JPS632945B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel ketals of 2-halo-1-(6'-methoxy-2'-naphthyl)-propan-1-one. The novel ketal of the present invention is represented by the following general formula (), and this compound generates 2-(6'-methoxy-2'-naphthyl)-propionic acid ester by rearrangement in the presence of a Lewis acid. do. This reaction is expressed by the following reaction equation: In the formula and, R is a hydrogen atom or a bromine atom; R′ is an alkyl group having 1 to 6 carbon atoms; R″ is an alkyl group having 1 to 6 carbon atoms; or R′ and R″ are together an alkylene group having 2 to 6 carbon atoms which together with the -O-C-O- group forms a heterocycle; X is a halogen atom; Y is an alkyl group having 1 to 6 carbon atoms;
Represents a substituted alkyl group or benzyl group having 2 to 6 carbon atoms. The ester represented by the general formula is naproxen (=D-2-(6'-methoxy-2'-
Naproxen is widely used in medicine because of its anti-inflammatory, sedative, and antipyretic activities. Most of the known synthetic methods for producing alpha-aryl alkanoic acids involve replacing the aromatic ring with an acyl group. The reason for this is that such substitutions can be carried out in high yields and with a high degree of regioselectivity.
In the next step, the acyl moiety is converted to an alkane moiety via a Dalzene reaction, via a modified Witzig reaction using methoxycarbenylide in place of carbenylide, via a Grignard reaction,
or via cyanidrine or via reduction to alcohol followed by halogenation and treatment with cyanide or carbon monoxide. All of the above methods have many drawbacks. This is because these methods involve many steps, typically have low yields, and the reaction reagents are expensive and highly contaminating. In view of the above, numerous efforts have been made to produce aryl-alkanoic acids by rearrangement of acyl derivatives. The known oxidative rearrangement is the Wilgerrodt reaction,
This reaction has industrial value only for producing arylacetic acids from arylmethyl-ketones, but many purification steps are required to remove sulfur-containing by-products to obtain good yields. It is not possible. GB 1535690 discloses the following steps: (i) acylation of an aromatic hydrocarbon, (ii) conversion of the ketone thus obtained into the corresponding ketal, (iii) production of an enol ether from the corresponding ketal. and (iv) rearrangement of the enol ether with thallium ions in an organic liquid containing at least one equivalent of a nucleophilic compound per equivalent of the enol ether. This method has the disadvantage that thallium ions may react with aromatic moieties and produce some by-products. Alkanoic acids produced by this synthetic method always contain trace amounts of thallium as a metal and/or organometallic compound, and thallium is extremely toxic and therefore dangerous. Surprisingly, the inventors discovered that Lewis acids (J.March-Advanced Organic Chemistry,
Mc Graw―Hill and Kogakusha e.2 edt., 236
~8; Chem.Rev., 75 , No. 1, 1-20) acted as a catalyst in producing the ester of the formula by rearranging the ketal of the formula. To achieve the rearrangement, the process is carried out such that the catalyst exhibits a large affinity for the halogen atom but a small affinity for the oxygen atom of the ketal group in the alpha-halo-ketal (). The catalyst acts as a reducing agent to produce alpha-halo
Conditions that would convert the ketal () into ketals and/or ketones should be avoided. Catalysts that can be used include acetate, propionate,
Benzoate, trifluoromethanesulfonate,
organic salts such as methanesulfonates, etc., as well as chlorides, bromides, iodides of copper, magnesium, calcium, zinc, cadmium, barium, mercury, tin, antimony, bismuth, manganese, iron, cobalt, nickel and palladium; Inorganic salts such as sulfates. In preferred examples, ZnCl ₂ , CoCl ₂ , ZnBr ₂ , SnCl ₂ ,
FeCl ₂ , FeCl ₃ , NiBr ₂ , CdCl ₂ , MgCl ₂ , HgCl ₂ ,
Hg ₂ Cl ₂ , SbCl ₃ , BaCl ₂ , CaCl ₂ , CuCl, CuCl ₂ ,
Metal halides such as MnCl ₂ , SnCl ₄ , BiCl ₃ , PdCl ₂ are used. The catalyst can be introduced directly into the reaction medium,
