KR101069699B1 - Process for preparing intermediate used for preparation of photochromic naphthopyran dyes - Google Patents

Abstract

The present invention relates to a novel method for producing a naphthopyran-based photochromic dye, the synthetic yield is higher than the existing method can be obtained economically.

Naphthopyran, photochromic, dye, naphthol, cyclization reaction, base, yield

Description

Process for the preparation of intermediates used in the preparation of naphthopyran-based photochromic dyes {PROCESS FOR PREPARING INTERMEDIATE USED FOR PREPARATION OF PHOTOCHROMIC NAPHTHOPYRAN DYES}

The present invention relates to a process for the preparation of intermediates used in the preparation of naphthopyran-based photochromic dyes.

Photochromic naphthopyran-based compounds react to light energy of a specific wavelength such as ultraviolet light and, when absorbing light of a specific wavelength, exhibit a reversible color change. As a changing material, it is used in ophthalmic lenses, contact lenses, sun protection glasses, filter cameras, optical devices of photographic instruments, optics and observation devices.

In general, the naphthopyran-based compound represented by the following formula (1) can be obtained by the pyran ring ring reaction of the substituted naphthol derivative of the formula (2) and the propazyl alcohol of the formula (3) [L. Merlini, Advances in Heterocyclic Chemistry , 1975 , 18 , 159/9,; R. Guglielmetti, Photochromism: Molecules and Systems Studies in Organic Chemistry, 1990 , 40 , chp. 8; S. Gronowitz et al., Acta. Pharm. Suec, 1978 , 15 , 337; R, F Frank et al., J. Chem, Soc. Chem. Commun. , 1984 761; Organic Reactions , 1951 , 6 , 1; US Patent Nos. 5,066,818 and 4,990,287; International Patent Publications WO 92/09593 and WO 95/05382.

[Formula 1]

[Formula 2]

(3)

Where

R is alkoxy, alkylamino, dialkylamino, cycloalkoxy or cyclicamino and the like,

R ¹ is amino, dialkylamino, cyclicamino or morpholino and the like,

R ² and R ³ represent hydrogen, lower alkoxy, alkylamino, dialkylamino, cyclicalkylamino or morpholino and the like.

In general, in the method for preparing a naphthopyran-based compound, substituted naphthol derivatives of Formula 2 are prepared as in Scheme 1 [ Organic Reactions , vol VI, chapter 1, p. 1-73, John Wiley & Sons. Inc. NewYork; International Patent Publication WO 98/14443.

R in Scheme 1 is as defined in Chemical Formulas 1 to 3.

As in Scheme 1, in order to prepare carboxyaminonaphthol in which the substituent R ¹ of the compound of Formula 2 is substituted with an amine, it must be reacted in four steps from the substituted carboxynaphthol. That is, in the above scheme, the alcohol of aminocarboxynaphthol is converted into an acetyl group and then reacted with an acyl halide, which is then reacted with an amine to form an amide compound, and then the ester of the compound is hydrolyzed in the presence of an acid. Is performed by In this reaction, there is a disadvantage in that the use of thionyl chloride is costly to treat the odor and by-products.

Alternatively, substituted naphthol derivatives are reacted with para-substituted toluene, maleic anhydride, and di-t-butyl-peroxide as initiators, which are then reacted in the presence of a base and acidified to form a diacid. A method of obtaining a substance, and cyclization using strong sulfuric acid to synthesize a tetraral derivative, followed by oxidation reaction in the presence of oxygen and base (US Patent No. 6,106,744, PPG Industries, Inc.) has been reported.

In addition, amino naphthoic acid is reacted with alkyl- or benzyl-chloroformate to obtain a compound of formula 4, and then substituted with an R ¹ group-containing amine to prepare a compound of formula 2, and the compound of Formula 3 A method for preparing a naphthopyran-based compound of Chemical Formula 1 by reacting with a substituted propazyl alcohol has been disclosed (Korean Patent No. 10-0649959).

[Formula 4]

In Chemical Formula 4, R and R ¹ are as defined in Chemical Formulas 1 to 3, and R 'is methyl, ethyl, isobutyl, or benzyl.

However, there is still a need for a method capable of effectively preparing a naphthopyran-based compound in a simpler manner.

Accordingly, it is an object of the present invention to provide a method for producing naphthopyran-based photochromic dyes more efficiently in high yield.

