Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~$~7Çi~
- Cas~ 600-G739
IMPROVE~IEI~T~ I~ QR RE:LATI~G TO ORG~NIC CO~5PO~NI~S
_
This invention provides a process for the
production of compounds of formula I,
~ CH
R3 ~ ~H
~4
in vhi.ch Rl and R2, whi.ch may be the same or dif~
ferent, each signifies alkyl or 1 to 3
carbon atoms t the total nunl~er of car-
bon atoms in Rl and R2 not exceeding
~, ho~7ever,
either R3 and R4 are the same or different and
each si.gnifies hydrogen, fluorine, chor
ine, straight chain alkyl or alkoxy of
1 to 4 carbon atoms, or trifluoromethyl,
provided that R~ is in position 5- or 6- f
-and that no more than one of R3 and R4
is tri~1.uoro~ethyl,
or R3 and R~ together signify alkylene
~ dioxy of 1 or 2 car~on atoms,
; ~If~j`~
7~
6~0-6739
and X is -CN, COOR, in ~Jhich R is hydrogen
or alkyl of 1 to 5 carbon atoms, or
o
-C ~ Y1, in which
Y and Yl, which may be the same or
different each signifies hydrogen,
5 . fluorine, chlorine, straight chain
alkyl or alkoxy o 1 to 4 carbon
atoms, or trifluoromethyl, provided
that no more than one of Y and Yl is
. trifluoromethyl,
comprising reacting together, in liquid medium, a com-
pound of formula II,
3 ~ NH2 II
R4 X
in which R3, R~ and X are as defined above,
a compound of formula III,
Rl
: C=O III
R /
: 2
~ in which Rl and ~2 are as deiined above,
605-673g
~7~
borohydride, and an acid, or the reaction product of a
borohydride and an acid.
Suitable boroh~drides for use in the process of
the invention include conventional reducin~ borohydrides,
in particular alkali metal borohydrides in which the alkali
metal is the only metal present, moxe particularly alkali
metal borotetrahydrides~ such as lithiwn borohydride, potas-
sium ~orohydride or, preferably, sodium borohydride. Other
alkali metal reducing borohydrides which may be employed
include sodium cyanoborohydride.
The borohydride is preerably employed in
finely divided form. Preferably, it has a particle size
which passes through a Tyler Standard Screen No. 20,
more preferably No. 60. More preEerably still, the boro-
hydride is in powdered form.
A wide ~ariety of acids may be employed inthe process of the invention and, naturally, the pre-
erred reaction conditions will depend to some extent at
least on the nature of the acid employed as well as an
other actors such as the nature of the starting materials
and the borohydride employed. The invention will, how-
ever~ now be described with reference to three generally
preferred em~odiments.
.
.
,; . ,
~7~4~ 600-673~
In the first embodiment ~embodiment a)], th~
acld employed is a strong acid, in particular an acid having
a pH no higher than 2, pre~erably O.S to 1.5, more prefer-
ably about 1, in a 10~ aqueous solution. Suitable such
acids include mineral acids, such as sulphuric acid,
hydrochloric acid, hydrobromic acid, phosphoric acid and
nitric acid,and organic derivatives of mlneral acids,
e.g. methane-, ethane- or ~-toluenesulphonic acid. While
certain carboxylic acids, e.g. trifluoroacetic acid also
fall within this definition and may be employed, they are
not preferred in this embodiment since they may lead to
undesirable by-products. Par~icularly less preferred
in this respect are carboxylic acids having a plurality of
` ~ carboxylic groups, e.`g. oxalic acid. Picric acid may
also be used but is not preferred. The preferred acid
for use in this embodlment is sulphuric acid.
- In this embodiment, the process is suitably
effected at a temperature of from 0 to 35Cr preferably
10 to 30C, more preferably 15 to 28C.
As indicatedt the reac~ion is effected in
liquid medium, e~g. in solution. The reaction medium
is preferably provided, at least in paxtl by employing
4 ~
- . ~ , ' '-
'
~A~J,',~3f..
evOO-~739
~ ~97~
the compound of formula III in excess, in particular at
least 20~ excess, in relation to the compound of formula
II. More particularly, the mol ratio of the compound of
formula III to the compound of formula II is desirably,
at least 3:1, preferably at least 4:1, more preferably
at least 8:1. For practical purposes, the upper limit
is about 70:1 and the most preferred ranges are 15:1 to
50:1, in particular 20:1 to 45:1.
The reaction mlxture should also desirably
contain at least a small quantity of water, sufficient to
initiate the reaction. Excessi-~e quantities of water,
may,.however, slow or halt altogether the reaction.
