KR100683274B1 - Process for preparing substituted benzopyran compounds - Google Patents

Abstract

The present invention relates to a novel process for preparing a substituted benzopyran compound represented by the following formula (1), a novel intermediate compound corresponding thereto, and a novel process for preparing the intermediate compound described above.

In Formula 1, R ¹ , R ² , R ³ , R ⁴ , A and Y are as defined in the detailed description of the invention, respectively.

Benzopyran Compound

Description

Process for preparing substituted benzopyran compounds

The present invention relates to a novel process for the preparation of substituted benzopyran compounds and to corresponding novel intermediate compounds and novel processes for the preparation of the intermediate compounds described above.

The substituted benzopyran compound to be synthesized by the present invention is a compound known from European Patent No. 0173516 and the like, and is well known as a therapeutic agent for diseases caused by leukotriene and 5-α-reductase because it has activity as a leukotriene antagonist.

As a prior art related to the manufacturing method of the present invention, Japanese Patent Laid-Open No. 3-95144 discloses a 3-amino- represented by the following formula (C) through a four-step manufacturing process from a phenol compound represented by the following formula (A). A method for producing a 2-hydroxyacetophenone compound is known, which is not an economical synthesis method due to its long production route, and particularly in the reduction reaction (a) for introducing an amino group using Pd / C. It has been pointed out that there are many difficulties in industrial application due to the risk of fire and explosion because of the hydrogenation reaction.

In the above scheme, X represents a halogen atom.

In addition, the synthesis techniques known from U.S. Patent No. 5,675,036, U.S. Patent No. 5,597,929, and International Publication No. WO94 / 12492 use acetophenone compound (D) having a structure that is difficult to synthesize as a reaction intermediate, as well as via amines. It is not suitable for safety and environmental reasons, since SOCl _{2 which} is highly explosive and highly corrosive must be used to synthesize the acyl chloride (E) required when introducing an amide group from the compound. It is also difficult to control this in commercial production because the acyl chloride produced is generally unstable.

The present invention relates to a novel process for the preparation of some of the benzopyran compounds described in European Patent Registration No. 0173516, which is safer compared to the production methods known to date and is industrially useful due to the much smaller reaction steps. . In particular, the manufacturing method according to the present invention follows a convergent path, which is more efficient than the existing linear path, and in particular, there is no dangerous reaction such as hydrogenation, and the intermediate material generated during the reaction process is stable and easy to obtain separation. It has one advantage.

The present invention is characterized by a method for preparing a substituted benzopyran compound represented by the following formula (1), a novel intermediate compound used for the preparation thereof, and a method for preparing the intermediate compound:

[Formula 1]

In Chemical Formula 1,

R ¹ is selected from C _1-20 alkyl group, C _2-20 alkenyl group, C _2-20 alkynyl group, phenyl group, naphthalenyl group and indanyl group, each of which is C _1-20 alkyl group, C _2-20 alkenyl group and C 1 to 2 substituents selected from _2-20 alkynyl groups (up to at least 5 of the carbons constituting these substituents are optionally oxygen, sulfur, nitrogen, halogen, benzene ring, thiophene ring, naphthalene ring, C _{4 -7} may be substituted with a carbocyclic ring, carbonyl group, carbonyloxy group, hydroxy group, carboxyl group, azido group or nitro group);

R ² and R ⁴ are each independently substituted with a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkyl group substituted with 1 to 3 aryl groups, a C _1-6 alkoxycarbonyl group, an aryl group C _1-6 alkoxycarbonyl group, aryloxycarbonyl group, C _1-6 alkoxyC _1-6 alkyl group, C _3-9 trialkyltin group, triaryltin group, or C _3-9 trialkylsilyl group, wherein “aryl group” Or "aryl" is a phenyl group or a phenyl group substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkyl group and a C _1-6 alkoxy group;

R ³ is a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio group, or -COOR ⁵ (wherein, R ⁵ is a hydrogen atom or a C _{1 -6} alkyl group;

A is a single bond or a C _1-10 alkylene group, C _2-10 alkenylene group, or C _2-10 alkynylene group unsubstituted or substituted with 1 to 3 substituents selected from a C _1-10 alkyl group and a phenyl group Is;

X is a halogen atom;

Y is an oxygen atom or a sulfur atom.

