was subjected to silica gel chromatography, eluting
with dichloromethane. Fractions containing substantially
pure 4-bromo-5-methoxyphenol were combined and concentrated
under reduced pressure to provide 24.1 gm (37%) of a white
crystalline solid (m. p. - 68-69°C).
1H-NMR(CDC13): 8 7.34 (d, 1H), 6.45 (d, 1H), 6.33 (dd, 1H),
4.9 (br s, 1H), 3.85 (s, 3H).
2-(2-bromo-5-methoxyphenoxy)acetaldehyde diethyl acetal
A mixture of 16.0 gm (78.8 mMol) 2-bromo-5-methoxyphen-
ol, 10.9 gm (78.8 mMol) potassium carbonate, and 15.5 gm
(78.8 mMol) bromoacetaldehyde diethyl acetal in 300 mL
dimethylformamide was heated at 142oC for 16 hours. The
reaction mixture was then cooled to room temperature and
diluted with 100 mL 2N sodium hydroxide followed by 500 mL
ethyl acetate. This mixture was washed twice with 1L of
water. The combined aqueous washes were extracted twice
with 300 mL portions of ethyl acetate. All organic phases



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were combined, washed with 1L of water, washed with 1L of
saturated aqueous sodium chloride, dried over magnesium
sulfate and concentrated under reduced pressure to provide
the desired compound as a dark amber oil..
Cyclization
A mixture of 17 gm polyphosphoric acid in 500 mL
chlorobenzene was heated to 80oC with stirring. To this
mixture was added dropwise over 30 minutes a solution of 16
gm (50.13 mMol) 2-(2-bromo-5-methoxyphenoxy)acetaldehyde
diethyl acetal in 100 mL chlorobenzene. The resulting
mixture was stirred for 5 hours at 80°C and 2 hours at
120oC. The reaction mixture was cooled to room temperature
and the chlorobenzene solution was decanted from the
polyphosphoric acid phase. The remaining residue was washed
with five 200 mL portions of diethyl ether. All of the
organic phases were combined and concentrated under reduced
pressure to provide a dark amber oil. This oil was
subjected to silica gel chromatography, eluting with a
gradient of hexane containing from 0-5o ethyl acetate.
Fractions containing product were combined and concentrated
under reduced pressure to provide 11.3 gm (990) of the title
compound as a white, crystalline solid (m. p. - 60-62oC).
EA: Calculated for CgH7Br02: Theory: C, 47.61; H, 3.11.
Found: C, 47.40; H, 3.37.
Preparation III
5-bromo-6-methoxybenzofuran
Beginning with 23 gm (113.3 mMol) 4-bromo-5-methoxy-
phenol, 16.2 gm of the title compound were prepared as a
white crystalline solid essentially by the procedure of
Preparation II.



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Preparation IV
4-bromobenzofuran and 6-bromobenzofuran
2-(3-bromophenoxy)acetaldehyde diethyl acetal
A solution of 10 gm (57.8 mMol) 3-bromophenol in 25 mL
dimethylformamide was added dropwise to a mixture of 2.8 gm
(70 mMol) sodium hydride (60o suspension in mineral oil) in
30 mL dimethylformamide. The reaction mixture was stirred
for one hour after the addition was complete. To the
reaction mixture was then added 9.7 mL (64.5 mMol)
bromoacetaldehyde diethyl acetal and the resulting mixture
was stirred at 153°C for 2 hours. The reaction mixture was
then allowed to cool to room temperature and was diluted
with 300 mL diethyl ether. This mixture was then washed
with two 150 ml portions of water, washed with 50 mL
saturated aqueous sodium chloride, dried over magesium
sulfate and concentrated under reduced pressure to provide
about 17 gm of the desired compound.
1H-NMR(CDC13): 8 7.15-7.05 (m, 2H), 6.85 (dd, 1H), 4.8 (t,
1H), 3.95 (d, 2H), 3.8-3.55 (m, 4H), 1.25 (t, 6H).
Cyclization
A mixture of 17 gm (57.8 mMol) 2-(3-bromophenoxy)acet-
aldehyde diethyl acetal and 17.5 gm polyphosphoric acid in
400 mL chlorobenzene was heated to 80°C for 2 hours. The
reaction mixture was cooled to room temperature and the
chlorobenzene was decanted from the polyphosphoric acid.
The polyphosphoric acid was washed with two 150 mL portions
of diethyl ether. All or the organic phases were combined
and concentrated under reduced pressure. The residue was
redissolved in diethyl ether and the organic phases were
washed with saturated aqueous sodium bicarbonate, water, and
saturated aqueous sodium chloride, dried over magnesium
sulfate and concentrated under reduced pressure. The



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residual oil was subjected to silica gel chromatography,
eluting with hexane.
Fractions containing the faster eluting isomer were
combined and concentrated under reduced pressure to provide
1.7 gm (150) 4-bromobenzofuran.
EA: Calculated for C8H5Br0: Theory: C, 48.77; H, 2.56.
Found: C, 48.89; H, 2.72.
Fractions containing the slower eluting isomer were
combined and concentrated under reduced pressure to provide
2.5 gm (220) 6-bromobenzofuran.
EA: Calculated for C8H5Br0: Theory: C, 48.77; H, 2.56.
Found: C, 48.89; H, 2.67.
Preparation V
5-bromobenzofuran
Beginning with 10 gm (57.8 mMol) 4-bromophenol, 4.2 gm
(380) of the title compound were prepared essentially by the
procedure described.in Preparation IV.
EA: Calculated for C8H5Br0: Theory: C, 48.77; H, 2.56.
Found: C, 48.51; H, 2.46.
Preparation VI
7-bromobenzofuran
Beginning with 10 gm (57.8 mMol) 2-bromophenol, 5 gm
(450) of the title compound were prepared essentially by the
procedure described in Preparation IV.
EA.: Calculated for C8H5Br0: Theory: C, 48.77; H, 2.56.
Found: C, 49.02; H, 2.82.



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Preparation VII
5-methoxy-7-bromobenzofuran
2-bromo-4-methoxyphenol
A solution of 2.6 mL (100 mMol) bromine in 10 mL carbon
disulfide was added dropwise over 30 minutes to a solution
of 12.4 gm (100 mMol) 4-methoxyphenol in 20 mL carbon
disulfide at 0°C. After 30 minutes an additional 1 mL of
bromine in 10 mL carbon disulfide are added dropwise. The
reaction mixture was then concentrated under reduced
pressure and the residue was dissolved in diethyl ether.
This solution was washed sequentially with 100 mL water and
100 mL saturated aqueous sodium chloride, dried over
magnesium sulfate and concentrated under reduced pressure.
The residue was subjected to silica gel chromatography,
eluting with a gradient of hexane containing from 0 to 200
ethyl acetate. Fractions containing product were combined
and concentrated under reduced pressure to provide 11.6 gm
(570) of the desired compound as a crystalline solid.
1H-NMR(CDC13): 8 7.0 (d, 1H), 6.95 (d, 1H), 6.8 (dd, 1H),
5.15 (s, 1H), 3.75 (s, 3H).
Beginning with 11.5 gm (56.9 mMol) 2-bromo-4-methoxy-
phenol, 4.5 gm (350) of the title compound were prepared
essentially by the procedure described in Preparation IV.
EA: Calculated for C9H7Br02: Theory: C, 47.61; H, 3.11.
Found: C, 47.79; H, 3.13.
Preparation VIII
6-methoxy-7-bromobenzofuran
2-bromo-3-methoxyphenol
A solution of 22 gm (177.4 mMol) 3-methoxyphenol in 30
mL dihydropyran was added dropwise to a solution of 100 mg
(0.525 mMol) p-toluenesulfonic acid monohydrate in 10 mL
dihydropyran while cooling in an ice/water bath. After



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stirring for 1 hour the reaction mixture was diluted with
300 mL diethyl ether and then washed sequentially with 100
mL 0.1 N sodium hydroxide and 100 mL saturated aqueous
sodium chloride. The remaining organic phase was dried over
magnesium sulfate and concentrated under reduced pressure.
The resulting oil was distilled. The fraction distilling at
110-130°C was collected and then partitioned between 5 N
sodium hydroxide and diethyl ether. The organic phase was
separated, washed sequentially with water and saturated
aqueous sodium chloride, dried over magnesium sulfate and
concentrated under reduced pressure to provide 27.1 gm (730)
of tetrahydropyran-2-yl 3-methoxyphenyl ether.
1H-NMR(CDC13): 8 7.18 (t, 1H), 6.65-6.60 (m, 2H), 6.50 (dd,
1H), 5.4 (t, 1H), 3.95-3.90,(m, 1H), 3.80 (s, 3H), 3.62-3.55
(m, 1H); 2.0-1.6 (m, 6H).
33 mL (52.8 mMol) n-butyllithium -(1.6 M in hexane)were
added dropwise to a solution 10 gm (48.1 mMol) tetrahydro-
pyran-2-yl 3-methoxyphenyl ether in 100 mL tetrahydrofuran
over 15 minutes. After stirring for 2.5 hours at room
temperature, the reaction mixture was cooled to 0°C and then
4.6 mL (53.2 mMol) 1,2-dibromoethane were added dropwise.
The reaction mixture was then allowed to stir at room
temperature for about 14 hours. The reaction mixture was
then diluted with 50 mL 1 N hydrochloric acid and was
stirred for 1 hour. The aqueous phase was extracted with
three 100 mL portions of diethyl ether. The organic phases
were combined and extracted well with 5 N sodium hydroxide.
These basic aqueous extracts were combined and cooled in an
ice/water bath. The pH of this aqueous solution was
adjusted to about 1 with 5 N hydrochloric.acid and then
extracted with three 100 mL portions of diethyl ether.
These ether extracts were combined and washed with saturated
aqueous sodium chloride, dried over magnesium sulfate and



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concentrated under reduced pressure. The resulting residue
was subjected to silica gel chromatography, eluting with a
gradient of hexane containing from 0 to 10% ethyl acetate.
Fractions containing the desired compound were. combined and
concentrated under reduced pressure to provide 2.91 gm (300)
of a residue which crystallized upon standing.
EA: Calculated for C7H7Br02: Theory: C, 41.41; H, 3.48.
Found: C, 41.81; H, 3.46.
Beginning with 6.9 gm (34 mMol) 2-bromo-3-methoxy-
phenol, 3.2 gm (410) of the title compound were prepared as
a white fluffy solid essentially by the procedure described
in Preparation IV.
High Resolution MS: Calculated for CgH7Br02: Theory:
225.9629. Found: 225.9626.
Preparation IX
4-fluoro-7-bromobenzofuran
Beginning with 5 gm (26 mMol) 2-bromo-5-fluorophenol
and 6.5 gm (39 mMol) bromoacetaldehyde ethylene glycol
acetal, 3.3 gm (59%) of the title compound were prepared
essentially by the procedure described in Preparation IV.
EA: Calculated for C8H4BrF0: Theory: C, 44.69; H, 1.88.
Found: C, 44.44; H, 1.91.
Preparation X
5-bromo-7-fluorobenzofuran
Beginning with 20.5 gm (108 mMol) 2-fluoro-4-bromo-
phenol, 3.0 gm (130) of the title compound were prepared
essentially by the procedure described in Preparation I.
1H-NMR(CDC13): 8 7.65 (d, J=2.4 Hz, 1H), 7.50 (d, J=1.5 Hz,
1H), 7.19 (dd, JH=1.5 Hz, JF=8.3 Hz, 1H), 6.76 (m, 1H).



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Preparation XI
6-fluoro-7-bromobenzofuran
Beginning with 7.5 gm (39.3 mMol) 2-bromo-3-
fluorophenol, 10.83 gm (900) 2-(2-bromo-3-fluorophenoxy)-
acetaldehyde diethyl acetal was prepared essentially as
described in Preparation IV.
Beginning with 5.0 gm (16.3 mMol) of 2-(2-bromo-3-
fluorophenoxy)acetaldehyde diethyl acetal, 2.2 gm (630) of
the title compound were prepared essentially as described in
Preparation IV.
Preparation XII
5-chloro-7-bromobenzofuran
Beginning with 25 gm (120.5 mMol) 2-bromo-4-chloro-
phenol, 41.16 gm crude 2-(2-bromo-4-chlorophenoxy)-
acetaldehyde diethyl acetal was prepared essentially as
described in Preparation IV. A sample of this crude
material was subjected to silica gel chromatography to
provide an analytical sample.
EA: Calculated for C12H16BrC103: Theory: C, 44.54; H,
4.98. Found: C, 44.75; H, 4.97.
Beginning with 20 gm (61.8 mMol) of 2-(2-bromo-4-
chlorophenoxy)acetaldehyde diethyl acetal, 4.48 gm (310) of
the title compound were prepared as a crystalline solid
essentially as described in Preparation I.
EA: Calculated for C8H4BrCl0: Theory: C, 41.51; H, 1.74.
Found: C, 41.67; H, 1.78.
Preparation XIII
4,5-difluoro-7-bromobenzofuran
Beginning with 5 gm (23.9 mMol) 2-bromo-4,5-difluoro--
phenol, 7.05 gm (910) 2-(2-bromo-4,5-difluorophenoxy)-
acetaldehyde diethyl acetal were prepared essentially as
described in Preparation IV.



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EA: Calculated for C12H15BrF203: Theory: C, 44.33; H,
4.65. Found: C, 44.34; H, 4.41.
Beginning with 6.60 gm (20.3 mMol) of 2-(2-bromo-4,5-
difluorophenoxy)acetaldehyde diethyl acetal, 0.42 gm (90) of
the title compound were prepared as a crystalline solid
essentially as described in Preparation I.
EA: Calculated for C8H3BrF20: Theory: C, 41.24; H, 1.30.
Found: C, 41.20; H, 1.51.
Preparation XIV
3-methyl-5-fluoro-7-bromobenzofuran
1-(2-bromo-4-fluorophenoxy)-2-propanone
A mixture of 1.9 gm (10 mMol) 2-bromo-4-fluorophenol,
0.92 gm (10 mMol) chloroacetone, 0.1 gm potassium iodide,
and 1.4 gm (10 mMol) potassium carbonate in 100 mL
tetrahydrofuran was heated at reflux for 4 hours. The
mixture was concentrated under reduced pressure and the
residue partitioned between dichloromethane and 1 N sodium
hydroxide. The phases were separated and the aqueous phase
extracted well with dichloromethane. The organic phases
were combined, washed with 1 N sodium hydroxide, dried over
sodium sulfate and concentrated under reduced pressure. The
residual was subjected to silica gel chromatography, eluting
with hexane containing 20o ethyl acetate. Fractions
containing product were combined and concentrated under
reduced pressure to provide 2.7 gm (1000) of the desired
compound as a white solid.
Cyclization
Beginning with 2.7 gm (10 mMol) 1-(2-bromo-4-
fluorophenoxy)-2-propanone and 15 gm polyphosphoric acid,
2.03 gm (81%) of the title compound were prepared as a
yellow crystalline solid essentially as described in
Preparation II.



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Preparation XV
2-methyl-5-fluoro-7-bromobenzofuran
Ethyl 2-(2-bromo-4-fluorophenoxy)propionate
A mixture of 15 gm (78.5 mMol) 2-bromo-4-fluorophenol,
11.2 mL (86.4 mMol) ethyl 2-bromopropionate, and 13 gm (94.2
mMol) potassium carbonate was heated at reflux for 3 hours.
At this point 0.1 gm potassium iodide were added and reflux
continued for another 2 hours. The reaction mixture was
partitioned between water and ethyl acetate. The phases
were separated and the aqueous phase was extracted well with
ethyl acetate. The organic phases were combined, washed
with saturated aqueous sodium chloride, dried over sodium
sulfate, and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography, eluting
with hexane containing 5o ethyl acetate. Fractions
containing product were combined and concentrated under
reduced pressure to provide 19.8 gm (870) of the desired
compound as a clear oil.
2-(2-bromo-4-fluorophenoxy)propionaldehyde
A solution of 19.4 gm (66.7 mMol) ethyl 2-(2-bromo-4-
fluorophenoxy)propionate in 400 mL toluene was cooled to
-78°C at which point 100 mL (100 mMol) diisobutylaluminum
hydride (1 M in toluene) were added dropwise over 35
minutes. The reaction mixture was stirred at -78oC for an
additional 20 minutes after the addition was complete and
then the reaction was quenched by the addition of methanol.
The reaction mixture was warmed to room temperature and then
treated with saturated aqueous sodium potassium carbonate.
The mixture was stirred for 30 minutes and was then
extracted well with ethyl acetate. The organic phases were
combined, dried over sodium sulfate, and concentrated under



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reduced pressure to.provide 16.9 gm of crude desired
compound.
Cyclization
Beginning with 16.5 gm of the crude aldehyde, 5.2 gm
(34% for the reduction and cyclization) of the title
compound were prepared essentially as described in
Preparation 'II.
Preparation XVI
5-nitro-7-bromobenzofuran
Potassium 5-nitro-7-bromobenzofuran-2-carboxylate
A mixture of 11.0 gm (44.7 mMol) 2-hydroxy-3-bromo-5-
nitrobenzaldehyde, 5.56 gm (40.24 mMol) potassium carbonate,
and 8.0 mL (46.95 mMol) diethyl bromomalonate in 55 mL 2-
butanone was heated at reflux for 5 hours. The reaction
mixture was cooled to room temperature and concentrated
under reduced pressure. The residue was partitioned between
450 mL diethyl ether and 250 mL water and the aqueous phase
was adjusted to pH of about 1 by the addition of dilute
sulfuric acid. The phases were separated and the aqueous
phase was extracted with two 150 mL portions of diethyl
ether. The organic phases were combined, washed with 50 mL
saturated aqueous sodium chloride, dried over magnesium
sulfate and concentrated under reduced pressure. The
residual solid was dissolved in 200 mL ethanol to which were
added 4.8 gm (85.5 mMoL) potassium hydroxide. The resulting
suspension was warmed on a steam bath for 1 hour. The
suspension was then cooled to room temperature. After about
18 hours the mixture was filtered and dried under reduced
pressure to provide 14.1 gm (980) of the desired compound as
an orange solid.
13C_~R(DMSO-d6): 8 160.3, 159.8, 154.0, 143.9, 129.7,
122.2, 117.7, 108.0, 103.8.



