JP2000229944A - Production of 6-hydroxy-2-oxo-1,2,3,4-terrahydroquinoline - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially safely and easily obtain the subject compound at low cost and in high yield useful as a synthetic intermediate for cilostazol of a thrombosis medicine by reacting substituted benzochloropropionyl amide with Lewis acid in the presence of homogenizer. SOLUTION: This compound is represented by the formula II and obtained by reacting N-(4-substituted-benzo)-3-chloropropionylamide of formula I (R is H, methyl or ethyl) with Lewis acid (e.g. decahydronaphthalene) in the presence of a homogenizer. The reaction is performed using preferably 2-10 mol more preferably 3-5 mol Lewis acid based on the compound of formula I and preferably 1-20 ml/g more preferably 1-5 mg/g homogenizing agent and preferably at 0-200 deg.C for 2-18 h more preferably at 120-150 deg.C for 6-10 h.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to cilostazol (Cilosol).
6-Hydroxy-2 useful as a synthetic intermediate for stazol)
-Oxo-1,2,3,4-tetrahydroquinoline.

[0002]

2. Description of the Related Art Cilostazol is used as a therapeutic agent for thrombosis, and its chemical name is 6- [4- (1-cyclohexyl-5-tetrazolyl) butoxy] -1,2,3,4-tetrahydro-2-oxo. It is quinoline, and its structural formula is represented by the following general formula (V).

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[0003] The cilostazol represented by the general formula (V) is a synthetic intermediate of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline represented by the general formula (I) and 5-halobutyl. -1-cyclohexyltetrasol can be produced (Chem. Pharm. Bull. 3
1, 1151-1157 (1983)).

A method for producing a compound of the general formula (VII) having a structure similar to that of the compound of the general formula (I) has been reported (Ber. 60, 858-864 (1927)). According to this method, as shown in the following reaction formula, the compound represented by the general formula (VII) is converted to a N- (4-substituted-benzo)-
It is produced by cyclizing 3-chloropropionylamide in the molten state in the presence of an acid catalyst, aluminum chloride.

Embedded image (In the formula, X is a hydrogen atom, a chlorine atom, an amino group, a phenyl group, a methyl group, or an ethoxy group.)

In this method, aluminum chloride and a compound of the general formula (VI) are used at a rather high temperature (200 to 240) without using a solvent.
C), special equipment is required. In addition, since it is difficult to make the reaction uniform, the yield is low and uneconomical, and there is a disadvantage that it involves danger.

The compounds of the general formula (I) can also be prepared via nitrocinnamic acid derivatives (Journal of
the American Chemical Society, 66, 1442-1443
(1944)). Specifically, as shown in the following reaction formula, the compound of the general formula (I) is obtained by reducing and cyclizing the alkyl 5-hydroxy-2-nitrocinnamate represented by the general formula (X). .

Embedded image (In the formula, R is a hydrogen atom, a methyl group, or an ethyl group.)

In this process, the starting materials, 5-hydroxy-2-nitrobenzaldehyde of the general formula (VIII) and alkyl 3-hydroxycinnamate of the general formula (IX), are very expensive, There is a danger of explosion because it reacts under conditions. Furthermore, in the hydrogenation reaction, a special device is required in order to handle a compressed gas, and there is a disadvantage that industrialization is difficult because hydrogen having a very high risk of ignition is used. .

A method for producing a compound of the general formula (I) using a cinnamic acid derivative is also known (Journal
of the American Chemical Society, 89, 7131-7
132 (1962)). In this method, as shown in the following reaction formula, the compound of the general formula (I) is a compound of the general formula (XIII)
Produced by cyclizing hydroxycinnamohydroxamic acid.

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The process comprises the steps of starting a compound of general formula (XI)
3- (3-hydroxyphenyl) propionic acid is inefficient due to the very high cost and the need for three reaction steps from the starting material, resulting in a final product yield of 52%.
% Is a disadvantage.