인 경우이다.In preparing the substituted benzopyran compound represented by Formula 1, preferably, R ¹ is a phenyl group or a substituted phenyl group, wherein the substituted phenyl group is a C _1-20 alkyl group, C _2-20 alkenyl group, and C _2- 1 to 2 substituents selected from ₂₀ alkynyl groups (up to at least 5 of the carbons constituting these substituents are optionally an oxygen atom, a sulfur atom, a nitrogen atom, a halogen atom, a benzene ring, a thiophene ring, a naphthalene ring, C _4-7 Carbocyclic ring, carbonyl group, carbonyloxy group, hydroxy group, carboxyl group, azido group or nitro group). More preferably, R ¹ is a phenyl group substituted with one substituent selected from those exemplified above in the p- position of the phenyl group, and particularly preferably

If

In preparing the substituted benzopyran compound represented by Formula 1, preferably, R ² and R ⁴ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkyl group substituted with 1 to 3 aryl groups Or a C _1-6 alkoxycarbonyl group. More preferably, R ² and R ⁴ are each independently a hydrogen atom.

In preparing the substituted benzopyran compound represented by Formula 1, preferably R ³ is a hydrogen atom.

In preparing the substituted benzopyran compound represented by Formula 1, Preferably, A is a single bond, or methylene, ethylene, unsubstituted or substituted with 1 to 3 substituents selected from C _1-10 alkyl and phenyl groups. In the case of trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethynylene groups. More preferably, A is a single bond.

The method for preparing a substituted benzopyran compound represented by Chemical Formula 1 according to the present invention may be prepared by reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3, as shown in Scheme 1 below:

In Reaction Scheme 1, R ¹ , R ² , R ³ , R ⁴ , A, X and Y are as defined in Formula 1, respectively.

The preparation method according to Scheme 1 is carried out by heating and refluxing in the presence of a palladium or copper catalyst, a ligand and a base using an organic solvent. At this time, as the organic solvent in an organic solvent having a high polarity, for example dimethylformamide, N -methylpyrrolidinone, pyridine, 1,4-dioxane, C _1-6 alkanol (methanol, ethanol, t- butanol) The sole solvent selected or a mixed solvent thereof is used, and preferably dimethylformamide is used. As a catalyst, a palladium or copper-containing compound is used in the range of 0.1 to 100 mol% with respect to the reactant. Preferably, the catalyst is selected from copper iodide, copper chloride and Cu ₂ O, and particularly preferably copper iodide (CuI) is to use. As the ligand, for example, a ligand of diamines or phosphines is used in a range of 0.5 to 3 equivalents based on the amount of catalyst used, and preferably N , N' -dimethylethylenediamine, trans- N , N'- 1 as ligands. It is selected from among, 2-cyclohexanediamine and trans- N , N' -dimethyl-1,2-cyclohexanediamine, and particularly preferably from N , N' -dimethylethylenediamine. Bases include, for example, alkali metal alkoxides such as potassium t- butoxide, potassium methoxide, sodium methoxide, hydrides such as sodium hydride, potassium hydride, alkali metal carbonates such as potassium carbonate, cesium carbonate, sodium carbonate, Or an alkali metal phosphate such as potassium phosphate or sodium phosphate in a range of 1 to 10 equivalents relative to the substrate, and preferably an alkali metal phosphate as a base.

 In the preparation method according to Scheme 1, a particularly preferred embodiment is a compound represented by the following formula (2a) and a compound represented by the following formula (3a), salts or solvates thereof (e.g. hydrates) The reaction is to prepare a substituted benzopyran compound, a salt thereof, or a solvate thereof (e.g., a hydrate) represented by the following Chemical Formula 1a.

In performing the preparation method according to Scheme 1a, particularly preferably, 70 to 100 using copper iodide as a catalyst, N , N' -dimethylethylenediamine as a ligand and potassium phosphate as a base in a dimethylformamide solvent Stirring at least one day at ℃.

Meanwhile, the compound represented by Chemical Formula 2 (particularly, the compound represented by Chemical Formula 2a) and the compound represented by Chemical Formula 3 (in particular, Chemical Formula) used as a reactant in performing the method of preparing Scheme 1 according to the present invention. Compound represented by 3a) is a novel intermediate compound used in the synthesis of the compound represented by the formula (1). Therefore, the present invention includes a compound represented by the above formula (2) and a compound represented by the above formula (3) as a novel intermediate compound in the scope of the present invention.

As a novel intermediate compound according to the present invention, the compound represented by Chemical Formula 2 may be prepared by hydrolyzing the compound represented by the following Chemical Formula 4, as shown in the following Scheme 2.

In Reaction Scheme 2, R ¹ , R ² , A and Y are as defined in Formula 1, respectively.

