KR840002103B1 - Process for preparing carbostyril derivatives - Google Patents

Abstract

Carbostyril derivatives(I) were prepared from compd.(II), where W = vinylene or ethylene gp. substituted randomly with a methyl gp.; D = C2 - C6 alkylene gp., C3 - C6 hydroxy alkylene gp. or xylylene gp.; m = 0, 1, 2; R1 = H or C1 - C3 alkyl gp.; R2 = C3 - C6 cycloalkyl gp., C6 - C10 aryl gp., C7-C11 aralkylagp., C4-C9 hetero aryl gp. or C5- C10 hetero aralkyl gp. R3,R4 = H or halogen atom, C1 - C4 alkyl gp., amino, acetyl amino or nitro or nitro gp.; and Z = nuclear-philic substituting radical such as hydroxy gp., halogen atom, alkoxy or aryloxy gp.

Description

Method for preparing carbostyryl derivative

The present invention relates to a novel process for the preparation of carbostyryl derivatives of the following general formula (I).

In the above formula,

W represents a vinylene group or an ethylene group optionally substituted by a methyl group,

D represents a straight or branched chain alkylene group having 2 to 6 carbon atoms, a straight or branched chain hydroxyalkylene group having 3 to 6 carbon atoms or a xylylene group,

m represents 0,1 or 2,

R ₁ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

R ₂ is a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, a nitrogen atom, an oxygen atom, a sulfur atom, a nitrogen atom and an oxygen or sulfur atom, or two nitrogen atoms, respectively A heteroaryl group having 4 to 9 carbon atoms or a heteroaralkyl group having 5 to 10 carbon atoms, wherein the aromatic nucleus mentioned above is an alkyl group having 1 to 4 carbon atoms, hydroxy, methoxy, amino, acetylamino, Mono- or di-substituted by nitro, carboxyl, cyclohexyl, phenyl groups or halogen atoms, and the above-mentioned monosubstituted phenyl groups are further alkyl groups having 1 to 4 carbon atoms, halogen atoms or alkyl having 1 to 4 carbon atoms. Mono- or di-substituted by a group and a halogen atom (wherein the substituents of the phenyl nucleus may be the same or different)], 1,2,4-triazolyl, triphenylmethyl, 4,5-bis- (p-chlorophenyl) -oxazol-2-yl, N-methyl-cyclohexylamino-carbonylmethyl or amino-iminomethyl group, R ₂ also represents m is 1 Or when D represents a straight or branched hydroxyalkylene group or a xylylene group having 3 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms,

R ₃ and R ₄ may be the same or different and represent a hydrogen atom or a halogen atom, an alkyl group having 1 to 4 carbon atoms, amino, acetylamino or nitro group.

The compound of formula (I) has useful pharmacological properties. These compounds not only have positive myotropes but also antithrombotic action.

According to the present invention, the carbostyryl derivative of the general formula (I) may be prepared by ring-closing a compound of the general formula (II), which is formed randomly in the reaction mixture.

In the above formula,

D, W, R ₁ to R ₄ and m have the same meaning as described above,

Z represents a nucleophilic substituent such as a hydroxy group, a halogen atom, an alkoxy, aryloxy or an alkoxy group.

The ring closure reaction is suitably or at an elevated temperature, for example from 50 to 200 ° C., preferably from 80 to 150 ° C., or in excess of a solvent such as glacial acetic acid, tetrahydrofuran, dioxane, chloroform, toluene, ethanol It is preferred to carry out in the presence of a condensing agent such as sulfuric acid, concentrated hydrochloric acid, phosphoric acid or thionyl chloride in the condensing agent. However, this reaction can also be carried out in the absence of solvents and / or condensing agents.

The compounds of formula (II) used as starting materials do not need to be separated. These compounds can be prepared in situ from the corresponding nitro compounds, for example nitrogroups are hydrogenated catalysts such as palladium / charcoal, palladium / calcium carbonate or palladium / calcium carbonate + lead acetate [Lindlar-catalyst]. Reduction in the presence of hydrogen, reduction in the presence of acid to metals such as iron, tin or zinc, or salts such as iron (II) sulfate, zinc chloride (II), chromium (II) chloride or sodium dithionite Or reduced to hydrazine in the presence of Raney-Nickel.