Preferably, the ~Jater is provided by employing the
strony acid in àqueous solution, pre~erably having a
concentration of from 10 to 90%, more preferably 15 to
70~, more preferably 25 to 60% by weight~
The reaction mixture may also contain additional
inertl organic solvents, in particular polar solvents
inc~uding ethers, such as dioxane and tetrahydrofuran,
and alcohols corresponding to the compound of formula
III, e.g. isopropanol.
It is preferred that the acid be employed in
a molæ ratio not greater than 12:1 in relation to the
compound of formula IIy preferably not greatex than 5:1,
~5 more preferably not greater tha~ 4:1. Most preferably,
the acid, partlcularly when it. is sulphuric aci~ is used
. ' ...
'; - ' ' , ' :
6~0-~73g
- : -
in a molar ratio of 1:1 to 3:1, in particular 1.15:1 to
. 2:1 based on the compound of formula II.
It will, however, be appreciated that the con-
stitution of the reaction mixture, in particular the con-
tent of compound III, water, acid and other organic
solvents may be varied subject to the preferred require-
ments that the compound II be substantially in solution
with other liquid components of the reaction system and
: that the composition is such that the reaction is substan-
tially initiated.
It is also desirable that the acid be
employed in at least a slight molar equivalent excess
in relation to the borohydride. Thus, the acid may react
~7ith the borohydride to form a product which also partici
i 15 pates in the reduction to obtain the desired product,
~ach acid hydrogen, i.e. hydrogen ion,in the acid
- . reacting with l mole of borohydride~ The excess of acid
employed is desirably such that the pH of the reaction
mlxture ~s maintained at no higher than 2 t preferably
: 2D 0.5 to 1.5, more preferably about 1Ø TG this end,
an excess, on the basis of hydrogen ions in the acid to
; moles of borohydride (i.e. molax equivalent excess) of
; from 1.0 to 50%, preferably 1~5 to 25% of the acid is
~uitably employed.
.
~7~
600-6739
Subject to this, the molar ratio o~ boro-
hydride to the compound II is suitably at least 1.7:1
(pre~erably no higher than 8:1), preferably from 2:1 to
6:1, more preferably ~rom 2:1 to 4:1 and desirably 2:1
~o 3:1.
In this embodiment, it is preferred to estab-
lish a solution by mixing the compounds II and III, in
appropriate proportions and an aqueous solution of the
strong acid. The borohydride is then suitably added at a
rate desired for control of the reaction. Alternatively,
although less preerred, the acid and borohydxide may
be added alternately in small quantitites, provided that
the amount of acid present in the systems at any one time
exGeeds the quantity of borohydride on a molar equivalent
basis. The reactants may also be added at a temperature
below the reaction temperature, and the temperatuxe then
raise~ to initiate the reaction. The reaction time may,
for example, vary from 20 minutes to 10 hours~ more usually
30 ~inutes to 4 hours.
The resulting reaction product may contain some
compound I in non-free base form, e.g. acid addition sait
form~ Such forms may be converted into the free base form
in conventional manner, e.g. by treatment with a strong
base, e.g. sodium hydroxide~ or an annydrous tertiary amine.
- 7 -
.
~,A~'ADh
~7$~ 600-6739
In a second embodiment [embodiment b)3, the
acid employed may be a saturated aliphatic carboxylic
acid of 2 to 4 carbon atoms containing the only carbon
and hydro~en in addition to at least 1 carboxylic acid
group, ancl having a pH of from 3.0 to 5.0, preferably
3.5 to 5.0, more preferably 4.0 to 4.6, in 98% by weight
aqueous solution. Suitable such acids include mono-
carboxylic acids, such as aceti~ and propionic acids,
preferably acetic acid.
In this embodiment, the process is suitably
effected at a temperature of from 10 to 35C, prefer-
ably 15 to 30C, more preferably 15 to 28C.
~ n this embodiment, the molar ratio of the
borohydride to the compound II is desirably from 1.7:~
to 4:1, preferably 2:1 to 3:2:1, more preferably 2:1 to
2O8:1, Again, an exeess of the acid in relation to the
horohydxide is desixably employed. In this embodiment,
however, the acid desixably also serves as a co-solvent
~uch that substantial quantitltes are conveniently
employed. In particular, the molar ratio of the acid to
the c~mpound II is at least 6:1, suitably from 6 :1 to
50:1, preferably 8:1 to 30:1, more preferably 10:1 to
20~1,
-
'
-
,
I.~hN~
~7~ 6U0-6739
~he process is desirably effected in a solu-
tion of co-solvents comprising the indicated excess of
carboxylic acid and an excess of the compound III.
