DK145338B - ANALOGY PROCEDURE FOR PREPARING L 2- (6-METHOXY-2-NAPHTHYL) -1-PROPANOL - Google Patents

Description

Μ®) VREL / OD PUBLICATION MANUAL 145338 (61) Supplement to Pat. 141165 DENMARK »" "" t el. "C 07 c <3/23 § (21) Application No. 691 6/69 (22) Filed on JO de C. 1 9 ^ 9 (24) Running day JO Dec. 19 ^ 9 (44) The application submitted and the act of proclamation published on 1 November 1982

DIRECTORATE OF

PATENT AND TRADEMARKET SYSTEM (»I $ Te ^ 19§l, 862453, VS

JO. eep. 19, 862454 US

JO. eep. 19 &), 862455 US

JO. September 1969, 862471, US

JO. September 1969, 862475, US

JO. βep. 1969, 862498, US

JO. eep. 1969, 8625OI, US

<71) SYNTEX CORPORATION, Panama, PA.

(72) Inventor: John Hans Pried, US: Ian Thomas Harrison, US: Peter Harold Nelson, US.

(74) Plenipotentiary in the proceedings:

The company Chas. Skin (54) Analogous procedure for the preparation of 1- 2- (6-methoxy-2-naphthyl) -1-propanol.

Patent No. 141,165 relates to an analogous process for the preparation of 1- (6-methoxy-2-naphthyl) -1-propanol or derivatives thereof of the formula CH

3 wherein R · is hydroxy, acetoxy or propionoxy, and the peculiar feature of the main patent is that a racemic mixture or the d-isomer of one compound of the formula: with a) lithium aluminum hydride in an inert organic ether at a temperature between 0 ° C and the boiling point of the solvent used; or b) diborane in tetra = hydrofuran at a temperature between ca. 0 ° C and approx. 65 ° C, and when R 1 is acetoxy or propionoxy the hydroxy group present is acylated, and the reaction product, if necessary, is cleaved to prepare the 1-isomer.

The present invention relates to other analogous methods for the preparation of 2- (6-methoxy-2-naphthyl) -1-propanol of the formula: CH

In CH-OH

and the method according to the invention is characterized by the characterizing part of the claim.

The compound of the present invention is effective against inflammation, pain and fever, and is consequently used in the treatment of inflammation, pain and pyrexia in mammals. Eg. For example, inflammatory conditions in the muscular skeletal system, skeletal joints and other tissues can be treated. Accordingly, this compound is useful for the treatment of conditions characterized by inflammation, such as rheumatism, concussion, laceration, joint inflammation, fractures, post-traumatic conditions and arthritis.

A comparison between oral effects of dl and the 1 propanol compounds shows that while the dl compound has an 8 times more potent effect on fever than aspirin and a 7 times stronger effect on inflammation than phenylbutazone, the 1-propanol compound has a 22 and 12 times more potent than the known compounds, i.e., the 1 compound is almost 3 or almost 2 times as effective as the known d1 compound.

Regardless of which of the processes A, B, C, D, E, F or G used in the preparation of 1- (6-methoxy-2-naphthyl) -1-propanol, the process of the invention is terminated by a cleavage of dl 2 - (6-methoxy-2-naphthyl) -l-propanol. The latter compound may be optically cleaved such as by selective biodegradation or by the preparation of diastereoisomeric salts of the phthalic acid ester of 2- (6-methoxy-2-naphthyl) -1-propanol with a cleaved optically active amine base such as cinchonldine and subsequent isolation of the formed isomers by fractional crystallization. The separated isomeric salts are then acidified to form the respective ester, which is then hydrolyzed to give the corresponding 1- (6-methoxy-2-naphthyl) -1-propanol.

Method A can be illustrated by the following formulas: 1

CH, CHX

I 3 I 3. ^ Ns> «^ SsyCH-CH2 ^ B.

3 (I) X 3 (Ia) 2] / CH 3

The trisubstituted boranes of formula Ia are prepared by reacting the compound of formula 1 with diborane in an ether solvent.