In the case where m represents 1 in the corresponding nitro compound, the reduction of the nitro group can be suitably carried out using an equivalent amount of reducing agent, for example iron (II) sulfate, tin chloride (II), chromium chloride (II) Or by using a metal salt such as sodium dithionite or hydrogen in the presence of an inactivated hydrogenation catalyst, for example in the presence of palladium / calcium carbonate + lead acetate. For example in the presence of palladium / charcoal, the sulfoxide group is also partially reduced.

Also in the case where W represents a vinylene group in the corresponding nitro compound, this group is the corresponding ethylene group, in particular if the reduction reaction is carried out using catalytically activated hydrogen, for example hydrogen in the presence of palladium / charcoal. Can be hydrogenated.

Compounds of formula (II) used as starting materials are known in part from the literature and can be obtained according to known methods.

,

-디할로겐 알칸으로 알킬화하고 계속해서 상응하는 머캅토 화합물과 반응시키고, 이어서 임의로 과산화수소로 산화하여 수득한다.That is, the compound of formula (II) is obtained by reducing the corresponding nitro compound, which nitro compound corresponds to the corresponding 2-nitro-5-hydroxy compound.

,

Obtained by alkylation with dihalogen alkanes and subsequent reaction with the corresponding mercapto compound, followed by optionally oxidation with hydrogen peroxide.

The invention is illustrated in detail by the following examples.

Example 1

6- [4- (2-pyridylsulfonyl) -butoxy] -3,4-dihydro-carbostyryl

a) 2-nitro-5-hydroxy-cinnamic acid methyl ester

21.0 g of 2-nitro-5-hydroxycinnamic acid (SN Chakravarti and PLN RaO, Chem. Soc. 1938, 1972) are dissolved in 200 ml of methanol, and 86 ml of thionyl chloride is added to the solution with stirring over 45 minutes, At this time, the temperature rises to 36 ° C. After stirring for a further 25 minutes, the reaction mixture is cooled in an ice bath to afford 18.6 g of 2-nitro-5-hydroxy-cinnamic acid methyl ester. Melting point: 201 to 203 캜.

b) 2-nitro-5-bromobutoxy-cinnamic acid methyl ester

A mixture of 22.3 g of 2-nitro-5-hydroxy-cinnamic acid methyl ester, 59.7 ml of 1,4-dibromobutane and 13.8 g of potassium carbonate in 200 ml of dimethylsulfoxide is stirred at room temperature for 15 hours. After addition of 800 ml of water, the reaction mixture is extracted with chloroform and the solvent is evaporated before 31.7 g of 2-nitro-5-bromo-butoxy-cinnamic acid methyl ester is separated. Melting point: 60.5 to 63 ° C.

c) 2-nitro-5- [4- (2-pyridylmercapto) -butoxy] -cinnamic acid methyl-ester

After stirring a mixture of 5 g of potassium carbonate and 4.0 g of 2-mercaptopyridine in 100 ml of dimethyl sulfoxide for 60 minutes, 10.75 g of 2-nitro-5-bromobutoxy-cinnamic acid methyl ester was added thereto and the mixture was allowed to stand at room temperature. Stir for 18 h. 400 ml of water are added and the oil phase reaction product is separated by ether extraction. Yield: 11.0 g (94.2% of theory)

d) 2-nitro-5- [4- (2-pyridylsulfonyl) -butoxy] -cinnamic acid methyl ester

7.0 g of 2-nitro-5- [4- (2-pyridylsulfonyl) -butoxy] -cinnamic acid methyl ester is dissolved in 70 ml of acetic acid and 5.0 ml of 35% hydrogen peroxide is added and the mixture is left at room temperature for 3 days. After distilling off glacial acetic acid, the reaction product is recrystallized from chloroform / methanol. Yield 3.5 g (46.2% of theory). Melting point: 118 to 121 ° C.

e) 6- [4- (2-pyridylsulfonyl) -butoxy] -3,4-dihydrocarbostyryl

Hydrogenation of 2.1 g of 2-nitro-5- [4- (2-pyridylsulfonyl) -butoxy] -cinnamic acid methyl ester dissolved in 20 ml of glacial acetic acid to 0.5 g of 10% palladium / charcoal at room temperature and 3 bar hydrogen pressure do. After glacial acetic acid is distilled off, the residue is refluxed with 20 ml of concentrated hydrochloric acid for 4 hours. The reaction product is neutralized with 2N sodium hydroxide solution and extracted with chloroform. The evaporated residue is recrystallized from xylene. Yield: 1.06 g (55.6% of theory), Melting point: 121 to 123 ° C.