Thus, the molar ratio o~ the compound III to the com-
pound II is suitably, at least 3:1, preferably at least
4:1, more preferably at least 6:1, the upper practical
l~d!mit being about 50:1. Most preferably, the molar ratio
is from 8:1 to 30:1, in particular 10:1 to 20:1.
Other inert organic solvents~ for example
those indicated above in connection with embodi-
ment a) may also be included in the reaction mixture.
The carboxylic acid employed w~ll also normally con-
tain small amounts of water, and these can be tolerated.
Desirably, however, ~Jater should be present in amounts
not exceeding 8%, in particular no more than 5~, by
; - ~7eight based on the carboxylic acid. Conveniently,
: the reaction is effected in a so1ution containin~ 0 1
to 2.5g by weight of water based on the carboxylic acid.
:
Tn general, the process is, in this embodi-
; 20 ment, suitably effected by adding the borohydxide to
a solution of the other reactants. The reaction is
xothermic so that the ~ate of addition should be con-
.
trolled such that the reaction temperature does not
, :
increase undesirably. Preferably, the additions are
,. . .
. ~ .
9 _
., :
,, ~ .
.
~7~ oo 6l3~
ef~ected at a temperature of at least 10C, preferably
at least 15C. Preferably, the rate of addition is
controlled such that the temperature o~ the resultin~
mixture does not exceed 35C, preferably 30C and
more preferably 25C, and that the temperature increase
following each addition is not more than 10C, preferably
5C, more preferably 2C. Suitably each addition spans
at least 30 minutes, preferably at least 50 minutes and
the number and size of the portions can be determined
from the desired temperature increases. The total
reaction time may, for example~ vary from 40 minutes to
10 hours, more usually 1 to 4 hours.
In a third, and most preferred, embodiment of
- the invention ~emhodiment c~,the acid employed is a
so~called "ri.gid, co--planar carboxy and/or sulpho
dibasic organic acid". By this is meant, dibasic organic
acids in which the acid groups are carboxylic (-CO0~
and/or sulphonic ~SO3H) acid groups and are geometric-
ally fixed i.n coplanar relationship, i.e. are in the same
geometric plane. Such acids can be divided into three
main classes, namely:-
1) acyclic,unsaturated dibasic acids, having a carbon
to carbon double bond~ the carbon atoms of which
.
'' .
~ 10. ~;, .
. ' ' , . .
~ ~ ,~, ' ' , ' " .
, ~ ,
- .
~7~
600-6739
each bear one o the acid functions, and the com-
pounds bein~ in cis-isomerie form, for example
maleic acid;
2) cyclic unsaturated dibasie acids, having ring
carbon to carbon bond unsaturation and in which
two ring carbon atoms having earhon to carbon bond
unsataration each bear one of the acid functions
; and are either
a) adjaeent to eaeh other, e.g. o-phthalic acid,
1,2-benzenedisulphonic acid, 2-carboxybenzene-
: sulphonic acid, o-dicarboxynaphthalenes, e.g
2,3-diearboY~ynaphthalene, or o-disulphonaphthal-
enes, e.gO 2 t 3-disulponaphthalene,
or b) adjacent to the fused carbon atom of (co~mon to~
t~70 fused xings, e.g. naphthalic acid;
3) eyclic dibasic acids in which each of two saturaied
ring carbon atoms bears one of the acid functions
which are fixed rigidly either endo- or exo- with
,, .
respect to eaeh other by reason of the structure o~
20 the molecule,e.g. bicyclor2,2-l~hepta-5-en-2,3-
diearbox.ylic acid.
. The preferred such acids are those of
elasses.l and 2a), in particular bf formula IV,
.' , .
- 11
,
. . . . . .
.
., '~ ' ' - ~
~ .
`J~
600-6739
~7~
;~1~ / AClH
,, IV
AC 2}~
in which ACl and AC2 are each -COO- or -SO3- and
are in cis configuration to each other,
and Zl and Z2 are each hydrogen or an
organic residue, preferably a hydro-
carbon residue, the radicals Zl and
Z2 optionally being joined together.
Preferably, the two acid functions in the
dibasic acids employed are the same and, more preferably,
they are each -COOH.
While such acids may be employed in similar
manner to that described above for other, it is pref
erred, in this embodiment, to effect the process by
reactiny, in liquid medium? in particular solution, the
compounds of foxmula II and III with the reaction prod-
uct of the rigld, coplan r carboxy and/or sulpho dibasic
- : organi~ acid and a borotetrahydride, in particular an
alkali metal borohydride.
Such reaction product is a b~r~ contai~ing salt
. belie~ed, at least predominantly, to have the formula V/
' ~ ,. . ' ' ' - "
~ - 12 ~
''' ' ' ' . ..
.
