Note: Descriptions are shown in the official language in which they were submitted.
`` iO~21~0
The present invention relates to industrial
products which are particularly useful in therapeutics as
active medicaments in the cardiovascular field, in part-
icular as hypolipidaemiant, hypocholesterolaemiant and
cholagogic agents. It also relates to processes for
synthesising these products and their application in
- therapeutics.
More especially, the invention is directed to:
1) - the compounds of formula II hereinafter, which are
new industrial products useful in therapeutics;
2) - the compounds of formula I hereinafter, which are
particularly involved as intermediates in the synthesis of
the compounds of formula II and which are also useful in
therapeutics, and except for some products aiready described
in French Patents Nos. 2,035,821 and 2,157,853, the compounds
of formula I are new products; `
3) - the new processes for synthesising compounds of formula
I and II; and
~ 4) - the therapeutic application of the new compounds I and
:~ 20 II, particularly as hypolipidaemiant, hypocholesterolaemiant
and cholagogic agents.
According to the invention the following acids
are proposed: -
` ~-(alkyl-carbonyl)-, _-(cycloalkyl-carbonyl), _-(aryl-
~ carbonyl)-, _-(heteroaryl-carbonyl) , _-[~-alkyl_x-hydroxy)
- methyl~ (4-cycloalkyl-~-hydroxy)-methyl], p-[(~-aryl-x-
hydroxy]methyl)- and p-((~-heteroaryl-~-hydroxy)methyl)-
phenoxyalkyl- carboxylic acids and their derivatives (in
. . .
particular the derivatives which result from (i) esterification
` and amidification of the carboxylic acid group, and (ii)
esterification and etherification of the ~-hydroxy group on
the one hand, or conversion of the _-carbonyl group to the
- 2 - ~ ~
~ ... . ~ ~
'`
.
10~2110
acetal gro~p on the other hand), which have the following
formulae: X5
A-C~3 O-C-COY
Xo
:- X5
A-CH 4~ CH3 II
OR ' \~J R
.. X4 - .
in which A represents methyl, ethyl, _-propyl, isopropyl,
_-butyl
Xl
X2 ~ ~ ~ ~ 2 5
[where Xl, X2 and X3 are the same or different and each
; represents H, Cl, Br, F, CF3, NO2, NH2, OH, Cl_4 alkyl gr~up Cl_4, alkoxy
: group, benzyloxy group, aoetylamino group, acetoxy group, CHO,
; 10 COOH, OC(CH3)2COYl (where Yl is preferably OH or Cl 4
alkoxy); X6 represents O or S; and X7 represents H, Cl, Br];
R, X4 and X5, which are identical or different, each re-
presents a hydrogen atom or a Cl 4 alkyl group; X is O or
OCH2CH2O, Y represents H, OH, OM (where M is a metal or a
: stoichiometric portion of a metal), a Cl 12 alkoxy group
(whose hydrocarbon radical is straight-chain or branched),
a C3 8 cycloalkyloxy group, a Cl 4 alkylthio group, a 2,3-
dihydroxypropyloxy group, a 4-(2,2-dimethyl-1,3-dioxolanyl)-
methyleneoxy group, which is derived from the preceding
group and has the formula:
- 3 -
.... .. .
,
,
, . , . . ~
iO'7Z110
O-CH2
o o
.`' X
H3C C 3
a phenoxy group, a substituted phenoxy group (particularly
a p-chlorophenoxy group), a 3-pyridyl-methyleneoxy group,
a 5-(2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl)-methyl-
eneoxy group, which has the formula:
CH20H
-O-CH ~ OH
: ~N
. CH
- 1 2 2 2NZlZ2' 0CH2cH2NZlz2 or (CH2) CNZlZ group
(where m is an integer from 1 to 4 and Zl and Z2 are Cl 4
.
alkyl groups, and Zl and Z2 together with the nitrogen atom
to which they are joined may form a 5- to 7-membered N-hetero-
cyclic group which may contain a second heteroatom such as O
.~ and N and may be substituted), or a group
O-~C~213-~2L- C 30 ~ C ~ Cl
~ R' represents hydrogen, a Cl 4 alkyl group or an acetyl
'~ group; and their addition salts.
Examples of the metal represented by M are Na, K,
. 1/2Ca, 1/2Mg, 1/2Zn, and 1/3A1, preferably Na or K.
The alkyl, alkoxy and alkylthio groups in the
.~ compounds according to the invention contain a straight-chain
. 20 or branched hydrocarbon radical. Among the Cl 4 alkyl groups,
the methyl group is preferred for Xl, X2, X3, X4 X5, R and R'
.~ is methyl, while hydrogen, methyl, ethyl, isopropyl and n-
` butyl are preferred for Zl and Z2'
- 4 -
~ .
' '. ' `' ~ .
`` lO~ZllO
The Cl 12 alkoxy groups include the following
preferred groups: methoxy, ethoxy, isopropyloxy, isobutyl-
oxy, tert.butyloxy, l-octyloxy, l-dodecyloxy, 2-pentyloxy
and 3-pentyloxy.
The C3 8 cycloalkyloxy groups preferred are the
cyclopentyloxy, cyclohexyloxy and cyclooctyloxy groups.
: . Of the 5- to 7-membered N-heterocyclic NZlZ2 groups,
which are optionally substituted, the pyrrolidino, morpho-
lino, piperidino, 4-methylpiperidino, 4-methylpiperazino,
4-phenylpiperazino, 4-_-chlorophenyl-piperazino and hexamethyl-
;~ eneimino groups are particularly intended.
Of the Y groups containing at least one nitrogen
atom, the preferred
~ ; .
., .
2()
'
''~ '
.~ ` ' .
..
!.
- 4a -
. ~, .
.', ~
~- '''~
.: :
107Z110
groupS for Y = NZlZ2 are the N(CH3)2, N(C2H5)2, N(n=c4Hg
piperidino and morpholino groups; the preferred groups for
Y = NHCH2CH2NZlZ2 are the 2~dimethylamino-ethylamino and 2-
diethylamino-ethylamino groups; the preferred groups for
Y = OCH2CH2NZlZ2 are the hexamethyleneiminoethoxy, morpho-
linoethoxy,piperidinoethoxy and 2-diethylaminoethoxy groups.
By the term addition salts are understood the
`amm~nium salts and acid-addition salts obtained with the
compounds of formulae I and II which have at least one amino
group. The acid addition salts may be prepared by reacting
~- the base with a mineral or organic acid, particularly with
hydrochloric, fumaric, maleic and oxalic acids.
More particularly, this invention provides a method
; of preparing a compound of formula:
¦5 1 3
~ ~ - O-C-CO-Y (Il)
. X
in which A is a methyl, ethyl, n-propyl, isopropyl, n-butyl,
~, ' . ''
isobutyl or cyclohexyl group or a group of formula
., X
2 ~ ~X7 ~ or ~ c2~s
twhere each of Xl, X2 and X3, which are identical or differ-
ent is H, Cl, Br, F, CF3, NO2, NH2, OH, Cl_4 alkyl~ Cl_4
alkoxy, benzyloxy, acetamido, acetoxy, CHO, COOH, a radical
- ~ 5
107Z110
CH3
--O--C--COY,
~H3
where Y is OH or Cl 4 alkoxy; X6 is O or S; and X7 is H, Cl
or Br]; each of R, X4 and X5, which are identical or differ-
ent, is hydrogen or Cl 4 alkyl; Y is H, OH, OM (where M is a
metallic residue), Cl_l2 alkoxy, in which the chain is
straight or branched, C3_8 cycloalkyloxy, Cl_4 alkYlthio~
2,~-dihydroxypropyloxy, 4-(2,2-dimethyl-1,3-dioxolannyl)-
methyleneoxy, which has the formula
O-CH2
X
H3C CH3
phenoxy, substituted phenoxy, 3-pyridylmethyleneoxy, 5-(2-
methyl-3-hydroxy-4-hydroxymethlylpyridyl)-methyleneoxy, which
has the formula:
CH2H
-- , ,
OH
2 ~
N CH
. 3
a NZ Z , NHCH2CH2Nzlz2~ CH2CH2NZlZ2 2 m 1 2
(where m is an integer from 1 to 4 and Zl and Z2 are Cl 4
- alkyl groups, or Zl and Z2 together with the nitrogen atom
- to which they are joined may form a 5- to 7-membered N- het-
,, .
erocyclic group which may contain a second heteroatom such
. as O and N and may be substituted), or a group
OICH2~3-O-oc-c- ~ ~ 1
,' ~
5a
iO'7Z110
R' represents hydrogen, a Cl-C4 alkyl group or an acetyl
~roup; and their addition salts; comprising reducing a com-
pound of formula
X5
A-C ~ O-C-CO-Y
O ~ R
X4
where A, X4, X5, R and Y are as defined above with an organic
reducing agent and if necessary substituting the product to
etherification or acetylation.
