Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR THE PREPARATION OF 6-(PERFLUOROALKYL)URACIL
COMPOUNDS FROM UREA COMPOUNDS
BACKGROUND OF THE INVENTION
6-(Perfluoroalkyl)uracil compounds are useful as
herbicidal agents and methods for their preparation are
known in the art. 6-(Perfluoroalkyl)uracil compounds may
be prepared by reacting 2-(N,N-disubstituted)amino-4-
(perfluoroalkyl)-1,3-oxazin-6-one compounds with amine
compounds.
Bull. Soc. Chem. Belg., 101(4), pages 313-321 (1992)
discloses that 2-(N,N-dialkyl)amino-4-(trifluoromethyl)-
1,3-oxazin-6-one compounds are prepared by reacting ethyl
3-amino-4,4,4-trifluorocrotonate with phosgene iminium
chloride compounds. However, this method is not entirely
satisfactory because the required phosgene iminium
chloride compounds are difficult to handle and relatively
expensive. Accordingly, a need exists in the art for an
improved process for the preparation of 6-(perfluoro-
alkyl)uracil compounds which avoids the use of 2-(N,N-
disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one
compounds.
It is, therefore, an obrject of the present invention
to provide an improved process for the preparation of 6-
(perfluoroalkyl)uracil compounds which avoids the use of
2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-
6-one compounds.
Other objects and advantages of the present
invention will be apparent to those skilled in the art
from the description below and the appended claims.
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SUMMARY OF THE INVENTION
The present invention provides a new process for the
preparation of 6-(perfluoroalkyl)uracil compounds having
the structural formula I
Y
I
CnF2n+~ N~O
N\
Q
O
(I)
wherein
n is an integer of 1, 2, 3, 4, 5 or 6;
Y is hydrogen or C1-Csalkyl; and
Q is a Cl-C6alkyl group or an optionally substituted
phenyl, benzyl, heteroaryl or methyleneheteroaryl
group,
which process comprises:
(a) reacting a urea compound having the structural
formula II
CnF'2n+yC0 Z
2 2
HN
~O
~'N~
Z Z1
(II)
wherein
Z and Z= are each independently C1-Cealkyl or Z and Z1
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may be taken together with the atom to which they
are attached to form a 4- to 7-membered ring wherein
ZZ1 is represented by - (CH2) 20 (CHZ) 2- or
-(CHz)m- where m is an integer of 3, 4, 5 or 6;
ZZ is C1-Csalkyl or benzyl optionally substituted on
the phenyl ring with any combination of from one to
three halogen, C1-C4alkyl or C1-CQhaloalkyl groups;
and
n is as described above,
with an amine compound having the structural formula III
Q~2
(III)
wherein Q is as described above in the presence of an
acid or base to form the 6-(perfluoroalkyl)uracil
compound of formula I wherein Y is hydrogen; and
(b) optionally alkylating the formula I compound
wherein Y is hydrogen, to form a formula I compound
wheren Y is C1-C6 alkyl.
DETAILED DESCRIPTION OF THE INVENTION
In a preferred embodiment of the present invention,
the 6-(perfluoroalkyl)uracil compounds of formula I
wherein Y is hydrogen are prepared by reacting a urea
compound of formula II with an amine compound of formula
III and an acid or base, preferably at a temperature
ranging from about 20°C to 150°C, in the presence of a
solvent.
In another preferred embodiment of the present
invention, the double bond in the formula II compounds is
predominately in the (Z)- configuration.
Advantageously, the present invention provides an
improved process for the preparation of 6-(perfluoro-
alkyl)uracil compounds which avoids the use of 2-(N,N-
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disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one
compounds.
The product formula I compounds may be isolated
using conventional isolation procedures such as diluting
the reaction mixture with water and separating the
product or extracting the product with a suitable
extraction solvent. In the isolation procedure,
conventional extraction solvents such as diethyl ether,
ethyl acetate, toluene, methylene chloride, and the like,
and mixtures thereof may be utilized.
Acids suitable for use in this invention include
organic acids including, but not limited to, C1-Csalkanoic
acids such as formic acid, acetic acid, propionic acid
and the like; and mineral acids including, but not
limited to, hydrochloric acid, sulfuric acid, phosphoric
acid and the like. A preferred acid is acetic acid.
Bases suitable for use in the process of the present
invention include, but are not limited to, tri(C1-C6_
alkyl)amines such as trimethylamine, triethylamine,
tripropylamine, tributylamine, diisopropylethylamine and
the like; heterocyclic tertiary amines such as 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo-
[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane,
pyridine, substituted pyridines, quinoline, substituted
quinolines and the like; and alkali metal C1-C6alkoxides
such as potassium tert-butoxide, sodium tert-butoxide and
the like. Preferred bases include 1,8-diazabicyclo-
[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene.
Solvents suitable for use in step (a) of the process
of this invention include, but are not limited to,
carboxylic acid amides such as N,N-dimethylformamide,
N,N-dimethylacetamide and the like; dialkyl sulfoxides
such as dimethyl sulfoxide and the like; aromatic
hydrocarbons such as toluene, benzene, xylenes,
mesitylene and the like; halogenated aromatic hydro-
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carbons such as chlorobenzene, fluorobenzene and the
like; aliphatic hydrocarbons such as pentane, hexane,
heptane and the like; halogenated aliphatic hydrocarbons
such as methylene chloride, chloroform, carbon tetra-
s chloride, 1,2-dichloroethane and the like; alcohols such
as methanol, ethanol, n-propanol, sec-propanol and the
like; alkanoic acids such as formic acid, acetic acid,
propionic acid and the like; ketones such as acetone,
methyl ethyl ketone and the like; ethers such as diethyl
ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and
the like; nitriles such as acetonitrile, propionitrile
and the like; and water; and mixtures thereof. It should
be understood that a solvent should be chosen which does
not adversely react with the acid or base. In
particular, an alkanoic acid generally would not be a
suitable solvent when a base is used.
Alkylation procedures suitable for use in this
invention include conventional procedures known in the
art. In a preferred embodiment of this invention, the
step (b) alkylation procedure comprises reacting the
formula I compound wherein Y is hydrogen with an alkyl
halide having the structural formula IV or a
dialkylsulfate ester having the structural formula V
O
XY or YOSOY
(IV) ll
0
(V)
wherein X is chlorine, bromine or iodine, and Y is
C1-C6alkyl in the presence of a base.
Bases suitable for use in the alkylation procedures
of this invention include conventional bases known in the
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art including, but not limited to, alkali metal hydrides
such as sodium hydride and the like; alkali metal
C1-Csalkoxides such as potassium tert-butoxide, sodium
tert-butoxide and the like; alkali metal hydroxides such
as potassium hydroxide, sodium hydroxide and the like;
alkali metal carbonates such as sodium carbonate,
potassium carbonate and the like; alkaline earth metal
hydroxides such as calcium hydroxide and the like; and
alkaline earth metal carbonates such as calcium carbonate
and the like.
Preferred formula II compounds for use in the
process of this invention are those wherein
Z and Z1 are each independently C1-C6alkyl;
Zz is Cl-C4alkyl ; and
n is 1.
More preferred urea compounds of formula II for use
in the process of the present invention are those wherein
Z and Z1 are the same and represent methyl or ethyl;
Z2 is methyl or ethyl; and
n is 1.
Preferred formula I compounds which may be prepared
by the process of the present invention are those wherein
n is 1;
Y is hydrogen or C1-Cqalkyl;
-G ~
GZ
C2 i s \ I .
Xi ~ X3 ;
X2
G is CHz or a bond;
Gl is CXS or N;
Gz is CX4 or N;
X1 is hydrogen, halogen or a Cl-Csalkyl group optionally
substituted with one epoxy group,
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Xz i s hydrogen , hal ogen NRRl , COzRz , C ( O ) R3 , OR4 , S02R5 ,
SO2NR6R., , C ( Re ) ( OR9 ) z , C ( Rl o ) =NORl1, C ( Riz ) =C ( R13 ) _
C ( OR14 ) =NORls , CH20-NCO2Rls ,
1,3-dioxolane optionally substituted with one
C1-Csalkoxy group or one or two C1-C4alkyl
groups,
1,3-dioxolinone optionally substituted with one
C1-Csalkoxy group or one or two C1-C4alkyl
groups, or
C1-C4alkyl optionally substituted with. one COZRz group
and one halogen atom, and
X3 is hydrogen, halogen, C1-C4haloalkyl, COZRl." cyano,
Cl-C4haloalkoxy, ORlB or C:-C4alkyl, or
when X1 and Xz are taken together with the atoms to whim
they are attached, they may form a five- or six-
membered ring wherein XlXz or XzXl is represented by:
-OC (Rzo) (Rzi) O-, -CHzS (O) pN (Rzz) -, -SC (Rza) =N-, -CH=CH-
CH(Rii)O-. -OC(O)N-, -SC(Rz4)=N-, -ON(Rzs)C(O)-,
-OC (COzRzs) =C (Rz~) -, -NC (Rze) =C (SRz9) -, -CH=C (C02R3o) O-,
-CHZCH (R31) O- or -OC (R3z) (R33) C (O) -, or
when Xz and X3 are taken together with the atoms to which
they are attached, they may form a five- or six-
membered ring wherein XZX3 or X3Xz is represented by:
-NC (R34) =NC (S) -, -N (R3s) N=C (R36) -, -N (R3~) C (R3g) =N-,
-N (R3g) C (O) CH20-, -N (R39) C (O) CH=CH-, -S-N=C (R4o) -,
-O-N=C (R41) -, -N=N-N (Raz) -, -C (R43) (R44) C (O) N (R4s) - or
-N (R46) C (O) C (R4.,) (R48) -;
X4 is hydrogen, halogen or OR19
Xs is hydrogen or halogen;
R, Rs6, Rs4~ Rss. R,o. R." and R91 are each independently
hydrogen, SOzR49, Cl-C4alkyl, C3-C,cycloalkyl,
C3-Csalkenyl, C3-C6alkynyl, phenyl or benzyl;
Rl is hydrogen, SOZRso, C (O) Rsl, amino or Cl-C4alkyl
optionally substituted with COZRsz or C (O) Rss
3 5 Rz , R16 , Rl~, Rzs , R3o ~ Rsa . R~s ~ R~s ~ Raz and Ra$ are each
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_g_
independently hydrogen, C1-C$haloalkyl, C3-Csalkenyl,
C3-Csalkynyl, phenyl, benzyl, furfuryl, pyridyl,
thienyl,
C1-Cgalkyl optionally substituted with CO2Rs4,
morpholine or C (O) Rss, or
an alkali metal, an alkaline earth metal, ammonium
or organic ammonium cation;
Rs ~ Rss ~ Rs.,. Rel. R85 and R89 are each independently
hydrogen,
C1-Csalkyl, C3-C6alkenyl, C3-C6alkynyl, NR.s6Rs" phenyl
or benzyl;
R4, R18, R19 and Rss are each independently hydrogen,
Cl-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, Cl-C4haloalkyl,
C ( O ) Rs$ , C ( S ) Rs9 or benzyl ;
RS and R.,z are each independently Cl-C6alkyl, Cl-
Cshaloalkyl ,
imidazole or indazole;
Rs ~ Rii ~ Riz ~ Ria . Ris ~ Rzo ~ Rzl ~ Rzz ~ Rzs . Rze . Rz9 ~ R31 ~ R3z ~
R33 ,
R3s ~ Ras ~ R46 ~ R63 and Reo are each independently
hydrogen or Cl-C4alkyl;
R, is hydrogen, C3-C6alkenyl, C3-Csalkynyl, benzyl, or
Cl-C4alkyl optionally substituted with cyano or
C (O) R62,
R8 and Rz., are each independently hydrogen, Cl-CQalkyl or
Cl-C4alkoxy;
R9 and R9o are each independently Cl-Csalkyl;
Rlo is hydrogen, Cl-Csalkyl, phenyl or benzyl;
R13 ~ Rz4 and R36 are each independently hydrogen, Cl-Csalkyl
or halogen;
3 0 Rz3 is hydrogen or NR63R64
R34 is hydrogen, Cl-C4alkyl or Cl-C4haloalkyl;
R3, is hydrogen, Cl-C4alkyl or Cz-Cealkoxyalkyl;
R3g and R39 are each independently hydrogen, Cl-C4alkyl,
Cl-C4haloalkyl, C3-Csalkenyl or C3-Csalkynyl;
R4o, R41 and R4z are each independently hydrogen, halogen,
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cyano , OR65 , C ( O ) R66 , C ( S ) R6., , COzRse , C ( =NOR69 ) .