.
a7~ J~
~00~6739
X ~ M ~ V
~ \ H e
in which X is the anionic residue o~ the rigid
co-planar carboxy and/or sulpho dibasic
or~anlc acid,
and M is an equivalent of the metal cation
derived from the borotetrahydride employed.
Thus, for example, in the case of the use
of acids of ~ormula IV, the reaction product is believed,
~ predominately at least,to have the structure Va,
: Zl ~AC1 / Va
~C~ / \
-in which Zl~ Z2~ ACl, ~-C2 and M are as defined above,
In the case of o-phthalic acid the reaction
product is believed predominately to be of formula Vaa,
O H
\/ ~ ~ M ~ ~aa
O O H
in which M is as defined above,
13 ~
'
_ .............. .
.~ . ' ' . , .
~ 7~ 60~-6739
In the case of naphthalic acid, the reaction
product is believed predominately to be of formula Vab,
B ~ 0 M ~ Vab
O ~ H
O
in which M is as defined above~
As will be evident, M is prefera~ly an
alkali metal cation, in paxticular a lithium, potassium
or, more preferably, sodium cation.
The reaction products of the xigid, coplanar
carboxy and/or sulpho dibasic organic acids and tetra-
borohydrides are reducing agents in their own right
and also form part of the pxesent invention.
Quite generally, the~ may be produced by
reaction of the acid with the tetraborohydride, in
llquid medium and at a temperature of from -40 to
~5C, the mol ratio of the acid to ~he tetraborohydrid~
; ~ 15 being fron~ 0.7:l to at least 5:1.
Preferred methods of producing these
reaction products will now be described with reference
to their use in the proces~ of the invention.
.,
:; . :
.
~ - 14 ~
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,
.
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~76~ 600-~739
.
In this embodiment, the process is suitably
effected at a temperature of from 0C to 100C, preferably
~0 to ~5C, more preferably 30 to 65C. As indicated, the
reaction is effected in liquid medium, preferably solution.
The reaction medium is suitably provide~, at least in
part,by employing an excess of the compound of formula
III. In particular, the mol ratio of the compound of
formula III to the compound of formula II is desirably
as indicated above in connection with embodiment a).
As with embodiment a), the reaction mixture may ada-
itionally comprise other inert organic solvents, in
particular those indicated in connection with embodiment
a). Small amounts of water may also be present in the
reaction mixture due to their presence in commercial
grades of starting materials. The quantity of water
present should preferably not, however, exceed 8% by
weight of the total solvent present (the term "solvent"
excluding the quantity of compound III which enters
into reaction with the compound II) and preferably
5hould not exceed 2%, more preferably 0.5% by weight of
the solvent~ Conveniently, the water is present in an
amount of from 0.05 to 0.4% by weight based on the to~al
solvent.
.
. ` , ,
-- 15 --
. ~ '' ' .
~@~7~ 60~-~7~
The reaction product of the rigid, coplanar
carboxy and/or sulpho dihasic organic acid and the
tetraborollydride ~i.e. the boron-containing salt) may
conveniently be produced in situ, i.e. in the presence
of at least one other o~ the reactants, or ex situ. The
mol rat.io o the borohydride or boron-containing salt
(expressed as borohydride in situ reaction and the
boron containing salt in ex situ reactions~ to the com-
pound of formula II is desirably from 0.7:1 to 2.5 1,
preferably 0.7:1 to 1l65:1, more preferably 1:1 to 1.5:1,
in particular 1;1 to 1.3:1, more particularly 1:1 to
1.15:1.
As indicated, the boron containing salt is
suitably produced in situ or ex situ,but is preferably
produced ln situ For in situ production, the reaction
is conveniently carried out in the presence of the
compound of formula III which provides a reaction medium,
: ~ and the other components of the reaction mixture includ-
lng the compound of formula II. The borohydride is
- 20 thus conveniently added to a mixture of the other
xeactants, desirably at a temperature lower than the
actual reaction temperature, for example 0to 30C,
preferably 10 to 25C. The temperature is then conveni-
ently raised, for example to 30 to 85C, preerably
~5 40 to 65C, after an initial reaction between the boro-
,
; - 16 -
7Ç~
~00-673g
hydride and the acid has taken place, in order to com-
plete any remaining salt-forming reaction and establish
conditions ~avouring the final substitution.
The mol ratio of rigid acid to horohy~ride
in the in situ production of the boron-containing salt
is conveniently from 0.7:1 to 10:1, preferably 1:1 to
, 2:1, more preferably 1.1:1 to 1.8:1, in particular
1 to 1.6:1. Thus, it is desirable that free acid
be present in the reaction mixture to stabilise the
boron-containing salt~ The free acid may be provided
by an excess of the rigid acid being employed. Alter-
' natively, another acid, prefera~]y a carboxylic acid,may be included in the reaction mixture.