Alternatively, it can be produced within the reaction system. Preferably, the catalyst is used in catalytic amounts. No benefit is observed when using higher amounts. Preferably, the rearrangement is carried out in the presence of a suitable diluent. Examples of such diluents are aliphatic halogenated hydrocarbons, aliphatic cyclic hydrocarbons, lower diluents such as dichloroethane, trichloroethane, chlorobenzene, toluene, methylene chloride, methanol, trimethyl orthoformate and mixtures thereof. Alcohols, fatty acids and their esters, aromatic hydrocarbons and aromatic halogenated hydrocarbons. The rearrangement is carried out at temperatures ranging from about 0° C. to the reflux temperature of the diluent. In a preferred embodiment, a high boiling point diluent is used, considering that either the ketal () or the ester () is stable at high temperatures. The reaction time depends on the reactivity of the ketal, the catalyst activity and the reaction time. The reaction time therefore has a very wide range, ranging from about 1/2 to 160 hours. The meaning of Y in the general formula relates to the nature of the ketal and/or diluent. When R′ and R″ represent an alkyl group or a benzyl group and the diluent is not a nucleophilic compound, Y
is the same as R′ and R″. When alcohol is used as a diluent,
The alcohol participates in an esterification and/or transesterification process to form an ester of the general formula where Y represents the alkyl group of the alcohol used as diluent. When an alkylene-alpha-halo-ketal () is rearranged, Y in the ester of the formula represents a halo-alkyl group. The reason for this is that the halogen atom (X in the formula)
is substituted for one hydroxyl group of the glycol used as the substance, and the other hydroxyl group participates in the formation of an ester group. Furthermore, since scrambling may occur between the anion of the metal salt and the halogen atom (X in the formula) during the rearrangement process, the anion of the metal salt may be used as a substituent instead of X. It may exist in Y. Novel halo-ketals () are obtained by (i) halogenation of the ketone followed by the alpha-
They are easily prepared in high yields from the corresponding ketones by ketalizing the halo-ketone or (ii) ketalizing the ketone followed by halogenating the ketal thus obtained. The ketalization step can be carried out in a conventional manner using an alcohol in the presence of an acid catalyst and an orthoester. When producing ketal from glycol,
It is common to remove the water produced during the reaction by azeotropic distillation, for example with benzene, toluene, xylene, trichloroethane, etc. Introducing a halogen atom into the alpha position of a carbonyl group or ketal group can be done using sulfuryl chloride, cupric chloride, cupric bromide, N-bromo-succinamide, pyridine or pyrrolidone-perbromide hydrobromide. It can be done by The halogenation, ketalization and rearrangement steps of the alpha-halo-ketal of the general formula can be carried out in the same reactor, without isolation of intermediate products, and in the presence of the same diluent. The ketones used as starting materials in the present invention can be prepared by acylating 2-methoxy-naphthalene or 1-halo-2-methoxy-naphthalene according to the Friedel-Crafts reaction. Furthermore, 2-halo-1-(5'-bromo-6'-methoxy-2'-naphthyl)-propan-1-one is 6-methoxy-2-propionyl-naphthalene or 2-halo-1-(6 It can be produced by brominating '-methoxy-2'-naphthyl)-propan-1-one by a conventional method. 1-(5′-bromo-6′-methoxy-2′-naphthyl)-propan-1-one and 2-halo-1-
(5'-bromo-6'-methoxy-2'-naphthyl)-propan-1-one is a new compound. Removal of the bromine atom from the 5-position of the naphthalene ring is
It is carried out by conventional methods such as catalytic hydrogenation or reduction using zinc and acetic acid or zinc and formic acid. Next, the present invention will be explained with reference to Examples and Reference Examples. In the examples, IR spectra were recorded with nujol/NaCl and NMR spectra were recorded with nujol/NaCl.