The present invention to achieve the above object,

1) reacting aminonaphtholic acid with alkyl- or benzyl-chloroformate to prepare a compound of formula (4);

2) substituting a compound of Formula 4 with an amine compound to prepare a compound of Formula 2;

3) reacting the halogen-substituted benzophenone with a nucleophilic compound in the presence of a base, followed by reaction with sodium acetylide to prepare a compound of formula 3; And

4) providing a method for preparing a naphthopyran-based photochromic dye comprising the step of reacting a compound of formula (2) with a compound of formula (3):

In Chemical Formulas 1 to 4,

R is alkoxy, alkylamino, dialkylamino, cycloalkoxy, or cyclicamino,

R 'is methyl, ethyl, isobutyl, or benzyl,

R ¹ is amino, dialkylamino, cyclicamino, or morpholino,

R ² and R ³ are hydrogen, lower alkoxy, alkylamino, dialkylamino, cyclicalkylamino, or morpholino.

According to the method for preparing a naphthopyran-based compound of the present invention, the naphthopyran-based photochromic dye can be produced in high yield by preparing the intermediate product in high purity and high yield under simpler and milder conditions than conventional methods.

Hereinafter, the present invention will be described in more detail.

In the method for producing a naphthopyran compound according to the present invention,

The amino naphthoic acid of step 1) is reacted with hydrochloric acid and potassium hydroxide sequentially to the result obtained by reacting the substituted benzaldehyde compound and the substituted alkyl succinate compound in the presence of a base at preferably 60 to 100 ℃ and acetic anhydride. Can be prepared. At this time, the base is preferably t-butoxy potassium, and it is preferable to remove the t-butanol generated after the reaction.

In addition, the base that can be used in the production method of the present invention, at least one selected from the group consisting of kalium carbonate, calcium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, butoxy potassium and methoxy potassium Inorganic bases; Or at least one organic base selected from the group consisting of triethylamine, diisopropylethylamine and DBU (1,8-diazabicyclo [5.4.0] -7-undecene); Or mixtures thereof.

In addition, the amine compounds usable in step 2) include morpholine, dialkylamine, cyclic amine, and the like, and the amount of the amine compound may be 2.0 to 2.4 equivalents.

In addition, as the nucleophilic compound of step 3), lower alcohol, alkylamine, dialkylamine, cyclicalkylamine, morpholine and the like may be used.

The reaction solvents usable in steps 1) to 3) include tetrahydrofuran, toluene, benzene, acetone, acetonitrile, alcohol, dimethylformamide, dimethyl ether, ethyl acetate, chloroform, water, and the like. Preferably, tetrahydrofuran, acetone, acetonitrile, dimethylformamide, dimethyl ether, ethyl acetate, chloroform, etc. are mentioned.

In addition, step 4) may be carried out in the presence of an acid catalyst, and the acid catalyst may be used as a catalytic amount of acidic alumina, acetic acid, trifluoroacetic acid, silica, paratoluenesulfonic acid, clay, acidic clay, acid resin, and the like. It is possible to use a mixture of two or more catalysts. At this time, benzene, toluene, xylene, methylene chloride, chloroform or carbon tetrachloride may be used as the reaction solvent.

The reaction temperature in the above steps 1) to 3) is 0 ° C to 50 ° C, preferably 0 ° C to room temperature.

In more detail, the naphthol derivative of Formula 2 may be synthesized according to the following procedure:

a.1) a benzaldehyde compound (1 equivalent) and a succinate compound (0.8 to 1.3 equivalents) are mixed, and an organic base (e.g., t-butoxy potassium, 1.0 to 1.5 equivalents) dissolved in an organic solvent is added thereto to inertness. Reflux for 1 to 3 hours at a temperature of 60 to 100 ° C. under gas;

a.2) After completion of the reaction, by-product distillation (t-butanol, etc.) of the reaction solvent and alcohols is removed by distillation under reduced pressure and refluxed for 2 to 4 hours by adding 2 to 4 equivalents of acetic anhydride;

a.3) Thereafter, the material obtained by removing the solvent by distillation under reduced pressure is dissolved in methanol, and then concentrated with hydrochloric acid, followed by stirring sufficiently;

a.4) Cool the reaction solution and filter the resulting solid to give the result. Scheme 2 below illustrates the procedures of steps a.1) to a.4) above when substituent R in formula 2 is dialkylamino;

Wherein R, R ¹ and R ² are as defined above.

a.5) The resultant obtained in step a.4) is placed in a water-soluble alcohol and reacted with a base to obtain a carboxynaphthol compound;

a.6) the carboxynaphthol compound is reacted with alkyl- or benzyl-chloroformate in the presence of a base to prepare an activated ester form (Formula 4);

a.7) Substituted reaction with amine to prepare substituted carboxyaminonaphthol of formula (2). Scheme 3 below illustrates the procedures of a.6) and a.7) above;

Wherein R, R 'and R ¹ are as defined above.