As indicated, the boron-containing salt may
also be produced ex situ. In this event, the reaction
is suitably effecked in an inert solven~, such as tetra-
hydrofuran. The reaction temperature is from minus 40
to plus 85C, preferably 0 to 35C, more preferably
10 to 30C. The mole ratio of rigid acid to borohydride
may suitably be somewhat lower than for in situ production.
and may, for example, be from 0.7 :1 to 5:1, preferably
1:1 to 2:1, more preferably 1.1:1 to 1.8:1, in particular
1 to 1.5:1, more particularly 1.1:1 to 1.3:1. The
reaction ~s conveniently effe~ted by adding the boro-
~ 17 ~
, .
,. . . .
' ` '
~7~ 600-6739
hydride in stages to a solution of the ri~id acid, the
rate of addition being controlled so as to maintain the
desired reaction temperature. The resultin~ horon-
containing salt may be maintained in the solution in
which it is formed and such solution used di--ectly in
the next step. Alternatively, the sa't may be isolated
and purified using conventional techniques.
As indicated, the production of the boron
containing salt is preferably effected in solution. It
will be appreciated, however, that the ~uanLity and
quality of various reactants may be such that the reac-
tion system as a whole is a mixture or multiphase system
involving, for example, a suspension or slurry of a por-
tion of one or more of the ingredients.
~he resulting compounds~of formula I may be
isolated and purified using conventional techniques.
Where required, ~ree base forms thereof may be converted
- 1nto acid addition sal~ forms in conventional manner, and
vice versa.
The compounds of formula I are kno~m inter-
mediates for the production of pharmaceutically active
compound~, in particular compounds of formula VII,
- lS -
7~
,: CII
12 VII
R3~N ~Fo
~N
,' 1
1~ R2, R3, R4, Y and Yl are as defined
. above,
which are known anti-inflammatory agents.
The invention also provides a process for
the production of a compound of formula VII, stated
above, comprising cyclising a compound of Formula I,
stated above, in which X is -C ~ Yl, in which Y
and Yl are as defined above, with a reagent containing
a [N-C-O] linkage, characterised in tha-t said compound
of formula I is produced by reacting, in accordance with
the process of the invention, a compound of formula II,
stated above, with a compound of formula III, stated
above, and, where required, converting a resulting com-
pound of formula I, in which X is -CN or -COOR, in which
. 15 R is as defined above, into a compound of formula I, in
., O
which X is C ~ Yl, in which Y and Yl are as defined
above.
6 o o - 6 7 3 9
The cyclisation may be effected in kno~m
manner, suitable reagents containing a [NCOl linkage
being well-known and including urea and alkylcarbamates.
The interconversion, where required, of compounds of
formula I may also be effected in known manner, compounds
in which X is CN or COO~ being, for example,reacted with
an appropriate aryl Grignard reagent or aryl lithium
compound, with subsequent hydrolysis o~ the reaction
product. Compounds in which X is -COO alkyl may first
be converted to compounds in which X is -COOH by, e.g.
hydrolysis.
The preferred compounds of formula I (and
VII) are those in which Rl, R2, R3, 4,
following significances:-
Rl, R2 ~ CH3;
either R4 = H
an~ R3 - CH3~
or R3 ~ R~ = WO--CH2-O-;
Y = H;
Yl = H ox F.
rrhe most preferred compounds ha~te combinations of the
above preferred significances.
The follQwing E~amples illustrate the inven-
- tion.
- 20 -
~ ~ 7 ~ ~ ~ 600-6739
EX~MPLES 1 to 19: 2-(N-Isopropylamino)-4-methylbenzo-
E~ [Embodiment a~ -
Examples 1-19 as recorded in the following
~able I represent trials in ~hich the amount of 4-methyl-
2-amlnobenzophenone ~a compound II in amount of 21.1 g
or 0.1 mol) is held constant and the amount of other
reaction system components including acetone (the
compound III), borohydride (sodium borohydride), acid
(sulphuric acid) and water are varied. In these examples,
the reaction syste~ is maintained.at 20-25C, throughout
.the reaction and the rate of addition of the borohydride
is controlled accordingly, such addition requiring in
most cases about 60 minutes, after which the reRction
system is stlrred for an additional 60 minutes~ followed
by filtering. The filtrate is concentrated and the
residue dissolved in about 88 ml oE heptane and the
resulting solution extracted first with 20 ml of 4N
ammonium h~droxide solution ? then three times each with
10 ml o 2N suIphuric acid, ana then washed with 10 mls
of 0.5N sulphuric acid. The heptane is distilled off
to obtain the desired 2 (~-isopropylamino)-4-methyl-
benzophenone which boils at 180-185C/5 mm Hg.
