Note: Descriptions are shown in the official language in which they were submitted.
WOg3/02036 P~T/~S9~0~901
~ 1 ~127
,
r :
:
. ~
:1 5
10~ ~:TITLE OF THE INY~IC~
NOVEL~PROCESS:EOR AROMATIC BROMINATION~ :
; RELAT~D~APPLIC8'~ION
The pre~ent patent application i B a
con~i~uation-in-part~of copendin~;~applic-ation Seri~al ~:
No.~730,364;,;fl1e~d~;July:15,~1991
:BA~K~ ND~:~F TH~INV~NTI~
N-Bromosu~ imide~ NBS) i~ a well:~ ~n:~ ~ khe~i~e
or i~ ea~ent~:w ich~is useful lD~;bro ination:~and/o:r:~ :
`oxid~atiQn o~:~a~w:ide:~a~ie~y:or~ganic moietie~:under a :
wide ~ariet~y~of reaction conditi s.~ ~:A~re~iew~ of~
chemietry~:is~f~ound~in:J~.S.~Pizey~ Syntheti~Reag:ents, : : ~
ol.~;2i~John~Wiley? New York,~ ~1974?: ~at pages 1-63. ::
hile~ ~S~bromination8~0f~aromatic moietie6~have~ been~
p~rfo~med in`polar ~nd:~:non-polar o~ganic ~ol~ent:æ~and
in~:aqueous: aci~dic solution,- there;have ~een no ~
rcpo~ts~of~NBS:brcm:inàtions utlilizing aqueou's alkali ;
'~,"'i ~
~, ",. ~
w093J02036 PCT~US92~05901
~ ~ 1 ~ 7
. 601utîons as the reaction medium. Utilization of
,5, such a basic medium has the advantage in that
i hydrogen bromid~e, generated in the reaction, is
scavenged by the sol~ent, thereby reducing the
po~sible side reactions associated with its pre~ence
in soluti~n. Multlple brominations are also not
~, obser~ed.
. Dibromodimethylhydantoin (DBDM~), while not
as widely employed as NBS, is a versatile organic
10 reagen~ (for a review see : Reed , R. A., .Chem. Prod .,
:~:; 23, 299 (1960)). It offers the advantage of being
more stable and less costly on a bromine equivalent
.. basi~ than NBS. Pre~ious disclosed bromination~ of
aromatic sub~tra~ed using DBDMH were run in refluxing
~CCl4 or ~C13. DBDM~ is al~o used as a pool
: ;;: disin~ectant. ~ : :
Remoxipri~de I ((S)-3-brQmo-N-t(l-ethyl-
2-pyrrolidi~yl)methyl3-2,6-dimethoxybenzamidej, ~h~
below, is:a k~own~an~ipsychotic agent (U.S. Pat. No.
20~ 4,232,037). Prep~aration of remoxipride typically
: involves a convergent synthe~i~ wherein a ~uitably
activated 3-bromo-2,6-dimetho~ybenzoic ~cid II is
coupled with the enantiomerically pure aminomethyl
:: pyr r oli d ine III .
~: ' - -
0
,
",~ :
~.,
.,: ~
; .,
;,~,.....
~,'
,G'~S~"
i ~ ~" ',
WO 93/02036 PCr/US92/0~01
~ 1 ~ 1 2 7
Z + H
C2
Br : OCH3
II III
1 0
~ ~ :
~ '
~ : , :
:20~ C2H5
Br: ~ OCH3 ~ ~ ~
Z = ~ClI VATI NG GROUP
,
,, ~
, . ~ :
:;:::~: :
.,
""i .
WO 93/0~036 PCl /VS92/0~901
~112127 4 ; ~
Preparation of Intermediate I~a the
precur~or of compound II typically in~olves
brominat~on of commereially a~railable
2, 6-dimethoxybenzoic acid employirlg bromine and
5 dioxane ~s sho~al be~ow.
CCOH COOH .;
~0 1 ~
~`,~ Dioxl~ne/13rorrin~
IVa ;; ;.
;.
''' -' ~`, ` ",
Although good yields of the Intexmediate IVa ;
are obtained ~rom the reaction, æeveral impuritie~
shown be:Low, resu1t f~om the further reac~1on os~ the /; ;
produ~t and bromia~e and/oF the hsrdrogen bromide ;;~
gerlerated in ~he reactio
: : ' ,, ~ ~, .
3 0
;
' ~
.
~': :
W0 93/02036 ~ 12 7 PCI/US~2tO~901
'
, .
,
', ' ,~
; COOH
.. S ~ ~ CH30~J~DH :
~r
COO~ : ~ COO}I
O ~ 3y~oc~ .~H3o~oH
r~Br ~ Br~i3r
The~ins~ant ~invention~ ~p~r~vide~ aD~ improved~
romin~ti~n ~p~:o~és~s~ :f~or ~he preparation of brominated
aromatic~compounds~which~result~in~quantitatively:
2Q ~ fewe$:~o~ t:he~i;mpurities::~that are aæsoclated uith~ ~ ~
pr:e~iou~s disclo~e~d:~bromination;proces~es. :~ :
:The:~ sta~t inyention a~sa~ pr~videg a novel
reaction:~co~dition`for~bromination~;of:aromatic ~ :
compou~ds~wi:th:;N-bromosuccini2lde or~
Z5 ~ dibrom~dimethylhyd~antoi~n~uherein the solvent iæ an ~ :
aqueous alk~li 801uti~n.
urther, the instant in~cntion to provides
an impro~ed pr~ces~ for the preparation of
3-bromo-Z~6-dime~hoxybenzoic:acid~ha~in~ higher
~3~0~ yields and fewer impurities than processes previo~sly
-~ ~ nown in~the ~rt.