a Cl-Cealkyl, C3-C,cycloalkyl, C2-Cealkenyl or
Cz-Csalkynyl group, wherein each group is
optionally substituted with any combination of
one to six halogen atoms, one to three C1-Clo-
alkoxy groups, one or two C1-Cshaloalkoxy
groups , one or two NR,oR.,l groups , one or two
S(O)qR.,2 groups, one or two cyano groups, one or
two C3-C,cycloalkyl groups, one OSOZR.,3 group,
one or two C ( O ) R,4 groups , one or two COZR~S
groups, one or two C(O)SR.,6 groups, one or two
C (O) NR.,.,R,B groups, one to three OR.,9 groups, one
or two P(O)(OR$o)z groups, one 1,3-dioxolane
optionally substituted with one to three
C1-C4alkyl groups, or one 1,3-dioxane optionally
substituted with one to three C1-C4alkyl groups,
or
phenyl or benzyl optionally substituted with any
combination of one to three halogen atoms, one
to three C,-Csalkyl groups, one to three C1-
C6alkoxy groups, one C3-C.,cycloalkyl group, one
Cl-C4haloalkyl group, one Cl-C4alkylthio group,
one cyano group, one nitro group, one C(O)Rgl
group, one COzR82 group, one ORg3 group, one SR84
group, one Cl-C6alkoxymethyl group, one
hydroxymethyl group, one C3-Cealkenyloxymethyl
group, or one C1-Cehaloalkoxymethyl group;
R4a ~ R44 i R4, and R48 are each independently hydrogen,
Cl-C4alkyl, Cl-C4haloalkyl, C3-Csalkenyl, C3-Csalkynyl
or C3-C.,cycloalkyl, or R43 and R44 or R4., and R48 may be
taken together with the atom to which they are
attached to form a C3-C.,cycloalkyl group;
R4s~ Rso and R86 are each independently C1-C6alkyl, NR93R94,
Cl-C4haloakyl, C3-C6alkenyl, C3-C6alkynyl or benzyl;
3 5 R51, R52 , R53 , R54 , R55 , RS., , Rss , R59 ~ R6o ~ R61 ~ R6z ~ R.,1.
R,3 ~ R.,4 ,
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R.,B , R8, and R92 are each independently hydrogen,
Cl-C6alkyl, C3-C,cycloalkyl, C1-C6haloalkyl,
C3-C6alkenyl, C3-C6alkynyl, phenyl or benzyl;
R.,9, R83 and Rg4 are each independently hydrogen,
C (O) Res, SOZRes, Cl-C6haloalkyl, CZ-C6alkenyl,
CS-Cacycloalkenyl, CZ-C6alkynyl, phenyl, benzyl, or
Cl-Cloalkyl optionally substituted with one hydroxyl,
benzyloxy, OC (O) RB~, C1-Csalkoxy, CO2R88, C (O) Re9,
C ( OR9o ) 2 , C ( O ) NR91R92 or cyano group ;
R93 and R94 are each independently hydrogen,.Cl-C4haloalkyl,
CZ-Csalkenyl, C3-Cscycloalkyl,
Cl-C$alkyl optionally substituted with one or two
C1-C4alkoxy groups or one cyanoalkyl group, or
benzyl or phenyl optionally substituted with any
combination of one to three halogen atoms, one
to three C1-C4alkyl groups, one to three
C1-C4haloalkyl groups, one to three C1-C4alkoxy
groups, one to three Cl-C4haloalkoxy groups, one
cyano group or one nitro group, and
when R93 and R94 are taken together with the atom to
which they are attached, they form a 5- to 12-
membered monocvclic or fused bicyclic, heterocyclic
ring optionally substituted with one or more groups
independently selected from halogen, cyano, nitro,
amino, hydroxyl, C1-C4alkyl, C1-C4haloalkyl,
Cl-C4alkoxy, Cl-C4haloalkoxy and Cl-C4haloalkylsulfonyl
groups; and
p and q are each independently 0, 1 or 2; and
the optical isomers, diastereomers and/or tautomers
thereof.
More preferred formula I herbicidal agents which may
be prepared by the process of this invention are those
wherein
n is 1;
Y is hydrogen or methyl;
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G % i'G
Q is
X1 X3
Xa
G is CHZ or a bond;
Gl is CXS or N;
Gz is CX4 or N;
Xl is hydrogen, fluorine or Cl-C3alkyl optionally
substituted with one epoxy group;
X2 is hydrogen, halogen NRR1, CO2R2 , C ( 0 ) R3 , OR4 , S02R5 ,
SO2NR6R~ , C ( Re ) ( OR9 ) 2 , C ( Ri o ) =NORll , C ( Rlz ) =C ( R13 ) _
C ( OR14 ) =NORls , CH20-NCOZRls
1,3-dioxolane optionally substituted with one
Cl-C6alkoxy group or one or two C1-C4alkyl
groups,
1,3-dioxolinone optionally substituted with one
C1-Csalkoxy group or one or two C,-C4alkyl
groups, or
C1-C4alkyl optionally substituted with one COZRZ group
and one halogen atom, and
X3 is hydrogen, halogen, C1-C4haloalkyl, COZR1" cyano,
Cl-C4haloalkoxy, OR18 or Cl-C4alkyl, or
when X1 and X2 are taken together with the atoms to which
they are attached, they may form a five- or six-
membered ring wherein XlXz or XZX1 is represented by:
-OC (R2o) (R21) 0-, -CHZS (O) PN (R22) -, -SC (R23) =N-,
-CH=CH-CH (Rll) O-, -OC (O) N-, -SC (Rz4) =N-, -ON (R25) C (O) -,
-OC ( C02R26 ) =CH- , -NC ( Rze ) =C ( SR29 ) - , - CH=C ( COZR3o ) O- ,
-CHZCH (R31) O- or -OC (R32) (R33) C (0) -, or
when XZ and X3 are taken together with the atoms to which
they are attached, they may form a five- or six-
membered ring wherein XZX3 or X3X2 is represented by:
-NC (R34) =NC (S) - ~ -N (R35) N=C (R36) -, -N (R3.,) C (R38) =N-,
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-N (R38) C (0) CH20-, -N (R39) C (O) CH=CH-, -S-N=C
(R4o) -.
-O-N=C (R41) -, -N=N-N (R4z) -. -C (R43) (R44) C (O)
N (R45) - or
-N (R46) C (O) C (R4~) (R48) -;
X4 is hydrogen, halogen or ORl9;
Xs is hydrogen or halogen;
R, R64, R69 and R" are each independently hydrogen,
SOZR49 or Cl-C4alkyl ;
Rl is hydrogen, SOzRso, C (O) R51, amino or Cl-C4alkyl
optionally substituted with COZRsz or C (O) Rsa
Rz, Ri6. Rl~, Rz6~ R3o. R6e. R~s. R~6. Rez and Ree .are
each
independently hydrogen, C3-C6alkenyl or Cl-C4alkyl
optionally substituted with COzR54, morpholine or
C (O) Rss
R3. R66. R6, ~ Res and R89 are each independently hydrogen,
Cl-C4alkyl or NR56R5~;
R4, R18 and Rl9 are each independently hydrogen,
Cl-C4alkyl, Cl-C4haloalkyl, C (O) R58, C3-C4alkenyl
or
C3 - C4 alkynyl ;
R56 is SOZR49;
R5, is hydrogen or Cl-C4alkyl;
RS and R.,z are each independently NR6oR61 or indazole;
Rs. Rm Riz. R14~ Rls. Rzo. Rzl, Rzz, Rzs, Rze, Rz9, R31,
R3z, R33,
R35 ~ R45 ~ R46 and Reo are each independently -hydrogen
or
methyl;
R., is Cl-C4alkyl optionally substituted with cyano or
C (O) R6z%
RB is hydrogen or Cl-C4alkoxy;
R9 and R9o are each independently Cl-C4alkyl ;
Rlo is hydrogen or Cl-C3alkyl ;
3 0 R13 , Rz4 and R36 are each independently hydrogen or
chlorine;
Rz3 1S NR63R64 ~
R34 is Cl-C3haloalkyl;
R3, is Cz-C4alkoxyalkyl ;
R3$ and R39 are each independently Cl-C3haloalkyl, Cl-C3alkyl
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or propargyl;
R4o, R41 and R42 are each independently hydrogen, C (0) Rss,
C (S) Rs~, CO2Rs8, C (=NORs9) .
Cl-C3alkyl optionally substituted with any combi-
nation of one or two halogen atoms, one or two
C1-C3alkoxy groups, one or two C1-C3haloalkoxy
groups, one SO2R,2 group, one or two cyano
groups, one C3-Cscycloalkyl group, one OSOzR.,3
group , one C ( O ) R,4 group , one CO2R,s group , one
C ( 0 ) SR.,s group , one C ( O ) NR.,.,R.,B group , one to two
OR,9 groups , one P ( O ) ( OReo ) 2 group , one 1, 3 -
dioxolane group or one 1,3-dioxane group, or
phenyl optionally substituted with any combination
of one halogen atom, one or two methyl groups,
one methoxy group, one halomethyl group or one
OR83 group ;
R43 ~ R44 ~ R4, and R4g are each independently hydrogen or
methyl , or R43 and R44 or R4, and R48 may be taken
together with the atom to which they are
attached to form a cyclopropyl group;
R49, Rs0 and Res are each independently C1-C4alkyl or NR93R94%
Rsi , R52 . R53 . R54 , Rss , R58 . Rs0 . R61. Rsz . R~3 ~ Rya , R~8 and R8~
are
each independently hydrogen, C1-C4alkyl or C1-C4halo-
alkyl;
R.,9 and R83 are each independently hydrogen, C (O) Res,
SOzR$s, Cl-CQhaloalkyl, C3-C4alkenyl or
Cl-C3alkyl substituted with one OC (0) R8."