Example 2

6- [4- (2-pyridylsulfonyl) -butoxy] -carbostyryl

A mixture of 2.0 g of 2-nitro-5- [4- (2-pyridylsulfonyl) -butoxy] -cinnamic acid methyl ester and 3.0 g of sodium dithionite was refluxed in 20 ml of water and 10 ml of ethanol for 4 hours to obtain Obtain a solution. The reaction mixture is evaporated and boiled under reflux with 20 ml of concentrated hydrochloric acid for 3 hours. After neutralization with 2N sodium hydroxide solution, the reaction product is extracted with ether and recrystallized from xylene by addition of a small amount of dimethylformamide. Yield: 0.5 g (29% of theory), Melting point: 176 to 179 ° C

This material can be obtained in a similar manner using hydrogen in the presence of a Lindla catalyst (palladium partially inactivated by lead) instead of sodium dithionite as reducing agent. This yields 6- [4- (2-pyridylsulfonyl) -butoxy] -carbostyryl after only the nitro group has been reduced and treated with concentrated hydrochloric acid.

Example 3

6- [4- (3,4-Dichlorophenylmercapto) -butoxy] -carbostyryl

2-nitro-5 [4- (3,4-dichlorophenylmercapto) -butoxy] cinnamic acid methyl ester [melting point: 91-92 ° C, 2-nitro-5-hydroxy-cinnamic acid methyl ester and 4- 4.5 g of (3,4-dichlorophenylmercapto) -butylbromide] is refluxed for 4 hours with 13.9 g of sodium dithionite in a mixture of 50 ml of ethanol and 50 ml of water. After removing the solvent, the residue was refluxed with 100 ml of concentrated hydrochloric acid for 4 hours. The crystalline material obtained is suction filtered and recrystallized from xylene. Yield: 1.2 g (31% of theory), Melting point: 144 占 폚.

Example 4

6- [4- (3,4-Dichlorophenyl-sulfinyl) -butoxy] -carbostyryl

a) 2-nitro-5- [4- (3,4-dichlorophenylsulfinyl) -butoxy] -cinnamic acid methyl ester

11.2 g of 2-nitro-5-hydroxy-cinnamic acid methyl ester is dissolved in 150 ml of dimethyl sulfoxide. The solution is mixed with 9.2 g of anhydrous potassium carbonate and stirred for 15 minutes. 16.5 g of 4- (3,4-dichloro-phenylsulfinyl) -butylbromide are added and the mixture is stirred at room temperature for 40 hours. The reaction mixture is diluted with 1,000 ml of water and extracted with a mixture of 200 ml of chloroform and 100 ml of methanol. After evaporating the organic solvent, an oily residue is obtained which is treated with ether to give a crystalline material. Yield: 13 g (57% of theory), Melting point: 78 to 81 ° C.

b) 2-amino-5- [4- (3,4-dichloro phenylsulfinyl) -butoxy] -cinnamic acid methyl ester

4.2 g of 2-nitro-5- [4- (3,4-dichloro phenylsulfinyl) -butoxy] -cinnamic acid methyl ester was reacted with a Lindla-catalyst (in lead acetate) in 100 ml of methanol at room temperature and hydrogen pressure of 3 bar. Hydrogenated with 0.5 g of partially inactivated palladium on calcium carbonate) for 12 hours. After removing the catalyst, the dendritic black residue obtained by evaporating the solvent is used directly for the next reaction.

c) 6- [4- (3,4-dichloro phenylsulfinyl) -butoxy] -carbostyryl

The 2-amino-5- [4- (3,4-dichloro phenylsulfinyl) -butoxy] -cinnamic acid methyl ester obtained in b) is boiled with 80 ml of 5N hydrochloric acid for 3 hours, and filtered upon heating. . After cooling the filtrate, colorless crystals are obtained. Yield: 2.1 g (56% of theory), Melting point: 191 to 192 ° C.

