KR100302346B1 - A method of preparing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline - Google Patents

Abstract

The present invention relates to a method for preparing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline of formula (1) useful as an intermediate in the preparation of cilostazol, a thrombus therapeutic agent.

Description

Method for preparing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline {A method of preparing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline}

The present invention relates to a process for preparing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline of formula (1) useful as an intermediate in the preparation of cilostazol.

Cilostazol is a drug used as a thrombolytic agent, and its chemical name is 6- [4- (1-cyclohexyl-5-tetrazolyl) butoxy] -1,2,3,4-tetrahydro-2-oxoquinoline And, the structural formula is the same as the formula (5).

The cilostazol of Formula 5 is prepared by reacting 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline and 5-halobutyl-1-cyclohexyl tetrazole of Formula 1 as an intermediate. Chem. Pharm. Bull., Vol. 31, 1151-1157 (1983).

As a prior art with regard to the preparation of compounds of formula (1), methods for preparing compounds of formula (7) similar to those of formula (1) have been disclosed. 60, 858-864 (1927). In other words, this process is characterized by the acid-catalyzed N- (4-substituted-benz) -3-chloropropionylamide of formula 6 with aluminum chloride, as shown in Scheme 1, to obtain a compound of formula 7 by cyclization in the molten state. To prepare.

Wherein X is a hydrogen atom, chloro, amino, phenyl, methyl or ethoxy group.

The main drawback of this method is that it is difficult to industrialize due to the nonuniform reaction by mixing a toxic solid aluminum chloride and a compound of Chemical Formula 6 without using a solvent and reacting it at an extremely high temperature (200-240 ° C.). Since it is difficult to react evenly, it is necessary to perform additional processes such as recrystallization due to low purity due to side reactions, and low yield (80%) of the target product, which is not economical and involves risk.

In addition, a method of preparing a compound of Formula 1 via a nitrocinnamic acid derivative has been disclosed. See Journal of the American Chemical Society, Vol. 66, 1442-1443 (1944). This method is a method for preparing the compound of formula 1 by reduction and cyclization from 5-hydroxy-2-nitrocinnamic acid alkyl of formula 10 as shown in Scheme 2.

R is a hydrogen atom, methyl or ethyl group.

This method is very expensive and the reaction is carried out under pressurized conditions, since 5-hydroxy-2-nitrobenzaldehyde of formula 8 and alkyl hydroxy 3-nacinaldehyde of formula 9, which are starting materials of formula 10, have a risk of explosion and hydrogen It requires a special device for handling the compressed gas for the reaction and there is a disadvantage in that it is difficult to industrialize because it uses a very high risk of ignition.

A process for preparing a compound of Formula 1 using cinnamic acid derivatives has also been disclosed. Journal of the American Chemical Society, Vol. 89, 7131-7132 (1962). This method is a method for preparing a compound of formula 1 by cyclization from 3-hydroxycinnamohydrosamic acid of formula 13 as shown in Scheme 3.

The main drawback of this method is that the 3- (3-hydroxyphenyl) propionic acid of formula 11, which is the starting material of formula 13, is very expensive and is prepared in three steps from the starting material. The yield of the process is also low as 52%.

In addition, methods for preparing compounds of Formula 16 that are similar to those of Formula 1 have been disclosed. See Journal of Organic Chemistry, Vol. 36, 3975-3979 (1971). This method synthesized the compound of formula 15 by cyclization from 4-substituted-acrylanilide of formula 14 and then dealkylation reaction to 6-hydroxy-3-substituted-4-hydrocarbostyryl of formula 16. It is a method of manufacturing.

Wherein R is hydrogen, methyl or ethyl, and R ₁ is an alkyl or electron donating group.

The main disadvantage of this method is that it is industrially inadequate as a photoreaction and its yield is very low as 13% upon photoreaction with a compound of formula 15.

Accordingly, the present inventors have made efforts to solve the problems of the conventional manufacturing method as described above, the production of safe and simple high yield 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline. The present invention can be completed.