; It will be seen that in some sf the Examples
~n the following Table, the yields of product are rel~ -
- 21 -
, .
.
~ ~ 7 ~ ~ 600~6739
atively low. It will be appreciated that such Examples
have been carried out with a view to determininy the
ideal reaction parameters and do not illustrate prefer-
red methods of effecting the invention. Nevertheless,
by adjusting one or more of the reactlon parameters, even
in such Examples, the yields can be substantially
increased.
,, .
. - 22 -
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~n c)~ r~ ~ r~ n a~ ~ ~
0\o ~
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~n Lo ~n ~n ~n ~n ~n ~ ~n ~ ~ ~ ~ ~ ~ ~
o o o o o o o ~ o o o o o o o o o r- ~r
... O . ... . ..... .....
~1 rl
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~r ~ r o ~ 9 0 0 -
os: . ........................ ......
m ooo O O ooco O 0OOOO ooococo
æ
L~l h
O ~1) ~ N ~ rn ~ n Ln Ln Ln Ll~ - - .
. ~1 ~ O O O ';I~
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H
~ ~ n n n n ~ n r~ ~ n ~ u~ ~ ~ oo ~ ~ n ~
h O .. . . ,~ . ,~ . . . . . .. . . . . .
O O ~ ~ ~ ~ ~ ~ ~
~: 0
4J ~
O ~ n
O n n n n n ~ n ~ w r~ n ~9 ~
~1a) ... . . ... . ...... .....
O t) ~1 ~i C~l ~I r-l ') r~ N N
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a
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o o n ~n ~n Ln In Ln In ~n o ~n o ~ o o r~ Ln o ~n Ln
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~ U ,I N ~1 ,I N ~1 ,~
O
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~1 ~ ~ ~ m ~O t~ t~ ~ O ~I N r~ n ~g t~ co ~
~ -23-
~~7644 ~00-673~
EX~MPL~ 20: 2-(N-Isopropylamino)-4-methylbenzophenone
~ ~ .
[Embodiment a)]
To a solution of 63.3 g of 2-amino-4-methyl-
benzophenone in 722 ml of acetone is added 87 g of 49%
aqueous sulphuric acid. The mixture is cooled to 20C.
With stirring, and by portionwise addition, 31.2 g of
sodium borohydride is added to the mixture over a period
of 70 minutes. After the addition, the mixture is stirred
for an additional 5 hours at 25~C. The suspended solids
are filtered and then washed with 300 ml of acetone. The
acetone solutions are combined and concentrated. To the
concentrate is added 200 ml of heptane and 60 ml of
4N ammonium hydroxide~ The liquîd layers are separated,
then the heptane phase is washed with 20 ml of water,
extracted twice with 20 ml of 2N sulphuric acid each
time, and then washed to neutrality with water. The
heptane phase is then dried over magnesium sulphate,
; filtered and concentrated under vacuum to-a constant
weight of 74.5 g or crude yield of 98~, which is shown
by analysis to constitute an actual yield of about 95% of
the desired 2-(N-1sopropylamino)-~-methylbenzoph~nolle.
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EXR~PLE 21: 2-(N-Xso~p~_am no?-4-methylbenzophenone
[Embodiment a)]
In manner analogous to Example 20 but replacing
the sulphur.ic acid with 114 g of 28~ aqueous HCl, and
stirring the reaction mi~ture for only 1 hour after
addition of borohydride, the same product is obtained
in a crude yield of 100~ and an actual yield of 96~.
EXAMPLF. 22: ?- ~N-Isopropylamino)-4-methylbenzophenone
tEmbodiment a)~
In manner analogous to Example 20 employing
an equivalent amount of 30~ aqueous sulphuric acid, the
same product is obtained in good yield.
EXAMPLE 23: 2-(N-Isopropylamino)-4-methylbenzophenone
; ~Embodiment a~
To a 12 litre capacity flas~ equipped with
stirrer and thermometer and secured in an ice/water bath
are added~ sequentially with stirring, 3.9 litres of
acetone, 528~3 g of 2-amino-4-methyl~en~ophenone, 462 ml
of water and 263 g of 98% sulphuric acid while control-
? lin~ the temperature at 20C. There is then added,with
~tirring,200 g of sodium borohydrlde at a xate of 72 g
-- 2s
~7~ 600-6739
per hour while controlling the temperature of the resul-
ting reaction mixture at 20-25C, Following addition of
the borohydride,the reaction mixture is stirred at 20-25c
for 4 hours followed by filtering off the precipitated
solids which are washed with 1.5 litres of acetone. The
filtrate and acetone washings are combined and acetone
evaporated in vacuo. The heavy orange coloured liquid
_ .