;,"
,."
'~
:,, ~ :
;~
",, ~
"~
~ , ~,
sj~
,~..,
- W~93~02036 PCT/US92JOS90l
y~ .
I ~ r~ ~s s~ 7S
s DETAIL~D D~SCRIPTION OF T~E I~ IQN
The pre~ent in~ention provides a nove1
process for the preparation of a bromoaromatic '~
~5 compound, having the ~ormula ~V:
~-- R
R1 ~ R3
Elr J~R4
IV
~ :
::: :
,
lS wherein ; ~ ~
Rl,~RZ, R4, and~R5 are independently:selected from:
: (a)~hydrogen,~
b) Cl-C6-alky1,
2~0~ (c) C1-C6-a~1koxy,: ~;
(e) -~02E~
(f) -C02(Cl-C6-a1~y1)
N(Cl-C6-alkYl)2t
: - or Rl, R2, R3, R4~, or ~5 on adjacent r~lng carbons
may be combined to form a O-(C~2)n-0- ~esidue;
. .
provided that at least one of R1, ~2, R4, or R5 is
~ o -C0
:
,~ ,.,
R3 is C1-C6-a1koxy or -N~Cl-C6 a1kyl)2. or R2 and R3
: or ~3 and R4 are combined to form a -0-(C~2)n 0-
residue; and
:'~
~r7S,~
W093/02036 PCT/VS9~/05901
2 1 1 ~
7 --
n i~ l to 3;
.~ .
: which comprise~:
treating an aromatic compound o~ the formula V:
: R2
R3
1 0 ~KA\
~: :. ' V
wher:ein:the æubstituent Rl, R2, R3, R4, and R5:are
:15 ~ as:~-described her~ein above; ~ ~ :
in~;~an~aqueous:alka1i ~olution
w;ith~a~brominating~agent selected from~
20~ a) N-bromo8uccin:imide, and~
(b) l,3-dibromo-5,5-dimethylhyda~toin;
at a:t~empe~ature and for a length of time sùfficient
to:~ptimally con~er:t th~;compou~d~:o~formula Y to the
:2~5~ comp~ound 0f formula IV or a sa~t thereof; and
then optionally treating the reaction mi~ture with an
acid to ~orm theicompounid of formula IV. ~ I
~ :
:~ : ~ :
,, ~ ::
~' ~ '
, .:
',!i.,'.
W~93/02~36 PCT/US92/05901
? ~
. .~ .~. ;, ~ ~ I -- 8
The term "aqueous alkali solution~ includes
solution of an alkali base in an aqueou~ solvent and
the like.
. ,,~ .
;~ The term "alkali base" include6 strong
S alkali ba~es, which include sodium hydroxide1 lithium
hydroxide, potassium hyd~oxide and the like. A
.
;~ . preferred alkali:base is sodium hydroæide.
The term 'laqueous 801~ent" include~ wate~
and ~olutions of wa~er and a water miscible
co-solvent(s). The term ~water miscible co-sol~ent1'
includes low-molecular-weight alcohols, dimethoxy-
ethanej tetrahydrofuran and the like. A pre~erred
,
aqueous ~olvent is water.
The te~m "low-molecular-weight alcohol"
~:~includes~hydro~yalkane~compound~ having~from 1 to 4
carbon~atoms~and~:includes branched and ~traight hain
alcohols. The term includes~methanol,:ethanol,~
is~-propanol:~and~the like~
:The~term~"temperature , . .~ ufficieDt to
2~Q ;:~:opt;imally convert~the~eompound~:of~t~he~formula ~to a
:salt~of the compound of the~formula IV1' repre~ent~ a
temper~atùre ~ufficiently high~to main~ain con~er~ion
of~:the star~ing:material V but al~o ~ufficien~ly low
to avoid~-;decomposi~ion of`the ~tartin~ material and
:25 ::-~the~pr:~duct. The t~rm includes te:mper:atures between
0 ~ and 30~C. A preferred temperature ia between 23
and 29~C.
~ . : , : .
~ 30
, , ,
: ~ ~; ::
,
~,
~:
`- WO 93/02Q36 ~ PCr/US92/05901
The term ~length of time sufficient to
- optimally convert the compounds of the formula Y to a
-~salt of the eompound of the formula IV~' repre~ent~ a
period of ti~De ~uff iciently long to convert the
5 maximum amount of the ~tarting material to the salt
of the compound of the f ormula IV. The term includes
times of 1 to 40 hours. A preferred length of time
is a time length between 4 and 25 hour~s.