In the preparation method according to Scheme 2, an amide group is introduced by performing a hydrolysis reaction using a base under conditions using water, an organic solvent or a mixed solvent thereof. Base / solvent conditions applied to the hydrolysis reaction of the present invention will be apparent to those skilled in the art, and specifically include, for example, water monosolvent, C _1-6 alkanol monosolvent such as methanol, ethanol or t- butanol and these It is performed by using a suitable solvent such as using a mixed solvent of and alkali hydroxide such as sodium hydroxide and potassium hydroxide as a base.

In carrying out the hydrolysis reaction according to Scheme 2, a particularly preferred embodiment is potassium hydroxide / t- to a compound represented by the following formula (4a), a salt thereof or a solvate thereof (e.g. hydrate), as represented by the following Scheme 2a: The reaction is performed under butanol conditions to prepare a compound represented by the following Chemical Formula 2a, a salt thereof, or a solvate thereof (eg, a hydrate).

In addition, the compound represented by the formula (3) as a novel intermediate compound according to the present invention, as shown in the following reaction scheme (a) by reacting the compound represented by the following formula (5) and the compound represented by the following formula (6) After preparing the compound represented by (b) it can be prepared by ring-closure reaction.

In Scheme 3, R ³ , R ^4, and X are as defined in Formula 1, respectively, and Z represents an activated leaving group.

(이때, R⁸은 C_1-6알킬기, 임의로 치환된 페닐기 또는 임의로 치환된 페닐C_1-6알킬기이고, Y는 각각 독립적으로 산소원자 또는 황원자 임)이다. 활성화된 이탈기(Z)로서 바람직하게는 R⁷O- 이고, 이때 R⁷가 C_1-6 알킬기, 임의로 치환된 페닐기 또는 임의로 치환된 페닐C_1-6알킬기인 경우이고, 더욱 바람직하게는, R⁷가 C_1-6알킬기, 예를 들면 메틸기, 에틸기, i-부틸기 또는 t-부틸기인 경우이고, 가장 바람직하게는 R⁷가 에틸기인 경우이다.As an activated leaving group (Z) according to Scheme 3, for example, an activated amide group represented by a halogen atom, -N (R ⁶ ) (OR ⁶ ), wherein R ⁶ is a C _1-6 alkyl group, R ⁷ O-, R ⁷ S- or R ⁷ SO ₂ O-, wherein R ⁷ is a C _1-6 alkyl group, an optionally substituted phenyl group or an optionally substituted phenylC _1-6 alkyl group, or

Wherein R ⁸ is a C _1-6 alkyl group, an optionally substituted phenyl group or an optionally substituted _{phenylC 1-6} alkyl group, and Y is each independently an oxygen atom or a sulfur atom. Activated leaving group (Z) is preferably R ⁷ O-, wherein R ⁷ is a C _1-6 alkyl group, an optionally substituted phenyl group or an optionally substituted _{phenylC 1-6} alkyl group, more preferably, R ⁷ is a C _1-6 alkyl group such as a methyl group, ethyl group, i- butyl group or t - butyl group, most preferably when R ⁷ is an ethyl group.

In performing the preparation method according to Scheme 3, in the case of the process (a), dimethylformamide, ether solvent such as tetrahydrofuran, toluene, benzene, hexane or C _1-6 alkanol (for example, methanol, ethanol in an organic solvent such as t- butanol), for example, alkali metal alkoxides such as potassium t- butoxide, sodium methoxide or potassium methoxide, hydrides such as sodium hydride, or potassium amide or sodium amide It is carried out in the presence of an amide base.

In carrying out the preparation method according to Scheme 3, the ring closure reaction of step (b) is carried out in the presence of an acid. For example, the ring-closure reaction can be carried out in the presence of sulfuric acid in C _1-6 alkanol or acetic acid as a solvent medium, and also in the presence of hydrochloric acid in a mixed solvent of C _1-6 alkanol / tetrahydrofuran. can do. In addition, the acid / solvent conditions to be substituted will be apparent to those skilled in the art, for example hydrobromic acid, in a suitable solvent such as water, C _1-6 alkanol, and unsaturated carbocyclic ring hydrocarbons such as benzene or toluene, Acids such as hydroiodic acid, perchloric acid or p- toluenesulfonic acid and Lewis acids such as aluminum trichloride titanium tetrachloride can be used. Preferably, the ring closure reaction is carried out in the presence of sulfuric acid in a methanol solvent.