Accordingly, an object of the present invention is to provide a method for preparing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline of formula (1).

The present invention provides a process for reacting N- (4-substituted-benz) -3-chloropropionylamide of formula (2) with Lewis acid in the presence of a homogenizing agent, 6-hydroxy-2-oxo-1 of formula (1), It relates to a method for producing 2,3,4-tetrahydroquinoline.

Reaction path of the present invention is represented by the reaction scheme 5.

In which R is hydrogen, methyl or ethyl.

Homogenizer is a solvent that helps to uniformly react at lower temperature without unreacted material by quenching uniformly turbidity of two or more reactants to alleviate the uneven reaction progress and the decrease of heat transfer which are problems in the reaction in the molten state. Homogenizing agents usable in the production process according to the invention include decahydronaphthalene; High boiling ether compounds such as diphenyl ether, isoamyl ether, benzylethyl ether, diglyme, triglyme and the like; Or hydrocarbon compounds such as β-pinene, limonene, tetraline and the like. Most preferred is decahydronaphthalene.

Lewis acid catalysts usable in the production process according to the invention include aluminum chloride, zinc chloride or titanium tetrachloride, of which aluminum chloride is preferred.

The reaction conditions are preferably carried out at 0 to 200 ° C. for 2 to 18 hours.

The compound of formula 2 used as starting material can be obtained in high yield (97%) by reacting 4-substituted-aniline of formula 3 with 3-chloropropionyl chloride of formula 4.

At this time, the reaction conditions are preferably carried out at a temperature of 5 ℃ to 100 ℃ in a polar organic solvent such as ethyl acetate, dimethylformamide and dimethyl sulfoxide or a non-polar organic solvent such as hexane and benzene.

The 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline of formula 1 prepared according to the process of the present invention can be used as an intermediate in the preparation of cilostazol, a medicament useful as a therapeutic agent for thrombosis.

The following examples are set forth to illustrate the invention described above but are not intended to limit the scope of the invention.

Example 1: Preparation of N- (4-hydroxybenz) -3-chloropropionylamide (2)

1000 ml of ethyl acetate and 109.1 g (1 mol) of 4-hydroxyaniline were added to a flask equipped with a magnetic stirrer under nitrogen stream, and 190.5 g (1.5 mol) of 3-chloropropionyl chloride diluted in 500 ml of ethyl acetate was slowly added dropwise at room temperature. Stir vigorously for the next 1 hour. 1000 ml of saturated sodium carbonate was added to the reaction solution to completely dissolve the salt. The organic layer was separated, and the organic layer was washed with 500 ml of water again. The separated organic layer was dried with forget-me-not and distilled under reduced pressure to remove the solvent, and the residue was crystallized in isopropanol and water. This gave 189.7 g (95%) of light purple N- (4-hydroxybenz) -3-chloropropionylamide.

Melting Point: 127 ° to 129 ° (Measured: 128 ° to 129 °)

IR: ν _max (cm ⁻¹ ) 3300 (NH strech), 3200 (OH strech), 1655 (C = O strech),

1561, 1508, 1412, 1264, 1200, 980, 839

H ¹ NMR: δ 2.75 (2H, t, ClCH ₂ C H ₂ CO—)

3.86 (2H, t, ClC H ₂ CH ₂ CO-)

6.67 ~ 7.38 (4H, q, Aromatic C H- )

9.17 (1H, s, H OPh-)

9.79 (1H, s, ClCH ₂ CH ₂ CON H- )

Example 2: Preparation of N- (4-methoxybenz) -3-chloropropionylamide (2)

1000 ml of ethyl acetate and 123.2 g (1 mol) of 4-methoxyaniline were added to a flask equipped with a magnetic stirrer under nitrogen stream, and 190.5 g (1.5 mol) of 3-chloropropionyl chloride diluted in 500 ml of ethyl acetate was slowly added dropwise at room temperature. Stir vigorously for the next 1 hour. 1000 ml of saturated sodium carbonate was added to the reaction solution to completely dissolve the salt. The organic layer was separated, and the organic layer was washed with 500 ml of water again. The separated organic layer was dried with forget-me-not and distilled under reduced pressure to remove the solvent, and the residue was crystallized in isopropanol and water. To give 207.3 g (97%) of light purple N- (4-methoxybenz) -3-chloropropionylamide.