Recorded on a 60MHz spectrometer. Chemical shifts are expressed in delta [ppm]. Example 1 (a) 2-bromo-1,1-dimethoxy-1-
(6′-methoxy-2′-naphthyl)-propane (A) 2-bromo-1-(6′-methoxy-2′-naphthyl)-propan-1-one (257 g, 0.877 mol) (Bull.Soc. Chim.Fr., 1962 , 90) and methyl orthoformate (271.5g,
2.56 mol), methanesulfonic acid (1.7 g),
The mixture with methanol (700ml) was maintained at 45°C for 24 hours with stirring. The reaction mixture was poured into saturated sodium carbonate solution with vigorous stirring and mixed with ethyl ether (2 x 500 ml).
Extracted with. The organic extracts were combined and washed with 2% sodium bicarbonate solution. By vacuum evaporating the solvent, 2-bromo-
1,1-dimethoxy-1-(6'-methoxy-
2′-naphthyl)-propane (290g, 0.855mol,
Yield: 97.5%) was obtained. An analytically pure sample was obtained by crystallization from a methanol/methyl orthoformate mixture.
Melting point: 87-89℃. IR: No C=O stretching. 2.5~3.2
There are no bands in the micron region. NMR: (CDCl ₃ /TMS): 1.53 (d, 3H,
J=7Hz); 3.26 (s, 3H); 3.43 (s, 3H);
3.90 (s, 3H); 4.50 (q, 1H, J=7Hz), 7
~7.98 (m, 6H). (b) 2-chloro-1,1-dimethoxy-1-
(6'-methoxy-2'-naphthyl)-propane (B) CuCl ₂ 2H ₂ O (24.56 g, 0.144 mol), lithium chloride (3.06 g, 0.072 mol), and 1-(6'-methoxy- 2′-naphthyl)-propan-1-one (12.9g, 0.060mol) (J.Chem.SOC.(C), 1966 ,
181)) and DMF (40 ml)
The mixture was maintained at 80°C for 5 hours with stirring. The solution was poured into 3% hydrochloric acid and extracted with ethyl ether (2x100ml). The combined organic extracts were washed with water, dried over Na ₂ SO ₄ and the solvent was removed under vacuum. The residue was crystallized from ethanol to give chloroketone (10.1 g),
0.41 mol, yield: 68%) was obtained as analytically pure product. Melting point: 76-78℃. IR: 1680cm ^-1 (C=O stretching) NMR: (CDCl ₃ /TMS): 1.72 (d, 3H,
J = 7Hz); 3.84 (s, 3H); 5.35 (q, 1H, J
=7Hz); 6.9-8.5 (m, 6H). 2-chloro-1-(6'-methoxy-2'-naphthyl)-propan-1-one (6 g, 24.1 mmol), methyl orthoformate (8 g, 75.4 mmol), and methanesulfonic acid 10.5 ml, 7.7 mmol ) and methanol (18 ml) was heated under reflux for 30 hours. The reaction mixture was cooled to room temperature. The precipitated white solid was collected by filtration, washed with water with a mixture of methyl orthoformate and methanol, and dried. In this way, the target compound (5.35 g, 18 mmol, yield = 75%)
I got it. Melting point: 92-94℃. IR: No C=O stretching. 2.5~3.2
There are no bands in the micron region. NMR: (CH ₂ Cl ₂ /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) 2-bromo-1,1-diethoxy-1-
(6′-methoxy-2′-naphthyl)-propane(C) 2-bromo-1,1-dimethoxy-1-
(6'-Methoxy-2'-naphthyl)-propane (obtained as described in Example 1a) (3.39 g, 10
mmol) and methyl orthoformate (1.34 g, 9
mmol) and methanesulfonic acid (0.098g, 1
A solution of 1 mmol) in ethanol (30 ml) was maintained at 46° C. for 2 hours. The reaction mixture was poured into saturated sodium carbonate solution with vigorous stirring and extracted with ethyl ether (2x250ml). The combined organic extracts were washed with 2% sodium bicarbonate solution and dried over Na ₂ CO ₃ . By vacuum evaporating the solvent, 2-bromo-
1,1-diethoxy-(6'-methoxy-2'-naphthyl)-propane (3.67 g, 10 mmol, yield: 100%) was obtained as an oil. IR: No C=O stretching. 2.5~3.2
There are no bands in the micron region. NMR: (CCl ₄ /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;
1H, J=7Hz); 7.00-8.00 (m, 6H). (d) 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)-1,3-dioxolane
(D) 2-bromo-1,1-dimethoxy-1-
(6'-Methoxy-2'-naphthyl)-propane (1 g, 2.94 mmol) (obtained as described in Example 1a), methyl orthoformate (0.5 ml, 4.7 mmol), BF ₃ .Ft ₂ O (0.3 ml) and ethylene glycol (10 ml, 180 mmol) was maintained at 50°C for 3 hours. This was cooled to room temperature, poured into saturated sodium carbonate solution with vigorous stirring, and mixed with ethyl ether (2 x 250 ml).