CO2R8g , C ( O ) R89 , C ( OR90 ) 2 or cyano group ;
R93 and R94 are each independently hydrogen or Cl-Cealkyl;
and
p is 0 , 1 or 2 .
The process of the present invention is especially
useful for the preparation of 6-(trifluoromethyl)uracil
compounds having the structural formula VI
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Y
I
F3C N~O
IN / R4o
O. \ I ~N
XS S
(VI)
wherein
Y is hydrogen or methyl;
XS is hydrogen or halogen;
R4o is hydrogen, C (0) R66, C (S) R6" COZR68,
Cl-C3alkyl optionally substituted with any
combination of one or two halogen atoms,
one or two C1-C3alkoxy groups, one or two
C1-C3haloalkoxy groups, one SOzR.,2 group, one or
two cyano groups, one C3-Cscycloalkyl group, one
OS02R.,3 group, one or two OR.,9 groups, one
P(O)(OReo)2 group, one 1,3-dioxolane group or
one 1,3-dioxane group, or
phenyl. optionally substituted with any combination
of one halogen atom, one or two methyl groups,
one methoxy group, one halomethyl group or one
2 0 OR83 group ;
R66, R6" Res and R89 are each independently hydrogen,
Cl-C4alkyl or NR56R5.,;
R56 1S SOZR49
R5, is hydrogen or Cl-C4alkyl;
R49 and R86 are each independently Cl-C4alkyl or NR93R94
R93 and R94 are each independently hydrogen or Cl-CEalkyl ;
R68 and Ree are each independently hydrogen, C3-Csalkenyl or
Cl-C4alkyl optionally substituted with COzR54,
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morpholine or C (O) Rss
Rs4. Rss ~ Rso. Rs~. R,3 and Re., are each independently
hydrogen, Cl-C4alkyl or Cl-C4haloalkyl;
R.,z is NR6pR61 or indazole;
R~9 and R83 are each independently hydrogen C (O) Res, SOzR86,
Cl-CQhaloalkyl, C3-C4alkenyl or
Cl-C3alkyl substituted with one OC (O) Re." CO2Ra8.
C (O) Re9, C (OR9o) 2 or cyano group;
Reo is hydrogen or methyl; and
R9o is C1-C4alkyl.
Exemplary of halogen hereinabove are fluorine,
chlorine, bromine and iodine. The terms "halomethyl",
"C -C haloalk 1", "C -C haloalk 1" "C -C haloalkox "
i a Y i a Y . i a Y ~
"Cl-C4haloalkoxy" and "Cl-CBhaloalkoxymethyl" are defined as
a methyl, Cl-CQalkyl, C,-Cealkyl, Cl-C3alkoxy, Cl-C4alkoxy or
Cl-Cealkoxymethyl group substituted with one or more
halogen atoms. In formula I above, alkali metals include
sodium, potassium and lithium, and alkaline earth metals
include calcium and magnesium. Organic ammonium cations
suitable for use in the present invention include, but
are not limited to, a group consisting of a positively
charged nitrogen atom joined to from one to four
aliphatic groups, each containing from one to sixteen
carbon atoms.
In formula I above, 5- to 12-membered monocyclic or
fused bicyclic, heterocyclic rings include, but are not
limited to, benzimidazole, imidazole, imidazoline-2-
thione, indole, isatoic anhydride, morpholine,
piperazine, piperidine, purine, pyrazole, pyrrole,
pyrrolidine and 1,2,4-triazole rings wherein each ring is
optionally substituted with one or more groups
independently selected from halogen, cyano, nitro, amino,
hydroxyl, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy,
Cl-C4haloalkoxy, or Cl-C4haloalkylsulfonyl groups .
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Starting formula II urea compounds may be prepared
by reacting a ~3-amino-Vii- (perfluoroalkyl) acrylate compound
having the structural formula VII
CnF2n+~ ~ CO Z
2 2
~2
(VII)
wherein n and ZZ are as described hereinabove with a base
and a carbamoyl chloride compound having the structural
formula VIII
Z~ O
N-'~
Z ~ Cl
(VIII)
wherein Z and Z1 are as described hereinabove.
Formula VII (3-amino-(3- (perf luoroalkyl ) acrylate
compounds are known in the art and may be prepared
according to the procedures described in U.S. 5,777,154;
Journal of Heterocyclic Chemistry, 9, pages 513-522
(1972); and Institute of Chemistry, Urals Scientific
Center, Academy of Sciences of the USSR, Sverdlovsk,
pages 1442-1447 (1987) - English translation of Zhurnal
Organicheskoi Khimii, 22(8), pages 1603-1609 (1986).
Carbamoyl chloride compounds of formula VIII are
known in the art and may be prepared by conventional
procedures. In addition, certain formula VIII carbamoyl
chloride compounds are commercially available.
Amine compounds having the structural formula IIIa
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X1
H2N / R4o
()
\ I iN
XS S
(IIIa)
wherein X1, XS and R4o are as described hereinabove, may be
prepared, as shown in Flow Diagram I, by cyclizing a
ketone of formula IX with sulfur and ammonium hydroxide
or ammonia to form a nitrobenzisothiazole of formula X,
and reducing the formula X compound using conventional
reducing agents such as iron in acetic acid.
FLOW DIAGRAM I
X1 O
OZN /
I R4o
XS C1
(IX)
S NH3 or NH40H
X1
OZN / R4o
\ I ~N
XS S
(X)
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FLOW DIAGRAM I (cont.)
[H]
X1
H2N / R4o
,IN
XS S
(IIIa)
Starting amine compounds having the structural
formula IIIb
X1
HZN / R4i
\ I IN
XS O
(IIIb)
wherein X1, XS and R41 are as described hereinabove, may be
prepared, as illustrated in Flow Diagram II, by reacting
a ketone of formula XI with hydroxylamine hydrochloride
optionally in the presence of sodium acetate to form an
oxime of formula XII, cyclizing the formula XII compound
with a base such as potassium hydroxide to form a
nitrobenzisoxazole of formula XIII, and reducing the
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formula XIII compound using conventional reducing agents
such as tin(II) chloride in acetic acid.
FLOW DIAGRAM II
X1 O
OaN /
R41
XS C1
(XI)
NH20H ~ HCl
Xl NOH
OaN /
R4i
\
XS Cl
(XII)
Base
r
X1
OZN / R4i
\ ~ ,N
XS O
(XIII)
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FLOW DIAGRAM II (coast.)
[H]
X1
H2N / R4i
\ I ~N
XS O
(IIIb)
Alternatively, formula XIII nitrobenzisoxazole
compounds may be prepared, as shown in Flow Diagram III,
by reacting a ketone of formula XIV with hydroxylamine
hydrochloride optionally in the presence of a base such
as sodium acetate to form an oxime of formula XV,
cyclizing the formula XV compound with 1,1'-carbonyl-
diimidazole in the presence of a base such as tri-
ethylamine to form a benzisoxazole of formula XVI, and
nitrating the formula XVI compound using conventional
methods such as a nitric acid/sulfuric acid mixture.
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FLOW DIAGRAM III
X1 O
/ w
I R4~
XS OH
(XIV)
NHZOH ~ HC1
Xl NOH
/ w
I R41
XS OH
(XV)
O
Base N, N-C -N
X1
/ R41
\ I ~N
XS O
(XVI)
HN03 ~HzS04
Xi
02N / R4i
\ I iN
XS O
(XIII)
Intermediate compounds of formulas X and XIII
wherein R4o and R41 are OR65 may be prepared, as shown in
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Flow Diagram IV, by nitrating a benzisoxazol-3-0l or
benzisothiazol-3-0l of formula XVII with a conventional
nitrating agent such as a nitric acid/sulfuric acid
mixture to form a 5-nitrobenzisoxazol-3-0l or 5-
nitrobenzisothiazol-3-0l of formula XVIII, and reacting
the formula XVIII compound with an electrophile of
formula XIX in the presence of a base such as potassium
carbonate.
FLOW DIAGRAM IV
X1
OH
w
XS J
( XVI I )
(J = O or S)
HNO3 /H2SO4
Xi
OZN / OH
XS J
(XVIII)
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FLOW DIAGRAM IV (cont.)
Base XR6s
(XIX)
(X = C1, Br or I)
X1
OZN / OR6s
\ I ~N
Xs J
Formula X and XIII intermediate compounds wherein R4o
and R41 are C1 or Br may be prepared, as shown in Flow
Diagram V, by reacting a 5-nitrobenzisoxazol-3-0l or 5-
nitrobenzisothiazol-3-0l of formula XVIII with
phosphorous oxychloride, phosphorous oxybromide or
phosphorous pentabromide.
FLOW DIAGRAM V
X1
OzN / OH
\ I ~N
Xs J
(XVIII)
(J = O or S)
POC13 ~ POBr3 or PBr3
X1
02N / ( Cl or Br )
\ I
Xs J
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Other methods for the preparation of formula IIIa
and IIIb amine compounds will become apparent from the
examples set forth below. In addition, certain compounds
of formulas IIIa, IIIb, X and XIII may be converted into
other compounds of formulas IIIa, IIIb, X and XIII by
using conventional procedures known to those skilled in
the art.
Other formula III amine compounds are known in the
art and may be prepared according to the procedures
described in EP 561319-A; EP 540023-A; EP 545206-A;
EP 542685-A; EP 473551-A; EP 476697-A; EP 489480-A;
EP 496595-A; EP 420194-A; EP 648749-A; EP 705829-A;
EP 714602-A; JP 9241245; JP 9301973; U.S. 5,169,430;
U.S. 5,310,723; U.S. 5,324,854; U.S. 5,391,541;
U.S. 5,399,543; U.S. 5,484,763; U.S. 5,523,278;
U.S. 5,602,077; U.S. 5,661,108; WO 93/14073; WO 94/10155;
WO 94/24128; WO 91/07393; WO 91/107392; WO 95/04461;
WO 95/05079; WO 95/05080; WO 95/17096; WO 95/25725;
WO 95/29168; WO 95/32952; WO 95/33746; WO 96/02518;
WO 96/08151; WO 96/14315; WO 96/28442; WO 96/34859;
WO 96/35679; WO 97/01541; WO 97/01542; WO 97/05118;
WO 97/07105; WO 97/08170; WO 97/08171; WO 97/08953;
WO 97/12884; WO 97/12886; WO 97/29094; WO 97/29105;
WO 97/34484; WO 97/35845; WO 97/42176; WO 97/42188;
WO 97/45418; WO 97/47607; WO 98/02422; WO 98/06706;
WO 98/08824; WO 98/27057; WO 98/27067; WO 98/27082; and
WO 98/27088, among others.