A method is also known for producing a compound represented by the general formula (XVI) having a similar structure to the compound of the general formula (I) according to the following reaction formula (Journal of t.
he Organic Chemistry, 36, 3975-3979 (1971)). In this method, a compound of the general formula (XV) is synthesized by cyclizing a 4-substituted-acrylanilide of the general formula (XIV),
This is dealkylated to produce 6-hydroxy-3-substituted-4-hydrocarbostyril represented by the general formula (XVI).

Embedded image (In the formula, R is a hydrogen atom, a methyl group or an ethyl group, and R ₁ is an alkyl group or an electron donating group.)

This method has a problem in that, when the compound of the general formula (XV) is produced, an industrially inappropriate photoreaction is performed and the yield is as low as 13%.

[0012]

DISCLOSURE OF THE INVENTION The present invention provides an industrially safe, simple and inexpensive 6-hydroxy-2-yield with good yield.
An object of the present invention is to provide a method for producing oxo-1,2,3,4-tetrahydroquinoline.

[0013]

Means for Solving the Problems The inventors of the present invention have conducted studies to solve the above-mentioned problems in the conventional production method, and as a result, have found that 6-hydroxy-2-oxo-1 is safe, easily and in good yield. The present invention was completed by finding a method for producing 2,2,3,4-tetrahydroquinoline. That is, the present invention provides a general formula (N) comprising reacting N- (4-substituted-benzo) -3-chloropropionylamide represented by the following general formula (II) with a Lewis acid in the presence of a homogenizing agent. 6-hydroxy-2-oxo-1,2,3,4 represented by I)
-To provide a method for producing tetrahydroquinoline.

Embedded image

Embedded image (In the formula, R is a hydrogen atom, a methyl group or an ethyl group.)

BEST MODE FOR CARRYING OUT THE INVENTION

The reaction step in the production method of the present invention is represented by the following reaction formula.

Embedded image (In the formula, R is a hydrogen atom, a methyl group or an ethyl group.)

The term "homogenizing agent" in the present invention means that two or more kinds of reactants are uniformly turbid to improve uneven reaction progress which is a problem at the time of reaction in a molten state, and to reduce heat transfer. It is a substance that relaxes. In other words, it is a solvent that eliminates unreacted substances and allows the reaction to proceed uniformly at a lower temperature. Examples of the homogenizing agent used in the production method of the present invention include decahydronaphthalene; a high-boiling ether compound such as diphenyl ether, isoamyl ether, benzylethyl ether, diglyme, and triglyme; and a hydrocarbon such as β-pinene, limonene, and tetralin. Compounds. Of these, decahydronaphthalene is most preferred.

Examples of the Lewis acid catalyst used in the production method of the present invention include aluminum chloride, zinc chloride and titanium tetrachloride, and aluminum chloride is particularly preferably used. In the reaction, the Lewis acid is used in an amount of 2 to 10 mol, preferably 3 to 5 mol, based on the compound of the general formula (II),
Use a homogenizing agent in an amount of 1 to 20 ml / g, preferably 1 to 5 ml / g.
The reaction is performed at 200 ° C., preferably 120 to 150 ° C., for 2 to 18 hours, preferably 6 to 10 hours.

The compound of the general formula (I) as a reaction product can be purified by a known method, for example, recrystallization from methanol and the like.

The starting compound represented by the general formula (II) is prepared by reacting a 4-substituted aniline of the general formula (III) with 3-chloropropionyl chloride represented by the general formula (IV). , In high yield (97%).

Embedded image (In the formula, R is a hydrogen atom, a methyl group or an ethyl group.)

This reaction is carried out in a polar organic solvent such as ethyl acetate, dimethylformamide and dimethylsulfoxide or a non-polar organic solvent such as hexane and benzene at 10 to 30 ° C. for 1 to 3 hours. At this time, 4-substitution-
For aniline, 3-chloropropionyl chloride
1 to 5 mol, preferably 1.2 to 2 mol, the above solvent is 5 to 20 ml /
Use g.

The obtained compound of the general formula (II) can be purified by a known method such as recrystallization from a mixed solution of isopropanol and water.