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5-nitro-7-bromobenzofuran-2-carboxylic acid
A mixture of 11.5 gm (35.5 mMol) potassium 5-nitro-7-
bromobenzofuran-2-carboxylate and 36 gm Dowex 50WX8-200
resin in 1.6 L methanol was stirred for 1 hour at room.
temperature. The mixture was filtered and the filtrate
concentrated under reduced pressure. The residue was
diluted with about 80 mL of methanol and heated on the steam
bath with stirring. The mixture was cooled to room
temperature and filtered. The residual solid was dried
under vacuum to provide 6.7 gm (66%) of the desired compound
as a gold solid.
m.p. - 257oC (dec.)
MS(FD): m/e = 285, 287 (M+)
EA: Calculated for C9H4N05Br: Theory: C, 37.79; H, 1.41;
N, 4.90. Found: C, 37.81; H, 1.55; N, 4.77.
Decarboxylation
A sonicated mixture of 0.42 gm (1.47 mMol) 5-nitro-7-
bromobenzofuran-2-carboxylic acid and 0.085 gm copper powder
in 10 mL freshly distilled quinoline was heated at 185°C
under nitrogen for 7 minutes. The reaction mixture was
cooled to room temperature and filtered. The solid
recovered was washed with two 20 mL portions of
dichloromethane and these washes were combined with the
filtrate. The filtrate was then diluted with 70 mL
dichloromethane and was washed sequentially with two 100 mL
portions of 1 N hydrochloric acid, and 50 mL 4:1 saturated
aqueous sodium chloride:5 N sodium hydroxide. The remaining
organics were dried over sodium sulfate and concentrated
under reduced pressure. The residue was subjected to silica
gel chromatography, eluting with hexane containing 10o ethyl
acetate. Fractions containing product were combined and
concentrated under reduced pressure. The residual solid was



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crystallized from hexane to provide 0.15 gm (42o) of the
title compound as fine, light orange needles.
m.p. - 90-92°C
MS(FD): m/e = 241, 243 (M+)
EA: Calculated for C8H4N03Br: Theory: C, 39.70; H, 1.67;
N, 5.79. Found: C, 40.05; H, 2.03; N, 5.67.
Preparation XVII
N-tert-butoxycarbonyl-2-methylaziridine
A mixture containing 11 mL (0.142 mMol) 2-methylaziri-
dine in 300 mL dichloromethane and 300 mL saturated aqueous
sodium bicarbonate was cooled to OoC. To the mixture were
added 30.9 gm (0.142 mMol) di-tert-butyldicarbonate and
stirring was continued for 18 hours as the temperature was
allowed to gradually increase to room temperature. The
phases were separated and the organic phase was washed with
200 mL of water, dried over magnesium sulfate, and
concentrated under reduced pressure to provide 22.6 gm of
the title compound.
1H-NMR(CDC13): 8 2.45-2.35 (m, 1H), 2.20 (d, J=5.9 Hz, 1H),
1.84 (d, J=3.7 Hz, 1H), 1.42 (s, 9H), 1.23 (d, J=5.9 Hz,
3H) .
Preparation XVIII
(R)-N-tert-butoxycarbonyl-2-methylaziridine
(R)-N-tert-butoxycarbonyl-2-amino-1-propanol
A solution of 10 gm (133 mMol) (R)-2-amino-1-propanol
and 14.8 gm (146.5 mMol) triethylamine in 500 mL
tetrahydrofuran was cooled to 0°C. To this solution was
added all at once 30 gm (133 mMol) di-tert-butyl
Bicarbonate. The reaction mixture was allowed to stir for
about 18 hours at room temperature. The reaction mixture
was then concentrated under reduced pressure and the
resulting residue was dissolved in 300 mL ethyl acetate.



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This solution was washed twice with 200 mL of water, once
with 200 mL of saturated aqueous sodium chloride, dried over
magnesium sulfate and concentrated under reduced pressure to
provide 22 gm (940) of the desired compound as a yellow oil.
1H-NMR(CDC13): 8 4.71 (m, 1H), 3.72 (m, 1H), 3.59-3.46 (m,
2H) , 2 . 86 (m, 1H) .
(R)-N-tert-butoxycarbonyl-O-methanesulfonyl-2-amino-1-
propanol
A solution of 22.0 gm (125.6 mMol) (R)-N-tert-
butoxycarbonyl-2-amino-1-propanol and 19.5 gm (150.7 mMol)
diisopropylethylamine in 450 mL dichloromethane was cooled
to 0°C. To this solution was added dropwise 10.7 mL (138.2
mMol) methanesulfonyl chloride at a rate to maintain the
temperature of the reaction mixture at from 0°C to 10°C.
Once the addition was complete the reaction mixture was
stirred at 0°C for about one hour. The reaction mixture was
washed twice with 200 mL portions of water, once with 200 mL
saturated aqueous sodium chloride, dried over magnesium
sulfate and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography, eluting
with 1:1 hexane: ethyl acetate. Fractions containing product
were combined and concentrated under reduced pressure. The
residue was crystallized from hexane and ethyl acetate to
provide 19.4 gm (610) of the desired compound in two crops
(m. p. - 65-68°C).
1H-NMR(CDC13): 8 4.59 (m, 1H), 4.20 (m, 1H), 4.14, 4.12
(dd, 1H), 3.95 (m, 1H), 3.01 (s, 3H), 1.42 (s, 9H), 1.21 (d,
3H), 1.41 (s, 9H), 1.08 (d, 2H).
Cyclization
A solution of 5 gm (19.7 mMol)(R)-N-tert-butoxy-
carbonyl-O-methanesulfonyl-2-amino-1-propanol in 100 mL
tetrahydrofuran was cooled to -78°C under a nitrogen



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atmosphere. To this solution was added dropwise 19.94 mL
(19.94 mMol) lithium bis(trimethylsilyl)amide (1.0 N in
tetrahydrofuran). The reaction mixture was to warm
gradually to room temperature over about 18 hours. The
reaction mixture was diluted with diethyl ether and the
resulting solution was washed with water, washed with
saturated aqueous sodium chloride, dried over magesium
sulfate, and concentrated under reduced pressure to provide
the title compound as a yellow oil.
OR: [a]D20 = -22.86° (c=1.03, CHC13)
Preparation XIX
(S)-N-tert-butoxycarbonyl-2-methylaziridine
Beginning with (S)-2-amino-1-propanol, the title
compound was prepared essentially as described in
Preparation XVIII.
OR: [a]D20 - +34.95° (c=1.03, CH2C12)
Preparation XX
3-trifluoromethyl-5-fluoro-7-bromobenzofuran
A solution of 2.10 gm (16.7 mMol) 1-trifluoromethyl-
prop-1-en-3-ol, 3.19 gm (16.7 mMol) 2-bromo-4-fluorophenol,
and 4.81 gm (18.4 mMol) triphenylphosphine in 25 mL
dichloromethane was cooled to 0°C and then 2.9 mL (18.4
mMol) diethyl azodicarboxylate were added. The reaction
mixture was stirred for 1 hour at room temperature and then
the reaction mixture was directly subjected to flash silica
gel chromatography, eluting with 20:1 hexane: ethyl acetate.
Fractions containing product were combined and concentrated
under reduced pressure to provide 6 gm of crude 1-(1-
trifluoromethylprop-1-en-3-yloxy)-2-bromo-4-fluorobenzene.
1.0 gm (3.34 mMol) 1-(1-trifluoromethylprop-1-en-3- '
yloxy)-2-bromo-4-fluorobenzene was heated at 250oC for 3
hours. The reaction mixture, containing primarily 2-(3-



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trifluoromethylprop-1-en-3-yl)-4-fluoro-6-bromophenol, was
diluted with dichloromethane and the solution cooled to
-78oC. This solution was then treated with excess ozone and
was stirred at -78°C until the 2-(3-trifluoromethylprop-1-
en-3-yl)-4-fluoro-6-bromophenol was consumed as measured by
thin layer chromatography. At this point the ozone was
purged from the reaction with oxygen and then 0.88 gm (3.34
mMol) triphenylphosphine were added. The mixture was stored
at -20°C for about 64 hours. The reaction mixture was then
concentrated under reduced pressure and the residue
subjected to flash silica gel chromatography, eluting with
hexane containing 10o ethyl acetate. Fractions containing
the desired compound were combined and concentrated under
reduced pressure to provide 2-hydroxy-3-trifluoromethyl-5-
fluoro-7-bromo-2,3-dihydrobenzofuran. A solution of this
dihydrobenzofuran in 10 mL toluene was treated with 4 drops
of sulfuric acid and was stirred at reflux for 10 minutes.
The reaction mixture was cooled to room temperature and was
then washed with saturated aqueous sodium bicarbonate. The
organic phase was separated and concentrated under reduced
pressure. The residue was subjected to flash silica gel
chromatography, eluting~with hexane. Fractions containing
product were combined and concentrated under reduced
pressure to provide the title compound.
Preparation XXI
5-methoxycarbonyl-7-bromobenzofuran
Beginning with methyl 3-bromo-4-allyloxybenzoate, the
title compound was prepared essentially as described in
Preparation XX.



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Preparation XXII
N-tert-butoxycarbonyl 1-(5-carboxybenzofur-7-yl)-2
aminopropane
A mixture of 0.341 gm (1.02 mMol) N-tert-butoxycarbonyl
1-(5-methoxycarbonylbenzofur-7-yl)-2-aminopropane (EXAMPLE
41) and 0.204 gm (5.1 mMol) sodium hydroxide in 2 mL ethanol
and 0.5 mL water was stirred at room temperature for 18
hours. The reaction mixture was concentrated under reduced
pressure and the residue dissolved in water. This aqueous
solution was washed with ethyl acetate and the organic phase
discarded. The remaining aqueous phase was made acidic by
the addition of aqueous potassium hydrogen sulfate. The
aqueous phase was again extracted with ethyl acetate. This
organic phase was dried over magnesium sulfate and
concentrated under reduced pressure. The residue was
crystallized from a mixture of chloroform and hexane to
provide 0.300 gm (920) of the title compound as a white
crystalline solid in two crops.
EA: Calculated for C17H21N05: Theory: C, 63.94; H, 6.63;
N, 4.39. Found: C, 63.78; H, 6.75; N, 4.34.
Preparation XXIII
3-ethyl-5-fluoro-7-bromobenzofuran
Beginning with pent-2-en-1-yl 2-bromo-4-fluorophenyl
ether, the title compound was prepared essentially as
described in Preparation XX.
Preparation XXIV
3-isopropyl-5-fluoro-7-bromobenzofuran
Beginning with 4-methylpent-2-en-1-yl 2-bromo-4-
fluorophenyl ether, the title compound was prepared
essentially as described in Preparation XX.



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Preparation XXV
3,4-dimethyl-5-fluoro-7-bromobenzofuran
Beginning with but-2-en-1-yl 2-bromo-4-fluoro-5-
methylphenyl ether, the title compound was prepared
essentially as described in Preparation XX.
Preparation XXVI
4-chloro-5-fluoro-7-bromobenzofuran
Bromination
A mixture of 5 gm (34.1 mMol) 3-chloro-4-fluorophenol
and 1.76 mL (34.1 mMol) bromine in 20 mL carbon disulfide
was stirred at room temperature for 18 hours. The reaction
mixture was concentrated under reduced pressure and the
residue was dissolved in dichloromethane, washed with water,
dried over sodium sulfate and concentrated under reduced
pressure to provide a mixture of 2-bromo-4-fluoro-5-
chlorophenol and 2-bromo-3-chloro-4-fluorophenol.
Ether formation
This mixture of bromination isomers was combined with
12 gm allyl bromide and 13.6 gm potassium carbonate in 90 mL
dimethylformamide. After stirring at room temperature for
2.5 hours, the mixture was partitioned between
dichloromethane and water. The organic phases were
combined, dried over sodium sulfate and concentrated under
reduced pressure to provide 9.7 gm of a mixture of allyl
ether isomers.
Rearrangement/ozonolysis/dehydration
The mixture of allyl ethers was reacted as described in
Preparation XX to provide 0.49 gm of the title compound as a
white crystalline solid.
m.p. - 84-85°C



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1H-NMR(300 MHz, CDC13): b 7.73 (d, J = 2.1 Hz, 1H; 7.29 (d,
8.8 Hz, 1H); 6.92 (d, J = 2.1 Hz, 1H).
Preparation XXVII
4-trifluoromethyl-7-bromobenzofuran
Beginning with 4-trifluoromethylphenol, the title
compound was prepared essentially as described in
Preparation XXVI.
Preparation XXVIII
5-trifluoromethyl-7-bromobenzofuran
Beginning with 5-trifluoromethylphenol, the title
compound was prepared essentially as described in
Preparation XXVI.
Preparation XXIX
4,5,6-trifluoro-7-bromobenzofuran
Beginning with 3,4,5-trifluorophenol, the title
compound was prepared essentially as described in
Preparation XXVI.
Preparation
4,6-dimethyl-5-chloro-7-bromobenzofuran
Beginning with 3,5-dimethyl-4-chlorophenol, the title
compound was prepared essentially as described in
Preparation XXVI.
Preparation XXXI
Alternate Synthesis of 4,5-difluoro-7-bromobenzofuran
2-bromo-4,5-difluorophenyl allyl ether
A mixture of 79.4 gm (0.38 mole) 2-bromo-4,5-
difluorophenol and 79 gm (0.57 mole) potassium carbonate in
200 mL dimethylformamide was stirred at room temperature for
30 minutes. At this point 33 mL (0.38 mMol) allyl bromide



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were added and the resulting mixture was stirred for 18
hours at room temperature. The reaction mixture was then
diluted with diethyl ether and washed with water followed by
saturated aqueous sodium chloride. The remaining organics
were dried over magnesium sulfate and concentrated under
reduced pressure to provide 90 gm (960) of the desired
compound.
2-allyl-3,4-difluoro-6-bromophenol
15 gm (60.5 mMol) 2-bromo-4,5-difluorophenyl allyl
ether was heated at 200°C for 2 hours under a nitrogen
atmosphere. The reaction mixture was cooled to room
temperature and filtered through a pad of celite. The
celite pad was washed with 500 mL hexane and the filtrate
concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography, eluting with
hexane. Fractions containing product were combined and
concentrated under reduced pressure to provide 9.7 gm (650)
of the desired compound.
(2-hydroxy-3-bromo-5,6-difluorophenyl)acetaldehyde
A solution of 7.8 gm (31.45 mMol) 2-allyl-3,4-difluoro-
6-bromophenol in 100 mL dichloromethane and 20 mL methanol
was cooled to -78°C and was then saturated with ozone.
After 20 minutes the reaction mixture was purged with
nitrogen for 10 minutes and was then treated with 5 mL
dimethylsulfide. The reaction mixture was allowed to warm
gradually to room temperature. After 15 hours the reaction
mixture was concentrated under reduced pressure to provide
the title compound.
Cyclization
A mixture of 7.5 gm Amberlyst l5Tt' resin in 150 mL
chlorobenzene was heated at 160°C and the solvent distilled



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to remove water. The reaction mixture was cooled to 120°C
and then a solution of 31.45 mMol (2-hydroxy-3-bromo-5,6-
difluorophenyl)acetaldehyde in chlorobenzene was added
dropwise. The temperature was again increased to 160°C and
solvent distilled. After 1.5 hours, the reaction mixture
was filtered and the filtrate concentrated under reduced
pressure. The residue was subjected to silica gel
chromatography, eluting with hexane. Fractions containing
product were combined and concentrated under reduced
pressure to provide 3.9 gm (530) of the title compound as a
white solid.
m.p. - 46.5-48°C
Preparation xxxII
5-hydroxymethyl-7-bromobenzofuran
A solution of 0.63 gm (2.46 mMol) 5-methoxycarbonyl-7-
bromobenzofuran in 10 mL toluene was cooled to -78°C. When
material precipitated, 5 mL dichloromethane were added to
effect solution. To this solution were then slowly added
1.5 mL (8.6 mMol) diisobutylaluminum hydride and the
reaction mixture was allowed to warm gradually to room
temperature. After 10 minutes the reaction was quenched by
the addition of methanol followed by 1.5 gm sodium fluoride
and 50 mL water and then Rochelle's salt solution. The
mixture was diluted with additional dichloromethane and was
stirred vigorously for about 1 hour. The phases were
separated and the aqueous phase extracted well with ethyl
acetate. The organic phases were combined and concentrated
under reduced pressure. The residue.was crystallized from
hexane and dichloromethane to provide 0.46 gm (820) of the
title compound as a white crystalline solid.



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Preparation XXXIII
5-methoxymethyl-7-bromobenzofuran
A solution of 0.372 gm (0.40 mMol) 5-hydroxymethyl-7-
bromobenzofuran in tetrahydrofuran was added to a mixture of
1.80 mMol sodium hydride (60o suspension in mineral oil) in
2 mL tetrahydrofuran. After stirring at room temperature
for 1 hour, 204 ~.L iodomethane were added and stirring was
continued for 2.5 hours. The reaction mixture was quenched
by the addition of water and the resulting mixture was
extracted well with ethyl acetate. The organic phase was
concentrated under reduced pressure to provide a nearly
quantitative yield of the title compound.
Preparation XXXIV
5-[N,N-dimethyl]carboxamido-7-bromobenzofuran
A solution of 0.52 gm (2.03 mMol) 5-methoxycarbonyl-7-
bromobenzofuran and 0.41 gm (10.13 mMol) sodium hydroxide in
4 mL ethanol was stirred at room temperature until all of
the starting material had been consumed. The reaction
mixture was concentrated under reduced pressure and the
residue dissolved in water. This solution was then made
basic by the addition of 1N sodium hydroxide and was
extracted well with ethyl acetate. The remaining aqueous
phase was made acidic (pH about 2) by treatment with
potassium hydrogen sulfate and the resulting solid removed
by filtration. The aqueous phase was extracted well with
ethyl acetate and the organics were combined and
concentrated under reduced pressure to provide 0.40 gm (82%)
of 5-carboxy-7-bromobenzofuran as an off-white solid.
MS(FD): m/e = 240 (M-1)
A mixture of 0.22 gm (0.92 mMol) 5-carboxy-7-bromoben-
zofuran, 0.19 gm (1.01 mMol) 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride, 0.074 gm (0.92 mMol)
dimethylamine hydrochloride, and 0.38 ~,L (2.75 mMol)



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triethylamine in 1 mL dichloromethane was stirred at room
temperature for 18 hours. The reaction mixture was diluted
with ethyl acetate and quenched with dilute aqueous sodium
hydroxide. The phases were separated and the aqueous phase
extracted well with ethyl acetate. The organic phases were
combined, washed sequentially with water and saturated
aqueous sodium chloride, dried over sodium sulfate and
concentrated under reduced pressure. The residue was
subjected to silica gel chromatography, eluting with hexane
containing 20% ethyl acetate. Fractions containing product
were combined and concentrated under reduced pressure to
provide the title compound.
Preparation XXXV
4-bromo-5-fluoro-, and 5-fluoro-6-bromobenzofuran
O-acetyl 3-bromo-4-fluorophenol
A solution of 1.09 gm (5 mMol) 3-bromo-4-fluoroaceto-
phenone and 3.45 gm (20 mMol) m-chloroperbenzoic acid (700)
in 15 mL dichloromethane was heated at reflux for 18 hours.
An additional 3.45 gm m-chloroperbenzoic acid were added and
reflux continued for about 12 hours. At this point an
additional 1.4 gm m-chloroperbenzoic acid were added and
reflux continued for 18 hours. The reaction mixture was
cooled to room temperature and was then diluted with 50 mL
diethyl ether. The resulting mixture was cooled to 0°C and
was then treated with 15 mL 20o aqueous sodium thiosulfate.
The resulting slurry was stirred for about 1 hour and then
the phases separated. The organic phase was washed
sequentially with 3 x 20 mL 20% aqueous sodium thiosulfate
followed by 3 x 20 mL saturated aqueous sodium chloride.
The organic phase was then dried over sodium sulfate and
concentrated under reduced pressure. The residue was
subjected to silica gel chromatography, eluting with 10:1
hexane: diethyl ether. Fractions containing product were