~` The term ~a salt of the compound of formula
10 ; IV~ includes the salt of a carboxylic:acid moie~y of
the product IV (if such a moiety~ :i8 p~re:æen~) which
corresponds::to ~he alkali base employed in ~he
a~ueous alkali solu~ion. The term includes the
odium salt, lithium salt, potassium sal~ and the
15 like~
The term ~acid~ includes anhydrous acids and
aqueous:acidic æolution~
- The term ~'lanhydrous acid" includes gaseous:
miner;al acids such:~as hydrogen;bromide, hydrogen~
20~ :chl:oride~and the like.
The term~"aque~us acidic solution~ inc;ludes~
solutions of a mineral acid or ~ulfuric acid in an
aqueous æolvent.: The term "minera~l acid:~ include~
: hydrogen:chloride,~hydrogen b~omide and the li~e. A
2s ~preferred aqueous acidic solution i~agueous
: : hydrobromic acid.
, ~ ~
:~
~ 3
,~
.,
W093/0203~ P~T/US92/~S901
1 ~ 7
-- 10 --
One embodiment of the process of the in~t~nt
invention is that process wherein the brominati~g
agent emplsyed is N-bromosuccinimide in an amount
selected frol~ a value in the range between 1.0 to 1.5
molar e~ui~alent~ with respect to ~tarting aromatic
compou~d V.
In a clas~:of this embodiment i~f the process
wherein the amount of the alkali base in the aqueous :
alkali ~olution employed is selected from a value in
the range~between 1.0 and 3.5 molar equivaIents with
. respect io ~tarting aromatic compound V.
In a ~ubcla~fs of this class of the instant
: invention i~ ~he process wherein the ratio of the
molar equivalent~amount o~ alkali base remaining
after any a:cid~:moiety present in the ~tarting
aromatic compound~V ha~ been neutralized to the molar
: equivalent of N-bromo~uccinimide utilized is~elected
from~a value in ~the range between 1.0 and 1.25.
In anot~er:clas~ of thi~ embodiment is the
2~ procef~s of the instant invention:wherein the acid
treate:d reaction mi~ture is cooled and~filtered:to
pr~ovide the compound of the formula rv.~
In another clas~ of thss embodimen~ i~ the
prccess o~ ;the ins:tant invention wherein the acid
treated reaction mi~ture is eætrac~2d with a suitable
organic sol~ent which after washing, drying and:
evaporating to dryrless provides the compound of the
crmula IV.
Another embodiment of the instant invention
3~ that process wherein the brominating agent
Jf: ~ employed ig dibromodimethylhydantoin in an amount
:l ~ gef~ected f~om a value in the range between 0.505 to
fi
:
f
i!
..,~
~,
' W093/~2036 PCT/US92/05901
-- 11
0.55 molar equivalents with respect to starting
~romatic compound ~.
In a class of this embodiment iæ the process
), wherein the amount o~ the alkali base in the aqueous
alkali ~olution employed is seleeted from a value in
the range between 1.01 and 1.1 molar equi~ale~ts with
respect to starting aromatic compound V.
In a ~ubclass of this class o~ the instant
~: invention is ~he process wherein the ratio of the
molar equi~alent amount of alkali base remaining
after any ~cid moiety present in the starting
aromatic compound V-ha~ been neutralized to ~he molar
:: equivalent of dibromodimethylhydsntoin utilized is
: selected frQm a ~alue:in the range between 0.1 and
lS : 1.25 : ~ ~
One embodiment of the instant invention is
;the:process for the preparation of~a~bromobenzoic
ac~id, having~the;f~rmula IVa:
~ :: : : CO2H
CH35 ~ CH3
^ : Br
: :
: : IVa
3~
::~ "
,
-
,,
, .,
: " ~,
~, '
'
Wos3/02036 PCTlUS~2tOS90~
2 Ll ~ ~ 27 12 -
which comprise~:
' treating a benzoic acid of the formula Va:
.. i.
: ;; .-i,
~ ~ CO~H
d3CO~ "OC}~
,
: 1 0
~a
in an aqueous alkaIi solution
~. ! "
WIT~N-bromosuccinimide at a tempera~ure and~ for~a
:leng~th of time sufficient to optimally conYert the
::c~mpound s~:formula Va to the compound of formula IVa :
: ::or ~a~; ~alt of the~compound of formula IVa; and
then optionally::treating the reaction~mixture ~ith an
acid,~
One cla~æ of this embodiment of the process
: o~:~he:instant invention is th~at process wherein the
: : amount ~of N-bromosuccinimide employed:is selerted
;25~ from a ~alue in the~range betweer~ l.O to l.~ moIar
equivalents with respect to starting
2,6-dimetho~ybenzoic acid.
In!a~subclass of this embodiment is the-~ ! "
process whereln the am~unt~of the al~ali base in ~he
~: : 30 squeous ~l~ali solutio~ employed is selected from a
Yalue in the range betw~en 2.0 and 2.5 molar
. equivalen~ with ~espec~ to starting
:,i 2~-dimetho~ybenzoic acid.
