Note: Descriptions are shown in the official language in which they were submitted.
;13~
i
1 This application is a divisional application
from Canadian patent application serial number 371,692
filed on February 25, 1981.
This invention relates to new compounds,
2-halo-1-(6'-methoxy-2'-naphthyl)-propan-1-one of the
general formula (I) and processes for their ~roduction.
Such compounds are useful for preparing esters of
2-(6'-methoxy-2'-naphthyl)-propionic acid via rearrangement
of the compounds of the general formula (I) in the presence
of a Lewis acid. These esters are in turn useful in-
termediates for the preparation of such compounds as
Naproxen (trade mark) which is a drug having useful
antiphloyistic, analgetic and antipyretic activity.
The compounds of the general formula (I) are
represented as follows:
R'O~ ,OR"
~ C-CHX-CH3
CH30 (I)
wherein R is selected from the group consisting of a
hydrogen and a halogen atom;
R' is selected from the group consisting of an
alkyl radical having 1 to 6 carbon atoms and
a benzyl radical;
R" is selected from the group consisting of an
al~yl radical having 1 to 6 carbon atoms and
a benzyl radical;
r~
1 R' and R"~ together, may form an alkylene
radical having 2 to 6 carbon atoms, which,
together with the -O-C-O- group, may form a
heterocyclic ring; and
X is a halogen atom.
It is an object of the present invention to pro-
vide new compounds of the general formula (I).
It is a further object of the present invention
to provide new processes for the production of the
compounds of the general formula (I).
To this end, in one of its aspects, the invention
provides a process for preparing compounds of the general
formula (I)
/ ~ ~ ,OR
CH30
R (I)
wherein R is selected from the group consisting of a
hydrogen and a halogen atom;
R' is selected from the group consisting of an
alkyl radical having 1 to 6 carbon atoms and
a benæyl radical;
R" is selected from the group consisting of an
alkyl radical having 1 to 6 carbon atoms and a
benzyl radical;
,~
6134~
1 R' and R", together, may form an alkylcne radical
having 2 to 6 carbon atoms, which, together with
the -O-C-O group, may form a heterocyclic ring;
and
X is a halogen atom;
which comprises selecting a process from the group of
processes consisting of:
(a) halogenation of the corresponaing ketone
followed by subsequent ketalization of the thus
obtained alpha-halo-ketone;
(b) ketalization of the corresponding ketone
followed by subsequent halogenation of the thus
obtained ketal.
In another of its aspects, the invention pro-
vides compounds of the general formula (I) as defined
hereinbefore.
Further objects and advantages of the present
invention will appear from the following description.
The compounds of this invention are used in a
new process for preparing esters of 2-(6'-methoxy-2'~
naphtyl)-propionic acid via rearrangement of the new
ketals of 2-halo-1-(6'-methoxy-2'-naphtyl)-propan-1
one in the presence of a Lewis acid.
34~ ~
r More particularly this new process is represent-
ed by the following scheme:
CH30 / ~ 3 ~ ~ ` \CH-COOY
R R
(I) (II)
- 3a -
~X~
1 wherein R is selected from the group comprisi.ng a hydro-
gen and a halogen atom;
R' is selected from the group comprising an alkyl
radical having from 1 to 6 carbon atoms and
a benzyl radical;
R" is selected from the group comprising an alkyl
radical having from 1 to 6 carbon atoms and a
benzyl radical;
R' and R", together, may form an alkylene radical
having 2-6 carbon atoms which, together with
the -O-C-O- group, may form an heterocyclic
ring;
X is a halogen atom;
Y is selected from the group comprising an alkyl
radical having from 1 to 6 carbon atoms, a sub-
stituted alkyl radical having from 2 to 6 carbon
atoms and a benzyl radical.
The esters of general formula II are useful as intermediate
products for preparing Naproxen* (= D-2-(6'-methoxy-2'-
naphtyl)-propionic acid) which is widely used as a drug
owing to its antiphlogisic, analgetic and antipyretic
activity.