Extracted with. The organic extracts were combined and washed with 2% sodium bicarbonate solution. Vapor evaporation of the solvent yielded 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)-1,3-dioxolane (0.97 g, 2.82
mmol, yield: 98%). Analytically pure product was obtained by crystallization from methanol. Melting point: 75℃. IR: No C=O stretching. 2.5~3.2
There are no bands in the micron region. NMR: (CDCl ₃ /TMS): 1.60 (d, 3H,
J=7Hz); 3.90 (s, 3H); 3.90 (m, 2H);
4.13 (m, 2H); 4.48 (q, 1H, 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-propanediol (10.5 g, 138
p-toluenesulfonic acid hydrate (1 g, 5.3 mmol), and benzene (50 ml) were refluxed and stirred together in a flask under a Dean-Stark trap. The reaction mixture was added dropwise to well-stirred saturated sodium carbonate solution (100ml) and extracted with benzene (2 x 100ml). The combined organic solutions were washed with 2% sodium bicarbonate solution, dried over Na ₂ CO ₃ , filtered and concentrated under vacuum to give 2-(1′-bromoethyl)-2-(6′- Methoxy-2'-naphthyl)-1,3-dioxane (11.9 g, 34 mmol, yield: 100%) was obtained as an oil. IR: No C=O stretching. No band exists in the 2.5-3.2 micron region. NMR: (CH ₂ Cl ₂ /TMS): 1.20 (m,
2H); 1.68 (d, 3H, J=7Hz); 3.90 (m,
4H); 3.96 (s, 3H); 4.30 (q, 1H, J=7
Hz); 7.12-7.98 (m, 6H). (f) 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)-4,5-dimethyl-
1,3-Dioxolane (F) Produced by the method described in Example 1e. Reagent: (+)-2,3-butanediol (10g,
111 mmol), 2-bromo-1-(6′-
Methoxy-2'-naphthyl)-propane-
1-one (10 g, 34 mmol) Catalyst: p-toluenesulfonic acid hydrate (1 g,
5.25 mmol) Solvent: Benzene (50 ml) Reaction time: 7 hours Product: 12.3 g, 33.7 mmol, Yield: 99%,
as an oil. IR: No C=O stretching. 2.5~3.2
There are no bands in the micron region. NMR: (CDCl ₃ /TMS): 1.23 (m, 6H);
1.53 (broad d, 3H, J=7Hz); 3.65 (m,
2H); 3.83 (s, 3H); 4.43 (g, 1H, J=7
Hz); 7.00-8.00 (m, 6H). (g) 2-(1'-bromoethyl)-2-(5'-bromo-6'-methoxy-2'-naphthyl)-1,3-
Dioxolane (G) A solution of 2-bromo-1-(6'-methoxy-2'-naphthyl)-propan-1-one (29.3 g, 100 mmol) in chloroform (200 ml) was maintained at room temperature. The solution was stirred and to it was added bromine (7.9 g, 100 mmol) over 30 minutes. The precipitate formed was filtered and heated at reflux with methanol. This heterogeneous mixture was cooled to room temperature, insoluble matter was separated, washed with methanol, dried, and
-Brom-1-(5'-brom-6'-methoxy-
2'-naphthyl)-propane-1-one (24g,
64.3 mmol; yield: 64%) was obtained. Melting point:
168-170℃. IR: 1680cm ^-1 (C=O stretching) NMR: (CDCl ₃ /TMS): 1.95 (d, 3H,
J = 7Hz): 4.08 (s, 3H); 5.43 (g, 1H, J
=7Hz); 7.23-8.60 (m, 5H). 2-bromo-1- by the method described in Example 1e
(5′-bromo-6′-methoxy-2′-naphthyl)—
Propan-1-one is converted into 2-(1'-bromoethyl)-2-(5'-bromo-6'-methoxy-2'-
(naphthyl)-1,3-dioxolane. Reagents: ethylene glycol (33.3g, 0.54mol), 2-bromo-1-(5'-bromo-
6′-methoxy-2′-naphthyl)-propan-1-one (20 g, 0.054 mol) Catalyst: p-toluenesulfonic acid hydrate (1 g,
Solvent: Toluene (25 ml) Reaction time: 8 hours Product: 22.1 g, 53 mmol, 99% yield; Melting point: 103-104°C (methanol) IR: No C=O stretching. 2.5~3.2