Various methods for synthesising the compounds I
and II and their intermediates are given hereinafter. These
methods which relate to compounds where A = substituted
phenyl can of course be directly transferred to compounds
where A = heteroaryl.
The products prepared in accordance with these
methods are given in Tables I, II and III hereinafter. Some
of the hydroxyketone intermediate compounds formed in the
- synthesis of compounds in accordance with the present inven-
. tion have been set out in Table IV.
~- In accordance with the invention there are provided
therapeutically useful compositions, particularly for the
treatment of hyperlipaemia and containing as active ingred- -
ient a pharmaceutically active quantity of at least one
compound of formula I or II or a non-toxic acid addition
",~
salt thereof, in association with a physiologically accept-
able excipient.
The compounds of formula II are obtained:
l) Yrom compounds of formula I according to the reaction
-; scheme I:
,, .
5b
lO~ZllO
REACTION SCHEME I
A-C ~ / ~ CH3
O ~ R
X4 \
A-CIL~ , 2 < ~ ~A-C~ C-COY (IIa)
OH R OH OH ~ R
4 ~ X / x4 \ NaH
~ CH3 ~ CH3COCl X5 /IRCH
A-CH ~ / ~ O-C-COY ~ , 3
i - . O-C-CH ~ R A-CH ~ 1 \~ O-C-COY
`~ O R4 X4 R
A-C3 ~ 0--C--C02E~
OR' R
X4
.
The following comments may be made concerning this
reaction scheme: -
a) the step I )IIa is preferentially effected using
potassium borohydride, but it is also possible to use a -;
. metal isopropylate.
b) if A is
: .
,. X
- X~
- X
: ~ .
and (i) Xl, X2 or X3 = NO2, the reducing medium (step I
IIa) affects this NO2 group; this type of compound should
therefore be prepared by a method which produces an alcohol
~- group in a non-reducing medium (corresponds to item 2 under
preparation of (4'-chlorophenyl)-(2-phenoxy-2-methylpropionic
-B 6 -
.'' . .
' : ~ ' - ' . ' ' :
iO~2110
acid) carbinol), (ii) Xl, X2 or X3 = OH or NH2, the compounds
II in which R' alkyl and acetyl are obtained indirectly; the
OH or NH2 group should in fact be introduced last of all via
a N02 group: the step N02---~ OH is effected by a process
known per se; the step NO2 ~NH2 is affected by catalytic
reduction.
EXAr~PLE
Preparation of (4'-chlorophenyl)-(2-phenoxy-2-methylpropionic
acid isopropyl ester?_carbinol (alternative name isopropyl
2-[4-(p-chloro-~-hydroxybenzyl)-phenoxy ]-2-methyl propionate)
,
Cl ~ CHOH ~ , 2
.
350 g of isopropyl 2-[4-(p-chlorobenzoyl)-phenoxy]-
. 2-methylpropionate is dissolved in 4200 cm3 of methanol in an
~ Erlenmeyer flask, 60 g of KBH4 is added and the mixture is
, stirred for 8 hours at ambient temperature; the methanol is
.,~
then evaporated and the residue is taken up in water and
methylene chloride; the organic phase is washed with water
until neutral and then dried, and the methylene chloride is
evaporated in vacuo; the remaining very clear oily residue
is almost always very pure and may be used for any purpose;
the yield is quantitative; (if a small amount of the initial
ketone remains this can easily be removed simply by treating
it with Girard's T reagent). ND = 1.5428
Preparation of (4'-chlorophenyl)-(2-phenoxy-2-methylpropionic
acid) carbinol
A conventional hydrolysis in 4N NaOH for 6 hours at
80-85C gives the expected acid-alcohol :
-- 7
'' - ~ - '
.
-
10~7Z110
Yield : 95% ; m.p. = 132C
2) Directly without proceeding via a ketone
In this process one of the techniques for obtainingcompounds of structure I is used - see section Ab3 herein-
after; this is the method which is especially preferred to
obtain compounds II where Xl, X2 or X3 = NO2.
3) According to a special process, shown in reaction as
follows.
REACTION SCHEME II
x5 x5
A-CHOH ~ _ OCH3 AlCl~ or ~ A-CH ~ OH
HBr 48~ '
4 4
X = Cl,Br
.` ' ~
X5
ace ~ A-CH ~ / ~ CH3 aqueous
CHC13 X ~ CH3 NaOH H O
i~ X4
, X5
- A-CH ~ O-C-CO2H > IIa
OH CH3
- 4
All the stages in reaction scheme II are con-
ventional. However, this particular reaction mechanism is
unsuitable for synthesising alcohols IIa where Xl, X2 or X3 =
NH2, OH, CF3 or-alkoxy.
The methods dealing with the synthesis of compounds
of formula I are summarised hereinafter.
A - DIRECT ACCESS TO COMPOUNDS OF FORMULA I
:
-- 8
. .
.
ZllO
a - Methods employing a Friedel-Crafts reaction
Method Aal :
ACOCl + ~ O C COY Lewis ~ (I)
(III) R
X4
(IV)
The two industrial or known reaetants III and IV
are reacted in a solvent which is particularly suitable for
earrying out a Friedel-Crafts reaction (carbon disulphide,
dichloroethane, benzene, methylene chloride, nitrobenzene,
, nitromethane, compound IV itself). The eatalyst is a Lewis
acid seleeted from aluminium ehloride, tin tetrachloride,
titanium tetraehloride, boron trlfluoride and antimony penta-
fluoride. This matter eompound (SbF5) must definitely be used
to earry out the reaetion when one of the substituents Xl, X2
or X3 is the radieal CF3.
If one of the substituents Xl, X2 or X3 is NH2 or
OH, this method may not be used direetly, and it is necessary
either to proteet these groups via aeetyl in the form
NH-C-CH3 and O-C-CH3, or earry out the Friedel-Crafts reaetion
,- ..
. O ' O
on a eompound III, bearing a group whieh will readily produce
NH2 and OH, for example a N02 group. Since the step N02--~NH2
- is a eonventional reduetion, the step NO2 ~OH may be earried
out direetly in aeeordance with a process known per se.
As regards the substituents Y in compound IV which
enable this type of reactionto be cæried out, the preferred are
OCH3 and OC2H5, while the OH group should be exeluded.
'' '
:~ _ g _
~ -B~ ~
.
~ 'ZllO
Method Aa2:
X
A + Cl-C ~ O-C-COY Lewis
~ R acid )
.
All the comments in the preceding paragraph apply
equally in this case and should be observed in exactly the
same manner when performing this reaction scheme, which relates
solely to compounds in which A is aryl or heteroar~l.
