CA1261340A - Ketals of 2-halo-1-(6'-methoxy-2'-naphthyl)-propan- 1-one - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to novel compounds of the general formula (I) (I) wherein R is selected from the group consisting of 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 alkyl radical havina 1 to 6 carbon atoms and a benzyl radical;
R' and R" , together, may form an alkylene radical having 2 to 6 carbon atoms, which together with the group, may form a hetrocyclic ring;
and X is a halogen atom;
and processes for preparing same. Such compounds are useful as intermediate compounds for the preparation of compounds which in turn are used as intermediates for preparing Naproxen (trade mark) which is a drug having good anti-phlogistic, analgesic and antipyritic activity.

Description

;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

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 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.

~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 ` 1~6~34~

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).

.
~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.

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) '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 ~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) 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).

. _ . . _ . . . _ . .
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.

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.

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.

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.

- ~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.

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%).

~X~;13~

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;

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.

1~6~34~

TABLE

~ ~ u~ ~ In Ul o co o o o Cl~ O a) ~ ~ o _ O^
~ u~ In U) ~ O O O O O O U~ O U~ O ~n O In o u~ o o _~r ~ ~ ~ ~ o~ ,~ ~ ~ ~ ~ ~r ~ ~ ~ ~r ~D ~r E~
_ . I

H
E~
H
F:~ r) ~ ~ r` O N O ~ O O ~ Ul ~ ') N O ~1 ~ N ~ ~ 1 l¢ rt ~ . _ _ . . .__ _ O ~ ~ O ~ O O
E~ ~ o ~ ~ ~ o ~ o ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ o 1 5 ~ ~ _ ~_ _ + _ _ _ + _ ~ ~ _ _ _, + _ + _ _ _ .
H O ~ C~ -- c ) O U -- O ~ O C~ -- C~ -- ~) O W

O ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ _~
~ ~ U~ U~
_ ~r ~ ~ n ~ ~: a ~ ~ ~ a a ~ a ~ n ~ ~ .
;~

~ I^ ^ ^
_ . . . Ln o ~ ~ ,1 ~ ~ ~ U) ,~ i~ ~ ~ ~ ~ ~ ,~
E~ _ _ _ _ _ _ ~
l ~ ~ ~) ~ ~1 ~ ~J ~ ~ ~ N ~1 ~ ~I ~ ~) ~ ~r Q
m m v cJ ~ o ~ C ~

..

~6~3~

TABL:E:
...... .... __ ~ co ~ c~ 9 0 CO ~ O ~ O O O O O C~
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
~ ~l ~ ~ ~ ~ ~ ~D ~ ~r ~ ~ ~ ~n a~
E~ ~ ~ ~ ~ ,~
~ . . . ____ . .

H .

0 H ~r ~ D O 0 E~ . . ,~ ~ ,~ ~ ~ ~I r-l ~ O U~
._ ~î . ~ ~ ~
~ ' ^ ~ ~ ~ O L~ I` ,_ _ : ^ ^ ^ O O O O ~ ~ O U:~ O U~ O Ul O 11') 11') 11') 1~ O O O ~I ~ I ' E~ ~ ~ ~_ t`
~. _ _ _ _ _ P ~ ~ C) ~ C~ ~ ~ ~ ~ U ~ ~
~ o m o ~ ~ w o ~ ~ ~ o ~ o o ~ o o H E~
_ . .

O
b 2 0 _ Lr~ o o o o o co , ~ o o ~~
~! ~ ~, I` o o ,.~
E~ _ _ _ _ _ _ _. _ _ _ _ ~ _ _ _ ~
~ a ~ m ~ ~ n ~
. _ _. . .... .
a ~o ~ ~ O
_, ~ ~ Lr) r~
~ ~ ~ ~ a~ u~ t` o ~ n ~ ~ ~ ~ 1-- ~D
E~ ~ o l_ , , . . ~
u~ ~ O ~ ~ ~ co ~ .
~ ~ O
E~ m = o = = = = = =
C~
_