There are no bands in the micron region. NMR: (CDCl ₃ /TMS): 1.60 (d, 3H,
J=7Hz); 4.00 (m, 2H); 4.03 (s, 3H);
4.16 (m, 2H); 4.46 (q, 1H, 7Hz): 7.20~
8.36 (m, 5H). Reference example 2 dl-2-(6'-methoxy-2-naphthyl)-propionic acid (a) 2-bromo-1-(6'-methoxy-2'-naphthyl)propan-1-one (5.86g, 20 Kent completely diluted a mixture of methyl orthoformate (6 ml), methanesulfonic acid (0.2 ml, 3.1 mmol), and methanol (16 ml).
The mixture was stirred and refluxed until it was converted to -bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphthyl)-propane. Red cuprous oxide (1.44 g, 10 mmol) was added to the solution thus obtained; the reactant mixture was refluxed for 24 hours with stirring. The suspension was cooled to ambient temperature and then poured into water, the resulting suspension was acidified with hydrochloric acid and extracted with methylene chloride. The organic phase was separated, the solvent was removed under reduced pressure and the residue was dissolved in methanol containing 30% aqueous sodium hydroxide solution.
The solution was heated under reflux for 2 hours, cooled to ambient temperature, poured into water and extracted with methylene chloride. The aqueous layer was acidified with dilute hydrochloric acid and extracted with methylene chloride. The organic extracts were collected and dried over anhydrous sodium sulfate, then the solvent was removed under reduced pressure.
3.95 g of dl-2-(6'-methoxy-2'-naphthyl)-propionic acid (melting point: 158-160°C) was obtained. Yield: 86% of theory based on the brom-kent used as starting material. (b) 2-bromo-1-(6'-methoxy-2'-naphthyl)-propan-1-one (5.86 g, 20 mmol), methyl orthoformate (6 ml), and p-
A mixture of toluenesulfonic acid hydrate (0.19 g, 1 mmol) and methanol (16 ml) was mixed with 2
The mixture was stirred and refluxed until the conversion to -bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphthyl)-propane was complete. Red cuprous oxide (0.4 g, 2.8 mmol) was added to the solution thus obtained and the mixture thus obtained was refluxed for 80 hours with stirring. This reaction mixture was treated according to the method described in Reference Example 2a to obtain dl-2-(6'-methoxy-2'-naphthyl)-propionic acid (3.6 g). The yield was 78% of theory based on the brom-kent used as starting material. (c) 2-bromo-1,1-dimethoxy-1-
(6′-methoxy-2′-naphthyl)-propane (20 mmol) and cuprous bromide (10 mmol)
, methyl orthoformate (4 ml), and methanol (16 ml) was stirred and refluxed for 160 hours. dl-2-(6'-methoxy-2'-naphthyl)-propionic acid was obtained by the method described in Reference Example 2a. The cuprous salt was recovered quantitatively and the salt was suitable for recycling. The yield was 70% of theory based on the bromoketone used as starting material. (d) 2-bromo-1-(6'-methoxy-2'-naphthyl)-propan-1-one (2.93 g, 10 mmol), methyl orthoformate (3 ml), and methanesulfonic acid (0.1 ml, A mixture of 1.35 mmol) and methanol (8 ml) was added to
1,1-dimethoxy-1-(6'-methoxy-
Reflux with stirring until complete conversion to 2'-naphthyl)-propane. Cupric benzoate (3.3 g, 11 mmol) and copper powder (0.7 g, 0.11 mmol) were added to the solution thus obtained.