The known synthetic routes for preparing alpha
aryl-alcanoic acids involve the substitution of the
aromatic ring with an acyl radical because this sub-
stitution may be carried out with high yields and with a
*Trade Mark
-- 4
6~340
1 high positional selectivity. The subsequent step consists
of the transformation of the acyl moiety into the
alkanoic moiety via Darzen reaction, via a variation of
the Wittig reaction which comprises the use of methoxy-
carbenylides instead of carbenylides, via the Grignard
reaction, via cyanidrine or via reduction to an alcohol,
subsequent halogenation and treatment with a cyanide or
carbon monoxide.
All of the above mentioned procedures present
many drawbacks because they involve many steps; the yields
are usually low and the reagents are expensive and
highly polluting.
In consideration of these disadvantages, many
efforts have been made to prepare aryl-alkanoic acids
lS via the rearrangement of the acyl-derivatives.
A known oxidative rearrangement is the Willgerodt
reaction, but it is of industrial value only for preparing
the arylacetic acids from the arylmethyl-ketones and it
does not produce good yields because of the many puri-
fications that are needed for eliminating the sulfur-
containing by-products.
British patent 1,535,690 describes a process
which comprises (i) the acylation of an aromatic
hydrocarbon (ii) the reaction of the ketone thus obtained
to prepare the corresponding ketal (iii) the generation of
an enol ether from the corresponding ketal (iv) the
126~3~0
. .
1 rearrangement of the enol ether with thallium ions in
an organic liquid containing, per equivalent of the
enol ether at least one equivalent of a nucleophilic
compound. This process suffers from the disadvantage that
thallium can react with the aromatic moiety to form some
by-products.
The alkanoic acids prepared according to this
synthetic route always contain traces of thallium as
metal and/or as metal-organic product and are potentially
dangerous because of the very high toxicity of thallium.
Surprisingly, it has been now found that Lewis
acids (J. March - Advanced Organic Chemistry, McGraw-Hill
and Kogakusha e. 2nd edition, 236-8; Chem. Rev., 75, No. 1,
1-20) act as catalysts in preparing esters of formula II
via rearrangement pathway of ketals of formula I.
In order to produce such rearrangement, the
process is carried out in such a way that the catalysts
exerts a good affinity toward the halogen atom and a poor
affinity toward the oxygen atom of the ketal group in the
alpha-halo-ketal (I).
Meantime, the condition when the catalysts acts
as a reducing agent and transforms alpha-halo-ketals (I)
into ketals and/or ketones, must be avoided.
Catalysts that may be used according to this
invention are the organic salts, such as acetate, propion-
ate,benzoate, trifluoromethane sulphonate, methane
x~
1 sulphonate, etc. as well as the inorganic salts such as
chloride, bromide, iodide, sulphate etc. of Copper,
Magnesium, Calcium, Zinc, Cadmium, Barium, Mercurcy, Tin,
Antimony, Bismuth, Manganese, Iron, Cobalt, Nickel and
Palladium.
A preferred embodiment of this process contem-
plates the use of metal halides such as ~nC12, CoC12,
ZnBr2, SnC12, FeC12, FeC13, NiBr2~ CdC12, MgC12, HgC12,
Hg2C12, SbC13, BaC12, CaC12, CuCl,CuC12,~nC12, BiC13, PdC12.
The catalyst may be introduced directly into the
reaction medium; alternatively, it is formed "in situ".
The catalyst is preferably used in a catalytic
amount; larger quantities do not afford appreciable
advantages.
The rearrangement according to this process
is preferably carried out in the presence of a suitable
diluent. Examples of such diluents are the aliphatic
halo-hydrocarbons, aliphatic cyclic-hydrocarbons, lower
alcohols, aliphatic acids and their esters, aromatic hydro-
carbons and aromatic halo-hydrocarbons such as dichloro-
ethane, trichloroethane, chlorobenzene, toluene, methylene
chloride, methanol, trimethyl orthoformate, and their
mixtures.
The rearrangement contemplated by this process
is conducted at a temperature in the range from about OC
to the reflux temperature of the diluent.
-- 7 --
~i134~
1 Considering that either ketals (I) or esters
(II) are stable at high temperature, a preferred embodi-
ment of this process contemplates the use of high
boiling diluents.
The reaction time differs according to the ketal
reactivity, the catalyst activity and the reaction
temperature; so it is very wide and it is within the
range from about 1/2 hour to about 160 hours.