As regards the compound 5
Cl-C~O-C-COY
O ~ R
.. - X4
this is obtained in a conventional manner according to one -
- 10 of the following reaction pathways:
X5 oontrolled
- - ~ ,CH3 esterification HO2 ~ ~O-C-COY .-
- 2 ~ O-C-CO H ~ 3
¦PC15
HO2C ~ OH
X4 \ X
CH3 ~ ~ ~ CH3 SO ~ Cl-C 4 ~ CH3
H2C ~ O-C-COY or Pcl5 X R
4 4
.~ .
-- 10 --
.' ~ , ' .
....
107Z1~0
b - Processes employing an organo-magnesium compound
These processes in fact utilise the property of
organo-magnesium compounds by which they give ketones when
reacted with a nitrile or acid chloride: ketones I will thus
be obtained; if the same organo-magnesium compound is reacted
not with a nitrile or acid chloride but with an aldehyde, an
alcohol of formula II is directly obtained.
Method Abl
use of a nitrile
.
~-CN + BrMg - ~ O-C-COY ) (I)
X4 (VI)
The condensation is carried out at a temperature
between -10C and +30C in the solvent which was used to
prepare the organo-magnesium compound VI (ether or THF). This
organo-magnesium compound VI may in all cases be-prepared from
, . Xs
; <jl \ ~ CH3
R
X4
after salifying the acid group with NaOH(Y = ONa) or, better,
by CH3MgI or C2H5MgBr (Y = OMgI, OMgBr respectively).
The preparation of the organo-magnesium compound
properly speaking: Br )MgBr, is effected by reacting the
bromine derivative thus protected with magnesium, in ether or
anhydrous THF. However, it is preferable to carry out the two
. operations in one to prepare the "dimagnesium" compound VIa by
: . -- 11 --
~B
. ~,~
..
`` lO~ZllO
exchange with C~3MgI.
Br ~ O-C-CO2H + 2C~3MgI ) IMg ~ o-C-CO
X4 4
(VIa)
Example illustrating this method
' ':
Preparation of 2-[(para-benzoyl)-phenoxy]-2-methyl-propionic
acld
26 g (0.1 mole) of 2-[(para- bromo )-phenoxy]-2-
methyl-propionic acid is dissoved in 200 cc of anhydrous THF
and placed in a 500 cc flask. The mixture is cooled in an ice
~ bath and 0.2 mole of methylmagnesium iodide (prepared in
'! 10 solution of THF) is added slowly. After this addition, the
temperature is allowed to rise and the mixture stirred at
ambient temperature for 1 1/2 hours. Then slowly and drop by ~
drop a solution of 4.1 g (0.1 mole) of benzonitrile in 20 cc - -
of THF is added and the mixture is stirred for 2 hours 30 --
minutes at ambient temperature. The reaction mixture is poured
on to 500 cc of 10% hydrochloric acid, cooled by 500 g of ice,
and vigorously stirred. The reaction mixture is extracted with
ether and the ethereal phases are washed, dried and decolorised.
The ether solvent is evaporated under vacuum and the oily
residue placed in a desiccator under vacuum. 2-[(para-benzoyl)-
' phenoxy]-2-methylpropionic acid slowly crystallises (22 g).
The yield is 77% and the melting point 130C.
Method Ab2
Use of an acid chloride
, ~ CH3
- ACOCl + BrMg ~ / ~ O-C-COY ~ I
~ ~ R
_ X4
s ~ (VI)
L ~
- 12 -
` 10'7ZliO
In this case the condensation is carried out at a
lower temperature (between -30C and +10C), care being taken
to see that the acid chloride is never in excess (it is the
acid chloride which will be added to the organo-magnesium
compound).
On the other hand, the use of a copper halide (Cusr,
- CuCl, CuI) which is reacted with Vi (mole per mole) before
adding the acid chloride very often gives better yields. The
preparation of VI is carried out as mentioned above.
Non-limiting Example
Preparation of 2-[(para-4'-fluorobenzoyl)-phenoxy]-2-methyl-
proFionic acid
0.1 mole of dimagnesium halide of formula
~, .
IMg~ ~--C--co2MgI
is prepared in a 500 cc flask by the method described above.
The reaction mixture is cooled to -25C and 19 g (0.1 mole)
of cuprous iodide is added. A solution of 10.7 g (0.1 mole)
of _-fluorobenzoyl chloride in 50 cc of THF is added drop by
drop over half-an-hour through a dropping funnel. The temp-
erature is then allowed to rise to 15 to 20C and the mixturepoured on to 500 cc of 10% HCl and 500 g of ice. After
extraction with ether, and washing, drying and decolorisation
of the ethereal phases, the solvent is evaporated under vacuum
to give a solid residue of the desired acid. Yield 20 g
(68%), melting point 160C.
Method Ab3
~ use of an aldehyde
r
` i ~ ~ 13
..
iO~ZllO
x5
ACHO + BrMg ~ / ~ CH3 _ _ ) IIa
~ R
X4
~ The condensation is carried out at a temperature
: between -10C and +30C, in the solvent which was used in the
preparation of the organo-magnesium compound VI (ether of THF).
As regards VI compounds, it is obtained as described above.
Non-l_miting Example ~:
Preparation of 2-[p-( ~-para-nitrobenzyl-~-hydroxy)-methyl]- :
phenoxy-2-methyl propionic acid -
-:
',: '.
O N ~ ~ CH ~ CH3
0.1 mole of the dimagnesium halide is prepared in a
500 cc flask as described aboue. The reaction mixture is
cooled in an ice bath and at that temperature a solution of
15 g (0.1 mole) of p-nitrobenzaldehyde in 30 cc of THF is
added slowly. The mixture is allowed to return to ambient
temperature over a period of 2 hours whereupon it is hydrolysed
and treated as decribed above. The desired acid alcohol
produced is a solid melting at 148C. Yield 71 g (64%)..
These methods Abl, Ab2 or Ab3 do not ensure direct
access to compounds I or II when A is
X2
: X3
.,~ ,
where Xl, X2 or X3 are incompatible with a reaction involving
organo-magnesium compounds. This is also the case where Xl,
L ~ - 14 -
i- .
ZllO
X2 or X3 = NH2 and OH; in this case the compounds of formula I
and II are obtained via Xl, X2 or X3 = NO2 as described in Aal.
c - processes using a phenol
direct access to the isobutyric acid group
.
There are three possibilities, which are summarised
. in the following reaction scheme :
X5
. A-C ~ O-C-C02H ~ I
X4 R = CH3
0~
rn3
VII ~ O-C-COY
or ~ 3
H 5
;:~ ~ CH3
A-C ~ O-C-COY
.. `1 4
- I (R = CH3)
. Method Acl employing "acetone-chloroform" is pre-
ferred when R = CH3, since it gives good yields; A slight
10 modification to the method may be made, by isolating as an
intermediate the acetone + chloroform reaction product, namely
-:~ CH3 Cl
.'''' ' . _
-: and reacting this compound with the hydroxyketone VII in
alkaline medium.
.,, _
~ . - 15 -
-
lOqZ~10
EXAMPLE
Preparation of 2-(4-(p-chlorobenzoyl)-phenoxy)-2-methyl-
propionic acid
12 1 of anhydrous acetone, 1.395 kg (6 moles) of 4-
chloro-4-hydroxy-benzophenone and 1.44 kg (6 moles) of soda are
placed in a 20-litre flask; the reaction mixture is heated 1 to
` 2 hours under reflux to form the phenate, the source of heat is
removed, and a mixture of 2.16 kg of chloroform (18 moles)
diluted in 3.5 litres of acetone is then added.