~, ,:,.,;,
,,,.,.,~
s ..- ~
"~1 :
' l
~,~
WO93Jo2036 PCT/US92/05901
2~ 127
- 13 -
; Exempli~ying thi~ subclass of this cla~s of
the instant inYention is the process wherein the
ratio of ~he molar equivalent amount of alkali base
remaining after the acid moiety of the
2,6-dimetho~ybenzoic acid has been neutralized to the
molar equi~alent of N-bromosuccinimide utilized is
selected from a value in the range between 1.0 and
. 1.25.
In another ~ubclass of this ~mbodiment i~
l~ the process of the instant invention wher~in the acid
: treated reaction mixture is cooled and filtered to
provide the compound o~ the formula IVa.
In another subcla~s of thi~ embodiment is
:: the process of the instant in~ention wherein the acid
treated reacti~n mi~ture i~ ex~racted with a ~uitable
organi:c ~olve~t which after wash:in~, drying and
evaporating to dryness provide~ the compvund of the
~ ~ ~formula ~Va. :
; 20
The following ~ynthetic Scheme 1 il~u~trate~
a reac~ion ~equence in which the proceæs of the
instant inv ntion~i~ employed. It is under~tood that
this scheme is meant to be illustrati~Je and i~ not
: limiting.
1: "
, . . .
,,,,,,,.,~
'~
. . -- .. .
,.
. ~
W093/02036 PCT/US92/0~901
21 1~v~27
- 14 _
SC:E~EM~3 1
,.
~2 bronL~ation ~2
R~ gone, R
~ : Li, or K R5
: ' 10
V IV
n words relative to the equations, the
aromatic~ compound of the formula Y iæ dissol~ed in an
aque~us alkali:~o1:ution containing a excess amount o~
e~uivalents of base,~uch ~s aqueous:NaO~ ~olution,
: aqueous ~0~ solution, methanolic aqueous NaO~ and the
like. The olution is then treated:with a ~uitable
brominating age~t:,~uch as ~-bromosuccinimide or~
1,3-dibromo-5,5-dimethyl- hydantoin, and the reaction
mixture is stirred~at room temperature ~or:a period
- of time,;such as 2-hours to 24 hours. ;~The react on
mixture ii~ then tested by a pota~ium iodide starch
paper test (SPT) tstarch iodide:tes~ paper that has
been wetted with agueous acetic acid; l/l; v/v)] a~d
if the test is positive, an oxidan~-neutralizi:~g
alt, such as ~od!ium sul~ite and the like, ls added.
;~ The reaction mixture is th~n treated with an acid or
an acidic aqueous solution and cooled in an ice
~;~:j bath. If the
: .
"~
.J
.
WO 93/02036 Pcr/us92~o~9o 1
127
- 15 -
product ~ormed is insoluble in the work~up Folution,
f iltration of the mixture provides the crude psoduct
~i IV which may be used as is in a subsequent reaction
-3 or further purified. If isolation by filtration i~
S not appropriate a standard organic sol~rent extracti~e
work-up roay be employed.
The following synthetic Scheme 2 illustra~es
a reaction sequence in which the process vf an
10 embodiment of the instant in~rention is employed. It
is understood that this scheme is meant to be
~; illustrative and is not limiting.
: ~ 15
.
: 2 0
,.
,
~: 2
' .
:~. 3D
~,1
' : ".
;~'
^:'
"
~''v'
,.,
,~,
,", ' ...
WO ~3/0~036 PCr/U592tO59~1
~12127 - 16-
S~ E 2
. .
.
S CO2H ' CO2M
CO 1 OCH3 H~CO~ 1 ,OCH3
aqueous
M- Na,
Va Li, or ~ /
1 ~ ~ / O
C02M ~ ~3r-N~
H ,CO~,OCH3
~ ~ ~ Br /~
CO2H
20 ~ K3C0~X~I3 ~ ::
Br J~J
: : : : : I Va :
:25
:' ~ :
, ,
: 3 0
.., :
~.
.
~ ::
,. . .
,~
,,1
W093/02036 PCT/US92/05901
~ Z127
- 17 -
In words relative to the equations,
`. 2,6-dimethoxybenzoic acid Va is dissolved in an
aqueous alkali solution containing an e~ce~s amo~nt
of equi~alents of ba~e, ~ch as aqueous NaO~
solution9 aqueous ~O~ solution and the like, to
provide a alkaline solution of the salt VI. The
solutio~ is then treated with N-bromosucci~imide
~j (NBS~ and the reaction mixture is stirred at ~oom
temperature for a period of time, such as 2 hours to
24 hours. ~The ~eaction mixture is then tested by a
potassium:iodide starch paper test (SPT) tstarch
lodide te~t paper that has been wetted with aqueous
: acetic acid; 1/1; ~Jv)} and if the test i~ positive,
n oxi~dant- neutralizing salt, ~uch as sodium sulfite
and the:like, i~ added. The reactio~:mixture i~ then
treated;with an acid or`an acidic aqueou~ EolUt ion ~
and:co;oled~in an ice bath. Filtration:of the miæture
provides the crud~ product IVa which may be used as
:: is:~in a~ubsequent reaction or further purified.