residue; is treated with 2 litres of heptane and 350 ml
of 4N ammonium hydroxide and stirred thoroughly until
khe resulting solids are dissolved. The aqueous phase is
separated and the organic phase washed three times
each with 125 ml of 2N sulphuric acid and then washed
with 120 ml of 0.5N ammonium hydroxide. The organic
phase is then distilled under vacuum at 80C to a con-
lS stant wei~ht of 594 g of 2-(N-isopropylamino)-4-me~hyl-
benzophenone, b.p. 180~185C/5 mm Hg. 9 yield 94%.
.
EX~PLE Z~: 2-(N-Iso~o~ylamino)-4-methylbenzoph~none
[Embodiment a)J
Example 22 is repeated employing a hydrogen
ion equivaient of
a~ methanesulphonic acid
b) nitric acid
c) hyarobromic acid
d~ trifluoroacetic acid
or e) picric acid
.NA~
~ 600-6739
to obtain the same product in yields of at least 70%,
In the preparation employin~ trifluoroacetic acid, trace
amounts of by-product ~2-~trifluoroethsrlamino)-g-methyl-
benzophenolle] are detected and the production of this
by-product increases with incxeased acid concentration.
EX~lPLE 25: ~Embodiment a)]
-
In manner analogous to any one of Examples 1
to 24, employing appropriate starting materials in
approximately equivalent amounts, the following compounds
may he obtained:-
a) 2~(N-isopropylamino)-5-chlorobenzophenone;
b) 2-(N-isopropylamino)~4,5-methylenedioxy benzophenone;
c) 2-(N-isopropylamino)-4'-~luorobenzophenone.
EX~IPLE 26: 2-~N-Iso~ro~vlamino)-4-methvlbenzo~henone
- 15 ~Embodiment b)]
To a solution of 21~1 g of 2-amino-4-m.ethyl-
benzophenone in 100 ml of acetone is added 100 ml of
~lacial acetic acid. The solution is cooled to 20C.
With stirring/ and by portionwise addition, 10 g of
sodium borohydride is added to the solution over a
- perlod of 70 minutes. After the addition, the solution
stirred for an addi-tional 20 minutes at 20CJ and
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extracted with 100 ml of chloroform and 50 ml of
water. The aqueous phase is extracted twice using S0 ml
of chloroform each time. All the chloroform extracts
are then combined and treated with 150 ml of 20~
ammonium hydroxide. The chloro~orm phase is dried over
magnesium sulphate, filtered and concentrated by distil-
lation to a constant weiaht of 25 g or a crude 99% yield
of 2-(N-isopropy~aminG)-4-methylbenzophenone, providing
an actual yield o~ pure material of at least 90%.
EX~MPLE 27: 2-(N-Isoprop~lamino)-4-methylbenzophenone
.. . ~ . . _ . ,.
[Embodiment ~)]
Repeatin~ E~ample 26, but employing a mol
equivalent of propionic acid in place of the acetic acid~
the same product is obtained in 85% yield.
EXP~PLE 28: 2-(N-IsoprGpylamino)-4-methylbenzophenone
.. _. A_.... _ . _.._.._ ..
[~mbodiment b)]
- Repeating Example 26, but employing in
the reaction system ~7ater introduced by using 90%~ 60~
- and 36~ by weight aqueous ace~ic acid, the s~me product
is obtainAd in yields of, rPspectively 59%, 27% and 9%.
28 -
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EXAMPLE 2~: ~Embodiment b)]
In manner analogous to any one of Examples 26
to 28, employing appropriate startin~ materials in appro~-
imately equivalent amounts, the products indicated. in
Example 25 may be obtained.
EXA~IPLE 30: 2-~N-Iso~ropylamino)-4-methylbenzophenone
- lEmbodiment c)]
422.6 g ~2 moles) of 2-amino-4-methylbenzo-
phenone is dissolved in 2.34 litres (40.29 molesj of
.acetone, and, with stirring, 540 g (3.25 moles) of o-
phthalic acid is ad~ed~ To the resulting suspension is
added, portionwise, 80 g (2.14 moles) of sodium boro-
hydride over a period of 45 minutes and in a manner such
as to keep the reaction mixture at 20-25C. At the end
- 15 of the addition, the cooliny is altered such as to allow
the temperature to rise to 30-35~C, and this temperature
is maintained for 30 minutes. The cooling means is
removed and the temperature carefully increased to 50C,
and regulated at 50~55C for 90 minutes. The mixture
is then cooled at 15C, 808 g of 8% aqueous NaOH (1.6~5
- moles~ is added, the phases are separated and the acetone
phase (upper layer) recovered and concentrated. The
watex layer is extracted with 1 litre of heptane, and
_ ~g _
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~he concentrated acetone phase added to the heptane
extract. The heptane solution is washed with 250 ml of
H20, then concentrated by distillation to obtain 496 g of
2-(N-isoprop~lamino)-~-methylbenzophenone, b.p. 180-185C/
5 mm (Yield 99%).