The addition of the mixture is sufficient to maintain
reflux for at least 6 hours; after 4 hours (when one-quarter of
the mixture remains to be added) the exothermicity of the
reaction decreases, and heating is recommenced to maintain the
reflux for 6 to 8 hours after the end of the addition; the
mixture is allowed to cool and the sodium chloride which has
; precipitated is filtered off (the sodlum salt of the desired
acid is dissolved in the acetone); the acetone is evaporated
in vacuo and the residue is dissolved in the minimum amount of --`
lukewarm water (approximately 35C); this aqueous phase is
washed very carefully with dichloroethane (3 - 4 times) and is
then acidified to a pH-value of 1 by HCl while cooling, where-
upon the acid precipitates; the reaction mixture is shaken
vigorously, and after 30 minutes this acid is suction-dried,
washed with copious amounts of water and then dried.
Weight = 1.61 kg; m.p. - 182C; Yield : 85%
:~ This acid contains a few traces (3 to 4~) of unreacted
phenol, but since all the other impurities have been able to
be eliminated by means of this simple treatment it would be
quite pointless to carry out purification of this acid with
;~ 30 sodium bicarbonate (this is industrially very beneficial).
; To obtain the acid pure as such, it is recrystallised
` in toluene; m.p. = 185C.
.
- - 16 -
`L `~
10'7Z~10
C,H3
Method Ac2 ~mploying Br - C - COY
(the bromine may be replaced by Cl or I) is particularly pre-
ferred when R = H or when one of the substituents X1, X2 or X3
of the group A is NO2 or CF3. This condensation is carried
out in ethyl alcohol or isobutyl methyl ketone in the presence
of K2CO3.
Non-limiting Example
Preparation of Ethyl 2-[4-(para-chlorobenzoyl)-phenoxy]-
propionate
0.75 mole (17S g) of 4'-chloro-4-hydroxy-benzo-
phenone, 1.5 1 of methylisobutylketone, 0.975 mole (134 g) of
K2CO3 and 0.8 mole (145 g) of ethyl 2-bromopropionate are
placed in a 2-litre flask. The mixture is heated at reflux
- for 8 hours with vigorous agitation whereupon the reaction
mixture is cooled and filtered on a Buchner funnel. The
solvent is then evaporated under vacuum and the residue distilled;
the desired ester is recovered at 198 to 201C under 0.1 mm of
mercury. Yield 190 g (76%).
The reaction (method Ac3) using 2-hydroxy-isobutyric
acid, invoIves a dehydration which can be carried out in solution
of DMF or toluene either (i) in an acid medium (H2S04, para-
toluene-sulphonic acid) or (ii) in an alkaline medium, with
. .
mechanism (i) being preferred. This method is derived from the
description of German Patent Application DOS No. P 2112 272 5.
In the preferred method, which uses acetone-chloro-
` form, the following acid is obtained as an intermediate compound:
.~ - . .
X5
A-C ~/ ~ O-C-CO H
~ CH3
X4
~ - 17 -
,~
~' .
10~2ilO
This is then converted to an amide or ester as the case may be.
The conversion of the acids of formula I into amides
and esters is given below in a general manner:
Conversion into amide or ester (tertiary alcohol, alcohol amide
,
or 3-pyridyl-methanol).
First the acid chloride is synthetised from the acid ~-
and phosphorus pentachloride until cold (0-5C). The acid
chloride is reacted with the amine or alcohol desired in the
presence of a tertiary amine (triethylamine or pyridine) to
neutralise the hydrochloric acid formed.
Non-limiting Example
Preparation of the amido-ester of formula
Cl ~ " ~ O-c-co2-(cH ) C N /
; CH3 o Me
32 g (0.1 mole) of 2[4-(_-chlorobenzoyl)-phenoxy)-2-
methylpropionic acid is suspended in 250 cc of dry toluene, and
cooled in an ice bath. 20 g of phosphorous pentachloride is
-~ then added little by little. The reaction mixture is stirred
for 2 hours at this temperature and when everything has dissolved,
the toluene and the phosphorus oxychloride formed are evaporated
off. The solid residue, which has a melting point of 80C, is
recrystallised from hexane: it is the acid chloride. To purify
this crude material, it is re-dissolved in the minimum quantity -
of toluene and 0.1 mole of pyridine (8 g) and, slowly, 0.1 mole
(13 g) of 4-hydroxy-N,N-dimethyl-butyramide is added. The
reaction is completed by heating for 1 hour on a water bath at
50C. Then the mixture is allowed to cool and the pyridinium
hydrochloride filtered off. The filtered organic phase is
washed wlth water, dried and decolorised and the solvent is
evaporated off under vacuum. The desired ester crystallises.
- ~ ~ - 18 -
' ~
, - : -
lO~ZllO
Yield 35 g (22%). Melting point 92C.
Conversion into ester (using a secondary or primary alcohol)
Direct esterification is carried out, the ester-
ification process being one which has particularly been
investigated and adapted for use with a secondary alcohol.
Accordingly, this original process can be used in the case of
a primary alcohol with reaction kinetics which are definitely
faster; this method consists in carrying out esterification
with a relatively small amount of the chosen alcohol (1 to
1.5 litres of alcohol per 1 kg of acid of formula I and 0.6 kg
of sulphuric acid per 1 kg of acid of formula I).
EXAMPLE
:' .
Preparation of 2-(4-(p-chlorobenzoyl)-phenoxy)-2-methyl-
~pionic acid isopropyl ester
1 kg of the preceding acid is suspended in 1.5 1 of
isopropanol; 600 g of sulphuric acid is slowly added and the
reaction mixture is refluxed for 12 hours. The mixture is
allowed to cool, the ester crystallises, is carefully suction
dried, is washed with 1% concentration soda while shaking, is
suction dried again, and is recrystallised in 1.5 1 of iso-
propanol in the presence of animal charcoal; the product which ~,
recrystallises is pure :
Weight = 1.020 kg ; m.p. - 80C ; Yield : 85%
Transformation into ester (with an amino alcohol or alcohol
amide)
The reaction may of course be carried out with the
acid chloride, but the preferred method is a transesterification
starting from a simple ester (methyl ester for example) and the
chosen aminoalcohol or alcohol amide. The catalyst may be
sodium, a metal isopropylate (titanium isopropylate being
preferred) or APTS.
- 18a -
.
~,,c,,,~,~
iO~ZllO
Non-limiting Example
Preparation of Diethylaminoethyl 2-(p-benzoylphenoxy)-2-methyl-
propionate
C ~O-C-C02-CH -CH -N /
O CH3 Et
299 g (1 mole) of methyl 2-(p-benzoylphenoxy)-2-
methylpropionate, 30 g of titanium isopropylate and 117 g
(1 mole) of diethylaminoethanol are placed in a 500-cc flask.
The reaction mixture is heated for 45 minutes at 120C (interior
temperature) so as to distil off all the alcohol formed. The
mixture is then allowed to cool and poured on to 10% hydro-
chloric acid ln the presence of ether. The aqueous phase is
made alkaline and then extracted with methylene chloride. The
organic phase is carefully washed with water, then dried,
decolorised and concentrated under vacuum. The residual oil
is the desired ester. Yield 264 g, 69%. The maliate salt ~ -
melts at 62C.
For the preparation of hydroxyketones VII
X5
(~ OH
,. . ~
X4
; the common starting material for all the products prepared by
the methods Ac contemplated are those obtained by one of the
- following two methods:
.
:` ~ - 19 -
.' .
L P~ :
;. .
07 21 10
ffl e first reaction scheme is carried out regardless of the A
group
X5 X5
A-C-Cl + ~ 3 ~ 1l ~ 3 de~ethylat~>on V
X4 X4
In the seoond method the reaction is carried out wherein A is
5 the group
., X
X2 ~ . -
. A = ~ ~ -, as follows:
~' X/\=/
.'. '
, X5 X5.