The ether solvents suitable for this reaction are not critical. Suitable ethers include diethyl ether, diglyme and tetrahydrofuran.

4 145338

This reaction can be carried out at a temperature of 0 to 40 ° C.

The time required for this reaction depends on the temperature, but times from 1 to 6 hours are usually sufficient.

The compound of formula II is prepared by treating the compound of formula Ia with hydrogen peroxide in an aqueous solution of an inorganic base such as an alkali metal hydroxide or carbonate, e.g. sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, or · - · potassium carbonate. Base concentrations in the solution can be from 1 to 10% by weight%. The amount of hydrogen peroxide in the solution should be at least 3 and preferably above 5 molar equivalents.

This reaction is carried out at a temperature of 0 to 60 ° C, preferably at approx. 40 ° C. The time required for the reaction depends on the temperature. Times from 30 minutes to 12 hours are usually sufficient. The compound of formula II is then separated from the reaction mixture in the usual manner. The reaction mixture can e.g. is extracted with ether and the ether phase is evaporated to dryness to give 2- (6-methoxy-2-napthyl) -1-propanol, which is recrystallized from acetone / hexane. Alternatively, other methods including chromatography can be used to isolate the compound of formula II.

The starting compound of formula I can be prepared by reacting 2-acetyl-6-methoxynaphthalene (a known compound) with methyl magnesium bromide in tetrahydrofuran (THF) at reflux temperature, followed by addition of a mineral acid and a further reflux period, diluting the reaction mixture with water and extracting it. aqueous mixture with chloroform. The chloroform extracts are then dried and evaporated to dryness to give the compound of formula I.

Process B can be illustrated by the following formulas: prr CH, Rfcrcr 3 (Ib) (II) wherein M is MgCl, MgBr, Mgl, Li, Na, K, Zneller Cd-jyg, preferably MgCl, MgBr or Lacking.

The compound of formula XI is prepared by treating the compound of formula Ib with formaldehyde, preferably as paraformaldehyde, at a temperature of 40 ° C to the reflux temperature of the mixture until a molar equivalent of formaldehyde has reacted with the compound of formula Ib. Usually times from 1 hour to 48 hours are sufficient for this reaction, the time depending on the temperature of the reaction mixture. The reaction mixture is then acidified with a suitable acid, preferably a dilute acid of the type described above, and the compound of formula II is separated from the reaction mixture by conventional methods. The intermediate reaction mixture can e.g. is evaporated to dryness and the residue is acidified with a dilute acid and diluted with water to precipitate the compound of formula II. This can be isolated by filtration and recrystallized from acetone / hexane. Alternatively, the compound of formula II can be removed by extraction with ether or a corresponding solvent and the ether phase is evaporated to give a residue which is recrystallized from acetone / hexane. Other conventional separation methods including chromatography may also be used.

Starting compounds of formula Ib are prepared by a process which can be illustrated as follows: CH 3

CH 3 O

-3 (A) 3 <B> CH,

JT'T

CH = O

(Ib) 145338 6 In the above formulas, M has the previously defined meaning and X is iodine, bromine or chlorine.

The compounds of formula (B) are prepared by the following procedure. The compounds of formula (A) are reduced to the corresponding alcohol by treatment with sodium borohydride in ethanol at room temperature for 30 minutes followed by gentle acidification of the reaction mixture with dilute hydrochloric acid and extraction of the reaction mixture with diethyl ether. The ether phase is evaporated to dryness to give the alcohol. The residue is reacted with p-toluenesulfonyl chloride in pyridine at room temperature for approx. 15 hours followed by washing with dilute hydrochloric acid, extraction with ether and evaporation of the ether phase to give the corresponding p-toluenesulfonate. The residue from this reaction is then reacted with excess lithium halide (lithium bromide, chloride or iodide) in acetone for 24 hours at room temperature, and then the reaction mixture is diluted with water and extracted with ether. The ether phase is then evaporated to dryness to give the corresponding halides of formula (B).