; X~20 ~ The:following ~ynthetic Scheme 3 illustrates
a~reaction ~equence~i~ which the~proce~ of the:
: instant in~ention is employed in the synthe~is o~
, ~
remo~iprid~e. It is understood that this ~cheme:i~
: meallt to be illu~tr~tive and is not limiting
~ ,
'~:' :~
:
"
'~'
,,,,,5,
:~
:i
WO 93/02036 P~/USg2l05901
..
` - 18-
H~ C2~35~
O H
~i L-l?rc-llru- VIIl
~; ' : ,
l G ~ H
X : IX
. :
: V~I C2
3 C ~ ONH
r C CE~ C2~
E~DXI PRI DE CRUDE
:
~ ;
',~,' ,
,. . .
w~93/02036 PcT/vss2/os9ol
~ r 1 I~J 1 2 7
- 19 -
In words rela~ive to the equations, the
aminomethylpyrrolidine component VII of remo~ipride
, is prepared from enantiomerically pure L-proline
i YIII. To this end L proline is esterified and the
ester treated with ammonia in a ~ui~able ~olvent,
such as methanol 9 ethanol and the li~e, to pro~ide
the amide I~. The amide i~ ring N-ethylated by
treati~g it with an aklylating agen~ such as ethyl
bromide and the like, in the pre~ence of a ba~e, 6uch
lo as potassium carbo~ate, sodium carbonate, and the
like, in a suitable solvent such as ethanol. The
amide ~ i~ subsequently reduced with a suitable
reducing agent, æuch as lithium alumi~um hydride and
the like, to provide compound ~
The bromodimethoxybenzoic acid IYa, prepar~d
a~ descr~bed in Scheme:2, is treated with an
~ ~ .
.ac~ivating re:agentj ~uch as thionyl chl~ride,
~: : carbo~yl~diimida~ole a~d ~he like, to~provide an
activated acid wh;ich i~ reacted, without i~olation,
with compound:~II, to provide ~rude remoxipride I.
The in~ention is furthe~r defined by
:reference to the following Example~ 1 through 4,
which are meant~to be illustrative and not limiting.
Example 1, Method:F, is provided as repre~entative of
previouæly known:preparation~ of the intermediate
IVa, and is included for comparl~on with the proces~
~:- of the embodiment:of the instant invention. All
t~emperatures are in degreés Celsius. Ail purity
-~. : percentages of the crude product are we:ight
:~ 3b perçentages a~d were determined by HPLC (YMC AQ-301
column (S-5 12~A ODS) rever~e phase; mobile pha~e:
s8% o 07M p~ 1.8 phosphate buffer, 487O C~3CN; 225 nm
~ '1
.:J
.. ..
,,," - ., -, .,, ", - ., .,, ", ., , ,, - , ,, . ,, . ~ ,
` W093/0~036 PCT/US92tO5901
21~ 21~7 2~ -
. detection) and yield~ of the desired product are
i given based o~ pure mono-brominated product. All
impurity percentages disclosed were determined by
~PLC and are area percentage6 relative to the desired
r
product.
i
.. ~ ~
, ~ :
Prep~ra~isn of 3- Br~mo 2.6-dimethoxvbenzoi~ Acid
: Method A:: Preparation Usi~g N-Bromosuccinimide and
A~ueQus Sodium ~ydroxide ~t 2 hourg 10 mi~ u~icn
; A 500 mL~round-bottomed 4-neckét:24/40 ST:
S react~io~ ves~el, ~i~téd with a mechanical ~tirrer and
di:gitâl~ thermometer:,~was charged with~8:.0 grams of
powde:re:d 2,6-dimetho ~ benzoic acid ;(DMBA)
(Aldrich-99%, 43.473 mmol), 50 mL of:deionized water
nd 18.25~mL~(2.1 equiv.) of aqueous 5N NaOH ~oln.
20: ~ The~mi~ure ~as stirred, di~solving the~acid and: t~ne
:temperature ~ose t:o 30C. The:s~olution~wa~:cooled to
C with ~n ice water bath and mai~tained at that
temperature~. Then 8.20 grams~of powdered ~ :
N-~romosuccinimidc (Aldrich ~7P)~ was added with
: brisk ~irring to:the old ~olution. The reac~ion
~: temperature rose to 8C o~er two minutes then cooled
back to 4C over an add;tional 4 m~inutes. The
cooling b th was removed and the reaction was allowed
to warm to room temperature reaichin~ 21C a~ter 0.5
hr. and Z6C after about one hour. The temperature
ro~e to 27 to 28~C ~or the remaining reaction time.
The total time since NBS additio~ was 2 hr. 10 min.
. . i
,~.i
:,~"
: , ,,
W093J02036 f~ 7 PCT/USg2/o~gol
- 21 -
. The reaction at this point ga~e a po~i~ive
potassium iodide ~tarch paper test (SPT). The
reaction wa~ then ~reated with 0.5 gm Na2SO3 which
~=. ' resulted in a negative SPT. The reaction was diluted
with 50 mL vf water and was treated, in portion~,
with 12 mL concentrated aqueous EBr (2.43 equi~.)
causing precipitation of the product. The mi~ure
was cooled ~o ice bath temperature and filtered off
(fritted glass funnel, M porosity). The solid was
;; 10 slurried and washed in portions with 125 mL of ice
cold pure water:(the pE at the end of the filtration
ro~e to 3C. The precipitate was suction dried under
-: a nitrogen stre~m and then dried overnight under high
acuum~at 75C. ~The product wei~hed-9~95 gm. which
lS by ~PLC analysi~ contained 1.1 wt.% of unreacted
~: .
tarting material/1;.4% yield and 97.9 wt.% of the
desi:red~monobrominated product/85.8% yîeld: and:no
: dete~ctable water:by Karl Fischer: ~ ) titration.