The meaning of Y in the general formula II is
related to the nature of the ketal and/or the diluent.
When R' and R" are an alkyl radical or benzyl
radicals and the diluent is not a nucleophilic compound,
Y has the same meaning of R' and R".
When an alcohol is used as a diluent, it may
also take part in the esterification and/or transester-
ification step by forming esters of general formula II
wherein Y is the alkyl radical of the alcohol used as
diluent. When an alkylene-alpha-halo-ketal (I) is re-
arranged, then Y (in the ester II) means an halo-alkyl-
radical because the halogen atom (X in formula I)
replaces one hydroxyl-group of glycol used as precursor
whereas the other hydroxyl-group takes part in the form-
ation of the ester group.
Furthermore, scrambling between the anion of the
metal salt and the halogen-atom (X in formula I) may take
place during the rearrangement step so that the anion of
the metal salt may be present as substituent instead of
X in the radical Y.
lZ6i~
1 The new halo-ketals (I) are prepared in an easy
way and in high yields from the corresponding ketones
either ~i) by halogenation of the ketone and subsequent
ketalization of the thus obtained alpha-halo-ketone or
(ii) by ketalization of the ketone and subsequent halo-
genation of the thus obtained ketal.
The ketalization step may be carried out accord-
ing to conventional procedures by means of an alcohol in
the presence of an acid catalyst and of an ortho ester.
When the ketal is prepared from a glycol, the
water which is formed during the reaction is usually
removed by azeotropic distillation, for example with
benzene, toluene, xylene, trichloroethane, etc.
The introduction of the halogen-atom in alpha
position of the carbonyl group or of the ketal group may
be carried out by means of conventional reagents such as
sulfuryl chloride, cupric chloride, cupric bromide, N
bromo-succinamide, pyridine or pyrrolidone-perbromide
hydrobromide.
The halogenation step, the ketalization step
and the rearrangement of alpha-halo-ketals of general
formula I can be carried out in the same reaction vessel
without isolating any intermediate product and in the
presence of the same diluent.
lZ~134()
1 The ketones that are used as starting material
may be prepared by acylating 2-methoxy-naphtalene
or l-halo-2-methoxy-naphtalene according to the Friedel-
Crafts reaction.
In addition 2-halo-1-(5'-bromo-6'-methoxy-2'-
naphtyl)-propan-l-one may be prepared via conventional
bromination of 6-methoxy-2-propionyl-naphtalene or of 2
halo-l-(6'-methoxy-2'-naphtyl)-propan-1-one.
The removal of the halogen atom (for example, a
bromine atom) from 5-position of the naphtalene ring is
carried out according to conventional procedures such as
catalytic hydrogenation or reduction by means of Zinc and
acetic acid or Zinc and formic acid.
The following specific description is given to
enable those skilled in this art to more clearly under-
stand and practice the present invention. It should not
be considered as a limitation upon the scope of the
invention but merely as being illustrative and represent-
ative thereof.
For all of the examples I.R. spectra have been
recorded in Nujol*/NaCl; whereas N.M.R. spectra have been
recorded with a 60 MHz spectrometer. The chemical shifts
have been expressed in delta [ppm].
*Trade Mark
-- 10 --
` 1~6~34~
1 EXAMPLE 1
a) 2-bromo-1,1 dimethoxy-1-(6'-methoxy-2'-naphthyl)-
propane (A)
A mixture of 2-bromo-1-(6'-methoxy-2'-naphthyl)-
propan-l-one (257 g, 0.877 mol) (prepared according to
Bull. Soc. Chim. Fr., 1962, 90), trimethyl orthoformate
(271.5 g, 2.56 mol), methanesulfonic acid (1.7 g) and of
methanol (700 ml) is kept, under stirring, at 45C for
24 h. The reaction mixture is poured, under vigorous
10 stirring, into a saturated sodium carbonate solution and
extracted with ethyl ether (2 x 500 ml).
The combined organic extract is washed with a
2% sodium hydrogen carbonate solution.
Evaporation of the solvent in vacuo leaves 2-
15 bromo-l, 1-dimethoxy-1-(6'-methoxy-2'-naphthyl)-propane
(290 g, 0.855 mol, yield: 97.5%).