The compounds of formula Ib wherein M is MgCl, MgBr or Mgl (the preferred compounds) are prepared by reacting the corresponding halide of formula (B) in tetrahydrofuran with an excess of magnesium powder at ca. 45 ° C. The reaction product is then separated from the metal excess. The same process can be used to prepare the corresponding compounds of formula I wherein M is Li or zn ± / 2 'by replacing the magnesium powder with the corresponding lithium or zinc powder.

The compounds of formula Ib in which M is cd] / 2 'are prepared by treating the corresponding compound in which M is MgBr with cadmium chloride in tetrahydrofuran at room temperature for approx. 30 minutes. To prepare the compounds of formula Ib wherein M is Na or K, this procedure is repeated, but the cadmium chloride is replaced with finely divided sodium or potassium.

Process C may be elucidated by the following formulas: In the first step of the process, the process is to react the compound of formula Ic, a known compound, with propylene oxide in the presence of a Lewis acid in an inert organic solvent until 2- (6-methoxy-2-naphthyl) -1-propanol is formed.

Any Lewis acid can be used for this reaction, e.g. aluminum chloride, aluminum bromide, stannous chloride, boron trifluoride, boron trichloride, boron tribromide, zinc chloride and zinc bromide.

Any inert organic solvent for the reactants can be used in this process. Suitable solvents include aromatic solvents such as benzene and toluene, substituted aromatic solvents such as nitrobenzene, carbon disulfide and chlorinated alkanes such as 1,1,2,2-tetrachloroethane, carbon tetrachloride and chloroform.

The reaction is carried out at a temperature from -10 ° C to 40 ° C, preferably from -10 ° C to 20 ° C. The time required for the reaction depends on the reaction temperature, with times from 30 minutes to 24 hours usually being sufficient. The reaction mixture is then acidified with an aqueous acidic solution.

The compound of formula II is then separated from the reaction mixture in the usual manner. The reaction mixture can e.g. extracted with ether or a similar solvent, preferably after acidification with a dilute acidic solution. Any strong inorganic or organic acid can be used as the acid. Suitable acids include trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, daltic acid, hydrobromic acid, hydrogen iodide acid, sulfuric acid and phosphoric acid. The ether phase is then evaporated in vacuo. The residue is then chromatographed on alumina and elution with ether gives 2- (6-methoxy-2-naphthyl) -1-propanol.

145338 8

Method D can be elucidated by the following formulas: CH3 CH3 fif! ch3 ° (Id) 3 (II) The first step of the process comprises reacting the compound of formula Id with a metal hydride in an ether solvent in the presence of a Lewis acid.

Suitable metal hydrides include diborane, lithium aluminum hydride, sodium borohydride, potassium borohydride and lithium borohydride. It is not critical which metal hydride is used.

Any Lewis acid can be used in this reaction. Suitable Lewis acids include aluminum chloride, boron trichloride, boron trifluoride, boron trifluoride diethyl ether, aluminum bromide and boron tribromide.

Any ether solvent can be used for this reaction. Suitable ethers include diethyl ether, tetrahydropyran, tetrahydrofuran or dimethoxyethane. The reaction temperature is not critical for this reaction, as temperatures from -10 to 60 ° C are suitable. The time required for the reaction depends on the reaction temperature and times from 4 hours to 1 day are usually sufficient.

The compound of formula II is then separated from the reaction mixture in the usual manner. The reaction mixture can e.g. diluted with water or mixed with ice and extracted with diethyl ether or a similar solvent. The organic phase is then separated, dried and evaporated to dryness and the residue is crystallized from acetone / hexane to give the compound of formula II. Chromatography can also be used to purify and / or isolate the compound of formula II.

Process E can be illustrated by the following formulas: ™ 2 CH3 / C-CH2OH ΓΤΤ CH3 ° (le) 3 (II)

The compounds of formula II are prepared by reacting the compounds of formula I1 with hydrogen in the presence of a hydrogenation catalyst in an inert organic solvent.

Suitable hydrogenation catalysts for this reaction include palladium, platinum, ruthenium, rhodium or trichlorotris (methylpropyl = phenylphosphine) rhodium.