~ Method~B: Preparation Using N-Bromosuccinimide and
Aqueous Sodium Hy~dro~ide at 4 hour 20 min.
: Durati~n
A 5 liter round bottomed 4 neck 24/40 ST.
reaction ves~el, fi$ted with a mechanical stirrer and
digital thermometer,:was charged with 104 grams of
po~dered 2,6-d:imethoxybenzoic acid CAldrich 9~%),
~: (565 mmol) 255 mL of 5N aqueous NaO~, (1275 mmol,
: 2.256 equiY.~)':and 650- mL of water. Thë mixture was
irred to d~i~solve the DMBA then cooled to 0C with
~ 3~ an ice/MeO~ bath. To the reaction mixture was added
; ~ : : powdered N-bromosuccinimide (Aldrich 99%) ~121.9
grams, 1.2 equi~.) in portions: ninety grams of NBS
-
: ~
WG93/02036 PCT/US92/05901
L h~; - 22 -
was add~d over two minutes and the reaction
temperature rose to 5C then another 31.9 grams was
added. The reaction mixture was cooled to 2C then
the cooling bath was remo~ed allowing the reaction
temperature to rise to room temperature. After 4 hr.
and 20 min. the reaction ga~e a positive SPT. The
reaction mixture was treated with 8 grams of sodium
sulfite which resulted i~ a negative SPT. The
insolubles were fil~ered from the reaction mixture
and the filtrate returned to the reaction vessel. An
additional 65Q mL of water was added to the
filtrate. Concentrated 48% aqueous hydrobromic acid
(167.`57 mL, 2.6 equi~ was added to the reaction
mixture~oYer 1 min. whieh caused the product to
precipitate . The ~;:thick reaction mix~ure wa~ diluted
with~ SOO~; mL of~ water and cooled to 0-5C, then
ered~through a 3 liter filter funnel with a (M)
porosity~f:rittèd di~k. The solid~ was washed with an:
additional 1150 mL of water in portions. The 15ast
filtrates~gave a weak positive test fo~ bromides.
The solid~ was suction dried under nitrogen then under
hi~h Yacuum at 60:~C overnight:to provide 140.8 grams
of the désired p~oduct (92.7% yield; 97.1% w~.% pure
containing 0.29 wt.% of unreac~ed starting material
and no detectable water by RF titratio~).
Method C: Preparation Using N-Bromosuccinimide and
Aqueo1us Sodium ~Iydroxide at 21 hour 34 min.
Vw~ation
~ n
: JV A 5 liter round-bottomed 4-necked 24/40 ST.
~'' reaction ~es~el, fitted with a mechanical stirrer and
~digital thermometer. was charged with 104 grams of
~/~
: WOs3/02036 PcT/~ss2/ossol 1
2~ .127
- 23 -
.~ .
, powdered ~,6-dimethoxybenzoic acid (Aldrich 99%,
565.1 mmol), 255 mL of 5N aqueous NaOE (1275 mmol,
:~ 2.256 equi~.) and 650 mL of water. The mixture was
stirred to diæsolve the DMBA then cooled ~o 1C. To
. 5 the reaction mixture was added powdered
s, N-~romosuccinimide (121.93 grams, Aldrich 99%, 1.2
equiv~ in por~ions: about 90 grams was added o~er
three minute~ and the reaction temperature rose to
8OC. The reaction temperature then decreased to 6C
and the remaining NBS was added. The temperature
rose again to 8C and then the reaction mixture
cooled down to 3C and the ice/water cooling bath was
removed. The temperature of the reaction mixture wa~
allowed ~to ri~e t~room temperature. ~:ter 21 hr. 34
15 min. the reaction ~mixture gaYe a weakly positi~e
: : SPT. The:: reaction mixture~ is treated with 2 . 0 gram~
of ~odium~:sulfite which resulted in a negative SPT.
The reac~ion mixtu~e was filtered:to remove a ~.mall
amount:of~ insoluble matter. The fi~tered reaction
20 mixture was returned to a clean 5 litz r reac~ion
essel and diluted~with 650 m~ of water. To the
stirred reaction mixture:was ad:ded 167.57 mL o~
: concentrated 48% aqueous HBr o~er three minutes. :A
; :copious precipitate formed. The miture was ~tirred
~ 25 and cooled to 3C and the solids were filtered off
;~ ~ through a 3 L (M) porosity ~u~nel with ~ fritted
disk. The sQlid wa~ washed with 1352 mL of i!ce cold
~ water in portions then dried with suction under
:~ ~ - nitrogen and then overnight at 60C under high
: ~ 3a ~acuum. The isol~ted product weight was 142.9 grams
t 94.82% yield/97.91 wt.% pure which when eorrected for
~ sa~ple u~ed in ~PLC reaction monitoring calculates to
: '
.j',9,
W~93/02036 PCT/US92/~901
2 1 1 ~ 7 24 -
;; 143.7 grams/95:.4% yield. The product contained
. residual ~tarting material of 0.14 HPLC area % and no
.; detectable water by KF titration. The following
~~ impurities were detec~ed by ~PLC i~ the crude
s 5 product: succi~imide: 0.573 area X; 3,5-dibromo
2,6-dimethoxybenzoic acid: 0.146 area ~/O; and
.. 315-dibromo 2-hydroxy-6-methoxybenzoic ~cid: 0.OlZ
. ~ - area %.