An analytically pure sample is prepared by
crystallization from a methanol/trimethyl orthoformate
mixture; m.p. 87-89C.
I.R.: C=O stretching is absent. No band is
present in the 2.5-3.2 microns region.
N.M.R.: (CDC13/TMS): 1.53 (d, 3H, ~=7Hz);
3.26 (s, 3H); 3.43 (s, 3H); 3.90 (s, 3H); 4.50 (q, lH,
J=7Hz), 7-7.98 (m, 6ll).
-- 11 --
.
~130~
1 b) 2-chloro-1, 1-dime;t'ho'x~-1'-(6'-methoxy-2'-na~hthyl)
. . . _
-pr'opane (B)
A mixture of CuC12.2ll2O)(24.56 g, 0.144 mol),
lithium chloride (3.06 g, 0.072 mol), 1-(6'-methoxy-2'-
naphthyl)-propan-l-one (12.9 g, 0.060 mol)(prepared
according to J. Chem. Soc. (C), 1966, 181) and of DMF
(40 ml) is kept, under stirring, at 80C for 5 h.
The solution is poured into a 3% hydrochloric
acid, extracted with ethylether (2 x 100 ml). The combined
organic extract is washed with water, dried on Na2SO4
and the solvent is removed in vacuo. The residue is
crystallized from ethanol to.give the chloroketone
(10.1 g, 0.41 mol, yield: 68%) as analytically pure
product, m.p. 76-78C.
I.R.: 1680 cm 1 (C=O stretching).
N.M.R.: (CDC13/TMS): 1.72 (d, 3H, J=7Hz); 3.84
(s, 3H); 5.35 (q, lH, J=7Hz); 6.9-8.5 (m, 6H).,
A mixture of 2-chloro-1-(6'-methoxy-2'-naphtyl)
-propan-l-one (6 g, 24.1 mmol), trimethyl orthoformate
(8 g, 75.4 mmol), methanesulfonic acid (0.5 ml, 7.7 mmol)
and of methanol (18 ml) is heated at reflux for 30 h. The
reaction mixture is cooled to room temperature. The white
solid which precipitates is collected by filtration,
washed with a mixture of trimethyl orthoformate and
methanol and dried; 5.35 g, 18 mmol, yield: 75%; m.p.
92-94C
- 12 -
12~i13~0
1 I.R.: C=O stretching is absent. No band is
present in the 2.5-3.2 microns region.
N.M.R.: (CH2C12/TMS): 1.42 (d, 3H, J=7Hz); 3.3
(s, 3H); 3.45 (s, 3H); 3.95 (s, 3H); 6.85-8.35 (m, 6H).
c) ?-bromo-l, 1=diethoxy-1-(6'-methoxy-2'-naphthyl)-
propane (C)
A solution of 2-bromo-1, 1-dimethoxy-1-(6'-
- methoxy-2'-naphthyl)-propane (obtained according to Example
la) (3.39 g, 10 mmol), triethyl orthoformate (1.34 g, 9
mmol) and of methansulfonic acid (0.098 g, 1 mmol) in
ethanol (30 ml) is kept at 46~C for 2 h.
The reaction mixture is poured, under vigorous
stirring, into a saturated sodium carbonate solution and
extracted with ethyl ether (2 x 250 ml). The combined
organic extract is washed with a 2~ sodium hydrogen
carbonate solution and dried on Na2CO3.
Evaporation of the solvent in vacuo leaves
2-bromo-1, 1-diethoxy-1-(6'-methoxy-2'-naphthyl)-propane
(3.67 g, 10 mmol, yield: 100%) as oil.
I~R.: C=O stre~ching is absent. No band is
present in the 2.5-3.2 microns region.
N.M.R.: (CC14/TMS~: 1.23 (t, 6H, J=7Hz); 1.53
(d, 3H, J=7Hz); 3.43 (q, 4H, J=7Hz); 3.90 (s, 3H); 4.50
~q, lH, J=7Hz); 7.00-8.00 (m, 6H).
d) 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)-1, 3-
dioxolane (D)
- 13
'LX6~
i.