The 6-hydroxy-2-oxo-1,2,3,4 of the general formula (I) prepared according to the process of the present invention
-Tetrahydroquinoline is useful as a synthetic intermediate for cilostazol, a therapeutic agent for thrombosis.

[0022]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto.

Example 1 N- (4-hydroxybenz)
Production of zo) -3-chloropropionylamide (II) A flask containing a magnetic stirrer under a nitrogen stream
1,000 ml of ethyl acetate and 4-hydroxyaniline 10
9.1 g (1 mol) were added. Dilute with 500 ml of ethyl acetate at room temperature
190.5 g (1.5 mol) of 3-chloropropionyl chloride
After slowly dropping the solution, the reaction solution is vigorously stirred for 1 hour.
Stirred. 1000 ml of saturated sodium carbonate was added to the reaction solution.
Dissolve the salt completely, separate the organic layer and wash with 500 ml of water
did. Dry the separated organic layer using magnesium sulfate
Then, the solvent was removed by distillation under reduced pressure. The residue is isopropa
Crystallized with a mixture of phenol and water, light purple N- (4-
(Hydroxybenzo) -3-chloropropionylamide 18
9.7 g (95%) were obtained. Melting point: 127-129 [deg.] C (actual measurement: 128-129 [deg.] C). IR: νmax (cm^-1) 3300 (N-H strech), 3200 (O-H strec)
h), 1655 (C = O strech), 	 1561, 1508, 1412, 1264,
1200, 980, 839.¹ H NMR: δ 2.75 (2H, t, ClCH_TwoCH ₂ CO-), 3.86 (2H,
t, ClCH ₂ CH_TwoCO-), 6.67 to 7.38 (4H, q, Aromatic CH
-), 9.17 (1H, s,HOPh-), 9.79 (1H, s, ClCH_TwoCH_TwoCONH
-).

Example 2 N- (4-methoxybenz)
Production of zo) -3-chloropropionylamide (II) A flask containing a magnetic stirrer under a nitrogen stream
1000 ml of ethyl acetate and 4-methoxyaniline 123.
2 g (1 mol) were added. 3-chlorodiluted with 500 ml of ethyl acetate
Add 190.5 g (1.5 mol) of lopropionyl chloride at room temperature
After slowly dripping into the container, vigorously stir the reaction solution for 1 hour
did. 1000 ml of saturated sodium carbonate was added to this reaction solution, and salt was added.
Was completely dissolved, the organic layer was separated and washed with 500 ml of water.
Was. The separated organic layer is dried using magnesium sulfate.
And the solvent was removed by distillation under reduced pressure. The residue is isopropa
Crystallized with a mixture of phenol and water, light purple N- (4-
Methoxybenz) -3-chloropropionylamide 20
7.3 g (97%) were obtained. Melting point: 120-122 ° C (actual measurement: 121-122 ° C). IR: νmax (cm^-1) 3275 (N-H strech), 1653 (C = O stre
ch), 1605, 1549, 1512,1301, 1244, 1030, 929, 829.¹ H NMR: δ 2.79 (2H, t, ClCH_TwoCH ₂ CO-), 3.79 (3H,
s, CH ₃ OPh-), 3.88 (2H, t, ClCH ₂ CH_TwoCO-), 6.85-7.43
 (4H, q, Aromatic CH-), 7.43 (1H, s, ClCH_TwoCH _TwoCONH
-).