.' ~ .
~ethod D: Pxeparation U~ing N-Bromoæuccinimide and
Aq~ous P~tassium ydro~ide _ :
- A 500 mL round-bottomed 4-~ecked 24/40 ST.
reaction ve~sel, fitted with a mechanical ~tirrer and
digit~l thermomet~r~, was charged:wi~h 8.0 grams of
: powdered~2,6-dimetho~ybenzoic acid (Aldrich ~9%,
; 43~t473 mmol)~, 7.02~gm. potas:sium:hydroxide (86.8%
pure , 2 . 5 ~ equiY ., ~108.68 mmol) and 4S mL of water.
:The reaction mi~ture wa~ ~tirred and heated to 50C
to~olubulize the mi~ture. The mixture~was cooled to
~1C~ and~9.~38 gram~of powdered N-bro~osuccinimide,
(99% pure,:~l.2 equi~.) was added to the reaction
ixture. The:~tempsrature of the reaction mixture:
ro~e to 10C:and then the cooling bath wa~ remo~ed.
The r~ac~ion was warmed to room temperature and was
5~ ~stirred for a total of 27 hours. The r~eaction at
this point gave a wPakly positi~e SPT. ;The reaction
mixture was treated with 1 gm of æodium sulfite which
resulted in the reaction mixture giving a negative
- SPT. The reaction mixture was cooled to 0 - 1C and
3~ wa~ acidified with 15.95 mL of concentrated
~`~ hydrobromic acid ~add~d in portions o~er 1 min.).
The copious p~ecipitatcd reaction mixture wa~
: '
, ~ ,
~ ':
, ~
WO 93/~2036 PCI/lJS92/0!;901 ~ ;~
21-~127
.,, .; "
- 25 - ;~
'.'.'` ''."
f iltered cold through a f ritted glass suction
funnel. The filtrate~was used to aid in the
transfer, th~en the precipitate ~as washed with 125 mL ; .-:
: of ice cold lN aqueous ~Br in portions, then ~uction
S dried under ~itrogen. The precipitate was dried
overnight a~ 60-C. The product weighed 10~5 gm whsch ;:~:
by ~PLC analysis contain~d 1. 9 wt .% o~ unreact~d . :
starti~g material/2.:6% yield and 90.1 wt.~/. of the
desired product (83.3% yd.~ and no detectable water
:~10~ by~KF~titration.
Method E: Preparati:on:Using Dibromodimethylhydantoin ~:~
Z,6-Dimethoxybsnzoic acid (99.:0;g~, 538
15~ mmols) is~stirred~with 500 mL of water at r:oom : ~;
temperature, followed~by the addition:of~5N~aqueous~
NaOH~ llO:~;mL, 550~mo~1). The~resulting orange : :~
:solution i:s cooled;t~::20C by:a cold wate;r bath and
DBDM~(80.2 g,~272.~1~mmols) is~ a~dded in:~portion~:over ~
2~0~ 5 min.~while mainta`in:ing the::in~ernal temperature~at :: I :
<25~C~ :Thé mixture uas:~allowed to~st:ir~at~20-~5C~
for 4.`~5~hours and worked up~as describe:d:~i:n~Method A
he~r:einabove. :The~:G~rude~product was recrystallized~
rom~aqueous ethanol:to p~ovide 122.6 g of the ~ -:
5~de~sired~product. ~:Analytical eva:luatîon of the~
product and the mother liquoræ from the :
re~c~ystalli~atlon:i~dicated;a 9fO.0%:assay yi~1d of , ;:~
the 3-bromo-2,6-dimethoxybenzoic acid and a 2.1% ~
: assay yield~of 3,5-d:ibromo-2,6-dimethoxybenzoi;c acid.
30 :
:
,
~: :,.................................................................. . .