1 A mixture of 2-bromo-1, 1-dimethoxy-1-(6'-
methoxy-2'-naphthyl)-propane (1 g, 2.94 mmol) (obtained
according to Example la), trimethyl orthoformate
(0.5 ml, 4.7 mmol), BF3Et2O)(0.3 ml), and of ethylene
glycol (10 ml, 180 mmol) is kept at 50C for 3 h. It
is cooled to room temperature and poured, under vigorous
stirring, into a saturated sodium carbonate solution and
extracted with ethyl ether ( 2 x 250 ml).
The combined organic extract is washed with a
2% sodium hydrogen carbonate solution.
Evaporation of the solvent in vacuo leaves 2-
(l'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)-1, 3-dioxolane
(0.97 g, 2.82 mmol, yield: 98~).
An analytically pure product is obtained by
crystallization from methanol, m.p. 75C.
I.R.: C=O stretching is absent. No band is
present in the 2.5-3.2 microns region.
N.M.R.: (CDC13/TMS): 1.60 (d, 3EI, J-7Hz); 3.90
(s, 3H); 3.90 (m, 2H); 4.13 (m, 2H); 4.48 (q, lH, J=7Hz);
7.04-7.92 (m, 6H).
e) 2-(1'-bromoethYl)-2-(6'-methoxy-2'-naphthyl)-1,3-
dioxane (E)
2-bromo-1-(6'-methoxy-2'-naphthyl)-propan-1-
one (10 g, 34 mmol), 1,3-propandiol (10.5 g, 138 mmol),
para-toluensulfonic acid hydrate (1 g, 5.3 mmol) and benzene
(50 ml) are refluxed and stirred together for 1 h in a
flask beneath a Dean-Stark trap.
~L~613-~
1 The reaction mixture is added dropwise to a
well stirred saturated sodium carbonate solution (100 ml),
extracted with benzene (2 x 100 ml). The combined organic
solution is washed with a 2% sodium hydrogen carbonate
solution, dried (Na2CO3), filtered and concentrated in
vacuo to give 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)
-1, 3-dioxane tll.9 g, 34 mmol, yield: 100%) as oil.
I.R.: C=O stretching is absent. No band is
present in the 2.5-3.2 microns region.
N-M-R-: (CH2C12/TMS): 1.20 (m, 2H); 1.68
(d, 3H, J=7Hz); 3.90 (m, 4H); 3.96 (s, 3H); 4.30 (q, lH,
J=7Hz); 7.12-7.98 (m, 6H).
f) 2-(1'-bromoethyl?-2-(6'-methoxy-2'-naphthyl)-4, 5-
dimethyl-l, 3-dioxolane (F)
The preparation is carried out according to the
method described in Example le.
Reagent_: (+)-2,3-butanediol (10 g, 111 mmol),
2-bromo-1-(6'-methoxy-2'-naphthyl)-propan-1-one (10 g,
34 mmol)
Catalyst- para-toluenesulfonic acid hydrate
(1 g, 5.25 mmol)
Solvent: benzene (50 ml)
Reaction time: 7 h
.
Yield: 12.3 g, 33.7 mmol, 99%, as oil
I.R.: C=O stretching is absent. No band in the
2.5-3.2 microns region
- 15 -
~3~
1 N.M.R.: (CDC13/TMS): 1.23 (m, 611); 1.53 (broad
d, 3H, J=7Hz); 3.65 ~m, 2H); 3.83 (s, 3H); 4.43 (q, lH,
J=7Hz); 7.00-8.00 (m, 6H).
g) 2-(1'-bromo-ethyl)-2-(5'-bromo-6'-methoxy-2'-naphthyl)
-1, 3-dioxolane (G)
Bromine (7.9 g, 100 mmol) is added, in 30 minutes,
to a stirred solution of 2-bromo-1-(6'-methoxy-2'-naphthyl)
-propan-l-one (29.3 g, 100 mmol) in chloroform (200 ml),
kept at room temperature.
The precipitate is filtered and heated at reflux
with methanol.