Example 3 Production of N- (4-ethoxybenzo) -3-chloropropionylamide (II) 1000 ml of ethyl acetate and 4-ethoxyaniline 137 were placed in a flask containing a magnetic stirrer under a nitrogen stream. .
2 g (1 mol) were added. After 190.5 g (1.5 mol) of 3-chloropropionyl chloride diluted with 500 ml of ethyl acetate was slowly dropped into the flask at room temperature, the reaction solution was vigorously stirred for 1 hour. After adding 1000 ml of saturated sodium carbonate to the reaction solution to completely dissolve the salt, the organic layer was separated and washed with 500 ml of water. The separated organic layer was dried using magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was crystallized in a mixture of isopropanol and water to give a light purple N
214.0 g (94%) of-(4-ethoxybenzo) -3-chloropropionylamide were obtained. Melting point: 117-119 ° C (actual measurement: 118-119 ° C). IR: νmax (cm ^-1 ) 3280 (NH strech), 1653 (C = O st
rech), 1605, 1548, 1511, 1308, 1241, 1047, 931, 83
0. ¹ H NMR: δ1.40 (3H, t, CH 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 (2
H, q, CH ₃ C H ₂ OPh-), 6.82 to 7.40 (4H, q, Aromatic C H
-), 7.56 (1H, s, ClCH ₂ CH ₂ CON H- ).

Example 4 Production of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (I) Under a nitrogen stream, 500 ml of decahydronaphthalene was placed in a flask containing a magnetic stirrer. 199.1 g of N- (4-hydroxybenzo) -3-chloropropionylamide (1
mol) and 667 g (5 mol) of aluminum chloride, the temperature was slowly raised from room temperature, and the mixture was stirred and reacted at 150 ° C. for 8 hours. The resulting solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, and the mixture was vigorously stirred and pulverized. The product was collected by filtration and washed with water and chloroform. The product collected by filtration was dried in vacuo and 6-hydroxy-2-oxo-
146.9 g (90%) of 1,2,3,4-tetrahydroquinoline were obtained. Melting point: 235-237 [deg.] C (actual measurement: 236-237 [deg.] C). IR: νmax (cm ^-1 ) 3315 (NH strech), 3200 (OH str
ech), 1649 (C = O strech), 1502, 1392, 1287, 1252, 1
151, 1116, 963, 813, 777. ¹ H 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 6-Hydroxybenzo-2
Preparation of -oxo-1,2,3,4-tetrahydroquinoline (I) 500 ml of decahydronaphthalene and N- (4-methoxybenzo) -3-chloropropionyl in a flask containing a magnetic stirrer under a nitrogen stream. Amide 213.7g (1mo
l) and 667 g (5 mol) of aluminum chloride were added. The temperature was slowly raised from room temperature, and the reaction solution was stirred at 150 ° C. for 8 hours to react. The resulting solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, and the mixture was vigorously stirred and pulverized.
The product was collected by filtration and washed with water and chloroform. The product obtained by filtration was dried in vacuo, and 155.0 g of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (95%
%). Melting point, IR and ¹ H NMR data are the same as in Example 4.

Example 6 Production of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (I) Under a nitrogen stream, 500 ml of decahydronaphthalene was placed in a flask containing a magnetic stirrer. 227.7 g of N- (4-methoxybenzo) -3-chloropropionylamide (1mo
After l) and 667 g (5 mol) of aluminum chloride were added, the temperature was slowly raised from room temperature, and the mixture was stirred and reacted at 150 ° C. for 8 hours. The resulting solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, stirred vigorously and pulverized. The product was collected by filtration and washed with water and chloroform. The product collected by filtration was dried in vacuo and 6-hydroxy-2-oxo-
145.2 g (89%) of 1,2,3,4-tetrahydroquinoline were obtained. Melting point, IR and ¹ H NMR data are the same as in Example 4.

Example 7 Production of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (I) Under a nitrogen stream, 500 ml of decahydronaphthalene was placed in a flask containing a magnetic stirrer. 213.7 g of N- (4-methoxybenzo) -3-chloropropionylamide (1mo
l) and 681.5 g (5 mol) of zinc chloride were added. The temperature was slowly raised from room temperature, and the reaction solution was stirred at 150 ° C. for 12 hours to react. The resulting solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, and the mixture was vigorously stirred and pulverized. The product was collected by filtration and washed with water and chloroform. The product obtained by filtration was dried in vacuo and 143.6 g (88%) of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline.
I got Melting point, IR and ¹ H NMR data are the same as in Example 4.