:, , ,
`:
~, ~ ' .'.'`
. . ,
'`
,,
wos3/o2o36 PCT~US92/OS~01 ~ ~
2 ~ 1 1 2 7
- 26 - ~
' `' " '
~=~_ '''' '
(Illustrati~e of Prior Process)
A 2 liter round-bottomed flask wa~ charged
with 72 gram'~. of 2,6-dimetho~ybenzoic acid (99%, ~:~
391.2 mmol) and 237 gxams of dio~ane. The solution
was cooled to 15 and bromine (62.11 grams, 99.~%, 1
eguiv.) w s added dropwise over 2 hours while the
temperature was maintained at 17 ts 19C. The ~;reacti~n mixture was stirred at 20C for 2 hour~
lo ~hen 50 mL of water~ was added dropwi~e over ~0 mins.
to the mixture. The mixture was then cooled to 15C
and an additional 834 mL of water was a;dded dropwlse
over a 2 hour period. The reaction mixture was aged
at 15C for 3 houis~and~the;solid whi~h ~ormed wa~
5 ~ collected by filtration and washed with 60~mL of
water. ~The solid~was dr~ied under high~ Yacuum at 70C
for 12 hour~ tQ prQYide 87.9 g 0~ the crude desired
product (93.0% pure~,~ 79% yield). The following -;~
impur~ities were detected by ~PLC in the crude
~reaction product: 3,5-dibromo-2,6-dimethoxybenz~ic
acid: 0.385~area~%;~3,5-dibromo-2-hydroxy- ;
- ~ 6-methoxybenzoic acid: 4.05 area %;~and ~ ;~
3-broms-2-hyd~oxy-6-methoxy benzoic~acid: 2.91 area~%.
25~ ~ ~ XAMPLE 2
Svnthesis o~ 2-BrQm,o-3~4.5-trim~thoxy~nzoi~ Acid
U~ing the procedure described herein above -`
~ in E~ample 17 Method E, 3~4,5-trimet~oxybenzoic acid
;~ 3~ was broml~ated with DBDMH to provide the following ; `~
,..
xe~ul~ (a~say yields) after reac~ing ~or 25 hours at `. ~
" . ,
~Z~" C: ~ ~
: ~ .
,:~
.:
~ ' ~
; ~:
W093/02036 pcT/us~2/o~snl
- 21~ ?127 : ~;
- 27 -
2-bromo-3,4,5-trimethoxybenzoic acid: 91.1Z;
3,4~5-trimethoxybenzoic acid: 3.7%;
2,6-dibromo-3,4,5-trimethoxybenzoic acid: 2.0%.
~Q~
Synthesis of ~ Q~Q=~ dimç~ho~y~nzoic Acid
: ~sing the procedure described herein above
in Example 1, Method ~, 2,3-dimethoxybenzoic acid was ::
brominated with DBDM~ t:o provide the following
results (assay yield~) af~er reacting for 22 hvurs at. ~.
20-25C:
6~bromo-2,3-dimethoxybenzoic acid: 90.3%; .
2,3-dimethoxybenzoic acid: 7.7%;
15~ ~ 5-bromo-2,3-dimethoxybenzoic acid: 2.5%.
AMPLE 4 ~
yI~he~ f ~-BromQpiperonYlic ~cid : ~;
20 ~ sing the~procedure descrlbed:her~ein abo~e ~-
in Example l$ Method E, plperonylic acid wa6
brominatcd with DBDME to provide the ~ollowing
r:esult~ ~a~say yields) af~er reacting for 22 hou~s at
~::: : 20-2~C~
2-bromopiperonylic acid: 86.0%;
,
pipero~yIic ~cid: 7.7%. :~
EXAMPLE 5
~5~ is of 5--Bromo-2-methoxYbenzoic :Acid
. ..~::
: Method A: ~Æ~-ination with ~-Br~mosuc~inimide and ~
: ~ '' '~;
.
W093/02036 PCT/US92/05901
2112127~ - 28 - ~
,
o-Anis~c acid (4.56g, 30 mmols) was charged :~
~ ~ in a 250 mL flask and a æolution:of 2.64g (66 mmol~
j of NaO~ i~ 47 mL of water was added. The anisic acid :~
~as dissolved wi~h stirring and the ~olution then
`- 5 cooled ~o 0 to 5C with an ice/methanol bath. ~BS
(6.41g, 36 mmol) was added in portions~tc the
reac~ion fla~k and after the addition was complete
the reactio~was allowed to warm to room
~: :temperature. The: reaction was stirred at room :~;
lo ~ tempesature for 48 hours and was monitoréd ky : ~-
: analytical LC during this time. At the end of the 48
: : hou~s another 002: equiY~ (5 mmol) of NBS was addedjto :~
the r~eaction:~mi~~ure~ and the reaction mi:~ture was
sti:rréd:at room temperature for an additional 7
5:~ hour:s.~ Workup~as~ describe~d i:n Example:l, Method A, : -.
p~rovid;ed~:7.34g~of~a~:solid (~98.5%~pure by:HPLC, 1~.5%
; of~ :Bolid: is~unr~a~ted~EtartiIlg material;; 93% yield.3
The~f~iltr~ate;~f~rom~the solid contains anot:her 2% yield
of brominated~product~
Method B: rominat:ion with Dibrom~dimethvlh~dantoin
nd::NaQ~
Using~th~e~procedure described her;ein~above:
: in Example l,~Met~od E, o-anisic a~i~ was bromina~ed
25~ with DB ~ ~o provide the following resultæ (a~say~
yields) af~er~:reacting for 18 hours at 20-25~C:
5-~romo-2-metho~ benzoic ac,i,d: 98%. j .
he isolated prc~duct contains 0 . 3 wt% of
unreacted product,
:; ~
,,~ :~ :
",, :
. :
:~' :: : ~ :
:
~ :~