The heterogeneous mixture is cooled to room
temperature, the insoluble is filtered, washed with
methanol and dried: 2-bromo-1-(5'-bromo-6'-methoxy-2'-
naphthyl)-propan-l-one (24 g, 64.3 mmol; yield: 64~);
m.p. 168-170C:
I.R.: 1680 cm 1 (C=O stretching)
N.M.R.: (CDC13/TMS): 1.95 (d, 3H, J=7Hz);
4.08 (s, 3H); 5.43 (q, lH, J=7Hz); 7.23-8.60 (m, 5H).
The 2-bromo-1-(5'-bromo-6'-methoxy-2'-naphthyl)
-propan-l-one is converted into 2-(1'-bromoethyl)-2-(5'-
bromo-6'-methoxy-2'-naphthyl)-1, 3-dioxolane according to
the method described in example le.
Reagents: ethylene glycol (33.3 g, 0.54 mol),
2-bromo-1-(5'-bromo-6'-methoxy-2'-naphthyl)-propan-1-one
(20 g, 0.054 mol)
- 16 -
1 Catalyst: para-toluenesulfonic acid hydrate
(1 g, 5.3 mmol)
Solvent: toluene (25 ml)
~eaction time: 8 h
Yield: 22.1 g, 53 mmol, 99%; m.p. 103~104C
(methanol)
I.R.: C=O stretching is absent. No band is
present in the 2.5-3.2 microns region.
N.M.R.: (CDC13/TMS): 1.60 (d, 3H, J=7Hz);
4.00 (m, 2H); 4.03 (s, 3H); 4.16 (m, 2H); 4.46 (q, lH,
7Hz); 7.20-8.36 (m, 5H).
EXAMPLE 2
. _ . . _ . . . _ . .
dl-2-(6'-methoxy-2'-naphthyl)-propionic aci_
a) A mixture of 2-bromo-1-(6'-methoxy-2'-
naphthyl)propan-i-one (5.86 g, 20 mmol), trimethyl ortho-
formate (6 ml), methanesulfonic acid (0.2 ml, 3.1 mmol)
and methanol (16 ml) is refluxed under stirring until
the ketone is completely transformed into 2-bromo-1, 1-
dimethoxy-l-(6'-methoxy-2'-naphthyl)-propane.
To the solution thus obtained red cuprous
oxide (1.44 g, 10 mmol) is added; the reaction mixture
is refluxed under stirring for 24 h.
The suspension is cooled to room temperature
and poured into water, the resulting suspension is acid-
ified with hydrochloric acid and extracted with methylene
chloride. The organic layer is separated and the solvent
is removed under reduced pressure; the residue is dissolved
1 in methanol containing 30% sodium hydroxide aqueous
solution. This solution is heated at reflux for 2
hours cooled to room temperature, poured into water and
extracted with methylene chloride. The aqueous layer is
acidified with diluted hydrochloric acid and extracted with
methylene chloride.
The organic extracts are collected and dried
over anhydrous sodium sulphate, then the solvent is
removed under reduced pressure to give 3.95 g of dl-2-
(6'-methoxy-2'-naphthyl)-propionic acid melting at
158-160C.
Yield, 86% of the .theoretical aMount as to the
bromo-ketone used as starting product.
b) A mixture of 2-bromo-1-(6'-methoxy-2'-
naphthyl)-propan-l-one (5.86 g, 20 mmol); trimethyl
orthoformate (6 ml), p-toluene-sulfonic acid hydrate
(0.19 g, 1 mmol) and methanol (16 ml) is refluxed under
stirring until the transformation into 2-bromo-1, 1-
dimethoxy-l-(6'-methoxy-2'-naphthyl)-propane is complete.
To the solution thus obtained red coprous oxide
(0.4 g, 2.8 mmol) is added; the thus obtained mixture is
refluxed under stirring for 80 h.
By working up the reaction mixture according to
the procedure disclosed in the Example 2a dl-2-(6'-meth-
oxy-2'-naphthyl)-propionic acid (3.6 g) is obtained.
- 18 -
61;~
1 Yield 78% of the theoretical amount as to the
bromo-ketone used as starting material.
c) A mixture of 2-bromo~l, l-dimethoxy-l-
(6'-methoxy-2'-naphthyl)-propane (20 mmol), cuprous
bromide (10 mmol), trimethyl orthoformate (4 ml) and
methanol (16 ml) is refluxed under stirring for 160 h.