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combined and concentrated under reduced pressure to provide
680 of the desired compound
3-bromo-4-fluorophenol
A solution of 0.80 gm (3.43 mMol) O-acetyl 3-bromo-4-
fluorophenol in 10 mL 6% diisopropylethylamine in methanol
was stirred at room temperature for 8 hours. The reaction
mixture was concentrated under reduced pressure at 0°C to
provide the desired compound.
3-bromo-4-fluorophenyl allyl ether
A mixture of 0.65 gm (3.43 mMol) 3-bromo-4-fluoro-
phenol, 0.60 mL (6.86 mMol) allyl bromide, and 0.71 gm (5.15
mMol) potassium carbonate in 6 mL acetone was stirred at
reflux for 13 hours. The reaction mixture was concentrated
under reduced pressure and the residue subjected to silica
gel chromatography, eluting with hexane. Fractions
containing product were combined and concentrated under
reduced pressure to provide 610 of the desired compound.
Claisen rearrangement
3-bromo-4-fluorophenyl allyl ether was placed in a
sealed tube and was deoxygenated by bubbling nitrogen
through the liquid. The tube was sealed and then heated at
230°C for 3 hours. After cooling to room temperature, the
mixture is subjected to silica gel chromatography, eluting
with 8:1 hexane: diethyl ether. The faster eluting product
isomer was 2-allyl-4-fluoro-5-bromophenol. The slower
eluting isomer was 2-allyl-3-bromo-4-fluorophenol. The
isomers were isolated in a ratio of 3:2 respectively.
4-bromo-5-fluorobenzofuran
Beginning with 3 gm (13 mMol) 2-allyl-3-bromo-4-fluoro-
phenol, the title compound was prepared in 98% yield



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essentially by the procedure described in Preparation XXXI
with the exception that the cyclization/dehydration step was
performed using sulfuric acid in toluene.
5-fluoro-6-bromobenzofuran
Beginning with 3.5 gm (15 mMol) 2-allyl-4-fluoro-5-
bromophenol, the title compound was prepared in 90o yield
essentially by the procedure described in Preparation XXXI
with the exception that the cyclization/dehydration step was
performed using sulfuric acid in toluene.
Preparation _x_x_xVI
Alternate Synthesis of 4-chloro-5-fluoro-7-bromobenzofuran
A mixture of 90.4 gm (0.40 mole) 2-bromo-4-fluoro-5-
chlorophenol (containing 100 2-bromo-3-chloro-4-fluorophen-
ol) and 64 gm (0.45 mole) hexamethylenetetramine was cooled
in an ice bath. To this cooled mixture were added 306 mL
trifluoroacetic acid. After stirring at about 0°C for 15
minutes, the reaction mixture was heated at reflux for 1.5
hours. The reaction mixture was then cooled in an ice bath
and treated with 439 mL of water followed by 220 mL 500
sulfuric acid. The reaction mixture was stirred without
cooling for two hours. The reaction mixture was then
diluted with 500 mL water and the resulting solid collected
by filtration. The solid was washed with water until the
wash was neutral (pH about 7). The solid was dried under
reduced pressure and was then subjected to silica gel
chromatography, eluting with a gradient of hexane containing
from 0-2o ethyl acetate. Fractions containing the desired
compound were combined and concentrated under reduced
pressure to provide 57 gm (62%) 2-hydroxy-3-bromo-5-fluoro-
6-chlorobenzaldehyde.
A suspension of 49.2 gm (0.19 mole) 2-hydroxy-3-bromo-
5-fluoro-6-chlorobenzaldehyde and 127 gm (0.29 mole)



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(bromomethyl)tr.iphenylphosphonium bromide in 230 mL tetrahy-
drofuran was cooled to 0°C under a nitrogen atmosphere. To
this were added dropwise 330 mL (0.33 mole) potassium tert-
butoxide (1M in tetrahydrofuran) over 3 hours. An
additional 90 mL (0.09 mole) potassium tert-butoxide (1M in
tetrahydrofuran) were then added to react remaining starting
material. The reaction mixture was diluted with 700 mL of
hexane and the resulting precipitate removed by filtration.
The recovered solid was slurried in 300 mL hexane and
filtered 4 times. The combined filtrates were washed with 2
x 500 mL water followed by 500 mL saturated aqueous sodium
chloride. The remaining organics were dried over sodium
sulfate and concentrated under reduced pressure to provide a
residual solid. This solid was slurried and filtered with 4
x 300 mL diethyl ether to remove triphenylphosphine oxide.
The filtrates were concentrated and the residue subjected to
silica gel chromatography, eluting with.hexane. Fractions
containing product were combined and concentrated under
reduced pressure to provide 40 gm (830) of the title
compound as a white solid.
Preparation XXXVII
4,6-difluoro-7-bromobenzofuran
A solution of 2.6 gm (20 mMol) 3,5-difluorophenol in 20
mL carbon disulfide was cooled to 0°C and then a solution of
1.02 mL (20 mMol) bromine in 10 mL carbon disulfide was
added dropwise over 30 minutes. After stirring for an
additional 30 minutes, the reaction mixture was warmed to
room temperature and stirred for 1.5 hours. The reaction
mixture was diluted with 200 mL diethyl ether and was washed
sequentially with aqueous sodium metabisulfite and saturated
aqueous sodium chloride. The organic phase was then dried
over sodium sulfate and concentrated under reduced pressure.



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The residue was vacuum distilled to provide 2.5 gm (600) of
2-bromo-3,5-difluorophenol (b. p. - 65°C (5 mm Hg)).
Beginning with 2-bromo-3,5-difluorophenol, the title
compound was prepared essentially as described in
Preparation XXII.
HRMS: Calculated for C$H30BrFz: 231.9335. Found:
231.9342.
EXAMPLE 1
1-(benzofur-5-yl)-2-aminopropane hydrochloride
1-(benzofur-5-yl)-2-propanone
A mixture of 1.90 gm (10 mMol) 5-bromobenzofuran, 183
mg (0.6 mMol) trio-tolyl)phosphine, 4.3 mL (15 mMol)
tributyl tin methoxide, and 1.7 mL (15.4 mMol) isopropenyl
acetate in 55 mL toluene was sparged with nitrogen for 15
minutes. To this mixture were then added 54 mg (0.3 mMol)
palladium(II) chloride and the mixture was heated to 100°C
for 3 hours. The reaction mixture was cooled to room
temperature and concentrated under reduced pressure. The
residue was filtered through a bed of 100 gm silica gel,
eluting with 1 liter of 1:1 hexane: ethyl acetate. Fractions
containing crude product were combined and concentrated
under reduced pressure. The residue was subjected to silica
gel chromatography, eluting with a gradient of hexane
containing from 0-20o ethyl acetate. Fractions containing
product were combined and concentrated under reduced
pressure to provide about 1.8 gm of the desired compound as
an oil which gradually crystallized.
High Resolution MS: Calculated for C11H1102~ Theory:
175.0759. Found: 175.0756.
Reductive Amination
A mixture of 1 gm (5.7 mMol) 1-(benzofur-5-yl)-2-
propanone, 8.9 gm (115 mMol) ammonium acetate, and 2.8 gm



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powdered 3A molecular sieves in 60 mL methanol was stirred
at room temperature for 1 hour. To this mixture were then
added 5.8 mL (5.8 rilMol) sodium cyanoborohydride (1.0 M in
tetrahydrofuran) and the mixture was stirred for an
additional 5 hours at room temperature under a nitrogen
atmosphere. The reaction mixture was then filtered over a
pad~of celite and the pad was rinsed with 200 mL methanol
and 200 mL dichloromethane. The combined filtrates were
concentrated under reduced pressure and the resultant
residue was partitioned between 200 mL dichloromethane and
mL water. The mixture was washed with two 25 mL portions
of 5 N sodium hydroxide. The combined aqueous extracts were
extracted with three 100 mL portions of dichloromethane.
All of the organic phases were combined, washed with 25 mL
15 0.1 N sodium hydroxide followed by 25 mL water, dried over
magnesium sulfate and concentrated under reduced pressure.
The residue was subjected to silica gel chromatography,
eluting with a gradient of dichloromethane containing 6~
methanol to dichloromethane containing 9o methanol and 90
20 concentrated ammonium hydroxide. Fractions containing
product were combined and concentrated under reduced
pressure to provide 0.498 gm (490) of 1-(benzofur-5-yl)-2-
aminopropane.
This amine was dissolved in 20 mL ethyl acetate and
then a 1 N solution of hydrogen chloride in diethyl ether
was added dropwise. The resulting slurry was filtered, the
solid washed with 3 mL ethyl acetate, and the solid dried
under vacuum to provide 0.548 gm (910) of the title
compound.
m.p. - 166-168oC
EA: Calculated for C11H13N0-HCl: C, 62.41; H, 6.67; N,
6.62. Found: C, 62.19; H, 6.49; N, 6.60.



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EXAMPLE 2
1-(benzofur-4-yl)-2-aminopropane hydrochloride
Beginning with 1.50 gm (7.65 mMol) 4-bromobenzofuran,
0.898 gm (670) of 1-(benzofur-4-yl)-2-propanone were
prepared essentially as described in Example 1.
High Resolution MS: Calculated for C11H11~2~ Theory:
175.0759. Found: 175.0756.
This ketone was converted to 0.637 gm (480) 1-
(benzofur-4-yl)-2-aminopropane essentially as described in
Example 1. This amine was converted to the hydrochloride
salt to provide the title compound.
EA: Calculated for C11H13N0-HCl: C, 62.41; H, 6.67; N,
6.62. Found: C, 62.11; H, 6.47; N, 6.58.
EXAMPLE 3
1-(benzofur-6-yl)-2-aminopropane hydrochloride
Beginning with 1.96 gm (10 mMol) 6-bromobenzofuran,
1.48 gm (850) 1-(benzofur-6-yl)-2-propanone were prepared
essentially as described in Example 1.
High Resolution MS: Calculated for C11H11~2~ Theory:
175.0759. Found: 175.0756.
1.0 gm (5.7 mMol) of this ketone was converted to 0.32
gm (37%) of 1-(benzofur-6-yl)-2-aminopropane .essentially as
described in Example 1. This amine was converted to the
hydrochloride salt to provide the title compound.
EA: Calculated for C11H13N0-HCl: C, 62.41; H, 6.67; N,
6.62. Found: C, 62.49; H, 6.65; N, 6.63.
EXAMPLE 4
1-(benzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 1.96 gm (10 mMol) 7-bromobenzofuran,
1.80 gm (1000) 1-(benzofur-7-yl)-2-propanone were prepared
essentially as described in Example 1.



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High Resolution MS: Calculated for C11H11~2= Theory:
175.0759. Found: 175.0760.
This ketone was converted to 0.83 gm (47%) of 1-
(benzofur-7-yl)-2-aminopropane essentially as described in
Example 1. This amine was converted to the hydrochloride
salt to provide the title compound.
EA: Calculated for C11H13N0-HCl: C, 62:41; H, 6.67; N,
6.62. Found: C, 62.19; H, 6.63; N, 6.93.
EXAMPLE 5
1-(4-methoxybenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 0.27 gm (1.18 mMol) 4-methoxy-7-
bromobenzofuran, 0.18 gm (760) 1-(4-methoxybenzofur-7-yl)-2-
propanone were prepared essentially as described in Example
1.
m.p. - 82-83°C
EA: Calculated for C12H12~3~ 'Theory: C, 70.58; H, 5.92.
Found: C, 70.70; H, 5.77.
0.15 gm (0.74 mMol) of this ketone was converted to
0.074 gm (49%) of 1-(4-methoxybenzofur-7-yl)-2-aminopropane
essentially as described in Example 1. This amine was
converted to the hydrochloride salt to provide the title
compound.
EA: Calculated for C12H15N~2-HCl: C, 59.63; H, 6.67; N,
5.79. Found: ~C, 59.53; H, 6.41; N, 5.54.
EXAMPLE 6
1-(5-methoxybenzofur-7-yl)-2-aminopropane hydrochloride
. Beginning with 2.26 gm (10 mMol) 5-methoxy-7-
bromobenzofuran, 1.75 gm (860) 1-(5-methoxybenzofur-7-yl)-2-
propanone were prepared essentially as described in Example
1. 1.0 gm (4.9 mMol) of this ketone was converted to 0.55
gm (540) of 1-(5-methoxybenzofur-7-yl)-2-aminopropane
essentially as described in Example 1. This amine was



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converted to the hydrochloride salt to provide the title
compound.
m.p. - 166-168°C
EA: Calculated for~C12H15N~2-HCl: C, 59.63; H, 6.67; N,
5.79. Found: C, 59.84; H, 6.62; N, 5.77.
EXAMPLE 7
1-(6-methoxybenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 1.0 gm (4.4 mMol) 6-methoxy-7-
bromobenzofuran, 0.86 gm (950) 1-(6-methoxybenzofur-7-yl)-2-
propanone were prepared essentially as described in Example
1.
High Resolution MS: Calculated for C12H13~3~ Theory:
205.0865. Found: 205.0866.
0.82 gm (4.0 mMol) of this ketone was converted to 0.62
gm (750) of 1-(6-methoxybenzofur-7-yl)-2-aminopropane
essentially as described in Example 1. This amine was
converted to the hydrochloride salt to provide the title
compound.
m.p. - 144-146°C
EA: Calculated for C12H15N~2-HC1: C, 59.63; H, 6.67; N,
5.79. Found: C, 59.44; H, 6.50; N, 6.02.
EXAMPLE 8
1-(6-methoxybenzofur-5-yl)-2-aminopropane hydrochloride
Beginning with 1.0 gm (4.4 mMol) 5-bromo-6-methoxy-
benzofuran, 0.81 gm (90%) 1-(6-methoxybenzofur-5-yl)-2-
propanone were prepared essentially as described in Example
1.
High Resolution MS: Calculated for C12H13~3~ Theory:
205.0865. Found: 205.0862.
0.85 gm (4.2 mMol) of this ketone was converted to 0.43
gm (50%) of 1-(6-methoxybenzofur-5-yl)-2-aminopropane
essentially as described in Example 1. This amine was



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converted to the hydrochloride salt to provide the title
compound.
EXAMPLE 9
1-(4-fluorobenzofur-7-yl)-2-aminopropane oxalate
Beginning with 0.30 gm (1.4 mMol) 4-fluoro-7-bromo-
benzofuran, 0.14 gm (500) 1-(4-fluorobenzofur-7-yl)-2-
propanone were prepared essentially as described in Example
1.
This ketone was converted to 0.73 gm (540) of 1-(4-
fluorobenzofur-7-yl)-2-aminopropane essentially as described
in Example 1. This amine was converted to the oxalate salt
to provide the title compound.
m.p. - 172-174oC
MS(FD): m/e = 194 (M+1)
EXAMPLE 10
1-(5-fluorobenzofur-7-yl)-2-aminopropane hydrochloride
N-tert-butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-
aminopropane
A mixture of 19 gm (88.8 mMol) 5-fluoro-7-bromobenzo-
furan and 4.7 gm (193.3 mMol) magnesium turnings in 300 mL
diethyl ether was stirred at 40oC while 7.6 mL (88.2 mMol)
1,2-dibromoethane were added dropwise over 15 minutes.
Thirty minutes after the addition was complete, the reaction
mixture was cooled to -lOoC. To this cooled mixture were
then added 6.76 gm (32.8 mMol) copper(I) bromide-
dimethylsulfide complex all at once followed by
the dropwise addition of 13 gm (82.8 mMol) of N-tert-
butoxycarbonyl-2-methylaziridine and 20 mL diethyl ether.
The resulting mixture was stirred for 2 hours at -10-OoC.
The reaction mixture was then diluted 1.5 L ethyl acetate
and 150 mL of water. The resulting slurry was filtered
through a pad of celite and the celite pad was washed with



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two 150 ml portions of ethyl acetate. The filtrate was
separated and the organic phase was extracted with two 200
mL portions of water and one 200 mL portion of saturated
aqueous sodium chloride. The remaining organic phase was
then dried over magnesium sulfate and concentrated under
reduced pressure. The residue was crystallized from hexane
containing 20% ethyl acetate. This solid was subjected to
silica gel chromatography, eluting with a gradient of hexane
containing from 0-20o ethyl acetate. Fractions containing
product were combined and concentrated under reduced
pressure. The residue was crystallized from hexane to
provide 13.5 gm (56%) of the desired compound.
1H-NMR(CDC13): cS7.63 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 2.6
Hz, J = 8.1 Hz, 1H), 6.83 (dd, J = 2.6 Hz, J = 9.9 Hz, 1H),
6.71 (d, J = 2.2 Hz, 1H), 4.44 (bs, 1H), 4.07 (bs, 1H), 2.99
(m, 2H), 1.37 (s, 9H), 1.11 (d, J = 6.6 Hz, 3H).
Deprotection
A mixture of 0.50 gm (1.7 mMol) N-tert-butoxycarbonyl
1-(5-fluorobenzofur-7-yl)-2-aminopropane in 6 mL 4N hydrogen
chloride in dioxane was stirred for 1 hour at room
temperature. The reaction mixture was concentrated under
reduced pressure and the residue was suspended in 70 mL
diethyl ether. The suspension was stirred for 16 hours at
room temperature and was filtered to provide 0.37 gm (95o)
of the title compound.
EA: Calculated for C11H12NOF-HCl: C, 57.52; H, 5.71; N,
6.10. Found: C, 57.40; H, 5.66; N, 5.92.