In order to facilitate a further understanding of
this invention, the following examples are presented
primarily for the purpose of illustrating more specific
details thereof. The scope of the invention should not
be deemed limited by the examples but encompasses the
entire subject matter defined in the claims.
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EXAMPLE 1
Preparation of Ethvl 3-((N,N-dimethylcarbamoyl)amino~-
4,4,4-trifluorocrotonate, (Z)-
CF3\ ~C02CZH5 H3 C\ 0
N
H3C C1
CF\/~
NaH 3~CO2CzH5
~ HN~O
~ INY~
H3 C ~3
Ethyl 3-amino-4,4,4-trifluorocrotonate (18.4 g, 100
mmol) is added to a stirred solution of sodium hydride
(60% in mineral oil, 9.6 g, 250 mmol) in N,N-dimethyl-
formamide (60 mL) at 5°C under nitrogen over a 60 minute
period. The reaction mixture is allowed to warm to and
held at room temperature for 15 minutes, cooled to 5°C,
and treated with dimethylcarbamoylchloride (21.6g, 200
mmol) over a 60 minute period. The resultant solution is
then warmed to and held at room temperature for 2 hours,
diluted with water (150 mL), and extracted with ethyl
acetate (2 x 150 mL). The combined organic layers are
dried, filtered and concentrated, and the mineral oil
layer is removed to obtain a residue. Flash column
chromatography of the residue on silica gel using a 85:15
hexanes/ethyl acetate solution gives the title product as
a yellow liquid (18.1 g, 71% yield) : 1H NMR (DMSO-ds) 8
9.18 (s,lH), 5.85 (s, 1H), 4.20 (q, 2H), 2.89 (s, 6H),
1.18 (t, 3H) ; 19F NMR 8 -65.7 (s) .
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Using essentially the same procedure, the following
compounds are obtained:
CF
s ~ C02Zz
HN
~O
~IN~
Z Z1
(Z)- configuration
Z Z1 ZZ m °C Yield (%)
CZHS CZHS CZHS yellow oil 88
- (CHZ) 4- CzHs 54-57 37
CH3 CH3 CH3
CZHS CzHs CH3
- ( CHz ) 4 - CH3
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EXAMPLE 2
Preparation of 3-(3-Methyl-1,2-benzoisothiazol-5-yl)-6-
(trifluoromethyl)-2,4(1H,4H)-pyrimidinedione
CF~/~
3~ CO2CZH5 H2N CH3
HN~O
\
,N~ S
H3C CH3
H
CF3 N~O
INS CHa
CH3COZH /
O \ ~ ,N
S
A solution of ethyl 3-[(N,N-dimethylcarbamoyl)-
amino]-4,4,4-trifluorocrotonate, (Z)- (1.15 g. 4.5 mmol)
and 5-amino-3-methyl-1,2-benzoisothiazole (0.75 g, 4.5
mmol) in glacial acetic acid (7 mL) is held at gentle
reflux for 1 hour, cooled, and diluted with water. The
resultant aqueous mixture is filtered to obtain a solid.
The solid is washed with water and dried to give the
title product (1.3 g, 88% yield) which is identified by 1H
and 19F NMR spectral analyses.
Following essentially the same procedure, but using
the appropriate reagents, the following compounds are
obtained:
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a~
,d CO N
N
v.
o o
a
~z
x ~ o
z/
o
b
cn
U
O
3
N
O
U
x x
0 0
x x
O
U U
N
x
z
a
x x
N N
~
x U U
U
N
U
N
N
z
z ~ v
N
x v -z
v
v -z
a
\
/
\
/
Ni ~ x
U
N~
U
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..
a~
CO N
N
~1
o o
a
-z b
xz ~ o
o
a~
N
r~ 1~ n 1~
(s, Cl1 -r-I
U
O
3
O
U
t~
x x
0 0
x x
O
U U
N
x
z
a
x x
N N
x x
x V U U
U
N
U
N
U
N ~ U
U -z
a
\
/
NI v x
U
NI ~ x
U
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EXAMPLE 3
Preparation of 2'-Chloro-2-methoxy-5-methyl-5'-
nitrobenzophenone
O OCH3
OzN ~ C1
/ + I / + A1C13
C1
CH
3
O OCH3
OzN
/ /
C1
CH
3
A mixture of aluminum chloride (33.3 g, 25.0 mmol)
in methylene chloride is cooled to about 5 °C, treated
over one hour with p-methylanisole (31.6 g, 25.0 mmol)
while maintaining the reaction mixture temperature below
°C, treated over 20 minutes with a solution of
10 2-chloro-5-nitrobenzoyl chloride (50.0 g, 22.7 mmol) in
methylene chloride while maintaining the reaction mixture
temperature below 10 °C, warmed to and stirred at room
temperature for 60 minutes, and poured onto ice. The
resultant aqueous mixture is treated with concentrated
hydrochloric acid (50 mL) and extracted with methylene
chloride. The organic extract is dried over anhydrous
magnesium sulfate and concentrated in vacuo to give a
yellow solid. After placing the solid in a Kugelrohr
apparatus at 40 °C to remove residual p-methylanisole, the
title product is obtained as a beige solid (68.8 g,
99.10) which is identified by NMR spectral analyses.
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Using essentially the same procedure, the following
compounds are obtained:
~~z
~ Wi
W
OzN
O
XS Ya3
X XS W Wl WZ W W mp C
C1 H
Cl H H I H H OCH3 115-116.5
Cl H H H CH3 H OCH3
Cl H H H CZHS H H
Cl H H CH3 CH3 H OCH3
Cl H H H OCH3 H H 108-112
C1 H H CzHs H H OCH3 9 8 - 9
9 . 5
C1 H H H OCH3 H CH3 91-92
Cl H H H CH3 H H 95.5-96.5
Cl H H H SCH3 H H 127-128
C1 H H H CH3 H OCH3 91- 9 2
. 5
Cl H H H CzHS H H
Cl H H H C1 H H 88.5-90.5
Cl H H H F H H 68-69.5
C1 H H C1 H H OCH3 124-126
Cl H H OCH3 H H OCH3 71-73
Cl H H H OCH3 H OCH3 98-100
C1 H H CH3 CH3 H OCH3 12 7 -12
9
C1 H H H C1 H OCH3 96-99
C1 H CH3 H CH3 H OCH3 10 8 . 5
-110
Cl H H H H CH3 OCH3 71-74
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X3 XS W W1 WZ W W mp CC
Cl H H H N ( CH3 H H
) -
S02CH3
C1 H H CH3 Cl H OCH3 126-128
Cl H H CH3 H CH3 OCH3 110 -112
Cl H CH3 CH3 CH3 H OCH3 104 -10
6
Cl H H CH (CH3) H H OCH3 69-71
2
Cl H H CH3 H H H
Cl H H H H H CN
C1 H H H H H OCH3
Cl H H OCH3 H H H
Cl H H F H H OCH3
Cl H H H F H OCH3
C1 H H H H H SCH3
Cl H H H H H CH3
Cl H H H H H F
Cl H H SCH3 H H H
Cl H H H OCH3 H H
Cl H H - ( CHZ H OCH3
) 3 -
C1 F H H H H H
F F H CH3 H H OCH3
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EXAMPLE 4
Preparation of 3-(6-Methoxy-m-tolyl)-5-vitro-1,2-
benzisothiazole
O OCH3
02N ~ \ ~ \
+ NH40H + S8
/ /
Cl
CH
3
OZN
Ammonium hydroxide (350 mL of a 30% solution, 270
mmol) is added to a mixture of 2'-chloro-2-methoxy-5-
methyl-5'-nitrobenzophenone (68.7 g, 22.5 mmol) and
sulfur (7.57 g, 23.6 mmol) in N,N-dimethylformamide. The
resultant reaction mixture is stirred at 80 °C for 19.5
hours, cooled to 40 °C, treated with additional ammonium
hydroxide (50 mL of a 30o solution), stirred at 80 °C for
25 hours, cooled, and poured onto ice. The resultant
aqueous mixture is filtered to obtain the title product
as a yellow solid (63.5 g, 93.90) which is identified by
NMR spectral analyses.
Using essentially the same procedure, the following
compounds are obtained:
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O N
z
H H CH3 H OCH3 201-203
H CH3 CH3 H OCH3 199-200
H CH3 H H H 116.5-117.5
H H C1 H OCH3 229-231
H H H CH3 OCH3 134-136
H H H H CN 187.5-189
H H H H OCH3 193-198
H H OCH3 H H 201-203
H OCH3 H H H 174-175
H F H H OCH3 224-226
H CZHS H H OCH3 153 -154 .
5
H H CH3 H H 188-189
H H N ( CH3 ) S02CH3H H
H CH3 C1 H OCH3 230-234
H I H H OCH3
H H SCH3 H H 177.5-178.5
H H OCH3 H CH3 131-13 5
H H F H H 226-228
H H Cl H H 217.5-219
H H F H OCH3 224-225
H H H H SCH3 114.5-115.5
H H CH3 H OCH3 201-203
H OCH3 H H OCH3 19 5 -19 6
H H H H CH3 145-146
H H H H F 181-182
H H OCH3 H OCH3 171-172.5
H SCH3 H H H 139-140.5
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W W1 W W3 W mp C
H CH3 H CH3 OCH3
CH3 CH3 CH3 H OCH3
H CH ( CH3 ) H H OCH3
z
H H CH3 CH3 OCH3
H - ( CHZ ) 3 H OCH3
-
EXAMPLE 5
Preparation of 3-Methyl-5-vitro-1,2-benzisothiazole
O
02N I ~ CH3
+ NH3 + S$
C1
02N / CH3
iN
S
Ammonia (45 g, 2,642 mmol) is bubbled into methanol
at -40 °C in a steel bomb. Sulfur (30.5 g, 95.0 mmol) and
2'-chloro-5'-nitroacetophenone (19 g, 95.0 mmol) are then
added. The bomb is sealed and heated at about 90 °C
overnight. After cooling, the reaction mixture is
removed from the bomb and concentrated in vacuo to obtain
a residue. The residue is diluted with methylene
chloride, passed through a plug of silica gel and
concentrated in vacuo to give the title product as an
orange solid (12.0 g) which is identified by NMR spectral
analyses.
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Using essentially the same procedure, the following
compounds are obtained:
OZN / R4o
\ ~N
S
Ro
H
CzHS
CzHs
EXAMPLE 6
Preparation of 5-Amino-3-(6-methoxy-m-tolyl)-1,2-
benzisothiazole
OzN + Fe + CH3C02H --
H N
z
3
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A mixture of 3-(6-methoxy-m-tolyl)-5-nitro-1,2-
benzisothiazole (63.0 g, 0.210 mol), 5o acetic acid
(1.52 L, 1.21 mol) and ethyl acetate (975 mL) is heated
to 65 °C, treated portionwise with iron powder (58.6 g,
1.05 mol), stirred at 65 °C, and filtered through quartz
filter paper. The filtrate phases are separated and the
aqueous phase is extracted with ethyl acetate. The
organic phase and extracts are combined, washed
sequentially with water and brine, dried over anhydrous
magnesium sulfate, and concentrated in vacuo to obtain
the title product as an orange oil (55.7 g, 98.10) which
is identified by NMR spectral analyses.