The reaction is carried out in an inert organic solvent, e.g. a liquid alkanol such as methanol or ethanol, esters such as ethyl acetate, ethers such as diethyl ether, tetrahydrofuran, tetrahydropyran and dimethoxyethane, and hydrocarbons such as n ~ hexane, benzene. toluene and xylene. Halogenated hydrocarbons are disadvantageous as they usually deactivate the catalyst.

The reaction can be carried out in an acidic, neutral or basic solution. The reaction is preferably conducted under neutral conditions.

The temperature at which the reaction is carried out is not critical. The reaction may, e.g. is carried out at a temperature of 0 ° C to the boiling temperature of the solvent or even higher temperatures (if the system is pressurized). The reaction is carried out until hydrogenation occurs, usually from 15 minutes to 48 hours. Usually 2 hours is sufficient.

The compound of formula II is then separated from the reaction mixture by conventional methods such as filtration to remove the catalyst, followed by evaporation.

The starting compound of formula Ie can e.g. is prepared by treating a 6-methoxy-2-naphthylacetic acid ester with formaldehyde or paraformaldehyde and an alkali metal alkoxide in dimethyl sulfoxide, followed by acidification of the reaction mixture. There is thus obtained 2- (6-methoxy-2-naphthyl) acrylic acid (Formula If) which upon reduction with lithium aluminum hydride in an ether solvent such as diethyl = ether gives the corresponding 2 "(6-methoxy-2-naphthyl) -2-propene -l-ol of formula le.

Process F can be elucidated by the following formulas: ch20 ch,

M O »I, O

C-C_QH CH-CH2-OH

W 3 (II)

The compound of formula II is prepared by reacting the compound of formula If with diborane in an ether solvent.

The ether solvent for this reaction is not critical. Suitable ethers include diethyl ether, dimethoxyethane, tetrahydrofuran, and tetrahydropyran. At least 1 molar equivalent and preferably 2 molar equivalents of diborane are included in the reaction mixture.

the temperature of this reaction is not critical as temperatures from -10 ° C to 30 ° C and preferably from 0 ° C to 20 ° C are satisfactory.

The time required for the reaction depends on the reaction temperature, but times from 1 to 12 hours are usually sufficient.

Excess diborane is preferably decomposed before separating the product from the reaction mixture. Diboran excess can e.g. is decomposed by adding any organic or inorganic acid to the reaction mixture. Acetic acid is e.g. a suitable organic acid.

145338 11

The compound of formula II is then separated from the reaction mixture in the usual manner. The reaction mixture can e.g. is diluted with water and extracted with ether and the ether phase is separated and evaporated to dryness to give the compound of formula IX. Chromatography can also be used to purify and / or isolate the compound of formula II.

Process G can be illustrated by the following formulas: CH3

CH-CH2-OH

CH30 dg) (ii)

The first step of the process G according to the invention is to react the compound of formula Ig with a compound of formula X10 CH3-CH-CH2-0-C-R6 wherein X1 is chlorine, bromine or iodine and R6 is a C C--CC alkyl, Cg-C1Q aryl or Cg-C ^ ^ aralkyl group, in the presence of a Lewis acid in an inert organic solvent, until a 2- (6-methoxy-2-naphthyl) -1- propanol-C1-C24 alkyl, -Cg-C10 aryl or -cg-G10 aralkyl = carboxylate is formed.

Any Lewis acid can be used for this reaction, e.g., aluminum chloride, aluminum bromide, stannous chloride, boron trifluoride, boron trichloride and boron tribromide.

Any inert organic solvent for the reactants can be used in this process. Suitable solvents include aromatic solvents such as benzene and toluene, substituted aromatic solvents such as nitrobenzene, carbon dioxide sulfide and chlorinated alkanes such as 1,1,2,2-tetrachloroethane, carbon tetrachloride and chlorochrome.

U5338 12

The reaction is carried out at a temperature from -10 ° C to 40 ° C, preferably from -10 ° C to 20 ° C. The time required for the reaction depends on the reaction temperature, with times from 30 minutes to 48 hours usually being sufficient.