1 and 2 are respectively substituted with a compound of formula (2) wherein R is dialkylamino, R ¹ is methyl and a compound of formula (2) wherein R is dialkylamino, R ¹ is morpholine, ie methylester and morpholine X-ray structure analysis of naphthol derivatives. As a result, the hydrogen bond between the molecules is located, and the carbonyl group at the C2 position is higher in the naphthol derivative in which the methyl ester is present, and lower in the morpholine-substituted naphthol derivative.

In addition, according to the method according to the present invention, the propazyl alcohol compound of Formula 3 may be synthesized by the following procedure:

b.1) benzophenone (1 equivalent) in which the para position is substituted with halogen is placed in an organic solvent, and the nucleophilic compound (R ² , 1 to 1.4 equivalents) to be substituted in the presence of a base (1 to 1.4 equivalents) is added to 120 The reaction is carried out at -170 ° C for 3 to 5 hours to obtain benzophenone in which the para position is substituted with R ² . Scheme 4 below shows the case where R ² is piperidinyl and R ³ is hydrogen;

Wherein X is Cl or F.

b.2) The para position obtained in b.1) has a benzophenone substituted with R ² , and is generally known as a method (see, for example, US Patent No. 5,274,132) as shown in Scheme 5 below. To prepare a compound.

Wherein R ² and R ³ are as defined above.

c) Finally, according to the method according to the present invention, the substituted naphthopyran-based compound of the present invention (Formula 1) is substituted carboxyaminonaphthol (Formula 2) obtained by the steps a.1) to a.7) ) And the substituted propazyl alcohol (Formula 3) obtained by the steps b.1) and b.2) can be prepared by a pyran ring reaction as shown in Scheme 6 below.

In the above formula, R, R ¹ , R ² and R ³ are as defined above.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1: Preparation of 6- (dimethylamino) -4-hydroxy-2-naphthol acid

A solution obtained by dissolving 150 g (1 equiv) of N, N-dimethylamino benzaldehyde, 162 g (1.1 equiv) of dimethyl succinate, and 167 g (1.2 equiv) of t-butoxypotassium in 800 mL of anhydrous toluene was carried out under 80 to nitrogen. It was refluxed at 90 ° C. for 2 hours. After completion of the reaction, the reaction solvent (toluene) and by-products of alcohols (t-butanol, methanol, etc.) were distilled under reduced pressure in a reactor to remove 250 mL, and 350 mL of acetic anhydride was added and refluxed for 3 hours. After completion of the reaction, distillation under reduced pressure completely removes the solvent. The obtained material was dissolved in 200 mL of methanol and sodium hydroxide in 800 ml of water, and then refluxed at 80 to 90 ° C. for 4 hours. Upon completion of the reaction, the solvent was distilled off completely, neutralized to pH 6.0-5.0 with 2M HCl aqueous solution, and extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to obtain 195 g (yield: 84%) of the target substance.

Example 2 Synthesis of 1-phenyl- (1- (4-piperidin-1-yl) -phenyl) prop-2-yn-1-ol

30 g (1 equiv) of (4-fluorophenyl) (phenyl) methanone, 18 mL (1.2 equiv) of piperidine and 42 g (1.2 equiv) of t-butoxy potassium were added to 150 mL of dimethylsulfoxide at 140 to 150 ° C. At reflux for 4 hours and cooled to room temperature. Thereafter, 1.2 L of ice water was added to the reactor and stirred for about 30 minutes to produce an ocher solid. After the stirring was completed, a solid was precipitated by a reduced pressure filter, which was further stirred for 30 minutes with normal-hexane, followed by filtration and drying. The dried product was placed in a reaction vessel and the inside was vacuumed, and then saturated with acetylene gas. 200 mL of anhydrous tetrahydrofuran solution was added to the saturated reaction vessel by the syringe. 43 mL of 18% xylene / normal hexane phosphorus sodium acetylide was added thereto and stirred at room temperature for 24 hours, followed by pouring water and extracting with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated until a solid was formed, and then recrystallized with normal hexane to obtain 36.9 g (yield: 84%) of the title compound.