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EXAMPLE 11
(S)-1-(5-fluorobenzofur-7-yl)-2-aminopropane hydrochloride
(S)-N-tert-butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-
aminopropane
Beginning with 0.94 gm (4.4 mMol) 5-fluoro-7-bromoben-
zofuran and 0.63 mg (4 mMol) (S)-(+)-N-tert-butoxycarbonyl-
2-methylaziridine, 0.534 gm (46%) of the desired compound
were prepared essentially as described in Example 10.
m.p. - 120-121oC
1H-NMR(CDC13): b7.63 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 2.6
Hz, J = 8.1 Hz, 1H), 6.83 (dd, J = 2.6 Hz, J = 9.9 Hz, 1H),
6.71 (d, J = 2.2 Hz, 1H), 4.44 (bs, 1H), 4.07 (bs, 1H), 2.99
(m, 2H), 1.37 (s, 9H), 1.11 (d, J = 6.6 Hz, 3H).
MS(FD): m/e = 294 (M+1)
EA: Calculated for C16H20N03F: C, 65.51; H, 6.87; N, 4.77.
Found: C, 65.75; H, 7.10; N, 4.84.
OR: [oc,]D20 = +24.79° (c = 1.03, CH2C12)
Deprotection
Beginning with 0.50 gm (1.7 mMol) (S)-N-tert-
butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane,
0.37 gm (950) of the title compound were prepared
essentially as described in Example 10.
EA: Calculated for C11H12NOF-HC1: C, 57.52; H, 5.71; N,
6.10. Found: C, 57.44; H, 5.42; N, 6.28.
OR: [oc]D20 = +11.64° (c = 1.03, CH30H)
EXAMPLE 12
(R)-1-(5-fluorobenzofur-7-yl)-2-aminopropane hydrochloride
(R)-N-tert-butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-
aminopropane
Beginning with 5.7 gm (26.6 mMol) 5-fluoro-7-bromoben-
zofuran and 3.9 gm (24.8 mMol) (R)-(-)-N-tert-butoxycarbon-



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yl-2-methylaziridine, 3.22 gm (440) of the desired compound
were prepared essentially as described in Example 10.
MS(FD): m/e = 294 (M+1)
OR: (pc,]D20 = -2g.g9o (c = 1.03, CH30H)
Deprotection
Beginning with 0.50 gm (1.7 mMol) (R)-N-tert-
butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane,
0.37 gm (95%) of the title compound were prepared
essentially as described in Example 10.
EA: Calculated for C11H12NOF-HC1: C, 57.52; H, 5.71; N,
6.10. Found: C, 57.75; H, 5.50; N, 6.26.
EXAMPLE 13
1-(7-fluorobenzofur-5-yl)-2-aminopropane hydrochloride
Beginning with 0.28 gm (1.3 mMol) 5-bromo-7-fluoro-
benzofuran, 0.26 gm (100%) 1-(7-fluorobenzofur-5-yl)-2-
propanone were prepared essentially as described in Example
1.
1H-NMR(CDC13): 8 7.64 (d, J=2.1 Hz, 1H), 7.18 (s, 1H), 6.89
(d, J=11.3 Hz, 1H), 6.76 (m, 1H), 3.75 (s, 2H), 2.17 (s,
3H).
This ketone was converted to 0.082 gm (320) of 1-(7-
fluorobenzofur-5-yl)-2-aminopropane essentially as described
in Example 1. This amine was converted to the hydrochloride
salt to provide the title compound.
1H-NMR(DMSO-d6): 8 8.07 (s, 1H), 7.94 (br s, 2H), 7.33 (s,
1H), 7.15 (d, J=11.8 Hz, 1H), 7.02 (s, 1H), 3.44 (m, 1H),
2.99 (dd, J=6.2, 13.4 Hz, 1H), 2.77 (dd, J=8.1, 13.2 Hz,
1H), 1.11 (d, J=6.2 Hz, 1H).



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EXAMPLE 14
1-(6-fluorobenzofur-7-yl)-2-aminopropane oxalate
Beginning with 0.44 gm (2.05 mMol) 6-fluoro-7-bromo-
benzofuran, 1-(6-fluorobenzofur-7-yl)-2-propanone were
prepared essentially as described in Example 1. This ketone
was converted to 0.18 gm (370) of 1-(6-fluorobenzofur-7-yl)-
2-aminopropane essentially as described in Example 1. This
amine was converted to the oxalate salt to provide the title
compound.
m.p. - 200-202°C
MS(FD): m/e = 194.3 (M+1)
EA: Calculated for C11H12NOF-C2H204: C, 55.12; H, 4.98; N,
4.94. Found: C, 55.40; H, 5.17; N, 5.05.
EXAMPLE 15
1-(5-chlorobenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 1.00 gm (4.32 mMol) 5-chloro-7-fluoro-
benzofuran, 0.81 gm (90%) 1-(5-chlorobenzofur-7-yl)-2-
propanone were prepared essentially as described in Example
1.
High Resolution MS: Calculated for C11H1002C1: Theory:
209.0369. Found: 209.0367.
This ketone (0.70 gm, 3.35 mMol) was converted to 0.69
gm (99%) of 1-(5-chlorobenzofur-7-yl)-2-aminopropane
essentially as described in Example 1. This amine was
converted to the hydrochloride salt to provide the title
compound.
EA: Calculated for C11H12NOC1-HCl: C, 53.68; H, 5.32; N,
5.69. Found: C, 53.92; H, 5.34; N, 5.62.



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EXAMPLE 16
1-(2-bromo-5-fluorobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl 1-(2-bromo-5-fluorobenzofur-7-yl)-2-
aminopropane
To a solution of 0.50 gm (1.71 mMol) N-tert-butoxycar-
bonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane in 17 mL
tetrahydrofuran at -78oC were added 2.4 mL (3.84 mMol) n-
butyllithium (1.6 M in hexane) dropwise. The resulting
mixture was stirred for 1.5 hour and then 0.16 mL (1.86
mMol) dibromoethane were added. After stirring for an
additional hour the reaction mixture was poured into a
mixture of 25 mL saturated aqueous sodium bicarbonate and 50
mL diethyl ether. The phases were separated and the organic
phase was washed with saturated aqueous sodium chloride.
All aqueous phases were combined and extracted with 50 mL
diethyl ether. All organic phases were combined, washed
with saturated aqueous sodium chloride, dried over magnesium
sulfate and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography, eluting
with a gradient of hexane containing from 0 to 15o ethyl
acetate. Fractions containing product were combined and
concentrated under reduced pressure to provide 0.53 gm (890)
of the desired compound.
EA: Calculated for C16H19BrFN03: Theory: C, 51.63; H,
5.14; N, 3.76. Found: C, 51.51; H, 4.96; N, 3.70.
Deprotection
Beginning with 0.35 gm (0.94 mMol) N-tert-butoxycar-
bonyl 1-(2-bromo-5-fluorobenzofur-7-yl)-2-aminopropane, 0.15
gm (590) of the title compound were prepared essentially as
described in EXAMPLE 10.
MS(FD): m/e = 272, 274 (M+1)



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EA: Calculated for C11H11NOBrF-HCl: C, 42.82; H, 3.92; N,
4.54. Found: C, 43.11; H, 4.09; N, 4.47.
EXAMPLE 17
(S)-1-(2-bromo-5-fluorobenzofur-7-yl)-2-aminopropane
hydrochloride
(S)-N-tert-butoxycarbonyl 1-(2-bromo-5-fluorobenzofur-7-yl)-
2-aminopropane
Beginning with 0.29 gm (1.0 mMol) (S)-N-tert-butoxycar-
bonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane, 0.18 gm
(480) of the desired compound were prepared essentially as
described in EXAMPLE 16.
EA: Calculated for C16H19BrFN03: Theory: C, 51.63; H,
5.14; N, 3.76. Found: C, 51.83; H, 5.19; N, 3.81.
Deprotection
Beginning with 0.18 gm (0.48 mMol) (S)-N-tert-
butoxycarbonyl 1-(2-bromo-5-fluorobenzofur-7-yl)-2-
aminopropane, 0.12 gm (820) of the title compound were
prepared essentially as described in EXAMPLE 10.
m.p. - 202-205
MS(FD): m/e = 272, 274 (M+1)
EA: Calculated for C11H11NOBrF-HC1: C, 42.82; H, 3.92; N,
4.54. Found: C, 44.28; H, 4.24; N, 4.34.
EXAMPLE 18
1-(3-bromo-5-fluorobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl 1-(2,3-dibromo-2,3-dihydro-5-
fluorobenzofur-7-yl)-2-aminopropane
To a solution of 0.50 gm (1.7 mMol) N-tert-
butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane in
17 mL carbon disulfide were added 50 ~.L (0.97 mMol) bromine
and the reaction mixture was stirred for 4 hours at room



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temperature. A additional 50 ~.L of bromine were added and
stirring was continued for 16 hours. The reaction mixture
was concentrated under reduced pressure to provide 0.75 gm
(98%) of the desired compound.
N-tert-butoxycarbonyl 1-(3-bromo-5-fluorobenzofur-7-yl)-2-
aminopropane
This dibrominated material was dissolved in 15 mL
dimethylsulfoxide and then 0.51 mL (3.41 mMol) 1,8-diaza-
bicyclo[5.4.0]undec-7-ene were added dropwise. After
stirring for 4 hours at room temperature under a nitrogen
atmosphere, the reaction mixture was diluted with 200 mL
ethyl acetate and extracted with two 25 mL portions of 0.1 N
hydrochloric acid. The organic phase was washed with
sequentially with saturated aqueous sodium bicarbonate and
saturated aqueous sodium chloride, dried over sodium sulfate
and concentrated under reduced pressure. The residue was
subjected to silica gel chromatography, eluting with
chloroform containing 1o diethyl ether. Fractions
containing primarily the desired compound were combined and
concentrated under reduced pressure. The residue was
crystallized from hexane to provide the desired compound as
a crystalline solid.
Alternatively, a solution of 4.09 mMol of the dibromide
in 50 mL ethanol was cooled to OoC. To this solution was
added 6.54 mL (6.54 mMoL) potassium hydroxide (1M in
ethanol) dropwise. The reaction mixture was allowed to warm
gradually to room temperature. The desired compound was
recovered by concentration of the reaction mixture under
reduced pressure.
1H-NMR(CDC13): ~ 7.70 (s, 1H), 7.08 (dd, 1H), 6.95 (dd,
1H), 4.4 (br s, 1H), 4.05 (br m, 1H), 3.05 (m, 2H), 1.4 (s,
9H), 1.15 (d, 3H).



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Deprotection
Beginning with 0.37 gm (0.98 mMol) N-tert-butoxycarbon-
y1 1-(3-bromo-5-fluorobenzofur-7-yl)-2-aminopropane, 0.16 gm
(530) of the title compound were prepared essentially as
described in EXAMPLE 10.
EA: Calculated for C11H11NOBrF-HCl: C, 42.82; H, 3.92; N,
4.54. Found: C, 42.60; H, 3.92; N, 4.60.
EXAMPLE 19
1-(2-chloro-5-fluorobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl 1-(2-chloro-5-fluorobenzofur-7-yl)-2-
aminopropane
Beginning with 0.29 gm (1.0 mMol) N-tert-butoxycar-
bonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane and 0.16 gm
(1.20 mMol) N-chlorosuccinimide, 0.14 gm (43%) of the
desired compound were prepared essentially as described in
EXAMPLE 16.
m.p. - 133-135oC
MS(FD): m/e = 327, 329 (M+)
EA: Calculated for C16H19C1FN03: Theory: C, 58.63; H,
5.84; N, 4.27. Found: C, 58.80; H, 5.94; N, 4.28.
Deprotection
Beginning with 0.12 gm (0.38 mMol) N-tert-
butoxycarbonyl 1-(2-chloro-5-fluorobenzofur-7-yl)-2-
aminopropane, 0.088 gm (880) of the title compound were
prepared essentially as described in EXAMPLE 10.
m.p. - 188°C
EA: Calculated for C11H11NOC1F-HCl: C, 50.02; H, 4.58; N,
5.30. Found: C, 49.83; H, 4.53; N, 5.13.



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EXAMPLE 20
1-(3-chloro-5-fluorobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl 1-(2,3-dichloro-2,3-dihydro-5-fluoro-
benzofur-7-yl)-2-aminopropane
To a stirred solution of 0..50 gm (1.70 mMol) N-tert-
butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane in
mL diethyl ether at 0°C under a nitrogen atmosphere were
added 4.6 mL (1.8 mMol) chlorine (0.4 M in diethyl ether)
10 and this mixture was stirred at 0oC for 1 hour. An
additional 2 mL (0.8 mMol) of the chlorine solution were
added and the reaction mixture was stirred for an additional
30 minutes at room temperature. A further 2 mL (0.8 mMol)
of the chlorine solution were added and stirring was
continued for an additional hour. A final 4 mL (1.6 mMol)
portion of the chlorine solution were added and the mixture
was stirred for 16 hours at 0°C. The reaction mixture was
then diluted with 40 mL diethyl ether and washed with 30 mL
1N sodium thiosulfate followed by 10 mL saturated aqueous
sodium chloride. The reaction mixture was dried over sodium
sulfate and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography, eluting
with hexane containing 7% ethyl acetate. Fractions
containing product were combined and concentrated under
reduced pressure to provide 0.30 gm (480) of the desired
compound as a white solid. This material is unstable and
must be used immediately.
N-tert-butoxycarbonyl 1-(3-chloro-5-fluorobenzofur-7-yl)-2-
aminopropane
A mixture of 0.30 gm (0.82 mMol) N-tent-butoxycarbonyl
1-(2,3-dichloro-2,3-dihydro-5-fluorobenzofur-7-yl)-2-
aminopropane and 0.135 gm 18-crown-6 in 6.5 mL 1M potassium
tert-butoxide in tert-butanol was stirred at 35°C for 1



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hour. The reaction mixture was diluted with 4 mL tert-
butanol was continued for an additional 2.5 hours. The
reaction mixture was cooled to room temperature and diluted
with 50 mL diethyl ether followed by 5 mL water and 20 mL
saturated aqueous ammonium chloride. The phases were
separated and the aqueous phase was extracted with 25 mL
diethyl ether. The organic phases were combined, dried over
sodium sulfate and concentrated under reduced pressure to
provide an off-white solid. This solid residue was
subjected to silica gel chromatography, eluting with hexane
containing 7% ethyl acetate. Fractions containing the
desired compound were combined and concentrated under
reduced pressure to provide 0.151 gm (560) of the desired
compound as a white solid.
m.p. - 127-129°C
MS(FD): m/e = 327, 329 (M+)
EA: Calculated for C16H19N03C1F: C, 58.63; H, 5.84; N,
4.27. Found: C, 58.83; H, 5.54; N, 4.10.
Deprotection
Beginning with 0.14 gm (0.42 mMol) N-tert-
butoxycarbonyl 1-(3-chloro-5-fluorobenzofur-7-yl)-2-
aminopropane, 0.10 gm (900) of the title compound were
prepared essentially as described in EXAMPLE 10.
m.p. - 172-174oC
EA: Calculated for C11H11NOC1F-HCl: C, 50.02; H, 4.58; N,
5.30. Found: C, 50.19; H, 4.79; N, 5.32.
EXAMPLE 21
1-(4,5-difluorobenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 0.38 gm (1.61 mMol) 4,5-difluoro-7-
bromobenzofuran, 0.31 gm (920) 1-(4,5-difluorobenzofur-7-
yl)-2-propanone were prepared essentially as described in
Example 1.



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High Resolution MS: Calculated for C11H902F2: Theory:
211.0571. Found: 211.0573.
Beginning with 0.26 gm (1.25 mMol) 1-(4,5-difluoroben-
zofur-7-yl)-2-propanone, 0.14 gm (51%) of 1-(4,5-difluoro-
benzofur-5-yl)-2-aminopropane were prepared essentially as
described in Example 1. This amine was converted to the
hydrochloride salt to provide the title compound.
EA: Calculated for C11H11NOF2-HC1: C, 53.35; H, 4.88; N,
5.66. Found: C, 53.18; H, 4.77; N, 5.60.
EXAMPLE 22
1-(3-methyl-5-fluorobenzofur-7-yl)-2-aminopropane oxalate
Beginning with 1.0 gm (4.37 mMol) 3-methyl-5-fluoro-7
bromobenzofuran, 1.1 gm crude 1-(3-methyl-5-fluorobenzofur
7-yl)-2-propanone were prepared essentially as described in
Example 1.
Beginning with 1.0 gm (4.85 mMol) 1-(3-methyl-4-
fluorobenzofur-7-yl)-2-propanone, 0.37 gm (370) of 1-(3-
methyl-5-fluorobenzofur-7-yl)-2-aminopropane were prepared
essentially as described in Example 1. This amine was
converted to the oxalate salt to provide the title compound.
m.p. - 201-202°C
MS(FD): m/e = 208 (M+1)
EA: Calculated for C12H14NOF-C2H204: C, 56.56; H, 5.43; N,
4.71. Found: C, 56.57; H, 4.66; N, 4.96.
EXAMPLE 23
1-(2-methyl-5-fluorobenzofur-7-yl)-2-aminopropane oxalate
Beginning with 0.75 gm (3.27 mMol) 2-methyl-5-fluoro-7-
bromobenzofuran, 0.76 gm crude 1-(2-methyl-5-fluorobenzofur-
7-yl)-2-propanone were prepared essentially as described in
Example 1.
Beginning with 0.67 gm (3.25 mMol) 1-(2-methyl-4-
fluorobenzofur-7-yl)-2-propanone, 0.31 gm (47%) of 1-(2-



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methyl-5-fluorobenzofur-7-yl)-2-aminopropane were prepared
essentially as described in Example 1. This amine was
converted to the oxalate salt to provide the title compound.
EXAMPLE 24
1-(3-cyano-5-fluorobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl 1-(3-cyano-5-fluorobenzofur-7-yl)-2-
aminopropane
A mixture of 0.20 gm (0.54 mMol) N-tent-butoxycarbonyl
1-(3-bromo-5-fluorobenzofur-7-yl)-2-aminopropane, 0.95 gm (5
mMol) copper(I) iodide, and 0.43 gm (4.78 mMol) copper(I)
cyanide in 10 mL dimethylformamide was purged with nitrogen
for 15 minutes. The mixture was then heated at 120°C. An
additional equivalent of copper(I) iodide and copper(I)
cyanide were added and the reaction continued at 120°C for
about 16 hours. After cooling to room temperature the
reaction mixture was diluted with dichloromethane and then
silica gel was added. The solvents were removed under
reduced pressure and the dry silica gel remaining was loaded
on the top of a silica gel column. The column was then
eluted with a gradient of hexane containing from 17o to 200
ethyl acetate. Fractions containing product were combined
and concentrated under reduced pressure to provide 0.010 gm
(6%) of the desired compound.
High Resolution MS: Calculated for C17H2pN203F: Theory:
319.1458. Found: 319.1461.
Deprotection
Beginning with 0.010 gm (0.03 mMol) N-tert-
butoxycarbonyl 1-(3-cyano-5-fluorobenzofur-7-yl)-2-
aminopropane, 0.0075 gm (980) of the title compound were
prepared essentially as described in EXAMPLE 10.