The reaction product is then hydrolyzed to form the free alcohol by treatment with base or by treatment with a strong acid. For basic hydrolysis, a solution of a strong base such as sodium or potassium hydroxide in a suitable solvent such as water is mixed with the reaction mixture and the reaction mixture is kept at a temperature of 25 ° C to the reflux temperature until hydrolysis occurs. Usually, 10 minutes to 6 hours is sufficient for this hydrolysis.

Alternatively, the reaction mixture is mixed with a solution of a strong organic or inorganic acid such as trifluoroacetic acid, p-toluenesulphonic acid, hydrochloric acid, hydrobromic acid, hydrogen iodide acid, sulfuric acid or phosphoric acid at a temperature of at least 60 ° C and preferably from 90 ° C to the boiling point of the mixture. until hydrolysis occurs. Suitable solvents for the acid include water, vinegar = acid and aqueous alcohols.

The product of formula II is then separated from the reaction mixture in the usual manner. The reaction mixture can e.g. extracted with ether or a similar solvent, the ether phase is washed with water for neutral reaction, dried and evaporated to dryness to give the compound of formula II. Chromatography can also be used to purify and / or isolate the product of formula II.

The compounds of formula I g and the 2-halo-1-propanol-alkyl, -aryl and -aralkyl carboxylates are well known compounds.

The invention is further illustrated by the following examples.

145338 13

Example 1 (Method A)

A solution of 10 g of 6-methoxy-2- (2-propenyl) naphthalene in 100 ml of ether is treated with a solution of dlborane in tetrahydrofuran until analysis by thin layer chromatography shows that the reaction is complete. The mixture is then treated at 0 ° C red 50 ml of 3N aqueous sodium hydroxide and 20 ml of 30% hydrogen peroxide added in portions over a period of 30 minutes. After stirring for 4 hours at 40 ° C, water is added to the reaction mixture and the product is extracted with ether. The ether phase is evaporated to dryness to give dl-2- (6-methoxyxy-2-naphthyl) -1-propanol, m.p. 88.6 ° C (recrystallization from acetone / hexane).

Example 2.

A mixture of 22 g of dl-2- (6-methoxy-2-naphthyl) -1-propanol, 30 g of phthal * = acid anhydride and 500 ml of pyridine is stirred for 6 hours at room temperature.

The resulting mixture is then diluted with water and extracted with methylene chloride. The combined extracts are washed with water, aqueous 0, 1N hydrochloric acid and with water for neutral reaction, dried over sodium sulfate and evaporated to dryness to give the phthalic acid ester which is crystallized from aqueous ethanol.

This ester (36 g), 29 g cinchonidine and 500 ml methanol is stirred for 2 hours. The mixture is then allowed to stand until the crystallization is complete. The crystals are removed by filtration and washed with methanol (the filtrate and washings are collected). The crystals are then recrystallized from methanol, filtered, washed and dried. The pure crystals are added to 600 ml of 0.2N hydrochloric acid, and the resulting mixture is stirred for 2 hours and then extracted with diethyl ether. The extracts are combined, washed with water for neutral reaction, dried over sodium sulfate and evaporated.

The resulting residue is added to a mixture of 5 g of sodium hydroxide, 250 ml of water and 250 ml of tetrahydrofuran. After the resulting mixture has been allowed to stand for 2 hours at 23 ° C, the mixture is extracted with methylene chloride. The combined extracts are washed with aqueous acid and then with water for neutral reaction, dried over sodium sulfate and evaporated to give one of the optical isomers of 2- (6-methoxy-2-naphthyl) -1-propanol, namely - (6-irethoxy-2-naphthyl) -1-propanol, srrp. 88-89 ° C [α] D = -17 °.

The combined filtrates and washings are evaporated and the residue is treated as described above for cleavage of c inconidine all and hydrolysis of the ester to form the second optical isomer of 2- (6-methoxy-2-naphthyl) -1-propanol, viz. 2- (6-methoxy-2-naphthyl) -1-propanol, m.p. 88-89 ° C.