Example 3: Preparation of 6- (dimethylamino) -4-hydroxy-2-naphthol

150 g (1 equiv) of N, N-dimethylamino benzaldehyde, 162 g (1.1 equiv) of dimethylsuccinate, and 167 g (1.2 equiv) of t-butoxypotassium were dissolved in 800 mL of anhydrous toluene and refluxed for 2 hours. After completion of the reaction, 250 mL of t-butanol and toluene were distilled under reduced pressure, 350 mL of acetic anhydride was added and refluxed for 3 hours, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 500 mL of methanol, and 50 mL of concentrated hydrochloric acid was added thereto, followed by stirring at room temperature overnight. After cooling the reaction solution, the resulting solid was filtered to give 256 g of the target compound.

Example 4 Preparation of 2,2-bis (4-methoxyphenyl) -5-morpholinylcarbonyl-9-dimethylamino-2H-naphthol [1,2-b] pyran

In a 100 mL flask, 1 g (3.33 mol) of 1 - morpholinocarbonyl-7-dimethylamino-1-naphthol, 0.9 g (3.33 mol) of 4,4-dimethoxyphenyl-propazol alcohol, and 4 g of aluminum oxide And 4 g of silica gel were added, 50 mL of toluene was added thereto, and a Deanstock device was connected to reflux. After 2 hours, 0.06 g (0.1 equivalent) of paratoluenesulfonic acid was added thereto, and the mixture was further refluxed. When the reaction mixture was hot, the mixture was washed with toluene, concentrated and separated and purified by silica gel column chromatography (hexane: ethyl acetate: toluene = 1: 1: 2) to obtain 0.82 g (yield 45%) of the title compound.

TLC-Hexane: EA = 1: 1 (Rf = 0.5)

1 H NMR (CDCl ₃ , ppm): δ 7.58 (d, 1H), 7.44 (d, 2H), 7.18 (m, 4H), 7.00 (d, 2H), 6.81 (d, 2H), 6.58 (d, 2H ), 5.96 (d, 1H), 3.78 (s, 6H), 3.68 (br, 3H), 2.83 (s, 6H)

Example 5 Preparation of 2,2-bis (4-methoxyphenyl) -5-pipedicarbonyl-9-dimethylamino-2H-naphtho [1,2-b] pyran

1 g (3.35 mol) of 3-piperinocarbonyl-7-dimethylamino-1-naphthol, 0.9 g (3.35 mol) of 4,4-dimethoxyphenyl-propazyl alcohol, 3.4 g of aluminum oxide and 4 g of silica gel In the same manner as in Example 4 to obtain the desired compound 0.59 g (yield 33%).

TLC-Hexane: EA = 1: 1 (Rf = 0.5)

1 H NMR (CDCl ₃ , ppm): δ 7.59 (d, 1H), 7.45 (d, 2H), 7.17 (m, 4H), 7.00 (d, 2H), 6.80 (d, 3H), 6.59 (s, 1H) ), 6.53 (d, 1H), 5.97 (d, 1H), 3.84 (s, 6H), 3.50 (br, 4H), 2.81 (s, 6H), 1.64 (br, 6H)

Example 6 Preparation of 2-phenyl-2- (4-piperidinyl) phenyl-5-morpholinocarbonyl-9-dimethylamino-2H-naphthol [1,2-b] pyran

1 g (3.35 mol) of 3-morpholinocarbonyl-7-dimethylamino-1-naphthol, 0.9 g (3.35 mol) of 4,4-dimethoxyphenyl-propazyl alcohol, 3.4 g of aluminum oxide and 3.4 g of silica gel Was added and prepared in the same manner as in Example 4 to obtain 0.63 g (yield 31.6%) of the target compound.

TLC-Hexane: EA = 1: 1 (Rf = 0.5)

1 H NMR (CDCl ₃ , ppm): δ 7.59 (d, 1H), 7.45 (d, 2H), 7.17 (m, 4H), 7.00 (d, 2H), 6.80 (d, 3H), 6.59 (s, 1H) ), 6.53 (d, 1H), 5.97 (d, 1H), 3.84 (s, 6H), 3.50 (br, 4H), 2.81 (s, 6H), 1.64 (br, 6H)

1A and 1B show X-ray structure analysis results of a naphthol derivative substituted with methyl ester.

2A and 2B show X-ray structure analysis results of naphthol derivatives substituted with morpholine.

Claims (9)

Reacting a halogen-substituted benzophenone at the para position with C _3-5 cyclicamine in dimethylsulfoxide (DMSO) in the presence of t-butoxypotassium at a temperature of 140-150 ° C. followed by sodium acetylide. To prepare a compound of Formula 3 (3)

In Formula 3, one of R ² and R ³ is hydrogen and the other is C _{3-5 cyclicamino} . delete delete delete delete delete delete delete delete

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