Using essentially the same procedure, the following
compounds are obtained:
H2N / R4o
\ ( ,N
Xs
Xs R a mp ~C
H H
H CN 118.5-120
H CH3 112 -113 . 5
H CZHS
\ CH3
H ~ /
179-181
OCH
3
\ CZHs
H ,~ / 90-91
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Xs R o mp °C~C
CH3
\
F /
OCH3
H ~ / 130-130.5
CH
3
H ~ CH3
152-153
OCH
3
\
H ~ / 121.5-123
SCH
3
OCH
3
H \
108.5-109.5
O CH
3
H \
158.5-161
OCH
3
\
H ~ / 101.5-102.5
F
H ~ / 104-105
CH
3
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XS R o mp ~C
OCH3
H I / 191-192.5
OCH3
S CH
3
H
I /
OCH3
H I /
CH3
H I / 128-129
H
OCH3
I
H
64
/
CH
3
SCH3
H I / 108.5-109.5
Cl
H ( / 133-134
F
H I / 114.5-115
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Xs R o mP oC
OCH
\ 3
H ~ / 152-153.5
CH
3
F
H ~ / 146-147
OCH3
CH
3
\
H ~ / 60-65
OCH3
F
H ~ / 143-145
OCH
3
CH
3
H ( / 100-101
H I /
OCH3
CH3
\ C1
H 125-127
OCH3
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Xs R o mn ~C
C1
H I / 172-174
OCH3
H I / 146-147
CN
CH
3
H I / 161-162
1' CH3
OCH
3
CH
3
H3C ~ CH3
H I / 173-175
OCH3
Calls
H
I/
OCH
3
CH (CH3 ) z
H
I
OCH
3
CH3
H I/
1' CH3
OCH3
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Xs R o mP oC
\ N ( CH3 ) 602 CH3
H
F CH3
F
H CHZCOZCZHs
H C ( CH3 ) 2COzC2Hs
H OCHzCN
H OCH3
H OCH ( CH3 ) a
H OCHZCH=CHZ
H O CHz C=CH
H OCHZCO2CH3
EXAMPLE 7
Preparation of 2-Chloro-2'-methoxy-5'-methyl-5-
nitrobenzophenone, oxime
O OCH3
02N
NH20H- HC1
/ /
C1
CH
3
NOH OCH
3
02N ~ \ ~ \
/ /
Cl
CH
3
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A mixture of 2-chloro-2'-methoxy-5'-methyl-5-nitro-
benzophenone (90.0 g, 0.294 mol) in ethanol is treated
with a solution of hydroxylamine hydrochloride (102.3 g,
1.47 mol) in water, refluxed overnight, and poured onto
ice. The resultant aqueous mixture is filtered to obtain
a solid. The solid is washed with water and dried in a
hot vacuum oven overnight to give the title product as a
white solid (84.2 g) which is identified by 1H NMR
spectral analysis.
Using essentially the same procedure, the following
compounds are obtained:
NOH W
OzN
XS . / Cl ~W2
Wa
H OCH3 H H 173-178
H H H H 143-145
H H OCH3 H 191-192.5
H OCH3 H F
H H OCH2COZCH3 H 150-155
H OCH3 H CH3 185.5-186.5
F OCH3 H CH3
and
NOH
02N
i ~H3
C1
mp 165-167°C
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EXAMPLE 8
Preparation of 3-(6-Methoxy-m-tolyl)-5-vitro-1,2-
benzisoxazole
NOH OCH
3
~zN
KOH
~Cl
CH
3
O N
z
f
3
v
A mixture of 2-chloro-2'-methoxy-5'-methyl-5-nitro-
benzophenone, oxime (84.0 g, 0.262 mol) in ethanol is
warmed to 65 °C, treated with 150 mL of 10% potassium
hydroxide solution over 25 minutes, heated to 78 °C over
one hour, cooled, and poured onto ice. The resultant
aqueous mixture is filtered to obtain a solid. The solid
is washed with water, dried, recrystallized from N,N-
dimethylformamide, washed sequentially with N,N-dimethyl-
formamide and ethanol, and dried in a vacuum oven at 80 °C
to give the title product as a solid (mp 225-226 °C) which
is identified by 1H NMR spectral analysis.
Using essentially the same procedure, the following
compounds are obtained:
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W,
W2
02N
XS v
XS W W1 W mP C
.
H OCH3 H H 170-171
H H H H 138-139
H H H OCH3 205-207
F OCH3 CH3 H
and
O2N ~ CH3
0
mp 84.5-86.5°C
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EXAMPLE 9
Preparation of 5-Amino-3-(6-methoxy-m-tolyl)-1,2-
benzisoxazole and 5-Amino-4-chloro-3-(6-methoxy-m-tolyl)-
1,2-benzisoxazole
CH
3
OzN ' ( / -f- SnCl2 - a Hz0
/ OiN OCH3
CH3C02H H N
2 +
HC1
3
V
H N
z
3
A mixture of 3-(6-methoxy-m-tolyl)-5-nitro-1,2-
benzisoxazole (20.0 g, 0.0703 mol) in acetic acid (380
mL) is warmed, treated with a warm solution of tin(II)
chloride dehydrate (47.4 g, 0.210 mol) in concentrated
hydrochloric acid (110 mL), refluxed for one hour, cooled
to 10 °C, and concentrated in vacuo to obtain a gum. The
gum is added to water with stirring to obtain a slurry.
The slurry is treated with 80 g of 50o sodium hydroxide
solution, stirred at 60 °C to 80 °C over one hour, cooled,
and decanted to obtain a residue. A mixture of the
residue in ethanol is treated with potassium hydroxide
(10 g), heated overnight, cooled to room temperature,
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neutralized with hydrochloric acid, and concentrated in
vacuo to obtain a residue. The residue is diluted with
ethyl acetate and filtered. The filtrate is concentrated
in vacuo and chromatographed using silica gel and a 2%
ethyl acetate in methylene chloride solution to give the
title products as semi-solids which are identified by
elemental and mass spectral analyses.
Using essentially the same procedure, the following
compounds are obtained:
H2N ~ R.4i
/ ,N
XS O
Xs R 1
H
H CH3
H C1
H OCH2CO2CH3
H OCH ( CH3 ) 2
H OCH ( CH3 ) COZCH3
F OCHZCOzCH3
H OCH3
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EXAMPLE 10
Preparation of m-Fluorophenyl acetate
+ CH3C (O) C1 +
F / OH
N
O
a
F / O CH
3
A solution of 3-fluorophenol (100 g, 0.890 mol) in
methylene chloride is cooled to 0 °C to 5 °C, treated with
pyridine (75.0 mL, 0.930 mol), stirred for several
minutes, treated dropwise with acetyl chloride (66.0 mL,
0.930 mol) while maintaining the reaction mixture
temperature below 17 °C, stirred at ice-bath temperature
for two hours, warmed to room temperature, and poured
into an ice-water mixture. The organic phase is
separated, washed with brine, dried over anhydrous
magnesium sulfate, and concentrated in vacuo to obtain
the title product as a yellow oil which is identified by
1H NMR spectral analysis.
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EXAMPLE 11
Preparation of 4'-Fluoro-2'-hydroxyacetophenone
O
O
A1C13 -,. ~ ~ CH
3
F / O~CH /
F OOH
m-Fluorophenyl acetate (123 g, 0.798 mol) is cooled
with an ice-bath, treated portionwise with aluminum
chloride (150 g, 1.12 mol), stirred at 190 °C for one
hour, and cooled to obtain a solid. A mixture of ice,
water and hydrochloric acid, and methylene chloride are
added to the solid. The resultant mixture is stirred for
several minutes, and the phases are separated. The
organic phase is washed sequentially with water,
saturated sodium hydrogen carbonate solution and brine,
dried over anhydrous magnesium sulfate, and concentrated
in vacuo to obtain the title product (99.0 g) which is
identified by 1H NMR spectral analysis.
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EXAMPLE 12
Preparation of 4'-Fluoro-2'-hydroxyacetophenone,
oxime
0
~CH -~ NH20H ~ HCl -~ CH3C02Na
3
/
F OH
NOH
~CH3
F OH
A mixture of 4~-fluoro-2~-hydroxyacetophenone (99.0
g, 0.640 mol), hydroxylamine hydrochloride (89.0 g, 1.28
mol), and sodium acetate (79.0 g, 0.960 mol) in methanol
is refluxed for one hour and poured into an ice-water
mixture. The resultant aqueous mixture is filtered to
obtain a solid. The solid is dissolved in methylene
chloride, and the resultant organic solution is dried
over anhydrous magnesium sulfate, concentrated in vacuo,
diluted with hexanes, and filtered to give the title
product as a solid (55.0 g, mp 112-114 °C) which is
identified by 1H NMR spectral analysis.
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EXAMPLE 13
Preparation of 6-Fluoro-3-methyl-1,2-benzisoxazole
NOH
CH -~ N~ 101 ~N ~" N ( C2H5 ) 3
( ~N C N'
~/
F OH
CH
3
/ ~N
F O
A mixture of 4'-fluoro-2'-hydroxyacetophenone, oxime
(47.0 g, 0.278 mol) in tetrahydrofuran is heated to just
under reflux, treated with a solution of 1,1'-carbonyl-
diimidazole (55.0 g, 0.340 mol) and triethylamine (39.0
g, 0.390 mol) in tetrahydrofuran, refluxed for one hour,
cooled, concentrated in vacuo, and poured into an ice-
water mixture. The resultant aqueous mixture is
extracted with ether. The organic extracts are combined,
washed sequentially with saturated ammonium chloride
solution and brine, dried over anhydrous magnesium
sulfate, and concentrated in vacuo to obtain an oil.
Column chromatography of the oil using silica gel and a
methylene chloride/hexanes solution (1:1) gives the title
product as a yellow oil which is identified by 1H NMR
spectral analysis.
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EXAMPLE 14
Preparation of 6-Fluoro-3-methyl-5-nitro-1,2-benz-
isoxazole
CH3 02N \ CH3
HN~3~H2SO4 -ti
F / O'N F / O/N.
A mixture of 6-fluoro-3-methyl-1,2-benzisoxazole
(23.5 g, 0.156 mol) in concentrated sulfuric acid is
cooled with an ice-bath, treated dropwise with 90% nitric
acid (8.50 mL) while maintaining the reaction mixture
temperature below 15 °C, stirred for one hour at ice-bath
temperature, treated with additional 90o nitric acid
(5.80 mL), warmed to and stirred at room temperature
overnight, and poured onto ice. The resultant aqueous
mixture is filtered to obtain a solid. The solid is air-
dried and dissolved in methylene chloride. The resultant
organic solution is dried over anhydrous magnesium
sulfate, diluted with hexanes, and filtered to give the
title product as a purple solid which is identified by 1H
NMR spectral analysis.