Claims (22)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing compounds of the general formula (I) (I) wherein R is selected from the group consisting of a hydrogen and a bromine 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 alkyl radical having 1 to 6 carbon atoms and a benzyl radical;
R' and R", together, may form an alkylene radical having 2 to 6 carbon atoms, which, together with the group, may form a heterocyclic ring; and X is a halogen atom;
which comprises selecting a process from the group of processes consisting of:
1. Claim 1 continued (a) halogenation of the corresponding 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.
2. 2. Compounds of the general formula (I) as defined in claim 1.
3. 3. A process as claimed in claim 1 wherein said ketalization step is carried out by means of an alcohol in the presence of an acid catalyst and of an ortho ester.
4. 4. A process as claimed in claim 1 wherein said ketalization step is carried out by means of a glycol while removing the water which is formed during the reaction by azeotropic distillation with a suitable solvent.
5. 5. A process as claimed in claim 4 wherein the azeotropic distillation is performed with benzene, toluene, xylene or trichloroethane.
6. 6. A process as claimed in claim 1 wherein said halogenation step is carried out by means of sulfuryl chloride, cupric chloride, cupric bromide, N-bromo-succinamide, pyridine or pyrrolidone-perbromide hydro-bromide.
7. 7. A process as claimed in claim 1 wherein said corresponding ketone is prepared by acylating 2-methoxy-naphthalene or 1-halo-2-methoxy-naphthalene using a Friedal-Crafts reaction.
8. 8. A process as claimed in claim 1 wherein said corresponding ketone is prepared by bromination of 6-methoxy-2-propionyl-naphthalene or of a 2-halo-1-(6'-methoxy-2'-naphthyl)-propan-1-one.
9. 9. A process as claimed in claim 1 for preparing 2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphthyl)-propane which comprises brominating 1-(6'-methoxy-2'-naphthyl)-propan-1-one followed by ketalization with methanol, trimethyl orthoformate and methansulfonic acid.
10. 10. 2-Bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphthyl) propane.
11. 11. A process as claimed in claim 1 for preparing 2-chloro-1,1-dimethoxy-1-(6'-methoxy-2'-naphthyl)-propane which comprises chlorinating l-(6'-methoxy-2'-naphthyl)-propane-1-one followed by ketalization with methanol, trimethylorthoformate and methansulfonic acid.
12. 12. 2-Chloro-1,1-dimethoxy-1-(6'-methoxy-2'-naphthyl)-propane.
13. 13. A process as claimed in claim 1 for preparing 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)-1,3-dioxolane which comprises brominating 1-(6'-methoxy-2'-naphthyl)-propan-1-one followed by ketalization with ethylene glycol, trimethylorthoformate and boron trifluoride ethanoate.
14. 14. 2-(1'-Bromoethyl)-2-(6'-methoxy-2'-naphthyl)-1,3-dioxolane.
15. 15. A process as clalmed in claim 1 for preparing 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)-1,3-dioxane which comprises brominating 1-(6'-methoxy-2'-naphthyl)-propane-1-one followed by ketalization with 1,3-propane-diol and p-toluenesulfonic acid hydrate while removing the water which is formed by azeotropic distillation with benzene.
16. 16. 2-(1'-Bromoethyl)-2-(6'-methoxy-2'-naphthyl)-1,3-dioxane.
17. 17. A process as claimed in claim 1 for preparing 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)-4,5-dimethyl-1,3-dioxolane which comprises brominating 1-(6-methoxy-2'-naphthyl)-propan-1-one followed by ketalization with 2,3-butanediol and p-toluenesulfonic acid hydrate while removing the water which is formed by azeotropic distillations with benzene.
18. 18. 2-(1'-Bromoethyl)-2-(6'-methoxy-2'-naphthyl)-4,5-dimethyl-1,3-dioxolane.
19. 19. A process as claimed in claim 1 for preparing 2-(1'-bromoethyl)-2-(5'-bromo-6'-methoxy-2'-naphthyl)-1,3-dioxolane which comprises brominating 1-(6'-methoxy-2'-naphthyl)-propan-1-one to afford 2-bromo-1-(5'-bromo-6'-methoxy-2'-naphthyl)-propan-1-one followed by ketalization with ethylene glycol and p-toluenesulfonic acid hydrate while removing the water which is formed by azeotropic distillation with toluene.
20. 20. 2-(1'-Bromoethyl)-2-(5'-bromo-6'-methoxy-2'-naphthyl)-1,3-dioxolane.
21. 21. A process as claimed in claim 1 wherein R' and R" are each selected from an alkyl radical having 1 to 6 carbon atoms and R' and R" together may form an alkylene radical having 2 to 6 carbon atoms, which, together with the group may form a heterocyclic ring selected from a 1,3-dioxolane ring and a 1,3-dioxane ring.
22. 22. A compound as claimed in claim 2 wherein R' and R" are each selected from an alkyl radical having 1 to 6 carbon atoms and R' and R" together may form an alkylene radical having 2 to 6 carbon atoms, which, together with the group may form a heterocyclic ring selected from a 1,3-dioxolane ring and a 1,3-dioxane ring.