When iron powder and 80% acetic acid were used as the reducing agent of 2-nitro-5- [4- (3,4-dichloro phenylsulfinyl) -butoxy] -cinnamic acid methyl ester in the reaction process described above, 6- [ 4- (3,4-dichloro phenylsulfinyl) -butoxy] -carbostyryl is obtained as reaction product.

Example 5

2-nitro-5- (3,4-dichloro phenylsulfinyl) -butoxy-cinnamic acid methyl ester

2.3 g are hydrogenated at room temperature and 3 bar hydrogen pressure, in a similar manner as in Example 5b) in 20 ml glacial acetic acid and 0.2 g palladium / charcoal for 7 hours. After removing the catalyst, glacial acetic acid is distilled off and the residue is boiled with 40 ml of 5N hydrochloric acid for 1 hour. After cooling, the reaction mixture is extracted with a small amount of chloroform and separated by chromatography on a thin plate (Merck silica gel 60F ₂₅₄ ) using ethylene chloride / methanol 9: 1. The resulting compound is confirmed by ultraviolet and iodine spray treatment.

R _f value 0.30: 6- [4- (3,4-Dichlorophenylsulfinyl) -butoxy] -carbostyryl, blue violet by iodine spray.

R _f value 0.42: 6- [4- (3,4-Dichlorophenylmercapto) -butoxy] -carbostyryl, initially orange-yellow by iodine spray, then gradually grey-violet ).

R _f value 0.45: 6- [4- (3,4-Dichlorophenylsulfinyl) -butoxy] -3,4-dihydro-carbostyryl, apparent orange-yellow by iodine spray.

R _f value 0.57: 6- [4- (3,4-Dichlorophenylmercapto) -butoxy] -3,4-dihydro-carbostyryl, pale yellow by iodine spray.

The following compounds are prepared by methods analogous to the methods of the foregoing examples:

6- (4-phenylmercapto-butoxy) -3,4-dihydro carbostyryl, melting point: 121.5 to 123 ° C.

6- (4-phenylsulfinylbutoxy) -3,4-dihydrocarbostyryl, melting point: 144.5 to 145.5 ° C.

6- (4-phenylsulfonylbutoxy) -3,4-dihydrocarbostyryl, melting point: 157.5 to 158 ° C.

6- [4- (2-pyridylmercapto) -butoxy] -3,4-dihydro-carbostyryl, melting point: 123-124.5 ° C.

6- [4- (2-pyridylsulfinyl) -butoxy] -3,4-dihydro-carbostyryl, melting point: 144.5 to 146 ° C.

6- [4- (2-pyridylsulfonyl) -butoxy] -3,4-dihydro-carbostyryl, melting point: 123.8 to 125 ° C.

6- (2-phenylsulfinyl-ethoxy) -3,4-dihydrocarbostyryl, Melting point: 171 to 172 캜.

6- (4-benzylsulfinyl-butoxy) -3,4-dihydrocarbostyryl, melting point: 141.5 to 142 ° C.

6- [4- (4-chlorophenylsulfinyl) -butoxy] -3,4-dihydrocarbostyryl, Melting point: 148-149.5 degreeC.

6- (4-cyclohexylsulfinyl-butoxy) -3,4-dihydrocarbostyryl, melting point: 153 to 155.5 ° C.

6- [4- (2-naphthylsulfinyl) -butoxy] -3,4-dihydrocarbostyryl, melting point: 147.5 to 148.5 ° C.

6- [4- (2-methoxyphenylsulfinyl) -butoxy] -3,4-dihydro-carbostyryl, melting point: 130.5 to 133 ° C.

6- (4-phenylsulfinyl-butoxy) -carbostyryl, melting point: 181 to 182.5 ° C.

6- [4- (4-Hydroxy-3,5-di-tert-butyl-phenylsulfinyl) -butoxy] -carbostyryl, melting point: 192-194 degreeC.

6- [4- (3,4-Dichlorophenylsulfinyl) -butoxy] -carbostyryl, Melting point: 191-196 degreeC.

4-Methyl-6- (4-phenylsulfinyl-butoxy) -carbostyryl, melting point: 167 to 168 ° C.