. Cl-C ~ OCH A A-C ~ OCH i~
O ~ 3 ~ ~ 3 demethylat n VII
X4 x4
. . . .
, .
':
`,.
'
- l9a -
.. ~ .
. k. ~
. . ,
.,. , , ~ ..
.
., .
10"~110
A similar technique has also been contemplated con-
cerning the first step paragraph Aa. The second demethylation
stage is conducted with 48% HBr or aluminium chloride of
pyridinium hydrochloride.
Non-limiting Example
Preparation of 4'-chloro-4-hydroxybenzophenone :
510 g of a~nium chloride (3.82 M), then 3.5 1 of
dry methylene chloride, and, slowly, 430 g (4 M) of anisole
are added to a 5-litre flask; the fl~ask is cooled to maintain
- 10 the temperature at about 25C, and 600 g (3.44 M) of 4-chloro-
benzoyl chloride is then added dropwise; the reaction mixture
is next heated 6 hours under reflux, is left to cool to about
25C, and the reaction mixture is poured onto 5 kg o~ ice and ~- -
0.5 1 of concentrated HCl; the mixture is stirred well during
this hydrolysis; the methylene chloride phase is decanted,
washed once with water, and transferred to another 5-litre -
vessel. The methylene chloride is removed by evaporation and
replaced in the flask by 2 1 of chlorobenzene; a Dean-Stark
apparatus is connected and the reaction mixture is refluxed to
dehydrate the medium; when this operation is compleLe the
mixture is cooled to approximately 50C and 800 g (6 M) of
aluminium chloride is added; the reaction mixture is heated 1
hour 30 minutes under reflux (very gentle reflux), and de-
- methylation proceeds rapidly; the reaction mixture is cooled
and poured onto 6 kg of ice and 0.5 1 of concentrated HCl;
the mixture is stirred for 1 hour 30 minutes and the precipitate
is dried; the latter is washed with water, with methylene
chloride, and then dried:
Weight = 720 g ; m.p. = 178C ; Yield : 90
~ = ~lethods using an organometallic compound
It is possible to use the methods previously des-
~ - 20 -
- . .
. .
.
10~2110
cribed in paragraph Ab or in paragraph ~al below (organo-
lithium compounds). The following reaction scheme and non-
limiting example are given to illustrate this method.
X15
COCl BrMg ~
A--¦- + L ffl ~ OCH3
~ \
X4 ~ X15
A-C ~ OCH déméthylation
~ Cl ~ OC~3 X4
- X4
Non-limiting Example
Preparation of 3'-trifluoromethyl-4-hydroxybenzophenone
0.15 mole (90 cc) of n-butyl lithium is cooled to
-70C in ether. 34 g (0.1 mole) of 3-trifluoromethyl-bromo-
benzene is added drop by drop. The mixture is stirred for 5
- 10 minutes at -70C after the addition and, still at that
temperature, 23 g (0.15 mole) of sodium 4-methoxyphenyl-
carboxylate is added. The temperature is allowed to rise to
the amblent and the mixture is then stirred for 16 hours at
ambient temperature. ~he mixture is hydrolysed and extracted
with ether and the ethereal phase is washed with water, dried,
decolorised, and concentrated. There remains an oil which
crystallises from hexane. Yield 32 g (76%). ~elting point
65C.
To carry out demethylation, the 32 g of the oil
- 20 obtained in the preceding paragraph is refluxed for 30 minutes
with 170 g of pyridinium hydrochloride. The mixture is allowed
. .
- 21 -
- ~B
.
10'~110
to cool, taken up in 10% hydrochloric acid and extracted with
ether and the ethereal phase is extracted with 2N soda than
acidified with HCl. The product is precipitated. Yield 28g.
Melting Point 129C.
y - Method using a bromine derivative
X x5
A-C~ 3r ~ " ~3 OCH3 denethy ation > VII
X4 X4
Non-limiting Example
Preparation of 4-(~-thenoyl)-phenol -
.
~ C ~ OH
- O
' 10 A mixture of 20 g of 4-(~-thenoyl)-bromobenzene, 4 g
of anhydrous cupric oxide and 10 g of sodium methoxide in 130 cc
of anhydrous methanol is refluxed for 20 hours in a 250 cc flask.
Subsequently the mixture is filtered and the methanol evaporated
off, resulting in a yield of 15.3 g of 4-(~-thenoyl)-anisole.
(Melting point 73C). This is demethylated with aluminium
chloride in chloroben~ene as described above and 13 g of the
desired phenol is obtained. Yield 85%. Melting point 86C.
- Particular Instance
. ~ . .
Production of
, ~ . .
2\~C Cl ~ 03
X3 X5
where at least 2 substituents are methoxy.
:' ' .
- 22 -
.
'. '
`` 10'7Z110
In the first stage the ether chosen need not be a
methyl ether and a t-butyl of the formula
X ~ ~ CH3
X O CH3
X5
is synthesised by one of the three preoeding methods ~, ~ or ~
from which the hydroxyketone VII methoxylated at Xl, X2 or X3
can easily be regenerated (by APTS for example).
Methods not lnvolving the intermediate ether
: The OH residue of VII is introduced 1) directly by
A-COCl + ~ - OH ~ > A-C ~ } OH
This method gives excellent yields when A is aLkyl.
2) by an intermediate sulphonic acid
X5 x5
alkaline ~
A-C~/ \~SO H . . - t A-C ~ )-- OH
,/ 3 fuslon "
. X4 X4
- 3) by an intermediate nitro compound
~- X5 x5
A-C~NO2 ) A-C~ OH
. X4 X'4
This last method is generally interesting and on the other
hand of particular interest for preparing a final product of
formula I having a hydroxy substituent (for example Xl, X2 or
~j ` -- 2 3
'
iO~2110
X3 in radical A). This method has been used several times and
it is illustrated below by two examples.
Non-limitin~ Example
Preparation of 4'-chloro-4-hydroxybenzophenone
250 cc of DMSO and 4.8 g sodium hydride are placed -
in a 500 cc flask and heated at 70C for 1 hour, by which time
the solution has become clear. A solution of 24.2 g (0.2 mole)
of benzaldoxime in 100 cc of DMSO is then added drop by drop.
The solution is maintained at 70C for 1 hour, then allowed to
cool to 15C. A solution of 26 g (0.1 mole) of 4'-chloro-4-
nitrobenzophenone in lS0 cc of DMSO is then added. The reaction
mixture is stirred for 20 hours at ambient temperature and then
poured into acidulated water. The mixture is extracted with
ether and then with ether containing 2N caustic soda. On
acidification the product is precipitated. Yield 15 g (65~).
Melting point 178C.
Non-limiting Example
- Preparation of Isopropyl 2-[4-(4-hydroxybenzoyl)-phenoxy]-2-
methylpropionate
HO~ " ~O-C-C02 - CH~
' CH 3 3
- The mode of operation is identical with the above;
however, to avoid the saponification of the ester function of
the starting material, which has the formula
-- ~ C ~ C C 2
- . O CH 3 CH 3
~ the latter is dissolved in DMSO at 8C and the
:,'
,; sodlum salt of benzaldoxime suspended in DMSO, (first stage in
~ the preparation) is added little by little with a spatula. The.,
- 24 -
-
.
- .. . .
10'7Z~10
treatment is identical with that indicated in the preceding
example and the desired product is obtained in a yield of 76%,
melting point 124C.
In Table IV below all the hydroxyketones used, and
their mode of operation are set out: it is also indicated which
of them are novel compounds.