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High Resolution MS: Calculated for C12H11N203F= Theory:
219.0933. Found: 219.0434.
EXAMPLE 25
1-(2-carboxamido-5-fluorobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl 1-(3-carboxy-5-fluorobenzofur-7-yl)-2-
aminopropane
A solution of 0.20 gm (0.68 mMol) N-tert-butoxycarbonyl
1-(5-fluorobenzofur-7-yl)-2-aminopropane in 35 mL tetrahy-
drofuran was cooled~to -78oC under a nitrogen atmosphere.
To this solution were then added 0.96 mL (1.53 mMoL) n-
butyllithium (1.6 M in hexane) dropwise, resulting in an
orange solution. After 15 minutes carbon dioxide gas was
bubbled into the reaction mixture, immediately discharging
the orange color. The reaction mixture was diluted with 200
mL ethyl acetate, washed sequentially with 100 mL of water
and 100 mL saturated aqueous sodium chloride, dried over
magnesium sulfate and concentrated under reduced pressure.
The residual solid was slurried in diethyl ether and
filtered, providing 0.14 gm (600) of the desired compound in
two crops.
EA: Calculated for C17H2pN05F: C, 60.53; H, 5.98; N, 4.15.
Found: C, 60.47; H, 5.84; N, 4.02.
N-tert-butoxycarbonyl 1-(2-carboxamido-5-fluorobenzofur-7-
yl)-2-aminopropane
To a solution of 0.20 gm (0.59 mMol) N-tert
butoxycarbonyl 1-(2-carboxy-5-fluorobenzofur-7-yl)-2
aminopropane in 30 mL tetrahydrofuran and 10 mL dichloro-
methane were added sequentially 0.09 gm (0.65 mMol) 1-
hydroxybenzotriazole and 0.11 mL (0.65 mMol) diisopropyleth-
ylamine. The reaction mixture was cooled to 0°C and then
0.12 gm (0.62 mMol) 1-(3-dimethylaminopropyl)-3-ethylcarbo-



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diimide hydrochloride. The reaction mixture was then
stirred for 3 hours at which point 0.03 mL (0.77 mMol)
ammonium hydroxide were added. After stirring about 20
hours at room temperature the reaction mixture was
concentrated under reduced pressure. The residue was
diluted with 300 mL ethyl acetate and washed with
sequentially with 100 mL 2 N sodium hydroxide, 200 mL
saturated aqueous ammonium chloride, 100 mL water, and 100
mL saturated aqueous sodium chloride, dried over magnesium
sulfate and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography, eluting
with 1:1 hexane: ethyl acetate. Fractions containing product
were combined and concentrated under reduced pressure to
provide 0.055 gm (280) of the desired compound.
Deprotection
Beginning with 0.05 gm (0.149 mMol) N-tert-
butoxycarbonyl 1-(2-carboxamido-5-fluorobenzofur-7-yl)-2-
aminopropane, the title compound was prepared essentially as
described in EXAMPLE 10.
High Resolution MS: Calculated for C12H13N2~2F~ Theory:
237.1039. Found: 237.1036.
EXAMPLE 26
1-(2-formyl-5-fluorobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl 1-(2-formyl-5-fluorobenzofur-7-yl)-2-
aml.nopropane
A solution of 0.50 gm (1.7 mMol) N-tert-butoxycarbonyl
1-(5-fluorobenzofur-7-yl)-2-aminopropane in 75 mL tetrahy-
drofuran was cooled to -78°C under a nitrogen atmosphere.
To this solution were then added 2.4 mL (3.81 mMoL) n-
butyllithium (1.6 M in hexane) dropwise, resulting in an
orange solution. After 5 minutes 0.66 mL (8.52 mMol)



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dimethylformamide were added dropwise. After stirring 18
hours at room temperature the reaction mixture was quenched
by addition of 20 mL saturated aqueous ammonium chloride.
The reaction mixture was partitioned between 300 mL ethyl
acetate and 300 mL water. The phases were separated and the
aqueous phase was extracted twice with 200 mL ethyl acetate.
The organic phases were combined and washed sequentially
with two 200 mL portions of water and one 200 mL portion of
saturated aqueous sodium chloride, dried over magnesium
sulfate and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography, eluting
with hexane containing 20% ethyl acetate. Fractions
containing product were combined and concentrated under
reduced pressure to provide 0.38 gm (690) of the desired
compound as a yellow solid.
Deprotection
Beginning with 0.20 gm (0.62 mMol) N-tert-
butoxycarbonyl 1-(2-formyl-5-fluorobenzofur-7-yl)-2-
aminopropane, the title compound was prepared essentially as
described in EXAMPLE 10.
EXAMPLE 27
1-(2-trimethylsilyl-5-fluorobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl-1-(2-trimethylsilyl-5-fluorobenzofur-
7-yl)-2-aminopropane
A solution of 0.20 gm (0.68 mMol) N-tert-butoxycarbonyl
1-(5-fluorobenzofur-7-yl)-2-aminopropane in 10 mL tetrahy-
drofuran was cooled to -78°C under a nitrogen atmosphere.
To this solution were then added 0.96 mL (1.53 mMoL) n-
butyllithium (1.6 M in hexane) dropwise, resulting in an
orange solution. After 50 minutes 0.14 mL (1.02 mMol)
trimethylsilylisocyanate were added dropwise. After 15



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minutes the reaction mixture was quenched by addition of 2
mL saturated aqueous ammonium chloride and was then allowed
to warm to room temperature. The reaction mixture was
partitioned between 150 mL ethyl acetate and 150 mL water.
The phases were separated and the organic phase was washed
sequentially with 150 mL water and 150 mL saturated aqueous
sodium chloride, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was
subjected to silica gel chromatography, eluting with 10:1
hexane: ethyl acetate. Fractions containing product were
combined and concentrated under reduced pressure to provide
the desired compound.
MS(FD): m/e = 365 (M+)
EA: Calculated for ClgH2gN03FSi: C, 62.43; H, 7.72; N,
3.83. Found: C, 62.68; H, 7.65; N, 3.83.
Deprotection
Beginning with 0.13 gm (0.34 mMol) N-tert-
butoxycarbonyl 1-(2-trimethylsilyl-5-fluorobenzofur-7-yl)-2
aminopropane, the title compound was prepared essentially as
described in EXAMPLE 10.
EXAMPLE 28
1-(2-[N'-phenyl]carboxamido-5-fluorobenzofur-7-yl)-2
aminopropane hydrochloride
N-tert-butoxycarbonyl 1-(2-[N'-phenyl]carboxamido-5-
fluorobenzofur-7-yl)-2-aminopropane
A solution of 0.20 gm (0.68 mMol) N-tert-butoxycarbonyl
1-(5-fluorobenzofur-7-yl)-2-aminopropane in 10 mL tetrahy-
drofuran was cooled to -78°C under a nitrogen atmosphere.
To this solution were then added 0.96 mL (1.53 mMoL) n-
butyllithium (1.6 M in hexane) dropwise, resulting in an
orange solution. After 30 minutes 0.11 mL (1.02 mMol)
phenylisocyanate were added dropwise. After about 1.5 hours



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the reaction mixture was quenched by addition of 2 mL
saturated aqueous ammonium chloride and was then allowed to
warm to room temperature. The reaction mixture was diluted
with dichloromethane and then silica gel was added. The
volatiles were removed under reduced pressure and the dry
silica gel was added to the top of silica gel column. The
column was then eluted with 6:1 hexane: ethyl acetate.
Fractions containing product were combined and concentrated
under reduced pressure to provide 0.096 gm (340) of the
desired compound as a white solid.
m.p. - 154-156oC
Deprotection
Beginning with 0.80 gm (0.19 mMol) N-tert-
butoxycarbonyl 1-(2-[N'-phenyl]carboxamido-5-fluorobenzofur-
7-yl)-2-aminopropane, 0.055 gm (810) of the title compound
were prepared as a white solid essentially as described in
EXAMPLE 10.
m.p. >260oC
EA: Calculated for C18H17N202F-HCl: C, 61.98; H, 5.20; N,
8.03. Found: C, 61.83; H, 5.28; N, 7.90.
EXAMPLE 29
1-(5-fluorobenzofur-7-yl)-3-aminobutane hydrochloride
Nitrogen was bubbled through a mixture of 1.0 gm (4.65
mMol) 5-fluoro-7-bromobenzofuran, 0.61 mL (6.98 mMol) 3-
buten-2-ol, 0.057 gm (0.186 mMol) trio-tolyl)phosphine, and
0.47 gm (5.58 mMol) sodium bicarbonate in 35 mL N-
methylpyrrolidinone for 10 minutes. To the mixture were
then added 0.021 gm (0.093 mMol) palladium(II) acetate and
the reaction mixture was heated to 140°C for 3 hours. The
reaction mixture was cooled to room temperature and diluted
with 500 mL ethyl acetate. The organic phase was washed
sequentially with three 500 mL portions of water and 500 mL



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saturated aqueous sodium chloride, dried over magnesium
sulfate and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography, eluting
with a gradient of hexane containing from 0-20o ethyl
acetate. Fractions containing product were combined and
concentrated under reduced pressure to provide 0.73 gm (760)
4-(5-fluorobenzofur-7-yl)-2-butanone as a yellow oil.
EA: Calculated for C12H1102F= C, 69.89; H, 5.38. Found:
C, 69.76; H, 5.29.
Beginning with 0.63 gm (3.05 mMol) 4-(5-fluorobenzofur-
7-yl)-2-butanone, 1-(5-fluorobenzofur-7-yl)-3-aminobutane
was prepared essentially as described in EXAMPLE 1. 0.36 gm
(1.73 mMol) of this amine were treated with hydrogen
chloride to prepare 0.32 gm (760) of the title compound as a
white solid.
EA: Calculated for C12H14NOF-HCl: C, 59.14; H, 6.20; N,
5.75. Found: C, 59.36; H, 6.18; N, 5.79.
EXAMPLE 30
1-(5-nitrobenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 3.8 gm (15.7 mMol) 5-nitro-7-bromobenzo-
furan, 2.4 gm (700) 1-(5-nitrobenzofur-7-yl)-2-propanone
were prepared as a pale yellow solid essentially as
described in Example 1.
Beginning with 0.28 gm (1.28 mMol) 1-(5-nitrobenzofur-
7-yl)-2-propanone, 0.15 gm (53%) of 1-(5-nitrobenzofur-7-
yl)-2-aminopropane were prepared as a light yellow, waxy
solid essentially as described in Example 1. This amine was
converted to the hydrochloride salt to provide the title
compound.
m.p. - 216-217oC (dec.)
MS(FD): m/e = 221 (M+1)
EA: Calculated for C11H12N20-HCl-0.1 H20: C, 51.11; H,
5.11; N, 10.84. Found: C, 50.95; H, 4.93; N, 10.67.



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EXAMPLE 31
1-(5-aminobenzofur-7-yl)-2-aminopropane dihydrochloride
N-tert-butoxycarbonyl 1-(5-nitrobenzofur-7-yl)-2-
aminopropane
A mixture of 1.60 gm (7.27 mMol) 1-(5-nitrobenzofur-7-
yl)-2-aminopropane, 1.01 mL (7.27 mMol) triethylamine, and
1.59 gm (7.27 mMol) di-tert-butyl Bicarbonate in 60 mL
dichloromethane was stirred at room temperature for 18
hours. The reaction mixture was diluted with 60 ml
dichloromethane and was then washed sequentially with two 50
mL portions of 0.1 N hydrochloric acid, 50 mL 2.5 N sodium
hydroxide, and 25 mL saturated aqueous sodium chloride. The
remaining organic phase was then dried over sodium sulfate
and concentrated under reduced pressure. The residue was
crystallized from diethyl ether to provide 1.72 gm (740) of
the desired compound as a white crystalline solid.
m.p. - 131-132°C
EA: Calculated for C16H20N2~5~ C. 59.99; H, 6.29; N, 8.75.
Found: C, 60.15; H, 6.35; N, 8.83.
N-tert-butoxycarbonyl 1-(5-[N'-tert-butoxycarbonyl]amino
benzofur-7-yl)-2-aminopropane
A mixture of 0.43 gm (1.34 mMol) crude N-tert-
butoxycarbonyl 1-(5-nitrobenzofur-7-yl)-2-aminopropane and
0.89 gm (13.4 mMol) zinc dust in 20 mL glacial acetic acid
was stirred at room temperature for 75 minutes. The
reaction mixture was filtered through a pad of celite and
the filter pad was washed with four 40 mL portions of
dichloromethane. The combined filtrates were neutralized by
the addition of 100 mL ice cold 5 N sodium hydroxide. The
phases were separated and the aqueous phase was extracted
with 40 mL dichloromethane. The organic phases were
combined, washed with 40 mL of 3:1 saturated aqueous sodium



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chloride:5 N sodium hydroxide, dried over sodium sulfate,
and concentrated under reduced pressure. The residue was
subjected to silica gel chromatography, eluting with 1:1
hexane: ethyl acetate. Fractions containing product were
combined and concentrated under reduced pressure to provide
0.20 gm of the desired compound as a pale yellow oil.
MS(ion spray): m/e = 391 (M+1)
Deprotection
Beginning with 0.20 gm (0.51 mMol) N-tert-
butoxycarbonyl 1-(5-[N'-tert-butoxycarbonyl]aminobenzofur-7-
yl)-2-aminopropane, 0.10 gm (740) of the title compound were
prepared as an off-white solid essentially as described in
EXAMPLE 10.
High Resolution MS: Calculated for C11H15N2~= Theory:
191.1184. Found: 191.1182.
EXAMPLE 32
1-(5-[N'-acetyl]aminobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl 1-(5-aminobenzofur-7-yl)-2-
aminopropane
A mixture of 0.23 gm (0.78 mMol) N-tert-butoxycarbonyl-
1-(5-aminobenzofur-7-yl)-2-aminopropane, 163 ~.L (1.17 mMol)
triethylamine, and 88 uL (0.93 mMol) acetic anhydride in 5
mL dichloromethane was stirred at room temperature under a
nitrogen atmosphere for 18 hours. The reaction mixture was
diluted with 35 mL dichloromethane and was washed
sequentially with 15 mL 0.5 N hydrochloric acid, 15 mL 1.0 N
sodium hydroxide, and 5 mL saturated aqueous sodium
chloride. The remaining organic phase was dried over sodium
sulfate and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography, eluting
with 6:4 ethyl acetate: hexane. Fractions containing product



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were combined and concentrated under reduced pressure to
provide 0.21 gm (800) of the desired compound as a pale
yellow foam.
High Resolution MS: Calculated for C18H25N204: Theory:
333.1814. Found: 333.1811.
Deprotection
Beginning with 0.049 gm (0.15 mMol) N-tert-
butoxycarbonyl 1-(5-[N'-acetyl]aminobenzofur-7-yl)-2-
aminopropane, 0.027 gm (680) of the title compound were
prepared as a pale yellow solid essentially as described in
EXAMPLE 10.
m.p. - 229-233°C (dec.)
EA: Calculated for C13H16N2~2-HCl-0.5 H20 C, 56.22; H,
6.53; N, 10.09. Found: C, 56.23; H, 6.27; N, 9.94.
EXAMPLE 33
1-(5-[N'-acetyl N'-methyl]aminobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl 1-(5-[N'-acetyl N'-methyl]aminobenzo-
fur-7-yl)-2-aminopropane
To a solution of 0.15 gm (0.45 mMol) N-tert-
butoxycarbonyl 1-(5-[N'-acetyl]aminobenzo-fur-7-yl)-2-
aminopropane in 4 mL tetrahydrofuran were added 0.018 gm
(0.45 mMol) sodium hydride (60o in mineral oil). The
reaction mixture was stirred for, l0 minutes at room
temperature under a nitrogen atmosphere, at which point 0.15
mL iodomethane were added. The reaction mixture was stirred
for 1.5 hour at room temperature and was then quenched with
1 mL saturated aqueous ammonium chloride. The reaction
mixture was diluted with 25 mL ethyl acetate and stirred
vigorously. The organic phase was decanted off and the
process was repeated. The combined organic extracts were
combined and concentrated under reduced pressure. The



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residual oily solid was subjected to flash silica gel
chromatography eluting with dichloromethane containing 4%
methanol. Fractions containing the desired product were
combined and concentrated under reduced pressure to provide
a yellow oil. The oil was dissolved in diethyl ether and
the solution was then concentrated under reduced pressure to
provide 0.121 gm (780) of the desired compound as an off-
white foam.
Deprotection
Beginning with 0.040 gm (0.12 mMol) N-tert-butoxy-
carbonyl 1-(5-[N'-acetyl N'-methyl]aminobenzo-fur-7-yl)-2-
aminopropane, 0.019 gm (58%) of the title compound were
prepared as a solid essentially as described in EXAMPLE 10.
MS(ion spray): m/e = 247 (M+)
EXAMPLE 34
1-(5-[N'-methyl]aminobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tent-butoxycarbonyl 1-(5-[N'-methyl]aminobenzofur-7-yl)-2-
aminopropane
A mixture of 0.081 gm (0.23 mMol) N-tert-butoxycarbonyl
1-(5-[N'-acetyl N'-methyl]aminobenzo-fur-7-yl)-2-amino-
propane, 0.065 gm (1.17 mMol) potassium hydroxide, 2 mL
methanol and 2 mL tetrahydrofuran was stirred at reflux for
2.5 hour. The reaction mixture was then allowed to stir at
room temperature for about 18 hours at which point it was
heated at reflux for 9 hours followed by about 18 hours at
room temperature. To this mixture were then added 0.5 mL
50% aqueous sodium hydroxide and 2 mL dioxane and the
resulting mixture was stirred at room temperature for about
18 hours. The reaction mixture was then partitioned between
2 mL of water and 25 mL diethyl ether. The organic phase
was separated, dried over sodium sulfate, and concentrated



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under reduced pressure. The residual oil was subjected to
flash silica gel chromatography, eluting with hexane
containing 30% ethyl acetate. Fractions containing the
desired product were combined and concentrated under reduced
pressure to provide 0.042 gm (600) of the desired compound
as a colorless oil.
High Resolution MS: Calculated for C17H25N203: Theory:
305.1865. Found: 305.1868.
Deprotection
Beginning with 0.039 gm (0.13 mMol) N-tert-butoxy-
carbonyl 1-(5-[N'-methyl]aminobenzo-fur-7-yl)-2-amino-
propane, 0.014 gm (390) of the title compound were prepared
as an off-white solid essentially as described in EXAMPLE
10.
High Resolution MS: Calculated for C12H17N20: Theory:
205.1341. Found: 205.1340.
EXAMPLE 35
1-(5-[N',N'-dimethyl]aminobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl 1-(5-[N',N'-dimethyl]aminobenzofur-7-
yl)-2-aminopropane
To a stirring mixture of 0.14 gm (0.48 mMol) 1-(5-
aminobenzofur-7-yl)-2-aminopropane, 0.38 mL (5 mMol)
formaldehyde (37% aqueous), and 0.091 gm sodium cyanoboro-
hydride in 2 mL acetonitrile were added dropwise 50 uL
glacial acetic acid over 3 minutes. The mixture was stirred
for 2 hours at room temperature at which point an additional
50 ~.L of glacial acetic acid were added. After stirring at
room temperature for 1.5 hours an additional charge of 0.38
mL (5 mMol) formaldehyde (37o aqueous), and 0.091 gm sodium
cyanoborohydride, 2 mL acetonitrile, and 50 ~.L glacial
acetic acid were added. After stirring for 1 hour at room



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temperature an additional 50 ~.L of glacial acetic acid were
added. After stirring for an additional 30 minutes, the
reaction mixture was diluted with 50 mL of diethyl ether and
was washed sequentially with 2 x15 mL 1N sodium hydroxide
and 1 x 15 mL saturated aqueous sodium chloride. The
organic phase was separated, dried over sodium sulfate, and
concentrated under reduced pressure. The residual oil was
subjected to flash silica gel chromatography, eluting with
1:l hexane: ethyl acetate. Fractions containing product were
combined and concentrated under reduced pressure to provide
0.087 gm (620) of the desired compound as a white foam.
High Resolution MS: Calculated for C18H27N203: Theory:
319.2022. Found: 319.2018.
Deprotection
Beginning with 0.040 gm (0.13 mMol) N-tert-butoxy-
carbonyl 1-(5-[N',N'-dimethyl]aminobenzofur-7-yl)-2-amino-
propane, 0.011 gm (29%) of the title compound were prepared
as an off-white solid essentially as described in EXAMPLE
10.
m.p. - 222-225°C (dec.)
High Resolution MS: Calculated for C13H19N2~~ Theory:
219.1497. Found: 219.1499.
EXAMPLE 36
N-benzyl N'-(7-(2-aminoprop-1-yl)benzofur-5-yl)urea
hydrochloride
N-benzyl N'-(7-(N"-tert-butoxycarbonyl-2-aminoprop-1-
yl)benzofur-5-yl)urea
A mixture of 0.10 gm (0.34 mMol) 1-(5-aminobenzofur-7-
yl)-2-aminopropane and 0.43 ~.L (0.34 mMol) benzyl isocyanate
in 4 mL dichloromethane was stirred at room temperature for
about 18 hours. The white suspension was diluted with 3 mL
diethyl ether and was filtered. The collected solid was