Example 3 (Method B) a) A solution of 12.5 g of 1-bromo-1- (6-methoxy-2-naphthyl) -ethane in 100 ml of tetrahydrofuran is slowly added to a stirred mixture of 10 g of magnesium powder in 100 ml of tetrahydrofuran. at 45 ° C. After the addition is complete, the mixture is stirred for 15 minutes and the solution is separated from the excess metal to give 1- (6-methoxy-2-naphthyl) -1-ethylmagnium = bromide.

If the above procedure is repeated, but if the magnesium powder is replaced with lithium or zinc powder, the corresponding 1- (6-methoxy-2-naphthyl) -1-ethyl lithium or zinc is formed.

The above solution (after separation from metal excess) is mixed with 7 g of cadmium chloride and the reaction mixture is stirred for 30 minutes to give a solution containing the corresponding 1- (6-methoxy-2-naphthyl) -1-ethyl cadmium.

Repeat this procedure but replace the cadmium chloride with finely divided sodium or potassium to give the corresponding 1- (6-methoxy-2-naphthyl) -1-ethyl sodium or potassium.

b) Add 5 g of paraformaldehyde to a solution of 0.1 equivalent of 1 "(6-methoxy-2-naphthyl) -1-ethylmagnium bromide in 20 ml of tetrahydrofuran, and reflux the mixture for 24 hours. The reaction mixture is then evaporated to dryness and the acid S with excess dilute hydrochloric acid and then diluted with water 2- (6-methoxy-2-naphthyl) -1-propanol is then precipitated from the mixture and removed by filtration and crystallized from acetone / hexane.

Repeat this procedure but replace 1- (6-methoxy-2-naphthyl} -1-ethylmagnium bromide with the corresponding 1- (6-methoxy-2-naphthyl) -1-ethylmagnium iodide, 1- (6-methoxy-2-naphthyl) ) -1-Ethylmagnium chloride, 1- (6-methoxy-2-naphthyl) -1-ethyl-lithium, 1- (6-methoxy-2-naphthyl) -1-ethyl-zinc, 1- (6-methoxy-2- naphthyl) -1-ethyl cadmium, 1- (6-methoxy-2-naphthyl) -1-ethyl sodium and 1- (6-methoxy-2-naphthyl) -1-ethyl potassium are obtained correspondingly 2- (6-methoxy-2- naphthyl) -1-propanol.

The 2- (6-methoxy-2-naphthyl) -1-propanol product prepared as described is cleaved e.g. as given in Example 2, to give the 1-optical isomer of 2- (6-methoxy-2-naphthyl) -1-propanol, m.p. 88-89 ° C.

Example 4 (Method C)

A solution of 16 g of 2-methoxynaphthalene in 250 ml of nitrobenzene containing 26 g of aluminum chloride is treated at 0 ° C with 6 g of propylene = oxide for 2 hours. After an additional 1 hour, the mixture is poured into 500 ml of aqueous 1N hydrochloric acid and the product is extracted with ether. Evaporation of the solvents in vacuo and chromatography of the residue on alumina, eluting with ether, gives 2- (6-methoxy-2-naphthyl) -1-propanol.

Repeat the procedure, but replace aluminum chloride with aluminum bromide, saphanochloride, boron trifluoride, boron trichloride and boron tribromide, or replace nitrobenzene with carbon disulfide, 1,1,2,2-tetrachloroethane or benzene, in each case 2- (6-methoxyphenyl) is obtained. 2-naphthyl) -1-propanol. The 1- (6-methoxy-2-naphthyl) -1-propanol product, prepared as described, is digested e.g. as given in Example 2, to give the 1-optical isomer of 2- (6-methoxy-2-naphthyl) -1-propanol, m.p. 88-89 ° C.

16 145338

Example 5 (Method D) a) 2-Acetyl-6-methoxynaphthalene was prepared as follows. Ni = trobenzene (14,000 ml) and 2-methoxynaphthalene (2000 g) were mixed under nitrogen and cooled to 0-5 ° C. To this solution was added aluminum trichloride (2600 g) in nitrobenzene (20,000 ml) pre-cooled to 0-5 ° C. Acetyl chloride (1300 g) was added to this mixture over a period of 30-40 minutes while maintaining the temperature below 25 ° C. After the addition of the acetyl chloride, the mixture was heated to 35 ° C and kept at this temperature for 10 hours.