Example 8 Production of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (I) Under a nitrogen stream, 500 ml of decahydronaphthalene was placed in a flask containing a magnetic stirrer. 213.7 g (1 mol) of N- (4-methoxybenzo) -3-chloropropionylamide and 948.5 g (5 mol) of titanium tetrachloride were added. The temperature was slowly raised from room temperature, and the reaction solution was stirred at 150 ° C. for 16 hours to react. The resulting solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, and the mixture was vigorously stirred and pulverized. The product was collected by filtration and washed with water and chloroform. The product collected by filtration was dried in vacuo and 6-hydroxy-2-oxo-
133.8 g (82%) of 1,2,3,4-tetrahydroquinoline were obtained. Melting point, IR and ¹ H NMR data are the same as in Example 4.

[0031]

According to the present invention, 6-hydroxy-2-
Oxo-1,2,3,4-tetrahydroquinoline can be easily produced with high yield. In addition, since no dangerous by-products are generated, it can be easily applied to industrial production. 6-Hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline obtained by the present invention is useful as a synthetic intermediate for cilostazol, a therapeutic agent for thrombosis.

Continuation of the front page (71) Applicant 599053001 535-3, Daeyang-ri, Yangkam-myun, Hwasun g-gun, Kyonggi-do 445-930, Korea (72) Inventor Park In Kyu South Korea Gyeonggido Swan Weong Seong Goon 462 Samwan Apartment 2-805 (72) Inventor Shin Sang Hoon South Korea Seoul Kangdong Amsadon 414-2 Kangdong Apartment 7-201 F-term (reference) 4C031 EA11

Claims (8)

[Claims] 1. N- (4-) represented by the following general formula (II)
Reacting the substituted-benzo) -3-chloropropionylamide with a Lewis acid in the presence of a homogenizing agent, the method comprising reacting 6-hydroxy-2-oxo-1,
A method for producing 2,3,4-tetrahydroquinoline. Embedded image Embedded image (In the formula, R is a hydrogen atom, a methyl group or an ethyl group.) 2. An N- (4-substituted-benzo) -3-chloropropionylamide represented by the general formula (II) is reacted with a 4-substituted-aniline represented by the general formula (III) in a solvent. The 6-hydroxy- according to claim 1, which is obtained by reacting 3-chloropropionyl chloride represented by (IV).
A method for producing 2-oxo-1,2,3,4-tetrahydroquinoline. Embedded image (In the formula, R is a hydrogen atom, a methyl group or an ethyl group.) 3. The homogenizing agent is decahydronaphthalene; a high boiling ether compound selected from the group consisting of diphenyl ether, isoamyl ether, benzylethyl ether, diglyme and triglyme; or from the group consisting of β-pinene, limonene and tetralin. 6. 6-Hydroxy-2- according to claim 1, which is a selected hydrocarbon compound.
A method for producing oxo-1,2,3,4-tetrahydroquinoline. 4. The compound of claim 1, wherein the Lewis acid is aluminum chloride, zinc chloride or titanium tetrachloride.
A method for producing hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline. 5. The 6-hydroxy-2-oxo- according to claim 1, wherein the reaction is carried out at 0 ° C. to 200 ° C. for 2 to 18 hours.
A method for producing 1,2,3,4-tetrahydroquinoline. 6. A reaction between a 4-substituted-aniline represented by the general formula (III) and 3-chloropropionyl chloride represented by the general formula (IV), wherein a solvent is ethyl acetate, dimethylformamide, dimethylsulfoxide, The method for producing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline according to claim 2, which is selected from the group consisting of hexane and benzene. 7. The reaction between a 4-substituted-aniline represented by the general formula (III) and 3-chloropropionyl chloride represented by the general formula (IV) is performed at 5 ° C. to 100 ° C.
6-hydroxy-2-oxo-1,2,3,4
-A method for producing tetrahydroquinoline. 8. A process for producing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline by the method according to any one of claims 1 to 7, and 6-hydroxy-2- obtained. A method for producing cilostazol, comprising the step of reacting oxo-1,2,3,4-tetrahydroquinoline with 5-halobutyl-1-cyclohexyltetrazol.