6- [4- (3,4-Dichlorophenylsulfonyl) -butoxy] -4,4-dihydrocarbostyryl, Melting point: 172-173 degreeC.

6- [4- (2,5-dichlorophenylsulfinyl) -butoxy] -3,4-dihydrocarbostyryl, melting point: 185 to 186 ° C.

6- [4- (2-pyridyl) -sulfonylbutoxy] -carbostyryl, melting point: 179 to 180 ° C.

6- [4- (2-naphthyl-sulfinyl) -butoxy] -3,4-dihydro-carbostyryl, melting point: 147.5 to 148.5 ° C.

6- [4- (4-biphenylylsulfinyl) butoxy] -carbostyryl, Melting point: 196-197 ° C.

6- [4- (2-quinolinylsulfinyl) -butoxy] -carbostyryl, melting point: 197 to 198 ° C.

6- [4- (4-cyclohexylsulfinyl) -butoxy] -carbostyryl, melting point: 169 to 170 ° C.

5-Bromo-6- (4-phenylsulfinyl butoxy) -carbostyryl, melting point: 190-191 ° C.

6- [2- (N-Methyl-N-cyclohexyl-carbamidomethyl-sulfinyl) -ethoxy] -carbostyryl, melting point: 128 to 130 ° C.

6- [4- (3,5-Dibromo-4-aminophenylsulfinyl) -butoxy] -3,4-dihydrocarbostyryl, Melting point: 144 to 146 캜.

6- [4- (3,5-Dibromo-4-aminophenylsulfinyl) -butoxy] -carbostyryl, melting point: 205 to 207 ° C.

6- [4- (3,4-cyclohexylphenylsulfinyl) -butoxy] -3,4-dihydrocarbostyryl, Melting point: 155 to 157 ° C.

6- [4- (4-cyclohexylphenylsulfinyl) -butoxy] -carbostyryl, melting point: 188 to 190 ° C.

6- [4- (4-tert-butylphenylsulfinyl) -butoxy] -carbostyryl, melting point: 164 to 166 캜.

6- [4- (3,4-dichlorophenylsulfinyl) -butoxy] -3,4-dihydrocarbostyryl, melting point: 106.5 to 108 ° C. Melting point: 148-149 degreeC (once with toluene and once with ethanol).

Claims (1)

A method for preparing a carbostyryl derivative of the following general formula (I), characterized by ring closure of the compound of the following general formula (II).

In the above formula, W represents a vinylene group or an ethylene group optionally substituted by a methyl group, D represents a straight or branched chain alkylene group having 2 to 6 carbon atoms, a straight or branched chain hydroxyalkylene group having 3 to 6 carbon atoms or a xylylene group, m represents 0,1 or 2, R ₁ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ₂ is a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, a nitrogen atom, an oxygen atom, a sulfur atom, a nitrogen atom and an oxygen or sulfur atom, or two nitrogen atoms, respectively A heteroaryl group having 4 to 9 carbon atoms or a heteroaralkyl group having 5 to 10 carbon atoms, wherein the aromatic nucleus mentioned above is an alkyl group having 1 to 4 carbon atoms, hydroxy, methoxy, amino, acetylamino, Mono- or di-substituted by a nitro, carboxyl, cyclohexyl, phenyl group or halogen atom, the above-mentioned monosubstituted phenyl group further comprises an alkyl group having 1 to 4 carbon atoms, a halogen atom or having 1 to 4 carbon atoms. Mono- or di-substituted by alkyl groups and halogen atoms (where the substituents of the phenyl nucleus may be the same or different)], 1,2,4-triazolyl, triphenylmethyl , 4,5-bis- (p-chlorophenyl) -oxazol-2-yl, N-methyl-cyclohexylaminocarbonylmethyl or amino-iminomethyl group, R ₂ also represents m is 1 Or when D represents a straight or branched hydroxyalkylene group or a xylylene group having 3 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, R ₃ and R ₄ may be the same or different and represent a hydrogen atom or a halogen atom, an alkyl group having 1 to 4 carbon atoms, amino, acetylamino or nitro group, Z represents a nucleophilic substituent such as a hydroxy group, a halogen atom, an alkoxy, aryloxy or aralkyloxy group.