The reaction mixture was repeatedly washed with water containing hydrochloric acid to remove organic impurities from the nitrobenzene layer and the nitrobenzene layer was concentrated in vacuo to a vigorous syrup. The 2-acetyl-6-methoxynaphthalene product was precipitated by the addition of methanol and then water, then filtered, washed, dried and crystallized from cyclohexane.

b) A mixture of dimethyl sulfoxide (4800 ml) and tetrahydrofuran (400 ml) was purified with nitrogen and cooled to 10-15 ° C. To this mixture was added sodium methoxide (500 g) and trimethylsulfonium iodide (1300 g). While maintaining the temperature of the mixture at 10-15 ° C, a solution of 2-acetyl-6-methoxy = naphthalene (100 g) in a mixture of dimethyl sulfoxide (2400 ml) and tetrahydrofuran (920 ml) was added over 30 minutes. ). After keeping the mixture temperature at 10-15 ° C for a further 15 minutes, the reaction mixture was diluted to a total volume of 50,000 ml with cold water and filtered, and the filter cake was washed with water until the washings were neutral. The product 2- (6-methoxy-2-naphthyl) propylene oxide was dried at 50 ° C.

c) A solution of 18 g of 2- (6-methoxy-2-naphthyl) propylene oxide in 500 ml of diethyl ether is treated at 0 ° C with 14 g of aluminum chloride and 200 ml of 1N diborane solution in tetrahydrofuran. The mixture is then allowed to stand at 20 ° C for 24 hours. The mixture is then mixed with ice and extracted with diethyl ether. The organic phase is evaporated to dryness and the residue is recrystallized from acetone / hexane to give 2- (6-meth = oxy-2-naphthyl) -1-propanol.

The 2- (6-methoxy-2-naphthyl) -1-propanol product prepared as described is cleaved e.g. as given in Example 2, to give the 1-optical isomer of 2- (6-methoxy-2-naphthyl) -1-propanol, m.p. 88-89 ° C.

Example 6

The procedure of Example 5c repeats, but diborane is replaced with an equivalent amount of lithium aluminum hydride, sodium borohydride, potassium borohydride or lithium borohydride, giving in each case 2- (6-methoxy-2-naphthyl) -1-propanol.

The 2- (6-methoxy-2-naphthyl) -1-propanol product prepared as described is cleaved e.g. as given in Example 2, to give the 1-optical isomer of 2- (6-methoxy-2-naphthyl) -1-propanol, m.p. 88-89 ° C.

Example 7

Repeat the procedure of Example 5c but replace aluminum chloride with boron trichloride, boron trifluoride, boron trifluoride diethyl ether, aluminum bromide, boron tribromide, in each case 2- (6-methoxy-2-naphthyl) -1-propanol is obtained.

The 2- (6-methoxy-2-naphthyl) -1-propanol product prepared as described is cleaved e.g. as given in Example 2, to give the 1-optical isomer of 2- (6-methoxy-2-naphthyl) -1-propanol, m.p. 88-89 ° C.

Example 8 (Method E)

A solution of 10 g of 2- (6-methoxy-2-naphthyl) -2-propen-1-one in 200 ml of ethyl acetate containing 0.5 g of a 5% palladium-on-carbon catalyst is hydrogenated for 2 hours at room temperature . Filtration of the reaction mixture and evaporation of the solvent from the filtrate yields 2- (6-methoxy-2-naphthyl) -1-propanol, which is recrystallized from acetone / hexane.

The 2- (6-methoxy-2-naphthyl) -1-propanol product prepared as described is cleaved e.g. as given in Example 2, to give the 1-optical isomer of 2- (6-methoxy-2-naphthyl) -1-propanol, m.p. 88-89 ° C.