By following the procedure disclosed in the
Example 2a ~1-2-(6'-methoxy-2'-naphthyl)-propionic acid
is obtained whereas the cuprous salt is recovered
quantitatively and it is suitable for being recycled.
Yield, 70~ of the theoretical amount as to
the bromo-ketone used as starting material.
d) A mixture of 2-bromo-1-(6'-methoxy-2'-
naphthyl)-propan-l-one (2.93 g, 10 mmol), trimethyl
orthoformate (3 ml), methanesulfonic acid (0.1 ml; 1.35
mmol) and methanol (8 ml) is refluxed under stirring
until the transformation into 2-bromo-1, l-dimethoxy-l-
(6'-methoxy-2'-naphthyl)-propane is complete.
To the solution thus obtained cupric benzoate
(3.3 g, 11 mmol) and copper powder (0.7 g, 11 mmol) are
added; the thus obtained mixture is refluxed under stirring
for 20 h.
By working up the reaction mixture according to
the procedure disclosed in the Example 2a dl-2-(6'-
methoxy-2'-naphthyl)-propionic acid (0.95 g, 4.1 mmol) is
obtained.
-- 19 --
1~13~t~
1 Yield, 41% of the theoretical amount as to the
bromo-ketone used as starting material.
Analogous results have been obtained by using
catalytic amounts of the catalyst.
e) A mixture of anhydrous cupric acetate
tO.9 g, 5 mmol), copper powder (0.32 g, 5 mmol), methane-
sulfonic acid ~0.7 mmol) and acetic anhydride (5 ml) is
stirred for 1 h at 65C.
To the mixture cooled to room temperature 2-
bromo-l, 1-dimethoxy-1-(6'-methoxy-2'-naph-thyl)-propane
(1.7 g, 5 mmol) is added.
The thus obtained mixture is heated to 65C and
maintained at this temperature, under stirring for 20 h.
By working up the reaction mixture according
to the procedure disclosed in the Example 2a dl-2-(6'-
methoxy-2'-naphthyl)-propionic acid (0.67 g) is obtained.
Yield, 58% of the theoretical amount as to the
bromo-ketone used as starting material~
Analogous results have been obtained by
using catalytic amounts of the catalyst.
f) A mixture of 2-bromo-1-(6'-methoxy-2'-
naphthyl)-propan-l-one (5.86 g, 20 mmol), trimethyl
orthoformate (6 ml), 96% sulfuric acid (0.51 ml, 5 mmol)
and of methanol (20 ml) is refluxed under stirring until
the transformation into 2-bromo-1,1-dimethoxy-1-(6'-
methoxy-2'-naphthyl)-propane is complete.
To the solution thus obtained red cuprous
oxide (2.88 g, 20 mmol) is added; the thus obtained mixture
is then refluxed under stirring for 16 h.
- 20 -
1341~
1 By working up the reaction mixture according
to the procedure disclosed in the Example 2a dl-2-(6'-
methoxy-2'-naphthyl)-propionic acid (3.85 g) is obtained.
Yield, 84% of the theoretical amount as to the
bromo-ketone.
Analogous results have been obtained by using
catalytic amounts of the catalyst.
g) A mixture of 2-bromo-1-(6'-methoxy-2'-
naphthyl)-propan-l-one (2.93 g, 10 mmol), triethyl
orthoformate (2 ml), methanesulfonic acid (0.2 ml, 2.7
mmol) and of ethanol (8 ml) is refluxed, under stirring,
for 48 h.
The solution of the ethyl-ketal thus obtained
is cooled to 65C and red cuprous oxide (2.88 g, 20 mmol)
added; the reaction mixture is then kept at 65C under
stirring for 8 h.
By working up the reaction mixture according to
the procedure disclosed in the Example 2a dl-2-(6'-
methoxy-2'-naphthyl)propionic acid (0.2 g, 0.87 mmolj is
obtained.
Yield, 85% of the theoretical amount as to the
bromo-ketone.
Analogous results have been obtained by using
catalytic amounts of the catalyst.