B - Access to compounds of formula I via products having a
poten~ial carboxylic acid group
The potential carboxylic acid group chosen is an
"isobutyric" aldehyde which is protected as an acetal:
CH3 / 3
..... O - C -C \ -OY3
R \ H
where Y is Cl 4 alkyl, preferably C2H5, so that the following
processes a) and b) can be employed:
a) Processes employing an organo-metallic compound
- The property which organo-metallic compounds have,
dependlng on their nature, of forming ketones when they are
; reacted with a nitrile, an acid chloride or a carboxylic acid
salt, is utilised : ketones of the formula:
,. ' X
A-C ~ ~ -C-C / OY (VIII)
X4
are thus obtained as intermediates. The aldehyde is re-
generated by hydrolysis of the acetal VIII and is oxidised to
the acid, the acid then being subjected to esterification or
amidation reactions.
Method Bal
use of an organo-lithium compound
The reaction mechanisms are sunlmarised herelnafter
(with Y3 and C2H5)
.~'
~ - 25 -
k~.
`- -, ` - . . : :
:
;.
- . . . . : -
iO7Z110
.
X5
B ~ O-C-C \ OEt ~ Li ~ -C-C\ OEt -~
X4 (IX) X4
X5 x5
~ CH3 /oEt H ~ ,CH3 KMnO4
A-C - ~ O-C-C- OEt ~ A-C ~ R O
X4 x4
(X)
; - A-C ~ CH3 >
O ~ R
X4
; The compound IX is lithiated with Bu-Li in ether at
a temperature between -70C and 0C, and the product thus
obtained is reacted with the sodium salt of the acid ACOOH
(or the-corresponding nitrile) at ambient temperature; the
ketone X thus obtained is treated in an acid medium and liberates
a ketone-aldehyde which is oxidised with potassium permanganate,
the acid obtained being esterified or amidated in accordance -
with the processes described previously. The compounds IX
;- . 10 are novel and are obtained conventionally in accordance with
, the following reaction scheme:
. ,CH3 ethyl , 3H / OH e
~' Br-C-CHO orthofonmate , \ ~ IX
R R OEt X5
Br ~ OH
., ~
~: x4
., .
., ,
! ~ ` 2 6
,: . -
.. ~ .,
,,, . . ~ , , .. ` ` ` ,
--- - ~-,: . . ' `
,
10'~2110
As has already been stated above (at Ab3), compounds X in which
A is Xl
X3~ ==J
and Xl, X2 or X3 - NH2 or OH cannot be obtained directly by
this method; such compounds are obtained from the corresponding
nitro derivative (Xl, X2 or X3 = NO2~.
Method Ba2
use of an organo-magnesium compound
, ,
X5 x5
Br ~ O-C-CH \ ~ BrMg ~ O C CH / ACOCl~
R OEt R OEt
X4 X4
The organo-magnesium compound may be obtained from IX either
; directly (Mg in ether or THF), or by exchange with CH3MgI.
Condensation of this organo-magnesium compound with an acid
chloride or a nitrile is subject to:the same comments as those
. expressed at Ab. Of course, the compounds where X or Xl, X2 or
X3 = OH or NH2 can only be obtained from a corresponding nitro
derivative.
b) Processes employing a "hydroxyketone"
.-~ This simply involves condensing a hydroxyketone with
a brominated acetal in alkaline medium according to the reaction
` X5
- 20 ~ CH3 / OEt
` - A-C-~ ~-OH + Br-C-CH ~ X
O ~ CH3 OEt
X4 ,CH3
the procedure being as described for Br - C - COY at Ac, the
condensation product X thus obtained beingRtreated as mentioned
above to give the compound I.
-~ ~ - 27 -
" L
..
iO'~ZllO
Non-limiting Example
Method for preparing compounds of formula I in which XO is
-O(CH2`,2-O-(1,3-dioxolane derivatives)
These compounds are obtained by the action of ethylene-
glycol in the presence of APTS on compounds of formula I in
which XO is oxygen and Y is other than hydrogen; the 1,3-
dioxolane derivatives are obtained. They cannot be converted
to the corresponding acids (Y=OH) by saponification. It is
~ necessary in fact to stop at the alkali salt ~XO = -O(CH2)20-
because acid cleaves the dioxolane ring previously formed and
Fegenerates the ketone acid.
- ' - .
P,
,.
-- 28 --
.`' .
,' : ' . . ` '
29 10';~2110
` -- ` e,~
¦~ o = ~ ~ oD
"
. . '
. . . . .,
=1'1 D . O O O O ..
O . . ' ' .
D D 1 ~ ¦
''. . . .
..'' ~-
,~ ? I '
. .
,,. . ~ ~
.. P~ ¢ ~ ~ ~ .
. .~ .. . . . . . . . .
.. . . . ~... ~ .
. . .
. .
.
.. ~ . ; . . ... .
. . . .
... . .
. . ~. .
~ lO~ZllO
~ . .
U
. ~ h ~ 0 0 0 r--
o h ~ ~D ~ co In 0
.~ ~ a .
:~'~
. .
.''. . ,` . .
- ~ ~ p ~ \ /' s~
.' .~ . .
. P~ ~
.
. ~ ,
. -
'~' L
. ~'' , ' ',
~ ~ ~? ? ~
.,-
,-., ~ . o ,, 0 0 0
. C~'Z
~ .
,.,. ~ o ¢ ¢ ¢ ¢ .
...
-. . .. . . ~ .. ...
... . . . ..
,. . . . . ~ ..
.. .. . . .
. .
~ iOq~llO
~q o
o h--~ C ~ ~ o 0
O ~R rl
p~ h ~ ~ ~
V ~ U V
~ u
Ca ~ ~
. e ~ ~ e
~ \/ ,,~ ~ a~
,0 . O . 0 0l . O, ,0
. . .
' ! ~ PS ~ . .
.
~C . , ' -
. .. . _ .
. . ~ : . .
... . , , .
~ ~ u
; '
~ ~ o 0 ~ ~ ~ l~
. o o a~ o o
~) z ~
:~ ~ -~ ¢ ¢ ¢ ¢ ¢ ~
:
: : : : :
iO'~ZllO
e
C~
h o ~ O --
~ a o ~ 0
~ p, h .@~ ~ ~ ~
0 C.~
. e ~ ~ .
P ~ m~ Or~
'~ '
.
. 1o1o -o o o. 1o
. __
H ~ ~<'1:1? ~ ~ ~ ~
xu)
.. '` , ~. . .. ~' . ,
`.' ' . , , ~.
X~
~. . , ,
r,,j ~ ' `
.
.''` 1 . . ~ ' .
.
, . ~ . ,~'
~ ~ S
.~ ,~-
~ ~ N ~ ~ ~ ~ N
., . __ I
.`.: e~ ~ . I~ a~ a~ o
. ~
6 ~ ¢ ¢ ¢ ~e
r ~ 1
' ' `''~
'
,.
.
-
33
~ 10~2110
r~ ~
h r ~ h ~ r.~ ~D u~ o
cs ~ r ~rl r ~
a o ~ .r .
~ r~"l . .
~ ~ - I¢
,.~ I ~ o ~ ,
~; c~ ,,
u~ ' . . . .
. . . ~ . P~ 1
.
. . ~ .
~. ~ ~ ' S ~ ~
~1
~ _~ ~
~ .
~;~ ' ' ~ . .
. ~ td ~ oo O ~ u~
. C~ Z 1~ C`~ ~ ~ ~)
C`J, ~
'' ] ~ ~ ¢ ¢ ~__ ¢~
_ . ....
...., .:
~ ' ' ' .
.. . .
' ' ' ' " : '
'. - : - ' '~ , :
' , . . , - " ~ '
. '
i~ iO7Z110
.
.
.
~ C~ U~
~~
h
a~
~ .i ~
,
.
._ .
. . ~
~ ~ /
U~ Z O :1 ' O O
~_ . I I ~ o
)-- ~ ~
H
.' ,.~
.'. ' X, ~
' " ' . ~ , .
j:' ~C~ - ~
,~ . . .