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washed with 2 x 1 mL diethyl ether and was dried under
reduced pressure to provide 0.101 gm (700) of the desired
compound as a white solid.
m.p. - 167-168oC
EA: Calculated for C24H2gN304: C, 68.07; H, 6.90; N, 9.92.
Found: C, 68.06; H, 7.01; N, 9.98.
Deprotection
Beginning with 0.082 gm (0.19 mMol) N-benzyl N'-(7-(N"-
tert-butoxycarbonyl-2-aminoprop-1-yl)benzofur-5-yl)urea,
0.054 gm (790) of the title compound were prepared as an
white solid essentially as described in EXAMPLE 10.
m.p. - 215-217oC (dec.)
EA: Calculated for C1gH21N3~2-HC1: C, 63.42; H, 6.16; N,
11.68. Found: C, 63.21; H, 6.33; N, 11.60.
EXAMPLE 37
1-(5-[N'-methoxyacetyl]aminobenzofur-7-yl)-2-aminopropane
hydrochloride
N-tert-butoxycarbonyl 1-(5-[N'-methoxyacetyl]aminobenzofur-
7-yl)-2-aminopropane
A solution~of 24 ~,L (0.31 mMol) methoxyacetic acid and
0.050 gm (0.31 mMol) carbonyldiimidazole in 2 mL tetrahydro-
furan was stirred at room temperature under a nitrogen
atmosphere for 45 minutes. At this point a solution of
0.090 gm (0.31 mMol) 1-(5-aminobenzofur-7-yl)-2-aminopropane
in 1 mL tetrahydrofuran was added and the reaction mixture
was stirred at room temperature for about 18 hours. The
reaction mixture was then heated at reflux for 5 hours and
was then diluted with 50 mL dichloromethane. This solution
was then washed sequentially with 1 x 15 mL 2 N sodium
hydroxide, 2 x 15 mL 1 N hydrochloric acid, and 1 x 15 mL
saturated aqueous sodium chloride. The remaining organics
were dried over sodium sulfate and concentrated under



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reduced pressure. The residual oil was subjected to flash
silica gel chromatography, eluting with 1:1 hexane: ethyl
acetate. Fractions containing product were combined and
concentrated under reduced pressure to provide 0.060 gm
(540) of the desired compound as a yellow-orange foam.
High Resolution MS: Calculated for C19H27N205: Theory:
363.1920. Found: 363.1918.
Deprotection
Beginning with 0.058 gm (0.16 mMol) N-tert-
butoxycarbonyl 1-(5-[N'-methoxyacetyl]aminobenzofur-7-yl)-2-
aminopropane, 0.036 gm (750) of the title compound were
prepared as an white solid essentially as described in
EXAMPLE 10.
m.p. - 240°C (dec.)
EA: Calculated for C19H21N3~2-HCl-0.5 H20 C, 54.64; H,
6.55; N, 9.10. Found: C, 54.64; H, 6.38; N, 8.85.
EXAMPLE 38
1-(5-hydroxybenzofur-7-yl)-2-aminopropane hydrochloride
A mixture of 0.73 gm (2.38 mMol) N-tert-butoxycarbonyl
1-(5-methoxybenzofur-7-yl)-2-aminopropane and 3.30 gm (28.52
mMol) pyridine hydrochloride were heated at 170°C in a
sealed tube for 15 hours. The mixture was cooled and the
residue was dissolved in dichloromethane containing 100
methanol and 1o ammonium hydroxide. The solution was
concentrated under reduced pressure and the pyridine
remaining in the residue was removed azeotropically by
diluting the residue with water and concentrating three
times. The residue was crystallized from ethanol: diethyl
ether. The 1-(5-hydroxybenzofur-7-yl)-2-aminopropane was
recovered in the second crop and the filtrate. 0.045 gm
(0.24 mMol) was treated with hydrochloric acid in diethyl
ether to provide the title compound.



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MS: m/e = 192 (M+1)
1H-NMR(DMSO-d6): b 9.2 (s, 1H), 8.07 (br s, 3H), 7.86 (d,
J=2 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.78 (d, J=2.0 Hz, 1H),
6.6 (d, J=2.4 Hz, 1H), 3.5 (br m, 1H), 3.12 (dd, J=5.4, 13.7
Hz, 1H), 2.87 (dd, J=9.3, 13.2 Hz, 1H), 1.08 (d, J=6.4 Hz,
3H).
EXAMPLE 39
1-amino-2-(5-fluorobenzofur-7-yl)propane
Ethyl 2-oxo-2-(5-fluorobenzofur-7-yl)acetate
A mixture of 1.01 gm (4.72 mMol) 5-fluoro-7-bromobenzo-
furan, 0:15 gm (6.14 mMol) magnesium(0), and 2 drops of 1,2-
dibromoethane in 1 mL diethyl ether was stirred at room
temperature until initiation of the Grignard formation had
occurred (about 5-10 minutes). The mixture was then diluted
with 8 mL of diethyl ether and heated at reflux for 30
minutes. This mixture was then added dropwise to a solution
of 1.38 gm (9.44 mMol) diethyl oxalate in 3 mL tetrahydro-
furan at -10°C. Once the addition was complete the reaction
mixture was allowed to warm to room temperature and was then
stirred at room temperature for 30 minutes. The reaction
mixture was diluted with 20 volumes of ethyl acetate and was
washed sequentially with 1N hydrochloric acid, water, and
saturated aqueous sodium chloride. The remaining organics
were concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography, eluting with
hexane containing 30o ethyl acetate. Fractions containing
the desired product were combined and concentrated under
reduced pressure to provide 0.894 gm (800) of the desired
compound.
Ethyl 2-acetoxy-2-(5-fluorobenzofur-7-yl)acetate
A mixture of 0.894 gm (3.78 mMol) ethyl 2-oxo-2-(5-
fluorobenzofur-7-yl)acetate and 0.143 gm (3.78 mMol) sodium



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borohydride in 5 mL ethanol was stirred at room temperature
for 1 hour. The reaction was quenched by the dropwise
addition of water arid was then concentrated under reduced
pressure. The residue was dissolved in ethyl acetate,
washed with water, and the organic phase concentrated under
reduced pressure. The residual oil was subjected to flash
silica gel chromatography, eluting with chloroform
containing 2% methanol. Fractions containing ethyl 2-
hydroxy-2-(5-fluorobenzofur-7-yl)acetate were combined and
concentrated under reduced pressure. This residue was
dissolved in 2.5 mL of pyridine and 2.5 mL acetic anhydride
and was stirred at room temperature for 1 hour. The
reaction mixture was then diluted with 25 volumes of ethyl
acetate, washed with water, and concentrated under reduced
pressure to provide 0.675 gm (640) of the desired compound.
MS: m/e = 281 (M+1)
Ethyl 2-(5-fluorobenzofur-7-yl)acetate
A mixture of 1.43 gm (5.10 mMol) ethyl 2-acetoxy-2-(5-
fluorobenzofur-7-yl)acetate, 7.31 gm (40.8 mMol) hexamethyl-
phosphoramide, 0.20 gm (6.12 mMol) methanol, and 153 mL
(15.3 mMol) samarium(II) iodide tetrahydrofuran complex
(0.1 M in tetrahydrofuran) was stirred at room temperature
under a nitrogen atmosphere for 15 minutes. The reaction
mixture was then diluted 10 fold with ethyl acetate, washed
with water, and concentrated under reduced pressure to
provide 1.09 gm (96%) of the desired compound.
Ethyl 2-(5-fluorobenzofur-7-yl)propionate
A solution of 1.09 gm (4.90 mMol) ethyl 2-(5-
fluorobenzofur-7-yl)acetate in 5 mL tetrahydrofuran was
cooled to -78°C. To this solution were slowly added 6.1 mL
(6.13 mMol) lithium diisopropylamide (1.0 M in tetrahydro-
furan) and the mixture was stirred at -78°C for 1 hour. To



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this solution were then added 0.76 mL (12.25 mMol)
iodomethane and the mixture was allowed to warm to room
temperature over 1-hour. The reaction mixture was then
diluted with ethyl acetate and the resulting solution washed
sequentially with water, saturated aqueous sodium
bicarbonate, and saturated aqueous sodium chloride. The
remaining organic phase was concentrated under reduced
pressure and the residue subjected to flash silica gel
chromatography, eluting with hexane containing 20% ethyl
acetate. Fractions containing product were combined and
concentrated under reduced pressure to provide 0.723 gm
(62%) of the desired compound.
2-(5-fluorobenzofur-7-yl)propionamide
To a solution of 0.27 gm (1.15 mMol) ethyl 2-(5-
fluorobenzofur-7-yl)propionate in 4 mL dimethylformamide
were added sequentially 0.16 mL (3.91 mMol) freshly
distilled formamide and 0.81 mL (0.80 mMol) sodium methoxide
(1 M in methanol) dropwise and the resulting mixture was
heated at 100°C for 45 minutes. The reaction mixture was
cooled to room temperature and was then diluted with 25
volumes of ethyl acetate. The mixture was then washed
sequentially with water and saturated aqueous sodium
chloride, and concentrated under reduced pressure. The
residue was subjected to flash silica gel chromatography,
eluting with 2:1 ethyl acetate: hexane. Fractions containing
product were combined and concentrated under reduced
pressure to provide 0.060 gm (250) of the desired compound.
MS: m/e = 208 (M+1)
Reduction of amide
To a solution of 0.06 gm (0.29 mMol) ethyl 2-(5-
fluorobenzofur-7-y1)propionamide in 1.5 mL tetrahydrofuran
were added 0.87 mL (0.87 mMol) borane tetrahydrofuran



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complex (1.0 M in tetrahydrofuran). The reaction mixture
was stirred at room temperature for 2 hours and was then
heated at reflux for 2 hours. The reaction mixture was
cooled to room temperature and was then concentrated under
reduced pressure. The residue was treated with a 1:1
mixture of methanol and 1N hydrochloric acid for 1 hour and
was again concentrated under reduced pressure. The residue
was dissolved in water, made basic with 5N sodium hydroxide,
and extracted well with ethyl acetate. The organic phases
were combined and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography, eluting
with ethyl acetate containing 5o methanol and 5%
triethylamine. Fractions containing product were combined
and concentrated under reduced pressure to provide the title
compound.
MS: m/e = 195 (M+2)
EXAMPLE 40
1-(3-trifluoromethyl-5-fluorobenzofur-7-yl)-2-aminopropane
oxalate
Beginning with 0.10 gm (0.35 mMol) 3-trifluoromethyl-5-
fluoro-7-bromobenzofuran, 1-(3-trifluoromethyl-5-fluoro-
benzofur-7-yl)-2-propanone were prepared essentially as
described in Example 1.
This ketone (0.042 gm, 0.17 mMol) was converted to
0.018 gm (42a) of 1-(3-trifluoromethyl-5-fluorobenzofur-7-
yl)-2-aminopropane essentially as described in Example 1.
This amine was converted to the oxalate salt to provide the
title compound.
MS: m/e = 263 (M+2)



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EXAMPLE 41
1-(5-methoxycarbonylbenzofur-7-yl)-2-aminopropane oxalate
Beginning with 1.00 gm (4.12 mMol) 5-methoxycarbonyl-7-
bromobenzofuran, 0.50 gm (550) 1-(5-(methoxycarbonyl)benzo-
fur-7-yl)-2-propanone were prepared essentially as described
in Example 1.
This ketone was converted to 0.38 gm (750) of 1-(5-
(methoxycarbonyl)benzofur-7-yl)-2-aminopropane essentially
as described in Example 1. This amine was converted to the
oxalate salt to provide the title compound.
Standard Procedure for Preparation of Amides
A mixture of 1 equivalent N-tert-butoxycarbonyl 1-(5-
carboxybenzofur-7-yl)-2-aminopropane, 1.2 equivalents 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and
1.2 equivalents of an appropriate amine in dichloromethane
are stirred at room temperature for about 18 hours. The
reaction mixture is then washed with water and concentrated
under reduced pressure. The residue is then crystallized
from a mixture of hexane and ethyl acetate to provide the N-
tert-butoxycarbonyl 1-(N'-[substituted] 5-carboxamidobenzo-
fur-7-yl)-2-aminopropane. This material is then treated
with trifluoroacetic acid followed by 1N hydrochloric acid
to de~rotect the 2-amino group. Lyophilization provides the
hydrochloride salts of the desired amides. This procedure
was applied to the preparation of the compounds of EXAMPLES
42-45.
EXAMPLE 42
1-(N'-[butyl] 5-carboxamidobenzofur-7-yl)-2-aminopropane
hydrochloride
Beginning with 0.050 gm (0.16 mMol) N-tert-butoxy-
carbonyl 1-(5-carboxybenzofur-7-yl)-2-aminopropane and 0.013



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gm (0.17 mMol) butylamine, the title compound was prepared
as previously described.
MS: m/e = 276 (M+2)
EXAMPLE 43
1-(N'-[benzyl] 5-carboxamidobenzofur-7-yl)-2-aminopropane
hydrochloride
Beginning with 0.050 gm (0.16 mMol) N-tert-butoxy
carbonyl 1-(5-carboxybenzofur-7-yl)-2-aminopropane and 0.018
gm (0.17 mMol) benzylamine, the title compound was prepared
as previously described.
MS: m/e = 308 (M+2)
EXAMPLE 44
1-(N'-[1-phenyleth-2-yl] 5-carboxamidobenzofur-7-yl)-2-
aminopropane hydrochloride
Beginning with 0.050 gm (0.16 mMol) N-tert-butoxy-
carbonyl 1-(5-carboxybenzofur-7-yl)-2-aminopropane and 0.021
gm (0.17 mMol) phenethylamine, the title compound was
prepared as previously described.
MS: m/e = 322 (M+1)
EXAMPLE 45
1-(N'-[1-(pyridin-2-yl)eth-2-yl] 5-carboxamidobenzofur-7-
yl)-2-aminopropane dihydrochloride
Beginning with 0.050 gm (0.16 mMol) N-tert-butoxy-
carbonyl 1-(5-carboxybenzofur-7-yl)-2-aminopropane and 0.021
gm (0.17 mMol) 1-(pyridin-2-yl)eth-2-ylamine, the title
compound was prepared as previously described.
MS: m/e = 325 (M+1)



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EXAMPLE 46
1-(N'-[1-(pyridin-2-yl)eth-2-yl] 5-carboxamidobenzofur-7
y1)-2-aminopropane oxalate
N-tert-butoxycarbonyl 1-(N'-[1-(pyridin-2-yl)eth-2-yl] 5-
carboxamidobenzofur-7-yl)-2-aminopropane
A mixture of 0.175 gm (0.55 mMol) N-tert-butoxycarbonyl
5-carboxybenzofur-7-yl)-2-aminopropane, 0.116 gm (0.60 mMol)
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
66 ~.L (0.55 mMol) 2-(2-ethylamino)pyridine, and a trace of
dimethylaminopyridine in 5 mL dichloromethane was stirred at
room temperature until all starting material was consumed.
The reaction mixture was then washed sequentially with
saturated aqueous sodium bicarbonate and saturated aqueous
sodium chloride, dried over sodium sulfate and concentrated
under reduced pressure. The residue was subjected to silica
gel chromatography, eluting with dichloromethane containing
1o methanol saturated with ammonia. Fractions containing
the desired product were combined and concentrated under
reduced pressure to provide 0.164 gm (70%) of the desired
compound as a white solid.
MS: m/e = 424 (M+1)
Deprotection
A mixture of 0.153 gm (0.36 mMo1) N-tert-butoxycarbonyl
1-(N'-[1-(pyridin-2-yl)eth-2-yl] 5-carboxamidobenzofur-7-
yl)-2-aminopropane and 3 mL trifluoroacetic acid was stirred
at room temperature for about 1.5 hours. The reaction
mixture was concentrated under reduced pressure and the
residue taken up in water. This aqueous solution was made
basic by the addition of aqueous sodium hydroxide. This
solution was extracted well with ethyl acetate. This
solution was treated with a solution of oxalic acid in ethyl
acetate and the solid collected to provide the title
compound.



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MS: m/e = 324 (M+)
EXAMPLE 47
1-(N'-[1-(pyridin-3-yl)eth-2-yl] 5-carboxamidobenzofur-7-
yl)-2-aminopropane dihydrochloride
Beginning with N-tert-butoxycarbonyl 5-carboxybenzofur-
7-yl)-2-aminopropane and 3-(2-ethylamino)pyridine, the title
compound was prepared essentially as described in EXAMPLE
46.
MS: m/e = 324 (M+)
EXAMPLE 48
1-(N'-[1-(pyridin-4-yl)eth-2-yl] 5-carboxamidobenzofur-7
yl)-2-aminopropane dihydrochloride
Beginning with N-tert-butoxycarbonyl 5-carboxybenzofur-
7-yl)-2-aminopropane and 4-(2-ethylamino)pyridine, the title
compound was prepared essentially as described in EXAMPLE
46.
MS: m/e = 324 (M+)
EXAMPLE 49
1-(N'-[carboxymethyl] 5-carboxamidobenzofur-7-yl)-2-
aminopropane trifluoroacetate
Beginning with N-tert-butoxycarbonyl 5-carboxybenzofur-
7-yl)-2-aminopropane and glycine tert-butyl ester
hydrochloride, the title compound was prepared essentially
as described in EXAMPLE 46.
EXAMPLE 50
1-(5-carboxamidobenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with N-tert-butoxycarbonyl 5-carboxybenzofur-
7-yl)-2-aminopropane and ammonium hydroxide, the title
compound was prepared essentially as described in EXAMPLE
46.