EX~IPLE 31: [Embodiment c)]
. .
In manner analo~ous to bxample 30, but
employing appropriate starting materials in approximately
equivalent amounts, the compounds indicated in Example
25 may be obtained.
.,
EX~IPLE 32: Sodium dlh~dro (phthala~o), borate (1-)
~Boron Salt]
O
~ C~O
\ B / ~a ~
To a stirred solution of 1008 g of phthalic
acid in 100 ml of tetrahydrofuran is added, portionwise~
1.6 g of powdered sodium borohydride over a period of 5
: minutes at 25-30C~ under ice cooling. The resulting
mixture is stirred at 25C for 16 hours, filtered and
the filtrate concentrated to a solid weighing 15.~ g
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which is triturated with chloroform, filtered and dried
under vacuum at 60C with a nitro~en sweep, to obtain
crude sodium dihydro (phthalato)borate tl-) as a white
solid which melts at 60C and decomposes into a white
foam at 150C.
EX~MPLE 33- Sodium dih dro( hthalato) borate (l-)
.. , _ Y P
[Boron Salt~
_
Repeating Example 32 but employing 1.15 g of
phthalic acid in place of 10.8 g, the same product is
obtained as a white solid, m.p. > 320C, a very slisht
amher colour appearin~ at 180C.
. .
~- EX~PLE 3~: 2-(N-Isoprop~lamino)-4-methylbenzophenone
[Embodiment c)]
The products of Examples 32 and 33 produce
the heading compound when reacted at a temperature of
from 30-35C with an appropriate mixture of 2-amino-
benæophenone and acetone.
~ 31
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EX~MPLE 35: ?-Iso~ropylamino-~-methvlb2nzonitrile
,
To a stirred mixture of 264 g of 2-amino-4-
methylbenzonitrile, 504 g of phthalic acid and 2.32 litres
of reagent grade acetone is added 80 g of sodium boro-
hydride portionwise over 40 minutes at a temperatureof 18-30C. The resulting solution is stirred for 30
minutes during which the temperature rises from 29-30C
to 35C and then drops to 34C. The resulting
solution is then heated from 34C to 53C over a period
of 30 minutes and then maintained at 55C for one hour.
The mixture is cooled to 37C, 500 ml of water is added
followed by addition of 417 g of 50% aqueous sodillm
hydroxide, after which the temperature is allowed to
rise to 56C to maintain the solution. An additional
92 ml of water is added and the acetone and aqueous salt
layers separated at 45-50C. The acetone layer is con-
centrated 1n vacuo to obtain a brown oil and salt solution
which is diluted with 800 ml of heptane and the aqueous
and heptane layers separated. The heptane layer is dried,
filtered and cooled to 10C to obtain the major portion
of the desired 2-isopropylamino-4-methylbenzonitrile,
m.p. 55-57C. Additional product is also recovered from
the mother liquor and phthalic acid is recovered to a
hi~h degree from aqueous salt layer above after
dilution with a total of 4.5 litres of water, filtering
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and acidifyin~ with sulphuric acid (other aqueous alkaline
solutions obtained in the work up being combined with
said aqueous salt layer).
EXAMPLE 36: ~-Isopropyl~nthranilic acid
To stirred mixture of 2.7 g of anthranilic acid
and 5.4 g of phthalic acid in 23 ml of acetone is added
0.7 g of powdered sodium borohydride over a period of
30 minutes at 20C - 30C. The resulting slurry is
then stirred at 35C - 40C for ~ hours, diluted with
25 ml of chloroform and filtered. The filtrate is
concentrated ln vacuo and the residue dissolved in
20 ml of chloroform and treated with 30 ml of hexane,
filtered and the filtrate concentrated 1n vacuo to obtain
a crude solid product which is recrystallised 5 times
from cyclohexane to obtain (second crop of fifth
recrystallisation) N-isopropylanthranilic acid, m,p.
109-109.5C.
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EXAMPLE 37:
.
In manner analogous to Example 36, but employing
a molar equivalent amount of anthranilic acid ethyl
ester in place of the anthranilic acld, N-isopropyl-
anthranilic acid ethyl ester is obtained.
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