',: .' . , ' - - - .
''' ., . , , '"..
. ~ ~ ~ 3 ~ o~3
. ~ ~ ~
, . .
.~ . .
~o r. oo --I C`~ ~
~ ~ ~ o o o
c~ æ ~ ~ ~ ~ ~ ~J
~ I~ o ~ ~
. ~ ~S ¢ ¢ ¢ ¢ ¢
t
.
.
, - , .
.
. -. . ~
107Z1~0
- 3
~ .
_ .., ~
a ~ A ~ ~ , "
~a o~
o h ~ ~ '
~ S a S . ~ = ~
. O . O O O O
- : .
~1 _ ~ s~
' ~1 ~u~ . s~ s~ -
. ~ . . .
. -; '
~ -.. ' . .
. ) . . . .
. . .
. .~ ~
~ o m c~ ~
. . ' .
. ~ . '
C~ ~ . U~
~: ~ O o o .~ ~
C~ ~O;
O ~ I I I I I
.,~., 1~ ¢ 'C ¢ ¢ ~ ~
_ .
~ '' " ~ ~ ' ''., " ' "
.. ' , ' : - '
'' ' ' ' " ' '' , ' - " . "' , '' " ' ' .
:. ' .
~6
10"~2110
. __
~ C~
h ~1 a ~ o ~ o~
~ ~ .a
,~ o h ~,~1
'." _ ' . .
. ., o, X o o
':~ . .
. ~ . ", ~ ~
, : , .
*~ . . ~
'`: . . , . i,
.' . . ' ~ T ~ ,
'',, . . _ __ , .
:. . '. ' . -, - , '.
-) . . .
.
.', . . ,
~ ~ oo ~ ~ U~ o ~
:. C~ Z ~I` '` - ~ a` ~D
.,
- ' , ~ .,: ¢ ¢ ¢ el: ¢
~ . .
'~.; . ' , - ~
10721~0
~ ~l -
^ h ~ ~ ~ `D ~o co ~
rl 5~ R
i ~ R 10 ~ '~I
~ h .~
_ ~
~ ' \ ~ \,/
. D: O o ' ~ O
. ._
`~ ' ) ' ~ P: ~
,' _ , , I
, XU~ S~ - ,
. , _
~C ~
~- ~ . .... _ .. "-
: ' : . .` ` .. .
. . .
¢` ' ' .` '
~ ~ ? ~
. o o ~ X
. ~ ¢
C~ ~ ~o ,~ ~1 o~
. o o o . ,, , .
.' ~ ~ ~ D
.. ~ ¢ ¢ ~ ~ ~ o . ,
,~ .
A
_
,
' ` ` .' ' '. ' ' '`` ' ~ . ~
'
~ 10~10
~re ~
h ~ ~` ~ ~ t~ ~D 1`
0 .
~0
O ;1~ h ~
~ h .~ .
P~ O ~ o ~
~'
, S~ ~f S~ S~
. ' . ~0 ~ ~ o O
.~ ~ . ' .
~ ) o . U ~ .
'',:.;j~ . '' ~ .
~., X, . ' ~Y
'' '
X~
., . - , .
'''` )' .' . -
';-. . . '
' .
~ ~ 3 ~3~3~3 3 3
..
.' . ~. ~ a~ a
. .
c) ~ n
¢ ~ ¢ ¢ ¢ ¢
____
., .
39 1072110
. ~ C.~ I
~ O 1~ ' ~ O
e~ ~'~
. ~ ~0 C~-~
. . .
. ~.'
,. \~ b' ~=~ ~-br' '^
. o o o o o
b^ b~ b' b' ~
xu` , ~ C -
'. ~ . . . .
x ,
~ ~ 3 ~3
~ ~
,' ~Oz: ~ `J
~_~ ~ o -
~, ~ ¢ ¢ ¢ ¢_
......
-' ~- - - .
.
4.o
~ :10'72110
- o ' - .
m c~ u~
C~ h _~ h c~ O ,~
R ~ o o ~
.,~ O
r~ h ~ dq
~ . : , .
'.
.. .
'. ' .` ~ ' o o . o
,~
o ~
~ l 1- ~ I
~C ~ ~ .
,, ~ ~ ' . . .
. ' ~ ~ . - . ..
. ', ,.
, .)
.., . , . .
: . J~ o J ~ s~
. ~ ~ .
. ..... . ..
'~o ~
- ~ -
~r B~ ~ ¢ ¢ 'C ~ , , ¢ ,
~ , ~ lOqZllO
~ - -
b~ h r~ h
'm ~ .~
P~ O ~ r .
. ' , . .
~ ~ ¦ \ / O
_ ~ O O
-' æ - O . O O . , . :-
. ~ . ~ d r ~
~ .
~. .' X :~: X ~
__ . ;* . .
~C ~ ~ iX ~ X
)- ~
~o
.. , , --o~ . ' .
V~ u~
-~' ~
.i P ~ ~ ~I C~l
O 1 ¢ ' ¢ ¢ ¢ '~`c 'C
~.
.
.- . .
:
.
- ' :
.
lOq2110
' ~j .
~ o 1
h--I ql o
~o
~o '~
o h ~ ~
P< o P~ o ,1 1
T T T T Z T
. ) .
~ ~ ~ " .
: '" ........ __ ..
. ~ .
. X~ ~ ' X
. ...
~C~ ~ ,
;'' 'j '" ~ . , , - - '-' . '.
. . -' ,. .
~:' ,: ~
m m ~ .
. oo I . . , I , . I
.. VX
. .. I
' ~ L~
I~
.. ~. ¢ ¢ ¢ ¢ C ¢ ¢
. ~ _. . ~
; ~.
:, :
.
~3
iO7Zllo
C~
_~ ~rl ~ O u~ O CO 1~ CO ~ O
C~ h 0 t~ ~ ~ ~ ~ ~ 1~ 1~
h r~l J C~ r1 _~
b~ r O
o h ~ ~
~.
r1
1 ~ ~3 '
.
. I P I \/
-
~ C~ ~ ~ U~ ~~ ~
C~
~ C~ )
O O O C C~ ..
I ~ ~ O O O O O
1 ~
P
.
. ~ .
.' ~ U~ '' ' ' ' 3
~ ~C. ~
.~ . : . `.D
. .
K ~ ~
.
.'~ . '
., ,J . ~ , .
~ . . .
.~: . ¢ . ` , -, .
~ W o
.'~. . O ~ ~
~ . '
.'~ ~ ~ ~ ~ ~ ~ `J ~. ~ . ~ ' .
~d ~ ` ~ c~l _l O
C~ ~ IC~ I I
~ O '- r1c.~
~d OD COoC~ co
.`.i' P ¢ ¢ ¢ ¢ ¢ ¢ ¢ .
` i B
~ .
.
. - :
.~ . .
4~ 't 107ZilO
o ' .
. ~ Z~ :~ .
o o o o o o o ~ ~ o
.: Co~ -
S :: ~ :~ .
0 ' . _ ~ ~ .
~ , .
,'~ x~r~ ~x~.' _ , .
.. : ~ . -~ . ~ ~ ~ ~ ~ ~ ~ ~ r~
., .
g,s~ l I~ u~ )u
1 ~ I ~ w
'1 X~ X~ X X ~ X ;~ .
:,.' . _ .
~C~ :~ ~ X I~ '
,'~ .
~.
.' . X~ S ~ C r! X
:~ ~ ~~
:~ . -l y y y y y y ~ y y
-~ x ~ ~
l ~ ~--~
~ ~ ~ o ~
. ~ ~ o
P~ m ~ ~ ~ q m m m ~
. ~2 __
., ~ ~ .
~; .... . '
:- .
` lO~ZllO
`::
~ ~ U
. .. ~ .. ~ ..