mmol) was added. The mixture thus obtained was refluxed for 20 hours with stirring. The reaction mixture was treated according to the method described in Reference Example 2a to produce dl-2-(6'-methoxy-2'-naphthyl).
-Propionic acid (0.95g, 4.1 mmol) was obtained. The yield was 41% of theory based on the bromoketone used as starting material. Similar results were obtained using a catalytic amount of catalyst. (e) A mixture of acetic anhydride (0.9 g, 5 mmol), copper powder (0.32 g, 5 mmol), methanesulfonic acid (0.7 mmol), and acetic anhydride (5 ml) was stirred at 65°C for 1 hour. . The mixture was cooled to room temperature and 2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphthyl)-propane (1.7 g, 5 mmol) was added thereto. The mixture thus obtained was heated to 65° C. and maintained at this temperature with stirring for 20 hours. This reaction mixture was treated according to the method described in Reference Example 2a to obtain dl-2-(6'-methoxy-2'-naphthyl)-propionic acid (0.67 g). The yield was 58% of theory based on the bromoketone used as starting material. Similar results were obtained using a catalytic amount of catalyst. (f) 2-bromo-1-(6'-methoxy-2'-naphthyl)-propan-1-one (5.86 g, 20 mmol) and methyl orthoformate (6 ml), 96%
A mixture of sulfuric acid (0.51 ml, 5 mmol) and methanol (20 ml) was heated until complete conversion to 2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphthyl)-propane. , and refluxed with stirring. Red cuprous oxide (2.88 g, 20 mmol) was added to the solution thus obtained, and the mixture thus obtained was then refluxed for 16 hours with stirring. After this reaction mixture was treated according to the method described in Reference Example 2a, dl-2-(6'-methoxy-2'-
Naphthyl)-propionic acid (3.85g) was obtained. Yield is 84% of theory based on bromoketone
It was hot. Similar results were obtained using a catalytic amount of catalyst. (g) 2-bromo-1-(6'-methoxy-2'-naphthyl)-propan-1-one (2.93 g, 10 mmol), methyl orthoformate (2 ml), and methanesulfonic acid (0.2 ml, 2.7 mmol) and ethanol (8 ml) while stirring.
Refluxed for 48 hours. The ethyl-ketal solution obtained in this way is
Cool to 65℃ and add red cuprous oxide (2.88g, 20
(mmol) was added and the reactant mixture was then maintained at 65° C. for 8 hours with stirring. By treating this reaction mixture as described in Reference Example 2a, dl-2-(6'-methoxy-
2'-naphthyl)-propionic acid (0.2 g, 0.87 mmol) was obtained. The yield is 8.7% of the theoretical amount based on bromoketone.
It was %. Similar results were obtained using a catalytic amount of catalyst. (h) A mixture of copper powder (0.65 g, 10.2 mmol), methanesulfonic acid (0.04 ml, 0.6 mmol), methyl orthoformate (1 ml), and methanol (4 ml) was heated under reflux under nitrogen atmosphere for 30 minutes. Heated for a minute. 2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphthyl) was added to this reaction mixture.