Melting Point: 120 ° to 122 ° (Actual: 121 ° to 122 °)

IR: ν _max (cm ^-1 ) 3275 (NH strech), 1653 (C = O strech), 1605, 1549, 1512, 1301, 1244, 1030, 929, 829

H ¹ NMR: δ 2.79 (2H, t, ClCH ₂ C H ₂ CO-)

3.79 (3H, s, C H ₃ OPh-)

3.88 (2H, t, Cl CH ₂ CH ₂ CO-)

6.85-7.43 (4H, q, Aromatic C H- )

7.43 (1H, s, ClCH ₂ CH ₂ CON H- )

Example 3: Preparation of N- (4-ethoxybenz) -3-chloropropionylamide (2)

1000 ml of ethyl acetate and 137.2 g (1 mol) of 4-ethoxyaniline were added to a flask equipped with a magnetic stirrer under nitrogen stream, and 190.5 g (1.5 mol) of 3-chloropropionyl chloride diluted in 500 ml of ethyl acetate was slowly added dropwise at room temperature. Stir vigorously for the next 1 hour. 1000 ml of saturated sodium carbonate was added to the reaction solution to completely dissolve the salt. The organic layer was separated, and the organic layer was washed with 500 ml of water again. The separated organic layer was dried with forget-me-not and distilled under reduced pressure to remove the solvent, and the residue was crystallized in isopropanol and water. To give 214.0 g (94%) of light purple N- (4-ethoxybenz) -3-chloropropionylamide.

Melting Point: 117 ° to 119 ° (Measured: 118 ° to 119 °)

IR: ν _max (cm ^-1 ) 3280 (NH strech), 1653 (C = O strech), 1605, 1548, 1511,

1308, 1241, 1047, 931, 830

H ¹ NMR: δ 1.40 (3H, t, C H ₃ CH ₂ OPh-)

2.77 (2H, t, ClCH ₂ C H ₂ CO-)

3.86 (2H, t, ClC H ₂ CH ₂ CO-)

4.01 (2H, q, CH ₃ C H ₂ OPh-)

6.82-7.40 (4H, q, Aromatic C H- )

7.56 (1H, s, ClCH ₂ CH ₂ CON H- )

Example 4: Preparation of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (1)

500 ml of decahydronaphthalene, 199.1 g (1 mol) of N- (4-hydroxybenz) -3-chloropropionylamide, and 667 g (5 mol) of aluminum chloride were added to a flask equipped with a magnetic stirrer under a nitrogen stream, and then gradually cooled to room temperature. The reaction mixture was stirred for 8 hours at 150 ° C. The resulting solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, the solid was vigorously stirred and triturated, filtered and washed with water and chloroform. The filtered product was vacuum dried to yield 146.9 g (90%) of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline.

Melting Point: 235 ° to 237 ° (Actual: 236 ° to 237 °)

IR: ν _max (cm ^-1 ) 3315 (NH strech), 3200 (OH strech), 1649 (C = O strech)

1502, 1392, 1287, 1252, 1151, 1116, 963, 813, 777

H ¹ NMR: δ 2.35 (2H, t, -CH ₂ C H ₂ CO-)

2.76 (2H, t, -C H ₂ CH ₂ CO-)

6.51 to 6.66 (3H, m, Aromatic C H- )

9.00 (1H, s, H OPh-)

9.79 (1H, s, -CH ₂ CH ₂ CON H- )

Example 5: Preparation of 6-hydroxybenz-2-oxo-1,2,3,4-tetrahydroquinoline (1)

500 ml of decahydronaphthalene, 213.7 g (1 mol) of N- (4-methoxybenz) -3-chloropropionylamide and 667 g (5 mol) of aluminum chloride were added to a flask equipped with a magnetic stirrer under a nitrogen stream, and then gradually cooled to room temperature. The reaction mixture was stirred for 8 hours at 150 ° C. The resulting solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, the solid was vigorously stirred and triturated, filtered and washed with water and chloroform. The filtered product was dried in vacuo to yield 155.0 g (95%) of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline.