P ~"~ 3 ~ O
ooo o o o. o o o ,
: .
,~. . ~: r r ~: $ r :: s r
'- ' " _ .
.' tl ~ :~ $~ $~ $~ T~
. . ' ~
~ ~ .--~ . .
_ . X $ ~ $ P: $ $ ~, ~: :C . ~
..~ _ . .
. ~: ~ $ :~ X
,." . ~ ~ ~ . ,-
'''~ ' ' X~ $ ~ $ $ $ $ $ $ :~:
_ .
x $ $ ~ $ $ r ~ $ $
' ~
. _I
X $
~ r
..,,' ,.~ ,. ,
O
_
- ~B~
- . ... . .
, ~ ~
. , , , .. ~ . . . . .
.. . . ~ - .. . . . .
.... . . . ~ ~ ~ . , -
- . - , .~ .
.:; - : .
4,~
loqzl~o
-
x~ o ~
~ ~ x ~
`J c~l ~ ~ ~ c~l c`l c`
~ ~ ~ ~ l~ ~ ~ ~ ~ ~ ~ ~ ~
$ O ~~ X X :r X X X X
c`l ~ o ~ ~ c~
~ x ~ x x ~ x c~ x $ ~ x t~ x t~ x c~
o o u o o o o o o o o o o o o o o o o o o o o
- ~ - -
--~ x~ x~ x~
_ ~: X ~ X ~ X ~ X ~ X :I X C C~ X ~ X ~:
:` l
~ l ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ` ~ ~ ~ ~ ~
.~ X ~X ~ X X ~ X X X X X X X X
~ -
~ -
X~ X ~ X ~ X :1 . X :~ X X ~: X X 5: X X~ X r: ~ X 1
,~ ~ ~ . ~ ~
H X X C~ 5: X :~: X X X X X S X :C X X X X O ~ X ~4 X :~
'' .,~ .'
,.,`'~ _ .
. ~ X~ X 1 X : X ~ x :~ :T' X ~ X X X 1 ~ 1 ~ X X :~
~. "
~ . ,~
X ~ XyyyyxXXyyxxIX:~X~:X
.. . `D `D ~O ~ .
: ~ . -- --~ ~ h h ~, _, X X
~ m ~ ~ ~ o o
_ IIIIIIIIIIII .,I
. .
c~ O ~ o ~ D r.
o
r . ~ ~ ~ ~ ~
- L~.
:
~7
lO~ZliO
~ ~ ~ X~ ~ ,~ ~,, X
~ 1
X~ OI
ooooooooooooo o o oo
~ I ~lss~ sssssss s s~ ss I
.. ~
.
.
,_ a: c~ u ~
: ~ _ . I ....
H ~C ~ ~ 1
1_1 . . .
.~ - .
X~ 1: ~ ~ X ~: 1 X ~ S ~
~`
X ~: X ~ $ ~ ~ X
~c~
X~ ~ 1 X
: - ~
:~
~ ~ o o
x ~z æ ~ z z ~4 ~ o o
I I ., I
C~l
... .
~,
O ~ ~ u~ ~ O ~
~ IIIII.IIIIIIII I I II
f~ a~ ~ ~4 ~ ~ ~ m P~ 4 ~ m ~ ~
~ _
_ ~-.
.
.
.
- .
.'' ' . ``
:. ' '
-
~ lO~ZllO
~ , .
. .
~ ,
. ~ o
`............... ~ ~, , '.
~ ~ ~ <.~ ~
^
~ .
:, o o o o o o o U~
~ .
. . a
_ . . .
_ _, . .
. . . ~ ~ ~ ~ ~ ~ ~ ~ .
. ~Y ~ d o ~
., . . 11 _.'
, I p~ U
c~ ~ l a
XU~ '~I X ~ ~ ''
. . C~
.`.' ~ . _ . ,~
E~ X X ~ n -' .
,: ) _ . . Il.
. X~ ~, ~ I o o, ~ :~
- u~ ~ D
, . ._
~ ~ .
X~ ~ 0~ 0~ 7 -
n n
.
o o
~ ~ x ~ ~ ~ a c~ a
C
. ~. ~ ~ ~ o o o o
X ~ , , , .. ..
.
O ~ D ~1
. ~ ~ D o
: ~ ~ ~ m ~ ~ m ~ :z;
r B~
. .
;'' ' ' .
4~q
10~110
~c~ ~
~l- ~
~-~`
o ~ o o
~ ~ ~7
` ,,; X~ ~
. .. ~.
~ ~ o - - .
''
~
. c~
: .
~ -c ~o~ ~
rl~ 1: ~ I
. . `
.
. ~ ` ` ` `
:
~6o
lO~Zl~O
. 1-
.
. _~ I~ I I r~ ~
. _
O O O ' O O
.
~: ~
,
., ~
,) 3~
~' ~ ~ '~
~1 . .
. ' _~ =O
- 1 1 ~ o
~ r ~
r,,~ ~ . ~ O
~ _~
~', .
~.~
'' ~~ ", O G~ "
'
~B. ~o
~ 107ZliO
X
.' . ,~ l
~ X~ $~ )
_ O O , O O O . -,
, -. . ~ ~ $~ ..
_
X ~ 1
~_ . :
. ~ . ' O O ~ O
N ~ o ~ ~0
'; ' ' . , ' . . '
'.''."'' . ' .
'~ . `
.. .
' ' _
, ' . ~0~ ~ J
C~' . '
~ . ~ ~ ~
'." : '1 ~
,",
.. ... , .. ~,
~, , .
.
lOqZllO
l ~
oD
. ~
~ ~: ~ o
. .
. . _
.. ~:
.
~.~ . ~ S , S 1 j
-) ' _ .
:~ ~ :: .
') ~ ~
-. ' . , .. : ,
.~ ' . . : ' '
.- . .
:.
-.' . . '' _
,. ` ~o j~ ~ .
.~ ~
,~ ~ C~
,
.
.
.' : ' . ~ .
~ 107~110
~ABLE IV
A-~ 011
. . . Mode oi
1~ I X4 ¦ X5 ¦ U ~. (C)~ preparAtio~ ¦
~ ~U I '
.' ~ ~
~ ~3- 1 U ~
. .......................... . ............................... .
~} 12-CU3 6-CU3
L"J ~-CU3 1 U 1 114
. ~ ~
~` ~ lOqZllO
TA131,E tV ( Cont . )
~lode ci
A X4X5 M.P. (C) preparation
.
8 ~ 8
'' ) _
Cl ~ H H 178
* ~Cl
,,) ~ ~U ~U ~
U ¦ ~ ¦ L68 ¦
. H3CO~ K U 165 1,~
- ~ ~ ~CU3 1 8 8
- . : '
.
-
., . , , - - . .
~ iO~ O
TWLE JV (Cont. )
[ A l X4 ¦ X5 ~I-P- ( C) ¦ prel~r~i* ¦
~ I U U ;~ ~
~; ~
~Jl-~ I N T P l~64
h
~ p ~ U 139 ~ ~,7
¦ ~ Cz115 ~
~B
:.~ ' " - . .
,.~ . 5~ lOq~llO
TABLE IV (Cont.)
A , ~ X5 ( o C ) ~ryr~ tio n
'.' : l ~
~ . ;~L H H 88 - a, y
_
4-chlorophényl 3-C~1 5-CE13 98
~ ' .
Note: -
New compound~ -
. . , ' ' . ,
,~ ) , . . .
; . -
-
.. ' .
~ .
. ~ ' .
... .
, . . . - . . - - . . . - - ,. . . - -
~- .. . . - . : - -.
,
: - . . . - . -
:' ' ' : '. ~ ' . ~; : .
- : ,,
- - , :
- . - ~ . : . . :
- . - - . - . :
- . : .