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MS: m/e = 219 (M+1)
EXAMPLE 51
1-(N'-[methyl] 5-carboxamidobenzofur-7-yl)-2-aminopropane
hydrochloride
Beginning with N-tert-butoxycarbonyl 5-carboXybenzofur-
7-yl)-2-aminopropane and methylamine hydrochloride, the
title compound was prepared essentially as described in
EXAMPLE 46.
MS: m/e = 233 (M+)
EA: Calculated for C13H17N202-HCl-0.2 H20 C, 57.33; H,
6.44; N, 10.29. Found: C, 57.20; H, 6.34; N, 9.97.
EXAMPLE 52
1-(N'-[isopropyl] 5-carboxamidobenzofur-7-yl)-2-aminopropane
hydrochloride
Beginning with N-tert-butoxycarbonyl 5-carboxybenzofur-
7-yl)-2-aminopropane and isopropylamine, the title compound
was prepared essentially as described in EXAMPLE 46.
MS: m/e = 261 (M+)
EA: Calculated for C15H21N2~2-HC1-0.5 H20 C, 58.91; H,
7.25; N, 9.16. Found: C, 58.88; H, 7.46; N, 9.13.
EXAMPLE 53
1-(5-isopropylbenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 0.33 gm (1.5 mMol) 1-(5-isopropyl-
benzofur-7-yl)-2-propanone, 0.22 gm (660) of 1-(5-isopropyl-
benzofur-7-yl)-2-aminopropane was prepared essentially as
described in Example 1. This amine was converted to the
hydrochloride salt to provide the title compound..
MS(FD): m/e = 218 (M+1)
EA: Calculated for C14H19N0-HC1: C, 66.26; H, 7.94; N,
5.52. Found: C, 66.29; H, 8.04; N, 5.77.



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EXAMPLE 54
1-(5-sec-butylbenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 0.32 gm (1.4 mMol) 1-(5-sec-butyl'-
benzofur-7-yl)-2-propanone, 1-(5-sec-butylbenzofur-7-yl)-2-
aminopropane was prepared essentially as described in
Example 1. This amine was converted to the hydrochloride
salt to provide the title compound.
MS(FD): m/e = 232 (M+1)
EXAMPLE 55
1-(5-tert-butylbenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 2.0 mMol 1-(5-tert-butylbenzofur-7-yl)-
2-propanone, 0.19 gm (390) of 1-(5-tert-butylbenzofur-7-yl)-
2-aminopropane was prepared essentially as described in
Example 1. This amine was converted to the hydrochloride
salt to provide the title compound.
MS(FD): m/e = 232 (M+1)
EA: Calculated for C14H1gN0-HC1-0.12 H20: C, 66.74; H,
8.30; N, 5.19. Found: C, 66.75; H, 8.36; N, 5.63.
EXAMPLE 56
1-(5-cyanobenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 0.142 gm (0.71 mMol) 1-(5-cyanobenzofur-
7-yl)-2-propanone, 0.077 gm (54%) 1-(5-cyanobenzofur-7-y1)-
2-aminopropane was prepared essentially as described in
Example 1. This amine was converted to the hydrochloride
salt to provide the title compound.
MS(FD): m/e = 201 (M+1)
EXAMPLE 57
1-(4-trifluoromethylbenzofur-7-yl)-2-aminopropane
hydrochloride
Beginning with 0.47 gm (1.77 mMol) 4-trifluoromethyl-7-
bromobenzofuran, 0.28 gm (660) 1-(4-trifluoromethylbenzofur-



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7-yl)-2-propanone were prepared essentially as described in
Example 1.
This ketone was converted to 1-(4-trifluoromethylbenzo-
fur-7-yl)-2-aminopropane essentially as described in Example
1. This amine was converted to the hydrochloride salt to
provide 0.13 gm (390) of the title compound.
EXAMPLE 58
1-(5-trifluoromethylbenzofur-7-yl)-2-aminopropane
hydrochloride
Beginning with 0.47 gm (1.77 mMol) 5-trifluoromethyl-7-
bromobenzofuran, 0.20 gm (48%) 1-(5-trifluoromethylbenzofur-
7-yl)-2-propanone were prepared essentially as described in
Example 1.
This ketone was converted to 1-(5-tri~luoromethylbenzo-
fur-7-yl)-2-aminopropane essentially as described in Example
1. This amine was converted to the hydrochloride salt to
provide 0.12 gm (510) of the title compound.
EA: Calculated for C12H12NOF3-HCl: C, 51.53; H, 4.69; N,
5.01. Found: C, 51.68; H, 4.64; N, 5.01.
EXAMPLE 59
(R)-1-(5-trifluoromethylbenzofur-7-yl)-2-aminopropane
hydrochloride
(R)-N-tert-butoxycarbonyl 1-(5-trifluoromethylbenzofur-7-
yl)-2-aminopropane
Beginning with 0.256 gm (0.97 mMol) 5-trifluoromethyl-
7-bromobenzofuran and 0.142 gm (0.90 mMol) (R)-(-)-N-tert-
butoxycarbon-yl-2-methylaziridine, 0.077 gm (230) of the
desired compound were prepared essentially as described in
Example 10.



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Deprotection
Beginning with 0.077 gm (0.22 mMol) (R)-N-tert-
butoxycarbonyl 1-(5-trifluoromethylbenzofur-7-yl)-2-
aminopropane, 0.018 gm (280) of the title compound were
prepared essentially as described in Example 10.
EXAMPLE 60
1-(5-hydroxymethylbenzofur-7-yl)-2-aminopropane
hydrochloride
A mixture of 0.12 gm (0.52 mMol) 5-hydroxymethyl-7-
bromobenzofuran , 0.070 gm (1.03 mMol) imidazole, and 0.078
gm (0.52 mMol) , 0.070 gm (1.03 mMol) imidazole, and 0.078
gm (0.52 mMol) tert-butyldimethylsilyl chloride in 1 mL
dimethylformamide was stirred at room temperature for 18
hours. The reaction mixture was diluted with hexane and
washed well with water. The remaining organics were dried
over magnesium sulfate and concentrated under reduced
pressure to provide 0.41 gm (82%) of 5-tert-
butyldimethylsilyloxymethyl-7-bromobenzofuran. This
material was reacted essentially as described in EXAMPLE 1
to provide 0.085 gm (240) 1-(5-tert-butyldimethylsilyloxy-
methylbenzofur-7-yl)-2-aminopropane. This material was
treated with tetrabutylammonium fluoride in tetrahydrofuran
for 1 hour at room temperature. The reaction mixture was
partitioned between ethyl acetate and water. The phases
were separated and the organic phase washed well with water.
The remaining organics were concentrated under reduced
pressure and the residue subjected to silica gel
chromatography, eluting with dichloromethane containing 20
methanol saturated with ammonia. Fractions containing
product were combined and concentrated under reduced
pressure to provide 0.028 gm (500) of 1-(5-hydroxymethyl-



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benzofur-7-yl)-2-aminopropane. The title compound was
prepared by reacting this amine with hydrochloric acid.
MS(FD): m/e = 207 (M+2)
EXAMPLE 61
1-(5-methoxymethylbenzofur-7-yl)-2-aminopropane
hydrochloride
Beginning with 0.40 gm (1.64 mMol) 5-methoxymethyl-7-
bromobenzofuran, 0.18 gm (510) 1-(5-methoxyinethylbenzofur-7-
yl)-2-propanone were prepared essentially as described in
Example 1.
This ketone was converted to 1-(5-methoxymethylbenzo-
fur-7-yl)-2-aminopropane essentially as described in Example
1. This amine was converted to the hydrochloride salt to
provide the title compound.
MS(FD): m/e = 220 (M+1)
EXAMPLE 62
1-(5-[N,N-dimethyl]carboxamidobenzofur-7-yl)-2-aminopropane
hydrochloride
Beginning with 0.10 gm (0:37 mMol)~5-[N,N-dimethyl]car-
boxamido-7-bromobenzofuran, 0.077 gm (85%) 1-(5-[N,N-
dimethyl]carboxamidobenzofur-7-yl)-2-propanone were prepared
essentially as described in Example 1.
This ketone was converted to 1-(5-[N,N-dimethyl]-
carboxamidobenzofur-7-yl)-2-aminopropane essentially as
described in Example 1. This amine was converted to the
hydrochloride salt to provide the title compound as a white
solid.
MS(FD): m/e = 247 (M+1)



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EXAMPLE 63
1-(4,6-dichlorobenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 4,6-dichloro-7-bromobenzofuran, the
title compound was prepared essentially as described in
EXAMPLE 1.
MS(FD): m/e = 244 (M+)
EA: Calculated for C11H10NOC12-HCl: C, 47.09; H, 4.31; N,
4.99. Found: C, 47.29; H, 4.01; N, 4.91.
EXAMPLE 64
1-(5-[4-chloro-5-fluorobenzofur-7-yl)-2-aminopropane
hydrochloride
Beginning with 0.24 gm (0.95 mMol) 4-chloro-5-fluoro-7-
bromobenzofuran, 0.14 gm (65%) 1-(4-chloro-5-fluorobenzofur-
7-yl)-2-propanone were prepared essentially as described in
Example 1.
This ketone was converted to 1-(4-chloro-5-fluoro-
benzofur-7-yl)-2-aminopropane essentially as described in
Example 1. This amine was converted to the hydrochloride
salt to provide 0.080 gm (490) of the title compound as a
white solid.
EXAMPLE 65
1-(4,5,6-trifluorobenzofur-7-yl)-2-aminopropane oxalate
Beginning with 4,5,6-trifluoro-7-bromobenzofuran, the
title compound was prepared essentially as described in
EXAMPLE 1.
MS(FD): m/e = 229 (M+)
EXAMPLE 66
1-(3-methylbenzofur-7-yl)-2-aminopropane oxalate
Beginning with 3-methyl-7-bromobenzofuran, the title
compound was prepared essentially as described in EXAMPLE 1.
MS(FD): m/e = 190 (M+1)



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EXAMPLE 67
1-(3-ethyl-5-fluorobenzofur-7-yl)-2-aminopropane oxalate
Beginning with 3-ethyl-5-fluoro-7-bromobenzofuran, the
title compound was prepared essentially as described in
EXAMPLE 1.
MS(FD): m/e = 222 (M+1)
EXAMPLE 68
1-(3-isopropyl-5-fluorobenzofur-7-yl)-2-aminopropane oxalate
Beginning with 3-isopropyl-5-fluoro-7-bromobenzofuran,
the title compound was prepared essentially as described in
EXAMPLE 1.
MS(FD): m/e = 236 (M+1)
EXAMPLE 69
1-(3-phenyl-5-fluorobenzofur-7-yl)-2-aminopropane oxalate
Beginning with 3-phenyl-5-fluoro-7-bromobenzofuran, the
title compound was prepared essentially as described in
EXAMPLE 1.
MS(FD): m/e = 252 (M+1)
EXAMPLE 70
1-(3,4-dimethyl-5-fluorobenzofur-7-yl)-2-aminopropane
oxalate
Beginning with 3,4-dimethyl-5-fluoro-7-bromobenzofuran,
the title compound was prepared essentially as described in
EXAMPLE 1.
MS(FD): m/e = 222 (M+1)



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EXAMPLE 71
1-(4,5,6-trimethylbenzofur-7-yl)-2-aminopropane oxalate
Beginning with 4,5,6-trimethyl-7-bromobenzofuran, the
title compound was prepared essentially as described in
EXAMPLE 1.
MS (FD) : m/e = 218 (M+1)
EXAMPLE 72
1-(4,6-dimethyl-5-chlorobenzofur-7-yl)-2-aminopropane
oxalate
Beginning with 4,6-dimethyl-5-chloro-7-bromobenzofuran,
the title compound was prepared essentially as described in
EXAMPLE 1.
EXAMPLE 73
2-(5-fluorobenzofur-7-yl)-1-aminoethane oxalate
Beginning with 2-(5-fluorobenzofur-7-yl)propionamide
(EXAMPLE 39), 2-(5-fluorobenzofur-7-yl)-1-aminoethane was
prepared by borane reduction essentially as described in
EXAMPLE 39. This amine was treated with oxalic acid to
provide the title compound.
MS: m/e = 181 (M+2)
EXAMPLE 74
2-(5-fluorobenzofur-7-yl)-1-aminobutane oxalate
Beginning with 5-fluoro-7-bromobenzofuran, 2-(5-
fluorobenzofur-7-yl)-1-aminobutane was prepared essentially
as described in EXAMPLE 39. This amine was treated with
oxalic acid to provide the title compound.
EXAMPLE 75
2-(5-fluorobenzofur-7-yl)-3-phenylprop-1-ylamine oxalate
Beginning with 5-fluoro-7-bromobenzofuran, 2-(5-
fluorobenzofur-7-yl)-3-phenylprop-1-ylamine was prepared



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essentially as described in EXAMPLE 39. This amine was
treated with oxalic acid to provide the title compound.
MS: m/e = 270 (M+1)
EXAMPLE 76
2-methyl-2-(5-fluorobenzofur-7-yl)-1-aminopropane
hydrochloride
Ethyl 2-methyl-2-(5-fluorobenzofur-7-yl)propionate
A solution of 0.17 gm (0.71 mMol) ethyl 2-(5-
fluorobenzofur-7-yl)propionate (EXAMPLE 39) in 2.5 mL
tetrahydrofuran was cooled to -78oC. To this solution were
added 0.89 mL (0.89 mMol) lithium bis(trimethylsilyl)amide
(1.0 M in hexane). After stirring at -78oC for 1 hour, the
reaction mixture was quenched by the addition of 0.13 mL
(2.13 mMol) iodomethane. The reaction mixture was allowed
to warm to room temperature and was diluted with ethyl
acetate. This mixture was then washed sequentially with
water, saturated aqueous sodium bicarbonate, and saturated
aqueous sodium chloride. The remaining organics were
concentrated under reduced pressure. The residue was
subjected to silica gel chromatography, eluting with hexane
containing 20% ethyl acetate. Fractions containing product
were combined and concentrated under reduced pressure to
provide 0.16 gm (900) of the desired compound.
2-methyl-2-(5-fluorobenzofur-7-yl)propionamide
A mixture of 0.156 gm (0.62 mMol) ethyl 2-methyl-2-(5-
fluorobenzofur-7-yl)propionate, 0.095 gm (2.12 mMol)
formamide, and 0.44 mL (0.44 mMol) sodium methoxide (1.0 M
in methanol) in 3 mL dimethylformamide was heated at 100°C
for 45 minutes. The reaction mixture was diluted with ethyl
acetate and the organics washed sequentially with water and
saturated aqueous sodium chloride. The organics were then
concentrated under reduced pressure and the residue



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subjected to silica gel chromatography, eluting with 2:1
hexane: ethyl acetate. Fractions containing product were
combined and concentrated under reduced pressure to provide
0.060 gm (250) of the desired compound.
Reduction
A mixture of 0.11 gm (0.49 mMol) 2-methyl-2-(5-
fluorobenzofur-7-yl)propionamide and 0.02 gm (0.49 mMol)
lithium aluminium hydride in 2 mL tetrahydrofuran was
stirred at room temperature for 1 hour. The reaction
mixture was then treated sequentially with 38 ~.L water,
38 ~.L 15o sodium hydroxide, and 0.11 uL water. The reaction
mixture was stirred vigorously for 1 hour and was then
filtered. The filtrate was concentrated under reduced
pressure to provide 0.018 gm (18%) 2-methyl-2-(5-
fluorobenzofur-7-yl)-1-aminopropane. The hydrochloride salt
was prepared to provide the title compound.
EXAMPLE 77
syn-3-(5-trifluoromethylbenzofur-7-yl)-2-aminobutane oxalate
3-(5-trifluoromethylbenzofur-7-yl)-2-butanone
A mixture of 0.27 gm (1.03 mMol) 5-trifluoromethyl-7-
bromobenzofuran, 0.50 gm (1.55 mMol) methoxy(tri-n-
butyl)tin, 0.18 gm (1.55 mMol) 2-acetoxy-2-butene, and 0.08
gm (0.10 mMol) bis[tri-o-tolylphosphine]palladium(II)
chloride in 2.5 mL toluene was heated at 100oC for 1 hour.
The reaction mixture was cooled to room temperature and
filtered through a pad of celite. The filtrate was
concentrated under reduced pressure and the residue
subjected to silica gel chromatography, eluting with 100
ethyl acetate in hexane. Fractions containing product were
combined and concentrated under reduced pressure to provide
0.090 gm (340) of the desired compound.



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3-(5-trifluoromethylbenzofur-7-yl)-2-butanol
A solution of 0.09 gm (0.35 mMol) 3-(5-trifluoromethyl-
benzofur-7-yl)-2-biztanone in ethanol was cooled to 0°C. To
this solution was added 0.013 gm (0.35 mMol) sodium
borohydride and the resulting mixture stirred for 30
minutes. The reaction mixture was then allowed to warm to
room temperature and was concentrated under reduced
pressure. The residue was taken up in ethyl acetate and
washed sequentially with 0.1 N hydrochloric acid, water, and
saturated aqueous sodium chloride. The remaining organic
phase was concentrated under reduced pressure and the
residue subjected to silica gel chromatography, eluting with
30o ethyl acetate in hexane. Fractions containing product
were combined and concentrated under reduced pressure to
provide 0.041 gm (450) of the desired compound.
syn-3-(5-trifluoromethylbenzofur-7-yl)-2-azidobutane
To a solution of 0.103 gm (0.40 mMol) 3-(5
trifluoromethylbenzofur-7-yl)-2-butanol and 0.21 gm (0.80
mMol) triphenylphosphine in 2 mL toluene were added 0.092 gm
(0.299 mMol) ZnN6-(pyridine)2 followed by the dropwise
addition of 0.16 gm (0.80 mMol) diisopropyl
azodicarboxylate. The reaction mixture was stirred for 2
hours at room temperature and was then filtered through a
pad of celite. The filtrate was concentrated under reduced
pressure and subjected to silica gel chromatography, eluting
with hexane. Fractions containing product were combined and
concentrated under reduced pressure to provide 0.040 gm
(35%) of the desired compound.
,,...a__-~.:...,.,
Beginning with 0.040 gm (0.14 mMol) syn-3-(5-
trifluoromethylbenzofur-7-yl)-2-azidobutane, the reduction



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is performed essentially as described in EXAMPLE 76 to
provide the title compound.
EXAMPLE 78
1-(5-fluorobenzofur-6-yl)-2-aminopropane fumarate
Beginning with 5-fluoro-6-bromobenzofuran, the title
compound was prepared as a white crystalline solid
essentially as described in EXAMPLE 1.
MS: m/e = 194(M+1)
EXAMPLE 79
1-(5-fluorobenzofur-4-yl)-2-aminopropane fumarate
Beginning with 5-fluoro-4-bromobenzofuran, the title
compound was prepared as a white crystalline solid
essentially as described in EXAMPLE 1.
MS: m/e = 194(M+1)
EXAMPLE 80
2-amino-3-methyl-4-(5-fluorobenzofur-7-yl)butane
hydrochloride
3-methyl-4-(5-fluorobenzofur-7-yl)pentan-2-one
A mixture of 1 gm (4.65 mMol) 5-fluoro-7-bromobenzo-
furan, 0.54 ml (5.23 mMol) 2-methyl-3-hydroxybut-1-ene, 9 mg
(0.04 mMol) palladium(II) acetate, 0.021 gm (0.08 mMol)
triphenylphosphine, and 0.44 gm (5.23 mMol) sodium
bicarbonate in 5 mL hexamethylphosphoramide was heated at
130°C for 3.5 hours. The reaction mixture was cooled to
room temperature and was then diluted with 100 mL diethyl
ether. The organic phase was washed sequentially with 2 x
20 mL water followed by 2 x 20 mL saturated aqueous sodium
chloride. The remaining organics were dried over sodium
sulfate and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography, eluting
with 10:1 hexane:diethyl ether. Fractions containing the



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desired product were combined and concentrated under reduced
pressure to provide the desired product in 81o yield as a
colorless oil.
Reductive Amination
Beginning with 0.34 gm (1.55 mMol) 3-methyl-4-(5-
fluorobenzofur-7-yl)pentan-2-one, the title compound was
prepared essentially as described in EXAMPLE 1.
MS: m/e = 222 (M+)
EXAMPLE 81
2-amino-4-(5-fluorobenzofur-7-yl)pentane fumarate
Beginning with 2 gm (9.3 mMol) 5-fluoro-7-bromobenzo-
furan and 1.07 mL (10.47 mMol) 4-hydroxypent-2-ene, the
title compound was prepared as a white crystalline solid
essentially as described in EXAMPLE 80.
MS: m/e = 222 (M+1)
EA: Calculated for C13H16NOF-C4H404: C, 60.53; H, 5.98; N,
4.15. Found: C, 60.30; H, 6.14; N, 4.00.
EXAMPLE 82
2-amino-3-methyl-4-(5-fluorobenzofur-6-yl)butane fumarate
Beginning with 0.50 gm (2.3 mMol) 5-fluoro-6-bromo
benzofuran and 0.27 mL (2.62 mMol) 2-methyl-3-hydroxybut-1
ene, the title compound was prepared as a white crystalline
solid essentially as described in EXAMPLE 80.
MS: m/e = 222 (M+)
EXAMPLE 83
2-amino-4-(5-fluorobenzofur-6-yl)pentane fumarate
Beginning with 0.33 gm (1.53 mMol) 5-fluoro-7-bromo-
benzofuran and 0.18 mL (1.73 mMol) 4-hydroxypent-2-ene, the
title compound was prepared as a white crystalline solid
essentially as described in EXAMPLE 80.