Example 9 (Method F)

A solution of 5 g of 2- (6-methoxy-2-naphthyl) acrylic acid in 20 ml of tetra = hydrofuran at 0 ° C is treated with 50 ml of 1N diborane in tetrahydrofuran. After 4 hours, excess diborane is decomposed by the addition of acetic acid until hydrogen is no longer developed from the reaction mixture. The reaction mixture is then mixed with water and extracted with ether, the ether phase is removed and evaporated to dryness to give 2- (6-methoxy-2-naphthyl) -1-propanol.

The 2- (6-methoxy-2-naphthyl) -1-propanol product prepared as described is cleaved e.g. as given in Example 2, to give the 1-optical isomer of 2- (6-methoxy-2-naphthyl) -1-propanol, m.p. 88-89 ° C.

Example 10 (Method G)

A solution of 16 g of 2-methoxynaphthalene in 250 ml of nitrobenzene containing 26 g of aluminum chloride is treated at 0 ° C with 6 g of 2-bromopropyl = acetate for 2 hours. After a further 1 hour, the mixture is mixed with 500 ml of a 5% methanolic hydrogen chloride solution and the mixture is refluxed for 12 hours, diluted with 2000 ml of water and extracted with ether · The ether phase is separated from the reaction mixture, washed with water to neutral reaction, dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel to give 2- (6-methoxy-2-naphthyl) -1-propanol.

The 2- (6-methoxy-2-naphthyl) -1-propanol product prepared as described is cleaved e.g. as given in Example 2, to give the 1-optical isomer of 2- (6-methoxy-2-naphthyl) -1-propanol, m.p. 88-89 ° C.

Claims (1)

Example 11 Repeat the procedure of Example 10, but replace aluminum chloride with aluminum bromide, stannous chloride, boron trifluoride, boron chloride, boron tribromide, in each case 2- (6-methoxy-2-naphthyl) -1-propanol is obtained. The 2- (6-methoxy-2-naphthyl) -1-propanol product prepared as described is cleaved e.g. as given in Example 2, to give the 1-optical isomer of 2- (6-methoxy-2-naphthyl) -1-propanol, with: m.p. 88-89 ° C. Example 12 Repeat the procedure of Example 10 but replace 2-bppm-1-propanol acetate with 2-chloro-1-propanol acetate, 2-iodo-1-propanol acetate or 2-bromo-1-propanol benzoate, in each case 2- (6) is obtained. methoxy-2-naphthyl) -1-propanol. The 2- (6-methoxy-2-naphthyl) -1-propanol product prepared as described is cleaved e.g. as given in Example 2, to give the 1-optical isomer of 2- (6-methoxy-2-naphthyl) -1-propanol, m.p. 88-89 ° C. Analogous process for the preparation of the 1-isars of 2- (6-methoxy-2-naphthyl) -1-propanol of the formula CH-I3 AV® II CH-OH CH30 characterized in that either 145338 A) reactes 6-methoxy-2- (2-propenyl) naphthalene with diborane to form a borane compound, of the formula: - B - R1 R1 wherein is -a 2- (6-methoxy-2-naphthyl) -1 -propyl group, which compound is reacted with hydrogen peroxide in an aqueous solution of an inorganic base, or B) converts a compound of formula CH ΧΎΥ'Η'Μ (Ib) wherein M is MgCl, MgBr, Mgl, Li, Na, K, Zn or Cd 2, with formaldehyde and then the reaction mixture treated with an acid, or C) reacted with 2-methoxynaphthalene with propylene oxide in the presence of Lewis acid in an inert organic solvent at -10 ° C to 40 ° C. (6-methoxy-2-naphthyl) -1-propanol is formed, or D) reactes 2- (6-methoxy-2-naphthyl) propylene oxide with a metal hydride in the presence of a Lewis acid in an etherop solvent, or E) treats 2- (6-methoxy-2-naphthyl) -2-propen-1-ol with hydrogen in the presence of a hydrogenation catalyst in an inert organic solvent, or F) treats 2- (6-methoxy-2) -naphthyl) acrylic acid with at least one molar equivalent of diborane in an ether solvent, or