Using essentially the same procedure, the following
compounds are obtained:
OZN ~ OH
/ O~N
s
Xs
g
C1
F
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EXAMPLE 15
Preparation of Methyl ((5-vitro-1,2-benzisoxazol-3-
vl) oxyl acetate
OH
02N
.~. BrCH2C02CH3 -t- K2C03
/ ,N
0
O N OCH2C02CH3
2
/ ,N
O
A mixture of 5-vitro-1,2-benzisoxazol-3-0l (3.90 g,
0.0220 mol) and potassium carbonate (4.17 g, 0.0300 mol)
in N,N-dimethylformamide is stirred for 30 minutes,
treated with methyl bromoacetate (3.96 g, 0.0260 mol),
stirred overnight at room temperature, and poured into an
acidic ice-water mixture. The resultant aqueous mixture
is extracted with ethyl acetate. The organic extracts
are combined, washed sequentially with water and brine,
dried over anhydrous magnesium sulfate, and concentrated
in vacuo to obtain a yellow oil. Column chromatography
of the oil using silica gel and a (1:1) to (4:1)
methylene chloride/hexanes gradient gives the title
product as a white solid (2.80 g, mp 72-73.5 °C) which is
identified by NMR spectral analyses.
Using essentially the same procedure, the following
compounds are obtained:
02N ~ R4i
/ O~N
s
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Xs R 1 m~ ~C
H OCH (CH3) 2 81-83
H OCHz CH=CH2 7 0 - 72
H OCH3 10-1.5-103
C1 OCH (CH3) COZCH3 98-100
F OCHzCO2CH3 104 -10 6
EXAMPLE 16
Preparation of 3-Chloro-5-vitro-1,2-benzisoxazole
O N OH O N C1
z \ z \
+ POC1 --
/ O~N 3 / O~N
A mixture of 5-vitro-1,2-benzisoxazol-3-0l (4.00 g,
0.0220 mol) and phosphorus oxychloride (40.0 mL, 65.8 g,
0.429 mol) is placed in a glass bomb, heated at 150-155 °C
for two hours, cooled overnight, concentrated in vacuo,
diluted with methylene chloride, and brought to about pH
8 with sodium hydrogen carbonate solution. The phases
are separated. The organic phase is washed sequentially
with water and brine, dried over anhydrous magnesium
sulfate, and concentrated in vacuo to obtain a residue.
Column chromatography of the residue using silica gel and
a methylene chloride/hexanes solution (1:1) gives the
title product as an amber oil which is identified by NMR
spectral analysis.
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EXAMPLE 17
Preparation of 2-Chloro-2'-methoxy-5-nitrobenzophen-
one
O2N \ C (O) Cl OCH3
Br ~ \
Cl /
1) CH3(CHz)3Li
2) ZnCl2
3) Pd [P(C6H5)s]4
0 OCH3
OZN ~ \ ~ \
c1
A solution of 2-bromoanisole (27.9 g, 145 mmol) in
diethyl ether is cooled to -70 °C, treated with
butyllithium (64.0 mL, 160 mmol), stirred at -70 °C for
one hour, treated with 0.5 M zinc chloride in
tetrahydrofuran solution (320 mL, 160 mmol), stirred for
one hour at -70 °C, warmed to about 0 °C, and concentrated
in vacuo to obtain a yellow-green oil. A solution of the
oil in tetrahydrofuran is treated sequentially with
tetrakis(triphenylphosphine)palladium(0) (5.00 g, 4.35
mmol) and a solution of 2-chloro-5-nitrobenzoyl chloride
(35.0 g, 159 mmol) in tetrahydrofuran, stirred for three
days, and poured into loo hydrochloric acid. The
resultant aqueous mixture is extracted with methylene
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chloride. The organic extracts are combined, washed
sequentially with water and brine, dried over anhydrous
magnesium sulfate, and concentrated in vacuo to obtain a
semi-solid. The solid is triturated with diethyl ether
to give the title product as a yellow solid which is
identified by NMR spectral analyses.
Using essentially the same procedure, the following
compounds are obtained:
O W
4
OzN ~ ~ ~ ~ W3
C1 ~Wz
W
i
W1 W2 W3 W mp C
H C1 H OCH3 96-99
H H CH3 OCH3 71- 74
F H H OCH3
C1 H H OCH3 124-126
OCH3 H H OCH3 71- 73
H OCH3 H OCH3 98-100
H F H OCH3
H H CH3 H 65-66.5
H H SCH3 H 87-88
H H H F 118-120
H H H CH3 78-79.5
H H H SCH3 123-124.5
H F H H
H H OCH3 H
H H H OCH3
H CH3 CH3 OCH3
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EXAMPLE 18
Preparation of 2-Chloro-2'-methoxy-5-nitrobenzhydrol
OCH3
+ Br ~ + M
g
Cl ~ /
OH OCH
3
cl
A solution of 2-bromoanisole (50.0 g, 0.267 mol) in
ether is added portionwise to a mixture of magnesium
(7.10 g, 0.293 mol) in ether. After the addition is
complete, the reaction mixture is heated at reflux for
one hour, diluted with ether, cooled to 0 °C, treated with
a solution of 2-chloro-5-nitrobenzaldehyde (39.0 g, 0.210
mol) in tetrahydrofuran, warmed to room temperature, and
diluted with an ice-water mixture. After acidifying the
aqueous mixture with hydrochloric acid (pH 2 - pH 3), the
organic phase is separated and the aqueous phase is
extracted with ether. The organic extracts are combined,
washed sequentially with 10% sodium hydrogen carbonate
solution and brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo to give the title product as a
brown gum.
Using essentially the same procedure, the following
compounds are obtained:
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OH W
4
OzN ~ \ ~ \ Wa
C1 Y
W
w w3 w
OCH3 H OCH3
CH3 H O CH3
F H OCH3
H OCH3 H
EXAMPLE 19
Preparation of 2-Chloro-2'-methoxy-5-nitrobenzo-
phenone
OH OCH
3
\ ~ \ .~. Cr03 -~- CH3C02H
C1
O OCH
3
/ Cl
A solution of chromium(VI) oxide (91.0 g, 0.919 mol)
in a water/acetic acid solution (1:4) is added
portionwise to 2-chloro-2~-methoxy-5-nitrobenzhydrol
(64.2 g, 0.219 mol) while maintaining the reaction
mixture temperature at 25 °C to 35 °C. The reaction
mixture is then stirred at 25 °C to 35 °C for one hour,
cooled, diluted with water, and concentrated in vacuo to
obtain a residue. The residue is diluted with water, and
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extracted with methylene chloride. The organic extracts
are combined, dried over anhydrous sodium sulfate, mixed
with silica gel (10 g), and filtered. The filtrate is
concentrated in vacuo to obtain an oil. A solution of
the oil in a methanol/water solution is decolorized with
charcoal and concentrated in vacuo to yield a residue.
Column chromatography of the residue using silica gel and
methylene chloride/hexanes solutions gives the title
product as a white solid.
Using essentially the same procedure,.the following
compounds are obtained:
O W
4
Wa
Cl Y
W
1
W W3 W mp ~C
OCH3 H OCH3
CH3 H OCH3 10 9 -111
F H OCH3 94 - 95
H OCH3 H 79 - 81
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EXAMPLE 20
Preparation of 2-Chloro-4-fluoro-5-nitrobenzoyl
chloride
OzN ~ C02H
C1C (O) C (O) Cl
F C1
O
OzN ~ ~ C1
F C1
A mixture of 2-chloro-4-fluoro-S-nitrobenzoic acid
(50.0 g, 0.228 mol) and N,N-dimethylformamide (5 drops)
in 1,2-dichloroethane is treated dropwise with oxalyl
chloride (30.8 mL, 0.353 mol), refluxed for 3 hours,
cooled, and concentrated in vacuo to obtain the title
product as an orange solid which is identified by NMR
spectral analyses.
Following essentially the same procedure, but using
2,4-difluoro-5-nitrobenzoic acid, 2,4-difluoro-5-
nitrobenzoyl chloride is obtained as a brown oil.
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EXAMPhE 21
Preparation of 2'-Chloro-4'-fluoro-5'-nitroaceto-
phenone
O
OZN ~ \ C1
..~ CH3ZnC1 -~- Pd [P (C6H5 ) 3 ~ 4
F C1
O
OaN ~ \ CH3
F C1
A 2 M solution of methylzinc chloride in tetra-
hydrofuran (5.00 mL, 10.1 mmol) is treated dropwise with
a solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride
(2.00 g, 8.40 mmol) in tetrahydrofuran, treated with
tetrakis(triphenylphosphine)palladium(0) (0.400 g, 0.350
mmol), stirred at room temperature for one hour, and
poured into 3 N hydrochloric acid. The resultant aqueous
mixture is extracted with ethyl acetate. The organic
extracts are combined, washed sequentially with water and
saturated sodium hydrogen carbonate solution, dried over
anhydrous magnesium sulfate, and concentrated in vacuo to
obtain a dark liquid. Flash column chromatography of the
liquid using silica gel and a methylene chloride in
hexanes solution (6:4) gives the title product as an off-
white solid (mp 66-68 °C) which is identified by NMR
spectral analyses.
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EXAMPLE 22
Preparation of 6-Amino-3-methyl-5-nitro-1.2-
benzisothiazole
O
OzN ~ \
~CH3 + ~40H + S8
F C1
CH3
OZN ( \
---s
H N / SAN
2
A mixture of 2'-chloro-4'-fluoro-5'-nitroaceto-
phenone (12.0 g, 0.0552 mol), sulfur (1.77 g, 0.0552
mol), 30% ammonium hydroxide solution (100 mL, 0.856
mol), and methanol is placed in a steel bomb, heated at
85 °C overnight, cooled, treated with additional sulfur
(0.270 g) and 30% ammonium hydroxide solution (50 mL),
heated at 85 °C overnight, cooled, filtered to remove
solids, and extracted with ethyl acetate. The organic
extracts are combined, washed sequentially with water and
brine, dried over anhydrous magnesium sulfate, and
concentrated in vacuo to obtain a solid. Flash column
chromatography of the solid using silica gel, and 0%, to
and 2o diethyl ether in methylene chloride solutions
gives the title product as an orange solid (4.19 g, mp
189-191 °C) which is identified by NMR spectral analyses.