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EXAMPLE 84
1-(4,6-difluorobenzofur-7-yl)-2-aminopropane hydrochloride
Beginning with 4,6-difluoro-7-bromobenzofuran, the
title compound was prepared essentially as described in
EXAMPLE 1.
MS: m/e = 212.1 (M+1)
EXAMPLE 85
1-(4,6-difluorobenzofur-7-yl)-2-methyl-3-aminobutane
hydrochloride
Beginning with 4,6-difluoro-7-bromobenzofuran, the
title compound was prepared essentially as described in
EXAMPLE 29.
MS: m/e = 240.3 (M+1)
EXAMPLE 86
cis- and trans-2-(5-fluorobenzofur-7-yl)-3-aminobutane
oxalate
Beginning with 5-fluoro-7-bromobenzofuran and 2-
acetoxybut-2-ene, the title compound was prepared
essentially as described in EXAMPLE 1.
EXAMPLE 87
traps-2-(5-fluorobenzofur-7-yl)-3-aminobutane hydrochloride
A mixture of cis- and traps-2-(5-fluorobenzofur-7-yl)-
3-aminobutane was subjected to high pressure liquid
chromatography to provide the title compound.
ISMS: m/e = 208.1 (M+1)
EXAMPLE 88
cis-2-(5-fluorobenzofur-7-yl)-3-aminobutane hydrochloride
Beginning with 5-fluoro-7-bromobenzofuran and 2-
acetoxy-2-butene, the title compound was prepared
essentially as described in EXAMPLE 77.



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ISMS: m/e = 208 (M+1)
EXAMPLE 89
1-(3-ethyl-4,6-dimethyl-5-chlorobenzofur-7-yl)-2
aminopropane hydrochloride
Beginning with 3-ethyl-4,6-dimethyl-5-chloro-7-bromo-
benzofuran, the title compound was prepared essentially as
described in EXAMPLE 1.
ISMS: m/e = 266.1 (M+1)
EXAMPLE 90
1-(3-pentyl-5-fluorobenzofur-7-yl)-2-aminopropane oxalate
Beginning with 3-pentyl-5-fluoro-7-bromobenzofuran, the
title compound was prepared essentially as described in
EXAMPLE 1.
ISMS: m/e = 264.1 (M+1)
EXAMPLE 91
1-(4-chloro-5-methoxycarbonylbenzofur-7-yl)-2-aminopropane
oxalate
Beginning with 4-chloro-5-methoxycarbonyl-7-bromo-
benzofuran, the title compound was prepared essentially as
described in EXAMPLE 1.
ISMS: m/e = 268 (M+1)
EXAMPLE 92
1-(5-fluoro-6-methylbenzofur-7-yl)-2-aminopropane
Beginning with 5-fluoro-6-methyl-7-bromobenzofuran, the
title compound was prepared essentially as described in
EXAMPLE 1.
MS: m/e = 208 (M+1)



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EXAMPLE 93
1-(3-methylbenzofur-4-yl)-2-aminopropane
Beginning with 3-methyl-4-bromobenzofuran, the title
compound was prepared essentially as described in EXAMPLE 1.
MS: m/e = 190 (M+1)
The ability of the compounds of. this invention to bind
to the 5-HT2c receptor subtype was measure essentially as
described by Wainscott (Wainscott, et al., Journal of
Pharmacology and Experimental Therapeutics, 276, 720-727
(1996)).
Membrane Preparation
AV12 cells stably transfected with the human 5-HT2c
receptors were grown in suspension and harvested by
centrifugation, resuspended in 50 mM tris-HCl, pH 7.4, and
frozen at -70oC. On the day of assay, an aliquot of cells
was thawed, resuspended in 40 mL of 50 mM tris-HCl, pH 7.4,
and centrifuged at 39,800 x g for 10 minutes at 4°C. The
resulting pellet was resuspended, incubated at 37oC for 10
minutes to remove endogenous serotonin, then centrifuged
twice more.
[1251]-DOI Binding for Determination of 5-HT2c Receptor
Affinity
Briefly, prepared cell membranes were added to
dilutions of compounds in a final solution containing 50 mM
tris-HCl, pH 7.4, 9.75 mM MgCl2, 0.5 mM EDTA, 10 ~.M
pargyline, 0.1o sodium ascorbate, and 0.1 nM [125I]-DOI,
with 10 ~,M mianserin for defining non-specific binding. All
incubations (800 ~,L) were performed at 37oC for 30 minutes
before harvesting onto GF/C filters prewet with 0.50
polyethyleneimine, with four 1 mL washes of ice-cold 50 mM



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tris-HCl, pH 7.4, and counting in a gamma counter.
Nonlinear regression analysis was performed on the
concentration response curves using a four parameter
logistic equation described by DeLean (DeLean, et al.,
Molecular Pharmacology, 21, 5-16 (1982)). IC50 values were
converted to Ki values using the Cheng-Prusoff equation
(Cheng, et al., Biochem. Pharmacol., 22, 3099-3108 (1973)).
Representative compounds of the present invention were
found to have affinity for the 5-HT2c receptor as measured
essentially by the procedure described supra.
The 5-HT2c receptor is functionally coupled to a G-
protein. Agonist activation of G-protein-coupled receptors
results in the release of GDP from the a-subunit of the G-
protein and the subsequent binding of GTP. The binding of
the stable analog [35S]-GTPyS is an indicator of this
receptor's activation.
[ 3 5 S ] -GTP'yS binding
The [35S]-GTP~yS binding assay was modified from
published conditions (Wainscott, et al., European Journal of
Pharmacology, 352, 117-124 (1998)). All incubations were
performed in triplicate in a total volume of 800 ~.L.
Compounds were diluted in 200 uL of water and were added to
400 ~,L of 50 mM Tris-HC1, pH 7.4, containing 10 mM MgCl2,
100 mM NaCl, 0.2 mM EGTA, 1 ~,M GDP, and 0.1 nM [35S]-GTP~yS.
Membrane homogenates from AV12 cells stably transfected with
the human 5-HT2c receptors (200 ~,L) were added and the tubes
were incubated for 60 minutes at 30°C. Incubations were
terminated by vacuum filtration through precooled GF/B
filters which were prewet with 20 mM Na4P207. The filters
were rapidly washed with 4 mL ice-cold 50 mM tris-HC1, pH



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7.4. [35S]-GTP~yS captured on the filters were determined by
liquid scintillation spectrometry. Data analysis was
performed as previously described, using 10 ~,M 5-HT to
define maximally stimulated binding levels.
Representative compounds of the present invention were
tested in the [35S]-GTP'yS assay and were found to be
agonists of the 5-HT2c receptor.
The ability of agonists of the 5-HT2c receptor in
general, and the compounds of the present invention in
particular, to treat obesity is demonstrated by testing in a
feeding assay.
Fasted Feeding Assay
Male rats were fasted for 18 hours prior to testing.
Rats were first assigned to either a treatment or control
group (N=8), then weighed, administered drug or vehicle
orally, and returned to their home cage. Thirty minutes
later, food was made available to the animals. The the food
and the food hopper was weighed before, one hour, two hours,
and four hours after food was made available to the test
animals. Weight of food consumed plus spillage by the
treatment animals was compared to food consumed plus
spillage by control animals using a one-way ANOVA, with a
Dunnett's post-hoc test.
Representative compounds of the present invention were
tested in the feeding assay and were found to reduce food
consumed by fasting rats.
While it is possible to administer a compound employed
in the methods of this invention directly without any
formulation, the compounds are usually administered in the
form of pharmaceutical compositions comprising a



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pharmaceutically acceptable excipient and at least one
active ingredient. These compositions can be administered
by a variety of routes including oral, rectal, transdermal,
subcutaneous, intravenous, intramuscular, and intranasal.
Many of the compounds employed in the methods of this
invention are effective as both injectable and oral
compositions. Such compositions are prepared in a manner
well known in the pharmaceutical art and comprise at least
one active compound . See, a . g . , REMINGTON' S PHARMACEUTICAL
SCIENCES, (16th ed. 1980) .
In making the compositions employed in the present
invention the active ingredient is usually mixed with an
excipient, diluted by an excipient or enclosed within such a
carrier which can be in the form of a capsule, sachet, paper
or other container. When the excipient serves as a diluent,
it can be a solid, semi-solid, or liquid material, which
acts as a vehicle, carrier or medium for the active
ingredient. Thus, the compositions can be in the form of
tablets, pills, powders, lozenges, sachets, cachets,
elixirs, suspensions, emulsions, solutions, syrups, aerosols
(as a solid or in a liquid medium), ointments containing for
example up to 10% by weight of the active compound, soft and
hard gelatin capsules, suppositories, sterile injectable
solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill
the active compound to provide the appropriate particle size
prior to combining with the other ingredients. If the
active compound is substantially insoluble, it ordinarily is
milled to a particle size of less than 200 mesh. If the
active compound is substantially water soluble, the particle
size is normally adjusted by milling to provide a
substantially uniform distribution in the formulation, e.g.
about 40 mesh.



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Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, syrup, and methyl cellulose. The
formulations can additionally include: lubricating agents
such as talc, magnesium stearate, and mineral oil; wetting
agents; emulsifying and suspending agents; preserving agents
such as methyl- and propylhydroxybenzoates; sweetening
agents; and flavoring agents. The compositions of the
invention can be formulated so as to provide quick,
sustained or delayed release of the active ingredient after
administration to the patient by employing procedures known
in the art.
The compositions are preferably formulated in a unit
dosage form, each dosage containing from about 0.05 to about
100 mg, more usually about 1.0 to about 30 mg, of the active
ingredient. The term "unit dosage form" refers to
physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to
produce the desired therapeutic effect, in association with
a suitable pharmaceutical excipient.
The active compounds are generally effective over a
wide dosage range. For examples, dosages per day normally
fall within the range of about 0.01 to about 30 mg/kg. In
the treatment of adult humans, the range of about 0.1 to
about 15 mg/kg/day, in single or divided dose, is especially
preferred. However, it will be understood that the amount
of the compound actually administered will be determined by
a physician, in the light of the relevant circumstances,
including the condition to be treated, the chosen route of
administration, the actual compound or compounds
administered, the age, weight, and response of the



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individual patient, and the severity of the patient's
symptoms, and therefore the above dosage ranges are not
intended to limit the scope of the invention in any way. In
some instances dosage levels below the lower limit of the
aforesaid range may be more than adequate, while in other
cases still larger doses may be employed without causing any
harmful side effect, provided that such larger doses are
first divided into several smaller doses for administration
throughout the day.
Formulation Example 1
Hard gelatin capsules containing the following
ingredients are prepared:
Quantity
Ingredient (mg/capsule)
Compound of Example 10 30.0
Starch 305.0
Magnesium stearate 5.0
The above ingredients are mixed and filled into hard
gelatin capsules in 340 mg quantities.



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Formulation Example 2
A tablet formula is prepared using the ingredients
below:
Quantity
Ingredient (mg/tablet)
Compound of Example 11 25.0
Cellulose, microcrystalline 200.0
Colloidal silicon dioxide 10.0
Stearic acid 5.0
The components are blended and compressed to form
tablets, each weighing 240 mg.
Formulation Example 3
A dry powder inhaler formulation is prepared
containing the following components:
Ingredient Weight o
Compound of Example 12 5
Lactose 95
The active mixture is mixed with the lactose and the
mixture is added to a dry powder inhaling appliance.



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Formulation Example 4
Tablets, each containing 30 mg of active ingredient,
are prepared as follows:
Quantity
Ingredient (mg/tablet)
Compound of Example 76 30.0 mg
Starch 45.0 mg
Microcrystalline cellulose 35.0 mg
Polyvinylpyrrolidone
(as 10% solution in water) 4.0 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1.0 mg
Total 120 mg
The active ingredient, starch and cellulose are
passed through a No. 20 mesh U.S. sieve and mixed
thoroughly. The solution of polyvinylpyrrolidone is
mixed with the resultant powders, which are then passed
through a 16 mesh U.S. sieve. The granules so produced
are dried at 50-60°C and passed through a 16 mesh U.S.
sieve. The sodium carboxymethyl starch, magnesium
stearate, and talc, previously passed through a No. 30
mesh U.S. sieve, are then added to the granules which,

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after mixing, are compressed on a tabl et machine to yield


tablets each weighing 120 mg.


Formulation Example 5



Capsules, each containing 40 mg o f medicament are


made as follows:


Quantity


Ingredient (mg/capsule)


Compound of Example 50 40.0 mg


Starch 109.0 mg



Magnesium stearate 1.0 mg


Total 150.0 mg


The active ingredient, cellulose, starch, and


magnesium stearate are blended, passed through a No. 20


mesh U.S. sieve, and filled into hard gelatin capsules in


150 mg quantities.


Formulation Example 6


Suppositories, each containing 25 mg of active


ingredient are made as follows:


Ingredient Amount


Compound of Example 59 25 mg


Saturated fatty acid glycerides to 2,000 mg





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The active ingredient is passed through a No. 60
mesh U.S. sieve and suspended in the saturated fatty acid
glycerides previously melted using the minimum heat
necessary. The mixture is then poured into a suppository
mold of nominal 2.0 g capacity and allowed to cool.
Formulation Example 7
Suspensions, each containing 50 mg of medicament per
5.0 ml dose are made as follows:
Ingredient Amount
Compound of Example 74 50.0 mg
Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose (110)
Microcrystalline cellulose (890) 50.0 mg
Sucrose 1.75 g
Sodium benzoate 10.0 mg
Flavor and Color q.v.
Purified water to 5.0 ml
The medicament, sucrose and xanthan gum are blended,
passed through a No. l0 mesh U.S. sieve, and then mixed
with a previously made solution of the microcrystalline
cellulose and sodium carboxymethyl cellulose in water.
The sodium benzoate, flavor, and color are diluted with



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some of the water and added with stirring. Sufficient
water is then added to produce the required volume.
Formulation Example 8
Capsules, each containing 15 mg of medicament, are
made as follows:
Quantity
Ingredient (mg/capsule)
Compound of Example 17 , 15.0 mg
407.0 mg
Starch
Magnesium stearate 3.0 mg
Total 425.0 mg
The active ingredient, cellulose, starch, and
magnesium stearate are blended, passed through a No. 20
mesh U.S. sieve, and filled into hard gelatin capsules in
425 mg quantities.



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Formulation Example 9
An intravenous formulation may be prepared as
follows
Ingredient Quantity
Compound of Example 39 250.0 mg
Isotonic saline 1000 ml
Formulation Example 10
A topical formulation may be prepared as follows:
Ingredient Quantity
Compound of Example 42 1-10 g
Emulsifying Wax 30 g
Liquid Paraffin 20 g
White Soft Paraffin to 100 g
The white soft paraffin is heated until molten. The
liquid paraffin and emulsifying wax are incorporated and
stirred until dissolved. The active ingredient is added
and stirring is continued until dispersed. The mixture
is then cooled until solid.



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Formulation Example 11
Sublingual or-buccal tablets, each containing 10 mg
of active ingredient, may be prepared as follows:
Quantity
Ingredient Per Tablet
Compound of Example 57 10.0 mg
Glycerol 210.5 mg
Water 143.0 mg
Sodium Citrate 4.5 mg
Polyvinyl Alcohol 26.5 mg
Polyvinylpyrrolidone 15.5 mg
Total 410.0 mg
The glycerol, water, sodium citrate, polyvinyl alcohol,
and polyvinylpyrrolidone are admixed together by
continuous stirring and maintaining the temperature at
about 90°C. When the polymers have gone into solution,
the solution is cooled to about 50-55°C and the
medicament is slowly admixed. The homogenous mixture is
poured into forms made of an inert material to produce a
drug-containing diffusion matrix having a thickness of
about 2-4 mm. This diffusion matrix is then cut to form
individual tablets having the appropriate size.
Another preferred formulation employed in the
methods of the present invention employs transdermal
delivery devices ("patches"). Such transdermal patches



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may be used to provide continuous or discontinuous
infusion of the compounds of the present invention in
controlled amounts: The construction and use of
transdermal patches for the delivery of pharmaceutical
agents is well known in the art. See, e.g., U.S. Patent
5,023,252, issued June 11 ,1991, herein incorporated by
reference. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of
pharmaceutical agents.
Frequently, it will be desirable or necessary
to introduce the pharmaceutical composition to the brain,
either directly or indirectly. Direct techniques usually
involve placement of a drug delivery catheter into the
host's ventricular system to bypass the blood-brain
barrier. One such implantable delivery system, used for
the transport of biological factors to specific
anatomical regions of the body, is described in U.S.
Patent 5,011,472, issued April 30, 1991, which is herein
incorporated by reference.
Indirect techniques, which are generally
preferred, usually involve formulating the compositions
to provide for drug latentiation by the conversion of
hydrophilic drugs into lipid-soluble drugs or prodrugs.
Latentiation is generally achieved through blocking of
the hydroxy, carbonyl, sulfate, and primary amine groups
present on the drug to render the drug more lipid soluble
and amenable to transportation across the blood-brain
barrier. Alternatively, the delivery of hydrophilic
drugs may be enhanced by intra-arterial infusion of
hypertonic solutions which can transiently open the
blood-brain barrier.
The type of formulation employed for the
administration of the compounds employed in the methods
of the present invention may be dictated by the



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particular compounds employed, the type of
pharmacokinetic profile desired from the route of
administration and the compound(s), and the state of the
patient.

Representative Drawing