In the preparation method according to Scheme 3, a particularly preferred embodiment is (a) a compound represented by the following Formula 5a and a compound represented by the following Formula 6a, a salt thereof, or a solvate thereof, as represented by the following Scheme 3a: Hydrate) to produce a compound represented by the following Chemical Formula 7a, a salt thereof, or a solvate thereof (e.g., a hydrate), and then (b) ring-closing the compound, a salt thereof, or a solvate thereof represented by the following Chemical Formula 3a: (Eg, hydrates).

On the other hand, the compound represented by Formula 7 (particularly, the compound represented by Formula 7a) synthesized as a reaction intermediate in performing the method of preparing Scheme 3 according to the present invention is a novel intermediate compound, so the present invention is an intermediate Compounds represented by the general formula (7) as a compound is also included in the scope of the present invention.

The compound represented by Formula 7 is represented as a di-keto type in the present invention for convenience, but the compound represented by Formula 7 may also exist as a keto-enol type and a cyclic hydroxy chromanone type. Therefore, the present invention includes all tautomeric forms of the compound represented by Chemical Formula 7.

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1.Preparation of 4- (4-phenylbutoxy) benzamide

To a solution of 4- (4-phenylbutoxy) benzonitrile (1.9 g, 7.5 mmol) and t -butanol (37 mL) was added sodium hydroxide (2.1 g, 38 mmol) and heated to reflux for 4 hours. The mixture was allowed to cool to room temperature and then poured into a mixture of water and methanol (4: 1, 100 mL). The precipitate obtained was filtered, washed with water and then vacuum dried to give the title compound (1.9 g, 94%) as a white solid.

¹ H NMR (300 MHz, DMSO -d ₆ ) δ 7.81-7.83 (m, 3H), 7.15-7.30 (m, 6H), 6.95 (d, J = 9.0 Hz, 2H), 4.04 (t, J = 5.9 Hz, 2H), 2.65 (t, J = 6.9 Hz, 2H), 1.73 (t, J = 3.2 Hz, 4H)

Example 2. Preparation of 2-iodo-6- [1,3-dioxo-3- (tetrazol-5-yl) propyl] phenol

Under nitrogen atmosphere, 2-hydroxy-3-iodoacetophenone (1.5 g, 5.7 mmol), ethyl-1H-tetrazol-5-carboxylate (1.1 g, 7.5 mmol) and potassium t- butoxide (3.2 g, 28.7 mmol) was added anhydrous dimethylformamide (30 mL) and stirred at 50 ° C. for 3 hours. After cooling the reaction solution to room temperature, it was slowly added to cold 1 N HCl (120 mL). The orange precipitate obtained was filtered, washed with water and then dried in vacuo to afford the title compound which was dissolved in heating with ethyl acetate, added hexane and left at 0 ° C. for 2 hours. The product was then filtered, washed with hexane and dried in vacuo to yield a yellow purified product (1.7 g, 83%).

¹ H NMR (300 MHz, DMSO -d ₆ ) δ 8.99 (br s, 1 H), 8.10 (dd, J = 7.7, 1.8 Hz, 1H), 7.80 (dd, J = 8.0, 1.7 Hz, 1H), 6.95 (t, J = 7.8 Hz, 1H), 3.57 (d, J = 16.5 Hz, 1H), 3.20 (d, J = 16.5 Hz, 1H)

Example 3. Preparation of 8-iodo-4-oxo-2-tetrazol-5-yl-1H-1-benzopyran

To the slurry in which the purified product (1.5 g, 4.2 mmol) prepared in Example 2 was mixed with methanol (20 mL), concentrated sulfuric acid (265 μL, 5.0 mmol) was added, and the reaction was heated to reflux for 7 hours. The mixture was allowed to cool to room temperature and then held at 0 ° C. for 1 hour. The resulting mixture was filtered and washed with cold methanol, water followed by cold methanol. The product was dried in vacuo to give the pale yellow title compound (1.3 g, 93%).