Melting point, IR, H ¹ NMR data are the same as in Example 4.

Example 6: Preparation of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (1)

500 ml of decahydronaphthalene, 227.7 g (1 mol) of N- (4-ethoxybenz) -3-chloropropionylamide and 667 g (5 mol) of aluminum chloride were placed in a flask equipped with a magnetic stirrer under a nitrogen stream, and then gradually cooled to room temperature. The reaction mixture was stirred for 8 hours at 150 ° C. The resulting solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, the solid was vigorously stirred and triturated, filtered and washed with water and chloroform. The filtered product was dried in vacuo to yield 145.2 g (89%) of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline.

Melting point, IR, H ¹ NMR data are the same as in Example 4.

Example 7: Preparation of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (1)

500 ml of decahydronaphthalene, 213.7 g (1 mol) of N- (4-methoxybenz) -3-chloropropionylamide and 681.5 g (5 mol) of zinc chloride were added to a flask equipped with a magnetic stirrer under a nitrogen stream, and then slowly at room temperature. The temperature was raised and reacted by stirring at 150 ° C. for 12 hours. The resulting solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, the solid was vigorously stirred and triturated, filtered and washed with water and chloroform. The filtered product was vacuum dried to yield 143.6 g (88%) of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline.

Melting point, IR, H ¹ NMR data are the same as in Example 4.

Example 8: Preparation of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (1)

In a flask equipped with a magnetic stirrer under a nitrogen stream, 500 ml of decahydronaphthalene, 213.7 g (1 mol) of N- (4-methoxybenz) -3-chloropropionylamide, and 948.5 g (5 mol) of titanium tetrachloride were added to a room temperature. The temperature was gradually raised at and reacted by stirring at 150 ° C. for 16 hours. The resulting solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, the solid was vigorously stirred and triturated, filtered and washed with water and chloroform. The filtered product was vacuum dried to give 133.8 g (82%) of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline.

Melting point, IR, H ¹ NMR data are the same as in Example 4.

As described above, the present invention provides an excellent method for preparing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline, which has a simple manufacturing process, little by-product formation, and high yield. This compound can be used as a useful intermediate in the preparation of cilostazol, which is useful as a thrombolytic agent.

Claims (5)

6-hydroxy-2-oxo-1 of Formula 1 comprising the step of reacting N- (4-substituted-benz) -3-chloropropionylamide of Formula 2 with Lewis acid in the presence of decahydronaphthalene as a homogenizing agent Method for preparing 2,3,4-tetrahydroquinoline. In which R is hydrogen, methyl or ethyl. The N- (4-substituted-benz) -3-chloropropionylamide of claim 2 is reacted with 4-substituted-aniline of formula 3 and 3-chloropropionyl chloride of formula 4 in the presence of a solvent. Method for producing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline, characterized in that it is prepared. In which R is hydrogen, methyl or ethyl. The process for producing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline according to claim 1, wherein the Lewis acid is aluminum chloride, zinc chloride or titanium tetrachloride. The process for preparing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline according to claim 1, wherein the reaction is performed at 0 ° C. to 200 ° C. for 2 to 18 hours. The 6-hydroxy-2 compound according to claim 2, wherein the reaction is carried out at a temperature of 5 ° C to 100 ° C in the presence of a solvent selected from the group consisting of ethyl acetate, dimethylformamide, dimethylsulfoxide, hexane and benzene. -Oxo-1,2,3,4-tetrahydroquinoline preparation method.