- 21 -
- ~X6134a\
1 h) A mixture of copper powder (0.65 g, ]0.2
mmol), methanesulfonic acid (0.04 ml, 0.6 mmol), trimethyl
orthoformate tl ml) and of methanol (4 ml) is heated at
reflux, under nitrogen, for 30 minutes.
2-bromo~ dimethoxy-1-(6'-methoxy-2'-
naphthyl)-prionic acid (1.7 g, 5 mmol) is added to the
reaction mixture, cooled to room temperature.
The reaction mixture is heated at reflux for
40 h, under stirring and under nitrogen.
dl-2-(6'-methoxy-2'-naphthyl)-propionic acid
(0.35 g, 1.5 mmol; yield 30%) (m.p. 158-160C) is
isolated by working up the reaction mixture as described
in Example a.
EXAMPLE 3
Methyl dl-2-(6'-methoxy-2'-naphthyl)-propionate
A solution is prepared by adding 2-bromo-1, 1-
dimethoxy-l-(6'-methoxy-2'-naphthyl)-propane (339 g, 1
mol) prepared according to the procedure disclosed in
the Example 2a, to 1000 ml of methylene chloride.
To this solution ZnC12 (19.8 g, 0.17 mol) is added under
stirring, at 20C.
The suspension is kept under stirring, at 20C
for 10 h. The suspension is then washed with 10% hydro-
chloric acid (2 x 250 ml) and the solvent is removed by
distillation under reduced pressure. The yield of the
methyl dl-2-(6'-methoxy-2'-naphthyl)-propionate is 215 g
(yield, 88%).
- 22 -
~X~;13~
1 EXAMPLE 4
2-bromoethyl-ester of dl-2-(5'-bromo-6'-methoxy-2'-
naphthyl)-propionic acid
A mixture of 2-(1'-bromoethyl)-2-(5'-bromo-
-6'-methoxy-2'-naphthyl)-1, 3-dioxolane (2 g, 4.8 mmol),
ZnBr2 (0.1 g, 0.45 mmol) and of toluene (5 ml) is heated
at reflux for 5 h. The reaction mixture is cooled,
poured into 3% hydrochloric acid (50 ml) and extracted
with toluene (2 x 50 ml). The combined organic extract
is washed wi~h water, dried (Na2SO4) and filtered.
Evaporation of the solvent under reduced pressure
gives 2-bromo-ethyl ester of 2-(5'-bromo-6'-methoxy-2'-
naphthyl)-propionic acid (1.98 g, 4.75 mmol; yield 98%).
An analytically pure sample is obtained by
crystallization from methanol; m.p. 78%-79C.
I.R.: 1730 cm 1 (C=O stretching absent)
N.M.R.: (CDC13/TMS): 1.57 (d, 3H, J=7Hz);
3.40 (t, 2H, J=7Hz); 3.94 (s, 3H); 3.94 (~, lH, 7Hz);
4.37 (t,2H, J-6Hz); 7.06-8.34 (m, 5H).
In an analogous manner several alpha-halo-
ketals have been rearranged in the presence of several
catalysts, in several solvent and at different temperatures.
The results that have been obtained are
summarized in the following table wherein:
The alpha-halo-ketals are indicated with the
capital letter which follows their chemical names in
Example l;
- 23 -
1 The solvents are indicated as M (methanol),
DCE (dichloroethane), MEC(methylene chloride), TMOF
(trimethyl orthoformate), TOL (toluene), TCE (tetra-
chloroethane), CB (chlorobenzene);
Yields as to the ketal used as starting
material are based on the propionic acid obtained via
hydrolisis of crude esters.
- 24 -
1~6~34~
TABLE
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H
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l¢ rt
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Q
m m v cJ ~ o ~ C ~
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-- 25 --
~6~3~
TABL:E:
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H ~ CS~ a~ ~ a~ a~ CO ~) ~1 ~ C~ . I ~ C~
. ~ - _ _
O^
C~ O ~`I O O O LO O O Ir) u~ O 1~ o O It~ O O
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O 11') 11') 11') 1~ O O O ~I ~ I '
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b
2 0 _ Lr~ o o o o o co
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E~ m = o = = = = = =
C~
_
-- 26 --