Using essentially the same procedure, the following
compound is obtained:
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O
2
H
z
EXAMPLE 23
Preparation of 6-Chloro-3-methyl-5-vitro-1,2-
benzisothiazole
CH3
OzN
H N ~ SHIN + (CHa ) 3C (O) NO -f- CuClz
z
CH3
OzN ~ \
C1 / SAN
A mixture of tert-butyl nitrite (3.30 mL, 0.0278
mol) and copper(II) chloride (2.98 g, 0.0222 mol) in
acetonitrile is heated to 65 °C, treated portionwise with
6-amino-3-methyl-5-vitro-1,2-benzisothiazole (3.88 g,
0.0185 mol), stirred at 65 °C, cooled to room temperature,
and poured into 20% hydrochloric acid. The resultant
aqueous mixture is extracted with ethyl acetate. The
organic extracts are combined, washed with 20o hydro-
chloric acid, dried over anhydrous magnesium sulfate, and
concentrated in vacuo to obtain a solid. Flash column
chromatography of the solid using silica gel and
methylene chloride/hexanes solutions (1:1 and 3:1) gives
the title product as a pale, yellow solid (2.54 g, mp
156-158 °C) which is identified by NMR spectral analyses.
Using essentially the same procedure, the following
compound is obtained:
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O N
Cl / SAN
EXAMPLE 24
Preparation of 6-Fluoro-3-methyl-5-nitro-1,2-
benzisothiazole
OZN ' CH3 02N \ CH3
II + KF ----~ ~ II
Cl / SAN F / SAN
A mixture of 6-chloro-3-methyl-5-nitro-1,2-
benzisothiazole (2.25 g, 9.80 mmol), potassium fluoride
(2.85 g, 49.0 mmol), and 18-crown-6 (1.50 g, 5.70 mmol)
in acetonitrile is heated in a sealed tube for 29 days,
filtered to remove solids, and partially concentrated in
vacuo to obtain a liquid. The liquid is diluted with
ethyl acetate, washed sequentially with water and brine,
dried over anhydrous magnesium sulfate, and concentrated
in vacuo to obtain a dark, brown solid. Flash column
chromatography of the solid using silica gel and a 10% to
50% ethyl acetate in hexanes gradient gives a yellow
solid containing two components. Flash column
chromatography of the yellow solid using silica gel and a
50% to 70% methylene chloride in hexanes gradient gives
the title product as a pale, yellow solid (0.870 g, mp
118-119 °C) which is identified by NMR spectral analyses.
Using essentially the same procedure, the following
compound is obtained:
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02N \ w
/ SAN
EXAMPLE 25
Prevaration of 2,2'-Dithiobisf5-nitrobenzoic acid]
02N ~ C02H
/
C1
1) (CH3)3C0 K+
2) Na2S ~9H20 + S8
3) HCl
02N ~ C02H
S
2
A mixture of 2-chloro-5-nitrobenzoic acid (100 g,
0.496 mol) in ethanol is treated portionwise with
potassium tert-butoxide (55.5 g, 0.495 mol), diluted with
additional ethanol, heated to reflux, treated portionwise
with a solution prepared from sodium sulfide nonahydrate
(60.0 g, 0.249 mol), sulfur (8.80 g, 0.274 mol) and
water, refluxed for two hours, cooled to room
temperature, and treated with concentrated hydrochloric
acid. The resultant acidic mixture is stirred for one
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hour and filtered to obtain a solid. The solid is washed
with water and air-dried to give the title product as a
yellow powder which is identified by NMR spectral
analysis.
EXAMPLE 26
Preparation of 5-Nitro-1,2-benzisothiazol-3(2Fi)-one
02N ~ C02H
S
2
1) SOC12
2 ) Br2
3) NH3
OaN O
S~~
A mixture of 2,2'-dithiobis[5-nitrobenzoic acid]
(44.6 g, 0.113 mol) and thionyl chloride (49.0 mL, 0.670
mol) in methylene chloride is treated with N,N-
dimethylformamide (0.800 mL), refluxed overnight,
concentrated in vacuo, and diluted with 1,2-
dichloroethane. The resultant organic solution is
treated with bromine (22.5 mL, 0.436 mo1), stirred at
room temperature for 20 minutes, refluxed for 3.5 hours,
and concentrated in vacuo to obtain a residue. A
solution of the residue in 1,2-dichloroethane is cooled
with an ice-water bath, treated with concentrated ammonia
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(112 mL) over 15 minutes, stirred at room temperature for
16 hours, cooled with an ice-water bath, and treated with
concentrated hydrochloric acid. The resultant aqueous
mixture is stirred at room temperature for one hour and
filtered to obtain a solid. The solid is washed with
water and air-dried to give the title product as a yellow
solid which is identified by NMR spectral analysis.
EXAMPLE 27
Preparation of 3-Chloro-5-vitro-1,2-benzisothiazole
O N O
2
+ POC13 + N[(CH2)3CH3~3
/ S~NH
OZN ~ C1
SAN
A mixture of 5-vitro-1,2-benzisothiazol-3(2H)-one
(10.0 g, 0.0510 mol), phosphorus oxychloride (40.0 mL,
0.429 mol) and tributylamine (12.0 mL, 0.050 mol) is
heated at 103-115 °C for six hours, stirred at room
temperature overnight, and poured into an ice-water
mixture. The resultant aqueous mixture is extracted with
methylene chloride. The combined organic extracts are
washed sequentially with water and saturated sodium
hydrogen carbonate solution, dried over anhydrous sodium
sulfate, and concentrated in vacuo to obtain a gum.
Column chromatography of the gum using silica gel and
methylene chloride gives the title product as an orange-
yellow solid which is identified by NMR spectral
analysis.
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EXAMPLE 28
Pret~aration of Ethyl a-cyano-5-vitro-1,2-benziso-
thiazole-3-acetate
OZN ~ C1
/ .IN
s
1) C2H50 Na+ + CH2 (CN) COZC2H5
2) HCl
CN
02N
C02CzH5
/ s~N
A sodium ethoxide solution (previously prepared from
ethanol and sodium (1.00 g, 0.0430 mol)) is cooled with
an ice-acetone bath, treated portionwise with ethyl
cyanoacetate (4.51 g, 0.0398 mol), stirred at room
temperature for 30 minutes, treated with 3-chloro-5-
vitro-1,2-benzisothiazole (4.27 g, 0.0199 mol), stirred
at room temperature overnight, cooled to 0 °C, and treated
dropwise with 10% hydrochloric acid (15.0 mL). The
resultant aqueous mixture is stirred at room temperature
for one hour and filtered to obtain a solid. The solid
is washed with ethanol and air-dried to give the title
product as a yellow solid which is identified by NMR
spectral analysis.
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EXAMPLE 29
Preparation of Ethyl 5-vitro-1,2-benzisothiazole-3-
acetate
CN
02N O
I ~ ~ COZC2H5 + CH3CC1 + CZHSOH
/ . ,N
S
02N ~ CH2C02C2H5
/ ~N
S
Ethyl a-cyano-5-vitro-1,2-benzisothiazole-3-acetate
(6.67 g, 0.0229 mol) is added to a solution of acetyl
chloride (67.0 mL) in ethanol. The reaction mixture is
refluxed overnight, cooled, and filtered to remove
solids. The resultant filtrate is concentrated in vacuo
to obtain a brown semi-solid. A mixture of the semi-
solid in diethyl ether is stirred for two hours and
filtered to obtain a solid. The solid is washed with
diethyl ether and air-dried to give the title product as
yellow crystals (1.04 g, mp 91-92 °C).
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EXAMPLE 30
Pret~aration of 5-Nitro-1,2-benzisothiazole-3-aceto-
nitrile
CN
OZN
~C02C2H5 + (CH3)2S0 + HZO
/ ,N
S
CHZCN
02N ~ \
/ SiN
A mixture of ethyl 5-nitro-1,2-benzisothiazole-3-
acetate (5.00 g, 17.2 mmol), water (1.00 mL), and methyl
sulfoxide (35.0 mL) is stirred at 107 °C for 24 hours,
stirred at room temperature for two days, and poured into
an ice-water mixture. The resultant aqueous mixture is
stirred for two hours and filtered to obtain a solid.
The solid is washed with water and air-dried to give the
title product as a tan solid.
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EXAMPLE 31
Preparation of a,a-Dimethyl-5-vitro-1,2-benziso-
thiazole-3-acetonitrile
02N \ CHzCN
+ NaH + CH3I
/ SAN
HaC CHs
OaN ~ \ w
CN
/ SiN
A mixture of 5-vitro-1,2-benzisothiazole-3-aceto-
nitrile (1.29 g, 5.89 mmol) in N,N-dimethylformamide is
cooled to -9 °C, treated with sodium hydride (1.00 g of a
60% dispersion in oil), stirred at -3 °C for 20 minutes,
treated with iodomethane (5.00 mL), stirred at room
temperature for four hours, and poured onto ice. The
resultant aqueous mixture is treated with 10%
hydrochloric acid and extracted with methylene chloride.
The combined organic extracts are washed sequentially
with water, saturated sodium hydrogen carbonate solution
and water, dried over anhydrous sodium sulfate, and
concentrated in vacuo to obtain a solid. column
chromatography of the solid using silica gel and
methylene chloride gives the title product as a yellow
solid which is identified by NMR spectral analysis.
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EXAMPLE 32
Preparation of Ethyl a,a-dimethyl-5-nitro-1,2-benz-
isothiazole-3-acetate
HaC CH3
OZN ~ ~ I \CN + HZS04 + C2HSOH
/ SiN
H3C CH3
OZN \ ~ \ COZCzHs
/ SAN
A mixture of a,a-dimethyl-5-vitro-1,2-benzisothia-
zole-3-acetonitrile (0.913 g, 3.69 mmol), water (0.450
mL), concentrated sulfuric acid (4.55 mL) and ethanol
(9.10 mL) is refluxed for one hour, cooled, and poured
onto ice. The resultant aqueous mixture is neutralized
with saturated sodium bicarbonate solution and extracted
with methylene chloride. The organic extract is washed
with water, dried over anhydrous sodium sulfate, and
concentrated in vacuo to obtain a solid. Column chroma-
tography of the solid using silica gel and methylene
chloride gives the title product as pale yellow crystals.
spectral analysis.
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EXAMPLE 33
Preparation of 5-Amino-3-chloro-1.2-benzisothiazole
p2N ~ C1
+ Fe + HCl + H20
/ SAN
HZN ~ Cl
/ ,N
S
A solution of 3-chloro-5-nitro-1,2-benzisothiazole
(2.00 g) in toluene is treated with iron powder (8.40 g,
325 mesh) and concentrated hydrochloric acid (8 drops),
heated to reflux, treated dropwise with water (8.00 mL),
refluxed for 35 minutes, cooled to room temperature, and
filtered through diatomaceous earth. The resultant
filtrate is concentrated in vacuo to obtain a residue.
Flash column chromatography of the residue using silica
gel and an ethyl acetate/hexanes solution (1:1) gives the
title product.