-Propionic acid (1.7 g, 5 mmol) was added and cooled to room temperature. The reactant mixture was heated at reflux for 40 hours under a nitrogen atmosphere with stirring. By treating this reaction mixture as described in Reference Example 2a, dl-2-(6'-methoxy-
2'-Naphthyl)-propionic acid (0.35 g, 1.5 mmol, 30% yield) (melting point: 158-160°C) was isolated. Reference Example 3 Methyl dl-2-(6'-methoxy-2'-naphthyl)propionate 2-bromo-1,1-dimethoxy-1-(6'-methoxy-
2'-naphthyl)-propane (339g, 1 mol)
A solution was made by adding to 1000 ml of methylene chloride. Add to this solution while stirring at 20℃.
_ZnCl2 (19.8g, 0.17mol) was added. The resulting suspension was maintained at 20°C for 10 hours with stirring. This suspension was then diluted with 10% hydrochloric acid (2x
250 ml) and the solvent was removed by vacuum distillation. dl-2-(6'-methoxy-2'-naphthyl)-
The yield of methyl propionate was 215 g (88% yield). Reference example 4 dl-2-(5'-bromo-6'-methoxy-2'-
2-(1'-bromoethyl)-2-(5'-bromo-6'-methoxy-2'-naphthyl)-1,3-dioxolane (2 g, 4.8 mmol) and ZnBr ₂ (0.1g,
A mixture of 0.45 mmol and toluene (5 ml) was heated at reflux for 5 hours. The reaction mixture was cooled, poured into 3% hydrochloric acid (50 mol) and extracted with toluene (2 x 50 ml). Combine the organic extracts,
It was then washed with water, dried over Na ₂ SO ₄ and filtered. The solvent was evaporated under reduced pressure to give 2-(5'-bromo-
2-bromo-ethyl ester of 6'-methoxy-2'-naphthyl)-propionic acid (1.98 g, 4.75 mmol; yield 98%) was obtained. An analytically pure sample (melting point: 78-79°C) was obtained by crystallization from methanol. IR: 1730cm ^-1 (without C=O stretching) NMR: (CDCl ₃ /TMS): 1.57 (d, 3H, J
= 7Hz) 3.40 (t, 2H, J = 7Hz); 3.94 (s,
3H); 3.94 (q, 1H, 7Hz); 4.37 (t, 2H, J=
6Hz); 7.06-8.34 (m, 5H). Several alpha-halo-ketals were rearranged in a similar manner using several catalysts and solvents and using different temperatures. The results obtained are summarized in the table below. In Table 1, -alpha-halo-ketal is indicated by the code written next to the chemical name in Example 1; -Solvents are M (methanol), DCE (dichloroethane), MEC (methylene chloride), TMOF (orthoformic acid). methyl), TOL (toluene), TCE (tetrachloroethane), CB (chlorobenzene); -Yields based on the ketal used as starting material are based on propionic acid obtained by hydrolysis of the crude ester. 【table】

Claims (1)

[Claims] 1. The following general formula: (R in the formula is a hydrogen atom or a bromine atom; R' is an alkyl group having 1 to 6 carbon atoms; R'' is an alkyl group having 1 to 6 carbon atoms; or R' and R'' are the same) 2-halo-1-(6'-methoxy-2' -naphthyl)-propane-1-one ketal. 2 2-bromo-1,1-dimethoxy-1-
The compound according to claim 1, which is (6'-methoxy-2'-naphthyl)-propane. 3 2-chloro-1,1-dimethoxy-1-
The compound according to claim 1, which is (6'-methoxy-2'-naphthyl)-propane. 4 2-bromo-1,1-diethoxy-1-
The compound according to claim 1, which is (6'-methoxy-2'-naphthyl)-propane. 5. The compound according to claim 1, which is 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)-1,3-dioxolane. 6. The compound according to claim 1, which is 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)-1,3-dioxane. 7 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphthyl)-4,5-dimethyl-1,
The compound according to claim 1, which is 3-dioxolane. 8. The compound according to claim 1, which is 2-(1'-bromoethyl)-2-(5'-bromo-6'-methoxy-2'-naphthyl)-1,3-dioxolane.