¹ H NMR (300 MHz, DMSO -d ₆ ) δ8.35 (dd, J = 7.7, 1.7 Hz, 1H), 8.07 (dd J = 7.8, 1.5 Hz, 1H), 7.33 (t, J = 8.0, 1H) , 7.11 (s, 1H)

Example 4. Preparation of 4-oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2-tetrazol-5-yl-4H-1-benzopyran

Under nitrogen atmosphere, the purification product of Example 1 (108 mg, 0.40 mmol), the purification product of Example 3 (68 mg, 0.20 mmol), copper iodide (11.4 mg, 0.04 mmol), potassium phosphate (255 mg, 0.80 mmol) and N , N' -dimethylethylenediamine (13 μL, 0.08 mmol) were mixed. Anhydrous dimethylformamide (1 mL) was added to the mixture and stirred at 100 ° C. for 2 days. The reaction solution was cooled to room temperature and poured into water (15 mL) to stop the reaction. Saturated aqueous hydrochloric acid solution was added to acidify the pH to 1-2. The resulting solid was filtered and the solid obtained was suspended in methanol (10 mL) and filtered to remove the remaining purified product of Example 1 above. The obtained solid was dissolved in methanol (7 mL) and sodium acetate (32 mg, 0.40 mmol), and then saturated aqueous hydrochloric acid was added to the obtained mother liquor. The resulting mixture was filtered, washed with cold methanol and dried in vacuo to give the title compound (77 mg, 81%) as pale yellow.

As described above, the present invention is useful for industrial use because the manufacturing process is relatively simple and safe compared to the prior art. In particular, each of the compounds represented by Formulas 2, 3 and 7, which are synthesized as reaction intermediates in the process of synthesizing the substituted benzopyran compound represented by Formula 1, has excellent stability as a novel intermediate material and has great utility. .

Claims (17)

Method for preparing a compound represented by the following formula (1), a salt thereof, or a solvate thereof, which is prepared by reacting a compound represented by the following formula (2) with a compound represented by the following formula (3):

Where R ¹ is selected from C _1-20 alkyl group, C _2-20 alkenyl group, C _2-20 alkynyl group, phenyl group, naphthalenyl group and indanyl group, each of which is C _1-20 alkyl group, C _2-20 alkenyl group and C 1 to 2 substituents selected from _2-20 alkynyl groups (up to at least 5 of the carbons constituting these substituents are optionally oxygen, sulfur, nitrogen, halogen, benzene ring, thiophene ring, naphthalene ring, C _{4 -7} may be substituted with a carbocyclic ring, carbonyl group, carbonyloxy group, hydroxy group, carboxyl group, azido group or nitro group); R ² and R ⁴ are each independently substituted with a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkyl group substituted with 1 to 3 aryl groups, a C _1-6 alkoxycarbonyl group, an aryl group C _1-6 alkoxycarbonyl group, aryloxycarbonyl group, C _1-6 alkoxyC _1-6 alkyl group, C _3-9 trialkyltin group, triaryltin group, or C _3-9 trialkylsilyl group, wherein “aryl Group "or" aryl "is a phenyl group or a phenyl group substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkyl group and a C _1-6 alkoxy group; R ³ is a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio group, or -COOR ⁵ (wherein, R ⁵ is a hydrogen atom or a C _{1 -6} alkyl group; A is a single bond or a C _1-10 alkylene group, C _2-10 alkenylene group, or C _2-10 alkynylene group unsubstituted or substituted with 1 to 3 substituents selected from a C _1-10 alkyl group and a phenyl group Is; X is a halogen atom; Y is an oxygen atom or a sulfur atom. The method of claim 1, wherein R ¹ is

R ² , R ³ and R ⁴ are each a hydrogen atom, A is a single bond and X is I, Br or Cl; Y is an oxygen atom. The process according to claim 1, wherein the reaction is carried out in the presence of a palladium or copper-containing compound catalyst, a diamine ligand and a base. The method of claim 3, wherein the reaction comprises a catalyst selected from copper iodide, copper chloride and Cu ₂ O, N , N′ -dimethylethylenediamine, trans- N , N′ -1,2-cyclohexanediamine and trans- N , And a ligand selected from N' -dimethyl-1,2-cyclohexanediamine and a base selected from cesium carbonate and potassium phosphate. The process according to claim 4, wherein the reaction is carried out in the presence of a copper iodide catalyst, N , N' -dimethylethylenediamine ligand and potassium phosphate base. The process according to claim 3, 4 or 5, wherein the reaction is performed under conditions using a dimethylformamide solvent. The method of claim 1, wherein the compound represented by the following Formula 2a and the compound represented by the following Formula 3a, a salt thereof, or a solvate thereof are reacted to prepare a compound represented by the following Formula 1a, a salt thereof, or a solvate thereof Manufacturing Method

8. The reaction according to claim 7, wherein the reaction is carried out under the conditions of using a dimethylformamide solvent, copper iodide catalyst, N , N' -dimethylethylenediamine ligand and potassium phosphate base. Process for producing at a temperature of ℃. delete delete delete delete delete delete delete delete delete