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EXAMPLE 34
Preparation of [(5-Nitro-1,2-benzisothiazol-3-vl)-
oxylacetonitrile
O
OzN
+ KzC03 + BrCH2CN
/ S~~
OZN OCH2CN
/ SiN
A mixture of 5-nitro-1,2-benzisothiazol-3(2H)-one
(17.5 g, 89.2 mmol) in N,N-dimethylformamide is treated
with potassium carbonate (18.5 g, 134 mmol), stirred at
room temperature for 30 minutes, treated with bromoaceto-
nitrile (16.0 g, 133 mmol), stirred at room temperature
overnight, and poured onto ice. The resultant aqueous
mixture is acidified to pH 3 with hydrochloric acid and
extracted with ethyl acetate. The combined organic
extracts are washed sequentially with water and brine,
dried over az~.hydrous magnesium sulfate, and concentrated
in vacuo to obtain a solid. Column chromatography of the
solid using silica gel and methylene chloride gives the
title product as a yellow solid (15.0 g, mp 123-124.5 °C).
Using essentially the same procedure, the following
compounds are obtained:
02N ~ R4o
/ ,N
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R4o mP ~C
OCH3 108-109
OCH ( CH3 ) 2
OCHZCH=CHZ
OCHZC=CH 115-117
OCHZCO2CH3
EXAMPLE 35
Preparation of 5-Nitro-1,2-benzisothiazole
02N / CHO OzN /
-F- NH40H + S a --
\ \ ~ ,N
C1 g
To a mixture of ammonium hydroxide (1000 ml) and
N,N-dimethylformamide is added 2-chloro-5-nitrobenz-
aldehyde (300 g, 1.62 mol) and sulfur (54.4 g, 1.70 mol).
The mixture is heated slowly to and stirred at 90 °C for
one hour, cooled to room temperature, poured onto ice,
and diluted with water. Filtration affords the title
compound as a yellow solid (277.1 g, 94.90).
Using essentially the same procedure, but using 2'-
chloro-5'-nitro-2-methyl-2-carboethoxypropiophenone,
ethyl a,a-dimethyl-5-nitro-1,2-benzisothiazole-3-acetate
is obtained as a solid (mp 75-77°C).
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EXAMPLE 36
Preparation of 3-Chloro-5-vitro-1,2-benzisothiazole
02N / CH3C02H 02N / C1
Cl2 ---
~N \ ~ N
S wSi
A suspension of 5-vitro-1,2-benzisothiazole (271 g,
1.50 mol) in acetic acid is heated to 80 °C to form a
solution. The heating source is removed and chlorine gas
is added continuously over six hours at 70-80 °C until
saturation of the mixture occurs. The mixture is cooled
to room temperature and stirred overnight. Filtration
affords the title compound as a yellow crystalline solid
(237 g, 73.6%) which is identified by NMR spectral
analysis.
EXAMPLE 37
Preparation of 2'-Chloro-2-methyl-2-carboethoxy
propiophenone
O
/ ~Cl CH3 CH3
+ Zinc +
C1 Br C02C2H5
O
COzC2H5
-~ /
C~ CHa
\ 3
Cl
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A mixture of 2-chlorobenzoyl chloride (52.2 g, 0.298
mol), ethyl 2-bromoisobutyrate (58.2 g, 0.298 mol) and
ether is added in portions to zinc foil (19.5 g, 0.298
mol) and the resultant mixture stirred at reflux for
three hours and overnight at room temperature. The
mixture is poured into cold, dilute sulfuric acid and the
organic layer is washed with saturated sodium bicarbonate
and brine, dried over anhydrous magnesium sulfate and
concentrated in vacuo to a yellow oil. The oil is
chromatographed on silica gel with hexanes:ethyl acetate
to afford the title compound as a colorless oil (41.8 g,
55.10) .
EXAMPLE 38
Preparation of 2'-Chloro-5'-vitro-2-methyl-2-
carboethox~rpropiophenone
O O
C02C2H5 H SO 02N / C02CzH5
2 4
CH3 CH3 + X03 ~ ~ ~ CH3 CH3
2o C1 C1
To concentrated sulfuric acid (15.0 ml) at 5 °C is
added 2'-chloro-2-methyl-2-carboethoxypropiophenone (4.00
g, 0.01570 mol) followed by dropwise addition of
concentrated nitric acid (900, 0.740 ml, 0.0204 mol).
After stirring 5 minutes, the mixture is poured onto ice
and extracted with ethyl acetate. The organic layers are
washed with saturated sodium bicarbonate and brine, dried
over anhydrous magnesium sulfate, filtered and
concentrated in vacuo to afford the title compound as a
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yellow oil (3.90 g, 83.0%) which is identified by NMR
spectral analysis.
EXAMPLE 39
Preparation of 1-Benzothiot~hen-2,3-dione
O / O
C1 + A1C13
\ C1
SH \ S O
To a solution of thiophenol (100 g, 0.907 mol) in
ether is added dropwise a solution of oxalyl chloride
(175 g, 1.38 mol) in ether. The mixture is stirred two
hours at reflux and concentrated in vacuo. The residue
is taken up in methylene chloride and cooled to 0 °C.
Aluminum chloride (145 g, 1.09 mol) is added in portions
such that the temperature does not exceed 25 °C. The
resultant mixture is stirred 30 minutes at reflux, cooled
to room temperature and poured into ice water with
stirring. The organic layer is washed with saturated
sodium bicarbonate, water and brine, dried over anhydrous
magnesium sulfate, filtered and concentrated in vacuo to
an orange solid which is recrystallized from methylene
chloride:hexanes to afford the title compound (102 g,
69.Oo) which is identified by NMR spectral analysis.
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EXAMPLE 40
Preparation of 1,2-Benzisothiazole-3-carboxamide
/ O / CONHZ
\ ~ -~ NH4OH -~- H2O2 .-
\)
s o s
To ammonium hydroxide (1.78 1) is added 1-
benzothiophen-2,3-dione (87.0 g, 0.530 mol) at 5-10 °C,
followed by hydrogen peroxide (30a aqueous, 178 ml). The
resultant mixture is filtered to obtain a yellow solid
which is dried (77.0 g, 81.70) and identified as the
title compound by NMR and IR spectral analysis.
EXAMPLE 41
Preparation of 3-Cyano-5-vitro-1,2-benzisothiazole
CONH
\ ~ IN
S
1) HNO3~HZsO4
2 ) POC13
02N / CN
\
s
A solution of 1,2-benzisothiazole-3-carboxamide
(12.0 g, 0.0674 mol) in concentrated sulfuric acid at 0-5
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°C is treated dropwise with nitric acid (900, 4.12 ml)
such that the temperature does not exceed 10 °C, stirred
one hour at 5 °C, and poured into ice water with vigorous
stirring. The resultant suspension is filtered to obtain
a solid. The solid is dried and recrystallized from
acetonitrile to afford a white solid (10.0 g) which is
treated with phosphorus oxychloride (60.0 ml). The
resultant mixture is stirred at 90-100 °C for 90 minutes,
cooled to room temperature, slowly poured into ice water
with stirring, and filtered to obtain a solid.
Recrystallization of the solid from methylene
chloride:hexanes gives the title compound as an orange
solid (8.00 g, 87.90, mp 168-170 °C) which is identified
by NMR and IR spectral analyses.
EX,P~MPLE 42
Preparation of 3-(6-Methoxy-m-tolyl)-6-amino-5-
nitro-1,2-benzisothiazole
CH
3
OZN
\ \ I -t- NH40H + S
F F
CH3 CH3
OZN / /
\ ~ IN OCH3
H2N Si
Ammonium hydroxide (330 ml) is added to a suspension
of 2',4'-difluoro-2-methoxy-5-methyl-5'-nitrobenzophenone
(60.0 g, 0.186 mol), sulfur (6.25 g, 0.195 mol) and N,N-
dimethylformamide on an ice bath. The resultant mixture
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is allowed to warm to 35 °C, heated gradually to 81 °C
over a two hour period, cooled to room temperature, and
poured into water. The resultant solid is taken up in
ethyl acetate and N,N-dimethylformamide, and washed with
water. The organic layer is concentrated in vacuo to
afford the title compound which is identified by NMR
spectral analysis.
EXAMPLE 43
Preparation of 3-(6-Methoxy-m-tolvl)-6-chloro-5-
nitro-1,2-benzisothiazole
3
\
02N / /
tert-butyl nitrite + CuCl2
\ N OCH3
H2N Si
CH3
--a 02N / /
\ ~ IN OCH3
C1 g
A mixture of tert-butyl nitrite (5.90 g, 0.0571
mol), copper chloride (6.20 g, 0.0457 mol) and
acetonitrile is heated to 65-75 °C, treated with 3-(6-
methoxy-m-tolyl)-6-amino-5-nitro-1,2-benzisothiazole
(12.0 g, 0.0381 mol) over 10 minutes, stirred for two
hours at 67-75 °C, treated with tert-butyl nitrite (1.50
ml) and copper chloride (1.00 g), stirred 40 minutes at
67-75°C, cooled to room temperature, and diluted with
ethyl acetate. The organic layer is washed with 100
hydrochloric acid and filtered. The filtrate is washed
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with water and concentrated in vacuo to afford the title
compound as a solid (10.6 g, 83.10) which is identified
by NMR and IR spectral analyses.
EXAMPLE 44
Preparation of 3-(6-Methoxy-m-tolyl)-6-fluoro-5-
nitro-1,2-benzisothiazole
OzN
C1
J
02N
+ KF + 18-crown-6
F~~S N OCH3
i
A mixture of 3-(6-methoxy-m-tolyl)-6-chloro-5-nitro-
1,2-benzisothiazole (7.30 g, 0.0218 mol), potassium
fluoride (6.33 g, 0.109 mol) 18-crown-6 (2.31 g, 0.0872
mol) and sulfolane is stirred 19 hours at 154°C, cooled to
room temperature, and poured into ice water. The
resultant solid is filtered and chromatographed on silica
gel with methylene chloride to afford a solid which is
recrystallized from acetonitrile to afford a tan powder.
The powder is recrystallized from ethyl acetate to give
the title compound as a tan solid (2.09 g, 29.90) which
is identified by NMR spectral analysis.
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EXAMPLE 45
Preparation of 5-Amino-4-bromo-6-fluoro-3-methyl-
1,2-benzisothiazole
CH3 O
HZN ~
\~ \ N=N
'r ~. N-Br .+,
S CN CN
F
O
Br
H2N / CH3
,N
F S
To a solution of 5-amino-6-fluoro-3-methyl-1,2-
benzisothiazole (0.600 g, 0.00329 mol) in 1,2-
dichloroethane is added N-bromosuccinimide (0.586 g,
0.00329 mol) followed by 1,1~-azobis(cyclohexanecarbo-
nitrile) (0.0200 g). The mixture is stirred two hours at
70 °C, additional N-bromosuccinimide (0.240 g, 0.00135
mol) is added, and the mixture is stirred 40 minutes at
70°C. The mixture is then cooled to room temperature,
filtered and concentrated in vacuo to obtain a residue.
The residue is chromatographed on silica gel to give the
title compound (0.870 g, 1000) which is identified by NMR
spectral analysis.
